| 1. |
池永直樹, 西原一善, 岩下俊光, 末原伸泰, 光山昌珠, 腹腔鏡補助下幽門側胃切除における小開腹創からの器械吻合 －手縫い吻合との比較・検討－, 外科, 68, 5, 559-563, 2006.04, 著者らが腹腔鏡補助下幽門側胃切除術を施行しBillroth I(B-I法)再建を行なった早期胃癌41例を,器械吻合群8例と手縫い吻合群33例に分け,これらを比較検討した.器械吻合はサーキュラーステイプラーを使用し,手縫い吻合はGambee法で行なった結果,小切開創の平均長,平均手術時間は両群間で有意差を認めなかったが,術後の縫合不全・通過障害は器械吻合群ではいずれも0例に対し,手縫い縫合群ではそれぞれ4例,6例で認められた.平均在院日数は器械縫合群25.8日,手縫い縫合群32.5日であった.以上より,サーキュラーステイプラーを用いたB-I法再建は通過障害や縫合不全を減らす安全性の高い吻合方法であることが示唆された. |
| 2. |
Tomonori Nakanoko, Eiji Oki, Mitsuhiko Ota, Naoki Ikenaga, Yuichi Hisamatsu, Takeo Toshima, Takahiro Kanno, Kotaro Tadano, Kenji Kawashima, Kenoki Ohuchida, Hajime Morohashi, Yuma Ebihara, Koshi Mimori, Masafumi Nakamura, Tomoharu Yoshizumi, Kenichi Hakamada, Satoshi Hirano, Norihiko Ikeda, Masaki Mori, Real-time telementoring with 3D drawing annotation in robotic surgery, Surg Endosc, 10.1007/s00464-023-10521-z., 37, 12, 9676-9683
, 2023.04, Abstract
Background: In telementoring, differences in teaching methods affect local surgeons' comprehension. Because the object to be operated on is a three-dimensional (3D) structure, voice or 2D annotation may not be sufficient to convey the instructor's intention. In this study, we examined the usefulness of telementoring using 3D drawing annotations in robotic surgery.
Methods: Kyushu University and Beppu Hospital are located 140 km apart, and the study was conducted using a Saroa™ surgical robot by RIVERFIELD Inc. using a commercial guarantee network on optical fiber. Twenty medical students performed vertical mattress suturing using a swine intestinal tract under surgical guidance at the Center for Advanced Medical Innovation Kyushu University. Surgical guidance was provided by Beppu Hospital using voice, 2D, and 3D drawing annotations. All robot operations were performed using 3D images, and only the annotations were independently switched between voice and 2D and 3D images. The operation time, needle movement, and performance were also evaluated.
Results: The 3D annotation group tended to have a shorter working time than the control group (25.6 ± 63.2 vs. - 36.7 ± 65.4 min, P = 0.06). The 3D annotation group had fewer retries than the control group (1.3 ± 1.7 vs. - 1.1 ± 0.7, P = 0.006), and there was a tendency for fewer needle drops (0.4 ± 0.7 vs. - 0.5 ± 0.9, P = 0.06). The 3D annotation group scored significantly higher than the control group on the Global Evaluate Assessment of Robot Skills (16.8 ± 2.0 vs. 22.8 ± 2.4, P = 0.04). The 3D annotation group also scored higher than the voice (13.4 ± 1.2) and 2D annotation (16.2 ± 1.8) groups (3D vs. voice: P = 0.03, 3D vs. 2D: P = 0.03).
Conclusion: Telementoring using 3D drawing annotation was shown to provide good comprehension and a smooth operation for local surgeons.
Keywords: 3D line drawing annotation; Real-time telementoring; Robotic surgery; Telesurgery.. |
| 3. |
Ikenaga N, Nishihara K, Iwashita T, Suehara N, Mitsuyama S, Long-Team Quality of Life After Laparoscopically Assisted Distal Gastrectomy for Gastric Cancer, J Laparoendosc Adv Surg Tech A, 10.1089/lap.2006.16.119, 16, 2, 119-123, 2006.04. |
| 4. |
Ikenaga N, Otomo N, Toyofuku A, Ueda Y, Toyoda K, Hayashi T, Nishikawa K, Tanaka M, Standardized uptake values (SUV) for breast carcinomas assessed by fluorodeoxyglucose-positron emission tomography (FDG-PET) correlate with prognostic factors, Am Surg, 73, 11, 1151-1157, 2007.04, Several studies have revealed the diagnostic value of fluorodeoxyglucose-positron emission tomography for breast carcinomas. However, breast carcinomas display considerable variation in 18F-labeled 2-fluoro-2-deoxy-D-glucose uptake, and few papers have reported the clinical utility of the standardized uptake values (SUV). The purpose of this study is to investigate the relationship between SUV assessed by positron emission tomography (PET) and the clinicopathological characteristics of breast carcinoma. We reviewed 52 breast carcinomas of 45 patients presented at our department between January 2004 and July 2005. We compared the histopathological findings of the breast carcinomas with the preoperative SUV. Of the 52 breast carcinomas, 49 (94%) were detected by preoperative PET. A positive correlation was found between the SUV and tumor size (P
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| 5. |
Ikenaga N, Ohuchida K, Mizumoto K, Yu J, Fujita H, Nakata K, Ueda J, Sato N, Nagai E, Tanaka M, S100A4 mRNA is a diagnostic and prognostic marker in pancreatic carcinoma, J Gastrointest Surg, 13, 10, 1852-1858, 2009.04, OBJECTIVE: The aim of this study is to evaluate the clinical significance of S100A4 mRNA expression in pancreatic cancer. MATERIALS AND METHODS: We obtained invasive ductal carcinoma (IDC) cells from ten lesions, intraductal papillary mucinous neoplasm (IPMN) cells from 20 lesions, and normal ductal cells from 20 normal pancreatic tissues by laser microdissection of frozen tissues. S100A4 expression was examined in the microdissected cells and in formalin-fixed paraffin-embedded (FFPE) samples of 87 pancreatic cancers by quantitative reverse transcription-polymerase chain reaction. RESULTS: IDC cells expressed higher levels of S100A4 than IPMN cells (P = 0.002) and normal ductal cells (P |
| 6. |
Ikenaga N, Chijiiwa K, Otani K, Ohuchida J, Uchiyama S, Kondo K, Clinicopathologic Characteristics of Hepatocellular Carcinoma with Bile Duct Invasion, J Gastrointest Surg, 13 , 3, 492-497, 2009.04, To clarify the characteristics of hepatocellular carcinoma (HCC) with bile duct invasion, we retrospectively analyzed clinical features and surgical outcome of HCC with bile duct invasion (b(+) group, n = 15) compared to those without bile duct invasion (b(-) group, n = 256). In the b(+) group, four patients (27%) showed obstructive jaundice, and a diagnosis of bile duct invasion was obtained preoperatively in seven patients (47%). The levels of serum bilirubin and carbohydrate antigen 19-9 were significantly higher in the b(+) group. Macroscopically, confluent multinodular type and infiltrative type were predominant in the b(+) group (P = 0.002). Microscopically, capsule infiltration (P = 0.040) and intrahepatic metastasis (P = 0.013) were predominant in the b(+) group. Portal vein invasion was associated significantly with the b(+) group (P = 0.004); however, the frequency of hepatic vein invasion was similar (P = 0.096). The median survival after r
e!
section was significantly shorter in the b(+) group than in the b(-) group (11.4 vs. 56.1 months, P = 0.002), and eight of 11 intrahepatic recurrences in the b(+) group occurred within 3 months after surgery. HCC with bile duct invasion has an infiltrative nature and a high risk of intrahepatic recurrence, resulting in poor prognosis.. |
| 7. |
Ikenaga N, Ohuchida K, Mizumoto K, Yu J, Kayashima T, Sakai H, Fujita H, Nakata K, Tanaka M
, MicroRNA-203 expression as a new prognostic marker of pancreatic adenocarcinoma
, Ann Surg Oncol, 17, 12, 3120-3128, 2010.04, BACKGROUND: Detection of aberrant microRNA (miR) expression may contribute to diagnosis and prognosis of various cancers. The aim of this study is to evaluate the correlation between miR-203 expression and prognosis of patients with pancreatic adenocarcinoma after curative resection.
METHODS: A total of 113 formalin-fixed paraffin-embedded tissue samples of pancreatic adenocarcinoma, 20 samples of chronic pancreatitis, and 8 samples of normal pancreas were obtained. We investigated the association of miR-203 expression measured by quantitative reverse-transcription polymerase chain reaction assays with clinicopathological parameters and survival times.
RESULTS: miR-203 was overexpressed in pancreatic adenocarcinoma samples compared with chronic pancreatitis (P
CONCLUSIONS: miR-203 expression is a new prognostic marker in pancreatic adenocarcinoma patients.
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| 8. |
Moriyama T, Ohuchida K, Mizumoto K, Cui L, Ikenaga N, Sato N, Tanaka M, Enhanced cell migration and invasion of CD133+ pancreatic cancer cells cocultured with pancreatic stromal cells, Cancer, 116
, 14, 3357-3368, 2010.04, BACKGROUND: Recently, cancer stem cells have been reported as a new therapeutic target in pancreatic cancer as well as other cancers, but the specific role of these cells is unknown. METHODS: The authors investigated the functional roles of CD133+ cells, 1 of the putative cancer stem cell candidates in pancreatic cancer. CD133 expression was assessed in human pancreatic cancer and cancer cell lines by quantitative real-time reverse transcriptase polymerase chain reaction and flow cytometry. Next, they compared the ability of CD133+ and CD133- cells to proliferate, migrate, and invade using 2 pancreatic cancer cell lines. In particular, they evaluated the relationship between CD133+ cells and primary pancreatic stromal cells. RESULTS: CD133 was expressed in primary human pancreatic cancer tissues and some cancer cell lines, whereas there was little expression in primary normal pancreatic epithelial cells and primary pancreatic stromal cells. CD133+ cells, isolated by flow cytometry, showed increased cell proliferation under anchorage-independent conditions (P<.01 and enhanced migration invasion particularly when cocultured with primary pancreatic stromal cells chemokine-related receptor-4 markedly overexpressed in cd133 may be responsible for the increased invasive ability of which express derived factor-1 ligand to cxcr4. conclusions: these data suggest that exhibit more aggressive behavior such as cell proliferation especially presence cells. targeting therapy interaction between cancer a new approach treatment cancer. copyright american society.>
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| 9. |
Ikenaga N, Ohuchida K, Mizumoto K, Yu J, Kayashima T, Hayashi A, Nakata K, Tanaka M
, Characterization of CD24 expression in intraductal papillary mucinous neoplasms and ductal carcinoma of the pancreas
, Hum Pathol, 41, 10, 1466-1474, 2010.04, CD24 is a molecule involved in cell adhesion and tumor metastasis. The aims of this study were (1) to evaluate the association between CD24 expression and the progression of intraductal papillary mucinous neoplasms of the pancreas and (2) to investigate the association between CD24 expression in pancreatic cancer and the prognosis of patients who underwent curative pancreatectomy. Immunohistochemical analysis of CD24 was performed for 95 intraductal papillary mucinous neoplasms of the pancreas and 83 pancreatic cancers. We investigated the association between CD24 expression and the histologic grade of intraductal papillary mucinous neoplasms of the pancreas, the clinicopathologic parameters of pancreatic cancers, and the survival time of pancreatic cancer patients who underwent pancreatectomy. The positive rates of CD24 expression in intraductal papillary mucinous adenoma, borderline intraductal papillary mucinous neoplasm, noninvasive intraductal papillary mucinous carcinoma, and invasive intraductal papillary mucinous carcinoma were 5 (20%) of 24, 12 (48%) of 25, 10 (43%) of 23, and 15 (65%) of 23, respectively. The CD24-positive rates were significantly higher in borderline intraductal papillary mucinous neoplasm and intraductal papillary mucinous carcinoma compared with intraductal papillary mucinous adenoma (P = .046 and P = .007, respectively). The staining scores, which were determined from the percentage of stained cells and the staining intensity, were significantly higher in invasive intraductal papillary mucinous carcinoma than in noninvasive intraductal papillary mucinous carcinoma (P = .043). In the pancreatic cancers, higher tumor stage (P = .007), nodal metastasis (P = .021), and higher-grade tumors (P
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| 10. |
Ikenaga N, Ohuchida K, Mizumoto K, Cui L, Kayashima T, Morimatsu K, Moriyama T, Nakata K, Fujita H, Tanaka M, CD10+ pancreatic stellate cells enhance the progression of pancreatic cancer , Gastroenterology, 139, 3, 1041-1051, 2010.04, Abstract
BACKGROUND & AIMS: Pancreatic stellate cells (PSCs) promote the progression of pancreatic cancer by producing extracellular matrix and soluble factors. However, the functional heterogeneity of PSCs has not been identified until now. Detailed characterization of the PSCs in human pancreatic cancer would provide a set of potential targets for stroma-directed therapy.
METHODS: We isolated PSCs from fresh pancreatic ductal adenocarcinoma tissue and sorted them by flow cytometry according to cell surface expression of CD10, which is a stromal prognostic marker for various tumors. We analyzed the functional differences between CD10(+) PSCs and CD10(-) PSCs.
RESULTS: Immunohistochemical analysis showed that the frequency of CD10 expression by PSCs was markedly higher in tumor tissue than in normal tissue (33.7% vs 0%, respectively, P = .028). In pancreatic ductal adenocarcinoma, CD10 expression by PSCs was associated with positive nodal metastases (P = .011) and a shorter survival time (P
CONCLUSIONS: CD10(+) PSCs enhance the progression of pancreatic cancer cells. CD10(+) PSCs may be a candidate for selective therapeutic targeting in the treatment of pancreatic cancer.
