tbuckley/cabot-search huggingface dataset:
Quality of life with neoadjuvant ipilimumab (IPI) and nivolumab (NIVO) versus adjuvant nivolumab in resectable stage III melanoma: 36-week data from the phase 3 NADINA trial.
Authors: Minke W. Lucas, Reetta Arokoski, Alexander M. Menzies, Saskia Pulleman, Robyn P.M. Saw, Winan J. van Houdt, Mark B Faries, Caroline Robert, Paolo Antonio Ascierto, Celeste Lebbe, Matteo S. Carlino, Ellen Kapiteijn, Karijn Suijkerbuijk, Piotr Rutkowski, Shahneen Sandhu, Astrid Aplonia Maria Van Der Veldt, Georgina V. Long, Christian U. Blank, Lonneke van de Poll-Franse, Judith Lijnsvelt
Journal: Journal of Clinical Oncology (2024)

LBA9584 Background: Neoadjuvant (neoadj) ipilimumab (IPI) + nivolumab (NIVO) showed improved event-free survival compared to adjuvant (adj) NIVO, but at the cost of increased immune related toxicity (irAEs). In the PRADO trial, impairment of health-related quality of life (HRQoL) was predominantly driven by the extent of the surgery and not by irAEs. To evaluate the effect of neoadj IPI+NIVO on HRQoL, we report the 36w HRQoL outcomes from the phase 3 NADINA trial. Methods: Eligible patients (pts) with resectable, macroscopic stage III melanoma were randomly assigned to receive 2 cycles of neoadj IPI+NIVO followed by a therapeutic lymph node dissection (TLND; w6) and only in partial- or non-responders, 1y of adj systemic treatment; or TLND (w0) followed by 12 cycles adj NIVO. EORTC QLQ-C30 questionnaires (qtn) were digitally collected at baseline, w6, w12 and thereafter q12w. The unadjusted HRQoL scores (scale 0-100) were assessed for pts who completed 39w of follow-up (FU) on January 12, 2024. Results: 261/423 randomized pts had 39w FU at data cutoff. 81% completed the qtn at BL, with thereafter an average compliance of 80%. QLQ-C30 data were available for 107 pts in the neoadj arm and 103 in the adj arm. Physical-, role-, emotional functioning, and pain were comparable between the neoadj and adj arm across all timepoints (Table), as were fatigue and the summary score. A numerical trend towards worsening of physical-, role functioning, and pain was seen at w6 for the adj arm and at w12 for the neoadj arm, representing the post-surgery QoL timepoints. Conclusion: Using fully digitalized data collection, this first HRQoL analysis of neoadj vs adj immunotherapy in stage III melanoma showed comparable results between the neoadj and adj arms. Physical-, role functioning, and pain were impaired in both groups at the first post-surgery timepoint. Clinical trial information: NCT04949113 . [Table: see text]
Phase III randomized trial evaluating tilsotolimod in combination with ipilimumab versus ipilimumab alone in patients with advanced refractory melanoma (ILLUMINATE 301).
