Local Bone Destruction Research Articles

MOTS-c is an effective target for treating cancer-induced bone pain through the induction of AMPK-mediated mitochondrial biogenesis.

Bone cancer pain (BCP), due to cancer bone metastasis and bone destruction, is a common symptom of tumors, including breast, prostate, and lung tumors. Patients often experience severe pain without effective treatment. Here, using a mouse model of bone cancer, we report that MOTS-c, a novel mitochondrial-derived peptide, confers remarkable protection against cancer pain and bone destruction. Briefly, we find that the plasma level of endogenous MOTS-c is significantly lower in the BCP group than in the sham group. Accordingly, intraperitoneal administration of MOTS-c robustly attenuates bone cancer-induced pain. These effects are blocked by compound C, an AMPK inhibitor. Furthermore, MOTS-c treatment significantly enhances AMPKα 1/2 phosphorylation. Interestingly, mechanical studies indicate that at the spinal cord level, MOTS-c relieves pain by restoring mitochondrial biogenesis, suppressing microglial activation, and decreasing the production of inflammatory factors, which directly contribute to neuronal modulation. However, in the periphery, MOTS-c protects against local bone destruction by modulating osteoclast and immune cell function in the tumor microenvironment, providing long-term relief from cancer pain. Additionally, we find that chronic administration of MOTS-c has little effect on liver, renal, lipid or cardiac function in mice. In conclusion, MOTS-c improves BCP through peripheral and central synergistic effects on nociceptors, immune cells, and osteoclasts, providing a pharmacological and biological rationale for the development of mitochondrial peptide-based therapeutic agents for cancer-induced pain.

Risk factors for occurrence and progression of external auditory canal cholesteatoma

ObjectiveExternal auditory canal cholesteatoma (EACC) is characterized by retained squamous debris within the external canal and variable amounts of localized bone destruction. The etiology of primary EACC remains incompletely understood. This study was conducted to analyze the clinical features and backgrounds of patients with primary EACC and to clarify the risk factors for the occurrence and progression of EACC. MethodsSixty-nine ears of 62 patients diagnosed with primary EACC were included in this study (EACC group). Additionally, 74 ears of 60 patients with chronic otitis media (COM) with perforation who underwent tympanoplasty or myringoplasty were included as controls (COM group). We retrospectively investigated the clinical features, life history, and medical history of the patients in both groups. In addition, to investigate the risk factors for progression of EACC, we compared the clinical features and medical history of patients with stage IV (advanced) disease versus stage I + II (mild) disease. ResultsThe inferior wall of the bony canal was the main structure affected in patients with primary EACC of all stages. The following factors were significantly more common in the EACC than COM group: older age, female sex, left-sided disease, osteoporosis, renal dysfunction, anemia, and treatment with bisphosphonates. Among these, the most significant factor associated with EACC was renal dysfunction (odds ratio, 11.4; 95 % confidence interval, 2.32–55.9). The significant factors observed in patients with stage IV disease were younger age, male sex, posterior wall involvement, and otorrhea. Surgical treatment was required for more than half of the patients with stage III and IV EACC. ConclusionPatients with renal dysfunction are at risk of primary EACC. In particular, younger patients and relatively younger elderly patients with posterior wall involvement have a risk of progression to advanced-stage EACC. Canalplasty should be considered in patients with EACC who have these risk factors to prevent progression to advanced-stage disease.

Identification of focal lesion characteristics in MRI which indicate presence of corresponding osteolytic lesion in CT in patients with multiple myeloma.

The presence of bone marrow focal lesions and osteolytic lesions in patients with multiple myeloma (MM) is of high prognostic significance for their individual outcome. It is not known yet why some focal lesions seen in MRI, reflecting localized bone marrow infiltration of myeloma cells, remain non-lytic, whereas others are associated with destruction of mineralized bone. In this study, we analyzed MRI characteristics of manually segmented focal lesions in MM patients to identify possible features that might discriminate lytic and non-lytic lesions. The initial cohort included a total of 140 patients with different stages of MM who had undergone both whole-body MRI and whole-body low-dose CT within 30 days, and of which 29 satisfied the inclusion criteria for this study. Focal lesions in MRI and corresponding osteolytic areas in CT were segmented manually. Analysis of the lesions included volume, location and first order texture features analysis. There were significantly more lytic lesions in the axial skeleton than in the appendicular skeleton (p = 0.037). Out of 926 focal lesions in the axial skeleton seen on MRI, 544 (59.3 %) were osteolytic. Analysis of volume and first order texture features showed differences in texture and volume between focal lesions in MRI with and without local bone destruction in CT, but these findings were not statistically significant. Neither morphological imaging characteristics like size and location nor first order texture features could predict whether focal lesions seen in MRI would exhibit corresponding bone destruction in CT. Studies performing biopsies of such lesions are ongoing.

