Nanopore DNA Sequencing Detected Chromothripsis-Induced PAFAH1B1::USP6 Rearrangement in Periosteal Solid Aneurysmal Bone Cyst Initially Diagnosed as Osteosarcoma.

An aneurysmal bone cyst (ABC) is a benign bone neoplasm that typically occurs during the first and second decades of life. ABC usually presents as a rapidly growing intramedullary expansile mass with multiple blood-filled cysts in the metaphysis of the long tubular bones. Here, we report a case of a periosteal solid ABC that was initially diagnosed as a high-grade surface osteosarcoma. A 10-year-old male was referred to our hospital for swelling and tenderness of the left upper arm. Radiography revealed periosteal mass without fluid-fluid levels. On performing open biopsy, the tumor showed hypercellular proliferation of uniform spindle to epithelioid cells with brisk mitotic activity (up to 12/2 mm2) and lace-like osteoid formation, which was diagnosed as a high-grade surface osteosarcoma. After one course of chemotherapy using adriamycin and cisplatin, peripheral sclerosis was conspicuous, which led to pathological review and revision of diagnosis as "possibly osteoblastoma." The patient was disease-free for 4 years after marginal resection and curettage. Retrospective nanopore DNA sequencing unexpectedly detected a PAFAH1B1::USP6 rearrangement. The fusion gene was further validated using reverse transcription-polymerase chain reaction and the diagnosis was revised to ABC. Chromothripsis involving chromosome 17 has also been identified. Methylation analysis classified the present tumor as an ABC or non-ossifying fibroma using t-distributed stochastic neighbor embedding and unsupervised hierarchical clustering. This case report highlights the utility of nanopore DNA sequencing for soft tissue and bone tumor diagnosis.

Metastasizing aneurysmal dermatofibroma initially diagnosed as angiosarcoma confirmed by CD63::PRKCD fusion gene detection with nanopore sequencing.

Dermatofibroma (DF) is a benign tumor that forms pedunculated lesions ranging in size from a few millimeters to 2 cm, usually affecting the extremities and trunks of young adults. Histopathologically, DF is characterized by the storiform proliferation of monomorphic fibroblast-like spindle cells. In addition to neoplastic cells, secondary elements such as foamy histiocytes, Touton-type giant cells, lymphoplasmacytes, and epidermal hyperplasia are characteristic histological features. Several histological variants, including atypical, cellular, aneurysmal, and lipidized variants, have been reported; cases with variant histologies are sometimes misdiagnosed as sarcomas. We present a case of metastasizing aneurysmal DF that was initially diagnosed as an angiosarcoma on biopsy. A 26-year-old woman was referred to our hospital with a gradually enlarging subcutaneous mass in her lower left leg. Positron emission tomography-computed tomography revealed high fluorodeoxyglucose uptake not only in the tumor but also in the left inguinal region. On biopsy, ERG and CD31-positive atypical spindle cells proliferated in slit-like spaces with extravasation, leading to the diagnosis of angiosarcoma. Histology of the wide-resection specimen was consistent with DF, and lymph node metastasis was also observed. Nanopore DNA sequencing detected CD63::PRKCD fusion and copy number gain, although CD63 was not included in the target region of adaptive sampling. This report highlights the importance of recognizing the unusual clinical, radiological, and pathological features of DF to avoid misdiagnosis, and the potential diagnostic utility of nanopore sequencer.

A multicentre retrospective study on extra-thoracic solitary fibrous tumour: preoperative MRI findings predict intraoperative findings and postoperative prognosis.

