Faculty Bibliography

PURPOSE/OBJECTIVE:EA1181 (ClinicalTrials.gov identifier: NCT04266249) is a single-arm trial evaluating neoadjuvant taxane, trastuzumab, and pertuzumab (THP) in patients with clinical stage II/IIIa human epidermal growth factor receptor 2 (HER2)-positive breast cancer. This report focuses on the secondary end points of pathologic complete response (pCR) rates and associated factors. The primary end point-3-year recurrence-free survival among patients achieving a pCR (ypT0/Tis, ypN0)-will be reported when data mature. METHODS:Patients received four cycles of trastuzumab and pertuzumab (HP) with either once per week paclitaxel (12 weeks) or docetaxel (every 3 weeks for four cycles), followed by surgery. Clinicopathologic characteristics were assessed in all patients. The HER2DX pCR score was determined using diagnostic biopsy samples in a representative subset. Logistic regression models identified factors associated with pCR. RESULTS:A total of 2,175 patients were enrolled (781 HER2+/estrogen receptor‑negative [ER-]; 1,394 HER2+/ER+). Of 2,141 patients who initiated THP, the overall pCR rate was 43.8%: 63.7% in HER2+/ER- and 32.4% in HER2+/ER+ tumors. Higher pCR rates were observed in tumors that were ER-negative or low ER expressing, progesterone receptor-negative or low expressing, HER2 immunohistochemistry (IHC) 3+, and in patients treated with once per week paclitaxel. T3 disease was associated with a lower pCR rate in HER2+/ER- tumors; otherwise, tumor (T) and nodal (N) stage did not significantly affect pCR. Among 569 patients assessed for HER2DX pCR scores, a high score was independently associated with higher pCR rates, after adjustment for clinicopathologic variables. CONCLUSION/CONCLUSIONS:Neoadjuvant THP achieved pCR in nearly two-thirds of patients with HER2+/ER- and one third with HER2+/ER+ breast cancer. Low hormone receptor expression, HER2 IHC 3+ status, once per week paclitaxel use, and a high HER2DX pCR score were independent predictors of pCR. These findings should help optimize risk stratification and treatment personalization for patients with HER2-positive breast cancer.

Microglia perform the function of CNS macrophages and act as the primary immune cells in the brain. They surveil the environment, phagocytose cellular debris, maintain homeostasis and respond to tissue damage. While under physiological conditions they play a role in supporting neurons, activated microglia participate directly in the degeneration of neurons in the substantia nigra, as the hallmark of the Parkinsons disease (PD). Their detrimental effects result from direct phagocytosis of dopaminergic neurons as well as via neuroinflammation and release of toxic reactive oxygen and nitrogen species. This pathological shift is driven by a complex interplay of genetic predispositions, such as LRRK2 and GBA mutations, and environmental triggers like toxins and gut dysbiosis.A central mechanism of this neurodegeneration involves extracellular α-synuclein acting as a danger signal (DAMP), which activates microglial Toll-like receptors (e.g., TLR2) to initiate a severe inflammatory cascade. Furthermore, the extreme biophysical stability of aggregated α-synuclein overwhelms the microglial endolysosomal network, leading to lysosomal failure, "frustrated phagocytosis," and the active propagation of the disease via exosomal shedding. Relieving this maladaptive chronic neuroinflammation is a primary therapeutic goal. Modern strategies aim to break this vicious cycle through precise interventions like NLRP3 inflammasome inhibition and autophagy enhancement. Concurrently, advanced fluid biomarkers, such as seed amplification assays (SAA), alongside multidimensional neuroimaging techniques (PET, SPECT, MRI), are proving crucial for detecting these early microglial and pathological changes to guide personalized, disease-modifying therapies of PD.

BACKGROUND/UNASSIGNED:It is unknown how the increased range of motion and improved gait mechanics provided by total ankle arthroplasty (TAA) affects the progression of subtalar arthritis compared with ankle arthrodesis (AA). We hypothesized that patients treated with TAA would have a lower incidence of postoperative subtalar arthrodesis (SA) compared to AA. METHODS/UNASSIGNED: <.05. RESULTS/UNASSIGNED: > .05). In a multivariate analysis, AA remained associated with increased risk of requiring SA (OR = 1.90, CI = 1.01-3.56). CONCLUSION/UNASSIGNED:In this study, we found a significantly higher incidence of subtalar arthrodesis following AA compared with TAA. Surgeons may consider the risk of progression to SA when deciding between TAA and AA for patients with advanced ankle arthritis, particularly in preoperative counseling for patients without existing subtalar arthritis, as TAA may offer an opportunity to mitigate this risk. LEVEL OF EVIDENCE/UNASSIGNED:Level III, retrospective comparative study.

BACKGROUND:People with multiple sclerosis (pwMS) treated with anti-CD20 monoclonal antibodies have an elevated infection risk, yet long-term comparative data with oral fumarates are limited. OBJECTIVE:To compare infection incidence, healthcare resource utilization, and relapse outcomes among pwMS receiving fumarate or anti-CD20 therapy for ⩾2 years. METHODS:This retrospective propensity-matched (1:2) analysis used US Komodo Health claims (1 January 2016-31 May 2022) for pwMS aged 18-64 years with ⩾2 years of continuous follow-up. Outcomes were assessed using Poisson generalized linear models. RESULTS: = 0.021). CONCLUSIONS:Fumarate therapy was associated with a lower infection risk versus anti-CD20s. The infection rate in the fumarates group remained relatively stable over time, but it progressively increased in the anti-CD20 group, with the most prominent differences observed at year 4 and beyond.

