A Novel Strategy for the Primary Prevention of Gastric Cancer: Serological Biomarker (GastroPanel®) Screening for Acid-Free Stomach Followed by Protection of the Risk Subjects with Slow-Release L-Cysteine (Acetium®) Volume 47- Issue 4

Kari Syrjänen*

• Department of Clinical Research, SMW Consultants, Ltd, Kaarina, Finland

Received: December 06, 2022;   Published: December 20, 2022

*Corresponding author: Kari Syrjänen, Department of Clinical Research, SMW Consultants, Ltd, Kaarina, Finland

DOI: 10.26717/BJSTR.2022.47.007546

Abstract PDF

Atrophic gastritis (AG) has a dual etiology:

1) Helicobacter pylori (Hp) infection, or

2) Autoimmune mechanism (AAG; autoimmune type of AG).

Hp-infection and AG/AAG are the two most important risk factors of gastric cancer (GC). Severe AG/AAG results in acid-free stomach colonized by Hp and other bacteria, producing acetaldehyde (Group I human carcinogen; IARC). Together with other conditions leading to a) acid-free stomach, e.g., chronic users of proton pump inhibitors (PPI), or b) increased exposure to acetaldehyde, e.g., cigarette smokers, alcohol intake, and ALDH2 enzyme mutations, AG/AAG-patients are at high-risk for GC. Both Hp, AG/AAG, and acid-free stomach can be diagnosed by non-invasive serological biomarker test (GastroPanel®, Biohit Oyj, Finland). GastroPanel® test also detects high-acid output predisposing to GERD (gastro-esophageal reflux disease) that bears an increased risk for Barrett’s esophagus and esophageal cancer (ESC). There is no vaccine against Helicobacter pylori, and no specific therapy for AG/AAG. Acetium® Capsule is a novel and safe (side effect-free) anti-carcinogenic formulation, designed for stomach protection by eliminating acetaldehyde in acid-free stomach. With the combined use of GastroPanel® test and Acetium® Capsule, one can reach an early diagnosis of these high-risk conditions and protect the stomach against acetaldehyde exposure. This new strategy could offer, for the first time, a real opportunity for the primary prevention not only of the substantial (>1 million annual new cases) global cancer burden due to GC, but also of the significant global comorbidity associated with AG/AAG and acid-free stomach. Confirmatory evidence can only be obtained by extensive implementation of this screen-and-prevent strategy:

a) Risk group detection by GastroPanel® and

b) Stomach protection by Acetium® Capsule.

Keywords: Gastric Cancer; Primary Prevention; Screening, Risk Groups; Serological Testing; Biomarkers; Atrophic Gastritis; Helicobacter Pylori; Acid-Free Stomach; Acetaldehyde; GastroPanel; Acetium Capsule; L-Cysteine; Protection; Harm Reduction

The pathogenesis of gastric cancer (GC) is well established. Most GCs develop through Correa Cascade, initiated by Helicobacter pylori (Hp) infection and progressing through different stages of atrophic gastritis (AG/AAG) and intestinal metaplasia (IM) to invasive GC [1-16]. In this process, AG/AAG plays a key role, leading to acid-free stomach. This in turn is colonized by Hp (and other bacteria) that produce acetaldehyde, classified as Group I human carcinogen by IARC [17-20]. Together with other conditions leading to a) acid-free stomach (E.g., chronic users of PPI medication) or b) conditions predisposing the subjects to increased exposure to acetaldehyde (e.g., cigarette smokers, alcohol intake, ALDH2 enzyme mutations), the AG/AAG-patients are at high-risk for GC [2- 20], well over 1 million new cases being diagnosed each year [1].

A Huge Global Morbidity is Preventable by the Novel Strategy

Globally,

1) The patients at risk for AG, and

2) Those subjected to increased exposure to acetaldehyde constitute an enormous disease burden.

Apart from being at increased risk for GC, these patients are likely to develop multiple serious comorbidities [2-20].

