tbuckley/cabot-search huggingface dataset:
Multicenter study evaluating the utility of AI-aided HER2 scoring in the clinically relevant categories.
Authors: Savitri Krishnamurthy, Rita Canas Marques, Piotr Borkowski, Justin Cates, Elisabeth Shearon, Gaetan MacGrogan, Qingqing Ding, Pranil Chandra, Emilie Morphew, Rawia Yassin, Keith Sweeney, Hongxia Sun, Michael Riben, Darren Wheeler, Yuval Globerson, Raz Ziv, Sevde Etoz, Maya Grinwald, Manuela Vecsler
Journal: Journal of Clinical Oncology (2024)

e15150 Background: The availability of multiple therapeutic options for breast cancer patients with varying levels of protein expression necessitates precise and standardized HER2 scoring. This study explored the clinical utility of AI-aided HER2 scoring of whole-slide digital images by pathologists in breast core needle biopsies and excisions. Methods: The study included patients (n=764) with multiple subtypes of invasive breast cancer from 3 US reference laboratories and 1 academic medical center. The non-interventional two-arm multi-reader study retrospectively compared manual digital vs. AI-aided HER2 scoring of 8 pathologists. The fully automated HER2 AI solution detects the invasive tumor area and then classifies the tumor cells based on staining pattern based and the 2023 ASCO/CAP guidelines to output slide-level HER2 score. Both study arms were compared to reference ground truth (GT) established by the consensus of two breast subspecialists, ground truthers (GTer), who reviewed the slides digitally. One site recorded the time taken for HER2 scoring of both arms to determine the efficacy of the HER2 AI solution. Results: The initial interobserver agreement among expert GT pathologists for each HER2 score, 0, 1+, 2+, 3+, were 83%, 63.8%, 46%, and 92.6, respectively. At the clinically meaningful cut-offs, the reader pathologists’ performance improved with the AI support. At the 0 vs. 1+/2+/3+ and 0/1+ vs 2+/3+ clinical cutoffs, the readers' accuracy was 86.3% vs 88.6% and 93.7%, 93.8% with and without AI support, respectively. The AI use contributed to approximately 12%-time savings for the readers at the medical center. The AI solution demonstrated high accuracy for HER2 scoring, with 89.2% agreement with GT for 0 vs 1+/2+/3+ scores and 93.1% for 0/1+ vs 2+/3+ cutoff. The results will be updated in the final submission with the additional site data. The reader feedback survey regarding the solution’s usability will also be presented. Conclusions: The pathologists demonstrated improvements in consistency, evidenced by inter-reader agreement and accuracy with the aid of the AI. The AI solution can improve efficiency toward accurate HER2 scoring. [Table: see text]
The Diagnostic Accuracy of SPECT Imaging in Patients With Suspected Pulmonary Embolism
Authors: Ji-In Bang, Won Woo Lee, Sang-Geon Cho, Miyoung Choi, Yoo Sung Song
Journal: Clinical Nuclear Medicine (2024)

