Annual Report 2022

Division of Pathology

Shumpei Ishikawa, Motohiro Kojima, Shingo Sakashita, Naoya Sakamoto, Ryo Morisue, Kenji Harada, Takahiro Iimura, Miki Kusumoto

Introduction

 The Division of Pathology is progressing research to elucidate molecular mechanisms of cancers and developing innovative diagnostics and therapeutics, using cutting-edge approaches based on pathology.

The Team and What We Do

• Research Activities: We aim to create the next-generation pathology by integrating innovative research. We attempt to merge novel technologies to contribute to the advancement and standardization of histopathology (A. Establishing standard pathological diagnostics by integrating new technologies and histopathological innovations). Our new research topics include (B) Acquiring information on the physical properties of tissues for pathological analyses, (C) Standardizing pathological images for AI-driven pathology, and (D) Developing new research models such as organoids. For the research of pathological innovations, we conduct (E) Cross-organ analyses of the tumor immune microenvironment in sarcoma-like cancers.
• Clinical Practice: Our staff also hold positions in the Department of Pathology and Clinical Laboratories of the hospital, performing pathological diagnoses (14,000 biopsy, 3,500 surgery, 5,000 cytology, and 4 autopsy specimens, annually). They are also involved in the operation of the biobank and the maintenance of ISO15189 and CAP accreditation. We organize weekly Clinical Pathology Conferences with various clinical departments and other conferences with residents to enhance education and research activities. We participate in weekly Expert Panels for cancer genomic profiling tests, contributing as key players in genomic medicine.

Research Activities

A Establishing standard pathological diagnostics by integrating new technologies and histopathological innovations

1. We aim to construct standardized pathological diagnostics by proposing objective staging and classifications across cancers. Our presentation at an international conference (published), advocated the classification of tumor invasion beyond the serosal elastic layer as pT3a, enabling the objective definition of high-risk colorectal cancers. We proposed on a paper the unification of nomenclatures for sarcomatoid cancers across organs, including the lungs, esophagus, pancreas, liver, biliary tract, kidney, uterus, and ovary, based on the features of tumor microenvironments. These achievements were presented at the Japanese Society of Pathology Meeting (Morioka, 2022). In collaboration with the research topic (C) below, we aim to standardize the pathological diagnostics through automation.

B Acquiring information on the physical properties of tissues for pathological analyses

1. We measured the physical properties of pancreatic cancer tissues and discovered the correlation of tumor stiffness with their immune microenvironments, for the first time in human tumors (published).

2. Alongside the stiffness, tumor interstitial pressure is being measured, accumulating information for liver cancers. This research is conducted under international collaborations with the University of Tokyo and the University of Cyprus. Our findings reveal that tumor interstitial pressure is influenced not only by the tumor itself but also by the tumor microenvironment.

C Standardizing pathological images for AI-driven pathology

1. We developed an AI to identify cancerous lesions in gastrectomy specimens and demonstrated that focus, brightness, and contrast influenced AI-driven inferences (under submission).

2. With Sakura Finetek Japan, we initiated research on the standardization of pathological diagnostics through automation. This includes studies on the inferences of H&E staining (how the thickness and staining affect AI) and the development of a fully automated machine for slide preparations. We began collecting gastric, esophageal, and colorectal cancer specimens.

3. We commenced the development of slide glasses as controls for H&E staining in collaboration with Matsunami Glass.

D Developing new research models such as organoids

1. We established gastric cancer organoids from human gastric cancer specimens.

2. In microarray analyses using organoids from a normal gastric mucosa, gastric cancer, and 5-FU/oxaliplatin-resistant gastric cancer, we discovered that the expression of PI3 was upregulated in 5-FU/oxaliplatin-resistant gastric cancer organoids. PI3 was confirmed to be overexpressed in gastric cancers and identified as a biomarker for poorer prognosis. In vitro studies showed that PI3 contributed to the resistance to 5-FU/oxaliplatin. This research was awarded the Young Investigator Poster Prize at the 81st Annual Meeting of the Japanese Cancer Association.

