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Biofilms are structured communities of microorganisms embedded in a self-produced extracellular polymeric substance (EPS) matrix, whose development significantly enhances microbial resistance to antibiotics, disinfectants, and host immune defenses, posing major challenges in clinical, industrial, and environmental settings. Compared with planktonic cells, biofilm-associated microorganisms can exhibit up to 10- to 1000-fold increased tolerance to antimicrobial agents, contributing to the persistence of biofilm-associated infections (BAIs). These infections remain difficult to eradicate due to reduced penetration, altered metabolic states, and the presence of dormant or persister cells. Anti-biofilm strategies can be broadly classified into physical approaches (e.g., ultrasound, mechanical stress, and light-based approaches) that target biofilm structure; chemical and enzymatic methods (e.g., EPS-degrading enzymes) that destabilize the matrix; and biological and molecular strategies (e.g., quorum-sensing (QS) inhibitors, anti-virulence agents, bacteriophages, phage-derived antimicrobial molecules, antimicrobial peptides, and natural bioactive compounds) that modulate biofilm development and integrity by targeting regulatory pathways and matrix stability through distinct mechanisms of action. Natural compounds, including lactoferrin, lactoferrin-derived peptides, and probiotic and postbiotic fractions of lactic acid bacteria (LAB), as well as plant-derived metabolites, have shown promising anti-biofilm effects, with efficacy often enhanced through complementary or potentially synergistic interactions. However, despite these advancements, clinical translation remains limited. For example, BAIs account for approximately 80% of chronic infections, with high recurrence rates and therapeutic failure reported in device-associated infections and chronic wounds. These limitations highlight the need for clinically translatable, multimodal approaches that integrate structural biofilm disruption, antimicrobial targeting, and host response modulation to design more effective and sustainable anti-biofilm strategies.
Significant correlations exist between the presence of intratumoral macrophages, tumor progression, and poor outcomes in triple-negative breast cancer (TNBC) with limited therapeutic options available for advanced-stage disease. Preclinical studies revealed that inhibition of myelomonocytic colony-stimulating factor 1 (CSF1) or its receptor (CSF1R) plus cytotoxic chemotherapy decreased primary tumor growth kinetics and pulmonary metastases by CD8+ T cell-dependent mechanisms. This translational study evaluated CSF1R inhibition combined with eribulin in metastatic TNBC and explored rational preclinical combination strategies with PD-1/PD-L1 blockade based on clinical immune correlate analyses. A nonrandomized, open-label phase Ib/2 trial (NCT01596751) evaluated pexidartinib (PLX3397), a CSF1R inhibitor (CSF1Ri), plus eribulin mesylate in heavily pretreated individuals with metastatic TNBC. Clinical efficacy was assessed alongside peripheral blood correlates. Preclinical studies in transgenic mammary adenocarcinoma models examined biomarker-driven therapy combinations. The 12-week progression-free survival rate was 36% (95% confidence interval, 22.2%-58.4%), with 44.8% of patients achieving clinical benefit; a subset experienced disease control beyond 6 months. Patients with partial response or stable disease demonstrated increased baseline leukocyte activation, including enrichment of CD8+ and CD4+ memory T cells and increased PD-1 expression on CD4+ T cells. In preclinical studies, CSF1Ri expanded the therapeutic index of PD-1 blockade, yielding transient tumor regression in ∼60% of mice and a transient expansion of effector and resident memory T cells. These clinical and preclinical findings provide rationale for therapies to increase the therapeutic index of αPD-1 therapy by diminishing the presence of T cell-suppressive myelomonocytic cells to improve outcomes for patients with refractory disease.
