tbuckley/cabot-search huggingface dataset:
A Phase II study assessing Long-Term Response to Ibrutinib Monotherapy in recurrent or refractory CNS Lymphoma
Authors: Christian Grommes, Subhiksha Nandakumar, Lauren R. Schaff, Igor Gavrilovic, Thomas J. Kaley, Craig P. Nolan, Jacqueline Stone, Alissa A. Thomas, Sarah S. Tang, Julia Wolfe, Alexis Bozza, Venissala Wongchai, Alisson Hyde, Emma Barrett, Elizabeth A. Lynch, Juli T. Madzsar, Andrew Lin, Anna F. Piotrowski, Elena Pentsova, Jasmine H. Francis, Vaios Hatzoglou, Nikolaus Schultz, Anne S. Reiner, Katherine S. Panageas, Lisa M. DeAngelis, Ingo K. Mellinghoff
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Ibrutinib is a first-in-class inhibitor of Bruton tyrosine kinase. We previously reported the safety and short-term antitumor activity of ibrutinib in 20 patients with relapsed or refractory (r/r) primary central nervous system (CNS) lymphoma (PCNSL) or secondary CNS lymphoma (SCNSL). Patients and Methods: We enrolled 26 additional patients with r/r PCNSL/SCNSL into the dose-expansion cohort of the trial into a combined cohort of 46 patients (31 with PCNSL and 15 with SCNSL). Patients received ibrutinib at 560 or 840 mg daily in the dose-escalation cohort and ibrutinib at 840 mg daily in the expansion cohort. The median follow-up was 49.9 and 62.1 months for patients with PCNSL and SCNSL, respectively. We sequenced DNA from available tumor biopsies and cerebrospinal fluid collected before and during ibrutinib therapy. Results: Tumor responses were observed in 23/31 (74%) patients with PCNSL and 9/15 (60%) patients with SCNSL, including 12 complete responses in PCNSL and 7 in SCNSL. The median progression-free survival (PFS) for PCNSL was 4.5 months [95% confidence interval (CI), 2.8–9.2] with 1-year PFS at 23.7% (95% CI, 12.4%–45.1%). The median duration of response in the 23 PCNSL responders was 5.5 months. The median PFS in SCNSL was 5.3 months (95% CI, 1.3–14.5) with a median duration of response of 8.7 months for the 9 responders. Exploratory biomarker analysis suggests that mutations in TBL1XR1 may be associated with a long-term response to ibrutinib in PCNSL (P = 0.0075). Clearance of ctDNA from cerebrospinal fluid was associated with complete and long-term ibrutinib responses. Conclusions: Our study confirms single-agent activity of ibrutinib in r/r CNS lymphoma and identifies molecular determinants of response based on long-term follow-up.
Left atrial function in patients with rheumatic mitral stenosis: addressing prognostic insights beyond atrial fibrillation prediction
Authors: Fernanda de Azevedo Figueiredo, William Antonio M Esteves, Judy Hung, Nayana Flamini Arantes Gomes, Cesar Augusto Taconeli, Alexandre Negrão Pantaleão, Matheus Assunção Rabello de Oliveira, Silvio Mendes de Magalhães, Luz Marina Tacuri Chavez, Timothy C Tan, Aditya Bhat, Robert A Levine, Maria Carmo Pereira Nunes
Journal:  (2024)

Rheumatic mitral stenosis (MS) frequently leads to impaired left atrial (LA) function because of pressure overload, highlighting the underlying atrial pathology. Two-dimensional speckle tracking echocardiography (2D-STE) offers early detection of LA dysfunction, potentially improving risk assessment in patients with MS. This study aims to evaluate the predictive value of LA function assessed by 2D-STE for clinical outcomes in patients with MS.
Rational Pharmacotherapy in Type 2 Diabetes: Danish Data From 2002 to 2020 on Mortality, Diabetes- Related Outcomes, Adverse Events, and Medication Expenses
Authors: Karl Sebastian Johansson, Espen Jimenez-Solem, Tonny Studsgaard Petersen, Mikkel Bring Christensen
Journal: Diabetes Care (2024)

