tbuckley/cabot-search huggingface dataset:
Adjuvant radiotherapy after curative resection of hepatocellular carcinoma with narrow margin (≤1 cm): A phase 2, multicenter, randomized controlled trial.
Authors: Kuang Ming, Zhenwei Peng, Zebin Chen, Shunli Shen, Bin Li
Journal: Journal of Clinical Oncology (2024)

722 Background: RAISE is a multicenter, randomized, open-label, parallel-group phase 2 trial, aiming to assess the efficacy and safety of intensity modulated radiation therapy (IMRT) compared with active surveillance in hepatocellular carcinoma (HCC) patients with narrow margin (≤ 1 cm) following curative resection. Methods: HCC patients with narrow margin were randomly assigned in a 1:1 ratio to receive either IMRT (Surgery-IMRT group) or active surveillance (Surgery group) after hepatectomy. Randomized stratification factors include tumor size (≤ 5 vs. &gt; 5 cm) and microvascular invasion (presence vs. absence). In the Surgery-IMRT group, patients received IMRT within 1-3 months after surgical resection. The prescription dose was planned at 50-60 gray in 25-30 fractions over 5-6 weeks. The primary endpoint was recurrence free survival (RFS). The secondary endpoints were safety and overall survival (OS). The planned sample size was 148 patients in total to obtain an improvement in the 2-year RFS rate from 45% to 65%, to detect a hazard ratio (HR) of 0.54, with a one-sided alpha of 5% and 80% power. Results: Between January 15, 2019, and September 15, 2023, 148 patients from 6 hospitals in China were randomized: 74 patients were allocated to the Surgery-IMRT group and 74 to the Surgery group. The median follow-up duration was 27.4 months (95% confidence interval [CI] 23.2-29.2 months). The 2-year RFS was 78.37% (95% CI 64.35%–87.40%) for the Surgery-IMRT group and 57.43% (95% CI 43.25%–69.28%) for the Surgery group (P=0.028). The median OS was not reached for the two groups. The following radiotherapy-related grade 3–4 adverse events were 3 thrombocytopenia, 3 neutropenia, and 1 hemoglobin decreased. Conclusions: In conclusion, this trial showed that the adjuvant IMRT following curative resection can bring survival benefits of RFS for HCC patients with narrow margin. Clinical trial information: NCT03732105 .
Lactate Utilization Enables Metabolic Escape to Confer Resistance to BET Inhibition in Acute Myeloid Leukemia
Authors: Andrew J. Monteith, Haley E. Ramsey, Alexander J. Silver, Donovan Brown, Dalton Greenwood, Brianna N. Smith, Ashley D. Wise, Juan Liu, Sarah D. Olmstead, Jackson Watke, Maria P. Arrate, Agnieszka E. Gorska, Londa Fuller, Jason W. Locasale, Matthew C. Stubbs, Jeffrey C. Rathmell, Michael R. Savona
Journal: Cancer Research (2024)

Abstract Impairing the BET family coactivator BRD4 with small-molecule inhibitors (BETi) showed encouraging preclinical activity in treating acute myeloid leukemia (AML). However, dose-limiting toxicities and limited clinical activity dampened the enthusiasm for BETi as a single agent. BETi resistance in AML myeloblasts was found to correlate with maintaining mitochondrial respiration, suggesting that identifying the metabolic pathway sustaining mitochondrial integrity could help develop approaches to improve BETi efficacy. Herein, we demonstrated that mitochondria-associated lactate dehydrogenase allows AML myeloblasts to utilize lactate as a metabolic bypass to fuel mitochondrial respiration and maintain cellular viability. Pharmacologically and genetically impairing lactate utilization rendered resistant myeloblasts susceptible to BET inhibition. Low-dose combinations of BETi and oxamate, a lactate dehydrogenase inhibitor, reduced in vivo expansion of BETi-resistant AML in cell line and patient-derived murine models. These results elucidate how AML myeloblasts metabolically adapt to BETi by consuming lactate and demonstrate that combining BETi with inhibitors of lactate utilization may be useful in AML treatment. Significance: Lactate utilization allows AML myeloblasts to maintain metabolic integrity and circumvent antileukemic therapy, which supports testing of lactate utilization inhibitors in clinical settings to overcome BET inhibitor resistance in AML. See related commentary by Boët and Sarry, p. 950
First-line pembrolizumab (pembro) plus chemotherapy (chemo) for advanced gastroesophageal junction cancer (GEJC) and esophageal adenocarcinoma (EAC): Analysis of KEYNOTE-590 and KEYNOTE-859 by tumor type.
Authors: Zev A. Wainberg, Kai-Keen Shiu, Fernando Rivera, Louise C. Medley, Morteza Aghmesheh, Richard Francis Dunne, Rajarshi Roy, Lucjan S. Wyrwicz, Timothy Larson, Jean-Philippe Metges, Wasat Mansoor, Eray Goekkurt, Luiz Carlos Moreira Antunes, Victor Castro Oliden, Erin Jensen, Sukrut Shah, Sonal Bordia, Pooja Bhagia, Maeve Aine Lowery
Journal: Journal of Clinical Oncology (2024)