Temporal kemiğin dev hücreli tümörü

Giant cell tumor (GCT) arises from undifferentiated mesenchymal cells of the bone marrow. GCT, a benign and locally aggressive tumor, is more commonly seen in the metaphysis of long bones. It may cause local bone destruction, recurrence, and pulmonary metastases (~1%). A 15-year-old male patient was admitted with complaints of swelling on the right face, a headache that has persisted for one year and progressively worsened in the last three months, and hearing loss. Craniotomy and total tumor excision were performed. Histopathological examination revealed a giant cell tumor of the bone. We present a case of temporal bone GCT with its clinical and radiologic features.

3D-printed biodegradable magnesium alloy scaffolds with zoledronic acid-loaded ceramic composite coating promote osteoporotic bone defect repair.

Osteoporotic fracture is one of the most serious complications of osteoporosis. Most fracture sites have bone defects, and restoring the balance between local osteogenesis and bone destruction is difficult during the repair of osteoporotic bone defects. In this study, we successfully fabricated three-dimensional (3D)-printed biodegradable magnesium alloy (Mg-Nd-Zn-Zr) scaffolds and prepared a zoledronic acid-loaded ceramic composite coating on the surface of the scaffolds. The osteogenic effect of Mg and the osteoclast inhibition effect of zoledronic acid were combined to promote osteoporotic bone defect repair. In vitro degradation and drug release experiments showed that the coating significantly reduced the degradation rate of 3D-printed Mg alloy scaffolds and achieved a slow release of loaded drugs. The degradation products of drug-loaded coating scaffolds can promote osteogenic differentiation of bone marrow mesenchymal stem cells as well as inhibit the formation of osteoclasts and the bone resorption by regulating the expression of related genes. Compared with the uncoated scaffolds, the drug-coated scaffolds degraded at a slower rate, and more new bone grew into these scaffolds. The healing rate and quality of the osteoporotic bone defects significantly improved in the drug-coated scaffold group. This study provides a new method for theoretical research and clinical treatment using functional materials for repairing osteoporotic bone defects.

Clinical outcomes of sinonasal inverted papilloma: a retrospective analysis of 139 cases.

Sinonasal inverted papilloma has a high tendency for recurrence, local bone destruction and risk of malignant transformation. Therefore, complete resection of the tumour is required, and close follow up is essential. This article describes the clinical outcomes, recurrence rate and malignant transformation rate of sinonasal inverted papilloma. In this study, 139 patients diagnosed with sinonasal inverted papilloma in our hospital from December 2010 to May 2022 were retrospectively analysed. All patients underwent endoscopic surgery. Sinonasal inverted papilloma occurred more often in males than in females. The mean age of patients with sinonasal inverted papilloma was 67.3 ± 5.7 years at diagnosis. The most prevalent site of origin was the maxillary sinus (50.4 per cent). The recurrence rate was 5.75 per cent, and the malignant transformation rate was 6.5 per cent. All patients in this study underwent endoscopic surgery. Meticulous resection and regular long-term follow ups are crucial to reducing sinonasal inverted papilloma recurrence after surgery.

HSC70 mediated autophagic degradation of oxidized PRL2 is responsible for osteoclastogenesis and inflammatory bone destruction.

