DNC News

Cancer Stinks

March 8, 2006

Subject: Dogs can smell cancer and may be trained to screen people.

The Joke:

A woman brings her poodle to the veterinarian. “Doctor,” she says, “I think Fido died in her sleep last night.”

  “Let's check it out,” says the vet and he carries out a Siamese cat followed by a Labrador retriever; both sniff at the inert form of Fido and wander away. The doctor turns to the woman and sadly explains that she was right, offers his sympathy and presents a bill for payment.

  “Twelve hundred and twenty five dollars, that can't be right, I thought your office visit was only twenty-five dollars,” exclaims the shocked woman.

“It still is but this includes a thousand for the CAT scan and two hundred for the lab work.”

Laugh now because this joke may soon be closer to the truth than we might have guessed. Dogs may soon be employed as early screening tools to detect cancer. Recent research suggests that dogs can do as well as any fancy high tech screening test in detecting breast and lung cancer.

Cancer stinks

Cancer increases oxidative stress in the body and increases the liver's production of cytochrome P-450 oxidase enzymes. The fats in the membranes surrounding the cells, in simple terms, go rancid and stink. The liver breaks down these rancid fats into chemicals the body can get rid of. These broken down rancid fats produce noticeable odors. To use fancy language, the lipid peroxidation of the polyunsaturated fatty acids in membranes produces alkanes and methylalkanes. These chemicals are then broken down by the cytochrome P-450 enzymes. This produces volatile organic compounds (VOCs), again a fancy term for chemicals which evaporate easily. Remember that term volatile organic acids and it's abbreviation, VOCs. A fancy term for smelly stuff. In the body VOCs diffuse through the lungs, evaporate and flow out in the breath. Using sensitive instruments researchers have been able to measure the different VOCs released in breath samples from cancer patients compared to people without cancer. A 2003 study using instruments to screen breath to test for breast cancer was slightly better mammogram (99.93% versus 99.89%) at saying when someone didn't have cancer but mammograms were still more accurate at saying when someone had cancer. [i] Lung cancer also produces distincctive VOCs patterns according to 1999 and 2003 publications and machines have been considered as a possible detection method. [ii] [iii]

Dogs have powerful noses, perhaps among the most sensitive in the natural world, able to detect certain chemicals in the part per trillion range. Probably more sensitive than scientific instruments; we don't see blood hounds being replaced in the near future. That dogs could be trained to detect these VOCs more accurately than a electronic instrument is not far fetched. Dogs have certainly proven their mettle at detecting hidden explosives and drugs

Sniffing Cancer in urine:

In a 2004 study published in the British Medical Journal, researchers trained dogs to detect bladder cancer from urine samples. The group used urine samples from 36 patients with bladder cancer, and 108 control samples from cancer-free individuals. Six dogs of varying ages and breeds underwent a seven month training course in cancer detection, carried out by trainers from Hearing Dogs for the Deaf.

In the final, double-blind experiment, each dog underwent nine separate tests in which they were shown an array of seven urine samples, one of which was cancerous, and told to lie down next to the cancerous one. The dogs correctly identified the cancer sample on 22 out of 54 occasions. This success rate of 41% is much higher than the 14% expected from chance alone. [iv] In the course of this research one of the the dogs kept identifying one of control samples, even though the donor had tested negative for bladder cancer. This led to further testing and that donor was found to have a kidney tumor. Interesting but far from impressive results. The newest studies are different.

Sniffing Cancer in Breath:

The newest cancer sniffing study published in the March 2006 issue of the Journal Integrative Cancer Therapies builds on these prior studies. This study is the first to test whether dogs can detect cancers only by sniffing the exhaled breath of cancer patients.

Five household dogs were trained over a 3-week period to detect lung or breast cancer by sniffing the breath of cancer participants. The experiment included 86 cancer patients (55 with lung cancer and 31 with breast cancer) and a control sample of 83 healthy patients. All cancer patients had recently been diagnosed with cancer through biopsy-confirmed conventional methods such as a mammogram, or CAT scan and had not yet undergone any chemotherapy treatment. The dogs were presented with breath samples from the cancer patients and the controls, captured in a special tube. The dogs were trained to give a positive identification of a cancer patient by sitting or lying down directly in front of a test station containing a cancer patient sample.