OBJECTIVE: The present study investigated the relationships between the preoperative and operative findings of solitary fibrous tumour (SFT) and between preoperative findings and prognosis. METHODS: We reviewed 50 SFT patients treated at our musculoskeletal oncology hospital group. We analyzed preoperative clinical findings, particularly MRI imaging findings, and intraoperative information as well as the relationship between preoperative findings and outcomes. RESULTS: Mean age was 48.9 years and the mean follow-up was 51.8 months. Prior to surgery, needle biopsy was performed on 27 patients and open biopsy on 14. T2-weighted images showed a high signal intensity in 24 patients and heterogeneous signal intensity in 20. Tumours had polylobular contours in 17 patients and smooth and round contours in 27. Collateral feeding vessels were detected in 22 patients. Gd-enhanced MRI was performed on 23 patients, and showed 15 with homogeneous enhancement and 8 with heterogeneous enhancement. Surgical times were significantly longer in patients with a retroperitoneal origin, a tumour of 10 cm or more, and polylobular-type tumours. Intraoperative blood loss was significantly greater in patients with a retroperitoneal origin and heterogeneous Gd-MRI-enhanced tumours. In histopathological evaluations, surgical margins were positive in 12 patients. Local recurrence was observed in one patient. Distant metastasis was noted in eight patients, four of whom had pulmonary metastases. Positive surgical margins were more common in polylobular-type tumours. Distant metastases were more likely to appear in patients with observable collateral feeding vessels and heterogeneous Gd-MRI enhancement. CONCLUSION: The present results suggest that preoperative clinical findings in SFT patients predict longer surgical times and the risk of increased intraoperative blood loss. Moreover, the risk of a positive surgical margin and postoperative distant metastases may be predicted based on preoperative MRI.

Optimal surgical margin for infiltrative soft tissue sarcomas: Assessing the efficacy of excising beyond the infiltration.

BACKGROUND: Tumor infiltration in soft tissue sarcoma (STS) is known to correlate with an inadequate surgical margin and poor local control. This study aims to determine whether the radiological infiltration (R-inf) in STS cor relates with histological infiltration (H-inf) and to devise methods to determine a resection margin for infiltrative STS. METHODS: We reviewed the medical records of 145 patients with high-grade STS. We measured the R-inf on short-T1 inversion recovery or gadolinium-enhanced fat-suppressed (GdFS) magnetic resonance imaging. In addition, we assessed H-inf as the infiltrative growth of atypical tumor cells. The local control rate (LCR) was assessed using the Kaplan-Meier method. RESULTS: A statistically significant positive correlation was found between H-inf and R-inf (P < 0.0001). The R-inf obtained from the GdFS images exhibited a stronger correlation with H-inf than that obtained from the short-T1 inversion recovery images. Univariate and multivariate analyses revealed that a positive H-inf significantly correlated with a poor LCR. Moreover, the contaminated margins, which included intrainfiltration margins, significantly correlated with a poor LCR compared with the wide margins. CONCLUSIONS: R-inf as assessed by the GdFS images significantly correlates with H-inf, suggesting that we should exercise the infiltrative STS beyond their R-infs detected by the GdFS images.

Efficacy of nerve growth factor antibody in a knee osteoarthritis pain model in mice.

BACKGROUND: Nerve growth factor (NGF) is not only an important factor in nerve growth but also a major contributor to the production of inflammation. It has been reported that inhibiting NGF could reduce several types of pain in several animal models. Here, we aimed to clarify the efficacy of NGF antibody in a knee osteoarthritis (OA) pain model in mice. METHOD: Six-week-old male C57BR/J mice were used (n = 30). Ten mice comprised the control group, which received saline injection into the right knee joints; the other 20 mice comprised the experimental group, which received monoiodoacetate (MIA) injection into the right knee joints. Three weeks after surgery, the 20 experimental mice were randomly placed into treatment groups which received either sterile saline (non-treat group: 10 mg/kg, i.p.) or an anti-NGF antibody (anti-NGF group: 10 mg/kg, i.p.). Simultaneously, all mice received fluorogold (FG) retrograde neurotracer injection into their right joints. In a behavioral study, we evaluated gait using the CatWalk quantitative gait analysis system before surgery, 3 weeks after surgery (before treatment), 4 weeks after surgery (one week after surgery), and 5 weeks after surgery (2 weeks after surgery). In immunohistochemical analysis, the right dorsal root ganglia (DRGs) from the L4-L6 levels were resected 5 weeks after surgery (2 weeks after surgery). They were immunostained for calcitonin gene-related peptide (CGRP), and the number of FG-labeled or CGRP-immunoreactive (IR) DRG neurons was counted. RESULTS: On gait analysis using the CatWalk system, duty cycle, swing speed, and print area were decreased in non-treat group compared with those in control group and improved in the anti-NGF group compared with those in non-treat group. CGRP expression in DRGs was up-regulated in non-treat group compared with that in control group and suppressed in the anti-NGF group compared with that in non-treat group (both p < 0.05). CONCLUSIONS: MIA injection into the knee joint induced gait impairment and the up-regulation of CGRP in DRG neurons in a knee OA pain model in mice. Intraperitoneal injection of anti-NGF antibody suppressed this impairment of gait and up-regulation of CGRP in DRG neurons. These finding suggest that anti-NGF therapy might be valuable in the treatment of OA pain in the knee.

