Comparison of Functional and Cosmetic Outcomes According to Fracture Level in Gartland Type III Pediatric Supracondylar Humerus Fractures.

Background: Supracondylar humerus (SCH) fractures in children have been traditionally categorized according to the Wilkins-modified Gartland classification scheme, which is solely based on the degree of displacement. As this classification does not consider fracture patterns in the coronal or sagittal plane, the relationship between the fracture pattern and prognosis in SCH fractures remains unclear. Therefore, the purpose of this study was to evaluate the relationship between the fracture level and prognosis of pediatric SCH fractures. Methods: Medical records and radiographs of 786 patients with SCH fractures who underwent surgical treatment between March 2004 and December 2017 were reviewed. A total of 192 patients were included in this study. Anteroposterior elbow radiographs taken at the time of injury were evaluated to obtain the level of fracture. Functional outcomes were evaluated based on modified Flynn grading at the last follow-up. Results: Of 192 patients included in this study, 24 (12.1%), 148 (74.8%), and 20 (10.1%) had fractures in zone 1 (metaphyseal-diaphyseal area), zone 2 (between zones 1 and 3), and zone 3 (metaphyseal-epiphyseal area), respectively. There were significant differences in age at the time of injury (p = 0.011), direction of fracture displacement (p = 0.014), and loss of carrying angle (p < 0.001) between fractures in zone 3 and those in zone 1 or zone 2. Zone 3 fractures and classic zone 2 fractures also showed significant difference in outcomes, with zone 3 fractures having more unsatisfactory outcome than classic zone 2 fractures (p = 0.049). Conclusions: For SCH fractures, varus deformity of the elbow was more common in zone 3 (metaphyseal-epiphyseal area) than in the other zones. Thus, pediatric orthopedic surgeons should be mindful of the possibility of cubitus varus deformity when treating SCH fractures in zone 3. A thorough postoperative follow-up is required.

Sirt6 Activation Ameliorates Inflammatory Bone Loss in Ligature-Induced Periodontitis in Mice.

Periodontitis is an inflammatory disease caused by microorganisms that induce the destruction of periodontal tissue. Inflamed and damaged tissue produces various inflammatory cytokines, which activate osteoclasts and induce alveolar bone loss and, eventually, tooth loss. Sirt6 expression suppresses inflammation and bone resorption; however, its role in periodontitis remains unclear. We hypothesized that Sirt6 has a protective role in periodontitis. To understand the role of Sirt6 in periodontitis, we compared periodontitis with ligature placement around the maxillary left second molar in 8-week-old control (C57BL/6J) male mice to Sirt6-overexpressing Tg (Sirt6Tg) mice, and we observed the resulting phenotypes using micro-CT. MDL801, a Sirt6 activator, was used as a therapy for periodontitis through oral gavage. Pro-inflammatory cytokines and increased osteoclast numbers were observed in alveolar bone tissue under periodontitis surgery. In the same condition, interestingly, protein levels from Sirt6 were the most downregulated among sirtuins in alveolar bone tissue. Based on micro-CT and CEJ-ABC distance, Sirt6Tg was observed to resist bone loss against ligature-induced periodontitis. Furthermore, the number of osteoclasts was significantly reduced in Sirt6Tg-ligated mice compared with control-ligated mice, although systemic inflammatory cytokines did not change. Consistent with this observation, we confirmed that bone loss was significantly reduced when MDL801, a Sirt6 activator, was included in the ligation mouse model. Our findings demonstrate that Sirt6 activation prevents bone loss against ligature-induced periodontitis. Thus, a Sirt6 activator may provide a new therapeutic approach for periodontitis.

Gene Panel Sequencing Identifies a Novel RYR1 p.Ser2300Pro Variant as Candidate for Malignant Hyperthermia with Multi-Minicore Myopathy.

