Clinical Tolerability Research Articles

Feasibility, Tolerability, and Preliminary Clinical Response of Fractionated Radiopharmaceutical Therapy with 213Bi-FAPI-46: Pilot Experience in Patients with End-Stage, Progressive Metastatic Tumors.

Radiopharmaceutical therapies (RPTs) based on fibroblast activation protein (FAP) and FAP inhibitors (FAPIs) are a new option for progressive metastatic cancer in patients pretreated multiple times. To date, published in-human data refer to initial experiences with β-emitting 90Y- and 177Lu-based RPT. However, the short tumor retention time of FAPI ligands is considered a major limitation of FAPI RPT. Therefore, fractionated FAPI RPT with 213Bi, an α-emitter with a half-life of 46 min, appears to be a promising FAPI RPT regimen. Here, we report on our initial experiences with regard to the feasibility, tolerability, and response of fractionated 213Bi-FAPI-46 RPT. Methods: Six patients (4 women and 2 men) with progressive metastatic solid tumors (3 colon cancer, 1 anal cancer, 1 breast cancer, and 1 prostate cancer) aged 16-77 y were treated with a mean of 1,609 MBq of 213Bi-FAPI-46, fractionated into 53 single applications (range, 5-12 RPT applications per patient; mean, 8.8 applications) over a period of up to 107 h per patient. Of the 6 patients, 4 patients received adjuvant treatment with pembrolizumab. 18F-FDG (4 patients) and 68Ga-FAPI-46 (5 patients) PET/CT scans were performed before and after RPT. PET images were assessed visually and by calculating total lesion glycolysis and total lesion FAPI. Results: RPT with 213Bi-FAPI-46 was well tolerated without adverse side effects. In terms of visual response assessment, there was 1 partial response (16.7%), 1 patient with stable disease (16.7%), and 4 patients with progressive disease (66.7%). Concordantly, total lesion glycolysis and total lesion FAPI were decreased in the responding patient (not applicable and -24.3%, respectively), slightly decreased in the patient with stable disease (-10.6% and -5.9%, respectively), and increased in the 4 patients with progression (mean, +104.4% and +321.3%, respectively). Conclusion: Fractionated FAPI RPT with the short-half-life α-emitter 213Bi-FAPI-46 is a promising approach that matches the pharmacokinetics of FAPI-46 better than the 177Lu- or 90Y-labeled compounds. In this pilot project, fractionated RPT with 213Bi-FAPI-46 showed good clinical tolerability and even led to regressive or stable disease in the short term in 2 of 6 patients. Further studies with larger patient cohorts are required to evaluate the actual efficacy and long-term effects of this variant of FAPI RPT.

Clinical Efficacy and Tolerability of Lemon Balm (Melissa officinalis L.) in Psychological Well-Being: A Review

Background: There is renewed interest in the use of ancient herbal remedies for their potential health benefits, particularly in the psychological domain. One herb that is receiving growing attention is lemon balm (Melissa officinalis L.) which has received considerable interest for its influence on the brain. Lemon balm boasts an array of phytochemicals, including rosmarinic acid, citral, oleanolic acid, and ursolic acid, which are believed to underpin these effects on psychological well-being. Pharmacological evidence from animal and cellular work reveals that lemon balm and its components may modulate several brain signalling pathways, including GABAergic, cholinergic, and serotonergic systems. Results/Conclusions: Although further robust randomised controlled trials using lemon balm are required, existing research indicates that lemon balm holds promise as a calming agent exhibiting both anxiolytic and anti-depressant properties and can elicit cognitive and sleep-quality enhancement.

Evaluating CDK4/6 Inhibitor Therapy in Elderly Patients with Metastatic Hormone Receptor-Positive, HER2-Negative Breast Cancer: A Retrospective Real-World Multicenter Study

Background: Metastatic HR+/HER2- breast cancer is commonly treated with CDK4/6 inhibitors in combination with endocrine therapy. However, the efficacy and safety of this approach in elderly patients (≥70 years) remain unclear, particularly in the context of real-world clinical practice. This study aims to evaluate the clinical outcomes and tolerability of CDK4/6 inhibitor treatments in this fragile population, which is often under-represented in randomized clinical trials. Patients and methods: This retrospective multicenter study included elderly patients with metastatic HR+/HER2-negative breast cancer receiving first-line CDK4/6 inhibitors. The primary endpoint was progression-free survival (PFS). The secondary endpoints focused on the overall survival (OS), safety, and tolerability, considering variables such as tumor subtype, age, comorbidities, and treatment specifics. Results: The median PFS and OS were slightly lower than those reported in clinical trials, reflecting the inclusion of a more fragile population. The luminal B subtype was linked to a poorer PFS, while other factors like age, BMI, and ECOG status did not significantly affect the outcomes. A safety analysis indicated a higher incidence of grade 3 or higher toxicities, especially in frail patients, leading to dose reductions. Despite these challenges, CDK4/6 inhibitors were generally well-tolerated, allowing most patients to continue therapy. Conclusions: CDK4/6 inhibitors with endocrine therapy are effective in elderly patients with metastatic HR+/HER2- breast cancer, though careful management is crucial to balance efficacy and minimize adverse events.