Sellar region neurocytoma (SELN) is a rare neoplasm whose relationship to other neurocytomas within the central nervous system (CNS) has remained unclear. Prior reports have variably classified SELN as a variant of extraventricular neurocytoma (EVN), while immunohistochemical and ultrastructural studies have suggested a hypothalamic origin. Here, we performed unsupervised clustering of DNA methylation data across a large pan-cancer reference set and identified SELN (n = 20) as distinct from other neurocytomas and regional mimics, as well as clustering with neuroendocrine tumors from other organ sites. SELN exhibited a CIMP-like phenotype, TTF1 negativity (0/8), and AVP (vasopressin) promoter hypomethylation, implicating a magnocellular hypothalamic cell of origin. In evaluable cases, a neuronal/neuroendocrine immunophenotype was observed (synaptophysin 8/8, chromogranin A 5/5) with absent pituitary transcription factor expression (PIT1 and TPIT negative 0/4). DNA sequencing (n = 5) and RNA-based fusion profiling (n = 4) did not detect recurrent mutations or gene fusions, respectively. Patients often presented with visual disturbances or headaches and spanned pediatric and older age groups (median 42 years, range 12.5-75), with no sex predilection. Despite locally aggressive imaging features in some cases (cavernous sinus invasion, carotid encasement, hydrocephalus), disease-free survival (n = 13) was comparable to central neurocytoma, with no disease-related deaths during the limited follow-up. Together, these findings support SELN as a molecularly distinct hypermethylated neuroendocrine-like epitype and clinicopathologic entity.

APG157DS is a multi-component investigational drug which is currently the subject of multiple cancer trials. It has shown promising efficacy in patients with head and neck cancer. We report its immuno-modulatory effect in a syngeneic mouse model of glioblastoma (GBM). Long-term treatment with APG157DS led to durable tumor remission in 50% of mice, while all vehicle-treated mice reached humane endpoints within 42 days. Mechanistically, the drug induced selective repolarization of tumor-associated macrophages (TAMs) from an immunosuppressive Arg1^high/iNOS^low phenotype to a tumoricidal Arg1^low/iNOS^high state, accompanied by increased intratumoral recruitment of activated (NKp46+) natural killer cells and CD8+ cytotoxic T-cells. APG157DS also suppressed vascular endothelial growth factor (VEGF) and Hypoxia-inducible factor 1-alpha (HIF-1α) expression in tumors, further impairing tumor growth. Notably, APG157DS did not elicit off-target macrophage activation in peripheral tissues such as the spleen, highlighting its selective immune targeting. These findings provide a mechanistic rationale for further clinical development of APG157DS in GBM and potentially other immune-evasive cancers.

OBJECTIVE:Cesarean delivery (CD) remains a key obstetric quality metric, particularly among nulliparous, term, singleton, vertex (NTSV) pregnancies. In 2024, NTSV CD rate at NYU-LI was 32.9%, exceeding The Joint Commission (TJC) benchmark of ≤30% and demonstrating racial and ethnic disparities. This study aimed to reduce the institutional NTSV CD rate to ≤30% through a multidisciplinary QI initiative while prospectively monitoring safety outcomes and racial disparities. STUDY DESIGN/METHODS:A single-site QI initiative was implemented from 2024-2025 incorporating provider education, patient-centered interventions (TeamBirth and structured labor huddles), standardized labor management, and performance monitoring through monthly case review, clinician feedback, and quarterly equity-focused data review. Outcome measures included monthly overall and quarterly race- and ethnicity-stratified NTSV CD rates. Process measures assessed adherence to evidence-based labor dystocia criteria. Balancing measures included postpartum hemorrhage (PPH) and TJC PC-06 rates. Temporal trends were evaluated using multivariable Poisson regression with adjustment for maternal age, gestational age at delivery, and body mass index. RESULTS:The overall NTSV CD rate decreased from 32.9% in 2024 to 27.8% in 2025, remaining below TJC benchmark in 10 of 12 months. Across the 8-quarter study period, there was a significant decline in the outcome over time (aRR per quarter 0.97, 95% CI 0.95-0.99, p=0.003). Reductions were observed across racial and ethnic groups, including among Black non-Hispanic patients (44.0% to 40.0%) and Asian non-Hispanic patients (37.0% to 29.6%). Adherence to evidence-based labor dystocia criteria remained high, while PPH and PC-06 rates remained stable. CONCLUSIONS:A standardized, multidisciplinary QI initiative was associated with NTSV cesarean delivery rate below the Joint Commission benchmark without increases in maternal or neonatal adverse outcomes. The initiative was also associated with partial reduction in racial disparities in cesarean delivery rates, although persistent inequities remained. Future PDSA cycles will focus on sustaining standardized care and advancing equitable obstetric outcomes.