Full-thickness chest wall resection for malignant chest wall tumors and postoperative problems.

Background: Chest wall malignant tumor (including primary and metastatic lesions) is rare, representing less than 5% of all thoracic malignancies. Local control of chest wall malignancies requires wide resection with tumor-free margins. These requirements increase the risk of thoracic cavity failure and subsequent pulmonary failure. The restoration strategy for chest wall defects comprises chest wall reconstruction and soft-tissue coverage. Various reconstruction methods have been used, but both evidence and guidelines for chest wall reconstruction remain lacking. The purposes of this study were to collate our institutional experience, evaluate the outcomes of full-thickness chest wall resection and reconstruction for patients with chest wall malignant tumor, and identify problems in current practice for chest wall reconstruction with a focus on local control, complications, pulmonary function and scoliosis. Methods: Participants comprised 30 patients with full-thickness chest wall malignant tumor who underwent chest wall resection and reconstruction between 1997 and 2021 in Mie University Hospital. All patients underwent chest wall resection of primary, recurrent or metastatic malignant tumors. A retrospective review was conducted for 32 operations. Results: Recurrence was observed after 5 operations. Total 5-year recurrence-free survival (RFS) rate was 79.3%. Diameter ≥5 cm was significantly associated with poor RFS. The postoperative complication rate was 18.8%. Flail chest was observed with resection of ≥3 ribs in anterior and lateral resections or with sternum resection without polyethylene methylmethacrylate reconstruction. Postoperative EFV1.0% did not show any significant decrease. Postoperative %VC decreased significantly with resection of ≥4 ribs or an area of >70 cm2. Postoperative scoliosis was observed in 8 of 28 patients. Posterior resection was associated with a high prevalence of scoliosis (88.9%). Conclusion: With chest wall reconstruction, risks of pulmonary impairment, flail chest and scoliosis were significantly increased. New strategies including indications for rigid reconstruction are needed to improve the outcomes of chest wall reconstruction.

A Novel Approach to Reducing Lung Metastasis in Osteosarcoma: Increasing Cell Stiffness with Carbenoxolone.

AIM: Primary malignant bone tumor osteosarcoma can metastasize to the lung. Diminishing lung metastasis would positively affect the prognosis of patients. Our previous studies demonstrated that highly metastatic osteosarcoma cell lines are significantly softer than low-metastasis cell lines. We therefore hypothesized that increasing cell stiffness would suppress metastasis by reducing cell motility. In this study, we tested whether carbenoxolone (CBX) increases the stiffness of LM8 osteosarcoma cells and prevents lung metastasis in vivo. METHODS: We evaluated the actin cytoskeletal structure and polymerization of CBX-treated LM8 cells using actin staining. Cell stiffness was measured using atomic force microscopy. Metastasis-related cell functions were analyzed using cell proliferation, wound healing, invasion, and cell adhesion assays. Furthermore, lung metastasis was examined in LM8-bearing mice administered with CBX. RESULTS: Treatment with CBX significantly increased actin staining intensity and stiffness of LM8 cells compared with vehicle-treated LM8 cells (p < 0.01). In Young's modulus images, compared with the control group, rigid fibrillate structures were observed in the CBX treatment group. CBX suppressed cell migration, invasion, and adhesion but not cell proliferation. The number of LM8 lung metastases were significantly reduced in the CBX administration group compared with the control group (p < 0.01). CONCLUSION: In this study, we demonstrated that CBX increases tumor cell stiffness and significantly reduces lung metastasis. Our study is the first to provide evidence that reducing cell motility by increasing cell stiffness might be effective as a novel anti-metastasis approach in vivo.

Do coagulation or fibrinolysis reflect the disease condition in patients with soft tissue sarcoma?