Muscle injury in rats induces upregulation of inflammatory cytokines in injured muscle and calcitonin gene-related peptide in dorsal root ganglia innervating the injured muscle.

INTRODUCTION: In this study we evaluated the relationships among the behavioral changes after muscle injury, histological changes, changes in inflammatory cytokines in the injured muscle, and changes in the sensory nervous system innervating the muscle in rats. METHODS: We established a model of muscle injury in rats using a dropped weight. Behavior was assessed using the CatWalk system. Subsequently, bilateral gastrocnemius muscles and dorsal root ganglia (DRGs) were resected. Muscles were stained with hematoxylin and eosin, and inflammatory cytokines in injured muscles were assayed. DRGs were immunostained for calcitonin gene-related peptide (CGRP). RESULTS: Changes of behavior and upregulation of inflammatory cytokines in injured muscles subsided within 2 days of injury. Repaired tissue was observed 3 weeks after injury. However, upregulation of CGRP in DRG neurons continued for 2 weeks after injury. CONCLUSION: These findings may explain in part the pathological mechanism of persistent muscle pain. Muscle Nerve 54: 776-782, 2016.

Single Intradiscal Administration of the Tumor Necrosis Factor-Alpha Inhibitor, Etanercept, for Patients with Discogenic Low Back Pain.

OBJECTIVE: To examine the analgesic effect of intradiscal administration of a tumor necrosis factor-αα (TNF-α) inhibitor in patients with discogenic low back pain (LBP). DESIGN: Prospective, randomized study. SETTING: Department of Orthopaedic Surgery, Chiba (Japan) University Hospital. SUBJECTS: Seventy-seven patients diagnosed with discogenic LBP. METHODS: Discogenic LBP patients were randomly assigned to the etanercept (n = 38; bupivacaine [2 mL] with etanercept [10 mg]) or control (n = 39; bupivacaine [2 mL]) groups. Patients received a single intradiscal injection. Numerical rating scale (NRS) scores for LBP at baseline, 1 day, and 1, 2, 4, and 8 weeks after the injection were recorded. The Oswestry disability index (ODI) scores at baseline and at 4 and 8 weeks after injection were evaluated. Postinjection complications were recorded and evaluated. RESULTS: In the etanercept group, the NRS scores were significantly lower than in the control group at every time point after the injection for 8 weeks (P < 0.05). Similarly, 4 weeks after the injection, the ODI score was lower in the etanercept group than in the control group (P < 0.05). However, the ODI scores were not significantly different at 8 weeks. Complications were not observed. CONCLUSIONS: Single intradiscal administration of a TNF-α inhibitor can alleviate intractable discogenic LBP for up to 8 weeks. TNF-α may be involved in discogenic pain pathogenesis. This procedure is a novel potential treatment; longer-term effectiveness trials are required in the future.

Marriage and fertility in long-term survivors of childhood, adolescent and young adult (AYA) high-grade sarcoma.

