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0 ONCOLOGY .ilarktt.t.Soderer a Friedrich !3'rba~ Gabriela Kornek1 Thomas ASricab ... . Dieter Y. Kvllerd GeorgJ.i'einlaendera i1lichael Hejrn7' FI'ernerSchertliairer~ ' Departulents of a Internal Medicine I, 5 Internal Medicine II, and 0 Department of Clinical Pathology, d Department of Pediatrics, Vienna University Medical School, Vienna, Austria ............................................... Key Words Helicobacter pylori Pancreatic cancer Introduction about 1,200 patients in the Austrian population every year, compared to 4,900 cases of colorectal cancer and Pancreatic cancer is one of the leading causes of cancer 2,300 cases of gastric cancer [3]. Despite certain improve- death in the Western world [1, 2]. According to recent ments in diagnosis and surgical treatment, the 5-year sur- data, a diagnosis of pancreatic cancer is established in vival rate is only about 3%; 80% of the patients die within KARGER Fat+4161 i061234 E-Mau tatperCk~>c:.ch w-zu:karyc.com O t997 S. KsyaAG. Basti W i 0.2414/9 S/O55I-0016515.00.'0 This zrdle is aso accnnbi: on!iaeac httRlr B io\t c4Net.co m! karga Marlvs Radcror, MD llepar.m,.`ra uf taurcal Medicine i Di~'uioo of Ocmlogt Ur.ircr~ry of Yic~z W5hr..~ga G~-td 1 S-?0 A-1090 YL=aa tAas:rii) 0 ThIS article is (or kldividuat use only and may not be further reproduced or stored etectronieally without written permission lrom the copyright holder. Unauthorized reproduction may result in finandal and other penalties. (c) KARGER SW(TZERLAND Clinical Study Oncology 1998;55:16-19 Association between Helicobacterpylori Cnfection and Pancreatic Cancer .................................................................................................. Abstract Purpose: In order to determine whether infection with Helfcobacter pylori might be associated with pancreatic adenocarcinoma, we performed a study to compare the H. pylori seroprevalence rate between patients with pancreatic carcinoma and matched control subjects. Patients and Methods: Blood sam- ples from 92 patients with histologically confirmed diagnosis of pancreatic adenocarcinoma admitted to our hospital between January 1994 and July 1995 were analyzed for the presence of IgG antibodies against H. pylori by a commercially available enzyme-linked immttnosorbent assay. Thirty patients with gastric cancer, 35 patients with colorectal cancer, and 27 healthy volun- teers served as controls. In addition to these serological analyses, tumor speci- mens from 20 patients with pancreatic adenocarcinoma were microscopically investigated for the presence of H. pylori. Results: 65% of pancreatic cancer patients and 69% of those with gastric cancer were found to be seropositive, while only 45% of the other controls tested positive. Statistical analysis revealed no difference in seropositivity between the cohort of patients suffer- ing from pancreatic and gastric cancer. The rate of seropositivity was more prominent, however, in pancreatic cancer patients when compared with those suffering from colorectal cancer combined with normal controls (p = 0.035), with an odds ratio of 2.1 (1.1-4.1). Microscopic evaluation of human pan- creatic cancer specimens showed no evidence for the presence of H. pylorf. Conclusion: Our data suggest an association between K pylori infection and pancreatic cancer. Despite demonstration of a positive relationship and its physiological plausibility, larger prospective studies are needed to confirm our preliminary findings and to assess H. pylori as a potential carcinogenic risk factor.

