This study examined the mediating effects of physical activity (PA) and basal metabolic rate (BMR) on the relationship between years since menopause and sarcopenia in community-dwelling elderly women. Based on AWGS 2019 criteria, 718 women aged ≥65 were classified into sarcopenia, possible sarcopenia, and control groups. Multiple logistic regression and mediator models were used to assess associations. BMR correlated with grip strength (r=0.292), ASMI (r=0.750), and years since menopause (r=-0.246). Years since menopause negatively correlated with grip strength and SPPB (r=-0.315, -0.381; p<0.05). It was a risk factor for possible sarcopenia (OR=1.05; 95 % CI: 1.03-1.08). Low BMR and medium PA (vs. high) increased sarcopenia risk (OR=0.95 and 2.72, respectively). Direct effect of years since menopause was β=-0.010 (p=0.001); total mediating effect was 0.019 (p<0.001), mainly through BMR (0.007) and PA (0.001). PA and BMR mediate the effect of years since menopause on sarcopenia risk. Longer duration since menopause decreases PA and BMR, elevating sarcopenia risk.
Non-canonical (i.e. unannotated) open reading frames (ncORFs) have until recently been omitted from reference genome annotations, despite evidence of their translation, limiting their incorporation into biomedical research. To address this, in 2022, we initiated the TransCODE consortium and built the first community-driven consensus catalog of human ncORFs, which was openly distributed to the research community via Ensembl-GENCODE. While this catalog represented a starting point for reference ncORF annotation, major technical and scientific issues remained. In particular, this initial catalog had no standardized framework to judge the evidence of translation for individual ncORFs. Here, we present an expanded and refined catalog of the human reference annotation of ncORFs. By incorporating more datasets and by lifting constraints on ORF length and start codon, we define a comprehensive set of 28 359 ncORFs that is nearly four times the size of the previous catalog. Furthermore, to aid users who wish to work with ncORFs with the strongest and most reproducible signals of translation, we utilized a data-driven framework (i.e. translation signature scores) to assess the accumulated evidence for any individual ncORF. Using this approach, we derive a subset of 10 127 ncORFs with translation evidence on par with canonical protein-coding genes, which we refer to as the primary set. This set can serve as a reliable reference for downstream analyses and validation, with a particular emphasis on high quality. Overall, this update reflects continuous community-driven efforts to make ncORFs accessible and actionable to the broader research public, and further iterations of the catalog will continue to expand and refine this resource.
Treatment of active, moderate-to-severe thyroid eye disease (TED) remains a challenge. Up to 55% of patients show an incomplete response to intravenous (IV) glucocorticoids (GCs), and relapses are common. Tocilizumab (TCZ), a monoclonal antibody against the interleukin-6 receptor, has been proposed as a second-line therapy for GC-resistant TED. We performed an open-label, prospective study at two tertiary TED referral centers (Warsaw, Poland; Belgrade, Serbia) from May 2022 to May 2025. Adults with active, moderate-to-severe, GC-resistant TED received TCZ 8 mg/kg IV every 4 weeks for four cycles and were followed for 24 weeks. Primary endpoints were (1) improvement in the composite ophthalmic score and (2) improvement in disease-specific quality of life (Graves' ophthalmopathy quality of life questionnaire [GO-QoL]). Secondary endpoints included changes in clinical activity score (CAS), proptosis, eyelid aperture, diplopia, thyrotropin receptor antibody (TRAb) levels, and safety. The trial was registered at ClinicalTrials.gov (NCT06367517). A total of 44 patients underwent TCZ treatment (Warsaw, n = 32; Belgrade, n = 12). Both primary endpoints were met by 20/32 (62.5%) patients at Warsaw and all 12/12 (100%) patients at Belgrade. CAS reduction by ≥2 points was observed in 24/32 (75%) and 12/12 (100%) patients, respectively. A reduction of ≥2 mm in proptosis occurred in 19/32 (59.4%) and 7/12 (58.3%). Diplopia improved by ≥1 grade in Gorman score in 7/32 (21.9%) and 6/12 (50%). Eyelid aperture decreased by ≥2 mm in 11/32 (34.4%) and 8/12 (66.7%). Median TRAb levels decreased from 7.0 to 2.1 IU/L (Warsaw) and from 4.7 to 2.0 IU/L (Belgrade). No patients experienced TED deterioration. Adverse events occurred in 18/44 (40.9%) patients (47 events, only 1 severe). In this prospective, real-world study conducted in two independent cohorts of patients with GC-resistant, active, moderate-to-severe TED, TCZ was associated with clinically meaningful improvements in composite ophthalmic score response, CAS, proptosis, and quality of life, with a generally acceptable safety profile. These findings support TCZ as an effective and safe second-line therapeutic option for GC-resistant TED.