Education

 Our group provided educational training for residents, senior residents, and pathology fellows of the National Cancer Center Hospital East, with publications of four peer-reviewed articles. These research articles, with the correspondence of the Division of Pathology, are expected to be presented as graduate theses. Our group provided research education for the doctoral program at the Graduate School of Biomedical and Health Sciences, Hiroshima University, achieving one peer-reviewed article. Our group is also mentoring a master’s student at the Graduate School of Frontier Sciences, the University of Tokyo, where our group has an affiliated program.

Future Prospects

 In close collaboration with the Department of Pathology and Clinical Laboratories of the hospital, our group aims to uncover novel pathobiology of cancers. By quantifying biologically meaningful spatial morphological and genomic information, our group is developing foundations for innovative diagnostic and therapeutic approaches. Our focus primarily lies in the spatial morphology and genomics associated with distinctive cancer pathobiology, which are enhanced by in vitro model systems. We are advancing methods for digitalizing histopathological specimens and developing AI-driven feature extractions for cancer pathology. By integrating innovative pathological research, we aim to deepen our understanding of cancer biology and identify potential therapeutic interventions.

List of papers published in 2022

Journal

1. Kajiwara Y, Oka S, Tanaka S, Nakamura T, Saito S, Fukunaga Y, Takamatsu M, Kawachi H, Hotta K, Ikematsu H, Kojima M, Saito Y, Yamada M, Kanemitsu Y, Sekine S, Nagata S, Yamada K, Kobayashi N, Ishihara S, Saitoh Y, Matsuda K, Togashi K, Komori K, Ishiguro M, Kuwai T, Okuyama T, Ohuchi A, Ohnuma S, Sakamoto K, Sugai T, Katsumata K, Matsushita HO, Yamano HO, Eda H, Uraoka T, Akimoto N, Kobayashi H, Ajioka Y, Sugihara K, Ueno H. Nomogram as a novel predictive tool for lymph node metastasis in T1 colorectal cancer treated with endoscopic resection: a nationwide, multicenter study. Gastrointestinal endoscopy, 97:1119-1128.e5, 2023

2. Matsuda Y, Ye J, Yamakawa K, Mukai Y, Azuma K, Wu L, Masutomi K, Yamashita T, Daigo Y, Miyagi Y, Yokose T, Oshima T, Ito H, Morinaga S, Kishida T, Minamoto T, Kojima M, Kaneko S, Haba R, Kontani K, Kanaji N, Okano K, Muto-Ishizuka M, Yokohira M, Saoo K, Imaida K, Suizu F. Association of longer telomere length in cancer cells and cancer-associated fibroblasts with worse prognosis. Journal of the National Cancer Institute, 115:208-218, 2023

3. Morishita Y, Sakashita S, Tomioka T, Okano W, Shinozaki T, Higashino T, Matsuura K, Hayashi R. Human papillomavirus-related multiphenotypic sinonasal carcinoma. Auris, nasus, larynx, 50:151-155, 2023

4. Kuroe T, Watanabe R, Morisue R, Miyazaki S, Kojima M, Murata SC, Nakai T, Taki T, Sakashita S, Sakamoto N, Matsubara N, Masuda H, Ushiku T, Ishii G. Dirty necrosis in renal cell carcinoma is associated with NETosis and systemic inflammation. Cancer medicine, 12:4557-4567, 2023

5. Konishi Y, Taki T, Nakai T, Kuroe T, Morisue R, Miyoshi T, Tane K, Samejima J, Aokage K, Miyazaki S, Sakamoto N, Sakashita S, Watanabe R, Kojima M, Suzuki K, Tsuboi M, Ishii G. Clinicopathological features and prognostic impact of dirty necrosis in metastatic lung cancers from the colon and rectum. Cancer science, 114:2169-2177, 2023

6. Tanaka Y, Nakai T, Suzuki A, Kagawa Y, Noritake O, Taki T, Hashimoto H, Sakai T, Shibata Y, Izumi H, Nosaki K, Udagawa H, Zenke Y, Matsumoto S, Yoh K, Miyazaki S, Sakamoto N, Sakashita S, Kojima M, Watanbe R, Tsuboi M, Goto K, Ishii G. Clinicopathological significance of peritumoral alveolar macrophages in patients with resected early-stage lung squamous cell carcinoma. Cancer immunology, immunotherapy, 72:2205-2215, 2023