Authors: Adi Diab, Paolo Antonio Ascierto, Reham Abdel-Wahab, Michele Maio, Sylvie Negrier, Laurent Mortier, Stéphane Dalle, Ivana Krajsova, Luis de la Cruz, Marie Thérèse Leccia, Michele Guida, Celeste Lebbe, Jean-Jacques Grob, Marcus O. Butler, Gino Kim In, Srinivas Chunduru, Shah Rahimian, Caroline Robert
Journal: Journal of Clinical Oncology (2024)

LBA9516 Background: There are limited treatment options for advanced melanoma that has progressed during or after immune checkpoint inhibitor therapy. Intratumoral (IT) immunotherapy may improve tumor-specific immune activation by promoting local tumor antigen presentation while avoiding systemic toxicities. The Phase 3 ILLUMINATE-301 study (NCT03445533) evaluated tilsotolimod, a toll-like receptor 9 agonist, with or without ipilimumab in patients with anti-programmed death-1 (PD-1)-advanced refractory melanoma. Methods: Patients with unresectable Stage III–IV melanoma that progressed during or after anti-PD-1 therapy were randomized 1:1 to receive 24 weeks of tilsotolimod plus ipilimumab or 10 weeks of ipilimumab alone. Nine IT injections of tilsotolimod were administered to a single designated lesion over 24 weeks. Intravenous ipilimumab 3 mg/kg was administered every 3 weeks from Week 2 in the tilsotolimod arm and Week 1 in the ipilimumab arm. The primary endpoint was efficacy measured using objective response rate (ORR; independent review) and overall survival (OS). Results: A total of481 patients received tilsotolimod plus ipilimumab (n = 238) or ipilimumab alone (n = 243). ORRs were 8.8% in the tilsotolimod arm and 8.6% in the ipilimumab arm, with disease control rates of 34.5% and 27.2%, respectively. Median OS was 11.6 months in the tilsotolimod arm and 10.0 months in the ipilimumab arm (hazard ratio (HR) 0.96 [95% confidence interval (CI) 0.77–1.19]; P = 0.7). Grade ≥3 treatment-emergent adverse events occurred in 61.1% and 55.5% of patients in the tilsotolimod and ipilimumab arms, respectively. Conclusion: Adding tilsotolimod to ipilimumab did not improve response or OS in patients with PD-1 refractory advanced melanoma. However, the results represent the largest prospective dataset reported to date on using ipilimumab in this setting and are a valuable addition to the knowledge base. Clinical trial information: NCT03445533 .
A-BRAVE trial: A phase III randomized trial with avelumab in early triple-negative breast cancer with residual disease after neoadjuvant chemotherapy or at high risk after primary surgery and adjuvant chemotherapy.
Authors: Pier Franco Conte, Maria Vittoria Dieci, Giancarlo Bisagni, Peter Schmid, Vittoria Fotia, Federico Piacentini, Michelino De Laurentiis, Adolfo G. Favaretto, Stefano Tamberi, Giulia Valeria Bianchi, Claudio Zamagni, Saverio Cinieri, Domenico C. Corsi, Lucia Del Mastro, Antonella Ferro, Alessandra Gennari, Marta Mion, Antonino Musolino, Gian Luca De Salvo, Valentina Guarneri
Journal: Journal of Clinical Oncology (2024)

LBA500 Background: Prognosis of pts with early triple negative breast cancer (TNBC) is still poor and new effective treatments are needed. TNBC is the most immunogenic BC subtype, and this may account for sensitivity to immune checkpoint inhibitors. The A-BRAVE trial was designed to evaluate the efficacy of avelumab, an anti PD-L1 antibody, as adjuvant treatment for pts with early TNBC at high risk. Methods: This is a phase III, multicentric, randomized adjuvant study comparing 1 year of treatment with the anti PD-L1 avelumab vs observation for TNBC pts considered at high risk of relapse. Pts were enrolled after they completed standard treatment with curative intent including surgery and neoadjuvant/adjuvant chemotherapy. High risk was defined as: 1) invasive residual disease (breast and/or nodes) after neoadjuvant chemotherapy (Stratum A), 2) &gt;pN2/any pT, pN1/pT2, or pN0/pT3 after primary surgery (Stratum B). Pts were randomly assigned (1:1, balanced for strata A and B) to Avelumab 10 mg/kg I.V. q2w for 1 year or observation. Co-primary endpoints were disease free survival (DFS) in the total population and in Stratum A. 474 pts were needed to detect, in the total population, an improvement from 60% to 73.6% 3-year DFS rate (HR 0.6; 90% power, 1-sided test, alfa 2%). 172 DFS events were required to perform the event-driven analysis. Assuming a proportion of 70-80% pts enrolled in Stratum A, the expected power to detect an HR 0.6 at alpha allocated in this subgroup is 70-79%. Overall survival was a secondary endpoint. Results: From June 2016 to October 2020, 477 pts were randomly assigned from 64 Italian and 6 UK centers. 11 pts (3 avelumab, 8 control) withdrew consent immediately after randomisation and are excluded from further analyses. 378 pts entered Stratum A (83%), of whom 99 (57 avelumab, 42 control) received further chemotherapy after surgery prior to enrollment in the trial. Efficacy results for the two co-primary DFS endpoints and the secondary OS endpoints are reported in the table. Conclusions: One year adjuvant avelumab versus control does not significantly improve DFS in high-risk TNBC patients. Nevertheless, the secondary enpoind OS was significanlty improved with avelumab vs control. RFS and DMFS will also be reported. A centralised collection of tumor tissue, plasma and feces has been performed and will allow a number of correlative studies. Clinical trial information: NCT02926196 . [Table: see text]
Treatment of hemophilic arthropathy by immunomodulatory extracellular vesicle delivered by liposome hybrid nanoparticles
Authors: Dong Wang, Wenzhe Chen, Jiali Chen, Du He, Yanli Pan, Pinger Wang, Qinghe Zeng, Mancang Gu, Peijian Tong, Di Chen, Hongting Jin
Journal: Bioactive Materials (2024)
Adjuvant PD-1 blockade with camrelizumab in high-risk locoregionally advanced nasopharyngeal carcinoma (DIPPER): A multicenter, open-label, phase 3, randomized controlled trial.
