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Ng D, Cyr D, Khan S, Dossa F, Swallow C, Kazazian K. Molecular mechanisms of metastatic peritoneal dissemination in gastric adenocarcinoma. Cancer Metastasis Rev 2025; 44:50. [PMID: 40317360 PMCID: PMC12049340 DOI: 10.1007/s10555-025-10265-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/05/2024] [Accepted: 04/17/2025] [Indexed: 05/07/2025]
Abstract
Peritoneal dissemination portends a dismal prognosis in patients with gastric adenocarcinoma in the context of limited effective treatments. The underlying cellular processes that drive gastric peritoneal carcinomatosis remain unclear, limiting the application of novel targeted therapies. In this comprehensive review, we aimed to identify and summarize all existing context-dependent molecular mechanisms that have been implicated in peritoneal dissemination and peritoneal carcinomatosis establishment from primary gastric adenocarcinoma. We applied a multilevel examination including data from in vivo murine models using human gastric cancer cell lines, in vitro technique-based studies, ex vivo models, and genomic/proteomic and molecular profiling analyses to report on various aspects of gastric cancer peritoneal metastasis biology. Mechanisms promoting peritoneal dissemination were grouped into three main functional categories: (1) intrinsic cancer cell biology, (2) cancer cell-peritoneal surface adhesion, and (3) peritoneal tumor microenvironment. We identified significant overlap among the three categories, indicating a complex interplay between multiple molecular mechanisms. By interrupting these pathways, peritoneal-directed therapies have the potential to improve quality and length of life in patients with high-risk primary gastric cancer.
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Affiliation(s)
- Deanna Ng
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
- Institute of Medical Science, University of Toronto, Toronto, Canada
- Department of Surgery, University of Toronto, Toronto, Canada
| | - David Cyr
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
- Institute of Medical Science, University of Toronto, Toronto, Canada
- Department of Surgery, University of Toronto, Toronto, Canada
| | - Shawn Khan
- Institute of Medical Science, University of Toronto, Toronto, Canada
- Department of Surgery, University of Toronto, Toronto, Canada
| | - Fahima Dossa
- Complex General Surgical Oncology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
| | - Carol Swallow
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, Canada
- Institute of Medical Science, University of Toronto, Toronto, Canada
- Department of Surgery, University of Toronto, Toronto, Canada
| | - Karineh Kazazian
- Department of Surgery, University of Toronto, Toronto, Canada.
- Department of Surgical Oncology, Toronto General Hospital, University Health Network, 200 Elizabeth Street, 10 Eaton North, Room 219, Toronto, M5G 2 C4, Canada.
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2
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Principe MAV, Gokgoz N, Prochazka P, Coward VS, Saini S, MacParland S, Gladdy R, Ferguson P, Wunder JS, Andrulis IL, Chung P, Griffin AM, White LM, Dickson BC, Tsoi KM. Identification of Malignancy in Peritumoral Edema in Soft Tissue Sarcoma: A Novel Targeted Molecular Approach. Ann Surg Oncol 2025; 32:1511-1521. [PMID: 39556178 DOI: 10.1245/s10434-024-16521-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2024] [Accepted: 10/30/2024] [Indexed: 11/19/2024]
Abstract
BACKGROUND Peritumoral edema on staging magnetic resonance imaging (MRI) is associated with higher local recurrence in soft tissue sarcoma (STS). This may relate to the presence of satellite malignant cells that are difficult to distinguish from benign atypia, leading to over- or undertreatment. This study evaluated a novel targeted molecular approach to identify malignancy in STS peritumoral planes as a means to improve personalized care. METHODS In the targeted molecular approach, whole-exome sequencing was employed to identify tumor-specific variants (TSVs), and peritumoral planes were assayed for malignancy, defined as two or more TSVs/plane, using droplet digital polymerase chain reaction (PCR). Feasibility was evaluated using a retrospective cohort (n = 8) in which planes with cellular atypia were tested. A prospective cohort (n = 8) then assayed all peritumoral planes with radiologic edema. RESULTS The targeted molecular approach identified malignancy in three of eight cases with cellular atypia of unknown significance (37.5%) and five of eight cases with peritumoral edema on staging MRI (62.5%). Peritumoral regions were heterogeneous; in none of the malignant cases did all sampled planes have evidence of tumor. Malignancy was also identified in regions without cellular atypia. Both cases with a local recurrence had molecular evidence of malignancy outside the main mass despite R0 margins. CONCLUSION This study describes a novel personalized approach to detect malignancy in peritumoral regions in STS and is the first to identify molecular evidence of tumor outside the main mass. While development of a clinical tool is underway, these findings support the current approach of treating all peritumoral edema as malignant.
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Affiliation(s)
- Miguel Alfonso V Principe
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Nalan Gokgoz
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Patrick Prochazka
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
| | - Victoria S Coward
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Sidharth Saini
- Department of Medical Imaging, University of Toronto, Toronto, ON, Canada
- Toronto Joint Department of Medical Imaging, University Health Network, Sinai Health System, Women's College Hospital, Toronto, ON, Canada
| | - Sonya MacParland
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Rebecca Gladdy
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
| | - Peter Ferguson
- Musculoskeletal Oncology Unit, Division of Orthopaedic Surgery, Department of Surgery, University of Toronto, Mount Sinai Hospital, Sinai Health, Toronto, ON, Canada
| | - Jay S Wunder
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
- Musculoskeletal Oncology Unit, Division of Orthopaedic Surgery, Department of Surgery, University of Toronto, Mount Sinai Hospital, Sinai Health, Toronto, ON, Canada
| | - Irene L Andrulis
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Molecular Genetics, University of Toronto, Toronto, ON, Canada
| | - Peter Chung
- Department of Radiation Oncology, Radiation Medicine Program, Princess Margaret Cancer Centre, Toronto, ON, Canada
| | - Anthony M Griffin
- Musculoskeletal Oncology Unit, Division of Orthopaedic Surgery, Department of Surgery, University of Toronto, Mount Sinai Hospital, Sinai Health, Toronto, ON, Canada
| | - Lawrence M White
- Department of Medical Imaging, University of Toronto, Toronto, ON, Canada
- Toronto Joint Department of Medical Imaging, University Health Network, Sinai Health System, Women's College Hospital, Toronto, ON, Canada
| | - Brendan C Dickson
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada
- Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, ON, Canada
| | - Kim M Tsoi
- Lunenfeld-Tanenbaum Research Institute, Sinai Health System, Toronto, ON, Canada.
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada.
- Musculoskeletal Oncology Unit, Division of Orthopaedic Surgery, Department of Surgery, University of Toronto, Mount Sinai Hospital, Sinai Health, Toronto, ON, Canada.
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Sato B, Kanda M, Ito S, Mochizuki Y, Teramoto H, Ishigure K, Murai T, Asada T, Ishiyama A, Matsushita H, Nakanishi K, Shimizu D, Tanaka C, Fujiwara M, Murotani K, Kodera Y. Proposal of the Second Cutoff of Serum Carcinoembryonic Antigen Levels to Stratify Patients into Low, Intermediate, and High Risks at Recurrences after Curative Resection of Gastric Cancer. Dig Surg 2023; 40:187-195. [PMID: 37699371 DOI: 10.1159/000533143] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/04/2022] [Accepted: 05/17/2023] [Indexed: 09/14/2023]
Abstract
INTRODUCTION Carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 are widely used for treating various cancers, with cutoff values of 5.0 ng/mL and 37.0 IU/mL, respectively. However, these cutoff values are not for specific diseases or purposes but are uniformly used for any disease and any purpose. It is also unclear as to whether patients are at equal risk of recurrence if they are below the cutoff values. This study aimed to investigate the optimal cutoff of serum tumor markers in the stratification of recurrence risk after curative resection of gastric cancer. METHODS We constructed a nine-center integrated database of patients who received gastrectomy between January 2010 and December 2014 with a 5-year follow-up period. We determined the cutoff value of preoperative serum tumor marker levels correlated with postoperative recurrences and evaluated its performance in risk stratification for recurrences in 948 patients with stage II/III gastric cancer who underwent radical resection. RESULTS The hazard ratio for postoperative recurrences increased at two points of preoperative CEA levels, 3.6 ng/mL and 5.0 ng/mL, which were set as cutoffs. These two cutoffs stratified relapse-free survival into three levels. CONCLUSIONS By adding a second cutoff value for preoperative serum CEA, which was proposed specifically for the prediction of recurrences, patients can be stratified into low-, intermediate-, and high-risk recurrences after curative resection of gastric cancer.
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Affiliation(s)
- Bin Sato
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan,
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Seiji Ito
- Department of Gastroenterological Surgery, Aichi Cancer Center, Nagoya, Japan
| | | | - Hitoshi Teramoto
- Department of Surgery, Yokkaichi Municipal Hospital, Yokkaichi, Japan
| | | | - Toshifumi Murai
- Department of Surgery, Ichinomiya Municipal Hospital, Ichinomiya, Japan
| | - Takahiro Asada
- Department of Surgery, Gifu Prefectural Tajimi Hospital, Tajimi, Japan
| | | | | | - Koki Nakanishi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Dai Shimizu
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
- Department of Medical Equipment and Supplies Management, Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kenta Murotani
- Biostatistics Center, Graduate School of Medicine, Kurume University, Kurume, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
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Nishimuta Y, Tsurumaru D, Kai S, Maehara J, Asayama Y, Oki E, Ishigami K. Extracellular volume fraction determined by equilibrium contrast-enhanced computed tomography: correlation with histopathological findings in gastric cancer. Jpn J Radiol 2023; 41:752-759. [PMID: 36735208 PMCID: PMC10313564 DOI: 10.1007/s11604-023-01393-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2022] [Accepted: 01/12/2023] [Indexed: 02/04/2023]
Abstract
PURPOSE To assess the relationship between histopathological features of gastric cancer and the extracellular volume fraction (ECV) measured by preoperative equilibrium contrast-enhanced computed tomography (CECT). MATERIALS AND METHODS The study group consisted of 66 patients with surgically resected gastric adenocarcinoma who underwent preoperative multiphasic CECT. Tumor ECVs were calculated using region-of-interest measurements within the gastric cancer and aorta of each case on unenhanced and equilibrium-phase images. The relationship between the mean ECV values and clinicopathological parameters was examined by univariate analysis. Parameters showing a significant difference in the former test were further tested by linear regression and receiver operating characteristic (ROC) curve analyses. RESULTS In the univariate analysis, the values of venous invasion (p = 0.0487) and tumor infiltration (INF) pattern (p < 0.0001) were significantly correlated with the tumor ECV. INF was significantly correlated (β = 0.57, p < 0.0001) in the linear regression analysis. The tumor ECV showed better diagnostic accuracy for predicting INF (INFa/b vs INFc), and the area under the ROC curve value was 0.89. CONCLUSION Tumor ECV determined by equilibrium CECT is significantly correlated with the pathological INF of gastric cancer.
