tbuckley/cabot-search huggingface dataset:
Efficacy and safety of deuruxolitinib, an oral selective Janus kinase inhibitor, in adults with alopecia areata: Results from the Phase 3 randomized, controlled trial (THRIVE-AA1)
Authors: Brett King, Maryanne M. Senna, Natasha A. Mesinkovska, Charles Lynde, Matthew Zirwas, Catherine Maari, Vimal H. Prajapati, Sheetal Sapra, Pawel Brzewski, Lawrence Osman, Sameh Hanna, Marni C. Wiseman, Colleen Hamilton, James Cassella
Journal: Journal of the American Academy of Dermatology (2024)

BackgroundAlopecia areata (AA) is a hair loss disorder that can seriously impact quality of life. Janus kinase (JAK) inhibitors, including deuruxolitinib, have previously demonstrated significant hair regrowth in AA.ObjectiveThe Phase 3 THRIVE-AA1 randomized, double-blinded, placebo-controlled trial (NCT04518995) evaluated the safety and efficacy of the oral JAK1/JAK2 inhibitor deuruxolitinib in adult patients with AA.MethodsPatients aged 18-65 years with ≥50% hair loss were randomized to deuruxolitinib 8 mg twice daily, deuruxolitinib 12 mg twice daily, or placebo for 24 weeks. The primary end point was the percentage of patients achieving a Severity of Alopecia Tool score ≤20. A key secondary end point was the percentage of satisfaction of hair patient-reported outcome responders.ResultsSignificantly higher proportions of patients taking deuruxolitinib met the primary end point (8 mg 29.6%; 12 mg 41.5% versus placebo 0.8%). Both deuruxolitinib doses achieved significant improvements in all secondary end points versus placebo, including satisfaction of hair patient-reported outcome (8 mg 42.1%; 12 mg 53.0% versus placebo 4.7%). Most treatment-emergent adverse events were mild or moderate, consistent with other oral JAK inhibitors.LimitationsFurther studies are required to understand longer-term safety, efficacy, and impact of treatment cessation.ConclusionBoth doses of deuruxolitinib were effective for hair regrowth. Patient satisfaction aligned with hair growth.
Intercellular interaction between FAP+ fibroblasts and CD150+ inflammatory monocytes mediates fibro-stenosis in Crohn’s disease
Authors: Bo-Jun Ke, Saeed Abdurahiman, Francesca Biscu, Gaia Zanella, Gabriele Dragoni, Sneha Santhosh, Veronica De Simone, Anissa Zouzaf, Lies van Baarle, Michelle Stakenborg, Veronika Bosáková, Yentl Van Rymenant, Emile Verhulst, Sare Verstockt, Elliott Klein, Gabriele Bislenghi, Albert Wolthuis, Jan Frič, Christine Breynaert, Andre D’Hoore, Pieter Van der Veken, Ingrid De Meester, Sara Lovisa, Lukas J.A.C. Hawinkels, Bram Verstockt, Gert De Hertogh, Séverine Vermeire, Gianluca Matteoli
Journal: Journal of Clinical Investigation (2024)

Crohn's disease (CD) is marked by recurring intestinal inflammation and tissue injury, often resulting in fibrostenosis and bowel obstruction, necessitating surgical intervention with high recurrence rates. To elucidate the mechanisms underlying fibrostenosis in CD, we analyzed the transcriptome of cells isolated from the transmural ileum of patients with CD, including a trio of lesions from each patient: non-affected, inflamed, and stenotic ileum samples, and compared them with samples from patients without CD. Our computational analysis revealed that profibrotic signals from a subset of monocyte-derived cells expressing CD150 induced a disease-specific fibroblast population, resulting in chronic inflammation and tissue fibrosis. The transcription factor TWIST1 was identified as a key modulator of fibroblast activation and extracellular matrix (ECM) deposition. Genetic and pharmacological inhibition of TWIST1 prevents fibroblast activation, reducing ECM production and collagen deposition. Our findings suggest that the myeloid-stromal axis may offer a promising therapeutic target to prevent fibrostenosis in CD.
Mutant IDH modulates suppressive myeloid populations in malignant glioma
Authors: Eric P. Grewal, Leland G.K. Richardson, Jing Sun, Rishab Ramapriyan, Maria Martinez-Lage, Julie J. Miller, Bob S. Carter, Daniel P. Cahill, William T. Curry, Bryan D. Choi
Journal: Clinical Cancer Research (2024)

