Little is known about the risk factors for cervical artery dissection (CEAD), a major cause of ischemic stroke (IS) in young adults. Hypertension, diabetes mellitus, smoking, hypercholesterolemia, ...and obesity are important risk factors for IS. However, their specific role in CEAD is poorly investigated. Our aim was to compare the prevalence of vascular risk factors in CEAD patients versus referents and patients who suffered an IS of a cause other than CEAD (non-CEAD IS) in the multicenter Cervical Artery Dissection and Ischemic Stroke Patients (CADISP) study.
The study sample comprised 690 CEAD patients (mean age, 44.2 ± 9.9 years; 43.9% women), 556 patients with a non-CEAD IS (44.7 ± 10.5 years; 39.9% women), and 1170 referents (45.9 ± 8.1 years; 44.1% women). We compared the prevalence of hypertension, diabetes mellitus, hypercholesterolemia, smoking, and obesity (body mass index ≥ 30 kg/m²) or overweightness (body mass index ≥ 25 kg/m² and <30 kg/m²) between the 3 groups using a multinomial logistic regression adjusted for country of inclusion, age, and gender. Compared with referents, CEAD patients had a lower prevalence of hypercholesterolemia (odds ratio 0.55; 95% confidence interval, 0.42 to 0.71; P<0.0001), obesity (odds ratio 0.37; 95% confidence interval, 0.26 to 0.52; P<0.0001), and overweightness (odds ratio 0.70; 95% confidence interval, 0.57 to 0.88; P=0.002) but were more frequently hypertensive (odds ratio 1.67; 95% confidence interval, 1.32 to 2.1; P<0.0001). All vascular risk factors were less frequent in CEAD patients compared with young patients with a non-CEAD IS. The latter were more frequently hypertensive, diabetic, and current smokers compared with referents.
These results, from the largest series to date, suggest that hypertension, although less prevalent than in patients with a non-CEAD IS, could be a risk factor of CEAD, whereas hypercholesterolemia, obesity, and overweightness are inversely associated with CEAD.
IntroductionEpilepsy surgery is the only curative treatment for patients with drug-resistant focal epilepsy. Stereoelectroencephalography (SEEG) is the gold standard to delineate the seizure-onset ...zone (SOZ). However, up to 40% of patients are subsequently not operated as no focal non-eloquent SOZ can be identified. The 5-SENSE Score is a 5-point score to predict whether a focal SOZ is likely to be identified by SEEG. This study aims to validate the 5-SENSE Score, improve score performance by incorporating auxiliary diagnostic methods and evaluate its concordance with expert decisions.Methods and analysisNon-interventional, observational, multicentre, prospective study including 200 patients with drug-resistant epilepsy aged ≥15 years undergoing SEEG for identification of a focal SOZ and 200 controls at 22 epilepsy surgery centres worldwide. The primary objective is to assess the diagnostic accuracy and generalisability of the 5-SENSE in predicting focality in SEEG in a prospective cohort. Secondary objectives are to optimise score performance by incorporating auxiliary diagnostic methods and to analyse concordance of the 5-SENSE Score with the expert decisions made in the multidisciplinary team discussion.Ethics and disseminationProspective multicentre validation of the 5-SENSE score may lead to its implementation into clinical practice to assist clinicians in the difficult decision of whether to proceed with implantation. This study will be conducted in accordance with the Tri-Council Policy Statement: Ethical Conduct for Research Involving Humans (2014). We plan to publish the study results in a peer-reviewed full-length original article and present its findings at scientific conferences.Trial registration numberNCT06138808.
We previously reported a strong IL4I1 gene expression in primary mediastinal B-cell lymphoma (PMBL) and recently identified the protein as a secreted L-phenylalanine oxidase, physiologically ...expressed by myeloid cells, which inhibits T-cell proliferation in vitro. Here, we analyzed the pattern of IL4I1 protein expression in 315 human lymphoid and non-lymphoid malignancies. Besides PMBL, IL4I1 expression in tumors was very frequent. IL4I1 was detected in tumor-associated macrophages from most of the tumors and in neoplastic cells from follicular lymphoma, classic and nodular lymphocyte predominant Hodgkin lymphomas and small lymphocytic lymphoma, three of which are germinal center derived. IL4I1-positive tumor cells were also detected in rare cases of solid cancers, mainly mesothelioma. The enzymatic activity paralleled protein expression, suggesting that IL4I1 is functional in vivo. Depending on the tumor type, IL4I1 may impact on different infiltrating lymphocyte populations with consequences on tumor evolution. In the particular case of follicular lymphoma cells, which are susceptible to antitumor cytotoxic T cells killing but depend on interactions with local T helper cells for survival, a high level of IL4I1 expression seems associated with the absence of bone marrow involvement and a better outcome. These findings plead for an evaluation of IL4I1 as a prognosis factor.
