p53-Armed Oncolytic Virotherapy Improves Radiosensitivity in Soft-Tissue Sarcoma by Suppressing BCL-xL Expression.

Soft-tissue sarcoma (STS) is a heterogeneous group of rare tumors originating predominantly from the embryonic mesoderm. Despite the development of combined modalities including radiotherapy, STSs are often refractory to antitumor modalities, and novel strategies that improve the prognosis of STS patients are needed. We previously demonstrated the therapeutic potential of two telomerase-specific replication-competent oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, in human STS cells. Here, we demonstrate in vitro and in vivo antitumor effects of OBP-702 in combination with ionizing radiation against human STS cells (HT1080, NMS-2, SYO-1). OBP-702 synergistically promoted the antitumor effect of ionizing radiation in the STS cells by suppressing the expression of B-cell lymphoma-X large (BCL-xL) and enhancing ionizing radiation-induced apoptosis. The in vivo experiments demonstrated that this combination therapy significantly suppressed STS tumors' growth. Our results suggest that OBP-702 is a promising antitumor reagent for promoting the radiosensitivity of STS tumors.

Retrospective Cohort Study of Early versus Delayed Ballon Kyphoplasty Intervention for Osteoporotic Vertebral Fracture Treatment.

Objectives: To investigate the outcomes of early balloon kyphoplasty (BKP) intervention compared with late intervention for osteoporotic vertebral fracture (OVF). Background: Osteoporotic vertebral fracture can lead to kyphotic deformity, severe back pain, depression, and disturbances in activities of daily living (ADL). Balloon kyphoplasty has been widely utilized to treat symptomatic OVFs and has proven to be a very effective surgical option for this condition. Furthermore, BKP is relatively a safe and effective method due to its reduced acrylic cement leakage and greater kyphosis correction. Materials and Methods: A retrospective cohort study was conducted at our hospital for patients who underwent BKP for osteoporotic vertebral fractures in the time frame between January 2020 and December 2022. Ninety-nine patients were included in this study, and they were classified into two groups: in total, 36 patients underwent early BKP intervention (EI) at <4 weeks, and 63 patients underwent late BKP intervention (LI) at ≥4 weeks. We performed a clinical, radiological and statistical comparative evaluation for the both groups with a mean follow-up of one year. Results: Adjacent segmental fractures were more frequently observed in the LI group compared to the EI group (33.3% vs. 13.9%, p = 0.034). There was a significant improvement in postoperative vertebral angles in both groups (p = 0.036). The cement volume injected was 7.42 mL in the EI, compared with 6.3 mL in the LI (p = 0.007). The mean surgery time was shorter in the EI, at 30.2 min, compared with 37.1 min for the LI, presenting a significant difference (p = 0.0004). There was no statistical difference in the pain visual analog scale (VAS) between the two groups (p = 0.711), and there was no statistical difference in cement leakage (p = 0.192). Conclusions/Level of Evidence: Early BKP for OVF treatment may achieve better outcomes and fewer adjacent segmental fractures than delayed intervention.

A Novel Technique for Basilar Invagination Treatment in a Patient with Klippel-Feil Syndrome: A Clinical Example and Brief Literature Review.

