Comparison of clinical outcome between surgical treatment and particle beam therapy for pelvic bone sarcomas: A retrospective multicenter study in Japan.

BACKGROUND: Few studies have compared the clinical outcomes of patients with pelvic bone sarcomas treated surgically and those treated with particle beam therapy. This is a multicenter retrospective cohort study which compared the clinical outcomes of patients with pelvic bone sarcoma who underwent surgical treatment and particle beam therapy in Japan. METHODS: A total of 116 patients with pelvic bone sarcoma treated at 19 specialized sarcoma centers in Japan were included in this study. Fifty-seven patients underwent surgery (surgery group), and 59 patients underwent particle beam therapy (particle beam group; carbon-ion radiotherapy: 55 patients, proton: four patients). RESULTS: The median age at primary tumor diagnosis was 52 years in the surgery group and 66 years in the particle beam group (P < 0.001), and the median tumor size was 9 cm in the surgery group and 8 cm in the particle beam group (P = 0.091). Overall survival (OS), local control (LC), and metastasis-free survival (MFS) rates were evaluated using the Kaplan-Meier method and compared among 116 patients with bone sarcoma (surgery group, 57 patients; particle beam group, 59 patients). After propensity score matching, the 3-year OS, LC, and MFS rates were 82.9% (95% confidence interval [CI], 60.5-93.2%), 66.0% (95% CI, 43.3-81.3%), and 78.4% (95% CI, 55.5-90.5%), respectively, in the surgery group and 64.9% (95% CI, 41.7-80.8%), 86.4% (95% CI, 63.3-95.4%), and 62.6% (95% CI, 38.5-79.4%), respectively, in the particle beam group. In chordoma patients, only surgery was significantly correlated with worse LC in the univariate analysis. CONCLUSIONS: The groups had no significant differences in the OS, LC, and MFS rates. Among the patients with chordomas, the 3-year LC rate in the particle beam group was significantly higher than in the surgery group.

Administration of Human-Derived Mesenchymal Stem Cells Activates Locally Stimulated Endogenous Neural Progenitors and Reduces Neurological Dysfunction in Mice after Ischemic Stroke.

Increasing evidence shows that the administration of mesenchymal stem cells (MSCs) is a promising option for various brain diseases, including ischemic stroke. Studies have demonstrated that MSC transplantation after ischemic stroke provides beneficial effects, such as neural regeneration, partially by activating endogenous neural stem/progenitor cells (NSPCs) in conventional neurogenic zones, such as the subventricular and subgranular zones. However, whether MSC transplantation regulates the fate of injury-induced NSPCs (iNSPCs) regionally activated at injured regions after ischemic stroke remains unclear. Therefore, mice were subjected to ischemic stroke, and mCherry-labeled human MSCs (h-MSCs) were transplanted around the injured sites of nestin-GFP transgenic mice. Immunohistochemistry of brain sections revealed that many GFP+ cells were observed around the grafted sites rather than in the regions in the subventricular zone, suggesting that transplanted mCherry+ h-MSCs stimulated GFP+ locally activated endogenous iNSPCs. In support of these findings, coculture studies have shown that h-MSCs promoted the proliferation and neural differentiation of iNSPCs extracted from ischemic areas. Furthermore, pathway analysis and gene ontology analysis using microarray data showed that the expression patterns of various genes related to self-renewal, neural differentiation, and synapse formation were changed in iNSPCs cocultured with h-MSCs. We also transplanted h-MSCs (5.0 × 104 cells/µL) transcranially into post-stroke mouse brains 6 weeks after middle cerebral artery occlusion. Compared with phosphate-buffered saline-injected controls, h-MSC transplantation displayed significantly improved neurological functions. These results suggest that h-MSC transplantation improves neurological function after ischemic stroke in part by regulating the fate of iNSPCs.

Outcomes of palliative surgery for bone metastasis of metastatic renal cell carcinoma in the era of targeted therapy.

