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Yamada D, Kobayashi S, Takahashi H, Akita H, Yamada T, Asaoka T, Shimizu J, Takeda Y, Yokoyama S, Tsujie M, Tomokuni A, Tanemura M, Morimoto O, Murakami M, Kim Y, Nakahira S, Hama N, Sugimoto K, Hashimoto K, Doki Y, Eguchi H. Randomized phase II study of gemcitabine and S-1 combination therapy versus gemcitabine and nanoparticle albumin-bound paclitaxel combination therapy as neoadjuvant chemotherapy for resectable/borderline resectable pancreatic ductal adenocarcinoma (PDAC-GS/GA-rP2, CSGO-HBP-015). Trials 2021; 22:568. [PMID: 34446057 PMCID: PMC8394677 DOI: 10.1186/s13063-021-05541-w] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Accepted: 08/13/2021] [Indexed: 11/10/2022] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease, and multimodal strategies, such as surgery plus neoadjuvant chemotherapy (NAC)/adjuvant chemotherapy, have been attempted to improve survival in patients with localized PDAC. To date, there is one prospective study providing evidence for the superiority of a neoadjuvant strategy over upfront surgery for localized PDAC. However, which NAC regimen is optimal remains unclear. METHODS A randomized, exploratory trial is performed to examine the clinical benefits of two chemotherapy regimens, gemcitabine plus S-1 (GS) and gemcitabine plus nab-paclitaxel (GA), as NAC for patients with planned PDAC resection. Patients are enrolled after the diagnosis of resectable or borderline resectable PDAC. They are randomly assigned to either NAC regimen. Adjuvant chemotherapy after curative resection is highly recommended for 6 months in both arms. The primary endpoint is tumor progression-free survival time, and secondary endpoints include the rate of curative resection, the completion rate of protocol therapy, the recurrence type, the overall survival time, and safety. The target sample size is set as at least 100. DISCUSSION This study is the first randomized phase II study comparing GS combination therapy with GA combination therapy as NAC for localized pancreatic cancer. TRIAL REGISTRATION UMIN Clinical Trials Registry UMIN000021484 . This trial began in April 2016.
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Affiliation(s)
- Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2-E2, Suita, Osaka, 565-0871, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2-E2, Suita, Osaka, 565-0871, Japan
| | - Hidenori Takahashi
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan
| | - Hirofumi Akita
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2-E2, Suita, Osaka, 565-0871, Japan
| | - Terumasa Yamada
- Department of Surgery, Higashiosaka City Medical Center, Higashiōsaka, Japan
| | - Tadafumi Asaoka
- Department of Gastroenterological Surgery, Osaka Police Hospital, Osaka, Japan
| | - Junzo Shimizu
- Department of Gastroenterological Surgery, Toyonaka Municipal Hospital, Toyonaka, Japan
| | - Yutaka Takeda
- Department of Gastroenterological Surgery, Kansai Rosai Hospital, Amagasaki, Japan
| | - Shigekazu Yokoyama
- Department of Gastroenterological Surgery, Hyogo Prefectural Nishinomiya Hospital, Nishinomiya, Japan
| | - Masanori Tsujie
- Department of Gastroenterological Surgery, Osaka Rosai Hospital, Sakai, Japan
| | - Akira Tomokuni
- Department of Gastroenterological Surgery, Osaka General Medical Center, Osaka, Japan
| | - Masahiro Tanemura
- Department of Gastroenterological Surgery, Rinku General Medical Center, Izumisano, Japan
| | - Osakuni Morimoto
- Department of Surgery, Japan Community Health Care Organization Osaka Hospital, Osaka, Japan
| | - Masahiro Murakami
- Department of Gastroenterological Surgery, Itami City Hospital, Itami, Japan
| | - Yongkook Kim
- Department of Surgery, Kaizuka City Hospital, Kaizuka, Japan
| | - Shin Nakahira
- Department of Surgery, Sakai City Medical Center, Sakai, Japan
| | - Naoki Hama
- Department of Surgery, Ikeda City Hospital, Ikeda, Japan
| | | | | | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2-E2, Suita, Osaka, 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2-E2, Suita, Osaka, 565-0871, Japan.
