Ricolinostat (ACY‐1215) induced inhibition of aggresome formation accelerates carfilzomib‐induced multiple myeloma cell death

Proteasome inhibition induces the accumulation of aggregated misfolded/ubiquitinated proteins in the aggresome; conversely, histone deacetylase 6 (HDAC6) inhibition blocks aggresome formation. Although this rationale has been the basis of proteasome inhibitor (PI) and HDAC6 inhibitor combination studies, the role of disruption of aggresome formation by HDAC6 inhibition has not yet been studied in multiple myeloma (MM). The present study aimed to evaluate the impact of carfilzomib (CFZ) in combination with a selective HDAC6 inhibitor (ricolinostat) in MM cells with respect to the aggresome‐proteolysis pathway. We observed that combination treatment of CFZ with ricolinostat triggered synergistic anti‐MM effects, even in bortezomib‐resistant cells. Immunofluorescent staining showed that CFZ increased the accumulation of ubiquitinated proteins and protein aggregates in the cytoplasm, as well as the engulfment of aggregated ubiquitinated proteins by autophagosomes, which was blocked by ricolinostat. Electron microscopy imaging showed increased autophagy triggered by CFZ, which was inhibited by the addition of ACY‐1215. Finally, an in vivo mouse xenograft study confirmed a decrease in tumour volume, associated with apoptosis, following treatment with CFZ in combination with ricolinostat. Our results suggest that ricolinostat inhibits aggresome formation, caused by CFZ‐induced inhibition of the proteasome pathway, resulting in enhanced apoptosis in MM cells.     

Detecting patient allergy: beware the LIE

INTRODUCTION

Allergy detection is important in surgical patients. Historically, the focus has been on drug allergies. There is increasing focus on non-drug allergy, specifically latex, iodine and elastoplast.

PATIENTS AND METHODS

The practice and knowledge of 24 pre-registration house officers was evaluated, with regard to patient allergy. For the second phase of the study, the cohort of 367 consecutive patients presenting to the orthopaedic pre-assessment clinic was prospectively assessed.

RESULTS

This prospective study demonstrates that standard history-taking misses a large number (38%) of such allergies.

CONCLUSIONS

With regard to allergy detection, we are living a LIE (by ignoring latex, iodine, elastoplast allergy). We suggest junior doctors should employ the mnemonic LIED (latex, iodine, elastoplast and drugs) when taking a medical history.     

Emerging concepts and spectrum of renal injury following Intravesical BCG for non-muscle invasive bladder cancer

Background

Intravesical Bacilli Calmette-Guerin (IVBCG) therapy for non-muscle invasive bladder cancer (NMIBC) has long been in use successfully. Albeit rarely, we still face with its safety concerns more than 25 years on since its approval by US Food and Drug Agency in 1990. Local and systemic infection following intravesical BCG is widely reported as compared to immune mediated local or systemic hypersensitivity reactions involving kidneys; acute kidney injury (AKI) and other renal manifestations are well reported but not of chronic kidney disease (CKD).

Case

An interesting case of a female was referred to nephrologists in advanced stages of CKD at an eGFR of 10 ml/min/1.73² following IVBCG for NMIBC. Our patient’s renal function plateaued when IVBCG was held; and worsened again when reinstilled. It introduces the concept of ‘repetitive’ immune mediated renal injury presenting as progressive CKD rather than AKI, as is generally reported. Although response was poor, corticosteroids stopped CKD progression to end stage renal disease.

Conclusions

We highlight the need for increased awareness and early recognition of IVBCG renal complications by both urologists and nephrologists in order to prevent progressive and irreversible renal damage. Low incidence of IVBCG renal complications may also be due to under recognition in the era prior to CKD Staging and AKI Network (and AKI e-alerts) that defined AKI as a rise in serum creatinine of ≥26umol/L; hence an unmet need for urgent prospective studies. Major literature review focuses on emerging spectrum of histopathological IVBCG related renal complications and their outcomes.

