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Matsubayashi H, Morizane C. Familial and hereditary pancreatic cancer in Japan. Fam Cancer 2024; 23:365-372. [PMID: 38733422 DOI: 10.1007/s10689-024-00395-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: 11/29/2023] [Accepted: 04/19/2024] [Indexed: 05/13/2024]
Abstract
As in Western countries, familial pancreatic cancer accounts for 5-7% of pancreatic cancer (PC) in Japan. Opportunities for diagnosing hereditary pancreatic cancer (HPC) are increasing owing to the coverage of companion diagnostics and cancer genomic profiling by national health insurance in patients with unresectable or recurrent PC refractory to standard chemotherapies. HPC is recognized in 7% of PCs and 15% of familial pancreatic cancer, including germline variants of BRCA1/2, ATM, PALB2, APC, and mismatch repair genes. Individuals with 5-fold or greater inherited risks of PC are recommended to undergo pancreatic surveillance according to Japanese guidelines. The imaging modalities for this surveillance include endoscopic ultrasound, magnetic resonance cholangiopancreatography, abdominal ultrasound, and enhanced computed tomography. Currently, a nationwide prospective surveillance study is ongoing in Japan. Platinum-based chemotherapy is an effective pancreatic cancer treatment in patients with variants of homologous recombination repair genes (BRCA1/2 and PALB2); however, the use of platinum regimens solely based on familial/personal cancer history remains controversial. The efficacy of olaparib maintenance therapy, as confirmed by the POLO study, has significantly impacted the clinical treatment of advanced PC patients in Japan. Since the initiation of precision cancer medicine in 2019, genetic medicine for PC patients has expanded in Japan.
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Affiliation(s)
- Hiroyuki Matsubayashi
- Division of Genetic Medicine Promotion and Endoscopy, Shizuoka Cancer Center, Shimonagakubo, Nagaizumi, Suntogun, Shizuoka, 411-8777, Japan.
| | - Chigusa Morizane
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, 104-0045, Japan
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2
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Tezuka K, Okamura Y, Sugiura T, Ito T, Yamamoto Y, Ashida R, Ohgi K, Otsuka S, Todaka A, Fukutomi A, Uesaka K. Predictive factors of survival in patients with borderline resectable pancreatic cancer who received neoadjuvant therapy. Pancreatology 2021; 21:1451-1459. [PMID: 34462214 DOI: 10.1016/j.pan.2021.08.009] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/18/2021] [Revised: 07/27/2021] [Accepted: 08/22/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND/OBJECTIVES This study aimed to develop the prognostic score (PS) based on clinical factors to stratify the prognosis in borderline resectable pancreatic cancer (BRPC) patients treated with neoadjuvant therapy (NAT). METHODS This retrospective study included 57 BRPC patients who received NAT between April 2012 and December 2017. A score was assigned to each prognostic factor available before and after NAT, according to their β coefficients. RESULTS Multivariate analysis identified the following six prognostic factors, and scores were assigned as follows: being a familial PC patient (HR 4.98, p = 0.029), post-NAT CA19-9 ≥37 U/ml (HR 3.08, p = 0.020), reduction rate of CA19-9 <70% (HR 3.71, p = 0.008), pre-NAT neutrophil-to-lymphocyte ratio ≥2.8 (HR 4.32, p = 0.003), and non-resection (HR 3.98, p = 0.009) were scored as 1; and post-NAT albumin-to-globulin ratio <1.33 (HR 8.31, p < 0.001) was scored as 2. The PS was calculated by summing the scores assigned to each prognostic factor. Patients were then classified into three risk groups (low- [0-1 points], moderate- [2-3 points], and high-risk [4-6 points] groups). Median overall survival in the low-, moderate-, and high-risk groups were not reached, 37.5 months, and 11.8 months, respectively, and there were significant differences in survival among the three groups (p < 0.01 in each group). CONCLUSIONS This study showed that the PS may be useful for predicting the prognosis of BRPC patients treated with NAT.