Objectives and Background: To present a novel technique of treatment for a patient with basilar invagination. Basilar invagination (BI) is a congenital condition that can compress the cervicomedullary junction, leading to neurological deficits. Severe cases require surgical intervention, but there is debate over the choice of approach. The anterior approach allows direct decompression but carries high complication rates, while the posterior approach provides indirect decompression and offers good stability with fewer complications. Materials and Methods: A 15-year-old boy with severe myelopathy presented to our hospital with neck pain, bilateral upper limb muscle weakness, and hand numbness persisting for 4 years. Additionally, he experienced increased numbness and gait disturbance three months before his visit. On examination, he exhibited hyperreflexia in both upper and lower limbs, muscle weakness in the bilateral upper limbs (MMT 4), bilateral hypoesthesia below the elbow and in both legs, mild urinary and bowel incontinence, and a spastic gait. Radiographs revealed severe basilar invagination (BI). Preoperative images showed severe BI and that the spinal cord was severely compressed with odontoid process. Results: The patient underwent posterior surgery with the C-arm free technique. All screws including occipital screws were inserted into the adequate position under navigation guidance. Reduction was achieved with skull rotation and distraction. A follow-up at one year showed the following results: Manual muscle testing results and sensory function tests showed almost full recovery, with bilateral arm recovery (MMT 5) and smooth walking. The cervical Japanese Orthopedic Association score of the patient improved from 9/17 to 16/17. Postoperative images showed excellent spinal cord decompression, and no major or severe complications had occurred. Conclusions: Basilar invagination alongside Klippel-Feil syndrome represents a relatively uncommon condition. Utilizing a posterior approach for treating reducible BI with a C-arm-free technique proved to be a safe method in addressing severe myelopathy. This novel navigation technique yields excellent outcomes for patients with BI.

Telomerase-specific oncolytic immunotherapy for promoting efficacy of PD-1 blockade in osteosarcoma.

Immune checkpoint inhibitors including anti-programmed cell death 1 (PD-1) antibody have recently improved clinical outcome in certain cancer patients; however, osteosarcoma (OS) patients are refractory to PD-1 blockade. Oncolytic virotherapy has emerged as novel immunogenic therapy to augment antitumor immune response. We developed a telomerase-specific replication-competent oncolytic adenovirus OBP-502 that induces lytic cell death via binding to integrins. In this study, we assessed the combined effect of PD-1 blockade and OBP-502 in OS cells. The expression of coxsackie and adenovirus receptor (CAR), integrins αvß3 and αvß5, and programmed cell death ligand 1 (PD-L1) was analyzed in two murine OS cells (K7M2, NHOS). The cytopathic activity of OBP-502 in both cells was analyzed using the XTT assay. OBP-502-induced immunogenic cell death was assessed by analyzing the level of extracellular ATP and high-mobility group box protein B1 (HMGB1). Subcutaneous tumor models for K7M2 and NHOS cells were used to evaluate the antitumor effect and number of tumor-infiltrating CD8+ cells in combination therapy. K7M2 and NHOS cells showed high expression of integrins αvß3 and αvß5, but not CAR. OBP-502 significantly suppressed the viability of both cells, in which PD-L1 expression and the release of ATP and HMGB1 were significantly increased. Intratumoral injection of OBP-502 significantly augmented the efficacy of PD-1 blockade on subcutaneous K2M2 and NHOS tumor models via enhancement of tumor-infiltrating CD8+ T cells. Our results suggest that telomerase-specific oncolytic virotherapy is a promising antitumor strategy to promote the efficacy of PD-1 blockade in OS.

Role of zoledronic acid in oncolytic virotherapy: Promotion of antitumor effect and prevention of bone destruction.

Osteosarcoma is an aggressive malignant bone tumor that causes bone destruction. Although tumor-specific replicating oncolytic adenovirus OBP-301 induces an antitumor effect in an osteosarcoma tumor, it cannot prevent bone destruction. Zoledronic acid (ZOL) is a clinically available agent that inhibits bone destruction. In this study, we investigated the potential of combination therapy with OBP-301 and ZOL against osteosarcomas with bone destruction. The antitumor activity of OBP-301 and ZOL in monotherapy or combination therapy was assessed using three human osteosarcoma cell lines (143B, MNNG/HOS, SaOS-2). The cytotoxic effect of OBP-301 and/or ZOL was measured by assay of cell apoptosis. The effect of OBP-301 and ZOL on osteoclast activation was investigated. The potential of combination therapy against tumor growth and bone destruction was analyzed using an orthotopic 143B osteosarcoma xenograft tumor model. OBP-301 and ZOL decreased the viability of human osteosarcoma cells. Combination therapy with OBP-301 and ZOL displayed a synergistic antitumor effect, in which OBP-301 promoted apoptosis through suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1). Combination therapy significantly inhibited tumor-mediated osteoclast activation, tumor growth and bone destruction compared to monotherapy. These results suggest that combination therapy of OBP-301 and ZOL suppresses osteosarcoma progression via suppression of MCL1 and osteoclast activation.

