Shigeki Kakunaga

Nectin-like molecule-1/TSLL1/SynCAM3 : a neural tissue-specific immunoglobulin-like cell-cell adhesion molecule localizing at non-junctional contact sites of presynaptic nerve terminals, axons and glia cell processes

Nectins are Ca2+-independent immunoglobulin-like cell-cell adhesion molecules and comprise a family of four members. At the mossy fiber terminals of hippocampus, nectin-1 and nectin-3 localize at the presynaptic and postsynaptic sides of synaptic junctions, respectively, and their trans-interactions play a role in formation of synapses in cooperation with N-cadherin. Nectins are associated with the actin cytoskeleton through afadin, a nectin- and actin-filament-binding protein. Five nectin-like molecules (Necls) which have domain structures similar to those of nectins have been identified and here we characterize Necl-1/TSLL1/SynCAM3, from now on referred to as Necl-1. Tissue distribution analysis showed that Necl-1 was specifically expressed in the neural tissue. Immunofluorescence and immunoelectron microscopy revealed that Necl-1 localized at the contact sites among axons, their terminals, and glia cell processes that cooperatively formed synapses, axon bundles and myelinated axons. Necl-1 showed Ca2+-independent homophilic cell-cell adhesion activity. It furthermore showed Ca2+-independent heterophilic cell-cell adhesion activity with Necl-2/IGSF4/RA175/SgIGSF/TSLC1/SynCAM1 from now on referred to as Necl-2, nectin-1 and nectin-3, but not with Necl-5 or nectin-2. The C-terminal cytoplasmic region of Necl-1 did not bind afadin but bound membrane-associated guanylate kinase subfamily members that contain the L27 domain, including Dlg3, Pals2 and CASK. These results indicate that Necl-1 is a neural-tissue-specific Ca2+-independent immunoglobulin-like cell-cell adhesion molecule which potentially has membrane-associated guanylate kinase subfamily member-binding activity and localizes at the non-junctional cell-cell contact sites.

Inhibition of cell movement and proliferation by cell–cell contact-induced interaction of Necl-5 with nectin-3

Immunoglobulin-like Necl-5/Tage4/poliovirus receptor (PVR)/CD155, originally identified as the PVR, has been shown to be up-regulated in cancer cells and to enhance growth factor–induced cell movement and proliferation. In addition, Necl-5 heterophilically trans-interacts with nectin-3, a cell–cell adhesion molecule known to form adherens junctions in cooperation with cadherin. We show here that Necl-5 was down-regulated from cell surface upon cell–cell contacts in NIH3T3 cells. This down-regulation of Necl-5 was initiated by its interaction with nectin-3 and was mainly mediated by clathrin-dependent endocytosis. Then, the down-regulation of Necl-5 induced in this way reduced movement and proliferation of NIH3T3 cells. These results indicate that the down-regulation of Necl-5 induced by its interaction with nectin-3 upon cell–cell contacts may be at least one mechanism underlying contact inhibition of cell movement and proliferation.

Objective tumor response to denosumab in patients with giant cell tumor of bone: a multicenter phase II trial

A RANK ligand-specific inhibitor, denosumab, was predicted to reduce osteolysis and control disease progression in patients with giant cell tumor of bone (GCTB). We report, for the first time, the results of the response of GCTB to denosumab obtained from a prospective independent imaging assessment. The findings demonstrate that denosumab has robust clinical efficacy in the treatment of GCTB.

Evaluation of delayed18F-FDG PET in differential diagnosis for malignant soft-tissue tumors

ObjectivePositron emission tomography (PET) with 2-deoxy-2-[18F]fiuoro-D-glucose (18F-FDG) has been used for the evaluation of soft-tissue tumors. However, the range of accumulation of18F-FDG for malignant soft-tissue lesions overlaps with that of benign lesions. The aim of this study is to investigate the usefulness of delayed18F-FDG PET imaging in the differentiation between malignant and benign soft-tissue tumors.MethodsFifty-six patients with soft-tissue tumors underwent whole body18F-FDG PET scan at 1 hour (early scan) and additional scan at 2 hours after injection (delayed scan). The standardized uptake value (SUVmax) of the tumor was determined, and the retention index (RI) was defined as the ratio of the increase in SUVmax between early and delayed scans to the SUVmax in the early scan. Surgical resection with histopathologic analysis confirmed the diagnosis.ResultsHistological examination proved 19 of 56 patients to have malignant soft-tissue tumors and the rest benign ones. In the scans of all 56 patients, there was a statistically significant difference in the SUVmax between malignant and benign lesions in the early scan (5.50 ± 5.32 and 3.10 ± 2.64, respectively, p < 0.05) and in the delayed scan (5.95 ± 6.40 and 3.23 ± 3.20, respectively, p < 0.05). The mean RI was not significantly different between malignant and benign soft-tissue tumors (0.94 ± 23.04 and -2.03 ± 25.33, respectively).ConclusionsIn the current patient population, no significant difference in the RI was found between malignant and benign soft-tissue lesions. Although the mean SUVmax in the delayed scan for malignant soft-tissue tumors was significantly higher than that for benign ones, there was a marked overlap. The delayed18F-FDG PET scan may have limited capability to differentiate malignant soft-tissue tumors from benign ones.

