Robert Likic

Immune-cold melanomas respond poorly to immune checkpoint blockade (ICB). We assessed whether RNA-seq-based immune subtyping and connectivity mapping could nominate repurposable compounds to shift immune-depleted melanoma toward an immune-enriched phenotype. Using RNA-seq from 432 The Cancer Genome Atlas Skin Cutaneous Melanoma cases, we assigned published molecular functional portrait subtypes and compared depleted (D, n = 169) with combined immune-enriched (IE + IE/F, n = 184) subtypes using limma-voom. The resulting 300-up/300-down signature underwent Library of Integrated Network-based Cellular Signatures L1000 connectivity mapping, with compound-level aggregation and mechanism-of-action annotation. The pipeline was rerun on two stratified split-half folds. Canonical cytotoxic and antigen-presentation genes ( CD8A , PDCD1 , CXCL9 , CXCL10 , CD3D , GZMB , PRF1 ) were depleted in D, validating the contrast. Raw connectivity-mapping hits were dominated by generic cytotoxic-stress compounds. After aggregation and filtering, DNA methyltransferase (DNMT) inhibitors showed the most consistent positive pattern; fdcyd, azacitidine, and RG-108, but not decitabine, were robust to sample-type sensitivity analysis. Class enrichment was not significant after correction [false discovery rate (FDR) q = 0.126]. Indoleamine 2,3-dioxygenase inhibitors trended negative (FDR q = 0.095), and mitogen-activated protein kinase kinase inhibitors showed no class-level pattern (FDR q = 0.698). Across both folds, all seven canonical genes replicated and all four DNMT inhibitors retained above-median ranks, but the cold-elevated signature module was markedly less stable than the hot-elevated module (25.7 vs. 88.7% overlap). This suggestive pattern converges with a phase II trial of azacitidine/carboplatin priming before anti-programmed death-ligand 1 rechallenge in ICB-resistant melanoma, supporting prospective evaluation.

Purpose: Over 30 years ago, the World Health Organization (WHO) published the Guide to Good Prescribing (GGP) with its accompanying six-step model for rational prescribing. While widely used and proven effective in teaching clinical pharmacology and therapeutics (CPT), the GGP has never been revised to reflect scientific, societal, technological, and educational developments. The aim of this study was to explore which elements could be revised to actualize its content. Methods: CPT teachers experienced with the GGP were recruited from all six WHO regions. Six online nominal group technique sessions were conducted to elicit and prioritize ideas for revising the GGP. Discussions were audio-recorded, transcribed verbatim, and analyzed using an inductive thematic approach to capture participants’ views on both content and optimal format of the renewed GGP. Results: Twenty-six participants shared136 ideas for the revision, grouped into three main areas: ideas about the usability, accessibility, and awareness of the GGP; ideas about the six-step framework; and ideas about background information or supplementary chapters. Suggestions for improving usability emphasized an interactive, digital platform for accessibility, continuous updates, and integrated resources. Regarding the six-step model, participants recommended retaining its structure while incorporating key considerations such as pharmacovigilance, shared decision-making, and deprescribing. Lastly, participants proposed supplementary information on topics such as therapeutic reasoning and special patient populations. Conclusion: Suggestions for revising the WHO GGP included integrating contemporary and societal prescribing considerations to enhance its relevance, educational impact and usability, thereby supporting safe and effective prescribing in modern clinical practice.

