Additional research may lead to precision medicine FMT treatments for patients with specific cancers
Research continues to show that the human gut microbiome plays a significant role in a person’s health and longevity. One recent example is a clinical trial study conducted by scientists at MD Anderson Cancer Center in Houston which demonstrated that fecal microbiota transplants (FMTs) can help in the eradication of some cancers.
If approved for clinical treatment of cancer, the use of FMT may increase the demand for diagnostic tests to verify that the approach worked in a patient.
Our guts are home to trillions of microorganisms (aka, microbiota), known as the gut microbiome, which serve many important functions in the body. The microbiome is a delicate ecosystem that can be pushed out of balance when unfavorable microbes outnumber advantageous ones.
An FMT is an uncomplicated and powerful method of repopulating the microbiome with beneficial microbes. The researchers at MD Anderson administered FMTs from donors with advanced cancers that had been completely cured by immunotherapy into the guts of patients whose cancers were not improving.
“[Early reports] demonstrate that gut microbiota is contributing to immunotherapy resistance in at least some patients and provide hope that by changing the microbiome, some will respond,” Jonathan Jacobs, MD, PhD, a gastroenterologist at the Fielding School of Public Health at the University of California, Los Angeles (UCLA), told NBC News. Jacobs was not involved in the MD Anderson research.
“These early reports of patients who were previously immunotherapy-resistant but experienced clinical response after receiving FMT [fecal transplants] and immunotherapy retreatment are very exciting,” said Jonathan Jacobs, MD, PhD (above), a gastroenterologist at the Fielding School of Public Health at the University of California, Los Angeles, in an interview with NBC News. (Photo copyright: UCLA.)
‘Miraculous’ Treatment for Cancer
Fecal microbiota transplant is a procedure where stool from a healthy donor is transplanted into the microbiome of a patient plagued by a certain medical condition. The procedure has been used as a standard treatment for recurrent Clostridioides difficile for years and is currently being studied as a potential cure for illnesses such as Parkinson’s disease, autism, obesity, and inflammatory bowel disease.
The premise of the MD Anderson clinical trial study was that gut bacteria from the now cancer-free individuals may assist the immune systems of the current patients to recognize and fight their cancers. The scientists focused their efforts on PD-1 immune checkpoint inhibitors that help keep white blood cell lymphocytes (T cells) from attacking other cells in the body.
PD-1 inhibitors are especially effective in treating tumors known as microsatellite instability-high cancer tumors. This type of tumor has an unusually large numbers of DNA mutations. PD-1 inhibitors help pinpoint these mutations and attack the cancerous tumors.
“They’re miraculous drugs,” Timothy Yeatman, MD, PhD, associate director of translational research at the Tampa General Hospital Cancer Institute, told NBC News. “They’ve been able to cure people with no chemotherapy, no radiotherapy, or no surgery.”
Yeatman also said that some patients “experience improvements that are barely believable: people with mere months to live who are then cured of their disease. In medical parlance, this is referred to as a complete response.”
FMT Treatment Brings Fast Results
Yinghong Wang, MD, PhD, a gastroenterology specialist and professor in the department of gastroenterology, hepatology and nutrition at MD Anderson, said in a news release that positive results for cancer patients undergoing the FMT treatment can appear expeditiously.
“The quickest response can be seen within 24 hours. Patients have reported having much better energy and appetite the next day. Some say they feel like a new person,” she said. “Usually, though, I’d recommend giving it at least a week. If two weeks pass by without any discernable benefit, it probably wasn’t effective.”
According to Wang, FMTs can be delivered by several methods that fall into two categories:
Lower GI tract: The colonoscopy method is used very frequently since it allows more thorough coverage of the colon’s interior walls and reduces the chance of leakage after the procedure. However, liquid donor stool can also be delivered via enema.
Upper GI tract: These include frozen or freeze-dried capsules that can be swallowed, as well as liquids that can be placed directly in the GI tract via a feeding tube or upper endoscopy procedure.
This ongoing pilot study at MD Anderson could aid in the advancement of using the gut microbiome to help the immune system fight all sorts of diseases.
