Enteroblastic adenocarcinoma of the ampulla of Vater / Adenocarcinoma enteroblástico de la ampolla de Vater

Adenocarcinoma with enteroblastic differentiation is a rare histologic subtype of adenocarcinoma of the gastrointestinal tract that shows unique histologic and immunohistochemical features that resemble fetal intestinal epithelium. This histological subtype has been widely described in the stomach, where it most frequently appears, but, in other locations, it is misdiagnosed because of the poor experience in routine diagnostic setting. Here we present a case of an 87-year-old male with an adenocarcinoma of the ampulla of Vater with enteroblastic differentiation with a literature review of the cases described of this subtype in this location to date. The anatomical peculiarity of the ampulla, joined with the infrequent nature of this histological subtype, makes this case of great interest to aid to better characterize the biological behavior of these tumors. (AU)

El adenocarcinoma con diferenciación enteroblástica es un subtipo histológico poco frecuente de adenocarcinoma gastrointestinal que muestra características histológicas e inmunohistoquímicas únicas que se asemejan al epitelio intestinal fetal. Este subtipo histológico ha sido ampliamente descrito en el estómago, donde aparece con mayor frecuencia, pero en otras localizaciones es mal diagnosticado debido a la poca experiencia en el diagnóstico de rutina. Presentamos un caso de un varón de 87 años con adenocarcinoma de ampolla de Vater con diferenciación enteroblástica, junto a una revisión bibliográfica de los casos descritos de este subtipo en esta localización hasta el momento. La peculiaridad anatómica de la ampolla, sumada al carácter poco frecuente de este subtipo histológico, dotan a este caso de gran interés para ayudar a caracterizar mejor el comportamiento biológico de estos tumores. (AU)

Applications of three-dimensional printing in percutaneous closure of aortic-to-right ventricle fistula after transcatheter aortic valve replacement: a case report.

Background: Percutaneous closure of aortic-to-right ventricle (ARV) fistula has emerged as an alternative to surgical management in selected cases. The use of three-dimensional (3D) printing in interventional planning for structural heart disease provides a concrete understanding, and it is useful in diagnostic assessment and to guide treatment approaches and to simulate procedures. Case summary: We report a case of a 70-year-old male presenting in cardiogenic shock due to severe aortic stenosis and reduced left ventricular ejection fraction. The patient had several comorbidities and was deemed not eligible for cardiac surgery. After transcatheter aortic valve replacement (TAVR), an ARV fistula was discovered on the TTE. Due to complex anatomical considerations, a 3D printed model of the patient's anatomy was employed to supplement the decision-making process and technical planning of percutaneous ARV closure. Successful closure of the fistula with the use of the Amplatzer atrial septal occluder was subsequently performed. Discussion: Three-dimensional printing improves the understanding of complex structures of cardiac diseases, allowing for enhanced planning and simulation of the procedure. This case, demonstrating the effective percutaneous closure of a TAVR-related ARV fistula facilitated by the use of 3D printed anatomical models in the pre-procedural phase, highlights the technology's potential in advancing patient-specific treatment approaches.

Prevalence and genotypic associations of epilepsy in Prader-Willi Syndrome: A systematic review and meta-analysis.

OBJECTIVE: To estimate the prevalence of epilepsy and febrile seizures and their association with genotype, i.e., 15q11-q13 deletions, uniparental chromosome 15 disomy (UPD) and other mutations, in the population with Prader-Willi syndrome (PWS). METHODS: A systematic search of Medline, Scopus, Web of Science and the Cochrane Library was conducted. Studies estimating the prevalence of seizures, epilepsy and febrile seizures in the PWS population were included. Meta-analyses of the prevalence of epilepsy and febrile seizures and their association with genotype using the prevalence ratio (PR) were performed. RESULTS: Fifteen studies were included. The prevalence of epilepsy was 0.11 (0.07, 0.15), similar to the prevalence of febrile seizures, with a prevalence of 0.09 (0.05, 0.13). The comparison "deletion vs. UPD" had a PR of 2.03 (0.90, 4.57) and 3.76 (1.54, 9.18) for epilepsy and febrile seizures. CONCLUSIONS: The prevalence of seizure disorders in PWS is higher than in the general population. In addition, deletions in 15q11-q13 may be associated with a higher risk of seizure disorders. Therefore, active screening for seizure disorders in PWS should improve the lives of these people. In addition, genotype could be used to stratify risk, even for epilepsy, although more studies or larger sample sizes are needed.

