The selective Cox-2 inhibitor Celecoxib suppresses angiogenesis and growth of secondary bone tumors: An intravital microscopy study in mice

BACKGROUND: The inhibition of angiogenesis is a promising strategy for the treatment of malignant primary and secondary tumors in addition to established therapies such as surgery, chemotherapy, and radiation. There is strong experimental evidence in primary tumors that Cyclooxygenase-2 (Cox-2) inhibition is a potent mechanism to reduce angiogenesis. For bone metastases which occur in up to 85% of the most frequent malignant primary tumors, the effects of Cox-2 inhibition on angiogenesis and tumor growth remain still unclear. Therefore, the aim of this study was to investigate the effects of Celecoxib, a selective Cox-2 inhibitor, on angiogenesis, microcirculation and growth of secondary bone tumors. METHODS: In 10 male severe combined immunodeficient (SCID) mice, pieces of A549 lung carcinomas were implanted into a newly developed cranial window preparation where the calvaria serves as the site for orthotopic implantation of the tumors. From day 8 after tumor implantation, five animals (Celecoxib) were treated daily with Celecoxib (30 mg/kg body weight, s.c.), and five animals (Control) with the equivalent amount of the CMC-based vehicle. Angiogenesis, microcirculation, and growth of A549 tumors were analyzed by means of intravital microscopy. Apoptosis was quantified using the TUNEL assay. RESULTS: Treatment with Celecoxib reduced both microvessel density and tumor growth. TUNEL reaction showed an increase in apoptotic cell death of tumor cells after treatment with Celecoxib as compared to Controls. CONCLUSION: Celecoxib is a potent inhibitor of tumor growth of secondary bone tumors in vivo which can be explained by its anti-angiogenic and pro-apoptotic effects. The results indicate that a combination of established therapy regimes with Cox-2 inhibition represents a possible application for the treatment of bone metastases

BMP Antagonists - A Possible Cause for Spinal Non-Fusion?

INTRODUCTION:Spinal fusion is a procedure where the intervertebral disc (IVD) is removed and two adjacent vertebrae are forced to fuse by compression. This procedure is the most commonly applied procedure to achieve spinal stability and relief of back pain. However, non-successful fusion leads to pseudo-athrosis and ongoing pain. There is increasing evidence that supraphysiological doses of BMP2 and burst-release of this cytokine did not generate satisfying results in clinical studies. Current hypothesis was raised that IVD cells and/or tissue seem to inhibit the action of BMP2. In this overview we summarize the current evidence that BMPs might be inhibited by the secretome of human IVD cells, i.e., nucleus pulposus cells (NPC), annulus fibrosus cells (AFC) and cartilaginous endplate (CEPC) cells. METHODS:We stimulated low-passage (2-3) human bonemarrow-derived mesenchymal stromal cells (MSCs) and femoral hip-derived osteoblasts (OBs) and co-cultured these with allogeneic IVD cells obtained from spinal surgery. We then stimulated MSCs and the OBs in monolayer and osteogenic medium, whereas IVD cells were kept in 3D alginate bead culture and separated by high density pore culture inserts (0.4 µm pore size). We quantified relative gene expression at bone-relevant genes, alkaline phosphatase (ALP) activity and Alizarin red (ALZR) staining after 21 days. Furthermore, to test the effect of a previously investigated BMP2 analog to block the inhibitors, cells were further stimulated with 100 ng/mL BMP2 and/or L51P. RESULTS:We found significant inhibitory effects of IVD cells onto MSCs undergoing differentiation in presence of NPC, AFC and CEPC as shown in reduced osteogenic gene expression, ALZR staining and ALP activity (N = 11 donors paired on each side). In the case of allogeneic human OBs only a trend towards inhibition could be demonstrated (N = 7 donors on each side). The addition of L51P to the coculture recovered ossification. On the side of the IVD cells BMP2 and/or L51P had a strong chondrogenic effect. DISCUSSION & CONCLUSIONS:Our data suggested evidence for inhibition for MSCs. However, OBs did not show the same inhibitory effects but showed a trend in presence of IVD’s secretome. This warrants for animal models where the donor variance can be better controlled. ACKNOWLEDGEMENTS:This work was supported by a start-up grant from the Center for Applied Biotechnology and Molecular Medicine (CABMM). Further funds were received from the Swiss Society of Orthopaedics (SGOT), the clinical trials unit (CTU) of Bern University Hospital, and by a Eurospine Task Force Research grant #2019_22

The pararectus approach-a versatile option in pelvic musculoskeletal tumor surgery.

