Breath testing as potential colorectal cancer screening tool.

Although colorectal cancer (CRC) screening is included in organized programs of many countries worldwide, there is still a place for better screening tools. In this study, 418 breath samples were collected from 65 patients with CRC, 22 with advanced or nonadvanced adenomas, and 122 control cases. All patients, including the controls, had undergone colonoscopy. The samples were analysed with two different techniques. The first technique relied on gas chromatography coupled with mass spectrometry (GC-MS) for identification and quantification of volatile organic compounds (VOCs). The T-test was used to identify significant VOCs (p values < 0.017). The second technique relied on sensor analysis with a pattern recognition method for building a breath pattern to identify different groups. Blind analysis or leave-one-out cross validation was conducted for validation. The GC-MS analysis revealed four significant VOCs that identified the tested groups; these were acetone and ethyl acetate (higher in CRC), ethanol and 4-methyl octane (lower in CRC). The sensor-analysis distinguished CRC from the control group with 85% sensitivity, 94% specificity and 91% accuracy. The performance of the sensors in identifying the advanced adenoma group from the non-advanced adenomas was 88% sensitivity, 100% specificity, and 94% accuracy. The performance of the sensors in identifying the advanced adenoma group was distinguished from the control group was 100% sensitivity, 88% specificity, and 94% accuracy. For summary, volatile marker testing by using sensor analysis is a promising noninvasive approach for CRC screening.

Detection of precancerous gastric lesions and gastric cancer through exhaled breath.

OBJECTIVES: Timely detection of gastric cancer (GC) and the related precancerous lesions could provide a tool for decreasing both cancer mortality and incidence. DESIGN: 968 breath samples were collected from 484 patients (including 99 with GC) for two different analyses. The first sample was analysed by gas chromatography linked to mass spectrometry (GCMS) while applying t test with multiple corrections (p value<0.017); the second by cross-reactive nanoarrays combined with pattern recognition. For the latter, 70% of the samples were randomly selected and used in the training set while the remaining 30% constituted the validation set. The operative link on gastric intestinal metaplasia (OLGIM) assessment staging system was used to stratify the presence/absence and risk level of precancerous lesions. Patients with OLGIM stages III-IV were considered to be at high risk. RESULTS: According to the GCMS results, patients with cancer as well as those at high risk had distinctive breath-print compositions. Eight significant volatile organic compounds (p value<0.017) were detected in exhaled breath in the different comparisons. The nanoarray analysis made it possible to discriminate between the patients with GC and the control group (OLGIM 0-IV) with 73% sensitivity, 98% specificity and 92% accuracy. The classification sensitivity, specificity, and accuracy between the subgroups was as follows: GC versus OLGIM 0-II-97%, 84% and 87%; GC versus OLGIM III-IV-93%, 80% and 90%; but OLGIM I-II versus OLGIM III-IV and dysplasia combined-83%, 60% and 61%, respectively. CONCLUSIONS: Nanoarray analysis could provide the missing non-invasive screening tool for GC and related precancerous lesions as well as for surveillance of the latter. TRIAL REGISTRATION NUMBER: Clinical Trials.gov number, NCT01420588 (3/11/2013).

Ultrasensitive silicon nanowire for real-world gas sensing: noninvasive diagnosis of cancer from breath volatolome.

We report on an ultrasensitive, molecularly modified silicon nanowire field effect transistor that brings together the lock-and-key and cross-reactive sensing worlds for the diagnosis of (gastric) cancer from exhaled volatolome. The sensor is able to selectively detect volatile organic compounds (VOCs) that are linked with gastric cancer conditions in exhaled breath and to discriminate them from environmental VOCs that exist in exhaled breath samples but do not relate to the gastric cancer per se. Using breath samples collected from actual patients with gastric cancer and from volunteers who do not have cancer, blind analysis validated the ability of the reported sensor to discriminate between gastric cancer and control conditions with >85% accuracy, irrespective of important confounding factors such as tobacco consumption and gender. The reported sensing approach paves the way to use the power of silicon nanowires for simple, inexpensive, portable, and noninvasive diagnosis of cancer and other disease conditions.

The effect of incisura angularis biopsy sampling on the assessment of gastritis stage.