Enteroblastic adenocarcinoma of the ampulla of Vater.

Adenocarcinoma with enteroblastic differentiation is a rare histologic subtype of adenocarcinoma of the gastrointestinal tract that shows unique histologic and immunohistochemical features that resemble fetal intestinal epithelium. This histological subtype has been widely described in the stomach, where it most frequently appears, but, in other locations, it is misdiagnosed because of the poor experience in routine diagnostic setting. Here we present a case of an 87-year-old male with an adenocarcinoma of the ampulla of Vater with enteroblastic differentiation with a literature review of the cases described of this subtype in this location to date. The anatomical peculiarity of the ampulla, joined with the infrequent nature of this histological subtype, makes this case of great interest to aid to better characterize the biological behavior of these tumors.

Involvement of CB1 and CB2 receptors in neuroprotective effects of cannabinoids in experimental TDP-43 related frontotemporal dementia using male mice.

BACKGROUND: The elevation of endocannabinoid levels through inhibiting their degradation afforded neuroprotection in CaMKIIα-TDP-43 mice, a conditional transgenic model of frontotemporal dementia. However, which cannabinoid receptors are mediating these benefits is still pending to be elucidated. METHODS: We have investigated the involvement of the CB1 and the CB2 receptor using chronic treatments with selective ligands in CaMKIIα-TDP-43 mice, analysis of their cognitive deterioration with the Novel Object Recognition test, and immunostaining for neuronal and glial markers in two areas of interest in frontotemporal dementia. RESULTS: Our results confirmed the therapeutic value of activating either the CB1 or the CB2 receptor, with improvements in the animal performance in the Novel Object Recognition test, preservation of pyramidal neurons, in particular in the medial prefrontal cortex, and attenuation of glial reactivity, in particular in the hippocampus. In addition, the activation of both CB1 and CB2 receptors reduced the elevated levels of TDP-43 in the medial prefrontal cortex of CaMKIIα-TDP-43 mice, an effect exerted by mechanisms that are currently under investigation. CONCLUSIONS: These data reinforce the notion that the activation of CB1 and CB2 receptors may represent a promising therapy against TDP-43-induced neuropathology in frontotemporal dementia. Future studies will have to confirm these benefits, in particular with one of the selective CB2 agonists used here, which has been thoroughly characterized for clinical development.

Exploring the Influence of Insulin Resistance on Arterial Stiffness in Healthy Adults: From the Metabolic and Cardiovascular Health Insights of the EVasCu Study.

Previous evidence associates insulin resistance with arterial stiffness in various pathologies, yet limited reports exist in healthy adults. Therefore, this study aims to estimate the association between insulin resistance and arterial stiffness in healthy adults. The cross-sectional EVasCu study enrolled 390 participants (42.05 ± 13.15 years). ANCOVAs, unadjusted (model 1) and adjusted (model 2), explored the association between arterial stiffness markers (aortic Pulse Wave Velocity [aPWV], Augmentation Index [AIx@75] and Cardio-Ankle Vascular Index [CAVI]), and insulin resistance markers (Homeostasis Model Assessment of Insulin Resistance [HOMA-IR], Quantitative Insulin Sensitivity Check Index [QUICKI] and Triglycerides-Glucose [TyG]). In model 1, all insulin resistance markers were associated with aPWV, HOMA-IR and QUICKI were associated with AIx@75, and the TyG index was associated with CAVI. In model 2, HOMA-IR and QUICKI increased aPWV by 0.179 and 0.156 m/s (p = 0.001 and p = 0.011), and AIx@75 by 4.17 and 5.39% (p = 0.009 and p = 0.003). The EVasCu study offers valuable insights into the relationship between insulin resistance and arterial stiffness in healthy adults, providing a deeper understanding of metabolic and cardiovascular health. By examining this influence, we embark on an intriguing exploration of how these factors interplay in the human body.