Covalent Bruton tyrosine kinase (BTK) inhibitors have advanced the treatment of Waldenström macroglobulinaemia; however, the occurrence of progression, intolerance, and acquired resistance are not fully understood. We aim to report on the safety and activity of pirtobrutinib (a highly selective, non-covalent BTK inhibitor) in patients with relapsed or refractory Waldenström macroglobulinaemia, including those who received previous covalent BTK inhibitors as part of the phase 1/2 BRUIN trial. The BRUIN study was an open-label, multicentre, phase 1/2 trial that enrolled patients with relapsed or refractory B-cell malignancies from 29 sites across eight countries. Patients aged 18 years or older who previously received BTK inhibitor-containing regimens, had an Eastern Cooperative Oncology Group performance status of 0-2, and histologically confirmed Waldenström macroglobulinaemia were eligible. In phase 1, patients received 100-300 mg oral pirtobrutinib once a day in 28-day cycles and the recommended phase 2 dose (RP2D) of 200 mg pirtobrutinib once a day was determined. The phase 2 primary endpoint was antitumour activity of pirtobrutinib based on objective response rate as assessed by an investigator in patients with chronic lymphocytic leukaemia, small lymphocytic leukaemia, or mantle cell lymphoma. In patients with Waldenström macroglobulinaemia, response was evaluated using the Sixth International Workshop on Waldenström Macroglobulinemia (IWWM-6) criteria. BRUIN is registered with ClinicalTrials.gov, NCT03740529 (completed). BRUIN recruited patients from Aug 12, 2019, to March 14, 2022, and 778 patients received pirtobrutinib. 80 patients had relapsed or refractory Waldenström macroglobulinaemia (n=18 in phase 1 and n=62 in phase 2), with a median age of 68·5 years (IQR 61·0-75·0). 52 (65%) patients were male and 28 (35%) were female. The median number of previous lines of systemic therapy was 3·0 (2·0-5·0). 63 (79%) patients received previous covalent BTK inhibitors. 73 (91%) received 200 mg pirtobrutinib once per day (the RP2D). Using IWWM-6 criteria, the objective response rate was 82·5% (95% CI 72·4-90·1), with one (1·3%) patient reaching complete response, eight (10·0%) reaching very good partial response, 49 (61·3%) reaching partial response, and eight (10·0%) reaching minor response. The median study follow-up was 35·0 months (17·7-47·7). The objective response rate was 81·0% (69·1-89·8) for those who received previous covalent BTK inhibitors and 88·2% (63·6-98·5) for covalent BTK inhibitor-naive patients. Grade 3 or higher treatment-emergent adverse events occurred in 57 (71%) patients, with the most common being neutropenia or neutrophil count decreased (15 [19%]) and anaemia (19 [24%]). Treatment-emergent deaths were reported in five (6%) patients (bacterial sepsis, intracranial haemorrhage, COVID-19 pneumonia, hypertensive cardiomegaly and pneumonia [n=1 each unrelated to treatment], and treatment-related necrotising pneumonia [n=1]). Treatment-emergent adverse events leading to dose reductions occurred in four (5%) patients and pirtobrutinib discontinuation in 12 (15%). Pirtobrutinib was highly active and well tolerated, regardless of previous exposure to covalent BTK inhibitors, and might be a promising new therapeutic option for patients with relapsed or refractory Waldenström macroglobulinaemia, particularly in those previously exposed to covalent BTK inhibitors, for whom durable and effective treatments are needed. Eli Lilly and Company.
Mitochondrial dysfunction connects obesity and metabolic dysfunction. We conducted a scoping review on mitochondria in obesity to (i) describe morpho-functional mitochondrial abnormalities across tissues and (ii) summarize mitochondria-directed lifestyle and pharmacological strategies and their metabolic effects. PubMed and Web of Science were searched, using relevant keywords. English-language original studies, clinical trials, and systematic reviews were qualitatively synthesized in a scoping review conducted in accordance with the PRISMA extension for Scoping Reviews and prospectively registered in the Open Science Framework. Sixty primary articles and cross-references describe nutrient overload-induced oxidative stress, disturbed mitochondrial dynamics and mitophagy, and maladaptive endoplasmic reticulum (ER)-mitochondria contacts across various organ tissues and cancer. These changes are associated with insulin resistance, steatotic liver disease, chronic kidney disease, cardiovascular dysfunction, impaired fertility, and tumor progression. Reported interventions include mitochondria-targeted antioxidants, AMPK/SIRT1/PGC-1α activators, modulators of ER-mitochondria coupling, microbiota-directed approaches, and lifestyle changes. Common mitochondrial signatures, excess reactive species, impaired quality control, and altered organelle crosstalk, underlie systemic metabolic derangement, supporting mitochondria as a unifying therapeutic target. Obesity involves widespread mitochondrial changes in various organs. Approaches that improve mitochondrial health through lifestyle and medication may help manage obesity complications and need thorough clinical testing.
