Faculty Bibliography

PURPOSE:The spatial arrangement of lymphocytes in the tumor bed (e.g., immune infiltrated, immune excluded, immune desert) is expected to reflect distinct immune evasion mechanisms and to associate with immunotherapy outcomes. However, data supporting these associations are scant and limited by the lack of a clear definition for lymphocyte infiltration patterns and the subjective nature of pathology-based approaches. EXPERIMENTAL DESIGN:We used multiplexed immunofluorescence to study major tumor-infiltrating lymphocyte (TIL) subsets with single-cell resolution in baseline whole-tissue section samples from NSCLC patients treated with immune checkpoint inhibitors (ICI). The spatial TIL patterns were analyzed using a qualitative pathologist-based approach, and an objective analysis of TIL density ratios in tumor/stromal tissues. The association of spatial patterns with outcomes was studied for different TIL markers. RESULTS:The analysis of CD8+ TIL patterns using qualitative assessment identified prominent limitations including the presence of a broad spectrum of phenotypes within most tumors and limited association with outcomes. The utilization of an objective method to classify NSCLCs showed the existence of at least three subgroups with partial overlap with those defined using visual patterns. Using this strategy, a subset of cases with "immune excluded-like" tumors showed prominently worse outcomes, suggesting reduced sensitivity to ICI; however, these results need to be validated. The analysis for other TIL subsets showed different results, underscoring the relevance of the marker selected for spatial TIL pattern evaluation and opportunities for market integration. CONCLUSIONS:Our results identified major challenges associated with the qualitative spatial TIL pattern evaluation. We devised a novel objective strategy to overcome some of these limitations that has strong biomarker potential.

STUDY DESIGN/METHODS:Retrospective Cohort Study. OBJECTIVE:To assess if there is a threshold of baseline disability beyond which the patient-reported outcomes after surgical correction of adult spinal deformity (ASD) are adversely impacted. BACKGROUND:Patient-reported outcomes vary after correction of adult spinal deformity, even when patients are optimally realigned. There is a paucity of literature examining the impact of baseline disability on patient-reported outcomes in ASD. METHODS:Patients with baseline (BL) and two-year data were included. Disability was ranked according to BL Oswestry Disability Index (ODI) into quintiles: Q1 (lowest ODI score) to Q5 (highest ODI score). Adjusted logistic regression analyses evaluated the likelihood of reaching ≥1 MCID in Scoliosis Research Society Outcomes Questionnaire (SRS-22) Pain, SRS-22 Activity, and Short Form-36 physical component summary at two years across disability groups Q1-Q4 with respect to Q5. Sensitivity tests were performed, excluding patients with any "0" Schwab modifiers at BL. RESULTS:Compared with patients in Q5, the odds of reaching MCID in SRS-22 Pain at 2Y were significantly higher for those in Q1 (OR: 3.771), Q2 (OR: 3.006), and Q3 (OR: 2.897), all P <0.021. Similarly, compared with patients in Q5, the odds of reaching MCID in SRS-22 Activity at two years were significantly higher for those in Q2 (OR: 3.454) and Q3 (OR: 2.801), both P <0.02. Lastly, compared with patients in Q5, odds of reaching MCID in Short Form-36 physical component summary at two years were significantly higher for patients in Q1 (OR: 5.350), Q2 (OR: 4.795), and Q3 (OR: 6.229), all P <0.004. CONCLUSIONS:This study found that patients presenting with moderate disability at BL (ODI<40) consistently surpassed health-related quality of life outcomes as compared with those presenting with greater levels of disability. We propose that a baseline ODI of 40 represents a disability threshold within which operative inte rvention maximizes patient-reported outcomes. Furthermore, delaying the intervention until patients progress to severe disability may limit the benefits of surgical correction in ASD patients. LEVEL OF EVIDENCE/METHODS:3.

OBJECTIVES/OBJECTIVE:Our primary objective was to quantify damage burden measured by Damage Index for Antiphospholipid Syndrome (DIAPS) in aPL-positive patients with or without a history of thrombosis in an international cohort (the APS ACTION cohort). Secondly, we aimed to identify clinical and laboratory characteristics associated with damage in aPL-positive patients. METHODS:In this cross-sectional study, we analysed the baseline damage in aPL-positive patients with or without APS classification. We excluded patients with other autoimmune diseases. We analysed the demographic, clinical and laboratory characteristics based on two subgroups: (i) thrombotic APS patients with high vs low damage; and (ii) non-thrombotic aPL-positive patients with vs without damage. RESULTS:Of the 826 aPL-positive patients included in the registry as of April 2020, 586 with no other systemic autoimmune diseases were included in the analysis (412 thrombotic and 174 non-thrombotic). In the thrombotic group, hyperlipidaemia (odds ratio [OR] 1.82; 95% CI 1.05, 3.15; adjusted P = 0.032), obesity (OR 2.14; 95% CI 1.23, 3.71; adjusted P = 0.007), aβ2GPI high titres (OR 2.33; 95% CI 1.36, 4.02; adjusted P = 0.002) and corticosteroid use (ever) (OR 3.73; 95% CI 1.80, 7.75; adjusted P < 0.001) were independently associated with high damage at baseline. In the non-thrombotic group, hypertension (OR 4.55; 95% CI 1.82, 11.35; adjusted P = 0.001) and hyperlipidaemia (OR 4.32; 95% CI 1.37, 13.65; adjusted P = 0.013) were independent predictors of damage at baseline; conversely, single aPL positivity was inversely correlated with damage (OR 0.24; 95% CI 0.075, 0.77; adjusted P = 0.016). CONCLUSIONS:DIAPS indicates substantial damage in aPL-positive patients in the APS ACTION cohort. Selected traditional cardiovascular risk factors, steroids use and specific aPL profiles may help to identify patients more prone to present with a higher damage burden.

