An optimal promoter regulating cytokine transgene expression is crucial for safe and effective oncolytic virus immunotherapy.

In general, ensuring safety is the top priority of a new modality. Although oncolytic virus armed with an immune stimulatory transgene (OVI) showed some promise, the strategic concept of simultaneously achieving maximum effectiveness and minimizing side effects has not been fully explored. We generated a variety of survivin-responsive "conditionally replicating adenoviruses that can target and treat cancer cells with multiple factors (m-CRAs)" (Surv.m-CRAs) armed with the granulocyte-macrophage colony-stimulating factor (GM-CSF) transgene downstream of various promoters using our m-CRA platform technology. We carefully analyzed both therapeutic and adverse effects of them in the in vivo syngeneic Syrian hamster cancer models. Surprisingly, an intratumor injection of a conventional OVI, which expresses the GM-CSF gene under the constitutively and strongly active "cytomegalovirus enhancer and ß-actin promoter", provoked systemic and lethal GM-CSF circulation and shortened overall survival (OS). In contrast, a new conceptual type of OVI, which expressed GM-CSF under the cancer-predominant and mildly active E2F promoter or the moderately active "Rous sarcoma virus long terminal repeat", not only abolished lethal adverse events but also prolonged OS and systemic anti-cancer immunity. Our study revealed a novel concept that optimal expression levels of an immune stimulatory transgene regulated by a suitable upstream promoter is crucial for achieving high safety and maximal therapeutic effects simultaneously in OVI therapy. These results pave the way for successful development of the next-generation OVI and alert researchers about possible problems with ongoing clinical trials.

Incidence and Risk Factors for Hyponatremia in Postoperative Spinal Surgery Patients.

Introduction: The incidence of hyponatremia after orthopedic surgery is high. Hyponatremia may prolong hospitalization and increase mortality, but few reports have identified risk factors for hyponatremia after spinal surgery. This study aims to determine the incidence and risk factors for hyponatremia after spinal surgery. Methods: A total of 200 patients aged 20 years or older who underwent spinal surgery at our hospital from 2020-2021 were recruited. Data on age, sex, height, weight, body mass index, operation duration, blood loss, albumin level, the geriatric nutritional risk index (GNRI), potassium level, the estimated glomerular filtration rate (eGFR), sodium level, length of hospital stay, history of hypertension, dialysis status, the occurrence of delirium during hospital stay, and oral medication use were collected. Comparisons between the postoperative hyponatremia group and the postoperative normonatremia group were conducted to evaluate the impact of hyponatremia on clinical outcomes. Results: Postoperative hyponatremia was observed in 56 (28%) of the 200 patients after spinal surgery. Comparison between the postoperative hyponatremia group with the postoperative normonatremia group revealed that the patients in the postoperative hyponatremia group were significantly older (72 versus 68.5 years, p<0.01). Postoperative hyponatremia was significantly associated with low GNRI values (100.8 versus 109.3, p<0.01), low eGFR values (59.2 versus 70.8 mL/min/1.73 m2, p<0.01), preoperative hyponatremia (138.5 vs. 141 mEq/L, p<0.01), and a high incidence of delirium (12.5% versus 2.7%, p=0.01). Older age (odds ratio=1.04, p=0.01) and preoperative hyponatremia (odds ratio=0.66, p value<0.01) were risk factors for postoperative hyponatremia. Conclusions: In addition to older age and preoperative hyponatremia, the study identified new risk factors for postoperative hyponatremia, which are preoperative undernutrition and impaired renal function. The incidence of delirium was significantly higher in the postoperative hyponatremia group, suggesting that correcting preoperative hyponatremia and ensuring good nutrition may prevent delirium and thereby shorten hospital stays.

Correlation between Acetabular Anteversion with a False-Profile View and Spinopelvic Parameters in Adult Spinal Deformity after Long-Segment Corrective Spinal Surgery.

