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Annual Report 2023

Division of Pathology

Shumpei Ishikawa, Motohiro Kojima, Shingo Sakashita, Naoya Sakamoto, Kana Morikyu, Takahiro Iimura, Miki Kusumoto

Introduction

 The Division of Pathology is advancing research to uncover the molecular mechanisms of cancer and to develop innovative diagnostics and therapies, utilizing state-of-the-art pathology-based approaches.

The Team and What We Do

  • Research Activities: In our research, we aimed to create "Next-generation Pathology through the Integration of Innovations" by creatively combining new technologies with pathological approaches, not only to contribute to the advancement of medicine but also to the standardization of pathological diagnosis (Project A: “Establishing Standardized Pathological Diagnostics through the Integration of New Technology and Pathological Innovation”). Additionally, we set the following goals: (B) Acquisition of Information on Tissue Properties and Pathological Analysis, (C) Standardization of Pathological Images for AI, and (D) Acquisition of Information from New Models, Including Organoids. We also focused on pathological innovation through Project E: "Cross-Organ Analysis of the Tumor Immune Microenvironment in Sarcomatoid Cancer." Each project was advanced individually while maintaining close collaboration to work toward the realization of next-generation pathology.
  • Clinical Activities: Our staff members hold concurrent appointments at Department of Pathology and Clinical Laboratories of the hospital, where they have been involved in pathology diagnostic activities (14,000 biopsy specimens, 3,500 surgical specimens, 5,000 cytology specimens, and four autopsies annually). In addition to pathological diagnosis, they have supported the management of the biobank and the maintenance of ISO 15189 and CAP accreditation. Furthermore, they organized weekly clinical pathology conferences (CPC) with various clinical departments, as well as conferences with residents to enhance both resident education and research activities. They also participated in weekly expert panels for the medical interpretation of cancer gene panel test results, contributing significantly as key figures in cancer genomic medicine.

    • Research Activities

    A Establishing Standardized Pathological Diagnostics through the Integration of New Technologies and Pathological Innovation

     Developed objective staging classifications and cross-organ sarcomatoid cancer analyses to improve diagnostic standardization. Demonstrated that tumors invading beyond the serosa elastic layer (pT3a) could objectively identify high-risk colorectal cancer cases. Initiated spatial genomics research to investigate cancer molecular mechanisms based on pathology.

    B Acquisition of Information on Tissue Properties and Pathological Analysis

     Conducted stiffness measurements in pancreatic cancer, uncovering relationships with pathological and immunological features, and demonstrated that preoperative therapy can alter these characteristics. Measured intratumoral pressure, particularly in liver cancer, in collaboration with the University of Tokyo and the University of Cyprus, revealing that intratumoral pressure is influenced by both tumor cells and surrounding tissue.

    C Standardization of Pathological Images for AI

     Developed AI for macroscopic lesion identification in gastrectomy specimens and demonstrated the impact of focus, brightness, and contrast on AI inference. Used digital image analysis to identify the residual tumor area as a prognostic factor for esophageal squamous cell carcinoma after neoadjuvant chemotherapy. Created an AI model to extract p16-positive oropharyngeal carcinoma features, making AI-based models more interpretable for pathologists. In partnership with Sakura Finetek Japan, studied the standardization of HE-stained slides and advanced automated sample preparation technologies. Continued development of HE-stained slide controls with Matsunami Glass Ind., Ltd.

    D Acquisition of Information from New Models, Including Organoids

     Established gastric cancer organoids and refined experimental models to analyze drug resistance mechanisms. Through gene expression analysis, identified PI3 overexpression in 5-FU/oxaliplatin -resistant gastric cancer organoids, further linking PI3 with resistance in gastric cancer through clinical and in vitro studies.

    Education

     Our group provided education to residents, senior residents, pathology trainees, etc., at the Hospital East and published four English-language papers, for which the Division of Pathology served as the responsible author. These papers included those which were used as doctoral dissertations. Currently, our group is also supervising two master’s students at the Graduate School of Frontier Sciences, The University of Tokyo, where we are engaged in a collaborative graduate program.