INTRODUCTION: The introduction of tyrosine kinase inhibitors has revolutionized treatment strategies for metastatic renal cell carcinoma (RCC) and has improved survival rates. The number of patients with bone metastases from RCC requiring surgery will increase as survival rates improve. However, there is insufficient evidence to standardize the treatment of bone metastases after the introduction of targeted therapy for metastatic RCC. We aimed to determine the outcomes of palliative surgical treatment of bone metastases in the extremities of patients with metastatic RCC. MATERIALS AND METHODS: We retrospectively reviewed 26 lesions from 17 patients who underwent surgery for extremity and acetabular bone metastases and were treated with targeted therapies for advanced RCC between 2008 and 2020. The median follow-up duration was 19 months (range, 4-76). We assessed the patients' activities of daily living, quality of life, and pain and analyzed their postoperative values relative to preoperative values. Postoperative overall survival (OS), local progression-free survival (LPFS), and the factors affecting them were evaluated using the Kaplan-Meier method and log-rank test. RESULTS: The 5-year OS and LPFS rates were 39.5% and 65.6%, respectively. The factors affecting OS were sex, Katagiri score, visceral metastases, and preoperative targeted therapy, while the factors affecting LPFS were pathologic fractures and surgical technique. CONCLUSION: In this study, the postoperative outcomes of palliative surgery for bone metastases from metastatic RCC were good. We suggest that systemic treatment should be prioritized over local control for advanced bone metastasis in RCC and surgery before pathological fracture should be performed for local control.

Identification and characterization of slow­cycling cells in Ewing sarcoma.

Ewing sarcoma (ES) is an aggressive primary malignant bone tumor that predominantly affects children and young adults. Multimodal treatment approaches have markedly improved the survival of patients with localized ES. However, local recurrence and distant metastasis following curative therapies remain a main concern for patients with ES. Recent studies have suggested that slow­cycling cells (SCCs) are associated with tumor progression, local recurrence and distant metastasis in various types of cancers. According to the results of these studies, it was hypothesized that SCCs may play a critical role in tumor progression, chemoresistance and local/distal recurrence in patients with ES. The present study applied a label­retaining system using carboxyfluorescein diacetate succinimidyl ester (CFSE) to identify and isolate SCCs in ES cell lines. In addition, the properties of SCCs, including sphere formation ability, cell cycle distribution and chemoresistance, in comparison with non­SCCs were investigated. RNA sequencing also revealed several upregulated genes in SCCs as compared with non­SCCs; the identified genes not only inhibited cell cycle progression, but also promoted the malignant properties of SCCs. On the whole, the present study successfully identified SCCs in ES cells through a label­retaining system using CFSE. Moreover, to the best of our knowledge, the present study is the first to describe the characteristic properties of SCCs in ES. The findings of this study, if confirmed, may prove to be useful in elucidating the underlying molecular mechanisms and identifying effective therapeutic targets for ES.

Clinical Outcomes and Prognostic Factors in Soft Tissue Sarcoma Patients After Unplanned Excision.

Purpose: Soft tissue sarcomas (STSs) constitute a group of rare, heterogeneous tumors representing approximately 1% of all cancers. Owing to the rarity and pathological diversity of the disease, unplanned excision (UE) has often been performed for STS, resulting in an unfavorable prognosis. This study aimed to clarify clinical outcomes and prognostic factors in STS patients who underwent UE. Patients and Methods: In a retrospective review of the medical records of patients with STS who underwent surgery at our institution between 1999 and 2015, patients were enrolled to either a UE group or a planned excision (PE) group. An analysis was then conducted to identify factors associated with prognosis after UE. Results: Of 134 patients undergoing surgery for STS, 110 were enrolled to the PE group and 24 to the UE group. The median size of the primary tumor was significantly smaller, and more lesions were located in the superficial layer in the UE group than in the PE group. In addition, plastic reconstruction after additional radical resection was required significantly more often in the UE group than in the PE group. No significant difference in overall survival, local recurrence-free survival, or disease-free survival (DFS) between the UE and PE groups was observed; however, metastasis-free survival was significantly better in the UE group. In the UE group, poorer DFS was associated with older age (≥61 years) and a larger primary tumor (≥2.9 cm). Conclusion: A prognosis similar to that in patients undergoing PE could be achieved by appropriate additional surgeries in patients initially undergoing UE. However, UE for STS should be avoided, especially in older patients and those with a larger primary tumor.

