Osteolytic Metastatic Lesions Research Articles

Comparison of Percutaneous Interventional Ablation-Osteoplasty-Reinforcement-Internal Fixation (AORIF), Long Intramedullary Nailing, and Hemiarthroplasty for the Treatment of Focal Metastatic Osteolytic Lesions in the Femoral Head and Neck

Osteolytic metastatic lesions in the femoral head and neck are traditionally treated with intramedullary long nailing (IM) or hemiarthroplasty (HA). Recovery, surgical complications, and medical co-morbidities delay oncologic care. This study sought to elucidate the comparative efficacy of percutaneous ablation-osteoplasty-reinforcement-internal fixation (AORIF), IM, and HA in stabilizing osteolytic lesions in the femoral head and neck. A retrospective study of 67 patients who underwent IM, AORIF, or HA for osteolytic femoral head and neck lesions was performed. Primary outcome was assessed using a combined pain and ambulatory score (Range 1-10: 1=bedbound, 10=normal ambulation) at firstfollow-up (~2weeks). Surgical complications associated with each treatment were compared. Sixty-seven patients (mean age, 65±13, 36 men and 31 women) underwent IM (40), AORIF (19), and HA (8) with a mean follow-up of 9±11months. Two patients in the IM group (5%), three in the AORIF group (16%), and none in the HA (0%) group required revision procedures. AORIF demonstrated superior early improvement in combined pain and ambulatory function scores by 3.0points [IQR=2.0] (IM p=0.0008, HA p=0.0190). Odds of post-operative complications was 10.3times higher in HA than IM (95% confidence interval 1.8 to 60.3). Future revision procedures were not found to be statistically significant between AORIF and IM (p=0.234). A minimally invasive interventional skeletal procedure for focal femoral head and neck osteolytic lesions may serve as an effective alternative treatment to traditional surgical approaches, conferring a shorter recovery time and fewer medical complications.

Procoxacin bidirectionally inhibits osteoblastic and osteoclastic activity in bone and suppresses bone metastasis of prostate cancer

BackgroundBone is the most common site of metastasis of prostate cancer (PCa). PCa invasion leads to a disruption of osteogenic-osteolytic balance and causes abnormal bone formation. The interaction between PCa and bone stromal cells, especially osteoblasts (OB), is considered essential for the disease progression. However, drugs that effectively block the cancer-bone interaction and regulate the osteogenic-osteolytic balance remain undiscovered.MethodsA reporter gene system was constructed to screen compounds that could inhibit PCa-induced OB activation from 631 compounds. Then, the pharmacological effects of a candidate drug, Procoxacin (Pro), on OBs, osteoclasts (OCs) and cancer-bone interaction were studied in cellular models. Intratibial inoculation, micro-CT and histological analysis were used to explore the effect of Pro on osteogenic and osteolytic metastatic lesions. Bioinformatic analysis and experiments including qPCR, western blotting and ELISA assay were used to identify the effector molecules of Pro in the cancer-bone microenvironment. Virtual screening, molecular docking, surface plasmon resonance assay and RNA knockdown were utilized to identify the drug target of Pro. Experiments including co-IP, western blotting and immunofluorescence were performed to reveal the role of Pro binding to its target. Intracardiac inoculation metastasis model and survival analysis were used to investigate the therapeutic effect of Pro on metastatic cancer.ResultsLuciferase reporter gene consisted of Runx2 binding sequence, OSE2, and Alp promotor could sensitively reflect the intensity of PCa-OB interaction. Pro best matched the screening criteria among 631 compounds in drug screening. Further study demonstrated that Pro effectively inhibited the PCa-induced osteoblastic changes without killing OBs or PCa cells and directly killed OCs or suppressed osteoclastic functions at very low concentrations. Mechanism study revealed that Pro broke the feedback loop of TGF-β/C-Raf/MAPK pathway by sandwiching into 14–3-3ζ/C-Raf complex and prevented its disassociation. Pro treatment alleviated both osteogenic and osteolytic lesions in PCa-involved bones and reduced the number of metastases of PCa in vivo.ConclusionsIn summary, our study provides a drug screening strategy based on the cancer-host microenvironment and demonstrates that Pro effectively inhibits both osteoblastic and osteoclastic lesions in PCa-involved bones, which makes it a promising therapeutic agent for PCa bone metastasis.Graphical

Transoral vertebroplasty for the treatment of C2 painful metastatic lesions; evaluation and outcome