Patients at Risk for AG

Included in this category, are

i) Elderly people,

ii) Those with autoimmune disease, as well as

iii) Patients infected with Hp [17-20].

The age-specific prevalence of AG increases with age, approaching 10% among people over 70 years [21]. According to conservative estimates, there are over 500 million people suffering from AG (mostly asymptomatic) worldwide [1,18,20]. In patients with autoimmune thyroid disease (AITD) or type I diabetes mellitus (DM1), the prevalence of AG or autoimmune AG (AAG) is increased up to 3- to 5-fold [22-29]. Given that the Hp-prevalence exceeds 80% in countries with the largest populations [30], the best estimates suggest that 50% of the word population (i.e., > 3.5 billion) are carriers of Hp-infection [31-33]. Although Hp itself is not directly carcinogenic, AG is the single most powerful risk factor of GC [30-33]. In 5-10% (up to 350 million) of Hp-infected patients, AG is moderate or severe, and the risk of GC increases in parallel with the severity of AG, up to 90-fold in patients with severe AG both in the corpus and antrum [31-34].

In addition to increasing the risk of GC, AG is associated with a wide variety of clinical sequels, many of which causing significant comorbidity particularly among elderly people [35,36]. In acidfree stomach, absorption of vitamin-B12, iron, calcium, zinc, and some drugs are impaired [35,36]. Iron deficiency anemia and osteoporosis are the clinically most relevant consequences of iron and calcium malabsorption, respectively [35], present in 20–40% of patients with AG/AAG [21], whereas pernicious anemia (PA) due to vitamin-B12 deficiency can be diagnosed in up to 15–25% of these patients [37]. Early detection of vitamin-B12 deficiency is the prerequisite for effective prevention of its potentially serious neurological complications, including Alzheimer’s disease, peripheral neuropathy, depression, and dementia [35,36,38,39].

People Subjected to Increased Exposure to Acetaldehyde

In this category, the most important risk groups include

i) Cigarette smokers

ii) Alcohol drinkers,

iii) Carriers of ALDH2 mutation, and

iv) Chronic users of PPI medication [17-20].

According to conservative estimates, there are 1.1 billion regular smokers worldwide [40-47]. Acetaldehyde is the major carcinogenic substance in cigarette smoke, predisposing cigarette smokers to acetaldehyde exposure in oral cavity and in upper gastrointestinal tract [17-20,48,49]. The same applies to alcohol intake, because acetaldehyde is the first metabolite of alcohol, and produced in the stomach from ethanol by local microbial oxidation [17-20,50]. Another well-known condition that increases the risk of acetaldehyde exposure is a point mutation in ALDH2-gene, resulting in deficient activity of the acetaldehyde metabolizing enzyme (ALDH2) [51,52]. Carriers of this ALDH2 mutation comprise some 500 million people, mostly residing in Asia. When drinking alcohol, the upper digestive tract mucosa of ALDH2-deficients is exposed via saliva to about 2-times and via gastric juice, up to 5-6 times higher acetaldehyde concentrations than in persons with active ALDH2-enzyme [51,52]. Due to this increased local acetaldehyde exposure, the risk of ALDH2-deficient alcohol drinkers for oral, pharyngeal, ESC and GC is many-fold compared to alcohol drinking ALDH2-actives [17-20,50-52].

Another risk group are the chronic users of PPI-medication. The global number of PPI-users is most likely far above 700 million people, and constantly increasing. According to two recent metaanalyses, chronic use of PPI-medication is associated with an increased risk of GC [53,54]. A denominator in common with AG and PPI-use is acetaldehyde, endogenously formed from ethanol [17-20,50-52]. Interestingly, the highest gastric juice acetaldehyde concentrations have been measured in ALDH2-deficient PPI-users [55].