Mutations in the isocitrate dehydrogenase (IDH) genes IDH1 and IDH2 have critical diagnostic and prognostic significance in diffuse gliomas. Neomorphic mutant IDH activity has been previously implicated in T-cell suppression; however, the effects of IDH mutations on intratumoral myeloid populations remain underexplored. In this study, we investigate the influence of IDH status on the myeloid compartment using human glioma specimens and preclinical models.
Systemic and skin-limited delayed-type drug hypersensitivity reactions associate with distinct resident and recruited T cell subsets
Authors: Pranali N. Shah, George A. Romar, Artür Manukyan, Wei-Che Ko, Pei-Chen Hsieh, Gustavo A. Velasquez, Elisa M. Schunkert, Xiaopeng Fu, Indira Guleria, Roderick T. Bronson, Kevin Wei, Abigail H. Waldman, Frank R. Vleugels, Marilyn G. Liang, Anita Giobbie-Hurder, Arash Mostaghimi, Birgitta A.R. Schmidt, Victor Barrera, Ruth K. Foreman, Manuel Garber, Sherrie J. Divito
Journal: Journal of Clinical Investigation (2024)

Delayed-type drug hypersensitivity reactions are major causes of morbidity and mortality. The origin, phenotype, and function of pathogenic T cells across the spectrum of severity require investigation. We leveraged recent technical advancements to study skin-resident memory T cells (TRMs) versus recruited T cell subsets in the pathogenesis of severe systemic forms of disease, Stevens-Johnson syndrome/toxic epidermal necrolysis (SJS/TEN) and drug reaction with eosinophilia and systemic symptoms (DRESS), and skin-limited disease, morbilliform drug eruption (MDE). Microscopy, bulk transcriptional profiling, and single-cell RNA-sequencing (scRNA-Seq) plus cellular indexing of transcriptomes and epitopes by sequencing (CITE-Seq) plus T cell receptor sequencing (TCR-Seq) supported clonal expansion and recruitment of cytotoxic CD8+ T cells from circulation into skin along with expanded and nonexpanded cytotoxic CD8+ skin TRM in SJS/TEN. Comparatively, MDE displayed a cytotoxic T cell profile in skin without appreciable expansion and recruitment of cytotoxic CD8+ T cells from circulation, implicating TRMs as potential protagonists in skin-limited disease. Mechanistic interrogation in patients unable to recruit T cells from circulation into skin and in a parallel mouse model supported that skin TRMs were sufficient to mediate MDE. Concomitantly, SJS/TEN displayed a reduced Treg signature compared with MDE. DRESS demonstrated recruitment of cytotoxic CD8+ T cells into skin as in SJS/TEN, yet a pro-Treg signature as in MDE. These findings have important implications for fundamental skin immunology and clinical care.
Study on the efficacy and toxicity of pamiparib combined with tamoxifen in the treatment of patients with epithelial ovarian cancer with biochemical recurrence during first-line PARPi maintenance therapy.
Authors: Yifan Meng, Jundong Li, Ting Wan
Journal: Journal of Clinical Oncology (2024)

