FLT3-directed UniCAR T-cell therapy of acute myeloid leukaemia.

Adaptor chimeric antigen receptor (CAR) T-cell therapy offers solutions for improved safety and antigen escape, which represent main obstacles for the clinical translation of CAR T-cell therapy in myeloid malignancies. The adaptor CAR T-cell platform 'UniCAR' is currently under early clinical investigation. Recently, the first proof of concept of a well-tolerated, rapidly switchable, CD123-directed UniCAR T-cell product treating patients with acute myeloid leukaemia (AML) was reported. Relapsed and refractory AML is prone to high plasticity under therapy pressure targeting one single tumour antigen. Thus, targeting of multiple tumour antigens seems to be required to achieve durable anti-tumour responses, underlining the need to further design alternative AML-specific target modules (TM) for the UniCAR platform. We here present the preclinical development of a novel FMS-like tyrosine kinase 3 (FLT3)-directed UniCAR T-cell therapy, which is highly effective for in vitro killing of both AML cell lines and primary AML samples. Furthermore, we show in vivo functionality in a murine xenograft model. PET analyses further demonstrate a short serum half-life of FLT3 TMs, which will enable a rapid on/off switch of UniCAR T cells. Overall, the presented preclinical data encourage the further development and clinical translation of FLT3-specific UniCAR T cells for the therapy of AML.

[Development of a chatbot (conversational app) for cataract surgery patients]. / Développement d'un chatbot (agent conversationnel) pour les patients en parcours de chirurgie de la cataracte.

INTRODUCTION: The goal of this study was to create and promote a type of chatbot or conversational app, for patients who need cataract surgery and to evaluate its acceptability. METHODS: Multicentric prospective clinical study in two phases. Phase I : distribution of a questionnaire of 20 questions (evaluating patients' knowledge about cataracts and cataract surgery and their expectations in terms of patient education). Statistical analysis was performed through factorial analysis with factor rotation and Cronbach's alpha calculation. Phase II : creation of a chatbot with a repertoire of question-answer sets. An acceptability analysis was performed using a second questionnaire inspired by the « SUS Score ¼. RESULTS: One hundred and six initial questionnaires were collected. The patients were mostly women (56.6 %), aged 60 to 79 years (81 %), retired (77.4 %), with no high school diploma (33.0 %), had never used a chatbot before (95.3 %) and were accustomed to using a smartphone (66.0 %). Patients evaluated their knowledge about cataracts as insufficient (51.8 %) and felt the need to receive additional information (81.1 %). The comprehensibility score of the first questionnaire was 91 (middle school level). The baseline data of the chatbot was composed of 316 questions with a median comprehensibility score of 101 (middle school level). The first test of the chatbot included 18 patients. The median connection time was 4min and 40seconds (standard deviation 6.6). The median of number of questions asked for each connection was 6.5 (standard deviation 6.7). Acceptability was good, with a mean Sus Score of 78.6/100 (standard deviation 11.9). CONCLUSION: This study shows the importance of information for cataract surgery patients. The creation of a chatbot for patients undergoing cataract surgery appears to be relevant in achieving this goal.

[First- and second-line hospital management of ophthalmologic emergencies: Clinical pathway study of 1360 patients]. / Prise en charge des urgences ophtalmologiques en premier et second recours hospitaliers : analyse du parcours de 1360 patients.

The general practitioner (GP) might offer a good alternative for the management of certain ophthalmologic emergencies in his or her practice, given the increasing demand for ophthalmological care and difficulties with access to ophthalmologists. The main objective of the study was to describe ophthalmological complaints and their management in general emergency departments compared to ophthalmological emergency departments in order to assess which pathologies can be treated by the GP. This was a single-center retrospective study at the University Hospital of Reims, based on consultation data from the general and ophthalmological emergency departments for all adult patients presenting for an ophthalmological problem in September 2019 and September 2020. Consultations where patients were brought back following a first emergency consultation and consultations for another non-ophthalmological reason were excluded. Out of 1360 consultations recorded, 16% of patients had initially consulted their GP. The 4 most frequent diagnoses were: "ocular trauma," "conjunctivitis," "eye pain" and "visual impairment." A prescription for medication was issued in 77% of cases, 37% of which were for antibiotics. Only 29% of consultations carried out in general emergency departments led to a request for a complementary ophthalmology consultation. The GP might therefore be able to manage certain ophthalmological emergencies in his or her practice as a first line and refer certain ophthalmologic emergencies. However, the training of GPs in this specialty must be reinforced in collaboration with ophthalmologists.