The dogs correctly detected 99% of the lung cancer samples, and made a mistake with only 1% of the healthy controls. With breast cancer, they correctly detected 88% of the positive samples, and made a mistake on only 2% of the controls. The study also confirmed that the dogs could detect the early stages of lung cancer and early breast cancer. [v] Note that it took only three weeks to train the dogs in this breath sniffing experiment while the urine sniffers were trained for seven months.

Other Diseases that Stink:

Cancer isn't the only disease that stinks and dogs aren't the only animal trained to detect disease. Angina produces it's own smell via VOCs. [vi] Schizophrenia [vii] and organ rejection in transplant recipients also produce distinctive VOCs. [viii] And dogs aren't the only animal being trained to detect disease. A giant African rat has been trained to smell out tuberculosis. [ix] Of course not everyone will trust a dog A group of Italian researchers didn't and created an electronic nose to sniff out lung cancer. [x]

Dogs in White Jackets:

If standard household dogs can be quickly trained to be this effective at cancer screening, one can only assume that specially selected breeds thoroughly trained will do a better job. Imagine a Channel 9 Health Fair of the future where a pack of dogs run down a line of people, each dog sniffing for a particular disease. Of course once you let your imagination start running with this one, it'll fetch up some interesting ideas. Do the dogs get to wear white coats? Dogs stationed as greeters in hospital lobbies, directing people to the appropriate specialty clinic. This will give new meaning to the term ‘working dog'. Should we call them ‘professional dogs'? Or perhaps this will give new meaning to ‘white collar jobs'?

That dead dog joke, while funny now, may not seem funny in years to come when we rely on animals as fundamental medical diagnosticians.

  References:

[i]

 
Erratum in:

•  Breast J. 2003 Jul-Aug;9(4):345.

Volatile markers of breast cancer in the breath.

Phillips M , Cataneo RN , Ditkoff BA , Fisher P , Greenberg J , Gunawardena R , Kwon CS , Rahbari-Oskoui F , Wong C .

Menssana Research Inc., Fort Lee , New Jersey 07024 , USA .

Breast cancer is accompanied by increased oxidative stress and induction of polymorphic cytochrome P-450 mixed oxidase enzymes (CYP). Both processes affect the abundance of volatile organic compounds (VOCs) in the breath because oxidative stress causes lipid peroxidation of polyunsaturated fatty acids in membranes, producing alkanes and methylalkanes which are catabolized by CYP. We performed a pilot study of breath VOCs, a potential new marker of disease in women with breast cancer. This was a combined case-control and cross-sectional study of women with abnormal mammograms scheduled for a breast biopsy. Breath samples were analyzed by gas chromatography and mass spectroscopy in order to determine the breath methylated alkane contour (BMAC), a three-dimensional display of the alveolar gradients (abundance in breath minus abundance in room air) of C4-C20 alkanes and monomethylated alkanes. BMACs in women with and without breast cancer were compared using forward stepwise discriminant analysis. Two hundred one breath samples were obtained from women with abnormal mammograms and biopsies read by two pathologists. There were 51 cases of breast cancer in 198 concordant biopsies. The breath test distinguished between women with breast cancer and healthy volunteers with a sensitivity of 94.1% (48/51) and a specificity of 73.8% (31/42) (cross-validated sensitivity 88.2% (45/51), specificity 73.8% (31/42)). Compared to women with abnormal mammograms and no cancer on biopsy, the breath test identified breast cancer with a sensitivity of 62.7% (32/51) and a specificity of 84.0% (42/50) (cross-validated sensitivity of 60.8% (31/51), specificity of 82.0% (41/50)). The negative predictive value (NPV) of a screening breath test for breast cancer was superior to a screening mammogram (99.93% versus 99.89%); the positive predictive value (PPV) of a screening mammogram was superior to a screening breath test (4.63% versus 1.29%). A breath test for markers of oxidative stress accurately identified women with breast cancer, with an NPV superior to a screening mammogram. This breath test could potentially be employed as a primary screen for breast cancer. Confirmatory studies in larger groups are required.

