Poor Patient Follow-up After Metal-on-Metal Total Hip Arthroplasty.

Routine follow-up approximately every 2 to 5 years after total hip arthroplasty (THA) is a common practice. However, although patients are informed of the importance of follow-up, our mean follow-up rate for patients after standard non-metal-on-metal (MOM) THA is only 19%. The US Food and Drug Administration has released several statements on the importance of follow-up every 2 years after MOM THA. With the potential risks of MOM THA apparently widely known, we report on our ability to obtain timely follow-up at 2 separate centers. Two separate centers performed 570 MOM THA procedures between 2002 and 2010. An attempt was made to reach every patient by either telephone or letter to obtain ion levels, radiographs, and examinations. Repeat telephone calls and/or letters to those not reached were made annually. Patients were told of the unique importance of follow-up at each contact. Of the patients, 43% had not been seen within the past 5 years, and only 26% had been seen within the past 2 years. Only 61% had their first measurement of ion levels, and only 30% of patients had a second set of measurement of ion levels. A total of 48 revisions occurred in this group, and 36 patients died. Despite the apparent widespread dissemination of information regarding the potential risks of MOM THA and concerted efforts to contact patients for follow-up, we have been able to achieve a follow-up rate of only 26%. This rate is only marginally better than the mean follow-up for non-MOM THA in our practices. The implications of this poor follow-up are unknown. [Orthopedics. 2022;45(4):e196-e200.].

Clinical characteristics associated with depression or anxiety among patients presenting for knee surgery.

BACKGROUND: Preoperative depression and anxiety in patients undergoing surgery have been shown to be associated with increased postoperative complications, decreased functional improvement, and long-term dissatisfaction. The purpose of this prospective study was to measure the relationship between a diagnosis of depression or anxiety and Patient-Reported Outcomes Measurement Information System (PROMIS) domains, as well as determine which preoperative factors are associated with depression or anxiety in patients undergoing knee surgery. We hypothesized that preoperative depression and/or anxiety would be associated with worse preoperative pain, function, and general health status. METHODS: Three-hundred and eighty-six patients undergoing knee surgery between 2015 and 2017 were administered health-related quality of life measures preoperatively, and their medical records were reviewed for relevant medical history. A propensity matched analysis was performed to determine clinical factors independently associated with preoperative depression and/or anxiety. RESULTS: The overall study population consisted of 216 males and 170 females, with a mean age of 39.4 ±â€¯16.2 years. From this overall cohort, 43 (11.1%) patients had a positive preoperative diagnosis of depression and/or anxiety. After controlling for covariate imbalances, preoperative depression/anxiety was independently associated with PROMIS Anxiety (p = 0.018), PROMIS Depression (p < 0.019), and Tegner pre-injury (p = 0.013) scores. Regression analysis also determined that preoperative depression/anxiety was independently associated with arthroscopic anterior cruciate ligament reconstruction (ACLR) (p = 0.004), total knee arthroplasty (TKA) (p = 0.019), and uni-compartmental knee arthroplasty (p < 0.05). CONCLUSION: The results support our hypothesis that preoperative depression/anxiety is associated with worse preoperative pain, function, and general health status. Furthermore, PROMIS Anxiety and Depression tools offer a reliable means of measuring psychological distress in the orthopaedic knee population. Similar to other studies, we also noted psychological comorbidity to be independently associated with ACLR and TKA.

Selective Agonists of Nuclear Retinoic Acid Receptor Gamma Inhibit Growth of HCS-2/8 Chondrosarcoma Cells.

Chondrosarcoma is the second most common primary bone sarcoma. Treatment of chondrosarcoma is limited to surgery due to radiation and chemotherapy resistance of this cancer. An ideal treatment for chondrosarcoma would be a well-tolerated, minimally invasive local or systemic treatment modality to halt or slow tumor growth prior to resection of local, unresectable local, or metastatic disease. Palovarotene, an agonist of nuclear retinoic acid receptor γ (RARγ) has shown therapeutic action for treatment of heterotopic ossification and osteochondroma without serious adverse effects in animal models. We hypothesized that selective agonists of RARγ would have an inhibitory effect on chondrosarcoma. All human chondrosarcoma specimens expressed RARγ as determined by immunohistochemical staining. The ΗCS-2/8 chondrosarcoma cell line, established from low-grade human chondrosarcoma, was used to examine the actions of RARγ agonists. In ΗCS2/8 pellet cultures, RARγ agonist treatment reduced the mass size and significantly decreased total glycosaminoglycan, protein amounts, and gene expression levels of cartilage matrix molecules when compared with control groups. Systemic treatment with RARγ agonists significantly inhibited the growth of ΗCS-2/8 cell transplants in vivo. Furthermore, local injection of RARγ agonist-loaded poly-lactic acid nanoparticles induced regression of the mass size of the transplants. Histologic analysis demonstrated that RARγ agonist treatment inhibited cell proliferation activity and stimulated encapsulation of the tumor. These findings indicate that RARγ agonists, including palovarotene, may have an anti-tumor effect on low-grade chondrosarcomas. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 38:1045-1051, 2020.

