Updated on 2023/07/03

写真a

 
IIDA Tadashi
 
Organization
Graduate School of Medicine Designated assistant professor
Title
Designated assistant professor

Degree 1

  1. Bachelor of Medicine ( 2009.3   University of Yamanashi ) 

 

Papers 75

  1. Development of anti-cancer drug effect enhancers by transforming cancer-associated fibroblasts

    IIDA Tadashi, MIZUTANI Yasuyuki, YAMAO Kentaro, ISHIKAWA Takuya, ONO Eizaburo, FUJISHIRO Mitsuhiro, ENOMOTO Atsushi, KAWASHIMA Hiroki

    Suizo   Vol. 38 ( 1 ) page: 37 - 43   2023.2

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    Language:Japanese   Publisher:Japan Pancreas Society  

    <p>One characteristic of pancreatic cancer, considered incurable, is fibrosis in the interstitium and associated tissue sclerosis. Tissue stiffness is known to induce increased intrastromal pressure and vascular collapse, inhibiting the penetration of anticancer drugs into the interstitium with delivery to cancer cells. Cancer-associated fibroblasts (CAFs) play a central role in the development of fibrosis in the stroma. Various therapies targeting CAFs have been developed but have not yet been successful. In this study, we demonstrated that inducing the expression of Meflin, a marker and functional molecule of tumor suppressive CAFs, in CAFs improves the sensitivity to chemotherapy of pancreatic cancer. Furthermore, a compound library screening revealed that AM80, a synthetic retinoid, effectively induces the expression of Meflin in CAFs and improves sensitivity to chemotherapy with improved drug delivery. Based on these results, the authors are conducting a clinical trial of AM80 in combination with conventional anticancer agents to treat patients with unresectable pancreatic cancer to evaluate the efficacy of AM80.</p>

    DOI: 10.2958/suizo.38.37

    CiNii Research

  2. Development of anti-cancer drug effect enhancers by transforming cancer-associated fibroblasts

    IIDA Tadashi, MIZUTANI Yasuyuki, YAMAO Kentaro, ISHIKAWA Takuya, ONO Eizaburo, FUJISHIRO Mitsuhiro, ENOMOTO Atsushi, KAWASHIMA Hiroki

    Suizo   Vol. 38 ( 1 ) page: 37 - 43   2023.2

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    Language:Japanese   Publisher:Japan Pancreas Society  

    <p>One characteristic of pancreatic cancer, considered incurable, is fibrosis in the interstitium and associated tissue sclerosis. Tissue stiffness is known to induce increased intrastromal pressure and vascular collapse, inhibiting the penetration of anticancer drugs into the interstitium with delivery to cancer cells. Cancer-associated fibroblasts (CAFs) play a central role in the development of fibrosis in the stroma. Various therapies targeting CAFs have been developed but have not yet been successful. In this study, we demonstrated that inducing the expression of Meflin, a marker and functional molecule of tumor suppressive CAFs, in CAFs improves the sensitivity to chemotherapy of pancreatic cancer. Furthermore, a compound library screening revealed that AM80, a synthetic retinoid, effectively induces the expression of Meflin in CAFs and improves sensitivity to chemotherapy with improved drug delivery. Based on these results, the authors are conducting a clinical trial of AM80 in combination with conventional anticancer agents to treat patients with unresectable pancreatic cancer to evaluate the efficacy of AM80.</p>

    DOI: 10.2958/suizo.38.37

    CiNii Research

  3. Accuracy of Serum Leucine-Rich Alpha-2 Glycoprotein in Evaluating Endoscopic Disease Activity in Crohn's Disease

    Kawamura Tatsuya, Yamamura Takeshi, Nakamura Masanao, Maeda Keiko, Sawada Tsunaki, Ishikawa Eri, Iida Tadashi, Mizutani Yasuyuki, Ishikawa Takuya, Kakushima Naomi, Furukawa Kazuhiro, Ohno Eizaburo, Honda Takashi, Kawashima Hiroki, Ishigami Masatoshi

    INFLAMMATORY BOWEL DISEASES   Vol. 29 ( 2 ) page: 245 - 253   2023.2

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    Language:English   Publisher:Inflammatory bowel diseases  

    BACKGROUND: Mucosal healing, confirmed by endoscopic evaluation, is the long-term goal of treatment for Crohn's disease (CD). Leucine-rich alpha-2 glycoprotein (LRG) is a new serum biomarker correlated with disease activity in inflammatory bowel disease. However, studies evaluating its relationship with CD, particularly in the context of small intestinal lesions, are scarce. The aim of this study was to investigate the accuracy of LRG in assessing endoscopic activity, especially remission, in patients with CD. METHODS: Between July 2020 and March 2021, 72 patients with CD who underwent LRG testing and double-balloon endoscopy at the same time were included. Endoscopic activity was evaluated using the applied Simple Endoscopic Score for Crohn's disease, including small intestine lesions. The relationship of LRG with clinical symptoms and endoscopic activity was assessed, and its predictive accuracy was evaluated. RESULTS: Leucine-rich alpha-2 glycoprotein showed a significant positive correlation with endoscopic activity (r = 0.619, P < .001), even in patients with active lesions in the small intestine (r = 0.626, P < .001). Multivariate logistic regression revealed that LRG was the only factor associated with endoscopic remission. An LRG cutoff value of 8.9 μg/mL had a sensitivity of 93.3%; specificity of 83.3%; positive predictive value of 96.6%; negative predictive value of 71.4%; accuracy of 91.7%; and area under the curve of 0.904 for the prediction of endoscopic remission. CONCLUSIONS: Leucine-rich alpha-2 glycoprotein can be used in assessing endoscopic activity and is a reliable marker of endoscopic remission in CD patients. It can be an intermediate target in the treatment of CD.

    DOI: 10.1093/ibd/izac076

    Web of Science

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    PubMed

  4. Accuracy of Serum Leucine-Rich Alpha-2 Glycoprotein in Evaluating Endoscopic Disease Activity in Crohn's Disease

    Kawamura Tatsuya, Yamamura Takeshi, Nakamura Masanao, Maeda Keiko, Sawada Tsunaki, Ishikawa Eri, Iida Tadashi, Mizutani Yasuyuki, Ishikawa Takuya, Kakushima Naomi, Furukawa Kazuhiro, Ohno Eizaburo, Honda Takashi, Kawashima Hiroki, Ishigami Masatoshi

    INFLAMMATORY BOWEL DISEASES   Vol. 29 ( 2 ) page: 245 - 253   2023.2

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    Language:English   Publisher:Inflammatory bowel diseases  

    BACKGROUND: Mucosal healing, confirmed by endoscopic evaluation, is the long-term goal of treatment for Crohn's disease (CD). Leucine-rich alpha-2 glycoprotein (LRG) is a new serum biomarker correlated with disease activity in inflammatory bowel disease. However, studies evaluating its relationship with CD, particularly in the context of small intestinal lesions, are scarce. The aim of this study was to investigate the accuracy of LRG in assessing endoscopic activity, especially remission, in patients with CD. METHODS: Between July 2020 and March 2021, 72 patients with CD who underwent LRG testing and double-balloon endoscopy at the same time were included. Endoscopic activity was evaluated using the applied Simple Endoscopic Score for Crohn's disease, including small intestine lesions. The relationship of LRG with clinical symptoms and endoscopic activity was assessed, and its predictive accuracy was evaluated. RESULTS: Leucine-rich alpha-2 glycoprotein showed a significant positive correlation with endoscopic activity (r = 0.619, P < .001), even in patients with active lesions in the small intestine (r = 0.626, P < .001). Multivariate logistic regression revealed that LRG was the only factor associated with endoscopic remission. An LRG cutoff value of 8.9 μg/mL had a sensitivity of 93.3%; specificity of 83.3%; positive predictive value of 96.6%; negative predictive value of 71.4%; accuracy of 91.7%; and area under the curve of 0.904 for the prediction of endoscopic remission. CONCLUSIONS: Leucine-rich alpha-2 glycoprotein can be used in assessing endoscopic activity and is a reliable marker of endoscopic remission in CD patients. It can be an intermediate target in the treatment of CD.

    DOI: 10.1093/ibd/izac076

    Web of Science

    Scopus

    PubMed

  5. CO2 enterography in endoscopic retrograde cholangiography using double-balloon endoscopy: A randomized clinical trial

    Murate Kentaro, Nakamura Masanao, Yamamura Takeshi, Maeda Keiko, Sawada Tsunaki, Ishikawa Eri, Kida Yuichi, Esaki Masaya, Hamazaki Motonobu, Iida Tadashi, Mizutani Yasuyuki, Yamao Kentaro, Ishikawa Takuya, Furukawa Kazuhiro, Ohno Eizaburo, Honda Takashi, Ishigami Masatoshi, Kinoshita Fumie, Ando Masahiko, Kawashima Hiroki

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY     2023.1

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    Language:English   Publisher:Journal of Gastroenterology and Hepatology (Australia)  

    Background and Aim: Double-balloon endoscopic retrograde cholangiography (DBERC) is a valuable procedure for patients with altered gastrointestinal anatomy. Nonetheless, it is time-consuming and burdensome for both patients and endoscopists, partly because route selection in the reconstructed bowel with complicating loop is challenging. Carbon dioxide insufflation enterography is reportedly useful for route selection in the blind loop. This prospective randomized clinical trial investigated the usefulness of carbon dioxide insufflation enterography for route selection by comparing it with conventional observation. Methods: Patients scheduled to undergo DBERC were consecutively registered. They were divided into carbon dioxide insufflation enterography and conventional groups via randomization according to stratification factors, type of reconstruction methods, and experience with DBERC. The primary endpoint was the correct rate of initial route selection. The secondary endpoints were the insertion time, examination time, amount of anesthesia drugs, and complications. Results: The correct rate of route selection was significantly higher in the carbon dioxide insufflation enterography group (23/25, 92%) than in the visual method (15/25, 60%) (P = 0.018). The insertion time was significantly shorter in the carbon dioxide insufflation enterography group than in the visual group (10.8 ± 11.1 min vs 29.8 ± 15.7 min; P < 0.001). No significant differences in complications were noted between the two groups. The amounts of sedatives and analgesics used were significantly lower in the carbon dioxide insufflation enterography group (P < 0.001 and P < 0.001, respectively). Conclusions: Carbon dioxide insufflation enterography can reduce the burden of DBERC on patients and endoscopists by shortening the examination time and reducing the amount of medication.

    DOI: 10.1111/jgh.16112

    Web of Science

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    PubMed

  6. CO2 enterography in endoscopic retrograde cholangiography using double-balloon endoscopy: A randomized clinical trial

    Murate Kentaro, Nakamura Masanao, Yamamura Takeshi, Maeda Keiko, Sawada Tsunaki, Ishikawa Eri, Kida Yuichi, Esaki Masaya, Hamazaki Motonobu, Iida Tadashi, Mizutani Yasuyuki, Yamao Kentaro, Ishikawa Takuya, Furukawa Kazuhiro, Ohno Eizaburo, Honda Takashi, Ishigami Masatoshi, Kinoshita Fumie, Ando Masahiko, Kawashima Hiroki

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY     2023.1

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    Language:English   Publisher:Journal of Gastroenterology and Hepatology (Australia)  

    Background and Aim: Double-balloon endoscopic retrograde cholangiography (DBERC) is a valuable procedure for patients with altered gastrointestinal anatomy. Nonetheless, it is time-consuming and burdensome for both patients and endoscopists, partly because route selection in the reconstructed bowel with complicating loop is challenging. Carbon dioxide insufflation enterography is reportedly useful for route selection in the blind loop. This prospective randomized clinical trial investigated the usefulness of carbon dioxide insufflation enterography for route selection by comparing it with conventional observation. Methods: Patients scheduled to undergo DBERC were consecutively registered. They were divided into carbon dioxide insufflation enterography and conventional groups via randomization according to stratification factors, type of reconstruction methods, and experience with DBERC. The primary endpoint was the correct rate of initial route selection. The secondary endpoints were the insertion time, examination time, amount of anesthesia drugs, and complications. Results: The correct rate of route selection was significantly higher in the carbon dioxide insufflation enterography group (23/25, 92%) than in the visual method (15/25, 60%) (P = 0.018). The insertion time was significantly shorter in the carbon dioxide insufflation enterography group than in the visual group (10.8 ± 11.1 min vs 29.8 ± 15.7 min; P < 0.001). No significant differences in complications were noted between the two groups. The amounts of sedatives and analgesics used were significantly lower in the carbon dioxide insufflation enterography group (P < 0.001 and P < 0.001, respectively). Conclusions: Carbon dioxide insufflation enterography can reduce the burden of DBERC on patients and endoscopists by shortening the examination time and reducing the amount of medication.

    DOI: 10.1111/jgh.16112

    Web of Science

    Scopus

    PubMed

  7. Analysis of immunologic comorbidities in ulcerative colitis patients: a tool to prevent exacerbations in ulcerative colitis cases

    Meza Miguel Ricardo Rodriguez, Nakamura Masanao, Yamamura Takeshi, Maeda Keiko, Sawada Tsunaki, Ishikawa Eri, Kakushima Naomi, Furukawa Kazuhiro, Iida Tadashi, Mizutani Yasuyuki, Ishikawa Takuya, Ohno Eizaburo, Honda Takashi, Kawashima Hiroki, Ishigami Masatoshi

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 84 ( 4 ) page: 733 - 745   2022.11

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    Language:English   Publisher:Nagoya Journal of Medical Science  

    There have been previous studies, especially in Western countries and even in some areas in Asia, about extra-intestinal manifestations (EIMs) and its link with the outcome of inflammatory bowel disease (IBD), which includes Crohn’s disease (CD), and ulcerative colitis (UC). This link is crucial when discussing a patient’s prognosis and important when dealing with UC management. The aim of this study was to clarify the most common comorbidities associated with UC, emphasizing immunologic comorbidities in Japan. This study was a retrospective analysis performed at Nagoya University Hospital. The data collection started in March, 2019, and continued for two years. We retrieved the medical records of 105 patients with UC diagnosis, from which the data of 176 EIMs were extracted and analyzed. Results showed that EIMs with UC in the active phase accounted for 43.7% of total EIMs. Twenty-six patients with immune-mediated inflammatory disease frequently had an active phase (odds ratio [OR] 3.84, 99% CI, 1.44–10.27). Comorbidities showing an active manifestation of symptoms and UC in the active phase were significantly correlated in patients with immunological comorbidities, such as peripheral arthritis (r = 0.97, p < 0.01) and rheumatoid arthritis (RA) (r = 0.99, p < 0.01), as well as in patients with primary sclerosis cholangitis (PSC) (r = 0.98, p < 0.01). In conclusion, this analysis suggests the importance of having full comprehension of how immunological comorbidities affect the natural development of UC, which is of vital importance to prevent further UC complications and properly adjust the management of the disease.

    DOI: 10.18999/nagjms.84.4.733

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  8. Analysis of immunologic comorbidities in ulcerative colitis patients: a tool to prevent exacerbations in ulcerative colitis cases

    Meza Miguel Ricardo Rodriguez, Nakamura Masanao, Yamamura Takeshi, Maeda Keiko, Sawada Tsunaki, Ishikawa Eri, Kakushima Naomi, Furukawa Kazuhiro, Iida Tadashi, Mizutani Yasuyuki, Ishikawa Takuya, Ohno Eizaburo, Honda Takashi, Kawashima Hiroki, Ishigami Masatoshi

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 84 ( 4 ) page: 733 - 745   2022.11

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    Language:English   Publisher:Nagoya Journal of Medical Science  

    There have been previous studies, especially in Western countries and even in some areas in Asia, about extra-intestinal manifestations (EIMs) and its link with the outcome of inflammatory bowel disease (IBD), which includes Crohn’s disease (CD), and ulcerative colitis (UC). This link is crucial when discussing a patient’s prognosis and important when dealing with UC management. The aim of this study was to clarify the most common comorbidities associated with UC, emphasizing immunologic comorbidities in Japan. This study was a retrospective analysis performed at Nagoya University Hospital. The data collection started in March, 2019, and continued for two years. We retrieved the medical records of 105 patients with UC diagnosis, from which the data of 176 EIMs were extracted and analyzed. Results showed that EIMs with UC in the active phase accounted for 43.7% of total EIMs. Twenty-six patients with immune-mediated inflammatory disease frequently had an active phase (odds ratio [OR] 3.84, 99% CI, 1.44–10.27). Comorbidities showing an active manifestation of symptoms and UC in the active phase were significantly correlated in patients with immunological comorbidities, such as peripheral arthritis (r = 0.97, p < 0.01) and rheumatoid arthritis (RA) (r = 0.99, p < 0.01), as well as in patients with primary sclerosis cholangitis (PSC) (r = 0.98, p < 0.01). In conclusion, this analysis suggests the importance of having full comprehension of how immunological comorbidities affect the natural development of UC, which is of vital importance to prevent further UC complications and properly adjust the management of the disease.

    DOI: 10.18999/nagjms.84.4.733

    Web of Science

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    PubMed

  9. The role of EUS elastography-guided fine needle biopsy in the histological diagnosis of solid pancreatic lesions: a prospective exploratory study

    Ohno Eizaburo, Kawashima Hiroki, Ishikawa Takuya, Mizutani Yasuyuki, Iida Tadashi, Nishio Ryo, Uetsuki Kota, Yashika Jun, Yamada Kenta, Yoshikawa Masakatsu, Gibo Noriaki, Aoki Toshinori, Kataoka Kunio, Mori Hiroshi, Takada Yoshihisa, Aoi Hironori, Takahashi Hidekazu, Yamamura Takeshi, Furukawa Kazuhiro, Nakamura Masanao, Shimoyama Yoshie, Hirooka Yoshiki, Fujishiro Mitsuhiro

    SCIENTIFIC REPORTS   Vol. 12 ( 1 ) page: 16603   2022.10

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    Language:English   Publisher:Scientific Reports  

    This study aimed to evaluate the feasibility and efficacy of Endoscopic ultrasound elastography-guided fine needle biopsy (EUS-EG-FNB) for the diagnosis of pancreatic mass lesions. EUS-EG images were classified into heterogeneous and homogeneous groups. For the heterogeneous group, EUS-FNB was separately performed in both hard areas and soft areas. Only samples obtained during the first two passes (hard/soft areas) were used to compare the diagnostic accuracy as well as the quality and quantity of the specimens. We investigated the association of EUS-EG findings using strain histogram analysis with the histological findings. Fifty-five patients were enrolled including 25 patients with heterogeneous group. The homogeneous group had significantly lower mean strain value (hard) lesions. The adequate sampling rates from hard and soft areas were 88 and 92%, respectively (P = 0.6374). Comparison of the diagnostic accuracy and the quality and quantity of the histological core between hard and soft areas showed no significant differences. In pancreatic adenocarcinoma cases, the proportion of fibrous stroma in the core tissue was significantly correlated with the elasticity of the region. (R2 = 0.1226: P = 0.0022) EUS-EG may reflect tissue composition in pancreatic tumors, however, EUS-EG did not affect either the quality and quantity of the tissues obtained. Clinical Trial Registry No: UMIN-000033073.

