J Gastrointest Canc DOI 10.1007/s12029-015-9729-9
CASE REPORT
Long-Term Survival of Patient with Epstein-Barr Virus-Positive Gastric Cancer Treated with Chemotherapy: Case Report Hideo Yanai 1 & Noboru Yahara 2 & Takumi Furuya 2 & Hiroto Hayashi 2 & Tomoyuki Murakami 3 & Yuzo Shimokawa 4 & Shigenori Sugihara 5
# Springer Science+Business Media New York 2015
Abbreviations EBV Epstein-Barr virus GC Gastric cancer EBER1 Epstein-Barr virus-encoded small RNA1 ISH In situ hybridization
Introduction Gastric cancer (GC) is one of the major health problems throughout the world. It is known that early detection and early therapy for GC lead to a favorable outcome. However, inoperable GC is still hard to treat, and further progress in chemotherapy is needed [1]. Recently, the association Epstein-Barr virus (EBV) has been detected in almost 10 %
of all cases of GC and 40 % of cancers of the remnant stomach. EBV-positive GC is mainly the poorly differentiated and tumor-infiltrating lymphocyte-rich type (lympho-epithelioma or gastric carcinoma with lymphoid stroma). The monoclonality of the EBV from individual GC lesions indicates the possible causal role of EBV in gastric carcinogenesis. The treatment outcome of advanced EBV-positive GC is reported to be better than that of EBV-negative GC [2–10]. However, accumulated data show some discrepancies between possible favorable chemotherapy outcomes in clinical EBV-positive GC and chemoresistance in EBV-positive GC lines [11–13]. Here, we report the long-term survival of a patient with EBV-positive GC who was treated with chemotherapy.
Methods
* Hideo Yanai [email protected] 1
Department of Clinical Research, National Hospital Organization Kanmon Medical Center, 1-1 Sotoura, Shimonoseki, Yamaguchi, Japan
2
Department of Surgery, National Hospital Organization Kanmon Medical Center, Shimonoseki, Yamaguchi, Japan
3
Department of Pathology, National Hospital Organization Kanmon Medical Center, Shimonoseki, Yamaguchi, Japan
4
Department of Gastroenterology, Aso Iizuka Hospital, Fukuoka, Japan
5
Department of Internal Medicine, Sugihara Internal Medicine & Digestive Disease Clinic, Shimonoseki, Japan
We initiated chemotherapy for 33 consecutive cases of advanced GC during the 24 months from January 2004 through December 2005 at the National Hospital Organization Kanmon Medical Center in Japan. We detected EBV using EBV-encoded small RNA1 in situ hybridization (EBER1 ISH) in the 22 cases for which paraffinembedded surgical or endoscopic biopsy specimens of GC lesions were available [14]. The chemotherapy for 15 cases was postoperative adjuvant therapy, and for seven inoperable cases, it was palliative. We used S1, paclitaxel, 5′-DFUR, or cisplatin (CDDP) for chemotherapy according to the patient’s condition and attending surgeon’s decision. We analyzed the clinical outcomes of these 22 cases after over 7 years in April 2013 using medical charts. This work was approved by the institutional review board.