BACKGROUND Pelvic tumors are usually resected through the utilitarian pelvic incision, an extended ilioinguinal/iliofemoral approach. The pararectus approach, an intrapelvic anatomical approach with extraperitoneal access to the pelvis, has been established previously for the treatment of pelvic and acetabular fractures. However, it has not been used to address pelvic tumors. The study aimed at investigating the feasibility of this approach for pelvic tumor surgery and the possibilities of combining this approach with standard approaches to the hip joint. METHODS Thirteen patients that underwent pelvic tumor resections were retrospectively reviewed. Tumor resections were performed through the pararectus (n = 10) or extended pararectus approach (n = 3). In six of those cases, the pararectus approach was combined with extrapelvic approaches including the modified Gibson (n = 4), the Kocher-Langenbeck (n = 1), and the trochanteric flip approach (n = 1). The mean follow-up was 32.6 ± 9.1 months. RESULTS In all cases, the tumor resections were carried out according to the preoperative plan. In seven of 13 cases, wide resections were performed; six of 13 cases were planned close resections. Four cases of major complications were observed (vascular injury, deep infection, iliac vein thrombosis, total hip arthroplasty dislocation). Minor complications were observed in two cases. One tumor recurred locally. At the final follow-up, 10 patients were alive, eight of those without evidence of disease. CONCLUSION The study demonstrated the suitability of the pararectus approach for pelvic tumor resections. The possibility to combine the approach with standard approaches to the hip joint allowed for single-stage reconstructions of the pelvis and the hip joint without sacrificing surgical margins and function. The pararectus approach is a versatile option adding to the established approaches for musculoskeletal tumor surgery of the pelvis

Seventy percent long-term survival of the repaired ACL after dynamic intraligamentary stabilization.

PURPOSE Primary repair of the anterior cruciate ligament (ACL) is regaining popularity. Long-term results are lacking. The purpose of the current study was to determine the survival of the primarily repaired ACL after dynamic intraligamentary stabilization. METHODS Between 2011 and 2013, 57 patients with acute proximal ACL ruptures underwent DIS repair within 3 weeks from injury and were available for final follow-up at least 5 years postoperatively. Failure as an end point was defined as conversion to ACL reconstruction, failure to restore stability with persisting laxity side-to-side laxity of > 5 mm or a late-traumatic re-rupture or loss of stability. Kaplan-Meier survival analysis was performed. RESULTS Kaplan-Meier survival analysis demonstrated an overall survival of 70.0% (standard error SE 6.6%) at 74 months follow-up. Patients performing competitive sports prior to injury demonstrated an inferior long-term ACL survival of 56.4% (SE 11.6%). Patients performing recreational sport activities demonstrated a survival rate of 79.2% (SE 7.7%). The one factor demonstrating a direct influence on failure after adjustment was a high-pre-injury level of physical (odds ratio 4.0 confidence interval 1.0-15.8, p = 0.04). CONCLUSION The minimum 5 years survival rate after primary ACL repair using this technique was 70%. This value dropped to 56% in highly active patients performing competitive sports. Patients not suffering failure of repair demonstrated adequate restoration of knee laxity and high satisfaction. This study not only underlines the potential of ACL repair, but also highlights the danger of the procedure if strict patient selection is not appreciated. LEVEL OF EVIDENCE Level IV

Celecoxib enhances radiation response of secondary bone tumors of a human non-small cell lung cancer via antiangiogenesis in vivo

Cyclooxygenase-2 (COX-2) inhibitors mediate a systemic antitumor activity via antiangiogenesis and seem to enhance the response of primary tumors to radiation. Radiosensitizing effects of COX-2 inhibition have not been reported for bone metastases. Therefore, the aim of this study was the investigation of the radiosensitizing effects of the selective COX-2 inhibitor celecoxib in secondary bone tumors of a non-small cell lung carcinoma in vivo

Ultrasonic cartilage thickness measurement is accurate, reproducible, and reliable—validation study using contrast-enhanced micro-CT

Abstract Background Ultrasonography is a fast and patient-friendly modality to assess cartilage thickness. However, inconsistent results regarding accuracy have been reported. Therefore, we asked what are (1) the accuracy, (2) reproducibility, and (3) reliability of ultrasonographic cartilage thickness measurement using contrast-enhanced micro-CT for validation? Methods A series of 50 cartilage–bone plugs were harvested from fresh bovine and porcine joints. Ultrasonic cartilage thickness was determined using an A-mode, 20-MHz hand-held ultrasonic probe with native (1580 m/s) and adjusted speed of sound (1696 m/s). All measurements were performed by two observers at two different occasions. Angle of insonation was controlled by tilting the device and recording minimal thickness. Retrieval of exact location for measurement was facilitated by aligning the circular design of both cartilage–bone plug and ultrasonic device. There was no soft tissue interference between cartilage surface and ultrasonic probe. Ground truth measurement was performed using micro-CT with iodine contrast agent and a voxel size of 16 μm. The mean cartilage thickness was 1.383 ± 0.402 mm (range, 0.588–2.460 mm). Results Mean accuracy was 0.074 ± 0.061 mm (0.002–0.256 mm) for native and 0.093 ± 0.098 mm (0.000–0.401 mm) for adjusted speed of sound. Bland–Altman analysis showed no systematic error. High correlation was found for native and adjusted speed of sound with contrast-enhanced micro-CT (both r = 0.973; p < 0.001). A perfect agreement for reproducibility (intraclass correlation coefficient [ICC] 0.992 and 0.994) and reliability (ICC 0.993, 95% confidence interval 0.990–0.995) was found. Conclusions Ultrasonic cartilage thickness measurement could be shown to be highly accurate, reliable, and reproducible. The A-mode ultrasonic cartilage thickness measurement is a fast and patient-friendly modality which can detect early joint degeneration and facilitate decision making in joint preserving surgery

