AIMS: CIC-rearranged sarcomas (CRS) are clinically aggressive undifferentiated round cell sarcomas (URCS), commonly driven by CIC::DUX4. Due to the repetitive nature of DUX4 and the variability of the fusion breakpoints, CIC::DUX4 fusion may be missed by molecular testing. Immunohistochemical (IHC) stains have been studied as surrogates for the CIC::DUX4 fusion. We aim to assess the performance of DUX4 IHC in the work-up of CRS and its expression in non-CRS round cell or epithelioid neoplasms. METHODS AND RESULTS: Cases of molecularly confirmed CRS (n = 48) and non-CRS (n = 105) were included. CRS cases consisted of 35 females and 13 males, with ages ranging from less than 1 year to 67 years (median = 41 years). Among the molecularly confirmed non-CRS cases, C-terminal DUX4 expression was investigated in Ewing sarcomas (38 cases), alveolar rhabdomyosarcomas (18 cases), desmoplastic small round cell tumours (12 cases) and synovial sarcomas (n = five), as well as in non-mesenchymal neoplasms such as SMARCA4/SMARCB1-deficient tumours (n = five), carcinomas of unknown primary (n = three) and haematolymphoid neoplasms (four cases). DUX4 IHC was considered positive when strong nuclear expression was detected in more than 50% of neoplastic cells. When used as a surrogate for the diagnosis of CRS, the sensitivity and specificity of DUX4 IHC was 98 and 100%, respectively. Only one CRS case was negative for DUX4 IHC and harboured a CIC::FOXO4 fusion. CONCLUSIONS: DUX4 IHC is a highly sensitive and specific surrogate marker for the presence of CIC::DUX4 fusion, demonstrating its utility in establishing a diagnosis of CRS.

• MeSH
• Child MeSH
• Adult MeSH
• Oncogene Proteins, Fusion * genetics   MeSH
• Gene Rearrangement MeSH
• Homeodomain Proteins * metabolism   genetics   MeSH
• Immunohistochemistry * MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Biomarkers, Tumor * metabolism   analysis   genetics   MeSH
• Soft Tissue Neoplasms diagnosis   pathology   genetics   metabolism   MeSH
• Child, Preschool MeSH
• Sarcoma * diagnosis   pathology   genetics   metabolism   MeSH
• Aged MeSH
• Sensitivity and Specificity MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Infant MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Young Adult MeSH
• Male MeSH
• Child, Preschool MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

OBJECTIVE: This study aimed to demonstrate the clinical equivalence of biosimilar QL1205 and reference ranibizumab, Lucentis, in patients with neovascular age-related macular degeneration (nAMD). DESIGN: This was a multicenter, double-masked, randomized, controlled phase III trial. PARTICIPANTS: Treatment-naive patients with active nAMD were randomly assigned to receive QL1205 or reference ranibizumab. METHODS: Patients received intravitreal injection of QL1205 or reference ranibizumab at a dose of 0.5 mg in the study eye once every 4 weeks for 48 weeks. MAIN OUTCOME MEASURES: The primary end point was change in best-corrected visual acuity (BCVA) by ETDRS letters at week 8 compared with baseline level. Biosimilarity of QL1205 to reference ranibizumab was assessed with an equivalence range for the difference in BCVA letters between -3.49 and +3.49. RESULTS: Between June 27, 2019 and June 8, 2021, 616 patients were randomized to the QL1205 group (n = 308) and the reference ranibizumab group (n = 308). The mean improvement of BCVA was +6.3 ± 9.13 ETDRS letters in the QL1205 group and +7.3 ± 8.82 ETDRS letters in the reference ranibizumab group at week 8. Both the 90% confidence interval (CI, -2.23 to 0.13) and 95% CI (-2.46 to 0.36) of the difference between the 2 treatment groups (P = 0.1434) were within the predefined equivalence range. Safety profiles were manageable in both groups. CONCLUSIONS: QL1205 was biosimilar to reference ranibizumab regarding clinical efficacy, ocular and systemic safety, as well as immunogenicity and pharmacokinetics profiles in the treatment of patients with nAMD. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