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Affiliation(s)
- Yusuke Nishimuta
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan.
| | - Daisuke Tsurumaru
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Satohiro Kai
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
- Department of Endoscopic Diagnostics and Therapeutics, Kyushu University Hospital, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Junki Maehara
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
- Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Yoshiki Asayama
- Department of Radiology, Faculty of Medicine, Oita University, Yufu City, Oita, 879-5593, Japan
| | - Eiji Oki
- Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
| | - Kousei Ishigami
- Department of Clinical Radiology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan
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Yang H, Sun J, Liu H, Liu X, She Y, Zhang W, Zhou J. Clinico-radiological nomogram for preoperatively predicting post-resection hepatic metastasis in patients with gastric adenocarcinoma. Br J Radiol 2022; 95:20220488. [PMID: 36181505 PMCID: PMC9733617 DOI: 10.1259/bjr.20220488] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Revised: 09/07/2022] [Accepted: 09/09/2022] [Indexed: 11/07/2022] Open
Abstract
OBJECTIVE To establish and validate a model comprising clinical and radiological features to pre-operatively predict post-resection hepatic metastasis (HM) in patients with gastric adenocarcinoma (GAC). METHODS We retrospectively analyzed 461 patients (HM, 106 patients); and non-metastasis (NM, 355 patients) who were confirmed to have GAC post-surgery. The patients were randomly divided into the training (n = 307) and testing (n = 154) cohorts in a 2:1 ratio. The main clinical risk factors were filtered using the least absolute shrinkage and selection operator algorithm according to their diagnostic value. The selected factors were then used to establish a clinical-radiological model using stepwise logistic regression. The Akaike's information criterion and receiver operating characteristic (ROC) analyses were used to evaluate the prediction performance of the model. RESULTS Logistic regression analysis showed that the peak enhancement phase, tumor location, alpha-fetoprotein, cancer antigen (CA)-125, CA724 levels, CT-based Tstage and arterial phase CT values were important independent predictors. Based on these predictors, the areas under the ROC curve of the training and testing cohorts were 0.864 and 0.832, respectively, for predicting post-operative HM. CONCLUSION This study built a synthetical nomogram using the pre-operative clinical and radiological features of patients to predict the likelihood of HM occurring after GAC surgery. It may help guide pre-operative clinical decision-making and benefit patients with GAC in the future. ADVANCES IN KNOWLEDGE 1. The combination of clinical risk factors and CT imaging features provided useful information for predicting HM in GAC.2. A clinicoradiological nomogram is a tool for the pre-operative prediction of HM in patients with GAC.
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Affiliation(s)
| | - Jianqing Sun
- Central Research Institute, United Imaging Healthcare, Shanghai, China
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Huang B, Rouvelas I, Nilsson M. Gastric and gastroesophageal junction cancer: Risk factors and prophylactic treatments for prevention of peritoneal recurrence after curative intent surgery. Ann Gastroenterol Surg 2022; 6:474-485. [PMID: 35847435 PMCID: PMC9271029 DOI: 10.1002/ags3.12565] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2021] [Revised: 02/13/2022] [Accepted: 03/01/2022] [Indexed: 11/08/2022] Open
Abstract
Aim Relapse after curative treatment for advanced gastric cancer, and especially peritoneal recurrence, is very common and has a dismal prognosis. The aim of this review is to summarize existing evidence regarding risk factors and prophylactic treatments intending to prevent peritoneal recurrence. Methods A structured search of relevant studies was conducted in MEDLINE, Embase, and the Cochrane Library. Results The main risk factors identified are advanced pathological T-stage (pT ≥ 3), regional lymph node involvement, diffuse/poorly cohesive type tumor, poorly differentiated cancer, and positive peritoneal wash cytology. Systemic chemotherapy in the perioperative or adjuvant setting improves survival for the patients but despite this peritoneal recurrence remains a common and yet an unsolved clinical problem. Different approaches of intraperitoneal chemotherapy such as hyperthermic intraperitoneal chemotherapy and early postoperative intraperitoneal chemotherapy have shown promising results as prophylactic treatments aiming to prevent peritoneal recurrence. Conclusion Future studies are warranted to find safe and effective treatments to prevent peritoneal recurrence.
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Affiliation(s)
- Biying Huang
- Department of Upper Abdominal DiseasesKarolinska University HospitalStockholmSweden
| | - Ioannis Rouvelas
- Department of Upper Abdominal DiseasesKarolinska University HospitalStockholmSweden
- Division of SurgeryDepartment of Clinical Science, Intervention and Technology (CLINTEC)Karolinska InstitutetStockholmSweden
| | - Magnus Nilsson
- Department of Upper Abdominal DiseasesKarolinska University HospitalStockholmSweden
- Division of SurgeryDepartment of Clinical Science, Intervention and Technology (CLINTEC)Karolinska InstitutetStockholmSweden
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Sugiyama I, Ando K, Sadzuka Y. The Basic Study of Liposome in Temperature-Sensitive Gel at Body Temperature for Treatment of Peritoneal Dissemination. Gels 2022; 8:gels8050252. [PMID: 35621550 PMCID: PMC9141445 DOI: 10.3390/gels8050252] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2022] [Revised: 04/15/2022] [Accepted: 04/18/2022] [Indexed: 12/17/2022] Open
Abstract
Peritoneal dissemination is a disease that is difficult to treat surgically because it is widely scattered and proliferates in the abdominal cavity. It is a challenge that even if the drug is administered directly into the abdominal cavity, it rapidly disappears from the abdominal cavity, and the therapeutic effect is not optimal, as expected. In this study, for a liposomal paclitaxel in temperature-sensitive gel that is a suspension before administration and a gel after intraperitoneal administration, the antitumor effect of this formulation was evaluated. Temperature-sensitive gels were prepared using methylcellulose, sodium citrate, and macrogol 4000 and mixed with liposomal paclitaxel. Liposomal paclitaxel containing temperature-sensitive gel in the body was administered into the peritoneal cavity of a mouse model of peritoneal dissemination; the number of cells was significantly reduced compared to a paclitaxel solution of liposomal paclitaxel. These results showed that the liposome in temperature-sensitive gel inhibited cell proliferation in the abdominal cavity. This formulation can be administered easily at room temperature, and it gels and remains in the abdominal cavity for a long period, resulting in a more substantial effect than the existing drug.
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Affiliation(s)
- Ikumi Sugiyama
- Department of Advanced Pharmaceutics, School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun 0208-3694, Japan;
- Correspondence: ; Tel.: +81-19-651-5111
| | - Kaana Ando
- Pharmaceutical and Health Sciences, Graduate School of Pharmaceutical Science, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun 0208-3694, Japan;
| | - Yasuyuki Sadzuka
- Department of Advanced Pharmaceutics, School of Pharmacy, Iwate Medical University, 1-1-1 Idaidori, Yahaba-cho, Shiwa-gun 0208-3694, Japan;
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Wang YF, Yin X, Fang TY, Wang YM, Zhang L, Zhang XH, Zhang DX, Zhang Y, Wang XB, Wang H, Xue YW. Prognostic significance of serum inflammation indices for different tumor infiltrative pattern types of gastric cancer. World J Gastrointest Oncol 2022; 14:897-919. [PMID: 35582101 PMCID: PMC9048526 DOI: 10.4251/wjgo.v14.i4.897] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2021] [Revised: 10/08/2021] [Accepted: 02/23/2022] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Inflammatory indices are considered to be potential prognostic biomarkers for patients with gastric cancer (GC). However, there is no evidence defining the prognostic significance of inflammatory indices for GC with different tumor infiltrative pattern (INF) types.
AIM To evaluate the significance of inflammatory indices and INF types in predicting the prognosis of patients with GC.
METHODS A total of 962 patients who underwent radical gastrectomy were retrospectively selected for this study. Patients were categorized into the expansive growth type (INFa), the intermediate type (INFb), and the infiltrative growth type (INFc) groups. The cutoff values of inflammatory indices were analyzed by receiver operating characteristic curves. The Kaplan–Meier method and log-rank test were used to analyze overall survival (OS). The chi-square test was used to analyze the association between inflammatory indices and clinical characteristics. The independent risk factors for prognosis in each group were analyzed by univariate and multivariate analyses based on logistic regression. Nomogram models were constructed by R studio.
RESULTS The INFc group had the worst OS (P < 0.001). The systemic immune-inflammation index (P = 0.039) and metastatic lymph node ratio (mLNR) (P = 0.003) were independent risk factors for prognosis in the INFa group. The platelet-lymphocyte ratio (PLR) (P = 0.018), age (P = 0.026), body mass index (P = 0.003), and postsurgical tumor node metastasis (pTNM) stage (P < 0.001) were independent risk factors for prognosis in the INFb group. The PLR (P = 0.021), pTNM stage (P = 0.028), age (P = 0.021), and mLNR (P = 0.002) were independent risk factors for prognosis in the INFc group. The area under the curve of the nomogram model for predicting 5-year survival in the INFa group, INFb group, and INFc group was 0.787, 0.823, and 0.781, respectively.
