Combination therapy with immune checkpoint inhibitors and denosumab improves clinical outcomes in non-small cell lung cancer with bone metastases.

BACKGROUND: The concomitant use of denosumab and immune checkpoint inhibitor (ICI) treatment may have synergistic effects and enhance antitumor activity; however, this has not been fully evaluated. This study aimed to evaluate the clinical outcomes of non-small cell lung cancer (NSCLC) patients with bone metastases receiving combination therapy and to identify the best combination regimen. METHODS: Eighty-six NSCLC patients with bone metastases who received ICI treatment were enrolled in this study. The patients were divided into two groups; a denosumab combination group (D + ICI group; n = 47) and a non-combination group (non-D + ICI group; n = 39). The response rate (RR) for bone metastases, disease control rate (DCR), overall survival (OS), real world progression-free survival (rwPFS), and the incidence of immune-related adverse events (irAEs) were evaluated. Additionally, the time when denosumab treatment should commence and concomitant treatment duration were evaluated. RESULTS: The D + ICI group showed significantly better RR (40.4 % vs. 20.5 %, p = 0.01), DCR (67.3 % vs. 38.7 %, p = 0.02), OS (14.2 vs. 8.6 months, p = 0.02), and rwPFS (7.4 vs. 3.6 months, p < 0.01) than the non-D + ICI group; however, incidence of irAEs showed no difference (29.7 % vs. 12.8 %, p = 0.07). Although clinical outcomes did not differ regardless of whether denosumab was initiated before or after ICI treatment, the group that received concomitant denosumab for more than four months had significantly better RR (46.2 % vs. 17.4 %, p = 0.03), OS (20.3 vs. 3.8 months, p < 0.01), and rwPFS (10.9 vs. 2.8 months, p < 0.01) than the group that received concomitant denosumab for less than four months. However, the landmark analysis showed no significant differences in OS (20.4 vs. 12.7 months, p = 0.11) and rwPFS (22.8 vs. 11.2 months, p = 0.21), and the results of denosumab duration were influenced by long-term survivors. CONCLUSION: Denosumab showed favorable synergistic effects with ICI treatment and may significantly improve the response to bone metastasis and prognosis without increasing the incidence of irAEs.

Membrane Formed Around Liquid Nitrogen-treated Bone Promotes Osteogenesis and Revitalization in a Rat Model.

BACKGROUND/AIM: This study aimed to investigate the structure and functions of the membrane formed around liquid nitrogen-treated bones in the osteogenesis and revitalization of frozen bone using a rat model. MATERIALS AND METHODS: Segmental defects were created in femurs of rats, and resected bones treated with liquid nitrogen [frozen bone (FB) group, n=20] or polymethylmethacrylate (PMMA group; n=20) were implanted as spacers. Histological analysis and quantitative real-time reverse transcription-polymerase chain reaction (qRT-PCR) of the membrane around each spacer were performed for bone morphogenetic protein 2 (BMP2), transforming growth factor (TGF)-ß1, and vascular endothelial growth factor (VEGF). Furthermore, in week 2, spacers were removed from both groups (n=5 each), and autologous cancellous bone (ACB) harvested from the ilium was grafted into the defect. Radiological analysis was performed until bone union was observed. RESULTS: In week 2, similar two-layered membrane structures were observed in both groups; these matured into fibrous tissues over time. At each evaluation point, qRT-PCR showed higher expression of all factors in the FB than in the PMMA group. In the ACB graft model, the mean period to bone union and new bone volume were significantly shorter and greater, respectively, in the FB. Chondrocytes invaded the osteotomy site from the membrane in the FB, suggesting that endochondral ossification may occur and be related to osteogenesis. Additionally, fibroblasts and capillaries in the membrane invaded the surface of treated bone in week 2, and osteocytes were observed around them in weeks 6 and 8. CONCLUSION: Fibrous membranous tissue formed around liquid nitrogen-treated bones may be vital for osteogenesis and revitalization of frozen bones.

What are the Optimal Systemic Treatment Options for Rhabdomyosarcoma?

