tbuckley/cabot-search huggingface dataset:
Developing targeted therapies for neuroblastoma by dissecting the effects of metabolic reprogramming on tumor microenvironments and progression
Authors: Wenyi Jin, Yubiao Zhang, Zhijie Zhao, Mingyong Gao
Journal: Theranostics (2024)

Rationale: Synergic reprogramming of metabolic dominates neuroblastoma (NB) progression.It is of great clinical implications to develop an individualized risk prognostication approach with stratification-guided therapeutic options for NB based on elucidating molecular mechanisms of metabolic reprogramming.Methods: With a machine learning-based multi-step program, the synergic mechanisms of metabolic reprogramming-driven malignant progression of NB were elucidated at single-cell and metabolite flux dimensions.Subsequently, a promising metabolic reprogramming-associated prognostic signature (MPS) and individualized therapeutic approaches based on MPS-stratification were developed and further validated independently using pre-clinical models.Results: MPS-identified MPS-I NB showed significantly higher activity of metabolic reprogramming than MPS-II counterparts.MPS demonstrated improved accuracy compared to current clinical characteristics [AUC: 0.915 vs. 0.657 (MYCN), 0.713 (INSS-stage), and 0.808 (INRG-stratification)] in predicting prognosis.AZD7762 and etoposide were identified as potent therapeutics against MPS-I and II NB, respectively.Subsequent biological tests revealed AZD7762 substantially inhibited growth, migration, and invasion of MPS-I NB cells, more effectively than that of MPS-II cells.Conversely, etoposide had better therapeutic effects on MPS-II NB cells.More encouragingly, AZD7762 and etoposide significantly inhibited in-vivo subcutaneous tumorigenesis, proliferation, and pulmonary metastasis in MPS-I and MPS-II samples, respectively; thereby prolonging survival of tumor-bearing mice.Mechanistically, AZD7762 and etoposide-induced apoptosis of the MPS-I and MPS-II cells, respectively, through mitochondria-dependent pathways; and MPS-I NB resisted etoposide-induced apoptosis by addiction of glutamate metabolism and acetyl coenzyme A. MPS-I NB progression was fueled by multiple metabolic reprogramming-driven factors including multidrug resistance, immunosuppressive and tumor-promoting inflammatory microenvironments.Immunologically, MPS-I NB suppressed immune cells via MIF and THBS signaling pathways.Metabolically, the malignant proliferation of MPS-I NB cells was remarkably supported by reprogrammed glutamate metabolism, tricarboxylic acid cycle, urea cycle, etc.Furthermore, MPS-I NB cells manifested a distinct tumor-promoting developmental lineage and self-communication patterns, as evidenced by enhanced oncogenic signaling pathways activated with development and self-communications.Conclusions: This study provides deep insights into the molecular mechanisms underlying metabolic reprogramming-mediated malignant progression of NB.It also sheds light on developing targeted medications guided by the novel precise risk prognostication approaches, which could contribute to a significantly improved therapeutic strategy for NB.
Testing patterns and prevalence of <i>PIK3CA</i>, <i>AKT1</i>, and <i>PTEN</i> alterations among patients (pts) with HR+/HER2- metastatic breast cancer (mBC) in the US.
Authors: Leah Park, Samantha L Thompson, James Roose, Yichen Lu, Moumita Chaki, Clara Lam, Bryan Iorgulescu
Journal: Journal of Clinical Oncology (2024)