7. Sakashita S, Sakamoto N, Kojima M, Taki T, Miyazaki S, Minakata N, Sasabe M, Kinoshita T, Ishii G, Ochiai A. Requirement of image standardization for AI-based macroscopic diagnosis for surgical specimens of gastric cancer. Journal of cancer research and clinical oncology, 2023

8. Akimoto E, Kuwata T, Shitara K, Kawazoe A, Sakamoto N, Ishii G, Ochiai A, Kinoshita T. Impact of Programmed Death-Ligand 1 Expression on Mismatch Repair Deficiency and Epstein-Barr Virus Status on Survival Outcomes in Patients with Stage II/III Gastric Cancer After Surgery. Annals of surgical oncology, 2023

9. Kotani D, Nakamura Y, Fujisawa T, Bando H, Sakamoto N, Johns AL, Park K, Casolino R, Yoshino T, Biankin AV. ICGC-ARGO precision medicine: an update on targeted therapy based on longitudinal analysis of tumour heterogeneity and evolution in colorectal cancer. The Lancet. Oncology, 24:20-21, 2023

10. Masuoka S, Hiyama T, Kuno H, Sekiya K, Sakashita S, Kobayashi T. Imaging Approach for Cervical Lymph Node Metastases from Unknown Primary Tumor. Radiographics, 43:e220071, 2023

11. Hattori H, Sakashita S, Tsuboi M, Ishii G, Tanaka T. Tumor-identification method for predicting recurrence of early-stage lung adenocarcinoma using digital pathology images by machine learning. Journal of pathology informatics, 14:100175, 2023

12. Narita Z, Okubo R, Sasaki Y, Takeda K, Ohmagari N, Yamaguchi K, Morisaki N, Sampei M, Ishitsuka K, Kojima M, Nishimura K, Inoue M, Yamamoto S, Konishi M, Miyo K, Mizoue T. Association of COVID-19-related discrimination with subsequent depression and suicidal ideation in healthcare workers. Journal of psychiatric research, 159:153-158, 2023

13. Tabata S, Kojima Y, Sakamoto T, Igarashi K, Umetsu K, Ishikawa T, Hirayama A, Kajino-Sakamoto R, Sakamoto N, Yasumoto KI, Okano K, Suzuki Y, Yachida S, Aoki M, Soga T. L-2hydroxyglutaric acid rewires amino acid metabolism in colorectal cancer via the mTOR-ATF4 axis. Oncogene, 42:1294-1307, 2023

14. Shrestha RM, Inoue Y, Yamamoto S, Fukunaga A, Sampei M, Okubo R, Morisaki N, Ohmagari N, Funaki T, Ishizuka K, Yamaguchi K, Sasaki Y, Takeda K, Miyama T, Kojima M, Nakagawa T, Nishimura K, Ogata S, Umezawa J, Tanaka S, Inoue M, Konishi M, Miyo K, Mizoue T. The association between experience of COVID-19-related discrimination and psychological distress among healthcare workers for six national medical research centers in Japan. Social psychiatry and psychiatric epidemiology, 1-9, 2023

15. Akimoto E, Kuwata T, Shitara K, Kawazoe A, Sakamoto N, Ishii G, Ochiai A, Kinoshita T. ASO Visual Abstract: Impact of Programmed Death-Ligand 1 Expression on Mismatch Repair Deficiency and Epstein-Barr Virus Status on Survival Outcomes in Patients with Stage II/III Gastric Cancer After Surgery. Annals of surgical oncology, 2023

16. Tsubokura M, Adegawa Y, Kojima M, Tanosaki R, Ohtake R, Kase Y, Iwashita N, Kasane M, Nakabayashi S, Takeuchi S, Kato K, Boku N, Kanemitsu Y, Okusaka T, Fujimoto H, Yonemori K, Ishiki H, Kawamura K, Satomi E, Matsushita H. Adverse effects of cell-free and concentrated ascites reinfusion therapy for malignant ascites: a single-institute experience. BMC cancer, 22:268, 2022

