Hebron University

We aim to inform the design of new diffusion MRI (dMRI) approaches for microvasculature quantification that enhance the biological specificity of imaging towards cancer. We adopted simulation-informed modelling of the vascular dMRI signal. We synthesised signals from 1500 synthetic vascular networks, for a variety of protocols (flow-compensated [FC], non-compensated [NC], hybrid), featuring different samplings and diffusion times. We estimated the number of independent, recoverable signal degrees of freedom in presence of noise (signal-to-noise ratio of 5), and ranked 12 microvascular metrics depending on the quality of their estimation. Lastly, we demonstrated the feasibility of estimating the top-ranking metrics on 3T dMRI of a healthy volunteer and of a metastatic colorectal cancer (CRC) patient. Both NC and FC synthetic vascular signals exhibited complex behaviour as, for example, non-zero kurtosis and diffusion time dependence. Two independent degrees of freedom appeared recoverable from directionally-averaged vascular signals (SNR of 5). Mean volumetric flow rate and an Apparent Network Branching (ANB) index maximised correlations between ground truth and estimated values in silico. In the patient, both and detected re-vascularisation after 3 months of targeted therapy against liver metastases, consistently with Intra-Voxel Incoherent Motion (IVIM) metrics. Simulation-based modelling of the vascular dMRI signal suggests and as the most promising metrics for tissue microvasculature characterisation. Their estimation in vivo appears feasible to capture general trends, and demonstrates contrasts that are biologically plausible, encouraging their usage in future studies.

Sustained seizure freedom without intolerable adverse events is the main goal of epilepsy treatment, but may be challenging to achieve for some patients, particularly following the failure of multiple anti-seizure medications (ASMs). A majority of days without seizures is another important clinical outcome that can lead to meaningful improvement in quality of life. The objective of this post-hoc analysis was to evaluate the percentage of seizure-free days by responder groups during the open-label extension (OLE) of study C017 with a focus on patients who achieved near-seizure freedom that was sustained during the duration of the study (≥ 90%-< 100% responders group). The study also evaluated retention rates and the impact of concomitant antiseizure medications. Study C017 (NCT01866111) was a double-blind, randomized, placebo-controlled, dose-response trial evaluating adults 18-70years old who were taking 1-3 concomitant ASMs. Participants completed the 18-week double-blind treatment period and entered the OLE. This post-hoc analysis quantified the proportion of seizure-free days by responder category and by number and type of concomitant ASMs. The occurrence and severity of treatment-emergent adverse events during the OLE were also reported. Sixty (16.9%) of the 354 study participants were≥90%-< 100% responders (median age 42.5years, 46.7% [n=28] female, median number of concomitant ASMs at baseline was 2). The study population also included 91 (25.7%) patients who were≥50%-< 75% responders, 62 (17.5%) patients who were≥75%-< 90% responders, and 13 (3.7%) patients who were 100% responders. The median duration of cenobamate exposure was 5.6years for the≥90%-< 100% responders; 1.8years for the non-responders; 5.5years for the≥50%-< 75% responders; 5.5years for the≥75%-< 90% responders; and 5.6years for the 100% responders. The percentage of seizure-free days during the entire OLE was 97.9% in the≥90%-< 100% responder group, compared to 93.5% in the≥75%-< 90% group and 83.9% in the≥50%-< 75% group. The number and mechanism of action of concomitant ASMs did not meaningfully impact the proportion of days without seizures. The percentage of days with seizures in the≥90%-< 100% responder group declined from 33.2% at baseline to 1.2% at Year 5. At Year 5, the≥90%-< 100% responder group had a high retention rate (90%). The most commonly occurring adverse events were dizziness, somnolence, and headache. Participants taking cenobamate who achieved≥90%-< 100% responder rates were seizure-free for nearly 98% of days during the 5years of the OLE. These results suggest that a high reduction of seizure burden can be achieved and maintained by many people with epilepsy taking cenobamate.

RET fusions appear in 1%-2% of non-small cell lung cancers (NSCLCs). The results from the ARROW study (ClinicalTrials.gov identifier: NCT03037385) supported US Food and Drug Administration approval of pralsetinib, an oral selective RET inhibitor, for metastatic RET-altered NSCLC and RET fusion-positive thyroid cancers. ARROW was a phase I/II open-label study of pralsetinib 400 mg once daily in RET fusion-positive NSCLCs. Coprimary end points were overall response rate (ORR) and safety. Key secondary end points included duration of response, progression-free survival, and overall survival (OS). At data lock (May 20, 2024), 281 patients initiated pralsetinib (median treatment duration, 15.0 months). ORR (measurable disease patients; n = 259) was 78% (95% CI, 69 to 86) for treatment-naïve patients and 63% (95% CI, 54 to 71) for prior platinum-based chemotherapy patients. Median OS was 44.3 months (95% CI, 30.9 to 53.1), 50.1 months (95% CI, 28.3 to not reached) in treatment-naïve patients, and 39.7 months (95% CI, 27.8 to 53.2) in prior platinum patients. Common grade ≥3 treatment-related adverse events were anemia (21%), hypertension (15%), and decreased neutrophils (13%). Three treatment-related deaths occurred (pneumonia, n = 2; interstitial lung disease and rhabdomyolysis, n = 1 each). Safety was consistent with previous ARROW reports; no hypersensitivity was reported in patients receiving prior immunotherapies. Pralsetinib produced robust, durable responses with manageable safety in treatment-naïve and previously treated patients with RET fusion-positive NSCLCs, confirming previous findings with longer follow-up.