The Clinical Effectiveness and Tolerability of Oseltamivir in Unvaccinated Pediatric Influenza Patients during Two Influenza Seasons after the COVID-19 Pandemic: The Impact of Comorbidities on Hospitalization for Influenza in Children

Antiviral therapy such as oseltamivir has been recommended for hospitalized children with suspected and confirmed influenza for almost 20 years. The therapy is officially authorized for newborns two weeks of age or older, however, questions about its safety and effectiveness still surround it. Our goals were to assess the epidemiological features of two consecutive seasonal influenza cases in children following the COVID-19 pandemic; to observe the clinical effectiveness and tolerability of oseltamivir in hospitalized children who were not vaccinated against influenza and had different influenza subtypes, including A(H1N1), A(H3N2), and B; and to identify specific comorbidities associated with influenza in children. We performed an observational study on 1300 children, enrolled between 1 October 2022 and 30 May 2023 and between 1 October 2023 and 4 May 2024, to the IX Pediatric Infectious Diseases Clinical Section of the National Institute of Infectious Diseases “Prof. Dr. Matei Balș”. During the 2022–2023 influenza season, 791 pediatric patients tested positive for influenza and received oseltamivir. Of these, 89% (704/791) had influenza A, with 86.4% having subtype A(H1N1) and 13.6% of cases having A(H3N2), and for influenza B, 11% (87/791) of the pediatric patients. Of the total group, 59% were male, and the median age was 2.4 years (1.02–9.28). For the 2023–2024 influenza season, 509 pediatric patients tested positive for influenza, with 56.9% being of the male gender and who were treated with oseltamivir. Of these patients, 81.6% had influenza A and 18.4% had influenza B. Treatment with neuraminidase inhibitors, specifically oseltamivir, 2 mg/kg/dose administered twice daily for 5 days, was well tolerated by the children, and we recorded no deaths. The duration of hospitalization for patients with a fever after the oseltamivir administration was significantly longer for patients with A(H1N1) infection than A(H3N2), during both seasons. We identified more complications in the 2022–2023 season and a decreasing number of influenza B for the 2023–2024 season. Among children with comorbidities, the most common were asthma, gastrointestinal diseases, and metabolic and endocrine diseases. In terms of effectiveness, oseltamivir significantly reduced the intensity of influenza symptoms, thus reducing the number of days of hospitalization (p = 0.001) as well as post-infection complications (p = 0.005) in both groups. In this study, we evaluated the clinical effectiveness of oseltamivir therapy for all influenza types/subtypes in children, and the length of hospitalization. We identified comorbidities associated with the prolonged duration of hospitalization. Influenza vaccination should be the main tool in the prevention of influenza and its complications in children, especially those with comorbidities.

Long-term performance monitoring of a-Si 1200 electronic portal imaging device for dosimetric applications.

Recently, dosimetri applications of the electronic portal imaging device (EPID) in radiotherapy have gained popularity. Confidence in the robust and reliable dosimetric performance of EPID detectors is essential for their clinical use. This study aimed to evaluate the dosimetric performance of the a-Si 1200 EPID and assess the long-term stability of its response. Weekly measurements were performed on two clinically used TrueBeam linear accelerators (linacs) equipped with a-Si 1200 EPID detectors over a 2-year period. They included dark and flood calibration fields, and EPID response to an open field corrected for the long-term machine output drift measured with the secondary absolute dosimeters: an ion chamber and an ion chamber array. All measurements were performed using five photon beam energies and two imaging modes: continuous and dosimetry. The measurements were analyzed for constancy and the presence of long-term trends. Comparisons were made between the two linacs for each beam energy. Pixel sensitivity matrices (PSM) were determined semi-annually and analyzed for long-term constancy for both treatment machines. The long-term variation of the dark and flood field signals, integrated across the EPID plane, over the entire observation period did not exceed 0.17% and 0.79%, respectively. The output-corrected EPID response showed long-term variation from 0.28% to 0.36%, depending on beam energy, while the short-term variation was 0.04%-0.07% for EPID and 0.02%-0.06% for secondary dosimeters. The long-term variation of secondary dosimeters was 0.2%-0.3%. PSMs were found to be stable to within 1% for 97.8% of pixels and 2% for 100% of pixels. Techniques to monitor and assess the long-term performance of the a-Si 1200 EPID as a dosimeter were developed and implemented using two TrueBeam linacs. The long-term variation of the EPID response was within clinical tolerance indicated in AAPM TG-142 report, and the detector was shown to be stable and reproducible for routine clinical dosimetry.