Background This meta-analysis and systematic review assessed the diagnostic accuracy of lung SPECT compared with lung planar imaging in patients with suspected acute pulmonary embolism (PE) or chronic thromboembolic pulmonary hypertension. Patients and Methods A search of Medline, Embase, and Cochrane databases identified suitable articles published before October 2023. Meta-analyses were performed to determine the diagnostic accuracy of SPECT imaging modalities, including perfusion (Q) SPECT, ventilation (V)/Q SPECT, Q SPECT/CT, and V/Q SPECT/CT. Network meta-analyses were performed to compare the diagnostic accuracy of SPECT and planar imaging in paired-design studies. Results Twenty-four articles (total n = 6576) were included in the analysis. For suspected acute PE, the respective sensitivity and specificity of SPECT imaging modalities were as follows: Q SPECT, 0.93 (95% confidence interval [CI], 0.87–0.99; I 2 = 49%) and 0.72 (95% CI, 0.54–0.95; I 2 = 94%); V/Q SPECT, 0.96 (95% CI, 0.94–0.98; I 2 = 51%) and 0.95 (95% CI, 0.92–0.98; I 2 = 80%); Q SPECT/CT, 0.93 (95% CI, 0.87–0.98; I 2 = 66%) and 0.82 (95% CI, 0.70–0.96; I 2 = 87%); and V/Q SPECT/CT, 0.97 (95% CI, 0.93–1.00; I 2 = 7%) and 0.98 (95% CI, 0.97–1.00; I 2 = 31%). The relative sensitivity and specificity of SPECT compared with planar imaging were 1.17 (95% CI, 1.06–1.30; P &lt; 0.001) and 1.14 (95% CI, 1.00–1.29; P = 0.05), respectively. For suspected chronic thromboembolic pulmonary hypertension, the pooled sensitivity and specificity of SPECT imaging were 0.97 (95% CI, 0.95–1.00; I 2 = 0%) and 0.91 (95% CI, 0.87–0.94; I 2 = 0%), respectively. Conclusions SPECT exhibited superior diagnostic performance for PE. V/Q SPECT/CT was the most accurate modality.
Diet and Tumor Genetics Conspire to Promote Prostate Cancer Metabolism and Shape the Tumor Microenvironment
Authors: Daniel E. Frigo
Journal: Cancer Research (2024)

Abstract Obesity has been linked to prostate cancer in a stage-dependent manner, having no association with cancer initiation but correlating with disease progression in men with prostate cancer. Given the rising obesity rate and its association to aggressive prostate cancer, there is a growing need to understand the mechanisms underlying this relationship to identify patients at increased risk of lethal disease and inform therapeutic approaches. In this issue of Cancer Research, Boufaied and colleagues describe how diets high in saturated fatty acids promote MYC-driven prostate cancer. Leveraging MYC-expressing genetically engineered and allograft mouse models fed either a control low-fat or high-fat diet (HFD) enriched in saturated fatty acids, the authors found using digital pathology that HFD-fed mice exhibited increased tumor invasion. Metabolomics, transcriptomics, immunoblotting, and positron emission tomography of tumors from these mice demonstrated that a HFD promoted a metabolic shift in the tumors towards glycolysis. These preclinical data were supported by findings from two large clinical cohorts revealing that men diagnosed with prostate cancer and who consumed high levels of saturated fatty acids possessed tumors bearing glycolytic signatures. Deconvolution analyses and immunohistochemistry validation showed that these tumors also displayed increased angiogenesis and infiltration of immunosuppressive macrophages and regulatory T cells, the latter of which was also correlated with high saturated fat intake–associated glycolytic signatures in patient tumors. Together, these findings suggest that diets rich in saturated fatty acids, rather than obesity alone, accelerate MYC-driven prostate cancers through shifting tumor metabolism and shaping the tumor microenvironment. See related article by Boufaied et al., p. 1834
Hydroxychloroquine Dose and Hospitalizations for Active Lupus
Authors: Jacquelyn Nestor, Hyon Choi, Christian Mancini, Baijun Zhou, Yuqing Zhang, Karen H. Costenbader, April Jorge
Journal: Arthritis & Rheumatology (2024)