Future Developments of FMT Research
MD Anderson has partnered with biotechnology startup Kanvas Biosciences, which developed a technology known as HiPR-FISH (high-phylogenetic-resolution microbiome mapping by fluorescence in situ hybridization) to examine the relationships between gut bacteria and the immune system. This tool enables scientists to identify key microbial strains and place those strains in a pill that MD Anderson will use in further research to determine if PD-1 inhibitors can help the immune system on a larger scale.
“We have essentially made a synthetic version of the superdonor stool and then optimized and immortalized it so that it can be reproduced and used in the treatment of cancer patients worldwide,” Matthew Cheng, MD, a trained medical microbiologist and co-founder and CEO of Kanvas, told NBC News.
More research and clinical trials are needed before fecal microbiota transplants can be used on a mainstream basis in the treatment of cancer. However, the MD Anderson research is promising in foreseeing the possibility that cancer patients who do not respond well to immunotherapy may have better luck through a personalized medicine approach geared to specific patients.
As such, the research is of interest to pathologists who want to learn more about the potential role of the human microbiome in precision medicine and clinical laboratory testing.
“It’s possible that even better outcomes could be obtained with a more precise understanding of the recipient’s microbiome, genetics, type of cancer, and antitumor immune responses, to select the optimal combinations,” said Jacobs in the NBC News interview.
This follows class action lawsuits in multiple states against insurance companies that deny millions of healthcare claims each year
Artificial intelligence (AI) has become ubiquitous in many aspects of healthcare. But perhaps its most controversial use is in the payer denial-of-claims process. Multiple states are pursuing legislation that would limit or outright ban AI’s use without physician involvement.
Clinical laboratories experience payment denials at both the prior authorization stage when a doctor orders a lab test as well as when the claim is submitted for reimbursement. And many labs perform tests for which they know they will not be paid just to maintain the client account relationships with doctors.
Now, several states are taking measures to protect patients from what some say is a dangerous trend to use AI algorithms only to review and deny medical claims for critical healthcare and clinical laboratory testing. This will be of interest to lab managers and those in charge of their lab’s revenue.
“Physicians and patients already face daunting challenges in navigating medical insurers’ bureaucratic administrative processes,” said Arizona Medical Association (ArMA) President Nadeem Kazi, MD, in a news release. “Taking physicians’ clinical experience out of these processes entirely is a misguided step,” he added.
However, on March 13, the Arizona Senate’s Finance Committee altered the language in its version of the bill. In it, AI is not specifically mentioned.
Instead, the bill’s language now “requires a medical director or healthcare provider, before a healthcare insurer may deny a claim or issue a direct denial of a prior authorization, to individually review any denial that involves medical necessity or experimental status or that requires the use of medical judgment and prohibits the director or provider from relying solely on recommendations derived from any other source during the prior authorization denial or claim denial review.”
Presumably, “any other source” includes AI-driven software platforms used by payers for prior authorization denials and claims processing.
“While AI promises innovation for several areas of healthcare, the review and denial of medical insurance claims—some of which represent life-changing treatments and procedures—should be left to physicians who can make nuanced clinical judgments,” said Shelby Job, ArMA communications director, in a statement following that state’s passage of the House bill in February.
The bill is now being debated in the Arizona Senate. If the Senate passes its version, the two sides will need to reconcile their bills.
“Patients deserve healthcare delivered by humans with compassionate medical expertise, not pattern-based computer algorithms designed by insurance companies,” said ArMA President Nadeem Kazi, MD (above), in a news release. (Photo copyright: Arizona Medical Association.)
Multiple States Move to Limit Use of AI in Claims Denials
In an Arizona House of Representatives Committee on Commerce meeting, state Republican representative Julie Willoughby, who is also an ER nurse, said that “she hopes the bill will protect Arizonians from losing healthcare access due to AI interference,” NBC News reported following passage of the House bill.
“What we’re asking for in this is that any claims that are denied have a provider look them over for completeness to ensure that there isn’t anything that the AI algorithm may not have accounted for,” she said.
If signed into law, the bill will require a medical director at the insurance carrier in question to “individually review each claim or prior authorization before a healthcare insurer is able to deny a claim for that patient,” NBC News noted.