J Gastrointest Canc
Results Result of EBER1 ISH Three of the 22 cases (13.6 %) were positive for EBER1. These three EBV-positive cases of GC were inoperable. The three EBV-positive patients were all male, and their mean age at initial chemotherapy was 71 years (range 57–80). The other 19 cases were EBV negative. The 19 EBV-negative GC patients consisted of 13 males and six females with a mean age of 73.5 years (57–91). The survival periods of the three EBV-positive inoperable patients were 10, 19, and over 108 months. The two patients who died had peritoneal dissemination. The only long-term survivor had direct invasion of the pancreas and swelling of lymph nodes at the splenic hilum on abdominal CT, but no ascites at the initial chemotherapy. One EBV-negative patient quits chemotherapy, and his outcome is unknown. Of the 18 EBV-negative patients whose outcomes are known, four were inoperable and were given palliative chemotherapy, and 14 were given postoperative adjuvant chemotherapy. The mean survival period of the four EBV-negative inoperable patients was 12.8 months (8–20). Details of EBV-Positive Long-Survival Case The patient was 80 years old at the time of diagnosis. He had a past history of distal partial gastrectomy for early gastric Fig. 1 Clinical features of the only long-term survivor of inoperable EBV-positive GC at the initial chemotherapy. a Endoscopic features of the advanced gastric cancer of the remnant stomach. b Abdominal CT pictures at initial chemotherapy. Direct invasion of the pancreas and dilation of the main pancreatic duct are observed. Lymph node swelling at the splenic hilum is also observed (arrows). c Pathologic features of the gastric biopsy specimen at initial chemotherapy (April 2004). Endoscopic biopsy reveals moderately to poorly differentiated-type adenocarcinoma (H&E stain). d All nuclei of gastric cancer cells were EpsteinBarr virus-encoded small RNA1 (EBER1) in situ hybridization (ISH) positive
cancer in the year 2001. That lesion was differentiated-type mucosal cancer without lymph node metastasis for which he underwent a curative operation. The lesion was EBV negative as demonstrated afterward by the EBER1 ISH test. In April 2004, another advanced gastric cancer of the remnant stomach was diagnosed (Fig. 1a). That tumor was endoscopically found to be ulcerated cancer without definite limits and had moderately to poorly differentiated histology on biopsy (Fig. 1b). In a biopsy specimen, the advanced gastric cancer was EBER1-positive (Fig. 1c). The tumor had directly invaded the pancreas with swelling of lymph nodes at the splenic hilum on abdominal CT, but with no ascites at the time of the initial chemotherapy (Fig. 1d). Tumor markers such as CEA and CA19-9 were within normal ranges. From these findings, his condition was judged to be inoperable, and palliative chemotherapy was started. His chemotherapy was initiated with S1 and CDDP. However, because of bone marrow suppression, it was changed to paclitaxel 60 mg/m2 +5′-DFUR 600 mg. Furthermore, because of an intestinal disorder (diarrhea), the drug was changed to paclitaxel 90 mg/m2 alone biweekly in a nearby clinic as outpatient treatment. The main tumor of the stomach gradually diminished to an endoscopically visible ulcer scarlike form by September 2008 (Fig. 2a). Abdominal CT detected no tumor lesion in March 2009 (Fig. 2b). The patient was temporarily hospitalized in March 2012 because of ischemic colitis. CT did not detect any findings of gastric cancer recurrence or distant metastasis. Endoscopically, the remnant
J Gastrointest Canc
Fig. 2 Effect of chemotherapy for the only long-term survivor of inoperable EBV-positive GC. a Endoscopic features of the gastric cancer of the remnant stomach 53 months after initial chemotherapy (September 2008). The tumor of the remnant stomach gradually diminished to an ulcer scar-like form (arrow). b Abdominal CT images 59 months after initial chemotherapy (March 2009). Abdominal CT detects no tumor lesion (arrows)
stomach showed an ulcer scar-like form as in 2008; however, a biopsy specimen still contained moderately differentiated adenocarcinoma. He was still alive in April 2013 as an outpatient of a nearby clinic, using paclitaxel 90 mg biweekly over 108 months (9 years) after the initial chemotherapy.
