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Colorectal cancer screening with odour material by canine scent detection

Authors:
  • Tokyo Metropolitan Cancer Detection Center

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Early detection and early treatment are of vital importance to the successful treatment of various cancers. The development of a novel screening method that is as economical and non-invasive as the faecal occult blood test (FOBT) for early detection of colorectal cancer (CRC) is needed. A study was undertaken using canine scent detection to determine whether odour material can become an effective tool in CRC screening. Exhaled breath and watery stool samples were obtained from patients with CRC and from healthy controls prior to colonoscopy. Each test group consisted of one sample from a patient with CRC and four control samples from volunteers without cancer. These five samples were randomly and separately placed into five boxes. A Labrador retriever specially trained in scent detection of cancer and a handler cooperated in the tests. The dog first smelled a standard breath sample from a patient with CRC, then smelled each sample station and sat down in front of the station in which a cancer scent was detected. 33 and 37 groups of breath and watery stool samples, respectively, were tested. Among patients with CRC and controls, the sensitivity of canine scent detection of breath samples compared with conventional diagnosis by colonoscopy was 0.91 and the specificity was 0.99. The sensitivity of canine scent detection of stool samples was 0.97 and the specificity was 0.99. The accuracy of canine scent detection was high even for early cancer. Canine scent detection was not confounded by current smoking, benign colorectal disease or inflammatory disease. This study shows that a specific cancer scent does indeed exist and that cancer-specific chemical compounds may be circulating throughout the body. These odour materials may become effective tools in CRC screening. In the future, studies designed to identify cancer-specific volatile organic compounds will be important for the development of new methods for early detection of CRC.
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Colorectal cancer screening with odour material by
canine scent detection
Hideto Sonoda,
1,6
Shunji Kohnoe,
1,6
Tetsuro Yamazato,
2
Yuji Satoh,
3
Gouki Morizono,
4
Kentaro Shikata,
5
Makoto Morita,
6
Akihiro Watanabe,
6
Masaru Morita,
1
Yoshihiro Kakeji,
1
Fumio Inoue,
4
Yoshihiko Maehara
1
ABSTRACT
Objective Early detection and early treatment are of vital
importance to the successful treatment of various
cancers. The development of a novel screening method
that is as economical and non-invasive as the faecal
occult blood test (FOBT) for early detection of colorectal
cancer (CRC) is needed. A study was undertaken using
canine scent detection to determine whether odour
material can become an effective tool in CRC screening.
Design Exhaled breath and watery stool samples were
obtained from patients with CRC and from healthy
controls prior to colonoscopy. Each test group consisted
of one sample from a patient with CRC and four control
samples from volunteers without cancer. These five
samples were randomly and separately placed into five
boxes. A Labrador retriever specially trained in scent
detection of cancer and a handler cooperated in the
tests. The dog first smelled a standard breath sample
from a patient with CRC, then smelled each sample
station and sat down in front of the station in which
a cancer scent was detected.
Results 33 and 37 groups of breath and watery stool
samples, respectively, were tested. Among patients with
CRC and controls, the sensitivity of canine scent
detection of breath samples compared with conventional
diagnosis by colonoscopy was 0.91 and the specificity
was 0.99. The sensitivity of canine scent detection of
stool samples was 0.97 and the specificity was 0.99.
The accuracy of canine scent detection was high even
for early cancer. Canine scent detection was not
confounded by current smoking, benign colorectal
disease or inflammatory disease.
Conclusions This study shows that a specific cancer
scent does indeed exist and that cancer-specific
chemical compounds may be circulating throughout the
body. These odour materials may become effective tools
in CRC screening. In the future, studies designed to
identify cancer-specific volatile organic compounds will
be important for the development of new methods for
early detection of CRC.
INTRODUCTION
Despite rapid progress in examination technology
and therapy for colorectal cancer (CRC), this
disease constitutes a signicant proportion of the
global burden of cancer morbidity and mortality.
1
Multiple professional organisations have recom-
mended screening for CRC
1e5
and many previous
studies have demonstrated the cost-effectiveness of
CRC screening.
6e11
Moreover, patients with
familial adenomatous polyposis or Lynch syndrome
are recommended to undergo frequent colonoscopy
to reduce the morbidity and mortality associated
with CRC.
