Relationship between MLH1, PMS2, MSH2 and MSH6 gene-specific alterations and tumor mutational burden in 1057 microsatellite instability-high solid tumors

Microsatellite instability-high (MSI-H) and tumor mutational burden (TMB) are predictive biomarkers for immune-checkpoint inhibitors (ICIs). Still, the relationship between the underlying cause(s) of MSI and TMB in tumors remains poorly defined. We investigated associations of TMB to mismatch repair (MMR) protein expression patterns by immunohistochemistry (IHC) and MMR mutations in a diverse sample of tumors. Hypothesized differences were identified by the protein/gene affected/mutated and the tumor histology/primary site. Overall, 1057 MSI-H tumors were identified from the 32 932 tested. MSI was examined by NGS using 7000+ target microsatellite loci. TMB was calculated using only nonsynonymous missense mutations sequenced with a 592-gene panel; a subset of MSI-H tumors also had MMR IHC performed. Analyses examined TMB by MMR protein heterodimer impacted (loss of MLH1/PMS2 vs. MSH2/MSH6 expression) and gene-specific mutations. The sample was 54.6% female; mean age was 63.5 years. Among IHC tested tumors, loss of co-expression of MLH1/PMS2 was more common (n = 544/705, 77.2%) than loss of MSH2/MSH6 (n = 81/705, 11.5%; P < .0001), and was associated with lower mean TMB (MLH1/PMS2: 25.03 mut/Mb vs MSH2/MSH6 46.83 mut/Mb; P < .0001). TMB also varied by tumor histology: colorectal cancers demonstrating MLH1/PMS2 loss had higher TMBs (33.14 mut/Mb) than endometrial cancers (20.60 mut/Mb) and other tumors (25.59 mut/Mb; P < .0001). MMR gene mutations were detected in 42.0% of tumors; among these, MSH6 mutations were most common (25.7%). MSH6 mutation patterns showed variability by tumor histology and TMB. TMB varies by underlying cause(s) of MSI and tumor histology; this heterogeneity may contribute to differences in response to ICI.     

Surgical management of the rheumatoid hand and wrist

Management of the patient with rheumatoid arthritis of the hand and wrist demands a methodical approach. Multidisciplinary assessment and treatment in conjunction with a rheumatologist and dedicated hand therapist are essential. Initial treatment should be conservative. However, when patients develop severe deformities refractory to medical treatment, or there is impending tendon rupture or nerve compression, surgical intervention is required. This article aims to provide a current review of the principles and common conditions in surgery for rheumatoid arthritis of the hand and wrist.     

Consensus guidelines for management of patellofemoral instability

BackgroundThe aim of this consensus process was to provide robust national guidelines to assist with decision making with regards to surgical management of patellofemoral instability.MethodsA national group of surgeons, physiotherapists, basic scientists and a radiologist with expert experience in patellofemoral instability was convened. A formal consensus process was undertaken using validated methodology. They reviewed the existing literature, performed a group consensus meeting to develop recommendations and followed this with a wider consultation meeting with an open invitation for final ratification. The guidelines were reviewed and authorised by the BASK executive committee, followed by the British Orthopaedic Association prior to final publication.ResultsThe review of the literature confirmed a significant absence of an evidence base to guide clinicians in the surgical management of patellofemoral instability. The consensus process outlined guidance relating to diagnosis and clinical assessment, appropriate imaging modalities, recommendations for surgical options and appropriate post operative physiotherapy. Following wide invitation to contribute to the final document, 102 people responded. Twenty six of those provided additional comments which were blinded, discussed and included or excluded following further discussion amongst the working group.ConclusionPatellofemoral instability is a complex pathology with multiple surgical options available to those who decide surgery is indicated. In the absence of a strong evidence base, these guidelines aim to assist with that decision making process and will pave the way for more robust clinical trials in the future.     

Current concepts in carpal instability: anatomy,classification and management

Carpal instability is a complex subject and the theories behind the pathoanatomy and management continue to evolve in the literature. The consequences of carpal instability for the patient can be significant and lead to functional impairment and long-term pain. We outline the normal anatomy of the carpus and relate the complex interactions between the ligamentous and bony structures to the patterns of injury both acute and chronic. We then go on to review current opinion on the classification, assessment and management of patients with carpal instability.