CONCLUSION The outcome of different INF types GC patients could be assessed by nomograms based on different inflammatory indices and clinicopathologic features.
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Affiliation(s)
- Yu-Fei Wang
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Xin Yin
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Tian-Yi Fang
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Yi-Min Wang
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Lei Zhang
- Department of Pathology, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Xing-Hai Zhang
- Department of Pathology, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Dao-Xu Zhang
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Yao Zhang
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Xi-Bo Wang
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Hao Wang
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
| | - Ying-Wei Xue
- Department of Gastroenterological Surgery, Harbin Medical University Cancer Hospital, Harbin 150081, Heilongjiang Province, China
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Xiang L, Jin S, Zheng P, Maswikiti EP, Yu Y, Gao L, Zhang J, Zhang Y, Chen H. Risk Assessment and Preventive Treatment for Peritoneal Recurrence Following Radical Resection for Gastric Cancer. Front Oncol 2022; 11:778152. [PMID: 35047394 PMCID: PMC8763009 DOI: 10.3389/fonc.2021.778152] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2021] [Accepted: 11/29/2021] [Indexed: 02/03/2023] Open
Abstract
As the most common recurrence pattern after radical gastric cancer resection, peritoneal recurrence is a major cause of mortality, which affects the prognosis of patients to a very large extent. Peritoneal status and risk of peritoneal recurrence can be evaluated by peritoneal lavage cytology, photodynamic diagnosis, imaging examination, and pathologic analysis. Presently, there is no standard approach for preventing peritoneal recurrence after radical surgery; furthermore, controversies exist regarding the effects of some preventive methods. Among the preventive methods, there are high expectations about the potential of preoperative therapy, surgical skill improvement, hyperthermic intraperitoneal chemotherapy, and postoperative treatment to reduce the incidence of peritoneal recurrence after radical gastrectomy. This study aimed to analyze the results of previous studies on the risk assessment and preventive methods of peritoneal recurrence after radical gastrectomy in recent years. We hope to provide references for better approach to clinical diagnosis and treatment strategies for peritoneal recurrence after radical gastrectomy.
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Affiliation(s)
- Lin Xiang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of Pathology, Lanzhou University Second Hospital, Lanzhou, China
| | - Shuai Jin
- Department of Technology, Beijing Weitai’an Pharmaceutical Ltd, Beijing, China
| | - Peng Zheng
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | | | - Yang Yu
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Lei Gao
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Jing Zhang
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
| | - Ying Zhang
- Department of Laboratory Medicine, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Hao Chen
- The Second Clinical Medical College, Lanzhou University, Lanzhou, China
- Department of Tumor Surgery, Lanzhou University Second Hospital, Lanzhou, China
- The Key Laboratory of the Digestive System Tumors of Gansu Province, Lanzhou University Second Hospital, Lanzhou, China
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Lelisho ME, Seid AA, Pandey D. A Case Study on Modeling the Time to Recurrence of Gastric Cancer Patients. J Gastrointest Cancer 2021; 53:218-228. [PMID: 34379265 DOI: 10.1007/s12029-021-00684-0] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/30/2021] [Indexed: 12/12/2022]
Abstract
BACKGROUND Gastric cancer is a malignant tumor of the stomach and it is one of the leading causes of death worldwide. The study aimed to model the time to first recurrence of gastric cancer patients at the Tikur Anbesa specialized hospital. METHODS The data for this study were gastric cancer patients followed up from January 1, 2013 to February 29, 2020 at Tikur Anbesa Specialized Hospital, Oncology Center, Addis Ababa. We used Weibull, log-logistic and lognormal as baseline hazard functions with the gamma and the inverse Gaussian frailty distributions. Data analyzed with the statistical software R. RESULTS The median recurrence time of the patients was about 23.96 months with a maximum recurrence time of 60.81 months, of which about 61.2% had first recurrences of gastric cancer. The clustering effect is significant in modeling the time to recurrence of gastric cancer. According to the result of the log-logistic inverse Gaussian frailty model, the sex of the patient, the tumor size, smoking habit, the treatment carried out, the vascular invasion, the stage of the disease, the helicobacter pylori infection and the histological type were the significant prognostic factors at 5% level of significance. CONCLUSION Inverse Gaussian frailty model is the model that best describes the time to recurrence of the gastric cancer data set. Gender of the patients, tumor size, treatment taken, vascular invasion, disease stage, helicobacter pylori infection and histological type were the determining prognostic factors. This requires measures to improve patient health and prevent relapse based on significant risk factors, and particular attention should be paid to patients with such factors.
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Affiliation(s)
- Mesfin Esayas Lelisho
- Department of Statistics, College of Natural Science and Computational, Mizan Tepi University, Tepi, Ethiopia
| | - Adem Aregaw Seid
- Department of Statistics, College of Natural Science and Computational, Mizan Tepi University, Tepi, Ethiopia
| | - Digvijay Pandey
- Department of Technical Education, IET, Dr. A.P.J.Abdul Kalam Technical University Uttar Pradesh, Lucknow, 226021, India.
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Lu Y, Cheng J, Cai W, Zhuo H, Wu G, Cai J. Inhibition of circRNA circVPS33B Reduces Warburg Effect and Tumor Growth Through Regulating the miR-873-5p/HNRNPK Axis in Infiltrative Gastric Cancer. Onco Targets Ther 2021; 14:3095-3108. [PMID: 34012268 PMCID: PMC8126971 DOI: 10.2147/ott.s292575] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2020] [Accepted: 04/02/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Circular RNA VPS33B (circVPS33B) has been revealed to be upregulated in gastric cancer (GC) tissues. However, the role of circVPS33B in infiltrative GC is indistinct. METHODS Expression of circVPS33B was detected using quantitative real-time polymerase chain reaction (qRT-PCR). The proliferation, migration, and invasion of infiltrative GC cells (XGC-1) were determined by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazoliumbromide (MTT), plate clone, wound-healing, or transwell assays. Protein levels were detected by Western blotting. Measurements of extracellular acidification rate (ECAR) and oxygen consumption rate (OCR) were executed using an XF96 extracellular flux analyzer. Glucose uptake and lactate production were analyzed by glycolysis assay. The regulatory mechanism of circVPS33B had been explored by bioinformatics analysis, dual-luciferase reporter assay, and/or RNA pull-down assay. In vivo tumorigenesis assay was executed to verify the oncogenicity of circVPS33B. RESULTS CircVPS33B was upregulated in infiltrative GC tissues and cells. CircVPS33B silencing decreased tumor growth in vivo and inhibited proliferation, migration, invasion, EMT, and Warburg effect of infiltrative GC cells in vitro. Mechanically, circVPS33B regulated heterogeneous nuclear ribonucleoprotein K (HNRNPK) expression via sponging miR-873-5p. Furthermore, miR-873-5p inhibitor offset circVPS33B knockdown-mediated effects on malignant behaviors and Warburg effect of infiltrative GC cells. HNRNPK overexpression reversed the inhibitory impact of miR-873-5p mimic on malignant behaviors and Warburg effect of infiltrative GC cells. CONCLUSION CircVPS33B accelerated Warburg effect and tumor growth through regulating the miR-873-5p/HNRNPK axis in infiltrative GC, manifesting that circVPS33B might be a potential target for infiltrative GC treatment.
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Affiliation(s)
- Yizhuo Lu
- Department of General Surgery, Zhongshan Hospital Xiamen University, Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, Fujian, 361004, People’s Republic of China
| | - Jia Cheng
- Department of Gastrointestinal Surgery, Zhongshan Hospital Xiamen University, Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, Fujian, 361004, People’s Republic of China
| | - Wangyu Cai
- Department of Gastrointestinal Surgery, Zhongshan Hospital Xiamen University, Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, Fujian, 361004, People’s Republic of China
| | - Huiqin Zhuo
- Department of Gastrointestinal Surgery, Zhongshan Hospital Xiamen University, Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, Fujian, 361004, People’s Republic of China
| | - Guoyang Wu
- Department of General Surgery, Zhongshan Hospital Xiamen University, Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, Fujian, 361004, People’s Republic of China
| | - Jianchun Cai
- Department of Gastrointestinal Surgery, Zhongshan Hospital Xiamen University, Institute of Gastrointestinal Oncology, School of Medicine, Xiamen University, Xiamen Municipal Key Laboratory of Gastrointestinal Oncology, Xiamen, Fujian, 361004, People’s Republic of China
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12
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Wei XL, Xu JY, Wang DS, Chen DL, Ren C, Li JN, Wang F, Wang FH, Xu RH. Baseline lesion number as an efficacy predictive and independent prognostic factor and its joint utility with TMB for PD-1 inhibitor treatment in advanced gastric cancer. Ther Adv Med Oncol 2021; 13:1758835921988996. [PMID: 33613701 PMCID: PMC7871293 DOI: 10.1177/1758835921988996] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2020] [Accepted: 12/22/2020] [Indexed: 12/20/2022] Open
Abstract
Background We previously reported tumor mutation burden (TMB) as a potential prognostic factor for patients with advanced gastric cancer (AGC) receiving immunotherapy. We aimed to comprehensively understand the impact of tumor burden and TMB on efficacy and prognosis in immunotherapy-treated AGC patients. Methods A total of 58 patients with refractory AGC receiving PD-1 inhibitor monotherapy from a phase Ib/II clinical trial (ClinicalTrials.gov identifier: NCT02915432) were retrospectively included. Univariate and multivariate logistical regression analyses and the Cox proportional hazards model were performed for prognostic value of baseline factors. Factors reflecting baseline tumor burden, including baseline lesion number (BLN), the maximum tumor size (MTS) and the sum of target lesion size (SLS) were analyzed. The objective response rate (ORR) and disease control rate (DCR) were compared by Chi-square test. Results In univariate analysis, high BLN was associated with poor median progression-free survival (mPFS) [1.7 months versus 3.4 months; hazard ratio (HR), 2.696, p < 0.05] and median overall survival (mOS) (3.2 months versus 7.6 months; HR, 1.997, p < 0.05), while high TMB was a positive prognostic factor. In multivariable analysis, both BLN and TMB were independent prognostic factors for mOS (BLN: HR, 2.782, p < 0.05; TMB: HR, 0.288, p < 0.05), while MTS or SLS had no association with survival. Better ORR and DCR were observed in the low BLN group (15.4% versus 5.3%, p > 0.05; 86.96% versus 54.29%, p < 0.05). When combining BLN and TMB, the best efficacy and survival were observed in the BLNlowTMBhigh group (ORR: 37.5%, DCR: 62.5%, mPFS and mOS: not reached). The worst efficacy and survival were shown in the BNLhighTMBlow group [ORR: 0% (0/15); DCR: 13.3%; mPFS: 1.7 months; mOS: 2.7 months (all p < 0.05)]. Conclusions BLN, rather than factors regarding baseline tumor size, is perhaps a potential predictor for benefit from immunotherapy and its combination with TMB could further risk-stratify patients with AGC receiving immunotherapy.