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Tomimaru Y, Eguchi H, Iwagami Y, Akita H, Noda T, Gotoh K, Kobayashi S, Nagano H, Mori M, Doki Y. Preoperative chemoradiotherapy using gemcitabine for pancreatic ductal adenocarcinoma in patients with impaired renal function. Cancer Chemother Pharmacol 2020; 85:537-545. [PMID: 31834436 DOI: 10.1007/s00280-019-04005-y] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2019] [Accepted: 12/04/2019] [Indexed: 10/25/2022]
Abstract
PURPOSE Preoperative chemoradiotherapy (CRT) can be a promising treatment for pancreatic ductal adenocarcinoma (PDAC). However, its administration for patients with impaired renal function has not been well investigated, let alone its clinical effect. We previously reported preliminary feasibility of CRT in PDAC patients with renal impairment. Herein, we aimed to investigate the clinical effects of preoperative CRT including safety and long-term prognosis in more PDAC patients with renal impairment as an extension to our previous work. METHODS This study enrolled twenty patients harboring resectable PDAC with creatinine clearance level less than 60 ml/min. Patients underwent preoperative CRT with gemcitabine, followed by surgery. The clinical effects of the therapy were evaluated in terms of safety and long-term prognosis. RESULTS Preoperative CRT was completed in all 20 patients. Grade 4 leukopenia/neutropenia was identified as an observed toxicity in four cases (20.0%). Renal function was not worsened after CRT. After CRT, 17 cases were judged resectable and underwent laparotomy. Pancreatic resection was performed in 15 of the 17 patients; it was not performed in two patients because of peritoneal dissemination. The 1-/3-/5-year cumulative survival rate from the initiation of CRT for the 20 patients was 88.8%/45.5%/22.8%. In the 15 patients, renal function was not worsened after surgery. CONCLUSION Our findings suggest that the clinical effects of preoperative CRT would be favorable in PDAC patients with renal impairment.
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Affiliation(s)
- Yoshito Tomimaru
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan.
| | - Yoshifumi Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
| | - Hirofumi Akita
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
| | - Kunihito Gotoh
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Ube, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, 2-2 Yamadaoka E-2, Suita, Osaka, 565-0871, Japan
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Yamada D, Takahashi H, Asukai K, Hasegawa S, Tomokuni A, Wada H, Akita H, Yasui M, Miyata H, Ishikawa O. Pathological complete response (pCR) with or without the residual intraductal carcinoma component following preoperative treatment for pancreatic cancer: Revisiting the definition of "pCR" from the prognostic standpoint. Ann Gastroenterol Surg 2019; 3:676-685. [PMID: 31788656 PMCID: PMC6875936 DOI: 10.1002/ags3.12288] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Revised: 08/15/2019] [Accepted: 09/04/2019] [Indexed: 12/22/2022] Open
Abstract
BACKGROUND AND AIM There are no previous reports describing the prognostic significance of the residual intraductal carcinoma component (carcinoma in situ [CIS]) following preoperative treatment for pancreatic ductal adenocarcinoma (PDAC). The aim of the present study was to investigate the prognostic significance of a minimal residual CIS in cases with complete absence of an invasive component after preoperative treatment for PDAC. METHODS Eighty-one of 594 PDAC patients with preoperative treatment and subsequent surgery in our institute showed remarkable remission in the invasive component, which included 48 patients with the minimal residual invasive component (Min-inv group) and 33 with absence of an invasive component (No-inv group). We assessed the survival of these patients in association with the presence or absence of an invasive component and intraductal CIS. RESULTS Five-year overall survival in the No-inv group patients was significantly better than that of the Min-inv group patients (82%/66%, P = .041). Among the 33 patients in the No-inv group, residual CIS was observed in 16 patients (CIS-positive group), and the remaining 17 patients had no residual CIS (CIS-negative group). There was no significant difference in survival between patients in the CIS-positive and CIS-negative groups (92%/78%, P = .31). CONCLUSIONS Residual CIS in the absence of an invasive component after preoperative treatment does not yield a prognostic impact after receiving perioperative treatment for PDAC. It might be reasonable to define pathological complete response (pCR) from the prognostic standpoint as follows: pCR is the complete absence of an invasive carcinoma component regardless of residual CIS.