California passed similar legislation in September that would “ensure that a licensed physician supervises the use of AI decision-making tools when they are used to inform decisions to approve, modify, or deny requests by providers,” NBC News reported.
The author of the California bill, Democratic senator Josh Becker, JD, argued upon the bill’s passing that AI “should never replace the expertise and judgment of physicians,” adding, “An algorithm cannot fully understand a patient’s unique medical history or needs, and its misuse can lead to devastating consequences.”
And in Texas, a bill introduced by Republican senator Charles Schwertner, MD, states that AI “should not be used as the ‘sole basis of a decision to wholly or partly deny, delay, or modify healthcare services,’” NBC News reported.
In a statement, the Texas Coalition of Patients said the bill is “crucial in ensuring that life-altering healthcare decisions remain in the hands of medical professionals rather than Big Insurance’s automated systems.”
In all, 11 states have introduced legislation to “to push back on artificial intelligence use in reviewing medical claims,” according to NBC News.
In May 2023, The Dark Report explored payer claims denials, and it was acknowledged back then that automated systems were already reviewing claims.
And then there are the lawsuits. According to The Guardian, Cigna, Humana, and UnitedHealth all face class-action lawsuits concerning the use of AI to “deny lifesaving care.”
Can AI Coexist with Human-based Care?
Although at this time AI may not understand the nuanced complexities of healthcare claims, there seem to be plenty of uses for it in healthcare decision-making. It can analyze large sets of data for diagnosis, transcribe medical documents using automatic speech recognition, and streamline administrative tasks––all of which can help a workforce plagued by staff burnout and shortages, Los Angeles Pacific University noted.
And though its use in payer claims reviews and denials is being resisted, AI will likely continue to help doctors diagnose disease and make better treatment decisions. Nevertheless, clinical laboratory and pathology workers should be aware of how the tool is being used and keep an eye out for suspicious claims denials.
Single genetic test can identify multiple pathogens and can be used by the UCSF clinical laboratory team to help physicians identify difficult to diagnose diseases
Continuing improvements in gene sequencing technologies and analytical software tools are enabling clinical laboratorians to diagnosis patients who have challenging symptoms. One such example is a new genomic test developed by researchers at University California, San Francisco (UCSF). The single test analyzes both RNA and DNA to detect almost any type of pathogen that may be the cause of specific illnesses.
The test uses a genomic sequencing technique known as metagenomics next-generation sequencing (mNGS). It works by sequencing genetic material found in blood, tissue, or body fluid samples and compares the sequenced data against a broad database of known pathogens to seek a match. Instead of looking for just one pathogen at a time, mNGS analyzes all of the nucleic acids, RNA, and DNA present in a sample simultaneously to detect nearly all pathogens, including viruses, bacteria, fungi, and parasites.
The mNGS test is not intended to replace existing clinical laboratory tests, but to help physicians diagnose an illness in cases where patients are experiencing severe symptoms, and where initial, commonplace tests are ineffective. In such cases, medical professionals require additional information to achieve a proper diagnosis.
“Our technology is deceptively simple,” said Charles Chiu, MD, PhD (above), professor of laboratory medicine and infectious diseases at UCSF and senior author of the studies in a news release. “By replacing multiple tests with a single test, we can take the lengthy guesswork out of diagnosing and treating infections.” The new technology may help physicians diagnose patients who have challenging symptoms and where current clinical laboratory testing is ineffective at identifying specific pathogens. (Photo copyright: University California San Francisco.)
Diagnostic Armamentarium for Physicians
According to an article published by the American Society for Microbiology (ASM) titled, “Metagenomic Next Generation Sequencing: How Does It Work and Is It Coming to Your Clinical Microbiology Lab?” mNGS is “running all nucleic acids in a sample, which may contain mixed populations of microorganisms, and assigning these to their reference genomes to understand which microbes are present and in what proportions. The ability to sequence and identify nucleic acids from multiple different taxa [plural for taxon] for metagenomic analysis makes this a powerful new platform that can simultaneously identify genetic material from entirely different kingdoms of organisms.”
The researchers developed the mNGS test years ago and it has produced promising results, including:
Diagnosing cases of encephalitis in transplant recipients to yellow fever in their organ donors.
