Rachid Abbas

Innovations méthodologiques dans le cycle de développement des médicaments avec l'avènement de l'immunothérapie: L'avènement de l'immunothérapie ciblée a posé d'importants défis aux méthodes conventionnelles de recherche en développement de médicaments. En combinant l'expertise clinique à la maîtrise statistique, nous avons élaboré des solutions analytiques novatrices pour surmonter les obstacles pratiques rencontrés dans des programmes d'essais cliniques impliquant des traitements d'immunothérapie ciblée dans plusieurs domaines thérapeutiques. L'émergence des inhibiteurs de points de contrôle en oncologie a remis en question le paradigme établi dans les études de recherche de dose, qui supposait une augmentation monotone de la toxicité avec les niveaux de dose. En réponse, nous avons conçu un nouveau schéma expérimental de recherche de dose qui ne nécessite pas de préciser à priori l'ordre des niveaux de dose. À travers un nombre important de simulations englobant divers scénarios présentant des relations dose-toxicité monotones et non-monotones, notre approche a montré sa supériorité, en particulier dans les scénarios déviant de la monotonicité. Avec le développement rapide des traitements par immunothérapie ciblée, nous préconisons l'exploration de schémas expérimentaux pouvant s'accommoder de relation dose-toxicité non monotones pour assurer un processus de sélection de doses plus efficace. Le profil de tolérance favorable des immunothérapies ciblées a accéléré les phases précoces du développement de médicaments, entraînant une pléthore de candidats médicaments nécessitant une évaluation d'efficacité dans des essais cliniques de phase II. Pour les tumeurs rares avec des environnements immunitaires complexes, comme l'ostéosarcome, un des défis est de pouvoir étudier de nombreuses cibles moléculaires potentielles alors que les cas incidents sont rares. Pour accélérer ces essais de phase II, nous avons introduit un nouveau schéma expérimental exploitant des données contrôle historiques et utilisant des règles adaptatives. Ce schéma expérimental utilise un critère de survie et permet la fermeture précoce des bras de traitement les moins efficaces lors des analyses intermédiaires. Nos travaux de simulation ont validé sa capacité à contrôler adéquatement le taux d'erreur de type I global et à améliorer la puissance empirique. En exploitant les données de contrôle historiques et des critères de survie, ce schéma expérimental innovant présente une stratégie prometteuse pour améliorer l'efficacité des essais d'immuno-oncologie de phase II. Une des limites des immunothérapies ciblées est l'apparition d'une réaction immunitaire dirigée contre le traitement. Ces évènements survenant après la randomisation nécessitent d'être analysés de façon appropriée car ils ont le potentiel de compromettre l'intégrité de l'essai. L'addendum ICH-E9R1 a diffusé le concept des estimands qui permettent de mieux aborder ces évènements. En s'appuyant sur ce cadre pour l'analyse principale d'un essai pivot dans la maladie d'Alzheimer, nous avons conçu une stratégie robuste pour traiter les événements intercurrents, englobant à la fois les événements liés au traitement ou non, soutenue par une méthode innovante d'analyse des données manquantes. Malgré les défis liés à la définition et à la classification des événements intercurrents, nous avons démontré les bénéfices des estimands, offrant des informations précieuses pour les prochains essais. Le développement de médicaments efficaces contre la maladie d'Alzheimer est un des principaux défis de l'industrie pharmaceutique. Afin d'améliorer l'exploitation des données des essais pivots, nous proposons d'utiliser l'émulation d'essais. En émulant des essais cibles évaluant des doses de traitement optimales, notre approche a fourni des estimations robustes avec une précision améliorée et un biais réduit par rapport à des analyses naïves. Notre étude souligne les avantages de l'émulation d'essais pour enrichir l'interprétation des données d'essais cliniques et le travail de préparation des prochains essais.