Afamitresgene autoleucel for advanced synovial sarcoma and myxoid round cell liposarcoma (SPEARHEAD-1): an international, open-label, phase 2 trial.

BACKGROUND: Afamitresgene autoleucel (afami-cel) showed acceptable safety and promising efficacy in a phase 1 trial (NCT03132922). The aim of this study was to further evaluate the efficacy of afami-cel for the treatment of patients with HLA-A*02 and MAGE-A4-expressing advanced synovial sarcoma or myxoid round cell liposarcoma. METHODS: SPEARHEAD-1 was an open-label, non-randomised, phase 2 trial done across 23 sites in Canada, the USA, and Europe. The trial included three cohorts, of which the main investigational cohort (cohort 1) is reported here. Cohort 1 included patients with HLA-A*02, aged 16-75 years, with metastatic or unresectable synovial sarcoma or myxoid round cell liposarcoma (confirmed by cytogenetics) expressing MAGE-A4, and who had received at least one previous line of anthracycline-containing or ifosfamide-containing chemotherapy. Patients received a single intravenous dose of afami-cel (transduced dose range 1·0 × 109-10·0 × 109 T cells) after lymphodepletion. The primary endpoint was overall response rate in cohort 1, assessed by a masked independent review committee using Response Evaluation Criteria in Solid Tumours (version 1.1) in the modified intention-to-treat population (all patients who received afami-cel). Adverse events, including those of special interest (cytokine release syndrome, prolonged cytopenia, and neurotoxicity), were monitored and are reported for the modified intention-to-treat population. This trial is registered at ClinicalTrials.gov, NCT04044768; recruitment is closed and follow-up is ongoing for cohorts 1 and 2, and recruitment is open for cohort 3. FINDINGS: Between Dec 17, 2019, and July 27, 2021, 52 patients with cytogenetically confirmed synovial sarcoma (n=44) and myxoid round cell liposarcoma (n=8) were enrolled and received afami-cel in cohort 1. Patients were heavily pre-treated (median three [IQR two to four] previous lines of systemic therapy). Median follow-up time was 32·6 months (IQR 29·4-36·1). Overall response rate was 37% (19 of 52; 95% CI 24-51) overall, 39% (17 of 44; 24-55) for patients with synovial sarcoma, and 25% (two of eight; 3-65) for patients with myxoid round cell liposarcoma. Cytokine release syndrome occurred in 37 (71%) of 52 of patients (one grade 3 event). Cytopenias were the most common grade 3 or worse adverse events (lymphopenia in 50 [96%], neutropenia 44 [85%], leukopenia 42 [81%] of 52 patients). No treatment-related deaths occurred. INTERPRETATION: Afami-cel treatment resulted in durable responses in heavily pre-treated patients with HLA-A*02 and MAGE-A4-expressing synovial sarcoma. This study shows that T-cell receptor therapy can be used to effectively target solid tumours and provides rationale to expand this approach to other solid malignancies. FUNDING: Adaptimmune.

Molecular Insights of Cholestasis in MDR2 Knockout Murine Liver Organoids.

MDR3 (multidrug resistance 3) deficiency in humans (MDR2 in mice) causes progressive familial intrahepatic cholestasis type 3 (PFIC3). PFIC3 is a lethal disease characterized by an early onset of intrahepatic cholestasis progressing to liver cirrhosis, a preneoplastic condition, putting individuals at risk of hepatocellular carcinoma (HCC). Hepatocyte-like organoids from MDR2-deficient mice (MDR2KO) were used in this work to study the molecular alterations caused by the deficiency of this transporter. Proteomic analysis by mass spectrometry allowed characterization of 279 proteins that were differentially expressed in MDR2KO compared with wild-type organoids. Functional enrichment analysis indicated alterations in three main cellular functions: (1) interaction with the extracellular matrix, (2) remodeling intermediary metabolism, and (3) cell proliferation and differentiation. The affected cellular processes were validated by orthogonal molecular biology techniques. Our results point to molecular mechanisms associated with PFIC3 that may drive the progression to liver cirrhosis and HCC and suggest proteins and cellular processes that could be targeted for the development of early detection strategies for these severe liver diseases.

