Summary Interferons can trigger robust anti-tumor responses following immune checkpoint blockade (ICB). However, chronic interferon signaling can also reshape tumor cell phenotypes, selecting for immune evasion mechanisms that drive resistance. In a cohort of 108 metastatic melanoma samples collected prior to first-line ICB, immune infiltration and bulk interferon gamma (IFNG) expression correlate with initial but not durable responses. Using a regression-based approach to deconvolve cancer cell signals from bulk tumors, we find that tumors from patients who initially respond but later acquire resistance exhibit heightened cancer cell-dependent IFN signaling at baseline, accompanied by MYC downregulation, dedifferentiation, and impaired major histocompatibility complex (MHC) class II induction. Genetically, acquired resistance also associates with reduced T cell interferon signaling, lower memory T cell activity, high tumor mutational burden, clonal diversification, and elevated subclonal neoantigen burden. These findings reveal baseline transcriptomic and genetic features distinguishing acquired resistance from durable ICB response, identifying candidate targets to prevent relapse and refine stratification.

The rapid expansion of point of care testing (POCT) has significantly transformed clinical decision-making, particularly in acute care settings. Cardiac biomarkers such as troponins (conventional and high sensitivity) and natriuretic peptides are increasingly being deployed at the bedside to expedite diagnosis and guide timely management [1]. While the clinical advantages of POCT are well recognized, its widespread implementation raises important ethical considerations that remain insufficiently addressed [2]. We aim to project that the rapid expansion of cardiac biomarker POCT has outpaced the development of practical ethical guidance for its implementation. In particular, challenges related to analytical reliability, accountability, quality oversight, equitable access, patient autonomy, and environmental sustainability require a structured ethical framework to support safe and clinically responsible use of POCT in cardiac care. One of the primary ethical concerns relates to the trade-off between speed and analytical accuracy. Although POCT offers faster turnaround times, variability in analytical performance compared to central laboratory assays may compromise diagnostic certainty [3]. This is particularly critical in the context of cardiac biomarkers, where even minor inaccuracies can lead to misclassification of myocardial infarction. In cardiac care, such errors carry particularly significant ethical implications because troponin results may directly influence urgent decisions regarding admission, invasive procedures, discharge, or withholding of treatment. This underscores the necessity of an ethical framework to ensure rapid testing does not compromise diagnostic integrity and patient safety.

The presence of thyroid tissue outside its normal anatomical location, between the second and fifth tracheal rings, is defined as ectopic thyroid tissue. Approximately one to three percent of ectopic thyroid tissue is located in the lateral neck. Most cases are asymptomatic and considered benign.However, lateral neck ectopic thyroid tissue may also represent metastatic disease from an occult primary thyroid carcinoma, making accurate diagnosis challenging. A 36-year-old male presented for microwave ablation of a large right-lobe thyroid nodule after five years of ultrasound surveillance. Progressive growth had been documented, and surgery was recommended, but the patient opted for minimally invasive treatment. Repeated fine-needle aspiration of the right-lobe nodule showed benign cytology, thyroid function tests were normal, and no cervical lymphadenopathy was detected. Clinical examination revealed a palpable right thyroid mass causing compressive symptoms and cosmetic concerns. Ultrasound demonstrated a parenchymatous-colloid nodule measuring 3.1 × 4.1 × 2.5 cm in the right lobe, a 0.2 cm micronodule in the left lobe, and an enlarged left lateral cervical lymph node with microcalcifications, highly suspicious for malignancy. During microwave ablation in November 2024, fine-needle aspiration of the suspicious lymph node suggested papillary carcinoma, possibly arising from ectopic thyroid tissue. In February 2025, right lobectomy with excision of lateral neck tissue and lymph node dissection was performed. Histopathology confirmed a benign right-lobe nodule and papillary carcinoma of conventional and follicular variants originating from ectopic thyroid tissue, with microscopic lymphatic invasion and no vascular invasion.Postoperative evaluation revealed elevated serum thyroglobulin levels of 123.6 ng/mL. Computed tomography identified enlarged lateral cervical lymph nodes. Completion thyroidectomy and removal of metastatic lymph nodes were performed. Histology demonstrated a 0.2 cm papillary microcarcinoma in the left thyroid lobe and metastases in three of eleven lymph nodes, while remaining thyroid tissue showed nodular colloid goiter. Follow-up computed tomography and whole-body scintigraphy were normal. The patient received radioactive iodine therapy I-131 150 mCi. Ectopic thyroid carcinoma of the lateral neck is a rare but clinically important entity. Papillary microcarcinoma, despite its small size, may exhibit aggressive behavior and requires careful evaluation. Thermal ablation enabled early detection, appropriate surgical management, and adjuvant therapy, resulting in a favorable oncological outcome and long-term disease control. This case highlights the importance of multidisciplinary assessment, imaging, and histopathological correlation in complex thyroid disease presentations in clinical practice.

