Papers - IIDA Tadashi

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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Language：Japanese   Publisher：BMC Cancer  

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.

DOI： 10.1186/s12885-022-09272-2

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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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Language：English   Publisher：Diagnostics  

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.

DOI： 10.3390/diagnostics12020434

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特集 内視鏡的乳頭切除術まるわかり [各論] 《Column》こうしている,術後の経口摂取開始

川嶋 啓揮, 大野 栄三郎, 石川 卓哉, 水谷 泰之, 飯田 忠

消化器内視鏡   Vol. 34 ( 1 ) page： 87 - 89   2022.1

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Publisher：東京医学社  

DOI： 10.24479/endo.0000000016

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特集 内視鏡的乳頭切除術まるわかり [各論] EP前の進展度診断の実際と限界

川嶋 啓揮, 大野 栄三郎, 石川 卓哉, 水谷 泰之, 飯田 忠, 植月 康太, 八鹿 潤, 山田 健太, 青木 聡典

消化器内視鏡   Vol. 34 ( 1 ) page： 39 - 43   2022.1

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Publisher：東京医学社  

DOI： 10.24479/endo.0000000007

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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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Language：Japanese   Publisher：Canadian Journal of Gastroenterology and Hepatology  

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.

DOI： 10.1155/2022/2737578

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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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Language：Japanese   Publisher：Pancreas  

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.

DOI： 10.1097/MPA.0000000000001966

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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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Language：Japanese   Publisher：Journal of Digestive Diseases  

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.

DOI： 10.1111/1751-2980.13077

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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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Language：Japanese   Publisher：Quantitative Imaging in Medicine and Surgery  

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.

DOI： 10.21037/qims-21-403

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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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Language：English   Publisher：Digestion  

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.

DOI： 10.1159/000521929

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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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Language：Japanese   Publisher：The Japanese Society of Gastroenterology  

<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>

DOI： 10.11405/nisshoshi.119.1043

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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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Language：Japanese   Publisher：The Japanese Society of Gastroenterology  

<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>

DOI： 10.11405/nisshoshi.119.1043

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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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Language：Japanese   Publisher：Japan Biliary Association  

DOI： 10.11210/tando.35.773

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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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Language：Japanese   Publisher：World Journal of Gastroenterology  

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.

DOI： 10.3748/wjg.v27.i41.7190

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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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Language：Japanese   Publisher：Frontiers in Cell and Developmental Biology  

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.

DOI： 10.3389/fcell.2021.749924

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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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Language：Japanese   Publisher：Pancreatology  

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.

DOI： 10.1016/j.pan.2021.07.001

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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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Language：Japanese   Publisher：Nagoya Journal of Medical Science  

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.

DOI： 10.18999/nagjms.83.3.655

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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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Language：Japanese   Publisher：Current Biology  

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.

DOI： 10.1016/j.cub.2021.04.078

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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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Language：Japanese   Publisher：Digestive Endoscopy  

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.

DOI： 10.1111/den.13881

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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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Language：Japanese   Publisher：Genes to Cells  

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.

DOI： 10.1111/gtc.12855

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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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Language：Japanese   Publisher：Pancreatology  

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.

DOI： 10.1016/j.pan.2021.02.014

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