BACKGROUND: Coagulation and fibrinolysis are distinct processes that are highly correlated. Cells control coagulation and fibrinolysis by expression of tissue factor and urokinase-type plasminogen activator receptor on their surface. Tumor cells express these proteins, adjust their microenvironment and induce tumor exacerbation. We hypothesized that the expression of plasma markers for coagulation and fibrinolysis in patients with soft tissue sarcomas (STSs) was dependent on the level of tumor malignancy. To elucidate which markers are predictive of recurrence, metastasis and prognosis, coagulation or fibrinolysis, we analyzed the correlation between plasma levels of thrombin-antithrombin III complex (TAT), soluble fibrin (SF), plasmin-α2 plasmin inhibitor complex (PIC), D-dimer (DD) and clinical parameters in patients with STSs. METHODS: TAT, SF, PIC or DD were measured in pre-treatment blood samples from 64 patients with primary STSs and analyzed with clinicopathological parameters, and 5-year recurrence free survival (RFS), 5-year metastasis free survival (MFS) and 5-year overall survival (OS) were evaluated. RESULTS: The metastasis group had significantly higher DD (p = 0.0394), PIC (p = 0.00532) and SF (p = 0.00249) concentrations than the group without metastasis. The group that died of disease showed significantly higher DD (p = 0.00105), PIC (p = 0.000542), SF (p = 0.000126) and TAT (p = 0.0373) than surviving patients. By dividing the patients into low and high groups, the group with high DD, PIC, SF and TAT showed significantly lower 5-year MFS and 5-year OS than the corresponding low group. Furthermore, in multivariate COX proportional hazard analysis of continuous variables for 5-year MFS, only PIC was found to be a significant factor (HR: 2.14). CONCLUSION: Fibrinolysis was better than coagulation at reflecting the disease condition of patients with STS. Notably, PIC levels ≥ 1.1 can not only predict the risk of metastasis and poor prognosis, but also increasing PIC levels correspond to further increases in risks of metastasis and poor prognosis.

Compound Library Screening for Synergistic Drug Combinations: mTOR Inhibitor and Proteasome Inhibitor Effective Against Osteosarcoma Cells.

BACKGROUND/AIM: The development of new drugs is urgently needed for new treatment strategies that can improve the prognosis of osteosarcoma (OS). In this study, we attempted to identify combinations of new molecular-targeted agents for OS. MATERIALS AND METHODS: A library containing 324 compounds was used. For the first screening, MG-63 OS cells were treated with each of the compounds and cell viability was measured. After the best candidate compound was decided, the compound was included in a second screening. The combination of most effective compounds was decided. The antiproliferative effect of the combination was examined and the cell signaling mechanism was evaluated by western blot analysis. 143B OS-bearing mice were used for in vivo antitumor testing. RESULTS: In the first screening, bortezomib was chosen as the effective drug. In the second screening with bortezomib, everolimus was chosen. This combination showed a synergistic inhibitory effect on cell proliferation when compared to monotherapy with each of these drugs alone. Compared to monotherapy, the combination therapy enhanced the levels of cleaved poly (ADP-ribose) polymerase, caspase-3, caspase-8 and caspase-9, phospho-c-Jun N-terminal kinase, and P38. In contrast, the levels of c-MYC proto-oncogene bHLH transcription factor, survivin, and phospho-cyclin D1 were reduced. The combination effectively induced apoptosis and interfered with cell cycle progression. In the in vivo analysis, the combination therapy significantly inhibited tumor growth. CONCLUSION: The combination of everolimus and bortezomib demonstrated a synergistic effect against OS both in vitro and in vivo. These results indicate that this combination may be useful as a novel therapeutic strategy for OS.

GPR64, Screened from Ewing Sarcoma Cells, Is a Potential Target for Antibody-Based Therapy for Various Sarcomas.

Ewing sarcoma is an aggressive and the second most common bone tumor in adolescent and young adult patients. The 5-year survival rate is 60-70% for localized disease but 30% for patients with metastases. Here, we aimed to identify a therapeutic target for Ewing sarcoma and evaluate antibody-based therapeutic agents using in vitro and in vivo models. We identified G protein-coupled receptor 64 (GPR64) as a therapeutic target for Ewing sarcoma via next-generation RNA-sequencing. GPR64v205 mRNA was expressed in HTB166, A673, MG63, 143B, HS-Sy II, and HT1080 cell lines as well as in Ewing sarcoma, undifferentiated pleomorphic sarcoma, leiomyosarcoma, dedifferentiated liposarcoma, and synovial sarcoma tissues. GPR64 expression was observed in 62.5% of sarcoma cases and was overexpressed in 33.9% cases. GPR64-specific monoclonal antibodies were tested as near-infrared probes for in vivo imaging using subcutaneous tumor mouse xenografts. Fluorescence intensity was stronger for the AF700-labeled anti-GPR64 antibody than that for the AF700-labeled isotype control antibody. GPR64 was detected in engrafted tumors of A673, 143B, HT1080, and the epididymis but not in other resected tissues. The anti-GPR64 antibody showed excellent binding to GPR64-positive tumors but not to healthy tissues. This antibody has potential for drug delivery in the antibody-based treatment of sarcomas.