Malignant hyperthermia (MH), a rare autosomal dominant pharmacogenetic disorder of skeletal muscle calcium regulation, is triggered by sevoflurane in susceptible individuals. We report a Korean having MH with multi-minicore myopathy functionally supported by RYR1-mediated intracellular Ca2+ release testing in B lymphocytes. A 14-year-old boy was admitted for the evaluation of progressive torticollis accompanied by cervicothoracic scoliosis. During the preoperative drape of the patient for the release of the sternocleidomastoid muscle under general anesthesia, his wrist and ankle were observed to have severe flexion contracture. The body temperature was 37.1 °C. To treat MH, the patient was administered a bolus of dantrolene intravenously (1.5 mg/kg) and sodium bicarbonate. After a few minutes, muscle rigidity, tachycardia, and EtCO2 all resolved. Next-generation panel sequencing for hereditary myopathy identified a novel RYR1 heterozygous missense variant (NM_000540.2: c.6898T > C; p.Ser2300Pro), which mapped to the MH2 domain of the protein, a hot spot for MH mutations. Ex vivo RYR1-mediated intracellular Ca2+ release testing in B lymphocytes showed hypersensitive Ca2+ responses to isoflurane and caffeine, resulting in an abnormal Ca2+ release only in the proband, not in his family members. Our findings expand the clinical and pathological spectra of information associated with MH with multi-minicore myopathy.

CK2α/CSNK2A1 Induces Resistance to Doxorubicin through SIRT6-Mediated Activation of the DNA Damage Repair Pathway.

CK2α/CSNK2A1 is involved in cancer progression by phosphorylating various signaling molecules. Considering the role of CSNK2A1 in cancer progression and the phosphorylation of SIRT6 and the role of SIRT6 in chemoresistance through the DNA damage repair pathway, CSNK2A1 and SIRT6 might be involved in resistance to conventional anti-cancer therapies. We evaluated the expression of CSNK2A1 and phosphorylated SIRT6 in the 37 osteosarcoma patients and investigated the effects of CSNK2A1 and the phosphorylation of SIRT6 on Ser338 on resistance to the anti-cancer effects of doxorubicin. Higher expression of CSNK2A1 and phosphorylated SIRT6 was associated with shorter survival in osteosarcoma patients. U2OS and KHOS/NP osteosarcoma cells with induced overexpression of CSNK2A1 were resistant to the cytotoxic effects of doxorubicin, and the knock-down of CSNK2A1 potentiated the cytotoxic effects of doxorubicin. CSNK2A1 overexpression-mediated resistance to doxorubicin was associated with SIRT6 phosphorylation and the induction of the DNA damage repair pathway molecules. CSNK2A1- and SIRT6-mediated resistance to doxorubicin in vivo was attenuated via mutation of SIRT6 at the Ser338 phosphorylation site. Emodin, a CSNK2A1 inhibitor, potentiated the cytotoxic effects of doxorubicin in osteosarcoma cells. This study suggests that blocking the CSNK2A1-SIRT6-DNA damage repair pathway might be a new therapeutic stratagem for osteosarcomas.

Expression of IL4Rα and IL13Rα1 are associated with poor prognosis of soft-tissue sarcoma of the extremities, superficial trunk, and retroperitoneum.

BACKGROUND: IL4Rα and IL13Rα1 are constituents of the type II IL4 receptor. Recently, IL4Rα and IL13Rα1 were reported to have roles in cancer progression and suggested as potential prognostic markers. However, studies on IL4Rα and IL13Rα1 in soft-tissue sarcomas have been limited. METHODS: This study investigated the immunohistochemical expression of IL4Rα and IL13Rα1 in 89 soft-tissue sarcomas of the extremities, superficial trunk, and retroperitoneum. Immunohistochemical staining for IL4Rα and IL13Rα1 were scored according to a combination of staining intensity and staining area in tissue microarray samples. Positivity for the immunohistochemical expression of IL4Rα and IL13Rα1 were determined using receiver operating curve analysis. Statistical analysis was performed using regression analysis and a chi-square test. RESULTS: In human soft-tissue sarcomas, immunohistochemical expression of IL4Rα was significantly associated with IL13Rα1 expression. Nuclear and cytoplasmic expression of IL4Rα and IL13Rα1 were significantly associated with shorter survival of soft-tissue sarcoma patients in univariate analysis. Multivariate analysis indicated that nuclear expression of IL4Rα and IL13Rα1 were independent indicators of shorter overall survival (IL4Rα; p = 0.002, IL13Rα1; p = 0.016) and relapse-free survival (IL4Rα; p = 0.022, IL13Rα1; p < 0.001) of soft-tissue sarcoma patients. Moreover, the co-expression pattern of nuclear IL4Rα and IL13Rα1 was an independent indicator of shorter survival of soft-tissue sarcoma patients (overall survival; overall p < 0.001, relapse-free survival; overall p < 0.001). CONCLUSIONS: This study suggests IL4Rα and IL13Rα1 are associated with the progression of soft-tissue sarcoma, and the expression of IL4Rα and IL13Rα1 might be novel prognostic indicators of soft-tissue sarcoma patients.