17. Adachi M, Aoyama N, Kojima M, Sakamoto N, Miyazaki S, Taki T, Watanabe R, Matsuura K, Kotani D, Kojima T, Fujita T, Tabuchi K, Ishii G, Sakashita S. The area of residual tumor predicts esophageal squamous cell carcinoma prognosis following neoadjuvant chemotherapy. Journal of cancer research and clinical oncology, 2022

18. Morishita Y, Takenouchi K, Sakashita S, Matsuura K, Hayashi R, Nakatsura T. Immunohistochemical Analysis of Common Cancer Antigens in Head and Neck Squamous Cell Carcinoma. Anticancer research, 42:5751-5761, 2022

19. Kotani D, Nakamura Y, Fujisawa T, Bando H, Sakamoto N, Johns AL, Park K, Casolino R, Yoshino T, Biankin AV. ICGC-ARGO precision medicine: targeted therapy according to longitudinal assessment of tumour heterogeneity in colorectal cancer. The Lancet. Oncology, 23:463-464, 2022

20. Eguchi Y, Nakai T, Kojima M, Wakabayashi M, Sakamoto N, Sakashita S, Miyazaki S, Taki T, Watanabe R, Watanuki R, Yamauchi C, Iwatani T, Mukohara T, Onishi T, Ishii G. Pathologic method for extracting good prognosis group in triple-negative breast cancer after neoadjuvant chemotherapy. Cancer science, 113:1507-1518, 2022

21. Nomura K, Nakai T, Nishina Y, Sakamoto N, Miyoshi T, Tane K, Samejima J, Aokage K, Kojima M, Sakashita S, Taki T, Miyazaki S, Watanabe R, Suzuki K, Tsuboi M, Ishii G. 18F-fluorodeoxyglucose uptake in PET is associated with the tumor microenvironment in metastatic lymph nodes and prognosis in N2 lung adenocarcinoma. Cancer science, 113:1488-1496, 2022

22. Niimi T, Nakai T, Aokage K, Tane K, Miyoshi T, Samejima J, Miyazaki S, Taki T, Sakamoto N, Sakashita S, Watanabe R, Kojima M, Suzuki K, Tsuboi M, Ishii G. Prognostic impact of count of extratumoral lymphatic permeation in lung adenocarcinoma and its relation to the immune microenvironment. Cancer science, 113:1497-1506, 2022

23. Tamiya Y, Nakai T, Suzuki A, Mimaki S, Tsuchihara K, Sato K, Yoh K, Matsumoto S, Zenke Y, Nosaki K, Izumi H, Shibata Y, Sakai T, Taki T, Miyazaki S, Watanabe R, Sakamoto N, Sakashita S, Kojima M, Hashimoto N, Tsuboi M, Goto K, Ishii G. The impact of tertiary lymphoid structures on clinicopathological, genetic and gene expression characteristics in lung adenocarcinoma. Lung cancer (Amsterdam, Netherlands), 174:125-132, 2022

24. Okunaka M, Kotani D, Demachi K, Fujiwara H, Sakashita S, Yoshino T, Fujita T, Kojima T. Significance of chemotherapy-free interval and tumor regression grade in patients with recurrent esophageal squamous cell carcinoma receiving chemotherapy with fluorouracil and platinum after esophagectomy following preoperative chemotherapy. Esophagus, 19:240-249, 2022

25. Chida K, Kawazoe A, Suzuki T, Kawazu M, Ueno T, Takenouchi K, Nakamura Y, Kuboki Y, Kotani D, Kojima T, Bando H, Mishima S, Kuwata T, Sakamoto N, Watanabe J, Mano H, Ikeda M, Shitara K, Endo I, Nakatsura T, Yoshino T. Transcriptomic Profiling of MSI-H/dMMR Gastrointestinal Tumors to Identify Determinants of Responsiveness to Anti-PD-1 Therapy. Clinical cancer research, 28:2110-2117, 2022