Objective We sought to determine the impact of hydroxychloroquine (HCQ) dose on the risk of hospitalizations for systemic lupus erythematosus (SLE). Methods We conducted a case‐crossover study within an academic health system, including patients with SLE who used HCQ and had ≥1 hospitalization for active SLE between January 2011 and December 2021. Case periods ended in hospitalization for SLE, whereas control periods did not. The exposures were the average weight‐based HCQ dose, categorized as ≤5 or &gt;5 mg/kg/day, and non–weight‐based HCQ dose, categorized as &lt;400 or 400 mg/day, assessed during each six‐month case or control period. Odds ratios (ORs) were calculated using conditional logistic regression and adjusted for prior disease activity, kidney function, glucocorticoid use, and other immunosuppressant use. Results Of 2,974 patients with SLE who used HCQ (mean age 36.5 years; 92% female), 584 had ≥1 hospitalization with primary discharge diagnosis of SLE. Of these, 122 had ≥1 hospitalization for active SLE while using HCQ and had ≥1 control period with HCQ use during the study period. Lower HCQ weight‐based dose (≤5 vs &gt;5 mg/kg/day) and non–weight‐based dose (&lt;400 vs 400 mg/day) were each associated with increased hospitalizations for active SLE (adjusted OR 4.20, 95% confidence interval [CI] 1.45–12.19, and adjusted OR 3.39, 95% CI 1.31–8.81). Conclusion The use of lower doses of HCQ was associated with an increased risk of hospitalizations for active SLE. Although the long‐term risk of HCQ retinopathy must be acknowledged, this must be balanced with the short‐term and cumulative risks of increased SLE activity. image
Obesogenic High-Fat Diet and MYC Cooperate to Promote Lactate Accumulation and Tumor Microenvironment Remodeling in Prostate Cancer
Authors: Nadia Boufaied, Paolo Chetta, Tarek Hallal, Stefano Cacciatore, Daniela Lalli, Carole Luthold, Kevin Homsy, Eddie L. Imada, Sudeepa Syamala, Cornelia Photopoulos, Anna Di Matteo, Anna de Polo, Alessandra Maria Storaci, Ying Huang, Francesca Giunchi, Patricia A. Sheridan, Gregory Michelotti, Quang-De Nguyen, Xin Zhao, Yang Liu, Elai Davicioni, Daniel E. Spratt, Simone Sabbioneda, Giovanni Maga, Lorelei A. Mucci, Claudia Ghigna, Luigi Marchionni, Lisa M. Butler, Leigh Ellis, François Bordeleau, Massimo Loda, Valentina Vaira, David P. Labbé, Giorgia Zadra
Journal: Cancer Research (2024)

Abstract Cancer cells exhibit metabolic plasticity to meet oncogene-driven dependencies while coping with nutrient availability. A better understanding of how systemic metabolism impacts the accumulation of metabolites that reprogram the tumor microenvironment (TME) and drive cancer could facilitate development of precision nutrition approaches. Using the Hi-MYC prostate cancer mouse model, we demonstrated that an obesogenic high-fat diet (HFD) rich in saturated fats accelerates the development of c-MYC–driven invasive prostate cancer through metabolic rewiring. Although c-MYC modulated key metabolic pathways, interaction with an obesogenic HFD was necessary to induce glycolysis and lactate accumulation in tumors. These metabolic changes were associated with augmented infiltration of CD206+ and PD-L1+ tumor-associated macrophages (TAM) and FOXP3+ regulatory T cells, as well as with the activation of transcriptional programs linked to disease progression and therapy resistance. Lactate itself also stimulated neoangiogenesis and prostate cancer cell migration, which were significantly reduced following treatment with the lactate dehydrogenase inhibitor FX11. In patients with prostate cancer, high saturated fat intake and increased body mass index were associated with tumor glycolytic features that promote the infiltration of M2-like TAMs. Finally, upregulation of lactate dehydrogenase, indicative of a lactagenic phenotype, was associated with a shorter time to biochemical recurrence in independent clinical cohorts. This work identifies cooperation between genetic drivers and systemic metabolism to hijack the TME and promote prostate cancer progression through oncometabolite accumulation. This sets the stage for the assessment of lactate as a prognostic biomarker and supports strategies of dietary intervention and direct lactagenesis blockade in treating advanced prostate cancer. Significance: Lactate accumulation driven by high-fat diet and MYC reprograms the tumor microenvironment and promotes prostate cancer progression, supporting the potential of lactate as a biomarker and therapeutic target in prostate cancer. See related commentary by Frigo, p. 1742
A Hypoxia-Epigenetics Axis Drives EMT in Pancreatic Cancer
Authors: Matthias Wirth, Günter Schneider
Journal: Cancer Research (2024)