ObjectiveA small number of studies supports vertebroplasty at the C2 vertebral body due to the documented technical challenges, the rarity of C2 osteolytic metastatic lesions, and the existence of potentially serious consequences linked to this particular anatomical area. Vertebroplasty, in such a situation, can be performed through a transoral, an anterolateral, or an open approach. All are supported by a limited number of studies with absence of a significant clinical trial assessing the efficacy, safety, and feasibility of vertebroplasty for the C2 vertebral body. We, herein, summarize a single-institution experience on C2 transoral vertebroplasty. Patients and MethodsThis is a retrospective analysis of the records of a single tertiary institute hospital and the clinical visits of nine patients with C2 osteolytic metastatic lesions treated by transoral fluoroscopically guided vertebroplasty between May 2016 and May 2021. ResultsThe median period of the last clinical follow-up was 23 months (range, 9–60 months). The intraoperative amount of polymethyl methacrylate (PMMA) injected and recorded in the surgical report was 2 mL (1.5–2.5 mL). Postoperative immediate imaging showed that the cement filling percentage in relation to the C2 mass was 70% (40–85%). The PMMA leakage through the needle track and into the paravertebral spaces was observed in only one patient (11.1%), without significant vascular and neurological consequences. Stability was maintained during the follow-up period. The postoperative median pain rating scale (PRS) score was 1 (0−2) immediately after the end of the operation and 0 (0−2) at the last visit. The recorded postoperative Pain Rating Scale (PRS) score was correlated with the cement filling percentage (rs= −0.9, p = 0.0008; Spearman correlation). ConclusionTransoral vertebroplasty is considered feasible and efficient technique in the treatment of secondary osteolytic lesions in the C2 vertebra. Further long-term and larger comparative randomized studies are required to perform a more comprehensive analysis of this technique.

Effects of Wnt-β-Catenin Signaling and Sclerostin on the Phenotypes of Rat Pheochromocytoma PC12 Cells.

Pheochromocytomas and paragangliomas (PPGLs) are classified into 3 major categories with distinct driver genes: pseudohypoxia, kinase signaling, and Wnt-altered subtypes. PPGLs in the Wnt-altered subtype are sporadic and tend to be aggressive with metastasis, where somatic gene fusions affecting mastermind-like 3 (MAML3) and somatic mutations in cold shock domain containing E1 (CSDE1) cause overactivation of Wnt-β-catenin signaling. However, the relation between Wnt-β-catenin signaling and the biological behavior of PPGLs remains unexplored. In rat pheochromocytoma PC12 cells, Wnt3a treatment enhanced cell proliferation and suppressed mRNA expression of tyrosine hydroxylase (TH), the rate-limiting enzyme of catecholamine biosynthesis, and dopamine secretion. We identified the expression of sclerostin in PC12 cells, which is known as an osteocyte-derived negative regulator for Wnt signaling-driven bone formation. Inhibition of endogenous Wnt pathway by XAV939 or sclerostin resulted in attenuated cell proliferation and increased TH expression. Furthermore, Wnt3a pretreatment suppressed bone morphogenetic protein (BMP)-induced Smad1/5/9 phosphorylation whereas BMPs enhanced sclerostin expression in PC12 cells. In the Wnt-altered subtype, the increased Wnt-β-catenin pathway may contribute the aggressive clinical behavior with reduced catecholamine production. Furthermore, upregulated expression of sclerostin by BMPs may explain the osteolytic metastatic lesions observed in metastatic PPGLs.

Radiomics analysis based on multiple parameters MR imaging in the spine: Predicting treatment response of osteolytic bone metastases to chemotherapy in breast cancer patients

PurposeTo assess the value of radiomics, apparent diffusion coefficient (ADC), intravoxel incoherent motion (IVIM) and stretched-exponential (SE) MR imaging in prediction of therapeutic response in patients with spinal metastases before chemotherapy. MethodsThirty-six patients with 190 osteolytic metastatic lesions from breast cancer were prospectively enrolled and underwent MR imaging before and after 6 months' treatment on a 1.5 T MRI. According to MDA criteria, 68 lesions were categorized as progressive disease (PD) and 122 lesions were categorized as stable or improvement (non-PD). The regions of interest (ROIs) were manually drawn on DWI, T1WI, T2WI and FS-T2WI by two radiologists with ITK-SNAP. The ADCall (multiple b-values method), IVIM parameters (D, D* and f) and SE parameters (DDC and α) were generated. The radiomics features were extracted from the ROIs. ResultsThe mean values of ADC, DDC, and D before treatment were significantly higher in non-PD group than those in PD group (P = 0.001). The radiomics based on ADCall had the highest AUC value (0.852), followed by that of the T2WI (0.829) and FS-T2WI (0.798). The radiomics model using ADCall and FS-T2WI showed excellent efficiency in predicting treatment response with AUCs of 0.905 and 0.873 in training and validation cohorts. The radiomics model had better performance than that of ADCall, D, and DDC for predicting treatment response of bone metastases. ConclusionRadiomics model based on ADCall and FS-T2WI could predict the treatment response and contribute to assisting clinicians in accurately choosing appropriate management.

