Enhancement of STroke REhabilitation with Levodopa (ESTREL): Rationale and design of a randomized placebo-controlled, double blind superiority trial.

RATIONALE: Novel therapeutic approaches are needed in stroke recovery. Whether pharmacological therapies are beneficial for enhancing stroke recovery is unclear. Dopamine is a neurotransmitter involved in motor learning, reward, and brain plasticity. Its prodrug levodopa is a promising agent for stroke recovery. AIM AND HYPOTHESIS: To investigate the hypothesis that levodopa, in addition to standardized rehabilitation therapy based on active task training, results in an enhancement of functional recovery in acute ischemic or hemorrhagic stroke patients compared to placebo. DESIGN: ESTREL (Enhancement of Stroke REhabilitation with Levodopa) is a randomized (ratio 1:1), multicenter, placebo-controlled, double-blind, parallel-group superiority trial. PARTICIPANTS: 610 participants (according to sample size calculation) with a clinically meaningful hemiparesis will be enrolled ⩽7 days after stroke onset. Key eligibility criteria include (i) in-hospital-rehabilitation required, (ii) capability to participate in rehabilitation, (iii) previous independence in daily living. INTERVENTION: Levodopa 100 mg/carbidopa 25 mg three times daily, administered for 5 weeks in addition to standardized rehabilitation. The study intervention will be initiated within 7 days after stroke onset. COMPARISON: Matching placebo plus standardized rehabilitation. OUTCOMES: The primary outcome is the between-group difference of the Fugl-Meyer-Motor Assessment (FMMA) total score measured 3 months after randomization. Secondary outcomes include patient-reported health and wellbeing (PROMIS 10 and 29), patient-reported assessment of improvement, Rivermead Mobility Index, modified Rankin Scale, National Institutes of Health Stroke Scale (NIHSS), and as measures of harm: mortality, recurrent stroke, and serious adverse events. CONCLUSION: The ESTREL trial will provide evidence of whether the use of Levodopa in addition to standardized rehabilitation in stroke patients leads to better functional recovery compared to rehabilitation alone.

Plain language summary of the FOENIX-CCA2 study: futibatinib for people with advanced bile duct cancer.

WHAT IS THIS SUMMARY ABOUT?: This summary describes the results from a phase 2 study called FOENIXCCA2. The study evaluated treatment with futibatinib in people with a rare form of advanced bile duct cancer called intrahepatic cholangiocarcinoma (or iCCA), where the tumors have changes in the structure of a gene called FGFR2. These changes include FGFR2 gene fusions. Bile duct cancer often returns after surgery or cannot be treated by surgery because the tumor has spread, so it requires treatment with chemotherapy. People live for a median of 1 year after their first chemotherapy treatment and 6 months after their second treatment. This study included people whose cancer had grown/spread after one or more chemotherapy treatments. The aims of the study were to see if futibatinib could shrink the size of tumors and stop the cancer from growing/spreading and to see how long people lived when treated with futibatinib. Clinicians also looked at side effects from taking futibatinib and at how it affected people's quality of life. WHAT WERE THE RESULTS?: Futibatinib treatment shrank tumors in over 80% of people who received treatment. Tumors shrank by at least 30% in 42% of people. Futibatinib stopped tumors from growing/spreading for a median of 9.7 months. People who took the medicine lived for a median of 21.7 months, and 72% of people were still alive after 1 year. Side effects from taking futibatinib were like those reported for similar medicines, and clinicians considered the side effects to be manageable by adjusting the dose of futibatinib or treating the side effects. Most people reported that their quality of life stayed the same or improved during the first 9 months of taking futibatinib. WHAT DO THE RESULTS MEAN?: The results support the use of futibatinib for treating people with advanced bile duct cancer. Based on the results of this study, futibatinib is now approved in the US, Europe, and Japan. Futibatinib is approved for treating adults with advanced bile duct cancer who have received previous treatment for their cancer, and whose tumors have a gene fusion or other change in the FGFR2 gene.Clinical Trial Registration: NCT02052778 (FOENIX-CCA2).