Authors: Jun Ma, Ying Sun, Ye-Lin Liang, Xu Liu, Liangfang Shen, Weihan Hu, Guangyuan Hu, Fangyun Xie, Ying Huang, Guorong Zou, Ning Zhang, Chuanben Chen, Xiaozhong Chen, Xiaodong Zhu, Yawei Yuan, Kunyu Yang, Feng Jin, Shu-Bin Hong, Hongyun Zhao, Ji-Bin Li
Journal: Journal of Clinical Oncology (2024)

LBA6000 Background: Patients with high-risk locoregionally advanced nasopharyngeal carcinoma (NPC) often experience disease relapse even after receiving standard-of-care treatment, e.g. induction chemotherapy (IC) followed by concurrent chemoradiotherapy (CCRT). The benefit of PD-1 inhibitor as adjuvant treatment following IC+CCRT in locoregionally advanced NPC remains unclear. Methods: Patients with high-risk locoregionally advanced NPC (T4N1M0 or T1-4N2-3M0) who have received gemcitabine and cisplatin (GP) IC and CCRT were recruited at 11 centers in China. They were randomly assigned (1:1) within 2 weeks after the last radiation dose to receive intravenous camrelizumab (200 mg once every 3 weeks for 12 cycles; Camrelizumab Arm) or observation (Standard-therapy Arm). The primary endpoint was event-free survival (EFS). It is estimated that approximately 442 patients would provide 80% power to detect a hazard ratio (HR) of 0.52 with a log-rank test at a two-sided α level of 0.05. Quality of life (QoL) was assessed by EORTC-C30. Results: A total of 450 patients were randomly assigned to the Camrelizumab Arm (n=226) and the Standard-therapy Arm (n=224). After a median follow-up of 37 months (corresponding to 41 months when calculated from the start of standard therapy), the estimated 3-year EFS was 86.9% in the Camrelizumab Arm and 77.4% in the Standard-therapy Arm (intention-to-treat population; HR 0.61, 95% CI 0.38–0.96; P = 0.03). The incidence of grade 3-4 adverse events (AEs) was 11.2% in the Camrelizumab Arm and 3.2% in the Standard-therapy Arm, including grade 3-4 immune-related AEs in 8 (3.9%) patients in the Camrelizumab Arm. Reactive capillary endothelial proliferation was the most common adverse event related to camrelizumab (RECP, 87.8%, 4 (1.8%) patients had grade 3 RECP). Treatment-related deaths occurred in 1 (&lt;1%) patients in the Camrelizumab group (subarachnoid hemorrhage) and 1 (&lt;1%) patients in the Standard-therapy group (nasopharyngeal necrosis). During treatment, there was no clinically meaningful deterioration of health-related quality of life associated with the use of adjuvant camrelizumab. Conclusions: Adjuvant PD-1 blockade with camrelizumab significantly improved EFS in high-risk locoregionally advanced NPC, with mild toxicity and comparable quality of life. Clinical trial information: NCT03427827 . [Table: see text]
Prognostic utility of ctDNA detection in the monarchE trial of adjuvant abemaciclib plus endocrine therapy (ET) in HR+, HER2-, node-positive, high-risk early breast cancer (EBC).
