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Prevalence and Patterns of Opioid Use in Chronic Pancreatitis
No full textIntroduction: Opioids are used to treat pain in chronic pancreatitis (CP), but little is known about current use patterns. The aim of this study was to characterize the utilization of opioids and associations with clinical characteristics in adult patients with CP.
Methods: This cross-sectional analysis used baseline data from participants with definite CP enrolled in a cohort study in the United States (PROspective Evaluation of CP for EpidEmiologic and Translational StuDies). Data on demographics, pain medication use, healthcare utilization, disability, and pain patterns were systematically collected in case report forms while quality of life was assessed with patient-reported outcome instruments. Opioid use was classified according to strength (weak or strong) and frequency (scheduled or as-needed).
Results: A total of 681 participants (n = 364, 53% male) were included: 299 (44%) were current opioid users (22% only weak opioids and 22% at least 1 strong opioid). Increasing frequency and severity of pain was associated with increase of weak, strong, as-needed, or scheduled opioids. Neuromodulators were used by ∼40% of participants; increasing use was associated with increasing frequency and severity of pain. On multivariate analysis, independent predictors associated with strength and frequency of current opioid use were pain patterns (odds ratios [ORs] 1.84-8.32 and ORs 1.92-8.52, respectively, P \u3c 0.001) and prior celiac plexus block (OR 3.54, 95% confidence intervals 1.82-6.87 and OR 3.42, 95% confidence intervals 1.76-6.64, respectively). Participants using opioids had higher prevalence of disability, healthcare utilization, and poorer quality of life.
Discussion: Opioid use in CP is common and associated with increased pain severity and constancy. These data provide foundational estimates for future trials that can elucidate the complex interactions between patient factors, pain, and interventions
BCL-2/BCL-XL Dual Inhibition Triggers Gasdermin D-Mediated Pyroptosis in Mantle Cell Lymphoma
No full textMesenchymal Stem Cells Loaded in Injectable Alginate Hydrogels Promote Liver Growth and Attenuate Liver Fibrosis in Cirrhotic Rats
No full textCirrhosis, a marker of severe liver diseases, limits future liver remnant (FLR) growth, preventing many cancer patients from undergoing surgery. While portal vein blockade (PVB) techniques are used to stimulate liver regeneration, 20-30% of patients still fail to achieve the required growth. Although mesenchymal stem cell (MSC) therapy improves PVB, its efficacy is limited by poor cell retention. To address this, we utilized alginate hydrogels to deliver MSCs and improve their retention. MSCs were loaded in the hydrogel and injected intraportally in cirrhotic rats. Liver volume, weights, enzyme levels, and histology were monitored. Results showed that the hydrogel maintained 89.0 ± 3.0% cell viability and gradually released MSCs for over two weeks. Furthermore, the rats injected with the MSC-loaded hydrogel demonstrated higher liver volumes (FLR ratio of 0.57 ± 0.32) and weights (FLR ratio of 0.84 ± 0.05). The treated rats exhibited more improved liver enzymes (AST: 72.75 ± 14.17 U/L, ALP: 135.67 ± 41.20 U/L, ALT: 46.00 ± 2.94 U/L) and decreased fibrotic areas in the liver (4.52 ± 0.22%) compared to the control group. Histology revealed increased retention when MSCs were delivered with the hydrogel (37.30 ± 16.10 MSCs/m
TIGIT Inhibitor M6223 As Monotherapy or in Combination With Bintrafusp Alfa in Patients With Advanced Solid Tumors: A First-in-Human, Phase 1, Dose-Escalation Trial
No full textBackground: M6223 is an intravenous (IV), Fc-competent, fully human, antagonistic, anti-T cell immunoreceptor with immunoglobulin and immunoreceptor tyrosine-based inhibitory motif domains (TIGIT) antibody. Bintrafusp alfa (BA) is a bifunctional fusion protein that simultaneously blocks nonredundant immunosuppressive TGF-β and PD-(L)1 pathways.
