Citations

Abstract Microglia-mediated neuroinflammation contributes to acute demyelination in neuromyelitis optica spectrum disorders (NMOSD). Soluble triggering receptor expressed on myeloid cells 2 (sTREM2) in the CSF has been associated with microglial activation in several neurodegenerative diseases. However, the basis for this immune-mediated attack and the pathophysiological role of sTREM2 in NMOSD remain to be elucidated. Here, we performed Mendelian randomization analysis and identified a genetic association between increased CSF sTREM2 and NMOSD risk. CSF sTREM2 was elevated in patients with NMOSD and was positively correlated with neural injury and other neuroinflammation markers. Single-cell RNA sequencing of human macrophage/microglia-like cells in CSF, a proxy for microglia, showed that increased CSF sTREM2 was positively associated with microglial dysfunction in patients with NMOSD. Furthermore, we demonstrated that sTREM2 is a reliable biomarker of microglial activation in a mouse model of NMOSD. Using unbiased transcriptomic and lipidomic screens, we identified that excessive activation, overwhelmed phagocytosis of myelin debris, suppressed lipid metabolism and enhanced glycolysis underlie sTREM2-mediated microglial dysfunction, possibly through the nuclear factor kappa B (NF-κB) signalling pathway. These molecular and cellular findings provide a mechanistic explanation for the genetic association between CSF sTREM2 and NMOSD risk and indicate that sTREM2 could be a potential biomarker of NMOSD progression and a therapeutic target for microglia-mediated neuroinflammation.

Background The increasing incidence of reverse total shoulder arthroplasties (RTSA) has led to an increase in revision surgery. We aimed to compare patients undergoing re-revision RTSA to a matched cohort undergoing first-revision RTSA. Methods A retrospective review of all revision RTSAs was performed at a single institution. Sixteen shoulders that underwent re-revision RTSA were matched 1:3 to shoulders that underwent revision RTSA with a minimum two-year follow-up. Outcome scores including the American Shoulder and Elbow Surgeons Shoulder Score (ASES), Short-Form 12 (SF-12), Shoulder Pain and Disability Index (SPADI), and Simple Shoulder Test (SST) scores, range of motion (ROM), and improvement from preoperative to postoperative outcomes after re-revision RTSA were assessed. Additionally, postoperative outcomes after re-revision RTSA were compared to patients that underwent first revision RTSA and subsequently compared to the minimal clinically important difference (MCID) values for the outcome scores and ROM measurements assessed. Results Sixteen shoulders that underwent re-revision RTSA and 78 revision RTSAs met the final inclusion criteria to be included in this study. Significant improvement from preoperative to postoperative re-revision RTSA was seen in the ASES score (p = 0.046), SPADI score (p = 0.044), SST (p = 0.008), abduction (p = 0.016), and elevation (p = 0.025), but not the SF-12 score (p = 0.396), external rotation (p = 0.449), or internal rotation (p = 0.451). Outcomes after revision RTSA were found to be superior to outcomes after re-revision RTSA for all outcome scores (ASES p = 0.029, SF-12 p = 0.018, SPADI p = 0.003) except the SST score (p = 0.080) and all ROM measures (p > 0.05 for all). Internal rotation was equivalent postoperatively between both groups. From preoperative to postoperative re-revision RTSA, the mean improvement exceeded the MCID for the SST score, abduction, forward elevation, and external rotation. When comparing postoperative revision RTSA to postoperative re-revision RTSA, the mean difference between revision and re-revision RTSA exceeded the MCID for the SPADI score and external rotation. The complication rate was 19% in shoulders undergoing first revision and 41% in shoulders undergoing re-revision RTSA. Conclusion Patients undergoing re-revision RTSA receive improvement in clinical outcomes, but do not achieve outcomes comparable to those achieved after first revision RTSA.