PURPOSE: We investigated the marital status and the presence or absence of children in survivors of childhood, adolescent and young adult (AYA) high-grade sarcoma and examined the influence of these factors on the quality of life (QOL) of these survivors. METHODS: Thirty-eight survivors of childhood and AYA high-grade sarcoma (18 males, 20 females) participated in a questionnaire survey on marital status and presence or absence of children, as well as on the health-related QOL (HR-QOL), using the Short Form 36 Health Survey. Diagnoses among these survivors were osteosarcoma (28 participants), Ewing's sarcoma (4 participants), synovial sarcoma (4 participants) and others (2 participants). RESULTS: Of the 18 males who participated in the survey, eight (44.4 %) were married, of whom five (62.5 %) had children. Fifteen (75.0 %) of the 20 females were married, of whom 14 (93.3 %) had children. The proportions of surviving male patients who were married and who had children, respectively, were lower than those of surviving female patients. The proportion of ifosfamide-treated men with children was significantly lower than that of non-ifosfamide-treated men (p = 0.018). With respect to the relationship between marital status and HR-QOL, the scores for the vitality and mental health domains of the SF-36 of survivors who were married were significantly higher than those of unmarried survivors. CONCLUSIONS: The results of our questionnaire survey reveal that among the male survivors of high-grade sarcoma, the proportions of those who were married and of those with children were lower than those of female survivors, suggesting that strategies providing support for marriage and child-rearing may be necessary for the male survivor group. In the married group, mental QOL was high.

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.

BACKGROUND: 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. METHODS: This study retrospectively examined 1070 patients treated with neoadjuvant chemotherapy and surgery for nonmetastatic osteosarcoma. Data from Japanese patients (n = 557) were used to develop multivariate nomograms based on Cox regression. Six clinical and pathologic variables were built into nomograms estimating the probability of MFS and OAS 3 and 5 years after diagnosis. The model was internally validated for discrimination and calibration with bootstrap resampling and was externally validated with an independent patient cohort from Korea (n = 513). RESULTS: A patient's age, tumor site, and histologic response were found to have a stronger influence on MFS and OAS in the model than sex, tumor size, or pathologic fracture. The nomograms and calibration plots based on these results well predicted the probability of MFS (concordance index, 0.631) and OAS (concordance index, 0.679). The concordance indices for external validation were 0.682 for MFS and 0.665 for OAS. CONCLUSIONS: The nomograms were externally validated and verified to be useful for the prediction of MFS and OAS and for the assessment of the postoperative prognosis. They can be used for counseling patients and for establishing appropriate surveillance strategies after surgery.

Oligo-Recurrence of Osteosarcoma Patients: Treatment Strategies for Pulmonary Metastases.

BACKGROUND: Distant metastases from osteosarcoma most commonly occur in the lungs. Osteosarcoma can be cured by complete surgical resection of all metastatic lesions if the number is limited (oligo-recurrence: ≤ 5 metastatic or recurrent lesions with controlled primary lesions). This study aimed to clarify the prognostic factors for osteosarcoma patients with pulmonary metastasis and determine their oligo-recurrence status. METHODS: Patients with conventional osteosarcoma who underwent definitive surgery for the primary lesion and at least one thoracotomy for pulmonary metastases were recruited to this retrospective study. Clinicopathological information was collected on each thoracotomy from 1976 to 2011, and was then analyzed statistically. We counted the number of resected nodules that were pathologically confirmed as metastatic lesions from osteosarcoma. RESULTS: In total, 151 thoracotomies in 71 patients were analyzed. Forty-seven patients (66 %) underwent up to two thoracotomies, and the maximum number of thoracotomies was six. The median number of resected nodules on each thoracotomy was two, and the median total size of metastatic lesions was 20 mm. Incomplete surgical remission [relative risk (RR) 3.42], a less than 1-year interval from a previous thoracotomy (RR 1.97), more than three resected nodules (RR 2.42); and total size of more than 30 mm for pulmonary metastases (RR 2.19) were independent predictors of increased risk of tumor death by multivariate analysis. CONCLUSIONS: We propose that factors contributing to oligo-recurrence of patients with pulmonary metastatic osteosarcoma include complete surgical remission, an interval from a previous thoracotomy, number of resected nodules, and total size of pulmonary metastases.

