Norwegian researchers reviewed large clinical trials of six common cancer screenings, including clinical laboratory tests, but some experts question the findings
Cancer screenings are a critical tool for diagnosis and treatment. But how much do they actually extend the lives of patients? According to researchers at the University of Oslo in Norway, not by much. They recently conducted a review and meta-analysis of 18 long-term clinical trials, five of the six most commonly used types of cancer screening—including two clinical laboratory tests—and found that with few exceptions, the screenings did not significantly extend lifespans.
The 18 long-term clinical trials included in the study were randomized trials that collectively included a total of 2.1 million participants. Median follow-up periods of 10 to 15 years were used to gauge estimated lifetime gain and mortality.
“The findings of this meta-analysis suggest that current evidence does not substantiate the claim that common cancer screening tests save lives by extending lifetime, except possibly for colorectal cancer screening with sigmoidoscopy,” the researchers wrote in their published paper.
The researchers noted, however, that their analysis does not suggest all screenings should be abandoned. They also acknowledged that some lives are saved by screenings.
“Without screening, these patients may have died of cancer because it would have been detected at a later, incurable stage,” the scientists wrote, MedPage Today reported. “Thus, these patients experience a gain in lifetime.”
Still, some independent experts questioned the validity of the findings.
Gastroenterologist Michael Bretthauer, MD, PhD (above), a professor at the University of Oslo in Norway led the research into cancer screenings. In their JAMA Internal Medicine paper, he and his team wrote, “The findings of this meta-analysis suggest that colorectal cancer screening with sigmoidoscopy may extend life by approximately three months; lifetime gain for other screening tests appears to be unlikely or uncertain.” How their findings might affect clinical laboratory and anatomic pathology screening for cancer remains to be seen. (Photo copyright: University of Oslo.)
Pros and Cons of Cancer Screening
The clinical trials, according to MedPage Today and Oncology Nursing News covered the following tests:
Mammography screening for breast cancer (two trials).
As reported in these trials, “colorectal cancer screening with sigmoidoscopy prolonged lifetime by 110 days, while fecal testing and mammography screening did not prolong life,” the researchers wrote. “An extension of 37 days was noted for prostate cancer screening with prostate-specific antigen testing and 107 days with lung cancer screening using computed tomography, but estimates are uncertain.”
The American Cancer Society (ACS) recommends certain types of screening tests to detect cancers and pre-cancers before they can spread, thus improving the chances for survival.
The ACS advises screenings for breast cancer, colorectal cancer, and cervical cancer regardless of whether the individual is considered high risk. Lung cancer screenings are advised for people with a history of smoking. Men who are 45 to 50 or older should discuss the pros and cons of prostate cancer screening with their healthcare providers, the ACS states.
A CNN report about the University of Oslo study noted that the benefits and drawbacks of cancer screening have long been well known to doctors.
“Some positive screening results are false positives, which can lead to unnecessary anxiety as well as additional screening that can be expensive,” CNN reported. “Tests can also give a false negative and thus a false sense of security. Sometimes too, treatment can be unnecessary, resulting in a net harm rather than a net benefit, studies show.”
In their JAMA paper, the University of Oslo researchers wrote, “The critical question is whether the benefits for the few are sufficiently large to warrant the associated harms for many. It is entirely possible that multicancer detection blood tests do save lives and warrant the attendant costs and harms. But we will never know unless we ask,” CNN reported.
Hidden Impact on Cancer Mortality
ACS Chief Scientific Officer William Dahut, MD, told CNN that screenings may have an impact on cancer mortality in ways that might not be apparent from randomized trials. He noted that there’s been a decline in deaths from cervical cancer and prostate cancer since doctors began advising routine testing.
“Cancer screening was never really designed to increase longevity,” Dahut said. “Screenings are really designed to decrease premature deaths from cancer.” For example, “if a person’s life expectancy at birth was 80, a cancer screening may prevent their premature death at 65, but it wouldn’t necessarily mean they’d live to be 90 instead of the predicted 80,” CNN reported.
