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Originally published as JCO Early Release 10.1200/JCO.2008.20.8587 on December 22 2008 © 2009 American Society of Clinical Oncology.
In ReplyDepartment of Gastrointestinal Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, TX We appreciate the thoughtful comments of Berrington de Gonzalez et al, who make two points related to our recently published article.1 First, they state, "The authors suggested that this was the first study to investigate an association between this [hepatitis B] virus and pancreatic cancer." In our report, we acknowledged the work by Berrington de Gonzalez et al related to the association between elevated liver enzymes and pancreatic cancer (cited as reference 43). However, we did not comment on the authors' report of a nonsignificant association between hepatitis B virus (HBV) surface antigen (HBsAg) and pancreatic cancer, because we believed that the analysis of this association was a post-hoc analysis, and the study was not designed to address the association between HBV infection and pancreatic cancer. Our reasons for this belief were, first, pancreatic cancer was diagnosed according to the International Statistical Classification of Diseases and Related Health Problems (C25, 10th revision; WHO); thus, the study included patients with all types of pancreatic neoplasms, including neuroendocrine and unspecified pancreatic tumors, rather than just patients with pancreatic adenocarcinoma. Second, patients with underlying liver diseases were excluded; thus, there was no information about the viral status of these patients, nor about the incidence of pancreatic cancer among these patients. Three, data on HBsAg were missing for 68% of the study population. Fourth, no information was provided regarding the laboratory methodology used for HBsAg testing, or whether the HBsAg-positive results were confirmed. False-positive HBsAg test results may have increased the denominator of the exposed cohort, and resulted in underestimation of the association between HBV exposure and pancreatic cancer. Fifth, no information was provided about antibodies to HBV core antigen (anti-HBc) and HBsAg. Because vertical transmission is the most common mode of HBV infection among Asians, some patients with long-term chronic HBV infection may experience spontaneous HBsAg seroclearance, and only be positive for anti-HBc.2 Given these reasons, and in light of guidelines for reporting observational studies in epidemiology,3 we believed that the study of Berrington de Gonzalez et al was not aimed at investigating the association between HBV and adenocarcinoma of the pancreas. With regard to their second point, Berrington de Gonzales et al ask "why resolved or occult hepatitis B viral infection would be associated with elevated pancreatic cancer risk. . .when readily detectable chronic infection is not." In our study, initial serum testing for HBsAg indicated positive results for six patients with pancreatic cancer, and for seven individuals of the control group. However, only one individual of the control group remained positive for HBsAg after confirmatory testing was performed twice, using an enzyme-linked immunosorbent assay (Abbott Laboratories, North Chicago, IL). Meanwhile, our results indicated a positive association between confirmed anti-HBc positivity and pancreatic cancer. Although chronic HBV infection is characterized by persistence of HBsAg, transmission of HBV infection by transfusion of blood positive for anti-HBc and negative for HBsAg has been previously reported.4 Moreover, it has been reported that the persistence of viral DNA in the liver, long after the resolution of HBV infection, is associated with liver inflammation.5 This may explain the reported increased risk of hepatocellular carcinoma in patients with anti-HBc6 or HBV surface antibody7 as the only marker of past HBV infection after successful antiviral therapy. We indicated in our report that our inability to perform HBV DNA analysis on serum and pancreatic tumor specimens precluded us from concluding that HBV plays a causative role in pancreatic cancer, and we concluded that histopathologic investigations are necessary for thorough assessment of the relationship between HBV and pancreatic cancer. AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. REFERENCES
1. Hassan MM, Li D, El-Deeb AS, et al: Association between hepatitis B virus and pancreatic cancer. J Clin Oncol 26:4557–4562, 2008. 2. Liaw YF, Sheen IS, Chen TJ, et al: Incidence, determinants and significance of delayed clearance of serum HBsAg in chronic hepatitis B virus infection: A prospective study. Hepatology 13:627–631, 1991.[CrossRef][Medline] 3. von Elm E, Altman DG, Egger M, et al: The Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) statement: Guidelines for reporting observational studies. Prev Med 45:247–251, 2007.[CrossRef][Medline] 4. Hoofnagle JH, Seeff LB, Bales ZB, et al: Type B hepatitis after transfusion with blood containing antibody to hepatitis B core antigen. N Engl J Med 298:1379–1383, 1978.[Abstract] 5. Bläckberg J, Kidd-Ljunggren K: Occult hepatitis B virus after acute self-limited infection persisting for 30 years without sequence variation. J Hepatol 33:992–997, 2000.[CrossRef][Medline] 6. Paterlini P, Driss F, Nalpas B, et al: Persistence of hepatitis B and hepatitis C viral genomes in primary liver cancers from HBsAg-negative patients: A study of a low-endemic area. Hepatology 17:20–29, 1993.[Medline] 7. Yu MC, Yuan JM, Ross RK, et al: Presence of antibodies to the hepatitis B surface antigen is associated with an excess risk for hepatocellular carcinoma among non-Asians in Los Angeles County, California. Hepatology 25:226–228, 1997.[CrossRef][Medline]
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Copyright © 2009 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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