Copyright © 2010 AGA Institute. Published by Elsevier Inc. All rights reserved.
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| 11. |
Nakata K, Ohuchida K, Mizumoto K, Kayashima T, Ikenaga N, Sakai H, Lin C, Fujita H, Otsuka T, Aishima S, Nagai E, Oda Y, Tanaka M, MicroRNA-10b is overexpressed in pancreatic cancer, promotes its invasiveness, and correlates with a poor prognosis., Surgery, 150, 5, 916-922, 2011.04, BACKGROUND:
MicroRNAs (miRNAs) have been gaining attention as new, key molecules that contribute to carcinogenesis. In pancreatic cancer, previous profiling analyses of miRNA expression have shown that several miRNAs are differently expressed in normal and cancerous tissues. Several pancreatic cancer-specific miRNAs differed, however, in each analysis.
METHODS:
We investigated the miRNA expression profiles of the pancreatic cancer cell lines CAPAN-1 and CFPAC1 and an immortalized human normal pancreatic ductal epithelial cell line (HPDE) using a high-throughput, TaqMan, qRT-PCR array analysis. We also analyzed the expression levels of this miRNA in microdissected (n = 15) and formalin-fixed, paraffin-embedded (FFPE) (n = 115) samples from pancreatic cancers by quantitative RT-PCR. Finally, we investigated the effects of this miRNA on the invasiveness of pancreatic cancer cells.
RESULTS:
Based on the microarray analysis, miR-372, miR-146a, miR-204, miR-10a, and miR-10b showed particularly large differences (>10-fold changes) between both pancreatic cell lines and HPDE cells. Thirteen of the 15 pancreatic cancer cell lines showed 2.1- to 36.4-fold (median, 15.3-fold) greater levels of miR-10b than HPDE cells. Microdissection analysis revealed that miR-10b exhibited greater expression levels in pancreatic cancer cells (n = 5) than in normal pancreatic ductal cells (n = 10) (P
CONCLUSION:
miR-10b is overexpressed in pancreatic cancer and may be involved in the invasiveness in pancreatic cancer cells, thereby leading to a poor prognosis.
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| 12. |
Ikenaga N, Ohuchida K, Mizumoto K, Akagawa S, Fujiwara K, Eguchi D, Kozono S, Ohtsuka T, Takahata S, Tanaka M, Pancreatic cancer cells enhance the ability of collagen internalization during epithelial-mesenchymal transition., PLoS One, 7, 7, e40434, 2012.04, Abstract
BACKGROUND:
Extracellular matrix (ECM) remodeling is predominantly mediated by fibroblasts using intracellular and extracellular pathways. Although it is well known that extracellular degradation of the ECM by proteases derived from cancer cells facilitates cellular invasion, the intracellular degradation of ECM components by cancer cells has not been clarified. The aim of this study was to characterize collagen internalization, which is the initial step of the intracellular degradation pathway in pancreatic cancer cells, in light of epithelial-mesenchymal transition (EMT).
METHODOLOGY/PRINCIPAL FINDINGS:
We analyzed the function of collagen internalization in two pancreatic cancer cell lines, SUIT-2 and KP-2, and pancreatic stellate cells (PSCs) using Oregon Green 488-gelatin. PSCs had a strong ability for collagen uptake, and the pancreatic cancer cells also internalized collagen although less efficiently. The collagen internalization abilities of SUIT-2 and KP-2 cells were promoted by EMT induced by human recombinant transforming growth factor β1 (P
CONCLUSIONS/SIGNIFICANCE:
Pancreatic cancer cells are capable of collagen internalization, which is enhanced by EMT. This ECM clearance system may be a novel mechanism for cellular invasion and a potential therapeutic target in pancreatic cancer.
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| 13. |
Fujiwara K, Ohuchida K, Mizumoto K, Shindo K, Eguchi D, Kozono S, Ikenaga N, Ohtsuka T, Takahata S, Aishima S, Tanaka M, CD271⁺ subpopulation of pancreatic stellate cells correlates with prognosis of pancreatic cancer and is regulated by interaction with cancer cells., PLoS One, 0.1371/journal.pone.0052682, 7, 12, e52682, 2012.04, Abstract
Pancreatic stellate cells (PSCs) play a crucial role in the aggressive behavior of pancreatic cancer. Although heterogeneity of PSCs has been identified, the functional differences remain unclear. We characterized CD271⁺ PSCs in human pancreatic cancer. Immunohistochemistry for CD271 was performed for 31 normal pancreatic tissues and 105 pancreatic ductal adenocarcinomas (PDACs). We performed flow cytometry and quantitative RT-PCR, and assessed CD271 expression in PSCs isolated from pancreatic tissues and the changes in CD271 expression in PSCs cocultured with cancer cells. We also investigated the pattern of CD271 expression in a SCID mouse xenograft model. In the immunohistochemical analyses, the CD271-high staining rates in pancreatic stroma in normal pancreatic tissues and PDACs were 2/31 (6.5%) and 29/105 (27.6%), respectively (p = 0.0069). In PDACs, CD271⁺ stromal cells were frequently observed on the edge rather than the center of the tumors. Stromal CD271 high expression was associated with a good prognosis (p = 0.0040). Flow cytometric analyses demonstrated CD271-positive rates in PSCs were 0-2.1%. Quantitative RT-PCR analyses revealed that CD271 mRNA expression was increased in PSCs after coculture with pancreatic cancer cells. However, the level of CD271 mRNA expression subsequently decreased after the transient increase. Furthermore, CD271 mRNA expression was decreased in PSCs migrating toward pancreatic cancer cells through Matrigel. In the xenograft model, CD271⁺ PSCs were present at tumor margins/periphery and were absent in the tumor core. In conclusion, CD271 was expressed in PSCs around pancreatic tumors, but not in the center of the tumors, and expression decreased after long coculture with pancreatic cancer cells or after movement toward pancreatic cancer cells. These findings suggest that CD271⁺ PSCs appear at the early stage of pancreatic carcinogenesis and that CD271 expression is significantly correlated with a better prognosis in patients with PDAC.. |
| 14. |
Yoshida S, Kornek M, Ikenaga N, Schmelzle M, Masuzaki R, Csizmadia E, Wu Y, Robson SC, Schuppan D, Sub-lethal heat treatment promotes epithelial-mesenchymal transition and enhances the malignant potential of hepatocellular carcinoma. , Hepatology, 58, 5, 1667-1680, 2013.04. |
| 15. |
Kozono S, Ohuchida K, Eguchi D, Ikenaga N, Fujiwara K, Cui L, Mizumoto K, Tanaka M, Pirfenidone inhibits pancreatic cancer desmoplasia by regulating stellate cells, Cancer Res, 73, 7, 2345-2356, 2013.04, Pancreatic stellate cells (PSCs), which are implicated in desmoplasia in pancreatic cancer, enhance the malignancy of cancer cells and confer resistance to established treatments. We investigated whether the antifibrotic agent pirfenidone can suppress desmoplasia and exert anti-tumor effects against pancreatic cancer. Primary PSCs were established from pancreatic cancer tissue obtained during surgery. In vitro, pirfenidone inhibited the proliferation, invasiveness, and migration of PSCs in a dose-dependent manner. Although supernatants of untreated PSCs increased the proliferation, invasiveness, and migration of pancreatic cancer cells (PCCs), supernatants of pirfenidone-treated PSCs decreased these effects. Exposure to PCC supernatant increased the production of platelet-derived growth factor-A, hepatic growth factor, collagen type I, fibronectin, and periostin in PSCs, which was significantly reduced by pirfenidone. Mice were subcutaneously implante
d with PCCs (SUIT-2 cells) andPSCs into the right flank and PCCs alone into the left flank. Oral administration of pirfenidone to these mice significantly reduced tumor growth of co-implanted PCCs and PSCs, but not of PCCs alone. Pirfenidone also decreased the proliferation of PSCs and the deposition of collagen type I and periostin in tumors. In mice with orthotopic tumors consisting of PCCs co-implanted with PSCs, pirfenidone suppressed tumor growth, reduced the number of peritoneal disseminated nodules, and reduced the incidence of liver metastasis. Pirfenidone in combination with gemcitabine more effectively suppressed orthotopic tumor growth compared with pirfenidone or gemcitabine alone. In conclusion, our findings indicate that pirfenidone is a promising antitumor agent for pancreatic cancer, owing to its suppression of desmoplasia through regulating PSCs.. |
| 16. |
Fujiwara K, Ohuchida K, Ohtsuka T, Mizumoto K, Shindo K, Ikenaga N, Cui L, Takahata S, Aishima S, Tanaka M, Migratory Activity of CD105+ Pancreatic Cancer Cells Is Strongly Enhanced by Pancreatic Stellate Cells
, Pancreas, 42, 8, 1283-1290, 2013.04, OBJECTIVES: CD105 expression correlates with prognosis for several cancers. However, its significance in pancreatic cancer is unclear.METHODS: We analyzed CD105 expression in resected pancreatic cancer tissue and pancreatic cancer cell lines, compared the properties of CD105 and CD105 cells using quantitative RT-PCR and migration assays, and evaluated the relationship between CD105 cells and pancreatic stellate cells (PSCs).RESULTS: Immunohistochemistry showed that the frequency of CD105 expression was higher in pancreatic cancer than that in normal tissue (8% vs 0%, respectively). In flow cytometry, CD105 was expressed in pancreatic cancer cells, whereas weak CD105 expression was detected in normal pancreatic ductal epithelial cells. Quantitative RT-PCR showed that E-cadherin mRNA expression was suppressed and vimentin mRNA was overexpressed in CD105 cells (P < 0.05). Migration of CD105 cancer cells was strongly enhanced (more than that of CD105 c
ells) in coculture with PSCs (P < 0.05). CD105 expression did not correlate to clinicopathologic characteristics or the Kaplan-Meier survival analysis.CONCLUSIONS: Suppression of an epithelial marker and overexpression of a mesenchymal marker suggest that epithelial-mesenchymal transition is induced in CD105 pancreatic cancer cells. CD105 pancreatic cancer cell migration is strongly enhanced by PSCs, suggesting that these cells play a role in the pancreatic cancer microenvironment.. |
| 17. |
Eguchi D, Ohuchida K, Kozono S, Ikenaga N, Shindo K, Cui L, Fujiwara K, Akagawa S, Ohtsuka T, Takahata S, Tokunaga S, Mizumoto K, Tanaka M, MAL2 expression predicts distant metastasis and short survival in pancreatic cancer, Surgery, 154, 3, 573-582, 2013.04, BACKGROUND:
Pancreatic cancer is associated with a devastating prognosis, partially because of its aggressive metastatic ability. Identification of prognostic markers of metastasis would be useful in the clinical management of postoperative patients with pancreatic cancer. Mal, T-cell differentiation protein 2 (MAL2) has been identified as a molecule predictive of metastases; the clinical relevance of MAL2 in pancreatic cancer is unknown.
METHODS:
Orthotopic human pancreatic cancer xenografts from the pancreatic cancer cell line SUIT-2 were established in nude mice. Only liver metastasis was harvested and cultured. These metastatic cycles were repeated 5 times to establish a highly metastatic cell line, termed metastatic SUIT-2 (MS). We investigated proliferation and motility of MS cells compared with those of the parent SUIT-2. Microarray analysis was performed to investigate differences in gene expression. We also performed immunohistochemical analysis of 89 formalin-fixed, paraffin-embedded human pancreatic cancer tissue samples to investigate the clinical significance of MAL2 expression.
RESULTS:
MS cells showed a greater metastatic rate after orthotopic implantation than parental SUIT-2. MS cells had increased motility but decreased proliferation compared with parental SUIT-2. Microarray analyses showed that 26 genes were significantly upregulated (>10-fold) in MS cells compared with parental SUIT-2, particularly MAL2 expression. Immunohistochemical analysis showed that high expression of MAL2 was associated with a lesser survival of postoperative patients (P = .03) and a high rate of distant metastasis (P = .008).
CONCLUSION:
We characterized a newly established pancreatic cancer cell line with highly metastatic potential. MAL2 is a promising predictive marker for distant metastasis and short survival in patients with resected pancreatic cancer.
Copyright © 2013 Mosby, Inc. All rights reserved.
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| 18. |
Mahawithitwong P, Ouchida K, Ikenaga N, Fujita H, Zhao M, Kozono S, Shindo K, Ohtsuka T, Mizumoto K, Tanaka M, Kindlin-2 expression in peritumoral stroma is associated with poor prognosis in pancreatic ductal adenocarcinoma., Pancreas, 42, 4, 663-669, 2013.04, OBJECTIVES:
Kindlin-2 is a novel focal adhesion protein reported to be expressed in breast, lung, and gastric cancers. This study aimed to investigate the significance of kindlin-2 expression in pancreatic ductal adenocarcinomas (PDACs).
METHODS:
We performed immunohistochemical analysis on kindlin-2 on PDAC samples from 95 patients. We investigated the association between kindlin-2 expression and clinicopathological parameters of PDAC and the survival time of patients with PDAC who underwent pancreatectomy.
RESULTS:
Kindlin-2 was highly expressed in the peritumoral stroma of PDACs. Stromal kindlin-2 expression was related to nodal metastasis (P = 0.03). Univariate analysis showed that patients with positive kindlin-2 expression had significantly shorter survival times than those with negative kindlin-2 expression (P = 0.01). In addition, multivariate analysis revealed that kindlin-2 expression was an independent factor of poor prognosis in patients with PDAC after R0 resection (RR = 2.15; P = 0.04).
