Acute otitis media (AOM) is a leading cause of antibiotic prescribing in children although many cases resolve without treatment. 'Watch and wait' or safety-net antibiotic prescriptions (SNAPs) are recommended to support antibiotic stewardship. However, SNAP use and dispensing patterns are not well captured in structured data. This study evaluated SNAP prescribing, dispensing and associated demographic and clinical factors using a large language model (LLM). Retrospective cross-sectional study of 4370 AOM encounters (ages 6 months-<18 years) from 1 January 2021 to 1 January 2024 at a single academic centre, including emergency and outpatient visits. An LLM reviewed clinician notes to classify prescriptions as immediate ('treatment today prescriptions' (TTPs)) or delayed (SNAP). Dispensing data were linked from Epic Clarity. Of 4370 encounters, 76.6% received TTP and 23.4% received SNAPs. Patients who spoke a language other than English and those in lower socio-economic quartiles were less likely to receive SNAPs (eg, average marginal effect (AME) = -8.0%, p<0.001). Boys were also less likely to receive SNAPs. SNAPs were less likely to be filled than TTPs (AME = -12.1%, p<0.001). Among patients who received a SNAP, time to dispensing did not differ significantly across demographic or clinical factors. SNAP prescribing varied across demographic and clinical groups, while dispensing patterns among SNAP recipients were similar across groups. These findings highlight variability in SNAP use and underscore the need for further research to better understand factors influencing prescribing and to support equitable antibiotic stewardship.
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The 2025-2026 Professional Affairs Committee was charged to (1) Socialize the Key Elements of Practice Redesign in Community Pharmacies within the Academy; (2) Pursue endorsement of the Key Elements of Practice Redesign in Community Pharmacies by the Joint Commission of Pharmacy Practitioners (JCPP); and (3) Recommend future considerations for AACP to pursue in advancing Community Pharmacy Practice. The committee socialized the Key Elements of Practice Redesign in Community Pharmacies by holding a focus group of employer representatives from community pharmacy practice, a focus group of pharmacists working in community pharmacy practice, presenting at a national pharmacy conference for continuing education credit, and conducting a continuing education (CE) webinar for pharmacists. Due to the creation, socialization, and release of the Key Elements of a Pharmacist Practice Management Ecosystem document by JCPP in January 2026, the second committee charge was achieved. Finally, the committee generated 3 recommendations for AACP and 5 suggestions for colleges and schools of pharmacy.
To develop phenotype algorithms for the detection of adverse events (AEs) or AE-proxies in electronic health records (EHRs), accounting for varying data availability. Multicentre study conducted as part of the Use Case POLAR_MI (POLypharmacy, drug interActions, Risks) of the German Medical Informatics Initiative (MII). Germany. Multidisciplinary teams from 10 German university sites within the MII. Not applicable. Literature- and consensus-based development and operationalisation of AE algorithms using structured EHR data, including a standardised, multicentre expert review process. Data categories used: International Classification of Diseases, 10th Revision (ICD-10) codes for diagnoses; Anatomical Therapeutic Chemical (ATC) codes and 'Pharmazentralnummern' (PZN; German eight-digit identification code for pharmaceutical products) for medications (used in the treatment of AEs); Logical Observation Identifiers Names and Codes (LOINC) for laboratory values and medical findings; and 'Operationen- und Prozedurenschlüssel' (OPS; German procedure classification) codes for medical and surgical procedures. We developed 82 algorithms for 48 AEs. Algorithms for the same AE varied by data categories or code selections. At the AE level, 31 AEs were covered exclusively by newly developed algorithms, and 17 AEs by at least one modified algorithm.Overall, 52 algorithms were based on a single data category, while 30 required multiple categories. ICD-10 codes were most commonly used (n=65 AE algorithms), followed by LOINC (n=27), ATC codes (n=18), OPS codes (n=11) and PZN (n=2). All phenotype algorithms were semantically modelled and can be executed using the publicly available Terminology- and Ontology-based Phenotyping (TOP) Framework, which supports export in various formats. We present a peer-reviewed set of algorithms for a large number of AEs, which can be implemented in structured routine electronic data sources and (pending validation studies) may support pharmacoepidemiologic research. The algorithms will be implementable across all 39 participating sites of the German MII. As a next step, we will empirically validate the algorithms against all information (including free text) contained in EHRs. Not applicable.