Effect of Botulinum Toxin Injections in the Treatment of Spasticity of Different Etiologies: An Umbrella Review.

BACKGROUND: Spasticity is a very common neurological sequelae that significantly impacts the quality of life of patients, affecting more than 12 million people worldwide. Botulinum toxin is considered a reversible treatment for spasticity, but due to the large amount of available evidence, synthesis seems necessary. Therefore, we conducted an overview of existing systematic reviews and meta-analyses to evaluate the effect of botulinum toxin injections in the treatment of spasticity of different etiologies. METHODS: A systematic search of different databases, including Pubmed, Scopus, the Cochrane Library, and Web of Science, was performed from inception to February 2024. Standardized mean differences (SMDs) and their respective 95% confidence intervals (CIs) were calculated to assess the effect of botulinum toxin compared to that of the control treatment using the Modified Ashworth Scale (MAS). All the statistical analyses were performed using STATA 15 software. RESULTS: 28 studies were included in the umbrella review. The effect of botulinum toxin injections on spasticity, as measured by the MAS, was significantly lower in all but three studies, although these studies also supported the intervention. The SMDs reported by the meta-analyses ranged from -0.98 to -0.01. CONCLUSION: Botulinum toxin injections were effective at treating spasticity of different etiologies, as indicated by the measurements on the MAS. This implies an improvement in muscle tone and, consequently, in the patient's mobility and quality of life.

Overview of the participation of community health workers in primary health care in 6 Latin American countries and a proposal for their integration into the health system: a qualitative study.

BACKGROUND: According to some health programmes, implementing primary health care through community health workers (CHWs) facilitates the connection between community and health services in Latin America. However, these are isolated processes that face different obstacles and would benefit from an overview of the corresponding health policies and programmes. OBJECTIVE: To provide an overview of CHW participation in 6 Latin American countries. METHODS: This exploratory qualitative study was based on 3 sources of information: a literature review, a review of public health policy documents, and interviews with experts who have led CHW programmes in 6 Latin American countries. RESULTS: The role of CHWs in Latin America and some advances in public health policies in the region were evidenced. However, limitations arising from variable implementation of the WHO guidelines on health programmes with CHWs were also apparent. CONCLUSIONS: CHWs contribute to the primary healthcare processes in the 6 Latin American countries studied in versatile and comprehensive ways. However, they constitute an underutilized human resource because they must provide various services that are not always relevant in different work contexts. Therefore, we propose a classification of the CHW profile, using the level of access to healthcare services of the population they serve as the main differentiator. This way, CHWs will not have to provide a wide range of services but only those most relevant to the specific needs of each community.

Monocyte distribution width (MDW): study of reference values in blood donors.

OBJECTIVES: Monocyte distribution width (MDW) is a new biomarker used as an early indicator of sepsis (ESId). It is often aids in the identification of patients who may develop sepsis. This study aims to establish the MDW reference interval (RI) within the healthy population of blood donors using EDTA-K2 as anticoagulant. Many hospitals use this biomarker as a means of identifying patients who present to the hospital with sepsis. METHODS: A total of 274 samples obtained from healthy donors were analyzed. MDW measurements were taken within 2 h post-extraction. The RI was estimated using various statistical methodologies, including the recommended CLSI EP28-A3c guideline, non-parametric and robust methods, along with the Harrell-Davis bootstrap method applied to the entire sample. RESULTS: The RI estimated through non-parametric method was 14.77 CI90 % (14.36-14.97)-21.13 CI90 % (20.89-21.68); RI using the robust method was 15.64-19.05 and RI using the Harrell-Davis bootstrap method was 14.73 CI90 % (14.53-14.92)-21.14 CI90 % (20.88-21.40). CONCLUSIONS: Based on clinical applicability, we recommend utilizing the RI derived from the non-parametric method, aligning with the CLSI recommendations. Furthermore, we consider that our results can be taken as a reference in other laboratories that serve a population similar to our study cohort.