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Oncolytic viruses (OVs) have emerged as a promising cancer therapy due to their natural selectivity to replicate in and destroy cancer cells. However, despite encouraging preclinical and early clinical outcomes, the therapeutic efficacy of OVs in solid tumors remains limited. Recently, OVs have been genetically modified to enhance tumor specificity, promote antitumor immune activation, and overcome barriers imposed by the tumor microenvironment (TME). Hepatocellular carcinoma presents a uniquely challenging solid tumor microenvironment for oncolytic virotherapy, characterized by dense fibrotic stroma, potent hepatic immune clearance, and immunosuppressive signaling that collectively limit viral delivery, intratumoral spread, and therapeutic efficacy. The review provides an updated overview of clinical and preclinical studies of naturally occurring and engineered OVs, with a particular focus on the biological and translational challenges that restrict their effectiveness in HCC. In addition, it highlights the strategies developed to overcome delivery barriers, immune clearance, and tumor heterogeneity, which represent key obstacles to durable therapeutic responses. Strategies such as stromal targeting, hypoxia-adapted constructs, and the use of 3D organoid models as mimic platforms to evaluate delivery and therapeutic strategies are also discussed. Finally, this review aims to integrate recent advances in viral engineering, immune modulation, and organoid models, and critically evaluates how these approaches, together with emerging clinical trial data, can inform the rational design of next-generation oncolytic viruses.
The HGF/SF (hepatocyte growth factor/scatter factor) receptor tyrosine kinase MET is overexpressed and/or activated in many tumors, providing therapeutic targets for antibody-drug conjugates and tyrosine kinase inhibitors. Reliable measurement of activated MET is fundamental for pharmacodynamic assessment of MET-targeted therapies and for expanded and proper use of such therapies in patients with tumors driven by activated MET with or without associated MET amplification or known activating mutations. To address the paucity of tools for directly measuring MET activation in tumor cells within patient biopsy specimens, we developed a robust, quantitative immunofluorescence microscopy assay to measure levels of pY1235MET and total MET in in vitro, in vivo, and patient tumor specimens. We validated this assay through assessment of MET inhibitor-treated preclinical models, peptide blocking experiments to demonstrate specificity, and concordance with corresponding measurements from the same specimens using a previously validated sandwich immunoassay of tumor lysates. Given the importance of plasma membrane-associated MET in initiating its canonical signaling cascades, as well as the demonstrated non-canonical signaling from nuclear localized MET in different tumor cell types and in response to various environmental stimuli, we developed assay capability to measure levels of pY1235MET and total MET within the plasma membrane or nucleus; these assays enable future explorations of the biological and clinical relevance of MET subcellular localization patterns. Finally, using tissue microarrays of over 50 resected tumor specimens from patients with colorectal carcinoma or non-small cell lung cancer, we demonstrated that tumor levels of pY1235MET do not always track total MET expression, suggesting that measurement of activated MET in tumor could hold potential as an independent biomarker to identify additional patients who might benefit from MET-directed targeted therapy-beyond those with tumor MET amplification, MET overexpression, or established MET-activating mutations.
A substantial proportion of individuals with a well-defined monogenic disorder remain without a genetic diagnosis. Low-level mosaic pathogenic variants are recognised as an underappreciated cause of monogenic disease but are technically challenging to detect, particularly in organ-specific conditions when affected tissue is inaccessible. We systematically investigated low-level mosaic variants in individuals with congenital hyperinsulinism (CHI: n = 1252) or neonatal diabetes (NDM: n = 312), two opposing pancreatic disorders of insulin secretion. We screened for established pathogenic variants with variant allele fraction (VAF) < 8% in dominant CHI (ABCC8, GCK, GLUD1, HK1) or dominant NDM (ABCC8, KCNJ11, INS) genes in targeted next-generation sequencing (tNGS) data using Mutect2. This called 40 variants across the four genes in 39 individuals with CHI. No candidate variants were found in the NDM cohort. Orthogonal validation of 35 variants using TaqMan-based droplet digital PCR (ddPCR) confirmed 26/35 variants. The median VAF for confirmed variants was 3.6% (1.0-7.8%), while false positives (9/35) predominantly had a VAF <1% with some overlap in VAF with true positives. This study shows that disease-causing low-level mosaic variants in dominant CHI genes can be detected in blood using tNGS but require orthogonal validation. These results provide a framework to improve diagnostic yield in organ-specific conditions where mosaic variants may represent an important missed cause of disease. This work was supported by a research grant from the University of Pennsylvania Orphan Disease Center in partnership with the Team CHIbra and Congenital Hyperinsulinism International [MDBR-23-020-CHI] and the Wellcome Trust [223187/Z/21/Z].