Dahut told CNN that fully assessing the impact of cancer screenings on life expectancy would require a clinical trial larger than those in the new study, and one that followed patients “for a very long time.”
“From its title, one would have expected this paper to be based on analysis of individual lifetime data. However, it is not,” he wrote in a compilation of expert commentary from the UK’s Science Media Center. “The paper’s conclusions are based on arithmetic manipulation of relative rates of all-cause mortality in some of the screening trials. It is therefore difficult to give credence to the claim that screening largely does not extend expected lifetime.”
He also questioned the inclusion of one particular trial in the University of Oslo study—the Canadian National Breast Screening Study—“as there is now public domain evidence of subversion of the randomization in this trial,” he added.
Another expert, Leigh Jackson, PhD, of the University of Exeter in the UK, described the University of Oslo study as “methodologically sound with some limitations which the authors clearly state.”
But he observed that “the focus on 2.1 million individuals is slightly misleading. The study considered many different screening tests and 2.1 million was indeed the total number of included patients, however, no calculation included that many people.”
Jackson also characterized the length of follow-up as a limitation. “This may have limited the amount of data included and also not considering longer follow-up may tend to underestimate the effects of screening,” he said.
This published study—along with the range of credible criticisms offered by other scientists—demonstrates how analysis of huge volumes of data is making it possible to tease out useful new insights. Clinical laboratory managers and pathologists can expect to see other examples of researchers assembling large quantities of data across different areas of medicine. This huge pools of data will be analyzed to determine the effectiveness of many medical procedures that have been performed for years with a belief that they are helpful.
Study also may have found relationship between atherosclerosis and cholesterol
Chinese scientists have developed a cutting-edge method for non-invasively monitoring blood cholesterol levels in humans. The innovative technology utilizes images of skin on hands and may eliminate the need for both invasive venipunctures and fasting for testing cholesterol. Given the large volumes of blood cholesterol tests currently performed by clinical laboratories, this new technology could have significant impact on cholesterol testing if further studies confirm its capabilities.
Notably, the Chinese researchers have apparently already developed a lab analyzer to perform the procedure and it is being used in clinical care. However, in the United States and other countries, this technology will require additional clinical studies and regulatory review before clinical laboratories would be able to use it in daily patient care.
The cholesterol sensing system consists of a detection reagent associated with a fluorescent group that binds to skin cholesterol, and a detection device. Cholesterol levels are easily obtained from the skin, according to the researchers, by analyzing the manner in which the skin absorbs and scatters light via a scanner.
Should this technology be validated for clinical care, it could replace other invasive clinical laboratory tests for cholesterol measurement.
The series of images above, taken from the researchers’ Lipids in Health and Disease published study, demonstrates how their non-invasive clinical laboratory test for total blood cholesterol is performed. Non-invasive clinical laboratory tests for monitoring biomarkers in the blood are always preferred by patients over veinous punctures and fasting. (Photo copyright: Hefei Institutes of Physical Science, Chinese Academy of Sciences.)
First Evidence of Relationship between Cholesterol and Atherosclerosis
“Just put your hands on, and the system will tell you the cholesterol data,” Yikun Wang, PhD, Professor, Department of Physical Sciences, Hefei Institutes of Physical Science, Chinese Academy of Sciences, and leader of the research team, told Diagnostics World. “Cholesterol is one of several types of fats (lipids) that play an important role in human body, we can track your fats in this simple way.”
To perform the testing, clinicians first clean the test site located on the fleshy edge of the palm of the hand with an alcohol swab. A patient’s non-dominant hand is used for the test as the skin on that hand is typically less abrasive and contains fewer melanocytes, which allows for more stable results. A plastic-coated annulus is then applied to the test site and the examined portion is positioned on the measuring hole of the detection system to measure the background light spectrum of the skin.
Once the background signal is ascertained, the detection reagent is added to the annulus until it is full. After 60 seconds, any excess detection reagent is removed from the annulus. A cleaning reagent is then added to the annulus for 30 seconds and removed with a sterile cotton swab. The treated portion of the skin is then placed over the measuring hole of the detection system and two spectrums of light are compared to measure the skin cholesterol, which accurately correlates to the cholesterol in the bloodstream.