345 Background: First-line (1L) treatment of GEJC and EAC is similar to that for gastric adenocarcinomas, based on evidence from 2 large phase 3 gastric and esophageal cancer trials. The phase 3 KEYNOTE-590 trial (NCT03189719) showed 1L pembro + chemo significantly improved OS and PFS in pts with esophageal cancer. The phase 3 KEYNOTE-859 trial (NCT03675737) showed 1L pembro + chemo significantly improved OS, PFS, and ORR in pts with HER2-negative gastric cancer or GEJC. This post hoc, exploratory analysis was conducted to examine the efficacy of 1L pembro + chemo in the GEJC and EAC subgroups of KEYNOTE-590 and the GEJ subgroup of KEYNOTE-859. Methods: Pts with untreated advanced EAC or Siewert type 1 adenocarcinoma of the GEJ (KEYNOTE-590) or HER2-negative GEJ adenocarcinoma (KEYNOTE-859), measurable disease per RECIST v1.1, and ECOG PS 0 or 1 were evaluated. In both studies, pts were randomly assigned 1:1 to receive pembro 200 mg IV or pbo every 3 wk (Q3W) for ≤35 cycles, each with chemo (5-fluorouracil + cisplatin [FP] in KEYNOTE-590; FP or capecitabine + oxaliplatin in KEYNOTE-859). Efficacy end points for this analysis were OS and PFS (per RECIST v1.1 by blinded independent central review) by tumor subtype. Database cutoff was July 2, 2020, for KEYNOTE-590 and July 1, 2022, for KEYNOTE-859. Results: Overall, 201 pts from KEYNOTE-590 (n=99 pembro + chemo; n=102 pbo + chemo) with GEJC or EAC and 334 pts from KEYNOTE-859 (n=149 pembro + chemo; n=185 pbo + chemo) with GEJC were included. In KEYNOTE-590, 91 pts had GEJC only (n=41 pembro + chemo; n=50 pbo + chemo) and 169 (n=82 pembro + chemo; n=87 pbo + chemo) had GEJC + EAC + CPS ≥1. In KEYNOTE-859, 287 pts (n=123 pembro + chemo; n=164 pbo + chemo) had GEJC + CPS ≥1. Demographic and baseline characteristics were well balanced. Median time from randomization to database cutoff for pts with GEJC and EAC was 23.5 mo (range, 15.3-33.6) in KEYNOTE-590 and 25.8 mo (range, 12.4-43.0) in KEYNOTE-859. Efficacy outcomes by tumor type are shown in the Table. Conclusions: Consistent with results from the ITT populations of KEYNOTE-590 and KEYNOTE-859, 1L pembro + chemo provided clinically meaningful improvement in OS and PFS vs chemo in pts with untreated advanced GEJC and EAC. These data support the use of 1L pembro + chemo for pts with advanced GEJC and EAC. Clinical trial information: NCT03189719 and NCT03675737 . [Table: see text]
Proteomic Biomarkers of Quantitative Interstitial Abnormalities in COPDGene and CARDIA Lung Study
Authors: Bina Choi, Gabrielle Y. Liu, Quanhu Sheng, Kaushik Amancherla, Andrew Perry, Xiaoning Huang, Ruben San José Estépar, Samuel Y. Ash, Weihua Guan, David R. Jacobs, Fernando J. Martinez, Ivan O. Rosas, Russell P. Bowler, Jonathan A. Kropski, Nicholas E. Banovich, Sadiya S. Khan, Raúl San José Estépar, Ravi Shah, Bharat Thyagarajan, Ravi Kalhan, George R. Washko
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