Clinical Outcome of Patients with Pelvic and Retroperitoneal Bone and Soft Tissue Sarcoma: A Retrospective Multicenter Study in Japan.

This study aimed to retrospectively analyze the clinical outcomes of patients with pelvic and retroperitoneal bone and soft tissue sarcoma (BSTS). Overall, 187 patients with BSTS in the pelvis and retroperitoneal region treated at 19 specialized sarcoma centers in Japan were included. The prognostic factors related to overall survival (OS), local control (LC), and progression-free survival (PFS) were evaluated. The 3-year OS and LC rates in the 187 patients were 71.7% and 79.1%, respectively. The 3-year PFS in 166 patients without any distant metastases at the time of primary tumor diagnosis was 48.6%. Osteosarcoma showed significantly worse OS and PFS than other sarcomas of the pelvis and retroperitoneum. In the univariate analyses, larger primary tumor size, soft tissue tumor, distant metastasis at the time of primary tumor diagnosis, P2 location, chemotherapy, and osteosarcoma were poor prognostic factors correlated with OS. Larger primary tumor size, higher age, soft tissue tumor, chemotherapy, and osteosarcoma were poor prognostic factors correlated with PFS in patients without any metastasis at the initial presentation. Larger primary tumor size was the only poor prognostic factor correlation with LC. This study has clarified the epidemiology and prognosis of patients with pelvic and retroperitoneal BSTS in Japan.

Regulatory roles of miRNAs 16, 133a, and 223 on osteoclastic bone destruction caused by breast cancer metastasis.

Osteolytic bone metastasis leads to skeletal­related events, resulting in a decline in the patient activities and survival; therefore, it is important to understand the mechanism underlying bone metastasis. Recent studies have suggested that microRNAs (miRNAs or miRs) are involved in osteoclast differentiation and/or osteolytic bone metastasis; however, the roles of miRNAs have not been elucidated. In the present study, the roles of miRNAs in bone destruction caused by breast cancer metastasis were investigated in vitro and in vivo. miR­16, miR­133a and miR­223 were transfected into a human breast cancer cell line, MDA­MB­231. The expression of osteolytic factors in conditioned medium (miR­CM) collected from the culture of transfected cells was assessed. To evaluate the effects of miRNAs on osteoclast differentiation and activities, tartrate­resistant acid phosphatase (TRAP) staining and bone resorptive assays were performed in osteoclasts following miR­CM treatment. To create in vivo bone metastasis models for histological and morphometric evaluation, miRNA­transfected MDA­MB­231 cells were transplanted into the proximal tibia of nude mice. Expression of osteolytic factors, including receptor activator for nuclear factor­κB ligand (RANKL), interleukin (IL)­1ß, IL­6, parathyroid hormone­related protein (PTHrP), and tumor necrosis factor (TNF), was increased in miR­16­CM, whereas it was decreased in both miR­133a­CM and miR­223­CM. TRAP staining and bone resorptive assays revealed that osteoclast function and activities were promoted by miR­16­CM treatment, whereas they were suppressed by miR­133a­CM and miR­223­CM. Consistent with in vitro findings, in vivo experiments revealed that the overexpression of miR­16 increased osteoclast activities and bone destruction in MDA­MB­231 cells, whereas the opposite results were observed in both miR­133a­ and miR­223­transfected MDA­MB­231 cells. Our results indicated that miR­16 promoted osteoclast activities and bone destruction caused by breast cancer metastasis in the bone microenvironment, whereas miR­133a and miR­223 suppressed them. These miRNAs could be potential biomarkers and therapeutic targets for breast cancer bone metastasis.

Surgical outcomes of metastatic bone tumors in the extremities (Surgical outcomes of bone metastases).