12e15
Early detection and early treat-
ment are critical for the successful treatment of
cancer and are excellent means for reducing both
1
Department of Surgery and
Science, Kyushu University at
Fukuoka, Fukuoka, Japan
2
Department of Internal
Medicine, Arita Kyoritsu
Hospital at Arita, Saga, Japan
3
St. Sugar Cancer Sniffing Dog
Training Center at
Minamibousou, Chiba, Japan
4
Department of General
Surgery, Arita Kyoritsu Hospital
at Arita, Saga, Japan
5
Department of Internal
Medicine, Fukuoka Dental
College Hospital at Fukuoka,
Fukuoka, Japan
6
Department of General
Surgery, Fukuoka Dental College
Hospital at Fukuoka, Fukuoka,
Japan
Correspondence to
Dr Hideto Sonoda, Department
of Surgery and Science
Graduate School of Medicine
Kyushu University 3-1-1
Midashi,Higashi-ku, Fukuoka
812-8582, Japan; hsonoda@
surg2.med.kyushu-u.ac.jp
Revised 23 November 2010
Accepted 7 December 2010
Published Online First
31 January 2011
This paper is freely available
online under the BMJ Journals
unlocked scheme, see http://
gut.bmj.com/site/about/
unlocked.xhtml
Significance of this study
What is already known about this subject?
<Canine olfactory detection of cancer has been
reported for melanoma as well as bladder, lung,
breast and ovarian cancer.
<It is reported that dogs can be trained to
distinguish breath samples of patients with lung
and breast cancer from those of control
volunteers and to distinguish ovarian cancer
tissues from control tissues with high accuracy.
<Several volatile organic compounds have been
identified as candidate substances for early
detection of cancer using gas chromatography/
mass spectroscopy in the exhaled breath of
patients with lung and breast cancer; while
these data are promising, they are preliminary
findings that should be interpreted with caution.
What are the new findings?
<In patients with colorectal cancer (CRC) and
controls, the sensitivity of canine scent detec-
tion of breath samples compared with conven-
tional diagnosis by colonoscopy was 0.91 and
the specificity was 0.99.
<The sensitivity of canine scent detection of
watery stool samples was 0.97 and the
specificity was 0.99.
<The accuracy of canine scent detection was
even higher for early-stage cancers.
<Canine scent detection was not confounded by
current smoking, benign colorectal disease,
inflammatory disease or the presence of
human haemoglobin or transferrin.
How might it impact on clinical practice in the
foreseeable future?
<Odour materials may become effective tools in
CRC screening. In the future, studies designed
to identify cancer-specific volatile organic
compounds will be important for the develop-
ment of new methods for early detection of
CRC.
<Identification of cancer-specific volatile organic
compounds will lead to solving the biological
character of cancer.
814 Gut 2011;60:814e819. doi:10.1136/gut.2010.218305
Colon
the economic burden and mortality. CRC therefore represents an
excellent example of the value of early detection.
The faecal occult blood test (FOBT) is currently the most
economic and non-invasive screening method for CRC, and
many patients with positive results subsequently undergo total
colonoscopy leading to a reduced incidence and mortality of
CRC.
23616
However, the positive predictive value of FOBT for
CRC is approximately 10%,
17e20 16 21
considering the impact of
closer examination by colonoscopy or barium enema. The devel-
opment of a novel more effective CRC screening method that is
as economical and non-invasive as FOBT is therefore needed.
There have been several anecdotal reports of canine scent
detection of skin cancer.
22 23
Moreover, Willis et al reported that
dogs can distinguish urine from patients with bladder cancer
with a mean success rate of 41%,
24
while McCulloch et al
reported that ordinary household dogs can be trained to distin-
guish breath samples of patients with lung and breast cancer
from those of control volunteers with high accuracy (sensitivity
and specicity of 0.99 and 0.99 in lung cancer and 0.88 and 0.98
in breast cancer, respectively).
25
Horvath et al reported that,
among ovarian cancer tissues and control tissues, the sensitivity
was 100% and the specicity was 97.5%.
26
In the present study we have conrmed the accuracy of canine
scent detection of breath samples and evaluated canine scent
detection of watery stool samples from patients with CRC. We
also examined whether the diagnostic performance of dogs is
affected by age, smoking, disease stage, cancer site, inamma-
tion or bleeding in patients with cancer or control individuals.
METHODS
Patient and control sample donors
Patients were enrolled from 20 June 2008 to 20 May 2009 at the
Fukuoka Dental College Medical and Dental Hospital and Arita
Kyoritsu Hospital. To prepare for colonoscopy, subjects ingested
2 l of a balanced electrolyte and polyethylene glycol 4000 solu-
tion (Niec, Ajinomoto Pharma, Tokyo, Japan). Patients were
required to be >20 years old. Patients and controls completed
a questionnaire about factors that could inuence volatile
molecules in the breath or watery stool samples including age,
physical symptoms (eg, abdominal pain or distention, bloody
faeces, constipation, diarrhoea, body weight loss and abdominal
tumour), history of cancer treatment, present use of anticoagu-
lants and smoking within the previous 2 weeks. Colorectal
diseases diagnosed primarily by colonoscopy were recorded in
detail and pathological examination of biopsy samples was
performed if necessary. Patients who had undergone cancer
surgery within the previous year, those who did not undergo
examination for cancer recurrence despite having undergone
cancer surgery more than 5 years previously and those currently
receiving chemotherapy were excluded. A serial number was
written on each sample at the time of collection to identify
individual information.