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Affiliation(s)
- Xiao-Li Wei
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jian-Ying Xu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - De-Shen Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Dong-Liang Chen
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Chao Ren
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Jia-Ning Li
- Department of Clinical Trial Center, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangzhou, China
| | - Feng Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou, Guangdong Province 510060, China
| | - Feng-Hua Wang
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou, Guangdong Province 510060, China
| | - Rui-Hua Xu
- Department of Medical Oncology, Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, 651 Dong Feng Road East, Guangzhou, Guangdong Province 510060, China
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13
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Development and validation of a CT-based radiomic nomogram for preoperative prediction of early recurrence in advanced gastric cancer. Radiother Oncol 2020; 145:13-20. [DOI: 10.1016/j.radonc.2019.11.023] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2019] [Revised: 11/21/2019] [Accepted: 11/23/2019] [Indexed: 02/07/2023]
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14
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Tumor infiltrative growth pattern correlates with the immune microenvironment and is an independent factor for lymph node metastasis and prognosis in stage T1 esophageal squamous cell carcinoma. Virchows Arch 2020; 477:401-408. [PMID: 32232560 DOI: 10.1007/s00428-020-02801-z] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/27/2020] [Revised: 03/12/2020] [Accepted: 03/18/2020] [Indexed: 12/17/2022]
Abstract
In this retrospective study, we analyzed the association between the tumor infiltrative growth pattern (INF) and tumor immune environment and its predictive value for lymph node metastasis and overall survival (OS) in stage T1 esophageal squamous cell carcinoma (ESCC). In total, 593 patients with a diagnosis of stage T1 ESCC who underwent esophagectomy and regional lymphadenectomy between 2009 and 2018 were included. The INF type and elements of the tumor immune microenvironment, including tumor infiltrative lymphocytes (TILs) and tertiary lymphoid structures (TLSs), were microscopically evaluated within the tumor invasive margin with hematoxylin and eosin (HE)-stained slices. The infiltrative-type INF (INFc) was associated with low-grade TILs and the absence of TLSs, deep tumor invasion, poorly differentiated phenotype. Multivariate logistic regression identified INFc as one of the independent risk factors for lymph node metastasis. INFc and low-grade TILs were independent inferior predictive factors for OS. A novel histologic risk stratification model was classified as INFa/b and high-grade TILs, INFa/b and low-grade TILs, INFc and high-grade TILs, and INFc and low-grade TILs. The Kaplan-Meier curves showed that INFa/b and high-grade TILs were associated with the best prognosis, and INFc and low-grade TILs were associated with the worst prognosis, and there was significant difference between groups. In conclusion, INFc is an independent risk factor for lymph node metastasis and an independent inferior prognostic factor for stage T1 ESCC. Furthermore, INFc is associated with immunosuppression, and the combination of the INF and TILs is useful for the risk stratification of prognosis.
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15
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Zhao B, Huang X, Zhang J, Luo R, Lu H, Xu H, Huang B. Clinicopathologic factors associated with recurrence and long-term survival in node-negative advanced gastric cancer patients. REVISTA ESPANOLA DE ENFERMEDADES DIGESTIVAS 2020; 111:111-120. [PMID: 30404528 DOI: 10.17235/reed.2018.5829/2018] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
Abstract
BACKGROUND despite a better prognosis in node-negative advanced gastric cancer (GC), a proportion of patients have a tumor recurrence within five years and eventually die due to cancer-related causes. The present study aimed to evaluate the predictive factors of tumor recurrence and long-term survival in node-negative advanced GC. METHODS a total of 646 node-negative advanced GC patients who underwent a curative gastrectomy in our institution were included in the study. The impact of different clinicopathologic factors on tumor recurrence and overall survival were analyzed. RESULTS tumor recurrences were observed in 181 patients and the cumulative recurrence rate at two-years and five-years were 50.8% and 86.2%, respectively. Lymphovascular invasion, advanced T stage (T3-T4) and an inadequate number of retrieved lymph nodes (LNs) were independent predictive factors of tumor recurrence in node-negative advanced GC. Older age, an upper 1/3 tumor, lymphovascular invasion, infiltration growth pattern (INFγ) and the depth of tumor invasion (T4 stage) were independently associated with long-term survival. With regard to node-negative patients with ≥ 15 retrieved LNs, infiltration growth pattern (INFγ) and advanced T stage (T3-T4) were independent risk factors for both tumor recurrence and long-term survival. CONCLUSION in addition to lymphovascular invasion, inadequate RLNs and advanced T stage, the prognostic significance of infiltration growth pattern in node-negative advanced GC was especially emphasized. These risk factors should be considered when selecting candidates for adjuvant chemotherapy and postoperative surveillance.
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Affiliation(s)
- Bochao Zhao
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, China
| | - Xinyu Huang
- Department of Clinical Medicine of year 2013, Liaoning University of Traditional Chinese Medicine
| | - Jiale Zhang
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, China
| | - Rui Luo
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, China
| | - Huiwen Lu
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, China
| | - Huimian Xu
- Department of Surgical Oncology, First Affiliated Hospital of China Medical University, China
| | - Baojun Huang
- Department of Surgical Oncology, Affiliated Hospital of China Medical University, China
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16
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Fujita K, Kanda M, Ito S, Mochizuki Y, Teramoto H, Ishigure K, Murai T, Asada T, Ishiyama A, Matsushita H, Tanaka C, Kobayashi D, Fujiwara M, Murotani K, Kodera Y. Association between Lymphovascular Invasion and Recurrence in Patients with pT1N+ or pT2–3N0 Gastric Cancer: a Multi-institutional Dataset Analysis. J Gastric Cancer 2020; 20:41-49. [PMID: 32269843 PMCID: PMC7105418 DOI: 10.5230/jgc.2020.20.e3] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/18/2019] [Revised: 11/19/2019] [Accepted: 12/16/2019] [Indexed: 11/20/2022] Open
Abstract
Purpose Patients with pathological stage T1N+ or T2–3N0 gastric cancer may experience disease recurrence following curative gastrectomy. However, the current Japanese Gastric Cancer Treatment Guidelines do not recommend postoperative adjuvant chemotherapy for such patients. This study aimed to identify the prognostic factors for patients with pT1N+ or pT2–3N0 gastric cancer using a multi-institutional dataset. Materials and Methods We retrospectively analyzed the data obtained from 401 patients with pT1N+ or pT2–3N0 gastric cancer who underwent curative gastrectomy at 9 institutions between 2010 and 2014. Results Of the 401 patients assessed, 24 (6.0%) experienced postoperative disease recurrence. Multivariate analysis revealed that age ≥70 years (hazard ratio [HR], 2.62; 95% confidence interval [CI], 1.09–7.23; P=0.030) and lymphatic and/or venous invasion (lymphovascular invasion (LVI): HR, 7.88; 95% CI, 1.66–140.9; P=0.005) were independent prognostic factors for poor recurrence-free survival. There was no significant association between LVI and the site of initial recurrence. Conclusions LVI is an indicator of poor prognosis in patients with pT1N+ or pT2–3N0 gastric cancer.
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Affiliation(s)
- Keizo Fujita
- Department of Surgery, Ichinomiya Municipal Hospital, Ichinomiya, Japan
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Seiji Ito
- Department of Gastroenterological Surgery, Aichi Cancer Center, Nagoya, Japan
| | | | - Hitoshi Teramoto
- Department of Surgery, Yokkaichi Municipal Hospital, Yokkaichi, Japan
| | | | - Toshifumi Murai
- Department of Surgery, Ichinomiya Municipal Hospital, Ichinomiya, Japan
| | - Takahiro Asada
- Department of Surgery, Gifu Prefectural Tajimi Hospital, Tajimi, Japan
| | | | | | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Daisuke Kobayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kenta Murotani
- Biostatistics Center, Graduate School of Medicine, Kurume University, Kurume, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
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Tsutsuyama M, Kanda M, Ito S, Mochizuki Y, Teramoto H, Ishigure K, Murai T, Asada T, Ishiyama A, Matsushita H, Tanaka C, Kobayashi D, Fujiwara M, Murotani K, Kodera Y. Tumor size ≥50 mm as an Independent Prognostic Factor for Patients with Stage II or III Gastric Cancer After Postoperative S-1 Monotherapy: Analysis of a Multi-institution Dataset. World J Surg 2019; 44:194-201. [PMID: 31552460 DOI: 10.1007/s00268-019-05198-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Little is known about the changes in prognostic factors after adjuvant S-1 monotherapy has become widespread as a standard of care for patients with gastric cancer (GC) in East Asia. The present study compared prognostic factors of patients with stage II/III GC treated with or without S-1 adjuvant to formulate appropriate risk stratification strategies. METHODS We designed a large multicenter dataset and retrospectively analyzed 847 patients with GC stage II or III, who underwent curative gastrectomy between 2010 and 2014. Clinicopathological features and prognostic factors were compared between the two patient groups: surgery-alone (n = 266) and S-1 adjuvant (n = 581). RESULTS There were no significant differences in pathological tumor depths, nodal status, and disease stages between groups. Recurrence-free survival was significantly longer in the S-1 adjuvant group. For the surgery-alone group, independent prognostic factors were (in order of hazard ratio): (1) invasive growth, (2) high preoperative carcinoembryonic antigen levels, (3) total gastrectomy. For the S-1 adjuvant group, macroscopic tumor size (≥50 mm) was identified as another independent prognostic factor next only to pN2/3. There was overlap between the survival curves of patients with tumor size ≥50 mm in both groups. After receiving adjuvant S-1 monotherapy, ≥50 mm patients had significantly higher prevalence of peritoneal and lymph node metastasis as initial recurrences compared with <50 mm patients. CONCLUSIONS Adjuvant S-1 monotherapy may alter listing of adverse prognostic factors of stage II and III patients. Macroscopic tumor size ≥50 mm may serve as an important determinant for risk stratification to identify patients who require more intensive treatment.