OPINION STATEMENT: Rhabdomyosarcoma, a soft tissue sarcoma commonly observed in childhood, requires multidisciplinary treatment, including surgical tumor resection, chemotherapy, and radiation therapy. Although long-term survival can be expected in patients with localized rhabdomyosarcoma, the clinical outcomes in patients with metastatic or unresectable rhabdomyosarcoma remain unsatisfactory. To improve the outcomes of rhabdomyosarcoma, it is important to explore effective systemic treatments for metastatic rhabdomyosarcoma. Currently, multiagent chemotherapy comprising vincristine, actinomycin D, and ifosfamide/cyclophosphamide remains standard systemic treatment for rhabdomyosarcoma. On the other hand, new treatment, such as immune checkpoint inhibitors and molecular targeted drugs, have demonstrated superior clinical outcomes compared to those of standard treatments in various type of malignancies. Therefore, it is necessary to assess the efficacies of these treatments in patients with rhabdomyosarcoma. Recent clinical studies have shown efficacies and safeties of temozolomide combined with vincristine/irinotecan, olaratumab combined with doxorubicin or vincristine/irinotecan, and long-term maintenance therapy. Furthermore, basic researches demonstrated new therapeutic targets. Future studies using these approaches are required to assess their clinical significances.

Combining dynamics of serum inflammatory and nutritional indicators as novel biomarkers in immune checkpoint inhibitor treatment of non-small-cell lung cancer with bone metastases.

OBJECTIVES: We aimed to investigate the association of the dynamics of serum inflammatory and nutritional indicators with immune checkpoint inhibitor (ICI) response in non-small-cell lung cancer (NSCLC) with bone metastases, and to develop a novel predictive scoring system based on these indicators. METHODS: Patients with NSCLC having bone metastases treated with ICIs were categorized as: the development cohort (January 2016 to March 2021, n = 60) and the validation cohort (April 2021 to June 2023, n = 40). Serum indicators of inflammation and nutrition such as C-reactive protein (CRP), neutrophil-to-lymphocyte ratio (NLR), albumin, prognostic nutritional index (PNI) were investigated before and six weeks after ICI initiation. The correlations of these dynamics with bone metastasis response rate (BoMRR) and overall survival (OS) were analyzed. A scoring system consisting of independent predictors was developed (IMMUNO-SCORE) and correlations with clinical outcomes were validated using the validation cohort. RESULTS: In the development cohort, multivariable analysis showed that NLR and PNI dynamics and CRP, NLR, and PNI dynamics were independent predictors of BoMRR and OS, respectively. The IMMUNO-SCORE consisting of NLR and PNI dynamics, which were the common predictors of the clinical outcomes, was significantly correlated with BoMRR (p < 0.01) and OS (p < 0.001) in cross-validation. The area under the curve of the score (0.786) was higher than individual NLR and PNI dynamics (0.72 and 0.684). CONCLUSION: Dynamics in NLR and PNI were demonstrated as biomarkers of treatment response and prognosis in ICI treatment of NSCLC with bone metastases, and the score combining these biomarkers was significantly correlated with clinical outcomes.

Clinical features of patients with carcinoma soft tissue metastases as surgical indications: a retrospective cohort study.

BACKGROUND: Soft-tissue metastasis of carcinoma is rare. In the present study, we investigated the surgical indications and clinical features of patients with soft tissue metastases of carcinoma. METHODS: In this retrospective cohort study, we enrolled 26 patients with soft tissue carcinoma metastasis referred to our department for treatment. Sex, age, location, size, depth, pain due to the tumor, primary origin, serum C-reactive protein (CRP) level, MRI examinations, diagnosis by a previous physician, carcinoma markers from blood, history of carcinoma, other metastases, performance status (PS), and surgical procedures were documented. Associations between variables and surgery were statistically analyzed. RESULTS: The primary cancer origin was found to be the lung (n = 10), kidney (n = 7), esophagus (n = 2), stomach (n = 1), breast (n = 1), liver (n = 1), ureter (n = 1), anus (n = 1), and unknown (n = 2). The mean CRP level of all patients was 2.3 mg/dL. Seven tumors (26.9%) were originally suspected to be soft tissue metastases of carcinoma, while 19 tumors (73.1%) were considered soft tissue sarcomas or inflammatory lesions by the previous treating physician. Twenty patients (76.9%) had other metastases. The PS of the 12 patients (46.2%) was zero. Eleven patients (42.3%) underwent surgery for soft tissue metastases. Diagnosis of soft tissue metastasis by a previous physician and good PS (p < 0.05) were significantly associated with surgery. CONCLUSION: Overall, the present results show that surgical indications for soft tissue metastasis of carcinoma include diagnosis by the referring physician or good PS of the patients.