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Affiliation(s)
- Koji Tezuka
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Yukiyasu Okamura
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan.
| | - Teiichi Sugiura
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Takaaki Ito
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Yusuke Yamamoto
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Ryo Ashida
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Katsuhisa Ohgi
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Shimpei Otsuka
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
| | - Akiko Todaka
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Akira Fukutomi
- Division of Gastrointestinal Oncology, Shizuoka Cancer Center, Shizuoka, Japan
| | - Katsuhiko Uesaka
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka, Japan
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3
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Tezuka K, Okamura Y, Sugiura T, Ito T, Yamamoto Y, Ashida R, Ohgi K, Uesaka K. The influence of familial pancreatic cancer on postoperative outcome in pancreatic cancer: relevance to adjuvant chemotherapy. J Gastroenterol 2021; 56:101-113. [PMID: 33094352 DOI: 10.1007/s00535-020-01730-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 09/12/2020] [Indexed: 02/04/2023]
Abstract
BACKGROUND Familial pancreatic cancer (FPC) is defined as a family in which at least two first-degree relatives have pancreatic cancer (PC). The prognostic significance of PC in an FPC family after surgery is not fully understood. METHODS This was a retrospective study of 427 patients who underwent pancreatectomy for pancreatic ductal adenocarcinoma between January 2008 and December 2016. PC patients who also had at least one first-degree relative with PC were defined as FPC patients. The associations between recurrence and clinicopathological characteristics were analyzed for both FPC and non-FPC patients. RESULTS FPC patients accounted for 31 of the 427 (7.3%) patients. Recurrence occurred in 72.1% of the total cohort and in 87.1% of the 31 FPC patients. Multivariate analysis showed that being an FPC patient was an independent predictor for relapse-free survival (RFS) (hazard ratio [HR] 1.52, P = 0.038). Although univariate analysis revealed that being an FPC patient was significantly associated with poorer overall survival (OS) (P < 0.001), multivariate analysis showed that being an FPC patient was not an independent predictor for OS (P = 0.164). Dichotomization of the 427 patients into those who received (n = 317: 17 FPC and 300 non-FPC patients) and did not receive (n = 110: 14 FPC and 96 non-FPC patients) adjuvant chemotherapy revealed that being an FPC patient was an independent predictor for RFS (HR 2.50, P < 0.001) and OS (HR 2.30, P = 0.003) only for patients who received adjuvant chemotherapy. CONCLUSIONS This study has shown that being an FPC patient is a significant prognostic indicator for PC patients who undergo resection and receive adjuvant chemotherapy.
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Affiliation(s)
- Koji Tezuka
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka Cancer Center Hospital, 1007, Shimo-Nagakubo, Sunto-Nagaizumi, Shizuoka, 411-8777, Japan
| | - Yukiyasu Okamura
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka Cancer Center Hospital, 1007, Shimo-Nagakubo, Sunto-Nagaizumi, Shizuoka, 411-8777, Japan.
