C/EBP homologous protein deficiency inhibits statin-induced myotoxicity.

It has been well established that HMG-CoA reductase inhibitors (statins) cause adverse side effects in skeletal muscle ranging from mild to fatal myotoxicity upon dose, drug interaction, and exercise. However, the underlying mechanisms by which statins induce myotoxicity have not been fully addressed. Recent reports showed that statins induce endoplasmic reticulum (ER) stress and cell death in immune cells and myoblasts in vitro. Therefore, the goal of study is to investigate the molecular mechanism by which statins induce skeletal muscle cell death and myopathy via the regulation of ER stress. Biochemical data showed that TUDCA, an ER stress inhibitor, inhibited atorvastatin- and simvastatin-induced protein cleavages of PARP-1 and caspase-3, respectively. Actually, statin treatment activated marker proteins of unfolded protein responses (UPR) including ATF6, CHOP, and spliced XBP1 and these responses were inhibited by TUDCA. In addition, statin treatment induced mRNA levels of UPR marker genes, suggesting that statins activate ER stress in a transcriptional regulation. The physiological relevance of ER stress in statin-induced myopathy was demonstrated in a mouse model of myopathy, in which instillation of simvastatin and atorvastatin led to myopathy. Notably, the reduction of muscular endurance in response to statin instillation was significantly improved in TUDCA treating group compared to vehicle control group. Moreover, CHOP deficiency mice showed restoration of statin-induced reduction of muscular endurance, suggesting that statin induces myopathy via ER stress and in a CHOP-dependent manner. Taken together, these findings indicate that statins specifically induce myopathy in an ER stress-dependent manner, suggesting the therapeutic potential of ER stress regulation in preventing adverse effects of statin.

Arthroscopic Excision of Delayed Diagnosed Intra-articular Osteoid Osteoma of the Elbow: A Case Report.

An intra-articular osteoid osteoma is a very rare cause of elbow pain, and its diagnosis and treatment remain challenging. Delayed diagnosis may lead to arthritic change of the joint. In this study, the authors present the occurrence of intra-articular osteoid osteoma in the right elbow of a 15-year-old male patient who presented with prolonged pain and limited motion owing to delayed diagnosis. After confirming the nidus of osteoid osteoma from radiographic evaluation, the lesion was completely removed arthroscopically. The patient presented a complete relief of symptoms and full range of motion. This is the first domestic report of successful arthroscopic treatment of an intra-articular osteoid osteoma of the elbow.

The impact of generalized joint laxity (GJL) on the posterior neck pain, cervical disc herniation, and cervical disc degeneration in the cervical spine.

BACKGROUND CONTEXT: Generalized joint laxity (GJL) can have a negative impact on lumbar spine pathology, including low back pain, disc degeneration, and disc herniation, but the relationship between GJL and cervical spine conditions remains unknown. PURPOSE: To investigate the relationship between GJL and cervical spine conditions, including the prevalence of posterior neck pain (PNP), cervical disc herniation (CDH), and cervical disc degeneration (CDD), in a young, active population. STUDY DESIGN: Retrospective 1:2 matched cohort (case-control) study from prospectively collected data PATIENT SAMPLE: Of a total of 1853 individuals reviewed, 73 individuals with GJL (study group, gruop A) and 146 without GJL (control group, Group B) were included in the study according to a 1:2 case-control matched design for age, sex, and body mass index. OUTCOME MEASURE: The primary outcome measure was the prevalence and intensity of PNP at enrollment based on a visual analogue scale score for pain. The secondary outcome measures were (1) clinical outcomes as measured with the neck disability index (NDI) and 12-item short form health survey (SF-12) at enrollment, and (2) radiological outcomes of CDH and CDD at enrollment. METHODS: We compared baseline data between groups. Descriptive statistical analyses were performed to compare the 2 groups in terms of the outcome measures. RESULTS: The prevalence and intensity of PNP were significantly greater in group A (patients with GJL) than in group B (patients without GJL) (prevalence: p=.02; intensity: p=.001). Clinical outcomes as measured with NDI and SF-12 did not differ significantly between groups. For radiologic outcomes, the prevalence of CDD was significantly greater in group A than in group B (p=.04), whereas the prevalence of CDH did not differ significantly between groups (p=.91). CONCLUSIONS: The current study revealed that GJL was closely related to the prevalence and intensity of PNP, suggesting that GJL may be a causative factor for PNP. In addition, GJL may contribute to the occurrence of CDD, but not CDH. Spine surgeons should screen for GJL in patientswith PNP and inform patients of its potential negative impact on disc degeneration of the cervical spine.

Imprint cytology of soft tissue myoepithelioma: a case study.