Development and validation of a nomogram to predict surgical site infection after soft-tissue sarcoma resection.

Aims: Surgical site infection (SSI) after soft-tissue sarcoma (STS) resection is a serious complication. The purpose of this retrospective study was to investigate the risk factors for SSI after STS resection, and to develop a nomogram that allows patient-specific risk assessment. Methods: A total of 547 patients with STS who underwent tumour resection between 2005 and 2021 were divided into a development cohort and a validation cohort. In the development cohort of 402 patients, the least absolute shrinkage and selection operator (LASSO) regression model was used to screen possible risk factors of SSI. To select risk factors and construct the prediction nomogram, multivariate logistic regression was used. The predictive power of the nomogram was evaluated by receiver operating curve (ROC) analysis in the validation cohort of 145 patients. Results: LASSO regression analysis selected possible risk factors for SSI, including age, diabetes, operating time, skin graft or flap, resected tumour size, smoking, and radiation therapy. Multivariate analysis revealed that age, diabetes, smoking during the previous year, operating time, and radiation therapy were independent risk factors for SSI. A nomogram was developed based on the results of multivariate logistic regression analysis. In the development cohort, the incidence of SSI was 4.5% in the low-risk group (risk score < 6.89) and 26.6% in the high-risk group (risk score ≥ 6.89; p < 0.001). In the validation cohort, the incidence of SSI was 2.0% in the low-risk group and 15.9% in the high-risk group (p = 0.004). Conclusion: Our nomogram will enable surgeons to assess the risk of SSI in patients with STS. In patients with high risk of SSI, frequent monitoring and aggressive interventions should be considered to prevent this.

Tumor-induced Osteomalacia Successfully Treated by En Bloc Tumor Excision and Reconstruction Using a Tumor-bearing Frozen Autograft: A Case Report.

BACKGROUND/AIM: Tumor-induced osteomalacia (TIO) is a rare pathology caused by overproduction of fibroblast growth factor 23 (FGF23). Its common clinical features include generalized muscle weakness, bone pain, and fractures. Complete resection of the offending tumor is the mainstay treatment. In this report, we present the first case of TIO by an FGF23 producing tumor treated using a tumor-bearing autograft treated with liquid nitrogen. CASE REPORT: A 63-year old female presented with generalized body pain, particularly in the left arm. The patient was diagnosed with a FGF23 producing tumor of the left humerus. Wide resection of the involved tumor was performed using a tumor-bearing autograft that was treated with liquid nitrogen. Postoperatively, the FGF23 and alkaline phosphatase (ALP) levels significantly decreased and inorganic phosphate normalized. There was also subsequent relief of generalized body pain. Immediately after the operation, range of motion of the left shoulder and elbow was initiated. The patient was instructed to perform forward flexion and abduction up to 90° with a rotational restraint. Almost complete bone union was observed at 12 months post procedure. Postoperative functional results were as follows: Musculoskeletal Tumor Society (MSTS) score of 27/30, 90% and International Society of Limb Salvage (ISOLS) score of 26/30, 87%. Ten years after the surgery, osteotomy line was completely obscured based on radiographs. The patient was disease free and without activity limitation. CONCLUSION: This is the first case report of wide excision of a FGF23 producing tumor and reconstruction using a tumor-bearing frozen autograft performed with excellent outcomes.

Case Report: Unresectable pulmonary metastases of a giant cell tumor of bone treated with denosumab: a case report and review of literature.

Giant cell tumors of bone (GCTB) sometimes metastasize to distant organs. In this case report, we present pulmonary metastases of GCTB mimicking malignancies. A 49-year-old man underwent two surgical treatments for a GCTB of the right proximal radius. At the time of the second surgery, no lesions were observed on chest radiography. Three years after surgery, the patient presented with cough and dyspnea, and chest radiography and computed tomography (CT) revealed multiple lung nodules. Positron emission tomography/CT revealed a high accumulation of 18F-fluoro-2-deoxy-D-glucose (18F-FDG) in multiple lesions. Based on the rapid growth and accumulation of 18F-FDG, a metastatic malignant tumor was suspected. CT-guided needle biopsy was performed, and the histology showed proliferation of spindle cells and multinuclear giant cells without malignant changes. Denosumab was administered because multiple lung lesions were unresectable. One month after denosumab treatment, CT showed marked shrinkage of the lesions, and the symptoms significantly improved. Eighteen months after the initial treatment with denosumab, the patient had no symptoms or tumor growth. Although its long-term efficacy and safety remain unclear, denosumab may be a treatment option for patients with unresectable pulmonary GCTB.