| | - Teiichi Sugiura
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka Cancer Center Hospital, 1007, Shimo-Nagakubo, Sunto-Nagaizumi, Shizuoka, 411-8777, Japan
| | - Takaaki Ito
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka Cancer Center Hospital, 1007, Shimo-Nagakubo, Sunto-Nagaizumi, Shizuoka, 411-8777, Japan
| | - Yusuke Yamamoto
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka Cancer Center Hospital, 1007, Shimo-Nagakubo, Sunto-Nagaizumi, Shizuoka, 411-8777, Japan
| | - Ryo Ashida
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka Cancer Center Hospital, 1007, Shimo-Nagakubo, Sunto-Nagaizumi, Shizuoka, 411-8777, Japan
| | - Katsuhisa Ohgi
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka Cancer Center Hospital, 1007, Shimo-Nagakubo, Sunto-Nagaizumi, Shizuoka, 411-8777, Japan
| | - Katsuhiko Uesaka
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka Cancer Center Hospital, 1007, Shimo-Nagakubo, Sunto-Nagaizumi, Shizuoka, 411-8777, Japan
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4
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Matsubayashi H, Takaori K, Morizane C, Kiyozumi Y. Familial Pancreatic Cancer and Surveillance of High-Risk Individuals. Gut Liver 2020; 13:498-505. [PMID: 30917631 PMCID: PMC6743804 DOI: 10.5009/gnl18449] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2018] [Revised: 12/04/2018] [Accepted: 12/13/2018] [Indexed: 12/15/2022] Open
Abstract
Family history of pancreatic cancer (PC) is a risk factor for PC development, and the risk level correlates with the number of affected families. A case of PC with ≥1 PC cases in the first-degree relative is broadly defined as familial pancreatic cancer (FPC) and accounts for 5% to 10% of total PC cases. FPC possesses several epidemiological, genetic and clinicopathological aspects that are distinct from those of conventional PCs. In Western countries, FPC registries have been established since the 1990s, and high-risk individuals are screened to detect early PCs. For the pharmacotherapy of FPC, especially in cases with germline pathogenic BRCA mutations, regimens using platinum and poly (ADP-ribose) polymerase inhibitor have recently been studied for their effectiveness. To date, the concept of FPC has prevailed in Western countries, and it has begun to infiltrate into Eastern countries. As the genetic background and environmental conditions vary in association with ethnicity and living area, we need to establish our own FPC registries and accumulate data in Asian countries.
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Affiliation(s)
- Hiroyuki Matsubayashi
- Divisions of Genetic Medicine Promotion, Shizuoka Cancer Center, Shizuoka, Japan.,Divisions of Endoscopy, Shizuoka Cancer Center, Shizuoka, Japan
| | - Kyoichi Takaori
- Department of Surgery, Kyoto University Graduate School of Medicine, Kyoto, Japan
| | - Chigusa Morizane
- Division of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Yoshimi Kiyozumi
- Divisions of Genetic Medicine Promotion, Shizuoka Cancer Center, Shizuoka, Japan
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5
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Matsubayashi H, Kiyozumi Y, Ishiwatari H, Uesaka K, Kikuyama M, Ono H. Surveillance of Individuals with a Family History of Pancreatic Cancer and Inherited Cancer Syndromes: A Strategy for Detecting Early Pancreatic Cancers. Diagnostics (Basel) 2019; 9:E169. [PMID: 31683730 PMCID: PMC6963266 DOI: 10.3390/diagnostics9040169] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2019] [Revised: 10/29/2019] [Accepted: 10/30/2019] [Indexed: 12/13/2022] Open
Abstract
A family history of pancreatic cancer (PC) is a risk factor of PC, and risk levels increase as affected families grow in number and/or develop PC at younger ages. Familial pancreatic cancer (FPC) is defined as a client having at least two PC cases in a first degree relatives. In the narrow sense, FPC does not include some inherited cancer syndromes that are known to increase the risks of PC, such as Peutz-Jeghers syndrome (PJS), hereditary pancreatitis (HP), hereditary breast ovarian cancer syndrome (HBOC), and so on. FPC accounts for 5%-10% of total PC diagnoses and is marked by several features in genetic, epidemiological, and clinicopathological findings that are similar to or distinct from conventional PC. Recent advances in genetic medicine have led to an increased ability to identify germline variants of cancer-associated genes. To date, high-risk individuals (HRIs) in many developed countries, including FPC kindreds and inherited cancer syndromes, are screened clinically to detect and treat early-stage PC. This article highlights the concept of FPC and the most recent data on its detection.
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Affiliation(s)
- Hiroyuki Matsubayashi
- Division of Endoscopy, Shizuoka Cancer Center, Shizuoka 411-8777, Japan.