Phase I investigation of the enhancer of zeste homolog 2 inhibitor, mevrometostat, plus enzalutamide showed promising antitumor activity versus enzalutamide alone in patients with metastatic castration-resistant prostate cancer (mCRPC) (NCT03460977). MEVPRO-1 (open label) and MEVPRO-2 (double blind) are ongoing, global, phase III, randomized studies evaluating efficacy and safety of mevrometostat plus enzalutamide in patients with mCRPC. MEVPRO-1 will include ~600 patients with ≥12 weeks of prior abiraterone treatment, Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0-2, testosterone ≤50 ng/dL, and life expectancy ≥6 months. MEVPRO-2 will include ~900 androgen receptor pathway inhibitor-naïve patients, with ECOG PS 0-1, testosterone ≤50 ng/dL, and life expectancy ≥12 months. Patients are randomized 1:1 to mevrometostat (875 mg twice daily with food) plus enzalutamide (160 mg once daily), or physician's choice of enzalutamide or docetaxel (MEVPRO-1) or enzalutamide (MEVPRO-2). Primary endpoint is radiographic progression-free survival (rPFS) per Response Evaluation Criteria in Solid Tumors 1.1 (soft tissue) and Prostate Cancer Working Group 3 criteria (bone) assessed by blinded independent central review. Overall survival is a secondary objective. Kaplan-Meier analysis will summarize time-to-event endpoints. Safety will be assessed. Results will evaluate whether mevrometostat plus enzalutamide can provide clinical benefit in patients with mCRPC.Clinical trial registration: www.clinicaltrials.gov identifiers are NCT06551324 (MEVPRO-1) and NCT06629779 (MEVPRO-2). What is this summary about?This summary describes two ongoing, large, international clinical trials: MEVPRO-1 and MEVPRO-2. The trials will study a new treatment approach for patients with metastatic castration-resistant prostate cancer, a type of prostate cancer that has spread and no longer responds to standard hormone treatments.Which medicines are being tested?The trials are testing mevrometostat, a new medicine that blocks a protein called enhancer of zeste homolog 2 (EZH2), which helps cancer cells grow and survive. Mevrometostat will be given with enzalutamide, a standard medicine for advanced prostate cancer.What are the designs of the MEVPRO-1 and MEVPRO-2 trials?MEVPRO‑1 will include about 600 patients whose cancer has already progressed after treatment with abiraterone, a standard medicine for advanced prostate cancer. Patients will receive either mevrometostat plus enzalutamide or the doctor’s choice of enzalutamide alone or chemotherapy (docetaxel). MEVPRO‑2 will include about 900 patients who have not previously received abiraterone or other androgen‑receptor pathway inhibitor therapies. Patients will receive either mevrometostat plus enzalutamide or enzalutamide aloneWhat are the aims of the MEVPRO-1 and MEVPRO-2 trials?The main goal of both MEVPRO-1 and MEVPRO-2 is to find out if adding mevrometostat to enzalutamide can stop the cancer from getting worse for longer than standard treatments. The studies will also look at overall survival, pain control, quality of life, and side effects to determine if the new combination provides better outcomes for patients.
Pyometra is a common and potentially life-threatening uterine infection in bitches, with severe local and systemic inflammation as symptoms. Studies exist on inflammatory markers in peripheral blood (PB), but little is known about their expression in uterine blood (UB). This study aimed to compare their concentrations simultaneously in UB and PB of bitches with pyometra, and to evaluate their diagnostic and prognostic potential. Twenty-two bitches with confirmed pyometra (13 closed-cervix and 9 open-cervix cases) and six healthy controls were enrolled. Blood samples were collected from the cephalic and uterine veins during ovariohysterectomy. The concentrations of IL-1α, IL-1β, IL-6 and IL-10 were measured using an ELISA validated for dogs, and C-reactive protein (CRP) was measured by an immunoturbidimetric assay. These five inflammatory markers were compared statistically between the three groups of dogs and two types of blood sample using the Mann-Whitney U and Wilcoxon tests. All markers were significantly elevated in affected bitches' UB and PB. The IL-6 concentrations were significantly higher in UB than in PB, suggesting local production of this cytokine. Conversely, the IL-10 levels were higher in PB, possibly reflecting a systemic regulatory response. The concentrations of IL-1α and IL-1β differed insignificantly from each other. Those of CRP were significantly higher in open-cervix than in closed-cervix pyometra, indicating a stronger acute-phase response. The results assign IL-6 and CRP a potential role as biomarkers for the diagnosis and prognosis of pyometra. Simultaneous analysis of uterine and systemic inflammatory responses provides insight into the disease's pathophysiology and may support more targeted therapeutic approaches.