OBJECTIVE:To systematically review the literature to evaluate clinical and surgical outcomes for technologies that facilitate vaginal surgical procedures. DATA SOURCES/METHODS:We systematically searched MEDLINE, EMBASE, and ClinicalTrials.gov from January 1990 to May 2022. METHODS OF STUDY SELECTION/METHODS:Comparative and single-arm studies with data on contemporary tools or technologies facilitating intraoperative performance of vaginal gynecologic surgical procedures for benign indications were included. Citations were independently double screened, and eligible full-text articles were extracted by two reviewers. Data collected included study characteristics, technology, patient demographics, and intraoperative and postoperative outcomes. Risk of bias for comparative studies was assessed using established methods, and restricted maximum likelihood model meta-analyses were conducted as indicated. TABULATION, INTEGRATION, AND RESULTS/RESULTS:The search yielded 8,658 abstracts, with 116 eligible studies that evaluated pedicle sealing devices (n=32), nonrobotic and robotic vaginal natural orifice transluminal endoscopic surgery (n=64), suture capture devices (n=17), loop ligatures (n=2), and table-mounted telescopic cameras (n=1). Based on 19 comparative studies, pedicle sealing devices lowered vaginal hysterectomy operative time by 15.9 minutes (95% CI, -23.3 to -85), blood loss by 36.9 mL (95% CI, -56.9 to -17.0), hospital stay by 0.2 days (95% CI, -0.4 to -0.1), and visual analog scale pain scores by 1.4 points on a subjective 10-point scale (95% CI, -1.7 to -1.1). Three nonrandomized comparative studies and 53 single-arm studies supported the feasibility of nonrobotic vaginal natural orifice transluminal endoscopic surgery for hysterectomy, adnexal surgery, pelvic reconstruction, and myomectomy. Data were limited for robotic vaginal natural orifice transluminal endoscopic surgery, suture capture devices, loop ligatures, and table-mounted cameras due to few studies or study heterogeneity. CONCLUSION/CONCLUSIONS:Pedicle sealing devices lower operative time and blood loss for vaginal hysterectomy, with modest reductions in hospital stay and pain scores. Although other technologies identified in the literature may have potential to facilitate vaginal surgical procedures and improve outcomes, additional comparative effectiveness research is needed. SYSTEMATIC REVIEW REGISTRATION/BACKGROUND:PROSPERO, CRD42022327490.

OBJECTIVE:In recent years, the academic medicine community has produced numerous statements and calls to action condemning racism. Though health equity work examining health disparities has expanded, few studies specifically name racism as an operational construct. As emergency departments serve a high proportion of patients with social and economic disadvantage rooted in structural racism, it is critically important that racism be a focus of our academic discourse. This study examines the frequency at which four prominent emergency medicine journals, Annals of Emergency Medicine, Academic Emergency Medicine, the American Journal of Emergency Medicine, and the Western Journal of Emergency Medicine, publish on health disparities and racism. METHODS:This is a descriptive analysis measuring the frequency of publications on health disparities and racism in U.S.-based emergency medicine journals from 2014 to 2021. The search strategies for the concepts of "racism" and "health disparities" used a combination of MeSH and keywords. These search strategies were developed based on prior literature and the MEDLINE/PubMed Health Disparities and Minority Health Search Strategy. Articles identified through the PubMed search were then reviewed by two authors for final inclusion. RESULTS:Since 2014, a total of 6248 articles were published by the four emergency medicine journals over the 8-year study period. Of those, 82 research papers that focused on health disparities were identified and only 16 that focused on racism. Most emergency medicine publications on racism and health disparities were in 2021. CONCLUSIONS:Our findings suggest that the national discourse on racism and calls to action within emergency medicine were followed by an increase in publications on health disparities and racism. Continued investigation is needed to evaluate these trends moving forward.