- Division of Genetic Medicine Promotion, Shizuoka Cancer Center, Shizuoka 411-8777, Japan.
| | - Yoshimi Kiyozumi
- Division of Genetic Medicine Promotion, Shizuoka Cancer Center, Shizuoka 411-8777, Japan.
| | | | - Katsuhiko Uesaka
- Division of Hepato-Biliary-Pancreatic Surgery, Shizuoka Cancer Center, Shizuoka 411-8777, Japan.
| | - Masataka Kikuyama
- Department of Gastroenterology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo 113-0021, Japan.
| | - Hiroyuki Ono
- Division of Endoscopy, Shizuoka Cancer Center, Shizuoka 411-8777, Japan.
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6
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Takai E, Yachida S, Shimizu K, Furuse J, Kubo E, Ohmoto A, Suzuki M, Hruban RH, Okusaka T, Morizane C, Furukawa T. Germline mutations in Japanese familial pancreatic cancer patients. Oncotarget 2018; 7:74227-74235. [PMID: 27732944 PMCID: PMC5342048 DOI: 10.18632/oncotarget.12490] [Citation(s) in RCA: 60] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2016] [Accepted: 09/29/2016] [Indexed: 02/07/2023] Open
Abstract
Clinicopathologic and genetic features of familial pancreatic cancer (FPC) in Asian countries remain largely unknown. The main purpose of this study was to determine the prevalence of FPC and to define causative FPC-predisposition genes in a Japanese cohort with pancreatic ductal adenocarcinoma (PDAC).We reviewed 1,197 patients with a pathologically proven PDAC and found that 88 (7.3%) were FPC patients who had at least one first-degree relative with PDAC. There were no significant differences between the FPC cases and sporadic cases in terms of gender, age, tumor location, stage, family history of any cancer except PDAC, and personal history of smoking, other cancers, diabetes mellitus and chronic pancreatitis. In the FPC patients, we then investigated the prevalence of germline mutations in 21 genes associated with hereditary predispositions for pancreatic, breast and ovarian cancers by means of the next-generation sequencing using a custom multiple-gene panel. We found that eight (14.5%) of the 54 FPC patients with available germline DNA carried deleterious mutations in BRCA2, PALB2, ATM, or MLH1. These results indicate that a significant fraction of patients with PDAC in Japan have a family history of pancreatic cancer, and some of them harbor deleterious causative mutations in known FPC predisposition genes.
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Affiliation(s)
- Erina Takai
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Shinichi Yachida
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Kyoko Shimizu
- Department of Gastroenterology, Institute of Gastroenterology, Tokyo Women's Medical University, Tokyo, Japan
| | - Junji Furuse
- Department of Medical Oncology, Kyorin University School of Medicine, Mitaka, Japan
| | - Emi Kubo
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Akihiro Ohmoto
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Masami Suzuki
- Division of Cancer Genomics, National Cancer Center Research Institute, Tokyo, Japan
| | - Ralph H Hruban
- Department of Pathology and Oncology, The Sol Goldman Pancreatic Cancer Research Center, The Johns Hopkins University School of Medicine, Baltimore, MD, USA
| | - Takuji Okusaka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Chigusa Morizane
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, Tokyo, Japan
| | - Toru Furukawa
- Institute for Integrated Medical Sciences, Tokyo Women's Medical University, Tokyo, Japan
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7
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Takata T, Ueda T, Sakasai-Sakai A, Takeuchi M. Generation of glyceraldehyde-derived advanced glycation end-products in pancreatic cancer cells and the potential of tumor promotion. World J Gastroenterol 2017; 23:4910-4919. [PMID: 28785145 PMCID: PMC5526761 DOI: 10.3748/wjg.v23.i27.4910] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/24/2017] [Revised: 05/10/2017] [Accepted: 06/19/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To determine the possibility that diabetes mellitus promotes pancreatic ductal adenocarcinoma via glyceraldehyde (GA)-derived advanced glycation-end products (GA-AGEs).