The Appalachian region experiences persistent health disparities and limited access to healthcare services. Ambulatory care pharmacists, including Board-Certified Ambulatory Care Pharmacists (BCACPs), can help address these gaps, but their distribution in Appalachia is not well described. To evaluate the distribution and population density of BCACPs in the United States, the Appalachian region, and rural Appalachian counties. This cross-sectional study used publicly available data from the Board of Pharmacy Specialties (BPS) and the Appalachian Regional Commission (ARC). BCACP data, including ZIP codes, were obtained from the BPS registry in August 2025. Counties were classified as Appalachian and further categorized as rural or non-rural using ARC definitions. BCACP density per 1,000,000 residents was calculated and compared across regions. Rate ratios (RR) with 95% confidence intervals (CI) were calculated using Poisson regression, with U.S. density as the reference. BCACP density was lower in the Appalachian region compared to the United States overall and was lowest in rural Appalachian counties. Compared with the national BCACP density, the BCACP rate was 24% lower in Appalachia (RR 0.76, 95% CI 0.69-0.85; p<0.001) and 73% lower in rural Appalachian counties (RR 0.27, 95% CI 0.15-0.47; p<0.001). BCACPs are underrepresented in Appalachia, highlighting a gap in access to specialized ambulatory care services. Addressing this gap will require targeted recruitment and retention strategies, including early pipeline development, financial incentives such as loan forgiveness, and ensuring practice sites are ready to support pharmacist integration. Expanding access to ambulatory care pharmacists may help improve care delivery and reduce health disparities in these communities.
Fabry disease is a rare, X-linked lysosomal storage disorder caused by deficient α-galactosidase A activity, leading to progressive accumulation of globotriaosylceramide in multiple tissues. Its estimated incidence ranges from 1 in 40,000 to 1 in 117,000 live births. Fabry disease manifests primarily as 2 phenotypes: classic (type 1), presenting in childhood with neuropathic pain, fatigue, thermal intolerance, and early multiorgan involvement; and late onset (type 2), typically manifesting in adulthood with predominant cardiac or renal complications. Timely diagnosis requires clinical suspicion combined with enzymatic assays and genetic testing; however, atypical presentations and variability in female patients often delay recognition, underscoring the necessity for heightened clinical vigilance. Current therapeutic approaches primarily focus on enzyme replacement therapy and pharmacologic chaperones, aimed at enhancing quality of life and delaying organ dysfunction. Optimal management necessitates an individualized, multidisciplinary strategy encompassing nephrology, cardiology, genetics, clinical pharmacy, and pain management. Emerging treatments, including next-generation enzyme replacement therapies, substrate reduction therapy, gene therapy, and mRNA-based therapeutics, offer promising avenues for more effective and durable outcomes. Ongoing clinical trials and comprehensive long-term outcome studies are crucial for refining these innovative therapeutic strategies and further advancing patient care.