Discussion In the present study, the EBV-positive rate for gastric cancer lesions was 13.6 %, which was in good accord with accumulated data [9, 14]. In inoperable cases, the mean survival period of 12.8 months for four cases of palliative chemotherapy for EBV-negative GC was not so different from the 10 and 19 months for two of the three EBV-positive cases. However, comparison between these two EBV-positive cases and the long-surviving case is necessary. Of the three inoperable EBV-positive patients, the two who died had peritoneal
dissemination. The long-term survivor had direct invasion of the pancreas and swelling of lymph nodes near the spleen on abdominal CT, but no ascites at the initial chemotherapy. This indicates the potential importance of the presence of peritoneal dissemination. There are some reports from other institutes of favorable chemotherapy outcomes for EBV-positive GC as in our case. Seya et al. reported one case of advanced EBV-positive GC with a complete response to preoperative chemotherapy with S1 and CDDP. Matsunou et al. reported two cases of advanced inoperable EBV-positive GC treated with chemotherapy that resulted in long-term survival [15, 16]. In contrast, in vitro studies indicate that latent EBV infection may lead to resistance to chemotherapy in GC cell lines. Seo et al. reported the contribution of EBV infection to chemoresistance of GC cells to 5-FU. Wang et al. reported the anti-apoptotic role of transfected BARF1 of EBV in EBV-negative GC cells. Shin et al. reported an association between EBV infection and chemoresistance to docetaxel in GC [11–13]. Thus, there are discrepancies between possible favorable chemotherapy outcomes in clinical EBV-positive GC and chemoresistance in EBV-positive GC lines. For clinical EBV-positive GC, the prognosis depends on the patient’s inflammatory response [17]. In cell line studies, the host immune response is absent. From this viewpoint, the absence of ascites of our long-surviving EBV-positive GC patient seems important. The two patients with EBV-positive GC who died had peritoneal dissemination. Ascites may occur in a space free from the host cellular immune response, and the presence of peritoneal dissemination may indicate chemoresistance of disseminated EBV-positive GC cells as reported in GC cell lines. Our limited experience with a small number of patients indicated that a favorable outcome of chemotherapy for EBV-positive inoperable GC without peritoneal dissemination was possible. EBER1 ISH for GC biopsy specimens before chemotherapy may be useful to predict the patient’s outcome. Furthermore, possible combination of anti-viral therapy and chemotherapy has been reported [18]. Peritoneal dissemination by itself likely indicates a poor prognosis, and comparing a patient without peritoneal dissemination to those having it without being able to correct for other covariates is not appropriate. We believe that further study of EBV-positive GC will lead to new possibilities for chemotherapy and immune therapy for cancer.
Conclusion We report the case of a single long-term survivor who was EBV positive and suggest further assessment of outcomes in larger groups of EBV-positive patients in order to determine
J Gastrointest Canc
whether this may suggest a prognostic role for EBV-positive status.
Conflicts of Interest The authors declare that they have no competing interests. Funding None
References 1. 2.
3.
4.
5.
6.
7.
Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ. Gastric cancer. Lancet. 2009;374:477–90. Burke AP, Yen TS, Shekitka KM, Sobin LH. Lymphoepithelial carcinoma of the stomach with Epstein-Barr virus demonstrated by polymerase chain reaction. Mod Pathol. 1990;3:377–80. Watanabe H, Enjoji M, Imai T. Gastric carcinoma with lymphoid stroma. Its morphologic characteristics and prognostic correlations. Cancer. 1976;38:232–43. Yanai H, Nishikawa J, Mizugaki Y, et al. Endoscopic and pathologic features of Epstein-Barr virus-associated gastric carcinoma. Gastrointest Endosc. 1997;45:236–42. Yanai H, Murakami T, Yoshiyama H, et al. Epstein-Barr virus-associated gastric carcinoma and atrophic gastritis. J Clin Gastroenterol. 1999;29:39–43. Nishikawa J, Yanai H, Hirano A, et al. High prevalence of EpsteinBarr virus in gastric remnant carcinoma after Billroth-II reconstruction. Scand J Gastroenterol. 2002;37:825–9. Imai S, Koizumi S, Sugiura M, et al. Gastric carcinoma: monoclonal epithelial malignant cells expressing Epstein-Barr virus latent infection protein. Proc Natl Acad Sci U S A. 1994;91:9131–5.
8.