the l.st year after diagnosis [4]. To date, little is known about the etiology and pathogenesis of cancer of the exo- crine pancreas. Several environmental factors have been reported to influence the development of this disease. Cib arette smoking is the most consistently reported risk fac- tor, which has been documented in epidemiologic studies [5-8]. Whereas its association with dietary habits and cof- fee or alcohol consumption remains a matter of debate [9-11], a history of peptic-ulcer surgery seems to increase the risk of pancreatic and other cancers of the digestive tract [12]. Increased cholecystokinin- and/or other gut hormone levels [13, 14] as well as the formation of N- nitroso compounds by nitrate-reductase-producing bacte- ria that proliferate in the hypoacidic environment after surgery [12] have been proposed as possible explanations for this association. During the last years, a causeal role of Helrcobacter pylori in the pathogenesis of peptic-ulcer disease has been firmly established [ 15]. Subsequently, this Gram-negative organism was also identified as a risk factor for gastric carcinoma [16, 17] and non-Hodgkins' lymphoma [18, 19]. Helicobacter species have also been demonstrated to ascend into the biliary tract of rodents, to colonize it and to cause chronic hepatitis and subsequent liver tumors which might be related to the production of a carcinogen [20]. Based on this first conclusive demonstration that specific K pylori species might be directly involved in cancer etiology, and according to the need to further define the relationship of this organism to other malig- nancies, the present study was initiated. We report here the fust study performed to investigate the association between H. pylori infection and pancreatic canc--r along with the results of a pathologic examination of human pancreatic cancer specimens. Patients and Methods The presence of IgG antibodies was investigated in patients with pancreatic cancer admitted to our institution between January 1994 and July 1995. Nmety-two patients with histologically verified ade- nocarcinoma of the pancreas were evaluated during this period. Blood samples were collected from all patients, immediately centri- fuged and stored at -80 ° C until final procession. These patients were matched by sex and age to 30 patients with gastric adenocarcinoma, 35 patients with colorectal cancer, and 27 healthy volunteers. Mea- surement of IgG antibodies to H. pylori was performed by using a commercially available enzyme-linked immunosorbent assay (Pylo- ri-Stat~r, Bio Whittaker, Walkersville, Md., USA). Procession of tb: blood samples was performed accordingto the guidelines of the man- ufacturer. This assay yields a 96% sensitivity and 944o specificity, as has been published before [21]. Assays were performed in dup:icate by an individual blinded to the nature of the underlying disease, and Hellcobacter pylori and Pancreatic Cancer Table 1. Characteristics of the study population and seroprevat- ence ofHi pylor! antibodies - Pancreatic cant2t ' Gastric 'cancet - Colorectal Normal cancei' ' "' con'trol Subjects, n 92 30 35 27 Sex, male/female 50/42 17/13 20/15 15/12 Median age, years 58 60 58 56 Range,years 33-81 37-76 32-85 21-81 Social class', % I 29 25 32 38 II 39 47 41 39 III 25 16 22 16 IV 7 12 5 7 V 0 0 0 0 H. pylori seroprevalence, 46 65 69 45 47 I Based on the current occupation classification system [40]. The assignment to a class group is determined by the perceived occupa- tional skill. Social class I = Skilled professionals (e.g. doctors, law- yers); class II = intermediate nonmanual (e.g. managers); class II1= skilled manual (e.g. technicians) and lower skilled nonmanual (e.g. clerks); class IV = partly skilled manual; class V = unskilled manual workers. random samples were analyzed a second time to check for accuracy and repeatability of measurements. Comparison between the differ- ent groups was performed using the y.z test, and odds ratios were cal- culated by logistic regression. Specimens from 20 of our pancreatic cancer patients who had undergone potentially curative or palliative bypass surgery were assessed for the presence of H. pylori by light microscopy using a con- ventional hemotoxylin-eosin stain. Pathologic evaluation was per- formed by a reference pathologist (F.W.) Results Table 1 shows the demographics of the populations studied and their H. pylorf seroprevalence rates. The four groups were well matched for sex, age and smoking habits. All were white and there was no major difference in the social class based on occupation. Among the patients with pancreatic cancer, a H. pylori seroprevalence rate of 65% could be demonstrated. In comparison, 69% of gastric cancer patients, 45% of colorectal cancer patients and 47% of the normal subjects were positive for H. pylori. Median IgG antibody concentrations were comparable between the four groups: 12.6 µg/m1 for pancreatic cancer (range 6-58.5 µg/ml), 15 µg/mI (range 4-98.7 µg/ml) for Oncology 1998;55:i6-19 17 This artide is for irxk3idual use only and may not be further reproduced or stored electronicany without wntten permission from the copyright ho/der. Unauthorized reproduction may result in financial antl other penalties. (c) KARGER SWITZERLAND