GastroPanel® Test Reveals the Risks Associated with AG/AAG and Acid-Free Stomach

As a response to an unmet need of a non-invasive, inexpensive test [56-58], Finnish biotechnology company Biohit Oyj developed a simple blood test based on a panel of serum pepsinogen I (PGI) and II (PGII), gastrin-17 (G-17) and Hp IgG antibodies (IgG-Hp) using ELISA technique (GastroPanel® test), proposed as the firstline diagnostic test for dyspeptic symptoms and for screening of the risk conditions of GC [59,60]. The interpretation of GastroPanel® test is made by GastroSoft® application that distinguishes eight biomarker profiles that define specific structural abnormalities and functional disturbances of the stomach [61-64]. These distinct profiles include:

1) Normal profile;

2) High acid output;

3) Low acid output;

4) Superficial Hp-associated gastritis, with three options (active Hp-infection; successful Hp-eradication; failed Hperadication);

5) Atrophic gastritis of the corpus (AGC);

6) Atrophic gastritis of the antrum (AGA);

7) Atrophic gastritis of the antrum and corpus (AGpan); and

8) The effect of PPI medication [61-66].

Taken together, GastroPanel® test diagnosis the grade and topography of AG, and in addition, discloses the status of gastric acid output. Noteworthy, it is not only the acid-free stomach that is a risk condition (for GC), but also high acid output bears an increased risk for ESC, by predisposing to GERD (gastro-esophageal reflux disease), erosive esophagitis and Barrett’s esophagus [7,15,16,64]. In GastroPanel®, the Hp IgG ELISA is complemented by the other three biomarkers which are sensitive indicators of mucosal inflammation [66]. This 4-marker panel makes GastroPanel® the most comprehensive Hp-test, devoid of the known shortcomings (false negative and false positive results) of the conventional Hptests (UBT, SAT) [66-70]. GastroPanel® is an ideal non-invasive test for diagnosing i) the patients at increased risk for GC, irrespective whether due to Hp-induced AG or AAG, as well as for monitoring ii) all those with acid-free stomach exposed to carcinogenic acetaldehyde due to any reasons (smokers, alcohol intake, ALDH2 mutation, chronic PPI users) (64,65,71-75).

Acetium® Capsule – An Anti-Carcinogenic Formulation for Protection of Acid-Free Stomach

The carcinogenic agent in common to all the risk conditions discussed above is acetaldehyde, classified as Group I human carcinogen by IARC in 2009 [71]. Apart from Helicobacter itself, which is capable of synthesizing acetaldehyde, other bacteria colonizing in acid-free stomach, are an abundant source of this carcinogenic substance [18-20]. It is the acid-free stomach (due to any cause listed above) that predisposes these subjects to increased acetaldehyde exposure with increased risk of GC [18-20,50-52]. According to the newly designed dual-strategy, all these special groups of patients should be

1) Closely monitored by GastroPanel® to disclose the patients at risk, to be examined by endoscopy; and

2) All those with acid-free stomach (irrespective its cause) should be administered Acetium® capsules for life-long protection of their stomach mucosa [50-52,66-75].

Acetium® Capsules are Highly Effective in Eliminating Acetaldehyde in Acid-Free Stomach

The well-known reaction whereby L-cysteine (a semi-essential amino acid) eliminates the toxicity of acetaldehyde by covalent binding to form a stable 2-methylthiazolidine-4-carboxylic acid (MTCA) [76], was exploited by Biohit Oyj in its innovation of Acetium® Capsule [77]. The novelty of this formulation of slowrelease L-cysteine is based on the local elimination of carcinogenic acetaldehyde in the stomach [18-20,50-52,77]. The efficacy of this Acetium® formulation has been conclusively demonstrated in three clinical trials in Finland [78], Sweden [79], and Japan [55].

Elimination of Acetaldehyde in Subjects with Acid-Free Stomach

In a placebo-controlled, double-blind study, Acetium® Capsules effectively eliminated ethanol-derived acetaldehyde in the gastric juice of patients with AG [78]. For several hours, the mean acetaldehyde level in gastric juice remained 2.6-times higher with placebo than with L-cysteine (p=0.005) [78]. These data confirm that Acetium® Capsules effectively decrease acetaldehyde in an acid-free stomach during alcohol exposure.