Introduction: Studies describing the relationship between the hip and spine have reported that corrective spinal surgery for adult spinal deformity (ASD) affects the orientation of the acetabulum. However, the extent to which spinal correction in ASD affects acetabular anteversion in the standing position is unclear, especially after total hip arthroplasty, for which dislocation is a concern. The purpose of this study was to evaluate changes in anterior acetabular coverage in the upright position due to extensive correction surgery for ASD. Methods: Thirty-six consecutive patients who had undergone spinal corrective surgery from the thoracolumbar region to the pelvis were enrolled and evaluated. The ventral-central-acetabular (VCA) angle and anterior acetabular head index (AAHI) were measured with a false-profile view to evaluate the relationship between acetabular anteversion in the standing position and spinopelvic parameters before and after surgery. The spinopelvic parameters measured included thoracic kyphosis, pelvic incidence, pelvic tilt (PT), sacral slope, lumbar lordosis (LL), sagittal vertical axis, and global tilt. Results: The VCA angle and AAHI were significantly increased after spinal deformity correction (p<0.001). The changes in LL and PT were correlated with the VCA angle (LL: right, ρ=0.56; left, ρ=0.55, p<0.001; PT: right, ρ=-0.59; left, ρ=-0.64, p<0.001) and AAHI (LL: right, ρ=0.51; left, ρ=0.58, p<0.01; PT: right, ρ=-0.52; left, ρ=-0.59, p<0.01), respectively. Linear regression analysis revealed that a 10° increase in LL results in 1.4°-1.9° and 1.6%-2% increases in the VCA angle and AAHI, respectively. Conclusions: Surgical correction for ASD significantly affects sagittal spinopelvic parameters, resulting in increased acetabular anteversion. The anterior coverage of the acetabulum in the postoperative standing position could be predicted with the intraoperatively measured LL, and evaluation using a false-profile was considered useful for treating ASD, particularly in patients after total hip arthroplasty.

Benefits of Collaboration Between the Wound, Ostomy, and Continence Nurse and Orthopedic Surgeon When Treating Skin Defects After Soft Tissue Sarcoma Resection: A Retrospective Case-Control Study.

PURPOSE: The purpose of this study was to evaluate the benefits of collaborative management between orthopedic surgery and WOC nurses in patients undergoing resection of subcutaneous sarcomas. DESIGN: Retrospective case-control study. SUBJECTS AND SETTING: The sample comprised 25 patients who underwent wide resection for soft tissue sarcoma, followed by 2-stage split-thickness skin grafting. Data collection occurred between January 2015 and April 2021 in a university hospital based in Kagoshima, Japan. For comparison, we categorized these patients into 2 groups: intervention group participants were managed by an orthopedic surgeon and a WOC nurse; nonintervention group members were managed without WOC nurse participation. METHODS: Patient background and treatment-related information was retrospectively collected from medical records and compared between the WOC nurse intervention group and the nonintervention group, including maximum tumor diameter, surgical time, maximum skin defect diameter, length of hospital stay, and time from surgery to complete wound healing. RESULTS: The average length of hospital stay was significantly shorter in the WOC nurse intervention group compared with the nonintervention group (38.3 days, SD = 8.0 vs 47.1 days, SD = 10.2; P = .023). CONCLUSION: Collaborative wound management with a WOC nurse resulted in a shorter hospital length of stay when compared to traditional management with WOC nurse involvement. Based on these findings, we assert that WOC nurses provide an important bridge between postoperative wound management in patients undergoing resection of subcutaneous sarcomas.

Impact of preoperative echocardiographic delay on timing of hip fracture surgery in elderly patients.

Objectives: Early surgery is recommended for hip fractures in elderly patients. This study was performed to evaluate factors contributing to delayed surgery and associated outcomes in a secondary hospital in Japan with a rehabilitation centre. Methods: We retrospectively reviewed the records of 895 patients aged >50 years [median age, 86 (81-91) years] treated for hip fractures at our institution from 2016 to 2020. We defined surgical delay as surgery performed >48 h after admission. We evaluated several risk factors for surgical delay and associated outcomes: mortality, length of hospital stay and walking status. Results: Binomial logistic regression analysis showed that several factors, including preoperative echocardiographic delay (odds ratio, 9.38; 95% confidence interval, 5.95-15.28), were risk factors for surgical delay. In the multiple regression analyses, surgical delay was a significant risk factor for a longer hospital stay (partial regression coefficient, 6.99; 95% confidence interval, 3.67-10.31). Conclusions: Our findings indicated that preoperative echocardiographic delay was one of the risk factors for surgical delay of hip fractures in elderly patients. Surgical delay was a risk factor for a longer hospital stay, including rehabilitation.