OBJECTIVE Developments in pharmacotherapy and management of type 2 diabetes may have shifted the balance of treatment benefits versus harms and costs over the past decades. This study aimed to describe the trends in this balance. RESEARCH DESIGN AND METHODS We followed the Danish population with type 2 diabetes between 2002 and 2020, analyzing their medication use in relation to treatment benefits (such as mortality and diabetes-related outcomes), adverse events, and medication costs. Using multivariate analyses, we adjusted for potential confounders, including age, sex, and socioeconomic status. RESULTS The study included 461,805 individuals. From 2002 to 2020, the median age increased from 66 to 68 years, and the mean number of comorbidities increased from 5.2 to 8.8. The overall incidence of cardiovascular, renal, and other important adverse clinical outcomes decreased. Similarly, the rate of some adverse events, such as gastric bleeding, hypoglycemia, and falls declined, whereas the incidence of electrolyte imbalances and ketoacidosis increased. The average per-patient cost was reduced by 8%, but total medication expenses increased by 148% due to an expanding population size, lowered costs of most cardiovascular medications, and increasing costs for glucose-lowering drugs. CONCLUSIONS Advancements in type 2 diabetes management have led to reduced risk of both diabetes-related outcomes and treatment harms, while maintaining relatively stable per-patient medication expenses. Although these trends are multifactorial, they suggest more rational pharmacotherapy. Still, increased risk of certain adverse events, along with increasing costs for glucose-lowering medications, underscores the need for ongoing vigilance and risk-benefit analysis.
Ancestral origins and admixture history of Kazakhs
Authors: Chang Lei, Jiaojiao Liu, Rui Zhang, Yuwen Pan, Yan Lu, Yang Gao, Xixian Ma, Yajun Yang, Yaqun Guan, Dolikun Mamatyusupu, Shuhua Xu
Journal: Molecular Biology and Evolution (2024)

Kazakh people, like many other populations that settled in Central Asia, demonstrate an array of mixed anthropological features of East Eurasian (EEA) and West Eurasian (WEA) populations, indicating a possible scenario of biological admixture between already differentiated EEA and WEA populations. However, their complex biological origin, genomic makeup, and genetic interaction with surrounding populations are not well understood. To decipher their genetic structure and population history, we conducted, to our knowledge, the first whole-genome sequencing study of Kazakhs residing in Xinjiang (KZK). We demonstrated that KZK derived their ancestries from 4 ancestral source populations: East Asian (∼39.7%), West Asian (∼28.6%), Siberian (∼23.6%), and South Asian (∼8.1%). The recognizable interactions of EEA and WEA ancestries in Kazakhs were dated back to the 15th century BCE. Kazakhs were genetically distinctive from the Uyghurs in terms of their overall genomic makeup, although the 2 populations were closely related in genetics, and both showed a substantial admixture of western and eastern peoples. Notably, we identified a considerable sex-biased admixture, with an excess of western males and eastern females contributing to the KZK gene pool. We further identified a set of genes that showed remarkable differentiation in KZK from the surrounding populations, including those associated with skin color (SLC24A5, OCA2), essential hypertension (HLA-DQB1), hypertension (MTHFR, SLC35F3), and neuron development (CNTNAP2). These results advance our understanding of the complex history of contacts between Western and Eastern Eurasians, especially those living or along the old Silk Road.
Older adults with cancer and common comorbidities—challenges and opportunities in improving their cancer treatment outcomes
Authors: Weiwei Chen, Rachel D Altshuler, Phil Daschner, Carolina Salvador Morales, Diane C St. Germain, Jennifer Guida, Pataje G S Prasanna, Jeffrey C Buchsbaum
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract The older American population is rapidly increasing, and millions of older adults will be cancer survivors with comorbidities. This population faces specific challenges regarding treatment and has unique clinical needs. Recognizing this need, the National Cancer Institute, in collaboration with the National Institute on Aging, hosted a webinar series, entitled Cancer, Aging, and Comorbidities. This commentary provides a reflection of 5 thematic areas covered by the webinar series, which was focused on improving cancer treatment for older adults with cancer and comorbidities: 1) the impact of comorbidities on treatment tolerability and patient outcomes; 2) the impact of comorbidities on cancer clinical trial design; 3) the development of wearable devices in measuring comorbidities in cancer treatment; 4) the effects of nutrition and the microbiome on cancer therapy; and 5) the role of senescence and senotherapy in age-related diseases. Advances have been made in these areas, however, many gaps and challenges exist and are discussed in this commentary. To improve cancer survivorship in older populations with comorbidities, aging and comorbidities must be jointly considered and incorporated across the spectrum of cancer research. This includes more basic research of the mechanisms linking comorbidities and cancer development and treatment response, building critical resources and infrastructure (eg, preclinical models and patient samples), conducting clinical trials focused on the older population, integrating geriatric assessment into cancer treatment, and incorporating novel technologies, such as wearable devices, into clinical trials and cancer care.
Eftilagimod alpha (soluble LAG-3 protein) combined with pembrolizumab as second-line therapy for patients with metastatic head and neck squamous cell carcinoma
Authors: Martin Forster, Irene Brana, Antonio L. Pousa, Bernard Doger, Patricia Roxburgh, Pawan Bajaj, Julio Peguero, Matthew Krebs, Enric Carcereny, Grisma Patel, Christian Mueller, Chrystelle Brignone, Frederic Triebel
Journal: Clinical Cancer Research (2024)

