Author(s): M¯arcis Leja 1 , Hu Liu 2 , Hossam Haick [*] 3
breath testing; gastric cancer; volatile organic compounds
Breath testing could provide a totally new, comprehensive detection and screening method for digestive cancers, which can affect in the entire digestive system: esophagus, stomach, small intestine, colon, rectum, anus, liver, pancreas, gallbladder and biliary system. Digestive cancers belong to the most widespread and deadly human cancers. Colorectal cancer and stomach cancer, for example, are the second leading causes of cancer deaths in the USA and worldwide, respectively  . Early presymptomatic detection is paramount in the management of digestive cancers, improving prognosis and treatment outcome. In cases where screening methods are available, there is still space for improvement. Upper endoscopy or colonoscopy, combined with biopsy and histopathological evaluation of tissue samples are highly accurate diagnostic methods for esophagus, stomach and colorectal cancer, but are plagued with prominent setbacks: the relentless and invasive procedures are inconvenient to the patients and still carry some risk to their health, although a small one [2,3] . Moreover, they are too costly and time-consuming for population-based screening.
Diagnostic breath testing would be extremely attractive, because it is totally noninvasive and painless to the individual, having no undesirable side effects [4-8] . Real-time breath testing by simply exhaling into an instrument would be especially useful, because the data could be immediately available to the clinician, allowing swift treatment decisions and reducing the number of visits to the clinic. Human breath is mainly composed of nitrogen, oxygen, carbon dioxide, water vapor and inert gases. In addition, thousands of volatile organic compounds (VOCs) are exhaled at very low concentrations (estimated as parts per trillion or parts per billion by volume of the exhaled breath) [4,5] . Part of these substances are of endogenous origin and could be characteristic for metabolic processes in the human body (including cancer), while several hundreds others are exogenic, that is, passing through the human body  . The latter could be considered as pollution or background noise. Nonetheless, these VOCs might also be relevant as exogenous markers of digestive cancers since particular individuals (having the disease or with particular activated metabolic pathways) might have a different capacity to accumulate and concentrate particular VOCs in the body  . Endogenous cancer-specific VOCs are released from the cancer cells and/or metabolic processes that are associated with cancer growth whereby different cancers emit different types and/or amounts of molecules. These VOCs are transported with the blood to the alveoli of the lung from where they are exhaled as measurable odorants. Therefore, cancer does not only have a smell, but, at least in theory, different cancers have different smells  .
The smell of cancer is far too delicate for direct human perception, but anecdotes of dogs perceiving cancer in their owners have been occasionally reported since 1989, prompting several scientific studies of this issue [9-12] . The canine sense of smell is generally 10,000-100,000 times superior to the human one: more than 800 gene sequences coding olfactory receptors have been identified in dogs  . Sonoda et...