1041 Background: Biomarkers play an essential role to inform treatment decisions in mBC. In hormone receptor positive/HER2 negative (HR+/HER2-) mBC, PIK3CA/AKT1/PTEN alterations are now actionable as pt selection biomarkers with the FDA’s Nov 2023 approval of the pan-AKT inhibitor capivasertib. Here we investigate the testing patterns and prevalence of PIK3CA/AKT1/PTEN alterations in mBC. Methods: This retrospective cohort study used two partially overlapping nationwide de-identified databases: the Flatiron Health electronic health record-derived database (FH DB) to assess next-generation sequencing (NGS) testing rates, and the Flatiron Health-Foundation Medicine clinico-genomic database (FH-FMI CGDB) to assess prevalence among tested. Pts were included if they were ≥18 years old and diagnosed with HR+/HER2- mBC from 1/1/17—6/30/22. Prevalence was assessed using any sample type or timing of testing post-mBC diagnosis and defined as pathogenic/likely pathogenic alterations as captured in FMI NGS testing. All analyses were summarized using descriptive statistics. Results: 8,049 (FH DB) and 2,912 (FH-FMI CGDB) pts were eligible. Overall, 37% of pts with mBC received NGS testing (3,002/8,049). Among pts in FH-FMI CGDB, 98% had PIK3CA tested (2,857/2,912) and 97% also had AKT1/PTEN tested (2,838/2,912) in the metastatic setting. The median time from mBC diagnosis to initial test was 148 days for PIK3CA and 188 days for AKT1/PTEN, and 92-93% of testing occurred after the start of first-line (1L) therapy (Table). 82% of PIK3CA testing was on tissue and 37% on liquid biopsy, with 19% of pts receiving both tissue and liquid biopsy. 77% of AKT1/PTEN testing was on tissue and 28% on liquid biopsy, with 5% of pts receiving both tissue and liquid biopsy. At least one PIK3CA/ AKT1/ PTEN alteration was detected in 55% of the pts (1,557/2857) tested for any of the markers, regardless of sample type. Conclusions: &lt;40% of pts with mBC received NGS testing from 2017-2021, suggesting opportunities for improving pts’ access to testing. Coupled with the high rate of PIK3CA/AKT1/PTEN alterations, NGS testing should be incorporated in routine clinical practice to identify optimal treatments. [Table: see text]
Racial disparities in the immunotherapeutic outcomes of patients with non-small cell lung cancer (NSCLC): An in-depth systematic review and meta-analysis.
Authors: Chalothorn Wannaphut, Sakditad Saowapa, Natchaya Polpichai, Phuuwadith Wattanachayakul, Pakin Lalitnithi, Manasawee Tanariyakul, Pharit Siladech
Journal: Journal of Clinical Oncology (2024)

1579 Background: The utilization of immunotherapy has become prevalent in the therapeutic approach to non-small cell lung cancer (NSCLC), owing to its association with enhanced survival outcomes. Nevertheless, a notable gap exists in the available information regarding potential variations in the survival benefits of immunotherapy based on the racial demographics of NSCLC patients. Methods: A systematic search for articles published until January 2023 was performed on PubMed, EMBASE, and Google Scholar databases. Articles that aligned with the research objective were included, while non-English articles, case reports, conference abstracts, studies combining immunotherapy with other cancer therapies, and studies on small-cell lung cancer were excluded. Data required for review and analysis was independently abstracted into separate Excel files by two reviewers. Furthermore, Statistical analyses were performed using the Review Manager software, and the methodological quality evaluation was done using the Newcastle Ottawa Scale. Results: Seven cohort studies were used for review and analysis. A subgroup analysis of data from these studies showed that Black/African American and Asian NSCLC patients receiving immunotherapy had improved overall survival (OS) than White patients (HR: 0.84; 95% CI: 0.75 – 0.95; p = 0.006 and HR: 0.53; 95% CI: 0.30 – 0.93; p = 0.03, respectively). However, the difference in OS is statistically insignificant when Hispanic patients are compared with white patients (HR: 0.68; 95% CI: 0.46 – 1.00; p = 0.05). On the other hand, the subgroup analyses did not demonstrate any significant difference in progression-free survival (PFS) when comparing Black/African American, Asian or Hispanic patients to White patients (HR: 0.93; 95% CI: 0.79 – 1.09; p = 0.35, HR: 0.89; 95% CI: 0.51 – 1.55; p = 0.69, and HR: 1.01; 95% CI: 0.82 – 1.23; p = 0.96, respectively). Conclusions: Among non-small cell lung cancer (NSCLC) patients undergoing immunotherapeutic interventions, it is discerned that Black/African American and Asian individuals exhibit superior overall survival (OS) outcomes compared to their White counterparts. However, it is noteworthy that the observed racial disparity does not appear to exert a discernible influence on the progression-free survival (PFS) of NSCLC patients subjected to immunotherapy.
The associations between poorer pain-related health status and increased hospitalisations and excess mortality in patients with rheumatoid arthritis (RA): a prospective cohort analysis using the Australian Rheumatology Association Database (ARAD)
Authors: Huai Leng Pisaniello, Susan Elizabeth Lester, Oscar Russell, Rachel Black, Joanna Tieu, Bethan Richards, Claire Barrett, Marissa Lassere, Lyn March, Rachelle Buchbinder, Catherine Hill, Samuel Lawrance Whittle
Journal: Annals of the Rheumatic Diseases (2024)
Comparative analysis of Keynote522 treatment outcomes in Hispanic versus non-Hispanic patients with breast cancer: A single tertiary center experience.
Authors: Ranjit Singh Banwait, Sarah Shaker, Aditi Sharma, Jay Parekh, Marcela Mazo- Canola
Journal: Journal of Clinical Oncology (2024)