Association between periodontal disease and malignant soft tissue sarcomas.

OBJECTIVE: Malignant soft tissue sarcoma (MSTS) is a rare disease, but is seen in patients undergoing orthopedic surgery. Although the association of periodontal disease with various cancers occurring in the oral cavity, gastrointestinal tract, lungs, and prostate, has been reported, the association between periodontal disease and MSTS remains unclear. This study investigated the association between periodontal disease and MSTS in patients undergoing orthopedic surgery. SUBJECTS AND METHODS: One hundred fifteen patients who underwent orthopedic surgery between 2017 and 2021 were retrospectively enrolled (mean age = 66.8 ± 10.7 years). The patient background was adjusted by the propensity score (PS). Subsequently, the association of periodontal disease with MSTS was analyzed using PS inverse probability of treatment weighting (IPTW). Periodontal status was determined by evaluating the periodontal inflamed surface area, which was calculated by measuring the periodontal probing pocket depth and detecting bleeding on probing. RESULTS: Multivariate logistic regression analysis after adjustment by the PS showed that severe periodontitis was significantly associated with MSTS (odds ratio 2.81, p = 0.04). Furthermore, IPTW showed that severe periodontitis was significantly associated with MSTS (odds ratio 3.21, p = 0.01). CONCLUSION: The results indicate an association between periodontal inflammation and MSTS.

Editorial Commentary: Bone Marrow Stimulation and Losartan Augmentation of Shoulder Rotator Cuff Repair.

Rotator cuff retear rates after repair have been variously reported as ranging from 5% to 40% for small to mediums tears and as high as 40% to 94% for large to massive tears. Thus strategies to enhance structural healing are relevant. In rabbits, combining oral losartan (which has antifibrotic effects by downregulating transforming growth factor-ß1) and bone marrow stimulation (BMS) of the greater tuberosity, showed improved rotator cuff repair pull-out strength and highly organized tendon matrix in a chronic injury model, whereas BMS alone did not improve the mechanical properties. However, clinical studies show that BMS techniques have a positive impact on healing and retear rates. BMS stimulates migration of mesenchymal stem cells from bone marrow to the lesion, and this approach has been widely used to fill cartilage defects by fibrocartilage metaplasia. BMS is a straightforward and cost-effective technique; the use of multiple deeper bone tunnels is recommended.

High prevalence of lumbar spinal stenosis in cases of idiopathic normal-pressure hydrocephalus affects improvements in gait disturbance after shunt operation.

Objective: Idiopathic normal-pressure hydrocephalus (iNPH) is characterized by symptoms of dementia, urinary incontinence, and gait disturbance; however, gait disturbance tends to persist after shunt surgery. Gait disturbance and urinary dysfunction are also major symptoms of lumbar spinal stenosis (LSS). Currently, the epidemiology of the complications of LSS in iNPH is unclear. Here, we evaluated the coexistence rate of LSS in iNPH cases. Methods: This was a retrospective case-control study. Between 2011 and 2017, 224 patients with a median age of 78 years, including 119 males, were diagnosed with iNPH and underwent lumboperitoneal shunts or ventriculoperitoneal shunts. LSS was diagnosed with magnetic resonance imaging by two spine surgeons. Age, sex, body mass index (BMI), Timed Up and Go (TUG) test, Mini Mental State Examination (MMSE) score, and urinary dysfunction were examined. We compared the changes in these variables in the group of patients with iNPH without LSS versus those with both iNPH and LSS. Results: Seventy-three iNPH patients (32.6%) with LSS had significantly higher age and BMI. The existence of LSS did not alter the postoperative improvement rates of MMSE and urinary dysfunction; however, TUG improvement was significantly impaired in the LSS-positive group. Conclusions: LSS affects improvements in gait disturbance of iNPH patients after shunt operation. Because our results revealed that one-third of iNPH patients were associated with LSS, gait disturbance observed in iNPH patients should be considered a potential complication of LSS.

Removal of a migrated acupuncture needle from the cervical spinal canal with removal confirmation by cone-beam computed tomography in a hybrid operating room.