Methods: This first-in-human, dose-escalation study in patients with advanced solid tumors (N=58; aged ≥18 years, ECOG PS≤1) evaluated M6223 alone (Part 1A, n=40; M6223 10-2400 mg every 2 weeks, n=32; M6223 2400 mg every 3 weeks, n=8) or with BA (Part 1B, n=18; M6223 300-1600 mg with BA 1200 mg; both every 2 weeks, intravenous). Primary objectives were safety, tolerability, maximum tolerated dose (MTD) and recommended dose for expansion (RDE). Additional objectives included pharmacokinetics, pharmacodynamics and clinical activity (NCT04457778).
Results: Two dose-limiting toxicities were observed: grade 3 adrenal insufficiency (Part 1A: M6223 900 mg every 2 weeks) and grade 3 anemia (Part 1B: M6223 300 mg, only BA related). MTD was not reached. Overall, median overall survival and progression-free survival were 7.6 (95% CI 4.9, 12.0) and 1.4 (95% CI 1.3, 1.8) months, respectively. Stable disease as best response was observed in 13 (32.5%) and 5 (27.8%) patients in parts 1A and 1B, respectively. M6223±BA displayed a linear pharmacokinetic profile. Anti-TIGIT mode-of-action-related pharmacodynamic effects were observed in peripheral blood and in tumor tissue. RDEs were 1600 mg every 2 weeks or 2400 mg every 3 weeks for M6223 monotherapy and 1600+1200 mg every 2 weeks for M6223+BA.
Conclusions: M6223±BA had a manageable safety profile, with RDEs defined for both monotherapy and combination therapy. Further evaluation of M6223 is ongoing in combination with the PD-L1 inhibitor avelumab in patients with advanced urothelial carcinoma (JAVELIN Bladder Medley; NCT05327530)
Interactive 3D Segmentation for Primary Gross Tumor Volume in Oropharyngeal Cancer
No full textRadiotherapy is the main treatment modality of oropharyngeal cancer (OPC), in which an accurate segmentation of primary gross tumor volume (GTVt) is essential but also challenging due to significant interobserver variability and the time consumed in manual tumor delineation. For such a challenge an interactive deep learning (DL) based approach offers the advantage of automatic high-performance segmentation with the flexibility for user correction when necessary. In this study, we investigate an interactive DL for GTVt segmentation in OPC by introducing a novel two-stage Interactive Click Refinement (2S-ICR) framework and implementing state-of-the-art algorithms. Using the 2021 HEad and neCK TumOR dataset for development and an external dataset from The University of Texas MD Anderson Cancer Center for evaluation, the 2S-ICR framework achieves a Dice similarity coefficient of 0.722 ± 0.142 without user interaction and 0.858 ± 0.050 after ten interactions, thus outperforming existing methods in both cases
Acquired Resistance in Cancer: Towards Targeted Therapeutic Strategies
Get PDFDevelopment of acquired therapeutic resistance limits the efficacy of cancer treatments and accounts for therapeutic failure in most patients. How resistance arises, varies across cancer types and differs depending on therapeutic modalities is incompletely understood. Novel strategies that address and overcome the various and complex resistance mechanisms necessitate a deep understanding of the underlying dynamics. We are at a crucial time when innovative technologies applied to patient-relevant tumour models have the potential to bridge the gap between fundamental research into mechanisms and timing of acquired resistance and clinical applications that translate these findings into actionable strategies to extend therapy efficacy. Unprecedented spatial and time-resolved high-throughput platforms generate vast amounts of data, from which increasingly complex information can be extracted and analysed through artificial intelligence and machine learning-based approaches. This Roadmap outlines key mechanisms that underlie the acquisition of therapeutic resistance in cancer and explores diverse modelling strategies. Clinically relevant, tractable models of disease and biomarker-driven precision approaches are poised to transform the landscape of acquired therapy resistance in cancer and its clinical management. Here, we propose an integrated strategy that leverages next-generation technologies to dissect the complexities of therapy resistance, shifting the paradigm from reactive management to predictive and proactive prevention
Phase 1/2 Trial of Encorafenib, Cetuximab, and Nivolumab in Microsatellite Stable BRAFV600E Metastatic Colorectal Cancer