    DOI: 10.1038/s41598-022-21178-4

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  10. The role of EUS elastography-guided fine needle biopsy in the histological diagnosis of solid pancreatic lesions: a prospective exploratory study

    Ohno Eizaburo, Kawashima Hiroki, Ishikawa Takuya, Mizutani Yasuyuki, Iida Tadashi, Nishio Ryo, Uetsuki Kota, Yashika Jun, Yamada Kenta, Yoshikawa Masakatsu, Gibo Noriaki, Aoki Toshinori, Kataoka Kunio, Mori Hiroshi, Takada Yoshihisa, Aoi Hironori, Takahashi Hidekazu, Yamamura Takeshi, Furukawa Kazuhiro, Nakamura Masanao, Shimoyama Yoshie, Hirooka Yoshiki, Fujishiro Mitsuhiro

    SCIENTIFIC REPORTS   Vol. 12 ( 1 ) page: 16603   2022.10

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    Language:English   Publisher:Scientific Reports  

    This study aimed to evaluate the feasibility and efficacy of Endoscopic ultrasound elastography-guided fine needle biopsy (EUS-EG-FNB) for the diagnosis of pancreatic mass lesions. EUS-EG images were classified into heterogeneous and homogeneous groups. For the heterogeneous group, EUS-FNB was separately performed in both hard areas and soft areas. Only samples obtained during the first two passes (hard/soft areas) were used to compare the diagnostic accuracy as well as the quality and quantity of the specimens. We investigated the association of EUS-EG findings using strain histogram analysis with the histological findings. Fifty-five patients were enrolled including 25 patients with heterogeneous group. The homogeneous group had significantly lower mean strain value (hard) lesions. The adequate sampling rates from hard and soft areas were 88 and 92%, respectively (P = 0.6374). Comparison of the diagnostic accuracy and the quality and quantity of the histological core between hard and soft areas showed no significant differences. In pancreatic adenocarcinoma cases, the proportion of fibrous stroma in the core tissue was significantly correlated with the elasticity of the region. (R2 = 0.1226: P = 0.0022) EUS-EG may reflect tissue composition in pancreatic tumors, however, EUS-EG did not affect either the quality and quantity of the tissues obtained. Clinical Trial Registry No: UMIN-000033073.

    DOI: 10.1038/s41598-022-21178-4

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  11. Author Correction: Variability measurements provide additional value to shear wave elastography in the diagnosis of pancreatic cancer.

    Yoshikawa M, Ishikawa T, Ohno E, Iida T, Furukawa K, Nakamura M, Honda T, Ishigami M, Kinoshita F, Kawashima H, Fujishiro M

    Scientific reports   Vol. 12 ( 1 ) page: 16190   2022.9

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    Language:English   Publisher:Scientific Reports  

    The original version of this Article contained an error. In the Materials and methods section, under the subheading ‘Study design’, the approval number of the Ethics Committee was incorrect. As a result, “The study was conducted with the approval of the Ethics Committee of Nagoya University Hospital and enrolled in the jRCT (CRB4180004).” now reads: “The study was conducted with the approval of the Ethics Committee of Nagoya University Hospital (approval number: 2014-0399).” The original Article has been corrected.

    DOI: 10.1038/s41598-022-21219-y

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  12. Author Correction: Variability measurements provide additional value to shear wave elastography in the diagnosis of pancreatic cancer.

    Yoshikawa M, Ishikawa T, Ohno E, Iida T, Furukawa K, Nakamura M, Honda T, Ishigami M, Kinoshita F, Kawashima H, Fujishiro M

    Scientific reports   Vol. 12 ( 1 ) page: 16190   2022.9

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    Language:English   Publisher:Scientific Reports  

    The original version of this Article contained an error. In the Materials and methods section, under the subheading ‘Study design’, the approval number of the Ethics Committee was incorrect. As a result, “The study was conducted with the approval of the Ethics Committee of Nagoya University Hospital and enrolled in the jRCT (CRB4180004).” now reads: “The study was conducted with the approval of the Ethics Committee of Nagoya University Hospital (approval number: 2014-0399).” The original Article has been corrected.

    DOI: 10.1038/s41598-022-21219-y

    Scopus

    PubMed

  13. Endoscopic management of perihilar cholangiocarcinoma

    Kawashima Hiroki, Ohno Eizaburo, Ishikawa Takuya, Mizutani Yasuyuki, Iida Tadashi, Yamamura Takeshi, Kakushima Naomi, Furukawa Kazuhiro, Nakamura Masanao

    DIGESTIVE ENDOSCOPY   Vol. 34 ( 6 ) page: 1147 - 1156   2022.9

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    Language:English   Publisher:Digestive Endoscopy  

    Endoscopic management for perihilar cholangiocarcinoma (PHCC) is evolving toward more accurate diagnosis and safer drainage. In imaging, it is important to diagnose the entire lesion using multidetector-row computed tomography to determine resectability and optimal surgical planning, followed by local diagnosis using endoscopic retrograde cholangiopancreatography. Video peroral cholangioscopy and probe-based confocal laser endomicroscopy have been newly introduced as diagnostic imaging methods and are being applied clinically. In transpapillary forceps biopsy for PHCC diagnosis, the location in the bile duct (for mapping biopsy) and the number of biopsy samples should be determined depending on resectability, the morphological type, and future surgical planning. Preoperative drainage has shifted from percutaneous transhepatic biliary drainage to endoscopic nasobiliary drainage given the possibility of seeding metastasis. In addition, considering potential patient discomfort from a nasal tube, the usefulness of the placement of a plastic stent above the papilla (inside stent) as a bridging therapy for surgery has been reported. For drainage of unresectable PHCC, the improved prognosis due to advances in chemotherapy has necessitated a strategy that accounts for reintervention. Thus, in addition to uncovered self-expandable metallic stents (SEMS), exchangeable slim fully covered SEMS and inside stents have started to be used. In addition to the conventional transpapillary approach, an endoscopic ultrasonography-guided approach has been introduced, and a combination of both methods has also been proposed. To improve the quality of life and prognosis of PHCC patients, endoscopists need to understand and be able to use the various methods of endoscopic management for PHCC.

    DOI: 10.1111/den.14317

    Web of Science

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    PubMed

  14. Endoscopic management of perihilar cholangiocarcinoma

    Kawashima Hiroki, Ohno Eizaburo, Ishikawa Takuya, Mizutani Yasuyuki, Iida Tadashi, Yamamura Takeshi, Kakushima Naomi, Furukawa Kazuhiro, Nakamura Masanao

    DIGESTIVE ENDOSCOPY   Vol. 34 ( 6 ) page: 1147 - 1156   2022.9

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    Language:English   Publisher:Digestive Endoscopy  

    Endoscopic management for perihilar cholangiocarcinoma (PHCC) is evolving toward more accurate diagnosis and safer drainage. In imaging, it is important to diagnose the entire lesion using multidetector-row computed tomography to determine resectability and optimal surgical planning, followed by local diagnosis using endoscopic retrograde cholangiopancreatography. Video peroral cholangioscopy and probe-based confocal laser endomicroscopy have been newly introduced as diagnostic imaging methods and are being applied clinically. In transpapillary forceps biopsy for PHCC diagnosis, the location in the bile duct (for mapping biopsy) and the number of biopsy samples should be determined depending on resectability, the morphological type, and future surgical planning. Preoperative drainage has shifted from percutaneous transhepatic biliary drainage to endoscopic nasobiliary drainage given the possibility of seeding metastasis. In addition, considering potential patient discomfort from a nasal tube, the usefulness of the placement of a plastic stent above the papilla (inside stent) as a bridging therapy for surgery has been reported. For drainage of unresectable PHCC, the improved prognosis due to advances in chemotherapy has necessitated a strategy that accounts for reintervention. Thus, in addition to uncovered self-expandable metallic stents (SEMS), exchangeable slim fully covered SEMS and inside stents have started to be used. In addition to the conventional transpapillary approach, an endoscopic ultrasonography-guided approach has been introduced, and a combination of both methods has also been proposed. To improve the quality of life and prognosis of PHCC patients, endoscopists need to understand and be able to use the various methods of endoscopic management for PHCC.

    DOI: 10.1111/den.14317

    Web of Science

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    PubMed

  15. Comparison of outcomes between secondary fully covered and uncovered self-expandable metal stents in the treatment of recurrent biliary obstruction of pancreatic cancer

    Kataoka Kunio, Kawashima Hiroki, Ohno Eizaburo, Ishikawa Takuya, Mizutani Yasuyuki, Iida Tadashi, Furukawa Kazuhiro, Nakamura Masanao, Honda Takashi, Ishigami Masatoshi, Fujishiro Mitsuhiro

    SURGICAL ENDOSCOPY AND OTHER INTERVENTIONAL TECHNIQUES   Vol. 36 ( 8 ) page: 5676 - 5683   2022.8

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    Language:English   Publisher:Surgical Endoscopy  

    Background: The overall survival (OS) of pancreatic cancer (PC) has been prolonged by advances in chemotherapy, and the number of cases of recurrent biliary obstruction (RBO) after self-expandable metal stent (SEMS) placement is expected to increase. We herein compared outcomes between secondary fully covered SEMS (FC) and uncovered SEMS (UC) for RBO of PC with FC placed as the 1st SEMS. Methods: Between May 2010 and March 2021, 62 PC patients who underwent SEMS exchange to FC (n = 34) or UC (n = 28) for RBO were retrospectively analyzed. Patient characteristics, OS, time to RBO (TRBO), and stent-related adverse events were compared between the FC and UC groups. Cox’s proportional hazard model was used to identify risk factors for RBO with the 2nd SEMS. Results: There was a significant difference between the FC and UC groups only in the 2nd SEMS diameter. Median OS and TRBO were 195 and 238 days in FC patients and 306 and 455 days in UC patients, respectively, with no significant differences between the two groups. No significant differences were observed in the stent-related adverse event rate. In multivariate analyses, only the 2nd SEMS diameter was significant (P = 0.009). Median TRBO were 455, 238, and 103 days in 10-mm UC, 10-mm FC, and 8-mm UC patients, with 10-mm UC patients having significantly longer TRBO than 10-mm FC and 8-mm UC patients (P = 0.020 and 0.001). Conclusion: SEMS exchange to 10-mm UC may be appropriate for RBO of PC with FC as the 1st SEMS.

    DOI: 10.1007/s00464-021-08981-2

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  16. Comparison of an Inside Stent and a Fully Covered Self-Expandable Metallic Stent as Preoperative Biliary Drainage for Patients with Resectable Perihilar Cholangiocarcinoma

    Mori Hiroshi, Kawashima Hiroki, Ohno Eizaburo, Ishikawa Takuya, Yamao Kentaro, Mizutani Yasuyuki, Iida Tadashi, Nakamura Masanao, Ishigami Masatoshi, Onoe Shunsuke, Mizuno Takashi, Ebata Tomoki, Fujishiro Mitsuhiro

    CANADIAN JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   Vol. 2022   page: 3005210   2022.7

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    Language:English   Publisher:Canadian Journal of Gastroenterology and Hepatology  

    Background. There is a need for a more tolerable preoperative biliary drainage (PBD) method for perihilar cholangiocarcinoma (PHCC). In recent years, inside stents (ISs) have attracted attention as a less suffering PBD method. Few studies have compared IS with a fully covered self-expandable metallic stent (FCSEMS) as PBD for resectable PHCC. The aim of this study is to compare them. Methods. This study involved 86 consecutive patients (IS: 51; FCSEMS: 35). The recurrent biliary obstruction (RBO) rate until undergoing surgery or being diagnosed as unresectable, time to RBO, factors related to RBO, incidence of adverse events related to endoscopic retrograde cholangiography, and postoperative complications associated with each stent were evaluated retrospectively. Results. There was no significant difference between the two groups in the incidence of adverse events after stent insertion. After propensity score matching, the mean (SD) time to RBO was 37.9 (30.2) days in the IS group and 45.1 (35.1) days in the FCSEMS group, with no significant difference (P=0.912, log-rank test). A total of 7/51 patients in the IS group and 3/35 patients in the FCSEMS group developed RBO. The only risk factor for RBO was bile duct obstruction of the future excisional liver lobe(s) due to stenting (HR 29.8, P=0.008) in the FCSEMS group, but risk factors could not be indicated in the IS group. There was no significant difference in the incidence of bile leakage or liver failure. In contrast, pancreatic fistula was significantly more common in the FCSEMS group (13/23 patients) than in the IS group (3/28 patients) (P<0.001), especially in patients who did not undergo pancreatectomy (P=0.001). Conclusions. As PBD, both IS and FCSEMS achieved low RBO rates. Compared with FCSEMS, IS shows no difference in RBO rate, is associated with fewer postoperative complications, and is considered an appropriate means of PBD for resectable PHCC. This trail is registered with UMIN000025631.

    DOI: 10.1155/2022/3005210

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  17. Endoscopic sphincterotomy and endoscopic biliary stenting do not affect the sensitivity of transpapillary forceps biopsy for the diagnosis of bile duct adenocarcinoma

    Aoki Toshinori, Ohno Eizaburo, Ishikawa Takuya, Mizutani Yasuyuki, Iida Tadashi, Yamao Kentaro, Yamamura Takeshi, Furukawa Kazuhiro, Nakamura Masanao, Honda Takashi, Ishigami Masatoshi, Yatsuya Hiroshi, Kawashima Hiroki

    BMC GASTROENTEROLOGY   Vol. 22 ( 1 ) page: 329   2022.7

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    Background: The pathological evaluation of tissues with cholangitis is considered difficult, which can often occur after endoscopic sphincterotomy (EST) and endoscopic biliary stenting (EBS). This study aimed to evaluate the influence of a history of EST and EBS on the sensitivity of transpapillary forceps bile duct biopsy (TB) for bile duct adenocarcinoma. Methods: This retrospective study included consecutive cases of bile duct adenocarcinoma in which TB was performed before July 2020 until the number exceeded that required to support statistical and noninferiority analyses of the sensitivity of TB between patients with and without each variable. The incidence of postprocedural adverse events related to each factor was also investigated. Results: Overall, 280 samples were required in each group, and 437 subjects (792 samples) were included. The sensitivity of TB was 63.6% for the subjects and 59.6% for the biopsy samples. For the biopsy samples, the sensitivity did not differ significantly between samples from patients with and without a history of EST (59.1% vs. 58.9%, P = 0.952) and EBS (62.1% vs. 55.4%, P = 0.065). The sensitivity was significantly higher for samples from patients with jaundice (67.9% vs. 57.0%, P = 0.008). There were significantly fewer procedure-related adverse events in patients with a history of EST (10.8% vs. 19.0%, P = 0.017) and EBS (12.0% vs. 21.7%, P = 0.005). Conclusions: A history of EST or EBS did not influence sensitivity of TB but significantly decreased the incidence of adverse events. To safely and reliably perform TB to diagnose bile duct adenocarcinoma, planning, including for EST and EBS, is necessary.

    DOI: 10.1186/s12876-022-02402-x

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  18. Comparison of an Inside Stent and a Fully Covered Self-Expandable Metallic Stent as Preoperative Biliary Drainage for Patients with Resectable Perihilar Cholangiocarcinoma

    Mori Hiroshi, Kawashima Hiroki, Ohno Eizaburo, Ishikawa Takuya, Yamao Kentaro, Mizutani Yasuyuki, Iida Tadashi, Nakamura Masanao, Ishigami Masatoshi, Onoe Shunsuke, Mizuno Takashi, Ebata Tomoki, Fujishiro Mitsuhiro

    CANADIAN JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   Vol. 2022   page: 3005210   2022.7

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    Background. There is a need for a more tolerable preoperative biliary drainage (PBD) method for perihilar cholangiocarcinoma (PHCC). In recent years, inside stents (ISs) have attracted attention as a less suffering PBD method. Few studies have compared IS with a fully covered self-expandable metallic stent (FCSEMS) as PBD for resectable PHCC. The aim of this study is to compare them. Methods. This study involved 86 consecutive patients (IS: 51; FCSEMS: 35). The recurrent biliary obstruction (RBO) rate until undergoing surgery or being diagnosed as unresectable, time to RBO, factors related to RBO, incidence of adverse events related to endoscopic retrograde cholangiography, and postoperative complications associated with each stent were evaluated retrospectively. Results. There was no significant difference between the two groups in the incidence of adverse events after stent insertion. After propensity score matching, the mean (SD) time to RBO was 37.9 (30.2) days in the IS group and 45.1 (35.1) days in the FCSEMS group, with no significant difference (P=0.912, log-rank test). A total of 7/51 patients in the IS group and 3/35 patients in the FCSEMS group developed RBO. The only risk factor for RBO was bile duct obstruction of the future excisional liver lobe(s) due to stenting (HR 29.8, P=0.008) in the FCSEMS group, but risk factors could not be indicated in the IS group. There was no significant difference in the incidence of bile leakage or liver failure. In contrast, pancreatic fistula was significantly more common in the FCSEMS group (13/23 patients) than in the IS group (3/28 patients) (P<0.001), especially in patients who did not undergo pancreatectomy (P=0.001). Conclusions. As PBD, both IS and FCSEMS achieved low RBO rates. Compared with FCSEMS, IS shows no difference in RBO rate, is associated with fewer postoperative complications, and is considered an appropriate means of PBD for resectable PHCC. This trail is registered with UMIN000025631.