Elimination of Acetaldehyde in Patients with AG

In the second study, slow-release L-cysteine decreased gastric juice acetaldehyde by a maximum of 87% at 60 min and the decline persisted for up to two hours [79]. These results implicate that i) an overall exposure of gastric mucosa to acetaldehyde is decreased by a mean of 68% (p<0.0001) with Acetium® Capsules and this effect continues for at least two hours; ii) MTCA remains stable in the gastric juice for up to three hours [79].

Acetaldehyde Elimination, ALDH2 Mutation and PPI-Treatment

The third clinical trial confirmed that Acetium® Capsule (2 x 100 mg) reduced the gastric juice acetaldehyde levels significantly (67%, 3-fold) also in PPI-treated individuals with either active or deficient ALDH2 enzyme [55]. This study in Japan, confirmed that the acetaldehyde-eliminating effect of Acetium® Capsules persisted for 2 hours after intake [55].

Combined Use of GastroPanel® and Acetium® Capsules Offers a Unique Opportunity for the Primary Prevention of GC

Some cancers are known to be preventable. In most cases, one can achieve only secondary prevention by using population-based screening programs to detect cancer precursor lesions that can be effectively treated. However, primary prevention, i.e., prevention of cancer development by any type of intervention, is rarely possible for any type of human cancer [1,8,43]. That would necessitate an early detection of the risk factors and their effective elimination before the carcinogenic process has progressed even to the stage of cancer precursor lesions. Theoretically, the combined use of

1) GastroPanel® test for i) targeted screening for early detection of the risk conditions of GC, and

2) Acetium® Capsules administered for elimination of acetaldehyde on daily basis for life-long, might offer, for the first time, such an opportunity for the primary prevention of GC.

As an extra bonus, this strategy should help alleviating the substantial comorbidity associated with AG and acid-free stomach, affecting up to half of the world population. In addition, a systematic screening by GastroPanel® would result in substantial savings in health care costs. As an example, modelled for Finland, (a country with 5.5 million people), a systematic GastroPanel® screening of 10 age-groups (50–60-year-old) would result in savings of over 800 million euro in the life-time costs otherwise spent in the management of these subjects according to the current practices [80]. At present, this evidence is circumstantial, i.e., based on acceptance of the simple concept that elimination of the key carcinogenic substance prevents the future cancer of it. How well this hypothesis holds true in real life remains to be seen and depends entirely on the extent of the clinical implementation of this suggested strategy: a combined use of risk group screening (by GastroPanel®) and protection of the high-risk stomach by the anticarcinogenic formulation (Acetium® Capsule) [81].

1. Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, et al. (2021) Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin 71(3): 209-249.
2. Howson CP, Hiyama T, Wynder EL (1986) The decline in gastric cancer: epidemiology of an unplanned triumph. Epidemiol Rev 8: 1-27.
3. Correa P, Haenszel W, Cuello C (1990) Gastric precancerous process in a high-risk population: cohort follow-up. Cancer Res 50: 4737-4740.
4. Plummer M, Franceschi S, Munoz N (2004) Epidemiology of gastric cancer. IARC Sci Publ (157): 311-326.
5. Buckland G, Agudo A, Lujan L, Jakszyn P, Bueno-de-Mesquita HB, et al. (2010) Adherence to a Mediterranean diet and risk of gastric adenocarcinoma within the European Prospective Investigation into Cancer and Nutrition (EPIC) cohort study. Am J Clin Nutr 91: 381-390.
6. Wong BC, Lam SK, Wong WM, China Gastric Cancer Study Group (2004) Helicobacter pylori eradication to prevent gastric cancer in a high-risk region of China: a randomized controlled trial. JAMA 291: 187-194.
7. Sipponen P, Kekki M, Haapakoski J, Ihamäki T, Siurala M (1985) Gastric cancer risk in chronic atrophic gastritis: statistical calculations of cross-sectional data. Int J Cancer 35: 173-177.
8. (1994) International Agency for Research on Cancer, World Health Organization. Schistosomes, liver flukes and Helicobacter pylori. IARC working group on the evaluation of carcinogenic risks to human. No. 61. Monogr Eval Carcinog Risks Hum 61: 218-220.
9. Inoue M (2017) Changing epidemiology of Helicobacter pylori in Japan. Gastric Cancer 20(Suppl 1): 3-7.
10. Kawai T, Moriyasu F, Tsuchida A (2016) Key issues associated with Helicobacter pylori eradication. Digestion 93: 19-23.
11. Malfertheiner P, Sipponen P, Naumann MH, pylori-Gastric Cancer Task Force (2005) Helicobacter pylori eradication has the potential to prevent gastric cancer: a state-of-the-art critique. Am J Gastroenterol 100: 2100-2115.
12. Malfertheiner P, Megraud F, O Morain CA, Gisbert JP, Kuipers EJ, et al. (2017) On behalf of the European Helicobacter and Microbiota Study Group and Consensus panel. Management of Helicobacter pylori infection—the Maastricht V/Florence Consensus Report. Gut 66: 6-30.
13. Uemura N, Okamoto S, Yamamoto S (2001) Helicobacter pylori infection and the development of gastric cancer. N Engl J Med 345: 784-789.
14. Ohata H, Kitauchi S, Yoshimura N (2004) Progression of chronic atrophic gastritis associated with Helicobacter pylori infection increases risk of gastric cancer. Int J Cancer 109: 138-143.
15. Varis K, Sipponen P, Laxen F, Samloff IM, Huttunen JK, et al. (2000) The Helsinki Gastritis Study Group. Implications of serum pepsinogen I in early endoscopic diagnosis of gastric cancer and dysplasia. Scand J Gastroenterol 35: 950-956.
16. Sipponen P, Price AB (2011) The Sydney system for classification of gastritis 20 years ago. J Gastroenterol Hepatol 26(Suppl 1): 31-34.
17. Secretan B, Straif K, Baan R, Grosse Y, El Ghissassi F, et al. WHO International Agency for Research on Cancer Monograph Working Group. (2009) A review of human carcinogens - Part E: tobacco, areca nut, alcohol, coal smoke, and salted fish. Lancet Oncol 10: 1033-1034.
18. Salaspuro M (2009) Acetaldehyde as a common denominator and cumulative carcinogen in digestive tract cancers. Scand J Gastroenterol 24: 1-15.
19. Salaspuro V, Salaspuro M (2004) Synergistic effect of alcohol drinking and smoking on in vivo acetaldehyde concentration in saliva. Int J Cancer 111: 480-486.
20. Salaspuro M (2011) Acetaldehyde and gastric cancer. J Digest Dis 12: 51-59.