Decentralized clinical trials using direct-to-participant recruitment can potentially engage large, representative participant pools. The objective of the study was to share insights on multichannel strategies for participant recruitment in the decentralized Heartline Study, a randomized trial testing the impact of a mobile application-based heart health program with the electrocardiogram and Irregular Rhythm Notification features on an Apple Watch for early diagnosis, treatment, and outcomes of atrial fibrillation. Eligible participants were U.S. adults aged ≥65 years with an iPhone and Medicare coverage. Multiple pathways for broad outreach were explored, including digital (eg, email, social media) and traditional channels (eg, direct mail, community outreach). Recruitment efforts were assessed and refined throughout the study to maximize reach. Across multiple channels, 321,272 Heartline Study applications were installed, with 34,244 participants (11%) completing enrollment (February 2020-December 2022) and 82% (28,155/34,244) completing baseline demographic assessments. Women accounted for 54.2% (15,258/28,155) of study participants; 93.0% identified as White (26,192/28,155), 2.8% Asian (781/28,155), 2.7% Black (747/28,155), and 2.5% Hispanic (699/28,155). Broad geographic representation throughout the United States was achieved. The Heartline Study demonstrated the ability to recruit large numbers of participants aged ≥65 years. A direct-to-participant approach across multiple channels achieved excellent gender and geographic diversity, enrolling a higher percentage of women than typical cardiology trials and participation from rural areas. However, less racial and ethnic representation was achieved, highlighting the need for additional strategies to meet this goal. Future trials may consider such multichannel recruitment approaches to support decentralized clinical trials. (A Study to Investigate if Early Atrial Fibrillation [AF] Diagnosis Reduces Risk of Events Like Stroke in the Real-World; NCT04276441).
Inhibition of WEE1, a tyrosine kinase responsible for G2 arrest, results in premature mitotic entry and double-strand DNA breaks. Adavosertib is a selective, ATP-competitive, and small-molecule WEE1 kinase inhibitor. In an adavosertib single-agent, Phase I trial, partial responses (PRs) were observed in patients with solid tumors carrying pathogenic variants (PVs) in BRCA1/2. In this trial, we further evaluated adavosertib in patients with PV in BRCA1/2 solid tumors. Eligible patients met criteria for the National Cancer Institute-Molecular Analysis for Therapy Choice master protocol and had a diagnosis of advanced BRCA-mutated solid tumor (germline or somatic mutations were accepted); 33 patients were enrolled, and 30 received study treatment. Adavosertib was administered orally, 300 mg once daily, with 5 days on and 2 days off over a 3 week cycle of 2 weeks on and 1 week off, until disease progression or unacceptable toxicity. Radiologic assessment was performed every three cycles. The primary end point was overall response rate (ORR); secondary end points included 6-month overall survival (OS6) and 6-month progression-free survival rate (PFS6). The ORR was 3.3% (90% CI, 0.2 to 14.9); the OS6 was 57.3% (90% CI, 41.9 to 72.7); the PFS6 was 23.4% (90% CI, 10.7 to 36.2). One PR (fallopian tube serous carcinoma) and six cases of stable disease (SD, >6 months) were observed. In patients with SD <6 months or progressive disease (nonresponders), significantly increased PI3K/AKT/mTOR signaling pathway gene transcripts suggested activation of this resistance mechanism. The primary reason for treatment discontinuation was disease progression. Common side effects included myelosuppression, fatigue, nausea, anemia, vomiting, and diarrhea. In heavily pretreated, advanced solid tumor patients with PV in BRCA1/2, adavosertib treatment resulted in low ORR, and this trial did not meet the primary end point.