Purpose: Describe clinical characteristics and outcome of Li–Fraumeni syndrome (LFS)‐associated osteosarcomas. Methods: TP53 germline pathogenic/likely pathogenic variant carriers diagnosed with osteosarcoma in France between 1980 and 2019 were identified via the French Li–Fraumeni database at Rouen University Hospital. Sixty‐five osteosarcomas in 52 patients with available clinical and histological data were included. The main clinical characteristics were compared with data from National Cancer Institute's SEER (Surveillance, Epidemiology, and End Results) for patients of the same age group. Results: Median age at first osteosarcoma diagnosis was 13.7 years (range: 5.9–36.7). Compared to unselected osteosarcomas, LFS‐associated osteosarcomas occurred more frequently in patients less than 10 years of age (23% vs. 9%), and when compared with osteosarcomas in patients less than 25 years were characterized by an excess of axial (16% vs. 10%) and jaw sites (15% vs. 3%) and histology with predominant chondroblastic component and periosteal subtypes (17% vs. 1%). Metastases incidence (25%) was as expected in osteosarcomas. After the first osteosarcoma treatment, the rate of good histologic response (62%) and the 5‐year progression‐free survival (55%, 95% confidence interval [CI]: 42.6−71.1) were as expected in unselected series of osteosarcomas, whereas the 5‐year event‐free survival was 36.5% [95% CI: 25.3−52.7] due to the high incidence of second malignancies reaching a 10‐year cumulative risk of 43.4% [95% CI: 28.5−57.5]. Conclusion: In osteosarcoma, young age at diagnosis, axial and jaw sites, histology with periosteal or chondroblastic subtype, and synchronous multifocal tumors should prompt suspicion of a germline TP53 mutation. Standard treatments are effective, but multiple malignancies impair prognosis. Early recognition of these patients is crucial for tailored therapy and follow‐up.

Purpose : Describe clinical characteristics and outcome of Li-Fraumeni-associated osteosarcomas. Methods : TP53 germline pathogenic/likely pathogenic variant carriers diagnosed with osteosarcoma in France between 1980 and 2019 were identified via the French Li-Fraumeni database at Rouen University Hospital. Sixty-five osteosarcomas in 52 patients with available clinical and histological data were included. The main clinical characteristics were compared with data from the SEER (National Cancer Institute’s Surveillance, Epidemiology, and End Results) for patients of the same age group. Results : Median age at first osteosarcoma diagnosis was 13.7 years (range:5.9-36.7). Compared to unselected osteosarcomas, LFS-associated osteosarcomas occurred more frequently in patients TP53 mutation. Standard treatments are effective, but multiple malignancies impair prognosis. Early recognition of these patients is crucial for tailored therapy and follow-up.

Background: Previous studies have shown that neutrophil‐to‐lymphocyte (NLR) ratio at diagnosis and early lymphocytes recovery on doxorubicin‐based chemotherapy, may impact the outcome in patients with osteosarcoma (OST). This study aimed to evaluate the prognostic value of hemogram parameters in patients with OST treated with high‐dose methotrexate and etoposide/ifosfamide (M‐EI) chemotherapy. Materials and methods: We retrospectively analyzed the prognostic value of various hemogram parameters at diagnosis and during therapy in a large consecutive cohort of patients with OST included in the French OS2006 trial and treated with M‐EI chemotherapy. Results: A total of 164 patients were analyzed. The median age was 14.7 years (interquartile range [IQR]: 11.7–17). Median follow‐up was 5.6 years (IQR: 3.3–7.7 years). Three‐year event‐free survival (EFS) and overall survival (OS) were 71.5% (95% confidence interval [CI]: 64%–78%) and 86.4% (95% CI: 80%–91%), respectively. In univariate analysis, blood count parameters at diagnosis and early lymphocyte recovery at Day 14 were not found prognostic of survival outcomes. By contrast, an increase of NLR ratio at Day 1 of the first EI chemotherapy (NLR‐W4) was associated with reduced OS in univariate ( p = .0044) and multivariate analysis (hazards ratio [HR] = 1.3, 95% CI: 1.1–1.5; p = .002), although not with EFS. After adjustment on histological response and metastatic status, an increase of the ratio NLR‐W4 of 1 was associated with an increased risk of death of 30%. Conclusions: We identified NLR‐W4 as a potential early biomarker for survival in patients with OST treated with M‐EI chemotherapy. Further studies are required to confirm the prognostic value of NLR and better identify immune mechanisms involved in disease surveillance.