Publication Types:

•  Evaluation Studies

•  Multicenter Study

[ii]

 
Comment in:

•  Lancet. 1999 Jun 5;353(9168):1897-8.

Volatile organic compounds in breath as markers of lung cancer: a cross-sectional study.

Phillips M , Gleeson K , Hughes JM , Greenberg J , Cataneo RN , Baker L , McVay WP .

Menssana Research Inc, Fort Lee , New Jersey , USA . menssana@bellatlantic.net

BACKGROUND: Many volatile organic compounds (VOCs), principally alkanes and benzene derivatives, have been identified in breath from patients with lung cancer. We investigated whether a combination of VOCs could identify such patients. METHODS: We collected breath samples from 108 patients with an abnormal chest radiograph who were scheduled for bronchoscopy. The samples were collected with a portable apparatus, then assayed by gas chromatography and mass spectroscopy. The alveolar gradient of each breath VOC, the difference between the amount in breath and in air, was calculated. Forward stepwise discriminant analysis was used to identify VOCs that discriminated between patients with and without lung cancer. FINDINGS: Lung cancer was confirmed histologically in 60 patients. A combination of 22 breath VOCs, predominantly alkanes, alkane derivatives, and benzene derivatives, discriminated between patients with and without lung cancer, regardless of stage (all p<0.0003). For stage 1 lung cancer, the 22 VOCs had 100% sensitivity and 81.3% specificity. Cross-validation of the combination correctly predicted the diagnosis in 71.7% patients with lung cancer and 66.7% of those without lung cancer. INTERPRETATION: In patients with an abnormal chest radiograph, a combination of 22 VOCs in breath samples distinguished between patients with and without lung cancer. Prospective studies are needed to confirm the usefulness of breath VOCs for detecting lung cancer in the general population.

PMID: 10371572 [PubMed - indexed for MEDLINE]

•  [iii] Multicenter Study

 
Comment in:

•  Chest. 2003 Jun;123(6):1788-92.

Detection of lung cancer with volatile markers in the breath.

Phillips M , Cataneo RN , Cummin AR , Gagliardi AJ , Gleeson K , Greenberg J , Maxfield RA , Rom WN .

Menssana Research Inc, Fort Lee , NJ 07024 , USA .

STUDY OBJECTIVES: To evaluate volatile organic compounds (VOCs) in the breath as tumor markers in lung cancer. Alkanes and monomethylated alkanes are oxidative stress products that are excreted in the breath, the catabolism of which may be accelerated by polymorphic cytochrome p450-mixed oxidase enzymes that are induced in patients with lung cancer. DESIGN: Combined case-control and cross-sectional study. SETTING: Five academic pulmonary medicine services in the United States and the United Kingdom . Patients and participants: One hundred seventy-eight bronchoscopy patients and 41 healthy volunteers. INTERVENTION: Breath samples were analyzed by gas chromatography and mass spectroscopy to determine alveolar gradients (ie, the abundance in breath minus the abundance in room air) of C4-C20 alkanes and monomethylated alkanes. MEASUREMENTS: Patients with primary lung cancer (PLC) were compared to healthy volunteers, and a predictive model was constructed using forward stepwise discriminant analysis of the alveolar gradients. This model was cross-validated with a leave-one-out jackknife technique and was tested in two additional groups of patients who had not been used to develop the model (ie, bronchoscopy patients in whom cancer was not detected, and patients with metastatic lung cancer [MLC]). RESULTS: Eighty-seven of 178 patients had lung cancer (PLC, 67 patients; MLC, 15 patients; undetermined, 5 patients). A predictive model employing nine VOCs identified PLC with a sensitivity of 89.6% (60 of 67 patients) and a specificity of 82.9% (34 of 41 patients). On cross-validation, the sensitivity was 85.1% (57 of 67 patients) and the specificity was 80.5% (33 of 41 patients). The stratification of patients by tobacco smoking status, histologic type of cancer, and TNM stage of cancer revealed no marked effects. In the two additional tests, the model predicted MLC with a sensitivity of 66.7% (10 of 15 patients), and it classified the cancer-negative bronchoscopy patients with a specificity of 37.4% (34 of 91 patients). CONCLUSIONS: Compared to healthy volunteers, patients with PLC had abnormal breath test findings that were consistent with the accelerated catabolism of alkanes and monomethylated alkanes. A predictive model employing nine of these VOCs exhibited sufficient sensitivity and specificity to be considered as a screen for lung cancer in a high-risk population such as adult smokers.