Lifileucel is a first-in-class autologous tumor-infiltrating lymphocyte (TIL) therapy for advanced/metastatic melanoma with progression after anti-programmed cell death protein 1 (PD-1) therapy and/or BRAF inhibitor therapy, if BRAF V600 mutations are present. In the C-144-01 phase 2 trial of lymphodepleting chemotherapy, lifileucel, and interleukin 2 (IL-2), cutaneous eruption occurred in 37.2% of individuals. These eruptions remain clinically and prognostically unknown. To examine cutaneous toxic effects development in the setting of lifileucel therapy, abstract clinical and histopathologic eruption features, and test for association with objective radiographic tumor response. A retrospective cohort study was performed at Mass General Brigham (MGB)/Dana-Farber Cancer Institute (DFCI) that included all patients treated with lifileucel, outside of active clinical trials. The analysis was completed in December 2025. All individuals received cyclophosphamide/fludarabine lymphodepletion, lifileucel, and 6 or fewer IL-2 infusions. Demographics, melanoma-specific factors (M stage, pre-TIL lactate dehydrogenase levels, and number of lines of prior systemic therapy), number of IL-2 doses received, eruption features, photography, and dermatopathologic findings were abstracted. Radiographic responses 30 to 41 days, 42 to 89 days, and 90 days or longer from TIL infusion per Response Evaluation Criteria in Solid Tumors (RECIST) were abstracted. Individuals were stratified as high IL-2 (4-6 doses) or low IL-2 (1-3 doses), for objective response rate (ORR) comparison as a descriptive sensitivity analysis. An unadjusted logistic regression modeled tumor response as a binary outcome with lifileucel-associated eruption occurrence as a binary predictor. Three adjusted models included IL-2 doses (age, sex, and demographic differences) and melanoma-specific factors as covariates. Per retrospective electronic medical health record review, among 44 individuals (34.1% female individuals; mean [SD] age, 54.8 [14.5] years), treated with lifileucel (median, 4.5 IL-2 doses), 22 (50.0%) developed an associated cutaneous eruption while hospitalized, after a median of 4 post-TIL days. Photographs from 14 of 22 individuals (63.6%) with available images demonstrated central-predominant, frequently purpuric morbilliform eruptions. ORRs did not significantly differ by IL-2 stratification (high IL-2: 50.0% vs low IL-2: 37.5%; P = .53). Cutaneous eruption development was associated with a 42-day response across analyses (analysis 1: OR, 7.29; 95% CI, 1.91-27.86; P = .004; OR, 7.65; 95% CI, 1.79-32.69; P = .006; analysis 2: OR, 11.95; 95% CI, 1.90-75.39; P = .008; analysis 3: OR, 9.73; 95% CI, 2.12-44.74; P = .003); 30-day responses were statistically similarly associated. All 90-day cutaneous eruption response analyses did not detect statistical significance. In this cohort study, lifileucel treatment was frequently complicated by purpuric morbilliform eruptions, which were prognostically favorable and associated with short-term response. The lifileucel-associated eruption may be a peritreatment efficacy marker, assessable during the TIL treatment hospitalization prior to traditional 42-day restaging.
We examined the potential of combining EEG signals from multiple individuals to identify critical events in a team task. In this study two subjects played a video game in which they had complementary roles, one player serving as a Bait to distract 5 enemy fortress and the other serving as a Shooter to destroy the fortress. Twenty-one pairs of subjects were analyzed. Critical events, destruction of the fortress and deaths of each player, evoked distinguishable P300-like responses from both players. Fortress kills could be best identified by combining the two EEG signals, while deaths could be best identified by focusing on the response of the player who died. Hidden semi-Markov models (HSMMs) achieved good identification of the events by combining information about the temporal distribution of these critical events with the conditional probability of the EEG activity. These findings indicate that we can track and improve by adaptively merging or selecting the signals from different team members.
A growing challenge in mobile robotics is the reliance on complex graphical interfaces and rigid control pipelines, which limit accessibility for non-expert users. This work introduces a latency-aware benchmarking framework that enables natural-language robot navigation by integrating multiple Large Language Models (LLMs) with the Robot Operating System 2 (ROS 2) Navigation 2 (Nav2) stack. The system allows robots to interpret and act upon free-form text instructions, replacing traditional Human-Machine Interfaces (HMIs) with conversational interaction. Using a simulated TurtleBot4 platform in Gazebo Fortress, we benchmarked a diverse set of contemporary LLMs, including GPT-3.5, GPT-4, GPT-5, Claude 3.7, Gemini 2.5, Mistral-7B Instruct, DeepSeek-R1, and LLaMA-3.3-70B, across three local planners, namely Dynamic Window Approach (DWB), Timed Elastic Band (TEB), and Regulated Pure Pursuit (RPP). The framework measures end-to-end response latency, instruction-parsing accuracy, path quality, and task success rate in standardised indoor scenarios. The results show that there are clear trade-offs between latency and accuracy, where smaller models respond quickly but have less spatial reasoning, while larger models have more consistent navigation intent but take longer to respond. The proposed framework is the first reproducible multi-LLM system with multi-planner evaluations within ROS 2, supporting the development of intuitive and latency-efficient natural-language interfaces for robot navigation.