METHODS PANC-1, a human pancreatic cancer cell line, was treated with 1-4 mmol/L GA for 24 h. The cell viability and intracellular GA-AGEs were measured by WST-8 assay and slot blotting. Moreover, immunostaining of PANC-1 cells with an anti-GA-AGE antibody was performed. Western blotting (WB) was used to analyze the molecular weight of GA-AGEs. Heat shock proteins 90α, 90β, 70, 27 and cleaved caspase-3 were analyzed by WB. In addition, PANC-1 cells were treated with GA-AGEs-bovine serum albumin (GA-AGEs-BSA), as a model of extracellular GA-AGEs, and proliferation of PANC-1 cells was measured.
RESULTS In PANC-1 cells, GA induced the production of GA-AGEs and cell death in a dose-dependent manner. PANC-1 cell viability was approximately 40% with a 2 mmol/L GA treatment and decreased to almost 0% with a 4 mmol/L GA treatment (each significant difference was P < 0.01). Cells treated with 2 and 4 mmol/L GA produced 6.4 and 21.2 μg/mg protein of GA-AGEs, respectively (P < 0.05 and P < 0.01). The dose-dependent production of some high-molecular-weight (HMW) complexes of HSP90β, HSP70, and HSP27 was observed following administration of GA. We considered HMW complexes to be dimers and trimers with GA-AGEs-mediated aggregation. Cleaved caspase-3 could not be detected with WB. Furthermore, 10 and 20 μg/mL GA-AGEs-BSA was 27% and 34% greater than that of control cells, respectively (P < 0.05 and P < 0.01).
CONCLUSION Although intracellular GA-AGEs induce pancreatic cancer cell death, their secretion and release may promote the proliferation of other pancreatic cancer cells.
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Matsubayashi H, Takaori K, Morizane C, Maguchi H, Mizuma M, Takahashi H, Wada K, Hosoi H, Yachida S, Suzuki M, Usui R, Furukawa T, Furuse J, Sato T, Ueno M, Kiyozumi Y, Hijioka S, Mizuno N, Terashima T, Mizumoto M, Kodama Y, Torishima M, Kawaguchi T, Ashida R, Kitano M, Hanada K, Furukawa M, Kawabe K, Majima Y, Shimosegawa T. Familial pancreatic cancer: Concept, management and issues. World J Gastroenterol 2017; 23:935-948. [PMID: 28246467 PMCID: PMC5311103 DOI: 10.3748/wjg.v23.i6.935] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2016] [Revised: 09/07/2016] [Accepted: 01/18/2017] [Indexed: 02/06/2023] Open
Abstract
Familial pancreatic cancer (FPC) is broadly defined as two first-degree-relatives with pancreatic cancer (PC) and accounts for 4%-10% of PC. Several genetic syndromes, including Peutz-Jeghers syndrome, hereditary pancreatitis, hereditary breast-ovarian cancer syndrome (HBOC), Lynch syndrome, and familial adenomatous polyposis (FAP), also have increased risks of PC, but the narrowest definition of FPC excludes these known syndromes. When compared with other familial tumors, proven genetic alterations are limited to a small proportion (< 20%) and the familial aggregation is usually modest. However, an ethnic deviation (Ashkenazi Jewish > Caucasian) and a younger onset are common also in FPC. In European countries, “anticipation” is reported in FPC families, as with other hereditary syndromes; a trend toward younger age and worse prognosis is recognized in the late years. The resected pancreases of FPC kindred often show multiple pancreatic intraepithelial neoplasia (PanIN) foci, with various K-ras mutations, similar to colorectal polyposis seen in the FAP patients. As with HBOC patients, a patient who is a BRCA mutation carrier with unresectable pancreatic cancer (accounting for 0%-19% of FPC patients) demonstrated better outcome following platinum and Poly (ADP-ribose) polymerase inhibitor treatment. Western countries have established FPC registries since the 1990s and several surveillance projects for high-risk individuals are now ongoing to detect early PCs. Improvement in lifestyle habits, including non-smoking, is recommended for individuals at risk. In Japan, the FPC study group was initiated in 2013 and the Japanese FPC registry was established in 2014 by the Japan Pancreas Society.