Osteoblasts/Osteocytes sirtuin6 Is Vital to Preventing Ischemic Osteonecrosis Through Targeting VDR-RANKL Signaling.

Ischemic osteonecrosis (ION) can produce permanent deformity and osteoarthritis in the femoral head and other joints. No biologic treatment has been established, and the molecular mechanisms involved in the pathogenesis of ION have not been elucidated. In this work, we found that treatment with sirtuin6 (Sirt6) suppressed inflammatory cytokines, bone resorption, progression of osteoarthritis, and reduced bone deformity in an ION mouse model. We used a deacetylase mutant adenovirus to confirm that those effects were caused by the deacetylase function of Sirt6. Among the osteoclastogenic factors of osteoblasts, only the receptor activator of NF-κb ligand (RANKL) level changed in response to Sirt6 knockout in primary osteoblasts. In particular, the vitamin D receptor physically interacted with Sirt6 and induced recruitment of Sirt6 around RANKL promoters. Finally, Tg mice overexpressing Sirt6 resisted osteocyte death, bone resorption, and progression of osteoarthritis after ischemic surgery, whereas osteoblast/osteocyte-specific Sirt6 knockout mice showed aggravated bone loss and severe deformity. Our findings demonstrate that administration of Sirt6 prevents bone loss and osteoarthritis in ischemic conditions. Activation of Sirt6 in osteoblasts/osteocytes could be a new therapeutic approach to treating ION of the femoral head and other bone regions. © 2020 American Society for Bone and Mineral Research (ASBMR).

Inhibition of SIRT6 potentiates the anti-tumor effect of doxorubicin through suppression of the DNA damage repair pathway in osteosarcoma.

BACKGROUND: SIRT6 has diverse roles in cells, and the role of SIRT6 in tumorigenesis is controversial. Considering the role of SIRT6 as an inducer of DNA damage repair, it might be involved in resistance to anti-cancer therapy. METHODS: We evaluated the prognostic significance of SIRT6 in 37 osteosarcomas and investigated the therapeutic efficacy of SIRT6 on the anticancer effects of doxorubicin, olaparib, and ATM inhibitor. RESULTS: Immunohistochemical expression of SIRT6 was significantly associated with shorter overall survival and relapse-free survival of osteosarcoma patients, especially in patients who received adjuvant chemotherapy. In U2OS and KHOS/NP osteosarcoma cells, knock-down of SIRT6 significantly potentiated apoptotic effects of doxorubicin and SIRT6 overexpression induced resistance to doxorubicin. Moreover, SIRT6 induced the DNA damage repair pathway and SIRT6-mediated resistance to doxorubicin was attenuated by blocking the DNA damage repair pathway with olaparib and ATM inhibitor. CONCLUSIONS: This study suggests that suppression of SIRT6 in combination with doxorubicin might be an effective modality in the treatment of osteosarcoma patients, especially for osteosarcomas with shorter survival with high expression of SIRT6.

Poly (ADP-Ribose) Polymerase Inhibitor Treatment as a Novel Therapy Attenuating Renal Ischemia-Reperfusion Injury.

Intrarenal robust inflammatory response following ischemia-reperfusion injury (IRI) is a major factor in the pathogenesis of renal injury in ischemic acute kidney injury (AKI). Although numerous studies have investigated various agents of immune modulation or suppression for ischemic AKI, few showed reproducible effects. We hypothesized that poly (ADP-ribose) polymerase (PARP) inhibitor may favorably change post-ischemic intrarenal immunologic micromilieu by reducing damage-associated molecular pattern (DAMP) signals and improve renal outcome in ischemic AKI. The effects of JPI-289 (a PARP inhibitor) on early renal injury in a murine IRI model and hypoxic HK-2 cell model were investigated. Bilateral IRI surgery was performed in three groups of 9-week-old male C57BL/6 mice (control, JPI-289 50 mg/kg, and JPI-289 100 mg/kg; n = 9-10 in each group). Saline or JPI-289 was intraperitoneally injected. Renal function deterioration was significantly attenuated in the JPI-289 treatment groups in a dose-dependent manner. Inflammatory cell infiltration and proinflammatory cytokine/chemokine expressions in the post-ischemic kidneys were also attenuated by JPI-289 treatment. JPI-289 treatment at 0.5 and 0.75 µg/ml facilitated the proliferation of hypoxic HK-2 cells. PARP inhibition with JPI-289 treatment showed favorable effects in ischemic AKI by attenuating intrarenal inflammatory cascade in a murine model and facilitating proliferation of hypoxic HK-2 cells.