The prognosis of osteosarcoma occurring as second malignancy of childhood cancers may be favorable: experience of two cancer centers in Japan.

BACKGROUND: Osteosarcoma as second malignancy of childhood cancers rarely occurs, and its clinical characteristics are unclear. METHODS: Patients with osteosarcoma occurring as second malignancy of childhood cancers were retrospectively surveyed. RESULTS: Of 323 patients with osteosarcoma registered in the database, 10 (3.1%) had a past history of childhood cancers. The mean age at the onset of the first childhood cancer was 2.7 years, and the diagnosis of the first childhood cancer was adrenocortical carcinoma, malignant teratoma, ovarian carcinoma, Ewing's sarcoma, and rhabdomyosarcoma in 1 patient each, and retinoblastoma in 5 patients. Osteosarcoma as second malignancy occurred 14.6 years after the first childhood cancer on average. Seven patients were alive and 3 died. In 1 patient, the cause of death was related to a complication of treatment for the first childhood cancer. Except for this patient, 7 (77.8%) of 9 patients survived with no disease (mean follow-up period: 10.9 years). CONCLUSIONS: Attention should be paid to complications of treatment for the first childhood cancer in the treatment for osteosarcoma occurring as second malignancy. The prognosis of osteosarcoma as second malignancy of childhood cancers may be more favorable than that of conventional osteosarcoma.

The prevalence and characteristics of low back pain among sitting workers in a Japanese manufacturing company.

BACKGROUND: Low back pain (LBP) is a major public health problem and the most common cause of workers' disability, resulting in substantial economic burden in terms of workers' compensation and medical costs. Sitting is a recognized potential risk factor for developing LBP. Therefore, eliminating risk factors associated with working conditions and individual work capacity may be beneficial in preventing LBP in sitting workers. The purpose of this prospective cross-sectional study is to investigate the prevalence of LBP and examine risk factors that contribute to the development of LBP in sitting workers at an electronics manufacturing company. METHODS: A cross-sectional survey was administered to all subjects to assess the prevalence of LBP persisting for at least 48 h during the recent week. Data on demographic characteristics and potential risk factors for LBP were collected at routine annual check-ups. Patients with LBP completed the Roland-Morris Disability Questionnaire (RDQ), which provided information on the attributes of LBP. Univariate and multivariate regression analyses examined the association between LBP and potential risk factors. RESULTS: Of the 1,329 sitting workers, 201 (15.1 %) acknowledged experiencing LBP during the recent week. In female workers, weight and body mass index were significantly correlated with the RDQ score. Univariate analyses identified male sex, prior history of LBP, height ≥170 cm, and weight ≥70 kg as significant risk factors of LBP. Multivariate logistic regression analyses identified prior history of LBP and past history of lumbar spine surgery as significant risk factors of LBP. CONCLUSIONS: This study characterized the prevalence and attributes of LBP in Japanese sitting workers and provided information about potential risk factors contributing to occurrence of LBP in the workplace.

Prognostic factors in elderly osteosarcoma patients: a multi-institutional retrospective study of 86 cases.

BACKGROUND: The occurrence of osteosarcoma in elderly patients has recently been increasing, and the outcome is poor. This multi-institutional retrospective study was conducted to investigate clinical features and prognostic factors in patients older than 40 years with osteosarcoma. METHODS: Patients with conventional high-grade osteosarcoma older than 40 years were recruited to this study. Secondary osteosarcoma arising from Paget's disease or irradiated bones was excluded. Information on tumor- and treatment-related factors was collected and statistically analyzed. The median follow-up was 57 months (range 8-244 months) for all surviving patients. RESULTS: A total of 86 patients were enrolled in this study. The median age at diagnosis was 61 years. Surgery and chemotherapy were conducted in 73 and 63 % of all patients, respectively. The 5-year overall and event-free survival rates were 38.8 and 34.0 %, respectively. Tumor site (extremity 57.9 %; axial 19.0 %; p < 0.0001), metastasis at diagnosis (yes 12.2 %; no 48.3 %; p < 0.0091), and definitive surgery (yes 56.2 %; no 10.6 %; p < 0.0001) were associated with overall survival. Although patients without metastasis who received definitive surgery were regarded as good candidates for chemotherapy, the addition of chemotherapy did not have any impact on the outcome (yes 63.4 %; no 65.2 %; p = 0.511). CONCLUSIONS: The present study revealed the distinct clinical features, such as the high incidence of truncal tumors or metastasis at diagnosis, in patients older than 40 years with osteosarcoma. Additionally, prognostic factor analyses revealed that tumor site, metastasis at diagnosis, definitive surgery, and surgical margins were significant prognostic factors, whereas chemotherapy did not influence survival.