OBJECTIVES: It is important to stratify patients according to the magnitude of risk for gastric cancer development; the OLGA (Operative Link for Gastritis Assessment) and OLGIM (Operative Link on Gastric Intestinal Metaplasia) staging systems of lesions in the stomach mucosa have been proposed for this purpose. There are some discrepancies in the current guidelines regarding the value of incisura angularis biopsies. The aim of our study was to assess the value of incisura angularis biopsy in staging gastritis according to the OLGA and OLGIM systems by examining the atrophic, metaplastic and inflammatory changes in the antrum, incisura angularis and corpus. PATIENTS AND METHODS: We enrolled 835 patients undergoing upper endoscopy. Three expert gastrointestinal pathologists graded biopsy specimens according to the Sydney classification and the stage of gastritis was assessed by the OLGA and OLGIM systems. RESULTS: The results demonstrated that severe atrophic, metaplastic and chronic inflammatory changes were more frequently observed in the incisura angularis mucosa than in the antrum or corpus mucosae (P<0.05). There was a general downgrading of stage by 18.0% for OLGA and by 4.0% for OLGIM when the incisura angularis was excluded from the staging. Furthermore, there was a 30-35% downgrading for high-risk OLGA/OLGIM stages. CONCLUSION: The incisura angularis undergoes more severe atrophic, metaplastic and chronic inflammatory changes than the antrum and corpus. Incisura angularis biopsies should be routinely included in the biopsy sampling protocol.

Gastritis staging: interobserver agreement by applying OLGA and OLGIM systems.

Atrophic gastritis remains a difficult histopathological diagnosis with low interobserver agreement. The aim of our study was to compare gastritis staging and interobserver agreement between general and expert gastrointestinal (GI) pathologists using Operative Link for Gastritis Assessment (OLGA) and Operative Link on Gastric Intestinal Metaplasia (OLGIM). We enrolled 835 patients undergoing upper endoscopy in the study. Two general and two expert gastrointestinal pathologists graded biopsy specimens according to the Sydney classification, and the stage of gastritis was assessed by OLGA and OLGIM system. Using OLGA, 280 (33.4 %) patients had gastritis (stage I-IV), whereas with OLGIM this was 167 (19.9 %). OLGA stage III- IV gastritis was observed in 25 patients, whereas by OLGIM stage III-IV was found in 23 patients. Interobserver agreement between expert GI pathologists for atrophy in the antrum, incisura angularis, and corpus was moderate (kappa = 0.53, 0.57 and 0.41, respectively, p < 0.0001), but almost perfect for intestinal metaplasia (kappa = 0.82, 0.80 and 0.81, respectively, p < 0.0001). However, interobserver agreement between general pathologists was poor for atrophy, but moderate for intestinal metaplasia. OLGIM staging provided the highest interobserver agreement, but a substantial proportion of potentially high-risk individuals would be missed if only OLGIM staging is applied. Therefore, we recommend to use a combination of OLGA and OLGIM for staging of chronic gastritis.

Geographical variation in the exhaled volatile organic compounds.

Breath-gas analysis has demonstrated that concentration profiles of volatile organic compounds (VOCs) could be used for detecting a variety of diseases, among them gastric cancer (GC) and peptic ulcer disease (PUD). Here, we explore how geographical variation affects the disease-specific changes in the chemical composition of breath samples, as compared to control states (less severe gastric conditions). Alveolar exhaled breath samples from 260 patients were collected at two remotely different geographic locations (China and Latvia), following similar breath-collection protocols. Each cohort included 130 patients that were matched in terms of diagnosis (37 GC/32 PUD/61 controls), average age, gender ratio and smoking habits. Helicobacter Pylori infection, which is a major cause for GC and PUD, was found in part of the patients, as well as in part of the controls, at both locations. The breath samples were analyzed by gas chromatography/mass spectrometry, using the same equipment and protocol-of-experiment. We observed similar characteristic differences in the chemical composition of the breath samples between the study groups at the two locations, even though the exact composition of the breath samples differed. Both in China and Latvia, the GC patients and controls could be distinguished by differences in the average levels of 6-methyl-5-hepten-2-one; PUD patients were distinguished from controls by the levels of aromatic compounds and alcohols; GC and PUD patients could not be distinguished at either site. This pilot study indicates the limitations of chemical breath-gas analysis alone for identifying gastric diseases based on the concentration profiles of separate VOCs in international patient cohorts. We assume that these limitations would apply to other diseases as well. The presented data could potentially be useful for developing an alternative, universally applicable diagnostic method that relies on the detection of changes in the collective patterns of the disease-specific classes of exhaled VOCs.

Interobserver variation in assessment of gastric premalignant lesions: higher agreement for intestinal metaplasia than for atrophy.