IgG4-related disease mimicking a liver abscess.

IgG4-related disease (IGRD) is a complex medical condition affecting multiple organs, including the liver. The condition is characterized by excessive production of IgG4 antibodies, leading to chronic inflammation and tissue damage. We present a case of a 37-year-old man with a history of chronic pancreatitis was diagnosed with a liver mass. Initial treatment included piperacillin and tazobactam, but the patient's condition worsened. An ultrasound-guided biopsy revealed increased IgG4 positive cells, leading to the diagnosis of an inflammatory pseudotumor associated with IGRD. The patient was treated with prednisone taper therapy, and the liver mass resolved after six months of corticoid treatment.

Transarterial Embolization for Adhesive Capsulitis of the Shoulder: Midterm Outcomes on Function and Pain Relief.

PURPOSE: To determine the safety and potential effectiveness of transarterial embolization for adhesive capsulitis of the shoulder. MATERIALS AND METHODS: This prospective study analyzed consecutive adult patients with adhesive capsulitis referred for embolization between January 2018 and May 2023 after a poor response to treatment (symptoms and limitation of motion in ≥2 axes; ≤120° flexion, ≤50° external rotation and/or internal rotation with the shoulder abducted 90°) persisting for >3 months after having completed ≥6 weeks of analgesics and physical therapy. Different types of pain and mobility were measured before embolization and 1, 3, and 6 months after embolization. Overall upper limb function (Quick Disabilities of Arm, Shoulder, and Hand) and patient satisfaction were measured before and 6 months after embolization. Long-term follow-up comprised telephone interviews and clinical history reviews. RESULTS: A total of 20 patients (12 [60%] women; median age, 50.7; interquartile ranges [IQR], 45‒55 years) were included; 6 (30%) had diabetes and 15 (75%) were off work. Median duration of symptoms before embolization was 39.4 weeks (IQR, 28‒49 weeks), and median duration of rehabilitation therapy was 12.8 weeks (IQR, 8‒16 weeks). Six months after embolization, significant improvements were observed in nocturnal pain (P = .003), pain on moving (P = .001), external rotation (P < .001), internal rotation (P < .001), active flexion (P < .001), passive flexion (P = .03), active abduction (P < .001), passive abduction (P < .001), and overall function (P < .001). Despite objective improvements, patient satisfaction was nearly unchanged. Only 1 patient experienced a mild adverse event. CONCLUSION: Transarterial embolization is safe and potentially effective in treating adhesive capsulitis of the shoulder refractory to conventional treatment. Clinical improvements were maintained in the mid to long term.

Validation of an early vascular aging construct model for comprehensive cardiovascular risk assessment using external risk indicators for improved clinical utility: data from the EVasCu study.

BACKGROUND: Cardiovascular diseases (CVDs) remain a major global health concern, necessitating advanced risk assessment beyond traditional factors. Early vascular aging (EVA), characterized by accelerated vascular changes, has gained importance in cardiovascular risk assessment. METHODS: The EVasCu study in Spain examined 390 healthy participants using noninvasive measurements. A construct of four variables (Pulse Pressure, Pulse Wave Velocity, Glycated Hemoglobin, Advanced Glycation End Products) was used for clustering. K-means clustering with principal component analysis revealed two clusters, healthy vascular aging (HVA) and early vascular aging (EVA). External validation variables included sociodemographic, adiposity, glycemic, inflammatory, lipid profile, vascular, and blood pressure factors. RESULTS: EVA cluster participants were older and exhibited higher adiposity, poorer glycemic control, dyslipidemia, altered vascular properties, and higher blood pressure. Significant differences were observed for age, smoking status, body mass index, waist circumference, fat percentage, glucose, insulin, C-reactive protein, diabetes prevalence, lipid profiles, arterial stiffness, and blood pressure levels. These findings demonstrate the association between traditional cardiovascular risk factors and EVA. CONCLUSIONS: This study validates a clustering model for EVA and highlights its association with established risk factors. EVA assessment can be integrated into clinical practice, allowing early intervention and personalized cardiovascular risk management.