Cytoskeletal Actin Structure in Osteosarcoma Cells Determines Metastatic Phenotype via Regulating Cell Stiffness, Migration, and Transmigration.

Osteosarcoma is the most common primary malignant bone tumor. The cause of death due to osteosarcoma is typically a consequence of metastasis to the lung. Controlling metastasis leads to improved prognosis for osteosarcoma patients. The cell stiffness of several tumor types is involved in metastatic potential; however, it is unclear whether the metastatic potential of osteosarcoma depends on cell stiffness. In this study, we analyzed the cell stiffness of the low metastatic Dunn cell line and its highly metastatic LM8 subline, and compared actin organization, cell proliferation, and metastasis. Actin cytoskeleton, polymerization, stiffness, and other cellular properties were analyzed. The organization of the actin cytoskeleton was evaluated by staining F-actin with Alexa Fluor 488 phalloidin. Cell stiffness was measured using Atomic Force Microscopy (AFM). Cell proliferation, migration, invasion, and adhesion were also evaluated. All experiments were performed using mouse osteosarcoma cell lines cultured in the absence and presence of cytochalasin. In LM8 cells, actin polymerization was strongly suppressed and actin levels were significantly lower than in Dunn cells. Stiffness evaluation revealed that LM8 cells were significantly softer than Dunn. Young's modulus images showed more rigid fibrillar structures were present in Dunn cells than in LM8 cells. LM8 cells also exhibited a significantly higher proliferation. The migration and invasion potential were also higher in LM8 cells, whereas the adhesion potential was higher in Dunn cells. The administration of cytochalasin resulted in actin filament fragmentation and decreased actin staining intensity and cell stiffness in both LM8 and Dunn cells. Cells with high metastatic potential exhibited lower actin levels and cell stiffness than cells with low metastatic potential. The metastatic phenotype is highly correlated to actin status and cell stiffness in osteosarcoma cells. These results suggest that evaluation of actin dynamics and cell stiffness is an important quantitative diagnostic parameter for predicting metastatic potential. We believe that these parameters represent new reliable quantitative indicators that can facilitate the development of new drugs against metastasis.

Significance of coagulation and fibrinolysis markers for benign and malignant soft tissue tumors.

BACKGROUND: The intimate relationship between coagulation and fibrinolysis in malignant tumors is a well-known phenomena, with the malignant phenotype enhancing coagulation and fibrinolysis. We hypothesized that soft tissue sarcoma (STS) affects the expression of coagulation and fibrinolysis markers, which could be used to distinguish STS from benign soft tissue tumors. We analyzed the correlations between plasma levels of D-dimer (DD), plasmin-α2 plasmin inhibitor complex (PIC), soluble fibrin (SF), and thrombin-antithrombin III complex (TAT) in benign soft tissue tumors and STS to elucidate whether these markers can be used to predict STS. METHODS: Plasma DD, PIC, SF and TAT levels in primary soft tissue tumors (benign 67, STS 68) were measured before biopsy or treatment. The marker levels were analyzed and compared to various clinicopathological parameters. RESULTS: In malignancy (STS), the average DD, PIC and SF levels were significantly higher than in benign tumors. Multivariate logistic analysis of continuous variables indicated that only PIC exhibited a significant difference (OR: 24.5, 95%CI: 3.55-170, p = 0.0012). Receiver operating characteristic curve analysis produced area under the curve values for DD: 0.691, PIC: 0.784, SF: 0.734 and TAT: 0.588. Youden's index was used to establish thresholds of 0.37 (DD), 0.80 (PIC), 0.90 (SF) and 0.82 (TAT). Threshold values for PIC and SF indicated high specificity (0.881, 0.791) and high positive predictive value (0.818, 0.745), respectively. The highest accuracy value among the markers was observed for PIC (0.704). Significant differences in multivariate analysis of binary variables were demonstrated by categorizing low and high groups based on their threshold, PIC (≥0.80) (OR: 3.36, 95%CI: 1.19-9.43, p = 0.0212) and SF (≥0.90) (OR: 2.63, 95%CI: 1.04-6.66, p = 0.0404) . CONCLUSIONS: Of the coagulation and fibrinolysis markers studied, increased PIC levels were related to STS and over 0.80 PIC was the most suitable for the prediction of STS, which, along with other diagnostic tools, represents a helpful subsidiary tool for the prediction of STS.