The environmental impact of medicines poses a significant threat to planetary and public health, making it essential to integrate environmental sustainability into prescribing practices. While the most effective measures to reduce environmental impact, such as reducing unnecessary prescriptions and medication waste, are consistent with appropriate prescribing and relatively straightforward, incorporating environmental considerations into choices between alternative medicines can raise complex ethical questions. This article examines these challenges in light of the established biomedical ethical principles of beneficence, nonmaleficence, justice and respect for autonomy, while considering values at both individual and societal levels and integrating perspectives from current literature in this field. It discusses how environmental sustainability, along with its associated population benefits, can be aligned with direct patient benefits and considers the implications for distributive and intergenerational justice, as well as for shared decision‐making and patient autonomy. It also explores the allocation of responsibilities among stakeholders and argues that environmentally sustainable prescribing should not be the sole responsibility of individuals. Ethical guidance should facilitate proportional, context‐sensitive, environmentally sustainable decision‐making, acknowledging that appropriate decisions also depend on factors such as disease severity and exact variations in treatment efficacy and safety. To this end, the article proposes three key steps: developing case‐based ethical analyses of prescribing dilemmas, translating these analyses into stakeholder‐informed value frameworks and embedding these frameworks in practical guidelines and decision aids. Together, these measures can support a responsible integration of environmental sustainability into prescribing practices, safeguarding high‐quality patient care while promoting the health of all current and future populations.

1. Immune checkpoint inhibitors (ICIs) have markedly improved clinical outcomes across multiple malignancies [1], including lung cancer, one of the most commonly diagnosed cancer worldwide and the ...

Improved survival among patients with neuroendocrine tumors (NETs), has increased attention to long-term oncologic outcomes, including second primary tumors (SPTs). However, their clinical patterns and timing remain incompletely characterized. In this retrospective single-center cohort study, we analyzed 201 patients with NETs diagnosed between 2005 and 2023. SPTs were defined according to Warren–Gates criteria and classified as synchronous (≤6 months) or metachronous (>6 months). Standardized incidence ratios were calculated using national cancer registry data. Predictors of SPT occurrence were explored using regression and competing-risk models. Thirty-five patients (17.4%) developed an additional malignancy. Patients with SPTs were older at NET diagnosis (median: 65 vs. 58 years; P = 0.006), while most other clinicopathological characteristics were similar. The most frequent SPTs were colorectal (26%), genitourinary (20%), and breast cancers (11%). SPTs were synchronous (71%), whereas metachronous tumors occurred at a median of 4.9 years after NET diagnosis. Standardized incidence ratios suggested an increased occurrence of colorectal, melanoma, and breast cancers, but estimates were imprecise because of limited event numbers. Older age at NET diagnosis independently predicted SPT occurrence (odds ratio: 1.62 per SD; 95% confidence interval: 1.07–2.54; P = 0.021), while no other variable reached statistical significance. Competing-risk analysis demonstrated metachronous SPTs of approximately 5–6% at 5 years and 7.5% at 10 years. Approximately one in six patients developed an additional malignancy, most frequently detected synchronously. Diagnostic intensity during initial staging may contribute to SPT detection, while long-term risk of metachronous tumors persists. These results support individualized follow-up with attention to gastrointestinal and site-specific cancer surveillance.

High-risk antibiotics remain indispensable in contemporary infectious diseases practice, yet they account for a disproportionate share of preventable toxicity, therapeutic drug monitoring complexity, and antimicrobial stewardship workload. Vancomycin, aminoglycosides, colistin, linezolid, daptomycin, selected beta-lactams, and amphotericin B are particularly challenging because clinically relevant exposure-toxicity relationships coexist with marked inter-patient variability and fragmented post-marketing safety surveillance. Artificial intelligence and real-world evidence are increasingly proposed as complementary approaches to address these limitations, although the evidence base remains heterogeneous and predominantly retrospective. This narrative review synthesises literature from PubMed/MEDLINE, Scopus, and Web of Science published between 2019 and April 2026, supplemented by citation chaining and regulatory pharmacovigilance resources, with studies prioritised by implementation maturity, external validation status, and stewardship relevance. Current evidence indicates that artificial intelligence may improve safety monitoring when embedded within clinically rich data environments: machine learning models show promising discrimination for nephrotoxicity and haematological toxicity in vancomycin, colistin, and linezolid therapy; natural language processing may enhance adverse drug event extraction from clinical text; and Bayesian, model-informed tools already demonstrate clinical utility in vancomycin and aminoglycoside dosing. However, prospective implementation data remain sparse, external validation is uncommon, and evidence that these tools improve real-world antibiotic safety outcomes, as opposed to predictive discrimination alone, remains limited. Artificial intelligence-enabled antibiotic safety monitoring is therefore transitioning from methodological promise towards conditional clinical utility rather than proven benefit. Near-term value is most likely to arise from integration with therapeutic drug monitoring, antimicrobial stewardship, and pharmacology-led clinical review rather than autonomous decision-making, with clinical pharmacologists and stewardship teams leading local implementation, validation, and governance of these tools.

