Renal Cell Carcinoma Bone Metastasis Research Articles

BIGH3 mediates apoptosis and gap junction failure in osteocytes during renal cell carcinoma bone metastasis progression

Renal cell carcinoma (RCC) bone metastatis progression is driven by crosstalk between tumor cells and the bone microenvironment, which includes osteoblasts, osteoclasts, and osteocytes. RCC bone metastases (RCCBM) are predominantly osteolytic and resistant to antiresorptive therapy. The molecular mechanisms underlying pathologic osteolysis and disruption of bone homeostasis remain incompletely understood. We previously reported that BIGH3/TGFBI (transforming growth factor-beta-induced protein ig-h3, shortened to BIGH3 henceforth) secreted by colonizing RCC cells drives osteolysis by inhibiting osteoblast differentiation, impairing healing of osteolytic lesions, which is reversible with osteoanabolic agents. Here, we report that BIGH3 induces osteocyte apoptosis in both human RCCBM tissue specimens and in a preclinical mouse model. We also demonstrate that BIGH3 reduces Cx43 expression, blocking gap junction (GJ) function and osteocyte network communication. BIGH3-mediated GJ inhibition is blocked by the lysosomal inhibitor hydroxychloroquine (HCQ), but not osteoanabolic agents. Our results broaden the understanding of pathologic osteolysis in RCCBM and indicate that targeting the BIGH3 mechanism could be a combinational strategy for the treatment of RCCBM-induced bone disease that overcomes the limited efficacy of antiresorptives that target osteoclasts.

Effect of Acridine Orange and Zoledronic Acid on Bone Metastasis in Renal Cell Carcinoma.

The increasing incidence of renal cell carcinoma (RCC) and its associated bone metastasis pose challenges in surgical interventions, warranting the exploration of novel therapeutic approaches. Therefore, this study aimed to assess the impact of hematogenously administering acridine orange (AO) alone and in combination with zoledronic acid (ZA) on bone metastasis in RCC. RENCA cells (1.0×106 cells/10 μl) were directly injected into the right femur of male BALB/c mice. The mice were categorized into four groups based on the applied therapeutic intervention and were euthanized after five weeks. Micro-computed tomography was performed to quantify the extent of periosteal reaction, indicative of bone metastasis, along the entire length of the femur. Tumor weight and volume were measured at euthanization. Hematoxylin and eosin staining was used to examine the extent of tumor development in the bone. Apoptotic cell, osteoclast, and vascular endothelial growth factor (VEGF)-positive cell counts were assessed using TdT-mediated dUTP-biotin nick end labeling, tartrate-resistant acid phosphatase staining, and VEGF staining, respectively. The periosteal reaction was significantly reduced in the intervention groups compared to the control group (p<0.05). The apoptotic cell numbers in the intervention groups surpassed that in the control group (p<0.05), whereas those of osteoclasts and VEGF-positive cells in the intervention groups were lower than those in the control group (p<0.05). AO hinders bone metastasis progression in RCC, and combination therapy with ZA may be more effective than AO administration alone.

Development of a New Focal Mouse Model of Bone Metastasis in Renal Cell Carcinoma.

Developing animal models of bone metastasis in renal cell carcinoma (RCC) is challenging as immunodeficient mice are required. The aim of this study was to develop a simple immune model of RCC bone metastasis. RENCA tumor cells were injected into the right femurs of BALB/c mice. Sixty mice were grouped into each twenty-mouse group according to the tumor cell concentration, and the presence or absence and extent of bone metastasis in the total length of the femur were compared using hematoxylin and eosin staining of the excised tissues. Bone metastasis was significantly higher in the high concentration group than in the other groups (p<0.05), with 10 mice developing bone metastasis at two weeks and nine mice developing bone metastasis at three weeks. The extent of bone metastasis was significantly greater in the high concentration group than in the other groups (p<0.05). Multiple logistic regression analysis was performed to examine the factors influencing bone metastasis, and only the high concentration was a significant factor (p<0.05). We developed a normal immunity mouse model of local bone metastasis from RCC. This model could prove valuable for research into the treatment of bone metastases in RCC.