Deep vein thrombosis of the upper extremity caused by central venous port in a patient with soft tissue sarcoma: A case report.

Deep vein thrombosis (DVT) more commonly occurs in the lower extremities, whereas involvement of the upper extremities is rare. The present case report describes the clinical course of the development and treatment of upper extremity DVT (UEDVT) following insertion of an indwelling central venous (CV) port in a patient with soft tissue sarcoma (STS) of the thigh. A 66-year-old man was referred to our hospital for STS treatment. The indwelling CV port was placed via the left subclavian vein, and two courses of neoadjuvant chemotherapy were administered. Two months after the catheter placement, DVT was detected from the left upper arm to the left internal jugular vein. Anticoagulation therapy with warfarin was started and DVT was undetectable at 5 months after surgery. In conclusion, DVT may occur in cancer patients who undergo treatment with indwelling CV ports. Therefore, screening should be conducted concurrently with surgical resection and chemotherapy for STS.

Anti-tumour effect of tocilizumab for osteosarcoma cell lines.

AIMS: Tocilizumab, an interleukin-6 (IL-6) receptor (IL-6R) targeting antibody, enhances the anti-tumour effect of conventional chemotherapy in preclinical models of cancer. We investigated the anti-tumour effect of tocilizumab in osteosarcoma (OS) cell lines. METHODS: We used the 143B, HOS, and Saos-2 human OS cell lines. We first analyzed the IL-6 gene expression and IL-6Rα protein expression in OS cells using reverse transcription real time quantitative-polymerase chain reaction (RT-qPCR) analysis and western blotting, respectively. We also assessed the effect of tocilizumab on OS cells using proliferation and invasion assay. RESULTS: The OS cell lines 143B, HOS, and Saos-2 expressed IL-6R. Recombinant human IL-6 treatment increased proliferation of 143B and HOS cells. Tocilizumab treatment decreased proliferation and invasion of 143B, HOS, and Saos-2. CONCLUSION: In conclusion, we confirmed the production of IL-6 and the expression of IL-6R in OS cells and demonstrated that tocilizumab inhibits proliferation and invasion in OS cells. Cite this article: Bone Joint Res 2020;9(11):821-826.

Prognostic Significance of Thrombomodulin mRNA in High-Grade Soft Tissue Sarcomas after 10 years.

OBJECTIVE: To elucidate the correlation between expression of thrombomodulin (TM) mRNA from 83 benign soft tissue tumors or soft tissue sarcomas (STS) and clinicopathological parameters and to analyze the outcome of high-grade STS patients after 10 years. METHODS: Total RNA was extracted from 83 primary soft tissue tumors (15 benign tumors, 68 STS). TM mRNA normalized to glyceraldehyde-3-phosphate dehydrogenase was measured with real-time quantitative polymerase chain reaction and compared to various clinicopathological parameters. The log-rank test and Cox proportional hazard analysis were used to evaluate recurrence-free survival, metastasis-free survival, and overall survival. RESULTS: Thrombomodulin mRNA levels were not significantly different between benign tumors and STS. In STS, TM mRNA levels were not significantly different between histologically high-grade (n = 57) and low-grade (n = 11) tumors. Following analysis of high-grade STS at the 10-year follow-up, 21 patients had experienced a recurrence, 22 patients had experienced metastasis, and 23 patients had died of disease (DOD). TM levels were significantly higher in patients with metastasis or DOD patients. Receiver operating characteristic analysis for identifying 5-year and 10-year DOD determined the threshold for best sensitivity and specificity as 0.283. We divided patients into those with high (<0.283) and low (≤0.283) TM mRNA levels. Based on Kaplan-Meier analysis, a significant difference between the two groups was seen for recurrence-free survival (5 years: low = 76.6%, high = 53.1%, 10 years: low: 67.0%, high 39.8%, P = 0.0122) and metastasis-free survival (5 years: low = 86.3%, high = 40.2%, 10 years: low: 73.3%, high: 35.2%, P = 0.00023). Furthermore, the high TM group showed significantly worse prognosis than the low TM group (5 years: low = 90.1%, high = 42.3%, 10 years: low: 76.4%, high 31.3%, P = 0.00031). Thus, high levels of TM mRNA are associated with highly recurrent and metastatic potential and lead to poor prognosis. In multivariate Cox proportional hazard analysis, only high TM showed a significant difference in metastasis-free survival (hazard ratio: 4.33, 95% confidence interval 1.61-11.6, P = 0.00359) and overall survival (hazard ratio: 3.69, 95% confidence interval 1.49-10.5, P = 0.00569). CONCLUSION: High levels of TM mRNA may be a significant predictor of recurrence, metastasis, and a poor outcome in STS patients after 10 years. TM is a candidate molecular marker and may be clinically useful for devising a therapeutic treatment strategy by prediction of prognosis.