BAT and MAT for diagnosis of peanut allergy: A systematic review and meta-analysis.

Basophil activation test (BAT) or the mast cell activation test (MAT) are two in vitro tests that are currently being studied in food allergy as diagnostic tools as an alternative to oral food challenges (OFCs). We conducted a meta-analysis on BAT and MAT, assessing their specificity and sensitivity in diagnosing peanut allergy. Six databases were searched for studies on patients suspected of having peanut allergy. Studies using BAT or MAT to peanut extract and/or component as diagnostic tools with results given in percentage of CD63 activation were included in this meta-analysis. Study quality was evaluated with the QUADAS-2 tool. On the 11 studies identified, eight focused exclusively on children, while three included a mixed population of adults and children. Only one study provided data on MAT, precluding us from conducting a statistical analysis. The diagnostic accuracy of BAT was higher when stimulated with peanut extract rather than Ara h 2 with a pooled specificity of 96% (95% CI: 0.89-0.98) and sensitivity of 0.86 (95% CI: 0.74-0.93). The sensitivity and specificity of BATs in discriminating between allergic and sensitized patients were studied as well, with pooled analysis revealing a sensitivity of 0.86 (95% CI: 0.74; 0.93) and a specificity of 0.97 (95% CI: 0.94, 0.98). BATs, when stimulated with peanut extracts, exhibit a satisfactory sensitivity and specificity for the diagnosis of peanut allergy and can help to discriminate between allergic individuals and those only sensitized to peanuts. More investigations on the potential for MATs diagnostic methods are warranted.

Can deepfakes be used to study emotion perception? A comparison of dynamic face stimuli.

Video recordings accurately capture facial expression movements; however, they are difficult for face perception researchers to standardise and manipulate. For this reason, dynamic morphs of photographs are often used, despite their lack of naturalistic facial motion. This study aimed to investigate how humans perceive emotions from faces using real videos and two different approaches to artificially generating dynamic expressions - dynamic morphs, and AI-synthesised deepfakes. Our participants perceived dynamic morphed expressions as less intense when compared with videos (all emotions) and deepfakes (fearful, happy, sad). Videos and deepfakes were perceived similarly. Additionally, they perceived morphed happiness and sadness, but not morphed anger or fear, as less genuine than other formats. Our findings support previous research indicating that social responses to morphed emotions are not representative of those to video recordings. The findings also suggest that deepfakes may offer a more suitable standardized stimulus type compared to morphs. Additionally, qualitative data were collected from participants and analysed using ChatGPT, a large language model. ChatGPT successfully identified themes in the data consistent with those identified by an independent human researcher. According to this analysis, our participants perceived dynamic morphs as less natural compared with videos and deepfakes. That participants perceived deepfakes and videos similarly suggests that deepfakes effectively replicate natural facial movements, making them a promising alternative for face perception research. The study contributes to the growing body of research exploring the usefulness of generative artificial intelligence for advancing the study of human perception.

Linguistics-based formalization of the antibody language as a basis for antibody language models.

Apparent parallels between natural language and antibody sequences have led to a surge in deep language models applied to antibody sequences for predicting cognate antigen recognition. However, a linguistic formal definition of antibody language does not exist, and insight into how antibody language models capture antibody-specific binding features remains largely uninterpretable. Here we describe how a linguistic formalization of the antibody language, by characterizing its tokens and grammar, could address current challenges in antibody language model rule mining.

S100A9: The Unusual Suspect Connecting Viral Infection and Inflammation.

The study of S100A9 in viral infections has seen increased interest since the COVID-19 pandemic. S100A8/A9 levels were found to be correlated with the severity of COVID-19 disease, cytokine storm, and changes in myeloid cell subsets. These data led to the hypothesis that S100A8/A9 proteins might play an active role in COVID-19 pathogenesis. This review explores the structures and functions of S100A8/9 and the current knowledge on the involvement of S100A8/A9 and its constituents in viral infections. The potential roles of S100A9 in SARS-CoV-2 infections are also discussed.

