A histology-based model for predicting microsatellite instability in colorectal cancers

Identifying colorectal cancers (CRCs) with high levels of microsatellite instability (MSI-H) is clinically important. MSI-H is a positive prognostic marker for CRC, a predictive marker for resistance to standard 5-fluorouracil-based adjuvant chemotherapy, and an important feature for identifying individuals and families with Lynch syndrome. Our aim was to compare and improve upon the existing predictive pathology models for MSI-H CRCs. We tested 2 existing models used to predict MSI-H tumors, (1) Revised Bethesda Guidelines and (2) MsPath, in our population-based cohort of CRCs diagnosed less than 75 years from Newfoundland (N=710). We also scored additional histologic features not described in the other models. From this analysis, we developed a model for the prediction of MSI-H CRCs; Pathologic Role in Determination of Instability in Colorectal Tumors (PREDICT). An independent pathologist validated this model in a second cohort of all CRCs (N=276). Tumor histology was a better predictor of MSI status than was personal and family history of cancer. MsPath identified MSI-H CRCs with a sensitivity of 92.1% and a specificity of 37.8%, whereas the Revised Bethesda Guidelines had a sensitivity of 81.3% and a specificity of 39.5%. PREDICT included some new histology features, including peritumoral lymphocytic reaction and increased proportion of plasma cells in the tumor stroma. PREDICT was superior to both existing models in the development cohort with a sensitivity of 97.4% and a specificity of 53.9%. In the validation cohort, sensitivity was 96.9% and specificity 76.6%. We conclude that PREDICT is a good predictor of MSI-H CRC.     

Diagnosing Periprosthetic Joint Infection: a Scoping Review

Purpose of ReviewThe goal of this review is to provide an up to date understanding of the utility and limitations of the current tests utilized in the diagnosis of periprosthetic joint infection (PJI) in total knee and hip arthroplasty.Recent FindingsDespite the growth in literature surrounding PJI diagnosis, there remains challenges in establishing a diagnosis of PJI. A combination of clinical, serum, and synovial tests and microbiologic and histologic examinations can yield a diagnosis in the majority of cases. Novel molecular and imaging studies may be beneficial for indeterminant cases. A number of emerging diagnostic tests have been proposed and may be incorporated into diagnostic algorithms in the future. Recently proposed stepwise diagnostic algorithms have shown high sensitivity and specificity.SummaryThe diagnosis of PJI remains challenging due to a lack of tests that can definitively rule out infection. Diagnosis and investigations should occur in a stepwise fashion. There has been a plethora of new diagnostic tests introduced in attempts to improve the accuracy of diagnostic algorithms. The definition and algorithms for the diagnoses of PJI will continue to evolve as new techniques and tests are introduced.     

Last Marrow Standing: Bone Marrow Transplantation for Acquired Bone Marrow Failure Conditions

Paroxysmal nocturnal hemoglobinuria, aplastic anemia, and myelodysplastic syndrome are a spectrum of acquired marrow failure, having a common pathologic thread of both immune dysregulation and the development of abnormal hematopoiesis. Allogeneic hematopoietic cell transplantation plays a critical role in the treatment of these disorders and, for many patients, is the only treatment modality with demonstrated curative potential. In recent years, there have been many breakthroughs in the understanding of the pathogenesis of these uncommon disorders. The subsequent advances in non-transplant therapies, along with concurrent improvement in outcomes after hematopoietic cell transplantation, necessitate continual appraisal of the indications, timing, and approaches to transplantation for acquired marrow failure syndromes. We review here contemporary and critical new findings driving current treatment decisions.     

A chemical biology screen identifies glucocorticoids that regulate c-maf expression by increasing its proteasomal degradation through up-regulation of ubiquitin

The oncogene c-maf is frequently overexpressed in multiple myeloma cell lines and patient samples and contributes to increased cellular proliferation in part by inducing cyclin D2 expression. To identify regulators of c-maf, we developed a chemical screen in NIH3T3 cells stably overexpressing c-maf and the cyclin D2 promoter driving luciferase. From a screen of 2400 off-patent drugs and chemicals, we identified glucocorticoids as c-maf-dependent inhibitors of cyclin D2 transactivation. In multiple myeloma cell lines, glucocorticoids reduced levels of c-maf protein without influencing corresponding mRNA levels. Subsequent studies demonstrated that glucocorticoids increased ubiquitination-dependent degradation of c-maf and up-regulated ubiquitin C mRNA. Moreover, ectopic expression of ubiquitin C recapitulated the effects of glucocorticoids, demonstrating regulation of c-maf protein through the abundance of the ubiquitin substrate. Thus, using a chemical biology approach, we identified a novel mechanism of action of glucocorticoids and a novel mechanism by which levels of c-maf protein are regulated by the abundance of the ubiquitin substrate.     

Structure and function, injury, pathology, and treatment of the medial collateral ligament of the knee

The medial collateral ligament (MCL) is the most commonly injured ligament of the knee. There is a spectrum of injury severity, and injuries may be acute or chronic. The MCL is also frequently injured in conjunction with other knee structures. Clinical evaluation of the knee is important to assess the degree of surgical acuity, but magnetic resonance imaging can provide details about the injury that may not be obvious clinically. In addition to injury, MCL bursitis can occur and may be treated with needle aspiration and corticosteroid injection. This review article covers the anatomy and biomechanics of the MCL, its injury patterns and approach to management, and MCL bursitis.