TPS5621 Background: A high proportion of ovarian cancer patients tend to have elevated CA-125 1-6 months before imaging recurrence. The time between biochemical recurrence (i.e., only elevated CA-125 without imaging finding or clinical symptoms) to imaging recurrence can be considered a "window period", and if the “window period” can be extended, it may convert platinum-resistant relapsed patients to platinum-sensitive patients, and ultimately improving patient outcomes. The timing of treatment for the biochemical recurrent patients has been controversial. Tamoxifen, an anti-estrogenic drug, is considered an effective option for these patients. Pamiparib (BGB-290) is an investigational small molecule inhibitor of PARP1 and PARP2. According to OReO study(NCT03106987), the "PARPi after PARPi" strategy is effective in recurrent ovarian cancer patients previously treated with a PARP inhibitor. Therefore, we aim to further explore the use of PARP inhibitors in maintenance therapy for patients with ovarian cancer. Methods: This study (NCT05669768) will evaluate the efficacy and toxicity of pamiparib and tamoxifen in ovarian cancer patients with biochemical recurrence during first-line PARPi maintenance therapy. The included ovarian cancer patients are required to achieve No Evidence of Disease (NED) or demonstrated a response following platinum-based chemotherapy, with normalized CA-125 levels. First-line maintenance treatment with a PARP inhibitor is mandatory, with a minimum interval of ≥6 months to biochemical recurrence. The trial design is interventional, employing a Simon two-stage design to estimate sample size. The primary outcome of the study is the CA-125 response rate, which was assessed according to the GCIG criteria. 1 The secondary outcome was Time to First Subsequent Therapy (TFST). Patients undergo regular assessments for tumor markers and imaging throughout treatment. If persistent elevation of tumor markers or the detection of recurrent lesions or distant metastases is observed, the patient is promptly removed from the study group. Standardized antitumor therapy is then initiated based on the patient's condition. The total planned enrollment is 46 participants, utilizing a single-group assignment and an open-label design. 1 of planned 12 patients for the first stage of accrual have been enrolled. Reference: 1. Rustin GJ, Vergote I, Eisenhauer E, et al. Definitions for response and progression in ovarian cancer clinical trials incorporating RECIST 1.1 and CA 125 agreed by the Gynecological Cancer Intergroup (GCIG). Int J Gynecol Cancer. 2011;21(2):419-423. Clinical trial information: NCT05669768 .
Laryngeal squamous cell carcinoma (LSCC) prognosis and machine learning insights.
Authors: Sakhr Abdulsalam Alshwayyat, Abdalwahab Alenezy, Mustafa Alshwayyat, Tala Abdulsalam Alshwayyat
Journal: Journal of Clinical Oncology (2024)

e18058 Background: LSCC has seen a rise in cases and deaths over the past 30 years. Considering the evolving therapeutic options available in the treatment landscape, we evaluated treatment approaches and developed a machine learning (ML) model for patients with LSCC without distant metastasis. Methods: Data from 2000 to 2020 were obtained from the National Cancer Institute Surveillance, Epidemiology, and End Results database with localized/regional stages only, including the glottis (GC), supraglottic (SuGC), and subglottic (SGC). Patients who were not diagnosed based on histology, previous history of cancer or other concurrent malignancies, or unknown data were excluded. T-tests and chi-square tests were used to compare variables, while the Kaplan-Meier estimator, log-rank tests, and Cox regression analysis identified prognostic factors for overall survival (OS) and cancer-specific survival (CSS). We constructed prognostic models using ML algorithms to predict the 5-year survival. Patient records were randomly divided into training (70 %) and validation (30 %) sets. A validation method incorporating the area under the curve (AUC) of the receiver operating characteristic curve was used to validate the accuracy and reliability of the ML models. Results: A total of 68,282 patients were included (43,434 with GC, 24,010 with SuGC, and 838 with SGC). Of the patients, 80.8% were males and 63.5% were over 60 years old and white (n=56,171). The tumors were &gt;2 cm in size (85.1%). The median patient age was 64 years, and the median tumor size was 3.2 cm. Of these patients, 36.5% underwent surgery with local tumor excision in 23.9 % and total laryngectomy in 5.7% of patients. White race, regional stage, large tumor size, and chemotherapy were poor prognostic factors for GC. Asian ethnicity, white race, and total laryngectomy were good prognostic factors for SuGC, whereas male sex and older age were poor prognostic factors. In terms of SCG "Surgery + adjuvant radiotherapy" was associated with better prognosis while regional and white race were associated with poor prognosis. Performance metrics for all ML algorithms are summarized in the Table. The factors that contributed the most to GC were the surgery type, stage, and age. Stage, surgery type, and race for SuGC and age, stage, and surgery type for SGC. Conclusions: ML models showed promising accuracy in predicting prognosis, highlighting the valuable contributions of factors such as surgery type, stage, age, and race. These findings offer insights into personalized treatment decisions and future research directions. [Table: see text]
Is the gemcitabin cisplatin doublet the optimal induction chemotherapy for non-Asian patients with NPC? Insights from a northeastern Moroccan cohort.
Authors: Oumaima Talbi, Samia Mhirech, Khadija Hinaje, Kaoutar Maadin, Hafssa Elhilali, Imad Chakri, Touria Bouhafa, Lamiae Amaadour, Karima Oualla, Zineb Benbrahim, Mellas Nawfel, Samia Arifi
Journal: Journal of Clinical Oncology (2024)