Plantar vein thrombosis: 17-year longitudinal study of consecutive patients from a Swiss academic center.

Background: Plantar vein thrombosis (PVT) is a rare condition. Less than 50 cases have been described in the literature. Evidence from interventional and observational studies is sparse or lacking. Objectives: To describe a consecutive cohort of patients diagnosed with PVT at a single academic institution over the past 17 years. Methods: We searched medical charts from patients managed at the University Hospital Zurich between 2005 and 2022. PVT was detected through sonography (eg, in the presence of a noncompressible deep vein) and/or magnetic resonance (eg, a vein with a filling defect on non-contrast-enhanced or contrast-enhanced imaging). The study was approved by the local ethics commission. Results: We identified 45 patients who had been assessed for PVT. After manual check of these cases, we selected 16 patients with a confirmed, objective diagnosis. Median age was 62 (25th-75th percentiles, 46-73) years, and 9 (56%) patients were women. All patients were symptomatic, usually reporting local pain in the foot (100%) and swelling (67%). The most frequent risk factors were cancer (n = 6; 38%) and prior deep vein thrombosis (n = 4; 25%). Overall, 80% of patients received oral anticoagulation and 20% received parenteral anticoagulation for a median of 90 days. Over a median follow-up of 17 months, 2 (12.5%) recurrent venous thromboembolism events were recorded following the discontinuation of anticoagulation. Index vein recanalization occurred in all 15 survivors. One patient died from cancer 2 years after PVT diagnosis. Conclusion: We provided initial information on the clinical characteristics, treatment, and course of PVT, which partly resembles that of distal deep vein thrombosis.

Qualitative evaluation of motives for acceptance or refusal of early palliative care in patients included in early-phase clinical trials in a French comprehensive cancer center: the PALPHA study.

PURPOSE: The integration of palliative care (PC) into oncological management is recommended well before the end of life. It improves quality of life and symptom control and reduces the aggressiveness of end-of-life care. However, its appropriate timing is still debated. Entry into an early-phase clinical trial (ECT) represents hopes for the patient when standard treatments have failed. It is an opportune moment to integrate PC to preserve the patient's general health status. The objective of this study was to evaluate the motives for acceptance or refusal of early PC management in patients included in an ECT. METHODS: Patients eligible to enter an ECT were identified and concomitant PC was proposed. All patients received exploratory interviews conducted by a researcher. Their contents were analyzed in a double-blind thematic analysis with a self-determination model. RESULTS: Motives for acceptance (PC acceptors: n = 27) were both intrinsic (e.g., pain relief, psychological support, anticipation of the future) and extrinsic (e.g., trust in the medical profession, for a relative, to support the advance of research). Motives for refusal (PC refusers: n = 3) were solely intrinsic (e.g., PC associated with death, negative representation of psychological support, no need for additional care, claim of independence). CONCLUSIONS: The motives of acceptors and refusers are not internalized in the same way and call for different autonomy needs. Acceptors and refusers are influenced by opposite representations of PC and a different perception of mixed management.

New evidence for the sensorimotor mismatch theory of weight perception and the size-weight illusion.

The size-weight illusion is a phenomenon where a smaller object is perceived heavier than an equally weighted larger object. The sensorimotor mismatch theory proposed that this illusion occurs because of a mismatch between efferent motor commands and afferent sensory feedback received when lifting large and small objects (i.e., the application of too little and too much lifting force, respectively). This explanation has been undermined by studies demonstrating a separation between the perceived weight of objects and the lifting forces that are applied on them. However, this research suffers from inconsistencies in the choice of lifting force measures reported. Therefore, we examined the contribution of sensorimotor mismatch in the perception of weight in the size-weight illusion and in non-size-weight illusion stimuli and evaluated the use of a lifting force aggregate measure comprising the four most common lifting force measures used in previous research. In doing so, the sensorimotor mismatch theory was mostly supported. In a size-weight illusion experiment, the lifting forces correlated with weight perception and, contrary to some earlier research, did not adapt over time. In a non-size-weight illusion experiment, switches between lifting light and heavy objects resulted in perceiving the weight of these objects differently compared to no switch trials, which mirrored differences in the manner participants applied forces on the objects. Additionally, we reveal that our force aggregate measure can allow for a more sensitive and objective examination of the effects of lifting forces on objects.