Clinical Implications of a Six-Protein Signature in Bone Metastasis of Renal Cell Carcinoma.

Bone metastases is prevalent from renal cell carcinoma (RCC) with poor quality of life and prognosis. Our previous proteomics analysis identified dysregulated proteins in the bone-tropism RCC cells. In this study, we further examined the clinical implications of these proteins using multiple clinical cohorts. We identified 6 proteins with significant upregulation in RCC tumor tissue in comparing to tumor adjacent normal tissue (p<0.05). High expression of these 6 protein-encoding genes significantly correlates with a poor survival in the TCGA-KIRC (Kidney renal clear cell carcinoma) cohort (log-rank test p=2.7e-05), and they all individually had a reverse-correlation with the gene expression of VHL and PBRM1 (p<0.001), and positive-correlation with the expression of VEGFA (p<0.001). Further gene set variation analysis (GSVA) revealed positive correlation with Th17 cells enrichment and negative CD8 T cell infiltration in the RCC tumor microenvironment. High expression of these 6 genes in pretreatment tumors favors longer overall survival (OS)(p=0.027) in anti-PDL1 treated patients (n=428). We treated one humeral metastases RCC patient with the anti-PDL1 antibody drug atezolizumab after examined the elevated expression of the 6 proteins in his nephrectomy tumor tissue, the tumor at the fracture site shrunk remarkably after four courses of treatment. These results altogether suggest a clinical implication of the 6-protein signature in RCC bone metastasis prognosis and response to immune-checkpoint inhibitor treatment.

The use of the flow-void sign on MRI: highly sensitive sign in detecting bone metastases from renal cell carcinoma.

To evaluate a range of pathologically proven malignant bone tumours, including primary bone sarcoma and metastatic bone lesions, referred to a tertiary referral centre for the presence of the flow-void sign on MR imaging. A retrospective search was performed using the radiology information system and oncology database in our institution to identify patients over the age of 40years referred with a solitary bone lesion. Patients with a range of pathologically proven malignant bone tumours, including primary bone tumours and metastatic bone lesions, were included in the study. MRI images were reviewed for the presence of the flow-void sign. The presence and type of the flow-void sign were correlated with lesion size. Two hundred and sixty-six cases were included in the study. Overall, the flow-void sign was identified in 40.9% of cases. The flow-void sign was most frequently seen in renal cell carcinoma metastasis (90.0%). The sign is highly sensitive (90%) for renal cell carcinoma metastases with a high negative predictive value (98.09%). When the flow-void sign is identified, the lesion is almost three times more likely to represent a renal cell carcinoma metastasis than any other malignant tumour in patients over the age of 40years with a solitary bone lesion. The flow-void sign is highly sensitive for renal cell carcinoma bone metastases and could negate the need for biopsy in patients with a known history of renal cell carcinoma or in whom an occult renal cell carcinoma is subsequently identified.

Reoperation after surgery for bone metastasis of renal cell carcinoma.

The prognosis of metastatic renal cell carcinoma (RCC) has markedly improved with the advent of molecular targeted therapies and immune checkpoint inhibitors. However, the therapeutic response in patients with bone metastasis remains low; therefore, surgery still plays a significant role in treatment of bone metastasis. It is important to maintain quality of life for patients with bone metastasis from RCC and avoid reoperation after surgery for bone metastasis. Therefore, we investigated the risk factors for reoperation after surgery in patients with bone metastasis from RCC. We retrospectively studied 103 bones of 97 patients who underwent surgery for bone metastasis of RCC from 2001 to 2023 at our institutions. Reoperation was performed in 10 (9.7%) of 103 bones. There was no correlation between reoperation-free survival and any of the following variables: preoperative and postoperative radiotherapy, site of bone metastasis, indication for surgery (solitary bone metastasis or impending or pathologic fractures), surgical method (intramedullary nailing fixation, curettage, or en bloc resection), preoperative embolization, or survival. The risk of reoperation for bone metastasis of RCC does not appear to be based on the surgical method.