Helping to identify the cause of a meningitis outbreak in Mexico among surgical patients.
Detecting a case of leptospirosis in a patient who was in a medically induced coma, which prompted doctors to prescribe penicillin and resulted in the full recovery of the patient.
Identifying the cause of neurological infections such as meningitis and encephalitis. The test successfully diagnosed 86% of neurological infections in more than 4,800 spinal fluid samples.
“Our mNGS test performs better than any other category of test for neurologic infections,” said Charles Chiu, MD, PhD, professor of laboratory medicine and infectious diseases at UCSF and senior author of the two studies, in a UCSF news release. “The results support its use as a critical part of the diagnostic armamentarium for physicians who are working up patients with infectious diseases.”
FDA Breakthrough Device Designation
The UCSF test has not yet been approved by the federal Food and Drug Administration (FDA), but it was granted a “breakthrough device” designation by the agency. This classification authorizes labs to use the test as a valid diagnosis method due to its potential ability to benefit patients.
Chiu told NBC News that the test costs about $3,000 per sample and fewer than 10 labs routinely use it due to several issues.
“Traditionally, it’s been used as a test of last resort, but that’s primarily because of issues involving, for instance, the cost of the test, the fact that it’s only available in specialized reference laboratories, and it also is quite laborious to run,” he said.
This type of lab testing is not feasible for most hospitals as it is costly and complicated, and because physicians may need assistance from clinical laboratory personnel who have the appropriate expertise to properly read test results.
“This just is not something that a clinical lab will be doing until somebody commercially puts it in a box with an easy button,” Susan Butler-Wu, PhD, associate professor of clinical pathology at the University of Southern California (USC), told NBC News. “It’s not a one-stop shop. It just can be helpful as an additional tool.”
Although the technology has some limitations, Chiu says the research performed by his team “raises the possibility that we perhaps should be considering running this test earlier” in symptomatic patients. He hopes the test will be used on a widespread basis in hospitals to diagnose various illnesses in the future.
“We need to get the cost down and we need to get the turnaround times down as well,” he told NBC.
Definitive Tool for Pathogen Detection
To increase access to the technology, Chiu and his colleagues founded Delve Bio, which is now the exclusive provider of the mNGS tool created at UCSF. In December, the company announced the commercial launch of Delve Detect, a metagenomic test for infectious diseases. According to its website, Delve Detect “offers genomic testing of cerebrospinal fluid (CSF) for more than 68,000 pathogens, with 48-hour turnaround time and metagenomics experts readily available to discuss results.”
“These findings support including mNGS as a core tool in the clinical workup for CNS [central nervous system] infections,” said Steve Miller, MD, PhD, UCSF volunteer clinical professor, laboratory medicine, and chief medical officer of Delve Bio in the UCSF news release. “mNGS offers the single most unbiased, complete and definitive tool for pathogen detection. Thanks to its ability to quickly diagnose an infection, mNGS helps guide management decisions and treatment for patients with meningitis and encephalitis, potentially reducing healthcare costs down the line.”
This mNGS test may prove to have the potential to greatly improve medical care for some infections and possibly expedite the detection of new viral threats. It is probable that clinical laboratories will soon be learning about and performing more tests of this nature in the future.
Good behavior in federal prison by the disgraced founder of the now-defunct clinical laboratory company earned her the reduction in her original sentence of 11 years
Elizabeth Holmes, founder of failed clinical laboratory blood analysis company Theranos, continues to serve a lengthy term in prison after being convicted of multiple counts of fraud in 2022. However, now comes news that good behavior at her federal prison has shortened her sentence by nearly two years, according to NBC News.
The latest reduction took Holmes’ release from December 2032 to August 2032 in her “11-plus-year (135 month) prison sentence for wire fraud and conspiracy,” NBC reported, adding that Holmes, though Theranos, “defrauded investors out of hundreds of millions of dollars.”
Holmes entered FPC Bryan, a federal prison camp in Bryan, Texas, to begin serving her term in May 2023.
“Holmes had her sentence computation done within the first 30 days of arriving at Bryan,” Forbes reported. Given Good Conduct Time (GCT), Holmes was given 608 days off calculated from the start of her sentence. “If she were to incur a disciplinary infraction, some of those days can be taken away. Most all prisoners receive 54 days per year of GCT based on the sentence imposed,” Forbes added.