    Future Prospects

     In close collaboration with the Department of Pathology and Clinical Laboratories at the Hospital East, we aim to identify characteristic pathological features across various types of cancer through diverse approaches. By quantifying spatial morphological and genomic information that is biologically significant, we strive to build a foundation for the development of novel diagnostic and therapeutic methods. Particularly within the Division of Pathology, we quantify spatial morphological and genomic data related to specific cancer pathologies and utilize in vitro models based on these findings to extract biologically meaningful insights. Specifically, our research efforts focus on standardizing sample preparation and image processing to digitalize pathological specimens and extract key features using AI technology. Additionally, we employ models that leverage distinctive morphological patterns to elucidate cancer pathogenesis and identify points for diagnostic and therapeutic intervention.

    List of papers published in 2023

    Journal

    1. Takei S, Tanaka Y, Lin YT, Koyama S, Fukuoka S, Hara H, Nakamura Y, Kuboki Y, Kotani D, Kojima T, Bando H, Mishima S, Ueno T, Kojima S, Wakabayashi M, Sakamoto N, Kojima M, Kuwata T, Yoshino T, Nishikawa H, Mano H, Endo I, Shitara K, Kawazoe A. Multiomic molecular characterization of the response to combination immunotherapy in MSS/pMMR metastatic colorectal cancer. Journal for immunotherapy of cancer, 12:e008210, 2024

    2. Minamide T, Ikematsu H, Kajiwara Y, Oka S, Ajioka Y, Ueno H. Impact of Lesion Location on Recurrence After Resection of T1 Colorectal Cancer: Post Hoc Analysis of a Nationwide Multicenter Cohort Study. Gastroenterology, 166:198-201.e3, 2024

    3. Hiyama T, Miyasaka Y, Kuno H, Sekiya K, Sakashita S, Shinozaki T, Kobayashi T. Posttreatment Head and Neck Cancer Imaging: Anatomic Considerations Based on Cancer Subsites. Radiographics, 44:e230099, 2024

    4. Hashimoto T, Nakamura Y, Mishima S, Nakayama I, Kotani D, Kawazoe A, Kuboki Y, Bando H, Kojima T, Iida N, Shibuki T, Imai M, Fujisawa T, Nagamine M, Sakamoto N, Kuwata T, Yoshino T, Shitara K. Whole-transcriptome sequencing in advanced gastric or gastroesophageal cancer: A deep dive into its clinical potential. Cancer science, 115:1622-1633, 2024

    5. Kitagawa S, Zenke Y, Taki T, Aokage K, Sakai T, Shibata Y, Izumi H, Nosaki K, Umemura S, Matsumoto S, Yoh K, Sakamoto N, Sakashita S, Kojima M, Tsuboi M, Goto K, Ishii G. Prognostic value of predominant subtype in pathological stage II-III lung adenocarcinoma with epidermal growth factor receptor mutation. Lung cancer (Amsterdam, Netherlands), 188:107453, 2024

    6. Okunaka M, Kotani D, Fujiwara H, Sato K, Fujiwara N, Mishima S, Sakashita S, Yoshino T, Fujita T, Kojima T. Prognosis of patients with residual pathological disease after neoadjuvant docetaxel, cisplatin, and 5-fluorouracil therapy and surgery for esophageal squamous cell carcinoma: a retrospective cohort study. Therapeutic advances in medical oncology, 16:17588359241229432, 2024

    7. Kagoura M, Kobayashi S, Kojima M, Kudo M, Sugimoto M, Konishi M, Gotohda N. Survival outcome of patient with pT1N0 biliary tract cancer treated with surgery alone. European journal of surgical oncology, 50:107980, 2024

    8. Oka S, Tanaka S, Kajiwara Y, 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, Sugihara K, Ueno H. Treatment Decision for Locally Resected T1 Colorectal Carcinoma-Verification of the Japanese Guideline Criteria for Additional Surgery Based on Long-Term Clinical Outcomes. The American journal of gastroenterology, 2024