Eftilagimod alpha (efti), a soluble LAG3 protein, activates antigen-presenting cells (APC) and downstream T cells. TACTI-002 (part C) evaluated whether combining efti with pembrolizumab led to strong antitumor responses in patients with second-line recurrent or metastatic head and neck squamous cell carcinoma (R/M HNSCC) while demonstrating good tolerability.
Circulating Tumor DNA Dynamics Reveal <i>KRAS G12C</i> Mutation Heterogeneity and Response to Treatment with the KRAS G12C Inhibitor Divarasib in Solid Tumors
Authors: Yoonha Choi, Neekesh V. Dharia, Tomi Jun, Julie Chang, Stephanie Royer-Joo, Kenneth K. Yau, Zoe J. Assaf, Junko Aimi, Smruthy Sivakumar, Meagan Montesion, Adrian Sacher, Patricia LoRusso, Jayesh Desai, Jennifer L. Schutzman, Zhen Shi
Journal: Clinical Cancer Research (2024)

To inform prognosis, treatment response, disease biology, and KRAS G12C mutation heterogeneity, we conducted exploratory circulating tumor DNA (ctDNA) profiling on 134 patients with solid tumors harboring a KRAS G12C mutation treated with single-agent divarasib (GDC-6036) in a phase 1 study.
CSF1R Inhibition in Patients With Advanced Solid Tumors or Tenosynovial Giant Cell Tumor: A Phase 1 Study of Vimseltinib
Authors: Hans Gelderblom, Albiruni Abdul. Razak, Matthew H. Taylor, Todd M. Bauer, Breelyn Wilky, Javier Martín-Broto, Alejandro Falcón. Gonzalez, Piotr Rutkowski, Bartlomiej Szostakowski, Thierry Alcindor, Ramy Saleh, Sofia Genta, Silvia Stacchiotti, Michiel van de Sande, Andrew J. Wagner, Nicholas Bernthal, Lara E. Davis, Jacqueline Vuky, Christopher Tait, Bahar Matin, Supraja Narasimhan, Maitreyi G. Sharma, Rodrigo Ruiz-Soto, Matthew L. Sherman, William D. Tap
Journal: Clinical Cancer Research (2024)