The Federal Bureau of Prisons (BOP) can additionally shave off up to a year through its Residential Drug Abuse Program (RDAP). “To qualify, the prisoner must not have a disqualifying offense, such as terrorism or gun charge, and voluntarily provided information that they had a drug or alcohol problem prior to their arrest. This disclosure has to be done prior to sentencing during the pre-sentence interview and must be also documented in the Presentence Report, a detailed report used by the BOP to determine things like classification and programming for the prisoner,” Forbes noted.
Additionally, the federal First Step Act, which President Trump signed into law in 2018, enables Holmes to “earn up to 365 days off any imposed sentence by participating in prison programming such as a self-improvement classes, a job, or religious activities,” Forbes reported.
Given the opportunities to shave time off her sentence, Holmes may ultimately serve just 66 months of her original 135 month sentence in federal prison.
Elizabeth Holmes (above) taken backstage at TechCrunch Disrupt San Francisco 2014 when Holmes was at the height of her fame and popularity. At this point, Theranos’ Edison blood testing device had not yet been shown to be a fake. But evidence was mounting as clinical laboratory scientists and anatomic pathologists became aware of the technology’s shortcomings. (Photo copyright: Max Morse/Wikimedia Commons.)
Fall of a Silicon Valley Darling
Theranos boasted breakthrough technology and became an almost overnight sensation in Silicon Valley when it burst onto the scene in 2003. Holmes, a then 19-year-old Stanford University dropout, claimed Theranos would “revolutionize the world of blood testing by reducing sample sizes to a single pin prick,” Quartz reported.
The height of the company saw Theranos valued at $9 billion, which came crashing down when the Wall Street Journal reported in 2015 that questionable accuracy and procedures were being followed by the company, CNN reported.
“From the moment Holmes concluded her presentation and stepped off the podium on Monday afternoon, she, her company, and her comments became the number one subject discussed by attendees in the halls between sessions and in the AACC exhibit hall,” Michel wrote, adding, “The executive team and the investors at Theranos have burned through their credibility with the media, the medical laboratory profession, and the public. In the future, the company’s claims will only be accepted if presented with scientific data developed according to accepted standards and reviewed by credible third parties. Much of this data also needs to be published in peer-reviewed medical journals held in highest esteem.”
Ultimately, investors who had jumped in early with financial support for Theranos were defrauded of hundreds of millions of dollars and Holmes was sentenced to 11 years/three months behind bars.
“Theranos had only ever performed roughly a dozen of the hundreds of tests it offered using its proprietary technology, and with questionable accuracy. It also came to light that Theranos was relying on third-party manufactured devices from traditional blood testing companies rather than its own technology,” CNN added.
The company shut down in 2018.
And so, the Elizabeth Holmes saga continues with reductions in her prison sentence for “good behavior.” The irony will likely not be lost on the anatomic pathologists, clinical laboratory scientists, and lab managers who followed the federal trials.
Doctors report difficulty differentiating COVID-19 from other viral infections, impacting clinical laboratory test orders
Because the SARS-CoV-2 coronavirus is in the same family of viruses that cause the common cold and influenza, virologists expected this virus—which caused the global COVID-19 pandemic—would evolve and mutate into a milder form of infection. Early evidence from this influenza season seems consistent with these expectations in ways that will influence how clinical laboratories offer tests for different respiratory viruses.
While new variants of the SARS-CoV-2 virus continue to appear, indications are that early in this flu season individuals infected with the more recent variants are experiencing milder symptoms when compared to the last few years. Doctors report they find it increasingly difficult to distinguish COVID-19 infections from allergies or the common cold because patients’ symptoms are less severe, according to NBC News.
This, of course, makes it challenging for doctors to know the most appropriate clinical laboratory tests to order to help them make accurate diagnoses.