gastric cancer, 9.4 µg/ml (range 2-77.0 µg/mI) for colorec- tal cancer and 8.2 µalml (range-2-57.7 µg/m1) for normal controls. Statistical analysis revealed no significant differ- ence between seropositivity in patients with pancreatic and gastric cancer, and no difference for the subgroup of patients with colorectal cancer and normal controls. There was a statistically significant difference, however, between patients with pancreatic cancer and individuals with colorectal neoplasias as well as healthy volunteers (p = 0.035). The odds ratio was 2.1 (1.1-4.1) forpancreat- ic cancer versus patients with colorectal cancer and nor- mal subjects, with no confounding role of social class in our patients. Microscopic evaluation of 20 tumor speci- mens from patients operated on for pancreatic cancer dis- played no evidence for colonization with H. pylori. The bacteria were absent not only from malignant tissue, but also from the ducts of surrounding normal pancreatic tis- sue. No inflammatory reactions typically observed in H. pylort gastritis were found. Discussion H. pylori has been implicated in the development of gastric cancer and low-grade gastric lymphoma [16-19]. Recent experimental findings in animal models have also raised the possibility that certain strains of this organism may be an etiologic factor or cofactor in the carcinogene- sis of other gastrointestinal carcinomas, specifically of liv- er tumors [20, 21]. In the present study, which to our knowledge is the first to investigate the seroprevalence of H. pylori in patients with pancreatic cancer, the rate of infection was 65%, and comparable to that of subjects suf- fering from gastric cancer (69 %). We believe that our results are accurate because we used serological testing methods that have been carefully validated in comparable populations ofpatients and con- trols [21, 22]. Despite certain limitations due to the small number of subjects, all groups in our trial were well matched regarding age, sex and social class, i.ee potential factors that can bias studies on the association ofH. pylori with disease [23, 24]. Furthermore, the observed rate of seropositivity in our gastric cancer patients (positive con- trol), colorectal cancer patients and healthy volunteers (negative controls) seems consistent with other series reported in the literature [22-27], including neighboring countries'such as Germany. Despite the fact that the rate of seropositivity is not known in the general Austrian pop- ulation, an estimated incidence of about 45% in asymp- tomatic subjects of the same average age and educational is Oncotogy 1998;55:16-19 standard as included in our study seems reasonable ac- cording to the literature. Despite demonstration of a high rate of H. pylori infec- tion in patients with pancreatic cancer, histopathoiogic examination of tumor specimens in 20 patients did not reveal the presence of H. pylorf. This finding, however, does not entirely rule out a positive relationship; in gastric cancer, H. pvlori bacteria do not colonize metaplastic or neoplastic tissue [28], and the cancer-related altered envi- ronment commonly results in eradication of infection. It seems possible that the same pathogenetic consequences of H. nvlori infection and/or cofactors believed to be rele- vant to gastric carcinogenesis [29-31] might be important in pancreatic cancer. The potent ia1 role of H. pylori in gas- tric as weII as in pancreatic carcinogenesis might be mediated by its association with an increased secretion of certain gut hormones, such as gastrin [32, 33] or somato- statin [34]. These gut hormones are known to increase the proliferation rate of gastric epithelium [29], as they have been shown to result in pancreatic hypertrophy [35, 36], and to stimulate the growth of ductal pancreatic adeno- carcinoma cell lines [37]. The increased formation of N- nitroso compounds by nitrate-reductase-producing bacte- ria proliferating in the hypoacidic stomach may represent another common pathogenetic mechanism, which would very well explain the higher than expected incidence of both malignancies in patients with a history of peptic ulcer surgery in one series [ 12]. In both tumor types, there are also a number of similarities in termsof epidemiologie and possible etiologic cofactors involved in malignancy. These include a poor socioeconomic status, diets deficient in fresh fruits and vegetables, and cigarette smoking [2, 38], all of which are conditions/risk factors that have also been associated with H. pylori infection [23, 24, 391. Despite suggestive evidence for an association between H. pylori infection and pancreatic cancer in this study, and despite the physiological plausibility for such an asso- ciation, a causal relationship between this organism and pancreatic carcinogenesis must remain speculative. The definitive role of Helicobacter species in cancer etiology has not been defined even in gastric cancer, and the rele- vant pathogenic mechanisms and/or host factors associat- ed with cancers are largely unknown. Still, additional seroepidemiologic data and larger case-control studies seem warranted in order to confirm our preliminary find- ings of a positive association between H. pylori infection and pancreatic cancer. Radererf WrbalKornekl2.4aca/KoUer/ Weinlaender/Hejna/Scheitha uer This article is for irxfivldual use only and may not be turther reproduced or stored etectronically without written ~ perrrrssion from the copyright twJder. Unauthorized reproduction may result in financlal and other penalties. (c) KARGER SWITZERIRND

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