Delays in diagnosis and surgery of sarcoma patients during the COVID-19 outbreak in Spain.

Background and objectives: Social distancing and quarantine implanted during the COVID-19 outbreak could have delayed the accession of oncologic patients to hospitals and treatments. This study analysed the management of sarcoma patients during this period in five Spanish hospitals. Design and methods: Clinical data from adult sarcoma patients, soft tissue and bone sarcomas, managed during the COVID-19 outbreak, from 15 March to 14 September 2020 (Covid cohort), were retrospectively collected and time for diagnosis, surgery and active treatments were compared with sarcoma patients managed during the same pre-pandemic period in 2018 (Control cohort). Results: A total of 126 and 182 new sarcoma patients were enrolled in the Covid and Control cohorts, respectively, who were mainly diagnosed as soft tissue sarcomas (81.0% and 80.8%) and at localized stage (80.2% and 79.1%). A diagnostic delay was observed in the Covid cohort with a median time for the diagnosis of 102.5 days (range 6-355) versus 83 days (range 5-328) in the Control cohort (p = 0.034). Moreover, a delay in surgery was observed in cases with localized disease from the Covid cohort with a median time of 96.0 days (range 11-265) versus 54.5 days (range 2-331) in the Control cohort (p = 0.034). However, a lower delay for neoadjuvant radiotherapy was observed in the Covid cohort with a median time from the diagnosis to the neoadjuvant radiotherapy of 47 days (range 27-105) versus 91 days (range 27-294) in the Control cohort (p = 0.039). No significant differences for adjuvant radiotherapy, neoadjuvant/adjuvant chemotherapy and neoadjuvant/adjuvant palliative chemotherapy were observed between both cohorts. Neither progression-free survival (PFS) nor overall survival (OS) was significantly different. Conclusion: Delays in diagnosis and surgery were retrospectively observed in sarcoma patients during the COVID-19 outbreak in Spain, while the time for neoadjuvant radiotherapy was reduced. However, no impact on the PFS and OS was observed.

Trabectedin and Radiotherapy in Endometrial Stromal Sarcoma: A Case Report.

Introduction: Endometrial stromal sarcoma (ESS) is a rare tumor that remains a diagnostic and therapeutic challenge to physicians worldwide. The metastatic setting implies a poor prognosis, with a 5-year survival rate below 40%. Patients with advanced-stage high-grade ESS (HG-ESS) have limited therapeutic options, often involving various chemotherapy regimens. Case Presentation: This report depicts the case of a 47-year-old female diagnosed with HG-ESS. She underwent several lines of treatment starting with radiotherapy and brachytherapy, followed by multiple lines of treatment including trabectedin over several months. After retreatment with trabectedin and achieving disease stabilization for 10 months, treatment was optimized by trabectedin combined with radiotherapy, leading to stable disease that is still ongoing and lasts for over 17 months. Conclusion: Our case underscores the challenging nature of treating patients with HG-ESS and highlights the safety of long-term retrial with trabectedin, coupled with radiotherapy administration. This approach maintained a durable stable disease response in the metastatic setting.

Trabectedin and low-dose radiation therapy in patients with advanced leiomyosarcoma.