Inflammation leads to systemic osteoporosis or local bone destruction, however, the underlying molecular mechanisms are still poorly understood. In this study, we report that PRL2 is a negative regulator of osteoclastogenesis and bone absorption. Mice with PRL2 deficiency exhibit a decrease in bone volume and an increase in osteoclast numbers. PRL2 negatively regulates RANKL-induced reactive oxygen species production through the activation of RAC1, thus PRL2 deficient osteoclast precursors have both increased osteoclast differentiation ability and bone resorptive capacity. During inflammation, oxidized PRL2 is a selected substrate of HSC70 and conditions of oxidative stress trigger rapid degradation of PRL2 by HSC70 mediated endosomal microautophagy and chaperone-mediated autophagy. Ablation of PRL2 in mouse models of inflammatory bone disease leads to an increase in the number of osteoclasts and exacerbation of bone damage. Moreover, reduced PRL2 protein levels in peripheral myeloid cells are highly correlated with bone destruction in a mouse arthritis model and in human rheumatoid arthritis, while the autophagy inhibitor hydroxychloroquine blocked inflammation-induced PRL2 degradation and bone destruction in vivo. Therefore, our findings identify PRL2 as a new regulator in osteoimmunity, providing a link between inflammation and osteoporosis. As such, PRL2 is a potential therapeutic target for inflammatory bone disease and inhibition of HSC70 mediated autophagic degradation of PRL2 may offer new therapeutic tools for the treatment of inflammatory bone disease.

Single-cell RNA analysis of chemokine expression in heterogeneous CD14+ monocytes with lipopolysaccharide-induced bone resorption

Lipopolysaccharide (LPS)-induced bone resorption has normally been found in inflammatory bone diseases, but the underlying mechanism is currently unclear. Since LPS binds to CD14 and activates Toll-like receptor 4 (TLR4) in monocytes, the present study focused on CD14+ monocytes and observed their responses after LPS treatment during the progression of local bone destruction. CD14+ monocytes were obtained from human peripheral blood mononuclear cells (PBMCs) by magnetic cell separation (MACS), and their classification was confirmed by fluorescence-activated cell sorting (FACS). Single-cell RNA sequencing (scRNA-seq) was further utilized to analyze their subpopulations, and the results showed that physiological CD14+ monocytes were heterogeneous and divided into 6 subsets, that could be easily agitated. After priming with a suitable concentration of LPS, heterogeneous CD14+ monocytes became pathological and expressed a large number of chemokines as a “cascade effect”. Some of these chemokines have been validated in an animal model of mouse calvarial bone invasion. Taken together, our research has linked enhanced chemokine expression with stimulation of heterogeneous CD14+ monocytes, and indicated that inflammatory responses caused by microbiome infection are responsible for the recruitment and mobilization of CD14+ monocytes into bone resorption sites, which may explain the pathogenesis of LPS-associated bone diseases.

Are fungi and EBV effective in cholesteatoma etiology?

Aim: Cholesteatoma is a commonly seen disease whose pathogenesis remains unknown. Although not a neoplastic process, it may progress to a fatal condition with local bone destruction. In this study, we aimed to present new insights concerning the etiology of cholesteatoma triggered by an inflammatory process.Materials and Methods: The study included 34 patients diagnosed with cholesteatoma upon mastoidectomy performed between 2011-2019. Due to a provisional diagnosis of cholesteatoma. The cases were investigated for the latent membrane protein (LMP-1) encoded by the Epstein-Barr Virus (EBV) using the immunohistochemical method and for the presence of fungi using Grocott’s methenamine silver (GMSII) stain.Results: No fungi was detected in any of the 34 patients by GMSII staining. Thirty-two of the 34 patients were negative with but a suspicious result was seen in 2 patients with the immunohistochemical EBV antibody. EBV-encoded RNA (EBER) analysis was applied to these 2 cases with the silver in situ hybridization method and no reaction was observed.Conclusion: In our study, we investigated the presence of fungi and EBV, which can trigger the inflammatory process. However, no EBV or fungi was detected in the tissues. Our study is the first to investigate the presence of EBV and fungi in formalin-fixed tissue in cases of aggressive cholesteatoma.

Osteosarcoma Arising in Fibrous Dysplasia of the Long Bone: Characteristic Images and Molecular Profiles.

Fibrous dysplasia (FD) is a benign fibro-osseous lesion that frequently involves the craniofacial bones and femur. Malignant transformation of FD is a rare occurrence. We report a 38-year-old woman with osteosarcoma (OS) arising from FD of the femur. Magnetic resonance imaging revealed a well-defined lesion in the medulla of the femur, with cortical thinning and local bone destruction. Wide excision of the femur was performed. Grossly, the inner part of the mass was hard and tan-gray in color, and the outer part of the mass adjacent to the cortex showed myxoid discoloration with infiltrative borders. Microscopically, most of the tumor consisted of curvilinear woven bone and fibrous stroma with bland spindle cells, which transitioned to the outer portion of the tumor, showing cellular proliferation of pleomorphic cells with frequent mitotic activity. Next-generation sequencing revealed GNAS and TP53 mutations, and the diagnosis of OS arising from FD was strongly supported. This case highlights the characteristic images and molecular features of the malignant transformation of FD.