Impact of infiltrative growth on the outcome of patients with undifferentiated pleomorphic sarcoma and myxofibrosarcoma.

BACKGROUND AND OBJECTIVES: Infiltrative growth, frequently observed in undifferentiated pleomorphic sarcoma (UPS) and myxofibrosarcoma (MFS), is often associated with a positive surgical margin as well as a local failure. The purpose of our study was to determine whether the radiographic growth patterns were associated with the outcomes of patients with UPS and MFS. METHODS: We reviewed 89 patients diagnosed with UPS or MFS and underwent initial surgery at our institute between 1994 and 2011. Growth patterns were assessed radiographically on preoperative MRI. Clinicopathological factors were collected and uni- and multivariate analyses were performed for survival. RESULTS: Infiltrative growth was observed in 21 patients (24%), which correlated with superficial tumors and positive surgical margin. Infiltrative growth correlated with poor disease-specific and distant failure-free survivals relative to non-infiltrative growth. Multivariate analysis confirmed that these factors remained as significant factors. Patients with non-infiltrative tumors resected inadequately exhibited slightly more favorable local control with postoperative radiotherapy, although no clinical benefit was seen for those with infiltrative tumors. CONCLUSIONS: Infiltrative growth was an adverse prognostic factor for not only local control, but also disease-specific and metastasis-free survival in patients with UPS and MFS. Radiotherapy could not salvage inadequately resected infiltrative tumors.

Evaluation of behavior and expression of NaV1.7 in dorsal root ganglia after sciatic nerve compression and application of nucleus pulposus in rats.

PURPOSE: The pathomechanisms of pain resulting from lumbar disc herniation have not been fully elucidated. Prostaglandins and cytokines generated at the inflammatory site produce associated pain; however, non-steroidal anti-inflammatory drugs and steroids are sometimes ineffective in patients. Tetrodotoxin-sensitive voltage-gated sodium (NaV) channels are related to sensory transmission in primary sensory nerves. The sodium channel NaV1.7 has emerged as an attractive analgesic target. The purpose of this study was to evaluate pain-related behavior and expression of NaV1.7 in dorsal root ganglia (DRG) after combined sciatic nerve compression and nucleus pulposus (NP) application in rats. METHODS: Rats were divided into three groups and underwent either sciatic nerve compression with NP for 2 s using forceps (n = 20), sham operation with neither compression nor NP (n = 20), or no operation (controls, n = 20). Mechanical hyperalgesia was measured every second day for three weeks using von Frey filaments. NaV1.7 expression in L5 DRG was examined 7 and 14 days after surgery using immunohistochemistry. The number of neurons immunoreactive for NaV1.7 was compared among the three groups. RESULTS: Mechanical hyperalgesia was found over the 14-day observation in the nerve compression plus NP application group, but not in the sham-operated or control groups (P < 0.05). NaV1.7 expression in L5 DRG was up-regulated in the nerve compression plus NP application group, compared with sham-operated and control rats (P < 0.01). CONCLUSIONS: Our results indicate that nerve compression plus NP application produces pain-related behavior. We conclude that NaV1.7 expression in DRG neurons may play an important role in mediating pain from sciatic nerves after compression injury and exposure to NP.