    9. Adachi M, Taki T, Sakamoto N, Kojima M, Hirao A, Matsuura K, Hayashi R, Tabuchi K, Ishikawa S, Ishii G, Sakashita S. Extracting interpretable features for pathologists using weakly supervised learning to predict p16 expression in oropharyngeal cancer. Scientific reports, 14:4506, 2024

    10. Nagasaki Y, Taki T, Nomura K, Tane K, Miyoshi T, Samejima J, Aokage K, Ohtani-Kim SJ, Kojima M, Sakashita S, Sakamoto N, Ishikawa S, Suzuki K, Tsuboi M, Ishii G. Spatial intratumor heterogeneity of programmed death-ligand 1 expression predicts poor prognosis in resected non-small cell lung cancer. Journal of the National Cancer Institute, djae053, 2024

    11. Shirane Y, Fujii Y, Ono A, Nakahara H, Hayes CN, Miura R, Murakami S, Sakamoto N, Uchikawa S, Fujino H, Nakahara T, Murakami E, Yamauchi M, Miki D, Kawaoka T, Arihiro K, Tsuge M, Oka S. Peripheral T Cell Subpopulations as a Potential Surrogate Biomarker during Atezolizumab plus Bevacizumab Treatment for Hepatocellular Carcinoma. Cancers, 16:1328, 2024

    12. Minakata N, Sakashita S, Wakabayashi M, Nakamura Y, Sunakawa H, Yoda Y, Ishii G, Yano T. Immunohistochemistry and oxygen saturation endoscopic imaging reveal hypoxia in submucosal invasive esophageal squamous cell carcinoma. Cancer medicine, 12:15809-15819, 2023

    13. 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

    14. Kojima M, Yokota M, Yanagisawa N, Kitamura S, Amemiya K, Kawano S, Tsukada Y, Sakuyama N, Nagayasu K, Hashimoto T, Nakashima K, Jiang K, Kanemitsu Y, Fujita F, Akiba J, Notohara K, Itakura J, Sekine S, Sakashita S, Sakamoto N, Ishikawa S, Nakanishi Y, Yao T, Liang WY, Lauwers GY, Ito M, Sakamoto K, Ishii G, Ochiai A. Assessment of Elastic Laminal Invasion Contributes to an Objective pT3 Subclassification in Colon Cancer. The American journal of surgical pathology, 47:1122-1133, 2023

    15. Miyasaka Y, Hiyama T, Kuno H, Shinozaki T, Sakashita S, Kobayashi T. Characteristic imaging findings in a patient with chronic expanding hematoma on the floor of the mouth. International cancer conference journal, 12:185-189, 2023

    16. Takeshita N, Enokida T, Okano S, Fujisawa T, Wada A, Sato M, Tanaka H, Tanaka N, Onaga R, Hoshi Y, Sakashita S, Ishii G, Tahara M. Weekly paclitaxel, carboplatin and cetuximab (PCE) combination followed by nivolumab for recurrent and/or metastatic squamous cell carcinoma of the head and neck (R/M SCCHN). Oral oncology, 147:106615, 2023

    17. 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

    18. Ohtani-Kim SJ, Taki T, Tane K, Miyoshi T, Samejima J, Aokage K, Nagasaki Y, Kojima M, Sakashita S, Watanabe R, Sakamoto N, Goto K, Tsuboi M, Ishii G. Efficacy of Preoperative Biopsy in Predicting the Newly Proposed Histologic Grade of Resected Lung Adenocarcinoma. Modern pathology, 36:100209, 2023

    19. Tanaka T, Umemura S, Miyoshi T, Nakai T, Noritake O, Suzuki J, Tane K, Samejima J, Aokage K, Mimaki S, Tsuchihara K, Taki T, Miyazaki S, Watanabe R, Sakashita S, Sakamoto N, Kojima M, Goto K, Ikeda N, Tsuboi M, Ishii G. The prognostic impact of a high number of peritumoral alveolar macrophages in neuroendocrine carcinoma in the lung. Pathology international, 73:497-508, 2023