Clinical effects of partially de-epithelized local flaps in repairing tubercular chest wall defects

Objective: To explore the clinical effects of partially de-epithelized local flaps in repairing tubercular chest wall defects. Methods: A retrospective observational study was conducted. From April 2010 to February 2021, twelve patients who met the inclusion criteria were admitted to the Department of Burns and Plastic Surgery of the Eighth Medical Center of PLA General Hospital, including 9 males and 3 females with age of (42±18) years. The sizes of tubercular chest wall defects of patients were ranged from 4 cm×3 cm×2 cm to 16 cm×8 cm×5 cm, which were all repaired with partial de-epithelized local flaps. The widths of flaps were equal to the widths of the defects, and the lengths of flaps were 2 cm longer than those of the defects. In one patient, the local flap was too large to close the donor site directly by suturing, so an autologous back free medium thickness skin graft was used for repair. In other patients, the collection areas of local flaps were small, and the donor areas of flaps were directly closed. The duration of operation, intraoperative bleeding, and postoperative drainage volume and indwelling time of drainage tube were observed and recorded. In two weeks after operation, the survival, color, and texture of flaps, the presence of subcutaneous hydrops and skin ulcer, and donor site healing including wound disruption, local infection, hematoma were observed. Chest X-ray, CT scan, or nuclear magnetic resonance imaging was performed in one month after operation to check whether new local hydrops and bone destruction occurred in the chest wall defects and the concomitant tuberculose focus of patients. All patients were followed up for more than 6 months to record whether the surgical incisions of the chest wall defects of the patients were complicated by hypertrophic scar, redness, swelling, and sinus. Results: In surgery, the patient had (104±18) min of operation duration, (119±53) mL of intraoperative bleeding, (134±49) mL of cumulative drainage of drainage tube, and (5.3±1.7) days of drainage tube indwelling time. In two weeks after operation, all the grafted local flaps survived, and the color and texture of flaps were similar to the surrounding normal skin. One patient had fluid leakage from the incision of chest wall defect area with the incision partially dehisced, which healed well after a phase Ⅱ operation; no wound infection, subcutaneous hydrops, or wound rupture occurred in other patients. The incisions of donor sites in all the patients healed well and no wound disruption, local infection, or hematoma occurred. One month after operation, no new bone destruction was observed in the operative region by chest imaging examination. Patients were followed up for 6 to 96 months, with one patient having wound swelling, ulceration, and sinus in the operative area of the chest wall defect in 12 months after surgery, which healed after phase Ⅱ operation; the incisions of chest wall defect wounds in other patients healed well and had no scar, redness and swelling, or sinus. Conclusions: Partially de-epithelized local flap could be used in repairing tubercular chest wall defect wounds, with the advantages of flexible flap design, minimal donor site injury, and good postoperative wound healing.

Retrospective analysis of massive epistaxis and pseudoaneurysms in nasopharyngeal carcinoma after radiotherapy.

Epistaxis after radiotherapy for nasopharyngeal carcinoma (NPC) is a common clinical critical illness, which often leads to death of patients. This article focuses on the relationship between massive epistaxis and pseudoaneurysm after radiotherapy in patients with NPC and discusses clinically relevant treatment strategies. A review was performed in 21 patients with massive epistaxis after radiotherapy for NPC from January 2011 to December 2019, and all of the patients were examined by computed tomography angiography (CTA). We also reviewed the English literature over the past 10years to analyze the characteristics and related causes of pseudoaneurysms in terms of the clinical stage of NPC, course of radiotherapy, and affected artery. An analysis was performed on the methods of endovascular interventional treatment of such pseudoaneurysms. Among the 21 patients, 19 cases had bone destruction of the skull base; 13 cases were also found to have tumor recurrence; 15 cases were in stage III or IV of NPC; pseudoaneurysms were observed in 14 cases, of which nine cases had pseudoaneurysms in the internal carotid artery (ICA), and the rest had pseudoaneurysms in the external carotid artery (ECA). These data were consistent with the results of the literature review. Analysis with imaging revealed that the petrous ICA was the common predilection site. There were 11 out of 14 cases of pseudoaneurysms with sentinel hemorrhage in the initial phase. All 14 pseudoaneurysm patients underwent endovascular interventional therapy, but one died from hemorrhagic shock during the procedure. No rebleeding was observed among the other patients during 72h after intravascular treatment. Nevertheless, regrettably two patients died on the 10th and 17th days after intervention. Pseudoaneurysm, which was a serious complication after radiotherapy in patients with NPC, could cause massive epistaxis with high mortality. The formation of a pseudoaneurysm was closely associated with a high carcinoma stage, re-radiotherapy, and local bone destruction and infection. Most cases had sentinel epistaxis, which was considered the bleeding characteristic. The imaging material prompted that pseudoaneurysm had a predisposition to the petrous part of the ICA, while the preferred therapy was endovascular embolization treatment.

