Citations

How the KRAS oncogene drives cancer growth remains poorly understood. Therefore, we established a systemwide portrait of KRAS- and extracellular signal–regulated kinase (ERK)–dependent gene transcription in KRAS-mutant cancer to delineate the molecular mechanisms of growth and of inhibitor resistance. Unexpectedly, our KRAS-dependent gene signature diverges substantially from the frequently cited Hallmark KRAS signaling gene signature, is driven predominantly through the ERK mitogen-activated protein kinase (MAPK) cascade, and accurately reflects KRAS- and ERK-regulated gene transcription in KRAS-mutant cancer patients. Integration with our ERK-regulated phospho- and total proteome highlights ERK deregulation of the anaphase promoting complex/cyclosome (APC/C) and other components of the cell cycle machinery as key processes that drive pancreatic ductal adenocarcinoma (PDAC) growth. Our findings elucidate mechanistically the critical role of ERK in driving KRAS-mutant tumor growth and in resistance to KRAS-ERK MAPK targeted therapies.

3525 Background: Recent clinical trials support regorafenib dose optimization (ReDO), a combination therapy with trifluridine/tipiracil and bevacizumab (TAS-BEV), and fruquintinib (FRUQ) for the treatment of refractory metastatic colorectal cancer (mCRC). This study evaluated relative cost-effectiveness of ReDO, TAS-BEV, and FRUQ for mCRC from a payer perspective in the United States. Methods: A Markov model was constructed to estimate total costs and quality-adjusted life years (QALY) for each treatment. In the base case, clinical parameters were obtained from the ReDOS study for ReDO, the SUNLIGHT study for TAS-BEV, and the FRESCO study for FRUQ. Economic parameters were obtained from IBM Micromedex RED BOOK for treatment costs and from the Centers for Medicare & Medicaid Services and the Agency for Healthcare Research and Quality for health care resource use. Incremental cost-effectiveness ratio (ICER) was used to evaluate relative cost-effectiveness of treatments. Model robustness was checked with deterministic (DSA) and probabilistic sensitivity analysis (PSA). A subgroup analysis was performed in patients with and without previous use of anti-VEGF therapy, but using the FRESCO-2 study for FRUQ because OS and PFS for this subgroup was unavailable in the FRESCO study. Results: In the base case, ReDO provided a higher QALY at a lower cost than TAS-BEV and FRUQ. During the first two months following treatment initiation, TAS-BEV had a higher total cost ($67,862) than ReDO ($44,695) and FRUQ ($48,688), partly due to the cost of managing neutropenia and using concomitant granulocyte colony stimulating factors (GCSF). The base case results were robust in DSA and PSA. Most influential parameters determining relative cost-effectiveness were related to treatment cost and effectiveness. In patients with previous anti-VEGF therapy, ReDO provided a higher QALY at a lower cost (0.571 QALY; $86,694) than TAS-BEV (0.490 QALY; $148,784) and FRUQ (0.411 QALY; $101,236). In patients without previous anti-VEGF therapy, TAS-BEV had a higher QALY (0.755 vs 0.571) and a higher cost ($232,701 vs $86,694) than ReDO, resulting in an ICER of $790,988 per QALY. Conclusions: ReDO was cost-effective compared with TAS-BEV and FRUQ, regardless of previous use of anti-VEGF therapy. In the base case, ReDO had a lower treatment cost than TAS-BEV and FRUQ, especially during the first month of dose optimization. TAS-BEV had the highest total cost, partly due to the cost of managing neutropenia and GCSF use. [Table: see text]

Abstract Objectives Large granular lymphocytic leukemia (LGLL) represents a rare neoplasm of mature T cells or natural killer (NK) cells, with an indolent clinical course. Diagnosing LGLL can be challenging because of overlapping features with reactive processes and other mimickers. Methods By presenting 2 challenging cases, we elucidate the differentiation of LGLL from its mimics and highlight potential diagnostic pitfalls. A comprehensive review of the clinicopathologic features of LGLL was conducted. Results Large granular lymphocytic leukemia displays a diverse spectrum of clinical presentations, morphologies, flow cytometric immunophenotypes, and molecular profiles. These features are also encountered in reactive conditions, T-cell clones of uncertain significance, and NK cell clones of uncertain significance. Conclusions In light of the intricate diagnostic landscape, LGLL workup must encompass clinical, morphologic, immunophenotypic, clonal, and molecular findings. Meeting major and minor diagnostic criteria is imperative for the accurate diagnosis of LGLL.