Graft Survivals after Reconstruction Using Tumor-Bearing Frozen Bone in the Extremities.

Tumor-bearing frozen autografts have been widely used for reconstruction of bone defects caused by tumor resection. However, some patients undergo removal of the grafted bone due to surgical site infection, tumor recurrence, or fractures of the grafted bone. In this retrospective cohort study, predictive factors for graft survival were investigated in 123 patients who underwent reconstructions using a tumor-bearing frozen autograft after bone tumor resection of the extremities. To determine the independent predictors of graft survival, the association between various parameters and graft survival was investigated. The graft survival rates were 83.2% at 5 years and 70.2% at 10 years. Among the 123 frozen autografts, 25 (20.3%) were removed because of complications. In univariate analyses, male sex, BMI of ≥23.6, tibia, and chemotherapy were significantly associated with poor graft survival, whereas the pedicle/hemicortical freezing procedure was significantly associated with better graft survival. Multivariate analysis using the Cox proportional hazards regression model revealed that BMI of ≥23.6 (HR, 3.4; p = 0.005), tibia (HR, 2.3; p = 0.047), and freezing procedure (HR, 0.3; p = 0.016) were independently associated with graft survival. Based on the results, pedicle or hemicortical freezing techniques are recommended in cases where these techniques can be applied.

A validation study for the utility of serum microRNA as a diagnostic and prognostic marker in patients with osteosarcoma.

In our previous study, osteosarcoma advanced locally, and metastasis was promoted through the secretion of large number of small extracellular vesicles, followed by suppressing osteoclastogenesis via the upregulation of microRNA (miR)-146a-5p. An additional 12 miRNAs in small extracellular vesicles were also detected ≥6× as frequently in high-grade malignancy with the capacity to metastasize as in those with a low metastatic potential. However, the utility of these 13 miRNAs for determining the prognosis or diagnosis of osteosarcoma has not been validated in the clinical setting. In the present study, the utility of these miRNAs as prognostic and diagnostic markers was therefore assessed. In total, 30 patients with osteosarcoma were retrospectively reviewed, and the survival rate was compared according to the serum miRNA levels in 27 patients treated with chemotherapy and surgery. In addition, to confirm diagnostic competency for osteosarcoma, the serum miRNA levels were compared with those in patients with other bone tumors (n=112) and healthy controls (n=275). The patients with osteosarcoma with high serum levels of several miRNAs (miR-146a-5p, miR-1260a, miR-487b-3p, miR-1260b and miR-4758-3p) exhibited an improved survival rate compared with those with low levels. In particular, patients with high serum levels of miR-1260a exhibited a significantly improved overall survival rate, metastasis-free survival rate and disease-free survival rate compared with those with low levels. Thus, serum miR-1260a may potentially be a prognostic marker for patients with osteosarcoma. Moreover, patients with osteosarcoma had higher serum miR-1261 levels than those with benign or intermediate-grade bone tumors and thus may be a potential therapeutic target, in addition to being useful for differentiating whether or not a bone tumor is high-grade. A larger investigation is required to clarify the actual utility of these miRNAs in the clinical setting.

Clinical Benefits of LigaSure™ for Surgical Amputation Without Tourniquet Use in Patients With Musculoskeletal Tumor.

BACKGROUND/AIM: Amputation is still a viable option for musculoskeletal tumors that are multi-compartmental, adjacent to neurovascular structures, and involving pathological fractures. Complications such as poor surgical margins, local recurrence and infection after limb salvage surgery are also indications for secondary amputation. An effective hemostatic technique is vital for preventing complications of massive blood loss and prolonged operative time. The use of LigaSure™ in the field of musculoskeletal oncology has not been well documented. PATIENTS AND METHODS: This retrospective study included 27 patients with musculoskeletal tumor who underwent amputation using either LigaSure™ system (n=12) or traditional hemostatic technique (n=15) from 1999 to 2020. The purpose of this study was to evaluate the effect of LigaSure™ in terms of intra-operative blood loss, blood transfusion rates, and duration of surgery. RESULTS: The use of LigaSure™ resulted in a significant decrease in intraoperative blood loss (p=0.027) and blood transfusion rates (p=0.020). There was no significant difference for the duration of surgery between the two groups (p=0.634). CONCLUSION: The LigaSure™ system can potentially improve clinical outcomes in patients with musculoskeletal tumor undergoing amputation surgeries. The LigaSure™ system is a safe and effective hemostatic tool for musculoskeletal tumor amputation surgeries.