STING suppresses bone cancer pain via immune and neuronal modulation

Patients with advanced stage cancers frequently suffer from severe pain as a result of bone metastasis and bone destruction, for which there is no efficacious treatment. Here, using multiple mouse models of bone cancer, we report that agonists of the immune regulator STING (stimulator of interferon genes) confer remarkable protection against cancer pain, bone destruction, and local tumor burden. Repeated systemic administration of STING agonists robustly attenuates bone cancer-induced pain and improves locomotor function. Interestingly, STING agonists produce acute pain relief through direct neuronal modulation. Additionally, STING agonists protect against local bone destruction and reduce local tumor burden through modulation of osteoclast and immune cell function in the tumor microenvironment, providing long-term cancer pain relief. Finally, these in vivo effects are dependent on host-intrinsic STING and IFN-I signaling. Overall, STING activation provides unique advantages in controlling bone cancer pain through distinct and synergistic actions on nociceptors, immune cells, and osteoclasts.

Characteristics of Ang-(1-7)/Mas-Mediated Amelioration of Joint Inflammation and Cardiac Complications in Mice With Collagen-Induced Arthritis.

ObjectivesRheumatoid arthritis (RA) is a disabling disease with a high incidence that is regularly accompanied by cardiovascular complications. Several studies have suggested that renin–angiotensin–aldosterone system (RAAS) is closely associated with RA. The aim of this study was to investigate the mechanisms underlying Angiotensin-(1–7) [Ang-(1–7)] and its Mas receptor agonist (AVE0991) on joint inflammation and cardiac complications in a collagen-induced arthritis (CIA) model.MethodsCollagen type II was injected into DBA/1 mice to construct an arthritis model. CIA mice were treated with Ang-(1–7) (2.0 mg/kg intraperitoneally) and AVE0991 (3.0 mg/kg intraperitoneally). The serum levels of inflammatory cytokines [tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1 β, IL-6, and C-reactive protein (CRP)] were determined by ELISA. The mitogen-activated protein kinase (MAPK) and nuclear factor-kappaB (NF-κB) signaling pathways in joint tissues and the transforming growth factor (TGF)-β/Smad pathway and levels of α-Smooth muscle action (SMA) and β-myosin heavy chain (MHC) protein expression in cardiac tissues were assessed by western blots. The levels of TGF-β/Smad pathway, α-SMA, and β-MHC RNA in cardiac tissues were analyzed by real time-PCR. The levels of receptor activator of nuclear factor kappa ligand (RANKL) and promoting matrix metalloproteinase (MMP)-3 expression in the ankle joints were detected by immunohistochemistry and real time-PCR.ResultsAng-(1–7) and AVE0991 reduced the levels of inflammatory cytokines and inhibited the MAPKs and NF-κB signaling pathways in ankle joint tissues, reduced RANKL and MMP3 expression, and ameliorated local joint inflammation and bone destruction compared with the control group. In addition, Ang-(1–7) and AVE0991 attenuated the TGF-β/Smad signaling pathway, reduced the levels of α-SMA and β-MHC expression, and diminished inflammatory cell infiltration into the myocardial interstitium and myocardial interstitial fibrosis in the hearts of CIA mice.ConclusionsAng-(1–7) alleviated joint damage caused by inflammation likely through the attenuation of NF-κB and MAPK pathways and ameliorated inflammation-induced cardiac fibrosis and activation of the TGF-β/Smad pathway. Moreover, Ang-(1–7) was likely mediated through the Mas receptor. This study provides theoretical evidence for exploring novel clinical therapeutic approaches for RA and its cardiac complications.