“Compared to in-situ detection used in the previous clinical research, our device may offer more accurate results for we can avoid the influence of pressure and skin background differences [person to person],” Wang said. “Study results offer the first evidence of a relationship between skin cholesterol and atherosclerotic disease in a Chinese population, which may be of great significance to researchers around the world.”
Initially, 154 patients diagnosed with acute coronary syndrome (ACS) between January 2020 and April 2021 were involved in the study. However, only 121 of those patients were included in the final study with the remaining being excluded due to at least one of the following criteria:
Severe hepatic (liver) or renal (kidney) insufficiency, and
Obesity.
Clinician Use Can Affect Accuracy of Test
Developed by researchers from the Hefei Institutes of Physical Science Chinese Academy of Sciences, and the University of Science and Technology of China, the researchers noted that how clinicians operate the device can have an impact on the accuracy of the test results.
“A critical step in the [testing] process that is subject to operator variability is blotting, which requires the operator to remove an unbound detector from the palm before adding the indicator,” Wang told Diagnostics World. “Excess residual indicator solution can result in falsely increased skin cholesterol levels. Considering this, we are planning to develop a simplified and standardized blotting procedure.”
Millions of people in the US live with illness that requires regular monitoring of blood cholesterol. Normal total cholesterol should be less than 200 milligrams per deciliter (mg/dL). According to the federal Centers for Disease Control and Prevention (CDC), nearly 94 million US adults over the age of 20 have total cholesterol levels higher than 200 mg/dL and 28 million adults have total cholesterol levels higher than 240 mg/dL. In addition, 7% of children and adolescents between the ages of six and 19 have high cholesterol. For these reasons, cholesterol testing represents a substantial portion of the clinical laboratory tests performed daily in this country.
This new non-invasive technology for monitoring total blood cholesterol in humans could greatly benefit patients, especially if it eliminates the need for venipunctures and fasting prior to testing. Clinical laboratory managers and pathologists may want to follow the progress of this new cholesterol testing technology as it demonstrates its value in China and is submitted for regulatory review in this country.
New nanotechnology device is significantly faster than typical rapid detection clinical laboratory tests and can be manufactured to identify not just COVID-19 at point of care, but other viruses as well
Researchers at the University of Central Florida (UCF) announced the development of an optical sensor that uses nanotechnology to identify viruses in blood samples in seconds with an impressive 95% accuracy. This breakthrough underscores the value of continued research into technologies that create novel diagnostic tests which offer increased accuracy, faster speed to answer, and lower cost than currently available clinical laboratory testing methods.
The innovative UCF device uses nanoscale patterns of gold that reflect the signature of a virus from a blood sample. UCF researchers claim the device can determine if an individual has a specific virus with a 95% accuracy rate. Different viruses can be identified by using their DNA sequences to selectively target each virus.
According to a UCF Today article, the University of Central Florida research team’s device closely matches the accuracy of widely-used polymerase chain reaction (PCR) tests. Additionally, the UCF device provides nearly instantaneous results and has an accuracy rate that’s a marked improvement over typical rapid antigen detection tests (RADT).
Debashis Chanda, PhD (above), holds up the nanotechnology biosensor he and his team at the University of Central Florida developed that can detect viruses in a blood sample in seconds with 95% accuracy and without the need for pre-preparation of the blood sample. Chanda is professor of physics at the NanoScience Technology Center and the College of Optics and Photonics (CREOL) at UCF. Should this detection device prove effective at instantly detecting viruses at the point of care, clinical laboratories worldwide could have a major new tool in the fight against not just COVID-19, but all viral pathogens. (Photo copyright: University of Central Florida.)
Genetic Virus Detection on a Chip
“The sensitive optical sensor, along with the rapid fabrication approach used in this work, promises the translation of this promising technology to any virus detection, including COVID-19 and its mutations, with high degree of specificity and accuracy,” Debashis Chanda, PhD, told UCF Today. Chanda is professor of physics at the NanoScience Technology Center at UCF and one of the authors of the study. “Here, we demonstrated a credible technique which combines PCR-like genetic coding and optics on a chip for accurate virus detection directly from blood.”
