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Late recurrence of hepatocellular carcinoma (HCC) following orthotopic liver transplant (OLT) is infrequently reported, and among cases, those isolated to the spine are rare. Prognoses are poor for this patient population, and no work has been undertaken to create uniform guidelines for management. Here, we report two cases of late recurrent HCC to the spine after OLT and favorable survival outcomes following intervention., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2024 Elsevier Inc. All rights reserved.)

Background: Immune checkpoint inhibitors (ICIs) have led to improved outcomes for many cancer types. However, their use can also precipitate immune-related adverse events (irAEs) that can affect any organ system. While irAEs are often mild, they rarely affect multiple organ systems concurrently and can be fatal., Case: We report a fatal case of myasthenia gravis, myositis, and cardiotoxicity overlap syndrome precipitated by the ICI pembrolizumab along with a brief review of available literature., Conclusion: Early recognition of high grade irAEs and prompt intervention is essential. Despite the poor prognosis of these overlap syndromes, current recommendations offer little guidance for severe cases and warrant a call for increased awareness and expansion of available therapeutics., (© 2024 The Author(s). Cancer Reports published by Wiley Periodicals LLC.)

Many acute myeloid leukemia (AML) patients exhibit hallmarks of immune exhaustion, such as increased myeloid-derived suppressor cells, suppressive regulatory T cells and dysfunctional T cells. Similarly, we have identified the same immune-related features, including exhausted CD8 + T cells (TEx) in a mouse model of AML. Here we show that inhibitors that target bromodomain and extra-terminal domain (BET) proteins affect tumor-intrinsic factors but also rescue T cell exhaustion and ICB resistance. Ex vivo treatment of cells from AML mice and AML patients with BET inhibitors (BETi) reversed CD8 + T cell exhaustion by restoring proliferative capacity and expansion of the more functional precursor-exhausted T cells. This reversal was enhanced by combined BETi and anti-PD1 treatment. BETi synergized with anti-PD1 in vivo, resulting in the reduction of circulating leukemia cells, enrichment of CD8 + T cells in the bone marrow, and increase in expression of Tcf7, Slamf6, and Cxcr5 in CD8 + T cells. Finally, we profiled the epigenomes of in vivo JQ1-treated AML-derived CD8 + T cells by single-cell ATAC-seq and found that JQ1 increases Tcf7 accessibility specifically in Tex cells, suggesting that BETi likely acts mechanistically by relieving repression of progenitor programs in Tex CD8 + T cells and maintaining a pool of anti-PD1 responsive CD8 + T cells., (© 2023. The Author(s).)

Acute myeloid leukemia (AML) remains difficult to treat due to mutational heterogeneity and the development of resistance to therapy. Targeted agents, such as MEK inhibitors, may be incorporated into treatment; however, the impact of MEK inhibitors on the immune microenvironment in AML is not well understood. A greater understanding of the implications of MEK inhibition on immune responses may lead to a greater understanding of immune evasion and more rational combinations with immunotherapies. This study describes the impact of trametinib on both T cells and AML blast cells by using an immunosuppressive mouse model of AML and primary patient samples. We also used a large AML database of functional drug screens to understand characteristics of trametinib-sensitive samples. In the mouse model, trametinib increased T-cell viability and restored T-cell proliferation. Importantly, we report greater proliferation in the CD8+CD44+ effector subpopulation and impaired activation of CD8+CD62L+ naive cells. Transcriptome analysis revealed that trametinib-sensitive samples have an inflammatory gene expression profile, and we also observed increased programmed cell death ligand 1 (PD-L1) expression on trametinib-sensitive samples. Finally, we found that trametinib consistently reduced PD-L1 and PD-L2 expression in a dose-dependent manner on the myeloid population. Altogether, our data present greater insight into the impact of trametinib on the immune microenvironment and characteristics of trametinib-sensitive patient samples., (© 2019 by The American Society of Hematology.)

Aryl hydrocarbon receptor (AhR) activation by high-affinity ligands mediates immunosuppression in association with increased regulatory T cells (Tregs), making this transcription factor an attractive therapeutic target for autoimmune diseases. We recently discovered 10-chloro-7H-benzimidazo[2,1-a]benzo[de]iso-quinolin-7-one (10-Cl-BBQ), a nanomolar affinity AhR ligand with immunosuppressive activity and favorable pharmacologic properties. In this study, we tested the consequences of AhR activation in the NOD model. Oral 10-Cl-BBQ treatment prevented islet infiltration without clinical toxicity, whereas AhR-deficient NOD mice were not protected. Suppression of insulitis was associated with an increased frequency, but not total number, of Foxp3(+) Tregs in the pancreas and pancreatic lymph nodes. The requirement for Foxp3(+) cells in AhR-induced suppression of insulitis was tested using NOD.Foxp3(DTR) mice, which show extensive islet infiltration upon treatment with diphtheria toxin. AhR activation prevented the development of insulitis caused by the depletion of Foxp3(+) cells, demonstrating that Foxp3(+) cells are not required for AhR-mediated suppression and furthermore that the AhR pathway is able to compensate for the absence of Foxp3(+) Tregs, countering current dogma. Concurrently, the development of disease-associated CD4(+)Nrp1(+)Foxp3(-)RORγt(+) cells was inhibited by AhR activation. Taken together, 10-Cl-BBQ is an effective, nontoxic AhR ligand for the intervention of immune-mediated diseases that functions independently of Foxp3(+) Tregs to suppress pathogenic T cell development., (Copyright © 2015 by The American Association of Immunologists, Inc.)