    DOI: 10.1155/2022/3005210

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  19. Endoscopic sphincterotomy and endoscopic biliary stenting do not affect the sensitivity of transpapillary forceps biopsy for the diagnosis of bile duct adenocarcinoma

    Aoki Toshinori, Ohno Eizaburo, Ishikawa Takuya, Mizutani Yasuyuki, Iida Tadashi, Yamao Kentaro, Yamamura Takeshi, Furukawa Kazuhiro, Nakamura Masanao, Honda Takashi, Ishigami Masatoshi, Yatsuya Hiroshi, Kawashima Hiroki

    BMC GASTROENTEROLOGY   Vol. 22 ( 1 ) page: 329   2022.7

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    Language:English   Publisher:BMC Gastroenterology  

    Background: The pathological evaluation of tissues with cholangitis is considered difficult, which can often occur after endoscopic sphincterotomy (EST) and endoscopic biliary stenting (EBS). This study aimed to evaluate the influence of a history of EST and EBS on the sensitivity of transpapillary forceps bile duct biopsy (TB) for bile duct adenocarcinoma. Methods: This retrospective study included consecutive cases of bile duct adenocarcinoma in which TB was performed before July 2020 until the number exceeded that required to support statistical and noninferiority analyses of the sensitivity of TB between patients with and without each variable. The incidence of postprocedural adverse events related to each factor was also investigated. Results: Overall, 280 samples were required in each group, and 437 subjects (792 samples) were included. The sensitivity of TB was 63.6% for the subjects and 59.6% for the biopsy samples. For the biopsy samples, the sensitivity did not differ significantly between samples from patients with and without a history of EST (59.1% vs. 58.9%, P = 0.952) and EBS (62.1% vs. 55.4%, P = 0.065). The sensitivity was significantly higher for samples from patients with jaundice (67.9% vs. 57.0%, P = 0.008). There were significantly fewer procedure-related adverse events in patients with a history of EST (10.8% vs. 19.0%, P = 0.017) and EBS (12.0% vs. 21.7%, P = 0.005). Conclusions: A history of EST or EBS did not influence sensitivity of TB but significantly decreased the incidence of adverse events. To safely and reliably perform TB to diagnose bile duct adenocarcinoma, planning, including for EST and EBS, is necessary.

    DOI: 10.1186/s12876-022-02402-x

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  20. Factors associated with misdiagnosis of preoperative endoscopic ultrasound in patients with pancreatic cystic neoplasms undergoing surgical resection

    Ohno Eizaburo, Ishikawa Takuya, Mizutani Yasuyuki, Iida Tadashi, Uetsuki Kota, Yashika Jun, Yamada Kenta, Gibo Noriaki, Aoki Toshinori, Kawashima Hiroki

    JOURNAL OF MEDICAL ULTRASONICS   Vol. 49 ( 3 ) page: 433 - 441   2022.7

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    Purpose: Pancreatic cystic lesions (PCLs) include various types of cysts. Accurate preoperative diagnosis is essential to avoid unnecessary surgery on benign cysts. In this study, we aimed to identify the factors associated with misdiagnosis in preoperative endoscopic ultrasound (EUS) imaging and clinicopathological findings for PCLs. Methods: This study included 302 surgically resected patients with PCLs who underwent preoperative EUS. The preoperative EUS findings were re-evaluated and compared with the pathological diagnosis. Additionally, the factors associated with misdiagnosis of PCLs were investigated by multivariate analysis. Results: The preoperative diagnoses of PCLs were intraductal papillary mucinous neoplasm (IPMN) in 213 patients (70.5%), mucinous cystic neoplasm (MCN) in 33 patients (10.9%), serous neoplasm (SN) in 7 patients (2.3%), cystic degeneration cyst of solid tumor in 46 patients (15.2%), and pancreatic cancer with cystic degeneration in three patients (1.0%). A discrepancy between preoperative and postoperative diagnosis was found in 47 patients (15.6%). Based on the pathological diagnosis, the sensitivity of preoperative EUS imaging was IPMN 97.6% (206/211), MCN 90.0% (18/19), cystic degeneration 87.1% (27/31), and SN 15.4% (2/13). Multivariate analysis revealed that main pancreatic duct (MPD) communication (− ) (odds ratio (OR), 4.54; 95% confidence interval (CI) 1.29–15.9), honeycomb-like structure (+) (OR, 14.7; 95% CI 2.61–83.3), and MPD size ≦ 2 mm (OR, 16.3; 95% CI 3.93–67.6) were independently associated with misdiagnosis. Conclusion: For cases in which MCN and cystic degeneration of solid tumor are presumed based on preoperative EUS imaging and cases with PCLs with a honeycomb-like structure, diagnosis with multimodalities or fluid analysis with EUS-guided fine-needle aspiration should be considered.

    DOI: 10.1007/s10396-022-01205-7

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  21. Good and Bad Stroma in Pancreatic Cancer: Relevance of Functional States of Cancer-Associated Fibroblasts

    Ando Ryota, Sakai Akihiro, Iida Tadashi, Kataoka Kunio, Mizutani Yasuyuki, Enomoto Atsushi

    CANCERS   Vol. 14 ( 14 )   2022.7

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    A well-known feature of human pancreatic ductal adenocarcinoma (PDAC) is the extensive proliferation of cancer-associated fibroblasts (CAFs) and highly fibrotic stroma. Recent evidence, based mainly on single-cell analyses, has identified various subsets of CAFs in PDAC mouse models. However, we do not know how these CAF subsets are involved in the progression and drug resistance of human PDAC. Additionally, it remains unclear whether these diverse CAFs have distinct origins and are indicators of genuinely distinct CAF lineages or reflect different states of the same CAFs depending on the tumor microenvironment. Interestingly, recent preclinical studies have started to characterize the nature of cancer-restraining CAFs and have identified their markers Meflin and collagen type I alpha 1. These studies have led to the development of strategies to induce changes in CAF phenotypes using chemical reagents or recombinant viruses, and some of them have been tested in clinical studies. These strategies have the unique potential to convert the so-called bad stroma to good stroma and may also have therapeutic implications for non-cancer diseases such as fibrotic diseases. Together with recently developed sophisticated strategies that specifically target distinct CAF subsets via adoptive cell transfer therapy, vaccination, and antibody–drug conjugates, any future findings arising from these clinical efforts may expand our understanding of the significance of CAF diversity in human PDAC.

    DOI: 10.3390/cancers14143315

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  22. Factors associated with misdiagnosis of preoperative endoscopic ultrasound in patients with pancreatic cystic neoplasms undergoing surgical resection

    Ohno Eizaburo, Ishikawa Takuya, Mizutani Yasuyuki, Iida Tadashi, Uetsuki Kota, Yashika Jun, Yamada Kenta, Gibo Noriaki, Aoki Toshinori, Kawashima Hiroki

    JOURNAL OF MEDICAL ULTRASONICS   Vol. 49 ( 3 ) page: 433 - 441   2022.7

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    Language:English   Publisher:Journal of Medical Ultrasonics  

    Purpose: Pancreatic cystic lesions (PCLs) include various types of cysts. Accurate preoperative diagnosis is essential to avoid unnecessary surgery on benign cysts. In this study, we aimed to identify the factors associated with misdiagnosis in preoperative endoscopic ultrasound (EUS) imaging and clinicopathological findings for PCLs. Methods: This study included 302 surgically resected patients with PCLs who underwent preoperative EUS. The preoperative EUS findings were re-evaluated and compared with the pathological diagnosis. Additionally, the factors associated with misdiagnosis of PCLs were investigated by multivariate analysis. Results: The preoperative diagnoses of PCLs were intraductal papillary mucinous neoplasm (IPMN) in 213 patients (70.5%), mucinous cystic neoplasm (MCN) in 33 patients (10.9%), serous neoplasm (SN) in 7 patients (2.3%), cystic degeneration cyst of solid tumor in 46 patients (15.2%), and pancreatic cancer with cystic degeneration in three patients (1.0%). A discrepancy between preoperative and postoperative diagnosis was found in 47 patients (15.6%). Based on the pathological diagnosis, the sensitivity of preoperative EUS imaging was IPMN 97.6% (206/211), MCN 90.0% (18/19), cystic degeneration 87.1% (27/31), and SN 15.4% (2/13). Multivariate analysis revealed that main pancreatic duct (MPD) communication (− ) (odds ratio (OR), 4.54; 95% confidence interval (CI) 1.29–15.9), honeycomb-like structure (+) (OR, 14.7; 95% CI 2.61–83.3), and MPD size ≦ 2 mm (OR, 16.3; 95% CI 3.93–67.6) were independently associated with misdiagnosis. Conclusion: For cases in which MCN and cystic degeneration of solid tumor are presumed based on preoperative EUS imaging and cases with PCLs with a honeycomb-like structure, diagnosis with multimodalities or fluid analysis with EUS-guided fine-needle aspiration should be considered.

    DOI: 10.1007/s10396-022-01205-7

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  23. Good and Bad Stroma in Pancreatic Cancer: Relevance of Functional States of Cancer-Associated Fibroblasts

    Ando Ryota, Sakai Akihiro, Iida Tadashi, Kataoka Kunio, Mizutani Yasuyuki, Enomoto Atsushi

    CANCERS   Vol. 14 ( 14 )   2022.7

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    Language:English   Publisher:Cancers  

    A well-known feature of human pancreatic ductal adenocarcinoma (PDAC) is the extensive proliferation of cancer-associated fibroblasts (CAFs) and highly fibrotic stroma. Recent evidence, based mainly on single-cell analyses, has identified various subsets of CAFs in PDAC mouse models. However, we do not know how these CAF subsets are involved in the progression and drug resistance of human PDAC. Additionally, it remains unclear whether these diverse CAFs have distinct origins and are indicators of genuinely distinct CAF lineages or reflect different states of the same CAFs depending on the tumor microenvironment. Interestingly, recent preclinical studies have started to characterize the nature of cancer-restraining CAFs and have identified their markers Meflin and collagen type I alpha 1. These studies have led to the development of strategies to induce changes in CAF phenotypes using chemical reagents or recombinant viruses, and some of them have been tested in clinical studies. These strategies have the unique potential to convert the so-called bad stroma to good stroma and may also have therapeutic implications for non-cancer diseases such as fibrotic diseases. Together with recently developed sophisticated strategies that specifically target distinct CAF subsets via adoptive cell transfer therapy, vaccination, and antibody–drug conjugates, any future findings arising from these clinical efforts may expand our understanding of the significance of CAF diversity in human PDAC.

    DOI: 10.3390/cancers14143315

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  24. Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to chemotherapeutics (Apr, 10.1038/s41388-022-02288-9, 2022)

    Iida Tadashi, Mizutani Yasuyuki, Esaki Nobutoshi, Ponik Suzanne M., Burkel Brian M., Weng Liang, Kuwata Keiko, Masamune Atsushi, Ishihara Seiichiro, Haga Hisashi, Kataoka Kunio, Mii Shinji, Shiraki Yukihiro, Ishikawa Takuya, Ohno Eizaburo, Kawashima Hiroki, Hirooka Yoshiki, Fujishiro Mitsuhiro, Takahashi Masahide, Enomoto Atsushi

    ONCOGENE   Vol. 41 ( 23 ) page: 3302 - 3302   2022.6

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    Affiliation 11 was assigned by mistake to Masahide Takahashi instead of Mitsuhiro Fujishiro The correct affiliation are Mitsuhiro Fujishiro2,11 Masahide Takahashi102Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan. 10International Center for Cell and Gene Therapy, Fujita Health University, Toyoake, Japan. 11Present address: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. The original article has been corrected.

    DOI: 10.1038/s41388-022-02336-4

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  25. Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to chemotherapeutics (Apr, 10.1038/s41388-022-02288-9, 2022)

    Iida Tadashi, Mizutani Yasuyuki, Esaki Nobutoshi, Ponik Suzanne M., Burkel Brian M., Weng Liang, Kuwata Keiko, Masamune Atsushi, Ishihara Seiichiro, Haga Hisashi, Kataoka Kunio, Mii Shinji, Shiraki Yukihiro, Ishikawa Takuya, Ohno Eizaburo, Kawashima Hiroki, Hirooka Yoshiki, Fujishiro Mitsuhiro, Takahashi Masahide, Enomoto Atsushi

    ONCOGENE   Vol. 41 ( 23 ) page: 3302 - 3302   2022.6

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    Affiliation 11 was assigned by mistake to Masahide Takahashi instead of Mitsuhiro Fujishiro The correct affiliation are Mitsuhiro Fujishiro2,11 Masahide Takahashi102Department of Gastroenterology and Hepatology, Nagoya University Graduate School of Medicine, Nagoya, Japan. 10International Center for Cell and Gene Therapy, Fujita Health University, Toyoake, Japan. 11Present address: Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan. The original article has been corrected.

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  26. Comparison of contrast-enhanced transabdominal ultrasonography following endoscopic ultrasonography with GD-EOB-DTPA-enhanced MRI for the sequential diagnosis of liver metastasis in patients with pancreatic cancer

    Ishikawa Takuya, Ohno Eizaburo, Mizutani Yasuyuki, Iida Tadashi, Koya Toshinari, Sasaki Yutaka, Ogawa Hiroshi, Kinoshita Fumie, Hirooka Yoshiki, Kawashima Hiroki

    JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES   Vol. 29 ( 6 ) page: 682 - 692   2022.6

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    Purpose: To compare contrast-enhanced transabdominal ultrasonography (CE-US) following contrast-enhanced harmonic endoscopic ultrasonography (CH-EUS) with enhanced magnetic resonance imaging using gadolinium-ethoxybenzyl-diethylenetriamine pentaacetic acid (EOB-MRI) in the diagnosis of liver metastases in patients with pancreatic cancer. Methods: Patients who underwent contrast-enhanced computed tomography for possible pancreatic cancer and required further evaluation with CH-EUS were enrolled in this study, and the diagnostic performance of CE-US following CH-EUS for liver metastasis was compared with that of EOB-MRI. Results: A total of 228 patients were included in the final analysis. Two hundred thirty-four hepatic lesions were found in 81 patients, and 178 lesions were finally diagnosed as metastases. EOB-MRI had a higher sensitivity (0.837 vs 0.949), while CE-US had a higher specificity and positive predictive value (PPV) (0.982 and 0.993 vs 0.911 and 0.971, respectively) in the diagnosis of liver metastasis. CE-US with defect reperfusion imaging had a higher diagnostic performance than EOB-MRI (0.866 vs 0.667) in the differentiation between liver metastasis and abscess. Conclusion: EOB-MRI had a higher sensitivity than CE-US for diagnosing liver metastasis in patients with pancreatic cancer, but CE-US following CH-EUS demonstrated a higher specificity and PPV than EOB-MRI and was especially useful in the differentiation between liver metastasis and abscess.

    DOI: 10.1002/jhbp.1097

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  27. Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to chemotherapeutics

    Iida Tadashi, Mizutani Yasuyuki, Esaki Nobutoshi, Ponik Suzanne M., Burkel Brian M., Weng Liang, Kuwata Keiko, Masamune Atsushi, Ishihara Seiichiro, Haga Hisashi, Kataoka Kunio, Mii Shinji, Shiraki Yukihiro, Ishikawa Takuya, Ohno Eizaburo, Kawashima Hiroki, Hirooka Yoshiki, Fujishiro Mitsuhiro, Takahashi Masahide, Enomoto Atsushi

    ONCOGENE   Vol. 41 ( 19 ) page: 2764 - 2777   2022.5

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    Previous therapeutic attempts to deplete cancer-associated fibroblasts (CAFs) or inhibit their proliferation in pancreatic ductal adenocarcinoma (PDAC) were not successful in mice or patients. Thus, CAFs may be tumor suppressive or heterogeneous, with distinct cancer-restraining and -promoting CAFs (rCAFs and pCAFs, respectively). Here, we showed that induced expression of the glycosylphosphatidylinositol-anchored protein Meflin, a rCAF-specific marker, in CAFs by genetic and pharmacological approaches improved the chemosensitivity of mouse PDAC. A chemical library screen identified Am80, a synthetic, nonnatural retinoid, as a reagent that effectively induced Meflin expression in CAFs. Am80 administration improved the sensitivity of PDAC to chemotherapeutics, accompanied by increases in tumor vessel area and intratumoral drug delivery. Mechanistically, Meflin was involved in the suppression of tissue stiffening by interacting with lysyl oxidase to inhibit its collagen crosslinking activity. These data suggested that modulation of CAF heterogeneity may represent a strategy for PDAC treatment.

    DOI: 10.1038/s41388-022-02288-9

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  28. Pharmacologic conversion of cancer-associated fibroblasts from a protumor phenotype to an antitumor phenotype improves the sensitivity of pancreatic cancer to chemotherapeutics

    Iida Tadashi, Mizutani Yasuyuki, Esaki Nobutoshi, Ponik Suzanne M., Burkel Brian M., Weng Liang, Kuwata Keiko, Masamune Atsushi, Ishihara Seiichiro, Haga Hisashi, Kataoka Kunio, Mii Shinji, Shiraki Yukihiro, Ishikawa Takuya, Ohno Eizaburo, Kawashima Hiroki, Hirooka Yoshiki, Fujishiro Mitsuhiro, Takahashi Masahide, Enomoto Atsushi

    ONCOGENE   Vol. 41 ( 19 ) page: 2764 - 2777   2022.5

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    Previous therapeutic attempts to deplete cancer-associated fibroblasts (CAFs) or inhibit their proliferation in pancreatic ductal adenocarcinoma (PDAC) were not successful in mice or patients. Thus, CAFs may be tumor suppressive or heterogeneous, with distinct cancer-restraining and -promoting CAFs (rCAFs and pCAFs, respectively). Here, we showed that induced expression of the glycosylphosphatidylinositol-anchored protein Meflin, a rCAF-specific marker, in CAFs by genetic and pharmacological approaches improved the chemosensitivity of mouse PDAC. A chemical library screen identified Am80, a synthetic, nonnatural retinoid, as a reagent that effectively induced Meflin expression in CAFs. Am80 administration improved the sensitivity of PDAC to chemotherapeutics, accompanied by increases in tumor vessel area and intratumoral drug delivery. Mechanistically, Meflin was involved in the suppression of tissue stiffening by interacting with lysyl oxidase to inhibit its collagen crosslinking activity. These data suggested that modulation of CAF heterogeneity may represent a strategy for PDAC treatment.