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Affiliation(s)
- Daisaku Yamada
- Department of Gastroenterological surgeryOsaka International Cancer InstituteOsakaJapan
| | - Hidenori Takahashi
- Department of Gastroenterological surgeryOsaka International Cancer InstituteOsakaJapan
| | - Kei Asukai
- Department of Gastroenterological surgeryOsaka International Cancer InstituteOsakaJapan
| | - Shinichiro Hasegawa
- Department of Gastroenterological surgeryOsaka International Cancer InstituteOsakaJapan
| | - Akira Tomokuni
- Department of Gastroenterological surgeryOsaka International Cancer InstituteOsakaJapan
| | - Hiroshi Wada
- Department of Gastroenterological surgeryOsaka International Cancer InstituteOsakaJapan
| | - Hirofumi Akita
- Department of Gastroenterological surgeryOsaka International Cancer InstituteOsakaJapan
| | - Masayohi Yasui
- Department of Gastroenterological surgeryOsaka International Cancer InstituteOsakaJapan
| | - Hiroshi Miyata
- Department of Gastroenterological surgeryOsaka International Cancer InstituteOsakaJapan
| | - Osamu Ishikawa
- Department of Gastroenterological surgeryOsaka International Cancer InstituteOsakaJapan
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Otsuru T, Kobayashi S, Wada H, Takahashi T, Gotoh K, Iwagami Y, Yamada D, Noda T, Asaoka T, Serada S, Fujimoto M, Eguchi H, Mori M, Doki Y, Naka T. Epithelial-mesenchymal transition via transforming growth factor beta in pancreatic cancer is potentiated by the inflammatory glycoprotein leucine-rich alpha-2 glycoprotein. Cancer Sci 2019; 110:985-996. [PMID: 30575211 PMCID: PMC6398893 DOI: 10.1111/cas.13918] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2018] [Revised: 12/17/2018] [Accepted: 12/18/2018] [Indexed: 12/15/2022] Open
Abstract
We previously showed that an inflammation‐related, molecule leucine‐rich alpha‐2 glycoprotein (LRG) enhances the transforming growth factor (TGF)‐β1‐induced phosphorylation of Smad proteins and is elevated in patients with pancreatic ductal adenocarcinoma (PDAC). As TGF‐β/Smad signaling is considered to play a key role in epithelial‐mesenchymal transition (EMT), we attempted to clarify the mechanism underlying LRG‐related EMT in relation to metastasis in PDAC. We cultured LRG‐overexpressing PDAC cells (Panc1/LRG) and evaluated the morphology, EMT‐related molecules and TGF‐β/Smad signaling pathway in these cells. We also assessed the LRG levels in plasma and resected specimens from patients with PDAC. Inflammatory cytokines induced LRG production in PDAC cells. A spindle‐like shape was visualized more frequently than other shapes in Panc1/LRG with TGF‐β1 exposure. The expression of E‐cadherin in Panc1/LRG was decreased with TGF‐β1 exposure. Invasion increased with TGF‐β1 stimulation of Panc1/LRG. The phosphorylation of smad2 in Panc1/LRG was increased in comparison with parental Panc1 under TGF‐β1 stimulation. In the plasma LRG‐high group, the recurrence rate tended to be higher and the recurrence‐free survival (RFS) tended to be worse in comparison with the plasma LRG‐low group. LRG enhanced EMT induced by TGF‐β signaling, thus indicating that LRG has a significant effect on the metastasis of PDAC.
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Affiliation(s)
- Toru Otsuru
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Tsuyoshi Takahashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Kunihito Gotoh
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Yoshifumi Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Tadafumi Asaoka
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Satoshi Serada
- Center for Intractable Immune Disease, Kochi University, Kochi, Japan
| | - Minoru Fujimoto
- Center for Intractable Immune Disease, Kochi University, Kochi, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Japan
| | - Testuji Naka
- Center for Intractable Immune Disease, Kochi University, Kochi, Japan
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Shinke G, Yamada D, Eguchi H, Iwagami Y, Asaoka T, Noda T, Wada H, Kawamoto K, Gotoh K, Kobayashi S, Takeda Y, Tanemura M, Mori M, Doki Y. Role of histone deacetylase 1 in distant metastasis of pancreatic ductal cancer. Cancer Sci 2018; 109:2520-2531. [PMID: 29917299 PMCID: PMC6113427 DOI: 10.1111/cas.13700] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/13/2018] [Accepted: 06/12/2018] [Indexed: 12/22/2022] Open
Abstract
Current therapies for pancreatic ductal cancer (PDAC) do not sufficiently control distant metastasis. Thus, new therapeutic targets are urgently needed. Numerous studies have suggested that the epithelial-mesenchymal transition (EMT) is pivotal for metastasis of carcinomas. The fact that the EMT is reversible suggests the possibility that it is induced by an epigenetic mechanism. In this study, we aimed to investigate the role of histone deacetylase 1 (HDAC1), which is an epigenetic mechanism on distant metastasis of PDAC. We investigated the HDAC1 expression in 103 resected PDAC specimens obtained from patients who were treated with/without preoperative therapy using immunohistochemistry. To validate the findings in the clinical samples, we evaluated the HDAC1 activity, the EMT-associated genes and the migration/invasion ability in vitro, and performed an HDAC1 inhibitor assay. The high expression of HDAC1 in clinical samples was significantly associated with poor progression-free survival, especially distant metastasis-free survival. In vitro, HDAC1 inhibitors decreased the invasion ability and reversed the EMT change; the only factor to show a concomitant decrease was the expression of SNAIL. We confirmed that the HDAC1 expression was associated with the SNAIL expression in clinical samples. Moreover, the resistant cells and parental cells did not show any significant differences in the expression of HDAC1; this was consistent with the finding that preoperative therapy did not alter the HDAC1 expression in clinical samples. The targeting of HDAC1, which could suppress metastasis by inhibiting the EMT, is a promising treatment option for PDAC.