Risk factors for L5-S1 disk height reduction after lumbar posterolateral floating fusion surgery.

STUDY DESIGN: This is a retrospective study. OBJECTIVE: To investigate the risk factors for radiographic L5-S1 disk height reduction after lumbar posterolateral floating fusion surgery. SUMMARY OF BACKGROUND DATA: We investigated data from 86 patients (45 men) who underwent posterolateral floating fusion surgery from 2007 to 2010. The follow-up was from 2 to 6 years. The mean age of the patients was 65.4 years. METHODS: L5-S1 disk height was calculated and >2 mm reduction was defined as significant. Age, sex, height, weight, body mass index, number of fused levels, grade of disk degeneration, disk height and diameter, sacrolumbar alignment, alignment of fused level, achievement of union, and proximal adjacent segment disorder at final follow-up were compared. Univariate and multivariate logistic regressions were performed. RESULTS: L5-S1 disk height reduction occurred in 14 patients (30.2%). The number of fused levels was significantly greater (1.8±0.8 vs. 1.4±0.6) in patients without disk height reduction. Radiology showed a significant change of L1-S1 sacrolumbar alignment after surgery in patients without disk height reduction (0.3±6.6 vs. -4.5±7.6 degrees). The height of the disk posterior to the L5-S1 intervertebral disk before surgery was significantly greater (7.3±2.1 vs. 6.1±2.1 mm) in patients without disk height reduction. In multivariate logistic regression analysis, fusion of >3 levels was a significant risk factor for L5-S1 disk height reduction. CONCLUSIONS: In posterolateral floating fusion surgery, there was a higher risk of L5-S1 disk height reduction and consequent foraminal stenosis in patients with multiple-level fusion. Surgical methods and fusion levels should be chosen after considering their association with L5-S1 disk height reduction.

The Combination of Auranofin and Celecoxib Suppresses Local Synovial Sarcoma Progression In Vivo.

BACKGROUND/AIM: Synovial sarcoma (SS) is a rare malignant tumor with a poor survival rate. We previously reported that a combination of auranofin (AUR), a thioredoxin reductase inhibitor, and celecoxib (CE), an anti-inflammatory drug, significantly impedes the local progression of osteosarcoma (OS). However, the role of redox regulation in SS remains to be elucidated. This study aimed to investigate the efficacy of combined treatment of AUR and CE on the local progression of SS in vivo. MATERIALS AND METHODS: Nu/nu mice were implanted with the human SS cell line, Aska-SS, and treated with vehicle control, AUR, or a combination of AUR and CE (AUR-CE). Primary tumor size and weight were evaluated for the study duration and upon resection, respectively. Hematoxylin and eosin (H&E) and Ki-67 staining were performed to assess the local progression of SS. RESULTS: A statistically significant reduction in tumor size and weight was observed in the AUR- and AUR-CE-treated groups upon excision compared to that in the vehicle-treated group. The AUR-CE-treated group showed synergistic inhibition of local tumor growth. H&E staining of local SS tumors revealed decreased cell density and nuclear deformation in the AUR- and AUR-CE-treated groups compared to those in the vehicle-treated group. Immunohistochemical staining revealed a statistically significant decrease in Ki-67-positive cells in the AUR-CE-treated group compared to the vehicle-treated group. CONCLUSION: The combination of AUR and CE showed significant potential for delaying the local progression of SS. These findings support the repurposing of AUR and CE as early treatment options for SS.

Thioredoxin Reductase Inhibitor Suppresses the Local Progression of Rhabdomyosarcoma With PDX Models.