Efficacy of perampanel by etiology in Japanese patients with epilepsy-subpopulation analysis of a prospective post-marketing observational study.

To examine the efficacy and safety of perampanel (PER) in patients with post-stroke epilepsy (PSE), brain tumor-related epilepsy (BTRE), and post-traumatic epilepsy (PTE) using Japanese real-world data. The prospective post-marketing observational study included patients with focal seizures with or without focal to bilateral tonic-clonic seizures who received PER combination therapy. The observation period was 24 or 52 weeks after the initial PER administration. The safety and efficacy analysis included 3716 and 3272 patients, respectively. This post hoc analysis examined responder rate (50% reduction in seizure frequency), seizure-free rate (proportion of patients who achieved seizure-free), and safety in patients included in the post-marketing study who had PSE, BTRE, and PTE in the 4 weeks prior to the last observation. Overall, 402, 272, and 186 patients were included in the PSE, BTRE, and PTE subpopulations, and 2867 controls in the "Other" population (etiologies other than PSE, BTRE, or PTE). Mean modal dose (the most frequently administered dose) values at 52 weeks were 3.38, 3.36, 3.64, and 4.04 mg/day for PSE, BTRE, PTE, and "Other," respectively; PER retention rates were 56.2%, 54.0%, 52.6%, and 59.7%, respectively. Responder rates (% [95% confidence interval]) were 82% (76.3%-86.5%), 78% (70.8%-83.7%), 67% (56.8%-75.6%), and 50% (47.9%-52.7%) for PSE, BTRE, PTE, and "Other," respectively, and seizure-free rates were 71% (64.5%-76.5%), 62% (54.1%-69.0%), 50% (40.6%-60.4%), and 28% (25.8%-30.1%), respectively. Adverse drug reactions tended to occur less frequently in the PSE (14.7%), BTRE (16.5%), and PTE (16.7%) subpopulations than in the "Other" population (26.3%). In real-world clinical conditions, efficacy and tolerability for PER combination therapy were observed at low PER doses for the PSE, BTRE, and PTE subpopulations. To find out how well the medication perampanel works and whether it is safe for people who have epilepsy after having had a stroke, brain tumor, or head injury, we used information from real-life medical situations in Japan. We looked at the data of about 3700 Japanese patients with epilepsy who were treated with perampanel. We found that perampanel was used at lower doses and better at controlling seizures, and had fewer side effects for patients with epilepsy caused by these etiologies than the control group.

Clinical utility of ultra long-term subcutaneous electroencephalographic monitoring in drug-resistant epilepsies: a "real world" pilot study.

This study was undertaken to assess the clinical utility, safety, and tolerability in epilepsy patients of ultra long-term monitoring with a novel subcutaneous electroencephalographic (EEG) device (sqEEG). Five patients with drug-resistant focal epilepsy were implanted (one patient bilaterally) with sqEEG. In phase 1, we assessed sqEEG sensitivity for seizure recording by recording seizures simultaneously with scalp EEG in the epilepsy monitoring unit (EMU). sqEEG was scored either visually (v-sqEEG) or by using a semiautomatic algorithm (EpiSight; E-sqEEG). In phase 2, the patients were monitored as outpatients for 3-6 months. sqEEG data were analyzed monthly, evaluating concordance of data obtained by v-sqEEG, E-sqEEG, and patients' diaries. v-sqEEG data were used to guide treatment adjustments. sqEEG-related side effects were assessed throughout the study. In phase 1, v-sqEEG detected all seizures recorded in the EMU in all patients, whereas E-sqEEG was as effective in three patients. In the other two patients, E-sqEEG detected only a proportion or none of the seizures, respectively. Sensitivity of E-sqEEG depended on the ictal EEG features. In phase 2, a 100% concordance between E-sqEEG and v-sqEEG in seizure detection was observed for the same three patients as in phase 1. In the other two patients (one implanted bilaterally), effectiveness of E-sqEEG in detecting seizure as compared to v-sqEEG ranged from 0% to 83%. v-sqEEG showed that all patients reported in their diaries fewer seizures than they actually suffered. In four of five patients, v-sqEEG showed that the treatment adjustments had been ineffective or associated with a seizure increment. The only side effect was an infection at the implantation site in one patient. The sqEEG system could collect reliable information on seizure activity, thus providing clinically relevant information. Sensitivity of EpiSight in detecting seizures varied across patients, depending on the ictal EEG features. sqEEG ultra long-term monitoring was feasible and well tolerated.