Colorectal cancer (CRC) is the third leading cause of cancer-related deaths in the United States. Despite advancements in detection and therapeutic options, patients with metastatic CRC continue to face poor survival rates. The heterogeneity of oncogenic alterations, including BRAF mutations, poses a substantial challenge in identifying optimal treatment approaches. Notably, BRAF non-V600 mutations, encompassing class II and class III mutations, exhibit the distinct patterns of the signaling pathways and responses to targeted therapies compared to BRAF V600 mutations (class I). Nevertheless, the current classification system may underestimate the complexity and heterogeneity of BRAF-mutant CRC. Ongoing clinical trials are actively investigating targeted therapies for BRAF non-V600 mutations, but they are being confronted with patient recruitment obstacles due to the genetic diversity of these alterations. Continued research is needed to refine mutation subtyping, identify effective treatment strategies, and improve outcomes for patients with BRAF non-V600-mutant CRC. Enhancing our understanding and management of this specific subgroup of CRC is crucial for developing personalized treatment approaches and advancing patient care. This manuscript provides a comprehensive overview of the recent advances in and perspectives on BRAF non-V600 alterations in colorectal cancer, including relevant ongoing clinical trials.

Background: In smaller studies, allograft-prosthetic composite (APC) has been used for proximal humerus bone loss with some success, although with notable complication risk. This systematic review and meta-analysis sought to describe outcomes and complications after proximal humerus APC and how major APC complications are defined in the literature. Methods: A systematic review was performed per Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines. PubMed/MEDLINE, EMBASE, Web of Science, and Cochrane were queried for articles on APC for proximal humeral bone loss secondary to tumor, fracture, or failed arthroplasty. Primary outcomes included postoperative range of motion, outcome scores (Musculoskeletal Tumor Society [MSTS], Simple Shoulder Test [SST], American Shoulder and Elbow Surgeons [ASES], Constant, visual analog scale [VAS], and subjective shoulder value [SSV]), and complication incidence. We also described individual study definitions of APC malunion/nonunion, methods of postoperative evaluation, malunion/nonunion rates, allograft fracture/fragmentation rates, and mean union time, when available. Secondarily, we compared hemiarthroplasty and reverse total shoulder arthroplasty. Results: Sixteen articles including 375 shoulders were evaluated (average age: 49 years, follow-up: 54 months). Fifty-seven percent of procedures were performed for tumors, 1% for proximal humerus trauma sequelae, and 42% for revision arthroplasty. Average postoperative forward elevation was 82° (69-94°), abduction 60° (30-90°), and external rotation 23° (17-28°). Average MSTS score was 82% (77%-87%), SST score 5.3 (4.5-6.1), ASES score 64 (54-74), Constant score 44 (38-50), VAS score 2.2 (1.7-2.7), and SSV 51 (45-58). There was a 51% complication rate with an 18% nonallograft surgical complication rate, 26% APC nonunion/malunion/resorption rate, and 10% APC fracture/fragmentation rate. Fifteen percent of nonunited APCs underwent secondary bone grafting; 3% required a new allograft; and overall revision rate was 12%. APC nonunion/malunion was defined in 2 of 16, malunion/nonunion rates in 14 of 16, fracture/fragmentation rates in 6 of 16, and mean union time (7 months) in 4 of 16 studies. Conclusion: APC reconstruction of the proximal humerus remains a treatment option, albeit with substantial complication rates. In addition, there is a need for APC literature to report institutional definitions of nonunion/malunion, postoperative evaluation, and time to union for a more standardized evaluation. Level of Evidence: Level IV ; systematic review. See Instructions for Authors for a complete description of levels of evidence.

