Danbury Hospital

Abstract Background: We hypothesized genes with frequent copy number amplifications in breast cancer resulting in overexpression of membrane proteins could serve as potential targets for novel antibody drug conjugates (ADC). Methods: DNA copy number aberrations (CNA) and mRNA expression data was retrieved from cBioPortal (https://www.cbioportal.org/) for 3,970 patients with breast cancer. We defined gene amplification as CNA value >2. Chi-square or Fisher’s Exact test was used to test for significant difference in amplification frequency between 3 clinical subtypes ER+ (n=2474), HER2+ (n=712), and TNBC (n=632). Wilcoxon signed-rank test was used to test if gene mRNA expression is higher in cancers with amplification compared to wild type. We shortlisted amplified genes as candidates if amplification has led to overexpression and the gene encoded a membrane protein based on information in the Protein Data Bank (https://www.rcsb.org/) and Human Protein Atlas (https://www.proteinatlas.org/). We retrieved normal tissue mRNA expression data from GTEx (https://www.gtexportal.org/home/) covering 21 different tissue types and compared candidate ADC target expression in cancer versus normal tissues using DESeq2. We prioritized ADC candidates by the following criteria (i) CNA frequency > 15% across all breast cancers or within a subtype (FDR<.0001) (ii) higher expression in amplified cancers (FDR<0.001), (iii) mean Log2 Fold expression > 1.5 in cancer compared to each normal tissue one by ones, and (iv) known membrane protein that is primarily located in the cell membrane and ability for internalization. Results: 963 unique genes were recurrently amplified and showed higher gene expression in amplified cancers across all breast cancers (722 genes) and/or significantly amplified only in ER+ (206 4 genes), HER2+ (216 200 genes), and TNBC (114 37 genes), and. how many were amplified in all subtypes?. Of the amplified and overexpressed genes, ⋯N=?...154 genes were membrane proteins. were membrane proteins. Among these membrane membrane proteins, 9 genes had higher expression in breast cancer than in normal tissues and primary located on cell membrane with ability for internalization. They (including HER2) are highlighted in Table 1 met all 4 criteria as potential novel ADC targets⋯N=?... had higher expression in breast cancer than in normal tissues. Nine genes (including HER2) highlighted in bold in Table 1 met all 4 criteria as potential novel ADC targets. Conclusion: We have identified several novel potential targets for ADC development in breast cancer. Citation Format: H. Lin, Y. Wang, J. Dai, L. Pusztai. Identifying recurrent gene amplifications in breast cancer for antibody drug conjugate development [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-04-13.

Background: Idiopathic pulmonary fibrosis (IPF) is an incurable disease marked by irreversible fibrosis and declining respiratory function. Nintedanib inhalation powder is a novel dry powder inhalation formulation of nintedanib consisting of Technosphere® particles that deliver active drug directly to the lungs, aiming to reduce systemic effects associated with oral treatment. The objective of the present work was to assess whether nintedanib dry powder inhalation (DPI) has the potential to provide improved safety and thus effectiveness compared with that of currently available therapeutic options for IPF. Methods: Three preclinical studies evaluated pharmacokinetic and toxicity outcomes associated with nintedanib inhalation powder. Two 28-day repeat-dose studies (one in rats and one in dogs), and a 6-month toxicity study in dogs assessed pulmonary and histological changes after inhaled nintedanib therapy. A phase 1, first-in-human, randomized, double-blind, placebo-controlled study evaluated the safety, tolerability, and pharmacokinetics of single and multiple ascending doses of nintedanib DPI versus placebo in healthy adults. Results: In the 28-day repeat-dose studies and the 6-month study, animals survived to scheduled necropsy without significant adverse findings, including no gastrointestinal adverse findings, and most achieved target pulmonary-deposited nintedanib concentrations. The phase 1 study demonstrated dose-proportional increases in nintedanib plasma concentrations after single doses and rapid absorption of nintedanib, with maximum concentrations within a few minutes of first dose at levels consistent with deep lung deposition. Nintedanib inhalation powder was considered safe and well tolerated throughout the study duration. Conclusion: Inhaled administration of nintedanib via DPI may offer advantages over oral therapies in patients with IPF, potentially reducing adverse effects associated with systemic exposure. Results of the preclinical and phase 1 studies support continued assessment of this formulation in patients with IPF and other pulmonary fibrotic diseases. Clinical Trial Registration Number: NCT06532942.