e12661 Background: The addition of pembrolizumab to neoadjuvant chemotherapy on the Keynote522 (KN522) clinical trial, changed the standard of care for early stage triple negative breast cancer (TNBC). This regimen demonstrated longer event free survival and higher percentage of patients with pathologic complete responses (pCR). However, limited data exist on the comparative outcomes between Hispanic and non-Hispanic patients in real-world settings as this patient population was likely underrepresented on the original trial. Methods: We conducted a retrospective analysis of patients with early stage TNBC treated on KN522 regimen and undergoing surgery at a single tertiary center from July 2021 to present. Patients were stratified into Hispanic and non-Hispanic ethnicity cohorts. The primary endpoint was pCR rate, and secondary endpoints was incidence of adverse effects (AEs). Results: Among a cohort of 41 patients identified, 26 (63%) were of Hispanic and 15 (37%) were non-Hispanic. The pCR rate was 50% among Hispanic and 53% among non-Hispanic patients (p=0.83). Hispanic patients experienced higher rates of anemia (88% vs. 67%, p=0.06), fatigue (85% vs. 60%, p=0.07), skin rash (46% vs. 27%, p=0.21), and endocrine toxicities (23% vs. 13%, p=0.21). However, Hispanic patient also had fewer hospitalizations (35% vs. 47%, p=0.44), dose-modifications (12% vs. 40%, p=0.53), dose omissions (19% vs. 33%, p=0.31), and showed higher KN522 completion rates (81% vs. 53%, p=0.06). Conclusions: Our findings indicate a comparable pCR rate between Hispanic and non-Hispanic patients with early-stage TNBC receiving KN522 therapy. While Hispanic patients exhibited higher incidences of certain adverse effects, they demonstrated lower rates of hospitalizations, dose modifications, and omissions, alongside a notably higher completion rate of the KN522 regimen. These trends may be attributed to various factors such as genetic predispositions, and potentially differential physiological responses to therapy within this ethnic group. These findings underscore the importance of including minorities, such as Hispanic patients, in clinical trial populations to ensure that treatment outcomes are representative of diverse patient demographics. [Table: see text]
Airway IL-1β is related to disease severity and mucociliary function in bronchiectasis
Authors: Lidia Perea, Mathieu Bottier, Erin Cant, Hollian Richardson, Alison J. Dicker, Morven Shuttleworth, Yan Hui Giam, Hani Abo-Leyah, Simon Finch, Jeffrey T-J. Huang, Michal Shteinberg, Pieter C. Goeminne, Eva Polverino, Josje Altenburg, Francesco Blasi, Tobias Welte, Stefano Aliberti, Oriol Sibila, James D. Chalmers, Amelia Shoemark
Journal: European Respiratory Journal (2024)