No full textThe BRAF inhibitor encorafenib and anti-epidermal growth factor receptor (EGFR) antibody cetuximab modestly improve survival for patients with microsatellite stable (MSS) BRAFV600E metastatic colorectal cancer (mCRC), characterized by higher immune activation than MSS BRAFwild-type colorectal cancer (CRC). In this phase 1/2 study (NCT04017650) of 26 participants with MSS BRAFV600E mCRC who received encorafenib, cetuximab, and anti-PD-1 antibody nivolumab, we report an overall response rate of 50% (95% confidence interval [CI] 29-71) and median progression-free survival of 7.4 months (95% CI, 5.6-9.6). Transcriptomic profiling of pretreatment biopsies and extracellular vesicle RNA (evRNA) isolated from plasma show enrichment of non-canonical mitogen-activated protein kinase (MAPK) signaling and immune activation signatures for responders. Complement pathway activation enriches in non-responder biopsies. On serial evRNA profiling, decreased MAPK signature and increased interferon gamma response signature associate with sustained treatment benefit. MSS BRAFV600E mCRC with baseline MAPK activation and immune activation signatures may benefit from the triple combination but not with complement pathway activation
De-Escalating Local Therapies Without Compromising Outcomes: Lessons From the Collision Trial
No full textDeciphering Transcriptomic Changes in Chemobrain: A Comprehensive Review
No full textChemotherapy-induced cognitive impairments (CICI), colloquially known as chemobrain, represents a profound and debilitating side effect experienced by a significant number of cancer survivors, impacting their memory, multitasking, and quality of life. This review critically evaluates the molecular mechanisms underlying CICI, with a particular focus on the insights gained from transcriptomic analyses. As cancer incidence rises globally, understanding the complex interplay between chemotherapy agents and their cognitive repercussions becomes increasingly vital. Key mechanisms implicated in CICI include blood-brain barrier disruption, neuroinflammation, and oxidative stress as a result of various chemotherapy treatments, such as doxorubicin, cisplatin, and paclitaxel. We delve into advanced transcriptomic methodologies including RNA sequencing, cDNA microarrays, and single-cell transcriptomics that elucidate the alteration in gene expression profiles associated with CICI and provide a deeper understanding of the underlying pathophysiological processes. Furthermore, we emphasize the importance of developing comprehensive single-cell atlases and employing spatial transcriptomics to uncover cellular heterogeneity and the spatial dynamics of gene expression across different brain regions. This review consolidates the existing literature on the transcriptomic profile of CICI, highlighting potential genes and pathways while suggesting future research avenues aimed at mitigating cognitive dysfunction. Ultimately, integrating transcriptomic findings with clinical insights is essential for the development of targeted, personalized interventions, thereby improving cognitive health and overall quality of life for cancer survivors dealing with long-term impacts of their treatment
Status of Abortion Curriculum in Genetic Counseling: Survey of Graduate Programs and Recent Graduates in the United States
No full textGenetic counselors (GCs) are trained to help individuals navigate the medical and psychological implications of genetic test results, familial conditions, and ultrasound anomalies. Therefore, familiarity with reproductive options, including abortion, is vital. However, previous studies have found gaps in GCs\u27 knowledge regarding abortion care and there are currently no recommendations regarding abortion curriculum. This study aimed to assess the state of abortion curriculum in genetic counseling graduate programs in the United States and to examine and compare the satisfaction levels of program representatives and recent graduates. Program representatives and recent graduates were invited to complete an anonymous survey evaluating the abortion curriculum, satisfaction with said curriculum, and perceived preparedness to counsel on abortion. Quantitative data from 46 program representatives and 123 recent graduates were analyzed using descriptive statistics and appropriate statistical analyses, including the Mann-Whitney U-test and the Kruskal-Wallis test. Large variability existed in the amount and types of abortion training. Results showed greater satisfaction and feelings of preparation to counsel on abortion in graduates whose program provided a dedicated abortion curriculum (p \u3c 0.001, p = 0.005). In addition, graduates with abortion counseling experience felt less prepared to counsel on abortion than their programs believed them to be (p = 0.04). Graduates perceived procedural timing, facilitation of genetic testing, and resources/support desired by patients before, during, or after an abortion, to be the most important topics, although these were not included in all programs\u27 curriculum. Program representatives and recent graduates alike noted that variability in clinical training is a barrier to abortion education. Our results demonstrate a need for curricular reform to reduce variability in training and ensure that all graduates receive the same foundational abortion education. Further research is needed to determine the scope of GCs in abortion care, as well as which topics and education formats are most helpful in graduate education