Iwakiri D, Takada K. Epstein-Barr virus and gastric cancers. In: Robertson ES, editor. Epstein-Barr virus. Norfolk: Caister Academic Press; 2005. p. 157–69. 9. Murphy G, Pfeiffer R, Camargo MC, Rabkin CS. Meta-analysis shows that prevalence of Epstein-Barr virus-positive gastric cancer differs based on sex and anatomic location. Gastroenterology. 2009;137:824–33. 10. Camargo MC, Kim WH, Chiaravalli AM, et al. Improved survival of gastric cancer with tumour Epstein-Barr virus positivity: an international pooled analysis. Gut. 2014;63:236–43. 11. Seo JS, Kim TG, Hong YS, Chen JY, Lee SK. Contribution of Epstein-Barr virus infection to chemoresistance of gastric carcinoma cells to 5-fluorouracil. Arch Pharm Res. 2011;34:635–43. 12. Wang Q, Tsao SW, Ooka T, et al. Anti-apoptotic role of BARF1 in gastric cancer cells. Cancer Lett. 2006;238:90–103. 13. Shin HJ, Kim D, Lee SK. Association between Epstein-Barr virus infection and chemoresistance to docetaxel in gastric carcinoma. Mol Cells. 2011;32:173–9. 14. Tokunaga M, Uemura Y, Tokudome T, et al. Epstein-Barr virus related gastric cancer in Japan: a molecular patho-epidemiological study. Acta Pathol Jpn. 1993;43:574–81. 15. Seya T, Tanaka N, Yokoi K, et al. Complete response of a patient with advanced gastric cancer, showing Epstein-Barr virus infection, to preoperative chemotherapy with S-1 and cisplatin. Int J Clin Oncol. 2007;12:472–7. 16. Matsunou H, Konishi F, Hori H, et al. Characteristics of EpsteinBarr virus-associated gastric carcinoma with lymphoid stroma in Japan. Cancer. 1996;77:1998–2004. 17. Song HJ, Srivastava A, Lee J, et al. Host inflammatory response predicts survival of patients with Epstein-Barr virus-associated gastric carcinoma. Gastroenterology. 2010;139:84–92. 18. Feng WH, Israel B, Raab-Traub N, Busson P, Kenney SC. Chemotherapy induces lytic EBV replication and confers ganciclovir susceptibility to EBV-positive epithelial cell tumors. Cancer Res. 2002;62:1920–6.
CASE REPORT
Long-Term Survival of Patient with Epstein-Barr Virus-Positive Gastric Cancer Treated with Chemotherapy: Case Report Hideo Yanai 1 & Noboru Yahara 2 & Takumi Furuya 2 & Hiroto Hayashi 2 & Tomoyuki Murakami 3 & Yuzo Shimokawa 4 & Shigenori Sugihara 5
# Springer Science+Business Media New York 2015
Abbreviations EBV Epstein-Barr virus GC Gastric cancer EBER1 Epstein-Barr virus-encoded small RNA1 ISH In situ hybridization
Introduction Gastric cancer (GC) is one of the major health problems throughout the world. It is known that early detection and early therapy for GC lead to a favorable outcome. However, inoperable GC is still hard to treat, and further progress in chemotherapy is needed [1]. Recently, the association Epstein-Barr virus (EBV) has been detected in almost 10 %
of all cases of GC and 40 % of cancers of the remnant stomach. EBV-positive GC is mainly the poorly differentiated and tumor-infiltrating lymphocyte-rich type (lympho-epithelioma or gastric carcinoma with lymphoid stroma). The monoclonality of the EBV from individual GC lesions indicates the possible causal role of EBV in gastric carcinogenesis. The treatment outcome of advanced EBV-positive GC is reported to be better than that of EBV-negative GC [2–10]. However, accumulated data show some discrepancies between possible favorable chemotherapy outcomes in clinical EBV-positive GC and chemoresistance in EBV-positive GC lines [11–13]. Here, we report the long-term survival of a patient with EBV-positive GC who was treated with chemotherapy.