The hormone vasopressin (AVP) controls renal water reabsorption by modulating the expression and trafficking of the water channel aquaporin-2 (AQP2) through the activation of the cAMP/PKA signal transduction pathway. Previous studies revealed that Olive Leaf Extract (OLE) counteracts the vasopressin-dependent AQP2 functions by stimulating the calcium-sensing receptor (CaSR). Here, the biological activities of p-Coumaric acid, a selective polyphenol in OLE, were investigated. Stimulation of renal collecting duct MCD4 cells with p-Coumaric acid at a concentration of 1 nM caused a significant intracellular calcium release. NPS-2143, a selective CaSR antagonist, abolished this increase. Molecular docking analysis revealed that p-Coumaric acid can form binding interactions with the binding pocket of Tecalcet, a known CaSR activator, likely suggesting that p-Coumaric acid may stimulate the CaSR. Confocal analysis and immunoblotting experiments showed that p-Coumaric acid impaired the DDAVP-dependent membrane expression of AQP2 and the consequent increase of the osmotic water permeability (Pf). Additionally, Fluorescence Resonance Energy Transfer (FRET) experiments demonstrated that p-Coumaric acid prevented the DDAVP-induced cAMP generation, consequently attenuating the AQP2 phosphorylation at serine 256. Together, these findings suggest that p-Coumaric acid may antagonize the effects of vasopressin, possibly by binding to and stimulating the CaSR.
To compare postpartum trajectories in body weight and cardiometabolic biomarkers between women with and without GDM, and to explore the moderating effect of progression to type 2 diabetes (T2DM). We used electronic primary care healthcare records and linked hospital episode records of women who gave birth between 2001 and 2021. Each woman with GDM was matched to four women without GDM based on age at delivery and delivery date (±3 months). We fitted mixed-effects multivariate linear models to map biomarker trajectories and extracted coefficients and 95% confidence intervals (CIs) for each year postpartum. A total of 43 572 women diagnosed with GDM were matched with 174 288 women without GDM in pregnancy. Across the 15-year follow-up, women with GDM weighed more (difference of 5.5 kg [95% CI: 5.3 to 5.7]), had higher HbA1c concentrations (4.4 mmol/mol [95% CI: 4.3 to 4.5]), systolic and diastolic blood pressure (2.6 mmHg [95% CI: 2.4 to 2.7] and 1.7 mmHg [1.6 to 1.8] higher, respectively), and low-density lipoprotein cholesterol (0.08 [95% CI: 0.06 to 0.10]). However, biomarkers increased at a slower rate during the follow-up period among women with GDM, except for HbA1c (increase of 9.3 mmol/mol [95% CI: 8.8 to 9.7] and 2.3 mmol/mol [95% CI: 1.9 to 2.6] in the GDM and non-GDM groups, respectively). Future Progression to type 2 diabetes moderated biomarker trajectories. Differences in biomarker trajectories in the early postpartum present an opportunity for early risk stratification and targeted prevention among women with previous GDM.
The efficient enrichment and simultaneous detection of trace levels of angiotensin (Ⅰ, Ⅱ, Ⅲ) and aldosterone in plasma pose certain technical challenges. Herein, we propose a novel strategy where a cationic covalent organic framework (Py-BPy2+-COF) was served as an attractive adsorption material for efficient enrichment of angiotensin (Ⅰ, Ⅱ, Ⅲ) and aldosterone. Adsorption experiments and model fitting revealed that Py-BPy2+-COF exhibited adsorption capacities ranging from 5.02 to 26.12 μg g-1 for the four target analytes. The Hirshfeld partition analysis elucidated that the interaction forces of angiotensin and aldosterone with Py-BPy2+-COF originated from electrostatic interactions, π-π stacking and hydrophobic interactions. Py-BPy2+-COF was employed as the sorbent packing in a 96-well plate coupled with liquid chromatography-tandem mass spectrometry, achieving high sensitivity, excellent reproducibility, high recoveries (80.1%-94.9%), low limits of detection (5-50 pg mL-1), and cost-effectiveness, while maintaining high extraction efficiency even after 10 repeated uses. This study provides a novel approach for the detection of angiotensin (Ⅰ, Ⅱ, Ⅲ) and aldosterone in plasma, and demonstrates the potential of cationic COFs as functional materials in biomedical analysis.