Evaluation of the effect of cannabidiol administration with and without nonsteroidal anti-inflammatory drugs in dogs with mobility disorders: a prospective, double-blind, crossover, placebo-controlled study.

With rapidly growing interest in the use of cannabidiol (CBD) in the management of pain and other conditions, more information is needed on the safety and efficacy of this supplement, particularly its co-administration with commonly used pharmaceuticals such as non-steroidal anti-inflammatory drugs (NSAIDs). This study sought to assess the effect of CBD in dogs with mobility impairments, as well as evaluate the clinical tolerance of CBD used together with NSAIDs. Forty-two client-owned dogs with diagnosed mobility impairments were enrolled in this prospective, double-blind, crossover, placebo-controlled study. Baseline data were collected for 10-14 days followed by random allocation to either placebo or CBD oil for 45 days with a 30-day washout period in between. CBD was dosed at 5 mg/kg orally every 12 h with masked placebo administered at equal volume. Outcome measures included objective gait analysis, accelerometry, and clinical metrology instruments. CBD plasma levels and serum biochemistry were also collected along with hepatic ultrasound if warranted. Thirty-eight dogs finished the study with thirty-nine included for at least partial analysis. Compared to baseline, dogs receiving CBD showed evidence of improved outcomes based on blinded veterinary assessments and accelerometer data. Compared to placebo, dogs receiving CBD showed some evidence of improved outcomes on CBPI, CSOM, and blinded veterinary assessments, but not for objective outcome measures. There was evidence of increased ALP when CBD was co-administered with NSAIDs compared to CBD administration alone. Additionally, there was evidence of ALT elevations with CBD and NSAID co-administration, but this elevation did not show evidence of an increase over CBD use alone. These results suggest a potential therapeutic benefit in the administration of CBD for the management of mobility impairments, but greater ALP elevations were seen when administered with NSAIDs. While the sample size of dogs that received further hepatic work-up for liver enzyme elevations is small, chosen diagnostics varied, and liver biopsies were not performed, there did not appear to be clinically apparent liver damage. Further research is needed to better understand the efficacy of CBD in a larger population of dogs and patient tolerance and safety when administered with NSAIDs or other medications long term.

Orally bioavailable RORγ/DHODH dual host-targeting small molecules with broad-spectrum antiviral activity

Host-directed antivirals (HDAs) represent an attractive treatment option and a strategy for pandemic preparedness, especially due to their potential broad-spectrum antiviral activity and high barrier to resistance development. Particularly, dual-targeting HDAs offer a promising approach for antiviral therapy by simultaneously disrupting multiple pathways essential for viral replication.Izumerogant (IMU-935) targets two host proteins, (i) the retinoic acid receptor-related orphan receptor γ isoform 1 (RORγ1), which modulates cellular cholesterol metabolism, and (ii) the enzyme dihydroorotate dehydrogenase (DHODH), which is involved in de novo pyrimidine synthesis. Here, we synthesized optimized derivatives of izumerogant and characterized their antiviral activity in comparison to a recently described structurally distinct RORγ/DHODH dual inhibitor. Cell culture-based infection models for enveloped and non-enveloped DNA and RNA viruses, as well as a retrovirus, demonstrated high potency and broad-spectrum activity against human viral pathogens for RORγ/DHODH dual inhibitors at nanomolar concentrations. Comparative analyses with equipotent single-target inhibitors in metabolite supplementation approaches revealed that the dual-targeting mode represents the mechanistic basis for the potent antiviral activity. For SARS-CoV-2, an optimized dual inhibitor completely blocked viral replication in human airway epithelial cells at 5 nM and displayed a synergistic drug interaction with the nucleoside analog molnupiravir. In a SARS-CoV-2 mouse model, treatment with a dual inhibitor alone, or in combination with molnupiravir, reduced the viral load by 7- and 58-fold, respectively.Considering the clinical safety, oral bioavailability, and tolerability of izumerogant in a recent Phase I study, izumerogant-like drugs represent potent dual-targeting antiviral HDAs with pronounced broad-spectrum activity for further clinical development.

Glutaminase inhibition in combination with azacytidine in myelodysplastic syndromes: a phase 1b/2 clinical trial and correlative analyses.