Authors: Sherene Loi, Stephen R. D. Johnston, Carlos L. Arteaga, Stephanie L. Graff, Sarat Chandarlapaty, Matthew P. Goetz, Christine Desmedt, Hironobu Sasano, Deli Liu, Vanessa Rodrik-Outmezguine, Anthony Sireci, Cynthia Sandoval, Helen H Won, Lacey M Litchfield, Nicholas C. Turner
Journal: Journal of Clinical Oncology (2024)

LBA507 Background: In monarchE (NCT03155997), 2 years of adjuvant abemaciclib + ET resulted in sustained improvement in invasive disease-free survival (IDFS; HR=0.680, 7.6% absolute benefit at 5 years) in patients (pts) with HR+, HER2-, node-positive, high-risk EBC. Here, we investigate the prognostic value of ctDNA detection and dynamics in pts from monarchE. Methods: Samples were analyzed from a selected pt subset (n=1397; abemaciclib + ET arm, n=685; ET arm, n=712), enriched for overall IDFS events compared to the total monarchE study population (IDFS event rate: 31% [433/1397] vs 18% [992/5637]). Pts had blood collected pre-study treatment (baseline) and at 3, 6, or 24 months. ctDNA detection was performed using the personalized, tumor informed Signatera ctDNA assay (Natera, Inc) and whole exome sequencing (WES) of matched primary tumor and normal required for assay design was performed. Results: Among 1397 pts, 65% (n=910) had sufficient plasma samples and WES performed, and all 910 had successful ctDNA assay testing. Among these 910 pts, the IDFS event rate was 27% (abemaciclib + ET, 23% [101/438]; ET alone, 31% [146/472]). Rates of ctDNA positivity (at baseline and any change from baseline) and associated IDFS events are shown in Table. Among pts with ctDNA positivity, 87% had an IDFS event in comparison to 15% with persistent ctDNA negative (-) status during the study. Conclusions: In a pt subset from monarchE enriched for IDFS events, ctDNA detection was relatively infrequent (&lt;20%); however, its detection at any time during the 24 months of study therapy was adversely prognostic. As compared to pts who had remaining ctDNA positive (+), pts who had clearance of ctDNA on therapy had lower risk of IDFS events, but the event risk still remained clinically meaningful in these pts. Clinical trial information: NCT03155997 . [Table: see text]
Active control of pharmacokinetics using light-responsive polymer-drug conjugates for boron neutron capture therapy
Authors: Daiki Tokura, Kakeru Konarita, Minoru Suzuki, Keisuke Ogata, Yuto Honda, Yutaka Miura, Nobuhiro Nishiyama, Takahiro Nomoto
Journal: Journal of Controlled Release (2024)

In boron neutron capture therapy (BNCT), boron drugs should exhibit high intratumoral boron concentrations during neutron irradiation, while being cleared from the blood and normal organs. However, it is usually challenging to achieve such tumor accumulation and quick clearance simultaneously in a temporally controlled manner. Here, we developed a polymer-drug conjugate that can actively control the clearance of the drugs from the blood. This polymer-drug conjugate is based on a biocompatible polymer that passively accumulates in tumors. Its side chains were conjugated with the low-molecular-weight boron drugs, which are immediately excreted by the kidneys, via photolabile linkers. In a murine subcutaneous tumor model, the polymer-drug conjugate could accumulate in the tumor with the high boron concentration ratio of the tumor to the surrounding normal tissue (∼10) after intravenous injection while a considerable amount remained in the bloodstream as well. Photoirradiation to blood vessels through the skin surface cleaved the linker to release the boron drug in the blood, allowing for its rapid clearance from the bloodstream. Meanwhile, the boron concentration in the tumor which was not photoirradiated could be maintained high, permitting strong BNCT effects. In clinical BNCT, the dose of thermal neutrons to solid tumors is determined by the maximum radiation exposure to normal organs. Thus, our polymer-drug conjugate may enable us to increase the therapeutic radiation dose to tumors in such a practical situation.