Background/Objectives: Peripheral arterial disease (PAD) and diabetes mellitus (DM) may produce different and overlapping plantar thermal patterns. This study descriptively characterized whole-foot temperature-distribution patterns in clinically defined healthy, PAD, DM, and combined PAD_DM cohorts. Methods: This single-center, exploratory, cross-sectional observational study included 73 participants: healthy controls (n = 21), isolated PAD (n = 13), isolated DM (n = 19), and combined PAD_DM (n = 20). Right- and left-foot temperature distributions were processed separately for each participant and interpreted as one paired bilateral thermal footprint using patient-level histograms, representative bilateral kernel density estimation (KDE) profiles, and a cohort-derived deterministic rule-based model. The model was developed from the present cohort and was not evaluated as an independent diagnostic classifier. Results: Among healthy controls, 11 of 21 participants (52.4%) were assigned to healthy and 8 of 21 (38.1%) to borderline healthy categories. In the DM cohort, 7 of 19 participants (36.8%) were assigned to DM, 3 of 19 (15.8%) to borderline healthy/suspected DM or controlled DM, 3 of 19 (15.8%) to DM suspected PAD, and 5 of 19 (26.3%) to PAD_DM. In the combined PAD_DM cohort, 15 of 20 participants (75.0%) were assigned to PAD_DM. The isolated PAD cohort was the most heterogeneous: 6 of 13 participants (46.2%) were assigned to PAD_DM, while none were assigned to the isolated PAD output. Conclusions: This exploratory, cross-sectional study demonstrated that whole-foot plantar temperature distributions can descriptively characterize differences among healthy individuals, patients with isolated DM, and those with combined PAD and DM. While healthy controls generally demonstrated symmetric thermal footprints, the DM cohort frequently exhibited globally elevated and compact temperature-distribution profiles, while mixed asymmetric patterns were common in participants with combined PAD and DM. In contrast, the isolated PAD cohort was characterized by pronounced thermal heterogeneity.

Primary central nervous system lymphoma (PCNSL) is a rare and aggressive form of diffuse large B ‐ cell lymphoma (DLBCL) characterized by infiltration of malignant B cells into the central nervous system (CNS). 1 Fit patients are treated with high ‐ dose methotrexate (HD ‐ MTX) – based polychemotherapy followed by thiotepa ‐ containing high ‐ dose chemotherapy and autologous stem cell transplantation (ASCT). 2 For patients unsuitable for ASCT, induction treatment is consolidated with high ‐ dose cytarabine and low ‐ dose whole ‐ brain radiotherapy (WBRT). 1,2 Patients unsuitable for HD ‐ MTX can receive first ‐ line treatment with a single alkylator, such as temozolomide (TMZ) and WBRT. Despite therapeutic advances and high response rates, over half of the patients with PCNSL relapse within 2 years after diagnosis. 3 TMZ maintenance treatment has been suggested to reduce relapse rates and improve overall survival (OS) for patients with post ‐ induction complete remission (CR) or partial remission (PR). Therefore, its administration is supported by international guidelines, including the European Hematology Association and European Society for Medical Oncology (EHA ‐ ESMO) joint recommendations 2 and the National Comprehensive Cancer Network (NCCN) Guidelines for B ‐ Cell Lymphomas (Version 3.2026). However, implementation of TMZ maintenance varies across clinical settings, allowing real ‐ world evaluation of the association between TMZ