Lenvatinib plus pembrolizumab for patients with previously treated advanced ovarian cancer: Results from the phase 2 multicohort LEAP-005 study.

OBJECTIVES: The phase 2, multicohort, open-label LEAP-005 study evaluated lenvatinib plus pembrolizumab in patients with previously treated advanced solid tumors. We report outcomes from the ovarian cancer cohort. METHODS: Eligible patients had metastatic/unresectable ovarian cancer and had received 3 previous lines of therapy. Patients received lenvatinib 20 mg/day plus pembrolizumab 200 mg every 3 weeks. Treatment continued until progression, unacceptable toxicity, or (for pembrolizumab) completion of 35 cycles. Primary endpoints were objective response rate (ORR) per RECIST version 1.1 and safety. Secondary endpoints included duration of response (DOR), progression-free survival (PFS), and overall survival (OS). RESULTS: Thirty-one patients were enrolled. 39% had high grade serous ovarian cancer, 23% were platinum-sensitive, 55% were platinum-resistant, 23% were platinum-refractory, and 84% had tumors that had a PD-L1 combined positive (CPS) score ≥1. ORR (95% CI) was 26% (12%-45%) by investigator assessment and 35% (19%-55%) by blinded independent central review (BICR). Per BICR, median DOR was 9.2 (1.5+ to 37.8+) months. ORRs (95% CI) by BICR were 35% (9/26 patients; 17%-56%) for PD-L1 CPS ≥ 1 disease and 50% (2/4 patients; 7%-93%) for PD-L1 CPS < 1 disease. Median (95% CI) PFS by BICR and OS were 6.2 (4.0-8.5) months and 21.3 (11.7-32.3) months, respectively. Treatment-related AEs occurred in 94% of patients (grade 3-4, 77%). One patient died from treatment-related hypovolemic shock. CONCLUSIONS: Lenvatinib plus pembrolizumab demonstrated antitumor activity as fourth line therapy in patients with advanced ovarian cancer, and no unanticipated safety signals were identified. Responses were observed regardless of PD-L1 status.

Composition and Element Distribution Mapping of γ' and γ″ Phases of Inconel 718 by High-Resolution Scanning Transmission Electron Microscopy and X-ray Energy-Dispersive Spectrometry.

The main strengthening mechanism for Inconel 718 (IN718), a Ni-based superalloy, is precipitation hardening by γ' and γ″ particles. It is thus essential, for good alloy performance, that precipitates with the desired chemical composition have adequate size and dispersion. The distribution of the γ' and γ″ phases and their chemical composition were investigated in the nickel-based Inconel 718 superalloy by taking advantage of the new capabilities of scanning transmission electron microscopy and energy-dispersive X-ray spectrometry using a windowless multiple detector, a high-brightness Schottky electron gun, and a spherical aberration corrector in the illumination probe optics. A small routine was developed to deconvolute the respective compositions of γ' and γ″ nanoprecipitates embedded in the γ matrix. Keeping the electron probe current low enough-a few hundred pA-prevented excessive irradiation damage during the acquisition of element maps and brought their spatial resolution down to the atomic column level to track their element compositions. The present results agree with and complement atomic probe tomography observations and Thermo-Calc predictions from the literature. The presence of an Al enrichment at the γ'/γ″ interface-which may control the γ″ phase coarsening-is observed in the last row of Al-Nb-Ti columns along this interface. In addition, a few columns with similar composition changes are found randomly distributed in the γ' phase.

The Impact of Anti-Amyloid Immunotherapies on Stroke Care.