    DOI: 10.1038/s41388-022-02288-9

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  29. Gelsolin as a Potential Biomarker for Endoscopic Activity and Mucosal Healing in Ulcerative Colitis

    Maeda Keiko, Nakamura Masanao, Yamamura Takeshi, Sawada Tsunaki, Ishikawa Eri, Oishi Akina, Ikegami Shuji, Kakushima Naomi, Furukawa Kazuhiro, Iida Tadashi, Mizutani Yasuyuki, Ishikawa Takuya, Ohno Eizaburo, Honda Takashi, Ishigami Masatoshi, Kawashima Hiroki

    BIOMEDICINES   Vol. 10 ( 4 )   2022.4

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    The therapeutic goal in ulcerative colitis is mucosal healing, which requires improved non-invasive biomarkers to evaluate disease activity. Gelsolin is associated with several autoimmune diseases, and here, we aimed to analyze its usefulness as a serological biomarker for clinical and endoscopic activities in ulcerative colitis. Patients with ulcerative colitis (n = 138) who had undergone blood tests and colonoscopy were included. Serum gelsolin was measured using enzyme-linked immunosorbent assay, and correlation between the gelsolin level and clinical and endoscopic activities was examined. The serum gelsolin level in patients with ulcerative colitis was significantly lower than that in healthy subjects, and it decreased in proportion to increasing Mayo score and Mayo endoscopic subscore. The area under the curve for correlation between clinical and endoscopic remission and serum gelsolin level was higher than that for C-reactive protein. Furthermore, in C-reactive protein-negative patients, the serum gelsolin level was lower in the active phase than in remission. Our findings indicate that the serum gelsolin level correlates with clinical and endoscopic activities in ulcerative colitis, has a higher sensitivity and specificity than C-reactive protein, and can detect mucosal healing, suggesting that gelsolin can be used as a biomarker for ulcerative colitis.

    DOI: 10.3390/biomedicines10040872

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  30. Pancreatic acinar cell carcinoma with predominant extension into the main pancreatic duct: A case report.

    Ishikawa T, Ohno E, Mizutani Y, Iida T, Kawashima H

    DEN open   Vol. 2 ( 1 ) page: e96   2022.4

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    DOI: 10.1002/deo2.96

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  31. Gelsolin as a Potential Biomarker for Endoscopic Activity and Mucosal Healing in Ulcerative Colitis

    Maeda Keiko, Nakamura Masanao, Yamamura Takeshi, Sawada Tsunaki, Ishikawa Eri, Oishi Akina, Ikegami Shuji, Kakushima Naomi, Furukawa Kazuhiro, Iida Tadashi, Mizutani Yasuyuki, Ishikawa Takuya, Ohno Eizaburo, Honda Takashi, Ishigami Masatoshi, Kawashima Hiroki

    BIOMEDICINES   Vol. 10 ( 4 )   2022.4

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    The therapeutic goal in ulcerative colitis is mucosal healing, which requires improved non-invasive biomarkers to evaluate disease activity. Gelsolin is associated with several autoimmune diseases, and here, we aimed to analyze its usefulness as a serological biomarker for clinical and endoscopic activities in ulcerative colitis. Patients with ulcerative colitis (n = 138) who had undergone blood tests and colonoscopy were included. Serum gelsolin was measured using enzyme-linked immunosorbent assay, and correlation between the gelsolin level and clinical and endoscopic activities was examined. The serum gelsolin level in patients with ulcerative colitis was significantly lower than that in healthy subjects, and it decreased in proportion to increasing Mayo score and Mayo endoscopic subscore. The area under the curve for correlation between clinical and endoscopic remission and serum gelsolin level was higher than that for C-reactive protein. Furthermore, in C-reactive protein-negative patients, the serum gelsolin level was lower in the active phase than in remission. Our findings indicate that the serum gelsolin level correlates with clinical and endoscopic activities in ulcerative colitis, has a higher sensitivity and specificity than C-reactive protein, and can detect mucosal healing, suggesting that gelsolin can be used as a biomarker for ulcerative colitis.

    DOI: 10.3390/biomedicines10040872

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  32. Pancreatic acinar cell carcinoma with predominant extension into the main pancreatic duct: A case report.

    Ishikawa T, Ohno E, Mizutani Y, Iida T, Kawashima H

    DEN open   Vol. 2 ( 1 ) page: e96   2022.4

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    DOI: 10.1002/deo2.96

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  33. Matrix remodeling-associated protein 8 is a marker of a subset of cancer-associated fibroblasts in pancreatic cancer

    Ichihara Ryosuke, Shiraki Yukihiro, Mizutani Yasuyuki, Iida Tadashi, Miyai Yuki, Esaki Nobutoshi, Kato Akira, Mii Shinji, Ando Ryota, Hayashi Masamichi, Takami Hideki, Fujii Tsutomu, Takahashi Masahide, Enomoto Atsushi

    PATHOLOGY INTERNATIONAL   Vol. 72 ( 3 ) page: 161 - 175   2022.3

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    Cancer-associated fibroblasts (CAFs), a compartment of the tumor microenvironment, were previously thought to be a uniform cell population that promotes cancer progression. However, recent studies have shown that CAFs are heterogeneous and that there are at least two types of CAFs, that is, cancer-promoting and -restraining CAFs. We previously identified Meflin as a candidate marker of cancer-restraining CAFs (rCAFs) in pancreatic ductal adenocarcinoma (PDAC). The precise nature of rCAFs, however, has remained elusive owing to a lack of understanding of their comprehensive gene signatures. Here, we screened genes whose expression correlated with Meflin in single-cell transcriptomic analyses of human cancers. Among the identified genes, we identified matrix remodeling-associated protein 8 (MXRA8), which encodes a type I transmembrane protein with unknown molecular function. Analysis of MXRA8 expression in human PDAC samples showed that MXRA8 was differentially co-expressed with other CAF markers. Moreover, in patients with PDAC or syngeneic tumors developed in MXRA8-knockout mice, MXRA8 expression did not affect the roles of CAFs in cancer progression, and the biological importance of MXRA8+ CAFs is still unclear. Overall, we identified MXRA8 as a new CAF marker; further studies are needed to determine the relevance of this marker.

    DOI: 10.1111/pin.13198

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  34. The Origin and Contribution of Cancer-Associated Fibroblasts in Colorectal Carcinogenesis

    Kobayashi Hiroki, Gieniec Krystyna A., Lannagan Tamsin R. M., Wang Tongtong, Asai Naoya, Mizutani Yasuyuki, Iida Tadashi, Ando Ryota, Thomas Elaine M., Sakai Akihiro, Suzuki Nobumi, Ichinose Mari, Wright Josephine A., Vrbanac Laura, Ng Jia Q., Goyne Jarrad, Radford Georgette, Lawrence Matthew J., Sammour Tarik, Hayakawa Yoku, Klebe Sonja, Shin Alice E., Asfaha Samuel, Bettington Mark L., Rieder Florian, Arpaia Nicholas, Danino Tal, Butler Lisa M., Burt Alastair D., Leedham Simon J., Rustgi Anil K., Mukherjee Siddhartha, Takahashi Masahide, Wang Timothy C., Enomoto Atsushi, Woods Susan L., Worthley Daniel L.

    GASTROENTEROLOGY   Vol. 162 ( 3 ) page: 890 - 906   2022.3

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    Background & Aims: Cancer-associated fibroblasts (CAFs) play an important role in colorectal cancer (CRC) progression and predict poor prognosis in CRC patients. However, the cellular origins of CAFs remain unknown, making it challenging to therapeutically target these cells. Here, we aimed to identify the origins and contribution of colorectal CAFs associated with poor prognosis. Methods: To elucidate CAF origins, we used a colitis-associated CRC mouse model in 5 different fate-mapping mouse lines with 5-bromodeoxyuridine dosing. RNA sequencing of fluorescence-activated cell sorting–purified CRC CAFs was performed to identify a potential therapeutic target in CAFs. To examine the prognostic significance of the stromal target, CRC patient RNA sequencing data and tissue microarray were used. CRC organoids were injected into the colons of knockout mice to assess the mechanism by which the stromal gene contributes to colorectal tumorigenesis. Results: Our lineage-tracing studies revealed that in CRC, many ACTA2+ CAFs emerge through proliferation from intestinal pericryptal leptin receptor (Lepr)+ cells. These Lepr-lineage CAFs, in turn, express melanoma cell adhesion molecule (MCAM), a CRC stroma-specific marker that we identified with the use of RNA sequencing. High MCAM expression induced by transforming growth factor β was inversely associated with patient survival in human CRC. In mice, stromal Mcam knockout attenuated orthotopically injected colorectal tumoroid growth and improved survival through decreased tumor-associated macrophage recruitment. Mechanistically, fibroblast MCAM interacted with interleukin-1 receptor 1 to augment nuclear factor κB–IL34/CCL8 signaling that promotes macrophage chemotaxis. Conclusions: In colorectal carcinogenesis, pericryptal Lepr-lineage cells proliferate to generate MCAM+ CAFs that shape the tumor-promoting immune microenvironment. Preventing the expansion/differentiation of Lepr-lineage CAFs or inhibiting MCAM activity could be effective therapeutic approaches for CRC.

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  35. The impact of the age-adjusted Charlson comorbidity index as a prognostic factor for endoscopic papillectomy in ampullary tumors

    Takada Yoshihisa, Kawashima Hiroki, Ohno Eizaburo, Ishikawa Takuya, Mizutani Yasuyuki, Iida Tadashi, Yamamura Takeshi, Kakushima Naomi, Furukawa Kazuhiro, Nakamura Masanao, Honda Takashi, Ishigami Masatoshi, Ito Akihiro, Hirooka Yoshiki

    JOURNAL OF GASTROENTEROLOGY   Vol. 57 ( 3 ) page: 199 - 207   2022.3

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    Background: The prognostic nutritional index (PNI) and Charlson comorbidity index (CCI) have been useful for predicting the prognosis based on nutritional condition and comorbidities in surgery and endoscopic mucosal dissection. The age-adjusted CCI (ACCI) has also been reported to be useful in surgery, but it has not been applied to endoscopic treatment. We therefore clarified the prognostic factors associated with ampullary tumors treated with endoscopic papillectomy (EP). Methods: From January 2003 to December 2020, 236 patients who underwent EP for sporadic ampullary tumors at Nagoya University Hospital were included in this study. The 5-year survival and ability to predict the prognosis were evaluated in terms of the sex, PNI, ACCI, final pathological diagnosis, and intraductal extension. Results: During a median follow-up period of 1558 days, 17 patients died. No patient died of the primary disease. The 5-year survival rate was 91.1%. In a univariate analysis, only a high ACCI (≥ 5) was extracted as a significant prognostic factor (Odds ratio, 12.2; 95% confidence interval, 3.81–39.3; p < 0.001). The 5-year survival rates for a low ACCI (≤ 4) and high ACCI were 96.6% and 73.5%, respectively (p < 0.001). Conclusions: A high ACCI is an important prognostic factor associated with the 5-year survival and a risk of death from other illness. Ampullary tumors suitable for EP are less likely to be a prognostic factor, and treatment-free follow-up may be acceptable in patients with a high ACCI.

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  36. 今月の主題 炎症性腸疾患の粘膜治癒を再考する 主題 Crohn病における小腸粘膜治癒評価の意義-小腸カプセル内視鏡の立場から

    中村 正直, 山村 健史, 前田 啓子, 澤田 つな騎, 石川 恵里, 角嶋 直美, 古川 和宏, 飯田 忠, 水谷 泰之, 石川 卓哉, 大野 栄三郎, 川嶋 啓揮, 藤城 光弘

    胃と腸   Vol. 57 ( 2 ) page: 183 - 189   2022.2

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    DOI: 10.11477/mf.1403202660

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  37. Safety and efficacy of MIKE-1 in patients with advanced pancreatic cancer: a study protocol for an open-label phase I/II investigator-initiated clinical trial based on a drug repositioning approach that reprograms the tumour stroma

    Mizutani Yasuyuki, Iida Tadashi, Ohno Eizaburo, Ishikawa Takuya, Kinoshita Fumie, Kuwatsuka Yachiyo, Imai Miwa, Shimizu Shinobu, Tsuruta Toshihisa, Enomoto Atsushi, Kawashima Hiroki, Fujishiro Mitsuhiro

    BMC CANCER   Vol. 22 ( 1 ) page: 205   2022.2

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    Background: Cancer-associated fibroblasts (CAFs) are an important component of the tumour microenvironment. Recent studies revealed CAFs are heterogeneous and CAF subset(s) that suppress cancer progression (cancer-restraining CAFs [rCAFs]) must exist in addition to well-characterised cancer-promoting CAFs (pCAFs). However, the identity and specific markers of rCAFs are not yet reported. We recently identified Meflin as a specific marker of rCAFs in pancreatic and colon cancers. Our studies revealed that rCAFs may represent proliferating resident fibroblasts. Interestingly, a lineage tracing experiment showed Meflin-positive rCAFs differentiate into α-smooth muscle actin-positive and Meflin-negative CAFs, which are generally hypothesised as pCAFs, during cancer progression. Using a pharmacological approach, we identified AM80, a synthetic unnatural retinoid, as a reagent that effectively converts Meflin-negative pCAFs to Meflin-positive rCAFs. We aimed to investigate the efficacy of a combination of AM80 and gemcitabine (GEM) and nab-paclitaxel (nab-PTX) in patients with advanced pancreatic cancer. Methods: The phase I part is a 3 + 3 design, open-label, and dose-finding study. The dose-limiting toxicity (DLT) of these combination therapies would be evaluated for 4 weeks. After the DLT evaluation period, if no disease progression is noted based on the Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or if the patient has no intolerable toxicity, administration of AM80 with GEM and nab-PTX would be continued for up to 24 weeks. The phase II part is an open-label, single-arm study. The maximum tolerated dose (MTD) of AM80 with GEM and nab-PTX, determined in phase I, would be administered until intolerable toxicity or disease progression occurs, up to a maximum of 24 weeks, to confirm efficacy and safety. The primary endpoints are frequency of DLT and MTD of AM80 with GEM and nab-PTX in the phase I part and response rate based on the RECIST in the phase II part. Given the historical control data, we hope that the response rate will be over 23% in phase II. Discussion: Strategies to convert pCAFs into rCAFs have been developed in recent years. We hypothesised that AM80 would be a promising enhancer of chemosensitivity and drug distribution through CAF conversion in the stroma. Trial registration: Clinicaltrial.gov: NCT05064618, registered on 1 October 2021. jRCT: jRCT2041210056, registered on 27 August 2021.

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  38. Development of a Novel Evaluation Method for Endoscopic Ultrasound-Guided Fine-Needle Biopsy in Pancreatic Diseases Using Artificial Intelligence

    Ishikawa Takuya, Hayakawa Masato, Suzuki Hirotaka, Ohno Eizaburo, Mizutani Yasuyuki, Iida Tadashi, Fujishiro Mitsuhiro, Kawashima Hiroki, Hotta Kazuhiro

    DIAGNOSTICS   Vol. 12 ( 2 )   2022.2

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    We aimed to develop a new artificial intelligence (AI)-based method for evaluating endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) specimens in pancreatic diseases using deep learning and contrastive learning. We analysed a total of 173 specimens from 96 patients who underwent EUS-FNB with a 22 G Franseen needle for pancreatic diseases. In the initial study, the deep learning method based on stereomicroscopic images of 98 EUS-FNB specimens from 63 patients showed an accuracy of 71.8% for predicting the histological diagnosis, which was lower than that of macroscopic on-site evaluation (MOSE) performed by EUS experts (81.6%). Then, we used image analysis software to mark the core tissues in the photomicrographs of EUS-FNB specimens after haematoxylin and eosin staining and verified whether the diagnostic performance could be improved by applying contrastive learning for the features of the stereomicroscopic images and stained images. The sensitivity, specificity, and accuracy of MOSE were 88.97%, 53.5%, and 83.24%, respectively, while those of the AI-based diagnostic method using contrastive learning were 90.34%, 53.5%, and 84.39%, respectively. The AI-based evaluation method using contrastive learning was comparable to MOSE performed by EUS experts and can be a novel objective evaluation method for EUS-FNB.

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  39. Usefulness of Macroscopic On-Site Evaluation Using a Stereomicroscope during EUS-FNB for Diagnosing Solid Pancreatic Lesions

    Ishikawa Takuya, Ohno Eizaburo, Mizutani Yasuyuki, Iida Tadashi, Uetsuki Kota, Yashika Jun, Yamada Kenta, Gibo Noriaki, Aoki Toshinori, Kataoka Kunio, Mori Hiroshi, Takada Yoshihisa, Takahashi Hidekazu, Aoi Hironori, Kato Katsuyuki, Yamamura Takeshi, Kakushima Naomi, Furukawa Kazuhiro, Nakamura Masanao, Hirooka Yoshiki, Kawashima Hiroki

    CANADIAN JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   Vol. 2022   page: 2737578   2022.1

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    Background/Aims. The usefulness of macroscopic on-site evaluation (MOSE) during endoscopic ultrasound-guided fine-needle biopsy (EUS-FNB) has been reported, but a specific method for MOSE has not been established. We aimed to investigate the usefulness of MOSE using a stereomicroscope (S-MOSE) for the diagnosis of solid pancreatic lesions (SPLs). Methods. We reviewed a total of 60 consecutive patients who underwent both S-MOSE and rapid on-site cytopathological evaluation (ROSE) during EUS-FNB between July 2019 and October 2020, and the usefulness of S-MOSE in comparison with histology was evaluated. A 22-gauge Franseen needle was used to perform EUS-FNB in all patients, and only the specimens obtained by the first pass were evaluated. The final diagnosis was based on the surgical specimen or the clinical course consistent with the EUS-FNB results. Results. The final diagnoses of the 60 patients included 45 patients with pancreatic ductal adenocarcinoma, 6 with autoimmune pancreatitis, 4 with mass-forming pancreatitis, 1 with pancreatic metastasis, 2 with pancreatic neuroendocrine tumor, and 2 with intraductal papillary mucinous carcinoma. The histological diagnostic accuracy of the first pass of EUS-FNB was 83.3% (50/60). The agreement between the S-MOSE and the histological diagnosis was 90% (54/60). The positive predictive value of S-MOSE for histological diagnosis was 90.7%, which can be an indicator of when to stop the EUS-FNB procedure. There were no immediate or delayed adverse events reported after the FNB based on the chart and medical visit history review. Conclusion. In the EUS-FNB of SPLs, S-MOSE can be an alternative to ROSE for specimen evaluation and has the potential to shorten the procedure time.