Epidemiology of early vs. Late recurrence among women with Early-Stage estrogen Receptor-Positive breast cancer in the pathways study
Authors: Alfredo V Chua, Haiyang Sheng, Emily Liang, Shipra Gandhi, Marilyn L Kwan, Isaac J Ergas, Janise M Roh, Cecile A Laurent, Li Yan, Thaer Khoury, Christine B Ambrosone, Lawrence H Kushi, Song Yao
Journal: JNCI Journal of the National Cancer Institute (2024)

Abstract Background Relatively little is known about the differences in prognostic factors for early vs late recurrence among women with early stage estrogen receptor–positive breast cancer. Methods We analyzed factors related to early (&amp;lt;5 years) vs late (≥5 years) recurrence in 2992 women with stage I-IIB estrogen receptor–positive breast cancer in the Pathways Study, a prospective cohort of women with breast cancer enrolled between 2006 and 2013, with ascertainment of recurrence and death through December 2021. Results After a median follow-up of 13.3 years, 341 (13.8%) women had recurrences, including 181 (53.7%) with late recurrence. Higher stage and grade were associated with recurrence regardless of timing, whereas progesterone receptor negativity was associated with early but not late recurrence. Receipt of endocrine therapy was associated with reduced risk of overall recurrence, but the length of endocrine therapy was not statistically significant in multivariable models. Minoritized racial and ethnic groups, including Asian, Black, and Hispanic women, had higher risk of early but not late recurrence compared to non-Hispanic White women. The trend of higher risk of early recurrence among these groups remained after adjustment for clinical, demographic, and socioeconomic factors but was statistically significant only in Asian women. Conclusions Our study revealed potentially important distinctions for early vs late recurrence, including the associations with progesterone receptor negativity and self-identified race and ethnicity. Possible higher risk of early recurrence among Asian, Black, and Hispanic women provides novel evidence for the existence of disparities in cancer outcomes, even within the breast cancer subtype indicative of generally good prognosis.
Stepwise dual-release microparticles of BMP-4 and SCF in induced pluripotent stem cell spheroids enhance differentiation into hematopoietic stem cells
Authors: Alvin Bacero Bello, Kevin Kent Vincent Canlas, Deogil Kim, Hansoo Park, Soo-Hong Lee
Journal: Journal of Controlled Release (2024)

Recently, the formation of three-dimensional (3D) cell aggregates known as embryoid bodies (EBs) grown in media supplemented with HSC-specific morphogens has been utilized for the directed differentiation of embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), into clinically relevant hematopoietic stem cells (HSCs). However, delivering growth factors and nutrients have become ineffective in inducing synchronous differentiation of cells due to their 3D conformation. Moreover, irregularly sized EBs often lead to the formation of necrotic cores in larger EBs, impairing differentiation. Here, we developed two gelatin microparticles (GelMPs) with different release patterns and two HSC-related growth factors conjugated to them. Slow and fast releasing GelMPs were conjugated with bone morphogenic factor-4 (BMP-4) and stem cell factor (SCF), respectively. The sequential presentation of BMP-4 and SCF in GelMPs resulted in efficient and effective hematopoietic differentiation, shown by the enhanced gene and protein expression of several mesoderm and HSC-related markers, and the increased concentration of released HSC-related cytokines. In the present study, we were able to generate CD34+, CD133+, and FLT3+ cells with similar cellular and molecular morphology as the naïve HSCs that can produce colony units of different blood cells, in vitro.
Drug solubilization in dog intestinal fluids with and without administration of lipid-based formulations
Authors: Albin Parrow, Aleksei Kabedev, Per Larsson, Pernilla Johansson, Bertil Abrahamsson, Christel A S Bergström
Journal: Journal of Controlled Release (2024)

The use of animal experiments can be minimized with computational models capable of reflecting the simulated environments. One such environment is intestinal fluid and the colloids formed in it. In this study we used molecular dynamics simulations to investigate solubilization patterns for three model drugs (carvedilol, felodipine and probucol) in dog intestinal fluid, a lipid-based formulation, and a mixture of both. We observed morphological transformations that lipids undergo due to the digestion process in the intestinal environment. Further, we evaluated the effect of bile salt concentration and observed the importance of interindividual variability. We applied two methods of estimating solubility enhancement based on the simulated data, of which one was in good qualitative agreement with the experimentally observed solubility enhancement. In addition to the computational simulations, we also measured solubility in i) aspirated dog intestinal fluid samples and ii) simulated canine intestinal fluid in the fasted state, and found there was no statistical difference between the two. Hence, a simplified dissolution medium suitable for in vitro studies provided physiologically relevant data for the systems explored. The computational protocol used in this study, coupled with in vitro studies using simulated intestinal fluids, can serve as a useful prescreening tool in the process of drug delivery strategies development.