Anti-amyloid immunotherapies have recently emerged as treatments for Alzheimer's disease. While these therapies have demonstrated efficacy in clearing amyloid-ß and slowing cognitive decline, they have also been associated with amyloid-related imaging abnormalities (ARIA) which include both edema (ARIA-E) and hemorrhage (ARIA-H). Given that ARIA have been associated with significant morbidity in cases of antithrombotic or thrombolytic therapy, an understanding of mechanisms of and risk factors for ARIA is of critical importance for stroke care. We discuss the latest data regarding mechanisms of ARIA, including the role of underlying cerebral amyloid angiopathy, and implications for ischemic stroke prevention and management.

Relationship between electronically monitored adherence to direct oral anticoagulants and ischemic or hemorrhagic events after an initial ischemic stroke-A case control study.

BACKGROUND: Patients with atrial fibrillation (AF) have a high risk for recurrent clinical events after an ischemic stroke. Direct oral anticoagulants (DOAC) are prescribed for secondary prevention. Adherence to DOAC is crucial mainly because of their short elimination half-life. Non-adherence to DOAC can negatively impact patients' outcomes. The relationship between (non-)adherence and recurrent clinical events is unknown in AF patients after initial stroke. We investigated adherence to DOAC in stroke survivors with AF who were included in the MAAESTRO study at the University Hospital Basel, Switzerland, between 2008 and 2022. METHODS: This study is a secondary analysis of data from MAAESTRO with a matched nested case-control design and 1:2 ratio. DOAC intake was measured with a small electronic device (Time4MedTM). We defined two arbitrary intervals of 17 days and 95 days as the longest time spans with electronic monitoring data per patient to maximize the number of participants with adequate amount of observation time available for analysis. Taking and timing adherence were calculated retrospectively i.e., prior to the recurrent event for cases. Trendline analysis of adherence over 95 days was calculated. Linear regression analysis was performed after adjusting for the co-variables age and daily pill burden. Sensitivity analysis was performed with controls for intervals in the reverse direction (prospectively). RESULTS: We analyzed 11 cases and 22 matched controls (mean age: 75.9 ± 9.2 years vs. 73.1 ± 8.4 years; n.s.) with similar stroke characteristics (NIHSS, mRS, MoCA) and 36.4% women in each group. Mean adherence values were high and similar between cases and controls (95 days taking: 87.0 ± 18.9% (cases) vs. 90.8 ± 9.8% (controls), n.s.; similar values for timing adherence). Six hemorrhagic and five ischemic events had occurred. Compared to controls, a significantly higher 95 days taking adherence was observed for hemorrhagic events (96.0 ± 5.0% (cases) vs. 88.1 ± 11.5% (controls); p<0.01) and a significantly lower 95 days taking adherence was observed for ischemic events (75.7 ± 24.8% (cases) vs. 94.2 ± 6.2% (controls), p = 0.024). Values for timing adherence were similar. A non-significant downward linear trend of adherence was observed over 95 days independently of the clinical events. The sensitivity analysis showed that the direction of the interval had negligible impact on the 95 days adherence. CONCLUSION: Because recurrent ischemic events after an AF-related stroke were associated with low adherence to DOAC <76%, adherence enhancing interventions seem crucial in anticoagulated AF-patients. However, AF-patients with high adherence might benefit from a regular re-assessment of the bleeding risk as hemorrhagic complications were associated with adherence to DOAC >96%. TRIAL REGISTRATION: ClinicalTrials.gov NCT03344146.

The impact of the herbicide glyphosate and its metabolites AMPA and MPA on the metabolism and functions of human blood neutrophils and their sex-dependent effects on reactive oxygen species and CXCL8/IL-8 production.