BACKGROUND: Either atrophy or intestinal metaplasia of the gastric mucosa are considered premalignant lesions. The new operative link for gastritis assessment staging system is based on the detection of atrophy, and the operative link for assessment of intestinal metaplasia staging system is based on the detection of intestinal metaplasia. Good interobserver agreement is necessary for identification of any premalignant condition. AIMS: The aim of this study was to compare the agreement between findings of gastric atrophy and intestinal metaplasia by expert and general pathologists and to analyze the possible reasons behind any possible disagreement. METHODS: Patients with dyspeptic symptoms, aged 55 years and above, without previous Helicobacter pylori eradication were enrolled and analyzed according to the updated Sydney Classification by two expert pathologists and an experienced general pathologist; the results were compared with the consensus driven by the two experts. RESULTS: Gastric biopsy specimens from 121 patients (91 women) were included in the analysis; the mean age of the patients was 67.4 years. H. pylori infection was present in 61.2% of patients. The level of agreement between the general pathologist and the two experts (κ-value) was 0.12, 0.46, and 0.87, respectively, for detecting atrophy in the corpus; 0.77, 0.77, and 0.65, respectively, for detecting intestinal metaplasia in the corpus; 0.06, 0.51, and 0.54, respectively, for detecting atrophy in the antrum; and 0.69, 0.85, and 0.79, respectively, for detecting metaplasia in the antrum. CONCLUSION: The agreement was substantially higher for intestinal metaplasia than for atrophy. This could result in discrepancies when the operative link for gastritis assessment and operative link for assessment of intestinal metaplasia staging systems are applied and can be caused by differences in the criteria used to define atrophy.

Performance of routine Helicobacter pylori tests in patients with atrophic gastritis.

BACKGROUND: Decreased density of H. pylori in atrophic gastritis may lead to low sensitivity of the routine tests. AIMS: To evaluate the accuracy of routinely used H. pylori tests in atrophic gastritis. METHODS: We compared 5 H. pylori diagnostic tests in 119 dyspeptic patients (28 males/91 females) with a mean age of 67 years (range 55-84). Patients with gastric cancer, peptic ulcer, previous gastric surgery, or those who have received eradication therapy were excluded. The following tests were performed: histology, rapid urease test (RUT), culture, 13C- urea breath tests (UBT), and H.pylori IgG/IgA antibody test (serology). RESULTS: Atrophic gastritis was diagnosed in 26.1% of the patients; H. pylori was present in 87.1%. In the group with atrophy, the sensitivity, specificity, positive predictive value, negative predictive value and overall accuracy were as follows: histology (100% for all parameters); UBT (96; 100; 100; 80; 97%); serology (96; 50; 93; 67; 90%); culture (96; 100; 100; 80; 97%); and RUT (78; 100; 100; 40; 81%), respectively. CONCLUSIONS: Histology, UBT and culture were the three best tests for diagnosing H. pylori infection. We cannot recommend using serology as a single test in a case of atrophy, but it would be reasonable to combine serology with one of the above tests.

Interleukin-1B and interleukin-1 receptor antagonist gene polymorphisms are not associated with premalignant gastric conditions: a combined haplotype analysis.

OBJECTIVE: Contradictory results have been reported about the role of interleukin-1B (IL1B) and IL1 receptor antagonist (IL1RN) alleles in gastric carcinogenesis. Here, IL1B and IL1RN polymorphisms were analyzed as genotypes and haplotypes in relation to the presence of atrophic gastritis (AG) and intestinal metaplasia in the stomach. METHODS: Two hundred and seventy-eight patients (212 Caucasians and 66 Asians) aged 50 years and above, referred for upper endoscopy because of dyspeptic symptoms, were included in the study. Gastric biopsies were histologically assessed according to the updated Sydney classification. Genomic DNA was typed for polymorphisms at position -3737, -1464, -511, -31 for the IL1B gene and the allele 2 of IL1RN using restriction fragment length polymorphism of amplified PCR fragments and intron-spanning PCR analysis, respectively. RESULTS: IL1B-1464-C/C genotype was associated with higher presence of AG in antrum of the stomach in Caucasians [odds ratio: 4.8 (95% confidence interval=1.7-14.3); P=0.028]. IL1B-1464-G/C genotype was associated with lower incidence of AG in corpus of the stomach in Asians [odds ratio: 0.7 (95% confidence interval=0.5-0.8); P=0.02]. IL1RN*2 allele was not linked with AG or intestinal metaplasia in all parts of the stomach both among Asians and Caucasians. Overall, data show that none of the major four IL1B polymorphisms (IL1B-3737C>T, -1464G>C, -511C>T, -31T>C) and the IL1RN*2 is individually, or in its haplotype configuration, linked to the presence of premalignant lesions in Caucasians. CONCLUSION: The determination of these IL1-related loci does not have any predictive value for stratification of subgroups with respect to gastric cancer risk.