Computed tomography characteristics of multiple myeloma and other osteolytic metastatic bone lesions.

Differentiation of multiple myeloma (MM) from osteolytic metastatic (OM) bone lesions may be critical in patients with lytic bone lesions but can be challenging for radiologists. To determine whether computed tomography (CT) can be used to distinguish between MM and other OM bone lesions. In this retrospective study, 320 lesions of 207 patients diagnosed with MM or OM, based on biopsy or clinical examination, were evaluated. Eight qualitative features were evaluated by two radiologists blinded to the diagnoses. The chi-square and Fisher exact tests, and logistic regression analysis, were used to evaluate the relationships between the CT findings and diagnoses. High-density areas were more common in OM than MM lesions (85.2% and 19%, P < 0.001), as were perilesional sclerosis (38.9% vs. 13.2%, P < 0.001), heterogeneity (on non-contrast CT images, 60% vs. 19.1%, P < 0.001; on contrast enhanced CT images, 80.6% vs. 28.2%, P < 0.001), and ill-defined margins (34.6% vs. 9.1%, P < 0.001). Similarly, OM lesions showed high-density areas more than MM in evaluation of skeletal system subgroups (vertebrae, 93.8% vs. 29.8%, P < 0.0001; thoracic cage bones, 69.6% vs. 19.2%, P < 0.001; pelvic bones and sacrum, 84.8% vs. 7.7%, P < 0.001; peripheral skeletal bones, 81.5% vs. 8.3%, P < 0.001). Logistic regression analysis revealed that the presence of a high-density area in the lesion increased the probability of a metastasis 25.88-fold (R2 = 0.516, P < 0.001). MM and OM lesions can be differentiated by CT; OM lesions exhibit high- density areas.

Abstract 3055: Xentuzumab, a humanized IGF-1 and IGF-2 ligand co-neutralizing monoclonal antibody, shows efficacy in a human breast cancer model of bone metastasis

Abstract Bone metastases are a frequent complication of cancer and are associated with considerable morbidity. Bones provide a permissive environment for metastatic colonization due to their dynamic turnover and an abundance of secreted factors that are required for bone maintenance. Insulin-like growth factors (IGF) are the most abundant growth factors in bone and are required for normal skeletal development and function. IGFs also promote cancer progression, aggressiveness, and treatment resistance via activation of the IGF-1 receptor (IGF-1R) and insulin receptor variant A (IR-A). Of specific relevance to bone metastases, excessive bone destruction in osteolytic metastatic lesions leads to a release of IGF-1 from the bone matrix, thus promoting proliferation of metastatic tumor cells, stimulating tumor cell homing to bones, and contributing to further enhancement of bone destruction. Therapeutic targeting of the IGF axis may therefore provide an effective method for treating bone metastases. The aim of this study was to explore the efficacy of the IGF-1/-2 ligand blocking antibody, xentuzumab (BI 836845[1]), alone and in combination with the mTOR inhibitor everolimus, in a breast cancer bone metastasis xenograft model. MDA-231-BoM cells[2], a subline of MDA-MB-231 selected in vivo for enhanced metastatic ability to bone, were injected intra-cardiacly to form bone metastases, and via tail vein to form lung/visceral metastases and treated with xentuzumab, everolimus, and the combination thereof. Tumor burden was monitored by bioluminescence imaging, and metastasis-associated osteolysis was measured by quantitative bone micro-computed tomography. Tumor-associated morbidity was evaluated by a multi-parameter health scoring scheme. Metastatic tumor burden in the bone was significantly reduced upon treatment with xentuzumab in monotherapy and in combination with everolimus vs. placebo. Xentuzumab (±everolimus) reduced the number and size of osteolytic lesions, delayed and diminished bone metastasis-associated morbidity, and prolonged survival. In contrast, the growth of lung/visceral metastases developing upon intravenous injection of tumor cells was not inhibited by xentuzumab. In summary, the IGF-1/-2 neutralizing antibody xentuzumab showed efficacy in a breast cancer bone metastasis model (with and without everolimus) but did not affect metastatic tumor growth in lung/visceral organs. A phase II trial evaluating the xentuzumab/ everolimus/ exemestane triple combination in HR+BC patients with non-visceral disease is currently ongoing (NCT03659136). [1] Friedbichler et al, 2014. Mol Cancer Ther 13(2):399 [2] Kang et al, 2003. Cancer Cell 3:537 Citation Format: Ulrike Weyer-Czernilofsky, Izabela Krecioch, Stephan Handschuh, Martin Glösmann, Mario Kuttke, Robin Jacob, Anna C. Obenauf. Xentuzumab, a humanized IGF-1 and IGF-2 ligand co-neutralizing monoclonal antibody, shows efficacy in a human breast cancer model of bone metastasis [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3055.