Significant levels of glyphosate, the world's most widely used herbicide, and its primary metabolites, AMPA and MPA, are detected in various human organs and body fluids, including blood. Several studies have associated the presence of glyphosate in humans with health problems, and effects on immune cells and their functions have been reported. However, the impact of this molecule and its metabolites on neutrophils, the most abundant leukocytes in the human bloodstream, is still poorly documented. We isolated neutrophils from human donor blood and investigated the effects of exposure to glyphosate, AMPA, and MPA on viability, energy metabolism, and essential antimicrobial functions in vitro. We observed that neutrophil viability was unaffected at the blood-relevant average concentrations of the general population and exposed workers, as well as at higher intoxication concentrations. Neutrophil energy metabolism was also not altered following exposure to the chemicals. However, while phagocytosis was unaffected, reactive oxygen species generation and CXCL8/IL-8 production were altered by exposure to the molecules. Alterations in function following exposure to glyphosate and metabolites differed according to the sex of the donors, which could be linked to glyphosate's known role as an endocrine disruptor. While ROS generation was increased in both sexes, male neutrophils exposed to glyphosate had increased intracellular production of CXCL8/IL-8, with no effect on female neutrophils. Conversely, exposure to the metabolites AMPA and MPA decreased extracellular production of this chemokine only in female neutrophils, with MPA also increasing intracellular production in male cells exposed to the chemoattractant N-formyl-methionine-leucyl-phenylalanine. Our study highlights the effects of glyphosate and its metabolites on the antimicrobial functions of neutrophils, which could be associated with health problems as future studies provide a better understanding of the risks associated with glyphosate use. Advances in knowledge will enable better and potentially stricter regulations to protect the public.

Assessing the feasibility of statistical inference using synthetic antibody-antigen datasets.

Simulation frameworks are useful to stress-test predictive models when data is scarce, or to assert model sensitivity to specific data distributions. Such frameworks often need to recapitulate several layers of data complexity, including emergent properties that arise implicitly from the interaction between simulation components. Antibody-antigen binding is a complex mechanism by which an antibody sequence wraps itself around an antigen with high affinity. In this study, we use a synthetic simulation framework for antibody-antigen folding and binding on a 3D lattice that include full details on the spatial conformation of both molecules. We investigate how emergent properties arise in this framework, in particular the physical proximity of amino acids, their presence on the binding interface, or the binding status of a sequence, and relate that to the individual and pairwise contributions of amino acids in statistical models for binding prediction. We show that weights learnt from a simple logistic regression model align with some but not all features of amino acids involved in the binding, and that predictive sequence binding patterns can be enriched. In particular, main effects correlated with the capacity of a sequence to bind any antigen, while statistical interactions were related to sequence specificity.

NF-κB subunits RelA and c-Rel selectively control CD4+ T cell function in multiple sclerosis and cancer.

The outcome of cancer and autoimmunity is often dictated by the effector functions of CD4+ conventional T cells (Tconv). Although activation of the NF-κB signaling pathway has long been implicated in Tconv biology, the cell-autonomous roles of the separate NF-κB transcription-factor subunits are unknown. Here, we dissected the contributions of the canonical NF-κB subunits RelA and c-Rel to Tconv function. RelA, rather than c-Rel, regulated Tconv activation and cytokine production at steady-state and was required for polarization toward the TH17 lineage in vitro. Accordingly, RelA-deficient mice were fully protected against neuroinflammation in a model of multiple sclerosis due to defective transition to a pathogenic TH17 gene-expression program. Conversely, Tconv-restricted ablation of c-Rel impaired their function in the microenvironment of transplanted tumors, resulting in enhanced cancer burden. Moreover, Tconv required c-Rel for the response to PD-1-blockade therapy. Our data reveal distinct roles for canonical NF-κB subunits in different disease contexts, paving the way for subunit-targeted immunotherapies.

The NF-κB RelA transcription factor is not required for CD8+ T-cell function in acute viral infection and cancer.

CD8+ T cells are critical mediators of pathogen clearance and anti-tumor immunity. Although signaling pathways leading to the activation of NF-κB transcription factors have crucial functions in the regulation of immune responses, the CD8+ T cell-autonomous roles of the different NF-κB subunits, are still unresolved. Here, we investigated the function of the ubiquitously expressed transcription factor RelA in CD8+ T-cell biology using a novel mouse model and gene-edited human cells. We found that CD8+ T cell-specific ablation of RelA markedly altered the transcriptome of ex vivo stimulated cells, but maintained the proliferative capacity of both mouse and human cells. In contrast, in vivo experiments showed that RelA deficiency did not affect the CD8+ T-cell response to acute viral infection or transplanted tumors. Our data suggest that in CD8+ T cells, RelA is dispensable for their protective activity in pathological contexts.