[Setting up Objective Structured Clinical Examination (OSCE) in ophthalmology]. / Mise en place des examens cliniques objectifs structurés (ECOS) facultaires en ophtalmologie.

Obective Structured Clinical Examinations (OSCE) are a reproducible and objective way to evaluate medical students and have been used for many years in English-speaking countries, Canada and Switzerland. They evaluate candidates more on the basis of their practical skills, know-how and interpersonal skills than on their theoretical knowledge. From a nationally validated, limited list of typical clinical situations, stations are set up by the teaching team with standardized patients played by actors, designed to test a variety of problem solving, technical, diagnostic, therapeutic, communication, examination, and history taking skills, possibly with simulation tools. Setting up a station, as well as creating an OSCE cycle with several stations through which the candidates rotate, requires significant preparation prior to the examination: creating the station scenario with precise instruction sheets for the candidates, simulated patients and evaluators, multiple stages of proofreading, verifying the required equipment and adapting rating scales. OSCEs seek to evaluate students "objectively," as they are the only variable in this type of examination, in which the scripts, materials and rating scales have been standardized to limit subjectivity. This examination method is a flagship measure of the reform of the second cycle of French medical studies. OSCEs are now part of the testing modalities for the 2021-2022 academic year and will be integrated into the National Dematerialized Examination (NDE) starting in May 2023. They may also be useful in validating the achievements of students and residents in various stages of training, as well as in continuing medical education (CME). We present herein the key elements of these new evaluation tools and their practical applications in the evaluation of students in ophthalmology.

[Retrospective evaluation of residencies in private ophthalmology practice from 2015 to 2018 in Champagne-Ardenne]. / Évaluation rétrospective de stages d'interne d'ophtalmologie en cabinet libéral de 2015 à 2018 en Champagne-Ardenne.

INTRODUCTION: Between 2010 and 2018, the quota for admission to ophthalmology residencies increased by 50 % (106 in 2010 vs 150 in 2018). In order to accommodate this increasing number of residents, the University Hospital of Reims formulated an agreement with the Regional Health Agency in May 2015 enabling certain ophthalmologists in the private sector to train a resident within their private practice for a semester. We will present the results of three and one half years of this experience. METHODS: Two retrospective questionnaires were created and completed. One was addressed to the host supervisor, the other to the resident. Their objective was to evaluate and standardize the experience from both points of view. The following aspects were explored: the extent to which the environment was welcoming, the resident's clinical ability and progress, the resident's surgical ability and progress, time-management, resident-patient relations and respective assessments. We also requested information on the number of residents hosted by each private practice as well as the positive and negative aspects of the internship for both the supervisor and the intern. RESULTS: Between May 2015 and October 2018 (seven semesters), 12 residents from the University Hospital of Reims did an internship with one of the six proposed private sector ophthalmologists in the Champagne-Ardennes region. The residents were between their second and eighth semesters of professional training. Seven residents did their first or second semester of ophthalmology training in a private practice. The survey results led to the conclusion of a positive experience for both trainer and trainee regarding the progress made by the resident, both clinically and surgically. CONCLUSION: Given the growing number of ophthalmology residents and the limits of the training capacity of hospital-based residencies, private sector internships with practitioners actively involved in teaching increase the training capacity for residents and complement the conventional hospital training.

Approche diagnostique et thérapeutique de la vasculopathie polypoïdale choroïdienne. Recommandations de la Fédération France Macula.

PURPOSE: To update the medical literature on the diagnostic and therapeutic approach to polypoidal choroidal vasculopathy (PCV) and to propose a treatment algorithm in agreement with French market approval, supported by the France Macula Federation (FFM). METHODS: Literature review and expert opinion. RESULTS: The diagnosis of PCV is based on multimodal imaging, including indocyanine green angiography (ICGA), which is considered the gold standard for the diagnosis of PCV. Regarding the therapeutic management of PCV, the FFM recommends treating PCV first-line either by monotherapy with intra-vitreal anti-vascular endothelial growth factor (anti-VEGF) injections, or by a combined treatment of photodynamic therapy (PDT) with Verteporfin and intra-vitreal anti-VEGF injections, depending on the location of the PCV.

[Is Holladay 2 formula acurate enough for calculating intraocular lens power in non-standard eyes?] / Intérêt de la formule Holladay 2 dans le calcul de la puissance de l'implant intraoculaire pour les yeux de biométrie hors normes.