Hyperthyroidism in pregnancy carries serious risks for both the pregnant individual and the fetus. Presenting symptoms may include fatigue, nausea, and palpitations. Timely diagnosis and intervention are challenging because clinical features overlap with physiological changes in pregnancy. This case report describes a diagnostically challenging presentation of thyrotoxicosis in pregnancy with neurological symptoms mimicking a stroke, which is atypical since stroke-like presentations are not typically associated with hyperthyroidism. This case highlights the importance of maintaining a broad differential in pregnant individuals with persistent, unexplained systemic symptoms.

e15544 Background: KRAS G12C inhibitors are potential treatment options for patients with KRAS G12C mutated colorectal cancer (CRC) patients, who make up to 3% of CRC patients. This systematic review and meta-analysis aimed at exploring the outcomes of KRAS G12C inhibitors in treating metastatic KRAS G12C mutated CRC patients. Methods: A systematic search was conducted on PubMed, Cochrane, and ClinicalTrials.gov following PRISMA guidelines and four studies reporting outcomes of KRAS G12C inhibitors in treating metastatic KRAS G12C mutated CRC patients were included after screening of 45 studies. The inter-study variance was assessed using the Der Simonian-Laird Estimator and pooled analysis was conducted with 95% confidence intervals using the ‘meta’ package in R (version 4.16-2). Results: A total of 331 patients from 4 studies (2023-2024) were included for analysis. The median age was 59.5 (24- 82) years and the majority were female (52%, n=173). One of the included studies was phase III while three were phase I/II trials. Adagrasib 51% (38% received Adagrasib in combination with cetuximab], Sotorasib 32%, and Divarasib 17% used KRAS G12C inhibitors. The median number of prior therapies was 3 (1-9) and fluoropyrimidines were the most used regimen (98%, n=323) followed by oxaliplatin (97%, n=320), and irinotecan (89%, n=296). The median follow-up time was 14.7 (0.1-13.9) months. The pooled rates of overall response (OR), stable disease (SD), and progressive disease (PD) were 26% (95% CI 0.21-0.31, I 2 =70%, p=0.02, n=326), 54% (95% CI 0.49-0.59, I 2 =0%, p=0.45, n=326), and 12.2% (95% CI 0.09-0.16, I 2 =76%, p<0.01, n=326), respectively. The pooled rates for complete remission (CR) and partial remission (PR) were 1.4% (95% CI 0.00- 0.03, I 2 =85%, p<0.01, n=326), and 26.1% (95% CI 0.21-0.31, I 2 =79%, p<0.01, n=326), respectively. At a median follow-up of 6 months, pooled progression-free survival (PFS) was 53.7% (95% CI 0.48-0.59, I 2 =0%, p=0.69, n=326) and pooled overall survival (OS) was 91.9% (95% CI 0.87-0.96, I 2 =66%, p=0.09, n=165). The median duration of response was 5.8 (2.3-8.3) months. Nausea (48%, n=160), diarrhea (46%, n=152), and vomiting (38%, n=126) were the most commonly reported adverse events. Conclusions: KRAS G12C inhibitors demonstrated promising efficacy in metastatic KRAS G12C mutated CRC with an acceptable toxicity profile. However, large studies with randomization are needed to consolidate these findings.