Ignore the Patella in Revision Total Knee Surgery: A Minimum 5-Year Follow-Up With Patella Component Retention.

BACKGROUND: In the setting of aseptic revision, a common question is: what should be done with the previously resurfaced patella? We report on a series of aseptic revision total knee arthroplasties (RTKA) where one or both components were revised and the patella was not. METHODS: The study group was 147 consecutive RTKA in 137 patients with a mean age of 70.1 ± 9.3 years where the patella was not revised. The average body mass index was 31.0 ± 5.4 kg/m2. Follow-up was a minimum of 5 years (range, 5 to 12 years). At final follow-up, 13 patients died and 2 patients were lost to follow-up leaving 122 patients and 130 knees available for review. Mean time from primary surgery to RTKA was 9.2 ± 5.5 years. Both components were revised in 50 knees, the femur only in 11 knees, the tibia only in 12 knees, and 57 had an isolated polyethylene revision. We found 5 patients with a mismatch between the patella and femoral components and 30 cases with patella component wear identified intraoperatively. RESULTS: At final follow-up, there were no reoperations on any patella and none were at risk of failure. There were 6 knees with a lateral patella tilt beyond 10°, but none were subluxed. Knee Society Scores averaged 85 ± 17.2 points at final follow-up. CONCLUSION: At midterm follow-up in this group of RTKA where the patella was not revised, we identified no subsequent failures of the patella. This is despite the presence of mild patella polyethylene wear and mismatched shapes in several knees. LEVEL OF EVIDENCE: III.

Hip fusion takedown to a total hip arthroplasty-is it worth it? A systematic review.

INTRODUCTION: Patients with surgically or spontaneously fused hips are often dissatisfied with their overall function and the debilitating effect on adjacent joints. Therefore, in properly selected patients, hip fusion-takedown and conversion to total hip arthroplasty (THA) can result in improved function and decreased pain. We aimed to (1) evaluate the indications for conversion, (2) evaluate the clinical outcomes, (3) analyze the overall complications, and (4) identify the overall satisfaction following the procedure. METHODS: A systematic and comprehensive literature search was performed to analyze studies evaluating conversion of hip fusion to THA. After reviewing 3,882 studies, 27 total studies (1,104 hips) met our inclusion/exclusion criteria and were included in our final analysis. A weighted mean of rates was determined for each complication, including infection, instability, loosening, nerve-related, abductor-related, venous thrombotic event, and revision. RESULTS: The study population consisted of 53.2% male and 46.8% female subjects. The mean age at time of conversion was 52 years (range 36-65 years), the mean time until follow-up was 9.2 years (range 2.5-17.3), and the mean duration of arthrodesis was 27.7 years (range 11-40.2). As measured by Harris Hip Score, overall clinical outcomes improved from 58.1 points (range 42.4-70 points) pre-operatively to 80.0 (range 62-93.5) post-operatively. The specific complication rates were 5.3% (range 0-43.6%) for infection, 2.6% (range 0-15.4%) for instability, 6.2% (range 0-17.2%) for loosening, 4.7% (range 0-13%) for nerve-related complications, 13.1% (range 0-87%) for abductor-related complications, and 1.2% (range 0-13%) for venous thrombotic events. The revision rate was 12.0% (range 0-43.6%). CONCLUSION: Takedown of a fused-hip can be a challenging procedure. Although patients can benefit functionally, both patients and surgeons need to be aware of the complications and increased risk of further revision procedures, which should be an important part of the pre-operative discussion.

Role of type II pneumocyte senescence in radiation-induced lung fibrosis.

BACKGROUND: Radiation is a commonly delivered therapeutic modality for cancer. The causes underlying the chronic, progressive nature of radiation injury in the lung are poorly understood. METHODS: C57Bl/6NCr mice were exposed to thoracic irradiation (n = 3 per dose and time point for tissue collection). Microarray analysis of gene expression from irradiated murine lung was performed using one-way analysis of variance with post hoc Scheffe analysis. Senescence and type II airway epithelial cell (AECII) count were assayed in irradiated murine lung tissue (n = 3 per condition). Irradiated mice were treated with diphenyleneiodonium (DPI), an inhibitor of NADPH oxidase (NOX), and fibrosis was assessed by collagen assays. All statistical tests were two-tailed. RESULTS: Gene expression in lung tissue from mice irradiated to 17.5 Gy clustered with that of aged unirradiated mice. Only fibrogenic exposures led to AECII senescence (0 Gy: 0.66% ± 0.67%; 5 Gy: 4.5% ± 1.19%; 17.5 Gy: 18.7% ± 3.05; P = .007) and depletion (0 Gy: 2.89 per alveolus ± 0.26; 5 Gy: 2.41 ± 0.19; 17.5 Gy: 1.6 ± 0.14; P < .001) at 30 weeks. Treatment of irradiated mice with DPI for 16 weeks markedly reduced collagen accumulation (5×6 Gy: 57.26 µg/lung ± 9.91; 5×6 Gy ± DPI: 36.54µg/lung ± 4.39; P = .03) and AECII senescence (5×6 Gy: 37.61% ± 4.82%; 5×6 Gy ± DPI: 12.38% ± 2.78; P < .001). CONCLUSIONS: These studies identify senescence as an important process in AECII in vivo and indicate that NOX is a critical mediator of radiation-induced AECII senescence and pulmonary fibrosis.