Breath sampling
Breath samples were acquired from the beginning to the end of
exhalation. Each subject exhaled between 100 and 200 ml into
a breath sampling bag (Otsuka Pharmaceutical Company, Tokyo,
Japan). The bags were then tted with their end caps and sealed in
ordinary grocery store Ziploc-style bags at 48C until presentation
to the dog. Only one sample was collected from each participant.
Watery stool sampling
A 50 ml watery stool sample was obtained by suction during
colonoscopy using a trachea aspirator kit (Sumitomo Bakelite
Company, Tokyo, Japan) between the rectum and descending
colon and preserved at 808C until ltration. The sample was
ltered with qualitative lter paper No. 2 (diameter 110 mm;
Tokyo Roshi Kaisha, Tokyo, Japan) and further ltered by Millex
GP lter (pore size 0.22 mm, diameter 33 mm, non-sterile type;
Millipore Co, Corrigiwohill, Co. Cork, Ireland). Next, 1 ml of
ltrated watery stool samples was enclosed in a 5 ml brown
glass screw cap bottle, sealed in an ordinary grocery store small
Ziploc-style bag and enclosed in a 50 ml polypropylene screw
cap tube and kept at 208C until presentation to the dog. Only
one sample was collected from each participant.
Dog and training
A specially trained 8-year-old female black Labrador retriever
from the St Sugar Cancer Snifng Dog Training Center (Chiba,
Japan) participated in the study. The dog was trained for water
rescue beginning in 2003 and then began training as a cancer
detection dog in 2005.
Each cancer detection training session was considered
complete when the dog could correctly distinguish between
breath samples from a cancer patient and four controls consec-
utively in dozens of trials. The fundamental training method
was a reward-based approach in which the correct behaviour is
rewarded by simultaneous play with a tennis ball. The breath
samples used in the training steps beginning in 2005 were
collected from several hundred patients with cancer and about
500 healthy volunteers recruited using the internet.
In the rst training step in 2005, breath samples from one
patient with oesophageal cancer and four controls were used.
The samples were removed from the breath-sampling bag and
placed into a paper cup which was then covered with a paper
lter for 2 days. The ve sample cups were placed on the oor by
the handler. First, the dog smelled the standard breath sample
from the patient with oesophageal cancer and then tried to
identify the cup containing the oesophageal cancer scent from
among the ve sample cups. If the dog correctly identied the
cancer sample it was rewarded with a tennis ball. A similar
training session was conducted using breath samples from
patients with lung cancer on the following day and was
performed again using breath samples from patients with gastric
cancer 2 days later.
In the second step the breath-sampling bag was used with the
end cap on. Breath-sampling bags containing oesophageal, lung
or gastric cancer scents originating from the same patient in
the rst step were chosen randomly for the 1-month training
period.
In the third step the dog rst smelled the breath sample from
one type of cancer as a standard sample and then tried to
identify the bag with the scent of another cancer. The training
was then continued by adding samples of other types of cancers
as well as controls.
The dog was already able to detect the following types of
cancer in patient breath samples prior to initiation of the present
study: oesophageal cancer, breast cancer, lung cancer, gastric
cancer, pancreatic cancer, hepatocellular carcinoma, chol-
angiocarcinoma, colorectal cancer, prostate cancer, uterine
cancer, ovarian cancer and bladder cancer.
Training and test room
The training and testing of the dog were conducted in
a 4.8 m38.0 m room with vinyl tiling and overhead uorescent
and natural window lighting. The room was not climate
controlled and average ambient temperatures during the study
(November 2008 through June 2009) ranged from 98Cto208C.
Gut 2011;60:814e819. doi:10.1136/gut.2010.218305 815
Colon
At the end of each study day the oor was wiped with water
and a damp mop.
Sample stations
Five sample stations were positioned on the oor of the room in
a single straight line spaced 52 cm apart. Each station consisted
of a light blue painted wooden storage container measuring
27 cm wide, 30 cm long and 20 cm high. Each station also
contained a wall 10 cm deep in which the breath sample bags or
the watery stool sample bottles were placed. The top of each
box was covered with metal netting to prevent the dog from
directly contacting the samples.
Breath and watery stool sample locations
In a single trial, the dog passed and sniffed each of the ve
stations (one cancer sample and four control samples). Both
patient and control samples were replaced with new samples
after the dog had sniffed all ve sample stations. Two to four
trials were performed on each day of testing.
Personnel
The dog handler called the dog into the room and encouraged
the dog to sniff the stations with the command Search!after
smelling the standard breath sample from the patient with CRC
at each test. No other people were in the room.