Application of Cytokines of the Bone Morphogenetic Protein (BMP) Family in Spinal Fusion - Effects on the Bone, Intervertebral Discs, and Mesenchymal Stromal Cells.

Low back pain is a prevalent socio-economic burden and is often associated with damaged or degenerated intervertebral discs (IVDs). When conservative therapy fails, removal of the IVD (discectomy), followed by intersomatic spinal fusion, is currently the standard practice in clinics. The remaining space is filled with an intersomatic device (cage) and bone substitutes to achieve disc height compensation and bone fusion. As a complication, in up to 30% of cases, spinal non-fusions result in a painful pseudoarthrosis. Bone morphogenetic proteins (BMPs) have been clinically applied with varied outcomes. Several members of the BMP family, such as BMP2, BMP4, BMP6, BMP7, and BMP9, are known to induce osteogenesis. Questions remain on why hyper-physiological doses of BMPs do not show beneficial effects in certain patients. In this respect, BMP antagonists secreted by mesenchymal cells, which might interfere with or block the action of BMPs, have drawn research attention as possible targets for the enhancement of spinal fusion or the prevention of non-unions. Examples of these antagonists are noggin, gremlin1 and 2, chordin, follistatin, BMP3, and twisted gastrulation. In this review, we discuss current evidence of the osteogenic effects of several members of the BMP family on osteoblasts, IVD cells, and mesenchymal stromal cells. We consider in vitro and in vivo studies performed in human, mouse, rat, and rabbit related to BMP and BMP antagonists in the last two decades. We give insights into the effects that BMP have on the ossification of the spine. Furthermore, the benefits, pitfalls, and possible safety concerns using these cytokines for the improvement of spinal fusion are discussed

Multiple myeloma-associated amyloidoma of the sacrum: case report and review of the literature.

Study Design Case report. Objectives With only two previously reported cases, localized amyloidosis of the sacrum is extremely rare. Here we report a 64-year-old woman with a large osteolytic lesion accompanied by weakness and paresthesia of the right leg and difficulties in bladder control. Methods Fine needle biopsy and standard staging procedures revealed a primary solitary amyloidoma that was treated with intralesional resection, lumbopelvic stabilization, and consolidation radiotherapy. Results Clinical follow-up revealed the diagnosis of multiple myeloma 9 months after initial treatment. At 12 months, no local recurrence has occurred, the neurologic symptoms have resolved, and the systemic disease is in remission. Conclusions Intralesional resection with adjuvant radiotherapy of the amyloidoma achieved good local tumor control with limited morbidity

Flap Reconstruction Outcome Following Surgical Resection of Soft Tissue and Bone Sarcoma in the Setting of (Neo)adjuvant Therapy: A Sarcoma Center Experience

Background: Soft tissue and bone sarcomas are heterogeneous groups of malignant tumors. The shift in their management, with an emphasis on limb salvage, has deemed the involvement of reconstructive surgeons an integral part of their multidisciplinary treatment. We present our experience with free and pedicled flaps in the reconstruction of sarcomas at a tertiary referral university hospital and major sarcoma center. Materials and Methods: All patients undergoing flap reconstruction after sarcoma resection over a 5-year period have been included in the study. Patient-related data and postoperative complications were collected retrospectively, ensuring a minimum follow-up of 3 years. Results: A total of 90 patients underwent treatment with 26 free flaps and 64 pedicled flaps. Postoperative complications occurred in 37.7% of patients, and the flap failure rate was 4.4%. Diabetes, alcohol consumption and male gender were associated with increased early necrosis of the flap. Preoperative chemotherapy significantly increased the occurrence of early infection and late dehiscence, while preoperative radiotherapy was associated with a higher incidence of lymphedema. Intraoperative radiotherapy was associated with late seromas and lymphedema. Conclusions: Reconstructive surgery with either pedicled or free flaps is reliable, but it can be demanding in the setting of sarcoma surgery. A higher complication rate is to be expected with neoadjuvant therapy and with certain comorbidities