21. Telaranta Keerie A, Kara R, Paloheimo L, Härkönen M, Sipponen P (2010) Prevalence of undiagnosed advanced atrophic corpus gastritis in Finland: an observational study among 4,256 volunteers without specific complaints. Scand J Gastroenterol 45: 1036-1041.
22. Whittingham S, Mackay IR (1985) Pernicious anemia and gastric atrophy. In: Rose NR, Mackay IR, (Eds.)., The autoimmune diseases. New York: Academic Press, pp. 243-266.
23. Jacobson DL, Gange SJ, Rose NR, Graham NM (1997) Epidemiology and estimated population burden of selected autoimmune diseases in the United States. Clin Immunol Immunopathol 84: 223-243.
24. Carmel R (1996) Prevalence of undiagnosed pernicious anemia in the elderly. Arch Intern Med 156: 1097-1100.
25. Centanni M, Marignani M, Gargano L, Corleto VD, Casini A, et al. (1999) Atrophic body gastritis in patients with autoimmune thyroid disease. An underdiagnosed association. Arch Intern Med 159: 1726-1730.
26. Irvine WJ, Scarth L, Clarke BF, Cullen R, Duncan LJP (1970) Thyroid and gastric autoimmunity in patients with diabetes mellitus. Lancet 2: 163-168.
27. Riley WJ, Toskes PP, Maclaren NK, Silverstein J (1982) Predictive value of gastric parietal cell autoantibodies as a marker for gastric and hematologic abnormalities associated with insulin dependent diabetes. Diabetes 31: 1051-1055.
28. De Block CEM, De Leeuw IH, Van Gaal LF (2008) Autoimmune Gastritis in Type 1 Diabetes: A Clinically Oriented Review. J Clin Endocrinol Metab 93: 363-371.
29. Strickland RG, Mackay I (1973) A reappraisal of the nature and significance of chronic atrophic gastritis. Am J Dig Dis 18: 426-440.
30. Park JY, Von Karsa L, Herrero R (2014) Prevention strategies for gastric cancer: a global perspective. Clin Endosc 47(6): 478-489.
31. Correa P (1992) Human gastric carcinogenesis: a multistep and multifactorial process. First American Cancer Society Award Lecture on Cancer Epidemiology and Prevention. Cancer Res 52: 6735-6749.
32. Carpenter C, Patalas E (2000) Case records of the Massachusetts General Hospital (Case 40–2000): a 38-year-old woman with gastric adenocarcinoma. N Engl J Med 343: 1951-1958.
33. Malfertheiner P, Sipponen P, Naumann MH, Pylori-Gastric Cancer Task Force (2005) Helicobacter pylori eradication has the potential to prevent gastric cancer: a state-of-the-art critique. Am J Gastroenterol 100: 2100-2115.
34. Malfertheiner P, Megraud F, O Morain CA, Gisbert JP, Kuipers EJ, et al. (2017) On behalf of the European Helicobacter and Microbiota Study Group and Consensus panel. Management of Helicobacter pylori infection—the Maastricht V/Florence Consensus Report. Gut 66: 6-30.
35. Sipponen P, Laxén F, Huotari K, Härkönen M (2003) Prevalence of low vitamin B12 and high homocysteine in serum in an elderly male population: association with atrophic gastritis and Helicobacter pylori infection. Scand J Gastroenterol 38: 1209-1216.
36. Sipponen P, Härkönen M (2010) Hypochlorhydric stomach: A risk condition for calcium malabsorption and osteoporosis? Scand J Gastroenterol 45: 133-138.
37. Toh BH, Alderuccio F (2004) Pernicious anaemia. Autoimmunity 37: 357-361.
38. Stabler S (2013) Vitamin B12 deficiency. N Engl J Med 368: 149-160.
39. Bolander Gouaille C (2002) Focus on Homocysteine and the Vitamins involved in its Metabolism. Berlin: Springer Verlag.
40. Mackay JL (1994) The fight against tobacco in developing countries. Tuber Lung Dis 75: 78-24.
41. Samet JM (2013) Tobacco smoking: the leading cause of preventable disease worldwide. Thorac Surg Clin 23: 103-112.
42. Chen ZM, Peto R, Iona A, Guo Y, Chen YP, et al. (2015) Emerging Tobacco-Related Cancer Risks in China: A Nationwide, Prospective Study of 0.5 Million Adults. Cancer 17: 3097-3106.