Hydrolyzed rice formulas (HRF) are a suitable option for the nutritional management of non-breastfed children with cow's milk allergy (CMA). Human milk oligosaccharides (HMOs) enhance gastrointestinal health, promote the growth of beneficial gut microbiota, and may reduce the incidence of infections and antibiotic use. There is currently no evidence regarding the hypoallergenicity of HRF containing HMOs. The purpose of this study is to demonstrate the hypoallergenicity of a new hydrolyzed rice protein-based formula containing two manufactured HMOs (HRF-HMO). RIGHT-HY is a multi-center randomized controlled study enrolling infants and children (60 days-3 years) with documented Immunoglobulin E-mediated CMA. Children will be randomized in a crossover fashion to double-blind placebo-controlled food challenges (DBPCFC) with HRF-HMO and an amino acid-based formula (AAF)-HMO, followed by a 7-days open challenge with HRF-HMO requiring a daily minimum intake of 240 ml. Both formulas contain 2-fucosyllactose and lacto-N-neotetraose (1.5 g/L). The primary objective is to demonstrate with 95% confidence that 90% of children with CMA do not develop allergic reactions to HRF-HMO under DBPCFC conditions. Up to 67 children will be enrolled to meet the hypoallergenicity criteria. This sample size allows for a 10% drop-out rate and occurrence of one allergic reaction. An interim analysis will be performed after 42 children have completed both food challenges to assess whether hypoallergenicity criteria have been met, in which case, the study will be stopped for success. Secondary endpoints include HRF-HMO intake and gastrointestinal tolerance during the week-long open challenge, and adverse events throughout the study. The RIGHT-HY study was approved by ethical committees of all participating sites. This study will be the first to generate robust evidence on the hypoallergenicity of this rice formula with added HMOs in children with CMA. The results of the study will be disseminated in peer-reviewed publications and presentations at scientific conferences. https://clinicaltrials.gov/study/NCT06633289, identifier NCT06633289.
Enhanced recovery after surgery (ERAS) is a multimodal perioperative care pathway designed to improve recovery, optimize patient outcomes, and enhance overall quality and satisfaction. Successful ERAS implementation requires continuous interprofessional collaboration among anesthesiologists, surgeons, nurses, nutritionists, physiatrists, and gerontologists, extending from preadmission to discharge. This consensus document, developed by the International Union of Angiology (IUA) Youth Committee and senior experts, outlines best practices for ERAS in vascular surgery. It synthesizes current evidence and expert opinions to provide a structured clinical pathway that enhances patient care and facilitates real-world application. This document has outlined key strategies to enhance perioperative outcomes in vascular surgery patients, a population at high risk for periprocedural complications, particularly cardiac events. The authors attempted to clarify and standardize key definitions and provide general guidance on broadly applying ERAS principles based on existing literature and clinical experience. While ERAS protocols for vascular surgery have been recently published by the Society for Vascular Surgery (SVS), this document offers a complementary perspective, addressing key perioperative steps and providing specific recommendations for both open and endovascular arterial procedures.