Enteropathic spondyloarthritis is a common, under-recognised musculoskeletal manifestation of inflammatory bowel disease and a potentially preventable contributor to long-term disability. Epidemiological, imaging, and biomarker data support a continuum from at-risk states (ie, high-risk inflammatory bowel disease phenotypes with early extraintestinal manifestations and non-specific pain), through subclinical MRI-defined or ultrasound-defined sacroiliac and entheseal inflammation, to early clinical enteropathic spondyloarthritis with overt synovitis, enthesitis, and inflammatory back pain, often after prolonged diagnostically ambiguous symptoms. This transition unfolds within a gut-derived inflammatory milieu shaped by type-3 immunity, dysbiosis, epithelial barrier dysfunction, gut-homing and tissue-resident lymphocyte circuits, and polygenic susceptibility, with only partial synchrony between intestinal and musculoskeletal trajectories. Clinically, these mechanisms yield phase-specific signatures in which faecal calprotectin, C-reactive protein, and HLA-B27 act as probabilistic modifiers, and power Doppler ultrasound and sacroiliac or spinal MRI enable recognition of inflammation before irreversible structural change. In this Review, we synthesise mechanistic and clinical evidence across the at-risk-to-early articular continuum (this term refers to individuals at-risk of enteropathic spondyloarthritis, individuals with subclinical musculoskeletal disease, and patients with early clinical articular disease). We propose a precision, dual-compartment strategy addressing both gut and joint involvement, integrating structured musculoskeletal screening, probability-guided imaging, and timely use of therapies with proven gut-joint efficacy into inflammatory bowel disease care, aiming to prevent diagnostic delay, limit structural damage, and reframe enteropathic spondyloarthritis as an interceptable, treat-to-target phenotype along the gut-joint axis.
Nuclear factor-kappa B (NF-κB) is a key transcription factor implicated in inflammation, immune regulation, and cancer progression, making it an important target for antioxidant and anti-inflammatory therapy for acne. The present study evaluated the synergistic NF-κB inhibitory potential of cinnamic acid and p-coumaric acid (p-CA) through molecular docking analysis, followed by formulation development and antioxidant assessment. Molecular docking was performed using AutoDock Vina v1.2.6 to investigate binding affinity and interaction profiles. Individual formulations containing cinnamic acid (1%) and p-CA (1%), as well as an equimolar combined formulation (0.5% each), were developed using hydrogel and oleogel phases to obtain a bigel system. Antioxidant activity was determined using the DPPH radical scavenging assay. Docking studies demonstrated binding energies of - 4.046 kcal/mol and - 4.400 kcal/mol for cinnamic acid and p-CA, respectively, whereas the combined ligand complex exhibited an enhanced binding affinity of - 7.837 kcal/mol. The improved interaction was stabilized through hydrogen bonding and hydrophobic interactions involving key amino acid residues, including ARG54, LEU251, GLU341, and THR342. In the antioxidant assay at 250 μg/mL, p-CA and cinnamic acid exhibited 16.76% and 14.02% inhibition, respectively, IC50 value of the cinnamic acid, p-coumaric acid and combined was found to be 750 µg/mL, 1160 µg/ mL, 810 µg/mL, while the equimolar bigel formulation demonstrated significantly higher radical scavenging activity (19.95%-28.55%), suggesting a synergistic effect. This research indicates that the combination of cinnamic acid and p-CA enhances molecular interactions with the NF-κB p50 subunit and improves antioxidant activity compared with the individual compounds. These integrated in silico and experimental results support the potential application of this combination in the development of multi-targeted natural formulations.
