Cyclin‐Dependent Kinase Inhibitor‐1‐Deficient Mice are Susceptible to Osteoarthritis Associated with Enhanced Inflammation

Osteoarthritis (OA) is a multifactorial disease, and recent data suggested that cell cycle–related proteins play a role in OA pathology. Cyclin‐dependent kinase (CDK) inhibitor 1 (p21) regulates activation of other CDKs, and recently, we reported that p21 deficiency induced susceptibility to OA induced by destabilization of the medial meniscus (DMM) surgery through STAT3‐signaling activation. However, the mechanisms associated with why p21 deficiency led to susceptibility to OA by the STAT3 pathway remain unknown. Therefore, we focused on joint inflammation to determine the mechanisms associated with p21 function during in vitro and in vivo OA progression. p21‐knockout (p21^?/?) mice were used to develop an in vivo OA model, and C57BL/6 (p21^+/+) mice with the same background as the p21^?/? mice were used as controls. Morphogenic changes were measured using micro‐CT, IL‐1β serum levels were detected by ELISA, and histological or immunohistological analyses were performed. Our results indicated that p21‐deficient DMM‐model mice exhibited significant subchondral bone destruction and cartilage degradation compared with wild‐type mice. Immunohistochemistry results revealed p21^?/? mice susceptibility to OA changes accompanied by macrophage infiltration and enhanced MMP‐3 and MMP‐13 expression through IL‐1β‐induced NF‐κB signaling. p21^?/? mice also showed subchondral bone destruction according to micro‐CT analysis, and cathepsin K staining revealed increased numbers of osteoclasts. Furthermore, p21^?/? mice displayed increased serum IL‐1β levels, and isolated chondrocytes from p21^?/? mice indicated elevated MMP‐3 and MMP‐13 expression with phosphorylation of IκB kinase complex in response to IL‐1β stimulation, whereas treatment with a specific p‐IκB kinase inhibitor attenuated MMP‐3 and MMP‐13 expression. Our results indicated that p21‐deficient DMM mice were susceptible to alterations in OA phenotype, including enhanced osteoclast expression, macrophage infiltration, and MMP expression through IL‐1β‐induced NF‐κB signaling, suggesting that p21 regulation may constitute a possible therapeutic strategy for OA treatment. © 2017 American Society for Bone and Mineral Research.     

IgG-class anti-PF4/heparin antibodies and symptomatic DVT in orthopedic surgery patients receiving different anti-thromboembolic prophylaxis therapeutics

Background  

Heparin-induced thrombocytopenia (HIT) is a thromboembolic complication that can occur with unfractionated heparin (UFH) or low molecular weight heparin (LMWH). Our objective was to determine and compare the incidence of IgG-class HIT antibodies in patients undergoing total hip arthroplasty (THA) or total knee arthroplasty (TKA) with different antithrombotic prophylaxis therapies and their contributions to the occurrence of venous thromboembolism (VTE).     

An autopsy case of Down's syndrome with moyamoya syndrome

We reported an autopsy case of Down's syndrome with moyamoya syndrome. A 30-year-old male with Down's syndrome suffered from a cerebral infarction and died of brain herniation. Cerebral angiography showed vascular abnormalities that were the same as moyamoya disease. Pathological findings revealed multiple stenosis of main trunk of the cerebral arteries. Pathologically, the stenosed vessels showed eccentric intimal thickness with cholesterin deposit, unlike moyamoya disease. There are only two previous reports of autopsied cases of Down's syndrome with moyamoya syndrome. We postulate that a protein encoded on chromosome 21 may be related to the pathogenesis of Down's syndrome with moyamoya syndrome.     

Successful treatment of a patient with penetrating injury of the esophagus and brachiocephalic artery due to migration of Kirschner wires.

Pins and wires offer the simplest and most effective tools for managing bone fractures and dislocations. Migration of these devices within the chest is rare, but can cause serious problems. The spontaneous migration of Kirschner wires from the right clavicle to the mediastinum resulted in penetrating injury of the esophagus and pseudo-aneurysm of the brachiocephalic artery in an 84-year-old patient. Two Kirschner wires were removed via a vertical incision on the right shoulder without thoracotomy and the brachiocephalic artery was replaced with a Dacron graft.     

h-prune Is an Independent Prognostic Marker for Survival in Esophageal Squamous Cell Carcinoma

Background  The human homologue of Drosophila prune (PRUNE, which encodes h-prune) protein interacts with glycogen synthase kinase 3 and promotes cell motility. The aim of our study was to investigate the impact of immunohistochemically detected h-prune expression on the survival of patients with esophageal squamous cell carcinoma (ESCC). Methods  Immunohistochemical staining of h-prune was performed for 205 surgically resected specimens of ESCC. Results  In total, 43 (21%) of 205 ESCC cases were positive for h-prune. h-prune-positive ESCC cases showed a more-advanced T stage (P < 0.0001), N stage (P < 0.0001), and tumor stage (P < 0.0001) than h-prune-negative ESCC cases. In the group of 116 stage II and III ESCC cases, recurrence of ESCC was frequently found in h-prune-positive cases. In patients with lung recurrence, the tumors were more likely to be h-prune positive than h-prune negative. Univariate analysis revealed that T stage (P < 0.0001), N stage (P < 0.0001), tumor stage (P < 0.0001), and h-prune staining (P < 0.0001) were significant prognostic factors for survival. Multivariate analysis indicated that N stage (P = 0.0182) and h-prune staining (P < 0.0001) were independent predictors for survival. Conclusions  These results indicate that immunostaining of h-prune is useful to identify patients at high risk for recurrence or poor prognosis associated with ESCC.     