• MeSH
• Biosimilar Pharmaceuticals * administration & dosage   adverse effects   MeSH
• Double-Blind Method MeSH
• Angiogenesis Inhibitors administration & dosage   adverse effects   MeSH
• Intravitreal Injections MeSH
• Middle Aged MeSH
• Humans MeSH
• Follow-Up Studies MeSH
• Tomography, Optical Coherence MeSH
• Ranibizumab * administration & dosage   adverse effects   MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Vascular Endothelial Growth Factor A antagonists & inhibitors   MeSH
• Wet Macular Degeneration * drug therapy   diagnosis   MeSH
• Treatment Outcome MeSH
• Dose-Response Relationship, Drug MeSH
• Visual Acuity * MeSH
• Check Tag
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged, 80 and over MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Randomized Controlled Trial MeSH

BACKGROUND: Prostate cancer (PCa) is a malignancy with significant immunosuppressive properties and limited immune activation. This immunosuppression is linked to reduced cytotoxic T cell activity, impaired antigen presentation, and elevated levels of immunosuppressive cytokines and immune checkpoint molecules. Studies demonstrate that cytotoxic CD8+ T cell infiltration correlates with improved survival, while increased regulatory T cells (Tregs) and tumor-associated macrophages (TAMs) are associated with worse outcomes and therapeutic resistance. Th1 cells are beneficial, whereas Th17 cells, producing interleukin-17 (IL-17), contribute to tumor progression. Tumor-associated neutrophils (TANs) and immune checkpoint molecules, such as PD-1/PD-L1 and T cell immunoglobulin-3 (TIM-3) are also linked to advanced stages of PCa. Chemotherapy holds promise in converting the "cold" tumor microenvironment (TME) to a "hot" one by depleting immunosuppressive cells and enhancing tumor immunogenicity. SUMMARY: This comprehensive review examines the immune microenvironment in PCa, focusing on the intricate interactions between immune and tumor cells in the TME. It highlights how TAMs, Tregs, cytotoxic T cells, and other immune cell types contribute to tumor progression or suppression and how PCa's low immunogenicity complicates immunotherapy. KEY MESSAGES: The infiltration of cytotoxic CD8+ T cells and Th1 cells correlates with better outcomes, while elevated T regs and TAMs promote tumor growth, metastasis, and resistance. TANs and natural killer (NK) cells exhibit dual roles, with higher NK cell levels linked to better prognoses. Immune checkpoint molecules like PD-1, PD-L1, and TIM-3 are associated with advanced disease. Chemotherapy can improve tumor immunogenicity by depleting T regs and myeloid-derived suppressor cells, offering therapeutic promise.

• MeSH
• Immunotherapy methods   MeSH
• Humans MeSH
• Tumor-Associated Macrophages immunology   MeSH
• Tumor Microenvironment * immunology   MeSH
• Prostatic Neoplasms * immunology   pathology   therapy   MeSH
• T-Lymphocytes, Regulatory immunology   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

Pegunigalsidase alfa, a PEGylated α-galactosidase A enzyme replacement therapy (ERT) for Fabry disease, has a longer plasma half-life than other ERTs administered intravenously every 2 weeks (E2W). BRIGHT (NCT03180840) was a phase III, open-label study in adults with Fabry disease, previously treated with agalsidase alfa or beta E2W for ≥3 years, who switched to 2 mg/kg pegunigalsidase alfa every 4 weeks (E4W) for 52 weeks. Primary objective assessed safety, including number of treatment-emergent adverse events (TEAEs). Thirty patients were enrolled (24 males); 23 previously received agalsidase beta. Pegunigalsidase alfa plasma concentrations remained above the lower limit of quantification throughout the 4-week dosing interval. Thirty-three of 182 TEAEs (in 9 patients) were considered treatment-related; all were mild/moderate. No patients developed de novo anti-drug antibodies (ADAs). In the efficacy analysis (n = 29), median (inter-quartile range) eGFR change from baseline over 52 weeks was -1.9 (-5.9; 1.8) mL/min/1.73 m2 (n = 28; males [n = 22]: -2.4 [-5.2; 3.2]; females [n = 6]: -0.7 [-9.2; 2.0]). Overall, median eGFR slope was -1.9 (-8.3; 1.9) mL/min/1.73 m2/year (ADA-negative [n = 20]: -1.2 [-6.4; 2.6]; ADA-positive [n = 9]: -8.4 [-11.6; -1.0]). Lyso-Gb3 concentrations were low and stable in females, with a slight increase in males (9/24 ADA-positive). The BRIGHT study results suggest that 2 mg/kg pegunigalsidase alfa E4W is tolerated well in stable adult patients with Fabry disease. Due to the low number of patients in this study, more research is needed to demonstrate the effects of pegunigalsidase alfa given E4W. Further evidence, outside of this clinical trial, should be factored in for physicians to prolong the biweekly ERT intervals to E4W. TAKE-HOME MESSAGE: Treatment with 2 mg/kg pegunigalsidase alfa every 4 weeks could offer a new treatment option for patients with Fabry disease.