PURPOSE/OBJECTIVE:To report a case of recurrent acute retinopathy associated with pseudoxanthoma elasticum and to propose a reappraisal of this entity based on multimodal imaging analysis. METHODS:Retrospective case report. High-resolution optical coherence tomography (high-res OCT), ultra-widefield imaging, and widefield swept-source OCT angiography and en face OCT were performed. RESULTS:A man in his 40s diagnosed with pseudoxanthoma elasticum and angioid streaks presented with two distinct episodes of acute retinopathy in his right eye during a one-year follow-up period. Acute retinopathy was characterized by rapid vision loss. High-res OCT showed multifocal hyperreflective lesions splitting the retinal pigment epithelium/Bruch membrane complex and associated with focal choroidal thickening. After the first episode, OCT angiography confirmed the development of macular neovascularization at the site of a previous inflammatory lesion. During the second episode, multimodal images showed findings consistent with epiphenomenon multiple evanescent white dot syndrome (EpiMEWDS). On en face widefield OCT, acute retinopathy was characterized by multiple hyperreflective spots scattered at the posterior pole. CONCLUSION/CONCLUSIONS:Recurrence of acute retinopathy can be observed in patients with pseudoxanthoma elasticum and angioid streaks. Multimodal imaging shows that some lesions of pseudoxanthoma elasticum-associated acute retinopathy closely resemble those of punctate inner choroidopathy/idiopathic multifocal choroiditis.

Brain-derived neurotrophic factor (BDNF) is important in the development and maintenance of neurons and their plasticity. Hippocampal BDNF has been implicated in Alzheimer's disease (AD) because hippocampal levels in AD patients and AD animal models are often downregulated, suggesting that reduced BDNF contributes to AD. However, the location where hippocampal BDNF protein is most highly expressed, the mossy fiber (MF) axons of dentate gyrus granule cells (GCs), has been understudied, and not in controlled conditions. Therefore, we evaluated MF BDNF protein in the Tg2576 mouse model of AD. Tg2576 and wild-type (WT) mice of both sexes were examined at 2-3 months of age, when amyloid-β (Aβ) is present in neurons but plaques are absent, and 11-20 months of age, after plaque accumulation. As shown previously, WT mice exhibited high levels of MF BDNF protein. Interestingly, there was no significant decline with age in either the genotype or sex. Notably, MF BDNF protein was correlated with GC ΔFosB, a transcription factor that increases after 1-2 weeks of elevated neuronal activity. We also report the novel finding that Aβ in GCs or the GC layer was minimal even at old ages. The results indicate that MF BDNF is stable in the Tg2576 mouse, and MF BDNF may remain unchanged due to increased GC neuronal activity, since BDNF expression is well known to be activity dependent. The resistance of GCs to long-term Aβ accumulation provides an opportunity to understand how to protect vulnerable neurons from increased Aβ levels and therefore has translational implications.

BACKGROUND:Sacituzumab govitecan (SG) is a Trop-2-directed antibody-drug conjugate containing cytotoxic SN-38, the active metabolite of irinotecan. SG received accelerated US Food and Drug Administration approval for locally advanced (LA) or metastatic urothelial carcinoma (mUC) previously treated with platinum-based chemotherapy and a checkpoint inhibitor, based on cohort 1 of the TROPHY-U-01 study. Mutations in the uridine diphosphate glucuronosyltransferase 1A1 (UGT1A1) gene are associated with increased adverse events (AEs) with irinotecan-based therapies. Whether UGT1A1 status could impact SG toxicity and efficacy remains unclear. PATIENTS AND METHODS/METHODS:TROPHY-U-01 (NCT03547973) is a multicohort, open-label, phase II registrational study. Cohort 1 includes patients with LA or mUC who progressed after platinum- and checkpoint inhibitor-based therapies. SG was administered at 10 mg/kg intravenously on days 1 and 8 of 21-day cycles. The primary endpoint was objective response rate (ORR) per central review; secondary endpoints included progression-free survival, overall survival, and safety. Post hoc safety analyses were exploratory with descriptive statistics. Updated analyses include longer follow-up. RESULTS:Cohort 1 included 113 patients. At a median follow-up of 10.5 months, ORR was 28% (95% CI 20.2% to 37.6%). Median progression-free survival and overall survival were 5.4 months (95% CI 3.5-6.9 months) and 10.9 months (95% CI 8.9-13.8 months), respectively. Occurrence of grade ≥3 treatment-related AEs and treatment-related discontinuation were consistent with prior reports. UGT1A1 status was wildtype (∗1|∗1) in 40%, heterozygous (∗1|∗28) in 42%, homozygous (∗28|∗28) in 12%, and missing in 6% of patients. In patients with ∗1|∗1, ∗1|∗28, and ∗28|∗28 genotypes, any grade treatment-related AEs occurred in 93%, 94%, and 100% of patients, respectively, and were managed similarly regardless of UGT1A1 status. CONCLUSIONS:With longer follow-up, the ORR remains high in patients with heavily pretreated LA or mUC. Safety data were consistent with the known SG toxicity profile. AE incidence varied across UGT1A1 subgroups; however, discontinuation rates remained relatively low for all groups.