GLP-1 receptor agonist–based therapy is of interest in Polyendocrine Metabolic Ovarian Syndrome (PMOS; formerly polycystic ovary syndrome [PCOS]) because obesity and insulin resistance may worsen hyperandrogenism, anovulation, and infertility. To systematically review randomized controlled trial evidence on the effects of GLP-1 receptor agonists on ovulatory function and reproductive hormonal parameters in women with Polyendocrine Metabolic Ovarian Syndrome. PubMed was searched from database inception to February 3, 2026. Eligible English-language randomized controlled trials included women with Polyendocrine Metabolic Ovarian Syndrome diagnosed according to established PCOS diagnostic criteria used in the original randomized controlled trials and compared a GLP-1 receptor agonist, alone or in combination with metformin, with metformin or placebo, reporting reproductive hormonal, menstrual, ovulatory, or pregnancy-related outcomes. Five randomized controlled trials involving 418 participants were included. Interventions used liraglutide or exenatide over 12–32 weeks. GLP-1 receptor agonist–based therapy was associated with improvements in body weight, body mass index, waist circumference, glucose parameters, insulin resistance, increased sex hormone-binding globulin, and reduced free androgen index. Menstrual cycle frequency, regularity, and recovery improved across studies; however, ovulation was not directly or consistently assessed. Pregnancy outcomes were reported in only two heterogeneous trials and appeared favorable versus metformin alone. GLP-1 receptor agonists appear promising for improving metabolic, androgen-related, and menstrual parameters in women with Polyendocrine Metabolic Ovarian Syndrome, but current evidence remains limited for direct ovulatory and fertility outcomes.

The important cereal pathogen Fusarium graminearum is not only able to produce trichothecene toxins, like deoxynivalenol, but also the plant hormone auxin (indole‐3‐acetic acid, IAA). Highly elevated levels of IAA and auxin derivatives such as IAA‐glucoside or IAA amino‐acid conjugates were observed in the susceptible wheat cultivar Apogee infected with F. graminearum. We report here that the fungal pathogen can hydrolyse tryptamine‐derived hydroxycinnamic acid amides produced in high amounts during plant defence and is able to convert the released tryptamine in high yield into IAA. We investigated the role of copper amine‐oxidase candidate genes, which code for enzymes converting tryptamine into the IAA precursor indole‐3‐acetaldehyde. After consecutive knock‐out of seven copper amine oxidases the resulting septuple‐mutant strain (aoxΔ7) had strongly reduced ability to produce auxin from tryptamine in vitro. Virulence of the aoxΔ7 mutant was significantly impaired while deoxynivalenol production in planta was comparable to the wild type. Our results indicate that F. graminearum, formerly presumed to be a toxin‐producing necrotroph, in an early biotrophic phase uses subterfuge by converting abundantly formed plant defence compounds into defence‐suppressing auxin.

Percolation properties of two types of inhomogeneous k-mers with different arrangements of conductive and nonconductive sites on a triangular lattice is studied by Monte Carlo simulations. The depositing objects are ‘Janus’ k-mers, with one conductive and one nonconductive side, and ‘patchy’ k-mers, with conductive ends and a nonconductive middle. We find that the percolation threshold strongly depends on the k-mer length, the number of nonconductive sites, and their spatial distribution. For both object types, the percolation threshold increases with the fraction of nonconductive sites. For fixed number of nonconductive sites, the threshold decreases monotonicaly with the object length. The presence of pre-existing conductive objects on the substrate can either hinder or enhance percolation, depending on their size and concentration.

Circadian rhythms regulate key biological processes central to cancer biology, including cell cycle control, DNA repair, metabolism, immune function, and drug pharmacokinetics. Experimental models consistently demonstrate marked time-of-day differences in the efficacy and toxicity of chemotherapy, targeted agents, and immunotherapies. Clinical studies of chronomodulated chemotherapy—particularly with fluoropyrimidines, platinum compounds, and anthracyclines—show reproducible reductions in treatment-related toxicity, while effects on survival outcomes remain variable and often sex dependent. Emerging clinical evidence also suggests that timing of immune checkpoint inhibitor administration may influence progression-free and overall survival across several tumor types. However, translation into routine oncology practice has been limited by interindividual variability in circadian phase, tumor-specific disruption of clock function, lack of validated biomarkers, and logistical constraints of time-specific drug delivery. Advances in circadian phenotyping, wearable monitoring, and adaptive dosing technologies now offer feasible pathways toward individualized, biology-driven treatment timing. This narrative review critically evaluates mechanistic, preclinical, and clinical evidence for chronotherapy across oncological treatment modalities and examines challenges and opportunities for its integration into precision cancer care.