BACKGROUND AND OBJECTIVES: This study aimed to compare outcomes of low Alberta Stroke Program Early Computed Tomography Score (ASPECTS) patients with stroke who underwent mechanical thrombectomy (MT) within 6 hours or 6 to 24 hours after stroke onset. METHODS: A retrospective cohort study was conducted using data from a large multicenter international registry from 2013 to 2023. Patients with low ASPECTS (2-5) who underwent MT for anterior circulation intracranial large vessel occlusion were included. A propensity matching analysis was conducted for patients presented in the early (<6 hours) vs late (6-24 hours) time window after symptom onset or last known normal. RESULTS: Among the 10 229 patients who underwent MT, 274 met the inclusion criteria. 122 (44.5%) patients were treated in the late window. Early window patients were older (median age, 74 years [IQR, 63-80] vs 66.5 years [IQR, 54-77]; P < .001), had lower proportion of female patients (40.1% vs 54.1%; P = .029), higher median admission National Institutes of Health Stroke Scale score (20 [IQR, 16-24] vs 19 [IQR, 14-22]; P = .004), and a higher prevalence of atrial fibrillation (46.1% vs 27.3; P = .002). Propensity matching yielded a well-matched cohort of 84 patients in each group. Comparing the matched cohorts showed there was no significant difference in acceptable outcomes at 90 days between the 2 groups (odds ratio = 0.90 [95% CI = 0.47-1.71]; P = .70). However, the rate of symptomatic ICH was significantly higher in the early window group compared with the late window group (odds ratio = 2.44 [95% CI = 1.06-6.02]; P = .04). CONCLUSION: Among patients with anterior circulation large vessel occlusion and low ASPECTS, MT seems to provide a similar benefit to functional outcome for patients presenting <6 hours or 6 to 24 hours after onset.

Chimeric antigen receptor (CAR) T cell immunotherapy for the treatment of neurological autoimmune diseases is promising, but CAR T cell kinetics and immune alterations after treatment are poorly understood. Here, we performed single-cell multi-omics sequencing of paired cerebrospinal fluid (CSF) and blood samples from patients with neuromyelitis optica spectrum disorder (NMOSD) treated with anti–B cell maturation antigen (BCMA) CAR T cells. Proliferating cytotoxic-like CD8 + CAR T cell clones were identified as the main effectors in autoimmunity. Anti-BCMA CAR T cells with enhanced features of chemotaxis efficiently crossed the blood-CSF barrier, eliminated plasmablasts and plasma cells in the CSF, and suppressed neuroinflammation. The CD44-expressing early memory phenotype in infusion products was potentially associated with CAR T cell persistence in autoimmunity. Moreover, CAR T cells from patients with NMOSD displayed distinctive features of suppressed cytotoxicity compared with those from hematological malignancies. Thus, we provide mechanistic insights into CAR T cell function in patients with neurological autoimmune disease.