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  40. Differentiation Between Solid Pseudopapillary Neoplasm of the Pancreas and Nonfunctional Pancreatic Neuroendocrine Neoplasm Using Endoscopic Ultrasound

    Kataoka Kunio, Ishikawa Takuya, Ohno Eizaburo, Mizutani Yasuyuki, Iida Tadashi, Furukawa Kazuhiro, Nakamura Masanao, Honda Takashi, Ishigami Masatoshi, Kawashima Hiroki, Hirooka Yoshiki, Fujishiro Mitsuhiro

    PANCREAS   Vol. 51 ( 1 ) page: 106 - 111   2022.1

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    Objectives We investigated the utility of endoscopic ultrasound (EUS) for differentiating between solid pseudopapillary neoplasm of the pancreas (SPN) and pancreatic neuroendocrine neoplasm (PanNEN). Methods A retrospective analysis was performed on 29 and 77 consecutive patients with pathologically proven SPN and nonfunctional PanNEN. In patients who underwent contrast-enhanced harmonic EUS (CH-EUS), lesions were classified into 3 vascular patterns (hypoechoic/isoechoic/hyperechoic), and the presence of "the alveolus nest sign,"which we previously reported as a characteristic feature of SPN on CH-EUS, was also assessed. Results Conventional EUS findings showed that calcification echoes were significantly more frequent in SPN lesions than in PanNEN lesions (19/29 [66%] vs 21/77 [27%], P = 0.001) as was internal isoechogenicity or hyperechogenicity (10/29 [34%] vs 11/77 [14%], P = 0.029). Contrast-enhanced harmonic EUS findings showed that SPN lesions more frequently had the isoechoic or hypoechoic vascular pattern, and significantly more frequently had the alveolus nest sign (18/25 [72%] vs 4/60 [7%], P < 0.001). In a multivariate analysis, the presence of the alveolus nest sign contributed the most to the SPN diagnosis (odds ratio, 70; 95% confidence interval, 6.2-786). Conclusions Endoscopic ultrasound, particularly the presence of the alveolus nest sign on CH-EUS, is useful for differentiating SPN from PanNEN.

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  41. Fish bone migration after pancreaticoduodenectomy: Incidence and treatment options

    Takada Yoshihisa, Ishikawa Takuya, Kawashima Hiroki, Mizutani Yasuyuki, Ohno Eisaburo, Iida Tadashi, Ogawa Hiroshi, Hayashi Masamichi, Takami Hideki, Onoe Shunsuke, Ishigami Masatoshi

    JOURNAL OF DIGESTIVE DISEASES   Vol. 23 ( 1 ) page: 44 - 49   2022.1

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    Objective: Migration of a fish bone to the bile duct or pancreatic duct is a possible complication after pancreaticoduodenectomy (PD). The aim of this study was to clarify the incidence and indications for intervention in such cases. Methods: We reviewed the cases with fish bone migration after PD detected on computed tomography (CT) scan between October 2000 and October 2020 were reviewed and the incidence of fish bone migration, presence of symptoms and signs, therapeutic modalities and patient outcomes were analyzed. Results: Among the 1475 PD procedures performed at our institution during the study period, 14 cases of fish bone migration were noted on CT, the incidence of which was 0.95% (14/1475). The time duration from surgery to the detection of fish bone ranged from 88 to 5902 days (median 917 d). Ten patients remained asymptomatic without therapeutic intervention for up to 2919 days (median 509 d). Four patients were treated by endoscopy, either at the patient's request (n = 1) or because of their symptoms (n = 3), and removal was successful in three cases but failed in one case in which the fish bone migrated to the right intrahepatic bile duct. No surgical treatment was required in any case. Conclusions: The incidence of fish bone migration on CT after PD was about 1%. Some cases resolved spontaneously, and most of the asymptomatic cases required no intervention. For symptomatic cases, endoscopic treatment should be considered first. It is important to confirm the location of the fish bone by CT and determine whether it can be removed.

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  42. Evaluation of ulcerative colitis activity using transabdominal ultrasound shear wave elastography

    Yamada Kenta, Ishikawa Takuya, Kawashima Hiroki, Ohno Eizaburo, Iida Tadashi, Ishikawa Eri, Mizutani Yasuyuki, Sawada Tsunaki, Maeda Keiko, Yamamura Takeshi, Kakushima Naomi, Furukawa Kazuhiro, Nakamura Masanao, Ishigami Masatoshi, Fujishiro Mitsuhiro

    QUANTITATIVE IMAGING IN MEDICINE AND SURGERY   Vol. 12 ( 1 ) page: 618 - 626   2022.1

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    Background: Transabdominal ultrasound (US) has been reported to be effective in the evaluation of ulcerative colitis (UC). US can measure shear wave elastography (SWE) and shear wave dispersion (SWD), which may be correlated with inflammation and necrosis. We aimed to investigate the relationship between UC activity and SWE and SWD. Methods: Patients with UC who underwent US within 2 days before or after a colonoscopy between April 2019 and March 2020 were included. SWE and SWD were measured in the sigmoid colon; the correlations of SWE and SWD with the Lichtiger index and the Ulcerative Colitis Endoscopic Index of Severity (UCEIS) were investigated. We also compared SWE and SWD between patients with mucosal healing and those in the active phase according to the UCEIS. Results: Twenty-six UC patients were enrolled. The median Lichtiger index, UCEIS, SWE values, and SWD values were 8 [interquartile range (IQR), 5.3–10.8], 4 (IQR, 3.3–5), 1.69 (IQR, 1.49–2.16) m/s, and 11.9 (IQR, 10.9–13.3) (m/s)/kHz, respectively. The Lichtiger index and UCEIS were negatively correlated with the SWE values (rs=−0.404 and rs=−0.506) but not with the SWD values (rs=0.004 and rs=0.002). The SWE values differed significantly between the mucosal healing and active phase groups [2.40 (IQR, 2.18–3.38) vs. 1.62 (IQR, 1.44–1.95) m/s, P=0.007], whereas the SWD values did not [13.1 (IQR, 7.05–21.6) vs. 11.9 (IQR, 11.1–13.2) (m/s)/kHz, P=0.918]. Conclusions: SWE may be useful for the evaluation of UC activity and could be a noninvasive method of assessing disease severity.

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  43. Preliminary Comparison of Endoscopic Brush and Net Catheters as the Sampling Tool to Analyze the Intestinal Mucus in the Rectum with Ulcerative Colitis Patients

    Nakamura Masanao, Maeda Keiko, Yamamoto Kenta, Yamamura Takeshi, Sawada Tsunaki, Ishikawa Eri, Kakushima Naomi, Furukawa Kazuhiro, Iida Tadashi, Mizutani Yasuyuki, Ishikawa Takuya, Ohno Eizaburo, Honda Takashi, Ishigami Masatoshi, Kawashima Hiroki

    DIGESTION   Vol. 103 ( 3 ) page: 232 - 243   2022

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    Background: The pathophysiology of ulcerative colitis (UC) remains unclear, but early lesions on the colorectal mucosal surface may play an important role in its etiology. Intestinal mucus samples, including inner and outer layers, are collected by net or brush catheters, but the quality of the samples obtained by each method has not been fully investigated. Objective: The purpose of this study was to compare the microbiome and protein content of intestinal mucus collected by net and brush catheters during colonoscopy. Methods: Intestinal mucus samples from the lower rectum of 4 patients with UC were collected using a net catheter, a brush catheter, and intestinal fluid suction. Microbiome and protein content were analyzed using 16S rRNA gene sequencing and mass spectrometry. Results: The patients demonstrated significant differences in microbiome alpha diversity (p < 0.05), but this difference was not observed between the sampling methods. Net catheter samples demonstrated higher total protein concentrations than brush catheter samples. The brush catheter group had more Lachnospira, a butyrate-producing bacterium, when compared to the net group. The brush catheter group also had more oral bacteria of Staphylococcus and Dialister in those with active phase when compared to the net group. Conclusions: Brush catheters are more likely to collect the intestinal mucus inner layer, whereas net catheters are more likely to collect larger samples that include the outer mucus layer, as well as the intestinal fluid. Two sampling methods with different types of collection of the mucosa may lead to different results among patients with mucosal vulnerabilities.

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  44. Leptomeningeal carcinomatosis from duodenal papillary carcinoma

    YAMADA Kenta, OHNO Eizaburo, ISHIKAWA Takuya, MIZUTANI Yasuyuki, IIDA Tadashi, UETSUKI Kota, YASHIKA Jun, AOKI Toshinori, MORI Hiroshi, KAWASHIMA Hiroki

    Nippon Shokakibyo Gakkai Zasshi   Vol. 119 ( 11 ) page: 1043 - 1047   2022

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    <p>A woman in her 50s presented with ataxia and repeated falls during 2nd line S-1 therapy for duodenal papillary carcinoma with metastasis. She was diagnosed with leptomeningeal carcinomatosis based on gadolinium contrast-enhanced magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) examination, although plain computed tomography (CT) and MRI of the head showed no intracranial occupying lesions. This is a rare leptomeningeal carcinomatosis case with duodenal papillary carcinoma as the primary lesion, although aggressive treatment was not possible due to the decreased consciousness level.</p>

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  45. Leptomeningeal carcinomatosis from duodenal papillary carcinoma

    YAMADA Kenta, OHNO Eizaburo, ISHIKAWA Takuya, MIZUTANI Yasuyuki, IIDA Tadashi, UETSUKI Kota, YASHIKA Jun, AOKI Toshinori, MORI Hiroshi, KAWASHIMA Hiroki

    Nippon Shokakibyo Gakkai Zasshi   Vol. 119 ( 11 ) page: 1043 - 1047   2022

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    <p>A woman in her 50s presented with ataxia and repeated falls during 2nd line S-1 therapy for duodenal papillary carcinoma with metastasis. She was diagnosed with leptomeningeal carcinomatosis based on gadolinium contrast-enhanced magnetic resonance imaging (MRI) and cerebrospinal fluid (CSF) examination, although plain computed tomography (CT) and MRI of the head showed no intracranial occupying lesions. This is a rare leptomeningeal carcinomatosis case with duodenal papillary carcinoma as the primary lesion, although aggressive treatment was not possible due to the decreased consciousness level.</p>

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  46. IgG4-related sclerosing cholangitis diagnosed by steroid trial

    Kawashima Hiroki, Ohno Eizaburo, Ishikawa Takuya, Mizutani Yasuyuki, Iida Tadashi, Yamada Kenta

    Tando   Vol. 35 ( 5 ) page: 773 - 777   2021.12

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    DOI: 10.11210/tando.35.773

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  47. Clinical characteristics of gastrointestinal immune-related adverse events of immune checkpoint inhibitors and their association with survival

    Yamada Kentaro, Sawada Tsunaki, Nakamura Masanao, Yamamura Takeshi, Maeda Keiko, Ishikawa Eri, Iida Tadashi, Mizutani Yasuyuki, Kakushima Naomi, Ishikawa Takuya, Furukawa Kazuhiro, Ohno Eizaburo, Honda Takashi, Kawashima Hiroki, Ishigami Masatoshi, Furune Satoshi, Hase Tetsunari, Yokota Kenji, Maeda Osamu, Hashimoto Naozumi, Akiyama Masashi, Ando Yuichi, Fujishiro Mitsuhiro

    WORLD JOURNAL OF GASTROENTEROLOGY   Vol. 27 ( 41 ) page: 7190 - 7206   2021.11

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    BACKGROUND Despite the popularity of immune checkpoint inhibitors (ICIs) in the treatment of advanced cancer, patients often develop gastrointestinal (GI) and non-GI immune- related adverse events (irAEs). The clinical characteristics and survival outcomes of GI-irAEs have not been fully elucidated in previous reports. This necessitates the evaluation of the impact of GI-irAEs on patients receiving ICI treatment. AIM To evaluate the clinical characteristics of GI-irAEs and their impact on survival in patients treated with ICIs. METHODS In this single-center, retrospective, observational study, we reviewed the records of 661 patients who received ICIs for various cancers at Nagoya University Hospital from September 2014 to August 2020. We analyzed the clinical characteristics of patients who received ICI treatment. We also evaluated the correlation between GI-irAE development and prognosis in non-small cell lung cancer (LC) and malignant melanoma (MM). Kaplan-Meier analysis was used to compare the median overall survival (OS). Multivariate Cox proportional hazards models were used to identify prognostic factors. A P value < 0.05 was considered statistically significant. RESULTS GI-irAEs occurred in 34 of 605 patients (5.6%) treated with an anti-programmed cell death-1/programmed death-ligand 1 (anti-PD-1/PD-L1) antibody alone and in nine of 56 patients (16.1%) treated with an anti-cytotoxic T-lymphocyte antigen 4 (CTLA-4) antibody alone or a combination of anti-PD-1 and anti-CTLA-4 antibodies. The cumulative incidence and median daily diarrhea frequency were significantly higher in patients receiving anti-CTLA-4 antibodies (P < 0.05). In 130 patients with MM, OS was significantly prolonged in the group that continued ICI treatment despite the development of GI-irAEs compared to the group that did not experience GI-irAEs (P = 0.035). In contrast, in 209 patients with non-small cell LC, there was no significant difference in OS between the groups. The multivariate analyses showed that a performance status of 2-3 (hazard ratio: 2.406; 95% confidence interval: 1.125-5.147; P = 0.024) was an independent predictive factor for OS in patients with MM. CONCLUSION Patients receiving anti-CTLA-4 antibodies develop GI-irAEs more frequently and with higher severity than those receiving anti-PD-1/PD-L1 antibodies. Continuing ICI treatment in patients with MM with GI-irAEs have better OS.

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  48. Roles of the Mesenchymal Stromal/Stem Cell Marker Meflin/Islr in Cancer Fibrosis

    Takahashi Masahide, Kobayashi Hiroki, Mizutani Yasuyuki, Hara Akitoshi, Iida Tadashi, Miyai Yuki, Asai Naoya, Enomoto Atsushi

    FRONTIERS IN CELL AND DEVELOPMENTAL BIOLOGY   Vol. 9   page: 749924   2021.10

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    Fibroblasts synthesise the extracellular matrix (ECM) such as collagen and elastin, the excessive accumulation of which can lead to fibrosis and organ dysfunction under pathological conditions. Cancer-associated fibroblasts (CAFs) are major constituents of the tumour microenvironment (TME) that accompany the desmoplastic reaction responsible for anti-cancer treatment resistance. Thus, it is important to dissect the roles of CAFs in the TME to develop new therapeutic strategies for refractory cancers. Recent progress in the studies of CAF biology suggests that the functions of CAFs are complicated and that they are composed of functionally distinct populations, including cancer-promoting CAFs (pCAFs) and cancer-restraining CAFs (rCAFs). We recently identified a new cell surface marker for rCAFs in pancreatic and colon cancers, designated as Meflin (mesenchymal stromal cell- and fibroblast-expressing Linx paralogue)/Islr (immunoglobulin super family containing leucine-rich repeat). Based on the distribution of Meflin/Islr-positive cells, we also considered it a specific candidate marker for mesenchymal stroma/stem cells. Meflin/Islr-positive CAFs have been shown to suppress cancer progression by being involved in regulating collagen structures and BMP signalling in the TME. This review describes the function of Meflin/Islr in cancer fibrosis as well as in cardiac and lung fibrosis and its potential in the development of new cancer therapeutics.

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  49. Differentiation between pancreatic metastases from renal cell carcinoma and pancreatic neuroendocrine neoplasm using endoscopic ultrasound

    Kataoka Kunio, Ishikawa Takuya, Ohno Eizaburo, Mizutani Yasuyuki, Iida Tadashi, Ishikawa Eri, Furukawa Kazuhiro, Nakamura Masanao, Honda Takashi, Ishigami Masatoshi, Kawashima Hiroki, Hirooka Yoshiki, Fujishiro Mitsuhiro

    PANCREATOLOGY   Vol. 21 ( 7 ) page: 1364 - 1370   2021.10

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    Objectives: Pancreatic metastases from renal cell carcinoma (PRCC) often appear many years after treatment of the primary tumor, and differentiation from pancreatic neuroendocrine neoplasm (PanNEN) can be challenging due to their hypervascularity. Here, we investigated the utility of endoscopic ultrasound (EUS) for differentiation of these conditions. Methods: A retrospective analysis was performed in 17 and 79 consecutive patients with pathologically proven PRCC and non-functional PanNEN who were examined by EUS. In cases examined by EUS elastography or contrast-enhanced harmonic EUS (CH-EUS), the lesions were classified as stiff or soft, or into three vascular patterns as hypoechoic, isoechoic, and hyperechoic. CH-EUS images at 20 s, 40 s, 60 s, 3 min and 5 min were used for evaluation. EUS images were independently reviewed by two readers who were blinded to all clinical information. Results: The patients with PRCC were significantly older than those with PanNEN (median, 71 (range, 45–81) vs. 58 (22–76), P = 0.001) and more often had multiple tumors (6/17 (35%) vs. 7/79 (9%), P = 0.010). In EUS findings, PRCC lesions significantly more frequently had a marginal hypoechoic zone (MHZ) (11/17 (65%) vs. 27/79 (34%), P = 0.028), being classified as soft (12/13 (92%) vs. 26/58 (45%), P = 0.002), and showed sustained hyperechoic vascular patterns at 5 min (7/8 (88%) vs. 4/59 (7%), P < 0.001) compared to PanNEN lesions. Conclusions: The presence of a MHZ, a soft lesion, and a sustained hyperechoic vascular pattern in EUS may be useful for differentiating PRCC from PanNEN.