Background: Acupuncture has become one of the most popular alternative medical treatments in the world. However, if the needle is inserted incorrectly into the body, various adverse events can occur and, in such cases, the needle should be removed. Acupuncture needles are very thin and fragile, making them difficult to detect and to confirm breakage or residual needle fragments during surgery. We report a case of a patient's self-placed acupuncture needle migrating into the cervical spinal canal and its surgical removal. We used cone-beam computed tomography in the hybrid operating room to confirm that the needle was removed in its entirety. Case presentation: A 37-year-old man presented with neck pain and gait disturbance.While he was self-acupuncturing, an acupuncture needle accidentally broke, and the remaining part of the needle penetrated and made contact with the cervical spinal cord. Cervical spine radiographs showed a metallic foreign body between the C1 and C2 spinous processes in the direction of the anterior cervical spine. Computed tomography images revealed that the acupuncture needle was penetrating the spinal canal and was in contact with the cervical cord. The acupuncture needle was removed under general anesthesia. The use of cone-beam computed tomography in the hybrid operating room allowed intraoperative confirmation that there was no breakage during needle removal, and no needle fragments were left behind. His symptoms disappeared without any complications after the operation. Conclusion: To the best of our knowledge, this is the first report of the removal of an acupuncture needle that migrated into the cervical spinal canal using cone-beam computed tomography in a hybrid operating room. Intraoperative cone-beam computed tomography is useful in patients with small, fragile foreign bodies for confirmation of the location of the object and to check for the presence of residual fragments.

Reconstruction Using a Fibular Autograft for Lumbosacral Spinal Deformity in Neurofibromatosis Type 1: A Report of 2 Cases.

CASES: We present 2 cases (19- and 40-year-old women) of lumbosacral spinal deformity with sacroiliac joint destruction. Reconstruction surgery using a fibular strut autograft was performed in both patients, and spinal reconstruction and fusion were successfully maintained without bone resorption for at least 7 years. CONCLUSION: This is the first report of reconstructive surgery using a fibular strut bone graft for lumbosacral deformity with destruction of the sacroiliac joint in patients with neurofibromatosis type 1 (NF-1). These findings suggest that reconstruction with a fibular strut autograft is useful for lumbosacral spinal deformity that includes destruction of the sacroiliac joints in NF-1.

Revision total hip arthroplasty using a Kerboull-type acetabular reinforcement device and allogeneic structural bone graft.

PURPOSE: One of the major problems in revision total hip arthroplasty (THA) is severe acetabular bone loss. The aim of our study was to evaluate the clinical outcomes of revision THA using a Kerboull-type reinforcement device (KT plate) and allogeneic structural bone graft. METHODS: This retrospective study evaluated 48 hips that underwent revision THA using a KT plate and allogeneic structural bone graft between 2008 and 2016, with a median follow-up of 6.2 years (range 3-12.6 years). Functional outcome was assessed using the Japanese Orthopaedic Association (JOA) hip score. Postoperative and follow-up radiographs were compared to assess migration and breakage of the implant. RESULTS: The mean JOA hip score improved from 45.6 (±16.3) points before surgery to 72.1 (±11.9) points at the most recent follow-up examination (p < 0.001). Two hips (4.2%) underwent re-revision THA because of cup loosening due to breakage of the KT plate. A total of 13 hips (27.1%) were classified as radiological failures. Binomial logistic regression analysis showed that a Kawanabe classification of stage 4, which indicates massive bone defects in the weight-bearing area, was a risk factor for radiological failure (odds ratio: 4.57; 95% confidence interval: 1.01-26.35). CONCLUSIONS: A KT plate with an allogeneic structural bone graft is a useful method of acetabular reconstruction in revision THA that restores bone stock and improves hip function. Our findings indicated that a Kawanabe classification of stage 4 was a risk factor for radiological failure of the implant.

Low geriatric nutritional risk index is a risk factor for death within 1 year following hip fracture.