Classification of the dog’s response
Correct responses were (1) indication by sitting down in front of
a sample station containing a cancer sample (a true positive in
sensitivity calculations): and (2) snifng but not indicating on
a control sample (true negative). Incorrect responses were (1)
indicating on a control sample (false positive); (2) snifng but
not indicating on a cancer sample (false negative); and (3)
hesitation, considered to be an incomplete reaction to either
cancer or control samples (either false positive or false negative
depending on whether hesitation was on a cancer or control
sample).
Testing
Tests were conducted from 13 November 2008 to 15 June 2009
because the dogs concentration tends to decrease during the hot
summer season. For each test, completely new samples were
used for both cases and controls; thus, each sample was only
used a single time. For each trial we used a random number table
to determine the location of the sample being tested in the line-
up. Before the tests the sample was placed in either a new bag or
new bottle to avoid contamination of the smell under preser-
vation, and the number described in the sample was converted
from the serial number into the test number at the same time.
The laboratory assistants replaced the samples. The identity of
the samples was blinded to the dog, the handler and the labo-
ratory assistants, thereby making the study double-blind. One
station contained a cancer sample and the remaining four
stations contained control samples. At the tests the dog smelled
the standard breath sample of CRC origin, after which the dog
passed the side of some boxes and sat down in front of the
station determined to contain a cancer scent, and then the
handler noted the result on an answer card on which the test
number was written. The card was transmitted to Fukuoka
Dental College by fax. After submission the answer was
explained to the handler and the dog as soon as possible because
the correct behaviour was rewarded with a tennis ball. The
cards were collected by mail. During the tests the dog did not
experience any adverse events, injuries or illness.
Occult blood test of watery stool samples
The ordinary FOBT kit, Quick Chaser Occult Blood Test Kit
(Mizuho Medy, Saga, Japan) was used for simultaneous detec-
tion of human haemoglobin and human transferrin in watery
stool samples. Watery stool samples were mixed with phosphate
buffered saline and reacted on the test plate. The test result was
judged by a laboratory medical technologist and a physician.
The result was dened as positive when human haemoglobin
and/or transferrin was positive.
Statistical analysis
Associations between questionnaire variables before colono-
scopy were tested by the Welch t test or
c
2
test. All statistical
differences of p<0.05 were deemed signicant. CRC staging was
based on Union Internationale Contre le Cancer (UICC) criteria.
During testing, experimenters monitored each trial and
recorded their observations on a digital versatile disc. The entire
dog performance dataset was audited for accuracy by comparing
answer cards with digital versatile disc records.
Diagnostic accuracy was calculated as sensitivity and speci-
city of the dogs indication of samples compared with the true
diagnosis conrmed by colonoscopy. Thus, the sensitivity (or
the true positive rate) of the tests is the proportion of cancer
samples correctly identied by the dog while the specicity (or
the true negative rate) is the proportion of control samples
negatively indicated by the dog.
RESULTS
Forty-eight samples were obtained from patients with CRC, 203
samples from volunteers with no history of cancer and 55
samples from patients with a previous history of cancer. For
breath tests, 33 samples from patients with CRC and 132
samples from control volunteers were used and, for watery stool
tests, 37 samples were used from patients with CRC and 148
samples from control volunteers. Each sample was only used once
during testing. The background characteristics were well
matched between cancer patients and control individuals, except
for age (table 1). Approximately half of the controls (47% of
breath samples, 50% of watery stool samples) had colorectal
polyps and a small proportion of the controls (6.1% of breath
samples, 10.5% of watery stool samples) had bleeding or
inammatory colorectal disease, including ischaemic colitis, non-
peculiar colitis or ulcer, ulcerative colitis, diverticular bleeding,
mesenteric panniculitis and chronic appendicitis (table 2).
Diagnostic accuracy: sensitivity and specificity in testing
To calculate sensitivity and specicity we designated the dogs
response to each sample sniffed as the unit of analysis (dened
above). Comparison of the judgement of the canine scent in the
breath or watery stool samples with a colonoscopy-conrmed
conventional diagnosis among cancer patients and controls gave
an overall sensitivity for canine scent detection of 0.91 and 0.97,
respectively, while the overall specicity was 0.99 and 0.99,
respectively (table 3).
During the course of 74 tests, four discrepancies occurred
between colonoscopy and the canine scent detection results
(1/38 watery stool tests and 3/36 breath tests). The discrep-
ancies occurred in the 22nd, 26th, 33rd and 45th tests. Moreover,
these discrepancies occurred in any of four tests on the afore-
mentioned test days. Interestingly, the watery stool sample that
yielded a discrepancy came from an individual whose breath
sample also resulted in a discrepancy. Samples from the three
patients who did not have colon cancer but whose samples
yielded positive results in the watery stool and/or breath tests
816 Gut 2011;60:814e819. doi:10.1136/gut.2010.218305
Colon
did not result in discrepancies on the other tests. These three
patients showed no signs of cancer during the 24 months
following sampling.