The team tested their device using samples of the Dengue virus that causes Dengue fever, a tropical disease spread by mosquitoes. The device can detect viruses directly from blood samples without the need for sample preparation or purification. This feature enables the testing to be timely and precise, which is critical for early detection and treatment of viruses. The chip’s capability also can help reduce the spread of viruses.
No Pre-processing or Sample Preparation Needed for Multi-virus Testing
The scientists confirmed their device’s effectiveness with multiple tests using varying virus concentration levels and solution environments, including environments with the presence of non-target virus biomarkers.
“A vast majority of biosensors demonstrations in the literature utilize buffer solutions as the test matrix to contain the target analyte,” Chanda told UCF Today. “However, these approaches are not practical in real-life applications because complex biological fluids, such as blood, containing the target biomarkers are the main source for sensing and at the same time the main source of protein fouling leading to sensor failure.”
The researchers believe their device can be easily adapted to detect other viruses and are optimistic about the future of the technology.
“Although there have been previous optical biosensing demonstrations in human serum, they still require off-line complex and dedicated sample preparation performed by skilled personnel—a commodity not available in typical point-of-care applications,” said Abraham Vazquez-Guardado, PhD, a Postdoctoral Fellow at Northwestern University who worked on the study, in the UCS Today article. “This work demonstrated for the first time an integrated device which separated plasma from the blood and detects the target virus without any pre-processing with potential for near future practical usages.”
More research and additional studies are needed to develop the University of Central Florida scientists’ technology and prove its efficacy. However, should the new chip prove viable for point-of-care testing, it would give clinical laboratories and microbiologists an ability to test blood samples without any advanced preparation. Combined with the claims for the device’s remarkable accuracy, that could be a boon not only for COVID-19 testing, but for testing other types of viruses as well.
MicroRNAs in urine could prove to be promising biomarkers in clinical laboratory tests designed to diagnose brain tumors regardless of the tumor’s size or malignancy, paving the way for early detection and treatment
Researchers at Nagoya University in Japan have developed a liquid biopsy test for brain cancer screening that, they claim, can identify brain tumors in patients with 100% sensitivity and 97% specificity, regardless of the tumor’s size or malignancy. Pathologists will be interested to learn that the research team developing this technology says it is simple and inexpensive enough to make it feasible for use in mass screening for brain tumors.
Neurologists, anatomic pathologists, and histopathologists know that brain tumors are one of the most challenging cancers to diagnose. This is partly due to the invasive nature of biopsying tissue in the brain. It’s also because—until recently—clinical laboratory tests based on liquid blood or urine biopsies were in the earliest stages of study and research and are still in development.
Thus, a non-invasive urine test with this level of accuracy that achieves clinical status would be a boon for the diagnosis of brain cancer.
Researchers at Japan’s Nagoya University believe they have developed just such a liquid biopsy test. In a recent study, they showed that microRNAs (tiny molecules of nucleic acid) in urine could be a promising biomarker for diagnosing brain tumors. Their novel microRNA-based liquid biopsy correctly identified 100% of patients with brain tumors.
Atsushi Natsume, MD, PhD (above), Associate Professor at Nagoya University, led the research team that created the simple, liquid biomarker urine test for central nervous system tumors that achieved 100% sensitivity and 97% specificity, regardless of the tumor’s size or malignancy. Such a non-invasive clinical laboratory test used clinically would be a boon to brain cancer diagnosis worldwide. (Photo copyright: Nagoya University.)
Well-fitted for Mass Screenings of Brain Cancer Patients
According to the National Cancer Institute (NCI), brain and other central nervous system (CNS) cancers represent 1.3% of all new cancer cases and have a five-year survival rate of only 32.6%.
In their published study, the Nagoya University scientists wrote, “There are no accurate mass screening methods for early detection of central nervous system (CNS) tumors. Recently, liquid biopsy has received a lot of attention for less-invasive cancer screening. Unlike other cancers, CNS tumors require efforts to find biomarkers due to the blood–brain barrier, which restricts molecular exchange between the parenchyma and blood.