Skeletal-Related Events in Renal Cell Carcinoma: Prediction With Alkaline Phosphatase (ALP), C-reactive Protein (CRP), Haemoglobin (Hb) and Erythrocyte Sedimentation Rate (ESR) (A.C.H.E.) Score for Risk Stratification.

Introduction Skeletal metastasis is catastrophic in patients with renal cell carcinoma (RCC), leading to skeletal-related events (SRE) such as nerve entrapment, hypercalcemia and even pathological fractures, which may require surgical intervention. The nature of the bone metastasis in advanced RCC is large, destructive, hyper-vascular and mostly lytic. The present retrospective analysis aims to identify potential risk factors for predicting SREs in advanced RCC with bone metastasis. Methods The clinical data of 42 patients with RCC and bone metastasis and at least one episode of SRE were reviewed, and the correlations between erythrocyte sedimentation rate (ESR), alkaline phosphatase (ALP), C-reactive protein (CRP), haemoglobin (Hb), carcinoembryonic antigen (CEA) and bone metastases were analysed. Risk factors were identified by multivariate logistic regression analysis. Bone metastasis was diagnosed on a bone scan. The receiver operating characteristic (ROC) curve calculated the cut-off value of the independent correlation factors. Results The areas under the ROC curve for ALP, Hb, CRP, and ESR were 0.84, 0.76, 0.86 and 0.88, respectively, suggesting excellent discriminatory capability of ALP, CRP, ESR and sufficient discriminative ability of Hb in predicting bone metastasis. Multivariate logistic regression analysis showed ALP, CRP, Hb and ESR associated with SRE and skeletal metastasis. Conclusion We propose that an A.C.H.E. score encompassing ALP, CRP, Hb, and ESR are potential risk factors for developing SRE and concomitant bone metastasis in advanced RCC patients. For new RCC patients, if values of ALP >128 U/L, CRP ≥74 mg/L, Hb <11.5 g/L, and ESR ≥55 mm/hr are detected, intensive monitoring and bone scanning are warranted as these cases are at a higher risk of skeletal events.

Outcomes of palliative surgery for bone metastasis of metastatic renal cell carcinoma in the era of targeted therapy

IntroductionThe introduction of tyrosine kinase inhibitors has revolutionized treatment strategies for metastatic renal cell carcinoma (RCC) and has improved survival rates. The number of patients with bone metastases from RCC requiring surgery will increase as survival rates improve. However, there is insufficient evidence to standardize the treatment of bone metastases after the introduction of targeted therapy for metastatic RCC. We aimed to determine the outcomes of palliative surgical treatment of bone metastases in the extremities of patients with metastatic RCC. Materials and methodsWe retrospectively reviewed 26 lesions from 17 patients who underwent surgery for extremity and acetabular bone metastases and were treated with targeted therapies for advanced RCC between 2008 and 2020. The median follow-up duration was 19 months (range, 4–76). We assessed the patients’ activities of daily living, quality of life, and pain and analyzed their postoperative values relative to preoperative values. Postoperative overall survival (OS), local progression-free survival (LPFS), and the factors affecting them were evaluated using the Kaplan-Meier method and log-rank test. ResultsThe 5-year OS and LPFS rates were 39.5% and 65.6%, respectively. The factors affecting OS were sex, Katagiri score, visceral metastases, and preoperative targeted therapy, while the factors affecting LPFS were pathologic fractures and surgical technique. ConclusionIn this study, the postoperative outcomes of palliative surgery for bone metastases from metastatic RCC were good. We suggest that systemic treatment should be prioritized over local control for advanced bone metastasis in RCC and surgery before pathological fracture should be performed for local control.