BACKGROUND: Skeletal related events due to metastatic bone tumors markedly affect the activities of daily living (ADL) and quality of life (QOL) in cancer patients. We focused on multidisciplinary therapy for metastatic bone tumors. This study aimed to evaluate the outcomes of surgical treatment for metastatic bone tumors in the extremities. METHODS: We retrospectively reviewed 114 patients who underwent surgical treatment for metastatic bone tumors of the extremities between 2008 and 2019 and 69 patients were reassessed for more than 6 months after surgery. The most common primary tumor was renal, followed by lung, thyroid, and breast cancers. We assessed 69 patients' performance status (PS), Barthel Index (BI) for ADL, EuroQol 5 Dimensions (EQ-5D) for QOL, and numerical rating scale (NRS) for pain and analyzed these postoperative values relative to preoperative values using Friedman's test. The postoperative overall survival and the prognostic factors were evaluated using the Kaplan-Meier method, the log-rank test and Cox proportional hazards analysis. RESULTS: The 1-year overall survival rate was 59%, and the median survival time after surgery was 20 months. Primary tumor, visceral metastasis, and surgical procedure were risk factors correlated with overall survival. PS, BI, EQ-5D, and NRS improved at 3 months after surgery and these improvements were maintained for 6 months after surgery regardless of the surgical procedure. CONCLUSIONS: The significant factors affecting survival after surgical treatment for bone metastases included the primary tumor, presence of visceral metastases, and internal fixation without tumor resection or curettage. Surgical treatment for metastatic bone tumors effectively reduced pain and improved PS, ADL, and QOL postoperatively after 3 months.

Clinical Outcome of the Patients With Brain Metastasis from Soft Tissue Sarcomas.

BACKGROUND/AIM: This study aimed to evaluate the association of clinical characteristics with treatment outcomes to ascertain the appropriate treatment options for soft tissue sarcomas (STS) patients with brain metastasis (BM). PATIENTS AND METHODS: Medical records of STS patients with BM who were treated in our institutions were retrospectively reviewed, and analyzed to identify the factors associated with post-BM survival. RESULTS: Among the 509 STS patients, BM occurred in five patients (0.98%). The median survival after BM was 1.5 months. Histological subtypes of the primary lesions in the five BM patients were: two synovial sarcomas, one myxoid liposarcoma, one alveolar soft part sarcoma, and one rhabdomyosarcoma. Among the five BM patients, the post-BM survival of two patients, who underwent surgery and postoperative radiotherapy, was longer than that of the other patients (p<0.01). CONCLUSION: Combined surgery and postoperative radiotherapy effectively managed symptoms and prolonged survival in STS patients with BM.

Chondrolipoma of the finger in a child: A case study.

Chondrolipoma is, based on the limited case reports available, an extremely rare histological variant of lipoma with the proliferation of mature adipocytes containing an area of true hyaline cartilage. Chondrolipoma is characterized by adult onset and is often identified in the breast, pharynx and tongue. The current study presents a case of chondrolipoma of the finger in an 11 year-old girl. Physical examination indicated a well-defined elastic soft mass, measuring 2.5x2 cm, on the dorsal aspect of the proximal phalanx of the left middle finger. Magnetic resonance imaging (MRI) revealed a well-circumscribed lesion with heterogeneous signal intensity. On T1- and T2-weighted images, the lesion indicated a predominantly marked hyperintense signal containing linear hypointense regions, and on fat-suppressed short-tau inversion recovery sequences, the lesion indicated a predominant hypointensity, with linear regions displaying hyperintensity. Marginal excision of the tumor was performed. Histologically, the major component of the tumor was mature adipose tissue containing a limited area of mature hyaline cartilage matrix, without lipoblasts or malignancy. The postoperative course of the patient was excellent, with no local recurrence three years after surgery. To the best of our knowledge, the current study outlines the first pediatric case of chondrolipoma arising in the finger.

Acquisition of cancer stem cell properties in osteosarcoma cells by defined factors.