Methods
* Hideo Yanai [email protected] 1
Department of Clinical Research, National Hospital Organization Kanmon Medical Center, 1-1 Sotoura, Shimonoseki, Yamaguchi, Japan
2
Department of Surgery, National Hospital Organization Kanmon Medical Center, Shimonoseki, Yamaguchi, Japan
3
Department of Pathology, National Hospital Organization Kanmon Medical Center, Shimonoseki, Yamaguchi, Japan
4
Department of Gastroenterology, Aso Iizuka Hospital, Fukuoka, Japan
5
Department of Internal Medicine, Sugihara Internal Medicine & Digestive Disease Clinic, Shimonoseki, Japan
We initiated chemotherapy for 33 consecutive cases of advanced GC during the 24 months from January 2004 through December 2005 at the National Hospital Organization Kanmon Medical Center in Japan. We detected EBV using EBV-encoded small RNA1 in situ hybridization (EBER1 ISH) in the 22 cases for which paraffinembedded surgical or endoscopic biopsy specimens of GC lesions were available [14]. The chemotherapy for 15 cases was postoperative adjuvant therapy, and for seven inoperable cases, it was palliative. We used S1, paclitaxel, 5′-DFUR, or cisplatin (CDDP) for chemotherapy according to the patient’s condition and attending surgeon’s decision. We analyzed the clinical outcomes of these 22 cases after over 7 years in April 2013 using medical charts. This work was approved by the institutional review board.
J Gastrointest Canc
Results Result of EBER1 ISH Three of the 22 cases (13.6 %) were positive for EBER1. These three EBV-positive cases of GC were inoperable. The three EBV-positive patients were all male, and their mean age at initial chemotherapy was 71 years (range 57–80). The other 19 cases were EBV negative. The 19 EBV-negative GC patients consisted of 13 males and six females with a mean age of 73.5 years (57–91). The survival periods of the three EBV-positive inoperable patients were 10, 19, and over 108 months. The two patients who died had peritoneal dissemination. The only long-term survivor had direct invasion of the pancreas and swelling of lymph nodes at the splenic hilum on abdominal CT, but no ascites at the initial chemotherapy. One EBV-negative patient quits chemotherapy, and his outcome is unknown. Of the 18 EBV-negative patients whose outcomes are known, four were inoperable and were given palliative chemotherapy, and 14 were given postoperative adjuvant chemotherapy. The mean survival period of the four EBV-negative inoperable patients was 12.8 months (8–20). Details of EBV-Positive Long-Survival Case The patient was 80 years old at the time of diagnosis. He had a past history of distal partial gastrectomy for early gastric Fig. 1 Clinical features of the only long-term survivor of inoperable EBV-positive GC at the initial chemotherapy. a Endoscopic features of the advanced gastric cancer of the remnant stomach. b Abdominal CT pictures at initial chemotherapy. Direct invasion of the pancreas and dilation of the main pancreatic duct are observed. Lymph node swelling at the splenic hilum is also observed (arrows). c Pathologic features of the gastric biopsy specimen at initial chemotherapy (April 2004). Endoscopic biopsy reveals moderately to poorly differentiated-type adenocarcinoma (H&E stain). d All nuclei of gastric cancer cells were EpsteinBarr virus-encoded small RNA1 (EBER1) in situ hybridization (ISH) positive
cancer in the year 2001. That lesion was differentiated-type mucosal cancer without lymph node metastasis for which he underwent a curative operation. The lesion was EBV negative as demonstrated afterward by the EBER1 ISH test. In April 2004, another advanced gastric cancer of the remnant stomach was diagnosed (Fig. 1a). That tumor was endoscopically found to be ulcerated cancer without definite limits and had moderately to poorly differentiated histology on biopsy (Fig. 1b). In a biopsy specimen, the advanced gastric cancer was EBER1-positive (Fig. 1c). The tumor had directly invaded the pancreas with swelling of lymph nodes at the splenic hilum on abdominal CT, but with no ascites at the time of the initial chemotherapy (Fig. 1d). Tumor markers such as CEA and CA19-9 were within normal ranges. From these findings, his condition was judged to be inoperable, and palliative chemotherapy was started. His chemotherapy was initiated with S1 and CDDP. However, because of bone marrow suppression, it was changed to paclitaxel 60 mg/m2 +5′-DFUR 600 mg. Furthermore, because of an intestinal disorder (diarrhea), the drug was changed to paclitaxel 90 mg/m2 alone biweekly in a nearby clinic as outpatient treatment. The main tumor of the stomach gradually diminished to an endoscopically visible ulcer scarlike form by September 2008 (Fig. 2a). Abdominal CT detected no tumor lesion in March 2009 (Fig. 2b). The patient was temporarily hospitalized in March 2012 because of ischemic colitis. CT did not detect any findings of gastric cancer recurrence or distant metastasis. Endoscopically, the remnant
J Gastrointest Canc
Fig. 2 Effect of chemotherapy for the only long-term survivor of inoperable EBV-positive GC. a Endoscopic features of the gastric cancer of the remnant stomach 53 months after initial chemotherapy (September 2008). The tumor of the remnant stomach gradually diminished to an ulcer scar-like form (arrow). b Abdominal CT images 59 months after initial chemotherapy (March 2009). Abdominal CT detects no tumor lesion (arrows)
stomach showed an ulcer scar-like form as in 2008; however, a biopsy specimen still contained moderately differentiated adenocarcinoma. He was still alive in April 2013 as an outpatient of a nearby clinic, using paclitaxel 90 mg biweekly over 108 months (9 years) after the initial chemotherapy.