CONCLUSIONS:
Kindlin-2 expression in stromal components is significantly associated with poor prognosis of patients with PDAC, suggesting that kindlin-2 is a prognostic marker for patients with PDAC.
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| 19. |
Mahawithitwong P, Ohuchida K, Ikenaga N, Fujita H, Zhao M, Kozono S, Shindo K, Ohtsuka T, Aishima S, Mizumoto K, Tanaka M, Kindlin-1 expression is involved in migration and invasion of pancreatic cancer , Int J Oncol, 42, 4, 1360-1366, 2013.04, Abstract
Kindlin-1 is a novel focal adhesion protein that belongs to the kindlin family. Expression of kindlin-1 has recently been reported in lung and colon cancers, but there have been no studies on its expression in pancreatic cancer. This study aimed to investigate the expression and function of kindlin-1 in pancreatic cancer. Quantitative RT-PCR of Kindlin-1 mRNA was performed in various pancreatic cancer cell lines as well as normal pancreatic epithelial cells and fibroblasts. Immunohistochemical analysis of kindlin-1 was performed for pancreatic cancer tissues. The effects of kindlin-1 on the proliferation, migration and invasion of pancreatic cancer cells were investigated using an RNA interference technique. Kindlin-1 mRNA was highly expressed in the pancreatic cancer cell lines, but only slightly expressed in normal pancreatic epithelial cells and fibroblasts. The Kindlin-1 protein was heterogeneously expressed in the cytoplasm and membrane of pancreatic cancer cells, while normal ductal epithelial cells and stromal cells showed no expression. In vitro experiments involving knockdown of kindlin-1 in AsPC-1 and KP-2 cells revealed that the migratory and invasive abilities of the cells were significantly decreased (P |
| 20. |
Eguchi D, Ikenaga N, Ohuchida K, Kozono S, Cui L, Fujiwara K, Fujino M, Ohtsuka T, Mizumoto K, Tanaka M, Hypoxia enhances the interaction between pancreatic stellate cells and cancer cells via increased secretion of connective tissue growth factor, Journal of surgical research, 181, 2, 225-233, 2013.04, Abstract
BACKGROUND:
Pancreatic cancer (PC), a hypovascular tumor, thrives under hypoxic conditions. Pancreatic stellate cells (PSCs) promote PC progression by secreting soluble factors, but their functions in hypoxia are poorly understood. This study aimed to clarify the effects of hypoxic conditions on the interaction between PC cells and PSCs.
METHODS:
We isolated human PSCs from fresh pancreatic ductal adenocarcinomas and analyzed functional differences in PSCs between normoxia (21% O(2)) and hypoxia (1% O(2)), including expression of various factors related to tumor-stromal interactions. We particularly analyzed effects on PC invasiveness of an overexpressed molecule-connective tissue growth factor (CTGF)-in PSCs under hypoxic conditions, using RNA interference techniques.
RESULTS:
Conditioned media from hypoxic PSCs enhanced PC cell invasiveness more intensely than that from normoxic PSCs (P
CONCLUSION:
Hypoxia induces PSCs' secretion of CTGF, leading to enhancement of PC invasiveness. CTGF derived from hypoxia-stimulated PSCs may be a new therapeutic target for pancreatic cancer.
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| 21. |
Akagawa S, Ohuchida K, Torata N, Hattori M, Eguchi D, Fujiwara K, Kozono S, Cui L, Ikenaga N, Ohtsuka T, Aishima S, Mizumoto K, Oda Y, Tanaka M, Peritoneal myofibroblasts at metastatic foci promote dissemination of pancreatic cancer, Int J Oncol, 45, 1, 113-120, 2014.04, Myofibroblasts in the stroma of pancreatic cancers promote tumor proliferation, invasion and metastasis by increasing extracellular matrix and secretion of several growth factors. In contrast, the role of myofibroblasts at peritoneally disseminated sites of pancreatic cancer has not yet been determined. This study was designed to assess the role of myofibroblasts at peritoneally disseminated sites of pancreatic cancer. Three primary cultures of human peritoneal myofibroblasts (hPMFs) were established from disseminated sites of pancreatic cancer and their interactions with the SUIT-2 and CAPAN-1 human pancreatic cancer cell lines were analyzed in vitro. Using a model in BALB/c nu/nu mice, we compared the dissemination ability of intraperitoneally implanted pancreatic cancer cells, with and without hPMFs, and examined the presence of green fluorescent protein (GFP)-labeled hPMFs at peritoneally disseminated sites in mice. hPMFs significantly promoted the migration and invasion of pancreatic cancer cells (P |
| 22. |
Fujimura Y, Ikenaga N, Ohuchida K, Setoyama D, Irie M, Miura D, Wariishi H, Murata M, Mizumoto K, Hashizume M, Tanaka M, Mass spectrometry-based metabolic profiling of gemcitabine-sensitive and gemcitabine-resistant pancreatic cancer cells, Pancreas, 43, 2, 311-318, 2014.04, Abstract
OBJECTIVES:
Gemcitabine resistance (GR) is one of the critical issues for therapy for pancreatic cancer, but the mechanism still remains unclear. Our aim was to increase the understanding of GR by metabolic profiling approach.
METHODS:
To establish GR cells, 2 human pancreatic cancer cell lines, SUIT-2 and CAPAN-1, were exposed to increasing concentration of gemcitabine. Both parental and chemoresistant cells obtained by this treatment were subjected to metabolic profiling based on liquid chromatography-mass spectrometry.
RESULTS:
Multivariate statistical analyses, both principal component analysis and orthogonal partial least squares discriminant analysis, distinguished metabolic signature of responsiveness and resistance to gemcitabine in both SUIT-2 and CAPAN-1 cells. Among significantly different (P CONCLUSIONS:
These results suggest that metabolic profiling can isolate distinct features of pancreatic cancer in the metabolome of gemcitabine-sensitive and GR cells. These findings may contribute to the biomarker discovery and an enhanced understanding of GR in pancreatic cancer.. |
| 23. |
Yoshida S, Ikenaga N, Liu SB, Peng ZW, Chung J, Sverdlov DY, Miyamoto M, Kim YO, Ogawa S, Arch RH, Schuppan D, Popov Y, co-first author, Extrahepatic platelet-derived growth factor-β, delivered by platelets, promotes activation of hepatic stellate cells and biliary fibrosis in mice, Gastroenterology, 147, 6, 1378-92, 2014.04, Abstract
BACKGROUND & AIMS:
Platelet-derived growth factor-β (PDGFB) is a mitogen for hepatic stellate cells (HSCs). We studied the cellular sources of PDGFB and the effects of a high-affinity monoclonal antibody against PDGFB (MOR8457) in mouse models of biliary fibrosis.
METHODS:
Cellular sources of PDGFB were identified using quantitative reverse-transcription polymerase chain reaction, biochemical, and immunohistologic methods. Mice with advanced biliary fibrosis, MDR2(Abcb4)-null mice, and C57Bl/6 (control) mice were placed on 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-supplemented diets and were given weekly intraperitoneal injections of MOR8457. Platelets were depleted from MDR2-null mice by injection of an antibody against CD41, or inhibited with diets containing low-dose aspirin. Liver tissues were collected and analyzed by quantitative reverse-transcription PCR and histologic and biochemical analyses.
RESULTS:
Levels of PDGFB protein, but not messenger RNA, were increased in fibrotic livers of MDR2-null mice, compared with control mice. Platelet clusters were detected in the hepatic endothelium, in close proximity to HSCs, and were identified as a source of PDGFB protein in MDR2-null mice. Levels of the PDGFB were increased in serum samples from patients with early stages of liver fibrosis of various etiologies (F1-2, n = 16; P CONCLUSIONS:
Platelets produce PDGFB to activate HSC and promote fibrosis in MDR2-null mice and mice on DDC-supplemented diets. Antiplatelet therapy or selective inhibition of PDGFB might reduce biliary fibrosis in patients with liver disease.
Copyright © 2014 AGA Institute. Published by Elsevier Inc. All rights reserved.
KEYWORDS:
Chronic Liver Injury; Mouse Model; PBC; PSC. |
| 24. |
Ikenaga N, Liu SB, Sverdlov DY, Yoshida S, Nasser I, Ke Q, Kang PM, Popov Y, A new Mdr2(-/-) mouse model of sclerosing cholangitis with rapid fibrosis progression, early-onset portal hypertension, and liver cancer, Am J Pathol, 185, 2, 325-334, 2015.04, Abstract
We previously characterized the Mdr2(Abcb4)(-/-) mouse as a reproducible model of chronic biliary liver disease. However, it demonstrates relatively slow fibrosis progression, possibly due to its fibrosis-resistant genetic background. We aimed to improve the model by moving it onto a fibrosis-susceptible background. We generated novel BALB/c.Mdr2(-/-) mouse via genetic backcross onto highly fibrosis-susceptible BALB/c substrain, identified in inbred mouse strain screening. Liver fibrosis, portal pressure, and hepatic tumor burden in BALB/c.Mdr2(-/-) mice were studied up to 1 year of age in direct comparison to parental strain FVB.Mdr2(-/-). BALB/c.Mdr2(-/-) mice developed periductular onion-skin type fibrotic lesions and pronounced ductular reaction starting from 4 weeks of age. Compared to parental strain, BALB/c.Mdr2(-/-) mice demonstrated dramatically accelerated liver fibrosis, with threefold increase in collagen deposition and bridging fibrosis/early signs of cirrhosis at 12 weeks. This was accompanied by early-onset severe portal hypertension and twofold to fourfold increase in profibrogenic transcripts Col1a1 [procollagen α1(I)], Tgfb1, and Timp1. Primary liver cancers in BALB/c.Mdr2(-/-) developed earlier, with greater tumor burden compared to FVB.Mdr2(-/-). BALB/c.Mdr2(-/-) mice have unprecedented degree and rapidity of hepatic fibrosis progression and clinically relevant cirrhosis complications, such as early-onset portal hypertension and primary liver cancers. This new model will facilitate development of antifibrotic drugs and studies into mechanisms of biliary fibrosis progression.
Copyright © 2015 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.. |
| 25. |
Liu SB, Ikenaga N, Peng ZW, Sverdlov DY, Greenstein A, Smith V, Schuppan D, Popov Y, Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice., FASEB J, 30, 4, 1599-1609, 2016.04, Abstract
Collagen stabilization through irreversible cross-linking is thought to promote hepatic fibrosis progression and limit its reversibility. However, the mechanism of this process remains poorly defined. We studied the functional contribution of lysyl oxidase (LOX) to collagen stabilization and hepatic fibrosis progression/reversalin vivousing chronic administration of irreversible LOX inhibitor β-aminopropionitrile (BAPN, or vehicle as control) in C57Bl/6J mice with carbon tetrachloride (CCl4)-induced fibrosis. Fibrotic matrix stability was directly assessed using a stepwise collagen extraction assay and fibrotic septae morphometry. Liver cells and fibrosis were studied by histologic, biochemical methods and quantitative real-time reverse-transcription PCR. During fibrosis progression, BAPN administration suppressed accumulation of cross-linked collagens, and fibrotic septae showed widening and collagen fibrils splitting, reminiscent of remodeling signs observed during fibrosis reversal. LOX inhibition attenuated hepatic stellate cell activation markers and promoted F4/80-positive scar-associated macrophage infiltration without an increase in liver injury. In reversal experiments, BAPN-treated fibrotic mice demonstrated accelerated fibrosis reversal after CCl4withdrawal. Our findings demonstrate for the first time that LOX contributes significantly to collagen stabilization in liver fibrosis, promotes fibrogenic activation of attenuated hepatic stellate cells, and limits fibrosis reversal. Our data support the concept of pharmacologic targeting of LOX pathway to inhibit liver fibrosis and promote its resolution.-Liu, S. B., Ikenaga, N., Peng, Z.-W., Sverdlov, D. Y., Greenstein, A., Smith, V., Schuppan, D., Popov, Y. Lysyl oxidase activity contributes to collagen stabilization during liver fibrosis progression and limits spontaneous fibrosis reversal in mice.. |
| 26. |
Peng ZW, Ikenaga N, Liu SB, Sverdlov DY, Vaid KA, Dixit R, Weinreb PH, Violette S, Sheppard D, Schuppan D, Popov Y, Integrin αvβ6 critically regulates hepatic progenitor cell function and promotes ductular reaction, fibrosis, and tumorigenesis., Hepatology, 63, 1, 217-232, 2016.04, Abstract
Integrin αvβ6 is rapidly up-regulated on cells of epithelial lineage during tissue injury, where one of its primary functions is activation of latent transforming growth factor beta 1 (TGFβ1). In human liver cirrhosis, αvβ6 is overexpressed by cells comprising the ductular reaction, and its inhibition suppresses experimental biliary fibrosis in rodents. Here, we show that αvβ6 is expressed on the actively proliferating subset of hepatic progenitor cells and is required for their progenitor function in vivo and in vitro through integrin αvβ6-dependent TGFβ1 activation. Freshly isolated αvβ6(+) liver cells demonstrate clonogenic potential and differentiate into cholangiocytes and functional hepatocytes in vitro, whereas colony formation by epithelial cell adhesion molecule-positive progenitor cells is blocked by αvβ6-neutralizing antibody and in integrin beta 6-deficient cells. Inhibition of progenitors by anti-αvβ6 antibody is recapitulated by TGFβ1 neutralization and rescued by addition of bioactive TGFβ1. Genetic disruption or selective targeting of αvβ6 with 3G9 antibody potently inhibits progenitor cell responses in mouse models of chronic biliary injury and protects from liver fibrosis and tumorigenesis, two conditions clinically associated with exacerbated ductular reaction.