Objective Previous studies indicate that eosinophils are recruited into the allograft following orthotopic liver transplantation and protect from ischaemia reperfusion (IR) injury. In the current studies, we aim to explore whether their protective function could outlast during liver repair. Design Eosinophil-deficient mice and adoptive transfer of bone marrow-derived eosinophils (bmEos) were employed to investigate the effects of eosinophils on tissue repair and regeneration after hepatic IR injury. Aside from exogenous cytokine or neutralising antibody treatments, mechanistic studies made use of a panel of mouse models of eosinophil-specific IL-4/IL-13-deletion, cell-specific IL-4rα-deletion in liver macrophages and hepatocytes and macrophage-specific deletion of heparin-binding epidermal growth factor-like growth factor (hb-egf). Result We observed that eosinophils persisted over a week following hepatic IR injury. Their peak accumulation coincided with that of hepatocyte proliferation. Functional studies showed that eosinophil deficiency was associated with a dramatic delay in liver repair, which was normalised by the adoptive transfer of bmEos. Mechanistic studies demonstrated that eosinophil-derived IL-4, but not IL-13, was critically involved in the reparative function of these cells. The data further revealed a selective role of macrophage-dependent IL-4 signalling in liver regeneration. Eosinophil-derived IL-4 stimulated macrophages to produce HB-EGF. Moreover, macrophage-specific hb-egf deletion impaired hepatocyte regeneration after IR injury. Conclusion Together, these studies uncovered an indispensable role of eosinophils in liver repair after acute injury and identified a novel crosstalk between eosinophils and macrophages through the IL-4/HB-EGF axis.

Abstract This retrospective study from Jiangsu Province Hospital elucidates the prevalence and impact of pediatric androgenetic alopecia (AGA). Over a period of 14 years, 133 patients under the age of 18 were studied, with manifestations appearing as early as 8 years of age. Of note, 39.8% had an overweight/obese and 78.2% reported a family history of AGA. Comorbidities included seborrhoeic dermatitis (51.9%), acne (42.9%) and sleep disorders (28.6%). In addition, 4.5% had polycystic ovarian syndrome. Hormonal imbalances such as low sex hormone-binding globulin (47.1%) and vitamin D deficiency (61%) were common, as was low ferritin (23.6%). Male AGA patterns were characterised by crown thinning and temporal variations, whereas females showed crown thinning with frontal hair retention. Trichoscopic differences were observed between genders and age groups. This study highlights the importance of individualised, stepwise and comprehensive treatment, prioritising hormonal disorders and comorbidities when treating hair loss with topical minoxidil. Encouraging patients to adhere to regular medication and follow-up appointments can lead to favourable outcomes.