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Affiliation(s)
- Masayuki Tsutsuyama
- Department of Gastroenterological Surgery, Aichi Cancer Center, Nagoya, Japan
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Seiji Ito
- Department of Gastroenterological Surgery, Aichi Cancer Center, Nagoya, Japan
| | | | - Hitoshi Teramoto
- Department of Surgery, Yokkaichi Municipal Hospital, Yokkaichi, Japan
| | | | - Toshifumi Murai
- Department of Surgery, Ichinomiya Municipal Hospital, Ichinomiya, Japan
| | - Takahiro Asada
- Department of Surgery, Gifu Prefectural Tajimi Hospital, Tajimi, Japan
| | | | | | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Daisuke Kobayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Kenta Murotani
- Biostatistics Center, Graduate School of Medicine, Kurume University, Kurume, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
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18
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Iizuka A, Kanda M, Ito S, Mochizuki Y, Teramoto H, Ishigure K, Murai T, Asada T, Ishiyama A, Matsushita H, Tanaka C, Kobayashi D, Fujiwara M, Murotani K, Kodera Y. Proposal of a Scoring Scale to Estimate Risk of the Discontinuation of S-1 Adjuvant Monotherapy in Patients with Stage II to III Gastric Cancer: A Multi-Institutional Dataset Analysis. World J Surg 2019; 43:2016-2024. [PMID: 30737551 DOI: 10.1007/s00268-019-04942-y] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Discontinuation of postoperative S-1 adjuvant monotherapy is a frequent problem in the management of patients with gastric cancer. METHODS A total of 355 stage II/III gastric cancer patients who underwent gastrectomy and adjuvant S-1 were retrospectively analyzed using a multicenter dataset. We randomly assigned patients into either discovery or validation cohort in a 2:1 ratio. In the discovery cohort, 29 parameters were assessed as candidate factors to predict discontinuation of S-1 adjuvant within 6 months. A scoring system was designed using independent risk factors identified by the multivariate analysis. Reproducibility was tested in the validation cohort. RESULTS Overall, 92 patients (25.9%) discontinued the treatment within 6 months because of adverse effects. Age, preoperative urea nitrogen (UN) and the preoperative albumin-to-bilirubin index (ALBI) showed the highest area under the curve (AUC) for the discontinuation of S-1 adjuvant within 6 months in each category: body status, blood tests and indices. In the multivariate analysis, age ≥ 64 years, preoperative UN ≥ 15.2 mg/dl and preoperative ALBI ≥ -0.265 were identified as independent risk factors. A scoring scale consisting of these three factors was developed for the prediction of drug discontinuation and demonstrated a greater AUC (0.728) than that of each of the three constituents. The time to treatment discontinuation decreased incrementally as the risk score increased. The reproducible findings were confirmed in the validation cohort. CONCLUSIONS We identified risk factors and developed a scoring scale to predict S-1 adjuvant monotherapy discontinuation in patients with stage II/III gastric cancer.
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Affiliation(s)
- Akimitsu Iizuka
- Department of Surgery, Okazaki City Hospital, Okazaki, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Seiji Ito
- Department of Gastroenterological Surgery, Aichi Cancer Center, Nagoya, Japan
| | | | - Hitoshi Teramoto
- Department of Surgery, Yokkaichi Municipal Hospital, Yokkaichi, Japan
| | | | - Toshifumi Murai
- Department of Surgery, Ichinomiya Municipal Hospital, Ichinomiya, Japan
| | - Takahiro Asada
- Department of Surgery, Gifu Prefectural Tajimi Hospital, Tajimi, Japan
| | | | | | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Daisuke Kobayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Kenta Murotani
- Biostatistics Center, Graduate School of Medicine, Kurume University, Kurume, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
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Jung YJ, Seo HS, Kim JH, Park CH, Lee HH. The Relevance of Serosal Exposure Without Nodal Metastasis in Resectional Gastric Cancer. Ann Surg Oncol 2019; 26:1772-1778. [PMID: 30767177 DOI: 10.1245/s10434-019-07221-1] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2018] [Indexed: 01/02/2023]
Abstract
BACKGROUND According to 8th AJCC/UICC TNM criteria, stage IIB includes pT1N3M0, pT2N2M0, pT3N1M0, and pT4aN0M0, which includes not only early gastric cancer but also locally advanced cancer. There are currently no data about whether there is any additional impact of serosal exposed cancer without nodal metastasis (pT4aN0) on patients' survival outcomes compared with other subgroups in IIB. METHODS Patients who underwent radical gastrectomy for gastric cancer patients were enrolled, including 427 patients in stage IIB; 20 (4.68%), 104 (24.35%), 172 (40.28%), and 131 (30.67%) patients were classified as pT1N3a, pT2N2, pT3N1, and pT4aN0, respectively. Clinicopathological characteristics, recurrence pattern, and survival and recurrence rates were analyzed according to the TNM subgroups. RESULTS Cancer-specific and relapse-free survival were significantly worse in serosal exposed cancer than in nonserosal exposed cancer in stage IIB (P = 0.019 and P = 0.015). Recurrence rate was highest in the pT4aN0 subgroup (29.0%) in stage IIB, and peritoneal metastasis was the most common pattern. Survival outcomes of the pT4aN0 subgroup were not significantly different from those of the stage IIIA or pT4aN1 subgroups. CONCLUSIONS Patients with serosal exposed cancer without nodal metastasis shows worse cancer specific and disease-free survival with higher incidence of peritoneal metastasis than other subgroups in stage IIB. Further surveillance studies, including staging laparoscopy and active adjuvant therapy, are required in this subgroup of patients.
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Affiliation(s)
- Yoon Ju Jung
- Division of Gastrointestinal Surgery, Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ho Seok Seo
- Division of Gastrointestinal Surgery, Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Ji Hyun Kim
- Division of Gastrointestinal Surgery, Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Cho Hyun Park
- Division of Gastrointestinal Surgery, Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea
| | - Han Hong Lee
- Division of Gastrointestinal Surgery, Department of Surgery, Seoul St. Mary's Hospital, College of Medicine, The Catholic University of Korea, Seoul, Korea. .,Catholic Cancer Research Institute, College of Medicine, The Catholic University of Korea, Seoul, Korea.
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Zhao B, Zhang J, Mei D, Huang X, Zou S, Luo R, Xu H, Huang B. Prognostic significance of tumour infiltration growth pattern in patients with advanced gastric cancer. J Clin Pathol 2018; 72:165-171. [DOI: 10.1136/jclinpath-2018-205403] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2018] [Revised: 10/29/2018] [Accepted: 11/03/2018] [Indexed: 11/03/2022]
Abstract
AimsThe prognostic significance of infiltration growth pattern (INF) in patients with gastric cancer (GC) remains controversial. In the present study, we evaluated the impact of INF pattern on the prognosis of patients with advanced GC.MethodsA total of 1455 patients with advanced GC who underwent curative gastrectomy in our institution were retrospectively analysed. All patients were histopathologically classified as INFa/b and INFc pattern according to the Japanese Classification of Gastric Cancer. The prognostic difference between two patterns was compared and clinicopathological features were analysed.ResultsThe prognosis of the patients with INFc pattern was poorer than that of those with INFa/b pattern (5-year disease-free survival, INFa/b: 48.4% vs INFc: 33.5%, p < 0.001), even when they were stratified according to lymph node metastasis and the tumour, node, metastases stage. In addition, the subgroup analysis indicated that INFc pattern was significantly associated with poorer prognosis of T2–T3 stage patients (T2, INFa/b: 72.7% vs INFc: 55.4%; T3, INFa/b: 47.4% vs INFc: 33.5%; p<0.001). However, a similar result was not observed among T4a stage patients (INFa/b: 26.8% vs INFc: 24.8%, p>0.05). The prognosis of T2 stage patients with INFc pattern was similar to that of T3 stage patients with INFa/b pattern (p>0.05). Also, there was no significantly prognostic difference between T3 stage patients with INFc pattern and T4a stage patients (p>0.05). The multivariate analysis indicated that INF pattern was an independent prognostic factor for patients with advanced GC (HR 1.259, 95%CI 1.089 to 1.454).ConclusionIn view of its prognostic significance, histopathological evaluation of INF pattern in surgically resected specimens should be recommended in patients with advanced GC.
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Significance of Preoperative Systemic Inflammation Score in Short-Term and Long-Term Outcomes of Patients with Pathological T2-4 Gastric Cancer After Radical Gastrectomy. World J Surg 2018; 42:3277-3285. [PMID: 29560531 DOI: 10.1007/s00268-018-4597-7] [Citation(s) in RCA: 26] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
BACKGROUND Surgical resection is the mainstay of treatment for patients with gastric cancer (GC). Development of a simple, high-performance, integrated scoring system is needed to provide appropriate management. This study aimed to evaluate predictive values of the systemic inflammation score (SIS) for short- and long-term outcomes of patients who underwent surgery for GC. METHODS A total of 187 patients who underwent gastrectomy for pT2-4 GC without preoperative treatment were analyzed. SIS was formulated based on serum albumin level and lymphocyte-monocyte ratio, and graded into SIS 0, 1, and 2. RESULTS Preoperative SIS was significantly associated with incidence of postoperative complications, showing a stepwise increased incidence in proportion to SIS in the entire cohort and all subgroups according to operative procedure and disease stage. Overall and disease-free survival times of patients in SIS 0, 1, and 2 shortened in a stepwise fashion. SIS was linked to prevalence of hematogenous metastasis as initial recurrence site. Survival differences between patients with SIS 2 and the others were particularly large in patients who underwent adjuvant chemotherapy. The continuation rate of adjuvant S-1 was lower in the SIS 2 group. CONCLUSION SIS represents a simple predictor for incidence of postoperative complications and survival in patients with pT2-4 GC.