Novel diagnostic model for bone metastases in renal cell carcinoma patients based on bone scintigraphy analyzed by computer-aided diagnosis software and bone turnover markers

BackgroundComputer-assisted diagnosis (CAD) systems for bone scans have been introduced as clinical quality assurance tools, but few studies have reported on its utility for renal cell carcinoma (RCC) patients. The aim of this study was to assess the diagnostic validity of the CAD system for bone scans and to construct a novel diagnostic system for bone metastases in RCC patients.MethodsWe evaluated bone scan images of 300 RCC patients. Artificial neural network (ANN) values, which represent the probability of abnormality, were calculated by BONENAVI, the CAD software for bone scans. By analyzing ANN values, we assessed the diagnostic validity of BONENAVI. Next, we selected 108 patients who underwent measurements of bone turnover markers and assessed the combined diagnostic validity of BONENAVI and bone turnover markers.ResultsForty-three out of 300 RCC patients had bone metastases. The AUC of ANN values was 0.764 and the optimum sensitivity and specificity were 83.7 and 62.7%. By logistic analysis of 108 cases, we found that ICTP, a bone resorption marker, could be a diagnostic marker. The AUC of ICTP was 0.776 and the optimum sensitivity and specificity were 57.1 and 86.8%. Subsequently, we developed a novel diagnostic model based on ANN values and ICTP. Using this model, the AUC was 0.849 and the optimum sensitivity and specificity were 76.2 and 80.7%.ConclusionBy combining the high sensitivity provided by BONENAVI and the high specificity provided by ICTP, we constructed a novel, high-accuracy diagnostic model for bone metastases in RCC patients.

Scheduling surgery after transarterial embolization: does timing make any difference to intraoperative blood loss for renal cell carcinoma bone metastases?

Our purpose is to clarify the optimal timing of surgery after transarterial embolization (TAE) for renal cell carcinoma (RCC) bone metastases. This retrospective study included 41 patients with RCC bone metastases embolized between 2013 and 2019. Different-sized particulate and/or liquid embolic agents were used for TAE. Embolizations were categorized into groups 1-3 according to the interval between TAE and surgery (group 1: <1 day, group 2: 1-3 days, group 3: >3 days). Degree of embolization after TAE was graded visually based on angiographic images (<50%, 50%-75%, 75%-90%, >90%). The relationship between the TAE-surgery interval and intraoperative blood loss (IBL) and the correlation between IBL and embolization grade were examined. Lesion sizes and the relationships among lesion localizations and contrast media usage, intervention time, and IBL were also analyzed. Forty-six pre-operative TAEs (single lesion at each session) were performed in this study (26 in group 1, 13 in group 2, 7 in group 3). Lesion sizes and distributions were similar between groups (p = 0.897); >75% devascularization was achieved in 40 (TAEs 86.96%), but the IBL showed no correlation with the embolization rate (r=0.032, p = 0.831). The TAE-surgery interval was 1-7 days. The median IBL in group 1 (750 mL; range, 150-3000 mL) was significantly lower than those in the other groups (p = 0.002). Contrast media usage (p = 0.482) and intervention times (p = 0.261) were similar for metastases at different localizations. IBL values after TAE were lower for extremity metastases (p = 0.003). Bone metastases of RCC are well-vascularized, and to achieve lowest IBL values, surgery should preferably be performed <1 day after TAE.

Expert consensus on diagnosis and treatment of renal cell cancer bone metastasis (2021 edition)

Bone is a common metastatic site of renal cell carcinoma (RCC), with about 30% of metastatic RCC patients are suffering from bone metastasis. More than 70% of RCC patients with bone metastasis may experience skeletal related events (SREs), which may severely impair patients' quality of life and even shorten their survival time. Therefore, SREs prevention has become one of the treatment objectives of RCC bone metastasis. Bone-modifying agents are the basic treatment of bone metastases in addition to anti-tumor therapy. The treatment of RCC bone metastasis also requires multi-disciplinary team and individualized comprehensive treatment strategies. To standardize the diagnosis and treatment of RCC bone metastasis in China, the expert group of Genitourinary Oncology Committee, Chinese Anti-cancer Association has formulated the expert consensus for the reference of clinical practice, to improve the general therapeutic level of RCC with bone metastasis and benefit more patients.