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Affiliation(s)
- Go Shinke
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yoshifumi Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Tadafumi Asaoka
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Surgery, Osaka International Cancer Institute, Osaka, Japan
| | - Koichi Kawamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Kunihito Gotoh
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yutaka Takeda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.,Department of Surgery, Kansai Rosai Hospital, Hyogo, Japan
| | - Masahiro Tanemura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan.,Department of Surgery, Osaka Police Hospital, Osaka, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka, Japan
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The investigation of the survival time after recurrence in patients with pancreatic ductal adenocarcinoma for individualization of adjuvant chemotherapy. Surg Today 2018; 48:952-962. [PMID: 29770847 DOI: 10.1007/s00595-018-1674-3] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 04/27/2018] [Indexed: 02/07/2023]
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is a lethal disease; however, the frequency of recurrence can be reduced if curative surgery following adjuvant chemotherapy is applied. At present, adjuvant chemotherapy is uniformly performed in all patients, as it is unclear which tumor types are controlled best or worst. We investigated patients with recurrence to establish the optimum treatment strategy. METHODS Of 138 patients who underwent curative surgery for PDAC, 85 developed recurrence. Comprehensive clinicopathological factors were investigated for their association with the survival time after recurrence (SAR). RESULTS The median SAR was 12.6 months. Treatments for recurrence included best supportive care, GEM-based therapy and S-1. The performance status [hazard ratio (HR) 0.12, P < 0.001], histological invasion of lymph vessels (HR 0.27, P < 0.001), kind of treatment for recurrence (HR 5.0, P < 0.001) and initial recurrence site (HR 2.9, P < 0.001) were independent significant risk factors for the SAR. The initial recurrence sites were the liver (n = 21, median SAR 8.8 months), lung (n = 10, 14.9 months), peritoneum (n = 6, 1.7 months), lymph nodes (n = 6, 14.7 months), local site (n = 17, 13.9 months) and multiple sites (n = 25, 10.1 months). A shorter recurrence-free survival (< 1 year) and higher postoperative CA19-9 level were significantly associated with critical recurrence (peritoneal/liver). CONCLUSIONS Several risk factors for SAR were detected in this study. Further investigations are needed to individualize the adjuvant chemotherapy for each patient with PDAC.
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Furukawa K, Tanemura M, Miyoshi E, Eguchi H, Nagano H, Matsunami K, Nagaoka S, Yamada D, Asaoka T, Noda T, Wada H, Kawamoto K, Goto K, Taniyama K, Mori M, Doki Y. A practical approach to pancreatic cancer immunotherapy using resected tumor lysate vaccines processed to express α-gal epitopes. PLoS One 2017; 12:e0184901. [PMID: 29077749 PMCID: PMC5659602 DOI: 10.1371/journal.pone.0184901] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2017] [Accepted: 09/03/2017] [Indexed: 12/23/2022] Open
Abstract
OBJECTIVES Single-agent immunotherapy is ineffective against poorly immunogenic cancers, including pancreatic ductal adenocarcinoma (PDAC). The aims of this study were to demonstrate the feasibility of production of novel autologous tumor lysate vaccines from resected PDAC tumors, and verify vaccine safety and efficacy. METHODS Fresh surgically resected tumors obtained from human patients were processed to enzymatically synthesize α-gal epitopes on the carbohydrate chains of membrane glycoproteins. Processed membranes were analyzed for the expression of α-gal epitopes and the binding of anti-Gal, and vaccine efficacy was assessed in vitro and in vivo. RESULTS Effective synthesis of α-gal epitopes was demonstrated after processing of PDAC tumor lysates from 10 different patients, and tumor lysates readily bound an anti-Gal monoclonal antibody. α-gal(+) PDAC tumor lysate vaccines elicited strong antibody production against multiple tumor-associated antigens and activated multiple tumor-specific T cells. The lysate vaccines stimulated a robust immune response in animal models, resulting in tumor suppression and a significant improvement in survival without any adverse events. CONCLUSIONS Our data suggest that α-gal(+) PDAC tumor lysate vaccination may be a practical and effective new immunotherapeutic approach for treating pancreatic cancer.