Epithelial ovarian cancer frequently recurs and becomes resistant to platinum chemotherapy. We investigated whether adding pembrolizumab to weekly paclitaxel, with or without bevacizumab, improves progression-free survival and overall survival compared with weekly paclitaxel, with or without bevacizumab, in participants with platinum-resistant recurrent ovarian cancer who had received one to two previous systemic regimens. ENGOT-ov65/KEYNOTE-B96 is a randomised, double-blind, phase 3 study conducted at 187 gynaecologic oncology centres in 25 countries in the Americas, Asia, Europe, and Oceania. Adults (≥18 years) with histologically confirmed epithelial ovarian, fallopian tube, or primary peritoneal carcinoma, who received one to two previous systemic therapies including at least one platinum regimen and who progressed 6 months or less after the last platinum regimen, were eligible. Participants were randomly assigned 1:1 to intravenous pembrolizumab 400 mg every 6 weeks for up to 18 cycles plus open-label intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 21-day cycle or intravenous placebo (saline solution) every 6 weeks for up to 18 cycles plus open-label intravenous paclitaxel 80 mg/m2 on days 1, 8, and 15 of each 21-day cycle; intravenous bevacizumab 10 mg/kg every 2 weeks was permitted per investigator. Randomisation was stratified by planned bevacizumab use, region, and PD-L1 combined positive score (CPS). The primary endpoint was investigator-assessed progression-free survival per RECIST version 1.1; the key secondary endpoint was overall survival. Results from two interim analyses and the final analysis are included in this Article. This study is registered with ClinicalTrials.gov, NCT05116189, and is now completed. Between Dec 13, 2021, and July 3, 2023, 643 female participants were randomly assigned; 322 to pembrolizumab plus paclitaxel and 321 to placebo plus paclitaxel. At the first interim analysis, pembrolizumab plus paclitaxel significantly improved progression-free survival versus placebo plus paclitaxel in both the PD-L1 CPS 1 or higher (median 8·3 months vs 7·2 months; hazard ratio [HR] 0·72; 95% CI 0·58-0·89; p=0·0014 α=0·012]) and overall populations (median 8·3 months vs 6·4 months; HR 0·70, 95% CI 0·58-0·84; p<0·0001, [α=0·0023]), meeting the prespecified criteria for confirmatory efficacy. At the second interim analysis, overall survival was significantly improved in the PD-L1 CPS 1 or higher population (median 18·2 months vs 14·0 months; HR 0·76, 95% CI 0·61-0·94; p=0·0053, [α=0·0083]). At the final analysis, overall survival was significantly improved in the overall population (median 17·7 months vs 14·0 months; HR 0·82, 95% CI 0·69-0·97; p=0·011 [α=0·024]). Grade 3 or worse treatment-related adverse events occurred in 217 (68%) of 320 participants in the pembrolizumab plus paclitaxel group versus 176 (55%) of 318 participants in the placebo plus paclitaxel group. The most common treatment-related adverse events (any grade) included anaemia, peripheral neuropathy, alopecia, fatigue, and nausea. Treatment-related adverse events resulted in death in four participants (1%) in the pembrolizumab plus paclitaxel group (colitis, interstitial lung disease, acute myeloid leukaemia, and intestinal perforation) and in five participants (2%) in the placebo plus paclitaxel group (cardiac failure, intestinal perforation [in two participants], and large-intestine perforation [in two participants]). Pembrolizumab plus weekly paclitaxel, with or without bevacizumab, significantly improved progression-free survival and overall survival in participants with platinum-resistant recurrent ovarian cancer who had received one to two previous systemic regimens, supporting this regimen as a new treatment option for this population. Funded by Merck Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc, Rahway, NJ, USA.
We sought to investigate the inter- and intra-country variation in paediatric heart transplantation (HTx) and mechanical circulatory support (MCS) availability and practice in Europe. Data was obtained through a survey circulated to paediatric transplant cardiologists identified through the Association of European Paediatric and Congenital Cardiology between November 2022 and March 2023. Twenty-eight respondents from twenty-eight European countries completed the survey. Twenty-four (86%) had paediatric and 25 (89%) had adult congenital HTx services. National paediatric HTx centre density ranged from 0.00 to 5.35 per 10 million inhabitants. Eighteen (64%) countries followed either Eurotransplant or Scandiatransplant protocols for organ allocation and 59% of the surveyed countries had low HTx volumes (< 4 paediatric HTx annually), based on the self-reported numbers. A ventricular assist device (VAD) programme was operational in 22 (79%) countries. In only 9 countries (38%), there were dedicated resources for HTx as part of the hospital budget; however, a vast majority (77%) reported that families suffered no cost when a VAD was utilised. Twenty-one countries (78%) reported limited intensive care unit beds and 14 (54%) reported that HTx impacted on congenital heart surgery cases. Only 12 of 27 countries (44%) had a standardised national protocol for post-HTx care. There was no correlation between paediatric HTx centre density, population or GDP per capita.  There is a high degree of variation both within and between the surveyed European countries with regard to paediatric HTx centre density, VAD availability, listing protocols, and post-HTx management. Multiple factors contribute to this heterogeneity, which makes standardisation of HTx listing and VAD criteria challenging. Increased cross-national collaborative efforts between European countries may strengthen both HTx and MCS availability and outcomes, especially in regions with several smaller neighbouring countries. • The care of paediatric heart transplant (HTx) and mechanical support (MCS) patients varies across Europe. • This paper elucidates the differences in transplant service organisation and the care of transplant and MCS patients in twenty-eight European countries. • These findings could potentially encourage broader open dialogue and facilitate collaboration across European paediatric HTx centres with development of standardised listing criteria, improved collective European registry data and creation of standards for screening post-HTx patients.