Abstract Purpose: Tenosynovial giant cell tumor (TGCT) is a locally aggressive neoplasm caused by dysregulation of the colony-stimulating factor 1 (CSF1) gene and overexpression of the CSF1 ligand. Surgery is the standard of care for most patients, but there are limited treatment options for patients with TGCT not amenable to surgery. This study evaluates vimseltinib, an investigational, oral, switch-control tyrosine kinase inhibitor designed to selectively and potently inhibit the CSF1 receptor. Patients and Methods: This first-in-human, multicenter, open-label phase I/II study of vimseltinib in patients with malignant solid tumors (N = 37) or TGCT not amenable to surgery (N = 32) followed a pharmacologically guided 3 + 3 study design (NCT03069469). The primary objectives were to assess safety and tolerability, determine the recommended phase II dose, and characterize the pharmacokinetics; exploratory objectives included pharmacodynamics and efficacy. Results: Vimseltinib was well tolerated; the majority of non-laboratory treatment-emergent adverse events were of grade 1/2 severity. There was no evidence of cholestatic hepatotoxicity or drug-induced liver injury. The recommended phase II dose was determined to be 30 mg twice weekly (no loading dose), and vimseltinib plasma exposure increased with the dose. In patients with TGCT, the median treatment duration was 25.1 months (range, 0.7–46.9), and the objective response rate as assessed by independent radiological review using RECIST version 1.1 was 72%. Conclusions: Vimseltinib demonstrated long-term tolerability, manageable safety, dose-dependent exposure, and robust antitumor activity in patients with TGCT not amenable to surgery.
HER2DX Genomic Assay in HER2-positive Early Breast Cancer Treated with Trastuzumab and Pertuzumab: A Correlative Analysis from PHERGain Phase II Trial
Authors: Antonio Llombart-Cussac, Jose Pérez-García, Fara Brasó-Maristany, Laia Paré, Guillermo Villacampa, Maria Gion, Peter Schmid, Marco Colleoni, Manuel R. Borrego, Patricia Galván, Joel S. Parker, Wesley Buckingham, Charles M. Perou, Patricia Villagrasa, Jose A. Guerrero, Miguel Sampayo-Cordero, Mario Mancino, Aleix Prat, Javier Cortés
Journal: Clinical Cancer Research (2024)

Abstract Purpose: The purpose of this study was to assess the predictive capability of HER2DX assay following (neo)adjuvant trastuzumab–pertuzumab (HP)–based therapy in HER2-positive (HER2+) early breast cancer. Experimental Design: HER2DX was analyzed in baseline pretreatment tumors from the PHERGain trial. Patients with stage I–IIIA HER2+ early breast cancer were randomized to group A [docetaxel, carboplatin, and HP (TCHP)] and group B (HP ± endocrine therapy). PET response was evaluated after two cycles. Group A received TCHP for six cycles regardless of PET response. Group B continued with HP ± endocrine therapy for six cycles (PET responders) or with TCHP for six cycles (PET nonresponders). The primary objective of this retrospective study was to associate the HER2DX pathologic complete response (pCR) score with pCR. The secondary objective was the association of the HER2DX risk score with 3-year invasive disease-free survival (iDFS). Results: HER2DX was performed on 292 (82.0%) tumors. The overall pCR rate was 38.0%, with pCR rates of 56.4% in group A and 33.8% in group B. In multivariable analysis including treatment and clinicopathologic factors, the HER2DX pCR score (continuous variable) significantly correlated with pCR [OR, 1.29; 95% confidence interval (CI), 1.10–1.54; P &amp;lt; 0.001]. HER2DX-defined pCR-high, -med, and -low groups exhibited pCR rates of 50.4%, 35.8%, and 23.2%, respectively (pCR-high vs. pCR-low OR, 3.27; 95% CI, 1.54–7.09; P &amp;lt; 0.001). In patients with residual disease, the HER2DX high-risk group demonstrated numerically worse 3-year iDFS than the low-risk group (89.8% vs. 100%; HR, 2.70; 95% CI, 0.60–12.18; P = 0.197). Conclusions: HER2DX predicts pCR in the context of neoadjuvant HP-based therapy, regardless of chemotherapy addition, and might identify patients at higher risk of recurrence among patients with residual disease.
Semaphorin 6D tunes amygdalar circuits for emotional, metabolic, and inflammatory outputs
Authors: Yoshimitsu Nakanishi, Mayuko Izumi, Hiroaki Matsushita, Yoshihisa Koyama, Diego Diez, Hyota Takamatsu, Shohei Koyama, Masayuki Nishide, Maiko Naito, Yumiko Mizuno, Yuta Yamaguchi, Tomoki Mae, Yu Noda, Kamon Nakaya, Satoshi Nojima, Fuminori Sugihara, Daisuke Okuzaki, Masahito Ikawa, Shoichi Shimada, Sujin Kang, Atsushi Kumanogoh
Journal: Neuron (2024)