    20. 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

    21. Kagawa Y, Nakai T, Taki T, Hashimoto H, Tanaka Y, Sakai T, Shibata Y, Izumi H, Nosaki K, Udagawa H, Zenke Y, Matsumoto S, Yoh K, Miyazaki S, Watanabe R, Kojima M, Sakashita S, Sakamoto N, Tsuboi M, Goto K, Ishii G. Prognostic impact and gene expression analysis of peri-tumoral alveolar macrophage in resected lung adenocarcinoma. Cancer science, 114:3423-3432, 2023

    22. 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, 149:4663-4673, 2023

    23. Du J, Kageyama SI, Yamashita R, Tanaka K, Okumura M, Motegi A, Hojo H, Nakamura M, Hirata H, Sunakawa H, Kotani D, Yano T, Kojima T, Hamaya Y, Kojima M, Nakamura Y, Suzuki A, Suzuki Y, Tsuchihara K, Akimoto T. Transposable elements potentiate radiotherapy-induced cellular immune reactions via RIG-I-mediated virus-sensing pathways. Communications biology, 6:818, 2023

    24. Oyoshi H, Du J, Sakai SA, Yamashita R, Okumura M, Motegi A, Hojo H, Nakamura M, Hirata H, Sunakawa H, Kotani D, Yano T, Kojima T, Nakamura Y, Kojima M, Suzuki A, Zenkoh J, Tsuchihara K, Akimoto T, Shibata A, Suzuki Y, Kageyama SI. Comprehensive single-cell analysis demonstrates radiotherapy-induced infiltration of macrophages expressing immunosuppressive genes into tumor in esophageal squamous cell carcinoma. Science advances, 9:eadh9069, 2023

    25. Igata Y, Kojima M, Suzuki T, Ishii G, Morisue R, Suzuki T, Kudo M, Sugimoto M, Kobayashi S, Martin JD, Stylianopoulos T, Cabral H, Kano MR, Konishi M, Gotohda N. Relationships between physical and immunological tumor microenvironment in pancreatic ductal adenocarcinoma. Cancer science, 114:3783-3792, 2023

    26. Morisue R, Kojima M, Suzuki T, Watanabe R, Sakamoto N, Sakashita S, Harada K, Nakai T, Ishii G, Nakatsura T, Gotohda N, Ishikawa S. Common clinicopathological and immunological features of sarcomatoid carcinoma across organs: A histomorphology-based cross-organ study. International journal of cancer, 153:1997-2010, 2023

    27. Satake T, Shibuki T, Watanabe K, Sasaki M, Imaoka H, Mitsunaga S, Kojima M, Ikeda M. Case Report: Atezolizumab plus bevacizumab for combined hepatocellular-cholangiocarcinoma. Frontiers in oncology, 13:1234113, 2023

    28. Oda S, Kuno H, Hiyama T, Sakashita S, Sasaki T, Kobayashi T. Computed tomography-based radiomic analysis for predicting pathological response and prognosis after neoadjuvant chemotherapy in patients with locally advanced esophageal cancer. Abdominal radiology (New York), 48:2503-2513, 2023

    29. 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, 149:5309-5319, 2023

    30. 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, 149:6467-6477, 2023

    31. 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

    32. 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

    33. 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

    34. Oda S, Kuno H, Hiyama T, Sakashita S, Sasaki T, Kobayashi T. Reply to letter to the editor: Computed tomography-based radiomic analysis for predicting pathological response and prognosis after neoadjuvant chemotherapy in patients with locally advanced esophageal cancer. Abdominal radiology (New York), 48:3035-3037, 2023

    35. Tsubosaka A, Komura D, Kakiuchi M, Katoh H, Onoyama T, Yamamoto A, Abe H, Seto Y, Ushiku T, Ishikawa S. Stomach encyclopedia: Combined single-cell and spatial transcriptomics reveal cell diversity and homeostatic regulation of human stomach. Cell reports, 42:113236, 2023

    36. 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

    37. 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

    38. 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