BACKGROUND: Cancer stem cells (CSCs) are considered to be responsible for tumor initiation, formation, and poor prognosis of cancer patients. However, the rarity of CSCs in clinical samples makes it difficult to elucidate characteristics of CSCs, especially in osteosarcoma (OS). The aim of this study is to verify whether it is possible to generate CSC-like cells by transducing defined factors into an OS cell line. METHODS: We retrovirally transduced the Octamer-binding transcription factor 3/4 (OCT3/4), Kruppel-like factor 4 (KLF4), and SRY-box transcription factor 2 (SOX2) genes into the MG-63 human OS cell line (MG-OKS). Parental and GFP-transduced MG-63 cells were used as negative control. We assessed the properties of the generated cells in vitro and in vivo. Multiple comparisons among groups were made using a one-way analysis of variance (ANOVA) followed by post hoc testing with Tukey's procedure. RESULTS: MG-OKS cells in vitro exhibited the significantly increased mRNA expression levels of CSC markers (CD24, CD26, and CD133), decreased cell growth, increased chemoresistance and cell migration, and enhanced sphere formation. Notably, MG-OKS cells cultured under osteogenic differentiation conditions showed strongly positive staining for both Alizarin Red S and alkaline phosphatase, indicating osteogenesis of the cells. Gene ontology analysis of microarray data revealed significant upregulation of epidermal-related genes. Tumors derived from MG-OKS cells in vivo were significantly larger than those from other cells in µCT analysis, and immunohistochemical staining showed that Ki-67, osteocalcin, and HIF-1α-positive cells were more frequently detected in the MG-OKS-derived tumors. CONCLUSIONS: In this study, we successfully generated OS CSC-like cells with significantly enhanced CSC properties following transduction of defined factors.

Prognostic influence of the treatment approach for pulmonary metastasis in patients with soft tissue sarcoma.

Soft tissue sarcomas (STSs) are rare heterogeneous malignancies of mesenchymal origin. Pulmonary metastases develop in approximately 50% of the patients with high-grade STS, being the major cause of mortality in patients with metastatic STS. Pulmonary metastasectomy has been reported to contribute to long-term survival; however, an appropriate treatment has not been established. We aimed to identify factors associated with post-metastasis survival in STS patients with pulmonary metastasis and determine the appropriate treatment for each patient. We retrospectively reviewed the records of metastatic STS patients treated between 2000 and 2017 and analyzed the clinico-pathologic variables to identify factors associated with the survival. The median survival after pulmonary metastasis was 20.6 months, and the 1-, 3-, and 5-year survival rates were 68.6%, 36.0%, and 25.1%, respectively. The survival was significantly greater in patients who underwent pulmonary metastasectomy than in those without surgery (38.9 months vs. 10.5 months; p < 0.0001). Among those who did not undergo surgery, the survival was significantly greater in patients who received chemotherapy than in those without chemotherapy (19.1 months vs. 6.3 months, p = 0.037). Multivariate analysis identified pulmonary metastasectomy as the most important prognostic factor for post-metastasis survival (Hazard ratio 5.623; 95% Confidence Interval 2.733-11.572; p < 0.0001). In conclusion, pulmonary metastasectomy was the most important prognostic factor for post-metastasis survival in patients with metastatic STS. In addition, chemotherapy could prolong survival in patients who were not eligible for pulmonary resection. Although we should carefully weigh the risks and benefits, appropriate treatment for pulmonary metastases could contribute to long-time survival.

Gemcitabine and docetaxel combination chemotherapy for advanced bone and soft tissue sarcomas: protocol for an open-label, non-randomised, Phase 2 study.