Myositis ossificans of the thigh causing external compression of the superficial femoral artery and vein: A case report.

RATIONALE: Myositis ossificans (MO) is a benign condition characterized by heterotopic bone formation in the skeletal muscle of extremities. Marked variation can occur in the incidence and location of the bone formed as well as resulting complications. Femoral vessel obstruction caused by MO is an extremely rare but disabling complication. Arterial occlusion may aggravate ischemic conditions, resulting in necrosis in the lower extremity. PATIENT CONCERNS: We report a 41-year-old female with progressive pain and swelling of the right thigh region for 1 year. DIAGNOSES: We diagnosed it as obstruction of the superficial femoral artery and vein caused by external compression of the MO between the sartorius and vastus medialis of the thigh. INTERVENTIONS AND OUTCOMES: Adherent tissues and mass were excised with care without damaging the femoral artery or the vein. However, normal morphology did not recover due to loss of elasticity of femoral vessels. Therefore, after resection of the narrowed region of the femoral artery, a femoral-to-femoral graft interposition using the greater saphenous vein was performed. At 12 months after the surgery, vessel reconstruction computed tomography images confirmed normal continuous flow of the femoral artery. LESSONS: Vascular compression and peripheral inflammatory response due to MO can cause loss of normal vascular morphology. Surgical excision of the mass and the involved femoral artery segment followed by femoral arterial reconstruction should be considered for lesions that do not spontaneously regress to prevent functional impairment and secondary complications in extremities.

Treatment Outcomes at Skeletal Maturity after Calcaneo-Cuboid-Cuneiform Osteotomy for Symptomatic Flatfoot Deformity in Children.

BACKGROUND: The purpose of this study was to evaluate clinical and radiological outcomes at skeletal maturity after a calcaneo-cuboid-cuneiform osteotomy (triple C osteotomy) for symptomatic flatfoot deformity compared with healthy young adult controls. METHODS: Nineteen patients (30 feet) who undergone a triple C osteotomy for idiopathic symptomatic flatfeet from July 2006 to April 2013 were compared with 19 controls (38 feet). Radiographic measurements at preoperative examination, 1-year postoperative follow-up, and follow-up at skeletal maturity were evaluated. Functional outcomes were assessed by using the validated visual analog scale foot and ankle (VAS-FA) and the modified American Orthopaedic Foot and Ankle Surgery (AOFAS) score. RESULTS: In the triple C osteotomy group, 11 of 12 radiographic measurements were significantly improved at 1 year postoperatively and the last follow-up (p < 0.001). There was no recurrence at skeletal maturity (p > 0.05). There were no significant differences in nine of 12 radiographic measurements between the triple C osteotomy group at maturity and the control group (p > 0.05). Average VAS-FA and AOFAS scores were significantly improved at the time of skeletal maturity (p < 0.001). CONCLUSIONS: Surgical correction of symptomatic flatfoot deformity in childhood resulted in favorable outcomes after the triple C osteotomy. Deformity correction was also maintained during follow-up at skeletal maturity.

Metformin coordinates osteoblast/osteoclast differentiation associated with ischemic osteonecrosis.

In this study, we aimed to identify a candidate drug that can activate endogenous Angiopoietin 1 (Ang1) expression via drug repositioning as a pharmacological treatment for avascular osteonecrosis. After incubation with 821 drugs from the Food and Drug Administration (FDA)-approved drug library, Ang1 expression in U2OS cell culture media was examined by ELISA. Metformin, the first-line medication for treatment of type 2 diabetes, was selected as a candidate for in vitro and in vivo experimental evaluation. Ang1 was induced, and alkaline phosphatase activity was increased by metformin treatment in U2OS and MG63 cells. Wound healing and migration assay showed increased osteoblastic cell mobility by metformin treatment in U2OS and MG63 cells. Metformin upregulated expression of protein markers for osteoblastic differentiation in U2OS and MG63 cells but inhibited osteoclastic differentiation in Raw264.7 cells. Metformin (25 mg/kg) protected against ischemic necrosis in the epiphysis of the rat femoral head by maintaining osteoblast/osteocyte function and vascular density but inhibiting osteoclast activity in the necrotic femoral head. These findings provide novel insight into the specific biomarkers that are targeted and regulated by metformin in osteoblast differentiation and contribute to understanding the effects of these FDA-approved small-molecule drugs as novel therapeutics for ischemic osteonecrosis.

