Increasing but levelling out risk of revision due to infection after total hip arthroplasty: a study on 108,854 primary THAs in the Norwegian Arthroplasty Register from 2005 to 2019

Background and purpose — Focus on prevention, surveillance, and treatment of infection after total hip arthroplasty (THA) in the last decade has resulted in new knowledge and guidelines. Previous publications have suggested an increased incidence of surgical revisions due to infection after THA. We assessed whether there have been changes in the risk of revision due to deep infection after primary THAs reported to the Norwegian Arthroplasty Register (NAR) over the period 2005–2019. Patients and methods — Primary THAs reported to the NAR from January 1, 2005 to December 31, 2019 were included. Adjusted Cox regression analyses with the first revision due to deep infection after primary THA were performed. We investigated changes in the risk of revision as a function of time of primary THA. Time was stratified into 5-year periods. We studied the whole population of THAs, and the subgroups: all-cemented, all-uncemented, reverse hybrid (cemented cup), and hybrid THAs (cemented stem). In addition, we investigated factors that were associated with the risk of revision, and changes in the time span from primary THA to revision. Results — Of the 108,854 primary THAs that met the inclusion criteria, 1,365 (1.3%) were revised due to deep infection. The risk of revision due to infection, at any time after primary surgery, increased through the period studied. Compared with THAs implanted in 2005–2009, the relative risk of revision due to infection was 1.4 (95% CI 1.2–1.7) for 2010–2014, and 1.6 (1.1–1.9) for 2015–2019. We found an increased risk for all types of implant fixation. Compared to 2005–2009, for all THAs, the risk of revision due to infection 0–30 days postoperatively was 2.2 (1.8–2.8) for 2010–2014 and 2.3 (1.8–2.9) for 2015–2019, 31–90 days postoperatively 1.0 (0.7–1.6) for 2010–2014 and 1.6 (1.0–2.5) for 2015–2019, and finally 91 days–1 year postoperatively 1.1 (0.7–1.8) for 2010–2014 and 1.6 (1.0–2.6) for 2015–2019. From 1 to 5 years postoperatively, the risk of revision due to infection was similar to 2005–2009 for both the subsequent time periods Interpretation — The risk of revision due to deep infection after THA increased throughout the period 2005–2019, but appears to have levelled out after 2010. The increase was mainly due to an increased risk of early revisions, and may partly have been caused by a change of practice rather than a change in the incidence of infection.publishedVersio

The HSP70 modulator MAL3-101 inhibits Merkel cell carcinoma

Merkel Cell Carcinoma (MCC) is a rare and highly aggressive neuroendocrine skin cancer for which no effective treatment is available. MCC represents a human cancer with the best experimental evidence for a causal role of a polyoma virus. Large T antigens (LTA) encoded by polyoma viruses are oncoproteins, which are thought to require support of cellular heat shock protein 70 (HSP70) to exert their transforming activity. Here we evaluated the capability of MAL3-101, a synthetic HSP70 inhibitor, to limit proliferation and survival of various MCC cell lines. Remarkably, MAL3-101 treatment resulted in considerable apoptosis in 5 out of 7 MCC cell lines. While this effect was not associated with the viral status of the MCC cells, quantitative mRNA expression analysis of the known HSP70 isoforms revealed a significant correlation between MAL3-101 sensitivity and HSC70 expression, the most prominent isoform in all cell lines. Moreover, MAL3-101 also exhibited in vivo antitumor activity in an MCC xenograft model suggesting that this substance or related compounds are potential therapeutics for the treatment of MCC in the future. © 2014 Adam et al

Increased risk of revision for infection in rheumatoid arthritis patients with total hip replacements