Monoclonal antibodies that target amyloid-beta (Aβ) have the potential to slow cognitive and functional decline in persons with early Alzheimer's disease. Gantenerumab is a subcutaneously administered, fully human, anti-Aβ IgG1 monoclonal antibody with highest affinity for aggregated Aβ that has been tested for the treatment of Alzheimer's disease. We conducted two phase 3 trials (GRADUATE I and II) involving participants 50 to 90 years of age with mild cognitive impairment or mild dementia due to Alzheimer's disease and evidence of amyloid plaques on positron-emission tomography (PET) or cerebrospinal fluid (CSF) testing. Participants were randomly assigned to receive gantenerumab or placebo every 2 weeks. The primary outcome was the change from baseline in the score on the Clinical Dementia Rating scale-Sum of Boxes (CDR-SB; range, 0 to 18, with higher scores indicating greater cognitive impairment) at week 116. A total of 985 and 980 participants were enrolled in the GRADUATE I and II trials, respectively. The baseline CDR-SB score was 3.7 in the GRADUATE I trial and 3.6 in the GRADUATE II trial. The change from baseline in the CDR-SB score at week 116 was 3.35 with gantenerumab and 3.65 with placebo in the GRADUATE I trial (difference, -0.31; 95% confidence interval [CI], -0.66 to 0.05; P = 0.10) and was 2.82 with gantenerumab and 3.01 with placebo in the GRADUATE II trial (difference, -0.19; 95% CI, -0.55 to 0.17; P = 0.30). At week 116, the difference in the amyloid level on PET between the gantenerumab group and the placebo group was -66.44 and -56.46 centiloids in the GRADUATE I and II trials, respectively, and amyloid-negative status was attained in 28.0% and 26.8% of the participants receiving gantenerumab in the two trials. Across both trials, participants receiving gantenerumab had lower CSF levels of phosphorylated tau 181 and higher levels of Aβ42 than those receiving placebo; the accumulation of aggregated tau on PET was similar in the two groups. Amyloid-related imaging abnormalities with edema (ARIA-E) occurred in 24.9% of the participants receiving gantenerumab, and symptomatic ARIA-E occurred in 5.0%. Among persons with early Alzheimer's disease, the use of gantenerumab led to a lower amyloid plaque burden than placebo at 116 weeks but was not associated with slower clinical decline. (Funded by F. Hoffmann-La Roche; GRADUATE I and II ClinicalTrials.gov numbers, NCT03444870 and NCT03443973, respectively.).

Introduction To evaluate the density of conjunctival goblet cells (GCs) from in vivo confocal microscopy (IVCM) and impression cytology (IC) and mucin expression in ten glaucomatous patients treated with preservative-free latanoprost (Monoprost®) Methods Ten glaucomatous patients (10 eyes) were enrolled. Conjunctiva was examined clinically and morphologically by IVCM and IC. Both IVCM and IC were performed at baseline, and after the 1st and 4th month of Monoprost® therapy. GC density (GCD) in cells⁄mm2 was the main outcome measurement. Results At baseline, mean GCD was 147+/-78 cells/mm2 for IVCM and 114+/-62 cells/mm2 for IC GCD. At month one, mean GCD was 149+/-69 and 120+/-56 measured with IVCM and IC, respectively (p=0.31 for IVCM and p=0.40 for IC). At month four, GCD increased to 162+/-81 and 134+/-61 measured with IVCM and IC, respectively (p=0.02 for IVCM and p=0.02 for IC). Conclusion Treatment with preservative-free (PF) latanoprost was associated with an increase in conjunctival GCD in glaucomatous eyes. Further studies are mandatory to verify this finding because its validation may have important consequences in the medical management of glaucoma.