İlaca Bağlı Olarak Çene Kemiklerinde Görülen Osteonekrozda Dental Yönetim ve Güncel Tedavi Yaklaşımları: Derleme

Today, antiresorptive and antiangiogenic drugs are used in the treatment of breast, prostate or lung cancer, hypercalcemia, multiple myeloma or osteolytic metastatic lesions. In addition to these diseases, they can also be used in the treatment of osteoporosis. Depending on the use of these drugs, osteonecrosis may occur in the maxilla and mandible. In this review, we aimed to provide information about the etiology, risk factors, clinical course, radiological features, current treatment protocols and dental approach of the osteonecrosis that develops due to drug use in the jaws.

Stent screw-assisted internal fixation (SAIF): clinical report of a novel approach to stabilizing and internally fixating vertebrae destroyed by malignancy.

Severe lytic cancerous lesions of the spine are associated with significant morbidity and treatment challenges. Stabilization and restoration of the axial load capability of the vertebral body (VB) are important to prevent or arrest vertebral collapse. Percutaneous stent screw-assisted internal fixation (SAIF), which anchors a VB stent/cement complex with pedicular screws to the posterior vertebral elements, is a minimally invasive, image-guided, 360° internal fixation technique that can be utilized in this patient cohort. The purpose of this study was to assess the feasibility, safety, and stabilization efficacy of VB reconstruction via the SAIF technique in a cohort of patients with extensive lytic vertebral lesions, who were considered to have an unstable or potentially unstable spine according to the Spinal Instability Neoplastic Score (SINS). This study was a retrospective assessment of a prospectively maintained database of a consecutive series of patients with neoplastic extensive extracompartmental osteolysis (Tomita type 4-6) of the VB treated with the SAIF technique. VB reconstruction was assessed on postprocedure plain radiographs and CT by two independent raters. Technical and clinical complications were recorded. Clinical and imaging follow-ups were assessed. Thirty-five patients with extensive osteolytic metastatic lesions of the VB underwent 36 SAIF procedures. SAIF was performed as a stand-alone procedure in 31/36 cases and was associated with posterior surgical fixation in 5/36 (4/5 with decompressive laminectomy). In 1 case an epidural cement leak required surgical decompression. VB reconstruction was categorized as satisfactory (excellent or good rating) by the two raters in 34/36 cases (94.5%) with an interrater reliability of 94.4% (Cohen's kappa of 0.8). Follow-up, ranging from 1 to 30 months, was available for 30/36 levels. Long-term follow-up (6-30 months, mean 11.5 months) was available for 16/36 levels. Stability during follow-up was noted in 29/30 cases. SAIF provides 360° nonfusion internal fixation that stabilizes the VB in patients with extensive lytic lesions that would otherwise be challenging to treat.

Cement augmentation for vertebral osteolytic metastatic lesions: an evaluation on postoperative CT

Objective: To evaluate the effectiveness of cement augmentation on the osteolytic lesion in patients with vertebral metastasis. Methods: A total of consecutive 132 patients with 268 vertebral metastatic lesions treated with PVP from January 2008 to December 2016 in Zhongda Hospital were enrolled in this study. Retrospective analysis of preoperative, postoperative 3 days, 3 months, 6 months, 12 months and ≥ 18 months imaging data on CT, the local control and progression of the tumor were evaluated by MDA response criteria. The local control rates were compared between the groups with the different rate of cement filling by Chi2-test. Results: Vertebroplasty procedures were performed successfully in all 268 vertebrae under DSA guidance, and the mean volume of PMMA injected in each vertebra was 0.7-8.5(3.9±1.5)ml.The rate of local control at 3 months, 6 months, 12 months and ≥18 months after PVP was respectively 98.9%, 95.1%, 91.8%, and 85.2%, the difference was statistically significant(all P<0.05). The local control rate showed a statistically significant relationship to the groups with the rate of cement filling at 6 months, 12 months and ≥18 months after PVP, but there was no statistical difference at postoperative 3 months. The rate of local control was higher in 68 patients with lung or gastrointestinal cancer than in 17 patients with liver or kidney cancer at 3 months, 6 months and 12 months, the difference was statistically significant (P<0.05). Conclusion: Cement augmentation has a local anti-tumor effect on vertebral osteolytic metastatic lesion, and the anti-tumor effect will decrease as the follow-up time extended.