Comparison between FOBT results and the dog’s judgement
The results of watery stool tests and conventional FOBTs were
compared to determine whether canine scent judgement relied
on blood. No correlation between canine scent judgement and
FOBT results was observed in patients with cancer (p¼0.51) or
controls (p¼0.68, table 4). The sensitivity and specicity of
FOBT with respect to CRC detection was 0.70 and 0.85,
respectively.
Mixture test of watery stool samples
To determine whether a specic cancer scent exists or if a partic-
ular natural scent vanishes in patients with cancer, we combined
ve watery stool samples into single mixture samples. One of
the mixture samples was composed of one sample of cancer
origin and four control samples, while four mixture samples
consisted of ve control samples each. Tests were performed three
times as described above. Cancer types included stage IIIa
ascending colon cancer, stage II transverse colon cancer and
stage 0 rectal cancer. The results of all three tests were correct.
DISCUSSION
We used the excellent ability of dogs to distinguish between
different scents to examine whether odour materials can be used
in the diagnosis of CRC. This study represents the rst step
towards the development of an early detection system using
odour materials from patients with CRC.
McCulloch et al previously reported the use of canine scent
judgement of breath samples for distinguishing between
controls and patients with lung and breast cancer.
25
We there-
fore evaluated canine scent detection of CRC rst with breath
samples and then with watery stool samples, which has not
been previously reported. We hypothesised that the watery stool
sample scent might be strong because the samples were collected
from nearer to the cancer than were the breath samples.
Conversely, the watery stool sample scents might have been
masked by various other scents such as short-chain fatty acids
and suldes present in the stool. Moreover, we were able to
compare scent detection with the FOBT by using the same stool
sample and to inspect it more quantitatively than using breath
samples. Indeed, despite various disrupting scents, the watery
stool sample tests were superior to the breath sample tests.
We compared the accuracy of canine scent judgement with
colonoscopic diagnosis using breath samples and watery stool
samples from patients with CRC and controls. For breath tests,
the sensitivity and specicity was 0.91 and 0.99, respectively
and, for watery stool tests, the sensitivity and specicity was
0.97 and 0.99, respectively. Moreover, canine scent judgement
even appeared to be highly accurate for early-stage CRC.
Canine scent judgement was not confounded by current
smoking, benign colorectal polyps, inammation or infection. A
statistically signicant difference in age distribution was noted
between cancer patients and controls (p¼0.001 for breath tests,
p<0.05 for watery stool tests). We therefore reanalysed samples
from patients and controls aged <80 years. In this subset anal-
ysis, no correlation between age and cancer status was observed
(p¼0.09 for 19 breath tests, p¼0.93 for 24 watery stool tests).
The sensitivity and specicity in this subset analysis for breath
tests was 0.95 and 0.99, respectively, while the sensitivity and
specicity were both 1.00 for watery stool tests.
There were four discrepancies among the 74 tests including
one of 38 watery stool tests and three of 36 breath tests between
the colonoscopy and canine cancer detection results. It is dif-
cult to specify the cause of these discrepancies owing to their
limited number. The discrepancies occurred in the 22nd, 26th,
33rd and 45th tests, not necessarily in the early tests. Moreover,
these discrepancies occurred in any of the four tests on the
aforementioned test days, not necessarily in those taken late in
the day. No correlation between the discrepancies and training
effect or fatigue was suspected. Interestingly, the watery stool
Table 1 Background characteristics of participants
Breath samples Watery stool samples
Cancer Control Cancer Control
(n[33) (n[132) p Value (n[37) (n[148) p Value
Gender (male) 15 64 0.75 16 86 0.10
Age (years) 71.0 (53e95) 65.0 (25e91) 0.001 70.2 (41e95) 64.6 (25e91) 0.035
Complaint before colonoscopy
Abdominal pain or distention 6 20 0.67 10 22 0.08
Bloody faeces 5 19 0.91 6 19 0.59
Constipation 6 24 1.0 7 24 0.69
Diarrhoea 3 8 0.53 4 14 0.95
Body weight loss 2 8 0.68 3 4 0.29
Abdominal tumour 2 1 0.19 2 1 0.19
No complaint 4 21 0.59 3 28 0.18
Past history of colorectal disease 1 20 0.11 2 22 0.13
Anticoagulant therapy 1 14 0.31 1 18 0.16
Smoked within 2 weeks 3 28 0.18 4 32 0.21
Table 2 Disease in control cases
Breath samples Watery stool samples
Number Rate Number Rate
Polyps 62 47.0% 74 50.0%
Diverticula 24 18.2% 44 29.7%
Haemorrhoids 4 3.0% 7 4.7%
Ischaemic colitis 3 2.3% 4 2.7%
Non-peculiar colitis or ulcers 2 1.5% 4 2.7%
Ulcerative colitis 2 1.5% 4 2.7%
Diverticular bleeding 0 0% 1 0.6%
Mesenteric panniculitis 1 0.8% 1 0.6%
Infectious colitis 0 0% 1 0.6%
Chronic appendicitis 0 0% 1 0.6%
Lynch syndrome 1 0.8% 1 0.6%
Multiple answers were allowed for benign disease.