PD49-06 EXTRACELLULAR VESICLES SECRETED BY BONE TROPIC RENAL CELL CARCINOMA INDUCE ANGIOGENESIS IN BONE MARROW WITH POTENTIAL TO FACILITATE BONE METASTASIS

INTRODUCTION AND OBJECTIVE:Bone metastasis of renal cell carcinoma (RCC) is associated with poor prognosis. However, the mechanisms underlying RCC bone metastasis remain unclear. Recently, extracel...

Bone-targeted therapy in patients with renal cell carcinoma bone metastases undergoing palliative surgery.

e16572 Background: RCC bone metastases (RCCBM) are found in 20-39% of patients and are becoming more prevalent. RCCBM cause significant morbidity and often require surgical intervention. Current bone-targeted therapies include bisphosphonates and denosumab. Previous literature has suggested that bisphosphonates do not improve survival or reduce skeletal related events and little has been published about the effect of denosumab. Here we present experience describing outcomes and therapeutic effect in patients with RCCBM following palliative surgery for bone metastasis. Methods: We performed a retrospective analysis of 226 patients with RCCBM who underwent orthopedic surgery at MD Anderson Cancer Center between 11/2005 – 8/2019. The Kaplan-Meier method and log-rank test were used to estimate and evaluate survival differences. Results: Patient characteristics included: median age 58.2, male 66.4%, clear cell histology 93.5%, metastatic at presentation 57.9%, nephrectomy 79.8% (63.9% prior to orthopedic intervention), received radiation to the surgical site (pre-op: 13.0%, post-op: 41.4%). First orthopedic intervention: resection arthroplasty 37.2%, curettage and intramedullary nailing (IMN) 18.6%, IMN 16.4%, open reduction internal fixation 15.0%, amputation 2.7%, 10.2% other. Pre-op therapy: bisphosphonate 12.4%, denosumab 5.8%, both 2.7%, none 79.2%. Post-op therapy: bisphosphonate 18.1%, denosumab 13.7%, both 0.9%, none 67.2%. With a median follow up of 3.1 years after first orthopedic intervention, median overall survival (OS) was 2.7 yr (95% CI 2.1 – 3.6). Progression free survival (PFS) was calculated from time of first surgery to either first progression or death; median PFS was 5.2 months (95% CI 4.6 – 7.5). Pre-op or post-op bone-targeted therapy was not significantly associated with PFS (yes vs no: Pre-op: median 3.4 vs 6.3 mth, p=0.42; Post-op: median 4.3 vs 5.8 mth, p=0.61) or OS (Pre-op: 2.1 vs 2.9 yr, p=0.45; Post-op: 2.4 vs 3.2 yr, p=0.18). Post-op denosumab compared to bisphosphonate was associated with increased PFS (9.6 vs 3.8 mth, p=0.03) and OS (3.3 vs 1.6 yr, p=0.02). However, post-op denosumab vs no bone-targeted therapy was not significantly associated with increased PFS (9.6 vs 5.8 mth, p=0.42) or OS (3.3 vs 3.2 yr, p=0.85). Of note, post-op bisphosphonate vs no bone-targeted therapy was associated with reduced PFS (3.8 vs 5.8 mth, p=0.04) and OS (1.6 vs 3.2 yr, p=0.01). Conclusion: Addition of bone-targeted therapy did not significantly improve PFS or OS in patients with RCCBM undergoing orthopedic intervention. Post-op denosumab was associated with better PFS and OS compared to bisphosphonates and bisphosphonates were associated with worse PFS and OS compared to no bone-targeted therapy. Patient selection for therapy may be an important source of bias. Prospective research is needed to clarify the role and selection of bone-targeted therapy in RCCBM patients.