A case of emphysematous cystitis caused by mechanical stimulation of pelvic fracture nonunion.

Emphysematous cystitis is a rare condition that develops due to tissue hyperglycemia and urinary tract infection by gas-producing bacteria. We report a case of emphysematous cystitis caused by mechanical stimulation of a pelvic fracture nonunion. An 80-year-old man was injured in a motorcycle accident and diagnosed with pelvic fracture. Seven days later, he had high fever and computed tomography (CT) revealed gas in the hematoma around the pelvic fracture and the abscess. Therefore, infection following the pelvic fracture was diagnosed. Despite multiple operations and antibiotics treatment, malformation and nonunion of the pelvis occurred. One month after starting weight bearing, emphysema of the bladder wall adjacent to the pubic fracture were found and spread throughout the bladder wall. With stopping of weight bearing, antibiotics treatment and a urinary catheter, emphysema disappeared after 2 months. It was considered that the pubic fracture fragment irritated the bladder wall due to weight bearing and emphysematous cystitis consequently developed.

Evolution, Current Trends, and Latest Advances of Endoscopic Spine Surgery.

Background: The aging of the population in developing and developed countries has led to a significant increase in the health burden of spinal diseases. These elderly patients often have a number of medical comorbidities due to aging. The need for minimally invasive techniques to address spinal disorders in this elderly population group cannot be stressed enough. Minimally invasive spine surgery (MISS) has several proven benefits, such as minimal muscle trauma, minimal bony resection, lesser postoperative pain, decreased infection rate, and shorter hospital stay. Methods: A comprehensive search of the literature was performed using PubMed. Results: Over the past 40 years, constant efforts have been made to develop newer techniques of spine surgery. Endoscopic spine surgery is one such subset of MISS, which has all the benefits of modern MISS. Endoscopic spine surgery was initially limited only to the treatment of lumbar disc herniation. With improvements in optics, endoscopes, endoscopic drills and shavers, and irrigation pumps, there has been a paradigm shift. Endoscopic spine surgery can now be performed with high magnification, thus allowing its application not only to lumbar spinal stenosis but also to spinal fusion surgeries and cervical and thoracic pathology as well. There has been increasing evidence in support of these newer techniques of spine surgery. Conclusions: For this report, we studied the currently available literature and outlined the historical evolution of endoscopic spine surgery, the various endoscopic systems and techniques available, and the current applications of endoscopic techniques as an alternative to traditional spinal surgery.

Evaluation and Rehabilitation after Adult Lumbar Spine Surgery.

Purpose: With an increase in the proportion of elderly patients, the global burden of spinal disease is on the rise. This is gradually expected to increase the number of surgical procedures all over the world in the near future. As we know, rehabilitation following spine surgery is critical for optimal recovery. However, the current literature lacks consensus regarding the appropriate post-operative rehabilitation protocol. The purpose of this review is to evaluate the optimal protocol for rehabilitation after lumbar spine surgery in adults. Materials and Methods: The goals of rehabilitation after lumbar spine surgery are to improve physical and psychosocial function and may include multiple modalities such as physical therapy, cognitive behavioral therapy, specialized instruments, and instructions to be followed during activities of daily living. In recent years, not only are a greater number of spine surgeries being performed, but various different techniques of lumbar spine surgery and spinal fusion have also emerged. (1) Our review summarizes post-operative rehabilitation under the following headings-1. Historical aspects, 2. Subjective functional outcomes, and (3) Actual rehabilitation measures, including balance. Results: Physical therapy programs need to be patient-specific and surgery-specific, such that they consider patient-reported outcome measures and take into consideration the technique of spinal fusion used and the muscle groups involved in these surgeries. By doing so, it is possible to assess the level of functional impairment and then specifically target the strengthening of those muscle groups affected by surgery whilst also improving impaired balance and allowing a return to daily activities. Conclusions: Rehabilitation is a multi-faceted journey to restore mobility, function, and quality of life. The current rehabilitation practice focuses on muscle strengthening, but the importance of spinal balance is less elaborated. We thus equally emphasize muscle strengthening and balance improvement post-lumbar spine surgery.

