January 9, 2025 | While envisioning the next phase of breath diagnostics, Ashish Chaudhary foresees a promising area for future research: expanding upon the notion of “breath diagnostics” to leverage volatile organic compounds (VOCs) from elsewhere.
VOCs from urine could be used to detect prostate cancer, for example, so in the grand scheme of things, “when we say breath diagnostics, we’re really talking about VOCs that are emanating from human subjects,” the Detect-ION CEO told Diagnostics World. If looked at carefully with the right AI tools, he said leveraging VOCs could lead to compelling healthcare solutions down the road.
All organs of the human body produce volatile compounds, Geraldine Lucchi, a research engineer specializing in mass spectrometry at ChemoSens - INRAE in France, told Diagnostics World. VOCs stem from chemical reactions within the body and are released by all humans, healthy or not. At her laboratory, Lucchi and colleagues have studied blood, sweat, hair, lung explants, and more.
In some diseases, changes in metabolic processes can occur early on, and researchers active in this field of study hope that VOCs can be used to detect changes even earlier than cell- or blood-based biomarkers. And because VOCs are continuously emitted, there are possibilities for real-time monitoring of changes in VOC profiles, which could offer valuable insights into disease progression or response to treatment.
New Study Aims to Detect Cancer from Skin-Emitted VOCs
Over 1,800 VOCs have been identified in humans so far, according to a group of researchers at the Manipal Institute of Technology and KLE Technological University in India, and roughly 500 of them are released through the skin.
In RSC Advances (DOI: 10.1039/D4RA01579G), they summarized research progress and tech advances in skin-based sample preparation techniques related to skin-emitted VOCs and non-invasive disease diagnosis and monitoring. They also addressed current challenges and limitations of skin sampling, such as the variability among human subjects, differences in skin depth, and the possibility of contamination during sampling. The sampling area and timing can also impact the data being measured.
Although gas chromatography-mass spectrometry and electronic noses have shown potential for odor profiling, “more research is needed to fully understand the pathophysiology associated with various human conditions and design reliable products,” they noted.
In the UK, a newly announced three-year clinical study will pursue the potential of utilizing a rapid, portable sensor to detect skin cancers from VOCs released by the skin. The study intends to identify VOCs specific to skin cancers and develop a device capable of detecting them. The project will be carried out by a group from the Department of Life and Environmental Sciences at Bournemouth University and the Oral and Maxillofacial Surgery Unit at University Hospitals Dorset in the UK.
General practitioners often assess possible skin cancer before deciding whether or not to refer a patient to a specialist, explained Richard Paul, a professor of bioanalytical chemistry at Bournemouth University. And because skin cancers can be challenging to diagnose, unnecessary referrals to specialists are commonplace. “Our research towards the development of a rapid sensor, specific to skin cancers and deployable in a point of care device is an exciting prospect, which would enable rapid detection of skin cancer in primary care, enhancing patient triage and improving patient outcomes,” he said.
Research Explores Potential of Urinary VOCs for Cancer Detection
A recent Frontiers in Oncology review paper (DOI: 10.3389/fonc.2024.1448760) offers a summary of published literature from the past 11 years, and especially the last five years, related to the use of urinary VOCs as possible biomarkers for different forms of cancer.
The Canadian researchers found that the most studied cancers included prostate, lung, breast, and bladder. A smaller number of studies examined cervical, colorectal, skin, and liver cancer, among others. Mass spectrometry and electronic noses were found to be the most commonly used tools for VOC detection. “Importantly, most studies which produced a VOC-based model of cancer detection observed a combined sensitivity and specificity above 150%, indicating that urine-based methods of cancer detection show considerable promise as a diagnostic tool,” they noted.
Among the 44 studies examined, the authors pointed out that 47 chemical species were correlated with cancer in at least two papers, suggesting they could be useful targets for future studies exploring urinary VOC cancer biomarkers. “Overall, it was concluded that research in this field has shown promising results, but more work may be needed before the widespread adoption of these techniques takes place,” they added.
In addition to this look back at progress made over the past decade, several studies have emerged in recent months, shedding new light on the promise of urinary VOCs as potential biomarkers.
According to a group of Australian researchers, it is unclear how urinary VOCs reflect the abnormal metabolic profile of individuals with kidney disease, so they set out to learn more. In a study that included 64 participants, they reported “novel links between urinary VOCs and tubulointerstitial histopathology.” Their findings in BMC Nephrology (DOI: 10.1186/s12882-024-03819-0) suggest that using urinary VOCs could be beneficial in assessing kidney disease status.