Bone Metastasis in Renal Cell Carcinoma Patients: Risk and Prognostic Factors and Nomograms.

Background Bone metastasis (BM) is one of the common sites of renal cell carcinoma (RCC), and patients with BM have a poorer prognosis. We aimed to develop two nomograms to quantify the risk of BM and predict the prognosis of RCC patients with BM. Methods We reviewed patients with diagnosed RCC with BM in the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2015. Multivariate logistic regression analysis was used to determine independent factors to predict BM in RCC patients. Univariate and multivariate Cox proportional hazards regression analyses were used to determine independent prognostic factors for BM in RCC patients. Two nomograms were established and evaluated by calibration curve, receiver operating characteristic (ROC) curve, and decision curve analysis (DCA). Results The study included 37,554 patients diagnosed with RCC in the SEER database, 537 of whom were BM patients. BM's risk factors included sex, tumor size, liver metastasis, lung metastasis, brain metastasis, N stage, T stage, histologic type, and grade in RCC patients. Currently, independent prognostic factors for RCC with BM included grade, histologic type, N stage, surgery, brain metastasis, and lung metastasis. The calibration curve, ROC curve, and DCA showed good performance for diagnostic and prognostic nomograms. Conclusions Nomograms were established to predict the risk of BM in RCC and the prognosis of RCC with BM, separately. These nomograms strengthen each patient's prognosis-based decision making, which is critical in improving the prognosis of patients.

Androgen receptor decreases renal cell carcinoma bone metastases via suppressing the osteolytic formation through altering a novel circEXOC7 regulatory axis.

BackgroundClear cell renal cell carcinoma (ccRCC) has gender differences, with the androgen receptor (AR) linked positively with metastasis to the lung. Its linkage to ccRCC bone metastases (RBMs), however, remains unclear.MethodsIn the current study, five human RCC and five RCC bone metastasis tissues were deeply sequenced using Arraystar human circRNA V2.0 microarray. We conducted gain‐of‐function screening in vitro and in vivo to elucidate the AR's role in the RBM. Loss/gain‐of‐function was also implemented to verify the roles of related non‐coding RNAs and proteins.ResultsWe uncovered that RBM also has a gender difference showing higher AR expression may be linked to fewer RBMs, which might involve suppressing osteolytic formation. Mechanism dissection indicates that AR can decrease the circular RNA EXOC7 (circEXOC7), expression via enhancing transcription of DHX9, a regulatory protein in circRNA biogenesis. The circEXOC7 can sponge/suppress miR‐149‐3p resulting in suppressing the CSF1 expression by directly binding to the 3′UTR region of CSF1 mRNA. Results from clinical epidemiological surveys also found that AR has a positive correlation with miR‐149‐3p and a negative correlation with CSF1 in AR‐positive ccRCC tissues. Preclinical studies with Balb/c nude mouse model also validated that targeting this newly verified AR/DHX9/circEXOC7/miR‐149‐3p/CSF1 signaling via altering circEXOC7 or AR could lead to suppressing the RBM progression.ConclusionsThese data showed that AR/DHX9/circEXOC7/miR‐149‐3p/CSF1 signaling acts as a valuable feature in the bone metastasis of renal cancer, which may benefit in suppressing the RBM progression.

Metatarsal metastasis from clear cell renal cell carcinoma: a case report and literature review