Novel predictors of immune checkpoint inhibitor response and prognosis in advanced non-small-cell lung cancer with bone metastasis.

BACKGROUNDS: Immune checkpoint inhibitors (ICIs) can significantly prolong the survival of patients with advanced non-small-cell lung cancer (NSCLC); however, few studies on the therapeutic effects of ICIs on bone metastases were performed. METHODS: This retrospective study aimed to investigate the therapeutic effects of ICIs and determine predictors of favorable ICI response and prognosis in 55 advanced NSCLC patients with bone metastases who initiated ICI treatment between 2016 and 2019, with a mean follow-up period of 23.2 months. Patients were classified into responders (complete or partial response) and non-responders (stable or progressive disease) according to the MD Anderson Cancer Center (MDA) criteria, and the predictors of therapeutic response were identified using multivariate logistic regression analysis. Furthermore, overall survival from the time of ICI administration to the final follow-up or death was evaluated, and prognostic predictors were identified using Cox proportional hazards regression analysis. RESULTS: ICI response rate was 30.9% (complete in three cases, partial in 14). Median survival time was 9.3 months, with 1-year and 2-year survival rates of 40.6% and 19.3%, respectively. Responders survived significantly longer than non-responders (p = 0.03). Based on the receiver operating characteristic curve, the predictive cutoff value of the pretreatment neutrophil-to-lymphocyte ratio (NLR) was 2.1. Multivariate analysis identified female sex (p = 0.03), use of ICIs as first-line therapy (p < 0.01), and NLR <2.1 (p = 0.03) as significant predictors of therapeutic response, whereas concomitant use of a bone-modifying agent (p < 0.01), Katagiri score ≤6 points (p < 0.01), and NLR <2.1 (p = 0.02) were identified as significant predictors of good prognosis. CONCLUSIONS: This study identified some novel predictors for favorable therapeutic response and prognosis in advanced NSCLC patients with bone metastases undergoing ICI treatment. Pretreatment NLR less than 2.1 can be considered the most important predictor.

Antibacterial effect and biological reaction of calcium phosphate cement impregnated with iodine for use in bone defects.

Calcium phosphate cement (CPC) is often used to repair bone defects that occur after bone tumor and fracture treatment. To address bone defect cases with a high infection risk, developing CPCs with a longlasting wide-spectrum antibacterial effect is critical. Povidone-iodine has a wide antibacterial spectrum. Though there have been some reports of CPC containing antibiotics, no report of CPC with iodine has been described. In this study, the antibacterial effect and biological reaction of CPC impregnated with iodine was investigated. Iodine release from CPC and bone cement with various iodine contents (2.5, 5, and 20%) was evaluated, and 5 %-iodine CPC retained more iodine than the other CPCs after one week. Antibacterial activity against Staphylococcus aureus and Escherichia coli was also investigated, showing that 5 %-iodine had an antibacterial effect for up to eight weeks. Cytocompatibility was assessed, and 5 %-iodine CPC showed the same amount of fibroblast colony formation as control samples. CPCs with varying iodine contents (0, 5, and 20%) were then inserted into lateral femora of Japanese white rabbits for histological analysis. Osteoconductivity was evaluated using scanning electron microscopy, and hematoxylin-eosin staining. Consecutive bone formation was observed around all CPCs at eight weeks. These results indicate that CPC impregnated with iodine exhibits antimicrobial activity and cytocompatibility, and therefore, it may be effective for bone defect cases with high infection risk.

Kimura's Disease Diagnosed in the Department of Orthopedic Surgery Treated With Wide Excision: Report of Two Cases.