Fluorescence-guided assessment of bone and soft-tissue sarcomas for predicting the efficacy of telomerase-specific oncolytic adenovirus.

Bone and soft-tissue sarcomas are rare malignancies with histological diversity and tumor heterogeneity, leading to the lack of a common molecular target. Telomerase is a key enzyme for keeping the telomere length and human telomerase reverse transcriptase (hTERT) expression is often activated in most human cancers, including bone and soft-tissue sarcomas. For targeting of telomerase-positive tumor cells, we developed OBP-301, a telomerase-specific replication-competent oncolytic adenovirus, in which the hTERT promoter regulates adenoviral E1 gene for tumor-specific viral replication. In this study, we present the diagnostic potential of green fluorescent protein (GFP)-expressing oncolytic adenovirus OBP-401 for assessing virotherapy sensitivity using bone and soft-tissue sarcomas. OBP-401-mediated GFP expression was significantly associated with the therapeutic efficacy of OBP-401 in human bone and soft-tissue sarcomas. In the tumor specimens from 68 patients, malignant and intermediate tumors demonstrated significantly higher expression levels of coxsackie and adenovirus receptor (CAR) and hTERT than benign tumors. OBP-401-mediated GFP expression was significantly increased in malignant and intermediate tumors with high expression levels of CAR and hTERT between 24 and 48 h after infection. Our results suggest that the OBP-401-based GFP expression system is a useful tool for predicting the therapeutic efficacy of oncolytic virotherapy on bone and soft-tissue sarcomas.

Perivascular epithelioid cell tumors (PEComas) of the bone and soft tissue: a Japanese Musculoskeletal Oncology Group (JMOG) multi-institutional study.

PURPOSE: Perivascular epithelioid cell tumors (PEComas) of the bone and soft tissues are rare mesenchymal neoplasms, some of which are malignant. However, their clinical and pathological characteristics remain unclear. This study was performed to investigate the clinical and pathological characteristics of PEComas in bone and soft tissues by leveraging information from the Japanese Musculoskeletal Oncology Group. METHODS: Nine patients, including four male and five female patients with a median age of 50 years, were retrospectively reviewed. PEComas of the visceral organs, including the uterus and retroperitoneum, were excluded. RESULTS: Eight tumors arose in the soft tissue and one in the bone, with a mean size of 8.8 cm. Four patients showed local recurrence or distant metastasis. The 1-year survival rate was 78%. Pathologically, eight tumors were classified as malignant and one as having uncertain malignancy potential. Half of the tumors showed high MIB-1 index values of > 30%. Immunohistochemically, the melanocyte marker HMB45 was expressed in 89% of the cases, and muscle-specific markers were expressed only in 30-50% of the cases. Transcription factor binding to IGHM enhancer 3 (TFE3) expression was positive in 100% of the patients. Tumors with high expression of TFE3 were classified as PEComas with malignant potential according to Folpe's classification. CONCLUSIONS: Bone and soft tissue PEComas may have a higher malignancy potential than other visceral PEComas and are more likely to develop as TFE3-rearranged PEComas.

Oncolytic virotherapy reverses chemoresistance in osteosarcoma by suppressing MDR1 expression.