Alendronate-functionalized porous nano-crystalsomes mitigate osteolysis and consequent inhibition of tumor growth in a tibia-induced metastasis model
Authors: Ravi Prakash Shukla, Pratiksha Tiwari, Anirban Sardar, Sandeep Urandur, Shalini Gautam, Disha Marwaha, Ashish Kumar Tripathi, Nikhil Rai, Ritu Trivedi, Prabhat Ranjan Mishra
Journal: Journal of Controlled Release (2024)
Polymeric cGAMP microparticles affect the immunogenicity of a broadly active influenza mRNA lipid nanoparticle vaccine
Authors: Dylan A Hendy, Yutian Ma, Timothy A Dixon, Connor T Murphy, Erik S Pena, Michael A Carlock, Ted M Ross, Eric M Bachelder, Kristy M Ainslie, Owen S Fenton
Journal: Journal of Controlled Release (2024)
Dual-targeted nanoparticulate drug delivery systems for enhancing triple-negative breast cancer treatment
Authors: Shunzhe Zheng, Meng Li, Wenqian Xu, Jiaxin Zhang, Guanting Li, Hongying Xiao, Xinying Liu, Jianbin Shi, Fengli Xia, Chutong Tian, Ken-Ichiro Kamei
Journal: Journal of Controlled Release (2024)
WED-324 Use of FIB4 as a screening test in the bariatric population instead of the NAFLD fibrosis score reduces referral rate to hepatology without reducing identification of significant fibrosis: a retrospective audit
Authors: Michael Carbonell, Craig Lennie, Nuala Davison, Naim Fakih Gomez, Veronica Greener, R. Daniel Abeles
Journal: Journal of Hepatology (2024)
SAT-215 Healthcare cost and resource utilization among patients with non-alcoholic steatohepatitis (NASH), stratified by glucagon-like peptide 1 receptor agonist (GLP-1) use in real world data
Authors: Yestle Kim, Jesse Fishman, Elliot Tapper, Dave Lewandowski, Taylor Marlin, Alina Bogdanov, Machaon Bonafede
Journal: Journal of Hepatology (2024)
FRI-197 Implication of recent international consensus criteria for metabolic hyperferritinemia diagnosis and grade in a large cohort of patient with hepatic iron content assessed by magnetic resonance imaging
Authors: Sophie Stephant, Oumnia Masrour, Laine Fabrice, Jeff Morcet, Yves Gandon, Edouard Bardou-Jacquet
Journal: Journal of Hepatology (2024)
SAT-196 A significant decrease in steatosis using non-invasive measurements during monitoring for life style changes in patients with MASLD: interim 6 m results of a monocentric study
Authors: Wouter Robaeys, Leen Heyens, Struyve Mathieu, Gert Stockmans, Kirsten Cardone, Joop Arends, Ger Koek, Geert Robaeys, Joris Penders, Sven Francque
Journal: Journal of Hepatology (2024)
WED-251 Plasma lipidomic profiling of subjects with overweight or obesity following treatment with the glucagon-like peptide 1/glucagon dual receptor agonist pemvidutide: an investigation of lipid signatures associated with metabolic dysfunction-associated steatohepatitis
Authors: John Suschak, Bertrand Georges, Sarah Browne, Cristina Alonso, M. Scot Roberts, M. Scott Harris
Journal: Journal of Hepatology (2024)
THU-500 Networks in focus: profile of immune-related adverse events in first-line immunotherapy for hepatocellular carcinoma
Authors: Marta Fortuny, Marta García-Calonge, Oscar Arrabal, Marco Sanduzzi Zamparelli, Andrés Castano-Garcia, Gemma Iserte, Ana Maria Piedra-Cerezal, Neus Llarch, Ezequiel Mauro, Alicia Mesa, Manuel Rodriguez, Belen Saborido, Jordi Rimola, Ferran Torres, Maria Varela, María Reig
Journal: Journal of Hepatology (2024)