Analyzing Longitudinal wb-MRI Data and Clinical Course in a Cohort of Former Smoldering Multiple Myeloma Patients: Connections between MRI Findings and Clinical Progression Patterns.

Simple SummarySmoldering multiple myeloma is a heterogenous precursor state of multiple myeloma—both the time until progression and the cause of progression vary within this subgroup. While the number of focal lesions in whole-body MRI (magnetic resonance imaging) is known to be of prognostic value, we investigated whether additional parameters like the size or growth dynamics of focal lesions or precisely quantified diffuse infiltration are connected to risk and cause of progression. We found that both the size and dynamics of focal lesions correlate with progression to multiple myeloma and with existence/appearance of corresponding osteolytic lesions in near-term computed tomography (CT) scans. Furthermore, a score combining intensity and extent of diffuse infiltration showed connections with risk of progression and decrease in hemoglobin. We conclude that these parameters from whole-body MRI can help to predict the clinical course of disease in smoldering multiple myeloma (SMM) patients, with implications for diagnostic follow-up and possibly more specified therapeutic approaches in the future.The purpose of this study was to analyze size and growth dynamics of focal lesions (FL) as well as to quantify diffuse infiltration (DI) in untreated smoldering multiple myeloma (SMM) patients and correlate those MRI features with timepoint and cause of progression. We investigated 199 whole-body magnetic resonance imaging (wb-MRI) scans originating from longitudinal imaging of 60 SMM patients and 39 computed tomography (CT) scans for corresponding osteolytic lesions (OL) in 17 patients. All FLs >5 mm were manually segmented to quantify volume and growth dynamics, and DI was scored, rating four compartments separately in T1- and fat-saturated T2-weighted images. The majority of patients with at least two FLs showed substantial spatial heterogeneity in growth dynamics. The volume of the largest FL (p = 0.001, c-index 0.72), the speed of growth of the fastest growing FL (p = 0.003, c-index 0.75), the DI score (DIS, p = 0.014, c-index 0.67), and its dynamic over time (DIS dynamic, p < 0.001, c-index 0.67) all significantly correlated with the time to progression. Size and growth dynamics of FLs correlated significantly with presence/appearance of OL in CT within 2 years after the respective MRI assessment (p = 0.016 and p = 0.022). DIS correlated with decrease of hemoglobin (p < 0.001). In conclusion, size and growth dynamics of FLs correlate with prognosis and local bone destruction. Connections between MRI findings and progression patterns (fast growing FL—OL; DIS—hemoglobin decrease) might enable more precise diagnostic and therapeutic approaches for SMM patients in the future.

Correlative Analysis of Massive Epistaxis and Pseudoaneurysms in Nasopharyngeal Carcinoma after Radiotherapy and a 10-Year Review

Objective: Massive epistaxis after radiotherapy for nasopharyngeal carcinoma (NPC) is a common clinical critical illness, which often leads to death of patients. This article focuses on the relationship between massive epistaxis and pseudoaneurysm after radiotherapy in patients with NPC and discusses clinically relevant treatment strategies. Methods: A review was performed in 21 patients with massive epistaxis after radiotherapy for NPC from January 2011 to December 2019, and all of the patients were examined by computed tomography angiography (CTA). We also reviewed the English literature over the past 10 years to analyse the characteristics and related causes of pseudoaneurysms in terms of the clinical stage of NPC, course of radiotherapy, and affected artery. An analysis was performed on the methods of endovascular interventional treatment of such pseudoaneurysms. Results: Among the 21 patients with massive epistaxis after radiotherapy for NPC, 19 (90%) cases had accompanying bone destruction of the skull base; 13 cases (62%) showed tumor recurrence; 15 cases (71%) were in stage III or IV of NPC; 14 cases (67%) had combined pseudoaneurysms, including 9 cases occurring in the internal carotid artery (ICA) and 5 cases occurring in the external carotid artery (ECA). These data were consistent with the results of literature review. On analysis with imaging, we found that such pseudoaneurysms are associated with necrosis and infection of the local bone and soft tissue, and that the petrous part of the ICA was the most common predilection site. We also found that 11 of 14 pseudoaneurysms caused sentinel hemorrhage in the initial phase. In addition to anterior and posterior nasal packing, endovascular interventional therapy was the most important management option. All 14 patients with pseudoaneurysms underwent endovascular interventional therapy, but 1 patient died due to hemorrhagic shock during the procedure. Among the others, 9 patients underwent occlusion of the ICA or ECA with a stainless-steel coil, and rebleeding did not occur again. One patient underwent selected vascular embolization with a covered stent. Direct occlusion of the pseudoaneurysm was performed in 3 patients. Conclusion: Pseudoaneurysm, which was a serious complication after radiotherapy in patients with NPC, could cause massive epistaxis with high mortality. The formation of a pseudoaneurysm was closely associated with a high carcinoma stage, re-radiotherapy, and local bone destruction and infection. Most cases had sentinel epistaxis, which was considered the bleeding characteristic. The imaging material prompted that pseudoaneurysm had a predisposition to the petrous part of the ICA, while the preferred therapy was endovascular embolization treatment.