Gut 2011;60:814e819. doi:10.1136/gut.2010.218305 817
Colon
sample that yielded a discrepancy came from an individual
whose breath sample also resulted in a discrepancy. Moreover,
when the watery stool test was repeated with different controls,
the dog hesitated a few times and then barely detected the rectal
cancer sample, leading to negative results in both the breath and
watery stool tests. It is thought that some cancers are difcult to
detect by canine scent.
No correlation between canine scent judgement and human
haemoglobin and transferrin was observed. Thus, canine scent
judgement does not appear to depend on human haemoglobin or
transferrin scents. All canine scent judgements of watery stool
sample mixture tests were correct, indicating that a speciccancer
scent indeed exists. The volatile organic compounds (VOCs)
detected during canine scent judgement presumably occur early in
the pathogenesis of CRC. As canine scent judgement can be used
on both breath samples and watery stool samples, these chem-
ical compounds may be circulating throughout the body.
To determine whether a specic cancer scent exists or if
a particular natural scent disappears in patients with cancer,
mixtures that included watery stool samples were tested. Tests
were performed three times as described above. The results of all
three tests were correct, thereby suggesting that a specic cancer
scent indeed exists.
Canine scent judgement for distinguishing between cancer
patients and controls has been reported for other cancer
types.
24e26
We obtained breath and watery stool samples from
patients with breast, stomach and prostate cancer who also
underwent colonoscopy. We also tested these samples using
breath samples from patients with CRC as the standard. Canine
scent judgement yielded correct answers for these cancers as
well (data not shown), suggesting that common scents may
exist among various cancer types. This is consistent with the
results of McCulloch et al which demonstrated the utility of
canine scent detection for lung and breast cancer
25
; however,
these results are not inconsistent with the existence of cancer-
specic scents.
It may be difcult to introduce canine scent judgement into
clinical practice owing to the expense and time required for the
dog trainer and for dog education. Scent ability and concentra-
tion vary between different dogs and also within the same dog
on different days. Moreover, each dog can only conduct tests for
a maximum of 10 years. It is therefore necessary to identify the
cancer-specic VOCs detected by dogs and to develop an early
cancer detection sensor that can be substituted for canine scent
judgement.
Breath VOCs have been reported as biomarkers of other
gastrointestinal disorders such as inammatory bowel disease,
ulcerative colitis and necrotising enterocolitis.
27e30
However,
these tests have not been widely accepted, largely due to tech-
nical difculties in measuring the pressure of exhaled VOCs, the
large variations in food intake, the variability in the required
time for bacterial colonisation and the poor predictive value of
a positive test.
Several VOCs have been identied as candidate substances for
early detection of cancer using gas chromatography/mass spec-
troscopy (GC/MS) in the exhaled breath of patients with lung
and breast cancer
31e38
; while these data are promising, they are
preliminary ndings that should be interpreted with caution. We
intend to evaluate these VOCs by chemical analysis and with
cancer detection dogs in the near future. Identication of cancer-
specic VOCs will lead to solving the biological character of
cancer. We hope that the results of the present study will provide
encouragement for the development of cancer detection and
solving the biological character of cancer using odour material.
Acknowledgements The authors thank Tomoe Fujino and Mika Ohnishi for their
valuable technical assistance. The sponsor of the trial had no role in the design or
conduct of the study, or in the analysis of the data. The corresponding author had
full access to the data and had final responsibility for the decision to submit the data
for publication. No compensation was given to subjects for providing breath
samples or watery stool samples.
Funding This study was funded by Fukuoka Dental College.
Competing interests None.
Ethics approval This study was conducted with the approval of the institutional
review boards at Fukuoka Dental College and Arita Kyoritsu Hospital and all subjects
provided written informed consent.
Provenance and peer review Not commissioned; externally peer reviewed.
REFERENCES
1. Boyle PLB, ed. World Cancer Report 2008. Lyon, France: IARC Press, 2008.
2. US Preventive Services Task Force. Screening for colorectal cancer: U.S.
Preventive Services Task Force recommendation statement. Ann Intern Med
2008;149:627e37.