PURPOSE: Hip fracture is common in older patients and is associated with high mortality and functional impairment. The Geriatric Nutritional Risk Index (GNRI) evaluates the risk of malnutrition-related complications, and the Barthel Index (BI) evaluates older patients' functional status. The study aim was to determine the risk factors for both death and decreased BI within 1 year after hip fracture. METHODS: We retrospectively reviewed the records of 108 patients who were treated for hip fractures in 10 public or private hospitals from February to July 2007. Participating facilities comprised eight public or private hospitals with 200-499 beds, and two private or orthopedic hospitals with 20-199 beds. We evaluated several risk factors for death and lower BI within 1 year after hip fracture. RESULTS: The mortality rate within 1 year postoperatively for patients who survived inpatient stay was 6.5% (7/108). The proportion of patients with decreased postoperative BI was 43.6% (44/101). Binomial logistic regression analysis showed that several factors, including low GNRI (odds ratio [OR]: 0.80; 95% confidence interval [CI: 0.68-0.93]), were risk factors for death within 1 year. Postoperative delirium (OR: 8.84 [1.52-51.6]), postinjury dementia (OR: 34.8 [3.01-402]), preinjury BI (OR: 1.05 [1.02-1.08]), and preinjury dementia (OR: 6.22 [1.73-22.4]) were risk factors for decreased postoperative BI. CONCLUSIONS: Our findings indicated that lower GNRI was a risk factor for death within 1 year of hip surgery and that delirium and dementia were among the risk factors for decreased BI 1 year after hip fracture.

Crucial role of high-mobility group box 2 in mouse ovarian follicular development through estrogen receptor beta.

High-mobility group box 2 (HMGB2) is a chromatin-associated protein that is an important regulator of gene transcription, recombination, and repair processes. The functional importance of HMGB2 has been reported in various organs, including the testis, heart, and cartilage. However, its role in the ovary is largely unknown. In this study, ovary tissues from wild-type (WT) and HMGB2-knock-out (KO) mice were examined by histopathological staining and immunohistochemistry. The ovary size and weight were significantly lower in HMGB2-KO mice than in age-matched WT littermates. Histopathological analysis revealed ovarian atrophy and progressive fibrosis in 10-month-old HMGB2-KO mouse ovaries. Compared to age-matched WT mice, the numbers of oocytes and developing follicles were significantly decreased at 2 months of age and were completely depleted at 10 months of age in HMGB2-KO mice. Immunohistochemistry revealed the expression of HMGB2 in the granulosa cells of developing follicles, oocytes, some corpora lutea, and stromal cells. Importantly, HMGB2-positive cells were co-localized with estrogen receptor beta (ERß), but not ERα. Estrogen response element-binding activity was demonstrated by southwestern histochemistry, and it was decreased in HMGB2-KO mouse ovaries. Cell proliferation activity was also decreased in HMGB2-KO mouse ovaries in parallel with the decreased folliculogenesis. These results indicated that the depletion of HMGB2 induced ovarian atrophy that was characterized by a decreased ovarian size and weight, progressive fibrosis, as well as decreased oocytes and folliculogenesis. In conclusion, we demonstrated the crucial role of HMGB2 in mouse ovarian folliculogenesis through ERß expression.

Depletion of high-mobility group box 2 causes seminiferous tubule atrophy via aberrant expression of androgen and estrogen receptors in mouse testis†.

High-mobility group box 2, a chromatin-associated protein that interacts with deoxyribonucleic acid, is implicated in multiple biological processes, including gene transcription, replication, and repair. High-mobility group box 2 is expressed in several tissues, including the testis; however, its functional role is largely unknown. Here, we elucidated the role of high-mobility group box 2 in spermatogenesis. Paraffin-embedded testicular tissues were obtained from 8-week-old and 1-year-old wild-type and knock-out mice. Testis weight and number of seminiferous tubules were decreased, whereas atrophic tubules were increased in high-mobility group box 2-depleted mice. Immunohistochemistry revealed that atrophic tubules contained Sertoli cells, but not germ cells. Moreover, decreased cell proliferation and increased apoptosis were demonstrated in high-mobility group box 2-depleted mouse testis. To elucidate the cause of tubule atrophy, we examined the expression of androgen and estrogen receptors, and the results indicated aberrant expression of androgen receptor and estrogen receptor alpha in Sertoli and Leydig cells. Southwestern histochemistry detected decreased estrogen response element-binding sites in high-mobility group box 2-depleted mouse testis. High-mobility group box 1, which has highly similar structure and function as high-mobility group box 2, was examined by immunohistochemistry and western blotting, which indicated increased expression in testis. These findings indicate a compensatory increase in high-mobility group box 1 expression in high-mobility group box 2 knock-out mouse testis. In summary, depletion of high-mobility group box 2 induced aberrant expression of androgen receptor and estrogen receptor alpha, leading to decreased germ cell proliferation and increased apoptosis which resulted in focal seminiferous tubule atrophy.