Temozolomide, a chemotherapy drug used to treat glioblastoma, has high-dose and dose-related side effects, limiting its use. Resveratrol, a natural polyphenol, showed potential in the treatment of glioblastoma. Many studies showed the synergistic activity of resveratrol and temozolomide against glioblastoma, but no analytical method for simultaneous estimation in a biological matrix is available till date. This study aimed to develop and validate a simple, rapid, and sensitive bioanalytical method using HPLC technique for simultaneous estimation of temozolomide and resveratrol in rat plasma and brain for pharmacokinetic study. Isocratic reversed-phase high-performance liquid chromatography (RP-HPLC) method using C18 column was used. Theophylline and caffeine were used as internal standards for Temozolomide and Resveratrol, respectively. The mobile phase methanol: 0.1% glacial acetic acid (30:70) with flow rate 1.0 mL/min and 310-nm wavelength was used. The LOD for temozolomide and resveratrol in the plasma was 0.96 and 1.29 μg/mL, respectively, whereas LOQ was 2.91 and 3.89 μg/mL, respectively. The LOD for temozolomide and resveratrol in brain homogenate was 1.01 and 1.24 μg/mL, respectively, whereas LOQ was 3.07 and 3.76 μg/mL, respectively. This analytical method can be used for simultaneous estimation of temozolomide and resveratrol in biological samples, with higher sensitivity, resulting in more meaningful and appropriate pharmacokinetic analysis.
Residual cardiovascular risk remains high after acute coronary syndrome (ACS) despite intensive LDL-cholesterol lowering. Elevated triglycerides may contribute to this risk. Although icosapent ethyl (IPE) has shown cardiovascular benefit in high-risk statin-treated patients, access in Italy is limited by Italian Medicines Agency (AIFA) reimbursement criteria, which are more restrictive than the European Medicines Agency (EMA) indications. We compared EMA and AIFA eligibility for IPE in a real-world post-ACS cohort, assessed the association of triglyceride levels and variability with 12-month ischemic recurrence, and explored the potential economic impact of broader IPE use. This retrospective observational study included 430 consecutive adults admitted for ACS to a tertiary hospital in Italy in 2024, with 12-month follow-up. During follow-up, 48 patients (11.2%) experienced recurrent ACS. Diabetes mellitus was independently associated with recurrence (OR 2.90, 95% CI 1.41-5.97; p = 0.004), whereas male sex was protective (OR 0.46, 95% CI 0.23-0.93; p = 0.030). Absolute triglyceride levels were not significantly associated with recurrence, whereas triglyceride variability was: the coefficient of variation remained independently associated with recurrent events (OR 1.04, 95% CI 1.00-1.09; p = 0.029). According to EMA criteria, 35 patients (8.1%) were eligible at discharge and 15 (3.5%) at first follow-up; under AIFA criteria, only one patient was eligible. A marked discrepancy exists between EMA indications and AIFA reimbursement criteria for IPE, resulting in restricted access for high-risk post-ACS patients. Broader access, aligned with current evidence, may improve secondary prevention and represent a cost-effective strategy.
PocketMaster is a flexible and automated tool for the analysis, clustering, and interpretation of protein pockets, enabling the exploration of structural diversity in functional and interacting regions of proteins. The tool provides multiple strategies for defining pocket alignment regions, along with various alignment algorithms and clustering approaches, allowing analyses to be customized for different research objectives. In addition, it automatically documents results and provides informative visualizations and reports. With these capabilities, PocketMaster can be particularly valuable in the early stages of drug design, where accurate analysis and selection of protein structures are essential. Using TYK2 as a case study, PocketMaster demonstrates its ability to identify conformational differences between kinase and pseudokinase domains, as well as subtypes of structures within each domain, reflecting the influence of various ligands and protein states. The estrogen receptor alpha (ERα) ligand-binding pocket was also analyzed as an additional case study, showing the tool's performance in capturing conformational variations in helix 12 (H12) between active (agonist-bound) and inactive (antagonist-bound) states. The results confirm known structural features and illustrate the potential of the tool for systematic exploration of protein pockets, quantitative assessment of differences, and support of rational drug design. The PocketMaster source code, together with example input files and documentation, can be accessed at https://github.com/narek-abelyan/PocketMaster.