Malignancies are reliant on glutamine as an energy source and a facilitator of aberrant DNA methylation. We demonstrate preclinical synergy of telaglenastat (CB-839), a selective glutaminase inhibitor, combined with azacytidine (AZA), followed by a single-arm, open-label, phase 1b/2 study in persons with advanced myelodysplastic syndrome (MDS). The dual primary endpoints evaluated clinical activity, safety and tolerability; secondary endpoints evaluated pharmacokinetics, pharmacodynamics, overall survival, event-free survival and duration of response. The dose-escalation study included six participants and the dose-expansion study included 24 participants. Therapy was well tolerated and led to an objective response rate of 70% with (marrow) complete remission in 53% of participants and a median overall survival of 11.6 months, with evidence of myeloid differentiation in responders determined by single-cell RNA sequencing. Glutamine transporter solute carrier family 38 member 1 in MDS stem cells was associated with clinical responses and predictive of worse prognosis in a large MDS cohort. These data demonstrate the safety and efficacy of CB-839 and AZA as a combined metabolic and epigenetic approach in MDS. ClinicalTrials.gov identifier: NCT03047993 .

Elexacaftor/tezacaftor/ivacaftor, a game-changer in cystic fibrosis: The Portuguese experience

BackgroundPhase 3 trials of elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) combination treatment in people with cystic fibrosis (CF) with ≥1 F508del-CFTR allele showed profound short-term effects on lung function, weight, and pulmonary exacerbations (PEx). The authors conducted a 12-month study to add evidence on the real-world long-term effectiveness and safety of CFTR modulator therapy with ELX/TEZ/IVA in Portuguese CF adult population. MethodsAmbispective, multicentre, observational, real-life study involving all the Portuguese CF Reference Centres. Adult patients on treatment with ELX/TEZ/IVA combination outside clinical trials were included. Demographics, efficacy, and safety variables on the first 12 months of treatment were compared with the pre-treatment year. Results132 adult people with CF were included, of which 119 completed 12 months treatment (mean duration of treatment 21.5 months). Mean age was 31.7 ± 11.0 years, 53 % patients were homozygous for the F508del variant, baseline sweat chloride was 86.7 ± 25.9 mmol/L and pre-treatment percent-predicted FEV1 was 77.9 ± 19.7 %. At 1 year, mean absolute change from baseline in FEV1 was +0.46L (95 % CI: 0.37, 0.55; p < 0.001) and +13.9 percentage points (95 % CI: 11.5, 16.2; p < 0.001). PEx episodes decreased by 78 % (p < 0.001) and hospitalizations for PEx decreased by 91.4 % (p < 0.001). Body mass index (BMI) increased 1.2 kg/m2 (95 % CI: 0.9, 1.5; p < 0.001). Mean sweat chloride variation was −44.5 mmol/L (95 % CI: −49.8, −39.2; p < 0.001). No correlation was found between sweat chloride and lung function (r = −0.116, p = 0.335). There were no major safety concerns. Of note, headache was reported in 7.6 % and neuropsychiatric manifestations occurred in 12.6 % treated patients, being anxiety and depressive disorders the most common. ConclusionsELX/TEZ/IVA treatment in Portuguese adults with CF was associated with significant improvement in lung function, a drop in PEx and PEx-related hospitalizations and increase in BMI at 12 months and was well tolerated. These results add knowledge to our understanding of clinical benefits and tolerability of ELX/TEZ/IVA. Careful evaluation of adverse effects of ELX/TEZ/IVA therapy and its determinants, mainly concerning mental health, are a research priority.

Real-world data on long-acting intramuscular maintenance therapy with cabotegravir and rilpivirine mirror Phase 3 results.

Cabotegravir, an integrase strand transfer inhibitor, and rilpivirine, an NNRTI, constitute the first long-acting (LA), injectable, two-drug ART regimen approved for the maintenance of virological suppression in persons living with HIV-1 (PLHIV). The aim of this study was to assess clinical effectiveness and tolerability of LA cabotegravir/rilpivirine in a real-world setting. We conducted a retrospective, single centre study, including all PLHIV receiving LA cabotegravir/rilpivirine as standard-of-care in our tertiary centre even if initiated in clinical trials. Between 2014 and 2022, 126 PLHIV initiated LA cabotegravir/rilpivirine. All were ART-experienced, and 98.4% had a viral load (VL) of <50 copies/mL before LA cabotegravir/rilpivirine initiation. Median BMI at cabotegravir/rilpivirine initiation was 24 IQR (23-28). During a median follow-up of 9 months IQR (7-24), 27 patients discontinued cabotegravir/rilpivirine because of virological failure, 6 for adverse events, 11 for personal reasons unrelated to treatment tolerance and 5 for other reasons. Virological failure was not associated with a higher BMI, nor with weight gain during LA intramuscular (IM) cabotegravir/rilpivirine treatment, inadequate cabotegravir and rilpivirine concentrations, VL blips or the use of oral lead-in (OLI) or not. No drug resistance-associated mutation emerged. Adverse events leading to treatment interruption were injection-site pain (n = 3) and neuropsychological side effects (n = 3). A correlation between BMI and both cabotegravir and rilpivirine concentrations at 1 month post-initiation of LA-IM cabotegravir/rilpivirine was observed, with no impact of OLI. Data from this real-world cohort of PLHIV who received cabotegravir/rilpivirine LA injections suggest that this regimen is effective and well tolerated. Virological failures were not associated with the acquisition of resistance mutations.