Surgical results of the resection of spinal meningioma with the inner layer of dura more than 10 years after surgery.

Most spinal meningiomas arise from the thoracic dura in middle-aged and elderly women. Simpson grade 1 resection is recommended to avoid recurrence. For ventral and ventrolateral tumors, reconstruction after total dural resection is difficult, and spinal fluid leakage is likely. To overcome this concern, Saito et al. developed the technique of resecting the tumor with the inner dural layer, preserving the outer dural layer. Although meningioma rarely recurs, the recurrence period is approximately 8 years postoperatively. No studies have evaluated long-term (> 10-year) outcomes of the Saito method. Here, we report 10 cases of the Saito method with > 10-year follow-up and compare outcomes with those of other standard approaches. Twenty-nine pathology-confirmed meningioma patients underwent surgery in our department, ten with the Saito method. We investigated resection method (dura mater treatment), pathological type, and recurrence and compared pre- and postoperative clinical findings. The median follow-up was 132 months. Recurrence occurred after Simpson grades 3 and 4 resection. Simpson grades 1, 2, and the Saito method resulted in no recurrence. Neurological symptoms improved in all patients at final follow-up. This is the first report of long-term outcomes of the Saito method. The method achieved good neurological improvement with no recurrence in > 10-year follow-up.

Glenoid bone resorption after Bankart repair: finite element analysis of postoperative stress distribution of the glenoid.

BACKGROUND: There are various modifications of the Bankart repair, and postoperative changes to the glenoid morphology after the repair are reported. Among the various procedures performed, a decrease in the lateral glenoid diameter might be related to the surgery that involves removal of the articular cartilage and repair of the labrum-anterior inferior glenohumeral ligament complex on the glenoid surface. This is in contrast to cases without significant bony Bankart lesions that are not on the edge of the glenoid. Thus, this study aimed to compare glenoid rim stress after Bankart repair using 2 methods of finite element analysis: a method of removing the anteroinferior cartilage and repairing the glenohumeral ligament complex on the glenoid and a method of preserving the cartilage and repairing the glenohumeral ligament complex on the glenoid edge. METHODS: Five preoperative computed tomography scans of patients with traumatic anterior instability who underwent arthroscopic Bankart repair were used. Two models simulating different surgical procedures were created as follows: in model G, a 5-mm-thick cartilage on the glenoid rim was removed between 2 and 7 o'clock, and the glenohumeral ligament complex was repaired on the medial edge of the glenoid bone where the cartilage was removed. In model E, the cartilage on the glenoid rim was not removed, and the glenohumeral ligament complex was repaired on the glenoid edge. The load stresses on the anteroinferior area of the glenoid after Bankart repair with models G and E were measured using finite element analysis. RESULTS: The stress on the glenoid at 3-4 o'clock was 3.16 MPa in model G and 6.42 MPa in model E (P = .043). The stress at 4-5 o'clock was 1.68 MPa in model G and 4.53 MPa in model E (P = .043). The stress at 5-6 o'clock was 2.26 MPa in model G and 3.93 MPa in model E (P = .043). CONCLUSION: Significantly lower load stresses were observed at the anteroinferior rim of the glenoid in model G than in model E.

Humeral bone resorption after reverse shoulder arthroplasty using uncemented stem.