e18057 Background: According to the latest guidelines for NPC, induction chemotherapy followed by concomitant chemoradiation therapy (CCRT) is recommended as the preferred standard of care for patients with locally advanced nasopharyngeal carcinoma (stage III-Iva). However, the optimal regimen for induction chemotherapy (IC) in patients with locally advanced NPC remains uncertain. Methods: We conducted a retrospective study between January 2016 and October 2022 at the "CHU Hassan II" Oncology Hospital in Fes, Morocco, to compare the efficacy and tolerability of two platinum-based induction therapy regimens: cisplatin gemcitabine (GC) and cisplatin doxorubicin (DP), in the treatment of newly diagnosed locally advanced NPC. The main objectives of this study were to compare the efficacy including objective response rates (ORR), PFS ,OS and safety. Results: After eligibility assessment, we included 105 cases (62 patients in the DP group and 43 in the GC group), including 65 men and 40 women, with a mean age of 49.5 years (range = 19-79years) and a Karnofsky score ranging from 87% to 100%. 34% of patients were diagnosed at stage IVA. In the DP group, 3% of patients (2 out of 62) achieved a complete response CR, 60% achieved a partial response PR,25% remained stable SD and 19% experienced progression. In the GC group, 2% of patients (1 out of 43) achieved a CR, 39.5% achieved a PR, 39.5% remained stable, and 19% experienced progression. A statistically significant difference in PR was observed between the two groups (p = 0.028) ,and the difference in terms of progression is approaching the limit of significance (p=0,06) after a median follow-up of 27 months (5,3 -82). The 2-year progression-free survival (PFS) was 70% in the DP group compared to 80% in the GC group; the 2-year overall survival (OS) was 75% in the DP group and 90% in the GC group. No significant survival difference was observed between the two groups Patients in the DP group exhibited less grade 3-4 thrombocytopenia but more grade 3-4 leukopenia and neutropenia compared to the GC group. Conclusions: In patients with locally advanced nasopharyngeal carcinoma, GC-based induction chemotherapy demonstrated superior ORR over the DP regimen with acceptable toxicities. Further studies are needed to validate these results.
Association of absolute neutrophil count with outcomes in patients with head and neck cancer treated with chemoradiation.
Authors: Jasmin Gill, Jas Virk, Fatemeh Fekrmandi, Austin Iovoli, Mark Farrugia, Sung Jun Ma, Anurag K. Singh
Journal: Journal of Clinical Oncology (2024)