CONCLUSION:
These results suggest that αvβ6 is a promising target for chronic fibrotic liver diseases and associated cancers.. |
| 27. |
Peng ZW, Rothweiler S, Wei G, Ikenaga N, Liu SB, Sverdlov DY, Vaid KA, Longhi MS, Kuang M, Robson SC, Popov YV, The ectonucleotidase ENTPD1/CD39 limits biliary injury and fibrosis in mouse models of sclerosing cholangitis, Hepatol Commun, 10.1002/hep4.1084, 1, 9, 957-972, 2017.04, Abstract
The pathogenesis of primary sclerosing cholangitis (PSC) and the mechanistic link to inflammatory bowel disease remain ill-defined. Ectonucleoside triphosphate diphosphohydrolase-1 (ENTPD1)/clusters of differentiation (CD) 39, the dominant purinergic ecto-enzyme, modulates intestinal inflammation. Here, we have explored the role of CD39 in biliary injury and fibrosis. The impact of CD39 deletion on disease severity was studied in multidrug resistance protein 2 (Mdr2)-/- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine mouse models of sclerosing cholangitis and biliary fibrosis. Antibody-mediated CD8+ T-cell depletion, selective gut decontamination, experimental colitis, and administration of stable adenosine triphosphate (ATP) agonist were performed. Retinoic acid-induced gut imprinting on T cells was studied in vitro. Over half of Mdr2-/-;CD39-/- double mutants, expected by Mendelian genetics, died in utero. Compared to Mdr2-/-;CD39+/+, surviving Mdr2-/-;CD39-/- mice demonstrated exacerbated liver injury, fibrosis, and ductular reaction. CD39 deficiency led to a selective increase in hepatic CD8+ T cells and integrin α4β7, a T-cell gut-tropism receptor. CD8+ cell depletion in Mdr2-/-;CD39-/- mice diminished hepatobiliary injury and fibrosis. Treatment with antibiotics attenuated, whereas dextran sulfate sodium-induced colitis exacerbated, liver fibrosis in Mdr2-/- mice. Colonic administration of αβ-ATP into CD39-sufficient Mdr2-/- mice triggered hepatic CD8+ cell influx and recapitulated the severe phenotype observed in Mdr2-/-;CD39-/- mice. In vitro, addition of ATP promoted the retinoic acid-induced imprinting of gut-homing integrin α4β7 on naive CD8+ cells. CD39 expression was relatively low in human normal or PSC livers but abundantly present on immune cells of the colon and further up-regulated in samples of patients with inflammatory bowel disease. Conclusion: CD39 deletion promotes biliary injury and fibrosis through gut-imprinted CD8+ T cells. Pharmacological modulation of purinergic signaling may represent a promising approach for the treatment of PSC. (Hepatology Communications 2017;1:957-972).. |
| 28. |
Ikenaga N, Peng ZW, Vaid KA, Liu SB, Yoshida S, Sverdlov DY, Mikels-Vigdal A, Smith V, Schuppan D, Popov YV, Selective targeting of lysyl oxidase-like 2 (LOXL2) suppresses hepatic fibrosis progression and accelerates its reversal, Gut, 10.1136/gutjnl-2016-312473, 66, 9, 1697-1708, 2017.04, BACKGROUND/AIMS:We studied the role of lysyl oxidase-like 2 (LOXL2) in collagen crosslinking and hepatic progenitor cell (HPC) differentiation, and the therapeutic efficacy of a LOXL2-blocking monoclonal antibody on liver fibrosis progression/reversal in mice.METHODS:Anti-LOXL2 antibody, control antilysyl oxidase antibody or placebo was administered during thioacetamide (TAA)-induced fibrosis progression or during recovery. Therapeutic efficacy in biliary fibrosis was tested in BALB/c.Mdr2-/- and 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC)-fed mice. Collagen crosslinking, fibrosis progression and reversal were assessed histologically and biochemically. HPC differentiation was studied in primary EpCAM(+) liver cells in vitro.RESULTS:LOXL2 was virtually absent from healthy but strongly induced in fibrotic liver, with predominant localisation within fibrotic septa. Delayed anti-LOXL2 treatment of active TAA fibrosis significantly reduced collagen cro
sslinking and histological signs of bridging fibrosis, with a 53% reduction in morphometric collagen deposition. In established TAA fibrosis, LOXL2 inhibition promoted fibrosis reversal, with enhanced splitting and thinning of fibrotic septa, and a 45% decrease in collagen area at 4 weeks of recovery. In the Mdr2-/- and DDC-induced models of biliary fibrosis, anti-LOXL2 antibody similarly achieved significant antifibrotic efficacy and suppressed the ductular reaction, while hepatocyte replication increased. Blocking LOXL2 had a profound direct effect on primary EpCAM(+) HPC behaviour in vitro, promoting their differentiation towards hepatocytes, while inhibiting ductal cell lineage commitment.CONCLUSIONS:LOXL2 mediates collagen crosslinking and fibrotic matrix stabilisation during liver fibrosis, and independently promotes fibrogenic HPC differentiation. By blocking these two convergent profibrotic pathways, therapeutic LOXL2 inhibition attenuates both parenchymal and
biliary fibrosis and promotes fibrosis reversal.. |
| 29. |
Mori Y, Nakata K, Ideno N, Ikenaga N, Okabe Y, Ishigami K, Oda Y, Nakamura M, Congenital biliary dilatation in the era of laparoscopic surgery, focusing on the high incidence of anatomical variations of the right hepatic artery, J Hepatobiliary Pancreat Sci, 10.1002/JHBP.819, 27, 11, 870-876, 2020.04, Abstract
Background: The present study aimed to evaluate anatomical variations of the right hepatic artery (RHA) in patients with congenital biliary dilatation (CBD) and the appropriate approach in laparoscopic surgery for CBD.
Methods: The medical records of 36 patients who underwent laparoscopic or open surgery for CBD from 1996 to 2018 were retrospectively reviewed. Radiological evaluation of the origin and course of the RHA in these 36 patients were compared with 195 control patients without CBD.
Results: The incidence of the RHA crossing anterior to the common hepatic duct (CHD) was significantly higher in patients with CBD than in those without CBD (33% versus 10%, P = .0001). There was no intraoperative injury of the RHA, irrespective of the course of the RHA. The CHD was divided at the caudal side of the RHA in 11 of 12 patients (92%) with the anterior type of RHA, and in 13 of 24 patients (54%) with the posterior type of RHA (P = .03).
Conclusions: Patients with CBD had a higher incidence of the RHA crossing anterior to the CHD than patients without CBD. Preservation of the RHA in each situation is necessary during surgery for CBD in the era of laparoscopic surgery.
. |
| 30. |
Akiko Sagara, Kohei Nakata, Sokichi Matsumoto, Weiyu Guan, Tomohiko Shinkawa, Chika Iwamoto, Naoki Ikenaga, Kenoki Ohuchida, Masafumi Nakamura, Repositioning of duloxetine to target pancreatic stellate cells, Oncol Lett, 10.3892/ol.2021.13005, 22, 4, 744, 2021.04, Abstract
Pancreatic cancer cells (PCCs) are surrounded by an abundant stroma, which is produced by pancreatic stellate cells (PSCs). PSCs promote tumor cell proliferation and invasion. The objective of the current study was to identify compounds that suppress PSC activation. Gene expression profiles of cancer-derived fibroblasts and normal fibroblasts were used, and the pathway analysis suggested altered pathways that were chosen for validation. It was found that the 'neuroactive ligand-receptor interaction' pathway from the Kyoto Encyclopedia of Genes and Genomes pathway analysis was one of the altered pathways. Several compounds related with this pathway were chosen, and changes in PSC activity were investigated using fluorescence staining of lipid droplets, reverse transcription-quantitative PCR, western blotting, and invasion and migration assays. Among these candidates, duloxetine, a serotonin-noradrenaline reuptake inhibitor, was found to suppress PSC activation and disrupt tumor-stromal interaction. Thus, duloxetine may be a potential drug for suppressing PSC activation and pancreatic cancer growth.
Keywords: drug repositioning; duloxetine; pancreatic cancer; pancreatic stellate cells; tumor microenvironment.. |
| 31. |
Akiko Sagara, Kohei Nakata, Tomohiro Yamashita, Weiyu Guan, Pingshan Zhong, Sokichi Matsumoto, Sho Endo, Chika Iwamoto, Koji Shindo, Naoki Ikenaga, Taiki Moriyama, Kenoki Ohuchida, Kazuhiro Mizumoto, Masafumi Nakamura, New high-throughput screening detects compounds that suppress pancreatic stellate cell activation and attenuate pancreatic cancer growth, Pancreatology, 10.1016/j.pan.2021.04.002, 21, 6, 1071-1080, 2021.04, Abstract
Background/objectives: Pancreatic stellate cells (PSCs) are involved in abundant desmoplasia, which promotes cancer cell aggressiveness and resistance to anti-cancer drugs. Therefore, PSCs are suggested to be a promising therapeutic target by attenuating PSC activation to inhibit tumor-stromal interactions with pancreatic cancer cells. Here, we developed a screen to identify compounds that reduce the activity of PSCs and investigated the effect of candidates on pancreatic cancer.
Methods: Lipid droplet accumulation in PSCs was used to observe differences in PSC activity and a new high-throughput screening platform that quantified lipid droplets in PSCs was established. A library of 3398 Food and Drug Administration-approved drugs was screened by this platform. Validation assays were performed in vitro and in vivo.
Results: Thirty-two compounds were finally selected as candidate compounds by screening. These compounds decreased α-smooth muscle actin expression and inhibited autophagic flux in PSCs in vitro. Among the candidates, three drugs selected for validation assays inhibited the proliferation and migration of PSCs and invasion of cancer cells by disrupting tumor-stromal interactions. Production of extracellular matrix molecules was also decreased significantly by this treatment. In vivo testing in xenograft models showed that dopamine antagonist zuclopenthixol suppressed tumor growth; this suppression was significantly increased when combined with gemcitabine.
Conclusions: A new screening platform that focused on the morphological features of PSCs was developed. Candidate drugs from this screening suppressed PSC activation and tumor growth. This screening system may be useful to discover new compounds that attenuate PSC activation.
Keywords: Cell-based screen; Dopamine antagonist; Pancreatic cancer; Pancreatic stellate cell; Stromal targeting therapy.. |
| 32. |
Haimin Feng, Taiki Moriyama, Kenoki Ohuchida, Nan Sheng, Chika Iwamoto, Koji Shindo, Kengo Shirahane, Naoki Ikenaga, Shuntaro Nagai, Kohei Nakata, Kazuhiro Mizumoto, Masafumi Nakamura, N-acetyl cysteine induces quiescent-like pancreatic stellate cells from an active state and attenuates cancer-stroma interactions, J Exp Clin Cancer Res, 10.1186/s13046-021-01939-1, 40, 133, 1-19, 2021.04, Background: Pancreatic stellate cells (PSCs) occupy the majority of the pancreatic cancer microenvironment, contributing to aggressive behavior of pancreatic cancer cells (PCCs). Recently, anti-fibrotic agents have proven to be an effective strategy against cancer, but clinical trials have shown little efficacy, and the driving mechanism remains unknown. N-acetyl-cysteine (NAC) is often used for pulmonary cystic fibrosis. Pioglitazone, an agonist of peroxisome proliferator-activated receptor gamma, was habitually used for type II diabetes, but recently reported to inhibit metastasis of PCCs. However, few studies have focused on the effects of these two agents on cancer-stromal interactions.
Method: We evaluated the expression of α-smooth muscle actin (α-SMA) and the number of lipid droplets in PSCs cultured with or without NAC. We also evaluated changes in invasiveness, viability, and oxidative level in PSCs and PCCs after NAC treatment. Using an indirect co-culture system, we investigated changes in viability, invasiveness, and migration of PSCs and PCCs. Combined treatment effects of NAC and Pioglitazone were evaluated in PSCs and PCCs. In vivo, we co-transplanted KPC-derived organoids and PSCs to evaluate the effects of NAC and Pioglitazone's combination therapy on subcutaneous tumor formation and splenic xenografted mouse models.
Results: In vitro, NAC inhibited the viability, invasiveness, and migration of PSCs at a low concentration, but not those of PCCs. NAC treatment significantly reduced oxidative stress level and expression of α-SMA, collagen type I in PSCs, which apparently present a quiescent-like state with a high number of lipid droplets. Co-cultured PSCs and PCCs mutually promoted the viability, invasiveness, and migration of each other. However, these promotion effects were attenuated by NAC treatment. Pioglitazone maintained the NAC-induced quiescent-like state of PSCs, which were reactivated by PCC-supernatant, and enhanced chemosensitivity of PCCs. In vivo, NAC and Pioglitazone's combination suppressed tumor growth and liver metastasis with fewer stromal components and oxidative stress level.
Conclusion: NAC suppressed activated PSCs and attenuated cancer-stromal interactions. NAC induces quiescent-like PSCs that were maintained in this state by pioglitazone treatment.. |
| 33. |
Kohei Nakata, Yasuhisa Mori, Naoki Ikenaga, Noboru Ideno, Yusuke Watanabe, Yoshihiro Miyasaka, Takao Ohtsuka, Masafumi Nakamura, Management of postoperative pancreatic fistula after pancreatoduodenectomy: Analysis of 600 cases of pancreatoduodenectomy patients over a 10-year period at a single institution, Surgery., 10.1016/j.surg.2021.01.010, 169, 6, 1446-1453, 2021.04, Abstract
Background: Although postoperative pancreatic fistula (POPF) is a common and critical complication of pancreatoduodenectomy (PD), effective strategies to prevent POPF have not yet been completely developed. Because appropriate management of POPF is important to reduce the mortality rate after PD, in this study we aimed to evaluate our approach for the management of POPF after PD, including the postoperative course.