Squamous cell carcinoma of the renal pelvis presenting as an integumentary neoplasm of the flank: A case report.

RATIONALE: Although chronic pyelonephritis and urolithiasis are established risk factors for squamous cell carcinoma (SCC), only a minority of patients with chronic urolithiasis eventually develop SCC. It is believed that the chronic irritation leads to squamous cell metaplasia that may subsequently develop into SCC. Although studies show that SSC generally spreads locally with associated symptoms of lymphadenopathy, metastasis to the lungs and liver have also been reported. However, cases spreading to the flank have yet to be reported. Therefore, the use of reconstructive techniques for the repair of extensive soft tissue defects in the flank region after extended retroperitoneal resection, is unknown. PATIENT CONCERNS: We report a 54-year-old man who presented with a 1-month history of an enlarged skin mass on the right flank. DIAGNOSES: The patient was subsequently diagnosed with metastatic SCC involving the patient's integumentary system near the flank region proximal to the right kidney following percutaneous nephrostomy. INTERVENTIONS: The skin mass and the surrounding muscle tissue of the right flank were excised with a wide resection margin including radial nephrectomy. The soft tissue defect after resection was reconstructed using a unilateral gluteus maximus myocutaneous V-Y advancement flap. OUTCOMES: No recurrence of the SSC was found on follow-up CT performed 12 months postoperatively. LESSONS: In patients with long-standing nephrolithiasis complicated by staghorn stone-related infections, biopsies from suspicious lesions detected during percutaneous nephrolithotomy may facilitate early diagnosis. The modified gluteus maximus V-Y advancement flap may be a useful technique for the reconstruction of extensive soft-tissue defects involving the flank region.

FAM83H is involved in stabilization of ß-catenin and progression of osteosarcomas.

BACKGROUND: FAM83H was initially identified as a protein essential for dental enamel formation. Recent reports have shown that FAM83H is also involved in the progression of human cancers in conjunction with tumor-associated molecules, such as MYC and ß-catenin. However, the role of FAM83H in sarcoma has not yet been investigated. METHODS: The expression and roles of FAM83H and ß-catenin were evaluated in human osteosarcomas from 34 patients and osteosarcoma cells. RESULTS: The expression of nuclear FAM83H, cytoplasmic FAM83H, and ß-catenin were significantly associated with each other and significantly associated with shorter survival of osteosarcoma patients by univariate analysis. In multivariate analysis, cytoplasmic expression of FAM83H was an independent indicator of shorter survival of osteosarcoma patients (overall survival; P <  0.001, relapse-free survival; P <  0.001). In U2OS, MG63, and KHOS/NP osteosarcoma cells, the knock-down of FAM83H decreased proliferation and invasion activity and overexpression of FAM83H increased proliferation and invasion activity. In KHOS/NP cells, knock-down of FAM83H significantly inhibited, and overexpression of FAM83H significantly increased in vivo growth of cells. In addition, the knock-down of FAM83H decreased protein expression of ß-catenin, active ß-catenin, cyclin D1, vimentin, and snail. Overexpression of FAM83H increased protein expression of ß-catenin, active ß-catenin, cyclin D1, vimentin, and snail. However, the expression of ß-catenin mRNA was not significantly altered with knock-down or overexpression of FAM83H. In addition, FAM83H and ß-catenin shown to directly interact via immunoprecipitation and nuclear and cytoplasmic localization of ß-catenin was decreased with knock-down of FAM83H. Moreover, the ubiquitination and proteasomal degradation of ß-catenin was increased with knock-down of FAM83H. CONCLUSIONS: This study suggests that FAM83H is involved in the progression of osteosarcomas via a mechanism involving the stabilization of ß-catenin and the promotion of proliferation and invasiveness of osteosarcomas.

Sirtuin 6 in preosteoclasts suppresses age- and estrogen deficiency-related bone loss by stabilizing estrogen receptor α.