e18593 Background: Myelofibrosis (MF) patients who progressed on Janus Kinase inhibitors (JAKi), and are ineligible for allogeneic stem cell transplant have poor prognoses and limited treatment options. Imetelstat, a telomerase inhibitor, demonstrated potential benefit in reversing bone marrow fibrosis in MF. This meta-analysis aims to evaluate outcomes of Imetelstat in MF patients. Methods: A comprehensive literature search was conducted on PubMed, Embase, ClinicalTrials.gov, Cochrane, and Google Scholar, adhering to PRISMA guidelines. Three prospective studies reporting outcomes of myelofibrosis (MF) in adult patients treated with Imetelstat were included after screening of 284 articles. The inter-study variance was calculated using the DerSimonian-Laird estimator proportions, and a 95% Confidence Interval (CI) was extracted to compute a pooled analysis using the ‘meta’ package by Schwarzer et al. in the R programming language (version 4.3.0). Results: A total of 197 MF patients were included for analysis. The median age was 67 (31-86) years and 62% were male. 58% had primary MF while 42% had MF secondary to essential thrombocytosis or polycythemia vera. JAK2 mutation was reported in 62% of patients and 9% had calreticulin (CALR) mutation. 37% of patients were treated with at least two prior lines of therapy, 26% were transfusion dependent, and 33% were refractory to JAKi. According to the dynamic international prognostic scoring system, 57% of patients had intermediate-risk disease, while 43% had high-risk disease. Baseline bone marrow (BM) fibrosis was reported in 58% of patients, and 62% had a spleen size greater than 15 cm. ECOG score was 1-2 in 80% of the patients while it was 2-3 in 20%. Imetelstat dosing was 9.7 mg/kg (76%) or 4.7 mg/kg (24%). The duration of Imetelstat treatment, reported by two studies, ranged from 22.3 to 25.1 months. The pooled overall survival (OS) at 1 year, as reported by two studies, was 80.95% (95% CI: 74.95-86.93, p=0.54, I²=0.0%). The median pooled OS ranged from 19.9 to 33.8 months. The pooled spleen volume reduction (SVR) of 10%, 20% and 35% was 22.40 (95% CI 0.0-50.76, p = 0.0001), 11.44 (95% CI 0.00-30.95, p = 0.0006), and 4.42 (95% CI 0.0-14.31, p = 0.0152), respectively, while the pooled reduction of more than one grade in BM fibrosis was reported in 14.79% (95% CI: 4.70-24.88, p=0.04, I²=67.5%) of patients. Most common reported adverse event was anemia (42%) followed by thrombocytopenia (41%), and diarrhea (37%). Conclusions: This meta-analysis shows good efficacy of Imetelstat in MF patients with an acceptable safety profile. However, results should be interpreted cautiously considering the small sample size and large clinical trials are needed to consolidate these findings.

Introduction: Immune checkpoint inhibitors (ICIs) have improved lung cancer treatment but are associated with an increased risk of cardiotoxicity. We investigated whether statins could mitigate ICI-associated cardiovascular risks in lung cancer patients. Methods: We performed a retrospective, propensity score-matched cohort study utilizing the TriNetX database. We identified lung cancer patients receiving ICIs between April 2013 and June 2023. We created two cohorts: statin users and non-users. The primary efficacy outcome was major adverse cardiovascular events (MACE), defined as a composite of myocardial infarction, ischemic stroke, and heart failure. The secondary efficacy outcomes were myocarditis and cardiac arrest. Safety outcomes were all-cause mortality and serious immune-related adverse events (irAEs). Results: A total of 16,650 lung cancer patients undergoing ICIs were identified, consisting of 6,812 statin users and 9,838 non-users. After propensity score matching, 4,379 patients were well-matched in baseline characteristics. Over a follow-up period of 12 months, statin use was associated with a lower risk of MACE (HR: 0.87, 95% CI: 0.78–0.98), primarily driven by reductions in myocardial infarction (HR: 0.75, 95% CI: 0.58-0.97) and heart failure (HR: 0.85, 95% CI: 0.74–0.98). For safety outcomes, statin use was associated with a reduction in all-cause mortality (HR: 0.83, 95% CI: 0.77–0.90) and did not result in an increased risk of serious irAEs. Conclusion: The use of statins in lung cancer patients with cardiovascular risk factors and without previous cardiovascular events undergoing immunotherapy was associated with a reduction in MACE and all-cause mortality without an increased risk of serious adverse events.