MEK1/2 inhibition enhances the radiosensitivity of cancer cells by downregulating survival and growth signals mediated by EGFR ligands.

The inhibition of the Ras/mitogen-activated protein kinase (Ras/MAPK) pathway through the suppression of mutated Ras or MAPK/extracellular signal-regulated kinase 1/2 (MEK1/2) has been shown to sensitize tumor cells to ionizing radiation (IR). The molecular mechanisms of this sensitization however, are not yet fully understood. In this study, we investigated the role of transforming growth factor-α (TGF-α) in the radiosensitizing effects of selumetinib, a selective inhibitor of MEK1/2. The expression of epidermal growth factor receptor (EGFR) ligands was assessed by ELISA in both Ras wild-type and Ras mutant cells that were exposed to radiation with or without selumetinib. The effects of selumetinib on the TGF-α/EGFR signaling cascade in response to radiation were examined by western blot analysis, clonogenic assay and by determing the yield of mitotic catastrophe. The treatment of cells with selumetinib reduced the basal and IR-induced secretion of TGF-α in both Ras wild-type and Ras mutant cell lines in vitro and in vivo. The reduction of TGF-α secretion was accompanied with a reduction in phosphorylated tumor necrosis factor-α converting enzyme (TACE) in the cells treated with selumetinib with or without IR. The treatment of cells with selumetinib with or without IR inhibited the phosphorylation of EGFR and checkpoint kinase 2 (Chk2), and reduced the expression of survivin. Supplementation with exogenous TGF-α partially rescued the selumetinib-treated cells from IR-induced cell death, restored EGFR and Chk2 phosphorylation and increased survivin expression. These data suggest that the inhibition of MEK1/2 with selumetinib may provide a mechanism to sensitize tumor cells to IR in a fashion that prevents the activation of the TGF-α autocrine loop following IR.

Determination of cytokine protein levels in oral secretions in patients undergoing radiotherapy for head and neck malignancies.

BACKGROUND: Cytokines may be elevated in tumor and normal tissues following irradiation. Cytokine expression in these tissues may predict for toxicity or tumor control. The purpose of this pilot study was to determine the feasibility of measuring local salivary cytokine levels using buccal sponges in patients receiving chemo-radiation for head and neck malignancies. PATIENTS AND METHODS: 11 patients with epithelial malignancies of the head and neck were recruiting to this study. All patients received radiotherapy to the head and neck region with doses ranging between 60 - 67.5 Gy. Chemotherapy was delivered concurrently with radiation in all patients. Salivary samples were obtained from high dose and low dose regions prior to treatment and at three intervals during treatment for assessment of cytokine levels (IL-4, IL-6, IL-8, IL-10, EGF, MCP-1, TNF-α, and VEGF). RESULTS: Cytokine levels were detectable in the salivary samples. Salivary cytokine levels of IL-4, IL-6, IL-8, EGF, MCP-1, TNF- α , and VEGF were higher in the high dose region compared to the low dose region at all time points (p < 0.05). A trend toward an increase in cytokine levels as radiation dose increased was observed for IL-6, IL-8, MCP-1, and TNF-α. CONCLUSION: Assessment of salivary cytokine levels may provide a novel method to follow local cytokine levels during radiotherapy and may provide a mechanism to study cytokine levels in a regional manner.

Enhancement of 5-fluorouracil-induced in vitro and in vivo radiosensitization with MEK inhibition.