Clinical outcome of latissimus dorsi reconstruction after wide resection of soft-tissue sarcoma.

BACKGROUND: We investigated the clinical outcomes of reconstruction using the latissimus dorsi (LD) flap after resection of soft-tissue sarcoma. MATERIALS AND METHODS: We analyzed 19 patients. Free LD flap was performed in 11 patients and pedicle flap in eight patients. The mean follow-up period after the surgery was 60 months. RESULTS: The mean age at diagnosis was 57 years. The mean tumor size was 9.8 cm. The median size of the LD flap was 140 × 100 mm. The mean surgical duration and bleeding were 510 min and 602 mL, respectively. Complications included partial skin and soft-tissue necrosis (n = 3) and wound dehiscence (n = 2). No additional free flap was not necessary for the closure of the defect due to the complications. The longer surgical duration was significantly associated with wound complications (P = 0.048). The 5-year survival rate was 80.7%, and the local recurrence-free survival rate was 89.2%. Two patients developed local recurrence, while 6 patients developed metastasis. None of the patients had any restrictions of daily life. CONCLUSION: The LD flap after surgical tumor resection in patients with soft-tissue sarcoma was useful for the coverage of soft tissue.

Soluble programmed death-ligand 1 rather than PD-L1 on tumor cells effectively predicts metastasis and prognosis in soft tissue sarcomas.

The soluble form of PD-L1 (sPD-L1) is related to a poor prognosis in various cancers. Comparisons of sPD-L1 and PD-L1 expressed on tumor cells in soft tissue tumor patients have not been reported. The purpose of this study was to analyze serum sPD-L1 and PD-L1 levels in soft tissue tumor patients. A total of 135 patients with primary soft tissue tumors were enrolled in this study. The sPD-L1 level was quantitatively measured by enzyme immunoassay, and PD-L1 expression on high grade sarcoma cells was analyzed immunohistologically. There were no significant differences in sPD-L1 levels between benign (48) and soft tissue sarcoma (STS) patients (87). In STS, the high sPD-L1 (>44.26 pg/mL) group had significantly lower metastasis-free survival (MS) and lower overall survival (OS) than the low sPD-L1 group (≤44.26 pg/mL) at 5 years using the log-rank test. On multivariate Cox proportional hazard analysis, the high sPD-L1 group had significant differences in MS and OS compared to the low sPD-L1 group. Between positive and negative immunostaining groups, recurrence-free survival (RS), MS, and OS were not significantly different. No correlation was found between immunostaining and sPD-L1 with the Kappa coefficient. The sPD-L1 concentration could predict future metastasis and prognosis in STS patients. High sPD-L1 in STS patients may be a target for treatment with checkpoint inhibitors.

Expression of Interleukin-6 and the Interleukin-6 Receptor Predicts the Clinical Outcomes of Patients with Soft Tissue Sarcomas.

Interleukin-6 (IL-6) affects the key parameters of oncogenesis, which increases the cell resistance to apoptosis, the proliferation of cancer cells, angiogenesis, invasion, malignancy, and the ability of tumor cells to respond to anticancer therapy. This study aimed to elucidate the association between IL-6 and IL-6 receptor (IL-6R) expression in tissues and clinical outcomes in patients with soft tissue sarcomas (STSs) because, to our knowledge, this has not been done before. We enrolled 86 patients with histologically-proven localized STSs who underwent surgical resection. The cohort included 48 men and 38 women, with a mean age of 65.6 years. The mean follow-up duration was 40.5 months. The expression of IL-6 and IL-6R was immunohistochemically determined. We analyzed prognostic factors for overall survival (OS) and metastasis-free survival (MFS). High IL-6 expression was observed in 23.3% (20/86), high IL-6R expression in 44.2% (38/86), and high expression of both in 16.3% (14/86) of patients. Multivariate analysis showed that a high expression of both IL-6 and IL-6R was a prognostic factor for OS and MFS. We found that this high expression indicated that the patient had a poor prognosis for OS and MFS.