Periprosthetic osteolysis (PPO) is the main cause of aseptic loosening after total joint arthroplasty, often resulting from wear particle-induced osteogenic impairment. Morroniside (Mor), a major bioactive iridoid glycoside from C. officinalis, has been shown to have protective effects in osteoporosis. However, its efficacy against wear particle-induced osteolysis remains elusive. Herein, we evaluated the anti-PPO efficacy of Mor using a CoCrMo particle (CoP)-induced murine calvarial osteolysis model, and investigated the protective effects and signalling pathways associated with osteogenesis in CoP-stimulated mice and MC3T3-E1 cells. The results demonstrated that Mor effectively attenuated CoP-induced osteolysis in mice. Additionally, it reversed osteogenic impairment in both CoP-stimulated mice and MC3T3-E1 cells. Mechanistically, this protection was mediated by activating the Wnt/β-catenin signalling pathway in both in vivo and in vitro models. Notably, inhibiting the Wnt signalling pathway with XAV939 abolished the protective effects of Mor in both models. These findings indicate that Mor alleviates CoP-induced osteolysis by restoring osteogenic function via the Wnt/β-catenin pathway, highlighting its potential as a therapeutic agent for PPO.
Cyclophosphamide (CP) has long been employed in cancer treatment as well as in therapeutic regimens for autoimmune diseases. Despite its clinical value, one of its major drawbacks is testicular damage which may be due to disruption of antioxidant defenses, amplification of inflammatory responses, and suppression of autophagy. Febuxostat is a xanthine oxidase inhibitor with promising antioxidant, anti-inflammatory, and autophagy-inducing effects. The present study investigated whether febuxostat could mitigate CP-induced testicular toxicity in a rat model. Fifty male Sprague-Dawley rats were aligned into five groups: a control group, a CP-only group, and three CP-treated groups receiving febuxostat at doses of 5, 10, or 15 mg/kg/day. Seminal fluid, blood samples, and testicular tissues were collected and analyzed through biochemical assays and pathological examinations. Febuxostat dose-dependently restored the hormonal balance, enhanced antioxidant defenses, increased sirtuin-1 levels, and modulated both NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome-driven pyroptosis and mammalian target of rapamycin (mTOR)-autophagy axis in the testicular tissues of CP-treated rats compared with CP-only rats. These improvements were consistently observed in the histopathological and immunohistochemical evaluations. Owing to its antioxidant, anti-inflammatory, autophagy-promoting, and pyroptosis-modulating effects, febuxostat may show promise as a potential therapeutic option for reducing CP-related gonadal dysfunction in males.
The pathogenesis of Parkinson's disease (PD) is driven by a vicious cycle of α-synuclein (α-Syn) aggregation and mitochondrial collapse. Breaking this pathogenic loop requires disease-modifying therapeutics capable of destabilizing the toxic structural core of α-Syn while simultaneously rescuing bioenergetic failure, highlighting an urgent need for novel dual-action neuroprotective agents. To identify and characterize A14, a novel small-molecule modulator, and evaluate its dual capacity to inhibit α-Syn fibrillization and mitigate downstream mitochondrial deficits in PD. Structure-based virtual screening was employed to identify A14 as a targeted inhibitor of the α-Syn fibril β-sheet interface. Its biophysical mechanisms were elucidated using multi-dimensional structural assays. In cellular models and A53T α-Syn transgenic mice, systematically evaluated the therapeutic efficacy, wherein transcriptomics and transmission electron microscopy were adopted to detect mitochondrial integrity, and functional magnetic resonance imaging (fMRI) together with electrophysiology were utilized for the assessment of nigral circuit function. A14 binds the β-sheet core of α-Syn fibrils with high affinity (Kd = 27.9 ± 2.16 nM), significantly reducing β-sheet content from 21.4% to 9.3% and redirecting the aggregation trajectory into small (< 20 nm), protease-sensitive intermediates. In neuronal models, A14 robustly reduced intracellular α-Syn inclusions via direct biophysical modulation, independent of major proteostasis pathways. In vivo, A14 disrupted the pathological interaction between α-Syn and mitochondria, rescuing cristae ultrastructure, oxidative phosphorylation, and overall bioenergetics. This coordinated restoration of proteostasis and mitochondrial function prevented dopaminergic neuron loss, normalized cortico-basal ganglia-nigral functional connectivity, and significantly ameliorated motor deficits in A53T transgenic mice. Our findings demonstrate that the A14 engages complementary mechanisms to inhibit α-Syn aggregation and rescue mitochondrial deficits. This dual action stabilizes proteostasis and sustains mitochondrial functionality, nominating A14 as a promising therapeutic candidate for the treatment of PD.