Background and purpose - Medical treatment of rheumatoid arthritis (RA) has changed dramatically over the last 15 years, including immune modulation. We investigated the risk of revision for infection after primary total hip replacement (THR) in patients with rheumatoid arthritis over a 16-year period, and compared it with that in THR patients with osteoarthritis (OA). Patients and methods - We identified 13,384 THRs in RA patients and 377,287 THRs in OA patients from 1995 through 2010 in a dataset from the Nordic Arthroplasty Register Association (NARA). Kaplan-Meier survival curves, with revision for infection as the endpoint, were constructed. Cox regression analyses were performed to calculate the relative risk (RR) of revision for infection adjusted for age, sex, fixation technique, and year of primary surgery. Results - RA patients had a 1.3 times (95% CI 1.0-1.6) higher risk of revision for infection. After 2001, this risk increased more for RA patients than for OA patients. During the first 3 months and from 8 years postoperatively, the risk of revision for infection was higher in RA patients with THRs fixated with antibiotic-loaded cement than in corresponding OA patients. Interpretation - We found a slightly higher overall risk of revision for infection in RA patients than in OA patients, but this difference was only present after 2001. In THRs with antibiotic-loaded cement, the risk of very early and late infections leading to revision was higher in RA patients than in OA patients.Peer reviewe

Activation of the PI3K/AKT Pathway in Merkel Cell Carcinoma

Merkel cell carcinoma (MCC) is a highly aggressive skin cancer with an increasing incidence. The understanding of the molecular carcinogenesis of MCC is limited. Here, we scrutinized the PI3K/AKT pathway, one of the major pathways activated in human cancer, in MCC. Immunohistochemical analysis of 41 tumor tissues and 9 MCC cell lines revealed high levels of AKT phosphorylation at threonine 308 in 88% of samples. Notably, the AKT phosphorylation was not correlated with the presence or absence of the Merkel cell polyoma virus (MCV). Accordingly, knock-down of the large and small T antigen by shRNA in MCV positive MCC cells did not affect phosphorylation of AKT. We also analyzed 46 MCC samples for activating PIK3CA and AKT1 mutations. Oncogenic PIK3CA mutations were found in 2/46 (4%) MCCs whereas mutations in exon 4 of AKT1 were absent. MCC cell lines demonstrated a high sensitivity towards the PI3K inhibitor LY-294002. This finding together with our observation that the PI3K/AKT pathway is activated in the majority of human MCCs identifies PI3K/AKT as a potential new therapeutic target for MCC patients

Increasing but levelling out risk of revision due to infection after total hip arthroplasty: a study on 108,854 primary THAs in the Norwegian Arthroplasty Register from 2005 to 2019

Background and purpose — Focus on prevention, surveillance, and treatment of infection after total hip arthroplasty (THA) in the last decade has resulted in new knowledge and guidelines. Previous publications have suggested an increased incidence of surgical revisions due to infection after THA. We assessed whether there have been changes in the risk of revision due to deep infection after primary THAs reported to the Norwegian Arthroplasty Register (NAR) over the period 2005–2019. Patients and methods — Primary THAs reported to the NAR from January 1, 2005 to December 31, 2019 were included. Adjusted Cox regression analyses with the first revision due to deep infection after primary THA were performed. We investigated changes in the risk of revision as a function of time of primary THA. Time was stratified into 5-year periods. We studied the whole population of THAs, and the subgroups: all-cemented, all-uncemented, reverse hybrid (cemented cup), and hybrid THAs (cemented stem). In addition, we investigated factors that were associated with the risk of revision, and changes in the time span from primary THA to revision. Results — Of the 108,854 primary THAs that met the inclusion criteria, 1,365 (1.3%) were revised due to deep infection. The risk of revision due to infection, at any time after primary surgery, increased through the period studied. Compared with THAs implanted in 2005–2009, the relative risk of revision due to infection was 1.4 (95% CI 1.2–1.7) for 2010–2014, and 1.6 (1.1–1.9) for 2015–2019. We found an increased risk for all types of implant fixation. Compared to 2005–2009, for all THAs, the risk of revision due to infection 0–30 days postoperatively was 2.2 (1.8–2.8) for 2010–2014 and 2.3 (1.8–2.9) for 2015–2019, 31–90 days postoperatively 1.0 (0.7–1.6) for 2010–2014 and 1.6 (1.0–2.5) for 2015–2019, and finally 91 days–1 year postoperatively 1.1 (0.7–1.8) for 2010–2014 and 1.6 (1.0–2.6) for 2015–2019. From 1 to 5 years postoperatively, the risk of revision due to infection was similar to 2005–2009 for both the subsequent time periods Interpretation — The risk of revision due to deep infection after THA increased throughout the period 2005–2019, but appears to have levelled out after 2010. The increase was mainly due to an increased risk of early revisions, and may partly have been caused by a change of practice rather than a change in the incidence of infection