Methods: This retrospective study included 605 consecutive patients who underwent PD at our hospital between 2010 and 2020. All patients who developed POPF were first managed conservatively, with drainage tubes placed during surgery retained to manage POPF. In cases wherein conservative treatment was unsuccessful, open drainage, followed by continuous negative pressure and continuous irrigation, was used. For open drainage, the surgical wound was opened bluntly (approximate length, 5 cm) under local anesthesia, and the fluid was directly and completely drained.
Results: The prevalence of POPF of grades B and C was 15.4% (n = 93) and 0.33% (n = 2), respectively. Of these patients, 1 required reoperation, 43 recovered with conservative management only, 47 required open drainage, and 4 required image-guided percutaneous drainage. Postoperative hemorrhage with a pseudoaneurysm was identified in 3 (0.66%) patients. The postoperative in-hospital mortality rate was low (n = 1, 0.16%). The rate of successful POPF management was 98.9%.
Conclusion: Based on our high success rate in POPF management, we consider open drainage to be a safe primary management method for POPF.. |
| 34. |
Ryuichiro Kimura, Takao Ohtsuka, Makoto Kubo, Atsuko Kajihara, Atsushi Fujii, Yusuke Watanabe, Yasuhisa Mori, Naoki Ikenaga, Kohei Nakata, Koji Shindo, Kenoki Ohuchida, Masafumi Nakamura, FoundationOne® CDx gene profiling in Japanese pancreatic ductal adenocarcinoma patients: a single-institution experience , Surgery Today, 10.1007/s00595-020-02123-2
, 51, 4, 619-626, 2021.04, Abstract
Purpose: The aim of this study was to investigate the genetic mutation profiles of Japanese pancreatic ductal adenocarcinoma (PDAC) patients.
Methods: Next-generation sequencing was performed using FoundationOne® CDx on 17 PDAC patients who were treated by surgical resection at Kyushu University Hospital between February 2016 and January 2019. The tumor mutational burden and microsatellite instability status were also assessed.
Results: There were 16 patients (94%) with KRAS mutations, 13 (76%) with TP53 mutations, three (18%) with SMAD4 mutations, and one (6%) with a CDKN2A mutation. All patients had at least one pathogenic variant or a likely pathogenic variant. No patient had targeted therapies that matched with any clinical benefit according to FoundationOne® CDx. An unresectable PDAC patient with BRCA2-mutant disease was successfully treated by conversion surgery using platinum-based neoadjuvant chemotherapy.
Conclusions: Currently, FoundationOne® CDx might be difficult to use on PDAC patients, although further investigations with larger study populations are called for.
Keywords: FoundationOne; Gene profiling; Next-generation sequencing; Pancreatic cancer; Pancreatic ductal adenocarcinoma.
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| 35. |
Kohei Nakata, Takao Ohtsuka, Yoshihiro Miyasaka, Yusuke Watanabe, Noboru Ideno, Yasuhisa Mori, Naoki Ikenaga, Masafumi Nakamura, Evaluation of relationship between splenic artery and pancreatic parenchyma using three-dimensional computed tomography for laparoscopic distal pancreatectomy, Langenbecks Arch Surg, 10.1007/s00423-021-02101-3, 406, 6, 1885-1895, 2021.04, Abstract
Aim: Isolating the root of the splenic artery (SPA) is a challenging procedure in laparoscopic distal pancreatectomy (LDP). We investigated the usefulness of evaluation of the relationship between the SPA and pancreatic parenchyma using three-dimensional computed tomography (3D-CT).
Methods: In total, 104 patients were evaluated. The relationship between the SPA and pancreatic parenchyma was classified into two types: buried and non-buried. Video clips of 50 patients who underwent LDP requiring isolation of the SPA root were reviewed to determine whether the classification is related to difficulty of LDP.
Results: Of the 50 assessed patients who underwent LDP, the relationship between the SPA and pancreatic parenchyma was the buried type in 30 (60.0%) and non-buried type in 20 (40.0%). The buried type was associated with a significantly longer median operative time than the non-buried type (285.0 vs. 235.5 min, respectively; P
Conclusion: Preoperative 3D-CT around the pancreas is practical for predicting the difficulty of SPA isolation and determining the safety of the procedure.. |
| 36. |
Sokichi Matsumoto, Kohei Nakata, Akiko Sagara, Weiyu Guan, Naoki Ikenaga, Kenoki Ohuchida, Masafumi Nakamura, Efficient pre-treatment for pancreatic cancer using chloroquine-loaded nanoparticles targeting pancreatic stellate cells, Oncol Lett, 10.3892/ol.2021.12894, 22, 2, 633-633, 2021.04, Abstract
Pancreatic stellate cells (PSCs) play a key role in desmoplastic stroma, which is a characteristic of pancreatic ductal adenocarcinoma (PDAC), and they also enhance the malignancy of pancreatic cancer cells. Our previous study reported chloroquine's mitigating effects on PSC activation; however, the drug is known to induce adverse effects in clinical practice. The present study aimed to reduce chloroquine doses and develop a useful pre-treatment that targets PSCs using nanoparticles. Poly lactic-co-glycolic acid (PLGA) nanoparticles were used as carriers and loaded with indocyanine green (Nano-ICG) or chloroquine (Nano-CQ). Tumor accumulation of Nano-ICG was evaluated using an in vivo imaging system. The effects of chloroquine, Nano-CQ and/or chemotherapy drug gemcitabine were investigated in an orthotopic xenograft mouse model. Nano-ICG selectively accumulated in pancreatic tumors and persisted therein for over 7 days after administration. Additionally, Nano-ICG accumulated in the peritoneal metastasized regions, but not in the liver, kidney and normal pancreatic tissues. Nano-CQ reduced the density of activated PSCs at lower chloroquine doses and significantly restrained tumor progression in combination with gemcitabine. In conclusion, the PLGA nanosystem successfully delivered the drug to pancreatic tumors. Nano-CQ efficiently reduced PSC activation and may be a promising novel pre-treatment strategy for PDAC.
Keywords: chloroquine; combination therapy; desmoplasia; nanoparticles; orthotopic xenograft; pancreatic cancer; pancreatic ductal adenocarcinoma; pre-treatment; stroma.. |
| 37. |
Naoki Ikenaga, Takao Ohtsuka, Kohei Nakata, Yusuke Watanabe, Yasuhisa Mori, Masafumi Nakamura, Clinical significance of postoperative acute pancreatitis after pancreatoduodenectomy and distal pancreatectomy, Surgery, 10.1016/j.surg.2020.06.040, 169, 4, 732-737, 2021.04, Abstract
Background: The definition of postoperative acute pancreatitis as a specific complication of pancreatic surgery was proposed in 2016. Its presence and relevance have not been established, especially after a distal pancreatectomy.
Methods: Medical records of 319 patients who underwent pancreatoduodenectomy or distal pancreatectomy were analyzed. Postoperative acute pancreatitis was defined as an increase in serum amylase activity greater than the upper normal limit on postoperative day 1, according to Connor's definition of postoperative acute pancreatitis.
Results: Postoperative acute pancreatitis occurred in 63.4% of 153 of the patients undergoing pancreatoduodenectomy and 65.7% of the 166 undergoing distal pancreatectomies. Patients who developed postoperative acute pancreatitis after pancreatoduodenectomy experienced an increase in the rate of morbidity (22.7% vs 7.1%; P = .0137), including postoperative pancreatic fistula (18.6% vs 1.8%; P = .024), resulting in greater postoperative stays (21 days vs 17 days; P = .0008). Postoperative acute pancreatitis in association with an increased serum C-reactive protein ≥18.0 mg/dL (which we defined as a clinically relevant postoperative acute pancreatitis) more strongly indicated the occurrence of severe complications (P = .0032) and was an independent predictor of postoperative pancreatic fistula after pancreatoduodenectomy (odds ratio, 3.03; P = .0448). Patients who developed postoperative acute pancreatitis after distal pancreatectomy experienced similar postoperative courses regarding morbidity and the duration of postoperative stay.
Conclusion: The clinical relevance of postoperative acute pancreatitis differs after a pancreatoduodenectomy versus a distal pancreatectomy. The development of effective strategies for preventing postoperative acute pancreatitis might improve surgical outcomes after pancreatoduodenectomy.. |
| 38. |
Chika Iwamoto, Kenoki Ohuchida, Tomohiko Shinkawa, Sho Okuda, Yoshiki Otsubo, Takashi Okumura, Akiko Sagara, Kazuhiro Koikawa, Yohei Ando, Koji Shindo, Naoki Ikenaga, Kohei Nakata, Taiki Moriyama, Yoshihiro Miyasaka, Takao Ohtsuka, Masatoshi Eto, Koichi Akashi, Masafumi Nakamura, Bone marrow-derived macrophages converted into cancer-associated fibroblast-like cells promote pancreatic cancer progression, Cancer Lett., 10.1016/j.canlet.2021.04.013, 1, 512, 15-27, 2021.04, Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by a desmoplastic reaction caused by cancer-associated fibroblasts (CAFs), which provokes treatment resistance. CAFs are newly proposed to be heterogeneous populations with different functions within the PDAC microenvironment. The most direct sources of CAFs are resident tissue fibroblasts and mesenchymal stem cells, however, the origins and functions of CAF subtypes remain unclear. Here, we established allogeneic bone marrow (BM) transplantation models using spontaneous PDAC mice, and then investigated what subtype cells derived from BM modulate the tumor microenvironment and affect the behavior of pancreatic cancer cells (PCCs). BM-derived multilineage hematopoietic cells were engrafted in recipient pancreas, and accumulated at the invasive front and central lesion of PDAC. We identified BM macrophages-derived CAFs in tumors. BM-derived macrophages treated with PCC-conditioned media expressed CAF markers. BM-derived macrophages led the local invasion of PCCs in vitro and enhanced the tumor invasive growth in vivo. Our data suggest that BM-derived cells are recruited to the pancreas during carcinogenesis and that the specific subpopulation of BM-derived macrophages partially converted into CAF-like cells, acted as leading cells, and facilitated pancreatic cancer progression. The control of the conversion of BM-derived macrophages into CAF-like cells may be a novel therapeutic strategy to suppress tumor growth.. |
| 39. |
Tomohiko Shinkawa, Kenoki Ohuchida, Yuki Mochida, Kukiko Sakihama, Chika Iwamoto, Toshiya Abe, Noboru Ideno, Yusuke Mizuuchi, Koji Shindo, Naoki Ikenaga, Taiki Moriyama, Kohei Nakata, Yoshinao Oda, Masafumi Nakamura, Subtypes in pancreatic ductal adenocarcinoma based on niche factor dependency show distinct drug treatment responses
, J Exp Clin Cancer Res, 10.1186/s13046-022-02301-9, 41, 89, 1-20, 2022.04, Abstract
Background: Pancreatic ductal adenocarcinoma (PDAC) is characterized by abundant stroma in which microenvironmental (niche) factors promote PDAC progression. In mouse models, reduction of the stroma increased the proportion of poorly differentiated PDAC with a worse prognosis. Here, we aimed to clarify the effects of stroma on PDAC that may define the PDAC phenotype and induce distinct therapeutic responses.
Methods: The molecular features of PDAC based on differentiation grade were clarified by genome and transcriptome analysis using PDAC organoids (PDOs). We identified the dependency on niche factors that might regulate the differentiation grade. A three-dimensional co-culture model with cancer-associated fibroblasts (CAFs) was generated to determine whether CAFs provide niche factors essential for differentiated PDAC. PDOs were subtyped based on niche factor dependency, and the therapeutic responses for each subtype were compared.
Results: The expression profiles of PDOs differed depending on the differentiation grade. Consistent with the distinct profiles, well differentiated types showed high niche dependency, while poorly differentiated types showed low niche dependency. The three-dimensional co-culture model revealed that well differentiated PDOs were strongly dependent on CAFs for growth, and moderately differentiated PDOs showed plasticity to change morphology depending on CAFs. Differentiated PDOs upregulated the expression of mevalonate pathway-related genes correlated with the niche dependency and were more sensitive to simvastatin than poorly differentiated PDOs.
Conclusions: Our findings suggest that CAFs maintain the differentiated PDAC phenotype through secreting niche factors and induce distinct drug responses. These results may lead to the development of novel subtype-based therapeutic strategies.
Keywords: Cancer-associated fibroblast; Organoid; Statin; Stroma-targeting therapy; Subtype-based therapy; Tumor differentiation; Tumor microenvironment.. |
| 40. |
Masatoshi Murakami, Nao Fujimori, Akihisa Ohno, Kazuhide Matsumoto, Katsuhito Teramatsu, Yu Takamatsu, Ayumu Takeno, Takamasa Oono, Toshiya Abe, Noboru Ideno, Naoki Ikenaga, Kohei Nakata, Masafumi Nakamura, Kousei Ishigami, Yoshihiro Ogawa, Predictive factors of operability after neoadjuvant chemotherapy in resectable or borderline resectable pancreatic cancer: a single-center retrospective study, Discover Oncology, 10.1007/s12672-021-00462-1, 13, 1, 2022.04, Abstract
Background/aims: Recently neoadjuvant chemotherapy (NAC) for pancreatic cancer has been shown to be superior to upfront surgery, but it remains a matter of debate for resectable cases. In clinical practice, some resectable cases may become unresectable after NAC. This study aimed to reveal the outcomes after NAC and to clarify the characteristics of unresected cases.