Background and objectives: Dimensional response is an unmet need in second lines of advanced soft tissue sarcomas (STS). Indeed, the three approved drugs, pazopanib, trabectedin, and eribulin, achieved an overall response rate (ORR) of less than 10%. This fact potentially hinders the options for fast symptomatic relief or surgical rescue. The combination of trabectedin plus low-dose radiation therapy (T-XRT) demonstrated a response rate of 60% in phase I/II trial, while real-life data achieved 32.5% ORR, probably due to a more relaxed timing between treatments. These results were obtained in progressing and advanced STS. In this study, the merged databases (trial plus real life) have been analyzed, with a special focus on leiomyosarcoma patients. Design and methods: As responses were seen in a wide range of sarcoma histologies (11), this study planned to analyze whether leiomyosarcoma, the largest subtype with 26 cases (30.6%) in this series, exhibited a better clinical outcome with this therapeutic strategy. In addition, four advanced and progressing leiomyosarcoma patients, all with extraordinarily long progression-free survival of over 18 months, were collected. Results: A total of 847 cycles of trabectedin were administered to 85 patients, with the median number of cycles per patient being 7 (1-45+). A trend toward a longer progression-free survival (PFS) was observed in leiomyosarcoma patients with median PFS (mPFS) of 9.9 months [95% confidence interval (CI): 1.1-18.7] versus 5.6 months (95% CI: 3.2-7.9) for the remaining histologies, p = 0.25. When leiomyosarcoma and liposarcoma were grouped, this difference reached statistical significance, probably due to the special sensitivity of myxoid liposarcoma. The mPFS for L-sarcomas was 12.7 months (95% CI: 7-18.5) versus 4.3 months (95% CI: 3.3-5.3) for the remaining histologies, p = 0.001. Cases with long-lasting disease control are detected among leiomyosarcoma patients. Conclusion: Even when extraordinarily long-lasting responses do exist among leiomyosarcoma patients treated with T-XR, we were unable to demonstrate a significant difference favoring leiomyosarcoma patients in clinical outcomes.

Apolar Extracts of St. John's Wort Alleviate the Effects of ß-Amyloid Toxicity in Early Alzheimer's Disease.

Hypericum perforatum (St. John's wort) has been described to be beneficial for the treatment of Alzheimer's disease (AD). Different extractions have demonstrated efficiency in mice and humans, esp. extracts with a low hypericin and hyperforin content to reduce side effects such as phototoxicity. In order to systematically elucidate the therapeutic effects of H. perforatum extracts with different polarities, APP-transgenic mice were treated with a total ethanol extract (TE), a polar extract obtained from TE, and an apolar supercritical CO2 (scCO2) extract. The scCO2 extract was formulated with silicon dioxide (SiO2) for better oral application. APP-transgenic mice were treated with several extracts (total, polar, apolar) at different concentrations. We established an early treatment paradigm from the age of 40 days until the age of 80 days, starting before the onset of cerebral ß-amyloid (Aß) deposition at 45 days of age. Their effects on intracerebral soluble and insoluble Aß were analyzed using biochemical analyses. Our study confirms that the scCO2H. perforatum formulation shows better biological activity against Aß-related pathological effects than the TE or polar extracts. Clinically, the treatment resulted in a dose-dependent improvement in food intake with augmentation of the body weight, and, biochemically, it resulted in a significant reduction in both soluble and insoluble Aß (-27% and -25%, respectively). We therefore recommend apolar H. perforatum extracts for the early oral treatment of patients with mild cognitive impairment or early AD.

Implementing pharmacogenetics in clinical trials: considerations about current methodological, ethical, and regulatory challenges.

INTRODUCTION: The implementation of pharmacogenetic analysis within clinical trials faces methodological, ethical, and regulatory challenges, as well as tackling the difficulty in obtaining actionable information with a sufficient level of evidence to enable its integration into routine clinical practice. AREAS COVERED: We discuss the current status of pharmacogenetics integration in clinical trials, underscore the associated challenges, and make some suggestions on the aspects to address in any clinical trial including a pharmacogenetic evaluation. We conducted a literature review, thoroughly reviewed the applicable regulations and available guidelines, and assessed the application dossiers submitted for evaluation to the Ethics committee of Hospital La Paz (Madrid, Spain) to extract information related to inclusion of pharmacogenetics evaluations. EXPERT OPINION: The integration of pharmacogenetics into clinical trials is becoming increasingly common. However, several regulatory, methodological and ethical aspects involved are insufficiently addressed. There is a need for specific and transparent guidelines that establish unified and compliant criteria for methodology, proper handling of samples in compliance with regulations, and the protection of data privacy and confidentiality. Participants should receive complete and appropriate information regarding the purpose, handling, storage, and transfer of their samples and data, and should have the right to decide about their processing.