BACKGROUND: Humeral stem loosening has gained attention as it has been identified as a cause of revision surgery in reverse shoulder arthroplasty (RSA). In RSA, humeral stem revision is very difficult if there is humeral bone loss because of stress shielding. Some studies of humeral bone resorption after anatomic shoulder arthroplasty have been published, but there are few detailed reports of humeral bone resorption after RSA. This study aimed to investigate the prevalence of humeral bone resorption after RSA procedures and to evaluate the risk factors for bone resorption. METHODS: This study included 48 shoulders that underwent RSA with an uncemented humeral stem from July 2014 to May 2017 and were followed up for more than 1 year. The prevalence of humeral bone resorption and risk factors were investigated. Logistic, multiple logistic, and multivariate logistic regression analyses were performed to evaluate the data. RESULTS: Grade 0 bone resorption, the most advanced grade, occurred in 8 shoulders (16.7%); grade 1, in 0 (0%); grade 2, in 17 (35.4%); grade 3, in 14 (29.2%); and grade 4, in 9 (18.8%). A high occurrence of bone absorption was observed in zones 1, 2, and 7. Grade 4 bone resorption did not occur in zones 3, 5, and 6. Female sex and an onlay-type stem were significant independent risk factors for grade 4 bone resorption. CONCLUSIONS: Bone resorption was frequently observed in the greater tuberosity, lateral diaphysis, and calcar region. Significant risk factors included female sex and an onlay-type stem.

Neurotensin receptor 1 is a new therapeutic target for human undifferentiated pleomorphic sarcoma growth.

Undifferentiated pleomorphic sarcoma (UPS) is the second most common soft tissue sarcoma. For patients with unresectable or metastatic disease, chemotherapies are considered, but in many cases they are not curative. There is a need to identify specific molecular dysregulations that can be therapeutic targets. We focused on neurotensin receptor 1 (NTSR1), which belongs to the G-protein-coupled receptor. NTSR1 expression was upregulated in specimens from patients with UPS. Real-time polymerase chain reaction showed that expression of NTSR1 messenger RNA was 5- to 7-fold increased in UPS cells compared with myoblasts. Western blot showed a high expression of NTSR1 protein in UPS cell lines. Knockdown of NTSR1 prevented UPS cell proliferation and invasion. We confirmed that SR48692, an inhibitor of NTSR1, exhibited antitumor activities in UPS cells. The combination index showed that SR48692 and standard chemotherapeutic drugs prevented UPS cell proliferation synergistically. Mouse xenograft models showed that SR48692 inhibited extracellular signal-regulated kinase phosphorylation and enhanced the response to standard chemotherapeutic drugs. Inhibition of NTSR1 improved the effect of standard chemotherapeutic drugs for UPS. SR48692 may be a new drug for targeted UPS therapy.

Tranilast enhances the effect of anticancer agents in osteosarcoma.

Tranilast [N­(3',4'­dimethoxycinnamoyl)­anthranilic acid], initially developed as an antiallergic drug, also exhibits a growth inhibitory effect on various types of cancer. Osteosarcoma is treated mainly with high­dose methotrexate, doxorubicin, cisplatin and ifosfamide; however, 20­30% of patients cannot be cured of metastatic disease. We investigated whether tranilast enhances the anticancer effects of chemotherapeutic drugs and analyzed its mechanism of action in osteosarcomas. Tranilast inhibited proliferation of HOS, 143B, U2OS and MG­63 osteosarcoma cells in a dose­dependent manner, as well as enhancing the effects of cisplatin and doxorubicin. The average combination index at effect levels for tranilast in combination with cisplatin was 0.57 in HOS, 0.4 in 143B, 0.39 in U2OS and 0.51 in MG­63 cells. Tranilast and cisplatin synergistically inhibited the viability of osteosarcoma cells. In flow cytometric analysis, although tranilast alone did not induce significant apoptosis, the combination of tranilast and cisplatin induced early and late apoptotic cell death. Expression of cleaved caspase­3, cleaved poly(ADP­ribose) polymerase and p­H2AX was enhanced by tranilast in combination with cisplatin. Tranilast alone increased expression of p21 and Bim protein in a dose­dependent manner. Cell cycle analysis using flow cytometry demonstrated that the combination of tranilast and cisplatin increased the number of cells in the G2/M phase. Compared with cisplatin alone, the combination increased levels of phospho­cyclin­dependent kinase 1 (Y15). In the 143B xenograft model, tumor growth was significantly inhibited by combined tranilast and cisplatin compared with the controls, whereas cisplatin alone did not significantly inhibit tumor growth. In conclusion, tranilast has a cytostatic effect on osteosarcoma cells and enhances the effect of anticancer drugs, especially cisplatin. Enhanced sensitivity to cisplatin was mediated by increased apoptosis through G2/M arrest. Since tranilast has been clinically approved and has few adverse effects, clinical trials of osteosarcoma chemotherapy in combination with tranilast are expected.