PMID: 12796197 [PubMed - indexed for MEDLINE]

[iv]

   
Comment in:

•  BMJ. 2004 Nov 27;329(7477):1286-7.

•  BMJ. 2004 Nov 27;329(7477):1286; author reply 1286.

•  BMJ. 2004 Sep 25;329(7468):715.

Olfactory detection of human bladder cancer by dogs: proof of principle study.

Willis CM , Church SM , Guest CM , Cook WA , McCarthy N , Bransbury AJ , Church MR , Church JC .

Department of Dermatology, Amersham Hospital , Amersham HP7 0JD. carolyn.willis@sbucks.nhs.uk

OBJECTIVE: To determine whether dogs can be trained to identify people with bladder cancer on the basis of urine odour more successfully than would be expected by chance alone. DESIGN: Experimental, "proof of principle" study in which six dogs were trained to discriminate between urine from patients with bladder cancer and urine from diseased and healthy controls and then evaluated in tests requiring the selection of one bladder cancer urine sample from six controls. PARTICIPANTS: 36 male and female patients (age range 48-90 years) presenting with new or recurrent transitional cell carcinoma of the bladder (27 samples used for training; 9 used for formal testing); 108 male and female controls (diseased and healthy, age range 18-85 years--54 samples used in training; 54 used for testing). MAIN OUTCOME MEASURE: Mean proportion of successes per dog achieved during evaluation, compared with an expected value of 1 in 7 (14%). RESULTS: Taken as a group, the dogs correctly selected urine from patients with bladder cancer on 22 out of 54 occasions. This gave a mean success rate of 41% (95% confidence intervals 23% to 58% under assumptions of normality, 26% to 52% using bootstrap methods), compared with 14% expected by chance alone. Multivariate analysis suggested that the dogs' capacity to recognise a characteristic bladder cancer odour was independent of other chemical aspects of the urine detectable by urinalysis. CONCLUSIONS: Dogs can be trained to distinguish patients with bladder cancer on the basis of urine odour more successfully than would be expected by chance alone. This suggests that tumour related volatile compounds are present in urine, imparting a characteristic odour signature distinct from those associated with secondary effects of the tumour, such as bleeding, inflammation, and infection.

Publication Types:

•  Clinical Trial

•  Multicenter Study

•  Randomized Controlled Trial

PMID: 15388612

[v]

 
Diagnostic accuracy of canine scent detection in early- and late-stage lung and breast cancers.

McCulloch M , Jezierski T , Broffman M , Hubbard A , Turner K , Janecki T .

Pine Street Foundation, San Anselmo , California . mcculloch@pinestreetfoundation.org.

Background: Lung and breast cancers are leading causes of cancer death worldwide. Prior exploratory work has shown that patterns of biochemical markers have been found in the exhaled breath of patients with lung and breast cancers that are distinguishable from those of controls. However, chemical analysis of exhaled breath has not shown suitability for individual clinical diagnosis. METHODS: The authors used a food reward-based method of training 5 ordinary household dogs to distinguish, by scent alone, exhaled breath samples of 55 lung and 31 breast cancer patients from those of 83 healthy controls. A correct indication of cancer samples by the dogs was sitting/lying in front of the sample. A correct response to control samples was to ignore the sample. The authors first trained the dogs in a 3-phase sequential process with gradually increasing levels of challenge. Once trained, the dogs' ability to distinguish cancer patients from controls was then tested using breath samples from subjects not previously encountered by the dogs. The researchers blinded both dog handlers and experimental observers to the identity of breath samples. The diagnostic accuracy data reported were obtained solely from the dogs' sniffing, in double-blinded conditions, of these breath samples obtained from subjects not previously encountered by the dogs during the training period. RESULTS: Among lung cancer patients and controls, overall sensitivity of canine scent detection compared to biopsy-confirmed conventional diagnosis was 0.99 (95% confidence interval [CI], 0.99, 1.00) and overall specificity 0.99 (95% CI, 0.96, 1.00). Among breast cancer patients and controls, sensitivity was 0.88 (95% CI, 0.75, 1.00) and specificity 0.98 (95% CI, 0.90, 0.99). Sensitivity and specificity were remarkably similar across all 4 stages of both diseases. CONCLUSION: Training was efficient and cancer identification was accurate; in a matter of weeks, ordinary household dogs with only basic behavioral "puppy training" were trained to accurately distinguish breath samples of lung and breast cancer patients from those of controls. This pilot work using canine scent detection demonstrates the validity of using a biological system to examine exhaled breath in the diagnostic identification of lung and breast cancers. Future work should closely examine the chemistry of exhaled breath to identify which chemical compounds can most accurately identify the presence of cancer.