PURPOSE: To evaluate the benefit of the Holladay 2 formula versus the 3rd generation formulae in calculating the IOL power in eyes with non-standard axial length or keratometry before cataract surgery. PATIENTS: Retrospectiv study from January to December 2015. The inclusion critaeria were axial length (AL) <22mm or >26mm, or average keratometry <42 D or >46 D, dividing the patients in 4 groups respectively. The 7 parameters required to calculate the Holladay 2 formula were collected. The final refractive result was turned into spherical equivalent to calculate the optimal power retrospectively. Then, the results obtained using the other formulae were compared with the optimal IOL power. RESULTS: One hundred and twenty-six eyes operated by two surgeons were included. In the high AL group (n=32), the SRK/T was the most accurate formula; regarding the low AL group (n=36), the Hoffer Q and Holladay 2 formulae performed better; for the steep cornea group (n=27), the Hoffer Q, Haigis, Holladay 1 and 2 formulae were not different; last, the Holladay 1 and 2 were more accurate in the flat cornea group (n=33). CONCLUSION: In our study, the Holladay 2 formula does not seem to be better than the others for calculating IOL power in non-standard eyes. Preoperative eye features in such non-standard cases should be taken into account before the surgery to choose the more suitable formula.

Pituitary apoplexy and rivaroxaban.

Pituitary apoplexy (PA), defined by the occurrence of a massive hemorrhagic necrotic rearrangement within a pituitary adenoma, is rare. Its occurrence can be associated with certain risk factors, including anticoagulation. We report the first case of PA with rivaroxaban which is one of the new oral anticoagulants: a 73 year-old patient presenting with severe headache and visual field deterioration. Surgery was performed. Radiotherapy treatment was decided three months after surgery because of tumor residue.

[Diagnostic and therapeutic contribution of microbiological analysis in severe microbial keratitis at Reims University Hospital between 2012 and 2014]. / Apport diagnostique et thérapeutique des prélèvements microbiologiques des abcès de cornées avec critères de gravité au CHU de Reims entre 2012 et 2014.

PURPOSE: To investigate the contribution of microbial analysis in the diagnosis and management of severe microbial keratitis. MATERIAL AND METHOD: This is a monocentric retrospective study at the University Hospital of Reims from January 2012 to December 2014. Corneal scrapings with infectious keratitis were subjected to routine bacterial and fungal culture. PCR was also performed to detect various viral DNA (VZV, CMV, EBV, HSV 1 & 2, adenovirus) and Acanthamoeba sp. DNA. All contact lens cases were analyzed if available. RESULTS: One hundred and six patients were hospitalized, including 30 contact lens wearers (28.3%). Sixty-four bacterial cultures were positive (68%). Twenty-five different bacterial species were identified with a majority of gram-positive bacteria (67.92%). Among contact lens wearers, the initial VA was better than non-wearers (P=0.0004) and 37% of bacteria identified (a plurality) were gram positive. Of 11 contact lens case analyzed, in only one case (3.3%) did the result correlate with the corneal culture. Only 9 samples from the 323 viral DNA extractions and real time PCR were positive (2.8%); 7 were HSV1. No prior antiviral therapy had been started. Fungal culture was positive in 2 of the 97 corneal samples taken and 63.6% of the contact lens cases (7/11 cases). Only one of the 40 Acanthamoeba sp. PCR's was positive. CONCLUSION: The systematic performance of microbiological investigations is a good diagnostic approach given the polymorphism of clinical presentations of corneal ulcers, which can sometimes be extremely misleading. Culture of contact lens cases appears ineffective for the detection and determination of the causative microorganism. The high incidence of Staphylococcus in bacterial keratitis and the prevalence of infections with gram-positive bacteria in contact lens wearers were noted.

Switching CAR T cells on and off: a novel modular platform for retargeting of T cells to AML blasts.

The adoptive transfer of CD19-specific chimeric antigen receptor engineered T cells (CAR T cells) resulted in encouraging clinical trials in indolent B-cell malignancies. However, they also show the limitations of this fascinating technology: CAR T cells can lead to even life-threatening off-tumor, on-target side effects if CAR T cells crossreact with healthy tissues. Here, we describe a novel modular universal CAR platform technology termed UniCAR that reduces the risk of on-target side effects by a rapid and reversible control of CAR T-cell reactivity. The UniCAR system consists of two components: (1) a CAR for an inert manipulation of T cells and (2) specific targeting modules (TMs) for redirecting UniCAR T cells in an individualized time- and target-dependent manner. UniCAR T cells can be armed against different tumor targets simply by replacement of the respective TM for (1) targeting more than one antigen simultaneously or subsequently to enhance efficacy and (2) reducing the risk for development of antigen-loss tumor variants under treatment. Here we provide 'proof of concept' for retargeting of UniCAR T cells to CD33- and/or CD123-positive acute myeloid leukemia blasts in vitro and in vivo.