Full-dose systemic thrombolysis reduces haemodynamic decompensation in intermediate-high risk pulmonary embolism (PE) but increases bleeding risk, and its real-world safety profile in ICU settings remains incompletely characterised. We describe treatment selection patterns, safety outcomes, and resource utilisation associated with systemic alteplase versus unfractionated heparin (UFH) in ICU-managed intermediate-high risk PE. Prospective single-centre cohort; 80 adults with CTPA-confirmed intermediate-high risk PE (2020-2024), 40 per arm. Outcomes included mortality, bleeding, clinical deterioration, and ICU and hospital length of stay (LOS). Firth penalised logistic regression was used for binary outcomes with complete separation; negative binomial regression with covariate adjustment (age, APACHE II, Charlson Comorbidity Index, PESI class) for LOS. Clinicians preferentially selected alteplase for younger patients with greater PE-specific severity markers, and UFH for older, more comorbid patients with higher physiological derangement. Major bleeding was rare in both groups (UFH 2/40; alteplase 1/40; P = 0.781), with no intracranial or fatal events. Clinical deterioration occurred exclusively in the UFH group (17.5% vs 0%; P = 0.012), though most events represented rescue thrombolysis, structurally unobservable in the alteplase arm; no residual signal persisted after its exclusion (adjusted OR 0.77; P = 0.89). ICU LOS (rate ratio 0.70; P = 0.007) and hospital LOS (rate ratio 0.73; P = 0.019) were shorter with alteplase after covariate adjustment. In this prospective ICU cohort of carefully selected intermediate-high risk PE patients, systemic alteplase was associated with a favourable safety profile and shorter hospitalisation. These hypothesis-generating findings support prospective studies targeting ICU-managed intermediate-high risk PE.

Statins exhibit pleiotropic effects on bone metabolism, including osteogenic and angiogenic activity. The aim of this pilot study was to evaluate whether local application of simvastatin combined with a bovine-derived xenogeneic bone substitute enhances histomorphometric outcomes of socket preservation compared with the bone substitute alone after a three-month healing period. This prospective split-mouth clinical study included nine patients requiring bilateral tooth extraction. One socket was treated with cerabone® plus alone (control), while the contralateral socket received cerabone® plus combined with locally applied simvastatin (1 mg/0.2 mL saline). Bone core biopsies were harvested three months after grafting and analyzed histomorphometrically. The proportions of newly formed bone (NB/TV), residual bone substitute material (BSM/TV), and connective tissue (CT/TV) were quantified. Paired t-tests and Wilcoxon signed-rank tests were used for statistical analysis. Histomorphometric analysis demonstrated a similar tissue composition in both groups. Connective tissue represented the predominant component in the control and statin-treated sites (59.1 ± 12.0% and 64.3 ± 9.4%, respectively; p = 0.31). Newly formed bone accounted for 31.0 ± 15.5% in the control group and 26.2 ± 11.6% in the statin group (p = 0.45). Residual bone substitute material showed comparable values between groups (9.9 ± 8.5% vs. 9.5 ± 9.7%; p = 0.91). No statistically significant differences were observed. The addition of locally applied simvastatin to a bovine-derived xenogeneic bone substitute did not result in significant histomorphometric differences in socket preservation after three months. At the tested dose and delivery method, simvastatin did not enhance early mineralized tissue formation compared with the bone substitute alone.