The validity of a biomarker method for indirect detection of gastric mucosal atrophy versus standard histopathology.

BACKGROUND: Atrophy of the stomach mucosa is considered to be premalignant lesion for gastric cancer development; easy identification of this condition from a blood-sample would allow identifying the group of individuals at increased risk for cancer development. AIMS: The objective of the current study was to validate a biomarker method (pepsinogen I/II ratio and gastrin-17) for indirect detection of atrophy of the stomach mucosa versus standard histopathology in Caucasian and Asian populations. METHODS: Altogether, 241 patients aged 55 and above referred for upper endoscopy due to dyspeptic symptoms (125 from Latvia, 76 from Lithuania, and 40 from Taiwan) were enrolled. Pepsinogen I, pepsinogen II, gastrin-17 (the latter after stimulation with protein-rich meal) and IgG/IgA antibodies to Helicobacter pylori infection were determined by ELISA method; standard histopathology according to the updated Sydney classification read by two independent expert pathologists was used for the comparison. RESULTS: Pepsinogen I/II ratio below 3 was well related to atrophy (moderate to severe) in the corpus part of the stomach (P < 0.0001) with 83.3% sensitivity and 87.1% specificity. Gastrin-17 below 5 pmol/L was related to atrophy in the antral part (P = 0.007) with 36.8% sensitivity and 86.5% specificity. CONCLUSIONS: Decreased pepsinogen I/II ratio is a reliable marker for atrophy in the corpus, and may be recommended for identification of individuals with this type of atrophy. The utility of gastrin-17 for the detection of atrophy in the antral part of the stomach still requires further evaluation due to the low sensitivity.

Precancerous gastric conditions in high Helicobacter pylori prevalence areas: comparison between Eastern European (Lithuanian, Latvian) and Asian (Taiwanese) patients.

UNLABELLED: The aim of the study was to compare the prevalence and severity of precancerous condition--gastric atrophy and intestinal metaplasia (IM) between Eastern European (Lithuania and Latvia) and Asian (Taiwan) countries in population older than 55 years. METHODS: Patients aged 55 years and older, referred for upper endoscopy due to dyspeptic symptoms, were included in the study. Gastric biopsies were histological investigated according modified Sydney classification. Helicobacter pylori (H. pylori) was detected if any two of three methods (urease test, histology, and serology) were positive. RESULTS: Overall 322 patients included: 52 from Taiwan (TW), 171 from Latvia (LV) and 99 from Lithuania (LT). There were 227 (70%) females and 95 (30%) males. The mean age of TW patients was significantly lower (61.0+/-5.8 years), than of LV (68.1+/-7.3 years) and LT (66.5+/-7.5 years) patients. H. pylori was established in 224 (69.6%) patients. H. pylori positivity was established in 43 (82.7%) TW patients, in 112 (65.5%) LV patients, and in 69 (69.7%) LT patients (P>0.05). In H. pylori-infected patients, any atrophy either in the corpus or in the antrum of the stomach was detected in 26 (60.5%) TW patients, in 40 (35.7%) LV patients, and in 36 (52.2%) LT patients (between TW and LV patients P<0.005). Severe atrophy (grade 2 or 3) detected in 8 (18.6%) TW patients, in 17 (15.2%) LV patients, and in 18 (26.1%) LT patients (P>0.05). Intestinal metaplasia was detected in 22 (51.2%) TW patients, in 37 (33.0%) LV patients and in 31 (44.9%) LT patients among countries (P>0.05). There were no significant differences in proportions of different degrees of both atrophy and intestinal metaplasia among countries. Intestinal metaplasia was found in 79 (77.5%) of 102 patients with any degree of atrophy and in 11 (9.0%) of 122 patients without atrophy (P<0.0001). We found strong statistically significant correlations between atrophy and intestinal metaplasia in antrum (r=0.89), P<0.01, and corpus (r= 0.73), P<0.01. CONCLUSIONS: The prevalence of H. pylori in the elderly population is still high in LT, LV, and TW. There are no significant differences in prevalence of gastric atrophy and intestinal metaplasia among TW, LT, and LV. There is a strong correlation between gastric atrophy and intestinal metaplasia.