Clinical study of 99mTc-3P-RGD2 peptide imaging in osteolytic bone metastasis.

ObjectiveTo investigate the value of integrin αvβ3 targeted imaging with 99mTc-HYNIC-PEG4-E[PEG4-c(RGDfk)]2 (99mTc-3P-RGD2) as a radiotracer in dectecting osteolytic bone metastases.MethodsThis is a retrospective study involving a cohort of 69 consecutive patients including 59 with lung cancer and 10 with other cancers. Patients were required to receive whole body scan (WBS) and regional SPECT/CT imaging with 99mTc-3P-RGD2 (RGD imaging) and 99mTc-MDP (MDP imaging) as a radiotracer successively within days. Final diagnosis was based on comprehensive assessment of all available data including case history, CT, MRI, SPECT/CT, PET/CT, histopathology and 6-12 months follow-up. Visual observation and semiquantitative analysis (T/N: tracer uptake ratio of osteolytic metastases to normal bone) of 99mTc-3P-RGD2 or 99mTc-MDP imaging were performed and their detective values for osteolytic metastases were compared.ResultsA total of 131 osteolytic metastatic lesions were retrospectively studied. Osteolytic metastases mainly presented as “hot region”, occasionally as “cool or normal region” on RGD imaging. The detection sensitivity of RGD WBS for osteolytic metastases was significantly higher than that of 99mTc-MDP WBS (80.9% vs. 46.6%, p<0.01). The sensitivity increased to 96.2% (126/131) when combining with SPECT/CT. 99mTc-3P-RGD2 imaging also promoted the detection of unknown primary tumor, lymph node metastases and offered information for clinical staging. T/N of 99mTc-3P-RGD2 in lung adenocarcinoma osteolytic metastases showed no statistical difference compared with that in squamous-cell carcinoma (6.84±3.46 vs. 7.33±3.22, t = 0.39, p = 0.71). Whereas, it was higher in osteolytic metastases from lung cancer than that from thyroid cancer (7.05±3.01 vs. 4.11±2.67, p = 0.03).Conclusion99mTc-3P-RGD2 peptide imaging showed great potential for detection of osteolytic bone metastasis due to high expression level of integrin αvβ3 on osteoclast and most tumor cells.

Influence of simultaneous targeting of the bone morphogenetic protein pathway and RANK/RANKL axis in osteolytic prostate cancer lesion in bone

Metastasis to bone is the leading cause of morbidity and mortality in advanced prostate cancer patients. Considering the complex reciprocal interactions between the tumor cells and the bone microenvironment, there is increasing interest in developing combination therapies targeting both the tumor growth and the bone microenvironment. In this study, we investigated the effect of simultaneous blockade of BMP pathway and RANK/RANKL axis in an osteolytic prostate cancer lesion in bone. We used a retroviral vector encoding noggin (RetroNoggin) to antagonize the effect of BMPs and RANK:Fc, which is a recombinant RANKL antagonist was used to inhibit RANK/RANKL axis. The tumor growth and bone loss were evaluated using plain radiographs, hind limb tumor measurements, micro PET/CT ( 18FDG and 18F-fluoride tracer), and histology. Tibias implanted with PC-3 cells developed pure osteolytic lesions at 2-weeks with progressive increase in cortical bone destruction at successive time points. Tibias implanted with PC-3 cells over expressing noggin (RetroNoggin) resulted in reduced tumor size and decreased bone loss compared to the implanted tibias in untreated control animals. RANK:Fc administration inhibited the formation of osteoclasts, delayed the development of osteolytic lesions, decreased bone loss and reduced tumor size in tibias implanted with PC-3 cells. The combination therapy with RANK:Fc and noggin over expression effectively delayed the radiographic development of osteolytic lesions, and decreased the bone loss and tumor burden compared to implanted tibias treated with noggin over expression alone. Furthermore, the animals treated with the combination strategy exhibited decreased bone loss (micro CT) and lower tumor burden (FDG micro PET) compared to animals treated with RANK:Fc alone. Combined blockade of RANK/RANKL axis and BMP pathway resulted in reduced tumor burden and decreased bone loss compared to inhibition of either individual pathway alone in osteolytic prostate cancer lesion in bone. These results suggest that simultaneous targeting of tumor cells and osteoclasts may be the most effective method of inhibiting the progression of established osteolytic metastatic lesions in vivo.