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Affiliation(s)
- Kenta Furukawa
- Department of Gastroenterological Surgery, Osaka Police Hospital, Osaka, Japan
| | - Masahiro Tanemura
- Department of Gastroenterological Surgery, Osaka Police Hospital, Osaka, Japan
| | - Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological, Breast and Endocrine Surgery, Yamaguchi University Graduate School of Medicine, Yamaguchi, Japan
| | - Katsuyoshi Matsunami
- Department of Phamacognosy, Hiroshima University Graduate School of Biomedical and Health sciences, Hiroshima, Japan
| | - Satoshi Nagaoka
- Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Daisaku Yamada
- Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Tadafumi Asaoka
- Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Takehiro Noda
- Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Hiroshi Wada
- Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Koichi Kawamoto
- Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kunihito Goto
- Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Kiyomi Taniyama
- Institute for Clinical Research, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Kure, Japan
| | - Masaki Mori
- Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
| | - Yuichiro Doki
- Department of Surgery, Osaka University Graduate School of Medicine, Osaka, Japan
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8
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Cao F, Li J, Li A, Li F. Radical antegrade modular pancreatosplenectomy versus standard procedure in the treatment of left-sided pancreatic cancer: A systemic review and meta-analysis. BMC Surg 2017; 17:67. [PMID: 28583142 PMCID: PMC5460359 DOI: 10.1186/s12893-017-0259-1] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2017] [Accepted: 05/15/2017] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Radical antegrade modular pancreatosplenectomy (RAMPS), first reported by Strasberg in 2003, has attracted increasing attention in the treatment of left-sided pancreatic cancer. The limited number of cases eligible for RAMPS makes it difficult to perform any prospective randomized trial of RAMPS versus the standard procedure. Therefore, we performed this systemic review and meta-analysis of the current data to clarify the role of the RAMPS procedure. METHODS A literature search was performed in electronic databases, including PubMed, Medline, Embase, CNKI and the Cochrane Library. Studies comparing RAMPS with the standard procedure were included in this meta-analysis. R0 resection rate, recurrence rate at the end of the follow-up, overall survival (OS) and disease-free survival (DFS) were measured as primary outcomes. Revman 5.3 was used to perform the analysis. RESULTS Six retrospective cohort studies with a total number of 378 patients were included in our analysis. Meta-analysis revealed that RAMPS was correlated with higher R0 resection rates [Odds Ratio (OR) 95% confidence interval (CI), 2.19 (1.16 ~ 4.13); P = 0.02] and successful harvest of more lymph nodes [weighted mean difference (WMD) 95% CI, 7.06 (4.52 ~ 9.60); P < 0.01] compared with the standard procedure. However, no statistically significant difference was found between the procedures with respect to recurrence rates [OR 95% CI, 0.66 (0.40 ~ 1.09); P = 0.10], OS [Hazard ratio (HR) 95% CI, 0.65 (0.42 ~ 1.00); P = 0.05] or DFS [HR 95% CI, 1.02 (0.62 ~ 1.68); P = 0.93]. CONCLUSIONS RAMPS is safe and oncologically superior to the standard procedure for the treatment of left-sided pancreatic cancer. However, high-grade evidence will be necessary to confirm the potential survival benefits of RAMPS.
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Affiliation(s)
- Feng Cao
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053 People’s Republic of China
| | - Jia Li
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053 People’s Republic of China
| | - Ang Li
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053 People’s Republic of China
| | - Fei Li
- Department of General Surgery, Xuanwu Hospital, Capital Medical University, Beijing, 100053 People’s Republic of China
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9
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Tomihara H, Yamada D, Eguchi H, Iwagami Y, Noda T, Asaoka T, Wada H, Kawamoto K, Gotoh K, Takeda Y, Tanemura M, Mori M, Doki Y. MicroRNA-181b-5p, ETS1, and the c-Met pathway exacerbate the prognosis of pancreatic ductal adenocarcinoma after radiation therapy. Cancer Sci 2017; 108:398-407. [PMID: 28064436 PMCID: PMC5378264 DOI: 10.1111/cas.13159] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2016] [Revised: 12/27/2016] [Accepted: 12/29/2016] [Indexed: 12/20/2022] Open
Abstract
Preoperative chemoradiation therapy (CRT) for pancreatic ductal adenocarcinoma (PDAC) has emerged as a reasonable strategy that shows good prognostic impact. However, after preoperative CRT, resected specimens show remnant tumor cells, which indicate that some tumor cells had acquired or were selected for resistance to CRT. Recently, two oncological mechanisms, the EMT and the presence of CSCs, were reported to be associated with resistance in various cancers. Previous reports showed that HGF could induce EMT in PDAC cells; moreover, the HGF receptor, c‐Met, was identified as a dominant pancreatic CSC marker. However, the clinical significance of c‐Met expression remains unclear. So, we hypothesized that remnant PDAC tissue after CRT might harbor cells with high c‐Met expression, and these cells may exacerbate patients’ prognosis. In the immunohistochemical analysis, we showed that preoperative CRT was significantly associated with high c‐Met expression; moreover, high c‐Met expression was a significant marker of a dismal prognosis. Next, we investigated mechanisms of c‐Met upregulation in PDAC cells. We established GEM‐resistant and radioresistant PDAC cells to analyze the transcriptome involved in c‐Met expression. The microarray data for the established radiation‐resistant PDAC cells indicated miR‐181b‐5p downregulation, which targets ETS1, one of the transcription factors for c‐Met, and it was shown that radiation exposure induced c‐Met expression through ETS1 increase by the suppression of miR‐181b‐5p. These results suggested that targeting these mechanisms may promote the development of a novel multidisciplinary treatment strategy for improving preoperative CRT efficiency.