[Adult orbital tumors]. / Tumeurs de l'orbite de l'adulte.

Orbital tumors are a rather frequent pathology. Their diagnosis and treatment may be difficult. They can be benign or malignant. All the tissues of the orbit can give rise to a tumor, resulting in their large number. Among the benign tumors, we have meningiomas and cavernous hemangiomas, and for the malignant tumors, lymphomas, metastasis, ENT tumors and lacrimal gland tumors in the adult. Usually the signs are nonspecific, with proptosis, oculomotor disturbance, inflammatory signs, pain and sometimes a mass. Imaging (CT, MRI and color Doppler ultrasound) shows the tumor, its location, extent and possible metastases. Biopsy and anatomic and cytopathologic examination confirm the type of benign or malignant tumor. Based on these three elements: clinical appearance, imaging and histology, the tumor will be treated, usually by a surgical approach according to the recommendations of a multidisciplinary tumor conference. Radiation therapy and chemotherapy may supplement the treatment.

Bispecific antibody releasing-mesenchymal stromal cell machinery for retargeting T cells towards acute myeloid leukemia blasts.

Bispecific antibodies (bsAbs) engaging T cells are emerging as a promising immunotherapeutic tool for the treatment of hematologic malignancies. Because their low molecular mass, bsAbs have short half-lives. To achieve clinical responses, they have to be infused into patients continously, for a long period of time. As a valid alternative we examined the use of mesenchymal stromal cells (MSCs) as autonomous cellular machines for the constant production of a recently described, fully humanized anti-CD33-anti-CD3 bsAb, which is capable of redirecting human T cells against CD33-expressing leukemic cells. The immortalized human MSC line SCP-1 was genetically modified into expressing bsAb at sufficient amounts to redirect T cells efficiently against CD33 presenting target cells, both in vitro and in an immunodeficient mouse model. Moreover, T cells of patients suffering from acute myeloid leukemia (AML) in blast crisis eliminated autologous leukemic cells in the presence of the bsAb secreting MSCs over time. The immune response against AML cells could be enhanced further by providing T cells an additional co-stimulus via the CD137-CD137 ligand axis through CD137L expression on MSCs. This study demonstrates that MSCs have the potential to be used as cellular production machines for bsAb-based tumor immunotherapy in the future.

[Tonometric response to acetazolamide in patients with retinal detachment]. / Réponse tonométrique à l'acétazolamide dans le décollement de rétine.

INTRODUCTION: Acetazolamide reduces intraocular pressure and stimulates absorption of subretinal fluid by the retinal pigment epithelium. Recording the intraocular pressure response to systemic acetazolamide might enable an indirect evaluation of retinal pigment epithelial carbonic anhydrase. METHODS: The intraocular pressure response to a standardized dose of intravenous acetazolamide (5mg/kg) was evaluated in a "case" group of 15 patients undergoing retinal detachment (RD) surgery and in a control group of 15 patients undergoing epiretinal membrane peeling. Intraocular pressure was measured with a handheld Perkins tonometer in a supine position before (t-2 min) and after the intravenous administration of acetazolamide (t+2 min, t+6 min, t+10 min and t+30 min). The mean variation of the intraocular pressure was compared between the two groups in the non-operated eye at each time point. RESULTS: A significant reduction of the intraocular pressure was observed in both groups at 2, 6 and 10 minutes (P<0.01) after the injection of acetazolamide (5mg/kg). The reduction was significantly lower in the group of patients who underwent retinal detachment surgery when compared with the group of patients in whom epiretinal membrane peeling had been performed. This difference remained significant up to 10 minutes (P<0.01 at t=2, 6 and 10 min). At t=30 min, the intraocular pressure reduction was comparable in both groups. DISCUSSION: The vitreous plays a fundamental role in the pathogenesis of retinal detachment via peripheral traction. However, since not all tears lead inevitably to retinal detachment, there must also be adherence factors which can prevent the latter. The response to acetazolamide differs significantly in patients undergoing retinal detachment surgery compared with patients treated with epiretinal membrane peeling. In the occurrence of retinal detachment, deficient photoreceptor adherence to the retinal pigment epithelium has been hypothesized. Further research should aim to correlate the tonometric response to acetazolamide with photoreceptor adherence.