Characterization of the Immune-Modulating Properties of Different β-Glucans on Myeloid Dendritic Cells.

In allergen-specific immunotherapy, adjuvants are explored for modulating allergen-specific Th2 immune responses to re-establish clinical tolerance. One promising class of adjuvants are β-glucans, which are naturally derived sugar structures and components of dietary fibers that activate C-type lectin (CLR)-, "Toll"-like receptors (TLRs), and complement receptors (CRs). We characterized the immune-modulating properties of six commercially available β-glucans, using immunological (receptor activation, cytokine secretion, and T cell modulating potential) as well as metabolic parameters (metabolic state) in mouse bone marrow-derived myeloid dendritic cells (mDCs). All tested β-glucans activated the CLR Dectin-1a, whereas TLR2 was predominantly activated by Zymosan. Further, the tested β-glucans differentially induced mDC-derived cytokine secretion and activation of mDC metabolism. Subsequent analyses focusing on Zymosan, Zymosan depleted, β-1,3 glucan, and β-1,3 1,6 glucan revealed robust mDC activation with the upregulation of the cluster of differentiation 40 (CD40), CD80, CD86, and MHCII to different extents. β-glucan-induced cytokine secretion was shown to be, in part, dependent on the activation of the intracellular Dectin-1 adapter molecule Syk. In co-cultures of mDCs with Th2-biased CD4+ T cells isolated from birch allergen Bet v 1 plus aluminum hydroxide (Alum)-sensitized mice, these four β-glucans suppressed allergen-induced IL-5 secretion, while only Zymosan and β-1,3 glucan significantly suppressed allergen-induced interferon gamma (IFNγ) secretion, suggesting the tested β-glucans to have distinct effects on mDC T cell priming capacity. Our experiments indicate that β-glucans have distinct immune-modulating properties, making them interesting adjuvants for future allergy treatment.

Androgen Receptor Inhibitors in Patients With Nonmetastatic Castration-Resistant Prostate Cancer

Novel androgen receptor inhibitors (ARIs; darolutamide, enzalutamide, and apalutamide) are standard-of-care treatments for nonmetastatic castration-resistant prostate cancer (nmCRPC). However, there are sparse data comparing their clinical use and tolerability. To compare clinical use and outcomes for darolutamide, enzalutamide, and apalutamide in patients with nmCRPC. This retrospective cohort study reviewed electronic medical records from the Precision Point Specialty network of US urology practices. Eligible patients had nmCRPC and no prior novel hormonal therapy and initiated novel ARI treatment between August 1, 2019, and March 31, 2022. Data were analyzed from February 1, 2019, to December 31, 2022. Patients were prescribed darolutamide, enzalutamide, or apalutamide as their first novel ARI for nmCRPC. The main outcome was a composite of 2 end points, treatment discontinuation and progression to metastatic CRPC (mCRPC), whichever occurred first. Both end points were also assessed separately. All 870 patients meeting eligibility criteria were included (362 receiving darolutamide [41.6%]; 382, enzalutamide [43.9%]; 126, apalutamide [14.5%]); mean (SD) age was 78.8 (8.7) years. Self-reported race was Black or African American in 187 patients (21.5%), White in 585 (67.2%), and other or unknown in 98 (11.3%). The darolutamide cohort had lower proportions of patients with a composite end point event (134 [37.0%] vs 201 [52.6%] for enzalutamide and 66 [52.4%] for apalutamide), discontinuation (110 [30.4%] for darolutamide vs 156 [40.8%] for enzalutamide and 58 [46.0%] for apalutamide), and progression to mCRPC (64 [17.7%] for darolutamide vs 108 [28.3%] for enzalutamide and 35 [27.8%] for apalutamide) during the study period. After adjusting for baseline covariates, patients receiving darolutamide had a lower risk of a composite end point event compared with enzalutamide (risk reduction, 33.8%; hazard ratio [HR], 0.66 [95% CI, 0.53-0.84]) and apalutamide (risk reduction, 35.1%; HR, 0.65 [95% CI, 0.48-0.88]). Similarly, patients receiving darolutamide had a lower risk of discontinuation compared with enzalutamide (risk reduction, 27.4%; HR, 0.73 [95% CI, 0.56-0.94]) and apalutamide (risk reduction, 39.1%; HR, 0.61 [95% CI, 0.44-0.85]) and a lower risk of progression to mCRPC compared with enzalutamide (risk reduction, 40.6%; HR, 0.59 [95% CI, 0.43-0.82]) and apalutamide (risk reduction, 35.3%; HR, 0.65 [95% CI, 0.42-0.99]). There was no difference between enzalutamide and apalutamide treatment across outcomes. In this large cohort study of patients with nmCRPC treated with novel ARIs, results suggest better tolerability for darolutamide compared with enzalutamide and apalutamide, which may be associated with a clinical effectiveness advantage. Comparative clinical studies are needed to guide treatment decisions in the absence of head-to-head clinical trials.