Epithelial-to-mesenchymal transition (EMT) is a classical cellular plasticity process induced by various cell-intrinsic and -extrinsic triggers. Although prominent factors, such as TGFβ, mediate EMT via well-characterized pathways, alternative avenues are less well understood. Transcriptomic subtyping of pancreatic ductal adenocarcinoma (PDAC) has demonstrated that basal-like PDACs enrich a mesenchymal-like expression program, emphasizing the relevance of EMT in the disease. In this issue of Cancer Research, Brown and colleagues demonstrate the tight connection of EMT to hypoxia. Through a detailed mechanistic analysis, the authors deciphered that hypoxia-induced signals are integrated by the histone H3 lysine 36 di-methylation (H3K36me2) mark. On the one hand, hypoxia decreased activity of the H3K36me2 eraser KDM2A, while on the other hand promoting stabilization of the H3K36me2 writer NSD2. Hypoxia diminished the expression of a set of serine-threonine phosphatases, subsequently resulting in SRC kinase family-dependent activation of canonical MEK, ERK, and JNK signaling to impinge on NSD2 expression. In addition, reduced expression of the protein phosphatase PP2Cδ was linked to increased NSD2 protein expression. These discoveries illuminate the close relationship of hypoxia signaling to the epigenetic machinery and cellular plasticity processes. See related article by Brown et al., p. 1764.
The Fe-S cluster biosynthesis in <i>Enterococcus faecium</i> is essential for anaerobic growth and gastrointestinal colonization
Authors: Linan Xu, Yajing Wu, Xiangpeng Yang, Xinxin Pang, Yansha Wu, Xingshuai Li, Xiayu Liu, Yuzhong Zhao, Lumin Yu, Peikun Wang, Bin Ye, Shijin Jiang, Junfei Ma, Xinglin Zhang
Journal: Gut Microbes (2024)

The facultative anaerobic Gram-positive bacterium
Disturbance in cerebral blood microcirculation and hypoxic-ischemic microenvironment are associated with the development of brain metastasis
Authors: Jenny Roesler, Daniel Spitzer, Xiaoxiong Jia, Synnøve Nymark Aasen, Kathleen Sommer, Bastian Roller, Niels Olshausen, Nils R Hebach, Nawid Albinger, Evelyn Ullrich, Ling Zhu, Fan Wang, Jadranka Macas, Marie-Therese Forster, Joachim P Steinbach, Lisa Sevenich, Kavi Devraj, Frits Thorsen, Matthia A Karreman, Karl H Plate, Yvonne Reiss, Patrick N Harter
Journal: Neuro-Oncology (2024)

Abstract Background Brain metastases (BM) constitute an increasing challenge in oncology due to their impact on neurological function, limited treatment options, and poor prognosis. BM occurs through extravasation of circulating tumor cells across the blood-brain barrier. However, the extravasation processes are still poorly understood. We here propose a brain colonization process which mimics infarction-like microenvironmental reactions, that are dependent on Angiopoietin-2 (Ang-2) and vascular endothelial growth factor (VEGF). Methods In this study, intracardiac BM models were used, and cerebral blood microcirculation was monitored by 2-photon microscopy through a cranial window. BM formation was observed using cranial magnetic resonance, bioluminescent imaging, and postmortem autopsy. Ang-2/VEGF targeting strategies and Ang-2 gain-of-function (GOF) mice were employed to interfere with BM formation. In addition, vascular and stromal factors as well as clinical outcomes were analyzed in BM patients. Results Blood vessel occlusions by cancer cells were detected, accompanied by significant disturbances of cerebral blood microcirculation, and focal stroke-like histological signs. Cerebral endothelial cells showed an elevated Ang-2 expression both in mouse and human BM. Ang-2 GOF resulted in an increased BM burden. Combined anti-Ang-2/anti-VEGF therapy led to a decrease in brain metastasis size and number. Ang-2 expression in tumor vessels of established human BM negatively correlated with survival. Conclusions Our observations revealed a relationship between disturbance of cerebral blood microcirculation and brain metastasis formation. This suggests that vessel occlusion by tumor cells facilitates brain metastatic extravasation and seeding, while combined inhibition of microenvironmental effects of Ang-2 and VEGF prevents the outgrowth of macrometastases.
Forecasting the Burden of Cardiovascular Disease and Stroke in the United States Through 2050—Prevalence of Risk Factors and Disease: A Presidential Advisory From the American Heart Association
Authors: Karen E. Joynt Maddox, Mitchell S.V. Elkind, Hugo J. Aparicio, Yvonne Commodore-Mensah, Sarah D. de Ferranti, William N. Dowd, Adrian F. Hernandez, Olga Khavjou, Erin D. Michos, Latha Palaniappan, Joanne Penko, Remy Poudel, Véronique L. Roger, Dhruv S. Kazi
Journal: Circulation (2024)