Constrained Total Hip Megaprosthesis for Primary Periacetabular Tumors

BackgroundLimb-salvage reconstruction for periacetabular malignant tumors is one of the most challenging problems in orthopaedic oncology. Reconstructive options include resection arthroplasty, endoprosthesis, allograft, recycled autobone graft, arthrodesis, and pseudarthrosis. However, no standard procedure exists because of rarity and clinical variability of the disease. We previously developed a megaprosthetic system with a constrained total hip mechanism (C-THA).Questions/purposesWe evaluated (1) survival of patients and C-THA; (2) postoperative function; and (3) complications.MethodsWe retrospectively reviewed 25 patients with primary periacetabular tumors treated using C-THA between 1985 and 2009. There were 18 male and seven female patients with a median age of 44 years (range, 16–72 years). They included 11 chondrosarcomas, eight osteosarcomas, two giant cell tumors of bone (one locally aggressive benign, one malignant), and others in four. Surgical margin was wide in 18 patients, marginal in five, and intralesional in two. The minimum postoperative followup for survivors was 32 months (median, 163 months; range, 32–285 months).ResultsThe 10-year overall survival rate of all patients was 47%. C-THA implants survived in 19 of 25 patients at last followup. Twenty-one patients acquired ambulatory activity. There were seven local recurrences, resulting in hemipelvectomy in one patient. Postoperative complications included deep infection in eight of the 25 patients, dislocation in four, and aseptic loosening in two, necessitating five revision surgeries and three implant removals.ConclusionsOur observations suggest C-THA using an acetabular reconstruction cup is a useful reconstructive option after resection of periacetabular malignant tumors despite frequent postoperative complications.Level of EvidenceLevel IV, therapeutic study. See Guidelines for Authors for a complete description of levels of evidence.

Development and external validation of nomograms predicting distant metastases and overall survival after neoadjuvant chemotherapy and surgery for patients with nonmetastatic osteosarcoma: A multi‐institutional study

In this era of individualized cancer treatment, data that could be applied to predicting the survival of patients with osteosarcoma are still limited because of the rarity of the disease and the difficulty in accumulating a sufficient number of patients. Therefore, a multi‐institutional collaboration was implemented to develop and externally validate nomograms that would predict metastasis‐free survival (MFS) and overall survival (OAS) for patients with nonmetastatic osteosarcoma.

Eleven Cases of Cardiac Metastases from Soft-tissue Sarcomas

OBJECTIVE Cardiac metastasis is a highly life-threatening condition because it leads to cardiac failure. However, it is difficult to diagnose because its precise clinical features are unknown. Here, we report 11 cases of cardiac metastasis from soft-tissue sarcoma, and discuss its diagnosis and treatment. METHODS Of 641 patients with soft-tissue sarcoma treated in our institute between 1996 and 2009, we retrospectively reviewed the medical records of 11 patients whose cardiac metastases were diagnosed while they were alive. RESULTS The most common primary tumor was leiomyosarcoma (n= 5), followed by clear cell sarcoma (n= 2). In all cases, metastases to other organs, including lungs (n= 10), soft tissues (n= 5) and bones (n= 4) were found along with cardiac metastases. Cardiac metastasis was diagnosed by echocardiography in six cases and by computed tomography in four cases. In four patients, cardiac metastasis was not detected by chest computed tomography as follow-up to lung metastases and echocardiography was required to make the diagnosis. Although five patients complained of exertional dyspnea, four were asymptomatic. Seven cases were treated with radiotherapy. No patient had surgery for their cardiac metastasis. The median survival of patients who received radiation therapy was 10.5 months; that of those who did not was 3.5 months. CONCLUSIONS Cardiac metastasis is often asymptomatic. Echocardiography is better than computed tomography for diagnosing cardiac metastasis, and should be considered in all patients presenting with soft-tissue metastases. Owing to the highly life-threatening nature of cardiac metastases and the possibility of soft-tissue dissemination, treatment with radiation therapy is recommended immediately on diagnosis.