BACKGROUND: The prognosis of patients with metastatic or advanced sarcomas is poor and there are few options for treatment. Several studies have shown that gemcitabine and docetaxel (GD) combination chemotherapy has antitumor activity against various subtypes of sarcoma. Recently, some studies have shown a favourable outcome for GD combination chemotherapy for relapsed high-grade osteosarcoma and spindle cell sarcoma of bone. If the effectiveness of GD is proven, this will result in new treatment options for advanced bone and soft tissue sarcomas (STS). The aim of this prospective Phase 2 study is to evaluate the efficacy and toxicity of the GD combination in patients with advanced bone sarcomas and STS. METHODS: This is a Phase 2, single-arm, open-label study to investigate the efficacy and safety of combination chemotherapy with GD for advanced bone sarcomas and STS and will enrol 20 patients. The patients will receive gemcitabine 900 mg/m2 on Days 1 and 8, and docetaxel 70 mg/m2 on Day 8 in 3-week cycles until disease progression or other evidence of treatment failure. The primary aim of this study is to analyse GD's effect on progression-free survival (PFS). The secondary objectives are to analyse treatment efficacy and safety in terms of response rate, tumour control rate, overall survival, and adverse event rate. The length of follow-up will be 5 years. DISCUSSION: This study will evaluate the efficacy and safety of combination therapy with gemcitabine and docetaxel for bone sarcomas and STS. If this combination proves to be acceptable, it could be used for as second, third, or later line therapy for patients with sarcomas (especially bone sarcomas). In the future, the role of various treatments, including GD therapy, will be clarified for specific subtypes of sarcoma. TRIAL REGISTRATION: This study was registered as UMIN000031004 (University Hospital Medical Information Network-Clinical Trial Registry: UMIN-CTR) on 1 March 1 2018 and with the Japan Registry of Clinical Trials (jRCT) as jRCTs051180042 on 30 January 2019. The posted information will be updated as needed to reflect protocol amendments and study progress.

Huge chronic expanding hematoma of the iliac bone following multiple hip surgeries: a case report.

BACKGROUND: Chronic expanding hematoma is a rare entity resulting from trauma or surgery. This condition usually occurs in soft tissue, such as the trunk or extremities, while chronic expanding hematoma arising from bone has not been reported previously. We describe an unusual case of a huge intraosseous chronic expanding hematoma arising from the ilium, which had grown over a 40-year period following hip surgeries. CASE PRESENTATION: A 57-year-old Japanese woman presented with a 1.5-year history of right hip pain. She had a history of bilateral developmental dysplasia of the hip and had undergone bilateral arthroplasties in childhood. A physical examination revealed a large, firm, immobile mass at her right ilium. Based on radiographic findings, a type of slow-growing bone tumor was suspected, and an incisional biopsy was performed. A histopathologic examination revealed large amounts of old clotted blood within the lesion, and the capsule of the lesion was composed of dense, fibrous, connective tissue. There was no evidence of neoplasia, and chronic expanding hematoma was suspected. The lesion was resistant to conservative treatment, and so we performed an internal hemipelvectomy (including the capsule of the mass) and a reconstruction by hip transposition 2.5 years after the incisional biopsy. There was no recurrence of chronic expanding hematoma at the most recent follow-up of 1 year and 8 months postoperatively. CONCLUSIONS: A chronic expanding hematoma is characterized by its persistence and increasing size more than 1 month after the trauma or surgical event suspected of causing hemorrhage. To the best of our knowledge, this is the first report of chronic expanding hematoma arising from bone. We performed internal hemipelvectomy and hip transposition, and there has so far been no recurrence. This disease may be considered a differential diagnosis for bone tumor when the patient has a history of surgery or trauma, regardless of how many years have passed since the index event.

Transcutaneous carbon dioxide application suppresses bone destruction caused by breast cancer metastasis.