43. Peto R, Lopez AD, Boreham J, Thun M, Heath C Jr (1992) Mortality from tobacco in developed countries: indirect estimation from national vital statistics. Lancet 339: 1268-1278.
44. Thun MJ, Carter BD, Feskanich D (2013) 50-year trends in smoking-related mortality in the United States. N Engl J Med 368: 351-364.
45. Pirie K, Peto R, Reeves GK, Green J, Beral V (2013) The 21st century hazards of smoking and benefits of stopping: A prospective study of one million women in the UK. Lancet 381: 133-141.
46. Ekpu VU, Brown AK (2015) The Economic impact of smoking and of reducing smoking prevalence: Review of evidence. Tobacco Use Insights 8: 1-35.
47. Doll R, Peto R, Boreham J, Sutherland I (2004) Mortality in relation to smoking: 50 years’ observations on male British doctors. BMJ 328: 1519.
48. Haussman HJ (2012) Use of hazard indices for a theoretical evaluation of cigarette smoke composition. Chem Res Toxicol 25: 794-810.
49. Cao J, Belluzzi JD, Loughlin SE, Keyler DE, Pentel PR, et al. (2007) Acetaldehyde, a major constituent of tobacco smoke, enhances behavioral, endocrine, and neuronal responses to nicotine in adolescent and adult rats. Neuropsychopharmacol 32: 2025-2035.
50. Seitz HK, Stickel F (2010) Acetaldehyde as an underestimated risk factor for cancer development: role of genetics in ethanol metabolism. Genes Nutr 5: 121-128.
51. Lachenmeier DW, Salaspuro M (2017) ALDH2-deficiency as genetic epidemiologic and biochemical model for the carcinogenicity of acetaldehyde. Regul Toxicol Pharmacol 86: 128-136.
52. Salaspuro M (2009) Acetaldehyde: a cumulative carcinogen in humans. Addiction. 104: 551-553.
53. Ahn JS, Eom CS, Jeon CY, Park SM (2013) Acid suppressive drugs and gastric cancer: A meta-analysis of observational studies. World J Gastroenterol 19: 2560-2568.
54. Tran Duy A, Spaetgens B, Hoes AW, de Wit NJ, Stehouwer CD (2016) Use of Proton Pump Inhibitors and Risks of Fundic Gland Polyps and Gastric Cancer: Systematic Review and Meta-analysis. Clin Gastroenterol Hepatol 14: 1706-1719.
55. Maejima R, Iijima K, Kaihovaara P, Hatta W, Koike T, et al. (2015) Effects of ALDH2 genotype, PPI treatment and L-cysteine on carcinogenic acetaldehyde in gastric juice and saliva after intra-gastric alcohol administration. PLoS One 10: e0120397.
56. Lomba Viana R, Dinis Ribeiro M, Fonseca F, Vieira AS, Bento MJ, et al. (2012) Serum pepsinogen test for early detection of gastric cancer in a European country. Eur J Gastroenterol Hepatol 24: 37-41.
57. Bornschein J, Selgrad M, Wex T, Kuester D, Malfertheiner P (2012) Serological assessment of gastric mucosal atrophy in gastric cancer. BMC Gastroenterol 12: 10.
58. Korstanje A, Den Hartog G, Biemond I, Lamers CB (2002) The serological gastric biopsy: a non-endoscopical diagnostic approach in management of the dyspeptic patient: significance for primary care based on a survey of the literature. Scand J Gastroenterol Suppl 236: 22-26.
59. Oksanen A, Sipponen P, Miettinen A, Sarna S, Rautelin H (2000) Evaluation of blood tests to normal gastric mucosa. Scand J Gastroenterol 35: 791-795.
60. Varis K, Sipponen P, Laxen F, Samloff IM, Huttunen JK, et al. (2000) The Helsinki Gastritis Study Group. Implications of serum pepsinogen I in early endoscopic diagnosis of gastric cancer and dysplasia. Scand J Gastroenterol 35: 950-956.
61. Syrjänen K (2017) Serum biomarker panel (GastroPanel®) and slow-release L-cysteine (Acetium® Capsule): Rationale for the primary prevention of gastric cancer. EC Gastroenterol Digest Syst 3(6): 172-192.