PMID: 16484712 [PubMed - in process]

[vi]

Breath markers of oxidative stress in patients with unstable angina.

Phillips M , Cataneo RN , Greenberg J , Grodman R , Salazar M .

Menssana Research Inc, Fort Lee , NJ 07024 , USA . menssana@bellatlantic.net

Cardiac chest pain is accompanied by oxidative stress, which generates alkanes and other volatile organic compounds (VOCs). These VOCs are excreted in the breath and could potentially provide a rational diagnostic marker of disease. The breath methylated alkane contour (BMAC), a 3-dimensional surface plot of C4-C20 alkanes and monomethylated alkanes, provides a comprehensive set of markers of oxidative stress. In this pilot study, we compared BMACs in patients with unstable angina pectoris and in healthy volunteers. Breath VOCs were analyzed in 30 patients with unstable angina confirmed by coronary angiography and in 38 age-matched healthy volunteers with no known history of heart disease (mean age +/- SD, 62.7 +/- 12.3 years and 62.5 +/- 10.0, not significant). BMACs in both groups were compared to identify the combination of VOCs that provided the best discrimination between the 2 groups. Forward stepwise entry discriminant analysis selected 8 VOCs to construct a predictive model that correctly classified unstable angina patients with sensitivity of 90% (27 of 30) and specificity of 73.7% (28 of 38). On cross-validation, sensitivity was 83.3% (25 of 30) and specificity was 71.1% (27 of 38). We conclude that the breath test distinguished between patients with unstable angina and healthy control subjects.

PMID: 12713676 [PubMed - indexed for MEDLINE]

[vii]

 
Volatile organic compounds in the breath of patients with schizophrenia.

Phillips M , Erickson GA , Sabas M , Smith JP , Greenberg J .

Department of Medicine, St Vincent's Medical Center of Richmond, Staten Island, NY 10310-1699, USA.

AIMS--To analyse the breath of patients with schizophrenia for the presence of abnormal volatile organic compounds. METHODS--A case comparison study was performed in two community hospitals in Staten Island , New York . Twenty five patients with schizophrenia, 26 patients with other psychiatric disorders, and 38 normal controls were studied. Alveolar breath samples were collected from all participants, and volatile organic compounds in the breath were assayed by gas chromatography with mass spectroscopy. Differences in the distribution of volatile organic compounds between the three groups were compared by computerised pattern recognition analysis. RESULTS--Forty eight different volatile organic compounds were observed in the breath samples. Three separate pattern recognition methods indicated an increased differentiation capability between the patients with schizophrenia and the other subjects. Pattern recognition category classification models using 11 of these volatile organic compounds identified the patients with schizophrenia with a sensitivity of 80.0% and a specificity of 61.9%. Volatile organic compounds in breath were not significantly affected by drug therapy, age, sex, smoking, diet, or race. CONCLUSIONS--Microanalysis of volatile organic compounds in breath combined with pattern recognition analysis of data may provide a new approach to the diagnosis and understanding of schizophrenia. The physiological basis of these findings is still speculative.

PMID: 7629295 [PubMed - indexed for MEDLINE]

•  [viii]

 
Patterns and significance of exhaled-breath biomarkers in lung transplant recipients with acute allograft rejection.