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Affiliation(s)
- Hideo Tomihara
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Daisaku Yamada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yoshifumi Iwagami
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Takehiro Noda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Tadafumi Asaoka
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Koichi Kawamoto
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Kunihito Gotoh
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yutaka Takeda
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.,Department of Surgery, Kansai Rosai Hospital, Hyogo, Japan
| | - Masahiro Tanemura
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.,Department of Surgery, Osaka Police Hospital, Osaka, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
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10
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Yamada D, Eguchi H, Asaoka T, Tomihara H, Noda T, Wada H, Kawamoto K, Gotoh K, Takeda Y, Tanemura M, Mori M, Doki Y. The basal nutritional state of PDAC patients is the dominant factor for completing adjuvant chemotherapy. Surg Today 2017; 47:1361-1371. [PMID: 28421348 DOI: 10.1007/s00595-017-1522-x] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2017] [Accepted: 03/13/2017] [Indexed: 12/19/2022]
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is highly lethal, and several clinical trials have shown that adjuvant chemotherapy after curative resection can improve the prognosis of these patients. However, the adjuvant chemotherapy completion rate is less than satisfactory. If this rate could be increased then the overall prognosis of PDAC might be improved; however, reports addressing this problem are insufficient. To elucidate the factors, we retrospectively investigated PDAC patients. METHODS Various factors of 121 PDAC patients undergoing R0 resection, including preoperatively treated patients, were investigated. Univariate and multivariate analyses were performed to investigate the factors that were associated with the completion of adjuvant chemotherapy. RESULTS The analysis identified age and the prognostic nutritional index (PNI) as significant independent factors. A receiver operating characteristic curve analysis of age yielded a cutoff value of 67 years (sensitivity, 64%; specificity, 78%). Univariate and multivariate analyses of the 61 patients who were over 67 years of age revealed that the PNI (odds ratio, 0.85; P = 0.048) and Evans grade (odds ratio, 0.041; P = 0.0010) were significant factors for the completion of chemotherapy. CONCLUSIONS The results of our investigation suggest that nutrition should be controlled in older PDAC patients to facilitate the completion of adjuvant chemotherapy.
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Affiliation(s)
- Daisaku Yamada
- Department of Gastroenterological Dr.surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2 (E2), Suita, 565-0871, Osaka, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Dr.surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2 (E2), Suita, 565-0871, Osaka, Japan.