Chinese expert consensus statement on the clinical diagnosis and treatment of breast cancer bone metastasis and bone related disease

: Breast cancer is one of the most common malignancy in Chinese women. Up to 80% of patients with metastatic breast cancer develop bone metastasis resulting in local bone destruction and skeletal-related events such as pathological fracture and spinal cord compression. Skeletal-related events pose an enormous impact on patients' motor function and quality of life. Therefore, prevention of skeletal-related events is one of the treatment objectives of breast cancer bone metastasis, which often requires participation of multidisciplinary team to optimize therapeutic regimen for individual. Standard anti-tumor therapy includes chemotherapy, endocrine therapy, targeted therapy, immunotherapy, etc. Bone-modifying agents are the basic treatment after the occurrence of bone metastases in addition to anti-tumor therapy. As the disease progresses, patients may receive bone radiotherapy and orthopedic surgery. The purpose of this expert’s consensus is to standardize diagnosis and treatment of breast cancer bone metastasis and improve the quality of life of patients.

Risk Factors for Local Bone Destruction Progression in Palliative Percutaneous Vertebroplasty for Vertebral Metastases and the Significance of Bone Cement Filling Rates

BACKGROUND: For palliative percutaneous vertebroplasty (PVP) for vertebral metastases, local bone destruction progression (LBDP) commonly occurs in the previously treated vertebrae. There were no studies regarding LBDP and its risk factors in previous reports, and there was no uniform evaluation method for the distribution of bone cement in the vertebrae. OBJECTIVES: We aimed to investigate the risk factors for LBDP after PVP for palliative treatments in patients with vertebral metastases. We also proposed that filling rates could be used as a simple evaluation method to detect vertebral metastases and explored its clinical significance. STUDY DESIGN: This was a retrospective study. SETTING: A university hospital. METHODS: A total of 48 patients and 54 vertebrae that had received PVP as a palliative treatment for vertebral metastases were recruited between October 2012 to October 2019 from the Shengjing Hospital of the China Medical University. We collected and evaluated the data including age, gender, cement filled completely or not, cement dose used, the cement distribution score, time of LBDP, and so on, and the filing rate we proposed was also included. RESULTS: This retrospective study divided 48 patients and 54 vertebrae into group A for those with an LBDP of less than 6 months (n = 41), and group B for those with an LBDP of 6 or more months (n = 13). The complete filling of bone cement and bone cement dose in group B was much higher than that in group A (2.85 ± 0.97 vs. 4.12 ± 1.77; P = 0.027), and the time of recurrent pain in group B was significantly higher compared with that in group A (8.46 ± 2.73 vs. 3.39 ± 1.63; P &lt; 0.0001). There was a statistical difference in the Saliou score and filling rate between the 2 groups (11.77 ± 3.17 vs. 9.34 ± 3.28, P = 0.023; 0.752 ± 0.227 vs. 0.489 ± 0.161, P &lt; 0.0001). Univariate logistic analysis showed that complete filling of cement, the cement dose, Saliou score, and filling rate were statistically significant predictors of LBDP occurring in less than 6 months. Multivariate logistic analysis showed that the filling rate was an independent predictor of patients with vertebral metastases developing LBDP in less than 6 months (odds ratio, &lt; 0.001; 95% confidence interval, &lt; 0.001–0.006; P = 0.0007). The cutoff value for the filling rate calculated from the receiver operating characteristic (ROC) curve analysis was 0.646, which could identify patients who had LBDP in less than 6 months of PVP with a sensitivity of 85.4% and specificity of 84.6%. The 6-month LBDP in the 0.646 or less ROC curve group was higher than that in the greater than 0.646 ROC curve group (97.22% vs. 55.56%, P &lt; 0.0001). LIMITATIONS: The retrospective nature and small sample size were significant. Variation in the time and state of bone cement injected during all PVP procedures was a bias. There was no pathological diagnosis of all vertebral metastases. CONCLUSIONS: The cement dose, complete filling of cement, Saliou score, and filling rate were factors negatively related to LBDP occurring in less than 6 months. Patients with lower filling rates are maybe more likely to have early LBDP compared with those with higher filling rates. KEY WORDS: Bone cement, distribution of bone cement, local bone destruction progression, percutaneous vertebroplasty, palliative treatment, vertebral metastases