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Nakagawa N, Kanda M, Ito S, Mochizuki Y, Teramoto H, Ishigure K, Murai T, Asada T, Ishiyama A, Matsushita H, Tanaka C, Kobayashi D, Fujiwara M, Murotani K, Kodera Y. Pathological tumor infiltrative pattern and sites of initial recurrence in stage II/III gastric cancer: Propensity score matching analysis of a multi-institutional dataset. Cancer Med 2018; 7:6020-6029. [PMID: 30411544 PMCID: PMC6308072 DOI: 10.1002/cam4.1868] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2018] [Revised: 09/27/2018] [Accepted: 10/22/2018] [Indexed: 12/23/2022] Open
Abstract
Background Advanced gastric cancer frequently recurs even after radical resection followed by adjuvant chemotherapy. The aim of this study was to evaluate the relationship between pathological infiltrative pattern (INF) and initial recurrence patterns in patients with stage II/III gastric cancer using a large multicenter database. Methods We retrospectively analyzed 1098 eligible patients who underwent curative gastrectomy for stage II/III gastric cancer at nine institutions between 2010 and 2014. Patients were categorized into the INF‐a/b and INF‐c groups and adjusted using propensity score matching. Results After propensity score matching, 686 patients (343 for each) were classified in the INF‐a/b and INF‐c groups. There were no significant differences in overall and disease‐free survival between the two groups. In the INF‐a/b group, frequencies of recurrence at the peritoneum, lymph node, and liver were equivalent. In contrast, the peritoneum was the most frequent site and accounted for 60% of the total recurrences in the INF‐c group. The cumulative peritoneal recurrence rate was significantly higher in the INF‐c group than in the INF‐a/b group (hazard ratio 2.47). INF‐c was a significant risk factor for peritoneal recurrences in most subgroups including age, sex, macroscopic type, tumor differentiation, and disease stage, and whether the postoperative treatment was given. Multivariate analysis identified INF‐c as an independent risk factor for peritoneal recurrences. The cumulative liver recurrence rate was significantly higher in the INF‐a/b group than in the INF‐c group (hazard ratio 3.44). Conclusions INF may represent an important predictor of recurrence patterns after curative resection of stage II/III gastric cancer.
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Affiliation(s)
- Nobuhiko Nakagawa
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Seiji Ito
- Department of Gastroenterological Surgery, Aichi Cancer Center, Nagoya, Japan
| | | | - Hitoshi Teramoto
- Department of Surgery, Yokkaichi Municipal Hospital, Yokkaichi, Japan
| | | | - Toshifumi Murai
- Department of Surgery, Ichinomiya Municipal Hospital, Ichinomiya, Japan
| | - Takahiro Asada
- Department of Surgery, Gifu Prefectural Tajimi Hospital, Tajimi, Japan
| | | | | | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Daisuke Kobayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kenta Murotani
- Biostatistics Center, Graduate School of Medicine, Kurume University, Kurume, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
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Kanda M, Tanaka C, Kobayashi D, Uda H, Inaoka K, Tanaka Y, Hayashi M, Iwata N, Yamada S, Fujii T, Sugimoto H, Murotani K, Fujiwara M, Kodera Y. Preoperative Albumin-Bilirubin Grade Predicts Recurrences After Radical Gastrectomy in Patients with pT2-4 Gastric Cancer. World J Surg 2018; 42:773-781. [PMID: 28920160 DOI: 10.1007/s00268-017-4234-x] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
BACKGROUND The albumin-bilirubin (ALBI) score was initially developed for assessing liver dysfunction severity and was suggested to have prognostic value in patients with hepatocellular carcinoma. We aimed to evaluate the prognostic impact of ALBI grade in patients with advanced gastric cancer (GC) after radical gastrectomy. METHODS This study included 283 patients who underwent radical gastrectomy for pT2-4 GC without preoperative treatment. ALBI was calculated as follows: (log10 bilirubin (μmol/L) × 0.66) + (albumin (g/L) × -0.0852) and categorized into grades 1 (≤-2.60), 2 (-2.60<, ≤-1.39) and 3 (-1.39<). RESULTS The median ALBI score was -2.96, and a number of patients in ALBI grades 1, 2 and 3 were 228, 55 and 0, respectively. Patients with ALBI grade 2 had a lower administration rate of adjuvant chemotherapy than those with ALBI grade 1, whereas no significant differences were found in morbidity rate and disease stage. The ALBI grade 2 group was more likely to have shorter disease-specific and disease-free survival compared with the ALBI grade 1 group. Multivariable analysis identified ALBI grade 2 as an independent prognostic factor for disease-free survival (hazard ratio 1.97, 95% confidence interval 1.10-3.47, p = 0.0242). Survival differences between ALBI grade 1 and 2 groups were increased in the patient subset that received adjuvant chemotherapy. ALBI grade 2 was correlated with a shortened duration of administration of postoperative S-1 adjuvant. CONCLUSIONS ALBI grade serves as a simple and promising predictive factor for disease-free and disease-specific survival in patients with pT2-4 GC after radical gastrectomy.
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Affiliation(s)
- Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
| | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Daisuke Kobayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Hiroaki Uda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Kenichi Inaoka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Yuri Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Naoki Iwata
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Tsutomu Fujii
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Hiroyuki Sugimoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Kenta Murotani
- Center for Clinical Research, Aichi Medical University, 1-1 Yazakokarimata, Nagakute, 4801195, Japan
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
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24
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Tanaka H, Kanda M, Miwa T, Tanaka C, Kobayashi D, Umeda S, Shibata M, Suenaga M, Hattori N, Hayashi M, Iwata N, Yamada S, Nakayama G, Fujiwara M, Kodera Y. Pattern-Specific Transcriptomics Identifies ASGR2 as a Predictor of Hematogenous Recurrence of Gastric Cancer. Mol Cancer Res 2018; 16:1420-1429. [DOI: 10.1158/1541-7786.mcr-17-0467] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2017] [Revised: 12/14/2017] [Accepted: 04/30/2018] [Indexed: 11/16/2022]
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Tanaka Y, Kanda M, Tanaka C, Kobayashi D, Mizuno A, Iwata N, Hayashi M, Niwa Y, Takami H, Yamada S, Fujii T, Nakayama G, Sugimoto H, Fujiwara M, Kodera Y. Usefulness of preoperative estimated glomerular filtration rate to predict complications after curative gastrectomy in patients with clinical T2-4 gastric cancer. Gastric Cancer 2017; 20:736-743. [PMID: 27734274 DOI: 10.1007/s10120-016-0657-6] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/02/2016] [Accepted: 10/02/2016] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastrectomy with systemic lymphadenectomy is the standard of care for resectable gastric cancer (GC), but it is sometimes associated with postoperative morbidity. Predicting complications is therefore an essential part of risk management in clinical practice. The renal function is routinely evaluated before surgery by blood examinations to determine dose of medication and infusion. However, the value of various parameters of renal function in prediction of postoperative complications remain unclear. METHODS We included 315 patients who underwent curative D2 gastrectomy for clinical T2-T4 GC without preoperative treatment, and evaluated the correlation between the incidence of postoperative complications and the indicators of renal function. RESULTS Forty-three patients experienced clinically relevant postoperative complications. Estimated glomerular filtration rate (eGFR) showed a higher area under the curve for predicting complications compared with urea nitrogen, creatinine, and creatinine clearance. The optimal eGFR cutoff value was 63.2 ml/min/1.73 m2, and eGFR < 63.2 was an independent risk factor for postoperative complications in multivariable analysis (odds ratio 4.67; 95 % confidence interval 2.16-10.5; p < 0.001). Particularly, the incidence of anastomotic leakage was significantly higher in patients with eGFR < 63.2 than those with eGFR ≥ 63.2 (9.4 % vs. 3.5 %). eGFR < 63.2 was also associated with a higher incidence of postoperative complications independent of age, body mass index, operative procedure, and clinical disease stage. Postoperative hospital stay was significantly longer in the eGFR < 63.2 group. CONCLUSIONS Preoperative eGFR is a simple and useful predictor for complications after gastrectomy in patients with GC and may improve clinical care and the process of obtaining informed consent.
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Affiliation(s)
- Yuri Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Daisuke Kobayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Akira Mizuno
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Naoki Iwata
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Yukiko Niwa
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Hideki Takami
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Tsutomu Fujii
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Goro Nakayama
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Hiroyuki Sugimoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
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26
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Inaoka K, Kanda M, Uda H, Tanaka Y, Tanaka C, Kobayashi D, Takami H, Iwata N, Hayashi M, Niwa Y, Yamada S, Fujii T, Sugimoto H, Murotani K, Fujiwara M, Kodera Y. Clinical utility of the platelet-lymphocyte ratio as a predictor of postoperative complications after radical gastrectomy for clinical T2-4 gastric cancer. World J Gastroenterol 2017; 23:2519-2526. [PMID: 28465636 PMCID: PMC5394515 DOI: 10.3748/wjg.v23.i14.2519] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/25/2016] [Revised: 01/25/2017] [Accepted: 03/20/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To identify simple and sensitive markers for postoperative complications after gastrectomy, the predictive values were compared among candidate preoperative factors.