Powassan virus (POWV) is a single-stranded RNA virus that belongs to the genus Orthoflavivirus, which is transmitted to humans through the bite of infected deer tick (Ixodes scapularis), with peak transmission during summer and fall. Most patients are asymptomatic; those who develop symptoms usually present with flu-like symptoms or neuroinvasive disease, including encephalitis, meningoencephalitis, or aseptic meningitis. The gold standard test for diagnosis is serological testing. The treatment is usually supportive care. In this case series, we have reported two cases that presented with fever, generalized weakness, and changes in mentation, later diagnosed with POWV meningoencephalitis. The magnetic resonance imaging (MRI) findings in the first case were suggestive of herpes simplex virus (HSV), imposing a diagnostic challenge. Patients might end up with cognitive impairment, speech difficulties, headaches, imbalance, and ophthalmoplegia as long-term consequences, and both of our cases had cognitive impairment, and one case had weakness, requiring further neuropsychiatry evaluation, as well as physical therapy. Although cases of POWV encephalitis are very rare, these cases describe the importance of serological testing for POWV, especially in endemic areas, in patients with a known or unknown history of tick bite.

Abstract Pulmonary sequestration is a rare congenital malformation involving non-functioning lung tissue that is isolated from the normal tracheobronchial tree and receives its arterial supply from an aberrant systemic artery, usually originating from the aorta. This condition is typically diagnosed in childhood but can remain asymptomatic and unrecognized until adulthood, when recurrent pulmonary infections or other complications prompt evaluation. In this case report, we present a 37-year-old male who immigrated from Ecuador in 2005 and had no significant past medical history. The patient initially presented to the emergency department in 2020 with symptoms of cough, dyspnea, and fever lasting for a week. Imaging studies revealed a large left lower lobe abscess (8.8 x 9.3 cm) with consolidation and a small pleural effusion. Tuberculosis was ruled out and patient was treated with prolonged course of antibiotics with a plan to repeat imaging after improvement, but the patient was lost to follow-up for three years. In 2023, the patient presented with hemoptysis and a history of trauma after falling from a roof. A repeat chest CT revealed hyperdense mass in the left lower lobe, at the site of the previous abscess, along with surrounding ground-glass opacities indicative of pneumonia. At this point, the possibility of a congenital anomaly, such as pulmonary sequestration, was raised, though no definitive diagnosis was made. The patient's pneumonia was managed with IV antibiotics, and repeat imaging after treatment revealed a persistent 12 cm complex mass in the left lower lobe. Despite the recommendation for surgical intervention due to suspected sequestration or an underlying infectious process, financial constraints led to the patient declining surgery at that time. In 2024, the patient returned with another episode of pneumonia and hemoptysis. Imaging findings were consistent with the previous observations, showing a complex cystic mass with areas of consolidation and air, suggestive of a recurrent pulmonary abscess. A thoracic surgery consultation led to an open thoracotomy and left lower lobectomy, during which cystic changes and aberrant vascular anatomy, consistent with pulmonary sequestration, were observed. Histopathological report also confirmed the diagnosis of pulmonary sequestration, a condition that likely contributed to his recurrent infections and pulmonary abscess formation over the years. This case underscores the importance of considering rare congenital anomalies like pulmonary sequestration in patients with recurrent pulmonary infections, particularly when imaging suggests a persistent or complex lung lesion. Early recognition and surgical intervention are essential in preventing recurrent infections and long-term complications.