Emerging evidence indicates that estrogen receptor (ER) α is an important modulator of bone homeostasis, which occurs partly by promoting osteoclast apoptosis. Sirtuin 6 (Sirt6) is an anti-aging molecule, and its deficiency in mice results in skeletal malformations associated with progeroid features. However, the effects of Sirt6 on ERα function in osteoclasts, and thus on aging- or estrogen deficiency-induced bone loss, have not been studied. Here, we show that myeloid-specific deletion of Sirt6 led to decreased ERα protein level and apoptotic cell death in preosteoclasts. Consequently, myeloid Sirt6 KO mice showed aggravated cancellous bone loss both with aging and following an ovariectomy compared to wild-type littermates. In contrast, Sirt6 transgenic mice were protected from ovariectomy-induced bone loss. Mechanistically, Sirt6 deacetylated ERα protein to prevent its proteasomal degradation, in which lysine 171 and lysine 299 were critical residues. Sirt6-mediated ERα stabilization promoted transcription of Fas ligand in preosteoclasts, resulting in apoptosis of osteoclasts. Finally, the level of Sirt6 in human preosteoclasts was correlated positively with bone density and ERα but negatively with age. In conclusion, our results suggest that deacetylation and upregulation of ERα by Sirt6 in preosteoclasts prevent bone loss by inhibiting osteoclast-mediated bone resorption. Activation of Sirt6 in preosteoclasts may provide a new therapeutic approach to attenuate osteoporosis in older or postmenopausal patients.

Effect of surgical approach for contralateral side hip arthroplasty in below knee amputees: a retrospective cohort study.

BACKGROUND: The gluteus medius muscle plays a very important role in the stability of the gait, especially in patients with amputation of the lower limbs. Therefore, choosing the appropriate type of approach for hip arthroplasty is very important. Hence, this study aimed to compare the outcomes and complications between the anterolateral approach (ALA) and posterior approach (PA) for hip arthroplasty in patients with contralateral below knee amputation. METHODS: From January 1999 to November 2014, 67 patients who underwent hip arthroplasty with contralateral below knee amputation were retrospectively analyzed. The study subjects were divided into two groups: the PA group (33 cases) and the ALA group (34 cases). The results of the clinical functional recovery with Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) score, Harris Hip Score, and activity of daily living scale were compared between the two groups. During the follow-up period, complications related to gait such as fall, dislocation, and periprosthetic fractures (PPFs) were investigated. RESULTS: The Harris Hip Score (p = 0.024) and the activity of the daily living scale (p = 0.043) of the ALA group were significantly lower at 3 months compared to the PA group, but no significant difference was observed between the two groups from 6 months postoperatively to the last follow-up. The WOMAC score was not significantly different between the two groups. Within 3 months after surgery, falls occurred in 3 cases in the PA group and in 11 cases in the ALA group (p = 0.019) Dislocation and PPF were caused by prosthesis-related trauma. Two dislocations and 1 PPF occurred 8 years postoperatively in the PA group. PPF occurred in 3 patients in the ALA group, of which 2 occurred within 3 months after surgery. CONCLUSION: Orthopedic surgeons should pay particular attention in patients with hip arthroplasty on the contralateral side hip who had below knee amputation because functional recovery is delayed until 3 months after ALA compared with PA.

Mid-to long-term results of total hip arthroplasty after contralateral lower extremity amputation.

OBJECTIVE: There is limited literature concerning the outcomes and role of THA as a surgical option for amputee patients. The aim of this study is to determine the mid-to long-term survival and complication rates of cementless total hip arthroplasty (THA) in patients with contralateral below knee amputations. METHODS: A retrospective review of 54 patients with below knee amputation were perfomed who underwent THA for osteoarthritis of the contralateral hip over a 5-year period between 1999 and 2014. Patients were monitored for at least 5 years and assessed with the Harris Hip Score and activities of daily living scale and by evaluating migration or osteolysis around the acetabular cup and femoral stems (amputee group). The amputee group was compared with a control group (non-amputee group) with the same number of patients. RESULTS: Differences in the Harris Hip Score (p = 0.021) and activities of daily living scale (p = 0.043) between the two groups were statistically significant lower in the amputee group at 3 months after surgery. However, no differences were found between the groups from 6 months postoperatively to the last follow-up (Harris Hip Score p = 0.812, activities of daily living scale p = 0.885). Radiologically, any cups or stems showed no signs of migration or osteolysis. In the amputee group, dislocation was found in 1 patient 2 months after arthroplasty (p = 0.315) and long stem revision surgery were performed on two patients due to periprosthetic fracture (p = 0.153). CONCLUSIONS: THA performed on the contralateral side of patients with below knee amputation is considered to be an effective treatment with good clinical and radiological results at mid-to long-term follow-up. LEVEL OF EVIDENCE: Level IV, therapeutic study.