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  50. Double common bile duct associated with pancreaticobiliary maljunction

    Yamada Kenta, Ishikawa Takuya, Ohno Eizaburo, Iida Tadashi, Suzuki Hirotaka, Uetsuki Kota, Yashika Jun, Yoshikawa Masakatsu, Takami Hideki, Inokawa Yoshikuni, Uchida Hiroo, Kawashima Hiroki, Fujishiro Mitsuhiro

    NAGOYA JOURNAL OF MEDICAL SCIENCE   Vol. 83 ( 3 ) page: 655 - 661   2021.8

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    A 45-year-old female was admitted to the hospital with a diagnosis of acute pancreatitis. A computed tomography scan showed two extrahepatic bile ducts. Magnetic resonance cholangiopancreatography suggested a stone in one of the bile ducts. Endoscopic retrograde cholangiopancreatography revealed two extrahepatic bile ducts joining at the hilum of the liver accompanied with pancreaticobiliary maljunction. Sphincterotomy was performed and a protein plug was drained from the bile duct. Several treatment options were discussed, and the patient was treated with laparoscopic cholecystectomy without extrahepatic bile duct resection and planned to be followed up considering the risk of carcinogenesis in the bile ducts.

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  51. The CD44/COL17A1 pathway promotes the formation of multilayered, transformed epithelia

    Kozawa Kei, Sekai Miho, Ohba Kenji, Ito Shoko, Sako Hiroaki, Maruyama Takeshi, Kakeno Mai, Shirai Takanobu, Kuromiya Keisuke, Kamasaki Tomoko, Kohashi Koki, Tanaka Shinya, Ishikawa Susumu, Sato Nanami, Asano Shota, Suzuki Hironori, Tanimura Nobuyuki, Mukai Yohei, Gotoh Noriko, Tanino Mishie, Tanaka Shinya, Natsuga Ken, Soga Tomoyoshi, Nakamura Tomonori, Yabuta Yukihiro, Saitou Mitinori, Ito Takahiro, Matsuura Kenkyo, Tsunoda Makoto, Kikumori Toyone, Iida Tadashi, Mizutani Yasuyuki, Miyai Yuki, Kaibuchi Kozo, Enomoto Atsushi, Fujita Yasuyuki

    CURRENT BIOLOGY   Vol. 31 ( 14 ) page: 3086 - +   2021.7

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    At the early stage of cancer development, oncogenic mutations often cause multilayered epithelial structures. However, the underlying molecular mechanism still remains enigmatic. By performing a series of screenings targeting plasma membrane proteins, we have found that collagen XVII (COL17A1) and CD44 accumulate in RasV12-, Src-, or ErbB2-transformed epithelial cells. In addition, the expression of COL17A1 and CD44 is also regulated by cell density and upon apical cell extrusion. We further demonstrate that the expression of COL17A1 and CD44 is profoundly upregulated at the upper layers of multilayered, transformed epithelia in vitro and in vivo. The accumulated COL17A1 and CD44 suppress mitochondrial membrane potential and reactive oxygen species (ROS) production. The diminished intracellular ROS level then promotes resistance against ferroptosis-mediated cell death upon cell extrusion, thereby positively regulating the formation of multilayered structures. To further understand the functional role of COL17A1, we performed comprehensive metabolome analysis and compared intracellular metabolites between RasV12 and COL17A1-knockout RasV12 cells. The data imply that COL17A1 regulates the metabolic pathway from the GABA shunt to mitochondrial complex I through succinate, thereby suppressing the ROS production. Moreover, we demonstrate that CD44 regulates membrane accumulation of COL17A1 in multilayered structures. These results suggest that CD44 and COL17A1 are crucial regulators for the clonal expansion of transformed cells within multilayered epithelia, thus being potential targets for early diagnosis and preventive treatment for precancerous lesions.

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  52. Endoscopic papillectomy for ampullary adenoma and early adenocarcinoma: Analysis of factors related to treatment outcome and long-term prognosis

    Kawashima Hiroki, Ohno Eizaburo, Ishikawa Takuya, Iida Tadashi, Tanaka Hiroyuki, Furukawa Kazuhiro, Nakamura Masanao, Honda Takashi, Hashimoto Senju, Itoh Akihiro, Ishigami Masatoshi, Hirooka Yoshiki, Fujishiro Mitsuhiro

    DIGESTIVE ENDOSCOPY   Vol. 33 ( 5 ) page: 858 - 869   2021.7

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    Objectives: There are few reports on the long-term prognosis of papillary tumors after endoscopic papillectomy. Here, we report a retrospective study of the therapeutic effects, long-term prognosis, and affecting factors. Methods: The inclusion criteria were papillary adenoma with/without an adenocarcinoma component on biopsy results and ≤10 mm intraductal extension, and the exclusion criteria were moderate to poorly differentiated adenocarcinoma on biopsy results. If no residual lesion was confirmed ≥6 months after the last endoscopic treatment, remission was defined. Subsequently, follow-up endoscopy was scheduled once a year. Surgery was required in the case of adenocarcinoma recurrence or intraductal lesions >10 mm. The rates of adverse events, remission, recurrence, and need for surgery were examined. The affecting factors were calculated. Results: There were a total of 253 subjects, including 65 with adenocarcinoma. Pancreatitis (7.5%), bleeding (9.1%) and perforation (2.8%) were observed as adverse events. Among 221 subjects with ≥6 months of follow-up, 212 (95.9%) were in remission. The cumulative recurrence rate using the Kaplan–Meier analysis at 5 years was 16.9% (22 cases), with the need for surgery in 5.9% (5 cases). Intraductal extension on preoperative diagnosis was the only significant risk factor for both recurrence (P < 0.001) and the need for surgery (P = 0.005). The presence of adenocarcinoma had no significant effect. Conclusion: Although remission was achieved in more than 95% of our patients, we observed a high rate of recurrence at the long-term follow-up, which was significantly associated with intraductal extension but not with the presence of adenocarcinoma.

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  53. Meflin defines mesenchymal stem cells and/or their early progenitors with multilineage differentiation capacity

    Hara Akitoshi, Kato Katsuhiro, Ishihara Toshikazu, Kobayashi Hiroki, Asai Naoya, Mii Shinji, Shiraki Yukihiro, Miyai Yuki, Ando Ryota, Mizutani Yasuyuki, Iida Tadashi, Takefuji Mikito, Murohara Toyoaki, Takahashi Masahide, Enomoto Atsushi

    GENES TO CELLS   Vol. 26 ( 7 ) page: 495 - 512   2021.7

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    Mesenchymal stem cells (MSCs) are the likely precursors of multiple lines of mesenchymal cells. The existence of bona fide MSCs with self-renewal capacity and differentiation potential into all mesenchymal lineages, however, has been unclear because of the lack of MSC-specific marker(s) that are not expressed by the terminally differentiated progeny. Meflin, a glycosylphosphatidylinositol-anchored protein, is an MSC marker candidate that is specifically expressed in rare stromal cells in all tissues. Our previous report showed that Meflin expression becomes down-regulated in bone marrow-derived MSCs cultured on plastic, making it difficult to examine the self-renewal and differentiation of Meflin-positive cells at the single-cell level. Here, we traced the lineage of Meflin-positive cells in postnatal and adult mice, showing that those cells differentiated into white and brown adipocytes, osteocytes, chondrocytes and skeletal myocytes. Interestingly, cells derived from Meflin-positive cells formed clusters of differentiated cells, implying the in situ proliferation of Meflin-positive cells or their lineage-committed progenitors. These results, taken together with previous findings that Meflin expression in cultured MSCs was lost upon their multilineage differentiation, suggest that Meflin is a useful potential marker to localize MSCs and/or their immature progenitors in multiple tissues.

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  54. An initial trial of quantitative evaluation of autoimmune pancreatitis using shear wave elastography and shear wave dispersion in transabdominal ultrasound

    Suzuki Hirotaka, Ishikawa Takuya, Ohno Eizaburo, Iida Tadashi, Uetsuki Kota, Yashika Jun, Yamada Kenta, Yoshikawa Masakatsu, Furukawa Kazuhiro, Nakamura Masanao, Honda Takashi, Ishigami Masatoshi, Kawashima Hiroki, Fujishiro Mitsuhiro

    PANCREATOLOGY   Vol. 21 ( 4 ) page: 682 - 687   2021.6

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    Background/Objectives: We aimed to examine therapeutic efficacy and prognosis prediction of autoimmune pancreatitis (AIP) using shear wave elastography (SWE) and shear wave dispersion (SWD) in transabdominal ultrasound (US). Methods: The subjects were 23 patients with diffuse type 1 AIP who underwent SWE and SWD, and 34 controls with a normal pancreas. Elasticity and dispersion were defined as the pancreatic elastic modulus (PEM) and dispersion slope, respectively. PEM and dispersion slope were compared between AIP and control cases, and the short-term therapeutic effect and long-term prognosis were examined. Results: PEM (30.9 vs. 6.6 kPa, P < 0.001) and dispersion slope (15.3 vs. 13.0 (m/sec)/kHz, P = 0.011) were significantly higher in AIP cases than in controls. Among the 17 AIP patients followed-up in two weeks after treatment, these parameters were 12.7 kPa and 10.5 (m/sec)/kHz with median decrease rate of 37.2% and 32.8%, respectively, which were significantly higher than the change in the size of pancreatic parenchyma (14.4%, P = 0.026). Fourteen of these subjects were followed up for >12 months, during which 2 had relapse; diabetes improved in 5 and worsened in 2; in 60% of cases, the pancreatic parenchyma was atrophied. The % change in PEM after two weeks was tended to be higher in non-atrophy cases. Conclusion: SWE and SWD measurement in US may be useful for quantitative assessment of AIP and evaluation of short-term treatment efficacy.

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  55. Immunohistochemical staining for IMP3 in patients with duodenal papilla tumors: assessment of the potential for diagnosing endoscopic resectability and predicting prognosis

    Tanaka Hiroyuki, Kawashima Hiroki, Ohno Eizaburo, Ishikawa Takuya, Iida Tadashi, Ishikawa Eri, Furukawa Kazuhiro, Nakamura Masanao, Honda Takashi, Shimoyama Yoshie, Miyahara Ryoji, Kawabe Naoto, Kuzuya Teiji, Hashimoto Senju, Ishigami Masatoshi, Hirooka Yoshiki, Fujishiro Mitsuhiro

    BMC GASTROENTEROLOGY   Vol. 21 ( 1 ) page: 224   2021.5

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    Background: Endoscopic papillectomy of duodenal papillary tumors (PT) is indicated for adenomas or well-differentiated adenocarcinomas that do not involve the sphincter of Oddi. However, there is currently no reliable pre-operative method to diagnose the infiltration in the sphincter of Oddi.’ Insulin-like growth factor 2 mRNA protein 3 (IMP3) staining is reportedly associated with advanced disease stage and clinical outcomes in many carcinomas. The aim of this retrospective study was to investigate the ability of diagnosing sphincter of Oddi involvement in PT and predicting the prognoses using IMP3 immunohistochemistry. Methods: Twenty-five resected specimens from patients with PT and 24 biopsy specimens from the same patients excluding one were immunostained for IMP3. The percentage of positive cells in the tumor was evaluated and compared with the final pathological diagnosis and prognosis. Results: The final pathological diagnoses were adenoma in 5 patients and adenocarcinoma in 20 patients (no sphincter of Oddi involvement in 5 and involvement in 15). The ability to diagnose sphincter of Oddi involvement based on the percentage of IMP3-positive cells in resected specimens and tissue biopsies was the area under the curve 0.8 and 0.78, respectively, of the receiver operating characteristic curve, and the accuracies were 80.0% and 75.0% (cutoff value: 10%), respectively. Moreover, patients with an IMP3-positive cell rate of ≥ 10% had a significantly worse prognosis (log-rank test P = 0.01). Conclusion: IMP3 immunostaining of resected and biopsy specimens from PT patients enables the diagnosis of sphincter of Oddi involvement objectively and is also effective in predicting the prognosis.

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  56. Measurement of fasting breath hydrogen concentration as a simple diagnostic method for pancreatic exocrine insufficiency

    Uetsuki Kota, Kawashima Hiroki, Ohno Eizaburo, Ishikawa Takuya, Iida Tadashi, Yamamoto Kenta, Furukawa Kazuhiro, Nakamura Masanao, Honda Takashi, Ishigami Masatoshi, Hirooka Yoshiki, Fujishiro Mitsuhiro

    BMC GASTROENTEROLOGY   Vol. 21 ( 1 ) page: 211   2021.5

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    Background: Pancreatic exocrine insufficiency (PEI) is associated with the outcome of pancreatic disease. However, there is no method for assessing PEI that can be used noninvasively and easily for outpatient. It has been reported that changes in intestinal bacteria caused by PEI may increase breath hydrogen concentration (BHC) levels during glucose or lactose loading. We have evaluated the usefulness of fasting breath hydrogen concentration (FBHC) measurement without glucose loading for the evaluation of PEI. Methods: Sixty patients underwent FBHC measurement, BT-PABA testing, and microbiome analysis. They were classified into PEI group (PABA excretion rate < 73.4%, n = 30) and non-PEI group (n = 30). The FBHC of the two groups were compared, and the diagnostic ability of PEI by them was evaluated. The 16 s rRNA (V3–V4) from fecal samples was analyzed by MiSeq. Results: FBHC levels was higher in the PEI group 15.70 (1.4 to 77.0) ppm than in the non-PEI group 2.80 (0.7 to 28.2) ppm (P < 0.0001). FBHC was negatively correlated with PABA excretion rate (r = − 0.523, P < 0.001). The cutoff value of FBHC of 10.7 ppm (95% CI: 0.678–0.913, P < 0.001) showed a sensitivity of 73.3% and specificity of 83.3% for PEI diagnosis. In the PEI group, there was a significant increase of relative abundance of phylum Firmicutes (P < 0.05) and the genus Clostridium (P < 0.05). Conclusion: FBHC shows good potential as a simple and repeatable test for the diagnosis of PEI. The elevated FBHC levels may be caused by hydrogen-producing bacteria such as Clostridium.

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  57. Diagnostic performance of endoscopic ultrasonography-guided elastography for solid pancreatic lesions: Shear-wave measurements versus strain elastography with histogram analysis

    Ohno Eizaburo, Kawashima Hiroki, Ishikawa Takuya, Iida Tadashi, Suzuki Hirotaka, Uetsuki Kota, Yashika Jun, Yamada Kenta, Yoshikawa Masakatsu, Gibo Noriaki, Aoki Toshinori, Kataoka Kunio, Mori Hiroshi, Yamamura Takeshi, Furukawa Kazuhiro, Nakamura Masanao, Hirooka Yoshiki, Fujishiro Mitsuhiro

    DIGESTIVE ENDOSCOPY   Vol. 33 ( 4 ) page: 629 - 638   2021.5

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    Background and aims: Endoscopic ultrasound (EUS) elastography (EUS-EG) is a minimally invasive diagnostic method for evaluating tissue elasticity. The aim of this study was to evaluate the feasibility of newly developed EUS shear-wave measurement (EUS-SWM) and to compare diagnostic performance between EUS-SWM and the conventional strain elastography (SE) for the measurement of elasticity of solid pancreatic lesions (SPLs). Methods: From December 2017 until August 2019, we retrospectively reviewed 64 consecutive cases with SPLs who underwent both EUS-SWM and SE. EUS-SWM was used to measure the shear-wave velocity, Vs (m/s), and the unique measurement reliability index, VsN (%), in the target lesion. SE images were assessed by strain histogram (SH) analysis, and the mean strain value of the elasticity index was measured. We evaluated the diagnostic performance of EUS-SWM and SE with SH to characterize the SPLs. Results: The Vs (m/s) values of SPLs were 2.19 for pancreatic cancer (PC), 1.31 for pancreatic neuroendocrine neoplasm (PanNEN), 2.56 for mass-forming pancreatitis (MFP) and 1.58 for metastatic tumors. Vs showed no significant difference based on the disease. The mean strain values were 45.5 for PC, 47.3 for PanNEN, and 74.5 for MFP. In the comparison of tissue elasticity between PC and MFP, Vs showed no significant difference (P = 0.5687); however, the mean strain value was significantly lower in PC cases (45.4 vs 74.5: P = 0.0007). Conclusion: Endoscopic ultrasound SWM tended to be unstable for the measurement of elasticity of SPLs, and conventional SE with SH was superior for their characterization.

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  58. Variability measurements provide additional value to shear wave elastography in the diagnosis of pancreatic cancer

    Yoshikawa Masakatsu, Ishikawa Takuya, Ohno Eizaburo, Iida Tadashi, Furukawa Kazuhiro, Nakamura Masanao, Honda Takashi, Ishigami Masatoshi, Kinoshita Fumie, Kawashima Hiroki, Fujishiro Mitsuhiro

    SCIENTIFIC REPORTS   Vol. 11 ( 1 ) page: 7409   2021.4

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    Shear wave elastography (SWE) is a technique to non-invasively and quantitatively evaluate tissue stiffness. We aimed to investigate whether we can differentiate pancreatic cancer (PC) from normal pancreatic parenchyma (NPP) by SWE using transabdominal ultrasound. We investigated a total of 106 patients (84 with NPP and 22 with PC) whose pancreatic elastic modulus was measured by two-dimensional SWE (2D-SWE). Intra-rater reliability in this study was examined, and three measurements were sufficiently reliable. There were no differences between the two groups in factors that could affect SWE measurements. The median value of the elastic modulus was 5.70 kPa in the PC patients and 5.66 kPa in the NPP group, which was not significantly different (P = 0.785). On the contrary, the range was 8.64 kPa and 4.72 kPa, with a significantly greater range in the PC patients (P = 0.001). In conclusion, the median elastic modulus measured by 2D-SWE was not significantly different between PC and NPP, and evaluating the obtained elastic modulus itself is not useful in differentiation. However, the variability was significantly greater in PC than in NPP. Evaluating the range of elasticities will provide additional information in SWE, which may be useful in the diagnosis of PC.