Studer SM , Orens JB , Rosas I , Krishnan JA , Cope KA , Yang S , Conte JV , Becker PB , Risby TH .

Department of Medicine, Division of Pulmonary and Critical Care Medicine, Johns Hopkins Medical Institutions, Baltimore , Maryland , USA . sean_studer@mssm.edu

BACKGROUND: Obliterative bronchiolitis ( OB ) remains one of the leading causes of death in lung transplant recipients after 2 years, and acute rejection (AR) of lung allograft is a major risk factor for OB. Treatment of AR may reduce the incidence of OB , although diagnosis of AR often requires bronchoscopic lung biopsy. In this study, we evaluated the utility of exhaled-breath biomarkers for the non-invasive diagnosis of AR. METHODS: We obtained breath samples from 44 consecutive lung transplant recipients who attended ambulatory follow-up visits for the Johns Hopkins Lung Transplant Program. Bronchoscopy within 7 days of their breath samples showed histopathology in 21 of these patients, and we included them in our analysis. We measured hydrocarbon markers of pro-oxidant events (ethane and 1-pentane), isoprene, acetone, and sulfur-containing compounds (hydrogen sulfide and carbonyl sulfide) in exhaled breath and compared their levels to the lung histopathology, graded as stable (non-rejection) or AR. None of the study subjects were diagnosed with OB or infection at the time of the clinical bronchoscopy. RESULTS: We found no significant difference in exhaled levels of hydrocarbons, acetone, or hydrogen sulfide between the stable and AR groups. However, we did find significant increase in exhaled carbonyl sulfide (COS) levels in AR subjects compared with stable subjects. We also observed a trend in 7 of 8 patients who had serial sets of breath and histopathology data that supported a role for COS as a breath biomarker of AR. CONCLUSIONS: This study demonstrated elevations in exhaled COS levels in subjects with AR compared with stable subjects, suggesting a diagnostic role for this non-invasive biomarker. Further exploration of breath analysis in lung transplant recipients is warranted to complement fiberoptic bronchoscopy and obviate the need for this procedure in some patients.

PMID: 11704475 [PubMed - indexed for MEDLINE]

[ix] Giant rats to sniff out tuberculosis

17:31 16 December 2003

NewScientist.com news service

Maggie McKee

[x]

 
Comment in:

•  Am J Respir Crit Care Med. 2005 Oct 15;172(8):1060; author reply 1060-1.

Detection of lung cancer by sensor array analyses of exhaled breath.

Machado RF , Laskowski D , Deffenderfer O , Burch T , Zheng S , Mazzone PJ , Mekhail T , Jennings C , Stoller JK , Pyle J , Duncan J , Dweik RA , Erzurum SC .

Department of Pathobiology, Lerner Research Institute, Cleveland , OH , USA .

RATIONALE: Electronic noses are successfully used in commercial applications, including detection and analysis of volatile organic compounds in the food industry. OBJECTIVES: We hypothesized that the electronic nose could identify and discriminate between lung diseases, especially bronchogenic carcinoma. METHODS: In a discovery and training phase, exhaled breath of 14 individuals with bronchogenic carcinoma and 45 healthy control subjects or control subjects without cancer was analyzed. Principal components and canonic discriminant analysis of the sensor data was used to determine whether exhaled gases could discriminate between cancer and noncancer. Discrimination between classes was performed using Mahalanobis distance. Support vector machine analysis was used to create and apply a cancer prediction model prospectively in a separate group of 76 individuals, 14 with and 62 without cancer. MAIN RESULTS: Principal components and canonic discriminant analysis demonstrated discrimination between samples from patients with lung cancer and those from other groups. In the validation study, the electronic nose had 71.4% sensitivity and 91.9% specificity for detecting lung cancer; positive and negative predictive values were 66.6 and 93.4%, respectively. In this population with a lung cancer prevalence of 18%, positive and negative predictive values were 66.6 and 94.5%, respectively. CONCLUSION: The exhaled breath of patients with lung cancer has distinct characteristics that can be identified with an electronic nose. The results provide feasibility to the concept of using the electronic nose for managing and detecting lung cancer.