Background: Advanced cutaneous T-cell lymphomas (CTCLs) remain an unmet medical need. Brentuximab vedotin (BV), an anti-CD30 antibody-drug conjugate (ADC) linked to monomethyl auristatin E (MMAE), do ...not deliver significant long-term improvements in patient outcomes. More recently, mogamulizumab and anti-KIR3DL2 provided encouraging results but new targeted therapies are needed. Inducible Co-Stimulator (ICOS), a T-cell costimulatory receptor involved in the development of CTCLs, arouses interest.
Methods: We used immunohistochemistry to study ICOS expression in skin biopsies of 23 patients with early-stage mycosis fungoides (MF), 12 with transformed MF (TMF) and 17 with Sézary Syndrome (SS), at diagnosis or in relapse. Skin samples from 12 patients with B-cell lymphomas, 14 with CD30 + lymphoproliferative disease (LPD), 12 with primary cutaneous CD4+ small/medium T-cell lympho-proliferative disorder and 13 with angioimmunoblastic T-cell lymphoma (AITL) were used as controls. ICOS expression by circulating Sézary cells and regulatory T cells (Tregs) in patients with SS was evaluated using flow cytometry and compared to healthy donors (HD) lymphocytes. In 5 patients with SS, we also analyzed concomitant biopsies from involved nodes.
Then, we investigated the efficacy of anti-ICOS ADCs generated by coupling murine anti-ICOS 314.8 monoclonal antibodies with MMAE and pyrrolobenzodiazepine (PBD), in comparison to BV. We used ICOS + CTCL cell lines (MyLa, MJ and HUT78), murine xenograft models with MyLa and ICOS + Patient Derived Xenografts (PDXs) from patients with SS and AITL.
In order to identify the best anti-ICOS clone that we should develop for a clinical trial, we evaluated the affinity of the antibody on the receptor, the internalization capacity of the antibody using pHAb Reactive Dyes kit (Promega®), and the ability of the antibody to act as an ADC using a secondary conjugate (Mab-ZAP kit, Advanced Targeting Systems®).
Results: ICOS was highly expressed by the cutaneous atypical lymphocytic infiltrates in respectively 61%, 75% and 88% of patients with early-stage MF, TMF and SS, such as in all the involved nodes. Double staining experiments which were performed in both skin and lymph node revealed that ICOS expression appears mainly restricted to neoplastic CD4 + T-cells, with rare ICOS +CD8 + T-cells in the tumor micro-environment. ICOS expression by circulating Sézary cells was strong: 69 ± 7.3% versus 38.8 ± 7.1% of non-tumoral CD4 + cells (p<0.009; CI95%: 8.7-51.6); and 31 ± 3.2% of CD4+ cells in HD (p<0.0001; CI95%: 20.3-46.3). Percentages of ICOS + Tregs were significantly higher in patients with SS than in HD.
In CTCL cell lines, we observed a significant dose-dependent decrease in cell viability in the presence of anti-ICOS-MMAE (IC50 = 8.2ng/mL) and anti-ICOS-PBD (IC50 = 1.2ng/mL) ADCs. In a mouse xenograft model (MyLa), anti-ICOS-MMAE ADCs provided a longer overall survival (OS) than BV (HR=15.2; CI95%: 3.2-71.1; p<0.0006). Finally, in ICOS + PDXs, anti-ICOS-MMAE ADCs significantly improved OS, and reduced the number of tumor cells in the blood, spleen, and bone marrow. No evidence of ADC toxicity was observed in treated mice.
Among 8 different anti-ICOS clones, clone 314.8 had the best affinity on MyLa and MJ cell lines. Clones 53.3, 293.1, 92.17, 88.2 and 279.1 also had good affinity to receptor, whereas clones 145.1 and 121.4 had poor affinity. Using the internalization pHAb reactive dyes kit, we found that clones 314.8, 53.3, 92.17, 88.2 internalized significantly better and faster than the other ones. In order to verify if there is a correlation between internalization capacity and ADC effect, clones 53.3, 92.17 and 145.1 were coupled to MMAE. While anti-ICOS-53.3 and anti-ICOS-92.17 ADCs had similar efficacy to anti-ICOS-314.8 ADCs on MyLa, anti-ICOS 145.1 ADCs resulted in significantly lower cell death. Finally, all clones showed good ability to act as ADCs with Mab-ZAP, excluding clones 279.1, 145.1 and 121.4.
Discussion: ICOS is a promising therapeutic target because it is expressed both by tumor T-cells and regulatory T-cells. We report for the first time the strong and frequent expression of ICOS in CTCLs, as well as the preclinical efficacy of anti-ICOS ADCs on CTCL cell line and PDXs. These results could be extended to the spectrum of follicular variant peripheral T-cell lymphomas.