BackgroundBone metastasis is known to occur in some patients with cancer, usually in the spine, pelvis or ribs, and less than 0.01% of patients have metastases in the foot bone, so metatarsal metastasis is quite rare. The initial symptoms of osseous metastases are swelling, pain, or both.Case presentationWe report a 68-year-old man with solitary metatarsal metastasis 26 months after a diagnosis of renal clear cell carcinoma. The patient suffered intermittent swelling of his right foot and pain for one year due to trauma and was not treated. The doctor attributed the symptoms to trauma, administering massage therapy and a plaster cast to the patient at the local clinic. After reviewing the medical records, we found that this patient had a history of clear cell renal cell carcinoma. The patient underwent radiological examination and open biopsy of the first metatarsal bone of the right foot. These findings confirmed that the patient had a metatarsal metastasis from clear cell renal cell carcinoma. The patient subsequently underwent right foot amputation. No local recurrence or distant metastasis was found after a 6-month follow-up.ConclusionClinicians should be aware of a history of renal cell carcinoma (RCC) and fully understand the patient’s past medical history. When treating patients with clear cell renal cell carcinoma who have unresolving bony pain or swelling, clinicians should always keep in mind the possibility of bone metastasis of RCC.

Abstract No. 711 Assessing effect of cryoablation and transarterial bland embolization of renal cell carcinoma bone metastases on systemic biomarkers of tumor immunity: a pilot investigation to help guide timing of immunotherapy relative to osseous metastasis treatment with embolization and cryoablation

Abstract No. 711 Assessing effect of cryoablation and transarterial bland embolization of renal cell carcinoma bone metastases on systemic biomarkers of tumor immunity: a pilot investigation to help guide timing of immunotherapy relative to osseous metastasis treatment with embolization and cryoablation

Condition assessment and treatment strategy selection for patients with renal cell carcinoma bone metastasis

Objective To investigate the assessment and treatment strategy of patients with renal cell carcinoma. Methods The clinical data of 43 patients with renal cell carcinoma and bone metastases admitted to the First Affiliated Hospital of Nanjing Medical University from January 2006 to December 2018 were retrospectively analyzed. The follow-up time was 6 years, with an average age of 55.4 years (21-87 years). There were 29 males, 14 females, 22 cases of limb bone metastasis, 12 cases of spinal metastasis, 9 cases of multiple bone metastasis, 21 cases of Fuhrman grade 1 and 2, 19 cases of T1, and 20 cases of N0. All patients were confirmed by postoperative pathological examination or imaging data suggesting that bone metastasis are from renal cell carcinoma. Forty-three patients underwent primary renal surgery, and molecular targeted therapy was used after the operation. The treatment process was smooth, no obvious discomfort, and postoperative pathology showed clear cell carcinoma.22 patients with limb bones metastasis and 12 patients with spinal metastasis included in the study all met the indications for secondary surgery after the disease assessment. After communicating with the patient, 13 patients with limbs metastasis and 6 patients with spinal metastasis received local treatment, including complete resection of the extremities and spinal fixation, the remaining 15 patients and 9 patients with multiple bone metastasis were treated conservatively. There were 19 patients in the local treatment group, 13 patients with limbs bone metastasis, 6 patients with spinal bone metastasis, the average age was 54.9 years, the average diameter of the primary tumor was 4.7 cm. There were 24 patients in the conservative treatment group, 9 patients with limbs metastasis, 6 patients with spinal metastases and 9 cases with multiple bone metastasis, with an average age of 56 years and a primary tumor diameter of 5.6 cm. Limb metastatic lesions were evaluated according to the patient's general condition, bone pain, fracture risk, and bone metastasis. Spinal lesions were evaluated according to Tokuhashi score, Harrington score, Tomita score, vertebral stability assessment, and molecular targeted therapy. Aminokinase inhibitors, conservative treatment with local radiotherapy and bisphosphonate treatment. Results During the follow-up period, the 1-year overall survival rate of the local treatment group was 100.0%, the 2-year overall survival rate was 89.4%, and the 5-year overall survival rate was 73.7%. The 1-year overall survival rate of the conservative treatment group was 87.5%, and the 2-year overall survival rate was 62.5%. The 5-year overall survival rate was 16.7%. The 2-year and 5-year survival rates of the local treatment group were statistically different (P=0.044, P=0.000) compared with the conservative treatment group. For patients with limb bone metastasis, the 5-year survival rate was significantly higher in patients receiving topical treatment than in the conservative treatment group (P=0.011). For spinal metastasis, spinal pain in the local treatment group was alleviated to varying degrees. No spinal instability and spasticity were observed after follow-up. In the spine patients who received conservative treatment, 3 patients developed paraplegia, which was statistically different from local treatment (P=0.046). Another 9 patients with multiple bone metastases did not undergo local surgery, and all died after multiple organ failure. Conclusions At the same time of molecular targeted therapy, according to the evaluation results, selective treatment of bone metastases with secondary surgical indications, including complete resection of the extremities and spinal fixation, can significantly improve the survival and quality of life of those patients. Key words: Carcinoma, renal cell; Bone metastasis; Condition evaluation; Treatment strategy; Complete resection; Spine fixation