Tissue homing and persistence of defined antigen-specific CD8+ tumor-reactive T-cell clones in long-term melanoma survivors.

Tumor antigen-specific cytotoxic T cells (CTLs) play a major role in the adaptive immune response to cancers. This CTL response is often insufficient because of functional impairment, tumor escape mechanisms, or inhibitory tumor microenvironment. However, little is known about the fate of given tumor-specific CTL clones in cancer patients. Studies in patients with favorable outcomes may be very informative. In this longitudinal study, we tracked, quantified, and characterized functionally defined antigen-specific T-cell clones ex vivo, in peripheral blood and at tumor sites, in two long-term melanoma survivors. MAGE-A10-specific CD8+ T-cell clones with high avidity to antigenic peptide and tumor lytic capabilities persisted in peripheral blood over more than 10 years, with quantitative variations correlating with the clinical course. These clones were also found in emerging metastases, and, in one patient, circulating clonal T cells displayed a fully differentiated effector phenotype at the time of relapse. Longevity, tumor homing, differentiation phenotype, and quantitative adaptation to the disease phases suggest the contribution of the tracked tumor-reactive clones in the tumor control of these long-term metastatic survivor patients. Focusing research on patients with favorable outcomes may help to identify parameters that are crucial for an efficient antitumor response and to optimize cancer immunotherapy

Experimental autoimmune encephalopathy (EAE)-induced hippocampal neuroinflammation and memory deficits are prevented with the non-opioid TLR2/TLR4 antagonist (+)-naltrexone

Multiple sclerosis (MS) is associated with burdensome memory impairments and preclinical literature suggests that these impairments are linked to neuroinflammation. Previously, we have shown that toll-like receptor 4 (TLR4) antagonists, such as (+)-naltrexone [(+)-NTX], block neuropathic pain and associated spinal inflammation in rats. Here we extend these findings to first demonstrate that (+)-NTX blocks TLR2 in addition to TLR4. Additionally, we examined in two rat strains whether (+)-NTX could attenuate learning and memory disturbances and associated neuroinflammation using a low-dose experimental autoimmune encephalomyelitis (EAE) model of MS. EAE is the most commonly used experimental model for the human inflammatory demyelinating disease, MS. This low-dose model avoided motor impairments that would confound learning and memory measurements. Fourteen days later, daily subcutaneous (+)-NTX or saline injections began and continued throughout the study. Contextual and auditory-fear conditioning were conducted at day 21 to assess hippocampal and amygdalar function. With this low-dose model, EAE impaired long-term, but not short-term, contextual fear memory; both long-term and short-term auditory-cued fear memory were spared. This was associated with increased mRNA for hippocampal interleukin-1β (IL-1β), TLR2, TLR4, NLRP3, and IL-17 and elevated expression of the microglial marker Iba1 in CA1 and DG regions of the hippocampus, confirming the neuroinflammation observed in higher-dose EAE models. Importantly, (+)-NTX completely prevented the EAE-induced memory impairments and robustly attenuated the associated proinflammatory effects. These findings suggest that (+)-NTX may exert therapeutic effects on memory function by dampening the neuroinflammatory response in the hippocampus through blockade of TLR2/TLR4. This study suggests that TLR2 and TLR4 antagonists may be effective at treating MS-related memory deficits