Table 4 Relationship between canine scent detection and human
haemoglobin and transferrin
Pathological
judgement
Judgement
by dog
Judgement by faecal
occult blood test
p ValuePositive Negative
Cancer Positive 25 11 0.51
Negative 1 0
Control Positive 0 1 0.68
Negative 22 125
Table 3 Accuracy of canine scent detection by site and stage of cancer
Site/stage
Breath samples Watery stool samples
0 I II III IV Total 0 I II III IV Total
Appendix 1/1 1/1 1/1 1/1
Caecum 1/1 1/1 1/1 1/1
Ascending 1/1 3/3 4/5* 2/2 10/11* 1/1 1/1 3/3 5/5 2/2 12/12
Transverse 1/1 1/1 1/1 1/1 2/2
Descending 1/1 1/1 2/2 1/1 1/1 2/2
Sigmoid 1/1 4/5 1/1 1/1 7/8 2/2 2/2 1/1 1/1 6/6
Rectum 1/1 1/2 1/1 3/3 4/4 10/11 2/2 1/2 2/2 4/4 3/3 12/13
R+S 1/1 1/1 1/1 1/1
Total 4/4 6/8 7/7 9/10* 7/7 33/36* 6/6 5/6 9/9 11/11 6/6 37/38
Sensitivity 1 0.67 1 0.89 1 0.91 1 0.8 1 1 1 0.97
Specificity 1 0.92 1 1 1 0.99 1 0.95 1 1 1 0.99
Number of true positives/total test number are shown.
*Hesitation occurred.
R+S, double rectal and sigmoid colon cancer.
818 Gut 2011;60:814e819. doi:10.1136/gut.2010.218305
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... Cancer detection has received the most attention, with 2/3 of the studies targeting one or more cancers. 5,[52][53][54][55][57][58][59][60][61][62][66][67][68][69][71][72][73][74]77,78,[80][81][82][85][86][87][88][91][92][93][94][95][96][97][99][100][101]105 The remaining studies targeted tuberculosis, MRSA, 84 Malaria, 36 UTI, 79 Clostridium difficile, 63,70,83,89,98 and Covid 19 [102][103][104][106][107][108][109][110] ( Figure 3). However, since the Covid-19 outbreak in 2020, already 8 original articles reporting the ability of dogs to detect Covid 19 have been published, and more will possibly follow. ...
... Those who did, however, reported working with controlled temperatures between 12°C and 20°C (see Supplementary Table 4). It can also be seen that, when not under control, this can negatively impact scent detection work, for instance, reported by Sonoda et al 60 Table 5). Focusing on these studies, the results usually decreased at first when shifting to double-blind. ...
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Background: Remote medical scent detection of cancer and infectious diseases with dogs and rats has been an increasing field of research these last 20 years. If validated, the possibility of implementing such a technique in the clinic raises many hopes. This systematic review was performed to determine the evidence and performance of such methods and assess their potential relevance in the clinic. Methods: Pubmed and Web of Science databases were independently searched based on PRISMA standards between 01/01/2000 and 01/05/2021. We included studies aiming at detecting cancers and infectious diseases affecting humans with dogs or rats. We excluded studies using other animals, studies aiming to detect agricultural diseases, diseases affecting animals, and others such as diabetes and neurodegenerative diseases. Only original articles were included. Data about patients' selection, samples, animal characteristics, animal training, testing configurations, and performances were recorded. Results: A total of 62 studies were included. Sensitivity and specificity varied a lot among studies: While some publications report low sensitivities of 0.17 and specificities around 0.29, others achieve rates of 1 sensitivity and specificity. Only 6 studies were evaluated in a double-blind screening-like situation. In general, the risk of performance bias was high in most evaluated studies, and the quality of the evidence found was low. Conclusions: Medical detection using animals' sense of smell lacks evidence and performances so far to be applied in the clinic. What odors the animals detect is not well understood. Further research should be conducted, focusing on patient selection, samples (choice of materials, standardization), and testing conditions. Interpolations of such results to free running detection (direct contact with humans) should be taken with extreme caution. Considering this synthesis, we discuss the challenges and highlight the excellent odor detection threshold exhibited by animals which represents a potential opportunity to develop an accessible and non-invasive method for disease detection.
... Der Einsatz von Tieren als diagnostisches Werkzeug für Krankheiten ist noch in Erforschung. Einige Studien belegen, dass Hunde in der Lage sind, verschiedene Tumore in Körperproben riechen zu können [80][81][82]. Afrikanische Riesenhamsterratten durch Riechen von Sputum-Proben Tuberkulosepatienten von Nichterkrankten unterscheiden [83,84]. Obwohl Tiere gegenüber aktuellen mikrobiologischen Standardverfahren in Bezug auf die Geschwindigkeit überlegen sind [42], sind diese für eine flächendeckende Anwendung zu kostenintensiv und im klinischen Alltag nicht praxistauglich [79]. ...