Methods: The medical records of 142 patients who underwent NAC between 2016 and 2020 were retrospectively reviewed. Patient characteristics, effectiveness of NAC, and outcomes were compared between the surgical group and non-surgical group (NSG). Furthermore, the risk of recurrence limited to in the patients who received NAC with gemcitabine plus nab-paclitaxel, which were mostly administered in this cohort, following R0/R1 resection was assessed.
Results: The overall and R0 resection rates after NAC were 89.1% and 79.7%, respectively. The neutrophil to lymphocyte ratio (NLR) > 2.78 (p = 0.0120) and anatomical borderline resectable pancreatic cancer (p = 0.0044) revealed a statistically significantly correlation with the NSG. On the other hand, NAC week IIA (P = 0.0003) were significantly associated with recurrence. The tumor response rate was approximately 26.1%, and three patients with ≥ 30% reduction of primary tumor lost excision opportunities because of metastasis, interstitial pneumonia, and vascular invasion.
Conclusions: This study shows incomplete tumor shrinkage benefits, but pre-NAC NLR is a predictive factor for predicting operability after NAC. The NLR can be easily calculated by normal blood test, and can be considered as a suitable marker of operability.
Keywords: Neoadjuvant chemotherapy; Operability; Pancreatic cancer; Pancreatic neoplasms; Recurrence.. |
| 41. |
Yuichi Nagakawa, Kohei Nakata, Hitoe Nishino, Takao Ohtsuka, Daisuke Ban, Horacio J Asbun, Ugo Boggi, Jin He, Michael L Kendrick, Chinnusamy Palanivelu, Rong Liu, Shin-E Wang, Chung-Ngai Tang, Kyoichi Takaori, Mohammed Abu Hilal, Brian K P Goh, Goro Honda, Jin-Young Jang, Chang Moo Kang, David A Kooby, Yoshiharu Nakamura, Shailesh V Shrikhande, Christopher L Wolfgang, Anusak Yiengpruksawan, Yoo-Seok Yoon, Yusuke Watanabe, Shingo Kozono, Ruben Ciria, Giammauro Berardi, Giovanni Maria Garbarino, Ryota Higuchi, Naoki Ikenaga, Yoshiya Ishikawa, Aya Maekawa, Yoshiki Murase, Giuseppe Zimmitti, Filipe Kunzler, Zi-Zheng Wang, Leon Sakuma, Chie Takishita, Hiroaki Osakabe, Itaru Endo, Masao Tanaka, Hiroki Yamaue, Minoru Tanabe, Go Wakabayashi, Akihiko Tsuchida, Masafumi Nakamura, International expert consensus on precision anatomy for minimally invasive pancreatoduodenectomy: PAM-HBP surgery project, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1081, 29, 1, 124-135, 2022.04, Abstract
Background: The anatomical structure around the pancreatic head is very complex and it is important to understand its precise anatomy and corresponding anatomical approach to safely perform minimally invasive pancreatoduodenectomy (MIPD). This consensus statement aimed to develop recommendations for elucidating the anatomy and surgical approaches to MIPD.
Methods: Studies identified via a comprehensive literature search were classified using the Scottish Intercollegiate Guidelines Network method. Delphi voting was conducted after experts had drafted recommendations, with a goal of obtaining >75% consensus. Experts discussed the revised recommendations with the validation committee and an international audience of 384 attendees. Finalized recommendations were made after a second round of online Delphi voting.
Results: Three clinical questions were addressed, providing six recommendations. All recommendations reached at least a consensus of 75%. Preoperatively evaluating the presence of anatomical variations and superior mesenteric artery (SMA) and superior mesenteric vein (SMV) branching patterns was recommended. Moreover, it was recommended to fully understand the anatomical approach to SMA and intraoperatively confirm the SMA course based on each anatomical landmark before initiating dissection.
Conclusions: MIPD experts suggest that surgical trainees perform resection based on precise anatomical landmarks for safe and reliable MIPD.
Keywords: consensus; minimally invasive surgical procedures; pancreatoduodenectomy; robotic surgery; superior mesenteric artery.. |
| 42. |
Daisuke Ban, Hitoe Nishino, Takao Ohtsuka, Yuichi Nagakawa, Mohammed Abu Hilal, Horacio J Asbun, Ugo Boggi, Brian K P Goh, Jin He, Goro Honda, Jin-Young Jan, Chang Moo Kang, Michael L Kendrick, David A Kooby, Rong Liu, Yoshiharu Nakamura, Kohei Nakata, Chinnusamy Palanivelu, Shailesh V Shrikhande, Kyoichi Takaori, Chung-Ngai Tang, Shin-E Wan, Christopher L Wolfgang, Anusak Yiengpruksawan, Yoo-Seok Yoon, Ruben Ciria, Giammauro Berardi, Giovanni Maria Garbarino, Ryota Higuchi, Naoki Ikenaga, Yoshiya Ishikawa, Shingo Kozono, Aya Maekawa, Yoshiki Murase, Yusuke Watanabe, Giuseppe Zimmitti, Filipe Kunzler, Zi-Zheng Wang, Leon Sakuma, Hiroaki Osakabe, Chie Takishita, Itaru Endo, Masao Tanaka, Hiroki Yamaue, Minoru Tanabe, Go Wakabayashi, Akihiko Tsuchida, Masafumi Nakamura, International Expert Consensus on Precision Anatomy for minimally invasive distal pancreatectomy: PAM-HBP Surgery Project, J Hepatobiliary Pancreat Sci, 10.1002/jhbp.1071, 29, 1, 161-173, 2022.04, Background: Surgical views with high resolution and magnification have enabled us to recognize the precise anatomical structures that can be used as landmarks during minimally invasive distal pancreatectomy (MIDP). This study aimed to validate the usefulness of anatomy-based approaches for MIDP before and during the Expert Consensus Meeting: Precision Anatomy for Minimally Invasive HBP Surgery (February 24, 2021).
Methods: Twenty-five international MIDP experts developed clinical questions regarding surgical anatomy and approaches for MIDP. Studies identified via a comprehensive literature search were classified using Scottish Intercollegiate Guidelines Network methodology. Online Delphi voting was conducted after experts had drafted the recommendations, with the goal of obtaining >75% consensus. Experts discussed the revised recommendations in front of the validation committee and an international audience of 384 attendees. Finalized recommendations were made after a second round of online Delphi voting.
Results: Four clinical questions were addressed, resulting in 10 recommendations. All recommendations reached at least a 75% consensus among experts.. |
| 43. |
Yusuke Watanabe, Kohei Nakata, Yasuhisa Mori, Noboru Ideno, Naoki Ikenaga, Takao Ohtsuka, Masafumi Nakamura, Extensive (subtotal) distal pancreatectomy for pancreatic ductal adenocarcinoma: a propensity score matched cohort study of short- and long-term outcomes compared with those of conventional distal pancreatectomy, Langenbecks Arch Surg, 10.1007/s00423-022-02453-4, 407, 4, 1479-1488, 2022.04, Abstract
Purpose: Extensive distal pancreatectomy (ExDP) can transect the pancreatic parenchyma more from the right side than conventional distal pancreatectomy (CDP) can. This study aimed to evaluate the short- and long-term outcomes of ExDP for pancreatic ductal adenocarcinoma (PDAC) of the pancreatic body, located adjacent to the portal vein (PV).
Methods: Medical records of 98 patients who underwent ExDP (n = 15) or CDP (n = 83) for PDAC were retrospectively reviewed. Short- and long-term outcomes of the two groups were compared. Propensity score matched analysis was additionally performed to minimize the impact of treatment allocation bias.
Results: In the total cohort, the CDP group had a significantly higher proportion of pancreatic tail lesions (P Conclusions: Surgical and oncological outcomes after ExDP for PDAC were acceptable and comparable to those after CDP. ExDP is a feasible procedure, and could be an option for the treatment of PDAC of the pancreatic body near PV.
Keywords: Distal pancreatectomy; Extensive distal pancreatectomy; Pancreatic cancer; Pancreatic ductal adenocarcinoma; Subtotal distal pancreatectomy.. |
| 44. |
Weiyu Guan, Kohei Nakata, Akiko Sagara, Chika Iwamoto, Sho Endo, Ryota Matsuda, Sokichi Matsumoto, Naoki Ikenaga, Koji Shindo, Taiki Moriyama, Hideya Onishi, Kenoki Ohuchida, Yoshinao Oda, Masafumi Nakamura, ERAP2 is a novel target involved in autophagy and activation of pancreatic stellate cells via UPR signaling pathway, Pancreatology, 10.1016/j.pan.2021.09.012, 22, 1, 9-19, 2022.04, Abstract
Background/objectives: Pancreatic ductal adenocarcinoma (PDAC) is characterized by excessive desmoplasia and autophagy-dependent tumorigenic growth. Pancreatic stellate cells (PSCs) as a predominant stromal cell type play a critical role in PDAC biology. We have previously reported that autophagy facilitates PSC activation, however, the mechanism remains unknown. We investigated the mechanism of autophagy in PSC activation.
Methods: We compared gene expression profiles between patient-derived PSCs from pancreatic cancer and chronic pancreatitis using a microarray. The stromal expression of target gene in specimen of PDAC patients (n = 63) was analyzed. The effect of target gene on autophagy and activation of PSCs was investigated by small interfering RNAs transfection, and the relationship between autophagy and ER stress was investigated. We analyzed the growth and fibrosis of xenografted tumor by orthotopic models.
Results: In analysis of gene expression microarray, endoplasmic reticulum aminopeptidase 2 (ERAP2) upregulated in cancer-associated PSCs was identified as the target gene. High stromal ERAP2 expression is associated with a poor prognosis of PDAC patients. Knockdown of ERAP2 inhibited unfolded protein response mediated autophagy, and led to inactivation of PSCs, thereby attenuating tumor-stromal interactions by inhibiting production of IL-6 and fibronectin. In vivo, the promoting effect of PSCs on xenografted tumor growth and fibrosis was inhibited by ERAP2 knockdown.
Conclusions: Our findings demonstrate a novel mechanism of PSCs activation regulated by autophagy. ERAP2 as a promising therapeutic target may provide a novel strategy for the treatment of PDAC.
Keywords: Endoplasmic reticulum stress; Stromal remodeling; Tumor-stromal interaction; Tunicamycin.. |
| 45. |
Yasuhisa Mori, Kohei Nakata, Noboru Ideno, Naoki Ikenaga, Yasuhiro Okabe, Masafumi Nakamura, Efficacy of Distal Pancreatectomy Combined With Modified DuVal Procedure in Patients With a High Risk of Postoperative Pancreatic Fistula, The American Surgeon, 10.1177/0003134821995088, 88, 6, 1244-1249, 2022.04, Abstract
Background: The incidence of postoperative pancreatic fistula (POPF) after distal pancreatectomy (DP) remains high. The present study aimed to clarify the efficacy of our modified DuVal (mDuVal) pancreatojejunostomy following DP in patients with a high risk of POPF.
Methods: The medical records of 346 consecutive patients who underwent DP between 2006 and 2016 were retrospectively reviewed. Perioperative features were compared between 24 patients undergoing mDuVal (mDuVal group) and 322 patients undergoing standard DP (standard DP group).
Results: Preoperative American Society of Anesthesiologists physical status 1 was more frequent in the standard group than in the mDuVal group (P = .02). The start of a solid diet after operation was significantly earlier in the mDuVal group than in the standard DP group (P = .01), while there were no significant differences between the groups for clinically relevant POPF, amylase concentration in the drainage fluid on postoperative day 1 and days 3-5, time to drain removal, additional intervention for POPF, overall complications, or postoperative hospital stay.
Discussion: The mDuVal procedure could be an option for patients with a high risk of POPF to improve the outcomes after DP. Further investigation involving large study populations is necessary to clarify the efficacy of this procedure.
Keywords: pancreatectomy; pancreatic fistula; postoperative complications.. |
| 46. |
Naoki Ikenaga, Kohei Nakata, Nobuhiro Fujita, Toshiya Abe, Noboru Ideno, Kousei Ishigami, Masafumi Nakamura, Clinical significance of postpancreatectomy acute pancreatitis defined by the International Study Group for Pancreatic Surgery, Ann Gastroenterol Surg, 10.1002/ags3.12587, 6, 6, 842-850, 2022.04. |
| 47. |
Sho Okuda, Kenoki Ohuchida, Koji Shindo, Taiki Moriyama, Jun Kawata, Koji Tamura, Masafumi Sada, Kinuko Nagayoshi, Yusuke Mizuuchi, Naoki Ikenaga, Kohei Nakata, Yoshinao Oda, Masafumi Nakamura, Clinical impact of remnant lymphatic invasion on the recurrence of esophageal squamous cell carcinoma after esophagectomy with neoadjuvant chemotherapy, Oncol Lett, 10.3892/ol.2022.13457, 24, 4, 337, 2022.04, For stage II and III esophageal squamous cell carcinoma (ESCC), neoadjuvant chemotherapy (NAC) followed by esophagectomy is recommended in the Japanese guidelines for the diagnosis and treatment of esophageal cancer. However, recurrence of ESCC is common regardless of the NAC regimen and surgical method, and NAC demonstrates limited efficacy against recurrence. Therefore, the present study was conducted to identify risk factors of recurrence of ESCC with surgery after NAC. The outcomes of 51 patients who underwent esophagectomy for ESCC after NAC from 2010 to 2017 at Kyushu University Hospital were retrospectively analyzed. A total of 52 patients with ESCC without NAC followed by esophagectomy from 2001 to 2017 were selected for comparison. Among patients who underwent NAC followed by surgery, only lymphatic invasion (LY; hazard ratio, 2.761; 95% CI, 1.86-6.43, P=0.018) was an independent factor significantly associated with 3-year recurrence-free survival in the multivariate analysis. In patients with pathologic lymph node metastasis (pN) and no LY after NAC, there was significantly less recurrence compared with patients with pN and LY (P=0.0085), whereas in patients without LY after NAC, the presence of pN was not significantly associated with recurrence (P=0.2401). There were significantly fewer LY (+) patients in the NAC (+) group (P=0.0158) compared with those in the NAC (-) group. The presence of LY was an independent risk factor for recurrence of ESCC after esophagectomy following NAC. Overall, adjuvant treatment after surgery may be required in cases with remnant LY after NAC.