“Additionally, because a satisfactory way to collect urinary biomarkers is lacking, urine-based liquid biopsy has not been fully investigated despite the fact that it has some advantages compared to blood or cerebrospinal fluid-based biopsy.
“Here, we have developed a mass-producible and sterilizable nanowire-based device that can extract urinary microRNAs efficiently. … Our findings demonstrate that urinary microRNAs extracted with the nanowire device offer a well-fitted strategy for mass screening of CNS tumors.”
The Nagoya University researchers focused on microRNA in urine as a biomarker for brain tumors because “urine can be collected easily without putting a burden on the human body,” said Atsushi Natsume, MD, PhD, Associate Professor in the Department of Neurosurgery at Nagoya University and a corresponding author of the study, in a news release.
A total of 119 urine and tumor samples were collected from patients admitted to 14 hospitals in Japan with CNS cancers between March 2017 and July 2020. The researchers used 100 urine samples from people without cancer to serve as a control for their test.
To extract the microRNA from the urine and acquire gene expression profiles, the research team designed an assembly-type microfluidic nanowire device using nanowire scaffolds containing 100 million zinc oxide nanowires. According to the scientists, the device can be sterilized and mass-produced, making it suitable for medical use. The instrument can extract a significantly greater variety and quantity of microRNAs from only a milliliter of urine compared to traditional methods, such as ultracentrifugation, the news release explained.
Simple Liquid-biopsy Test Could Save Thousands of Lives Each Year
While further studies and clinical trials will be necessary to affirm the noninvasive test’s accuracy, the Nagoya University researchers believe that, with the inclusion of additional technologies, a urine-based microRNA test could become a reliable biomarker for detecting brain tumors.
“In the future, by a combination of artificial intelligence and telemedicine, people will be able to know the presence of cancer, whereas doctors will be able to know the status of cancer patients just with a small amount of their daily urine,” Natsume said in the news release.
Biomarkers found in urine or blood samples that provide clinical laboratories with a simple, non-invasive procedure for early diagnosis of brain tumors could greatly increase the five-year survival rate for thousands of patients diagnosed with brain cancer each year. Such diagnostic technologies are also appropriate for hospitals and physicians interested in advancing patient-centered care.
The discovery is yet another factor that must be considered when developing a liquid biopsy test clinical laboratories can use to detect cancer
How often do disruptive elements present in Liquid biopsies result in misdiagnoses and unhelpful drug therapies for cancer? Researchers at the University of Washington School of Medicine (UW Medicine) in Seattle wanted to know. And the results of their study provide another useful insight for pathologists about the elements that circulate in human blood which must be understood so that liquid biopsy tests can be developed that are not affected by that factor.
Based on their case series study of 69 men with advanced prostate cancer, the UW Medicine researchers determined that 10% of men have a clonal hematopoiesis of indeterminate potential (CHIP) that can “interfere” with liquid biopsies and cause incorrect reports and unneeded prostate cancer treatment, according to their paper published in the journal JAMA Oncology.
The UW Medicine researchers advised testing for “variants in the cell-free DNA (cfDNA)” shed in blood plasma to enable appropriate treatment for people with already diagnosed prostate cancer, noted to a UW Medicine news release.
According to pathologist Colin Pritchard, MD, PhD, Associate Professor of Laboratory Medicine and Pathology at the UW Medicine, who led the research team, “clonal hematopoiesis can interfere with liquid biopsies. For example, mutations in the genes BRCA1, BRCA2, and ATM have been closely linked to cancer development.
“The good news is that, by looking at the blood cellular compartment, you can tell with pretty good certainty whether something is cancer, or something is hematopoiesis,” he said in the news release.
What Does CHIP Interference Mean to a Clinical Laboratory Blood Test?