• MeSH
• alpha-Galactosidase * administration & dosage   therapeutic use   MeSH
• Adult MeSH
• Enzyme Replacement Therapy * methods   MeSH
• Fabry Disease * drug therapy   MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Polyethylene Glycols administration & dosage   MeSH
• Recombinant Proteins * administration & dosage   therapeutic use   MeSH
• Drug Administration Schedule MeSH
• Aged MeSH
• Sphingolipids blood   MeSH
• Trihexosylceramides blood   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Young Adult MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH

OBJECTIVES: Decision-analytic models assessing the value of emerging Alzheimer's disease (AD) treatments are challenged by limited evidence on short-term trial outcomes and uncertainty in extrapolating long-term patient-relevant outcomes. To improve understanding and foster transparency and credibility in modeling methods, we cross-compared AD decision models in a hypothetical context of disease-modifying treatment for mild cognitive impairment (MCI) due to AD. METHODS: A benchmark scenario (US setting) was used with target population MCI due to AD and a set of synthetically generated hypothetical trial efficacy estimates. Treatment costs were excluded. Model predictions (10-year horizon) were assessed and discussed during a 2-day workshop. RESULTS: Nine modeling groups provided model predictions. Implementation of treatment effectiveness varied across models based on trial efficacy outcome selection (clinical dementia rating - sum of boxes, clinical dementia rating - global, mini-mental state examination, functional activities questionnaire) and analysis method (observed severity transitions, change from baseline, progression hazard ratio, or calibration to these). Predicted mean time in MCI ranged from 2.6 to 5.2 years for control strategy and from 0.1 to 1.0 years for difference between intervention and control strategies. Predicted quality-adjusted life-year gains ranged from 0.0 to 0.6 and incremental costs (excluding treatment costs) from -US$66 897 to US$11 896. CONCLUSIONS: Trial data can be implemented in different ways across health-economic models leading to large variation in model predictions. We recommend (1) addressing the choice of outcome measure and treatment effectiveness assumptions in sensitivity analysis, (2) a standardized reporting table for model predictions, and (3) exploring the use of registries for future AD treatments measuring long-term disease progression to reduce uncertainty of extrapolating short-term trial results by health-economic models.

• MeSH
• Alzheimer Disease * economics   drug therapy   MeSH
• Cost-Benefit Analysis * MeSH
• Models, Economic MeSH
• Cognitive Dysfunction * economics   MeSH
• Quality-Adjusted Life Years MeSH
• Humans MeSH
• Decision Support Techniques MeSH
• Disease Progression MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Comparative Study MeSH

BACKGROUND: Early life socioeconomic disadvantage and adverse experiences may lead to overeating, which is in turn associated with increased body mass index (BMI). However, recent evidence indicated that the association between childhood BMI and overeating might be bidirectional. This bidirectionality prompts the need for further investigation of early life predictors of BMI in childhood. OBJECTIVES: To longitudinally assess the directionality of the association between childhood BMI and perceived overeating and to investigate their antecedent early life predictors. METHODS: The sample included data from 5151 children from the ELSPAC study, collected between 18 months and 11 years of child age. The outcomes were child BMI and mother-reported overeating, assessed at the age of 3, 5, 7 and 11 years. Predictors included maternal BMI, maternal education, single parenthood, financial difficulties and adverse childhood experiences (ACEs) reported by parents and paediatricians. The random intercept cross-lagged panel model was applied. RESULTS: The mean child's BMI at age 3 was 15.59 kg/m2 and increased to 17.86 kg/m2 at age 11. The percentage of parent-reported overeating increased in the following period, from about 12% at age 3 to 17% at age 11. The results showed temporal stability in perceived overeating and BMI, with a bidirectional relationship strengthening over time. The child's BMI was associated with maternal BMI. Maternal BMI was positively associated with child-perceived overeating, but a stronger effect was found for ACEs. ACEs mediated the impact of maternal education, financial difficulties and single parenthood on overeating. CONCLUSIONS: We observed stable bidirectional associations between BMI and perceived overeating. The results indicated two main pathways: one linked to maternal BMI and early childhood BMI increase followed by perceived overeating and the second associated with ACEs mediating the effect of early childhood social factors on perceived overeating, leading to gradual BMI gain.