Hypoxia plays a significant role in cancer progression, including metastatic bone tumors. We previously reported that transcutaneous carbon dioxide (CO2) application could decrease tumor progression through the improvement of intratumor hypoxia. Therefore, we hypothesized that decreased hypoxia using transcutaneous CO2 could suppress progressive bone destruction in cancer metastasis. In the present study, we examined the effects of transcutaneous CO2 application on metastatic bone destruction using an animal model. The human breast cancer cell line MDA-MB-231 was cultured in vitro under three different oxygen conditions, and the effect of altered oxygen conditions on the expression of osteoclast-differentiation and osteolytic factors was assessed. An in vivo bone metastatic model of human breast cancer was created by intramedullary implantation of MDA-MB-231 cells into the tibia of nude mice, and treatment with 100% CO2 or a control was performed twice weekly for two weeks. Bone volume of the treated tibia was evaluated by micro-computed tomography (µCT), and following treatment, histological evaluation was performed by hematoxylin and eosin staining and immunohistochemical staining for hypoxia-inducible factor (HIF)-1α, osteoclast-differentiation and osteolytic factors, and tartrate-resistant acid phosphatase (TRAP) staining for osteoclast activity. In vitro experiments revealed that the mRNA expression of RANKL, PTHrP and IL-8 was significantly increased under hypoxic conditions and was subsequently reduced by reoxygenation. In vivo results by µCT revealed that bone destruction was suppressed by transcutaneous CO2, and that the expression of osteoclast-differentiation and osteolytic factors, as well as HIF-1α, was decreased in CO2-treated tumor tissues. In addition, multinucleated TRAP-positive osteoclasts were significantly decreased in CO2-treated tumor tissues. Hypoxic conditions promoted bone destruction in breast cancer metastasis, and reversal of hypoxia by transcutaneous CO2 application significantly inhibited metastatic bone destruction along with decreased osteoclast activity. The findings in this study strongly indicated that transcutaneous CO2 application could be a novel therapeutic strategy for treating metastatic bone destruction.

Successful First Gait of a Child With Hip-Disarticulation Prosthesis.

An infant boy underwent hip disarticulation for infantile fibrosarcoma immediately after birth. His rehabilitation began when he was 4 mos old and involved training with his left (residual) leg. He could stand with support at 12 mos. His initial prosthesis fitting was performed at the age of 13 mos. He could stand and walk with support at 15 mos of age and could walk with no additional support and go up and down stairs at 2 yrs. A single-axis prosthetic knee joint was introduced at the age of 2 yrs 3 mos. His first gait using a hip prosthesis was successful, and his prosthesis was replaced at appropriate intervals with no major problems. The authors believe that the key to achieving a successful prosthetic gait in children is good communication among the medical team, which should comprise an orthopedic doctor, rehabilitation doctor, nurse, physical therapist, prosthetist/orthotist, and the patient's parents.

Synergistic Effects of a Smac Mimetic with Doxorubicin Against Human Osteosarcoma.

BACKGROUND/AIM: Second mitochondria-derived activator of caspase (Smac) is a proapoptogenic mitochondrial protein that antagonizes inhibitors of apoptosis proteins (IAPs), resulting in induction of apoptosis. In the present study we investigated the effects of a Smac mimetic in combination with doxorubicin against osteosarcoma. MATERIALS AND METHODS: In vitro effects of the combination of a Smac mimetic AT-406 and doxorubicin on cell proliferation and apoptosis in osteosarcoma cell lines were examined using cell proliferation assays, flow cytometry, and immunoblot analyses. For in vivo experiments, human osteosarcoma xenografts were treated with combination of the two substances, and tumor volume and apoptotic activity in treated tumors were assessed. RESULTS: In vitro studies revealed that combination of the two substances significantly inhibited osteosarcoma proliferation with decreased cIAP1 expression and induced apoptosis in osteosarcoma cells. Combination of the two substances significantly suppressed osteosarcoma growth in vivo. Moreover, decreased cIAP1 expression and increased apoptotic activity were observed in tumors treated by their combination of the substances. CONCLUSION: The Smac mimetic AT-406 showed an apoptotic effect and a synergistic antitumor effect with doxorubicin on osteosarcoma. The combination of AT-406 and doxorubicin may serve as a novel therapeutic strategy for osteosarcoma treatment.

Osteoarthritis with permanent dislocation of the patella treated by total knee arthroplasty through a lateral approach: A report of two cases.

INTRODUCTION: Permanent dislocation of the patella (PDP) is a rare condition. In cases of PDP with tibiofemoral arthritis, total knee arthroplasty may be performed through a medial parapatellar approach with patellar realignment. In this article we present two cases of PDP with tibiofemoral osteoarthritis successfully treated via lateral approach TKA without any additional realignment procedure. We performed two total knee arthroplasties for PDP with lateral tibiofemoral arthritis through a lateral approach without any realignment procedure. Mobile bearing inserts were used to adjust rotational alignment. The patients showed improved functional outcomes (Japanese Orthopaedic Association Knee score and Oxford Knee Score), and improved range of motion. Three years postoperatively, the patellae remain stable without dislocation nor maltracking, maintaining a high functional score. CONCLUSION: To treat permanent dislocation of the patella with lateral knee osteoarthritis, TKA through a lateral approach have potential to be a new treatment option to achieve both a good outcome and repositioning of the patella.