Soft tissue myoepithelioma is a rare neoplasm composed of myoepithelial cells. Here, we describe the cytologic features of soft tissue myoepithelioma arising on the right forearm in an 18-year-old man. The excised tumor (3.0×1.8×1.5 cm) was well-demarcated, yellow-gray, soft, and myxoid. The cytologic smears showed round to spindle, epithelioid, and plasmacytoid cells in the myxoid background. The nuclei were uniform, round to ovoid, with finely distributed chromatin and eosinophilic or pale cytoplasm. The tumor cells demonstrated immunoreactivity for cytokeratin (AE1/AE3), epithelial membrane antigen, S100 protein, and glial fibrillary acidic protein. Electron microscopy showed intermediate filaments, desmosomes, and basal lamina.

Minimal invasive surgery for unicameral bone cyst using demineralized bone matrix: a case series.

BACKGROUND: Various treatments for unicameral bone cyst have been proposed. Recent concern focuses on the effectiveness of closed methods. This study evaluated the effectiveness of demineralized bone matrix as a graft material after intramedullary decompression for the treatment of unicameral bone cysts. METHODS: Between October 2008 and June 2010, twenty-five patients with a unicameral bone cyst were treated with intramedullary decompression followed by grafting of demineralized bone matrix. There were 21 males and 4 female patients with mean age of 11.1 years (range, 3-19 years). The proximal metaphysis of the humerus was affected in 12 patients, the proximal femur in five, the calcaneum in three, the distal femur in two, the tibia in two, and the radius in one. There were 17 active cysts and 8 latent cysts. Radiologic change was evaluated according to a modified Neer classification. Time to healing was defined as the period required achieving cortical thickening on the anteroposterior and lateral plain radiographs, as well as consolidation of the cyst. The patients were followed up for mean period of 23.9 months (range, 15-36 months). RESULTS: Nineteen of 25 cysts had completely consolidated after a single procedure. The mean time to healing was 6.6 months (range, 3-12 months). Four had incomplete healing radiographically but had no clinical symptom with enough cortical thickness to prevent fracture. None of these four cysts needed a second intervention until the last follow-up. Two of 25 patients required a second intervention because of cyst recurrence. All of the two had a radiographical healing of cyst after mean of 10 additional months of follow-up. CONCLUSIONS: A minimal invasive technique including the injection of DBM could serve as an excellent treatment method for unicameral bone cysts.

Tumor volume increase during preoperative chemotherapy as a novel predictor of local recurrence in extremity osteosarcoma.

BACKGROUND: Known risk factors (surgical margin, tumor necrosis) of local recurrence (LR) in osteosarcoma are determined by results available after surgery. However, relations between preoperative characteristics and LR have not been clearly defined. METHODS: We compared the clinicopathologic characteristics of 36 osteosarcoma patients with LR and 394 patients without LR after surgery. In addition, prognostic variables were evaluated to establish factors could influence LR. RESULTS: Compared to the non-LR group, the LR group showed an increase in tumor volume ratio (TVR) during preoperative chemotherapy (P < 0.01), inadequate surgical margin (P < 0.01), and poor histologic response (P < 0.01). Univariate analysis of data from 430 patients revealed that an increased TVR (P < 0.01), inadequate surgical margin (P < 0.01), poor histologic response (P < 0.01), and nonosteoblastic pathologic subtype (P = 0.04) were negatively related to LR-free survival. In multivariate analysis, an elevated TVR (P < 0.01, relative risk = 10.26) and inadequate surgical margin (P < 0.01, relative risk = 5.91) emerged as the key prognostic factors for LR. CONCLUSIONS: A TVR increase during preoperative chemotherapy could be used to predict patients at high risk of LR. This finding might be useful when considering surgical options to decrease the risk of LR.

Prediction model of chemotherapy response in osteosarcoma by 18F-FDG PET and MRI.

UNLABELLED: Response to neoadjuvant chemotherapy is a significant prognostic factor for osteosarcoma; however, this information can be determined only after surgical resection. If we could predict histologic response before surgery, it might be helpful for the planning of surgeries and tailoring of treatment. We evaluated the usefulness of (18)F-FDG PET for this purpose. METHODS: A total of 70 consecutive patients with a high-grade osteosarcoma treated at our institute were prospectively enrolled. All patients underwent (18)F-FDG PET and MRI before and after neoadjuvant chemotherapy. We analyzed the predictive values of 5 parameters, namely, maximum standardized uptake values (SUVs), before and after (SUV2) chemotherapy, SUV change ratio, tumor volume change ratio, and metabolic volume change ratio (MVCR) in terms of their abilities to discriminate responders from nonresponders. RESULTS: Patients with an SUV2 of less than or equal to 2 showed a good histologic response, and patients with an SUV2 of greater than 5 showed a poor histologic response. The histologic response of a patient with an intermediate SUV2 (2 < SUV2

Prognostic effect of inadvertent curettage without treatment delay in osteosarcoma.