26. Takahashi S, Ohno I, Ikeda M, Konishi M, Kobayashi T, Akimoto T, Kojima M, Morinaga S, Toyama H, Shimizu Y, Miyamoto A, Tomikawa M, Takakura N, Takayama W, Hirano S, Otsubo T, Nagino M, Kimura W, Sugimachi K, Uesaka K. Neoadjuvant S-1 With Concurrent Radiotherapy Followed by Surgery for Borderline Resectable Pancreatic Cancer: A Phase II Open-label Multicenter Prospective Trial (JASPAC05). Annals of surgery, 276:e510-e517, 2022

27. Yagi N, Suzuki T, Mizuno S, Kojima M, Kudo M, Sugimoto M, Kobayashi S, Gotohda N, Ishii G, Nakatsura T. Component with abundant immune-related cells in combined hepatocellular cholangiocarcinoma identified by cluster analysis. Cancer science, 113:1564-1574, 2022

28. Kudo M, Ishii G, Gotohda N, Konishi M, Takahashi S, Kobayashi S, Sugimoto M, Martin JD, Cabral H, Kojima M. Histological tumor necrosis in pancreatic cancer after neoadjuvant therapy. Oncology reports, 48:121, 2022

29. Matsuda Y, Yamashita T, Ye J, Yasukawa M, Yamakawa K, Mukai Y, Machitani M, Daigo Y, Miyagi Y, Yokose T, Oshima T, Ito H, Morinaga S, Kishida T, Minamoto T, Yamada S, Takei J, Kaneko MK, Kojima M, Kaneko S, Masaki T, Hirata M, Haba R, Kontani K, Kanaji N, Miyatake N, Okano K, Kato Y, Masutomi K. Phosphorylation of hTERT at threonine 249 is a novel tumor biomarker of aggressive cancer with poor prognosis in multiple organs. The Journal of pathology, 257:172-185, 2022

30. Kondo R, Sakamoto N, Harada K, Hashimoto H, Morisue R, Yanagihara K, Kinoshita T, Kojima M, Ishii G. Cancer-associated fibroblast-dependent and -independent invasion of gastric cancer cells. Journal of cancer research and clinical oncology, 2022

31. Panagi M, Mpekris F, Chen P, Voutouri C, Nakagawa Y, Martin JD, Hiroi T, Hashimoto H, Demetriou P, Pierides C, Samuel R, Stylianou A, Michael C, Fukushima S, Georgiou P, Papageorgis P, Papaphilippou PC, Koumas L, Costeas P, Ishii G, Kojima M, Kataoka K, Cabral H, Stylianopoulos T. Polymeric micelles effectively reprogram the tumor microenvironment to potentiate nano-immunotherapy in mouse breast cancer models. Nature communications, 13:7165, 2022

32. Harada K, Sakamoto N. Cancer organoid applications to investigate chemotherapy resistance. Frontiers in molecular biosciences, 9:1067207, 2022

33. Kumagai S, Koyama S, Itahashi K, Tanegashima T, Lin YT, Togashi Y, Kamada T, Irie T, Okumura G, Kono H, Ito D, Fujii R, Watanabe S, Sai A, Fukuoka S, Sugiyama E, Watanabe G, Owari T, Nishinakamura H, Sugiyama D, Maeda Y, Kawazoe A, Yukami H, Chida K, Ohara Y, Yoshida T, Shinno Y, Takeyasu Y, Shirasawa M, Nakama K, Aokage K, Suzuki J, Ishii G, Kuwata T, Sakamoto N, Kawazu M, Ueno T, Mori T, Yamazaki N, Tsuboi M, Yatabe Y, Kinoshita T, Doi T, Shitara K, Mano H, Nishikawa H. Lactic acid promotes PD-1 expression in regulatory T cells in highly glycolytic tumor microenvironments. Cancer cell, 40:201-218.e9, 2022

34. Bando H, Tsukada Y, Inamori K, Togashi Y, Koyama S, Kotani D, Fukuoka S, Yuki S, Komatsu Y, Homma S, Taketomi A, Uemura M, Kato T, Fukui M, Wakabayashi M, Nakamura N, Kojima M, Kawachi H, Kirsch R, Yoshida T, Suzuki Y, Sato A, Nishikawa H, Ito M, Yoshino T. Preoperative Chemoradiotherapy plus Nivolumab before Surgery in Patients with Microsatellite Stable and Microsatellite Instability-High Locally Advanced Rectal Cancer. Clinical cancer research, 28:1136-1146, 2022