PURPOSE: Gastrointestinal cancers frequently exhibit mutational activation of the Ras/MAPK pathway, which is implicated in resistance to ionizing radiation (IR) and chemotherapy. Concurrent radiotherapy and 5-fluorouracil (5-FU) based chemotherapy is commonly used for treatment of gastrointestinal malignancies. We previously reported radiosensitization with selumetinib, an inhibitor of MEK1/2. The purpose of the current study was to evaluate if selumetinib could enhance radiosensitivity induced by 5-FU. EXPERIMENTAL DESIGN: Clonogenic survival assays were carried out with the HT29 (colorectal), HCT116 (colorectal), and MiaPaca-2 (pancreatic) cell lines using pre-IR treatment with selumetinib, 5-FU and 5-FU+selumetinib. Cell proliferation was determined using a tetrazolium conversion assay. Mitotic catastrophe and DNA repair were analyzed using immunocytochemistry. Flow cytometry was used to analyze cell cycle and apoptosis. Growth delay was used to determine effects of 5-FU+selumetinib on in vivo tumor radiosensitivity. RESULTS: Pre-IR treatment with 5-FU+selumetinib significantly decreased clonogenic survival compared with either agent alone. Dose modifying factors at a surviving fraction of 0.1 for 5-FU+selumetinib was 1.78, 1.52, and 1.3 for HT29, HCT116, and MiaPaca-2, respectively. Cell proliferation was decreased by treatment with selumetinib+5-FU as compared with single agent treatment regardless of treatment sequencing. Enhancement of 5-FU cytotoxicity and 5-FU mediated radiosensitization with selumetinib treatment was accompanied by an increase in mitotic catastrophe and apoptosis, and reductions in Stat3 phosphorylation and survivin expression. In vivo, an additive growth delay was observed with 5-FU+selumetinib+3Gy versus 5-FU+3Gy and selumetinib alone. CONCLUSION: These data suggest that selumetinib can be used with 5-FU to augment radiation response.

Evaluation of the fullerene compound DF-1 as a radiation protector.

BACKGROUND: Fullerene compounds are known to possess antioxidant properties, a common property of chemical radioprotectors. DF-1 is a dendrofullerene nanoparticle with antioxidant properties previously found to be radioprotective in a zebrafish model. The purpose of this study was to evaluate the radioprotective effects of DF-1 in a murine model of lethal total body irradiation and to assess for selective radioprotection of normal cells versus tumor cells. METHODS: In vitro radioresponse was evaluated with clonogenic assays with human tumor cells and fibroblast lines in the presence of varying concentrations of DF-1 or vehicle. DNA double strand break induction and repair was evaluated with immunocytochemistry for gammaH2AX. Lethal total body irradiation was delivered with 137Cs after intraperitoneal delivery of DF-1 or vehicle control. Bone marrow hypoxia was evaluated with piminidazole uptake assessed by flow cytometry. RESULTS: DF-1 provided modest radioprotection of human cancer cell lines and fibroblast cell lines when delivered prior to irradiation (dose modifying factor or 1.1). There was no evidence of selective protection of fibroblasts versus tumor cells. Cells treated with DF-1 at radioprotective doses were found to have fewer gammaH2AX foci at 1 and 6 hours after irradiation compared to vehicle treated controls. The LD50/30 for C57Bl6/Ncr mice treated with a single 300 mg/kg dose of DF-1 pre-irradiation was 10.09 Gy (95% CI 9.58-10.26) versus 8.29 Gy (95% CI, 8.21-8.32) for control mice. No protective effects were seen with a single 200 mg/kg dose. No increase in pimonidazole uptake was appreciated in bone marrow of mice treated with DF-1 compared to vehicle controls. CONCLUSIONS: DF-1 has modest activity as a radiation protector in vivo. There was no evidence of selective protection from irradiation of normal versus tumor cells with DF-1.

A targeted analysis of cellular chaperones reveals contrasting roles for heat shock protein 70 in flock house virus RNA replication.

Cytosolic chaperones are a diverse group of ubiquitous proteins that play central roles in multiple processes within the cell, including protein translation, folding, intracellular trafficking, and quality control. These cellular proteins have also been implicated in the replication of numerous viruses, although the full extent of their involvement in viral replication is unknown. We have previously shown that the heat shock protein 40 (hsp40) chaperone encoded by the yeast YDJ1 gene facilitates RNA replication of flock house virus (FHV), a well-studied and versatile positive-sense RNA model virus. To further explore the roles of chaperones in FHV replication, we examined a panel of 30 yeast strains with single deletions of cytosolic proteins that have known or hypothesized chaperone activity. We found that the majority of cytosolic chaperone deletions had no impact on FHV RNA accumulation, with the notable exception of J-domain-containing hsp40 chaperones, where deletion of APJ1 reduced FHV RNA accumulation by 60%, while deletion of ZUO1, JJJ1, or JJJ2 markedly increased FHV RNA accumulation, by 4- to 40-fold. Further studies using cross complementation and double-deletion strains revealed that the contrasting effects of J domain proteins were reproduced by altering expression of the major cytosolic hsp70s encoded by the SSA and SSB families and were mediated in part by divergent effects on FHV RNA polymerase synthesis. These results identify hsp70 chaperones as critical regulators of FHV RNA replication and indicate that cellular chaperones can have both positive and negative regulatory effects on virus replication.