BACKGROUND: Unplanned primary surgery has been known to have a negative prognostic impact in osteosarcoma. METHODS: We identified 20 osteosarcoma patients that had undergone inadvertent surgery followed by adequate treatment without delay, and compared the clinicopathologic characteristics of these 20 case patients with those of 365 patients who underwent incisional biopsy. For survival analysis, 40 control patients matched for tumor size at presentation, tumor location, age and gender were selected from these 365 patients. RESULTS: Unusual initial clinicopathologic characteristics were frequently observed in the case patients, such as, an older age, a small tumor size, an unusual tumor location, and a lytic radiographic pattern. The 5-year overall survival rate in the case group was 89.4 +/- 7.1% and in the control group was 83.9 +/- 6.1%, and the 5-year event-free survival rate in the case group was 90.0 +/- 6.7% and in the control group was 76.8 +/- 6.8%. The log rank test revealed no survival difference between the case and control groups. CONCLUSIONS: As is the case for soft tissue sarcoma, inadvertent extensive curettage with no ensuing treatment delay was found to have no detrimental effect on overall- or event-free survival in osteosarcoma. Further study using a larger sample size is needed to confirm our results.

Prognostic effects of doctor-associated diagnostic delays in osteosarcoma.

INTRODUCTION: In this retrospective study, we evaluated to what extent diagnostic delays impact prognosis in osteosarcoma. MATERIALS AND METHODS: The authors identified 26 osteosarcoma patients who had undergone inappropriate procedure-associated diagnostic delays of more than 45 days after surgery, calculated overall survival rates, and analyzed clinicopathologic characteristics. RESULTS: Initial clinical impressions were of a benign bone tumor in 15 patients, fracture in 8, and infection in 3. After initial inappropriate procedures, primary surgeons failed to send a tissue sample to a pathologist for definite diagnosis in 12 cases, and pathologists made incorrect diagnoses in the other 14. The average doctor-associated diagnostic delay after inappropriate surgery for these 26 patients was 10.5 months. Following referral to our institute, 22 underwent both surgery and chemotherapy and the remaining 4 patients underwent chemotherapy only. Four of the 26 patients were alive at last follow-ups. Estimated 5- and 10-year overall survival rates were 26 and 10%, respectively. CONCLUSIONS: The present study shows that doctor-associated diagnostic delay superimposed on an inappropriate primary procedure has a significant detrimental effect on overall survival in osteosarcoma. This study demonstrates that surgeons and pathologists should spare no effort to minimize diagnostic errors and delays.

Growth patterns of osteosarcoma predict patient survival.

INTRODUCTION: In this retrospective study, we assessed tumor growth patterns as visualized on MR images, and examined whether tumor growth patterns correlate with clinicopathologic variables. In addition, we also evaluated the relationship between patient outcome and tumor growth pattern in the whole study cohort and in subsets of AJCC IIA and IIB patients. MATERIALS AND METHODS: We retrospectively reviewed 347 patients with Enneking stage IIB and AJCC stage II osteosarcoma that was treated with surgery and neoadjuvant chemotherapy at our institute. Patients were divided into three groups based on tumor growth pattern, namely, concentric, eccentric, and longitudinal groups. Fisher's exact test was performed to analyze correlations between tumor growth patterns and clinicopathological variables. Five-year metastasis-free survival and overall survival were evaluated using univariate and multivariate analyses. RESULTS: In terms of tumor growth patterns, 225 patients (64.8%) had a concentric, 71 (20.5%) an eccentric and 51 (14.7%) a longitudinal tumor. Eccentric tumors were usually small and responded well to chemotherapy, whereas concentric tumors were large and responded poorly. The prognostic significances of tumor growth patterns were confirmed by univariate and multivariate analyses. Among AJCC stage IIA patients, no survival difference was found according to growth pattern, whereas in AJCC stage IIB patients, longitudinal tumors were associated with significantly better survival than concentric tumors. CONCLUSIONS: Tumor growth pattern was found to be an independent prognostic factor in stage II osteosarcoma. Moreover, longitudinally growing tumors were associated with better survival in AJCC stage IIB patients. Our results suggest that tumor growth pattern could be used as an indicator of risk-adapted therapy when combined with other prognostic factors.

The clinical efficacy of (18)F-FDG-PET/CT in benign and malignant musculoskeletal tumors.