| | - Tadafumi Asaoka
- Department of Gastroenterological Dr.surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2 (E2), Suita, 565-0871, Osaka, Japan
| | - Hideo Tomihara
- Department of Gastroenterological Dr.surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2 (E2), Suita, 565-0871, Osaka, Japan
| | - Takehiro Noda
- Department of Gastroenterological Dr.surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2 (E2), Suita, 565-0871, Osaka, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Dr.surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2 (E2), Suita, 565-0871, Osaka, Japan
| | - Koichi Kawamoto
- Department of Gastroenterological Dr.surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2 (E2), Suita, 565-0871, Osaka, Japan
| | - Kunihito Gotoh
- Department of Gastroenterological Dr.surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2 (E2), Suita, 565-0871, Osaka, Japan
| | - Yutaka Takeda
- Department of Gastroenterological Dr.surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2 (E2), Suita, 565-0871, Osaka, Japan.,Department of Surgery, Kansai Rosai Hospital, Inabasou 3-1-69, Amagasaki, Hyogo, 660-8511, Japan
| | - Masahiro Tanemura
- Department of Gastroenterological Dr.surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2 (E2), Suita, 565-0871, Osaka, Japan.,Department of Surgery, Osaka Police Hospital, Tennoji-ku Kitayamacho 10-31, Osaka, Osaka, 543-0035, Japan
| | - Masaki Mori
- Department of Gastroenterological Dr.surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2 (E2), Suita, 565-0871, Osaka, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Dr.surgery, Graduate School of Medicine, Osaka University, Yamadaoka 2-2 (E2), Suita, 565-0871, Osaka, Japan
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11
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Preoperative chemoradiotherapy does not compromise the feasibility of adjuvant chemotherapy for patients with pancreatic ductal adenocarcinoma. Surg Today 2016; 47:218-226. [PMID: 27586014 DOI: 10.1007/s00595-016-1405-6] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2016] [Accepted: 05/10/2016] [Indexed: 12/25/2022]
Abstract
PURPOSE Preoperative chemoradiotherapy (CRT) is a novel, emerging treatment strategy for pancreatic ductal adenocarcinoma (PDAC), but it remains unclear whether post-surgery adjuvant chemotherapy is feasible following preoperative CRT. This retrospective study evaluates the feasibility of adjuvant therapy after preoperative CRT. METHODS The subjects of this study were 99 consecutive patients who underwent pancreatectomy for PDAC between January, 2007 and February, 2013 in our hospital. Sixty patients received preoperative CRT: as gemcitabine (GEM) and 40 Gy radiation in 28 (G-CRT group), and as GEM, S-1, and 50.4 Gy radiation in 32 (GS-CRT group). We also evaluated 39 patients who underwent surgery alone (SA group). We investigated adjuvant chemotherapy induction and completion rates and the frequency of adverse events rated ≥grade 3, based on Common Terminology Criteria for Adverse Events (version 4.0) in all three groups. RESULTS In the G-CRT, GS-CRT, and SA groups, the induction rates were 78 % (22/28), 78 % (25/32), and 72 % (28/39), respectively; completion rates were 86 % (19/22), 88 % (22/25), and 82 % (23/28), respectively; and adverse event frequencies were 36 % (8/22), 28 % (7/25), and 43 % (12/28), respectively. No significant difference was found among the three groups. CONCLUSION Preoperative CRT was demonstrated to be safe and did not compromise the feasibility of adjuvant chemotherapy.
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12
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Hasegawa S, Eguchi H, Tomokuni A, Tomimaru Y, Asaoka T, Wada H, Hama N, Kawamoto K, Kobayashi S, Marubashi S, Konnno M, Ishii H, Mori M, Doki Y, Nagano H. Pre-treatment neutrophil to lymphocyte ratio as a predictive marker for pathological response to preoperative chemoradiotherapy in pancreatic cancer. Oncol Lett 2015; 11:1560-1566. [PMID: 26893780 DOI: 10.3892/ol.2015.4057] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2014] [Accepted: 07/07/2015] [Indexed: 12/15/2022] Open
Abstract
An elevated neutrophil to lymphocyte ratio (NLR) has been reported to be associated with the pathological response to neoadjuvant therapies in numerous types of cancer. The aim of the current study was to clarify the association between pre-treatment NLR and the pathological response to preoperative chemoradiotherapy in pancreatic cancer patients. This retrospective analysis included data from 56 consecutive patients whose tumors were completely surgically resected. All patients received preoperative therapy, consisting of gemcitabine-based chemotherapy (alone or in combination with S-1) combined with 40 or 50.4 Gy irradiation, prior to surgery. Predictive factors, including NLR, platelet to lymphocyte ratio (PLR), modified Glasgow prognostic score and prognostic nutrition index, were measured prior to treatment. A comparison was made between those who responded well pathologically (good response group, Evans classification IIb/III) and those with a poor response (Evans I/IIa). NLR was determined to be significantly higher in the poor response group. Multivariate analysis identified an elevated NLR as an independent risk factor for the poor pathological response [odds ratio (OR), 5.35; P=0.0257]. The pre-treatment NLR (≥2.2/<2.2) was found to be a statistically significant predictive indicator of pathological response (P=0.00699). The results demonstrate that pre-treatment NLR may be a useful predictive marker for the pathological response to preoperative therapy in pancreatic cancer patients.