Quantitative interstitial abnormalities (QIAs) are early measures of lung injury automatically detected on chest computed tomography scans. QIAs are associated with impaired respiratory health and share features with advanced lung diseases, but their biological underpinnings are not well understood.
A phase 2/3 randomized study of CTX-009 combination in 2L biliary tract cancer: COMPANION-002.
Authors: Olivia Aranha, Milind M. Javle, Minori Koshiji Rosales, Zishuo Ian Hu, Amir A. Faridi, Scott Paulson, Donald A. Richards, Howard S. Hochster, David Cosgrove, Nilofer Saba Azad, Ursa Brown-Glaberman, Vivian Jean M. Cline, Nathan M. Shumway, Mohamedtaki Abdulaziz Tejani, Sujatha Nallapareddy, Ilyas Sahin, Mitesh J. Borad, Lipika Goyal, Robin Kate Kelley
Journal: Journal of Clinical Oncology (2024)

TPS587 Background: Biliary tract cancer (BTC) is characterized by generally poor prognoses with limited treatment options. Systemic chemotherapy usually begins with gemcitabine, platinum agents, and a checkpoint inhibitor followed by 5-FU and oxaliplatin, irinotecan or a taxane. Presently, there is no consensus second-line therapy for patients with BTC. The DLL/Notch signaling pathway has been described to be a major driver of cholangiocarcinogenesis and VEGF-A overexpression has been reported in BTC tumors, correlating with stage, metastasis, and prognosis of the disease. CTX-009 is a recombinant bispecific antibody that binds both delta-like ligand-4 (DLL4) and vascular endothelial growth factor A (VEGF-A). The antibody simultaneously inhibits the DLL4-Notch 1 and VEGF A-VEGF receptor signaling pathways. Methods: COMPANION-002 (CTX-009 -002) is an open-label, randomized, controlled study in patients in second line advanced or metastatic BTC. To be eligible, patients must have radiologically documented progression after a prior gemcitabine and platinum containing chemotherapy regimen as first line therapy for locally advanced unresectable or metastatic disease. 150 patients will be randomized in a 2:1 ratio to receive either CTX-009 plus paclitaxel or paclitaxel alone. The stratification factors to be used at randomization include stage (locally advanced vs. metastatic), anatomic subsite of primary tumor (intrahepatic cholangiocarcinoma vs. other, i.e. extrahepatic cholangiocarcinoma, gallbladder, or ampullary), and Eastern Cooperative Oncology Group (ECOG) Performance status (0 vs. 1). Patients will be treated in 28-day cycles, with CTX-009 administered at 10 mg/kg IV on Day 1 and 15, and paclitaxel administered at 80 mg/m2 on days 1, 8, and 15. The patients randomized to paclitaxel arm can crossover after disease progression if selection criteria continue to be met. The primary objective of the study is to assess the efficacy of CTX-009 in combination with paclitaxel vs. paclitaxel alone, as measured by Overall Response Rate (ORR) assessed by an Independent Central Radiology (ICR) review. Key secondary objectives include overall survival, progression-free survival, and duration of response. Clinical trial information: 251040.
Tumor Cell–Intrinsic p38 MAPK Signaling Promotes IL1α-Mediated Stromal Inflammation and Therapeutic Resistance in Pancreatic Cancer
Authors: Samara P. Singh, Austin R. Dosch, Siddharth Mehra, Iago De Castro Silva, Anna Bianchi, Vanessa T. Garrido, Zhiqun Zhou, Andrew Adams, Haleh Amirian, Edmond W. Box, Xiaodian Sun, Yuguang Ban, Jashodeep Datta, Nagaraj S. Nagathihalli, Nipun B. Merchant
Journal: Cancer Research (2024)

