Kosei Ando’s research while affiliated with Shiga University of Medical Science and other places

OBJECTIVE The purpose of this study was to clarify the clinical outcomes of spontaneous anterior interosseous nerve palsy (AINP) treated nonsurgically or surgically. METHODS The authors retrospectively evaluated the clinical course of 27 patients affected with AINP, treated nonsurgically or surgically. Thirteen patients underwent surgical treatment (interfascicular neurolysis), and 14 patients underwent conservative nonsurgical treatment. The mean patient age at the onset of symptoms was 49 years (range 17–77 years). The mean follow-up duration from onset to the latest follow-up examination was 23 months (range 12–38 months). RESULTS In 12 of 14 patients receiving conservative treatment, signs of recovery from the palsy were obtained within 6 months. These patients showed a recovery of manual muscle test (MMT) grade ≥ 3. In contrast, 2 patients who took more than 12 months from symptom onset to initial recovery showed poor recovery (MMT grade ≤ 2). Surgical treatment was performed in 13 patients because of no sign of recovery from palsy. The mean period from symptom onset to the operation was 8.4 months (range 6–14 months). Ten of 13 patients who underwent surgical treatment within 8 months after symptom onset showed good recovery, with MMT grade ≥ 4. However, 3 patients who underwent surgical treatment more than 12 months after onset showed recovery with MMT grade ≤ 3. CONCLUSIONS Conservative treatment for AINP may be continued when patients show signs of recovery within 6 months after symptom onset. In contrast, surgical treatment may be performed within 8 months from the onset of symptoms when the patients show no recovery signs for 6 months.

Background: Osteosarcoma is the most frequent form of malignant pediatric bone tumor. Despite the current therapeutic arsenal, patient life-expectancy remains low if metastases are detected at the time of diagnosis, justifying research into better knowledge at all stages of osteosarcoma ontogenesis and identification of new therapeutic targets. Receptor Activator of Nuclear factor κB (RANK)expression has been reported in osteosarcoma cells, raising the question of Receptor Activator of Nuclear factor κB Ligand (RANKL)/RANK signaling implications in these tumor cells (intrinsic), in addition to previously reported implications through osteoclast activation in the tumor microenvironment (extrinsic). Methods: Based on in vitro and in vivo experimentations using human and mouse osteosarcoma cell lines, the consequences on the main cellular processes of RANK expression in osteosarcoma cells were analyzed. Results: The results revealed that RANK expression had no impact on cell proliferation and tumor growth, but stimulated cellular differentiation and, in an immune-compromised environment, increased the number of lung metastases. The analysis of RANKL, RANK and osteoprotegerin (OPG) expressions in biopsies of a cohort of patients revealed that while RANK expression in osteosarcoma cells was not significantly different between patients with or without metastases at the time of diagnosis, the OPG/RANK ratio decreased significantly. Conclusion: Altogether, these results are in favor of RANKL-RANK signaling inhibition as an adjuvant for the treatment of osteosarcoma.

Partial growth plate arrest caused by trauma may lead to severe deformity and dysfunction. The Langenskiöld method is a surgical technique that involves resection of the physeal bar causing partial growth plate arrest. However, it is a technically demanding procedure. We used the Langenskiöld method under guidance with a navigation system and endoscopy and obtained good results in 2 cases. We consider that use of these tools can be a helpful adjunct to the carrying out this procedure.