BACKGROUND/AIM: Kimura's disease is a rare chronic inflammatory disorder that commonly affects the head and neck regions, occurring predominantly in Asian men. Elevated eosinophil count and IgE levels in the peripheral blood examination are suggestive of this disease. In this study we report two cases of Kimura's disease, treated with wide excision. CASE REPORT: The first case was a 58-year-old man presented with asymptomatic left neck mass. The second case was a 69-year-old man with swelling of the right upper arm, which was suggestive of soft tissue mass. Needle biopsy results were suggestive of Kimura's disease in both cases. Elevated WBCs at 8,380/µl (neutrophils: 45%, eosinophils: 33%) for the first case and 5,370/µl (neutrophils: 61.8%, eosinophils: 3.5%) for the second one, and serum IgE at 14.988 IU/ml for the first case and 1,315 IU/ml for the second one were observ. For definitive treatment and diagnosis, wide excisions were performed. Final histopathological results revealed Kimura's disease. Surgical margins were negative even though an ill-demarcated lesion for the first case and high infiltration to the muscle for second case were confirmed. CONCLUSION: Wide excision was performed in both cases of Kimura's disease and no recurrence was observed until the final follow-up. Wide excision with negative surgical margin should be recommended for the treatment of Kimura's disease.

A Viability Analysis of Tumor-Bearing Frozen Autograft for the Reconstruction After Resection of Malignant Bone Tumors Using 99m Tc-MDP Scintigraphy.

PURPOSE OF THE REPORT: Several methods are used to reconstruct bony defects after malignant tumor excision. Tumor-bearing frozen autograft reconstruction is a biological procedure in which tumor-bearing bone is reused after devitalization with liquid nitrogen to kill tumor cells. The viability of frozen autografts has not been fully evaluated over time. We therefore aimed to evaluate the viability of devitalized bone grafts, using 99m Tc-MDP scintigraphy. PATIENTS AND METHODS: Seventy-four patients who underwent frozen autograft reconstruction after the excision of a malignant bone tumor were enrolled. Two hundred forty-two postoperative 99m Tc-MDP scans were reviewed. For a quantitative analysis, the region of interest on the frozen bone segment and a symmetric region of interest on the contralateral normal area were manually set. The radioactive tracer uptake ratio was calculated by dividing the count density of the frozen bone segment by that of the contralateral normal area in each image. An uptake ratio of 0.9 to 1.1 was defined as a normalization of tracer uptake. RESULTS: Normalization of tracer uptake was achieved in 95% to 97% of the cases by 60 months postoperatively, and earlier in the middle zone and peripheral zone in the pedicle freezing group in comparison to the free freezing group (both P = 0.03). Fracture and nonunion was associated with a low uptake ratio, whereas infection was associated with a high uptake ratio before the occurrence of the event. CONCLUSIONS: The calculation of the uptake ratio using 99m Tc-MDP scans was an objective and accurate evaluation method. The period to normalization of tracer uptake in the pedicle frozen bone was significantly earlier than that in the free frozen bone. The postoperative complications can be also predicted.

Clinical Outcomes of Soft Tissue Sarcoma around the Elbow Joint: A Retrospective Single Institution Study.

Background: We report a retrospective case series analysis of clinical outcomes of patients with soft tissue sarcoma around the elbow. Methods: Twenty-two patients underwent surgical tumor excision between January 1999 and May 2017, with a mean follow-up of 85.2 months. Results: Six tumors were localized in the upper arm, nine in the elbow, and seven in the forearm. Sixteen tumors were deep-seated, and six were superficially located. Fifteen patients underwent wide excision, including one amputation, and 18 achieved (81.8%) negative margins histologically. Two local recurrences and four distant metastases developed. The mean Musculoskeletal Tumor Society score was 92.0% (range, 33.3-100). The 5-year local recurrence-free survival rate, metastasis-free survival rate, and overall survival rate were 90.0%, 77.0%, and 79.7%, respectively. Conclusions: Local control and limb function can have favorable outcomes when the tumor excised has a histologically negative margin without sacrificing the major structure.

Insufficiency fracture of the supra-acetabulum that required differentiation from a pathological fracture secondary to a malignant bone tumor: a case report.

BACKGROUND: The supra-acetabulum is a common site for malignant bone tumors, which can be difficult to differentiate from insufficiency fractures. We report a rare case of a stress fracture of the supra-acetabulum that required differentiation from a malignant bone tumor. CASE PRESENTATION: A 74-year-old Japanese man presented to the hospital because of right hip joint pain. X-rays showed no obvious abnormalities. Magnetic resonance imaging showed an abnormality in the right supra-acetabulum, and he was referred to our department. A linear, low-signal region and its surrounding equal signal region were observed at the same site in the T1-weighted image, and a linear low-signal region and high signal region were observed in the surrounding area in the T2-weighted image. On the contrast-enhanced magnetic resonance imaging, the lesion was still unclear and the whole area was gradually enhanced. A computed tomography-guided needle biopsy was performed, but no tumor cells were observed, therefore the lesion was presumed to be a fracture healing. The bone density was 66% for the lumbar spine (young adult mean, L2-4), and blood biochemistry showed an increase in alkaline phosphatase and total type I procollagen N-terminal propeptide. CONCLUSION: This case was diagnosed as an insufficiency fracture of the supra-acetabulum in a male patient with primary osteoporosis by biopsy specimen. Initially, a pathological fracture associated with a malignant lesion was considered. On magnetic resonance imaging, the boundary around the fracture line was unclear and a signal change that was gradually enhanced by gadolinium was observed. This is likely to be bone marrow edema associated with the stress fracture, and we believe this to be a useful finding that may help in differentiating a stress fracture from a pathological fracture secondary to a malignant lesion.