Pantoprazole (PPZ) Inhibits RANKL-Induced Osteoclast Formation and Function In Vitro and Prevents Lipopolysaccharide- (LPS-) Induced Inflammatory Calvarial Bone Loss In Vivo.

Bone remodeling is a process delicately balanced between osteoclastic bone resorption and osteoblastic bone formation. Osteoclasts (OCs) are multinucleated giant cells formed through the fusion of monocytic precursors of the hematopoietic stem cells lineage. OCs are the exclusive cells responsible for the resorption and degradation of the mineralized bone matrix. Pantoprazole (PPZ), a proton pump inhibitor (PPI), is commonly prescribed to reduce excess gastric acid production for conditions such as gastroesophageal reflux disease and peptic ulcer disease. Studies have found contradictory effects of PPI therapy on bone metabolism due to the lack of understanding of the exact underlying mechanism. In this study, we found that PPZ inhibits receptor activator of nuclear factor-κB (NF-κB) ligand- (RANKL-) induced osteoclastogenesis from bone marrow monocytic/macrophage (BMMs) precursors and the bone-resorbing activity of mature OCs. Correspondingly, the expression of OC marker genes was also attenuated. At the molecular level, PPZ treatment was associated with reduced activation of the ERK MAPK signaling pathways crucial to OC differentiation. Additionally, the in vivo administration of PPZ protected mice against lipopolysaccharide- (LPS-) induced inflammatory calvarial bone erosion, as a result of the reduced number and activity of OCs on the calvarial bone surface. Although PPI use is associated with increased risk of osteoporosis and bone fractures, our study provides evidence for the direct inhibitory effect of PPZ on OC formation and bone resorption in vitro and in vivo, suggesting a potential therapeutic use of PPZ in the treatment of osteolytic disease with localized bone destruction.

Hypercalcemia caused by humoral effects and bone damage indicate poor outcomes in newly diagnosed multiple myeloma patients.

BackgroundHypercalcemia of malignancy (HCM) is a serious metabolic complication, and the highest rates are in multiple myeloma (MM). The cause of hypercalcemia in newly diagnosed multiple myeloma (NDMM) remains unknown. We sought to evaluate the prognostic impact and mechanism of hypercalcemia in patients with symptomatic NDMM.MethodsWe studied all consecutive MM patients who were initially diagnosed and followed up at Beijing Jishuitan Hospital between February 2013 and December 2019; 357 patients were included in the retrospective analysis.ResultsA total of 16.8% of MM patients presented with hypercalcemia at the time of MM diagnosis. The presence of hypercalcemia was associated with higher serum levels of β2 microglobulin, creatinine, phosphorus, uric acid, procollagen I N‐terminal peptide, β‐carboxy‐terminal cross‐linking telopeptide of type I collagen and osteocalcin, lower serum levels of hemoglobin, parathyroid hormone (PTH), and advanced ISS and R‐ISS stages. Multivariate analysis showed that serum PTH, hemoglobin, creatinine, and uric acid levels were the main factors affecting hypercalcemia. The presence of hypercalcemia was associated with significantly inferior survival (40 months vs 57 months, p < 0.05) based on univariate analysis, and it remained an independent poor prognostic factor (HR: 1.854, 95% CI: 1.006‐3.415, adjusted p = 0.048) in a multivariate model that included age and R‐ISS stage.ConclusionThis study shows that hypercalcemia is associated with poor survival and is caused by manifold factors with humoral effects and local bone destruction.