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  59. Endoscopic ultrasound elastography for small solid pancreatic lesions with or without main pancreatic duct dilatation

    Kataoka Kunio, Ishikawa Takuya, Ohno Eizaburo, Iida Tadashi, Suzuki Hirotaka, Uetsuki Kota, Furukawa Kazuhiro, Nakamura Masanao, Honda Takashi, Ishigami Masatoshi, Kawashima Hiroki, Hirooka Yoshiki, Fujishiro Mitsuhiro

    PANCREATOLOGY   Vol. 21 ( 2 ) page: 451 - 458   2021.3

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    Background: /Objectives: Endoscopic ultrasound elastography (EUS-EG) is useful for diagnosis of small solid pancreatic lesions (SPLs), particularly in excluding pancreatic cancer (PC), but its dependence on main pancreatic duct dilatation (MPDD) has not been examined. We aimed to investigate EUS-EG for diagnosis of small SPLs with and without MPDD. Methods: Patients with pathologically diagnosed SPLs of ≤20 mm were included and retrospectively analyzed. Using the blue:green ratio, an EUS-EG image was classified as blue-dominant, equivalent, or green-dominant. Using multiple EUS-EG images per patient, a lesion with a greater number of blue-dominant than green-dominant images was classified as stiff, and the others as soft. EUS-EG images in random order were judged by three raters. Considering stiff SPLs as PC, diagnostic performance of EUS-EG was examined for SPLs with and without MPDD. Results: Of 126 cases analyzed, 65 (52%) were diagnosed as PC, and 63 (50%) had MPDD. A total of 1077 EUS-EG images were examined (kappa coefficient = 0.783). Lesions were classified as stiff in 91 cases and soft in 35 (kappa coefficient = 0.932). The ratio of stiff to soft lesions was significantly higher in PC than in non-PC (62:3 vs. 29:32, P < 0.001). The sensitivity, specificity, and negative predictive value of a stiff lesion with vs. without MPDD for diagnosis of PC were 94%, 23%, and 50% vs. 100%, 60%, and 100%, respectively. Conclusions: Using the EUS-EG stiffness classification for small SPLs, PC can be excluded with high confidence and concordance for a soft lesion without MPDD.

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  60. Utility of multiphase contrast enhancement patterns on CEH-EUS for the differential diagnosis of IPMN-derived and conventional pancreatic cancer

    Yashika Jun, Ohno Eizaburo, Ishikawa Takuya, Iida Tadashi, Suzuki Hirotaka, Uetsuki Kota, Yamada Kenta, Yoshikawa Masakatsu, Gibo Noriaki, Shimoyama Yoshie, Ishikawa Eri, Furukawa Kazuhiro, Nakamura Masanao, Honda Takashi, Ishigami Masatoshi, Hirooka Yoshiki, Kawashima Hiroki, Fujishiro Mitsuhiro

    PANCREATOLOGY   Vol. 21 ( 2 ) page: 390 - 396   2021.3

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    Background: Intraductal papillary mucinous neoplasm (IPMN) is reported as a high-risk factor for pancreatic cancer (PC) that includes IPMN-derived cancers (IPMC) and the development of invasive pancreatic ductal adenocarcinoma (PDAC) concomitant with IPMN. Since invasive IPMC and PDAC exhibit different oncological behaviors, their differentiation is clinically important. We aimed to investigate the use of contrast-enhanced harmonic endoscopic ultrasound (CEH-EUS) for the differential diagnosis between invasive IPMC and PDAC. Methods: This study involved 183 consecutive patients with PC (invasive IPMC: 42, PDAC concomitant with IPMN: 9, without IPMN: 132) who underwent CEH-EUS preoperatively. While investigating the patterns, enhanced effects in the solid part of the tumor were compared with those in the surrounding pancreatic parenchyma after administration of Sonazoid® and evaluated as hyperenhanced, isoenhanced, or hypoenhanced. We retrospectively compared the enhanced pattern of CEH-EUS by using multiphasic analysis and clinicopathological factors between invasive IPMC and PDAC. Results: In multiphase evaluations at 20, 40 and 60 s in CEH-EUS, 75.2% (106/141) of PDACs were hypoenhanced (−) at ≥2 of the 3 time points, with significant differences from those of invasive IPMC (P < 0.001). The solid tumor diameter was significantly larger in PDAC than in invasive IPMC, and the tumor stage and preoperative serum carbohydrate antigen 19-9 level were higher. After propensity score matching of stage and solid tumor diameter, contrast enhancement patterns were significantly more persistent in invasive IPMC than in PDAC (P = 0.0013). Conclusions: Multiphase evaluation using CEH-EUS is a useful method for differentiating between invasive IPMC and PDAC.

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  61. Clinical characteristics and long-term prognosis of autoimmune pancreatitis with renal lesions

    Ishikawa Takuya, Kawashima Hiroki, Ohno Eizaburo, Iida Tadashi, Suzuki Hirotaka, Uetsuki Kota, Yashika Jun, Yamada Kenta, Yoshikawa Masakatsu, Gibo Noriaki, Aoki Toshinori, Kataoka Kunio, Mori Hiroshi, Yamamura Takeshi, Furukawa Kazuhiro, Nakamura Masanao, Hirooka Yoshiki, Fujishiro Mitsuhiro

    SCIENTIFIC REPORTS   Vol. 11 ( 1 ) page: 406   2021.1

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    Autoimmune pancreatitis (AIP) is recognized as the pancreatic manifestation of a systemic IgG4-related disease that can involve various organs, including the kidney. However, renal lesions tend to be overlooked when AIP is diagnosed, and the clinical characteristics and long-term prognosis of AIP with renal lesions are unclear. We retrospectively reviewed 153 patients with AIP diagnosed at our hospital with a median follow-up period of 41 months (interquartile range, 10–86) and classified them into two groups: the KD group (n = 17), with characteristic renal imaging features, and the non-KD group (n = 136). Serum IgG4 levels were significantly higher in the KD group (663 vs. 304.5 mg/dl, P = 0.014). No differences were observed between the two groups in terms of steroid treatment [14/17 (82.4%) vs. 112/136 (82.4%), P = 1] or in the number of patients who exhibited exacerbation of renal function during treatment [1/17 (5.9%) vs. 8/136 (5.9%), P = 1]. However, the cumulative relapse rate was significantly higher in the KD group [61% vs. 21.9% (3 years), P < 0.001]. Patients in the KD group had different clinical features with high relapse rates compared with those in the non-KD group, and thus, it is important to confirm the presence of renal lesions in AIP patients.

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  62. Risks and characteristics of pancreatic cancer and pancreatic relapse in autoimmune pancreatitis patients

    Ishikawa Takuya, Kawashima Hiroki, Ohno Eizaburo, Iida Tadashi, Suzuki Hirotaka, Uetsuki Kota, Yamada Kenta, Yashika Jun, Yoshikawa Masakatsu, Gibo Noriaki, Aoki Toshinori, Kataoka Kunio, Mori Hiroshi, Fujishiro Mitsuhiro

    JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   Vol. 35 ( 12 ) page: 2281 - 2288   2020.12

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    Background and Aim: We examined the differences in the risks and characteristics of pancreatic relapse (PR) and pancreatic cancer (PC) in patients with autoimmune pancreatitis (AIP). Methods: We retrospectively reviewed 123 type 1 AIP patients with a median follow-up of 55 months (interquartile range, 27–98). The following items were evaluated: (i) cumulative relapse rates and risk factors, (ii) the incidence of PC, (iii) PR versus PC, and (iv) outcomes after the appearance of morphological changes in the pancreas (focal enlargement, apparent mass lesions, or main pancreatic duct dilation). Results: (i) The cumulative PR rates were 1.7% within 1 year, 11.5% within 3 years, and 22.6% within 5 years. Lack of maintenance therapy, IgG4-related sclerosing cholangitis, and IgG4-related kidney disease were identified as independent predictors of relapse. (ii) Two patients (1.6%) were diagnosed with PC at 17 and 22 months after initial AIP diagnosis. (iii) Thirteen (59.1%) and four (18.2%) patients with PR had focal enlargement and main pancreatic duct dilation, respectively. The median CA19-9 level at initial diagnosis was significantly higher in PC patients (21 vs 220.5 U/mL, P = 0.014). (iv) Eight PR patients underwent endoscopic ultrasound-guided fine-needle aspiration, none of whom had malignant findings. PC was diagnosed by ultrasound-guided fine-needle aspiration in both cancer patients. Conclusions: Although the incidence of PC is low, it may mimic PR in AIP patients. Surveillance is important, and when morphological changes occur, biopsy and evaluation of serum IgG4 and CA19-9 levels (particularly if the levels were high before) should be considered.

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  63. The Daple-CK1 epsilon complex regulates Dvl2 phosphorylation and canonical Wnt signaling

    Esaki Nobutoshi, Enomoto Atsushi, Takagishi Maki, Mizutani Yasuyuki, Iida Tadashi, Ushida Kaori, Shiraki Yukihiro, Mii Shinji, Takahashi Masahide

    BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS   Vol. 532 ( 3 ) page: 406 - 413   2020.11

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    The canonical Wnt signaling pathway plays a crucial role in embryonic development, tissue homeostasis and cancer progression. The binding of Wnt ligands to their cognate receptors, the Frizzled (Fzd) family of proteins, recruits Dishevelled segment polarity protein (Dvl) to the plasma membrane and induces its phosphorylation via casein kinase 1 (CK1), which leads to the activation of β-catenin. Previous studies showed that Dishevelled-associating protein with a high frequency of leucine residues (Daple) is an important component of the Wnt signaling pathway and essential for Dvl phosphorylation. However, the mechanism by which Daple promotes CK1-mediated phosphorylation of Dvl is not fully understood. In this study, we found that Daple overexpression induced CK1ε-mediated Dvl2 phosphorylation at threonine 224 (Thr224). A Daple mutant (Daple ΔGCV) that lacks a carboxyl-terminal motif to associate with Dvl, retained the ability to interact with CK1ε, but did not induce Dvl phosphorylation, suggesting the importance of the Daple/Dvl/CK1ε trimeric protein complex. We further found that Thr224 phosphorylation of Dvl was required for full activation of β-catenin transcriptional activity. Consistent with this, wild-type Daple promoted β-catenin transcriptional activity, following dissociation of β-catenin and axin. Finally, Wnt3a stimulation increased the membrane localization of Daple and its association with Dvl, and Daple knockdown attenuated Wnt3a-mediated β-catenin transcriptional activity. Collectively, these data suggested a essential role of spatial Daple localization in CK1ε-mediated activation of Dvl in the canonical Wnt signaling pathway.

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  64. Connective tissue growth factor produced by cancer-associated fibroblasts correlates with poor prognosis in epithelioid malignant pleural mesothelioma

    Ohara Yuuki, Enomoto Atsushi, Tsuyuki Yuta, Sato Kotaro, Iida Tadashi, Kobayashi Hiroki, Mizutani Yasuyuki, Miyai Yuki, Hara Akitoshi, Mii Shinji, Suzuki Jun, Yamashita Kyoko, Ito Fumiya, Motooka Yashiro, Misawa Nobuaki, Fukui Takayuki, Kawaguchi Koji, Yokoi Kohei, Toyokuni Shinya

    ONCOLOGY REPORTS   Vol. 44 ( 3 ) page: 838 - 848   2020.9

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    Malignant mesothelioma is an aggressive neoplasm for which effective treatments are lacking. We often encounter mesothelioma cases with a profound desmoplastic reaction, suggesting the involvement of cancer.associated fibroblasts (CAFs) in mesothelioma progression. While the roles of CAFs have been extensively studied in other tumors and have led to the view that the cancer stroma contains heterogeneous populations of CAFs, their roles in mesothelioma remain unknown. We previously showed that connective tissue growth factor (CTGF), a secreted protein, is produced by both mesothelioma cells and fibroblasts and promotes the invasion of mesothelioma cells in vitro. In this study, we examined the clinical relevance of CAFs in mesothelioma. Using surgical specimens of epithelioid malignant pleural mesothelioma, we evaluated the clinicopathological significance of the expression of α-smooth muscle actin (αSMA), the most widely used marker of CAFs, the expression of CTGF, and the extent of fibrosis by immunohistochemistry and Elastica.Masson staining. We also analyzed the expression of mesenchymal stromal cell. and fibroblast.expressing Linx paralogue (Meflin; ISLR), a recently reported CAF marker that labels cancer.restraining CAFs and differ from αSMA-positive CAFs, by in situ hybridization. The extent of fibrosis and CTGF expression in mesothelioma cells did not correlate with patient prognosis. However, the expression of αSMA and CTGF, but not Meflin, in CAFs correlated with poor prognosis. The data suggest that CTGF+ CAFs are involved in mesothelioma progression and represent a potential molecular target for mesothelioma therapy.

    DOI: 10.3892/or.2020.7669

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  65. これ一冊ですべてわかる消化器超音波検査 Ⅲ 胆膵領域 ③ 十二指腸乳頭腫瘍における超音波検査の役割

    川嶋 啓揮, 大野 栄三郎, 石川 卓哉, 飯田 忠, 鈴木 博貴, 藤城 光弘

    臨床消化器内科   Vol. 35 ( 9 ) page: 1038 - 1042   2020.8

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    DOI: 10.19020/cg.0000001278

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  66. Can contrast-enhanced harmonic endoscopic ultrasonography accurately diagnose main pancreatic duct involvement in intraductal papillary mucinous neoplasms?

    Ohno Eizaburo, Kawashima Hiroki, Ishikawa Takuya, Iida Tadashi, Suzuki Hirotaka, Uetsuki Kota, Yashika Jun, Yamada Kenta, Yoshikawa Masakatsu, Gibo Noriaki, Aoki Toshinori, Kataoka Kunio, Mori Hiroshi, Hirooka Yoshiki, Fujishiro Mitsuhiro

    PANCREATOLOGY   Vol. 20 ( 5 ) page: 887 - 894   2020.7

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    Background: Main pancreatic duct (MPD) involvement in branch duct-type intraductal papillary mucinous neoplasms (BD-IPMNs) is a high risk finding for malignant IPMNs. However, discrepancies exist in the identification of MPD involvement between imaging findings and pathological diagnosis. The purpose of this study was to evaluate the diagnostic accuracy of preoperative assessment of MPD involvement in IPMNs using contrast-enhanced harmonic endoscopic ultrasound (CH-EUS). Methods: This study involved 166 consecutive patients with BD-IPMNs who underwent surgical resection. CH-EUS was used to evaluate the MPD involvement according to the presence of mural nodules (MN) that advanced into the MPD or involved the MPD. The CH-EUS findings were compared with the pathological findings. Additionally, we analyzed the risk factors for malignant BD-IPMNs using multivariate analysis. Results: A total of 77, 51, and 38 patients were pathologically diagnosed with low-grade or intermediate-grade dysplasia, high-grade dysplasia and invasive IPMNs, respectively. MPD involvement was diagnosed using CH-EUS (MPD-inv.-EUS) in 90 (54.2%) patients with a sensitivity, specificity and accuracy of 83.5%, 87.0% and 84.9%, respectively. The malignancy rate in patients with MPD-inv.-EUS was 71.6% (63/90). Multivariate logistic regression analysis showed that MPD-inv.-EUS (OR, 3.61; 95% CI:1.45–8.98), age (OR, 5.70; 95% CI: 1.47–22.2), cyst size (OR, 2.45; 95% CI:1.04–5.78) and MN size (OR, 7.05; 95% CI:2.48–20.0) were significant for malignant BD-IPMNs. Conclusions: MPD-inv.-EUS accurately represents the pathological involvement of IPMN and may be a useful predictor of malignant BD-IPMNs.

    DOI: 10.1016/j.pan.2020.06.004

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  67. PROSPECTIVE MULTICENTER STUDY ON THE USEFULNESS OF EUS-GUIDED FINE NEEDLE BIOPSY FOR THE DIAGNOSIS OF AUTOIMMUNE PANCREATITIS USING A 22-GAUGE FRANSEEN NEEDLE

    Ishikawa Takuya, Kawashima Hiroki, Ohno Eizaburo, Nishio Ryo, Iida Tadashi, Suzuki Hirotaka, Uetsuki Kota, Yamada Kenta, Yashika Jun, Yoshikawa Masakatsu, Gibo Noriaki, Aoki Toshinori, Kataoka Kunio, Mori Hiroshi, Keiko Maeda, Sawada Tsunaki, Yamamura Takeshi, Furukawa Kazuhiro, Nakamura Masanao, Fujishiro Mitsuhiro

    GASTROINTESTINAL ENDOSCOPY   Vol. 91 ( 6 ) page: AB172 - AB172   2020.6

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  68. Usefulness of Transabdominal Three-dimensional Ultrasound for the Evaluation of Elevated Gallbladder Lesions

    Ishikawa Takuya, Kawashima Hiroki, Ohno Eizaburo, Iida Tadashi, Nishio Ryo, Suzuki Hirotaka, Uetsuki Kota, Yashika Jun, Yamada Kenta, Yoshikawa Masakatsu, Gibo Noriaki, Fujishiro Mitsuhiro

    Tando   Vol. 34 ( 2 ) page: 145 - 152   2020.5

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    <p>Transabdominal ultrasound is a non-invasive exam which can be the first choice for evaluation of gallbladder lesions. Recently, the technology of three-dimensional (3D) ultrasound has developed. In addition to the conventional findings, the 3D images were evaluated in 21 patients who underwent transabdominal 3D ultrasound for elevated gallbladder lesions (2 cancers and 19 benign polyps). The gallbladder cancer was significantly larger (21.5mm vs. 8mm, <i>P</i> = 0.019), and there were significant differences between the cancer and the benign polyps in the surface structure and with or without hyperechoic foci (<i>P</i> = 0.001, <i>P</i> = 0.029). All lesions can be clearly visualized by the 3D ultrasound and especially the maximum diameter, base, surface structure, and the presence of multiple lesions became easy to recognize. A transabdominal 3D ultrasound for elevated gallbladder lesions facilitates recognition of morphology and plays a supplementary role in the ultrasound diagnosis.</p>

    DOI: 10.11210/tando.34.145

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  69. Meflin-Positive Cancer-Associated Fibroblasts Inhibit Pancreatic Carcinogenesis

    Mizutani Yasuyuki, Kobayashi Hiroki, Iida Tadashi, Asai Naoya, Masamune Atsushi, Hara Akitoshi, Esaki Nobutoshi, Ushida Kaori, Mii Shinji, Shiraki Yukihiro, Ando Kenju, Weng Liang, Ishihara Seiichiro, Ponik Suzanne M., Conklin Matthew W., Haga Hisashi, Nagasaka Arata, Miyata Takaki, Matsuyama Makoto, Kobayashi Tomoe, Fujii Tsutomu, Yamada Suguru, Yamaguchi Junpei, Wang Tongtong, Woods Susan L., Worthley Daniel, Shimamura Teppei, Fujishiro Mitsuhiro, Hirooka Yoshiki, Enomoto Atsushi, Takahashi Masahide

    CANCER RESEARCH   Vol. 79 ( 20 ) page: 5367 - 5381   2019.10

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    Cancer-associated fibroblasts (CAF) constitute a major component of the tumor microenvironment. Recent observations in genetically engineered mouse models and clinical studies have suggested that there may exist at least two functionally different populations of CAFs, that is, cancer-promoting CAFs (pCAF) and cancer-restraining CAFs (rCAF). Although various pCAF markers have been identified, the identity of rCAFs remains unknown because of the lack of rCAF-specific marker(s). In this study, we found that Meflin, a glycosylphosphatidylinositol-anchored protein that is a marker of mesenchymal stromal/stem cells and maintains their undifferentiated state, is expressed by pancreatic stellate cells that are a source of CAFs in pancreatic ductal adenocarcinoma (PDAC). In situ hybridization analysis of 71 human PDAC tissues revealed that the infiltration of Meflin-positive CAFs correlated with favorable patient outcome. Consistent herewith, Meflin deficiency led to significant tumor progression with poorly differentiated histology in a PDAC mouse model. Similarly, genetic ablation of Meflin-positive CAFs resulted in poor differentiation of tumors in a syngeneic transplantation model. Conversely, delivery of a Meflin-expressing lentivirus into the tumor stroma or overexpression of Meflin in CAFs suppressed the growth of xenograft tumors. Lineage tracing revealed that Meflin-positive cells gave rise to a-smooth muscle actin-positive CAFs that are positive or negative for Meflin, suggesting a mechanism for generating CAF heterogeneity. Meflin deficiency or low expression resulted in straightened stromal collagen fibers, which represent a signature for aggressive tumors, in mouse or human PDAC tissues, respectively. Together, the data suggest that Meflin is a marker of rCAFs that suppress PDAC progression.

