Objective: We have established 4 histopathologic subtyping of high-grade serous ovarian cancer (HGSOC) and reported that the mesenchymal transition (MT) type has a worse prognosis than the other subtypes. In this study, we modified the histopathologic subtyping algorithm to achieve high interobserver agreement in whole slide imaging (WSI) and to characterize the tumor biology of MT type for treatment individualization. Methods: Four observers performed histopathological subtyping using WSI of HGSOC in The Cancer Genome Atlas data. As a validation set, cases from Kindai and Kyoto Universities were independently evaluated by the 4 observers to determine concordance rates. In addition, genes highly expressed in MT type were examined by gene ontology term analysis. Immunohistochemistry was also performed to validate the pathway analysis. Results: After algorithm modification, the kappa coefficient, which indicates interobserver agreement, was greater than 0.5 (moderate agreement) for the 4 classifications and greater than 0.7 (substantial agreement) for the 2 classifications (MT vs. non-MT). Gene expression analysis showed that gene ontology terms related to angiogenesis and immune response were enriched in the genes highly expressed in the MT type. CD31 positive microvessel density was higher in the MT type compared to the non-MT type, and tumor groups with high infiltration of CD8/CD103 positive immune cells were observed in the MT type. Conclusion We developed an algorithm for reproducible histopathologic subtyping classification of HGSOC using WSI. The results of this study may be useful for treatment individualization of HGSOC, including angiogenesis inhibitors and immunotherapy.

In dentistry, it is empirically known that the acute exacerbation of periodontal disease often occurs at the time of fatigue, but scientific verification has never been made about the relationship of fatigue and bleeding. In Kampo medicine, there is the concept of spleen failing to control the blood as bleeding at the time of fatigue. Kihito and kamikihito are often used for this condition. Spleen failing to control the blood means that lack of vital energy causes the bleeding. Kamikihito is most often used in the treatment of idiopathic thrombocytopenic purpura. Moreover, there have been some reports on the use of kamikihito in the treatment of gynecological fraud bleeding and aplastic anemia. However, there has been no report on the use of it in the treatment of gingival bleeding. In this case, neither cytopenia nor obvious coagulopathy was recognized. In Kampo medicine, not only spleen failing to control the blood but also blood stasis or blood heat is considered to be the cause of bleeding, but the effectiveness of kamikihito for this case suggested pathophysiology of spleen failing to control the blood. Kamikihito could be a choice to treat gingival bleeding at the time of fatigue.