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9
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Radon TP, Massat NJ, Jones R, Alrawashdeh W, Dumartin L, Ennis D, Duffy SW, Kocher HM, Pereira SP, Guarner posthumous L, Murta-Nascimento C, Real FX, Malats N, Neoptolemos J, Costello E, Greenhalf W, Lemoine NR, Crnogorac-Jurcevic T. Identification of a Three-Biomarker Panel in Urine for Early Detection of Pancreatic Adenocarcinoma. Clin Cancer Res 2015; 21:3512-21. [PMID: 26240291 PMCID: PMC4539580 DOI: 10.1158/1078-0432.ccr-14-2467] [Citation(s) in RCA: 129] [Impact Index Per Article: 12.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE Noninvasive biomarkers for early detection of pancreatic ductal adenocarcinoma (PDAC) are currently not available. Here, we aimed to identify a set of urine proteins able to distinguish patients with early-stage PDAC from healthy individuals. EXPERIMENTAL DESIGN Proteomes of 18 urine samples from healthy controls, chronic pancreatitis, and patients with PDAC (six/group) were assayed using GeLC/MS/MS analysis. The selected biomarkers were subsequently validated with ELISA assays using multiple logistic regression applied to a training dataset in a multicenter cohort comprising 488 urine samples. RESULTS LYVE-1, REG1A, and TFF1 were selected as candidate biomarkers. When comparing PDAC (n = 192) with healthy (n = 87) urine specimens, the resulting areas under the receiver-operating characteristic curves (AUC) of the panel were 0.89 [95% confidence interval (CI), 0.84-0.94] in the training (70% of the data) and 0.92 (95% CI, 0.86-0.98) in the validation (30% of the data) datasets. When comparing PDAC stage I-II (n = 71) with healthy urine specimens, the panel achieved AUCs of 0.90 (95% CI, 0.84-0.96) and 0.93 (95% CI, 0.84-1.00) in the training and validation datasets, respectively. In PDAC stage I-II and healthy samples with matching plasma CA19.9, the panel achieved a higher AUC of 0.97 (95% CI, 0.94-0.99) than CA19.9 (AUC = 0.88; 95% CI, 0.81-0.95, P = 0.005). Adding plasma CA19.9 to the panel increased the AUC from 0.97 (95% CI, 0.94-0.99) to 0.99 (95% CI, 0.97-1.00, P = 0.04), but did not improve the comparison of stage I-IIA PDAC (n = 17) with healthy urine. CONCLUSIONS We have established a novel, three-protein biomarker panel that is able to detect patients with early-stage pancreatic cancer in urine specimens.
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Affiliation(s)
- Tomasz P Radon
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Nathalie J Massat
- Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom
| | | | - Wasfi Alrawashdeh
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Laurent Dumartin
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Darren Ennis
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Stephen W Duffy
- Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom
| | - Hemant M Kocher
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Stephen P Pereira
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | | | | | - Francisco X Real
- Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Núria Malats
- Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - John Neoptolemos
- The NIHR Liverpool Pancreas Biomedical Research Unit, Liverpool, United Kingdom
| | - Eithne Costello
- The NIHR Liverpool Pancreas Biomedical Research Unit, Liverpool, United Kingdom
| | - William Greenhalf
- The NIHR Liverpool Pancreas Biomedical Research Unit, Liverpool, United Kingdom
| | - Nick R Lemoine
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Tatjana Crnogorac-Jurcevic
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
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10
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Kobayashi M, Shimodaira S, Nagai K, Ogasawara M, Takahashi H, Abe H, Tanii M, Okamoto M, Tsujitani SI, Yusa S, Ishidao T, Kishimoto J, Shibamoto Y, Nagaya M, Yonemitsu Y. Prognostic factors related to add-on dendritic cell vaccines on patients with inoperable pancreatic cancer receiving chemotherapy: a multicenter analysis. Cancer Immunol Immunother 2014; 63:797-806. [PMID: 24777613 PMCID: PMC11028555 DOI: 10.1007/s00262-014-1554-7] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/03/2014] [Accepted: 04/13/2014] [Indexed: 12/11/2022]