Rationale The inflammasome is a key regulatory complex of the inflammatory response leading to interleukin-1β (IL-1β) release and activation. IL-1β amplifies inflammatory responses and induces mucus secretion and hyperconcentration in other diseases. The role of IL-1β in bronchiectasis has not been investigated. Objectives To characterise the role of airway IL-1β in bronchiectasis, including the association with mucus properties, ciliary function, airway inflammation, microbiome and disease severity. Methods Stable bronchiectasis patients were enrolled in an international cohort study (n=269). IL-1β was measured in sputum supernatant. A validation cohort also had sputum rheology and hydration measured (n=53). For analysis, patients were stratified according to the median value of IL-1β in the population (high versus low) to compare disease severity, airway infection, microbiome (16S rRNA sequencing), inflammation and caspase-1 activity. Primary human nasal epithelial cells grown in air–liquid interface culture were used to study the effect of IL-1β on cilia function. Results Patients with high sputum IL-1β had more severe disease, increased caspase-1 activity and an increased T-helper type 1, T-helper type 2 and neutrophil inflammatory response compared with patients with low IL-1β. The active-dominant form of IL-1β was associated with increased disease severity. High IL-1β was related to higher relative abundance of Proteobacteria in the microbiome and increased mucus solid content and viscoelastic properties. Chronic IL-1β treatment reduced the functionality of cilia and tight junctions of epithelial cells in vitro . Conclusions A subset of stable bronchiectasis patients show increased airway IL-1β, suggesting pulmonary inflammasome activation is linked with more severe disease, airway infection, mucus dehydration and epithelial dysfunction.
Inhaled treprostinil in pulmonary hypertension associated with COPD: PERFECT study results
Authors: Steven D. Nathan, Rahul Argula, Maria G. Trivieri, Sameh Aziz, Elizabeth Gay, Boris Medarov, Joseph Parambil, Amresh Raina, Michael G. Risbano, Thenappan Thenappan, Jose Soto Soto, Heidi Bell, Victoria Lacasse, Prakash Sista, Michael Di Marino, Aimee Smart, Brittanie Hawkes, Elizabeth Nelson, Todd Bull, Victor Tapson, Aaron Waxman
Journal: European Respiratory Journal (2024)

Background Pulmonary hypertension (PH) accompanying COPD (PH-COPD) is associated with worse outcomes than COPD alone. There are currently no approved therapies to treat PH-COPD. The PERFECT study ( ClinicalTrials.gov : NCT03496623 ) evaluated the safety and efficacy of inhaled treprostinil (iTRE) in this patient population. Methods Patients with PH-COPD (mean pulmonary arterial pressure ≥30 mmHg and pulmonary vascular resistance ≥4 WU) were enrolled in a multicentre, randomised (1:1), double-blind, placebo-controlled, 12-week, crossover study. A contingent parallel design was also prespecified and implemented, based on a blinded interim analysis of missing data. Patients received treatment with iTRE up to 12 breaths (72 µg) 4 times daily or placebo. The primary efficacy end-point was change in peak 6-min walk distance (6MWD) at week 12. Results In total, 76 patients were randomised, 64 in the original crossover design and 12 in the contingent parallel design; 66 patients received iTRE and 58 received placebo. The study was terminated early at the recommendation of the data and safety monitoring committee based on the totality of evidence that iTRE increased the risk of serious adverse events and suggestive evidence of an increased risk of mortality. The change in 6MWD was numerically worse with iTRE exposure than with placebo exposure. Conclusions The risk–benefit observations associated with iTRE in patients with PH-COPD did not support continuation of the PERFECT study. The results of this study do not support iTRE as a viable treatment option in patients with PH-COPD.
Radiogenomics of homologous recombination deficiency (HRD) in breast cancer: Radiomics-based image biomarker for HRD.
Authors: Joonoh Lim, Pill Sun Paik, Jeongmin Lee, Brian Baek-Lok Oh, Ryul Kim, Young Seok Ju, Jeong Seok Lee, Minsuk Kwon, Sangmoon Lee, Won-Chul Lee
Journal: Journal of Clinical Oncology (2024)