Regulated neural-metabolic-inflammatory responses are essential for maintaining physiological homeostasis. However, the molecular machinery that coordinates neural, metabolic, and inflammatory responses is largely unknown. Here, we show that semaphorin 6D (SEMA6D) coordinates anxiogenic, metabolic, and inflammatory outputs from the amygdala by maintaining synaptic homeostasis. Using genome-wide approaches, we identify SEMA6D as a pleiotropic gene for both psychiatric and metabolic traits in human. Sema6d deficiency increases anxiety in mice. When fed a high-fat diet, Sema6d−/− mice display attenuated obesity and enhanced myelopoiesis compared with control mice due to higher sympathetic activity via the β3-adrenergic receptor. Genetic manipulation and spatial and single-nucleus transcriptomics reveal that SEMA6D in amygdalar interneurons is responsible for regulating anxiogenic and autonomic responses. Mechanistically, SEMA6D is required for synaptic maturation and γ-aminobutyric acid transmission. These results demonstrate that SEMA6D is important for the normal functioning of the neural circuits in the amygdala, coupling emotional, metabolic, and inflammatory responses.
Forecasting daily total pollen concentrations on a global scale
Authors: László Makra, Luca Coviello, Andrea Gobbi, Giuseppe Jurman, Cesare Furlanello, Mauro Brunato, Lewis H. Ziska, Jeremy J. Hess, Athanasios Damialis, Maria Pilar Plaza Garcia, Gábor Tusnády, Lilit Czibolya, István Ihász, Áron József Deák, Edit Mikó, Zita Dorner, Susan K. Harry, Nicolas Bruffaerts, Ann Packeu, Annika Saarto, Linnea Toiviainen, Maria Louna‐Korteniemi, Sanna Pätsi, Michel Thibaudon, Gilles Oliver, Athanasios Charalampopoulos, Despoina Vokou, Ewa Maria Przedpelska‐Wasowicz, Ellý Renée Guðjohnsen, Maira Bonini, Sevcan Celenk, Cumali Ozaslan, Jae‐Won Oh, Krista Sullivan, Linda Ford, Michelle Kelly, Estelle Levetin, Dorota Myszkowska, Elena Severova, Regula Gehrig, María Del Carmen Calderón‐Ezquerro, César Guerrero Guerra, Manuel Andres Leiva‐Guzmán, Germán Darío Ramón, Laura Beatriz Barrionuevo, Jonny Peter, Dilys Berman, Connie H. Katelaris, Janet M. Davies, Pamela Burton, Paul J. Beggs, Sandra María Vergamini, Rosa María Valencia‐Barrera, Claudia Traidl‐Hoffmann
Journal: Allergy (2024)

There is evidence that global anthropogenic climate change may be impacting floral phenology and the temporal and spatial characteristics of aero-allergenic pollen. Given the extent of current and future climate uncertainty, there is a need to strengthen predictive pollen forecasts.
Lipid-orchestrated paracrine circuit coordinates mast cell maturation and anaphylaxis through functional interaction with fibroblasts
Authors: Yoshitaka Taketomi, Takayoshi Higashi, Kuniyuki Kano, Yoshimi Miki, Chika Mochizuki, Shota Toyoshima, Yoshimichi Okayama, Yasumasa Nishito, Susumu Nakae, Satoshi Tanaka, Suzumi M. Tokuoka, Yoshiya Oda, Shigeyuki Shichino, Satoshi Ueha, Kouji Matsushima, Noriyuki Akahoshi, Satoshi Ishii, Jerold Chun, Junken Aoki, Makoto Murakami
Journal: Immunity (2024)