It is generally accepted that non-coding DNA constitutes the vast majority of most eukaryotic genomes and is concentrated at the nuclear periphery and nucleolar surface. Building upon this spatial organization, we have previously proposed that this layer of abundant, peripherally localized non-coding DNA functions as a 3D buffer that transiently absorbs or permanently excludes DNA damage to protect the genome and the relatively central exome from external and internal mutagens in somatic cells. This review explores the potential role of non-coding DNA as a physical barrier in genome safeguarding during early developmental stages and major evolutionary transitions. During gametogenesis and early embryogenesis the barrier is first provided by abundant non-coding DNA; as heterochromatin matures from non-coding DNA, many species programmatically eliminate the now-redundant non-coding DNA. Across evolution, whole-genome duplications and repeat amplification expand the shield, facilitating major evolutionary transitions such as vertebrate origins, water-to-land colonization and survival through mass-extinction crises. Conversely, in stable ecosystems selection favors genome streamlining: redundant non-coding DNA is lost to reduce fitness costs. Thus, the dosage of non-coding DNA is negatively correlated with the strength of apomorphic safeguards (adaptive immunity, viviparity) and positively correlated with ecological or developmental stress. By integrating comparative genomics, 3D nuclear architecture and evolution, we unify a single conceptual framework: non-coding DNA acts as a malleable fortress whose thickness is tuned to the variable need for genome protection during both ontogeny and phylogeny. This perspective offers new explanatory power for the accumulation or loss of non-coding DNA and can predict genome-size trajectories.
SLE is a chronic autoimmune disorder with a range of symptoms. While these are broadly reported in the literature, the symptom impact of SLE on patient health-related quality of life is less well documented. This qualitative interview study aimed to understand the nature and importance of skin symptoms, evaluate the content validity of the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) scale in SLE and assess what constitutes meaningful change in SLE-associated fatigue and skin symptoms. In August 2023, 60 min individual interviews were conducted virtually with 18 adults in the USA who self-reported a diagnosis of SLE and reported experiencing SLE-related fatigue within the prior 30 days. 17 participants also reported experiencing SLE-related skin symptoms. Participants described their experiences with these symptoms and their perceptions of the smallest meaningful improvement using their own words and using the Patient Global Impression of Severity (PGIS) and Patient Global Impression of Change (PGIC) scales. Cognitive debriefing was conducted to evaluate content validity of the 13-item FACIT-Fatigue scale (V.4) for SLE-related fatigue. Of the 18 participants interviewed (mean age 51.7 years (range 33-67 years)), 17 were female and nine were white. All participants acknowledged that all items of the FACIT-Fatigue scale were relevant to SLE-related fatigue and most could comprehend and answer all items without difficulty. 13 participants indicated that a one-point improvement in fatigue on the PGIS would be meaningful. All participants with skin symptoms understood the skin-specific PGIS and PGIC items without difficulty. A one-point improvement on the PGIS and 'a little better/moderately better' on the PGIC represented meaningful improvements in skin symptoms by most participants. These results support the use of the FACIT-Fatigue scale in SLE trials and suggest that even minimal improvements in fatigue and skin symptoms are meaningful to patients.