554 Background: Homologous recombination deficiency (HRD) in breast cancer is an actionable target, with treatment efficacy potentially linked to timely detection. Notably, BRCA1 and BRCA2 are key genes implicated in HRD, and their pathogenic germline mutations are crucial criteria for the use of poly (ADP-ribose) polymerase inhibitors (PARPi). Although germline BRCA1/2 mutations are detectable in only a small fraction (1-5%) of breast cancers, recent whole-genome sequencing (WGS) studies have revealed that up to 22% of breast cancers also exhibit HRD-like genomic characteristics, suggesting a broader potential for HRD-targeted therapy. This has spurred the development of genomic-feature-based HRD identification methods. However, the invasive and costly nature of these methods poses a challenge. This has prompted our investigation into non-invasive image biomarkers for HRD identification. Methods: Invasive breast cancer patients were recruited from March 2021 to August 2022. Eligibility criteria included availability of fresh-frozen tumor tissue for WGS and suitability for dynamic contrast-enhanced (DCE) MRI to facilitate radiomics analysis. The association between HRD and radiomic features as well as clinicopathologic factors was investigated through rigorous genomic and statistical analysis. Results: This study encompassed 145 patients aged 20 to 69 years, of whom 16.6% (24 out of 145) were genomically identified as HRD. All patients harboring pathogenic germline mutations in BRCA1 (n=3) or BRCA2 (n=2), along with concomitant somatic LOH, exhibited HRD. A comprehensive analysis of 214 radiomic features revealed that tumor sphericity, informational measure of correlation 1 (IMC1), size-zone non-uniformity normalized (SZNN), and small area emphasis (SAE) derived from subtracted early dynamic T1-weighted imaging were significantly correlated with HRD. Moreover, these radiomic features demonstrated substantial diagnostic value, as evidenced by their ROC-AUC and PR-AUC performance against baseline models: Sphericity (ROC: 0.62, p=0.055; PR: 0.22, p=0.053), SAE (ROC: 0.63, p=0.052; PR: 0.32, p=0.007), SZNN (ROC: 0.63, p=0.04; PR: 0.30, p=0.007), and IMC1 (ROC: 0.62, p=0.067; PR: 0.29, p=0.02). Additionally, our findings suggest that these radiomic features are more directly related to HRD than to the triple-negative phenotype, which is commonly linked to HRD. Conclusions: We found that four radiomic features from MRI have significant predictive value for identifying HRD in breast cancer. Given their fair predictability and immediate availability, these features are ideally suited for a screening approach, potentially identifying more patients eligible for targeted treatment. This finding represents a significant advancement in the fields of radiology and precision oncology, opening new avenues for patient-specific treatment strategies.
Nectin-4 expression in primary breast cancer and associated clinical outcomes.
Authors: Arielle J Medford, Andrzej Niemierko, Rachel Occhiogrosso Abelman, Nicholas Haradhvala, Justine Knape, Laura Spring, Gad Getz, Aditya Bardia
Journal: Journal of Clinical Oncology (2024)