Case report: Complete remission of bone metastasis from renal cell carcinoma in histopathological examination after treatment with immune checkpoint inhibitors.

Recently, the prognosis of metastatic renal cell carcinoma (mRCC) has improved owing to the development of immunotherapy using immune checkpoint inhibitors (ICIs). However, there have been few studies on the therapeutic effect of ICIs in bone metastases from renal cell carcinoma (RCC). We report a case in which pulmonary and humeral metastases from RCC were significantly ameliorated using ICIs, while surgery for a pathological fracture of the humerus significantly improved the patient's quality of life (QoL). A 70-year-old man who underwent a left nephrectomy for RCC developed multiple pulmonary metastases and humeral metastasis with a pathological fracture one year after surgery, and combined treatment with nivolumab and ipilimumab was initiated. After four courses of ICI treatment, multiple pulmonary metastases had almost disappeared, and the tumor at the fracture site had shrunk remarkably. However, the shoulder joint function had decreased due to the fracture, worsening his QoL. Therefore, he underwent surgery and returned to normal daily life one month after. Postoperative histopathological examination of bone and soft tissue at the fracture site revealed no malignancy. To our knowledge, this is the first case report of complete remission of bone metastasis of RCC based on histopathological examination with ICI treatment.

Primary Osteosarcoma in Patients Over 75 Years of Age: A Case Series and Literature Review.

BACKGROUND/AIM: Little is known about the clinical characteristics in older patients of ≥75 years of age with primary osteosarcoma due to its rarity. We aimed to understand the clinical characteristics in these patients in order to make an appropriate diagnosis and provide treatment. PATIENTS AND METHODS: The medical records of eight patients of ≥75 years of age with primary osteosarcoma were retrospectively reviewed. We investigated their clinical features, imaging findings, histopathological findings, treatment methods, and oncological outcomes. RESULTS: There were two male and six female patients, with a mean age of 80 years. The mean follow-up period was 44 months. The initial symptom was pain in five, swelling in two, and a mass in one. The initial diagnosis was osteoarthritis in two, lumbar canal stenosis in two, benign bone tumor in four. The mean period from the first time the patient noticed symptoms to referral was 25 months. Two patients had a history of surgical curettage at their previous hospital for bone tumor that was considered benign. Lung metastasis was observed at presentation in three patients. The mean tumor size was 129 mm in its greatest dimension. Surgical treatment was performed on six patients, including frozen autograft reconstruction in one. Carbon-ion radiotherapy was conducted in one patient due to an unresectable pelvic lesion. CONCLUSION: Diagnosis requires care because the radiological and histological findings of primary osteosarcoma in patients ≥75 years of age are often non-specific, in addition to their delayed consultation. Individualized treatment including surgical procedure and radiotherapy is essential for older patients to maintain a good quality of their lives.

Do Liquid Nitrogen-treated Tumor-bearing Nerve Grafts Have the Capacity to Regenerate, and Do They Pose a Risk of Local Recurrence? A Study in Rats.