A New Tool to Identify Pediatric Patients with Atypical Diabetes Associated with Gene Polymorphisms.

Background: Recent diabetes subclassifications have improved the differentiation between patients with type 1 diabetes mellitus (T1DM) and type 2 diabetes mellitus despite several overlapping features, yet without considering genetic forms of diabetes. We sought to facilitate the identification of monogenic diabetes by creating a new tool that we validated in a pediatric maturity-onset diabetes of the young (MODY) cohort. Methods: We first created the DIAgnose MOnogenic DIAbetes (DIAMODIA) criteria based on the pre-existing, but incomplete, MODY calculator. This new score is composed of four strong and five weak criteria, with patients having to display at least one weak and one strong criterion. Results: The effectiveness of the DIAMODIA criteria was evaluated in two patient cohorts, the first consisting of patients with confirmed MODY diabetes (n=34) and the second of patients with T1DM (n=390). These DIAMODIA criteria successfully detected 100% of MODY patients. Multiple correspondence analysis performed on the MODY and T1DM cohorts enabled us to differentiate MODY patients from T1DM. The three most relevant variables to distinguish a MODY from T1DM profile were: lower insulin-dose adjusted A1c score ≤9, glycemic target-adjusted A1c score ≤4.5, and absence of three anti-islet cell autoantibodies. Conclusion: We validated the DIAMODIA criteria, as it effectively identified all monogenic diabetes patients (MODY cohort) and succeeded to differentiate T1DM from MODY patients. The creation of this new and effective tool is likely to facilitate the characterization and therapeutic management of patients with atypical diabetes, and promptly referring them for genetic testing which would markedly improve clinical care and counseling, as well.

Xevinapant Combined with Pembrolizumab in Patients with Advanced, Pretreated, Colorectal and Pancreatic Cancer: Results of the Phase Ib/II CATRIPCA Trial.

PURPOSE: Xevinapant is an orally available inhibitor of apoptosis proteins (IAP) inhibitor. Preclinical data suggest that IAP antagonism may synergize with immune checkpoint blockers by modulating the NFκB pathway in immune cells. PATIENTS AND METHODS: Adult patients with non-high microsatellite instability advanced/metastatic pancreatic ductal adenocarcinoma (PDAC) or colorectal cancer were enrolled in this phase Ib/II study and received pembrolizumab 200 mg every 3 weeks intravenously, and ascending doses of oral xevinapant (100, 150, and 200 mg daily for 14 days on/7 days off). Dose escalation followed a 3+3 design with a 21-day dose-limiting toxicity (DLT) evaluation period. Following the determination of the recommended phase II dose (RP2D), 14 patients with PDAC and 14 patients with colorectal cancer were enrolled in expansion cohorts to assess preliminary efficacy. RESULTS: Forty-one patients (26 males) with a median age of 64 years were enrolled: 13 in the dose escalation and 28 in the two expansion cohorts. No DLT was observed during dose escalation. The RP2D was identified as xevinapant 200 mg/day + pembrolizumab 200 mg every 3 weeks. The most common adverse events (AE) were fatigue (37%), gastrointestinal AE (decreased appetite in 37%, nausea in 24%, stomatitis in 12%, and diarrhea and vomiting in 10% each), and cutaneous AE (pruritus, dry skin, and rash seen in 20%, 15%, and 15% of patients, respectively). The best overall response according to RECIST1.1 was partial response (confirmed) in 1 (3%), stable disease in 4 (10%), and progressive disease in 35 (88%). CONCLUSIONS: Xevinapant combined with pembrolizumab was well tolerated with no unexpected AEs. However, antitumor activity was low.