IO102-IO103, an investigational, immune-modulatory cancer vaccine, targets both tumor cells and immune-suppressive cells within the tumor microenvironment through activation and expansion of T cells against indoleamine 2,3-dioxygenase 1(IDO1)-positive and/or programmed death ligand 1 (PD-L1)-positive cells. This open-label, Phase 3 trial randomized 407 patients with untreated advanced melanoma in a 1:1 ratio to receive subcutaneous IO102-IO103 (85 μg each) plus pembrolizumab 200 mg intravenously every 3 weeks or pembrolizumab alone for up to 2 years. The primary endpoint was progression-free survival (PFS) by blinded independent central review per RECIST v1.1. The median PFS was 19.4 months (95% confidence interval [CI], 9.7 to not reached) for IO102-IO103 plus pembrolizumab versus 11.0 months (95% CI, 6.0 to 14.8) for pembrolizumab (hazard ratio [HR] [95% CI], 0.77 [0.58 to 1.00]; P = 0.0558); the statistical significance threshold (P ≤ 0.045) was missed. A longer PFS was observed in the combination arm across most subgroups, notably in patients with PD-L1-negative tumors (median PFS 16.6 versus 3.0 months [HR, 0.54; 95% CI, 0.35 to 0.85]), anti-PD-1 naïve patients (24.8 versus 11.0 months [HR, 0.74; 95% CI, 0.56 to 0.98]), proto-oncogene B-Raf (BRAF) mutated tumors, or elevated lactate dehydrogenase. There was no increase in the frequency of treatment-related adverse events grade ≥3 (14.5% versus 15.6%) or of serious adverse events (32.0% versus 32.3%) in the vaccine arm. Local vaccine-related injection site reactions were reported in 56.0% of patients and were mostly grade 1/2. IO102-IO103 plus pembrolizumab prolonged progression-free survival compared with pembrolizumab alone in patients with advanced melanoma in the first-line setting; however, statistical significance was missed for the primary endpoint. The combination was well tolerated with no added significant systemic toxicity. These data show the potential benefit of this combination in untreated advanced melanoma.
<b>Introduction:</b> Visceral artery compression syndromes are rare diseases with ambiguous symptoms, varying between patients.<b>Aim:</b> The aim of the paper was to review the disease's pathology, diagnosis and treatment.<b>Methods:</b> Review based on a MEDLINE database search.<b>Results:</b> Medial arcuate ligament syndrome (MALS) is caused by celiac trunk compression by the diaphragm's medial arcuate ligament. MALS is a diagnosis of exclusion because its symptoms are not clear-cut. Diagnostic imaging is based on Doppler ultrasound and computed tomography. Invasive treatment is aimed to decompress the celiac trunk with open, laparoscopic, or robotic methods, whereas endovascular procedures do not eliminate the disease cause. Superior mesenteric artery syndrome (SMAS) is a rare disease with symptoms resulting from compression of the duodenum between the superior mesenteric artery and the abdominal aorta. Symptoms may result from other pathologies within the abdominal cavity, therefore the diagnosis is based on exclusion of other gastrointestinal causes and on tomographic criteria. Conservative treatment is usually ineffective, while the choice of surgical methods requires individual assessment. Nutcracker syndrome (NCS) is characterized by symptoms caused by compression of the left renal vein by the superior mesenteric artery. Diagnosis is made after excluding other causes, as there are no established NCS diagnostic criteria. Doppler ultrasound and computed tomography are used in syndrome diagnosis, and its treatment should be individualized.<b>Conclusions:</b> The compression syndromes are rare diseases that occur significantly more frequently in women. Their diagnosis and treatment are a clinical challenge. A better pathophysiology understanding and the use of minimally invasive treatment techniques can improve the patient's quality of life.
Chemoradiotherapy (CRT) alone shows limited efficacy in improving outcomes for metastatic colorectal cancer (mCRC) patients. This study aimed to comprehensively evaluate the survival benefits of combining CRT with immunotherapy (CRT + IMT) in this population. Data from the SEER database were extracted for mCRC patients diagnosed between 2010-2015 and 2018-2020. Survival outcomes were assessed using Kaplan-Meier analysis, log-rank test, Cox regression, and propensity score matching (PSM) to minimize baseline differences between treatment groups, and multivariable Cox models were constructed based on variables selected by LASSO regression. A total of 2,451 patients were identified, with 1,888 receiving CRT alone and 563 CRT + IMT. After 1:2 PSM, 1,594 remained. Kaplan-Meier curves showed CRT + IMT significantly improved overall survival (OS, p<0.0001) and cancer-specific survival (CSS, p<0.0001). Multivariable Cox confirmed CRT + IMT as an independent predictor (OS HR=0.54, 95 % CI: 0.44-0.65; CSS HR=0.54, 95 % CI: 0.44-0.66). Favorable factors included distal colon/rectal tumors, surgery, and combined therapy, while older age (>60), advanced stage, N2, and metastasis predicted worse survival. The subgroup analyses revealed a more pronounced benefit in specific cohorts, and significant interactions were observed for factors such as histologic grade and nodal stage. The combination of CRT and immunotherapy confers a significant survival advantage over CRT alone in patients with mCRC, supporting its potential role in optimized treatment strategies.