METHODS Three-hundred and twelve patients with previously untreated clinical T2-4 gastric cancer who underwent a D2 standard gastrectomy (distal gastrectomy or total gastrectomy) were included in the analysis. Correlations between 21 parameters that can be determined by preoperative routine blood tests and clinically relevant postoperative complications (grade II or higher according to the Clavien-Dindo classification) were evaluated. The optimal cutoff values and clinical significance of the selected markers were further evaluated by subgroup analyses according to age, body mass index, operative procedure and clinical disease stage.
RESULTS Sixty-six patients (21.1%) experienced grade II or higher postoperative complications. The platelet-lymphocyte ratio (PLR, total lymphocyte count/platelet count × 100) exhibited the highest area under the curve value (0.639) for predicting postoperative complications among the 21 parameters, and the optimal cutoff value was determined to be 0.71 (sensitivity = 70%, specificity = 56%). In the univariate analysis, the odds ratio of a low PLR for the occurrence of postoperative complications was 2.94 (95%CI: 1.66-5.35, P < 0.001), and a multivariate binomial logistic analysis involving other potential risk factors identified a low PLR as an independent risk factor for postoperative complications (OR = 3.32, 95%CI: 1.82-6.25, P < 0.001). In subgroups classified according to age, body mass index, operative procedure and clinical disease stage, the low PLR group exhibited an increased incidence of postoperative complications.
CONCLUSION The preoperative PLR is a simple and useful predictor of complications after curative gastrectomy in patients with clinical T2-4 gastric cancer.
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GPR155 Serves as a Predictive Biomarker for Hematogenous Metastasis in Patients with Gastric Cancer. Sci Rep 2017; 7:42089. [PMID: 28165032 PMCID: PMC5292715 DOI: 10.1038/srep42089] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/02/2016] [Accepted: 01/04/2017] [Indexed: 12/15/2022] Open
Abstract
The prognosis of patients with gastric cancer (GC) with hematogenous metastasis is dismal. Identification of biomarkers specific for hematogenous metastasis is required to develop personalized treatments that improve patients' outcomes. Global expression profiling of GC tissues with synchronous hepatic metastasis without metastasis to the peritoneal cavity or distant lymph nodes was conducted using next-generation sequencing and identified the G protein-coupled receptor 155 (GPR155) as a candidate biomarker. GPR155 transcription was suppressed in GC cell lines compared with a nontumorigenic cell line. DNA methylation of the GPR155 promoter region was not detected, albeit 20% of GC cell lines harbored copy number loss at GPR155 locus. The expression levels of GPR155 mRNA correlated inversely with those of TWIST1 and WNT5B. Inhibition of GPR155 expression increased the levels of p-ERK1/2 and p-STAT1, significantly increased cell proliferation, and increased the invasiveness of a GC cell lines. GPR155 mRNA levels in GC clinical samples correlated with hematogenous metastasis and recurrence. Multivariate analysis revealed that reduced expression of GPR155 mRNA was an independent predictive marker of hematogenous metastasis. GPR155 may represent a biomarker for diagnosing and predicting hematogenous metastasis of GC.
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Tanaka H, Kanda M, Shimizu D, Tanaka C, Kobayashi D, Hayashi M, Iwata N, Yamada S, Fujii T, Nakayama G, Sugimoto H, Fujiwara M, Niwa Y, Kodera Y. FAM46C Serves as a Predictor of Hepatic Recurrence in Patients with Resectable Gastric Cancer. Ann Surg Oncol 2016; 24:3438-3445. [PMID: 27770343 DOI: 10.1245/s10434-016-5636-y] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2016] [Indexed: 12/16/2022]
Abstract
BACKGROUND Gastric cancer (GC) relapse can occur even if curative resection is achieved. Biomarkers predicting recurrence are needed to provide appropriate postoperative surveillance and perioperative therapeutic strategy. METHODS A global expression profiling was performed using tissues from GC patients with synchronous liver-confined metastasis. Family with sequence similarity 46, member C (FAM46C), was identified as a candidate biomarker. mRNA expression analysis, direct nucleotide sequencing, bisulfite sequencing and copy number assays for FAM46C were performed with eleven GC cell lines. Expression levels of FAM46C in primary GC tissues from 129 patients who underwent curative GC resection were determined and correlated with clinicopathological factors, including postoperative outcome. RESULTS Levels of FAM46C mRNA differed among GC cell lines. Point mutations in FAM46C were detected in five GC cell lines accompanied with reduced FAM46C transcription. No hypermethylation was found in the promoter region of FAM46C. Copy number alterations were found in six GC cell lines with differing FAM46C transcription levels. Reduced FAM46C mRNA expression levels were detected in 117 (91 %) GC specimens compared with adjacent noncancerous tissues. Low FAM46C expression levels were significantly associated with larger macroscopic GC tumor sizes. The low FAM46C expression group was likely to have shorter disease-free survival than the high group and low FAM46C level was identified as an independent risk factor for recurrence after curative resection. FAM46C expression levels were low in all cases that were later found to have hepatic recurrence. CONCLUSIONS Reduced GC expression of FAM46C is a potential biomarker to predict hepatic recurrence after curative gastrectomy.
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Affiliation(s)
- Haruyoshi Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Dai Shimizu
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Daisuke Kobayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Naoki Iwata
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tsutomu Fujii
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Goro Nakayama
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroyuki Sugimoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yukiko Niwa
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
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Kanda M, Tanaka C, Kobayashi D, Mizuno A, Tanaka Y, Takami H, Iwata N, Hayashi M, Niwa Y, Yamada S, Fujii T, Sugimoto H, Murotani K, Fujiwara M, Kodera Y. Proposal of the Coagulation Score as a Predictor for Short-Term and Long-Term Outcomes of Patients with Resectable Gastric Cancer. Ann Surg Oncol 2016; 24:502-509. [PMID: 27600621 DOI: 10.1245/s10434-016-5544-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Indexed: 12/13/2022]
Abstract
BACKGROUND Systemic hemostasis and thrombosis activation has been implicated in tumor progression and metastasis. This study aimed to investigate the use of coagulation factors as a novel prediction method for postoperative outcomes after curative gastrectomy in patients with stage II/III gastric cancer (GC). METHODS Overall, 126 patients with stage II/III GC who underwent gastrectomy between May 2003 and February 2016 were eligible for inclusion in the study. We retrospectively evaluated the predictive value of preoperative platelet count and plasma fibrinogen and d-dimer levels, and coagulation score (0: fibrinogen and d-dimer both below upper limits; 1: either fibrinogen or d-dimer over upper limits; 2: both fibrinogen and d-dimer over upper limits) for short- and long-term outcomes. RESULTS Postoperative complications were significantly more frequent in patients with elevated preoperative d-dimer levels compared with those with normal d-dimer levels (26 vs. 10 %; p = 0.032). The prevalence of postoperative complications showed a stepwise increase in proportion to the coagulation score. Patients with a coagulation score of 2 had significantly larger tumors (p = 0.013) and significantly greater intraoperative blood loss (p = 0.004) than those who scored 0 or 1. Coagulation score showed the highest values distinguished high-risk patients in overall and disease-free survival, and a coagulation score of 2 was an independent prognostic factor for recurrence. Patients with a coagulation score of 2 experienced a significantly higher prevalence of liver metastasis as an initial recurrence than those who scored 0 or 1 (p = 0.019). CONCLUSIONS The coagulation score is a simple and promising predictor for postoperative complications and recurrence after gastrectomy in stage II/III GC patients.
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Affiliation(s)
- Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Daisuke Kobayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Akira Mizuno
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuri Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideki Takami
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Naoki Iwata
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yukiko Niwa
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tsutomu Fujii
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroyuki Sugimoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kenta Murotani
- Center for Clinical Research, Aichi Medical University, Nagakute, Japan
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
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Kanda M, Kodera Y. Molecular mechanisms of peritoneal dissemination in gastric cancer. World J Gastroenterol 2016; 22:6829-6840. [PMID: 27570420 PMCID: PMC4974582 DOI: 10.3748/wjg.v22.i30.6829] [Citation(s) in RCA: 117] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/26/2016] [Revised: 05/31/2016] [Accepted: 06/15/2016] [Indexed: 02/06/2023] Open
Abstract
Peritoneal dissemination represents a devastating form of gastric cancer (GC) progression with a dismal prognosis. There is no effective therapy for this condition. The 5-year survival rate of patients with peritoneal dissemination is 2%, even including patients with only microscopic free cancer cells without macroscopic peritoneal nodules. The mechanism of peritoneal dissemination of GC involves several steps: detachment of cancer cells from the primary tumor, survival in the free abdominal cavity, attachment to the distant peritoneum, invasion into the subperitoneal space and proliferation with angiogenesis. These steps are not mutually exclusive, and combinations of different molecular mechanisms can occur in each process of peritoneal dissemination. A comprehensive understanding of the molecular events involved in peritoneal dissemination is important and should be systematically pursued. It is crucial to identify novel strategies for the prevention of this condition and for identification of markers of prognosis and the development of molecular-targeted therapies. In this review, we provide an overview of recently published articles addressing the molecular mechanisms of peritoneal dissemination of GC to provide an update on what is currently known in this field and to propose novel promising candidates for use in diagnosis and as therapeutic targets.