In their published study, the UW Medicine researchers stressed the “urgent need to understand cfDNA testing performance and sources of test interferences” in light of recent US Food and Drug Administration (FDA) clearance of two PARP inhibitors (PARPi) for prostate cancer:
“We found that a strikingly high proportion of DNA repair gene variants in the plasma of patients with advanced prostate cancer are attributable to CHIP,” the researchers wrote. “The CHIP variants were strongly correlated with increased age, and even higher than expected by age group.
“The high rate of CHIP may also be influenced by prior exposure to chemotherapy,” they added. “We are concerned that CHIP interference is causing false-positive cfDNA biomarker assessments that may result in patient harm from inappropriate treatment, and delays in delivering alternative effective treatment options.
“Without performing a whole-blood control, seven of 69 patients (10%) would have been misdiagnosed and incorrectly deemed eligible for PARP-inhibitor therapy based on CHIP interference in plasma. In fact, one patient in this series had a BRCA2 CHIP clone that had been previously reported by a commercial laboratory testing company with the recommendation to use a PARPi. To mitigate these risks, cfDNA results should be compared to results from whole-blood control or tumor tissue,” the researchers concluded.
To find the clinically relevant CHIP interference in prostate cancer cfDNA testing, researchers used the UW-OncoPlex assay (developed and clinically available at UW Medicine). The assay is a multiplexed next-generation sequencing panel aimed at detecting mutations in tumor tissues in more than 350 genes, according to the UW Medicine Laboratory and Pathology website.
“To improve cfDNA assay performance, we developed an approach that simultaneously analyzes plasma and paired whole-blood control samples. Using this paired testing approach, we sought to determine to what degree CHIP interferes with the results of prostate cancer cfDNA testing,” the researchers wrote in JAMA Oncology.
Men May Receive Unhelpful Prostate Cancer Drug Therapies
The research team studied test results from 69 men with advanced prostate cancer. They analyzed patients’ plasma cfDNA and whole-blood control samples.
Tumor sequencing enabled detection of germline (cells relating to preceding cells) variants from CHIP clones.
The UW Medicine study suggested CHIP variants “accounted for almost half of the somatic (non-germline) DNA repair mutations” detected by liquid biopsy, according to the news release.
> “About half the time when the plasma is thought to contain a mutation that would guide therapy with these drugs, it actually contains CHIP variants, not prostate cancer DNA variants. That means that in about half of those tested, a patient could be told that he should be administered a drug that is not indicated to treat to his cancer,” said Colin Pritchard, MD, PhD, pathologist and Associate Professor of Laboratory Medicine and Pathology at UW Medicine in the new release. (Photo copyright: University of Washington School of Medicine.)
Other detailed findings of the UW Medicine Study:
CHIP variants of 2% or more were detected in cfDNA from 13 of 69 men.
Seven men, or 10%, having advanced prostate cancer “had CHIP variants in DNA repair genes used to determine PARPi candidacy.
CHIP variants rose with age: 0% in those 40 to 50; 12.5% in men 51 to 60; 6.3% in those 61 to 70; 20.8% in men 71 to 80; and 71% in men 81 to 90.
Whole-blood control made it possible to distinguish prostate cancer variants from CHIP interference variants.
“Men with prostate cancer are at high risk of being misdiagnosed as being eligible for PARPi therapy using current cfDNA tests; assays should use a whole-blood control sample to distinguish CHIP variants from prostate cancer,” the researchers wrote in JAMA Oncology.
Liquid Biopsies Are ‘Here to Stay’
Surgical oncologist William Cance, MD, Chief Medical and Scientific Officer, American Cancer Society (ACS) in Atlanta, recognizes the challenge of tumor biology to liquid biopsies.
“Genetic abnormalities are only one piece of the puzzle. We need to look comprehensively at tumors for the best therapy, from their metabolic changes and protein signatures in the blood to the epigenetic modifications that may occur, as cancers take hold,” he told Oncology Times. “It’s not just shed DNA in the blood.”
The UW Medicine study demonstrates the importance of understanding how all elements in liquid biopsies interact to affect clinical laboratory test results.
“I think liquid biopsies are here to stay,” Cance told Oncology Times. “They’re all part of precision medicine, tailored to the individual.”