Conclusion: Collectively, our findings provide the preliminary basis for a therapeutic trial
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Lopez: Emergence Therapeutics: Current holder of individual stocks in a privately-held company. Bagot: Takeda: Membership on an entity's Board of Directors or advisory committees. Olive: ImCheck Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Emergence Therapeutics: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees; Alderaan Biotechnology: Current holder of individual stocks in a privately-held company, Membership on an entity's Board of Directors or advisory committees.
Summary
Long non‐coding RNAs (lncRNAs) comprise a family of non‐coding transcripts that are emerging as relevant gene expression regulators of different processes, including tumour development. To ...determine the possible contribution of lncRNA to the pathogenesis of follicular lymphoma (FL) we performed RNA‐sequencing at high depth sequencing in primary FL samples ranging from grade 1‐3A to aggressive grade 3B variants using unpurified (n = 16) and purified (n = 12) tumour cell suspensions from nodal samples. FL grade 3B had a significantly higher number of differentially expressed lncRNAs (dif‐lncRNAs) with potential target coding genes related to cell cycle regulation. Nine out of the 18 selected dif‐lncRNAs were validated by quantitative real time polymerase chain reaction in an independent series (n = 43) of FL. RP4‐694A7.2 was identified as the top deregulated lncRNA potentially involved in cell proliferation. RP4‐694A7.2 silencing in the WSU‐FSCCL FL cell line reduced cell proliferation due to a block in the G1/S phase. The relationship between RP4‐694A7.2 and proliferation was confirmed in primary samples as its expression levels positively related to the Ki‐67 proliferation index. In summary, lncRNAs are differentially expressed across the clinico‐biological spectrum of FL and a subset of them, related to cell cycle, may participate in cell proliferation regulation in these tumours.
Abstract only
TPS4597
Background: Non-clear cell renal cell carcinomas (nccRCC) account for approximately 25% of RCC patients (pts.). Data on treatment strategies for this heterogenous group of RCC ...are still limited, since most clinical trials focus on clear-cell RCC (ccRCC) histology. Recently combination therapies with immune checkpoint inhibitors (IO, avelumab or pembrolizumab) and tyrosinekinaseinhibitors (TKI) (axitinib) have been approved for treatment in RCC in all International Metastatic RCC Database Consortium (IMDC) risk groups. Additionally nivolumab and ipilimumab (IO/IO) has been approved for treatment in intermediate and high risk pts. showing a significant improvement in overall response rate (ORR), progression free (PFS), and overall survival (OS) compared to sunitinib. Moreover retrospective analysis in nccRCC pts. have shown promising results for IO-based therapies as well in these entities. Methods: In this prospective randomized phase-II multicenter European trial adults with advanced or metastatic nccRCC without prior systemic therapy are eligible. Other key inclusion criteria include: available tumor tissue, Karnofsky >70% and measurable disease per RECIST 1.1. All histological diagnoses are reviewed by a central pathologist. The study plans to randomize ̃306 pts. stratified for papillary or non-papillary non-clear cell histology and by the IMDC risk score. Pts. will be randomized 1:1 to either i) nivolumab 3mg/kg intravenously (IV) plus Ipilimumab 1mg/kg IV every 3 weeks for 4 doses followed by nivolumab fixed dose 240mg IV every 2 weeks or fixed dose 480mg IV every 4 weeks or ii) standard of care therapy according to the approved schedule. Treatment will be discontinued in case of unacceptable toxicity or withdrawal of informed consent. Pts may continue treatment beyond progression, if clinical benefit is achieved and treatment is well tolerated. Primary endpoint is the OS rate at 12 months. Secondary endpoints include OS rate at 6 and 18 months, median OS, PFS, ORR and quality of life. The trial is in progress and 214 patients (132 pts with papillary, 76 pts with non-papillary histology) have been enrolled until now. Clinical trial information: NCT03075423.
Maternal diet during pregnancy and early postnatal life influences the setting up of normal physiological functions in the offspring. Epigenetic mechanisms regulate cell differentiation during ...embryonic development and may mediate gene/environment interactions. We showed here that high methyl donors associated with normal protein content in maternal diet increased the in vitro proliferation rate of neural stem/progenitor cells isolated from rat E19 fetuses. Gene expression on whole hippocampi at weaning confirmed this effect as evidenced by the higher expression of the Nestin and Igf2 genes, suggesting a higher amount of undifferentiated precursor cells. Additionally, protein restriction reduced the expression of the insulin receptor gene, which is essential to the action of IGFII. Inhibition of DNA methylation in neural stem/progenitor cells in vitro increased the expression of the astrocyte-specific Gfap gene and decreased the expression of the neuron-specific Dcx gene, suggesting an impact on cell differentiation. Our data suggest a complex interaction between methyl donors and protein content in maternal diet that influence the expression of major growth factors and their receptors and therefore impact the proliferation and differentiation capacities of neural stem cells, either through external hormone signals or internal genomic regulation.
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