     

Endoscopic Management of Esophagorespiratory Fistulas: A Multicenter Retrospective Study of Techniques and Outcomes

Background and Aims

Esophagorespiratory fistulas (ERF) are a devastating complication of benign and malignant etiologies. ERF are associated with high mortality, short survival, and poor quality of life. We performed a multicenter analysis of patients with ERF undergoing endoscopic treatment.

Methods

Multicentre retrospective study.

Results

We analyzed 25 patients undergoing 35 procedures over an 8-year period. Our data showed high technical success rates (97.1% of procedures) and with good, but not ideal, clinical success rates (60% of procedures, 80% of patients), which were defined as fistula closure confirmed by radiographic or repeat endoscopic evaluation and/or a lack of recurrent episodes of clinical aspiration to focus on durable ERF closure as opposed to only initial success. Proximal ERF were the most difficult to manage with the lowest overall clinical success rates, highest rates of recurrent aspiration despite endoscopic therapy, highest adverse events, and shortest survival times. Adverse events occurred in 40.0% of our patients and were all minor. Treatment allowed for diet advancement in 75% of patients.

Conclusion

This represents the largest recent collection of US data and the first multicenter study evaluating the clinical success of multiple treatment modalities while stratifying data by fistula etiology and esophageal location. The endoscopic approaches detailed in this study offer a minimally invasive and safe choice for intervention with the potential to improve quality of life despite overall suboptimal clinical success and survivorship rates for in with ERF.

     

Early failure of a mobile-bearing unicompartmental knee replacement

Concerned by a perceived high revision rate, we retrospectively reviewed the survivorship of a series of 43 cemented, medial, mobile-bearing Preservation unicompartmental knee replacements implanted during a 2-year period at a single institution. The initial post-operative AP and lateral radiographs were independently assessed to test the hypothesis that suboptimal implantation of the prosthesis was responsible for early failure. An X-ray scoring system based on the criteria for assessing the Oxford mobile-bearing unicompartmental knee replacement was devised. The components of this score included assessment of prosthesis alignment, sizing and cementation. Nine (21%) LCS Preservation mobile-bearings prostheses had required revision at a mean of 22 months post-implantation. The commonest causes for failure were pain (44%) and tibial component loosening (33%). Analysis of post-operative radiographs showed no difference (n.s.) between the compound error scores for the revised and the surviving prostheses. No particular surgical error was identifiable leading to subsequent need for revision. The high failure rates shown in this study have led us to cease using this implant. The clinical relevance of this study is that the captive running track of the LCS mobile-bearing prosthesis may over constrain the meniscal component leading to early failure.     

Characterization of engineered tissue construct mechanical function by magnetic resonance imaging

Non‐invasive magnetic resonance imaging (MRI) is a technology that enables the characterization of multiple physical phenomena in living and engineered tissues. The mechanical function of engineered tissues is a primary endpoint for the successful regeneration of many biological tissues, such as articular cartilage, spine and heart. Here we demonstrate the application of MRI to characterize the mechanical function of engineered tissue. Phase contrast‐based methods were demonstrated to characterize detailed deformation fields throughout the interior of native and engineered tissue, using an articular cartilage defect model as a study system. MRI techniques revealed that strain fields varied non‐uniformly, depending on spatial position. Strains were highest in the tissue constructs compared to surrounding native cartilage. Tissue surface geometry corresponded to strain fields observed within the tissue interior near the surface. Strain fields were further evaluated with respect to the spatial variation in the concentration of glycosaminoglycans ([GAG]), critical proteoglycans in the extracellular matrix of cartilage, as determined by gadolinium‐enhanced imaging. [GAG] also varied non‐uniformly, depending on spatial position and was lowest in the tissue constructs compared to the surrounding cartilage. The use of multiple MRI techniques to assess tissue mechanical function provides complementary data and suggests that deformation is related to tissue geometry, underlying extracellular matrix constituents and the lack of tissue integration in the model system studied. Specialized and advanced MRI phase contrast‐based methods are valuable for the detailed characterization and evaluation of mechanical function of tissue‐engineered constructs. Copyright © 2009 John Wiley & Sons, Ltd.