Abstract: Document recommendation systems for locating relevant literature have mostly relied on methods developed a decade ago. This is largely due to the lack of a large offline gold-standard benchmark of relevant documents that cover a variety of research fields such that newly developed literature search techniques can be compared, improved and translated into practice. To overcome this bottleneck, we have established the RElevant LIterature SearcH consortium consisting of more than 1500 scientists from 84 countries, who have collectively annotated the relevance of over 180 000 PubMed-listed articles with regard to their respective seed (input) article/s. The majority of annotations were contributed by highly experienced, original authors of the seed articles. The collected data cover 76% of all unique PubMed Medical Subject Headings descriptors. No systematic biases were observed across different experience levels, research fields or time spent on annotations. More importantly, annotations of the same document pairs contributed by different scientists were highly concordant. We further show that the three representative baseline methods used to generate recommended articles for evaluation (Okapi Best Matching 25, Term Frequency–Inverse Document Frequency and PubMed Related Articles) had similar overall performances. Additionally, we found that these methods each tend to produce distinct collections of recommended articles, suggesting that a hybrid method may be required to completely capture all relevant articles. The established database server located at https://relishdb.ict.griffith.edu.au is freely available for the downloading of annotation data and the blind testing of new methods. We expect that this benchmark will be useful for stimulating the development of new powerful techniques for title and title/abstract-based search engines for relevant articles in biomedical research.

Abstract: Acute disseminated encephalomyelitis (ADEM) varies widely in symptoms and severity. Some cases are associated with massive life-threatening cerebral edema refractory to conventional medical management. CLINICAL PRESENTATION: A 51-year-old woman with ADEM who developed severe brain swelling and herniation despite aggressive medical management is described. INTERVENTION: A decompressive hemicraniectomy and durotomy led to rapid improvement and an excellent outcome. CONCLUSION: This case report reinforces the place of this procedure in the armamentarium of treatment options for patients with medically refractory brain swelling and elevated intracranial pressure caused by ADEM. The potential for an increase in the incidence of ADEM with more frequent smallpox vaccinations emphasizes the significance of redefining the full range of management options for this treatable disease.

Abstract: One percent to 8% of patients undergoing spinal instrumentation surgeries develop infections. There is no consensus on the medical and surgical management of these infections. Methods We conducted a retrospective chart review based on International Classification of Diseases, Ninth Revision, and Common Procedural Terminology codes relevant to spinal infections with hardware within Emory Healthcare over a 10-year period. Extracted data included patient demographics, clinical presentation, laboratory and microbiologic results, and surgical and medical management including choice and duration of suppressive therapy. Multivariable logistic regression was used to assess the association of length of use of suppressive antibiotics with treatment success and to identify predictors of use of suppressive antibiotics. Results Of 869 records, 124 met inclusion criteria. Fifty patients (40.3%) had an infection that occurred after hardware placement, mostly within 3 months postsurgery, while the remainder had vertebral osteomyelitis that required hardware placement. After initial intravenous antibiotic treatment for ≥4 weeks, 72 patients (64.5%) were given suppressive antibiotics. The overall treatment success rate was 78.2%. In spinal infections involving hardware with gram-negative rods, patients were less likely to receive suppressive antibiotics, less likely to have hardware removed, and less likely to have treatment success compared with patients with infections with Staphylococcus species. Conclusions Management of spinal infections involving hardware should be tailored to the timing of onset of infection and causative organism. Further studies are needed to determine best management practices, particularly for gram-negative rod infections where the role of further suppressive antibiotics and hardware removal may be warranted.