BACKGROUND: Cardiovascular disease and stroke are common and costly, and their prevalence is rising. Forecasts on the prevalence of risk factors and clinical events are crucial. METHODS: Using the 2015 to March 2020 National Health and Nutrition Examination Survey and 2015 to 2019 Medical Expenditure Panel Survey, we estimated trends in prevalence for cardiovascular risk factors based on adverse levels of Life’s Essential 8 and clinical cardiovascular disease and stroke. We projected through 2050, overall and by age and race and ethnicity, accounting for changes in disease prevalence and demographics. RESULTS: We estimate that among adults, prevalence of hypertension will increase from 51.2% in 2020 to 61.0% in 2050. Diabetes (16.3% to 26.8%) and obesity (43.1% to 60.6%) will increase, whereas hypercholesterolemia will decline (45.8% to 24.0%). The prevalences of poor diet, inadequate physical activity, and smoking are estimated to improve over time, whereas inadequate sleep will worsen. Prevalences of coronary disease (7.8% to 9.2%), heart failure (2.7% to 3.8%), stroke (3.9% to 6.4%), atrial fibrillation (1.7% to 2.4%), and total cardiovascular disease (11.3% to 15.0%) will rise. Clinical CVD will affect 45 million adults, and CVD including hypertension will affect more than 184 million adults by 2050 (&gt;61%). Similar trends are projected in children. Most adverse trends are projected to be worse among people identifying as American Indian/Alaska Native or multiracial, Black, or Hispanic. CONCLUSIONS: The prevalence of many cardiovascular risk factors and most established diseases will increase over the next 30 years. Clinical and public health interventions are needed to effectively manage, stem, and even reverse these adverse trends.
ARC-9: A randomized study to evaluate etrumadenant based treatment combinations in previously treated metastatic colorectal cancer (mCRC).
Authors: Zev A. Wainberg, Sae-Won Han, Soohyeon Lee, Keun-Wook Lee, Scott Kopetz, Jonathan Mizrahi, Yong Sang Hong, François Ghiringhelli, Antoine Italiano, David Tougeron, Brandon Beagle, Mathew Boakye, Tingting Zhao, Joon Rhee, Dimitry S. A. Nuyten, Michael Cecchini
Journal: Journal of Clinical Oncology (2024)