Keywords: esophageal squamous cell carcinoma; lymphatic invasion; neoadjuvant chemotherapy; recurrence factor.. |
| 48. |
Naoki Ikenaga, Kohei Nakata, Toshiya Abe, Noboru Ideno, Nao Fujimori, Takamasa Oono, Nobuhiro Fujita, Kousei Ishigami, Masafumi Nakamura, Risks and benefits of pancreaticoduodenectomy in patients aged 80 years and over, Langenbecks Arch Surg, 10.1007/s00423-023-02843-2., 408, 108, 108, 2023.04, Purpose: The frequency of pancreaticoduodenectomy is increasing in oldest old patients owing to population aging. We aimed to clarify the clinical significance of pancreaticoduodenectomy in patients aged ≥ 80 years with multiple underlying diseases.
Methods: A total of 649 consecutive patients who underwent pancreaticoduodenectomy from April 2010 to March 2021 in our institute were divided into two groups according to their age: ≥ 80 years (51) and ≤ 79 years (598). We compared mortality and morbidity between the groups. The age-related prognosis was analyzed in 302 patients who underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma treatment.
Results: There were no significant differences in morbidity (Clavien-Dindo classification grade III or higher; P = 0.1300), mortality (P = 0.0786), or postoperative hospital stay (P = 0.5763) between the groups. Patients aged ≥ 80 years, who underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma, had shorter overall survival than those aged ≤ 79 years (median survival time, 16.7 months vs. 32.7 months; P = 0.0206). However, the overall survival of patients aged ≥ 80 years who received perioperative chemotherapy was comparable to that of patients aged ≤ 79 years (P = 0.9795). In the multivariate analysis, the absence of perioperative chemotherapy was identified as an independent prognostic factor, while age ≥ 80 years was not. Perioperative chemotherapy was the sole independent prognostic factor in patients aged ≥ 80 years who underwent pancreaticoduodenectomy for pancreatic ductal adenocarcinoma.
Conclusions: Pancreaticoduodenectomy is safe for patients aged ≥ 80 years. The survival benefits of pancreaticoduodenectomy for patients with pancreatic ductal adenocarcinoma aged ≥ 80 years might be limited to those who can receive perioperative chemotherapy.
Keywords: Adenocarcinoma; Aged; Chemotherapy; Pancreaticoduodenectomy; Survival analysis.. |
| 49. |
Toshiya Abe, Kohei Nakata, So Nakamur, Noboru Ideno, Naoki Ikenaga, Nobuhiro Fujita, Kousei Ishigami, Kazuyoshi Nishihara, Masafumi Nakamura, Prognostic Impact of Preoperative Osteosarcopenia for Patients with Pancreatic Ductal Adenocarcinoma After Curative Resection, Ann Surg Oncol, 10.1245/s10434-023-13936-z, 30, 11, 6673-6679, 2023.04, Backgrounds: The clinical significance of preoperative osteosarcopenia in pancreatic ductal adenocarcinoma (PDAC) has not been fully studied. The purpose of this study was to evaluate the role of preoperative osteosarcopenia in predicting the survival of patients with PDAC.
Methods: We retrospectively analyzed 265 patients who underwent curative surgical resection for PDAC between 2012 and 2018 in two Japanese institutes. The skeletal muscle index at the L3 vertebrae and the bone mineral density at the Th11 vertebra were calculated for the evaluation of osteosarcopenia before surgery. The relationship between perioperative osteosarcopenia and clinicopathological factors and prognosis was analyzed.
Results: The median overall survival (OS) and disease-free survival (DFS) of patients with osteosarcopenia were significantly shorter than those of patients without osteosarcopenia (OS: 23 and 48 months, respectively, P Conclusions: Preoperative osteosarcopenia may be a useful prognostic factor in patients with PDAC who undergo surgical resection. Further studies are needed to assess whether perioperative, nutritional interventions and rehabilitation contribute to improving the prognosis of these patients.. |
| 50. |
Kohei Nakata, Toshiya Abe, Noboru Ideno, So Nakamura, Naoki Ikenaga, Kinuko Nagayoshi, Yusuke Mizuuchi, Taiki Moriyama, Kenoki Ohuchida, Masafumi Nakamura, Minimally invasive distal pancreatectomy for pancreatic cancer: cranial-to-caudal approach with identification of Gerota's fascia (with video), Surg Endosc, 10.1007/s00464-023-10438-7, 37, 11, 8901-8909, 2023.04, Background: Although radical antegrade modular pancreatosplenectomy for pancreatic ductal adenocarcinoma (PDAC) has become the gold standard procedure in open distal pancreatectomy, there has been no gold standardized procedure for PDAC in minimally invasive distal pancreatectomy (MIDP). In this study, we analyzed our novel cranial-to-caudal approach (CC approach) for patients undergoing MIDP and provide a video clip illustrating the details of the CC approach.
Methods: Ninety-four patients who underwent MIDP with splenectomy between 2016 and 2021 were included in this study. The CC approach was performed in 23 (24.5%) of the 94 patients. The concept of the CC approach is easy identification of Gerota's fascia from the cranial side of the pancreas and secure tumor removal (R0 resection) wrapped by Gerota's fascia. The short- and long-term outcomes were compared between the CC and non-CC approaches.
Results: The median operation time and blood loss were similar between the two groups. The ratios of grade ≥ B postoperative pancreatic fistula and Clavien-Dindo grade ≥ III complications were also comparable. All patients in the CC approach group achieved R0 resection, and the R0 ratio was similar in the two groups (p = 0.345). The 2-year survival rate in CC and non-CC approach groups was 87.5% and 83.6%, respectively (p = 0.903).
Conclusions: The details of the CC approach for MIDP were demonstrated based on an anatomical point of view. This approach has the potential to become a standardized approach for left-sided PDAC.
Keywords: Approach; Distal pancreatectomy; Minimally invasive pancreatectomy.. |
| 51. |
Shuang Fei, Kenoki Ohuchida, Shin Kibe, Zilong Yan, Chika Iwamoto, Tomohiko Shinkawa, Bo Zhang, Jun Kawata, Toshiya Abe, Noboru Ideno, Naoki Ikenaga, Kohei Nakata, Yoshinao Oda, Masafumi Nakamura, Involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia lesion of pancreatic cancer invasive front, Gastric Cancer, 10.1007/s00432-022-04554-5., 149, 9, 5885-5899, 2023.04, Purpose: This study aimed to demonstrate the involvement of angiogenesis in cancer-associated acinar-to-ductal metaplasia (CA-ADM) lesion of invasive front pancreatic ductal adenocarcinoma (PDAC) and investigate the possible mechanism.
Methods: Tissue samples from 128 patients with PDAC and 36 LSL-KrasG12D/+; LSL-Trp53R172H/+; Pdx-1-Cre mice were analyzed. Immunohistochemical assay was performed using HE, anti-CK19 and anti-amylase to confirm the presence of CA-ADM lesions, using anti-CD34 and anti-CD31 to measure microvessel density (MVD), and using anti-CD68, anti-CD163, anti-iNOS, or anti-MMP9 to evaluate the immune microenvironment. We performed multiplex immunohistochemical assay to detect the co-expression of MMP9 and CD68 on macrophage. We examined clinical outcomes and other clinicopathological factors to determine the significance of high-level MVD of CA-ADM on survival and liver metastasis. We performed tube formation assay to evaluate the effect of macrophage on angiogenic capacity in vitro.
Results: Angiogenesis was significantly abundant in CA-ADM lesions compared with that in PDAC lesions in human and mouse tissues. High-level MVD in CA-ADM lesions was an independent predictor of poor prognosis (P = 0.0047) and the recurrence of liver metastasis (P = 0.0027). More CD68-positive and CD163-positive macrophages were detected in CA-ADM lesions than in PDAC. The percentage of CD68-positive macrophages was positively correlated with MVD in CA-ADM lesions. Multiplex-immunostaining revealed that MMP9 was expressed in CD68-positive macrophages of CA-ADM lesions. In CA-ADM lesions, the percentage of macrophages was positively correlated with MMP9 expression, which positively correlated with microvessel density.
Conclusion: CA-ADM related angiogenesis is a promising predictive marker for poor prognosis of PDAC and may provide an attractive therapeutic target for PDAC.
Keywords: Angiogenesis; Cancer-associated acinar-to-ductal metaplasia; Liver metastasis; Macrophages; Pancreatic cancer; Prognosis.. |
| 52. |
Masataka Hayashi, Naoki Ikenaga, Kohei Nakata, Haizhen Luo, PingShan Zhong, Satomi Date, Koki Oyama, Nobuhiro Higashijima, Akihiro Kubo, Chika Iwamoto, Nobuhiro Torata, Toshiya Abe, Yutaka Yamada, Kenoki Ohuchida, Yoshinao Oda, Masafumi Nakamura, Intratumor Fusobacterium nucleatum promotes the progression of pancreatic cancer via the CXCL1-CXCR2 axis, Cancer Science, 10.1111/cas.15901 , 114, 9, 3666-3678, 2023.04, Intratumor bacteria modify the tumor immune microenvironment and influence outcomes of various tumors. Periodontal pathogen Fusobacterium nucleatum has been detected in pancreatic cancer tissues and is associated with poor prognosis. However, it remains unclear how F. nucleatum affects pancreatic cancer. Here, we compared clinical features with F. nucleatum colonization in pancreatic cancer tissues. F. nucleatum was detected in 15.5% (13/84) of pancreatic cancer patients. The tumor size was significantly larger in the F. nucleatum-positive group than in the negative group. To clarify the biological effect of intratumor F. nucleatum on pancreatic cancer progression, we performed migration/invasion assays and cytokine array analysis of cancer cells cocultured with F. nucleatum. F. nucleatum promoted CXCL1 secretion from pancreatic cancer cells, leading to cancer progression through autocrine signaling. Intratumor F. nucleatum suppressed tumor-infiltrating CD8+ T cells by recruiting myeloid-derived suppressor cells (MDSCs) to the tumor in an F. nucleatum-injected subcutaneous pancreatic cancer mouse model, resulting in tumor progression. Furthermore, tumor growth accelerated by F. nucleatum was suppressed by MDSC depletion or cytokine inhibitors. Intratumor F. nucleatum promoted pancreatic cancer progression through autocrine and paracrine mechanisms of the CXCL1-CXCR2 axis. Blockade of the CXCL1-CXCR2 axis may be a novel therapeutic approach for patients with intratumor F. nucleatum-positive pancreatic cancer.
Keywords: Fusobacterium nucleatum; CXCL1; CXCR2; pancreatic cancer; tumor immune microenvironment.. |
| 53. |
Naoki Ikenaga, Kohei Nakata, Masataka Hayashi, So Nakamura, Toshiya Abe, Noboru Ideno, Masatoshi Murakami, Nao Fujimori, Nobuhiro Fujita, Takuro Isoda, Shingo Baba, Kousei Ishigami, Yoshinao Oda, Masafumi Nakamura, Clinical Implications of FDG-PET in Pancreatic Ductal Adenocarcinoma Patients Treated with Neoadjuvant Therapy, J Gastrointest Surg, 10.1007/s11605-023-05591-2, 27, 2, 337-346, 2023.04, urpose: To evaluate the clinical significance of 18F-fluorodeoxyglucose positron emission tomography/computed tomography in patients with pancreatic ductal adenocarcinoma who underwent neoadjuvant therapy.
Methods: Among 285 consecutive patients who underwent pancreatic resection for pancreatic ductal adenocarcinoma between 2015 and 2021, 86 who underwent preoperative 18F-fluorodeoxyglucose positron emission tomography/computed tomography after completion of neoadjuvant treatment were reviewed. Among preoperative factors, including post-treatment maximum standardized uptake value, predictors of early recurrence and poor prognosis were identified using multivariate analysis for decision making in surgery.
Results: Nineteen (22%) patients with pancreatic ductal adenocarcinoma demonstrated high maximum standardized uptake (≥ 4.5). High post-treatment maximum standardized uptake (≥ 4.5) predicted early recurrence within 6 months after surgery and correlated with shorter recurrence-free survival. Elevated post-treatment CA19-9 level (> 37 U/ml) and maximum standardized uptake ≥ 4.5 were independent prognostic factors. Post-treatment, a high maximum standardized uptake value indicated a poorer prognosis than a low maximum standardized uptake value in both patients with elevated CA19-9 and normal CA19-9 levels. The median overall survival in patients with elevated post-treatment CA19-9 and high maximum standardized uptake was only 17 months; 67% experienced early recurrence. Dynamic changes in maximum standardized uptake during neoadjuvant therapy were correlated with pathological response to neoadjuvant therapy, but not with radiological response or change in CA19-9 level.