Abstract Pancreatic ductal adenocarcinoma (PDAC) is characterized by a KRAS-driven inflammatory program and a desmoplastic stroma, which contribute to the profoundly chemoresistant phenotype. The tumor stroma contains an abundance of cancer-associated fibroblasts (CAF), which engage in extensive paracrine cross-talk with tumor cells to perpetuate protumorigenic inflammation. IL1α, a pleiotropic, tumor cell–derived cytokine, plays a critical role in shaping the stromal landscape. To provide insights into the molecular mechanisms regulating IL1A expression in PDAC, we performed transcriptional profiling of The Cancer Genome Atlas datasets and pharmacologic screening in PDAC cells and identified p38α MAPK as a key positive regulator of IL1A expression. Both genetic and pharmacologic inhibition of p38 MAPK significantly diminished IL1α production in vitro. Chromatin- and coimmunoprecipitation analyses revealed that p38 MAPK coordinates the transcription factors Sp1 and the p65 subunit of NFκB to drive IL1A overexpression. Single-cell RNA sequencing of a highly desmoplastic murine PDAC model, Ptf1aCre/+; LSL-KrasG12D/+; Tgfbr2flox/flox (PKT), confirmed that p38 MAPK inhibition significantly decreases tumor cell–derived Il1a and attenuates the inflammatory CAF phenotype in a paracrine IL1α-dependent manner. Furthermore, p38 MAPK inhibition favorably modulated intratumoral immunosuppressive myeloid populations and augmented chemotherapeutic efficacy to substantially reduce tumor burden and improve overall survival in PKT mice. These findings illustrate a cellular mechanism of tumor cell–intrinsic p38-p65/Sp1-IL1α signaling that is responsible for sustaining stromal inflammation and CAF activation, offering an attractive therapeutic approach to enhance chemosensitivity in PDAC. Significance: Inhibition of p38 MAPK suppresses tumor cell–derived IL1α and attenuates the inflammatory stroma and immunosuppressive tumor microenvironment to overcome chemotherapeutic resistance in pancreatic cancer.
Clinical pharmacology profile of the claudin 18.2 antibody zolbetuximab.
Authors: Jianning Yang, Akihiro Yamada, Samuel J. Klempner, Sara Lonardi, Kohei Shitara, Rui-Hua Xu, David H. Ilson, Yoko Ueno, Masato Takeuchi, Janet Pavese, Tomasz Wojtkowski, Maria Matsangou, Srinivasu Poondru
Journal: Journal of Clinical Oncology (2024)

316 Background: Zolbetuximab is an investigational first-in-class chimeric (mouse/human) monoclonal antibody directed against the tight junction protein claudin 18.2 (CLDN18.2). Zolbetuximab is currently being developed as first-line treatment of patients with locally advanced unresectable or metastatic HER2 – gastric or gastroesophageal junction (GEJ) adenocarcinoma whose tumors are CLDN18.2 positive, in combination with fluoropyrimidine- and platinum-containing chemotherapy. Methods: The clinical pharmacology of zolbetuximab (pharmacokinetics [PK] and impact of covariates, potential for drug-drug interactions and QTc prolongation, exposure-response [E-R] for efficacy and safety, immunogenicity [antidrug antibodies; ADAs]) was characterized from 9 studies in adults with advanced CLDN18.2-positive adenocarcinoma of the stomach, esophagus, or GEJ. Results: Zolbetuximab exhibited dose-proportional PK at doses of 33 to 1000 mg/m 2 . Based on population PK modeling using data from 714 participants, zolbetuximab exposure (Table) was not meaningfully affected by sex, race/ethnicity, age, mild/moderate renal impairment, or mild hepatic impairment. Gastrectomy was predicted to increase C ave by 36%. Coadministration of zolbetuximab with chemotherapy did not show clinically meaningful changes in drug exposures of zolbetuximab or chemotherapy. At therapeutic doses, zolbetuximab had no clinically meaningful effect on QTc prolongation. In phase 3 studies, zolbetuximab (800 mg/m 2 loading dose/600 mg/m 2 Q3W) had a manageable safety profile and was associated with significant prolongation of progression-free survival (PFS) and overall survival (OS). E-R analyses suggested that higher zolbetuximab exposure may further prolong PFS and OS but with increased probability of gastrointestinal events and infusion-related reactions. E-R model simulations suggested comparable zolbetuximab efficacy and safety between the 800/600 mg/m 2 Q3W regimen and an alternative 800/400 mg/m 2 Q2W regimen for use in combination with chemotherapy. ADAs were detected in 4.4% of patients in phase 3 studies with no apparent impact on zolbetuximab PK, efficacy, or safety. Conclusions: The clinical pharmacology of zolbetuximab was well characterized using data from 9 clinical trials. The integrated data support the proposed 800/600 mg/m 2 Q3W regimen as well as an 800/400 mg/m 2 Q2W regimen in combination with chemotherapy. Clinical trial information: NCT00909025 , NCT01671774 , NCT03528629 , NCT04086758 , NCT01197885 , NCT01630083 , NCT03505320 , NCT03504397 , NCT03653507 . [Table: see text]
One-Year Survival and Hospital-Free Days in Critically Illness After Viral Pneumonia
Authors: Alice Atramont, Guillaume L. Martin, Mervyn Singer, Ayden Tajahmady, Emin Agamaliyev, Michael O. Harhay, Marc Leone, Matthieu Legrand
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"One-Year Survival and Hospital-Free Days in Critically Illness After Viral Pneumonia." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Psychological Treatment of Comorbid Insomnia and Depression: A Double-Blind Randomized Placebo-Controlled Trial
Authors: Kerstin Blom, Erik Forsell, Monica Hellberg, Cecilia Svanborg, Susanna Jernelöv, Viktor Kaldo
Journal: Psychotherapy and Psychosomatics (2024)