35. Loughrey MB, Webster F, Arends MJ, Brown I, Burgart LJ, Cunningham C, Flejou JF, Kakar S, Kirsch R, Kojima M, Lugli A, Rosty C, Sheahan K, West NP, Wilson RH, Nagtegaal ID. Dataset for Pathology Reporting of Colorectal Cancer: Recommendations From the International Collaboration on Cancer Reporting (ICCR). Annals of surgery, 275:e549-e561, 2022

36. Taniyama D, Sakamoto N, Takashima T, Takeda M, Pham QT, Ukai S, Maruyama R, Harada K, Babasaki T, Sekino Y, Hayashi T, Sentani K, Pommier Y, Murai J, Yasui W. Prognostic impact of Schlafen 11 in bladder cancer patients treated with platinum-based chemotherapy. Cancer science, 113:784-795, 2022

37. Notohara K, Kamisawa T, Furukawa T, Fukushima N, Uehara T, Kasashima S, Iwasaki E, Kanno A, Kawashima A, Kubota K, Kuraishi Y, Motoya M, Naitoh I, Nishino T, Sakagami J, Shimizu K, Tomono T, Aishima S, Fukumura Y, Hirabayashi K, Kojima M, Mitsuhashi T, Naito Y, Ohike N, Tajiri T, Yamaguchi H, Fujiwara H, Ibuki E, Kobayashi S, Miyaoka M, Nagase M, Nakashima J, Nakayama M, Oda S, Taniyama D, Tsuyama S, Watanabe S, Ikeura T, Kawa S, Okazaki K. Concordance of the histological diagnosis of type 1 autoimmune pancreatitis and its distinction from pancreatic ductal adenocarcinoma with endoscopic ultrasound-guided fine needle biopsy specimens: an interobserver agreement study. Virchows Archiv, 480:565-575, 2022

38. Masuoka S, Hiyama T, Kuno H, Morishita Y, Sakashita S, Kobayashi T. A case of Epstein-Barr virus-positive mucocutaneous ulcer of the hypopharynx: a mimicker of hypopharyngeal squamous cell carcinoma. International cancer conference journal, 11:71-74, 2022

39. Takashima K, Koga Y, Anzai T, Migita K, Yamaguchi T, Ishikawa A, Sakashita S, Yasunaga M, Yano T. Evaluation of Fluorescence Intensity and Antitumor Effect Using Real-Time Imaging in Photoimmunotherapy. Pharmaceuticals (Basel, Switzerland), 15:223, 2022

40. Fujimoto S, Matsuura K, Nakamura H, Sakashita S, Hayashi R. Adult T-Cell Leukemia/Lymphoma With Extranodal Involvement of the Hypopharynx. Cureus, 14:e22723, 2022

41. Yamamoto S, Tanaka A, Ohmagari N, Yamaguchi K, Ishitsuka K, Morisaki N, Kojima M, Nishikimi A, Tokuda H, Inoue M, Tanaka S, Umezawa J, Okubo R, Nishimura K, Konishi M, Miyo K, Mizoue T. Use of heated tobacco products, moderate alcohol drinking, and anti-SARS-CoV-2 IgG antibody titers after BNT162b2 vaccination among Japanese healthcare workers. Preventive medicine, 161:107123, 2022

42. Kanda Y, Doki N, Kojima M, Kako S, Inoue M, Uchida N, Onishi Y, Kamata R, Kotaki M, Kobayashi R, Tanaka J, Fukuda T, Fujii N, Miyamura K, Mori SI, Mori Y, Morishima Y, Yabe H, Atsuta Y, Kodera Y. Effect of Cryopreservation in Unrelated Bone Marrow and Peripheral Blood Stem Cell Transplantation in the Era of the COVID-19 Pandemic: An Update from the Japan Marrow Donor Program. Transplantation and cellular therapy, 28:677.e1-677.e6, 2022