Background: Osteosarcoma, the most frequent malignant primary bone tumor, is characterized by an osteoid tumor tissue formation associated to a tumor-induced osteolysis. Lung metastasis occurs in some osteosarcomas with dramatic consequence for patient lifespan. Expression of RANK has been reported in some osteosarcoma cells and the question of the potential repercussion on tumor growth, tumor-induced osteolysis and lung metastasis was raised. Methods: Human HOS, human MG63 and mouse MOS-J osteosarcoma cell-lines were transfected to stably over-express RANK and injected in para-tibia muscle of Nude mice and syngeneic C57BL/6 mice for MOS-J cells. Tumor growth was follow and associated osteolysis analyzed by micro-CT and histology comparatively to injections of native cells. Lung metastases were numbered in each group. Results: In Nude mouse RANK over-expression, whatever the cell-line considered (human or mouse), induces a significant increase of the number of lung metastasis while the tumor growth and the induced osteolysis are not affected. Injections of a RANKL blocking antibody reverse the impact of RANK over-expression on lung metastasis. In the C57BL/6, RANK over-expression has no impact on the lung metastasis and tumor-induced osteolysis. The tumor growth was slightly reduced. Conclusions: Reported data evidence that RANK expression by osteosarcoma cells has no significant effect on the tumor growth and tumor-induced osteolysis but in immune-deficient Nude mouse induces an important increase of the lung metastases dependently of RANKL stimulation. Citation Format: Benjamin Navet, Kosei Ando, Hideo Yagita, Christopher G. Mueller, Dominique Heymann, Frederic Lezot. RANK expression by osteosarcoma cells increases lung metastasis in Nude mouse while has no effect in immune-competent mouse. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 1439. doi:10.1158/1538-7445.AM2015-1439

Articular cartilage homeostasis involves modulation of chondrocyte matrix synthesis in response to mechanical stress (MS). We studied extracellular and intracellular mechanotransduction pathways mediating this response. We first confirmed rapid up-regulation of the putative chondro-protective cytokine, interleukin (IL)-4, as an immediate response to MS. We then studied the role of IL-4 by investigating responses to exogenous IL-4 or a specific IL-4 inhibitor, combined with MS. Next we investigated the intracellular second messengers. Since chondrocyte phenotype alters according to the extracellular environment, we characterized the response to mechanotransduction in 3-dimensionally embedded chondrocytes. Expression of aggrecan and type II collagen was significantly up-regulated by exogenous IL-4 whereas MS-induced matrix synthesis was inhibited by an IL-4 blocker. Further, MS-induced matrix synthesis was completely blocked by a p38 MAPK inhibitor, while it was only partially blocked by inhibitors of other putative second messengers. IL-4 mediates an extracellular pathway of mechanotransduction, perhaps via an autocrine/paracrine loop, while p38 mediates an intracellular pathway prevalent only in a 3-dimensional environment.

Receptor activator of nuclear factor-κB (RANK) and RANK ligand play a pivotal role in bone metabolism, and selective targeting of RANK signaling has become a promising therapeutic strategy in the management of resorptive bone diseases. Existing antibody-based therapies and novel inhibitors currently in development were designed to target the ligand, rather than the membrane receptor expressed on osteoclast precursors. We describe here an alternative approach to designing small peptides able to specifically bind to the hinge region of membrane RANK responsible for the conformational change upon RANKL association. A nonapeptide generated by this method was validated for its biological activity in vitro and in vivo and served as a lead compound for the generation of a series of peptide RANK antagonists derived from the original sequence. Our study presents a structure- and knowledge based strategy for the design of novel effective and affordable small peptide inhibitors specifically targeting the receptor RANK and opens a new therapeutic opportunity for the treatment of resorptive bone-disease. © 2014 American Society for Bone and Mineral Research.

Osteosarcoma is the most frequent malignant primary bone tumor and a main cause of cancer-related death in children and adolescents. Although long-term survival in localized osteosarcoma has improved to about 60% during the 1960s and 1970s, long-term survival in both localized and metastatic osteosarcoma has stagnated in the past several decades. Thus, current conventional therapy consists of multi-agent chemotherapy, surgery and radiation, which is not fully adequate for osteosarcoma treatment. Innovative drugs and approaches are needed to further improve outcome in osteosarcoma patients. This review describes the current management of osteosarcoma as well as potential new therapies.

Osteosarcoma is the most frequent malignant primary bone tumor characterized by a high potency to form lung metastases which is the main cause of death. Unfortunately, the conventional chemotherapy is not fully effective on osteosarcoma metastases. The progression of a primary tumor to metastasis requires multiple processes, which are neovascularization, proliferation, invasion, survival in the bloodstream, apoptosis resistance, arrest at a distant organ, and outgrowth in secondary sites. Consequently, recent studies have revealed new insights into the molecular mechanisms of metastasis development. The understanding of the mechanism of molecular alterations can provide the identification of novel therapeutic targets and/or prognostic markers for osteosarcoma treatment to improve the clinical outcome.