e18055 Background: Systematic inflammation plays an integral role in tumor development and metastasis. High neutrophil counts, among various peripheral blood biomarkers, have been shown to be associated with worse survival outcomes in multiple cancer types. To evaluate the absolute neutrophil count (ANC) as a prognostic biomarker in head and neck cancer, we performed an observational cohort study of patients undergoing definitive chemoradiation. Methods: Our institutional database at the Roswell Park Comprehensive Cancer Center was queried for patients with non-metastatic head and neck cancer who underwent definitive chemoradiation between June 2007 and April 2023. ANC was analyzed as a continuous variable. Survival outcomes were assessed using Kaplan-Meier method, log-rank tests, Cox proportional hazard multivariable (MVA) analyses. Fine-Gray MVA was used to analyze failure outcomes with death as a competing event. To reduce selection bias, propensity score matching was performed using ANC as a dichotomous variable with its median value as a cutoff. Subgroup analyses were performed among p16-negative and p16-positive cohorts. Results: A total of 668 patients who met our criteria. Median follow up was 30.3 months (interquartile range 9.9-60.7). Elevated ANC as a continuous variable was associated with worse overall survival (OS; adjusted hazards ratio [aHR] 1.02, 95% confidence interval [CI] 1.01-1.04, p=0.003), progression free survival (PFS; aHR 1.03, 95% CI 1.01-1.04, p&lt;0.001), and distant failure (DF; aHR 1.03, 95% CI 1.01-1.05, p=0.007), but not locoregional failure (LRF; aHR 1.02, 95% CI 1.00-1.05, p=0.10). Similar findings were noted among 278 matched pairs (OS: hazards ratio [HR] 1.66, 95% CI 1.23-2.26, p=0.001; PFS: HR 1.74, 95% CI 1.31-2.29, p&lt;0.001; LRF: HR 1.66, 95% CI 0.98-2.80, p=0.06; DF: HR 1.64, 95% CI 1.03-2.60, p=0.04). On subgroup analysis, among 118 patients with p16-negative tumors, elevated ANC as a continuous variable was not associated with OS (aHR 1.00, 95% CI 0.90-1.11, p=0.97) and PFS (aHR 0.97, 95% CI 0.87-1.08, p=0.54). The number of LRF (n=21) and DF (n=17) were too few to analyze in this subgroup. However, among 344 patients with p16-positive tumors, high ANC was associated with worse OS (aHR 1.03, 95% CI 1.00-1.06, p=0.046), PFS (aHR 1.05, 95% CI 1.02-1.07, p&lt;0.001), LRF (aHR 1.08, 95% CI 1.05-1.12, p&lt;0.001), and DF (aHR 1.04, 95% CI 1.01-1.08, p=0.02). Conclusions: Our study suggested that elevated ANC was an independent, adverse prognostic factor for worse survival and distant metastasis outcomes. Similar findings were also observed among patients with p16-positive tumors, with high ANC also associated with worse locoregional failure. Further studies are warranted to tailor interventions based on such biomarkers.
Implementing fragmentomics into real world screening interventions to evaluate clinical utility among individuals with elevated risk for lung cancer (FIRSTLUNG) L301.
Authors: Lindsey Behlen Cotton, Chris Cisar, Peter Brian Bach, Carolina Sheridan, Niti U. Trivedi, James Davis, Demetria Tennefoss
Journal: Journal of Clinical Oncology (2024)

TPS11189 Background: To optimize the impact of lung cancer screening at the healthcare system level, additional tools are needed to increase the benefits of screening. While low-dose computed tomography (LDCT) has been shown to improve lung cancer detection and reduce mortality, it is not without its risks, such as radiation exposure, false-positive results, and unnecessary interventions often leading to complications. The additional complexity of lung cancer screening is the subpar adherence to LDCT for eligible individuals, which undermines the benefits of screening. Therefore, there is a need for alternative non-invasive methodologies that exploit our understanding of the biology of cancer pathogenesis. This clinical utility study aims to observe how a non–invasive blood-based test impacts physician behavior and LDCT utilization. Methods: FIRSTLUNG 301 (NCT06145750) is a prospective, cluster randomized controlled trial (RCT) to observe the impact of the DELFI Lung cancer screening test on lung cancer screening utilization in primary care practices. Enrolled practices must meet the eligibility criteria of having a minimum of 50 actively engaged individuals in the practice eligible for lung cancer screening per the 2021 USPSTF criteria. These practices will be randomized 1:1:2 to Arm A1 (control), Arm A2 (control), or Arm B (intervention). Arm A practices will be randomized 1:1 into two groups (A1:A2) to observe the standard of care for lung cancer screening. Practices in A1 will be observed; practices in A2 will receive standard education on lung cancer screening for CME credit. Randomizing within Arms A1 and A2 aims to delineate the impact standard lung cancer screening education may have on utilization. Arm B (intervention) practices will receive education and have access to order the blood-based test for screen-eligible individuals that remained unscreened. The primary study endpoint is the proportion of practice-identified lung cancer screen-eligible individuals receiving a screening CT order and scan during the study period in the entirety of Arm A (control) versus Arm B (intervention). This RCT aims to understand the utilization and impact on lung cancer screening uptake after the DELFI blood-based test intended to inform clinical guidelines and policies focused on improving patient care and health outcomes. Progress: The study was initiated on October 31, 2023, with practice randomization. As of February 2024, the study is open for enrollment with an estimated primary study completion date of December 2025. Clinical trial information: NCT06145750 .
Arginine methylation of DDX3 by PRMT1 mediates mitochondrial homeostasis to promote breast cancer metastasis
Authors: Wen-Jing Hsu, Ming-Chen Chiang, Yi-Chun Chao, Yu-Chu Chang, Ming-Chien Hsu, Chu-Hung Chung, I-Lin Tsai, Cheng-Ying Chu, Han-Chung Wu, Ching-Chieh Yang, Chi-Ching Lee, Cheng-Wei Lin
Journal: Cancer Research (2024)