Discussion In the present study, the EBV-positive rate for gastric cancer lesions was 13.6 %, which was in good accord with accumulated data [9, 14]. In inoperable cases, the mean survival period of 12.8 months for four cases of palliative chemotherapy for EBV-negative GC was not so different from the 10 and 19 months for two of the three EBV-positive cases. However, comparison between these two EBV-positive cases and the long-surviving case is necessary. Of the three inoperable EBV-positive patients, the two who died had peritoneal
dissemination. The long-term survivor had direct invasion of the pancreas and swelling of lymph nodes near the spleen on abdominal CT, but no ascites at the initial chemotherapy. This indicates the potential importance of the presence of peritoneal dissemination. There are some reports from other institutes of favorable chemotherapy outcomes for EBV-positive GC as in our case. Seya et al. reported one case of advanced EBV-positive GC with a complete response to preoperative chemotherapy with S1 and CDDP. Matsunou et al. reported two cases of advanced inoperable EBV-positive GC treated with chemotherapy that resulted in long-term survival [15, 16]. In contrast, in vitro studies indicate that latent EBV infection may lead to resistance to chemotherapy in GC cell lines. Seo et al. reported the contribution of EBV infection to chemoresistance of GC cells to 5-FU. Wang et al. reported the anti-apoptotic role of transfected BARF1 of EBV in EBV-negative GC cells. Shin et al. reported an association between EBV infection and chemoresistance to docetaxel in GC [11–13]. Thus, there are discrepancies between possible favorable chemotherapy outcomes in clinical EBV-positive GC and chemoresistance in EBV-positive GC lines. For clinical EBV-positive GC, the prognosis depends on the patient’s inflammatory response [17]. In cell line studies, the host immune response is absent. From this viewpoint, the absence of ascites of our long-surviving EBV-positive GC patient seems important. The two patients with EBV-positive GC who died had peritoneal dissemination. Ascites may occur in a space free from the host cellular immune response, and the presence of peritoneal dissemination may indicate chemoresistance of disseminated EBV-positive GC cells as reported in GC cell lines. Our limited experience with a small number of patients indicated that a favorable outcome of chemotherapy for EBV-positive inoperable GC without peritoneal dissemination was possible. EBER1 ISH for GC biopsy specimens before chemotherapy may be useful to predict the patient’s outcome. Furthermore, possible combination of anti-viral therapy and chemotherapy has been reported [18]. Peritoneal dissemination by itself likely indicates a poor prognosis, and comparing a patient without peritoneal dissemination to those having it without being able to correct for other covariates is not appropriate. We believe that further study of EBV-positive GC will lead to new possibilities for chemotherapy and immune therapy for cancer.
Conclusion We report the case of a single long-term survivor who was EBV positive and suggest further assessment of outcomes in larger groups of EBV-positive patients in order to determine
J Gastrointest Canc
whether this may suggest a prognostic role for EBV-positive status.