BACKGROUND: Osteosarcoma (OS) is a malignant bone tumor primarily affecting children and adolescents. The prognosis of chemotherapy-refractory OS patients is poor. We developed a tumor suppressor p53-expressing oncolytic adenovirus (OBP-702) that exhibits antitumor effects against human OS cells. Here, we demonstrate the chemosensitizing effect of OBP-702 in human OS cells. MATERIALS AND METHODS: The in vitro and in vivo antitumor activities of doxorubicin (DOX) and OBP-702 were assessed using parental and DOX-resistant OS cells (U2OS, MNNG/HOS) and a DOX-resistant MNNG/HOS xenograft tumor model. RESULTS: DOX-resistant OS cells exhibited high multidrug resistant 1 (MDR1) expression, which was suppressed by OBP-702 or MDR1 siRNA, resulting in enhanced DOX-induced apoptosis. Compared to monotherapy, OBP-702 and DOX combination therapy significantly suppressed tumor growth in the DOX-resistant MNNG/HOS xenograft tumor model. CONCLUSION: Our results suggest that MDR1 is an attractive therapeutic target for chemoresistant OS. Tumor-specific virotherapy is thus a promising strategy for reversing chemoresistance in OS patients via suppression of MDR1 expression.

Oncolytic virotherapy promotes radiosensitivity in soft tissue sarcoma by suppressing anti-apoptotic MCL1 expression.

Soft tissue sarcoma (STS) is a rare cancer that develops from soft tissues in any part of the body. Despite major advances in the treatment of STS, patients are often refractory to conventional radiotherapy, leading to poor prognosis. Enhancement of sensitivity to radiotherapy would therefore improve the clinical outcome of STS patients. We previously revealed that the tumor-specific, replication-competent oncolytic adenovirus OBP-301 kills human sarcoma cells. In this study, we investigated the radiosensitizing effect of OBP-301 in human STS cells. The in vitro antitumor effect of OBP-301 and ionizing radiation in monotherapy or combination therapy was assessed using highly radiosensitive (RD-ES and SK-ES-1) and moderately radiosensitive (HT1080 and NMS-2) STS cell lines. The expression of markers for apoptosis and DNA damage were evaluated in STS cells after treatment. The therapeutic potential of combination therapy was further analyzed using SK-ES-1 and HT1080 cells in subcutaneous xenograft tumor models. The combination of OBP-301 and ionizing radiation showed a synergistic antitumor effect in all human STS cell lines tested, including those that show different radiosensitivity. OBP-301 was found to enhance irradiation-induced apoptosis and DNA damage via suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1), which was expressed at higher levels in moderately radiosensitive cell lines. The combination of OBP-301 and ionizing radiation showed a more profound antitumor effect compared to monotherapy in SK-ES-1 (highly radiosensitive) and HT1080 (moderately radiosensitive) subcutaneous xenograft tumors. OBP-301 is a promising antitumor reagent to improve the therapeutic potential of radiotherapy by increasing radiation-induced apoptosis in STS.

Minimally Invasive Cervical Pedicle Screw Fixation by a Posterolateral Approach for Acute Cervical Injury.

STUDY DESIGN: This is a retrospective case series. OBJECTIVE: To avoid lateral misplacement of midcervical pedicle screws, T.T., one of our authors, developed a method for minimally invasive cervical pedicle screw (MICEPS) fixation by a posterolateral approach. We reviewed our initial experience with this fixation for trauma cases. SUMMARY OF BACKGROUND DATA: Excellent clinical results with cervical screws have been reported for trauma cases. Although cervical pedicle screw fixation can be an essential part of reconstruction in spinal disorders, there is also a risk for injury to the vertebral artery. METHODS: This study included 56 consecutive patients who received surgery for cervical fractures. We inserted a total of 203 cervical pedicle screws. Nineteen patients were treated by conventional methods. Thirty-seven patients were treated by MICEPS fixation. According to the MICEPS fixation, 12 patients were treated by unilateral fusion, 25 patients by bilateral fusion. All pedicle screws were inserted using spinal navigation system in the both groups. RESULTS: The average surgical time was 217 minutes with the conventional pedicle screw fixation and 165 minutes with the MICEPS fixation (P=0.0014). The average intraoperative bleeding was 560 mL in the conventional fixation and 140 mL in the MICEPS fixation (P<0.0001). Clinically significant screw deviation was significantly lower in the MICEPS fixation group than in the conventional cervical pedicle screw group (P=0.0039). There was not any deep wound infection in both groups. CONCLUSIONS: This intramuscular approach allows for horizontal pedicle screw insertion. This technique is probably useful for reducing intraoperative bleeding. In this study, incidence of screw perforation was significantly lower in the MICEPS fixation group than in the conventional cervical pedicle screw group. In particular, neither of the misplaced screws was laterally deviated in the MICEPS group.