Mitoxantrone induces apoptosis in osteosarcoma cells through regulation of the Akt/FOXO3 pathway.

The outcome of chemotherapy for osteosarcoma have improved during the past decade and more patients have access to combination chemotherapy, but there has been no significant clinical progress in the patient survival rate. Recently, forkhead-box O3 (FOXO3) was identified as a pivotal transcription factor responsible for the transcriptional regulation of genes associated with suppression of cancer. The purpose of the present study was to screen small chemicals activating FOXO3 and elucidate their underlying mechanism. Using a drug discovery platform based on the phosphorylation status of FOXO3 in osteosarcoma cells, mitoxantrone (MTZ), a type of DNA-damaging agent, was selected as a possible FOXO3 activator from the food and drug administration-approved drug library. MTZ treatments significantly inhibited the phosphorylation level of Akt-pS473 and caused nuclear localization of FOXO3 in osteosarcoma cells. MTZ treatment inhibited proliferation in osteosarcoma cells in vitro, whereas silencing FOXO3 potently attenuates MTZ-mediated apoptosis in osteosarcoma cells. Taken together, the results indicated that MTZ induces apoptosis in osteosarcoma cells through an Akt/FOXO3-dependent mechanism.

The PARP inhibitor olaparib potentiates the effect of the DNA damaging agent doxorubicin in osteosarcoma.

BACKGROUND: PARP1 facilitates the recovery of DNA-damaged cells by recruiting DNA damage response molecules such as γH2AX and BRCA1/2, and plays a role in resistance to antitumor therapies. Therefore, PARP inhibition being evaluated as an anti-cancer therapy. However, there are limited studies regrading PARP inhibition in osteosarcoma. METHODS: We evaluated the expression of DNA damage response molecules in 35 human osteosarcomas and investigated the effects of co-treatment of the PARP inhibitor, olaparib, and doxorubicin in osteosarcoma cells. RESULTS: The expression patterns of PARP1, γH2AX, BRCA1, and BRCA2 were significantly associated with shorter survival of osteosarcoma patients. In osteosarcoma cells, knock-down of PARP1 and treatment of olaparib significantly inhibited proliferation of cells and induced apoptosis. Moreover, the anti-tumor effect was more significant with co-treatment of olaparib and doxorubicin in vitro and in vivo. CONCLUSIONS: This study suggests that combined use of a PARP inhibitor with doxorubicin, a DNA damaging agent, might be effective in the treatment of osteosarcoma patients, especially in the poor-prognostic subgroups of osteosarcoma expressing PARP1, γH2AX, or BRCA1/2.

An unusual mechanism of coracoid fracture in a beginner golfer.

Golfers may injure themselves as a result of repetitive asymmetrical loads exerted on the body by poor swing mechanics. If the repetitive sub-maximal loading is not removed, this repetitive loading will exceed the adaptive capacity of bone, eventually resulting in a stress fracture. Stress fracture of the scapula due to golfing is extremely rare. Only two cases of acromion fracture have been reported. A rare case of nontraumatic coracoid fracture in a 50-year-old female beginner golfer is reported here. The mechanism of injury is also discussed. Level of evidence Level IV.

Intra-articular osteochondroma of the posteroinferior femoral neck associated with hip joint osteochondromatosis: A case report.

Osteochondromas are usually extra-articular lesions originating from the metaphysis of long bones. Intra-articular osteochondromas may also occur, causing pain and discomfort and restricting the range of motion. Osteochondromas of the femoral neck are intra-articular lesions that are difficult to access for surgical resection, particularly when located posteriorly. We herein present a rare case of an intra-articular osteochondroma involving the posteroinferior aspect of the femoral neck associated with secondary synovial osteochondromatosis (SOC) of the hip joint in a 25-year-old woman. Determining the optimal treatment was difficult due to the high risk of avascular necrosis (AVN) following surgical excision. The patient was successfully treated with arthroscopic surgery and she remained in good condition at 2 years postoperatively, with a full range of motion of the hip joint, and without signs of limping, recurrence of the SOC, or AVN of the femoral head.