Conflicts of Interest The authors declare that they have no competing interests. Funding None
References 1. 2.
3.
4.
5.
6.
7.
Hartgrink HH, Jansen EP, van Grieken NC, van de Velde CJ. Gastric cancer. Lancet. 2009;374:477–90. Burke AP, Yen TS, Shekitka KM, Sobin LH. Lymphoepithelial carcinoma of the stomach with Epstein-Barr virus demonstrated by polymerase chain reaction. Mod Pathol. 1990;3:377–80. Watanabe H, Enjoji M, Imai T. Gastric carcinoma with lymphoid stroma. Its morphologic characteristics and prognostic correlations. Cancer. 1976;38:232–43. Yanai H, Nishikawa J, Mizugaki Y, et al. Endoscopic and pathologic features of Epstein-Barr virus-associated gastric carcinoma. Gastrointest Endosc. 1997;45:236–42. Yanai H, Murakami T, Yoshiyama H, et al. Epstein-Barr virus-associated gastric carcinoma and atrophic gastritis. J Clin Gastroenterol. 1999;29:39–43. Nishikawa J, Yanai H, Hirano A, et al. High prevalence of EpsteinBarr virus in gastric remnant carcinoma after Billroth-II reconstruction. Scand J Gastroenterol. 2002;37:825–9. Imai S, Koizumi S, Sugiura M, et al. Gastric carcinoma: monoclonal epithelial malignant cells expressing Epstein-Barr virus latent infection protein. Proc Natl Acad Sci U S A. 1994;91:9131–5.
8.
Iwakiri D, Takada K. Epstein-Barr virus and gastric cancers. In: Robertson ES, editor. Epstein-Barr virus. Norfolk: Caister Academic Press; 2005. p. 157–69. 9. Murphy G, Pfeiffer R, Camargo MC, Rabkin CS. Meta-analysis shows that prevalence of Epstein-Barr virus-positive gastric cancer differs based on sex and anatomic location. Gastroenterology. 2009;137:824–33. 10. Camargo MC, Kim WH, Chiaravalli AM, et al. Improved survival of gastric cancer with tumour Epstein-Barr virus positivity: an international pooled analysis. Gut. 2014;63:236–43. 11. Seo JS, Kim TG, Hong YS, Chen JY, Lee SK. Contribution of Epstein-Barr virus infection to chemoresistance of gastric carcinoma cells to 5-fluorouracil. Arch Pharm Res. 2011;34:635–43. 12. Wang Q, Tsao SW, Ooka T, et al. Anti-apoptotic role of BARF1 in gastric cancer cells. Cancer Lett. 2006;238:90–103. 13. Shin HJ, Kim D, Lee SK. Association between Epstein-Barr virus infection and chemoresistance to docetaxel in gastric carcinoma. Mol Cells. 2011;32:173–9. 14. Tokunaga M, Uemura Y, Tokudome T, et al. Epstein-Barr virus related gastric cancer in Japan: a molecular patho-epidemiological study. Acta Pathol Jpn. 1993;43:574–81. 15. Seya T, Tanaka N, Yokoi K, et al. Complete response of a patient with advanced gastric cancer, showing Epstein-Barr virus infection, to preoperative chemotherapy with S-1 and cisplatin. Int J Clin Oncol. 2007;12:472–7. 16. Matsunou H, Konishi F, Hori H, et al. Characteristics of EpsteinBarr virus-associated gastric carcinoma with lymphoid stroma in Japan. Cancer. 1996;77:1998–2004. 17. Song HJ, Srivastava A, Lee J, et al. Host inflammatory response predicts survival of patients with Epstein-Barr virus-associated gastric carcinoma. Gastroenterology. 2010;139:84–92. 18. Feng WH, Israel B, Raab-Traub N, Busson P, Kenney SC. Chemotherapy induces lytic EBV replication and confers ganciclovir susceptibility to EBV-positive epithelial cell tumors. Cancer Res. 2002;62:1920–6.