The CALYPSO study demonstrated activity of savolitinib and durvalumab in MET-driven papillary renal cancer (PRC). We report final efficacy outcomes and exploratory circulating tumor DNA (ctDNA) biomarker analysis. This single-arm phase II study evaluated savolitinib and durvalumab in treatment-naïve or pretreated PRC. End points included overall response rate (ORR), progression-free survival (PFS), and overall survival (OS). FoundationOne CDx assessed DNA alterations and MET/PD-L1 or MET/tumor mutational burden (TMB) copositivity. ctDNA collected at baseline and on treatment was correlated with outcomes. At 41-months median follow-up, ORR was 34% (95% CI, 20.0 to 51.0) in the intention-to-treat (ITT) population (N = 41) and 53% (95% CI, 28.0 to 77.0) in MET-driven patients (n = 17). Median PFS was 6.5 (95% CI, 2.7 to 12.0) versus 13.9 months (95% CI, 2.9 to 23.8), and OS was 18.3 (95% CI, 7.3 to 30.7) versus 27.4 months (95% CI, 9.3 to 37.4), in the ITT population and the MET-driven population, respectively. PD-L1 (66% positive) and TMB (median 2.5 mut/Mb) status did not correlate with response. Baseline ctDNA positivity (10/21) correlated with shorter OS (median 7.3 v 33.3 months), while ctDNA clearance and mean variant allele frequency reduction correlated with improved OS (median 31.3 v 7.2 and 31.3 v 15.5 months, respectively). Savolitinib plus durvalumab shows OS in MET-driven PRC, supporting the ongoing SAMETA RIII trial (ClinicalTrials.gov identifier: NCT05043090). ctDNA may be a useful predictive biomarker.

Amyand’s hernia defined as the presence of the appendix within an inguinal hernia sac, is rare in neonates and can deteriorate quickly. We report a preterm male twin (33 + 6 weeks; 1460 g) presenting at 1 month with 24 hours of progressive right inguinoscrotal swelling, erythema, irritability, and absent stooling. Exam showed a tender, nonreducible, non-transilluminating mass with abdominal distension. X-ray revealed dilated bowel loops; ultrasound suggested an indirect right inguinal hernia containing an inflamed appendix. Urgent inguinal exploration found incarcerated viable cecum and a gangrenous appendix. Appendectomy through the same incision with high sac ligation and posterior wall repair (no mesh) was performed. Recovery was uneventful: feeds resumed, weight gain continued, and the ipsilateral testis remained viable. This Type 2 Amyand’s hernia shows localized vascular compromise of the appendix in preterm infants and supports immediate targeted ultrasound and prompt surgery to avert perforation, sepsis, and gonadal injury.

Malaria remains a major cause of morbidity and mortality in Angola, where Plasmodium falciparum accounts for most infections. The widespread use of artemether-lumefantrine (AL) as first-line treatment and sulfadoxine-pyrimethamine (SP) for intermittent preventive treatment in pregnancy (IPTp) exerts selective pressure on local parasite populations. Molecular surveillance of drug resistance markers is essential to monitor susceptibility and anticipate changes that may influence treatment and prevention strategies. This study analyzed pfk13, pfmdr1, pfdhfr, and pfdhps polymorphisms in P. falciparum isolates from Cubal, Benguela province, to assess parasite genetic evolution under AL and SP pressure. A cross-sectional study was conducted between 2022 and 2023 at Hospital Nossa Senhora da Paz (Cubal). A total of 139 real-time PCR-confirmed P. falciparum infections were included. Dried blood spot samples underwent sequencing of the genes involved in resistance. Mutation and haplotype frequencies associated with antimalarial resistance were determined. Among 120 pfk13 sequences, mutations were detected in 12 isolates (10%), including five nonsynonymous variants, but none corresponded to validated or candidate markers of artemisinin resistance. In pfmdr1 (100 sequences), Y184F was the most prevalent mutation (43%), N86Y was rare (1%), and D1246Y was not detected. Seven additional pfmdr1 variants were identified. Of the 101 isolates correctly sequenced for pfdhfr/pfdhps, 77.2% carried the triple pfdhfr N51I/C59R/S108N mutation. In pfdhps, A437G was nearly fixed (98%), K540E showed moderate prevalence (23.8%), and A581G was absent. The most common pfdhps haplotypes were ISGKAA (64.4%) and ISGEAA (22.8%). Combined pfdhfr/pfdhps profiles classified 58.4% of isolates as "partially resistant" (IRNG) and 17.8% as "fully resistant" (IRNGE), with no "super-resistant" haplotypes. Additional single mutations not associated with SP resistance were also detected. This study provides an updated molecular profile of antimalarial resistance in a rural area of Angola. No validated or candidate pfk13 markers of artemisinin resistance were identified. However, the predominance of pfmdr1 haplotypes linked to reduced lumefantrine susceptibility raises concerns regarding AL efficacy. Although SP remains suitable for IPTp, the presence of the "fully resistant" haplotype (IRNGE) of pfdhfr/pfdhps highlight potential risks to long-term effectiveness. These findings reinforce the need for integrated molecular surveillance and periodic therapeutic efficacy studies to guide malaria control policies in rural Angola.