Abstract Imatinib mesylate (IM) has revolutionized the treatment of gastrointestinal stromal tumor (GIST). However, most patients inevitably acquire IM resistance. Second- and third-line treatments exhibit modest clinical benefits with a median time to disease progression of 4 to 6 months, highlighting the urgency for novel therapeutic approaches. Here, we report that the expression of BCL6, a known oncogenic driver and transcriptional repressor, was significantly induced in GIST cells following IM treatment. Elevated BCL6 levels suppressed apoptosis and contributed to IM resistance. Mechanistically, BCL6 recruited SIRT1 to the TP53 promoter to modulate histone acetylation and transcriptionally repress TP53 expression. The reduction in p53 subsequently attenuated cell apoptosis and promoted tolerance of GIST cells to IM. Concordantly, treatment of GIST cells showing high BCL6 expression with a BCL6 inhibitor, BI-3802, conferred IM sensitivity. Furthermore, BI-3802 showed striking synergy with IM in IM-responsive and IM-resistant GIST cells in vitro and in vivo. Thus, these findings reveal a role for BCL6 in IM resistance and suggest that a combination of BCL6 inhibitors and IM could be a potentially effective treatment for GIST. Significance: BCL6 drives resistance to imatinib by inhibiting p53-mediated apoptosis and can be targeted in combination with imatinib to synergistically suppress tumor growth, providing a therapeutic strategy for treating gastrointestinal stromal tumor.

Abstract Glioblastoma (GBM) is a lethal brain tumor with limited treatment options, due in part to the low blood-brain-barrier (BBB) penetrance of many anti-cancer compounds. Development of a non-invasive test that can measure drug delivery and target engagement in GBM represents an opportunity to enhance knowledge during early phase clinical trials of a new compound’s pharmacological suitability and potential efficacy. We present here data supporting that the cargo within extracellular vesicles (EV) can potentially serve as a liquid biopsy that reports on the pharmacodynamics of GBM therapeutics. We treated short-term cell cultures established from four patient-derived xenografts with vehicle, temozolomide, MLN4924, or arsenic trioxide. EVs were isolated from culture supernatants using size exclusion chromatography and then analyzed by RNA sequencing and mass spectrometry (proteomics) to characterize and compare cargo profiles for each condition. We found that depending on treatment, there were shared alterations in EV cargo between models in the expression of long non-coding RNAs, genes that are overrepresented in biological processes such as cytoplasmic translation and cellular macromolecule biosynthesis, and circular RNAs. Mass spectrometry of protein cargo further demonstrated both upregulated and downregulated peptide abundances with treatment compared to vehicle. Thus, our preliminary results indicate that EV cargo post-treatment may be a novel pharmacodynamic reporter in GBM. To allow for the selective interrogation of patient GBM-derived EVs, we have simultaneously pursued the identification of biomarkers to allow for immunoprecipitation of EVs from patient biofluids. Potential biomarkers, including PTPRZ1, B7H3, and IL13RA2, were screened across isolated EVs from both pre-clinical and clinical patient samples. Future efforts are focused on evaluating immunoprecipitated GBM-EVs from longitudinally collected patient biofluids. Overall, we anticipate that the results of this study will lead to development of a clinical test that reflects BBB penetration and tumor response, which will likely aid in novel drug development efforts.