&lt;b&gt;&lt;i&gt;Introduction:&lt;/i&gt;&lt;/b&gt; Insomnia and depression are highly prevalent disorders and commonly occur together. Cognitive behavioral therapy for insomnia, CBT-I, has been shown to be effective in treating insomnia and also comorbid depression. However, it is unclear whether effects of CBT-I on depression are specific or nonspecific. Also, depressive symptoms often remain too high after CBT-I, indicating a need for improved treatments. The objective was to determine whether combining CBT-I with CBT for depression, without increasing treatment length, reduces both insomnia and depression more than CBT for depression with a placebo insomnia intervention. &lt;b&gt;&lt;i&gt;Methods:&lt;/i&gt;&lt;/b&gt; A 12-week double-blind randomized controlled trial with a 6-month follow-up in a psychiatric setting using therapist-guided internet-delivered treatments was conducted. Patients (&lt;i&gt;N&lt;/i&gt; = 126) were diagnosed with insomnia disorder and major depression by physicians. Primary outcome measures were as follows: self-rating scales Insomnia Severity Index (ISI) and Montgomery-Åsberg Depression Rating Scale (MADRS-S). &lt;b&gt;&lt;i&gt;Results:&lt;/i&gt;&lt;/b&gt; The combined treatment showed specific effects on insomnia severity over the control treatment (&lt;i&gt;p&lt;/i&gt; = 0.007) but was not more effective in reducing depression severity. Within-group effects (Cohen’s &lt;i&gt;d&lt;/i&gt;) at post and at 6 months were as follows: ISI 1.40 and 1.42 (combined treatment), 0.95 and 1.00 (control); MADRS-S 0.97 and 1.12 (combined), 0.88 and 0.89 (control). &lt;b&gt;&lt;i&gt;Conclusions:&lt;/i&gt;&lt;/b&gt; CBT-I shows large specific effects on insomnia severity and is superior to control in this regard. Both treatments had similar effects on depression severity, i.e., combining CBT-I with CBT for depression did not enhance outcomes on depression compared to control. We suggest CBT-I should always be offered to patients with insomnia and depression comorbidity, possibly as the first-hand choice. Combining it with a psychological treatment for depression could be too burdening and may not be beneficial.
Glioblastoma and radiotherapy: A multicenter AI study for Survival Predictions from MRI (GRASP study)
Authors: Alysha Chelliah, David A Wood, Liane S Canas, Haris Shuaib, Stuart Currie, Kavi Fatania, Russell Frood, Chris Rowland-Hill, Stefanie Thust, Stephen J Wastling, Sean Tenant, Catherine McBain, Karen Foweraker, Matthew Williams, Qiquan Wang, Andrei Roman, Carmen Dragos, Mark MacDonald, Yue Hui Lau, Christian A Linares, Ahmed Bassiouny, Aysha Luis, Thomas Young, Juliet Brock, Edward Chandy, Erica Beaumont, Tai-Chung Lam, Liam Welsh, Joanne Lewis, Ryan Mathew, Eric Kerfoot, Richard Brown, Daniel Beasley, Jennifer Glendenning, Lucy Brazil, Angela Swampillai, Keyoumars Ashkan, Sébastien Ourselin, Marc Modat, Thomas C Booth
Journal: Neuro-Oncology (2024)