An Endocrine Society Clinical Practice Guideline on vitamin D was published in 2024. Its main objective was the use of vitamin D to lower the risk of disease in individuals without established indications for vitamin D treatment or 25-hydroxavitamin D (25(OH)D) testing. The methodology followed the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) and the Evidence-to-Decision (EtD) framework. Evidence from randomized controlled trials (RCTs) retrieved by a systematic review was prioritized to inform this guideline. It was concluded that vitamin D supplementation reduces rickets and respiratory tract infections in children, mortality in individuals aged 75 years or older, pregnancy complications (outcomes), and progression of prediabetes to diabetes mellitus. Consequently, empiric vitamin D supplementation was recommended for individuals aged 1 to 18 years and ≥75 years, pregnant women, and individuals with prediabetes. Empiric vitamin D supplementation is defined as a vitamin D intake that exceeds the Dietary Reference Intakes (DRIs) and is implemented without 25(OH)D testing. This article provides a comprehensive guideline summary and critical appraisal based on a narrative review on scientific publications regarding that guideline. Several publications discussed the 2024 Endocrine Society Clinical Practice Guideline on vitamin D. The main criticisms and discussion relate to unclear vitamin D dosages, guideline applicability to certain populations including controversy with previous vitamin D guidelines, and the implications of 25(OH)D testing. The 2024 Endocrine Society Clinical Practice Guideline on vitamin D followed a rigorous methodological approach with high quality standards but it leaves many open questions and uncertainties warranting clarification.
Endoluminal treatments are frequently used for male anterior urethral strictures (USs). We aim to summarize the current evidence assessing the clinical implications for each treatment. Details on epidemiology, diagnosis, open surgical management, and follow-up of US are beyond the scope of this paper, and we refer the reader to the full text Guidelines (Lumen et al., 2026) [1]. New evidence was identified using a priori criteria. Selected literature was summarized, and recommendations were developed to prioritize clinically important decisions. Direct vision internal urethrotomy (DVIU) is safe, with success rates improving for shorter, untreated bulbar US. Short recurrences after urethroplasty could be managed using DVIU. Single dilatation offers outcomes similar to those of DVIU, with reduced complications if visually controlled. Self-dilatation, urethral stents, and local corticosteroids could prolong treatment intervals but risk US worsening. Drug-coated balloon dilatation is a promising second-line endoluminal option for bulbar US. Endoluminal treatments for male anterior USs are safe, offering good long-term patency rates in selected situations. They are an alternative for patients aiming for a less invasive management but with low long-term success. Discussion of individual options and tailoring male anterior US treatment-including referring for urethroplasty when indicated-should be granted.
We report on the randomized portion of the phase 2, open-label CheckMate 650 trial (NCT02985957), in which docetaxel-experienced, biologically male patients with chemotherapy-refractory metastatic castration-resistant prostate cancer were randomized 2:2:1:2 to nivolumab 3 mg /kg plus ipilimumab 1 mg /kg (n = 73), nivolumab 1 mg /kg plus ipilimumab 3 mg /kg (n = 74), ipilimumab 3 mg /kg (n = 38), or cabazitaxel (n = 74). Primary endpoints were objective response rate and radiographic progression-free survival; key secondary endpoints included overall survival, prostate-specific antigen response rate, and safety. This portion of CheckMate 650 was not designed to statistically compare between cohorts. Respectively, objective response rates (95% CI) were 9.3% (2.6-22.1), 19.5% (8.8-34.9), 4.5% (0.1-22.8), and 12.2% (4.1-26.2), and median radiographic progression-free survival (95% CI) was 3.9 (2.2-7.6), 4.2 (3.3-5.6), 3.5 (2.1-5.8), and 7.9 (5.6-9.3) months. Respective incidence of grade ≥3 treatment-related adverse events was 28.8%, 30.1%, 18.4%, and 34.7%. Preliminary post hoc biomarker analyses in patients who received treatment with any immunotherapy regimen (i.e., treated with either of the nivolumab plus ipilimumab regimens or with ipilimumab alone, n = 12) identified a transcriptional signature, derived from the most highly expressed genes across cell types within select perivascular immune niches (comprising CD31+ endothelial, CD14+HLA-DR+ myeloid, and CD4+ and CD8+ T cells), which was associated with prolonged overall survival. These results provide further evidence of antitumor activity with nivolumab plus ipilimumab in select patients with metastatic castration-resistant prostate cancer and nominate a candidate prognostic biomarker that warrants confirmation in future prospective clinical trials.