Retrospective analysis of safety and efficacy of insulin-to-liraglutide switch in Japanese type 2 diabetes: A caution against inappropriate use in patients with reduced ß-cell function.

AIMS/INTRODUCTION: The safety and efficacy of insulin-to-liraglutide switch in type 2 diabetes has not been studied adequately. Here, we retrospectively characterize clinical parameters that might predict insulin-to-liraglutide treatment switch without termination due to hyperglycemia, and examine the effects of switching the therapies on glycated hemoglobin (HbA1c) and bodyweight in Japanese type 2 diabetes. MATERIALS AND METHODS: Japanese type 2 diabetes patients who underwent the switch of therapy were evaluated for their clinical data including ß-cell function-related indices, such as increment of serum C-peptide during glucagon stimulation test (GST-ΔCPR). HbA1c and bodyweight were analyzed in patients continuing with liraglutide after switching from insulin for 12 weeks. RESULTS: Of 147 patients, 28 failed in the switch due to hyperglycemia, nine failed because of other reasons and 110 continued with liraglutide for the 12-week period. Patients failing in the switch due to hyperglycemia showed longer duration and higher daily insulin dose, as well as lower GST-ΔCPR. Receiver-operating characteristic analysis showed that GST-ΔCPR of 1.34 ng/mL is a cut-off point for insulin-to-liraglutide switch without termination due to hyperglycemia. In patients continuing liraglutide for 12 weeks, the switch significantly reduced HbA1c and bodyweight with no severe hypoglycemia, irrespective of sulfonylurea co-administration, body mass index, duration and total daily insulin dose. The switch also significantly reduced the percentage of body fat and visceral fat areas. CONCLUSIONS: Insulin-to-liraglutide switch can improve glycemic control and reduce bodyweight in Japanese type 2 diabetes patients. However, caution must be taken with the switch in patients with reduced insulin secretory capacity as predicted by GST-ΔCPR.

Comparison of incretin immunoassays with or without plasma extraction: Incretin secretion in Japanese patients with type 2 diabetes.

UNLABELLED: Aims/Introduction: The effectiveness of incretin-based therapies in Asian type 2 diabetes requires investigation of the secretion and metabolism of glucose-dependent insulinotropic polypepide (GIP) and glucagon-like peptide 1 (GLP-1). Plasma extractions have been suggested to reduce variability in intact GLP-1 levels among individuals by removing interference that affects immunoassays, although no direct demonstration of this method has been reported. We have evaluated the effects of ethanol and solid-phase extractions on incretin immunoassays. We determined incretin levels during meal tolerance tests in Japanese patients with type 2 diabetes and characterized predictors for incretin secretion. MATERIALS AND METHODS: Japanese patients with type 2 diabetes (23 anti-diabetic drug-naïve and 18 treated with sulfonylurea [SU] alone) were subjected to meal tolerance tests, and incretin levels were determined by immunoassays with or without extraction. RESULTS: Intact GLP-1 levels determined by an intact GLP-1 immunoassay with ethanol and solid-phase extractions were lower than those determined without extraction. Intact GLP-1 levels determined by the extractions were highly correlated with each other, much more so than the levels with and without extraction. Total GLP-1 was unaffected by extractions, showing that extractions remove interference only in the case of intact GLP-1. Incretin secretion after meal ingestion was similar between drug-naïve and SU-treated patients. Fasting and postprandial GLP-1 levels were correlated positively with fasting free fatty acids and negatively with dipeptidyl peptidase-4 activity. CONCLUSIONS: Ethanol and solid-phase extractions remove interference for intact GLP-1 immunoassay. SU showed little effect on incretin secretion. GLP-1 and GIP secretion were predicted by different factors. (J Diabetes Invest, doi: 10.1111/j.2040-1124.2011.00141.x, 2012).