β-casomorphins (BCMs) are bioactive peptides generated from milk β-casein digestion, which interact with opioid and other receptors to affect both tumor cell proliferation and immune responses within the tumor microenvironment. This review is aimed at summarizing current evidence on the anti-proliferative and immunomodulatory activities of BCMs, in particular BCM-5 and BCM-7, and their relevance to cancer biology. Studies have shown that BCM-5 primarily inhibits cancer cell growth, whereas BCM-7, in addition, enhances anti-tumor immunity by promoting CD8+ T cell infiltration and reducing regulatory T cell populations. The review also discusses synthetic cyclic analogs designed to improve peptide stability and bioavailability, which demonstrate opioid-independent antiproliferative activities. By integration of mechanistic, in vitro, and in vivo data, this review emphasizes the potential of β-casomorphins and their derivatives as modulators of tumor progression and immune surveillance and identifies gaps in knowledge to guide future research in oncology.
Response to anti-programmed cell death protein-1 (anti-PD-1) immunotherapy remains limited in patients with metastatic non-small cell lung cancer (NSCLC), whose tumors exhibit low or absent programmed death-ligand 1 (PD-L1) expression, and subsequent second-line therapy has poor efficacy. To address this limitation, we evaluated the efficacy and safety of combined ipilimumab and nivolumab (IPI/NIVO) with subablative radiotherapy (RT) in patients with metastatic NSCLC with negative or low PD-L1 expression, who had progressed on prior anti-PD-1 therapy. This single-arm, prospective phase II trial aimed to enroll 30 evaluable patients with metastatic NSCLC exhibiting low (1-49%) or negative (<1%) PD-L1 tumor expression who had progressed after first-line anti-PD-1 therapy. Primary endpoints were safety, disease control rate (DCR), and objective response rate (ORR) at 6 and 12 weeks, assessed in non-irradiated tumor lesions. Treatment consisted of IPI 1 mg/kg every 6 weeks (Q6W) and NIVO 240 mg every 2 weeks for 6 weeks combined with subablative RT (3×8 Gy to 1-4 lesions). Thereafter, IPI 1 mg/kg Q6W and NIVO 360 mg every 3 weeks were continued. In 31 patients of the intention-to-treat population, ORR was 7% and 10% at 6 and 12 weeks, and reached 29% as the best response. DCR was 58% and 39% at 6 and 12 weeks. Overall survival (OS) differed significantly by best response, with a median OS of 3.1, 13.5 and 22.5 months for progressive disease, stable disease and partial/complete response (p<0.001). Baseline sum of longest diameters, together with age, blood inflammatory markers and albumin levels, were prognostic of treatment response. All patients experienced treatment-related adverse events (AEs), with grade 3 as the highest severity in eight patients (26%). Immune-related AEs led to treatment discontinuation in five patients (16%). Early T-cell activation in peripheral blood samples (day 8) was detectable and more pronounced in responders than in progressors. In patients with metastatic NSCLC and low or negative tumor PD-L1 expression, IPI/NIVO/RT was able to induce objective clinical responses in a subset of patients who had progressed after first-line anti-PD1 therapy. Treatment was associated with a strong T-cell activation, improved OS and an acceptable safety profile. 2020-001097-29.