Background: Ewing sarcoma (ES) is a rare and aggressive pediatric cancer. Numerous studies have attempted to identify new prognostic biomarkers. The predictive value of serum LDH and CRP has not been clearly described, to date. Methods: The objective of our retrospective study was to investigate the prognostic value of LDH and CRP levels and their association with overall survival in a series of ES patients. Results: Between 2004 and 2019, 89 ES patients were included. In a univariable analysis, high levels of LDH and CRP were associated with the worst prognosis. In a multivariable analysis, only higher LDH values remained associated with a lower survival. The high-LDH-level group experienced all 21 deaths registered in our population (24%) and about 90% of disease progressions. The 5-year overall survival was 66.4% in the high-LDH-level group, while no deaths were observed in the low-LDH-level group. The 5-year progression-free survival was 57.9% in the high-LDH-level group versus 80.4% in the low-LDH-level group. Conclusions: In our study, LDH levels at diagnosis were strongly correlated with the prognosis, and they might be considered a prognostic factor in Ewing sarcoma. The LDH value, along with its very low cost and its reproducibility in almost all centers, make it suitable as a potential prognostic biomarker in clinical practice.

The occurrence of cancer in newborns within the first 28 days of life is uncommon, with different clinical presentation from other age groups. Prenatal diagnosis is reported in about half of patients, while a genetic predisposition condition is supposed. The management of a newborn with cancer can be challenging and needs to be tailored according to the histology and the primary tumor site; surgery represents the main strategy, while chemotherapy should be considered with caution because of the higher toxicity and mortality due to different pharmacokinetics in neonates compared to older children. We describe the first Italian series over a 15-year period of patients affected by both benign and malignant neoplastic diseases diagnosed within the first 28 days of life; 74 newborns were diagnosed with neonatal tumors, representing 1.5% of the cancer population in the same period, and a prevalence of germ cell tumors (55%) and neuroblastoma (16%) was observed. Surgery was performed on 80% of patients, while chemotherapy was necessary for about 20% of patients. The 5-year overall survival (OS) exceeded 90%; treatment-related deaths are a major concern, representing 80% of overall deaths. A genetic/syndromic condition was detected in 16% of the population; additionally, a cancer predisposition syndrome (CPS) was identified in about 10% of patients. According to our experience, all newborns affected by cancer should warrant genetic counselling and a screening test for CPS.

Phase II immuno‐oncology clinical trials screen for efficacy an increasing number of treatments. In rare cancers, using historical control data is a pragmatic approach for speeding up clinical trials. The drop‐the‐losers design allows dropping off ineffective arms at interim analyses. We extended the original drop‐the‐losers design for a time‐to‐event outcome using a historical control through the one‐sample log‐rank statistic. Simulated trials featured three arms at the first stage, one at the second stage, nine scenarios, eight sample sizes with 5%‐ and 10%‐ nominal family‐wise error rate (FWER). A numerical algorithm is provided to solve power calculations at the design stage. Our design was compared with a group of three independent single‐arm trials (fixed design) with and without correction for multiplicity. Our design allowed strict control of the FWER at nominal levels while the misspecification of survival distribution and fixed design inflated the FWER up to three times the nominal level. The empirical power of our design increased with the sample size, the treatment effect and the number of effective treatments and dropped when more patients were recruited at the second stage. The fixed design with correction showed comparable power, while our design advantageously included more patients to the most promising arm. Recommendations for future applications are given. By taking advantage of the use of historical control data and a time‐to‐event outcome, the drop‐the‐losers design is a promising tool to meet the challenge of improving phase II clinical trials in immuno‐oncology.

In anaplastic lymphoma kinase (ALK)‐positive anaplastic large cell lymphoma (ALK+ ALCL), positive minimal residual disease (MRD+) after the first chemotherapy course was proven of strong prognostic significance. We aimed to validate these results in 138 French patients. Eighty‐seven patients had a detectable minimal disseminated disease at diagnosis (MDD+). Early MRD assessment was performed in 33 of 87 patients and was positive in 18 and negative in 15 (MRD−). Three‐year progression‐free survival was significantly correlated with the MDD/MRD status: 81.1% in MDD−, 69.6% in MDD+/MRD−, and 15.2% in MDD+/MRD+ patients. In conclusion, we confirmed on an independent cohort that the MDD/MRD status has strong prognosis significance in ALK+ ALCL.