A post-authorisation safety study (PASS) was conducted to assess the impact of LysaKare (2.5% Lysine-Arginine solution) on serum potassium concentrations and its safety/tolerability profile in patients with gastroenteropancreatic neuroendocrine tumours (GEP-NET) eligible for 177Lu-DOTATATE treatment. In a phase IV, multicentre, single-arm, open-label PASS, adults with somatostatin receptor-positive GEP-NET who were eligible for 177Lu-DOTATATE treatment received 1000 mL of LysaKare (monotherapy) intravenously over 4 h. The primary endpoint was the change in serum potassium levels over the course of 24 h. Secondary endpoints included the incidence of LysaKare-related adverse events (AEs) and changes in laboratory parameters. Forty-one patients were treated (median age, 57 years; 92.7% White and 7.3% Black; 53.7% male) and 40 completed post-treatment follow-up. Mean (standard deviation [SD]) serum potassium was 4.33 (0.397) mmol/L pre-dose, increasing by 0.60 (0.666) mmol/L after 4 h (time to maximum change, range, 2-24 h) before decreasing to around the pre-dose level: the mean (SD) increase after 24 h was 0.07 (0.396) mmol/L. Other electrolytes and blood gas components mostly showed transient changes that lasted ~24 h. A general trend of transient metabolic acidosis was also observed based on laboratory values. Serum potassium grade increased from baseline in 41.5% of patients. By comparison, five patients (12.2%) had a treatment-related AE of hyperkalaemia (grade 3, n = 1); all resolved within 24 h, either without treatment (n = 3) or following intravenous furosemide (n = 2). There were no serious AEs and no AEs leading to treatment discontinuation/interruption. This PASS identified no new safety signals attributable to LysaKare. Trial registration: EudraCT, 2019-004073-76. Registered 20/08/2020.
Fatigue, impaired sleep quality and daytime sleepiness, common in neurodegenerative and immune-mediated diseases, are debilitating and have serious societal and economic implications. Currently, measurement of these symptoms largely relies on self-reported questionnaires, which are burdensome for patients and lack sensitivity, granularity and reliability. Building on a preceding feasibility study and qualification advice of the European Medicines Agency, the Clinical Observational Study of the European project Identifying Digital Endpoints to Assess FAtigue, Sleep and acTivities of daily living in Neurodegenerative disorders and Immune-mediated inflammatory diseases (IDEA-FAST) investigates the relationship between digital and clinical parameters of the target concepts of fatigue, reduced sleep quality and daytime sleepiness. Between 2022 and 2025, 2000 people are being recruited at 24 European sites - 500 with Parkinson's disease, 500 with inflammatory bowel disease, 200 with each of the following diseases: Huntington's disease, rheumatoid arthritis, systemic lupus erythematosus, primary Sjögren's syndrome and 200 healthy volunteers. Participants are followed over a 24-week period with four visits, each including a 1-week assessment phase at home using CE-certified digital health (including active and passive) technologies. The latter collect information on physical activity, physiology, cognition as well as social interaction and behaviour as core dimensions of the target concepts. This study will help to develop reliable, valid and efficient digital endpoints of fatigue, impaired sleep quality and daytime sleepiness for use in future clinical studies and trials.
Haematopota pluvialis is a widely distributed hematophagic insect occurring across Eurasia. This horse fly may be a highly efficient mechanical vector of pathogens, including viruses, bacteria, and protozoa. Furthermore, its painful bites can cause local skin lesions and systemic symptoms. The aim of this study was to determine human exposure to H. pluvialis attacks in various types of open space habitats in Eastern Poland and to perform molecular screening of these tabanids for the presence of hematopathogens: Bartonella spp. and Anaplasma phagocytophilum. Specimens of H. pluvialis were collected at three distinct sites in Eastern Poland. The presence of Bartonella spp. and A. phagocytophilum was investigated using PCR-based methods. In total, 141 H. pluvialis females were analyzed. The molecular analysis of the rpoB gene fragment yielded one new haplotype of Bartonella sp. in 0.7% (1) of all studied samples, which may hypothetically exhibit zoonotic potential. Anaplasma phagocytophilum was not detected in the studied material. Moreover, a high level of human and animals exposure to horse fly bites was noted in the studied areas of Eastern Poland. The present results highlight the need for further targeted research on H. pluvialis to quantify pathogen prevalence, transmission efficiencies, and conditions facilitating pathogen transmission in natural settings.