A group of researchers from Thailand set out to assess the feasibility of a metal oxide biosensor platform using urine VOCs to detect genitourinary cancers, including kidney, bladder, and prostate cancer. The study included 64 participants divided into a cancer and non-cancer group, and five commercially available semiconductor sensors were selected to detect specific VOCs. The findings, published in Scientific Reports (DOI: 10.1038/s41598-024-54138-1), suggest that ethanol, hydrogen, iso-butane, and methane VOCs demonstrated potential for the diagnosis of genitourinary cancers. “Developing gas metal oxide sensors tailored to these compounds, and monitoring changes in electrical resistance, could serve as an innovative tool for identifying this specific type of cancer,” the authors concluded.
Researchers at the University of Texas at El Paso pointed out that the early detection of prostate cancer is essential for treatment success and survival—and that existing diagnostic methods like digital rectal examination and prostate-specific antigen testing have clear limitations. To explore the use of urinary VOCs as potential biomarkers for prostate cancer diagnosis, they gathered urine samples from 337 prostate cancer-positive patients and 233 controls and then developed a model. Findings published in the Journal of Applied Statistics (DOI: 10.1080/02664763.2024.2346355) “reveal that regularized logistic regression outperforms numerous other classifiers when analyzing the collected data,” they noted. Their newly developed diagnosis model achieved an Area Under the Curve (AUC) of 0.748 (compared to a PSA-based AUC of 0.540). The researchers concluded that the results reveal the potential of VOC-based diagnosis as a feasible approach for screening in clinical settings.
The same group, along with collaborators at Geisinger Clinic and Gilead Sciences, also studied the use of urinary VOCs to diagnose clear cell renal cell carcinoma (ccRCC). This disease makes up the majority of all renal cancer cases and often “remains asymptomatic until incidentally detected during unrelated abdominal imaging or at advanced stages.” To learn more, the researchers attempted to identify ccRCC-specific VOCs in the urine of patients with ccRCC. They studied 233 ccRCC patients and 43 healthy individuals and developed a ccRCC diagnostic model involving 24 VOC markers. Their findings, published in Metabolites (DOI: 10.3390/metabo14100546), demonstrated an AUC of 0.94, 86 percent sensitivity, and 92 percent specificity.
“This study highlights the feasibility of using urine as a reliable biospecimen for identifying VOC biomarkers in ccRCC,” the authors concluded. Although additional validation is needed, they say this study’s ability to distinguish between ccRCC and control groups “holds significant promise.”
In a pair of studies published in 2024, German researchers explored novel urine-based approaches for VOC-based detection of prostate and bladder cancer. In one study, they collected 56 samples from patients with prostate cancer and formed a control group of 53 healthy participants. The researchers then carried out measurements using an electronic nose and ion mobility spectrometry (IMS).
“While the first results with an electronic nose show some limitations, the approach can compete with other urine-based marker systems,” they wrote in The Prostate (DOI: 10.1002/pros.24692). “However, it seems less reliable than PSA testing.” They found IMS to be a more accurate approach than the electronic nose “with promising sensitivity and specificity” that calls for additional research, including gas chromatography/mass spectrometry, to further characterize the relevant metabolites identified by IMS.
In a related study published in the World Journal of Urology (DOI: 10.1007/s00345-024-05047-5), the researchers indicated that, so far, no urinary marker system has demonstrated the ability to substitute cystoscopy. The measurement of VOCs from urine is thought to be a promising alternative, however, so they studied urine samples from 30 patients with confirmed transitional cell carcinoma and 30 healthy controls using multicapillary column ion mobility spectrometry (MCC/IMS).
Their findings revealed eight peaks with “significantly differing intensity,” and five of those peaks were considered “highly significant.” Utilizing a six-step decision tree, MCC/IMS demonstrated a sensitivity of 90% and specificity of 100% in group separation.
Hendrik Heers, who was involved with both studies, told Diagnostics World the primary significance of this research is the proof of principle “that urine-based VOC analysis can diagnose bladder cancer, prostate cancer, and COVID.” This is especially relevant for bladder cancer, added the senior physician in the Clinic for Urology and Pediatric Urology at RWTH Aachen University Hospital because, in the future, it could help patients avoid cystoscopies—an uncomfortable, invasive diagnostic procedure.
Moving forward, the initial data will need to be validated. The researchers are currently examining the validation cohort for their bladder cancer study. They are also looking to use other methods of VOC detection to arrive at the most specific VOCs and distinguish between healthy and tumor samples.
When asked what excites him as he considers future possibilities in this field of study, Heers pointed out that “urinary VOC analysis has the potential to be a quick and non-invasive test for multiple diseases, both benign and malign.” Furthermore, the potential to help avoid other diagnostic tests could not only speed up the process but also save money along the way.
However, Heers also acknowledged lingering challenges: “While the principle of VOC-based diagnosis seems to be feasible for many diseases, we still need to figure out many details and standardize the tests in order to get reliable results in a real-world setting outside of clinical trials.”
Paul Nicolaus is a freelance writer specializing in science, nature, and health. Learn more at www.nicolauswriting.com.