Serum thrombomodulin as a metastatic and prognostic marker in soft tissue sarcomas.

BACKGROUND: Thrombomodulin (TM) has multiple biological functions and modulates not only anti-coagulation, but also cell proliferation, adhesion, and anti-inflammation activities. The main function of TM is to activate the anticoagulant pathway of protein C. Soluble TM is related to metastasis by its inactivation of thrombin. OBJECTIVES: To clarify the correlation between serum TM levels and clinicopathological parameters. METHODS: The plasma TM levels (FU/ml) of 135 primary soft tissue tumors (benign, 67; soft tissue sarcoma (STS), 68) were measured before biopsy or treatment. TM levels were analyzed and compared to various clinicopathological parameters. Log-rank test and Cox proportional analysis were used to evaluate recurrence-free survival, metastasis-free survival, and overall survival. RESULTS: STS tumors had significantly higher TM values (15.9) than benign tumors (13.7) (p= 0.0138). 5-year MFS was 81.1% in low TM and 40.0% in high TM (p= 0.00671), and 5-year OS was 85.5% in low and 52.5% in high TM in grades 1-3 (p= 0.0673). In multivariate COX proportional analysis, high-TM showed a significant difference (MFS: HR 4.37, p= 0.0147; OS: HR 3.60, p= 0.0557) in grades 1-3. CONCLUSIONS: We demonstrated that a high level of soluble TM has the potential to be a significant predictor of metastasis and poor prognosis in STS patients. TM is a candidate molecular marker for high metastatic potential and can be clinically useful for guiding therapeutic strategy.

Successful treatment with cryoablation in a patient with bone metastasis in the mid-shaft femur: a case report.

Background: Treatment of metastatic bone tumors is challenging due to the morbidity associated with patients with metastasis. The present case report described a patient with successful treatment of bone metastasis using cryoablation with plate and cementation to prevent fracture for bone metastasis of leiomyosarcoma in the mid-shaft of the femur. Case report: The metastatic tumor was located at intramedullary lesion of the femur. At first, cryoablation was performed under local anesthesia. After one week after cryoablation, curettage and fixation with plate and cementation were performed to prevent fracture. Tumor cells were not observed in the histopathological findings of the curettage tissue. Four years after cryoablation, there was no recurrence and the patient could walk without any support. Conclusion: We suggest that a tumor with limited cancellous bone and of a small size may undergo cryoablation. The prevention of fracture after cryoablation should be considered.

Efficacy of preoperative skin traction for hip fractures: a single-institution prospective randomized controlled trial of skin traction versus no traction.

BACKGROUND: Preoperative traction for hip fractures is of no benefit in semi-urgent surgery. However, its efficacy has not been assessed in cases in which emergency surgery was not possible. We evaluated the efficacy of preoperative skin traction for hip fractures in a level II trauma center in Japan where many patients undergo delayed surgery. METHODS: We undertook a randomized controlled trial. Eighty-one patients were randomized to be treated with skin traction (41 patients), or bed rest (40 patients). Preoperative pain was assessed by use of a visual analogue scale and the number of analgesics required. Fracture reduction was measured on the basis of leg-length and neck-shaft angle discrepancies on the radiograph on admission, a day before surgery, and after surgery. RESULTS: The mean time from admission to surgery was 7.5 days. Pain decreased markedly on the day after admission in both the traction and no-traction groups. No significant difference was found during the preoperative waiting period between the groups in either pain score or number of analgesics taken. No significant difference was found in radiographic data either before or after surgery, and satisfactory reduction was achieved after surgery irrespective of the use of skin traction. CONCLUSIONS: In our single-institution prospective randomized controlled trial, preoperative skin traction for patients with hip fracture had no effect on pain relief before surgery or reduction of fracture displacement during surgery, irrespective of preoperative waiting time.