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Affiliation(s)
- Shinichiro Hasegawa
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Akira Tomokuni
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Yoshito Tomimaru
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Tadafumi Asaoka
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Naoki Hama
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Koichi Kawamoto
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Shigeru Marubashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Masamitsu Konnno
- Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Hideshi Ishii
- Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan; Department of Cancer Profiling Discovery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Suita, Osaka 565-0871, Japan
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13
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Tanemura M, Miyoshi E, Nagano H, Eguchi H, Matsunami K, Taniyama K, Hatanaka N, Akamatsu H, Mori M, Doki Y. Cancer immunotherapy for pancreatic cancer utilizing α-gal epitope/natural anti-Gal antibody reaction. World J Gastroenterol 2015; 21:11396-11410. [PMID: 26523105 PMCID: PMC4616216 DOI: 10.3748/wjg.v21.i40.11396] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2015] [Revised: 07/02/2015] [Accepted: 08/30/2015] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has the poorest prognosis of all malignancies and is largely resistant to standard therapy. Novel treatments against PDAC are desperately needed. Anti-Gal is the most abundant natural antibody in humans, comprising about 1% of immunoglobulins and is also naturally produced in apes and Old World monkeys. The anti-Gal ligand is a carbohydrate antigen called "α-gal epitopes" with the structure Galα1-3Galβ1-4GlcNAc-R. These epitopes are expressed as major carbohydrate antigens in non-primate mammals, prosimians, and New World monkeys. Anti-Gal is exploited in cancer vaccines to increase the immunogenicity of antigen-presenting cells (APCs). Cancer cells or PDAC tumor lysates are processed to express α-gal epitopes. Vaccination with these components results in in vivo opsonization by anti-Gal IgG in PDAC patients. The Fc portion of the vaccine-bound anti-Gal interacts with Fcγ receptors of APCs, inducing uptake of the vaccine components, transport of the vaccine tumor membranes to draining lymph nodes, and processing and presentation of tumor-associated antigens (TAAs). Cancer vaccines expressing α-gal epitopes elicit strong antibody production against multiple TAAs contained in PDAC cells and induce activation of multiple tumor-specific T cells. Here, we review new areas of clinical importance related to the α-gal epitope/anti-Gal antibody reaction and the advantages in immunotherapy against PDAC.
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14
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Hasegawa S, Nagano H, Konno M, Eguchi H, Tomokuni A, Tomimaru Y, Wada H, Hama N, Kawamoto K, Kobayashi S, Marubashi S, Nishida N, Koseki J, Gotoh N, Ohno S, Yabuta N, Nojima H, Mori M, Doki Y, Ishii H. Cyclin G2: A novel independent prognostic marker in pancreatic cancer. Oncol Lett 2015; 10:2986-2990. [PMID: 26722276 DOI: 10.3892/ol.2015.3667] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2014] [Accepted: 06/02/2015] [Indexed: 12/15/2022] Open
Abstract
Unlike other cyclins that positively regulate the cell cycle, cyclin G2 (CCNG2) regulates cell proliferation as a tumor suppressor gene. A decreased CCNG2 expression serves as a marker for poor prognosis in several types of cancer. The aim of the present study was to clarify the correlation of CCNG2 expression with overall survival and histopathological factors in pancreatic cancer patients. This retrospective analysis included data from 36 consecutive patients who underwent complete surgical resection for pancreatic cancer and did not undergo any preoperative therapies. The association between prognoses and the expression of CCNG2 was assessed using immunohistochemical staining. Multivariate analysis identified that the expression of CCNG2 is an independent prognostic factor. In addition, the Kaplan-Meier curve for overall survival revealed that decreased expression of CCNG2 was a consistent indicator of poor prognosis in pancreatic cancer patients (P=0.0198). A decreased CCNG2 expression significantly correlated with venous invasion in tumor specimens and the tumor invasion depth. In conclusion, CCNG2 expression inversely reflected cancer progression and may be a novel, independent prognostic marker in pancreatic cancer.
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Affiliation(s)
- Shinichiro Hasegawa
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan ; Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Hiroaki Nagano
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Masamitsu Konno
- Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Hidetoshi Eguchi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Akira Tomokuni
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Yoshito Tomimaru
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Hiroshi Wada
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Naoki Hama
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Koichi Kawamoto
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Shogo Kobayashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Shigeru Marubashi
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Naohiro Nishida
- Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Jun Koseki
- Department of Cancer Profiling Discovery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Noriko Gotoh
- Division of Cancer Cell Biology, Cancer Research Institute of Kanazawa University, Kanazawa 920-1192, Japan
| | - Shouichi Ohno
- Department of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
| | - Norikazu Yabuta
- Department of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
| | - Hiroshi Nojima
- Department of Molecular Genetics, Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan
| | - Masaki Mori
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Yuichiro Doki
- Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
| | - Hideshi Ishii
- Department of Frontier Science for Cancer and Chemotherapy, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan ; Department of Cancer Profiling Discovery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
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