Clinical significance of circulating miR-25-3p as a novel diagnostic and prognostic biomarker in osteosarcoma.

BACKGROUND: Emerging evidence has suggested that circulating microRNAs (miRNAs) in body fluids have novel diagnostic and prognostic significance for patients with malignant diseases. The lack of useful biomarkers is a crucial problem of bone and soft tissue sarcomas; therefore, we investigated the circulating miRNA signature and its clinical relevance in osteosarcoma. METHODS: Global miRNA profiling was performed using patient serum collected from a discovery cohort of osteosarcoma patients and controls and cell culture media. The secretion of the detected miRNAs from osteosarcoma cells and clinical relevance of serum miRNA levels were evaluated using in vitro and in vivo models and a validation patient cohort. RESULTS: Discovery screening identified 236 serum miRNAs that were highly expressed in osteosarcoma patients compared with controls, and eight among these were also identified in the cell culture media. Upregulated expression levels of miR-17-5p and miR-25-3p were identified in osteosarcoma cells, and these were abundantly secreted into the culture media in tumor-derived exosomes. Serum miR-25-3p levels were significantly higher in osteosarcoma patients than in control individuals in the validation cohort, with favorable sensitivity and specificity compared with serum alkaline phosphatase. Furthermore, serum miR-25-3p levels at diagnosis were correlated with patient prognosis and reflected tumor burden in both in vivo models and patients; these associations were more sensitive than those of serum alkaline phosphatase. CONCLUSIONS: Serum-based circulating miR-25-3p may serve as a non-invasive blood-based biomarker for tumor monitoring and prognostic prediction in osteosarcoma patients.

Ablation of MCL1 expression by virally induced microRNA-29 reverses chemoresistance in human osteosarcomas.

Osteosarcoma is a rare disease diagnosed as malignant bone tumor. It is generally refractory to chemotherapy, which contributes to its poor prognosis. The reversal of chemoresistance is a major clinical challenge to improve the prognostic outcome of osteosarcoma patients. We developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301 (telomelysin) and assessed its synergistic effects with chemotherapeutic agents (cisplatin and doxorubicin) using human osteosarcoma cell lines and a xenograft tumor model. The molecular mechanism underlying the chemosensitizing effect of OBP-301 was evaluated in aspects of apoptosis induction. OBP-301 inhibits anti-apoptotic myeloid cell leukemia 1 (MCL1) expression, which in turn leads to chemosensitization in human osteosarcoma cells. The siRNA-mediated knockdown of MCL1 expression sensitized human osteosarcoma cells to common chemotherapeutic agents. We also found that upregulation of microRNA-29 targeting MCL1 via virally induced transcriptional factor E2F-1 activation was critical for the enhancement of chemotherapy-induced apoptosis in osteosarcoma cells. Telomerase-specific oncolytic adenovirus synergistically suppressed the viability of human osteosarcoma cells in combination with chemotherapeutic agents. The combination treatment also significantly inhibited tumor growth, as compared to monotherapy, in an osteosarcoma xenograft tumor model. Our data suggest that replicative virus-mediated tumor-specific MCL1 ablation may be a promising strategy to attenuate chemoresistance in osteosarcoma patients.