The aim was to predict survival of glioblastoma at 8 months after radiotherapy (a period allowing for completing a typical course of adjuvant temozolomide), by applying deep learning to the first brain MRI after radiotherapy completion.
Combination pharmacological therapy targeting multiple mechanisms of sleep apnoea: a randomised controlled cross-over trial
Authors: Scott A Sands, Jinny Collet, Laura K Gell, Nicole Calianese, Lauren B Hess, Daniel Vena, Ali Azarbarzin, Suzanne M Bertisch, Shane Landry, Luke Thomson, Simon A Joosten, Garun S Hamilton, Bradley A Edwards
Journal: Thorax (2024)

Acetazolamide and atomoxetine-plus-oxybutynin ('AtoOxy') can improve obstructive sleep apnoea (OSA) by stabilising ventilatory control and improving dilator muscle responsiveness respectively. Given the different pathophysiological mechanisms targeted by each intervention, we tested whether AtoOxy-plus-acetazolamide would be more efficacious than AtoOxy alone.
Can We Predict Acute Respiratory Distress Syndrome in Hematopoietic Stem Cell Recipients?
Authors: Bruno L. Ferreyro, Elie Azoulay
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"Can We Predict Acute Respiratory Distress Syndrome in Hematopoietic Stem Cell Recipients?." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.
Knockdown of calpain1 in lumbar motoneurons reduces spasticity after spinal cord injury in adult rats.
Authors: Marjorie Kerzonkuf, Jérémy Verneuil, Cécile Brocard, Nejada Dingu, Virginie Trouplin, Jose Jorge Ramirez Franco, Marc Bartoli, Frédéric Brocard, Hélène Bras
Journal: Molecular Therapy (2024)

<h2>Abstract</h2> Spasticity, impacting about 75% of patients with spinal cord injury (SCI), leads to hyperreflexia, muscle spasms and co-contractions of antagonist muscles, greatly affecting their quality of life. Spasticity primarily stems from the hyperexcitability of motoneurons below the lesion, driven by an upregulation of the persistent sodium current and a downregulation of chloride extrusion. This imbalance results from the post-SCI activation of calpain1, which cleaves Nav1.6 channels and KCC2 co-transporters. Our study was focused on mitigating spasticity by specifically targeting calpain1 in spinal motoneurons. We successfully transduced lumbar motoneurons in adult rats with SCI, using intrathecal administration of adeno-associated virus AAV6, carrying a ShRNA sequence against calpain1. This approach significantly reduced calpain-1 expression in transduced motoneurons, leading to a noticeable decrease in spasticity symptoms including hyperreflexia, muscle spasms and co-contractions in hindlimb muscles, particularly evident in the second month post-SCI. Additionally, this decrease that prevented the escalation of spasticity to a severe grade, paralleled with the restoration of KCC2 levels in transduced motoneurons, suggesting a reduced proteolytic activity of calpain1. These findings demonstrate that inhibiting calpain1 in motoneurons is a promising strategy for alleviating spasticity in SCI patients.
Neuromuscular Blockade Improves Results in Acute Respiratory Distress Syndrome: A Mechanism May Be Prevention of Expiratory Muscle Activity, Which Allows More Lung Expansion
Authors: Heder Jonathan de Vries, Gordon Drummond
Journal: American Journal of Respiratory and Critical Care Medicine (2024)

"Neuromuscular Blockade Improves Results in ARDS: A Mechanism May Be Prevention of Expiratory Muscle Activity, Which Allows More Lung Expansion." American Journal of Respiratory and Critical Care Medicine, 0(ja), pp.