OBJECTIVE: Most of the current clinical data on the role of 2-[(18)F]fluoro-2-deoxy-D -glucose positron emission tomography ((18)F-FDG-PET) in musculoskeletal tumors come from patients studied with PET and less frequently with hardware fusion PET/computed tomography (CT). And the number of cases in each report is too small to clarify the exact clinical efficacy of PET or PET/CT. This prompted us to analyze our experience with (18)F-FDG-PET/CT in a relatively large group of patients with musculoskeletal tumors. METHODS: (18)F-FDG-PET/CT was performed on 91 patients from May 2004 to June 2007. The final diagnosis was obtained from surgical biopsy in 83 patients (91%) and clinical follow-up in 8 (9%). We analyzed the characteristics and amount of (18)F-FDG uptake in soft tissue and bone tumors, and investigated the ability of (18)F-FDG-PET/CT to differentiate malignant from benign tumors. The cutoff maximum standardized uptake value (SUV(max)) was calculated using the receiver-operation characteristic curve method. Sensitivity, specificity, and diagnostic accuracy were calculated with cutoff SUV(max) and the final diagnosis. Unpaired t test was used for the statistical analysis. RESULTS: Final diagnosis revealed 19 benign soft tissue tumors (mean SUV(max) 4.7), 27 benign bone tumors (5.1), 25 malignant soft tissue tumors (8.8), and 20 malignant bone tumors (10.8). There was a significant difference in SUV(max) between benign and malignant musculoskeletal tumors in total (P < 0.002), soft tissue tumors (P < 0.05), and bone tumors (P < 0.02). Sensitivity, specificity, and diagnostic accuracy were 80%, 65.2%, and 73% in total with cutoff SUV(max) 3.8, 80%, 68.4%, and 75% in the soft tissue tumors with cutoff SUV(max) 3.8, and 80%, 63%, and 70% in the bone tumors with cutoff SUV(max) 3.7. CONCLUSIONS: (18)F-FDG-PET/CT reliably differentiated malignant soft tissue and bone tumors from benign ones, although there were many false-positive and false negative lesions. Further studies with all kinds of musculoskeletal tumors in large numbers are needed to improve the diagnostic accuracy of (18)F-FDG-PET/CT.

An examination of the efficacy of the 8 cm maximal tumor diameter cutoff for the subdivision of AJCC stage II osteosarcoma patients.

BACKGROUND: In the revised AJCC staging system a maximal tumor diameter of 8 cm was adopted as a cutoff for the subdivision of IIA and IIB osteosarcoma, but this cutoff was chosen based on limited information. METHODS: We retrospectively reviewed 347 patients with stage II osteosarcoma that were treated at our institute. We plotted a receiver operating characteristic (ROC) curve of maximal tumor diameter for the prediction of subsequent metastasis, and calculated diagnostic indices according for different cutoffs. RESULTS: A maximal tumor diameter greater than 8 cm was found to predict subsequent metastasis with a sensitivity of 76.3%, a specificity of 49.5%, and a positive predictive value of 49.0% Almost half of stage IIB patients subsequently developed metastasis, whereas only a quarter of stage IIA patients did so. Tumor size had no prognostic relevance for proximal humeral tumors. CONCLUSIONS: The present study shows that an 8 cm maximal tumor diameter cutoff is useful for subdividing AJCC stage II osteosarcoma patients in terms of predicting of a subsequent metastatic event. Our results suggest that the IIA and IIB subdivision in the AJCC staging system provides a basis for risk-adapted therapy when used in combination with other prognostic factors.

Subungual keratoacanthoma: ultrasound and magnetic resonance imaging findings.

Subungual keratoacanthoma is a rare, squamoproliferative neoplasm arising at the nail bed. It may cause erosion of the underlying bone. We report a case of subungual keratoacanthoma of the right thumb in a 63-year-old man. Radiographs showed cortical erosion of the distal phalanx of the right thumb. Ultrasonography showed a mixed echoic tumor. On magnetic resonance imaging (MRI), the tumor showed intermediate signal intensity on T1-weighted images and mixed intermediate and high signal intensity on T2-weighted images with peripheral thin rim enhancement.

Osteoblastoma as a cause of osteomalacia assessed by bone scan.

A 27-year-old female patient was admitted to our hospital with a history of leg pain and mass. She had a benign osteoblastoma in right tibia. Resection of the tumor without treatment by vitamin D antagonist resulted in rapid cure of the osteomalacia. Bone scintigraphy with Tc-99m MDP revealed multiple hot uptakes in initial scan, and follow up scan showed a clear resolution of the lesions.