Abstract
OBJECTIVE Dendritic cell (DC)-based cancer vaccines may have a significant benefit to patients with advanced pancreatic cancer. However, variations among clinical studies make it difficult to compare clinical outcomes. Here, we identified factors that determined the clinical benefits by analyzing data obtained at seven Japanese institutions that employed the same DC preparation and treatment regimens. METHODS Of 354 patients who met the inclusion criteria, 255 patients who received standard chemotherapy combined with peptide-pulsed DC vaccines were analyzed. RESULTS The mean survival time from diagnosis was 16.5 months (95 % CI 14.4-18.5) and that from the first vaccination was 9.9 months (95 % CI 8.0-12.9). Known prognostic baseline factors related to advanced pancreatic cancer, namely ECOG-PS, peritoneal metastasis, liver metastasis, and the prognostic nutrition index, were also representative. Importantly, we found that erythema reaction after vaccination was an independent and treatment-related prognostic factor for better survival and that OK-432 might be a good adjuvant enhancing the antitumor immunity during DC vaccination. CONCLUSIONS This is the first report of a multicenter clinical study suggesting the feasibility and possible clinical benefit of an add-on DC vaccine in patients with advanced pancreatic cancer who are undergoing chemotherapy. These findings need to be addressed in well-controlled prospective randomized trials.
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Affiliation(s)
| | - Shigetaka Shimodaira
- Cell Processing Center, Shinshu University Hospital, Matsumoto, Nagano, 390-8621 Japan
| | - Kazuhiro Nagai
- Transfusion and Cell Therapy Unit, Nagasaki University Hospital, Nagasaki, 852-8501 Japan
| | - Masahiro Ogasawara
- Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Hokkaido 003-0006 Japan
| | | | | | | | - Masato Okamoto
- Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, 160-8582 Japan
| | | | - Seiichi Yusa
- Research and Development Division, Tella Inc., Tokyo, Japan
| | | | - Junji Kishimoto
- Data Management Center, Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan
| | - Yuta Shibamoto
- Department of Radiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601 Japan
| | - Masaki Nagaya
- Seren Clinic Tokyo, 2-10-2, Shirokanedai, Minato-ku, Tokyo, 108-0071 Japan
- Department of Immunology, St. Marianna University, Kawasaki, 261-8511 Japan
| | - Yoshikazu Yonemitsu
- R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan
| | - The DC Vaccine Study Group at the Japan Society of Innovative Cell Therapy (J-SICT)
- Seren Clinic Nagoya, Nagoya, Aichi 460-0008 Japan
- Cell Processing Center, Shinshu University Hospital, Matsumoto, Nagano, 390-8621 Japan
- Transfusion and Cell Therapy Unit, Nagasaki University Hospital, Nagasaki, 852-8501 Japan
- Department of Hematology, Sapporo Hokuyu Hospital, Sapporo, Hokkaido 003-0006 Japan
- Seren Clinic Fukuoka, Fukuoka, 810-0001 Japan
- Seren Clinic Kobe, Kobe, Hyogo 650-0001 Japan
- Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo, 160-8582 Japan
- National Center for Global Health and Medicine, Tokyo, 162-8655 Japan
- Research and Development Division, Tella Inc., Tokyo, Japan
- Data Management Center, Center for Clinical and Translational Research, Kyushu University Hospital, Fukuoka, Japan
- Department of Radiology, Nagoya City University Graduate School of Medical Sciences, Nagoya, 467-8601 Japan
- Seren Clinic Tokyo, 2-10-2, Shirokanedai, Minato-ku, Tokyo, 108-0071 Japan
- Department of Immunology, St. Marianna University, Kawasaki, 261-8511 Japan
- R&D Laboratory for Innovative Biotherapeutics, Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812-8582 Japan
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