Dickkopf-1 Expression as a Marker for Predicting Clinical Outcome in Esophageal Squamous Cell Carcinoma

Background and Objectives  Dickkopf-1 (DKK1) is the inhibitor of the canonical Wnt signaling pathway, however it is highly transactivated in various cancers, suggesting the presence of unknown mechanism. Its implication in human esophageal squamous cell carcinoma (ESCC) has not been sufficiently investigated. Patients and Methods  We evaluated DKK1 protein expression in resected specimens from 170 patients with ESCC by immunohistochemistry. Tumors were categorized as positive or negative for DKK1. The relationships between DKK1 expression in ESCC and various clinicopathological parameters and prognosis (disease-free survival; DFS) were analyzed separately. Results  Immunohistochemically, 72 (42.4%) tumors were DKK1 positive while no significant staining was observed in the normal squamous epithelium except for few basal cells. There was no significant relationship between DKK1 expression in ESCC and any of the clinicopathological parameters tested in this study. Patients with DKK1-positive tumors had poorer DFS than those with negative ESCC (5-year DFS; 31.5% versus 53.6%, P = 0.0062). Univariate analysis showed a significant relationship between pT [hazard ratio (HR) = 2.944, 95% confidence interval (CI) = 1.713–5.059, P < 0.0001], number of pN (HR = 2.836, 95% CI = 1.866–4.309, P < 0.0001), lymphatic invasion (HR = 2.892, 95% CI = 1.336–6.262, P = 0.0070), and DKK1 expression (HR = 1.763, 95% CI = 1.167–2.663, P = 0.0071) and DFS. Multivariate analysis including the above four parameters identified pT (HR = 2.053, 95% CI = 1.157–3.645, P = 0.0140), pN number (HR = 2.107, 95% CI = 1.362–3.260, P = 0.0008), and DKK1 expression (HR = 1.813, 95% CI = 1.195–2.751, P = 0.0052) as independent and significant prognostic factors for DFS. Conclusion  Our data suggest the usefulness of DKK1 as a novel predictor of poor prognosis of patients with ESCC after curative resection and also as a therapeutic target for future tailored therapies against ESCC.     

Long-term clinical outcome of acetabular cup revision surgery: comparison of cemented cups,cementless cups,and cemented cups with reinforcement devices

The aim of the present study was to analyze the clinical and radiographic outcomes and Kaplan–Meier survivorship of patients who underwent revision surgeries of the acetabular cup that had sustained aseptic loosening. We reviewed 101 consecutive patients (120 hips; 10 men 11 hips; 91 women 109 hips; age at surgery 66 years; range 45–85) who underwent acetabular component revision surgery, at a follow-up period of 15.6 years (range 10–32). To evaluate the state of the acetabulum, acetabular bony defects were classified according to the AAOS classification based on intraoperative findings: type I (segmental deficiencies n = 24 hips), type II (cavity deficiency n = 48), type III (combined deficiency n = 46), and type IV (pelvic discontinuity n = 2). The Harris hip score improved from 42.5 ± 10.8 (mean ± SD) before surgery to 74.9 ± 14.6 points at follow-up. The survival rates of the acetabular revision surgery with cemented, cementless, and cemented cups plus reinforcement devices were 74, 66, and 82 %, respectively. The difference in the survival rate between the cemented and cementless group was marginal (p = 0.048 Gehan–Breslow–Wilcoxon, p = 0.061 log-rank), probably due to the early-stage failure cases in the cementless group. The cementless and reinforcement groups included nine early-stage failure cases. To prevent early-stage failure, we recommend the cementless cups for types I and II acetabular bone defects with adequate contact between host bone and acetabular component, and the cemented cup with or without reinforcement devices, together with restoration of bone stock by impaction or structured bone grafting, for cases lacking such contact.     

CD133 Expression at the Metastatic Site Predicts Patients’ Outcome in Colorectal Cancer with Synchronous Liver Metastasis

Background

CD133 is a transmembrane protein that is proposed to be a stem cell marker of colorectal cancer (CRC); however, the correlation between CD133 expression and survival of CRC patients with liver metastasis has not been fully examined.

Methods

CD133 expression was evaluated immunohistochemically, both in primary tumors and synchronous liver metastases of 88 consecutive CRC patients, as well as recurrent lesions in the remnant liver of 27 of these 88 patients. The relationship between CD133 expression and clinicopathological characteristics, recurrence-free survival, and overall survival (OS) was analyzed.

Results

CD133 expression in liver metastases (mCD133) was detected in 50 of 88 patients (56.8 %), and had significant correlation with CD133 expression in primary lesions (pCD133) (p < 0.001). CD133 expression in liver recurrent lesions (recCD133) also had a significant correlation with mCD133 (p < 0.001). mCD133+ patients had significantly longer disease-free survival (p = 0.043) and OS (p = 0.014) than mCD133? patients. In addition, mCD133+ patients had a significantly lower rate of extrahepatic recurrence (p < 0.001).

Conclusions

Patients without CD133 expression in liver metastasis had significantly shorter survival, perhaps because mCD133? patients had a significantly higher rate of extrahepatic recurrence.