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Die aktuelle COVID-19-Pandemie zeigt deutlich, wie sich Infektionskrankheiten weltweit verbreiten können. Neben Viruserkrankungen breiten sich auch multiresistente bakterielle Erreger weltweit aus. Dementsprechend besteht ein hoher Bedarf, durch frühzeitige Erkennung Erkrankte zu finden und Infektionswege zu unterbrechen. Herkömmliche kulturelle Verfahren benötigen minimalinvasive bzw. invasive Proben und dauern für Screeningmaßnahmen zu lange. Deshalb werden schnelle, nichtinvasive Verfahren benötigt. Im klassischen Griechenland verließen sich die Ärzte unter anderem auf ihren Geruchssinn, um Infektionen und andere Krankheiten zu differenzieren. Diese charakteristischen Gerüche sind flüchtige organische Substanzen (VOC), die im Rahmen des Metabolismus eines Organismus entstehen. Tiere, die einen besseren Geruchssinn haben, werden trainiert, bestimmte Krankheitserreger am Geruch zu unterscheiden. Allerdings ist der Einsatz von Tieren im klinischen Alltag nicht praktikabel. Es bietet sich an, auf technischem Weg diese VOCs zu analysieren. Ein technisches Verfahren, diese VOCs zu unterscheiden, ist die Ionenmobilitätsspektrometrie gekoppelt mit einer multikapillaren Gaschromatographiesäule (MCC-IMS). Hier zeigte sich, dass es sich bei dem Verfahren um eine schnelle, sensitive und verlässliche Methode handelt. Es ist bekannt, dass verschiedene Bakterien aufgrund des Metabolismus unterschiedliche VOCs und damit eigene spezifische Gerüche produzieren. Im ersten Schritt dieser Arbeit konnte gezeigt werden, dass die verschiedenen Bakterien in-vitro nach einer kurzen Inkubationszeitzeit von 90 Minuten anhand der VOCs differenziert werden können. Hier konnte analog zur Diagnose in biochemischen Testreihen eine hierarchische Klassifikation der Bakterien erfolgen. Im Gegensatz zu Bakterien haben Viren keinen eigenen Stoffwechsel. Ob virusinfizierte Zellen andere VOCs als nicht-infizierte Zellen freisetzen, wurde an Zellkulturen überprüft. Hier konnte gezeigt werden, dass sich die Fingerprints der VOCs in Zellkulturen infizierter Zellen mit Respiratorischen Synzytial-Viren (RSV) von nicht-infizierten Zellen unterscheiden. Virusinfektionen im intakten Organismus unterscheiden sich von den Zellkulturen dadurch, dass hier neben Veränderungen im Zellstoffwechsel auch durch Abwehrmechanismen VOCs freigesetzt werden können. Zur Überprüfung, inwiefern sich Infektionen im intakten Organismus ebenfalls anhand VOCs unterscheiden lassen, wurde bei Patienten mit und ohne Nachweis einer Influenza A Infektion als auch bei Patienten mit Verdacht auf SARS-CoV-2 (Schweres-akutes-Atemwegssyndrom-Coronavirus Typ 2) Infektion die Atemluft untersucht. Sowohl Influenza-infizierte als auch SARS-CoV-2 infizierte Patienten konnten untereinander und von nicht-infizierten Patienten mittels MCC-IMS Analyse der Atemluft unterschieden werden. Zusammenfassend erbringt die MCC-IMS ermutigende Resultate in der schnellen nichtinvasiven Erkennung von Infektionen sowohl in vitro als auch in vivo.
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There is overwhelming evidence that presence of cancer alters cellular metabolic processes, and these changes are manifested in emitted volatile organic compound (VOC) compositions of cancer cells. Here, we take a novel forward engineering approach by developing an insect olfactory neural circuit-based VOC sensor for cancer detection. We obtained oral cancer cell culture VOC-evoked extracellular neural responses from in vivo insect (locust) antennal lobe neurons. We employed biological neural computations of the antennal lobe circuitry for generating spatiotemporal neuronal response templates corresponding to each cell culture VOC mixture, and employed these neuronal templates to distinguish oral cancer cell lines (SAS, Ca9-22, and HSC-3) vs. a non-cancer cell line (HaCaT). Our results demonstrate that three different human oral cancers can be robustly distinguished from each other and from a non-cancer oral cell line. By using high-dimensional population neuronal response analysis and leave-one-trial-out methodology, our approach yielded high classification success for each cell line tested. Our analyses achieved 76–100% success in identifying cell lines by using the population neural response (n = 194) collected for the entire duration of the cell culture study. We also demonstrate this cancer detection technique can distinguish between different types of oral cancers and non-cancer at different time-matched points of growth. This brain-based cancer detection approach is fast as it can differentiate between VOC mixtures within 250 ms of stimulus onset. Our brain-based cancer detection system comprises a novel VOC sensing methodology that incorporates entire biological chemosensory arrays, biological signal transduction, and neuronal computations in a form of a forward-engineered technology for cancer VOC detection.
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