    DOI: 10.1158/0008-5472.CAN-19-0454

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  70. Identification of cancer-associated fibroblasts that suppress pancreatic cancer progression

    Enomoto Atsushi, Mizutani Yasuyuki, Kobayashi Hiroki, Iida Tadashi, Woods Susan L., Worthley Daniel L., Takahashi Masahide

    CANCER RESEARCH   Vol. 79 ( 13 )   2019.7

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  71. USEFULLNESS OF EUS-GUIDED SHEAR-WAVE MEASUREMENT (EUS-SWM) FOR THE ASSESSMENT OF ACTIVITIES OF AUTOIMMUNE PANCREATITIS; A PROSPECTIVE EXPLORATORY STUDY

    Ohno Eizaburo, Hirooka Yoshiki, Kawashima Hiroki, Ishikawa Takuya, Tanaka Hiroyuki, Sakai Daisuke, Iida Tadashi, Nishio Ryo, Suzuki Hirotaka, Uetsuki Kota, Yashika Jun, Yamada Kenta, Yoshikawa Masakatsu, Gibo Noriaki, Aoki Toshinori, Yamamura Takeshi, Furukawa Kazuhiro, Nakamura Masanao, Miyahara Ryoji

    GASTROINTESTINAL ENDOSCOPY   Vol. 89 ( 6 ) page: AB608 - AB608   2019.6

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  72. Clinical Impact of EUS-Guided Fine Needle Biopsy Using a Novel Franseen Needle for Histological Assessment of Pancreatic Diseases

    Ishikawa Takuya, Kawashima Hiroki, Ohno Eizaburo, Tanaka Hiroyuki, Sakai Daisuke, Iida Tadashi, Nishio Ryo, Yamamura Takeshi, Furukawa Kazuhiro, Nakamura Masanao, Miyahara Ryoji, Hashimoto Senju, Ishigami Masatoshi, Hirooka Yoshiki

    CANADIAN JOURNAL OF GASTROENTEROLOGY AND HEPATOLOGY   Vol. 2019   page: 8581743   2019

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    Language:Japanese   Publisher:Canadian Journal of Gastroenterology and Hepatology  

    Background and Aims. Several studies have shown the benefits of endoscopic ultrasound-guided fine needle biopsy (EUS-FNB) using a Franseen needle for histological assessment. However, studies focusing on pancreatic diseases are limited and the safety of this method has not been well assessed. We aimed to assess the current status and issues of EUS-FNB in the diagnosis of pancreatic diseases. Materials and Methods. We retrospectively reviewed 87 consecutive EUS-FNB specimens using either a 22-gauge Franseen needle (Group A, N = 51) or a conventional 22-gauge fine-needle aspiration needle (Group B, N = 36) for pancreatic diseases, and the diagnostic accuracy and safety were compared. Final diagnoses were obtained based on surgical pathology or a minimum six-month clinical follow-up. Results. Although the diagnostic accuracy for malignancy was 96.1% in Group A versus 88.9% in Group B, with no statistically significant difference (P = 0.19), the median sample area was significantly larger in Group A (4.07 versus 1.31mm 2 , P < 0.0001). There were no differences between the two needles in the locations from which the specimens were obtained. Adverse events occurred in one case (2%) in Group A (mild pancreatitis) and none in Group B with no statistical significance (P = 0.586). Although there was no case of bleeding defined as adverse events, 2 cases in Group A showed active bleeding during the procedure with increase in the echo-free space, which required CT scanning to rule out extravasation. Eventually, the bleeding stopped spontaneously. Conclusions. Given its guaranteed ability to obtain core specimens and comparable safety, and although the risk of bleeding should be kept in mind, EUS-FNB using a Franseen needle is likely to become a standard procedure for obtaining pancreatic tissue in the near future.

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  73. Increase in breath hydrogen concentration was correlated with the main pancreatic duct stenosis

    Sakai Daisuke, Hirooka Yoshiki, Kawashima Hiroki, Ohno Eizaburo, Ishikawa Takuya, Suhara Hiroki, Takeyama Tomoaki, Koya Toshinari, Tanaka Hiroyuki, Iida Tadashi, Nishio Ryo, Suzuki Hirotaka, Uetsuki Kota, Matsushita Masanobu, Yamamura Takeshi, Furukawa Kazuhiro, Funasaka Kohei, Nakamura Masanao, Miyahara Ryoji, Watanabe Osamu, Ishigami Masatoshi, Tsuruta Akihiro, Shin Woosuck, Goto Hidemi

    JOURNAL OF BREATH RESEARCH   Vol. 12 ( 3 ) page: 036004   2018.7

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    Background. Hydrogen is produced from unabsorbed carbohydrates in the intestine through degradation and metabolism by hydrogenase of intestinal bacteria. The hydrogen is then partially diffused into blood flow and released and detected in exhaled breath. Pancreatic juice production is decreased in patients with reduced pancreatic exocrine function, including those with pancreatic cancer, thus decreasing digestion and absorption of nutrients including carbohydrates, which may increase undigested carbohydrates in the intestine and increase breath hydrogen concentration (BHC). The aim of this study was to investigate the association between BHC and pancreatic diseases. Methods. A retrospective study was designed and 68 patients underwent morning fasting breath hydrogen test. Since there is no clear standard, normal BHC, the median of the measured values from the subjects (9 ppm) was adopted as the standard. The subjects were classified into those with a value exceeding the median (BHC high group: 32 patients) and a value equal to or below the median (BHC low group: 36 patients). Patients characteristics, blood test results and imaging findings characteristic of pancreatic diseases were compared between the groups. Results. The age was significantly higher (P = 0.010) and the incidences of pancreatic ductal adenocarcinoma and autoimmune pancreatitis were significantly higher (P = 0.018 and P = 0.004, respectively) in the BHC high group. With respect to the blood test items, the Alb level was significantly lower in the BHC high group (P = 0.005). With respect to the characteristic imaging findings of pancreatic diseases, the proportions of patients with pancreatic enlargement, the main pancreatic duct (MPD) stenosis, and the MPD dilatation were significantly higher in the BHC high group (P = 0.022, P < 0.001, and P = 0.002, respectively). On univariate analysis, only the MPD stenosis was extracted as an independent factor (P = 0.014). Conclusion. It was suggested that the fasting BHC is associated with pancreatic diseases causing stenosis of the MPD, including pancreatic cancer (UMIN000020777).

    DOI: 10.1088/1752-7163/aaaf77

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  74. USEFULLNESS OF CONTRAST-ENHANCED HARMONIC EUS(CH-EUS) FOR THE PREOPERATIVE ASSESSMENT OF MPD INVOLVEMENT IN IPMN; A RETROSPECTIVE COMPARISON STUDY OF CH-EUS AND IDUS

    Ohno Eizaburo, Hirooka Yoshiki, Kawashima Hiroki, Ishikawa Takuya, Suhara Hiroki, Takeyama Tomoaki, Koya Toshinari, Tanaka Hiroyuki, Sakai Daisuke, Nishio Ryo, Iida Tadashi, Suzuki Hirotaka, Uetsuki Kota, Matsushita Masanobu, Furukawa Kazuhiro, Yamamura Takeshi, Funasaka Kohei, Nakamura Masanao, Miyahara Ryoji, Watanabe Osamu, Goto Hidemi

    GASTROINTESTINAL ENDOSCOPY   Vol. 87 ( 6 ) page: AB426 - AB427   2018.6

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  75. USEFULNESS OF HISTOLOGICAL ASSESSMENT WITH EUS-GUIDED FINE NEEDLE BIOPSY USING A NEW CORE NEEDLE IN PANCREATIC DISEASES

    Ishikawa Takuya, Hirooka Yoshiki, Kawashima Hiroki, Ohno Eizaburo, Suhara Hiroki, Takeyama Tomoaki, Koya Toshinari, Tanaka Hiroyuki, Sakai Daisuke, Nishio Ryo, Iida Tadashi, Suzuki Hirotaka, Uetsuki Kota, Matsushita Masanobu, Yamamura Takeshi, Furukawa Kazuhiro, Funasaka Kohei, Nakamura Masanao, Miyahara Ryoji, Watanabe Osamu, Goto Hidemi

    GASTROINTESTINAL ENDOSCOPY   Vol. 87 ( 6 ) page: AB432 - AB433   2018.6

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KAKENHI (Grants-in-Aid for Scientific Research) 3

  1. 膵癌早期診断を目的とした、IPMNの病変及び周囲背景膵における遺伝子変異解析

    Grant number:22K08010  2022.4 - 2025.3

    科学研究費助成事業  基盤研究(C)

    大野 栄三郎, 石川 卓哉, 加藤 あす香, 川嶋 啓揮, 西田 一貴, 飯田 忠, 水谷 泰之

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    膵癌早期診断は喫緊の課題であるが、未だに高リスク群の絞り込みは不十分である。膵管内乳頭粘液性腫瘍(IPMN)は自身の悪性化に加え、通常型膵癌が高頻度に発生すると報告されている。本研究では、サーベイランス中の膵嚢胞症例中、手術例(膵癌または悪性IPMN疑い)における、切除病変の遺伝子変異プロファイルと周囲正常膵実質内の膵管上皮内腫瘍性病変(PanIN)の発症頻度および背景膵実質内膵管上皮における遺伝子変異プロファイルを同時に解析し、IPMN症例における膵管癌発生の超高リスク群の特徴を解明する。更にその結果を蓄積された臨床情報、画像情報、血液検体と対比し、膵発癌予測の新規バイオマーカーを探索する。

  2. 胆膵疾患の十二指腸主乳頭擦過採取による表在細菌叢プロファイル作成と臨床応用の探索

    Grant number:21K19897  2021.7 - 2024.3

    科学研究費助成事業  挑戦的研究(萌芽)

    川嶋 啓揮, 大野 栄三郎, 石川 卓哉, 飯田 忠, 中村 正直

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    本研究の目的は、胆膵疾患の十二指腸主乳頭(PV)のブラシ擦過採取による表層細菌叢プロファイル作成と将来の基礎研究・臨床応用の可能性を探索することである。Fusobacterium nucleatumと大腸癌の関連が報告され、膵癌についても腫瘍内細菌の存在が明らかとなり注目されている。しかし、膵癌以外の胆膵疾患に関する報告は乏しい。PVは胆管・膵管が開口し、病変を通過した胆汁・膵液にさらされており、直視下に低侵襲でサンプル採取出来る特徴をもつ。本研究はPV擦過採取による細菌叢解析を行い今後の胆膵疾患の表層細菌叢、手術検体による病変内細菌叢、PV表層細菌叢と臨床所見を比較検討できるかを探索する。
    本研究の目的は、胆膵疾患の十二指腸主乳頭(PV)のブラシ擦過採取による表層細菌叢プロファイル作成と将来の基礎研究・臨床応用の可能性を探索することである。膵癌についても腫瘍内細菌の存在が明らかとなり注目されている。しかし、膵癌以外の胆膵疾患に関する報告は乏しい。PVは胆管・膵管が開口し、病変を通過した胆汁・膵液にさらされており、直視下に低侵襲でサンプル採取出来る特徴をもつ。本研究はPV擦過採取による細菌叢解析を行い今後の胆膵疾患の表層細菌叢、手術検体による病変内細菌叢、PV表層細菌叢と臨床所見を比較検討できるかを探索する。
    2021年度で乳頭部腺腫11例、乳頭部癌6例、胆管癌14例に同意を取得し、サンプル採取を行った。乳頭部癌と腺腫では菌種に有意差が認められ、一部、大腸がんなど他の癌での増加が指摘されている菌種の増加が指摘され、α多様性にも有意差が認められた。胆管癌症例の乳頭部擦過による菌叢解析は可能であるが、胆管病変部のNGS解析可能率が50%を下回っており採取方法に工夫が必要だと考えられた。この結果により少なくとも、PVと胆管病変表層には細菌叢が存在しており、PVにおいては腺癌症例の菌種が有意に異なることが分かった。
    2022年度は、特に胆管病変の症例数を増やすとともに、解析率を改善できる取り組みも考慮する。乳頭部腺腫、腺癌症例については当院で施行している大腸腫瘍症例との比較検討を行うとともに、発癌メカニズムの解析につながるような基礎的発展研究の可能性も模索したい。
    症例数の蓄積は順調に進んでいる。PVと胆管病変表層には細菌叢が存在していることが分かり、解析も可能であり今後の研究の継続に期待が持てる。乳頭部腺腫、乳頭部腺癌症例では予想されていた菌種の増加が認められた。名古屋大学医学部附属病院消化器内科で施行している大腸腫瘍の研究との差異を見出しながら、症例数を増やすとともに、発癌メカニズムの解析など基礎的検討も考慮できる状況である。胆管病変部の解析率の改善に向けて原因検索を行っている状態であるが、症例数は増えているので解析数はまずまずの数字になっている。
    乳頭部腫瘍については大腸や他の消化器疾患における細菌叢との比較なども考慮していく。胆管病変については、まず多くの症例をエントリーして解析可能な症例数を増やすとともに採取方法の改善を模索する。摘出標本での擦過や組織採取も進めていきたい。

  3. 免疫チェックポイント阻害剤抵抗性を改善する革新的膵癌治療法の開発

    Grant number:21K07941  2021.4 - 2024.3

    科学研究費助成事業  基盤研究(C)

    飯田 忠, 大野 栄三郎, 石川 卓哉, 川嶋 啓揮, 藤城 光弘

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    Authorship:Principal investigator 

    Grant amount:\4030000 ( Direct Cost: \3100000 、 Indirect Cost:\930000 )

    膵がんに代表される難治がんは免疫チェックポイント阻害剤(以下ICI)に対して抵抗性であり、その原因としてCAFが重要な役割を担っている。近年の研究によりCAFを促進性から抑制性にリプログラム(CAF初期化)させることで抵抗性が改善される可能性が示唆されているがその有効性に関しては明らかとなっていない。我々はMeflinを指標とすることでCAF初期化薬の候補薬を既に同定しており、本研究ではこれらの薬剤とICIとの併用効果を検証し、間質をターゲットとした革新的新規治療法の確立を目指す。
    本研究ではAM80と免疫チェックポイント阻害剤との併用による腫瘍縮小効果の検証、非臨床検体を用いたAM80による免疫プロファイルの変化と作用機序の解明、さらには臨床検体を用いたAM80による免疫プロファイルの変化の検証を行う予定である。本年度はMeflinの発現量を上昇させる薬剤としてAM80を同定し、抗がん剤とAM80の併用において抗がん剤単剤投与群に比べ優位な縮小効果が得られることを確認し論文化(Iida T et al ,Oncogene,2022)を行った。このデータを基礎にして現在切除不能膵癌に対するAM80とゲムシタビン/ナブパクリタキセルの併用療法に関する治験を計画しプロトコール論文も作成している(Mizutani Y,Iida T et al ,BMC Cancer,2022)。治験は今年度より開始されており、今後臨床検体も得られる予定である(PMDA受付番号:2021-2196)。さらに膵癌細胞株(mT5)を用いICIとAM80の併用したところ、ICI単剤群と比べ優位な腫瘍縮小効果を確認することができている。引き続き他の膵癌細胞株、他のモデルマウスをを用いて検証を行っているところである。また、一細胞解析ではAM80非投与群と比べAM80投与群では癌関連線維芽細胞以外の細胞でも様々な変化が認められている。同時に条件をいくつか変えた腫瘍をRNAseqに提出しており一細胞解析の結果と比較検討する予定でいる。この検証は癌関連線維芽細胞との関連性を含めさらなるメカニズムの解明につながる可能性があり当初の計画通り実験は進んでいると考えている。
    計画通り順調に進んでいるため。
    今後の研究の中心はAM80投与群の免疫プロファイルの検証に移る予定である。AM80による免疫細胞への直接的な作用も考えられるが、癌関連線維芽細胞を中心としたメカニズムの解明へとつながるかどうかも含めメフリン欠失マウス等を用い検証する予定である。

Industrial property rights 1

  1. METHOD FOR SELECTING CANCER PATIENT FOR WHICH COMBINATION THERAPY OF RETINOID AND CANCER TREATMENT AGENT WILL BE EFFECTIVE, AND COMBINED DRUG OF RETINOID AND CANCER TREATMENT AGENT

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    Application no:PCT/JP2021/024382  Date applied:2021.6

    Date announced:2022.12