Purpose/Objective: This purpose of this study is to report on a cohort of patients with Early-onset pancreatic cancer (EOPC) (age < 55 years) who were treated with neoadjuvant chemotherapy and stereotactic body radiation therapy (SBRT) with or without surgical resection. Materials/Methods: This was a single-institution, retrospective review of patients with EOPC that was staged as either borderline resectable (BRPC) or locally advanced (LAPC) based on NCCN criteria and who were treated with upfront chemotherapy followed by SBRT, with or without subsequent surgical resection. Endpoints included overall survival (OS), local progression-free survival (LPFS), distant metastasis-free survival (DMFS), progression-free survival (PFS), and treatment-related toxicity. Results: From 2016 to 2021, 47 patients met the inclusion criteria. The median age was 50.4 years (range, 36.4-54.7 years). The median duration of induction chemotherapy was 4 months (range, 2.5-9.0 months). The SBRT dose for the majority (46/47, 97.9%) of patients was 33 Gy in five fractions. Surgical resection was performed in 33 patients (70.2%). The median OS, LPFS, DMFS, and PFS were 14.2 months, 11.6 months, 8.9 months, and 8.1 months respectively. Six-month and 1-year LPFS were 88.3% and 45.4%, respectively. Chemotherapy duration (≥4 months) was associated with improved median OS (16.5 vs. 10.1 months, p = 0.005), LPFS (10.1 vs. 4.9 months, p = 0.002), DMFS (9.7 vs. 5.2 months, p = 0.014), and PFS (9.7 vs. 5.2 months, p = 0.020). The normalization of CA 19-9 (≤34 vs. >34 U/mL) after chemotherapy was associated with improved median DMFS (not reached vs. 5.6 months, p = 0.003) and PFS (11.3 vs. 5.6 months, p = 0.022). Grade 3+ rates of chemotherapy and radiation-related toxicity were 14.9% and 2.1% respectively. The Clavien-Dindo 3b toxicity rate was 3.0%. Conclusions: In EOPC, an induction chemotherapy duration ≥4 months and the normalization of CA 19-9 after chemotherapy were associated with improved outcomes, suggesting a role for extended durations of systemic therapy titrated to CA 19-9 response before transitioning to local therapy. The high rate of local failure and the low rate of grade 3+ toxicity also suggest a role for intensifying local therapy in this population.
Phototherapy not only targets tumor cells for destruction but also triggers immunogenic cell death (ICD), thereby activating systemic immunity. Traditional photothermal therapy (PTT), however, damages adjacent normal tissues, and photodynamic therapy (PDT) creates severe hypoxia within tumor tissues, which promotes immune evasion and reduces the effectiveness of immunotherapy. In this study, we developed a biomimetic nanomodulators-cell membrane-coated gambogic acid/indocyanine green micelles loaded with HIF-1α siRNA (CM-IGM/siRNA) to achieve mild photothermal therapy (mPTT), enhance photodynamic therapy (PDT), and modulate the tumor microenvironment (TME). This platform utilizes gambogic acid (GA) to inhibit HSP90 expression and synergizes with HIF-1α siRNA to suppress HIF-1α expression, thereby ameliorating hypoxic and immunosuppressive TME. HSP90 inhibition further reduces tumor cell thermotolerance, enabling effective tumor cell ablation at mild hyperthermia temperatures (42-45 °C) characteristic of mPTT. Furthermore, we found that π-π stacking of GA with indocyanine green (ICG) enhances ICG photostability and boosts reactive oxygen species (ROS) generation. The elevated ROS production significantly improves PDT efficacy and, in combination with mPTT, potentiates the ICD of tumor cells. Overall, this strategy offers a significant advancement in cancer immunotherapy by improving the tumor microenvironment and enhancing immune activation.