62. Syrjänen K (2016) A Panel of serum biomarkers (GastroPanel®) in non-invasive diagnosis of atrophic gastritis. Systematic review and meta-analysis. Anticancer Res 36: 5133-5144.
63. Syrjänen K (2017) Serological biomarker panel (GastroPanel®): A test for non-invasive diagnosis of dyspeptic symptoms and for comprehensive detection of Helicobacter pylori infection. Biomark J 3: 1-10.
64. Syrjänen K, Eskelinen M, Peetsalu A, Sillakivi T, Sipponen P, et al. (2019) GastroPanel® Biomarker Panel: The most comprehensive test for Helicobacter pylori infection and its clinical sequelae. A critical review. Anticancer Res 39: 1091-1104.
65. Agréus L, Kuipers EJ, Kupcinskas L, Malfertheiner P, Di Mario F, et al. (2012) Rationale in diagnosis and screening of atrophic gastritis with stomach-specific plasma biomarkers. Scand J Gastroenterol 47: 136-147.
67. Syrjänen K, Eronen K (2016) Serological testing in management of dyspeptic patients and in screening of gastric cancer risks. J Gastrointest Disord Liver Funct 2(3): 1-5.
68. Syrjänen K (2017) Caveats in diagnosis of Helicobacter pylori infection can be avoided by a panel of serum biomarkers (GastroPanel®). An Invited Editorial. J Carcinog Mutagen 7(6): e123.
69. Syrjänen K (2017) False negative and false positive results in diagnosis of Helicobacter pylori infections can be avoided by a panel of serum biomarkers (GastroPanel®). MJ Gast 1(1): 007-014.
70. Mäki M, Söderström D, Paloheimo L, Hendolin P, Suovaniemi O, et al. (2020) Helicobacter pylori (Hp) IgG ELISA of the new-generation GastroPanel® is highly accurate in diagnosis of Hp-Infection in gastroscopy referral patients. Anticancer Res 40: 6387-6398.
71. Storskrubb T, Aro P, Ronkainen J, Sipponen P, Nyhlin H, et al. (2008) Serum biomarkers provide an accurate method for diagnosis of atrophic gastritis in a general population: the Kalixanda study. Scand J Gastroenterol 43: 1448-1455.
72. Wikström M (2012) Assessment of stomach health by “Chemical Gastroscopy”. Eur Gastroenterol Rev 2: 1-6.
73. Lomba Viana R, Dinis Ribeiro M, Fonseca F, Vieira AS, Bento MJ, et al. (2012) Serum pepsinogen test for early detection of gastric cancer in a European country. Eur J Gastroenterol Hepatol 24: 37-41.
74. Aine R, Kahar E, Aitokari K, Salminen J, Eklund C, et al. (2016) Atrophic gastritis (AG) and its clinical sequels among elderly people in Finland and Estonia. A comparative study using GastroPanel and B12-vitamin testing of the residents in assisted-housing facilities. J Aging Res Clin Pract 5: 194-202.
75. Koivurova OP, Ukkola O, Koivikko M, Ebeling T, Yliaska I, et al. (2020) Screening of the patients with autoimmune thyroid disease (AITD) and type 1 diabetes mellitus (DM1) for atrophic gastritis (AG) by serological biomarker testing (GastroPanel®). EC Gastroenterol Digest Syst 7: 181-195.
76. Sprince H, Parker CM, Smith GG, Gonzales LJ (1975) Protective action of ascorbic acid and sulfur compounds against acetaldehyde toxicity: implications in alcoholism and smoking. Agents Actions 5: 164-173.
77. Acetium®.
78. Linderborg K, Marvola T, Marvola M, Salaspuro M, Färkkilä M, et al. (2011) Reducing carcinogenic acetaldehyde exposure in the achlorhydric stomach with cysteine. Alcohol Clin Exp Res 35: 516-522.
79. Hellström PM, Hendolin P, Kaihovaara P, Kronberg L, Meierjohann A, et al. (2016) Slow-release L-cysteine capsule prevents gastric mucosa exposure to carcinogenic acetaldehyde: results of a randomised single-blinded, cross-over study of Helicobacter-associated atrophic gastritis. Scand J Gastroenterol 52: 230-237.
80. Screening Model.
81. (2019) State of the art GastroPanel and Acetium innovations for the unmet need.