Introduction Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have transformed the management of type 2 diabetes and obesity by improving glycemic control, promoting weight loss, and reducing cardiovascular risk. This study aimed to evaluate national trends in GLP-1 RA utilization and expenditure in Croatia between 2010 and 2024. Methods We conducted a nationwide, retrospective analysis using the International Medical Statistics and IQVIA pharmaceutical databases. Utilization was measured in defined daily doses per 1000 inhabitants per day, and financial expenditure was expressed in euros. Trends were contextualized within evolving clinical evidence, guideline recommendations, and healthcare reimbursement policies. Results Total noninsulin antidiabetic drug consumption more than doubled between 2010 and 2024, with the use of GLP-1 RAs rising from negligible at the time of market entry to that worth 15.99 defined daily doses per 1000 inhabitants per day in 2024, representing 16.1% of total prescriptions. Expenditure on GLP-1 RAs reached 42.07 million euros in 2024, accounting for 42.7% of total noninsulin antidiabetic spending. Semaglutide emerged as the dominant agent according to both utilization and cost, followed by dulaglutide and liraglutide. Obesity-specific indications were underutilized, largely due to lack of reimbursement. Conclusions GLP-1 RA prescribing has increased substantially in Croatia over the past decade, reflecting their growing therapeutic importance. However, economic constraints, restrictive reimbursement, and sociocultural barriers continue to limit access, particularly in obesity care. Our findings highlight the need to align reimbursement frameworks and clinical practice with emerging evidence to maximize the cardiometabolic and public health benefits of GLP-1 RAs.

Aim To determine the characteristics of early emergency department (ED) departures, including patients leaving without being seen and leaving during treatment, in a large tertiary center in Croatia. Methods We retrospectively reviewed ED visits at University Hospital Center Split from July 12, 2023, to July 12, 2024. The study enrolled patients who had been triaged but left before physician evaluation or before completing diagnostic workup. Pediatric, gynecologic, psychiatric, and infectious disease ED visits were excluded because these specialties are managed separately. Data on demographics, Australasian Triage Scale category, referral type, specialty routing, seasonal/circadian patterns, and 48-hour return visits were extracted from the hospital information system. Results Among 110 547 patients visiting the ED, 1420 (1.3%) departed early. Their median age was 40 years (interquartile range 25-59); 55.6% were male. Most were low-acuity patients (category 4: 60%; category 5: 29%). Early departures peaked in August-September and between 2 pm and 10 pm daily (maximum at 7 pm). Self-referred patients accounted for 65% of early departures, and 26% had been routed to orthopedics/trauma specialists. Only 5% left during treatment. Within 48 hours, 20% returned to the ED and 12% required other hospital evaluations. Conclusion Early ED departure rate was low. The patients were mostly young, male, low-acuity, and self-referred with trauma-related conditions, presenting during tourist surges and evening hours. These findings underscore the need for dynamic staffing, enhanced triage communication, targeted patient education, and seasonal preparedness to sustain efficient ED performance.

Hypogonadotropic hypogonadism is a rare but important cause of primary amenorrhea. Kallmann syndrome, characterized by gonadotropin-releasing hormone deficiency and anosmia, may be misdiagnosed when prolonged estrogen deficiency results in non-visualization of reproductive organs. A 26-year-old woman with primary amenorrhea and absent pubertal development had previously been diagnosed with uterine and ovarian agenesis. Hormone replacement therapy had been recommended but not initiated. At presentation, she had poor breast development (Tanner stage II), normal external genitalia, and pubic hair consistent with Tanner stage III/IV. Her history revealed progressive hyposmia evolving into anosmia. Hormonal evaluation confirmed hypogonadotropic hypogonadism, and the karyotype was 46,XX. Initial imaging again failed to visualize the uterus and ovaries, raising suspicion of Müllerian agenesis. Pituitary MRI showed hypoplasia, and bone densitometry revealed osteopenia. Estrogen therapy was initiated. Follow-up ultrasound demonstrated uterine development with appropriate endometrial thickness and visualization of adnexal structures. After five months, transvaginal ultrasound confirmed a normal uterus with a trilaminar endometrium and both ovaries, excluding Mayer-Rokitansky-Küster-Hauser syndrome. MRI of the olfactory region showed hypoplastic olfactory structures, confirming Kallmann syndrome. Progesterone was added, resulting in regular withdrawal bleeding. This case highlights that prolonged estrogen deficiency can lead to misdiagnosis as Müllerian agenesis on imaging. Timely recognition and hormone therapy are essential for accurate diagnosis, restoration of reproductive anatomy, and preservation of bone and reproductive health.