Insulinomas are the leading cause of hyperinsulinemic hypoglycemia in adults, but they can also present during childhood, and, when they do, diagnosis and localization of the lesion can be difficult. Moreover, differentiating between congenital hyperinsulinism (HI) and pediatric insulinomas is challenging because both diseases have similar presentations. Our objective was to review the clinical presentation, diagnostic characteristics, and success of methods for localization, treatment, and outcomes in pediatric patients with insulinomas. Retrospective study of patients with confirmed insulinoma treated at a single academic pediatric hospital between 2006 and 2024. Descriptive statistics and logistic regression models were used to quantify the data and discriminate between groups, respectively. The optimal operating point (OOP) for diagnostic laboratory data was used to maximize discrimination between insulinomas and HI, with prediction accuracy determined by the sensitivity and specificity at the OOP. We reviewed the records of 23 patients with insulinoma with a median age at presentation of 13 years. A positive family history of multiple endocrine neoplasia type 1 was recorded in 22%. The most common presenting symptom was altered mental status. Median plasma insulin and beta-hydroxybutyrate (BOHB) concentrations during hypoglycemia were 8.8 uIU/mL (61.1 pmol/L) and 0.3 mmol/L, respectively. Most patients had four imaging studies completed to localize their insulinoma. Twenty of the 23 patients reviewed had a single lesion successfully resected and were cured. Of these 20 patients, 12 had 18F-Fluoro-dihydroxyphenylalanine (18F-DOPA) positron emission tomography/computed tomography (PET/CT) completed, of which nine were positive (75%). Three patients had initial lesions localized and successfully resected but continued to have hypoglycemia requiring medical management. Median duration from presentation to surgery was 9 weeks. When comparing the critical samples of patients with insulinomas and HI, the combination of BOHB and insulin-like growth factor binding protein 1 at the time of hypoglycemia yielded a sensitivity and specificity of 0.89 and 0.84, respectively, for insulinoma versus HI when using a multivariate function on our cohorts. In this series, successful treatment of insulinomas took, on average, 9 weeks from diagnosis. Multiple imaging modalities were employed for preoperative lesion localization, with 18F-DOPA PET/CT and magnetic resonance imaging being the most successful. Improved imaging modalities are needed to localize insulinomas in pediatric patients and reduce the time between diagnosis and resection. We propose an algorithm to differentiate between pediatric insulinomas and congenital hyperinsulinism using laboratory data to quicken diagnosis and lessen time to treatment.
The continuous development of new imaging approaches, molecular phenotyping, genetic subtypes, prognosis assessments, and effective therapies across a range of disease states has created a need to redefine terminology and best practices for clinical trial conduct in patients with advanced prostate cancer. We convened an international expert committee of diverse working groups, the Prostate Cancer Working Group 4 (PCWG4), between 2016 and 2025. Our objective was to formulate updated criteria based on emerging evidence and clinical trial data in a biomarker context to provide guidance for clinical trial design, eligibility, and end point assessments for patients with advanced prostate cancer. PCWG4 redefines terminology around the disease state and previous therapies in a patient-centric context and terminology focused on androgen pathway modulation. We consider imaging, with a particular focus on positron emission tomography (PET)-defined disease. New recommendations are provided for disease state terminology, defining eligibility criteria, response and delay/prevent end points, intervals for reassessments including imaging, and patient-reported outcome determination. We provide recommendations in a biomarker-based context of use for the intended indication, reflective of patient benefit for specific interventions. We emphasize the need for development of validated PET imaging and molecular and phenotypic criteria as well as trial designs to appropriately risk stratify patients, predict and assess benefit, and measure post-treatment outcomes reliably in a trial framework. PCWG4 updates recommendations on patient and tumor characterization, therapy development, and imaging criteria and extends guidance into earlier androgen pathway modulator-naïve/sensitive disease states to reflect an evolving, heterogeneous, and diverse patient population to optimize treatment benefits for all patients.
Since the outbreak of the COVID-19 pandemic in 2020, people in Slovenia have faced a series of overlapping crises at both global and national levels, including the Russo-Ukrainian conflict, rising economic costs, and major natural disasters. Although extensive quantitative research has examined pandemic-related mental health outcomes, comparatively little is known about how individuals subjectively perceive multiple overlapping crises, given the cumulative and interactive nature of contemporary crises - situations in which crises across multiple systems become causally entangled and mutually amplify their effects. This study aimed to explore the perceived psychological consequences of multiple overlapping crises among adults in Slovenia, guided by the polycrisis framework. Using a qualitative research design based on Constructivist Grounded Theory, we conducted semi-structured, in-depth interviews between June and November 2023 with 24 participants (16 women, 8 men; mean age 49 years, range 21-76). Interviews were audio-recorded, manually transcribed, and analyzed using ATLAS.ti 24 software. Analysis involved initial and focused coding, constant comparison, and analytic memo-writing, continuing until theoretical saturation was reached. A total of 274 quotations were coded into 16 final codes. Three analytical categories of perceived psychological consequences emerged: duration (short-term vs. long-term), valence (positive vs. negative), and level of impact (individual vs. societal). Short-term consequences were predominantly individual-level experiences tied to the acute pandemic period, including negative outcomes (e.g., stress, mental health decline, social polarization) and positive outcomes (e.g., increased time with close ones, time in nature, reduced pressure). Positive long-term consequences included closer relationships and increased gratitude; negative ones included a reduced sense of safety, distrust in authorities, weaker social ties, and a perceived decline in social cohesion. Based on the analytical findings, we developed the Fortress Wall Model of Psychological Adaptation to Crisis, which conceptualizes the experience of compounding crises as a dynamic, phased psychological process. The findings underscore the need to address people's emotional experiences during acute crisis phases and to maintain monitoring and support of psychological well-being beyond the acute period, as negative consequences - particularly heightened uncertainty, distrust, and a diminished sense of safety - persist long after crises subside and are intensified by subsequent stressors.