31 Background: T-cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) inhibitor in combination with an anti-programmed cell death protein 1 (PD-1) antibody has shown antitumor activity in solid tumors. AdvanTIG-105 (NCT04047862) is a phase 1/1b open-label study designed to assess the safety and preliminary antitumor activity of OCI, an anti-TIGIT monoclonal antibody (mAb), + TIS, an anti-PD-1 mAb, in pts with unresectable, locally advanced or metastatic solid tumors. In the dose-escalation part, OCI + TIS was well tolerated with preliminary antitumor activity observed, and the recommended phase 2 dose (RP2D) of OCI 900 mg intravenously (IV) every three weeks (Q3W) + TIS 200 mg IV Q3W was established. We report results from the dose-expansion part (GC/GEJC Cohort 9) of the AdvanTIG-105 study. Methods: Eligible pts had histologically/cytologically confirmed stage IV GC/GEJC. Pts were excluded if they had squamous cell, undifferentiated or other histological types of GC, had GC/GEJC with positive HER2 expression, or if they had received any prior therapy for metastatic disease. Pts received either the RP2D of OCI + TIS with oxaliplatin + capecitabine Q3W for 6 cycles (C), followed by maintenance therapy with the RP2D of OCI + TIS, + capecitabine Q3W, or the RP2D of OCI + TIS with cisplatin + 5-fluorouracil Q3W for 6 C. Treatment continued until disease progression, intolerable toxicity, or withdrawal of consent. The primary endpoint was investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints included progression-free survival (PFS), duration of response (DoR), disease control rate (DCR) per RECIST v1.1, and safety. Results: As of September 29, 2022, 60 pts with a median age of 61.5 years (range 35-82) were enrolled; 59 were efficacy evaluable. Median study follow-up was 31.1 weeks (range 1.4-78.4). ORR was 50.8% (95% CI: 37.5, 64.1); DCR was 84.7% (95% CI: 73.0, 92.8) with a median DoR of 8.1 months (95% CI: 4.5, not evaluable [NE]). Median PFS was 8.2 months (95% CI: 5.8, NE). In a subgroup analysis, ORR in pts with PD-L1 tumor area positivity (TAP) score ≥5% (n=27) was 59.3% (95% CI: 38.8, 77.6), and 50.0% (95% CI: 30.7, 69.4) in pts with PD-L1 TAP <5% (n=28). All 60 pts reported ≥1 treatment-emergent adverse event (TEAE), the most common being anemia (43.3%) and platelet count decreased (41.7%). In total, 43 pts (71.7%) had ≥grade 3 TEAEs and 28 (46.7%) had serious adverse events. TEAEs leading to discontinuation of TIS and OCI occurred in 5 (8.3%) pts. TEAEs led to death in 2 (3.3%) pts; one event (neutropenic sepsis) was related to chemo, while the other (pulmonary embolism) was not treatment related. Conclusions: OCI 900 mg + TIS 200 mg + chemo was generally well tolerated and showed encouraging antitumor activity in pts with stage IV GC/GEJC. Clinical trial information: NCT04047862 .

Abstract Androgen receptor (AR) inhibition by androgen deprivation and/or antiandrogen administration is the mainstay therapy for advanced prostate cancer. However, most prostate cancers ultimately become resistant to these therapies, indicating the importance of identifying mechanisms driving resistance to improve patient outcomes. Here we demonstrated that acute treatment with the antiandrogen enzalutamide (ENZ) decreased glutathione (GSH) production, increased lipid peroxidation, and induced ferroptosis in prostate cancer cells. Consistently, meta-analysis of transcriptomic data linked the androgen-AR axis to metabolism-related biological processes, including lipid metabolism. The cystine transporter gene SLC7A11 was a key AR target, and full-length AR (AR-FL) transactivated SLC7A11 transcription by directly occupying the SLC7A11 promoter and putative enhancer regions. AR variants (AR-V) preferentially bound the SLC7A11 enhancer and upregulated SLC7A11 expression, thereby conferring resistance to ferroptosis induced by ENZ treatment. However, this effect was abolished following downregulation of AR-Vs using the dual CBP/p300 and BET inhibitor NEO2734. These findings reveal ferroptosis induction as an anticancer mechanism of antiandrogens and SLC7A11 as a direct target gene of AR-FL and AR-Vs. AR-V-mediated SLC7A11 expression represents a mechanism coupling ferroptosis resistance to prostate cancer progression. Significance: Upregulation of SLC7A11 can be induced by androgen receptor variants to inhibit antiandrogen-induced prostate cancer cell ferroptosis and to drive castration resistance in prostate cancer.

AbstractBackgroundEvidence on the impact of obesity on catheter ablation for ventricular tachycardia (VT) is scarce.Method and ResultsWe queried the Nationwide Readmissions Database to determine the hospital outcomes and procedural complications of VT ablation among the obese and nonobese populations. Obesity was associated with a more prolonged length of stay (p < .01), higher cost of hospitalization (p < .01), and higher rates of pericardial effusion or hemopericardium (p = .05) and vascular complications (p = .05). There was no significant difference in early mortality, 30‐day readmissions, and other procedural complications.ConclusionVT ablation could be performed relatively safely among patients with obesity.