Abstract Background: In patients with micro- and macrometastases in the sentinel lymph node (SLN) after neoadjuvant chemotherapy (NAC), additional positive nodes are found in &gt;60% of cases and axillary lymph node dissection (ALND) is currently considered standard of care. The likelihood of finding additional positive lymph nodes in patients with residual isolated tumor cells (ITCs) is unknown, and the benefit of ALND is unclear. As a consequence, surgical management of the axilla in these patients is not standardized. We sought to evaluate how often additional positive lymph nodes are found, to determine factors associated with ALND, and to compare oncological outcomes in patients treated with and without ALND after identification of residual ITCs in the SLN. Methods: Data were collected from 42 centers: 20 in the Oncoplastic Breast Consortium (OPBC) and EUBREAST networks, and 22 in North and South America. We included patients with cT1-4 N0-3 breast cancer at diagnosis who underwent NAC followed by axillary staging with either SLN biopsy (SLNB) or targeted axillary dissection (TAD) and were found to have residual ITCs [ypN0(i+)]. Single-tracer mapping was allowed for cN0 patients, while dual mapping or TAD was required for cN+ cases. Axillary treatment included completion ALND and/or nodal radiotherapy (RT). Competing risk analysis was performed to assess the cumulative incidence rates of any axillary recurrence (AR), locoregional recurrence (LRR), and any invasive (locoregional or distant) recurrence. Five-year cumulative incidence rates were compared between patients who underwent ALND and those who did not using the Gray’s test. Type I error rate was set to 0.05 (α). Results: We included 412 patients treated with NAC followed by surgery from 01/2009-05/2022. 146 (35.4%) had completion ALND and 266 (64.6%%) did not. Median patient age was 48 years. The majority (57%) of patients had clinical T2 tumors, and 68% had biopsy-proven N1 disease. Most were HR+/HER2- (41%) or HER2+ (39%). Most patients (80%) received anthracycline and taxane-based chemotherapy regimens. Nodal RT was administered to 83% of patients. The median number of SLNs with ITCs was 1. Patients treated with ALND were more likely to have ITCs detected on frozen section (61% v 6.7%, p&lt; 0.001), to have N2/3 disease at presentation (15.1% v 5.6%, p=0.001) and to have LVI (40% v 26%, p=0.004) (Table 1). There was no significant trend over time in the proportion of patients undergoing completion ALND during the study period (p=0.5). In the ALND group, additional positive nodes were found in 43/146 (29.5%) of cases, and consisted of macrometastases in 11/146 (7.5%), micrometastases in 9/146 (6.2%), and ITCs in 23/146 (15.8%). 5-year rates of any AR, LRR, and any invasive recurrence in the entire cohort were 2.7% (95% CI 1.2-5.4), 2.8% (95% CI 1.2-5.4) and 16% (95% CI 11-21), respectively. There was no statistical difference between patients who underwent ALND and those who did not in any of the 3 endpoints (2.2% v 3.1%, p=0.6), (2.6% v 3.0%, p=0.4) and (14% v 18%, p=0.12), respectively. Conclusion: The likelihood of finding additional positive lymph nodes in patients with ITCs after NAC is lower than in patients with residual micro- and macrometastases, and in the majority of cases, they contain ITCs. Nodal recurrence after omission of ALND is rare in this population. Overall, these results do not support routine ALND in patients with residual ITCs. Table 1. Clinicopathological Features of the Study Cohort, Stratified by Type of Axillary Surgery Frequency (row percent) reported for categorical variables, and median (IQR) reported for continuous variables. SLNB sentinel lymph node biopsy; TAD targeted axillary dissection; SLNs sentinel lymph nodes; LNs lymph nodes; pCR pathologic complete response; ACT anthracycline and taxane; AC anthracycline; H Herceptin, HP, Herceptin and Perjeta; TC taxol (or Taxotere) and carboplatinum; LVI lymphovascular invasion; BCS breast-conserving surgery. ^ Applied to HER2- tumors only (n=252). ^^ Applies to HER2+ tumors only (n=160). # LVI was present on core biopsy or final pathology. * Applies to BCS patients only (n=175). ** Applies to mastectomy patients only (n=237). Citation Format: Giacomo Montagna, Alison Laws, Massimo Ferrucci, Mary Mrdutt, Natália Polidorio, Varadan Sevilimedu, Tracy-Ann Moo, Andrea Barrio, Marissa K. Boyle, Flavia Vidal Cabero, Daniela Cocco, Fabio Corsi, Angelena Crown, Meghan R. Flanagan, Mehmet Ali Gulcelik, Callie Hlavin, Justyna Jelinska, Hasan Karanlik, Susan Kesmodel, Henry Kuerer, Sherko Küemmel, Cornelia Leo, Tehillah Menes, Melissa Pilewskie, Nina Pislar, Nicola Rocco, Jai Min Ryu, Leonardo Soares, Christoph Tausch, M. Umit Ugurlu, CICERO URBAN, Astrid Botty van de Bruele, Denise Vorburger, Fredrik Wärnberg, Anna Weiss, Austin Williams, Stephanie Wong, Steven G. Woodward, Susie X. Sun, Jennifer Q. Zhang, M. Firdos Ziauddin, Guldeniz Karadeniz Cakmak, Nuran Bese, Thorsten Kühn, Judy Boughey, Tari King, Nina Ditsch, Maggie Banys-Paluchowski, Monica Morrow, Walter Weber. Are nodal ITCs after neoadjuvant chemotherapy an indication for axillary dissection? The OPBC05/EUBREAST-14R/ICARO study [abstract]. In: Proceedings of the 2023 San Antonio Breast Cancer Symposium; 2023 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2024;84(9 Suppl):Abstract nr GS02-02.