Dysregulated mitochondrial dynamics and metabolism play important roles in tumorigenesis. Metastasizing tumor cells predominantly utilize mitochondrial metabolism, and regulators of metabolic reprogramming may provide reliable biomarkers for diagnosing cancer metastasis. Here, we identified a type I arginine methyltransferase-DEAD-box polypeptide 3, X-linked (PRMT1-DDX3) axis that promotes breast cancer metastasis by coordinating mitochondrial biogenesis and mitophagy to ensure mitochondrial quality control. Mechanistically, PRMT1 induces arginine methylation of DDX3, which enhances its protein stability and prevents proteasomal degradation. DDX3 mediates mitochondrial homeostasis by translocating to mitochondria where it facilitates phosphatase and tensin homology-induced kinase 1 translation in response to mitochondrial stress. Inhibition of DDX3 suppresses mitochondrial biogenesis and mitophagy, resulting in diminished cancer stemness and metastatic properties. Overall, this study uncovers a mechanism by which the PRMT1-DDX3 axis regulates mitochondrial homeostasis to support breast cancer metastasis, suggesting strategies for targeting metabolic vulnerabilities to treat metastatic breast cancer. Significance: DDX3 is stabilized by PRMT1-mediated arginine methylation and coordinates mitophagy and mitochondrial biogenesis by upregulating PINK1 to facilitate breast cancer progression.
Induction chemotherapy with nab-paclitaxel plus nedaplatin plus concurrent chemoradiotherapy in locally advanced nasopharyngeal carcinoma: A retrospective real-world study.
Authors: Yan Fengqin
Journal: Journal of Clinical Oncology (2024)

e18056 Background: Although induction chemotherapy (IC) plus concurrent chemoradiotherapy (CCRT) is recommended as standard treatment option of locally advanced nasopharyngeal carcinoma (NPC), the IC regimens conduct further study. Therefore, this study was evaluated the efficacy and safety of IC with nab-paclitaxel and nedaplatin followed by CCRT in locally advanced NPC. Methods: In this retrospective real-world study, 295 patients was enrolled, and all received nab-paclitaxel (260mg/m2/d) and nedaplatin (80mg/m2/d) –based IC every 3 weeks. Results: All patients completed the treatment plans. The ORR were 95.3% in the NP and 96.9% in the neck after IC, respectively. At the end of CCRT, the ORR were 97.3% in the NP and 97.3% in the neck nodes, respectively. 3 years survival outcomes were 96.4% of OS, 95.7% of LRRFS, 93.7% of DMFS, and 89.8% of PFS, respectively. During IC, all treatment-related adverse events occurred in 43.2%. The most frequent grade 3 toxicities were neutropenia (7.8%), leucopenia (4.4%), anaemia (0.3%), thrombopenia (2.4%) and hepatic injury (3.1%), respectively. Conclusions: IC with nab-paclitaxel and nedaplatin showed promising efficacy and safety profile in locally advanced NPC.