Background: Hashimoto's thyroiditis (HT) is the most common autoimmune thyroid disease and is characterized by the presence of thyroid peroxidase (anti-TPO) and thyroglobulin (anti-Tg) antibodies. However, the clinical and biochemical factors associated with these antibodies remain incompletely understood. Objective: To evaluate the associations between anti-TPO and anti-Tg antibody levels and demographic, clinical, biochemical, and lifestyle-related factors in patients with HT. Methods: This retrospective cross-sectional study included 100 patients with HT. Clinical, biochemical, and laboratory data were retrospectively collected from medical records. Group comparisons were performed using non-parametric tests, correlations were assessed using Spearman's rank analysis, and multivariable linear regression was used to identify independent predictors of log-transformed anti-TPO and anti-Tg levels. Results: Anti-TPO levels differed significantly according to TSH status and were independently associated with higher TSH concentrations, longer disease duration, and lower BMI. Smoking was the only independent predictor of anti-Tg levels. No significant associations were observed between thyroid autoantibody levels and age, sex, vitamin D status, or family history of thyroid disease. Conclusion: Anti-TPO and anti-Tg antibodies demonstrated distinct clinical associations in patients with HT. These findings support the complementary clinical value of both thyroid autoantibodies and should be confirmed in larger prospective multicenter studies.

Background Both Hashimoto’s thyroiditis and non-autoimmune hypothyroidism are highly prevalent thyroid disorders. While their clinical presentations overlap, they are driven by distinct pathophysiological mechanisms and potentially influenced by different genetic susceptibilities and environmental triggers, including prenatal solar exposure and vitamin D status. This study aimed to evaluate and compare the season of birth, serum vitamin D levels, body mass index (BMI), smoking habits, and family history of thyroid diseases between patients with Hashimoto’s thyroiditis and patients with non-autoimmune hypothyroidism in Tuzla Canton. Materials and methods This retrospective observational cross-sectional study reviewed the medical records of 200 patients evaluated and followed up at the Department of Nuclear Medicine and Radiology of a tertiary care university hospital in Bosnia and Herzegovina. Participants were equally divided into two groups: patients with Hashimoto’s thyroiditis (n = 100) and patients with non-autoimmune hypothyroidism (n = 100). Numerical variables were analyzed using the Mann-Whitney U and Kruskal-Wallis tests, while categorical variables were evaluated using the χ² test. Post hoc pairwise comparisons were performed with Bonferroni correction. Results The study population comprised 189 women (94.5%) and 11 men (5.5%). The distribution of birth seasons did not differ significantly between the groups (χ² = 2.444, df = 3, p = 0.485). Similarly, no statistically significant differences were observed in median serum vitamin D levels (p = 0.931) or smoking rates (23.0% in the Hashimoto’s group vs. 22.0% in the hypothyroid group, p = 0.866). However, patients with non-autoimmune hypothyroidism were significantly older (median: 59.0 vs. 49.0 years, p < 0.001) and presented with significantly higher BMI values (median: 28.20 kg/m² vs. 26.21 kg/m², p = 0.008) compared to those with Hashimoto’s thyroiditis. A positive family history of thyroid disease was significantly more frequent among patients with Hashimoto’s thyroiditis than those with hypothyroidism (62.0% vs. 47.0%, χ²= 4.537, df = 1, p = 0.033). Within the non-autoimmune hypothyroidism group, vitamin D levels differed significantly across BMI categories (p = 0.030), with overweight patients exhibiting significantly lower median vitamin D levels compared to normal-weight patients (median: 18.50 vs. 24.00, adjusted p = 0.045). Conclusion Season of birth, smoking status, and overall serum vitamin D levels do not distinguish Hashimoto’s thyroiditis from non-autoimmune hypothyroidism. However, patients with non-autoimmune hypothyroidism present with higher BMI, and those who are overweight are particularly prone to lower vitamin D levels. In contrast, Hashimoto’s thyroiditis is more strongly characterized by a positive family history of thyroid disease, highlighting a more pronounced hereditary component.