570 Background: Antibody-drug conjugates (ADC) selectively deliver chemotherapy to tumor cells expressing a target antigen. Currently approved ADCs in breast cancer target HER2 or Trop-2. Enfortumab vedotin, an ADC targeting Nectin-4, a cell adhesion molecule, is approved in advanced/metastatic urothelial cancer. This study evaluated the expression landscape of Nectin-4 in breast cancer and its association with clinical outcomes. Methods: Processed mRNAseq data was assessed for expression of the gene encoding Nectin-4 in primary breast cancer tissue and adjacent normal breast tissue from The Cancer Genome Atlas (TCGA), and normal tissue from the Genotype-Tissue Expression (GTEx) Project. Low gene expression was determined as &lt;100 transcripts per million (TPM). TCGA samples had been annotated for putative copy-number alterations using GISTIC 2.0; genes with a score of 2 were marked as amplified. Multivariable Cox regression analysis was used to analyze the association of low vs medium/high gene expression with disease-free survival (DFS) and overall survival (OS), adjusting for age, stage, and subtype. Results: RNA-Seq data was available for 1086 patients with primary breast cancer, including known hormone receptor positive (HR+)/HER2- (n=530), HER2+ (n=112), and triple negative breast cancer (TNBC) (n=120). NECTIN4was amplified in 15% of cases (n=165): 15% (n=78) in HR+, 15% (n=17) in HER2+ and 21% (n=25) in TNBC. NECTIN4 expression was medium/high in 356 (33%) patients: 149 (28%) HR+/HER2- (median 77.8 TPM, IQR 50.1-116.5), 32 (29%) HER2+ (median 73.7 TPM, IQR 51.9-107.8), and 59 (49%) TNBC (median 99.7 TPM, IQR 57.8-148.3). Median expression in normal breast tissue was 47 TPM (TCGA) &amp; 16.74 TPM (GTEx), and highest in normal skin at 205 TPM. In multivariable analysis, medium/high NECTIN4 expression was associated with worse OS (HR 1.96, 95% CI 1.32-2.99, p&lt;0.001). As a continuous variable, increasing NECTIN4 expression levels were associated with worse OS. After correcting for age, stage and subtype, for each 10-unit increase in NECTIN4TPM, the risk of death increased by 5% (HR 1.0050, 95% CI 1.0028 - 1.0072, p &lt; 0.001). Conclusions: NECTIN4 expression was higher in TNBC and associated with worse overall survival. The high expression level in normal skin possibly contributes to the cutaneous toxicity associated with enfortumab vedotin approval and requires careful consideration as ADCs targeting Nectin-4 are developed to target breast cancer.
Liver Transplant Costs and Activity After United Network for Organ Sharing Allocation Policy Changes
Authors: Ola Ahmed, Maria Bernadette Majella Doyle, Marwan S. Abouljoud, Diane Alonso, Ramesh Batra, Kenneth L. Brayman, Diane Brockmeier, Robert M. Cannon, Kenneth Chavin, Aaron M. Delman, Derek A. DuBay, Jan Finn, Jonathan A. Fridell, Barry S. Friedman, Danielle M. Fritze, Derek Ginos, David S. Goldberg, Glenn A. Halff, Seth J. Karp, Vivek K. Kohli, Sean C. Kumer, Alan Langnas, Jayme E. Locke, Daniel Maluf, Raphael P. H. Meier, Alejandro Mejia, Shaheed Merani, David C. Mulligan, Bobby Nibuhanupudy, Madhukar S. Patel, Shawn J. Pelletier, Shimul A. Shah, Parsia A. Vagefi, Rodrigo Vianna, Gazi B. Zibari, Teresa J. Shafer, Susan L. Orloff
Journal: JAMA Surgery (2024)

A new liver allocation policy was implemented by United Network for Organ Sharing (UNOS) in February 2020 with the stated intent of improving access to liver transplant (LT). There are growing concerns nationally regarding the implications this new system may have on LT costs, as well as access to a chance for LT, which have not been captured at a multicenter level.
Isotretinoin for Acne in Transgender and Gender-Diverse Individuals Receiving Masculinizing Hormone Therapy
Authors: James Choe, Ali Shields, Alana Ferreira, Sarah Gold, Jeromy W. Gotschall, Kanika Kamal, Austin Rios, Robin H. Wang, Emily Baumrin, Erica D. Dommasch, Howa Yeung, Jules B. Lipoff, John S. Barbieri
Journal: JAMA Dermatology (2024)

Masculinizing gender-affirming hormonal therapy is associated with the development of acne. While isotretinoin is a highly effective acne treatment, little is known about its effectiveness and safety among transgender and gender-diverse individuals receiving gender-affirming hormonal therapy.
Menstruation as the Next Vital Sign
Authors: Lauren C. Houghton
Journal: JAMA Network Open (2024)

Zifan Wang, PhD, MS; Gowtham Asokan, MS; Jukka-Pekka Onnela, DSc; Donna D. Baird, PhD; Anne Marie Z. Jukic, PhD, MSPH; Allen J. Wilcox, MD, PhD; Christine L. Curry, MD, PhD; Tyler Fischer-Colbrie, MBA; Michelle A. Williams, ScD; Russ Hauser, MD, ScD, MPH; Brent A. Coull, PhD; Shruthi Mahalingaiah, MD, MS