“It isn’t the same typical symptoms that we were seeing before. It’s a lot of congestion, sometimes sneezing, usually a mild sore throat,” Erick Eiting, MD, Vice Chair of Operations for Emergency Medicine at Mount Sinai Hospital in New York City, told NBC News. “Just about everyone who I’ve seen has had really mild symptoms. The only way that we knew that it was COVID was because we happened to be testing them.” Knowing which tests for respiratory viruses that clinical laboratories need to perform may soon be the challenge for doctors. (Photo copyright: Mt. Sinai.)
Milder COVID-19 Symptoms Follow a Pattern
Previous hallmarks of a COVID-19 infection included:
Loss of taste,
loss of smell,
dry cough,
fever,
sore throat,
diarrhea,
body aches,
headaches.
However, physicians now observe milder symptoms of the infection that follow a distinct pattern and which are mostly concentrated in the upper respiratory tract.
Grace McComsey, MD, Vice President of Research and Associate Chief Scientific Officer at University Hospitals Health System (UH) in Cleveland, Ohio, told NBC News that some patients have described their throat pain as “a burning sensation like they never had, even with Strep in the past.”
“Then, as soon as the congestion happens, it seems like the throat gets better,” she added.
In addition to the congestion, some patients are experiencing:
headache,
fever,
chills,
fatigue,
muscle aches,
post-nasal drip.
McComsey noted that fatigue and muscle aches usually only last a couple of days, but that the congestion can sometimes last a few weeks. She also estimated that only around 10-20% of her newest COVID patients are losing their sense of smell or taste, whereas early in the pandemic that number was closer to 60-70% of her patients.
Doctors also noted that fewer patients are requiring hospitalization and that many recover without the use of antivirals or other treatments.
“Especially since July, when this recent mini-surge started, younger people that have upper respiratory symptoms—cough, runny nose, sore throat, fever and chills—99% of the time they go home with supportive care,” said Michael Daignault, MD, an emergency physician at Providence Saint Joseph Medical Center in Burbank, California.
Milder SARS-CoV-2 Variants Should Still be Taken Seriously
Doctors have varying opinions regarding why the current COVID-19 variants are milder. Some believe the recent variants simply aren’t as good at infecting the lungs as previous variants.
“Overall, the severity of COVID-19 is much lower than it was a year ago and two years ago,” Dan Barouch, MD, PhD, Director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, told NBC News. “That’s not because the variants are less robust. It’s because the immune responses are higher.”
McComsey added that she doesn’t think mild cases should be ignored as she is still seeing new cases of long COVID with rapid heart rate and exercise intolerance being among the most common lingering symptoms. Re-infections also add to the risks associated with long COVID.
“What we’re seeing in long COVID clinics is not just the older strains that continue to be symptomatic and not getting better—we’re adding to that number with the new strain as well,” McComsey said. “That’s why I’m not taking this new wave any less seriously.”
Clinical Laboratory COVID-19 Testing May Decrease
According to Andrew Read, PhD, Interim Senior Vice President for Research and Evan Pugh University Professor of Biology and Entomology at Pennsylvania State University, there is nothing unexpected or startling about the coronavirus acquiring new mutations.
“When a mutation confers an interesting new trick that’s got an advantage, it’s going to be popping up in many different places,” Read told the New York Times. “Everything we see is just consistent with how you imagine virus evolution proceeding in a situation where a new virus has jumped into a novel host population.”
Data from the Centers for Disease Control and Prevention’s COVID-19 Data Tracker—which reports weekly hospitalizations, deaths, emergency department (ED) visits, and COVID-19 test positivity results—shows infection trends fluctuating, but overall, they are decreasing.
For the week of October 21, 2023, there were 16,186 hospitalizations due to COVID-19 compared to the highest week recorded (January 15, 2022) with 150,674 hospitalizations nationwide.
The highest number of deaths reported in a single week were 25,974 for the week of January 8, 2021, while 637 patients perished from COVID-19 during the week of October 21, 2023.
In January of 2021, COVID accounted for 13.8% of all ED visits and in October 2023, COVID-19 was responsible for 1.3% of ED visits.
“What I think we’re seeing is the virus continuing to evolve, and then leading to waves of infection, hopefully mostly mild in severity,” Barouch told The New York Times.
As severity of COVID-19 infections continues to fall, so, presumably, will demand for COVID-19 testing which has been a source of revenue for clinical laboratories for several years.