BACKGROUND/AIM: Chemoresistance in rhabdomyosarcoma (RMS) is associated with poor survival, necessitating the development of novel anticancer drugs. Auranofin (AUR), an anti-rheumatic drug, is a thioredoxin reductase (TXNRD) inhibitor with anticancer properties. Although patient-derived xenograft (PDX) models are essential for studying cancer biology, reports on sarcomas using the PDX model are scarce because of their rarity. This study aimed to investigate the effectiveness of AUR treatment in RMS using a PDX model to evaluate its impact on local progression. MATERIALS AND METHODS: A 20-year-old woman who was diagnosed with alveolar RMS was used to generate the PDX model. RMS PDX tumors were implanted in nude mice and divided into non-treated (vehicle) and treated (AUR) groups. Tumor volume and weight were evaluated, and immunohistochemical staining was performed to evaluate local progression of the sarcoma. The relationship between the TXNRD-1 expression and survival probability of patients with RMS was evaluated using publicly available expression cohorts. RESULTS: AUR significantly suppressed RMS tumor progression over time. It also significantly suppressed the tumor size and weight at the time of excision. Histological evaluation showed that AUR induced oxidative stress in the PDX mouse models and inhibited the local progression of RMS by inducing apoptosis. High TXNRD-1 expression was found to be a negative prognostic factor for overall survival in patients with RMS. CONCLUSION: AUR-induced inhibition of TXNRDs can significantly impede the local progression of RMS through the oxidative stress-apoptosis pathway as demonstrated in PDX models. Thus, targeting TXNRD inhibition may be a promising therapeutic strategy for the treatment of RMS.

Combined Auranofin and Celecoxib Suppresses the Local Progression and Pulmonary Metastases of Osteosarcoma In Vivo.

BACKGROUND/AIM: Osteosarcoma (OS) is a rare malignant tumor with a poor survival rate. Our previous study reported that auranofin (AUR), a thioredoxin reductase inhibitor, suppresses OS pulmonary metastases; however, the local progression of OS is not affected, in vivo. Nonetheless, the development of augmentation therapy with AUR to inhibit OS local progression remains challenging. Celecoxib (CE), an anti-inflammatory drug, potently enhances the therapeutic activity of AUR against colon cancer. Consequently, this study investigated the combined effects of AUR and CE on OS local progression and pulmonary metastases, in vivo. MATERIALS AND METHODS: C3H/HeSlc mice were implanted with the murine OS cell line, LM8. The mice were treated either with a vehicle control, AUR, or combination of AUR and CE (AUR-CE). The primary tumor size and weight were evaluated for the study duration and at resection, respectively. Hematoxylin and eosin and Ki-67 staining were performed to evaluate OS local progression and pulmonary metastases. RESULTS: Mice in the AUR-CE group showed statistically significantly suppressed tumor sizes and weights at the time of excision compared with those in the vehicle. The mice in the AUR group did not show a statistically significant effect. Histopathological analysis of the primary tumor revealed a statistically significant decrease of the Ki-67-positive cells in the AUR-CE group compared with the vehicle group. Histopathological and quantitative analyses demonstrated that the AUR and AUR-CE groups had statistically significant reductions in the development of OS pulmonary metastases compared with the vehicle group. CONCLUSION: The combination of AUR and CE significantly inhibited OS local progression and pulmonary metastases.

The diagnostic utility of cytology specimen in a case of EWSR1::NFATC2 sarcoma.

EWSR1::NFATC2 sarcoma, a rare round cell sarcoma constituting the majority of EWSR1::non-ETS sarcomas, has recently been defined in the latest WHO classification. To date, the cytological findings of EWSR1::NFATC2 sarcoma remain undocumented. We present the case of a 25-year-old man with a history of polyostotic fibrous dysplasia in the right leg, referred to our hospital with left thigh pain. Cytological findings included metachromasia, minimally pleomorphic round cells, and eosinophilic infiltration. There was no precursor fibrous dysplasia and the initial diagnosis was undifferentiated pleomorphic sarcoma. Following histologic review, we successfully performed immunocytochemistry and fluorescence in situ hybridization (FISH) on archival cytology specimens. The tumor cells were positive for NKX2-2, NKX3-1, and PAX7 and showed amplified 5' single signals of EWSR1 gene. Reverse transcriptase-polymerase chain reaction revealed an in-frame fusion of EWSR1 and NFATC2. This report describes the cytological features of EWSR1::NFATC2 sarcoma and highlights the diagnostic utility of archival cytology specimens.