Clear cell renal cell carcinoma bone metastasis: What should be considered in prognostic evaluation

IntroductionKnowledge of clear cell renal cell carcinoma bone metastasis (ccRCC-BM) remains scarce. This study depicts clinical, pathological and outcome features of the disease and provides suggestions to establish prognosis prediction system more appropriate for ccRCC-BM. Materials and methodsPatients with ccRCC-BM had clinical, pathological data collected. Kaplan-Meier survival analysis was used for outcome profiles. Prognostic risks were evaluated using MSKCC/Motzer score. Univariate and multivariate logistic regression were performed to investigate association between clinical, pathological features and prognosis. ResultsIn the series containing 106 ccRCC-BM patients with 4:1 male predominance, 44.3% of them had synchronous bone metastasis and 28.3% had multi-organ metastasis. Axial bone was prone to bone metastasis and the incidence of severe skeletal-related events was 54.7%. Curative bone lesion resection was performed in 70.7% patients. The median overall survival (mOS) time was 45 months for all and 32 months for those in unfavorable risk stratification. Shorter time to bone metastasis (TTBM) [OR 1.019, 95% CI (1.007, 1.031)], elderly age [OR 1.040, 95% CI (1.001, 1.080)], concomitant multi-organ metastasis [OR 3.883, 95% CI (1.375, 10.967)] and carbonic anhydrase (CA)-IX expression loss [OR 58.824, 95% CI (2.653, 1000)] were associated with poor prognosis. ConclusionThe outcome of ccRCC-BM remained poor in unfavorable risk stratification. Bone lesion resection accompanied by systematic therapy for selected patient could improve prognosis. Shorter TTBM, elderly age, concomitant multi-organ metastasis and the expression loss of CA-IX along with gender-bias, feasibility for surgical treatment are suggested to be incorporated in modified ccRCC-BM-specific prognosis prediction system.

Dysregulated HAI-2 Plays an Important Role in Renal Cell Carcinoma Bone Metastasis through Ligand-Dependent MET Phosphorylation.

MET, a c-met proto-oncogene product and hepatocyte growth factor (HGF) receptor, is known to play an important role in cancer progression, including bone metastasis. In a previous study, we reported increased expression of MET and matriptase, a novel activator of HGF, in bone metastasis. In this study, we employed a mouse model of renal cell carcinoma (RCC) bone metastasis to clarify the significance of the HGF/MET signaling axis and the regulator of HGF activator inhibitor type-2 (HAI-2). Luciferase-transfected 786-O cells were injected into the left cardiac ventricle of mice to prepare the mouse model of bone metastasis. The formation of bone metastasis was confirmed by whole-body bioluminescent imaging, and specimens were extracted. Expression of HGF/MET-related molecules was analyzed. Based on the results, we produced HAI-2 stable knockdown 786-O cells, and analyzed invasiveness and motility. Expression of HGF and matriptase was increased in bone metastasis compared with the control, while that of HAI-2 was decreased. Furthermore, we confirmed increased phosphorylation of MET in bone metastasis. The expression of matriptase was upregulated, and both invasiveness and motility were increased significantly by knockdown of HAI-2. The significance of ligand-dependent MET activation in RCC bone metastasis is considered, and HAI-2 may be an important regulator in this system.