• MeSH
• Child MeSH
• Hyperphagia * psychology   epidemiology   MeSH
• Body Mass Index * MeSH
• Infant MeSH
• Humans MeSH
• Longitudinal Studies MeSH
• Mothers psychology   statistics & numerical data   MeSH
• Adverse Childhood Experiences * statistics & numerical data   psychology   MeSH
• Pediatric Obesity * epidemiology   psychology   MeSH
• Child, Preschool MeSH
• Socioeconomic Factors MeSH
• Check Tag
• Child MeSH
• Infant MeSH
• Humans MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Vitamin B12, cobalamin, is indispensable for humans owing to its participation in two biochemical reactions: the conversion of l-methylmalonyl coenzyme A to succinyl coenzyme A, and the formation of methionine by methylation of homocysteine. Eukaryotes, encompassing plants, fungi, animals and humans, do not synthesise vitamin B12, in contrast to prokaryotes. Humans must consume it in their diet. The most important sources include meat, milk and dairy products, fish, shellfish and eggs. Due to this, vegetarians are at risk to develop a vitamin B12 deficiency and it is recommended that they consume fortified food. Vitamin B12 behaves differently to most vitamins of the B complex in several aspects, e.g. it is more stable, has a very specific mechanism of absorption and is stored in large amounts in the organism. This review summarises all its biological aspects (including its structure and natural sources as well as its stability in food, pharmacokinetics and physiological function) as well as causes, symptoms, diagnosis (with a summary of analytical methods for its measurement), prevention and treatment of its deficiency, and its pharmacological use and potential toxicity.

• MeSH
• Diet, Vegetarian MeSH
• Diet MeSH
• Food, Fortified MeSH
• Humans MeSH
• Vitamin B 12 Deficiency * diagnosis   prevention & control   drug therapy   etiology   MeSH
• Vitamin B 12 * pharmacokinetics   chemistry   metabolism   therapeutic use   physiology   adverse effects   administration & dosage   pharmacology   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Review MeSH

BACKGROUND: Anticoagulation during extracorporeal membrane oxygenation (ECMO) might still lead to severe bleeding complications. Heparin is the most frequently used anticoagulant, but novel drugs could be promising. Argatroban is a new alternative to heparin. To date, no robust studies have confirmed the clear superiority of argatroban (AG) over heparin, although it has some advantages and may be safer. STUDY DESIGN AND METHODS: An observational study was conducted in all adult veno-venous ECMO patients with COVID-19-associated acute respiratory distress syndrome admitted to the University Hospital Ostrava (n = 63). They were anticoagulated with heparin in the first period and with AG in the second period, targeting the same activated partial thromboplastin time (aPTT; 45-60 s). Bleeding complications requiring transfusion and life-threatening bleeding events were evaluated. The primary objective was to compare heparin and AG in terms of bleeding, transfusion requirements and mortality-related bleeding. RESULTS: The total time on ECMO per patient was 16 days with an in-hospital mortality of 55.6%. The red blood cell consumption in the AG group (median 2.7 transfusions/week) was significantly lower than in the heparin group (median 4.2 transfusions/week, p = 0.011). Life-threatening bleeding complications were higher in the heparin group compared to the AG group (35.7% vs. 10.2%, p = 0.035), and mortality-related bleeding complications were also higher in the heparin group (21.4% vs. 2.0%, p = 0.032). DISCUSSION: Argatroban is an interesting alternative to heparin with less bleeding, less need for red blood cell transfusions and improved safety of ECMO with less mortality-related bleeding.

• MeSH
• Anticoagulants * adverse effects   therapeutic use   MeSH
• Arginine * analogs & derivatives   MeSH
• COVID-19 complications   MeSH
• Adult MeSH
• Heparin * adverse effects   MeSH
• Hemorrhage * chemically induced   therapy   MeSH
• Pipecolic Acids * therapeutic use   administration & dosage   MeSH
• Middle Aged MeSH
• Humans MeSH
• Extracorporeal Membrane Oxygenation * MeSH
• Hospital Mortality MeSH
• SARS-CoV-2 MeSH
• Aged MeSH
• Sulfonamides * MeSH
• Respiratory Distress Syndrome therapy   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Observational Study MeSH
• Comparative Study MeSH