Intramedullary spinal cord metastasis following spontaneous malignant transformation from giant cell tumor of bone 16 years after pulmonary metastasis

Abstract Giant cell tumor (GCT) of the bone is a unique bone tumor that can behave in locally aggressive fashion despite its benign histological appearance, and the local recurrence rate is approximately 25-35% following curettage, supplemented with bone grafting, cementation, cryosurgery, or instillation of phenol or ethanol [1, 2]. Pulmonary metastases, or so-called pulmonary implants, are also a well-documented phenomenon in conventional GCT of the bone, with an incidence of from 1 to 9% of patients with GCT in the literature [3-7]. They have generally self-limited growth potential and a relatively good prognosis; thus, surgical resection of pulmonary metastatic lesions as much as feasible is the treatment of choice. However, approximately 25% of patients with unresectable metastasis eventually die of the disease [1]. Much more unusually, GCT of the bone can metastasize to extrapulmonary sites, including the bone (actually indistinguishable from multicentric GCT of the bone), scalp, prepuce, brain, and mediastinal and regional lymph nodes, especially in the presence of simultaneous pulmonary metastatic lesions [8, 9]. However, intramedullary spinal cord metastasis is an extremely rare event, even in cases of malignant tumors, such as lung and breast cancers [10, 11]. As far as we know, there have been no reports documenting intramedullary spinal cord metastasis from GCT of the bone with or without malignant transformation. The present report describes a patient presenting with an intramedullary spinal cord metastasis following spontaneous malignant transformation from conventional GCT of the bone 16 years after pulmonary metastasis. The patient was informed that data from the case would be submitted for publication and gave her consent during her lifetime.

Treatment outcomes of Japanese patients with Ewing sarcoma: differences between skeletal and extraskeletal Ewing sarcoma

OBJECTIVE The incidence of Ewing sarcoma is lower in non-Caucasian populations, compared with Caucasian populations, for unknown reasons. Most studies from western countries have reported improvement in outcomes following multi-agent chemotherapy, with no difference in outcome between skeletal and extraskeletal Ewing sarcoma. However, there are few studies of Ewing sarcoma in non-Caucasian populations, with especially few comparing outcomes between skeletal and extraskeletal Ewing sarcoma. Thus, the purpose of this study is to determine whether the outcomes and prognostic factors of Ewing sarcoma in the Japanese population are similar to those in Caucasian populations and to determine whether skeletal and extraskeletal Ewing sarcoma have similar outcomes in Japanese patients. METHODS We retrospectively evaluated the outcomes of 74 Japanese patients with Ewing sarcoma treated between 1981 and 2011 from the Osaka University Orthopaedic Oncology Group. RESULTS Extraskeletal Ewing sarcoma, tumors in the extremities, localized disease at presentation and diagnosis after 2000 were significantly associated with a favorable outcome. Among patients with localized disease at presentation, a significantly better outcome was observed for those with extraskeletal Ewing sarcoma, those who underwent a VDC/IE based or VAIA chemotherapy protocol, and those who were diagnosed after 2000. In the multivariable analyses, extraskeletal Ewing sarcoma was an independent predictor of increased overall survival among all patients and the subset of patients with localized disease. CONCLUSIONS The outcome of patients with Ewing sarcoma in Japan has improved in the last decade. The outcomes and prognostic factors are similar for Japanese and Caucasian patients, though in this series of Japanese patients, a better prognosis was observed for patients with extraskeletal rather than skeletal Ewing sarcoma.

Clinical outcomes of patients with epithelioid sarcomas: impact and management of nodal metastasis

PurposeAn epithelioid sarcoma is a rare histological subtype of a soft tissue sarcoma with a high local recurrence rate, which frequently shows lymph node metastasis. However, because of the rarity of this tumor, the impact of nodal metastasis and its appropriate management remain unclear. The present study investigated the clinical outcomes of patients with epithelioid sarcomas, with a focus on lymph node metastasis.MethodsWe retrospectively evaluated the clinical outcomes of 27 patients with epithelioid sarcomas treated between 1985 and 2015. The log-rank test was used to assess the prognostic variables.ResultsThe overall local recurrence rate was 33%, and the estimated overall 5-year survival rate was 62%. Hand and foot locations were associated with favorable overall survival. During the follow-up period, new nodal metastasis was noted in 14 patients (52%). The incidence of local recurrence was higher in patients with new nodal metastasis than in patients who did not develop nodal metastasis. The development of new nodal metastasis had a tendency to worsen survival; however, this association was not statistically significant. Lymphadenectomy did not affect overall survival.ConclusionsPeripheral tumor location is associated with a better prognosis. The development of new nodal metastasis tends to be associated with poor prognosis; however, among patients with nodal metastasis, resection of the metastatic lesions has a low impact on survival.