Interaction of mast cells (MCs) with fibroblasts is essential for MC maturation within tissue microenvironments, although the underlying mechanism is incompletely understood. Through a phenotypic screening of >30 mouse lines deficient in lipid-related genes, we found that deletion of the lysophosphatidic acid (LPA) receptor LPA
Pembrolizumab in combination with lenvatinib in participants with hepatocellular carcinoma (HCC) before liver transplant as neoadjuvant therapY—PLENTY pilot study
Authors: Zicheng Lv, Xuelin Xiang, June-kong Yong, Yi Zhou, Yichi Wu, Linman Li, Yuanhao Wang, Zijie Zhang, Qiang Xia, Hao Feng
Journal: International Journal of Surgery (2024)

Background: The high recurrent rate after liver transplantation (LT) remains a clinical challenge, especially for those exceeding the Milan criteria (MC) and with high RETREAT scores. Therefore, the authors aim to investigate whether neoadjuvant systemic therapy allows safely administered and effectively reduces post-LT recurrence for those patients. Methods: In this prospective, randomized, open-label, pilot study, patients with HCC exceeding the MC were randomly assigned to PLENTY or control group before LT. The primary endpoint of the study was the recurrence-free survival after LT. Results: Twenty-two patients were enrolled and randomly assigned: 11 to the PLENTY group and 11 to the control group. The 30-month tumor-specific RFS was 37.5% in the PLENTY group and 12.5% in the control group. The 12-month tumor-specific RFS after LT was significantly improved in the PLENTY group (87.5%) compared to the control group (37.5%) ( P =0·0022). The objective response rate in the PLENTY group was 30 and 60% when determined by RECIST 1.1 and mRECIST, respectively. Six patients (60%) had significant tumor necrosis, including three (30%) who had complete tumor necrosis at histopathology. No acute allograft rejection after LT occurred in the PLENTY and Control group. Conclusion: Neoadjuvant pembrolizumab plus lenvatinib before LT appears to be safe and feasible, associated with significantly better RFS for patients exceeding the MC. Despite the limitations of small sample size, this is the first RCT to evaluate neoadjuvant PD-1 blockade combined with tyrosine kinase inhibitors in LT recipients, the results of this study will inform future research.
Utilizing bifurcated allogeneic vein grafts: a novel approach for preventing sinistral portal hypertension following Pancreaticoduodenectomy. a 10-year before and after study
Authors: Jing Wang, Shao-cheng Lyu, Song-ping Cui, Jin-can Huang, Han-xuan Wang, Bin Hu, Qiang He, Ren Lang
Journal: International Journal of Surgery (2024)

Background: Sinistral portal hypertension (SPH) may occurs in patients with pancreatic carcinoma after pancreaticoduodenectomy (PD) with spleno-mesenterico-portal (S-M-P) cofluence resection. This study aimed to evaluate outcomes with the bifurcated allogeneic vein replacement in the prevention of SPH in pancreatic carcinoma patients. Materials and Methods: A total of 81 patients were included. We retrospectively collected clinicopathological data from 66 patients underwent PD with S-M-P confluence resection in our hospital from Jan. 2011 to Dec. 2021, compared the correlation between different venous reconstruction methods using log-rank tests and clinical outcomes through univariate and multivariate analyses. Secondly, we prospectively collected clinical data and outcomes of 15 patients who underwent splenic vein reconstruction from Jan. 2021 to Jan. 2023. Results: In the retrospective study, 43 cases received reconstruction by bifurcated allogeneic vein (Reconstruction group) and 23 cases received simply SV ligation (Ligation group). The preoperative platelet counts and spleen volume were similar between two groups ( P &gt;0.05). Nevertheless, at 1 month, 3 months and 6 months after operation, the related indexes of SPH such as platelet count, spleen volume, spleen volume ratio and esophagogastric varices (EGV) grade in Reconstruction group were better than those in Ligation group ( P &lt;0.05). 6 months after surgery, the incidence of SPH in Ligation group was significantly higher than in Reconstruction group (36.4% vs. 8.1%, respectively). In the prospective study, the incidence of SPH in patients undergoing SV reconstruction was 6.7% (1/15). Conclusion: Without compromising surgical outcomes, reconstruction of the S-M-P confluence by bifurcated allogeneic vein is a better method to avoid SPH in patients with advanced pancreatic carcinoma.