BACKGROUND: Under most circumstances, the resection of soft tissue sarcomas of the extremities can be limb-sparing, function-preserving oncologic resections with adequate margins. However, en bloc resection may require resection of the major peripheral nerves, causing poor function in the extremities. Although liquid nitrogen treatment has been used to sterilize malignant bone tumors, its use in the preparation of nerve grafts has, to our knowledge, not been reported. Hence, this study aimed to investigate the tumor recurrence and function after peripheral nerve reconstruction using liquid nitrogen-treated tumor-bearing nerves in a rat model. QUESTIONS/PURPOSES: (1) Do liquid nitrogen-treated frozen autografts have regeneration capabilities? (2) Do liquid nitrogen-treated tumor-bearing nerves cause any local recurrences in vivo in a rat model? METHODS: Experiment 1: Twelve-week-old female Wistar rats, each weighing 250 g to 300 g, were used. A 10-mm-long section of the right sciatic nerve was excised; the prepared nerve grafts were bridge-grafted through end-to-end suturing. The rats were grouped as follows: an autograft group, which underwent placement of a resected sciatic nerve after it was sutured in the reverse orientation, and a frozen autograft group, which underwent bridging of the nerve gap using a frozen autograft. The autograft was frozen in liquid nitrogen, thawed at room temperature, and then thawed in distilled water before application. The third group was a resection group in which the nerve gap was not reconstructed. Twenty-four rats were included in each group, and six rats per group were evaluated at 4, 12, 24, and 48 weeks postoperatively. To assess nerve regeneration after reconstruction using the frozen nerve graft in the nontumor rat model, we evaluated the sciatic functional index, tibialis anterior muscle wet weight ratio, electrophysiologic parameters (amplitude and latency), muscle fiber size (determined with Masson trichrome staining), lower limb muscle volume, and immunohistochemical findings (though neurofilament staining and S100 protein produced solely and uniformly by Schwann cells associated with axons). Lower limb muscle volume was calculated via CT before surgery (0 weeks) and at 4, 8, 12, 16, 20, 24, 32, 40, and 48 weeks after surgery. Experiment 2: Ten-week-old female nude rats (F344/NJcl-rnu/rnu rats), each weighing 100 g to 150 g, were injected with HT1080 (human fibrosarcoma) cells near the bilateral sciatic nerves. Two weeks after injection, the tumor grew to a 10-mm-diameter mass involving the sciatic nerves. Subsequently, the tumor was resected with the sciatic nerves, and tumor-bearing sciatic nerves were obtained. After liquid nitrogen treatment, the frozen tumor-bearing nerve graft was trimmed to a 5-mm-long tissue and implanted into another F344/NJcl-rnu/rnu rat, in which a 5-mm-long section of the sciatic nerve was resected to create a nerve gap. Experiment 2 was performed with 12 rats; six rats were evaluated at 24 and 48 weeks postoperatively. To assess nerve regeneration and tumor recurrence after nerve reconstruction using frozen tumor-bearing nerve grafts obtained from the nude rat with human fibrosarcoma involving the sciatic nerve, the sciatic nerve's function and histologic findings were evaluated in the same way as in Experiment 1. RESULTS: Experiment 1: The lower limb muscle volume decreased once at 4 weeks in the autograft and frozen autograft groups and gradually increased thereafter. The tibialis anterior muscle wet weight ratio, sciatic functional index, muscle fiber size, and electrophysiologic evaluation showed higher nerve regeneration potential in the autograft and frozen autograft groups than in the resection group. The median S100-positive areas (interquartile range [IQR]) in the autograft group were larger than those in the frozen autograft group at 12 weeks (0.83 [IQR 0.78 to 0.88] versus 0.57 [IQR 0.53 to 0.61], difference of medians 0.26; p = 0.04) and at 48 weeks (0.86 [IQR 0.83 to 0.99] versus 0.74 [IQR 0.69 to 0.81], difference of median 0.12; p = 0.03). Experiment 2: Lower limb muscle volume decreased at 4 weeks and gradually increased thereafter. The median muscle fiber size increased from 0.89 (IQR 0.75 to 0.90) at 24 weeks to 1.20 (IQR 1.08 to 1.34) at 48 weeks (difference of median 0.31; p< 0.01). The median amplitude increased from 0.60 (IQR 0.56 to 0.67) at 24 weeks to 0.81 (IQR 0.76 to 0.90) at 48 weeks (difference of median 0.21; p < 0.01). Despite tumor involvement and freezing treatment, tumor-bearing frozen grafts demonstrated nerve regeneration activity, with no local recurrence observed at 48 weeks postoperatively in nude rats. CONCLUSION: Tumor-bearing frozen nerve grafts demonstrated nerve regeneration activity, and there was no tumor recurrence in rats in vivo. CLINICAL RELEVANCE: A frozen nerve autograft has a similar regenerative potential to that of a nerve autograft. Although the findings in a rat model do not guarantee efficacy in humans, if they are substantiated by large-animal models, clinical trials will be needed to evaluate the efficacy of tumor-bearing frozen nerve grafts in humans.