Observational Study with a New Portable Cryosurgery Device, HYDROZID®, in Superficial Epidermal Lesions: An Indian Experience

Abstract Background: Cryosurgery remains an important treatment modality in dermatology practice. HYDROZID®, a new portable cryosurgery medical device using norflurane as a cryogen, was recently introduced in the Indian market. This paper reports the findings of the phase IV study conducted in India. Aims: This is a prospective phase IV study to evaluate its safety and efficacy in the treatment of superficial epidermal and dermal lesions. Methods: The study was conducted across 4 centres in India. The cryosurgery cycles were decided based on the skin lesion considered for the treatment. Safety and efficacy parameters were assessed at day 1, day 7, day 14, day 30 (±2) (end of treatment), and day 60 (±2) after the initial cryosurgery treatment. The local skin reactions scale, pain VAS scale, and Vancouver scale for assessment of pigmentation and scarring were used for the assessment of cutaneous reactions. Assessment of efficacy was done by evaluating the total disappearance of skin lesions at the end of the study visit. Results: Ninety-seven patients completed the study. The reported post-procedural pain was mild to moderate and subsided over the period of 24 hours. There was no pain observed in 84.76% of patients at the end of 24 hours. Complete disappearance of the lesion was seen in 47.4% of patients at the end of the study, while the reduction in the diameter of skin lesions by more than 50% was observed in 79.38% of patients. Conclusion: The data from this study support good clinical tolerability and safety of the Hydrozid® portable cryo device.

Intravenous ferric carboxymaltose versus oral ferrous sulphate for the treatment of moderate to severe postpartum anaemia in Nigerian women (IVON-PP): protocol for an open-label randomised controlled type 1 hybrid effectiveness-implementation trial

IntroductionPostpartum anaemia is often caused by iron deficiency with onset during the antepartum period and can be exacerbated by excessive blood loss at birth. Its prevalence is estimated as 50–80%...

A side-by-side comparison of fine-tuning options for treatment of medically refractory epilepsy: Antiseizure medications, vagus nerve stimulation and ketogenic diet therapies

There are many treatment options available for patients with medically refractory epilepsy including antiseizure medications, surgery, devices and ketogenic diet therapy. Ketogenic diet therapy has been shown to be a safe and effective treatment option in adult and pediatric patients. In order to obtain maximal clinical effectiveness and tolerability of any treatment option, adjustments are often necessary. This article outlines the “fine-tuning” options available for antiseizure medications, vagus nerve stimulation and ketogenic diet therapies and demonstrates that ketogenic diet therapies offer a wider array of personalizing and fine-tuning options.

A dermocosmetic product containing the sap of oat plantlets and Garcinia mangostana extract improves the clinical signs of acne.