3508 Background: Adenosine mediated signaling via A 2a and A 2b receptors impairs activation, proliferation, and cytotoxic activity of effector T cells resulting in inhibition of antitumor activity. Adenosine receptor blockade may therefore enhance therapeutic efficacy of chemo/immunotherapy regimens. Etrumadenant (E) is an orally bioavailable, selective, A 2a and A 2b receptor antagonist that has demonstrated safety and clinical activity in solid tumors when combined with chemo/immunotherapy. ARC-9 (NCT04660812), a Phase Ib/II trial evaluating the safety and efficacy of E combined with zimberelimab (Z) (anti-PD-1 antibody), and FOLFOX/bevacizumab (bev) regimens or novel therapies in 3 cohorts of patients (pts) with mCRC. While FOLFOX rechallenge is frequently used in the management of mCRC, no prospective trials have been performed to date. Methods: Cohort B enrolled pts who previously progressed on both oxaliplatin and irinotecan containing regimens.Pts were randomized 2:1 to EZFB: E (150 mg orally [PO] once daily [QD]) + Z (240 mg intravenous [IV] once every 2 weeks [Q2W]) + mFOLFOX-6 + bev (5 mg/kg IV Q2W), or regorafenib (rego) (160 mg PO QD [days 1-21 every 4 weeks]). Pts who progressed on rego were allowed to crossover to EZFB. The primary endpoint is progression-free survival (PFS) per RECIST 1.1 and overall survival (OS) is a key secondary endpoint. Results: In Cohort B, 112 pts were randomized. Baseline characteristics are comparable between arms. As of 13 Nov 2023, with median follow-up of 20.4 months (mo), EZFB demonstrated statistically significant improvement in PFS (HR 0.27, 95% CI 0.17-0.43, p &lt; 0.0001) and OS (HR 0.37, 95% CI 0.22-0.63, p = 0.0003) vs rego (Table). EZFB had an acceptable safety profile, consistent with the known FOLFOX/bev toxicity profile with no deaths related to study treatment in either arm. Conclusions: In this randomized phase II clinical trial, EZFBsignificantlyimproved efficacy outcomes compared to rego in refractory mCRC pts previously treated with 5-FU, oxaliplatin and irinotecan regimens with no unexpected toxicities. Further investigation of this promising regimen is warranted given the clinically meaningful PFS and OS improvement. Table Clinical trial information: NCT04660812 . [Table: see text]
The NAVigate-HPV Registry: A comprehensive biomarker evidence base for HPV-driven cancers.
Authors: Scott Roof, Glenn J. Hanna, Eleni M. Rettig, David M. Routman, Floyd Christopher Holsinger, Noah Kalman, Aarti K. Bhatia, Mihir R. Patel, Jamie Jabalee, Sue S. Yom, Sujith Baliga, Adam Raben, John Sims, John M. Kaczmar, Mihir K Bhayani, Barry Berger, Catherine Del Vecchio Fitz
Journal: Journal of Clinical Oncology (2024)

e15045 Background: Human papillomavirus (HPV) is an oncogenic driver of several human cancers, including those of the anal canal, uterine cervix, and head and neck (predominantly oropharynx). Despite advancements in our understanding of HPV-related cancers, there remains an unmet need for a comprehensive biomarker-driven registry to establish correlations between biomarker detectability and clinicopathologic features in patients diagnosed and treated for HPV-driven cancers. To address this need, the NAVigate-HPV Registry has been established to systematically collect and analyze integrated biomarker and clinical data from many U.S. cancer centers. Methods: NavDx (Naveris, Inc.) is a clinically validated blood-based assay detecting circulating cell-free tumor tissue modified viral (TTMV)-HPV DNA. The NAVigate-HPV Registry is a web-based data platform based on a centrally IRB approved protocol. Participating investigators will include providers that order NavDx tests in the routine clinical care of their patients and agree to the terms and conditions for use of the registry. Eligible subjects will have or have had an HPV-driven cancer (with an initial focus on HPV-driven oropharynx cancer with confirmatory tissue testing) and have received one or more NavDx blood tests during routine clinical care. Clinical data and TTMV-HPV DNA scores will be collected at enrollment and defined intervals over five years or until death. Results: In the initial phase, the registry has enlisted participation and established a steering committee composed of a representative from each of 14 institutions. These institutions are geographically diverse centers ranging from community hospitals to clinics and academic medical facilities. An IRB protocol governing the registry will maintain ethical standards, ensuring compliance and ethical conduct throughout the registry process. Data extraction methods have been previously established to evaluate an initial cohort of 543 patients (Hanna GJ, Roof SA, et. al 2023). Conclusions: Naveris and collaborators have together successfully launched the NAVigate-HPV registry with the aim of creating a robust database linking tumor biomarker results from NavDx with clinical outcomes data for HPV-related cancers. The NAVigate-HPV database is expected to encompass more than 1,000 patients within 1 year and grow to &gt; 5,000 patients within 5 years, serving as a powerful tool for precision cancer medicine in this patient cancer population. Establishing this registry will deepen insights into HPV-related cancers and advance diagnostic and therapeutic approaches to improve patient outcomes.