T-cell engager therapies, including bispecific T-cell engagers and the immune-mobilizing monoclonal T-cell receptor against cancer tebentafusp, are an emerging class of anticancer immunotherapy, with rapid expansion of the class since initial approval of blinatumomab in 2014 and with distinct dermatologic adverse events increasingly recognized across agents. Tebentafusp and talquetamab demonstrate highest rates of notable dermatologic toxicity reflecting on-target off-tumor cutaneous effects. Tebentafusp produces dermatologic adverse events in the majority of treated patients, characterized by diffuse erythematous and frequently photodistributed eruptions. Talquetamab is notable for a characteristic constellation of cutaneous, nail, and oral toxicities linked to target G protein-coupled receptor class C group 5 member D expression in keratinized tissues. Subcutaneous cluster of differentiation (CD)20- and B-cell maturation antigen-targeted agents frequently cause injection-site reactions, generally low-grade and self-limited. Blinatumomab and other CD19- and CD20-directed agents have been associated with a spectrum of heterogeneous rashes. Across agents, most dermatologic adverse events can be managed with topical corticosteroids, emollients, antihistamines, or brief courses of systemic corticosteroids without requiring treatment discontinuation. Recognition of these agent-specific and mechanistically linked patterns is essential for dermatologists as T-cell engager therapies become increasingly integrated into oncology practice.
Bexotegrast is an oral, once-daily, dual-selective inhibitor of integrins αvβ6 and αvβ1 in development for idiopathic pulmonary fibrosis (IPF). In the phase 2a study INTEGRIS-IPF study (NCT04396756), bexotegrast was well tolerated and showed antifibrotic activity. BEACON-IPF (NCT06097260) is a randomised, double-blind, placebo-controlled, dose-finding, operationally seamless, adaptive phase 2b/3 study evaluating the efficacy and safety of bexotegrast over 52 weeks in participants with IPF. The phase 2b dose selection cohort will enrol 360 participants randomised 1:1:1 to once-daily bexotegrast 160 mg, 320 mg or placebo. After enrolling the last participant in the phase 2b cohort and while conduct is ongoing, the phase 3 cohort will immediately begin enrolment with a 'seamless group' using the same 1:1:1 randomisation. Once the phase 2b cohort has completed and a dose has been selected, the remainder of the phase 3 cohort will be enrolled. Participants in the phase 2b cohort receiving the non-selected dose will be eligible for an open-label study at the selected phase 3 dose. Background therapy with pirfenidone or nintedanib is permitted in ≤70% of the study population. Participants must be adults (≥40 years), have an IPF diagnosis ≤7 years per 2018 international guidelines, per cent predicted forced vital capacity (FVCpp) ≥45% and diffusing capacity for carbon monoxide (haemoglobin adjusted) ≥30%. The primary endpoint is change from baseline in absolute FVC at week 52. Additional endpoints include safety and tolerability, time to disease progression, participant-reported symptom assessments and quantitative lung fibrosis extent. This study was approved by Advarra institutional review board (IRB; OHRP and Food and Drug Administration registration 00000971) and at each participating site by IRBs and local ethics review committees. Participants will provide written informed consent before taking part. Study results will be disseminated in peer-reviewed journals and international conferences targeted to medical, academic and patient communities. NCT06097260.