Acne vulgaris is a common chronic inflammatory disorder of the pilosebaceous unit, characterized by papules, pustules and/or nodules manifesting primarily on the face and/or upper back that can leave scars, post-inflammatory hyperpigmentation (PIH) and erythema (PIE). To evaluate the anti-inflammatory properties of a protein-free sap extruded from Rhealba® oat plantlets and a Garcinia mangostana extract on Cutibacterium acnes-induced inflammation invitro and assess the tolerability and efficacy of a dermocosmetic product containing these actives in subjects with mild-to-moderate acne. Monocyte-derived dendritic cells (Mo-DCs) from acne patients were stimulated with a planktonic culture of C. acnes and cytokine production was evaluated before and after addition of the test extracts by RT-PCR and ELISA. The clinical study was conducted in subjects with mild-to-moderate acne who applied the product to their face and upper back twice-daily for 2 months. Cutibacterium acnes-induced IL-6, IL-12p40, IL-10 and TNFα synthesis was reduced by the addition of the Garcinia mangostana extract and oat sap invitro. The clinical study included 54 subjects. The 2-month, twice-daily application of the test product to the whole face and acne-affected areas on the upper back was well tolerated. It led to significant decreases in the number of retentional (-21% for 69% of subjects at D57) and inflammatory (-35% for 79% of subjects at D57) acne lesions, as well as a decrease in Global Acne Evaluation severity scores (2.5 at D1, 2.2 at D29 and 2.1 at D57). The dermatologist also rated the product as effective or very effective in most subjects with PIE (82%; n = 33/40) and PIH (70%; n = 8/11) at D57. The actives demonstrated anti-inflammatory effects invitro, and the dermocosmetic product showed good clinical efficacy and tolerability in subjects with mild-to-moderate acne, supporting the use of this product in acne management.

Iraqi patients with a single-nucleotide polymorphism of interleukin-10 -1082G/A and interleukin-6 -174G/C susceptibility to asthma

The effects of genetic variations in the IL-10 -1082G/A gene and IL-6 -174G/C gene, as well as the genotypes and alleles linked to the prevalence of asthma disease, were investigated using a molecular and immunological study. Between October 2018 and the end of July 2020, 40 healthy individuals (20 females and 20 males) served as a control group for the study, which involved 50 asthmatic patients (31 females and 19 males) at the Allergy Centre, Al-Anbar Teaching Hospital, in Al-Anbar City. The study used the Single Specific Primer-Polymerase Chain Reaction (SSP-PCR) technique to show that the single nucleotide polymorphisms IL-10 -1082G/A and IL-6 -174G/C had a considerably high prevalence rate (P&lt;0.05) among asthma case and that there was an association between the polymorphism and the asthma risk. The findings indicate that asthma patients had considerably higher (P&lt;0.05) IL-10 A alleles and heterozygous GA genotypes (1082G/A) compared to the control group. Genetic variations affecting IL-10 production and the genotypes affecting IL-10 serum levels are associated with the occurrence of asthma and are attributed to the IL-10 -1082G/A promoter gene polymorphism. There was a strong correlation between cytokine levels, of disease development, and the genotypes of the AA and AG genes, indicating that IL-10 -1082A/G predisposition to asthma may be influenced by the gene promoter polymorphism. Asthma development and immunological markers (IL-10) are substantially correlated. One theory links allergic rhinitis to both the development of asthma and its risk. Inducing long-term immunological and clinical tolerance in patients was a good use of HDM immunotherapy. The current study's findings indicate a substantial difference between the asthma patients and the control group in terms of gene type and allele frequency of the IL-6 -174G/C polymorphism. The patients exhibited a higher prevalence of the G allele and the GG homozygous genotype than the control group. Therefore, it was shown that those with GG genotypes had a 2-fold increased probability of having asthma, indicating that patients were more prone to the condition.

Immediate Clinical Complications Occurring During Membrane Change in Patients on Veno-Venous Extracorporeal Membrane Oxygenation.

The clinical tolerance of extracorporeal membrane oxygenation (ECMO) membrane changes in acute respiratory distress syndrome (ARDS) patients under veno-venous ECMO (VV-ECMO) has not been reported. The aim of this study was to describe the tolerance of membrane change. Patients requiring VV-ECMO were retrospectively included between March 2020 and May 2022. In case of membrane dysfunction or an increase in hemolysis markers or an alteration in gas exchange, a membrane change was performed. The primary outcome was a composite measure defined as the occurrence of at least one of the following events within 1 hour of membrane change: severe hypoxemia, hemodynamic collapse, bradycardia, arrhythmia, cardiac arrest, and death. During the study period, 70 patients required a VV-ECMO, 29 (41%) of whom died. Thirty-two patients required a membrane change for a total of 56 changes. The primary outcome occurred for 33 (59%) changes. Arterial desaturation <80% occurred for all complicated membrane changes and cardiac arrest concerned nine changes (16%). Low tidal volume (VT), respiratory system compliance (Crs), PaO2, and high ECMO blood flow (QECMO) were associated with poor tolerance of membrane change. Threshold values of 130 ml for VT, 9.3 cm H2O for Crs, 72 mm Hg for PaO2, and 3.65 L/minute for QECMO best determined the risk of poor tolerance of membrane change.