We reviewed all articles published in three major orthopaedic journals from January 2010 to December 2014. Any article focusing on adult reconstruction of the hip or knee was reviewed for first and last authorship, institution, and level of evidence. Three institutions had authored work from arthroplasty faculty that fell within the top five most published institutions in all three journals, while one institution ranked first in all three journals. 43 of 67 (64.2%) reconstruction fellowships had at least one publication included in this study. The majority of the adult reconstruction literature published by faculty at U.S. reconstruction fellowships stems from a few academic centers with the ten most prolific institutions accounting for 65.9% of all U.S. fellowship publications., (Published by Elsevier Inc.)

Objective: To describe a single institution's experience after initiation of a protocol in which all primary total hip arthroplasty (THA) and total knee arthroplasty (TKA) patients were administered intravenous tranexamic acid (TXA) intraoperatively to decrease perioperative blood loss., Methods: A retrospective review of medical records at a single institution from February 2012 to April 2014. The TXA treatment group was compared to a control group. We reviewed intraoperative blood loss, preoperative hemoglobin (Hb) levels, postoperative day 0 to 2 Hb levels, transfusion rates, postoperative venous thromboembolism, and other complication rates., Results: 259 patients underwent either TKA (165) or THA (94). 121 received perioperative intravenous TXA and 138 did not. There was a statistically decreased rate of allogeneic blood transfusion (0 vs. 10, p = 0.003) as well as a higher postoperative day 2 Hb level (10.8 ± 1.1 vs. 10.2 ± 2.6 g/dL, p = 0.02) in the treatment group. There was no statistical difference in any variable measured in the THA group, though there was a trend toward higher postoperative Hb levels at all-time points measured., Conclusion: Intravenous TXA is a safe and effective drug to decrease perioperative blood loss and allogeneic transfusion in THA and TKA. There was no increased risk of venous thromboembolism or other complications in our review., (Reprint & Copyright © 2015 Association of Military Surgeons of the U.S.)

The efficacy and safety of three oral fluoroquinolones (lomefloxacin, levofloxacin, and ciprofloxacin) for the treatment of chronic osteomyelitis were analyzed. Twenty-seven patients had documented infections with quinolone-sensitive organisms and received either lomefloxacin, levofloxacin, or ciprofloxacin. Levofloxacin was effective therapy for 9 of 15 (60%) patients. Lomefloxacin was effective therapy for five of seven (71%) patients, and ciprofloxacin was effective therapy for two of five patients (40%). Average follow-up was 11.8 months for patients who completed the course of therapy, and the average duration of therapy was 60.6 days. Gram-positive bacteria were isolated from 18 patients, and 11 patients were cured. Oral fluoroquinolones can be safe, effective therapy if they are given for a prolonged course as treatment for infections caused by susceptible gram-positive as well as gram-negative organisms and in combination with adequate surgical debridement.

Various workers, including T. D. Stewart, claim that the aboriginal Americas were relatively disease-free because of the bering Strait cold-screen, eliminating many pathogens, and the paucity of zoonotic infections because of few domestic animals. Evidence of varying validity suggests that precontact Americns had their own strains of treponemic infections, bacillary and amoebic dysenteries, influenza and viral penumonia and other respiratory diseases, salmonellosis and perhaps other food poisoning, various arthritides, some endoparasites such as the ascarids, and several geographically circumscribed diseases such as the rickettsial verruca (Carrion's disease) and New World leishmaniasis and trypanosomiasis. Questionably aboriginal are tuberculosis and typhus. Accordingly, virtually all the "crowd-type" ecopathogenic diseases such as smallpox, yellow fever, typhoid, malaria, measles, pertussis, polio, etc., appear to have been absent from the New World, and were only brought in by White conquerors and their Black slaves. My hypothesis is that native American medical care systems--especially in the more culturally advanced areas--were sufficiently sophisticated to deal with native disease entities with reasonable competence. But native medical systems could not cope with the "crowd-type" disease imports that struck Indian and Eskimos as "virgin-field" populations. Reanalysis of native population losses through a genocidal combination of diease, war, slavery and attendant cultural disruption by Dobyns, Cook and others strongly suggest that traditiona estimates underplayed the death toll by a factor of the general order of ten. This would make for an immediately pre-contact Indian population of some 90-111 million instead of the tradition 8-11 million. Evidence is growing that Indians may have been no more susceptible to new pathogens that are other "virgin soil" populations, and thus their immune systems need not be considered less effective than those in other people. Present-day high mortality rates in Indians of both continents from infectious disease imports may be more socioeconomic than anything else.