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31
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Kanda M, Tanaka C, Kobayashi D, Tanaka H, Shimizu D, Shibata M, Takami H, Hayashi M, Iwata N, Niwa Y, Yamada S, Fujii T, Nakayama G, Fujiwara M, Kodera Y. Epigenetic suppression of the immunoregulator MZB1 is associated with the malignant phenotype of gastric cancer. Int J Cancer 2016; 139:2290-8. [PMID: 27459504 DOI: 10.1002/ijc.30286] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2016] [Accepted: 07/18/2016] [Indexed: 12/30/2022]
Abstract
Prediction of tumor recurrence after curative resection is critical for determining the prognosis of patients with gastric cancer (GC). The initiation and progression of GC are associated with inappropriate immune responses caused by chronic inflammation of the gastric mucosa. To identify immunoregulatory molecules involved in GC progression, GC cell lines and 200 pairs of tumor and normal tissues from patients with GC were analyzed for gene expression, amplification and methylation as well as function of a differentially expressed gene. The transcriptome analysis revealed that marginal zone B and B1 cell specific protein (MZB1) was expressed at significantly decreased levels in primary GC tissues when compared with the corresponding normal gastric mucosa. PCR array analysis exploring genes expressed cooperatively with MZB1 revealed that differential expression of MZB1 mRNA in GC cell lines correlated positively with the levels of the mRNAs encoding estrogen receptor 1 and desumoylating isopeptidase 1. Hypermethylation of the MZB1 promoter was frequent in cell lines with decreased levels of MZB1 mRNA. siRNA-mediated knockdown of MZB1 significantly increased proliferation, invasion and migration of GC cell lines. Low MZB1 expression was an independent prognostic factor for recurrence after curative gastrectomy and was associated significantly with increased hematogenous recurrence. MZB1 acts as a suppressor of GC. Low MZB1 expression in the primary GC tissue is predictive of recurrence after curative resection.
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Affiliation(s)
- Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Daisuke Kobayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Haruyoshi Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Dai Shimizu
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahiro Shibata
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideki Takami
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Naoki Iwata
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yukiko Niwa
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tsutomu Fujii
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Goro Nakayama
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
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Kanda M, Shimizu D, Fujii T, Tanaka H, Tanaka Y, Ezaka K, Shibata M, Takami H, Hashimoto R, Sueoka S, Iwata N, Kobayashi D, Tanaka C, Yamada S, Nakayama G, Sugimoto H, Koike M, Fujiwara M, Kodera Y. Neurotrophin Receptor-Interacting Melanoma Antigen-Encoding Gene Homolog is Associated with Malignant Phenotype of Gastric Cancer. Ann Surg Oncol 2016; 23:532-539. [PMID: 27364510 DOI: 10.1245/s10434-016-5375-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2016] [Indexed: 01/04/2023]
Abstract
BACKGROUND Identification of novel molecules implicated in the malignancy of gastric cancer (GC) is key to the development of personalized treatments and the improvement of patient outcome. Neurotrophin receptor-interacting melanoma antigen-encoding protein (NRAGE) regulates apoptosis and metastasis via interactions with various genes. This study aimed to evaluate the function and clinical significance of NRAGE in GC. METHODS The expression of NRAGE and its putative interacting genes apoptosis antagonizing transcription factor (AATF), p75 neurotrophin receptor (p75NTR), and proliferating cell nuclear antigen (PCNA) were determined in GC cell lines using reverse transcription-polymerase chain reaction (RT-PCR). The effect of NRAGE knockdown by small interfering RNA (siRNA) on GC cell behavior also was evaluated. In addition, NRAGE expression was determined in 179 pairs of resected gastric tissues. RESULTS Expression of NRAGE mRNA positively correlated with that of AATF, and NRAGE knockdown significantly decreased the proliferation, migration, and invasion of GC cells. The mean level of NRAGE mRNA expression was significantly higher in GC tissues than in corresponding adjacent normal tissues. The expression patterns of NRAGE mRNA and protein were closely correlated. A stepwise elevation in NRAGE mRNA expression in GC tissues was observed with increasing Union for International Cancer Control (UICC) stage. High NRAGE expression in GCs was associated with shortened recurrence-free survival and identified as an independent prognostic factor (hazard ratio, 1.83; 95 % CI, 1.12-3.02, p = 0.017). CONCLUSIONS The results indicate that NRAGE represents a putative oncogene associated with a malignant phenotype of GC. In GC, NRAGE may serve as a predictive biomarker and a target of molecular therapy.
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Affiliation(s)
- Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan.
| | - Dai Shimizu
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Tsutomu Fujii
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Haruyoshi Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yuri Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Kazuhiro Ezaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahiro Shibata
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hideki Takami
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Ryoji Hashimoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Satoshi Sueoka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Naoki Iwata
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Daisuke Kobayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Goro Nakayama
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Hiroyuki Sugimoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Masahiko Koike
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Japan
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Kanda M, Shimizu D, Fujii T, Tanaka H, Shibata M, Iwata N, Hayashi M, Kobayashi D, Tanaka C, Yamada S, Nakayama G, Sugimoto H, Koike M, Fujiwara M, Kodera Y. Protein arginine methyltransferase 5 is associated with malignant phenotype and peritoneal metastasis in gastric cancer. Int J Oncol 2016; 49:1195-202. [PMID: 27315569 DOI: 10.3892/ijo.2016.3584] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2016] [Accepted: 05/31/2016] [Indexed: 11/06/2022] Open
Abstract
Identification of novel gastric cancer (GC)-related molecules is necessary to improve management of patients with GC in both diagnostic and therapeutic aspects. The aim of the present study was to determine whether protein arginine methyltransferase 5 (PRMT5) acts as an oncogene in the progression of GC and whether it serves as a novel diagnostic marker and therapeutic target. We conducted global expression profiling of GC cell lines and RNA interference experiments to evaluate the effect of PRMT5 expression on the phenotype of GC cells. We analysed tissues of 179 patients with GC to assess the association of PRMT5 mRNA levels with clinicopathological factors. Differential expression of PRMT5 mRNA by GC cell lines correlated positively with the levels of GEMIN2, STAT3 and TGFB3. PRMT5 knockdown reduced the proliferation, invasion and migration of a GC cell line. PRMT5 mRNA levels were significantly higher in GC tissues than the corresponding adjacent normal tissues and were independent of tumour depth, differentiation and lymph node metastasis. High PRMT5 expression was an independent risk factor of positive peritoneal lavage cytology (odds ratio 3.90, P=0.003) and decreased survival. PRMT5 enhances the malignant phenotype of GC cell lines and its expression in gastric tissues may serve as a biomarker for patient stratification and a potential target of therapy.
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Affiliation(s)
- Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Dai Shimizu
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Tsutomu Fujii
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Haruyoshi Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Masahiro Shibata
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Naoki Iwata
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Daisuke Kobayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Suguru Yamada
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Goro Nakayama
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Hiroyuki Sugimoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Masahiko Koike
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya 466-8550, Japan
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Tokodai K, Narimatsu H, Nishida A, Takaya K, Hara Y, Kawagishi N, Hashizume E, Ohuchi N. Risk factors for recurrence in stage II/III colorectal cancer patients treated with curative surgery: The impact of postoperative tumor markers and an infiltrative growth pattern. J Surg Oncol 2016; 114:368-74. [DOI: 10.1002/jso.24320] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/10/2016] [Accepted: 05/21/2016] [Indexed: 12/22/2022]
Affiliation(s)
- Kazuaki Tokodai
- Department of Surgery; Nihonkai General Hospital; Japan
- Department of Advanced Surgical Science and Technology; Tohoku University; Japan
| | - Hiroto Narimatsu
- Cancer Prevention and Control Division; Kanagawa Cancer Center Research Institute; Japan
| | - Akiko Nishida
- Department of Pathology; Nihonkai General Hospital; Japan
| | - Kai Takaya
- Department of Surgery; Nihonkai General Hospital; Japan
| | - Yasuyuki Hara
- Department of Advanced Surgical Science and Technology; Tohoku University; Japan
| | - Naoki Kawagishi
- Department of Advanced Surgical Science and Technology; Tohoku University; Japan
| | | | - Noriaki Ohuchi
- Department of Advanced Surgical Science and Technology; Tohoku University; Japan
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Kanda M, Mizuno A, Tanaka C, Kobayashi D, Fujiwara M, Iwata N, Hayashi M, Yamada S, Nakayama G, Fujii T, Sugimoto H, Koike M, Takami H, Niwa Y, Murotani K, Kodera Y. Nutritional predictors for postoperative short-term and long-term outcomes of patients with gastric cancer. Medicine (Baltimore) 2016; 95:e3781. [PMID: 27310954 PMCID: PMC4998440 DOI: 10.1097/md.0000000000003781] [Citation(s) in RCA: 90] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Evidence indicates that impaired immunocompetence and nutritional status adversely affect short-term and long-term outcomes of patients with cancer. We aimed to evaluate the clinical significance of preoperative immunocompetence and nutritional status according to Onodera's prognostic nutrition index (PNI) among patients who underwent curative gastrectomy for gastric cancer (GC).This study included 260 patients with stage II/III GC who underwent R0 resection. The predictive values of preoperative nutritional status for postoperative outcome (morbidity and prognosis) were evaluated. Onodera's PNI was calculated as follows: 10 × serum albumin (g/dL) + 0.005 × lymphocyte count (per mm).The mean preoperative PNI was 47.8. The area under the curve for predicting complications was greater for PNI compared with the serum albumin concentration or lymphocyte count. Multivariate analysis identified preoperative PNI < 47 as an independent predictor of postoperative morbidity. Moreover, patients in the PNI < 47 group experienced significantly shorter overall and disease-free survival compared with those in the PNI ≥ 47 group, notably because of a higher prevalence of hematogenous metastasis as the initial recurrence. Subgroup analysis according to disease stage and postoperative adjuvant treatment revealed that the prognostic significance of PNI was more apparent in patients with stage II GC and in those who received adjuvant chemotherapy.Preoperative PNI is easy and inexpensive to determine, and our findings indicate that PNI served as a significant predictor of postoperative morbidity, prognosis, and recurrence patterns of patients with stage II/III GC.
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Affiliation(s)
- Mitsuro Kanda
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya
| | - Akira Mizuno
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya
| | - Chie Tanaka
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya
| | - Daisuke Kobayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya
| | - Michitaka Fujiwara
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya
| | - Naoki Iwata
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya
| | - Masamichi Hayashi
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya
| | - Suguru Yamada
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya
| | - Goro Nakayama
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya
| | - Tsutomu Fujii
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya
| | - Hiroyuki Sugimoto
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya
| | - Masahiko Koike
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya
| | - Hideki Takami
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya
| | - Yukiko Niwa
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya
| | - Kenta Murotani
- Center for Clinical Research, Aichi Medical University, Nagakute, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya
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