Conclusions: Post-treatment assessment using maximum standardized uptake value is useful for stratifying patients with pancreatic ductal adenocarcinoma who will benefit from surgery. Instead of subsequent curative resection, additional neoadjuvant therapy should be considered in patients with a persistently high maximum standardized uptake value.
Keywords: 18F-fluorodeoxyglucose positron emission tomography/computed tomography; Neoadjuvant; Pancreatic ductal adenocarcinoma; Recurrence; Standardized uptake value.. |
| 54. |
Naoki Ikenaga, Yoshihiro Miyasaka, Takao Ohtsuka, Kohei Nakata, Tomohiko Adachi, Susumu Eguchi, Kazuyoshi Nishihara, Masafumi Inomata, Hiroshi Kurahara, Toru Hisaka, Hideo Baba, Hiroaki Nagano, Toshiharu Ueki, Hirokazu Noshiro, Shoji Tokunaga, Kousei Ishigami, Masafumi Nakamura, ASO Visual Abstract: A Prospective, Multicenter, Phase II, Trial of Neoadjuvant Chemotherapy with Gemcitabine Plus Nab-Paclitaxel for Borderline Resectable Pancreatic Cancer with Arterial Involvement, Clinical Trial, 10.1245/s10434-022-12611-z, 30, 1, 205-206, 2023.04. |
| 55. |
Naoki Ikenaga, Yoshihiro Miyasaka, Takao Ohtsuka, Masafumi Nakamura, ASO Author Reflections: Novel Evidence on Neoadjuvant Chemotherapy for Borderline Resectable Pancreatic Cancer with Arterial Involvement, Ann Surg Oncol, 10.1245/s10434-022-12584-z., 30, 1, 203-204, 2023.04. |
| 56. |
Naoki Ikenaga, Yoshihiro Miyasaka, Takao Ohtsuka, Kohei Nakata, Tomohiko Adachi, Susumu Eguchi, Kazuyoshi Nishihara, Masafumi Inomata, Hiroshi Kurahara, Toru Hisaka, Hideo Baba, Hiroaki Nagano, Toshiharu Ueki, Hirokazu Noshiro, Shoji Tokunaga, Kousei Ishigami, Masafumi Nakamura, A Prospective Multicenter Phase II Trial of Neoadjuvant Chemotherapy with Gemcitabine Plus Nab-Paclitaxel for Borderline Resectable Pancreatic Cancer with Arterial Involvement, Ann Surg Oncol, 10.1245/s10434-022-12566-1
Abstract, 30, 1, 193-202, 2023.04, Background: Only two clinical trials have shown the effects of neoadjuvant treatment for borderline resectable pancreatic cancer with arterial involvement (BRPC-A). Here, we aimed to analyze the efficacy and safety of neoadjuvant gemcitabine plus nab-paclitaxel (GnP) for BRPC-A.
Patients and methods: A prospective, single-arm, multicenter phase II trial was conducted. Patients who were radiologically and histologically diagnosed with BRPC-A were enrolled. A central review was conducted to confirm the presence of BRPC-A. Patients received two to four cycles of GnP before surgery. The primary endpoint of the study was the R0 resection rate. Overall survival (OS) was evaluated in an ancillary study.
Results: Thirty-five patients were enrolled, of whom 33 were subjected to central review and 28 were confirmed to have BRPC-A. All eligible patients with BRPC-A received neoadjuvant GnP. Nineteen patients underwent pancreatic resections. Postoperative complications of Clavien-Dindo IIIa or lower were observed in 11 patients. No treatment-related mortalities were observed. R0 resection was achieved in 17 patients (89%); the R0 resection rate was 61% in eligible patients. One patient underwent curative resection after termination of the treatment protocol, resulting in an overall R0 resection rate of 64%. The median overall survival (OS) and 2-year OS rate were 24.9 months [95% confidence interval (CI) 19.0 months to not estimatable] and 53.6%, respectively. OS in patients with BRPC-A who achieved overall R0 resection was significantly longer than that in the other patients (p = 0.0255).. |
| 57. |
kohei Nakata, Toshiya Abe, Noboru Ideno, So Nakamura, Naoki Ikenaga, Kinuko Nagayoshi, Yusuke Mizuuchi, Taiki Moriyama, Kenoki Ohuchida, Masafumi Nakamura, A left-sided approach for wide mobilization of the pancreas with complete dissection of the Treitz ligament(with video), Surgical Endoscopy, 10.1007/s00464-023-10065-2, 37, 6, 4982-4989, 2023.04. |
| 58. |
Chikanori Tsutsumi, Kenoki Ohuchida, Naoki Katayama, Yutaka Yamada, Shoichi Nakamura, Sho Okuda, Yoshiki Otsubo, Chika Iwamoto, Nobuhiro Torata, Kohei Horioka, Koji Shindo, Yusuke Mizuuchi, Naoki Ikenaga, Kohei Nakata, Eishi Nagai, Takashi Morisaki, Yoshinao Oda, Masafumi Nakamura, Tumor-infiltrating monocytic myeloid-derived suppressor cells contribute to the development of an immunosuppressive tumor microenvironment in gastric cancer, Gastric Cancer, 10.1007/s10120-023-01456-4, 2024.04, Background
Gastric cancer (GC) is characterized by an immunosuppressive and treatment-resistant tumor immune microenvironment (TIME). Here, we investigated the roles of different immunosuppressive cell types in the development of the GC TIME.
Methods
Single-cell RNA sequencing (scRNA-seq) and multiplex immunostaining of samples from untreated or immune checkpoint inhibitor (ICI)-resistant GC patients were used to examine the correlation between certain immunosuppressive cells and the prognosis of GC patients.
Results
The results of the scRNA-seq analysis revealed that tumor-infiltrating monocytic myeloid-derived suppressor cells (TI-M-MDSCs) expressed higher levels of genes with immunosuppressive functions than other immunosuppressive cell types. Additionally, among the immunosuppressive cell types assessed, M-MDSCs were most significantly enriched in GC tissues relative to adjacent normal tissues. The M-MDSCs in GC tissues expressed significantly higher levels of these markers than adjacent normal tissues; moreover, their presence was most strongly associated with a poor prognosis among the immunosuppressive cells. Immediate early response 3 (IER3), which we identified as a differentially expressed gene between M-MDSCs of GC and adjacent normal tissues, was an independent poor prognostic factor in GC patients (P=0.0003). IER3+ M-MDSCs expressed higher levels of genes with immunosuppressive functions than IER3－ M-MDSCs and were more abundant in treatment-resistant than -responsive GC patie
nts.
Conclusions
The present study suggests that TI-M-MDSCs, especially IER3+ ones, may play a predominant role in the development of the immunosuppressive and ICI-resistant GC TIME.
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| 59. |
Takashi Taniguchi, Noboru Ideno, Tomoyuki Araki, Shun Miura, Masahiro Yamamoto, Tomoki Nakafusa, Nobuhiro Higashijima, Takeo Yamamoto, Koji Tamura, So Nakamura, Toshiya Abe, Naoki Ikenaga, Kohei Nakata, Kenoki Ohuchida, Yoshinao Oda, Takao Ohtsuka, Masafumi Nakamura, MicroRNA-20a in extracellular vesicles derived from duodenal fluid is a possible biomarker for pancreatic ductal adenocarcinoma, DEN Open, 10.1002/deo2.333, 4, 1, e333, 2024.04, Background: Pancreatic ductal adenocarcinoma (PDAC) has a high mortality rate owing to its late diagnosis and aggression. In addition, there are relatively few minimally invasive screening methods for the early detection of PDAC, making the identification of biomarkers for this disease a critical priority. Recent studies have reported that microRNAs in extracellular vesicles (EV-miRs) from bodily fluids can be useful for the diagnosis of PDACs. Given this, we designed this study to evaluate the utility of cancer EVs extracted from duodenal fluid (DF) and their resident EV-miRs as potential biomarkers for the detection of PDAC.
Methods: EV-miRs were evaluated and identified in the supernatants of various pancreatic cancer cell lines (Panc-1, SUIT2, and MIAPaca2), human pancreatic duct epithelial cells, and the DF from patients with PDAC and healthy controls. EVs were extracted using ultracentrifugation and the relative expression of EV-miR-20a was quantified.
Results: We collected a total of 34 DF samples (27 PDAC patients and seven controls) for evaluation and our data suggest that the relative expression levels of EV-miR-20a were significantly higher in patients with PDAC than in controls (p = 0.0025). In addition, EV-miR-20a expression could discriminate PDAC from control patients regardless of the location of the tumor with an area under the curve values of 0.88 and 0.88, respectively.
Conclusions: We confirmed the presence of EVs in the DF and suggest that the expression of EV-miR-20a in these samples may act as a potential diagnostic biomarker for PDAC.
Keywords: duodenal fluid; early detection; extracellular vesicle; microRNA; pancreatic ductal adenocarcinoma.. |
| 60. |
Taiki Moriyama, Kenoki Ohuchida, Takao Ohtsuka, Koji Shindo, Naoki Ikenaga, Kohei Nakata, Masafumi Nakamura, Higher incidence of cholelithiasis with Roux-en-Y reconstruction compared with Billroth-I after laparoscopic distal gastrectomy for gastric cancer: a retrospective cohort study, Langenbecks Arch Surg, 10.1007/s00423-024-03267-2, 409, 1, 75, 2024.04, Purpose: Cholelithiasis occurs often after gastrectomy. However, no consensus has been established regarding the difference in the incidence of postgastrectomy cholelithiasis with different reconstruction methods. In this study, we examined the frequency of cholelithiasis after two major reconstruction methods, namely Billroth-I (B-I) and Roux-en-Y (R-Y) following laparoscopic distal gastrectomy (LDG) for gastric cancer.
Methods: Among 696 gastric cancer patients who underwent LDG between April 2000 and March 2017, after applying the exclusion criteria, 284 patients who underwent B-I and 310 who underwent R-Y were examined retrospectively. The estimated incidence of cholelithiasis was compared between the methods, and factors associated with the development of cholelithiasis in the gallbladder and/or common bile duct were investigated.
Results: During the median follow-up of 61.2 months, 52 patients (8.8%) developed cholelithiasis postgastrectomy; 12 patients (4.2%) after B-I and 40 (12.9%) after R-Y (p = 0.0002). Among them, choledocholithiasis was more frequent in patients who underwent R-Y (n = 11, 27.5%) vs. B-I (n = 1, 8.3%) (p = 0.0056). Univariate and multivariate analyses revealed that male sex, body mass index > 22.5 kg/m2, and R-Y reconstruction were significant predictors of the development of postLDG cholelithiasis.
Conclusion: Regarding cholelithiasis development, B-I reconstruction should be preferred whenever possible during distal gastrectomy.
Keywords: Billroth-I; Cholelithiasis; Distal gastrectomy; Gastric cancer; Laparoscopy; Roux-en-Y.. |
| 61. |
Naoki Ikenaga, Tadayoshi Hashimoto, Junki Mizusawa, Ryo Kitabayashi, Yusuke Sano, Haruhiko Fukuda, Kohei Nakata, Kazuto Shibuya, Yuji Kitahata, Minoru Takada, Keiko Kamei, Hiroshi Kurahara, Daisuke Ban, Shogo Kobayashi, Hiroaki Nagano, Hajime Imamura, Michiaki Unno, Amane Takahashi, Shintaro Yagi, Hiroshi Wada, Hirofumi Shirakawa, Naoto Yamamoto, Seiko Hirono, Naoto Gotohda, Etsuro Hatano, Masafumi Nakamura, Makoto Ueno; on behalf of the Hepatobiliary and Pancreatic Oncology Group in Japan Clinical Oncology Group, A multi-institutional randomized phase III study comparing minimally invasive distal pancreatectomy versus open distal pancreatectomy for pancreatic cancer; Japan Clinical Oncology Group study JCOG2202 (LAPAN study), BMC cancer, 10.1186/s12885-024-11957-9, 24, 1, 231, 2024.04, Background: Minimally invasive distal pancreatectomy (MIDP), including laparoscopic and robotic distal pancreatectomy, has gained widespread acceptance over the last decade owing to its favorable short-term outcomes. However, evidence regarding its oncologic safety is insufficient. In March 2023, a randomized phase III study was launched in Japan to confirm the non-inferiority of overall survival in patients with resectable pancreatic cancer undergoing MIDP compared with that of patients undergoing open distal pancreatectomy (ODP).
Methods: This is a multi-institutional, randomized, phase III study. A total of 370 patients will be enrolled from 40 institutions within 4 years. The primary endpoint of this study is overall survival, and the secondary endpoints include relapse-free survival, proportion of patients undergoing radical resection, proportion of patients undergoing complete laparoscopic surgery, incidence of adverse surgical events, and length of postoperative hospital stay. Only a credentialed surgeon is eligible to perform both ODP and MIDP. All ODP and MIDP procedures will undergo centralized review using intraoperative photographs. The non-inferiority of MIDP to ODP in terms of overall survival will be statistically analyzed. Only if non-inferiority is confirmed will the analysis assess the superiority of MIDP over ODP.
Discussion: If our study demonstrates the non-inferiority of MIDP in terms of overall survival, it would validate its short-term advantages and establish its long-term clinical efficacy.
Trial registration: This trial is registered with the Japan Registry of Clinical Trials as jRCT 1,031,220,705 [ https://jrct.niph.go.jp/en-latest-detail/jRCT1031220705 ].
Keywords: Clinical trial; Laparoscopy; Minimally invasive surgical procedures; Pancreatectomy; Pancreatic neoplasm.. |