BACKGROUND: Modern trends in reconstructive surgery involve the use of free perforator flaps to reduce the donor site morbidity. The course of perforator vessels has a great anatomic variability and demands detailed knowledge of the anatomical relationships and the variability of the course of the perforators. The numerous modifications to perforator nomenclature proposed by various authors resulted in confusion rather than simplification. In our study, we focused on the hypothesis that a septocutaneous perforator traverses from the given source vessel to the deep fascia adherent to but not to within the septum itself. METHODS: Sixty-nine septocutaneous perforators from three different limb donor sites (lateral arm flap, anterolateral thigh flap, and radial forearm free flap) were collected from the gross pathology specimens of 14 fresh cadavers. The gross picture and the cross-sections with the histological cross-sections on different levels were examined to determine the position of the vessel to the septal tissue. RESULTS: Of the observed 69 septal perforators, 61 (88.5%) perforators were adherent to but not within the septum. The remaining eight (12.5%) perforators passed through the septum. All these eight perforators were found in multiple different cross-section levels (2 of 19 in lateral arm flap, 3 of 27 in anterolateral thigh flap, and 3 of 23 in radial forearm free flap). CONCLUSION: Although septocutaneous vessels appear identical macroscopically, microscopically two types of vessels with paraseptal and intraseptal pathways are observed. The majority of these vessels are merely adherent to the septum having a paraseptal pathway, while a minority are within the septum and are "true" septocutaneous perforators. It is advisable to dissect with a piece of the septum in order to avoid damage or injury to the perforator.

• MeSH
• Humans MeSH
• Cadaver MeSH
• Perforator Flap * blood supply   MeSH
• Forearm blood supply   surgery   MeSH
• Thigh blood supply   MeSH
• Free Tissue Flaps * blood supply   MeSH
• Plastic Surgery Procedures * methods   MeSH
• Check Tag
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH

Adrenocortical carcinoma (ACC) is a rare and aggressive malignancy with a high recurrence rate after surgical therapy with curative intent. Adjuvant radiotherapy (RT) and mitotane therapy have been proposed as options following the adrenalectomy. However, the efficacy of adjuvant RT or mitotane therapy remains controversial. We aimed to evaluate the efficacy of adjuvant therapy in patients who underwent adrenalectomy for localised ACC. The PubMed, Scopus, and Web of Science databases were queried on March 2024 for studies evaluating adjuvant therapies in patients treated with surgery for localized ACC (PROSPERO: CRD42024512849). The endpoints of interest were overall survival (OS) and recurrence-free survival (RFS). Hazard ratios (HR) with 95% confidence intervals (95%CI) were pooled in a random-effects model meta-analysis. One randomized controlled trial (n = 91) and eleven retrospective studies (n = 4,515) were included. Adjuvant mitotane therapy was associated with improved RFS (HR: 0.63, 95%CI: 0.44-0.92, p = 0.016), while adjuvant RT did not reach conventional levels of statistical significance (HR:0.79, 95%CI:0.58-1.06, p = 0.11). Conversely, Adjuvant RT was associated with improved OS (HR:0.69, 95%CI:0.58-0.83, p<0.001), whereas adjuvant mitotane did not (HR: 0.76, 95%CI: 0.57-1.02, p = 0.07). In the subgroup analyses, adjuvant mitotane was associated with better OS (HR:0.46, 95%CI: 0.30-0.69, p < 0.001) and RFS (HR:0.56, 95%CI: 0.32-0.98, p = 0.04) in patients with negative surgical margin. Both adjuvant RT and mitotane were found to be associated with improved oncologic outcomes in patients treated with adrenalectomy for localised ACC. While adjuvant RT significantly improved OS in general population, mitotane appears as an especially promising treatment option in patients with negative surgical margin. These data can support the shared decision-making process, better understanding of the risks, benefits, and effectiveness of these therapies is still needed to guide tailored management of each individual patient.

• MeSH
• Chemotherapy, Adjuvant MeSH
• Radiotherapy, Adjuvant methods   MeSH
• Adrenalectomy * methods   MeSH
• Adrenocortical Carcinoma * therapy   drug therapy   radiotherapy   MeSH
• Adrenal Cortex Neoplasms * therapy   drug therapy   surgery   radiotherapy   MeSH
• Antineoplastic Agents, Hormonal * therapeutic use   MeSH
• Humans MeSH
• Mitotane * therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Review MeSH
• Systematic Review MeSH