Abstract: Cholangiocarcinoma (CCA) is an aggressive malignancy of the biliary tract that carries an unfavorable prognosis. Recurrent, hotspot mutations in the IDH1 gene are found in 10–20% of CCAs and can be targeted with mutant IDH1 inhibitors, though objective responses leading to a reduction in tumor size are rare. 1 2 Mutant IDH1 has neomorphic enzymatic activity that results in the production of the oncometabolite D-2-hydroxyglutarate (D-2-HG). 3 D-2-HG promotes biliary tumor formation through cancer cell-intrinsic effects, 4–6 but D-2-HG can also act as a paracrine factor released by IDH1-mutant cancer cells into the tumor microenvironment to promote tumor growth through non-cell intrinsic mechanisms. 7 8 We have performed studies to determine the paracrine effects of D-2-HG on fibroblasts to further examine the CCA tumor microenvironment. Methods To determine if fibroblasts are paracrine targets of D-2-HG in the CCA TME, we treated LX-2 hepatic stellate fibroblast cells with 0–50mM exogenous D-2-HG and utilized liquid chromatography-mass spectrometry to quantify the amount of intracellular D-2-HG. D-2-HG treated LX-2 fibroblasts and controls were then examined for changes in gene expression across 579 immune-related genes using the Nanostring platform. In partnership with Tempus, bulk RNA sequencing of IDH1-mutant (N=52) and wild type (N=403) CCA patient tumor samples was performed and CIBERSORT was used for deconvolution of gene expression data to define tumor-infiltrating immune cell populations. Results Intracellular D-2-HG was increased in LX-2 cells treated with exogenous D-2-HG compared to controls (figure 1A). D-2-HG treated fibroblasts showed significant changes in immune-related gene expression with significant increases in expression of genes involved in immunometabolism, TLR signaling, and inflammasome signaling—as indicated by unsupervised hierarchical clustering (figure 1B). The most upregulated gene in D-2-HG-conditioned LX-2 fibroblasts is SPP1 (figure 1C). We further identified that human IDH1-mutant CCA samples have a unique tumor immune microenvironment (figure 2A) and a significantly higher number of infiltrating M2 macrophages compared to wild-type controls (figure 2B). Abstract 944 Figure 1 D-2-HG induces gene expression changes in fibroblasts. (A) Mass-spec analysis of intracellular D-2-HG levels in LX-2 fibroblasts treated with control or D-2-HG containing media. (B) Gene expression patterns for 579 immune-related genes in the Nanostring Human Immunology V2 panel for LX-2 cells treated with control media (pink) or 50mM D-2-HG (gray) for 48 hours. D-2-HG treated cells have a distinct gene expression pattern as indicated by unsupervised hierarchical clustering. (C) Normalized mRNA expression for selected genes in LX-2 cells treated with control (black) or 50mM D-2-HG (red) containing media reveal upregulation of multiple genes that may alter the tumor immune microenvironment in CCA (*P 〈 0.05, **P≤0.01). Abstract 944 Figure 2 The infiltrating immune cell populations in IDH1-mutant CCA. (A) RNA sequencing data from IDH1-mutant and wild-type CCA tumor samples was deconvoluted with CIBERSORT to define tumor-infiltrating immune cell populations. Cell populations with significant increases or decreases (Mann-Whitney U test, p 〈 0.01) are plotted in a color spectrum to represent Log2FC in IDH1-mutant vs. wild-type tumors. (B) Box plot of the proportion of tumor-infiltrating immune cells identified as M2 macrophages in IDH1 wild-type (turquoise) and IDH1-mutant (gold) patient tumor samples (***P 〈 0.001) Conclusions D-2-HG significantly alters gene expression in hepatic stellate cells, precursors to cancer-associated fibroblasts in CCA. 9 The most upregulated gene in D-2-HG conditioned fibroblasts was SPP1, which has been implicated in the recruitment and polarization of immunosuppressive M2 macrophages leading to decreased antitumor immunity. 10–12 Interestingly, our analyses of resected human CCA samples showed that the IDH1-mutant CCA tumor immune microenvironment is characterized by an increase in M2 macrophages. Further study of how D-2-HG dysregulates fibroblast gene expression and affects tumor-infiltrating immune cell populations is warranted. References Crispo F, Pietrafesa M, Condelli V, Maddalena F, Bruno G, Piscazzi A, et al . 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Oncogene 2013; 32 :528–535. Wei J, Marisetty A, Schrand B, Gabrusiewicz K, Hashimoto Y, Ott M, et al . Osteopontin mediates glioblastoma-associated macrophage infiltration and is a potential therapeutic target. J Clin Invest 2019; 129 :137–149. Ethics Approval This study was approved by the Johns Hopkins Hospital IRB: IRB approval number CR00023377.