[CAR-T cells therapy in solid tumors : where are we now ?] / Les CAR-T cells dans le traitement des tumeurs solides : où en sommes-nous ?

Chimeric antigen receptor T cells (also known as CAR-T cells) have already made their way into the therapeutic arsenal of specific hematological cancers, significantly improving the prognosis of patients. The prospect of such an innovative and effective treatment in solid tumors is very attractive. For this reason, several clinical studies have been initiated. Unfortunately, the antigenic heterogeneity and microenvironmental hostility of these solid tumors currently limit the effectiveness of CAR-T cells. New strategies are being sought to counteract these therapeutic obstacles.

Les lymphocytes T porteurs d'un récepteur antigénique chimérique, appelés CAR-T cells, ont déjà fait leur chemin dans l'arsenal thérapeutique de certains cancers hématologiques, améliorant significativement le pronostic des patients. La perspective d'un tel traitement, aussi innovant qu'efficace, dans les tumeurs solides est très attrayante. C'est la raison pour laquelle plusieurs études cliniques ont vu le jour. Malheureusement, l'hétérogénéité antigénique et l'hostilité micro-environnementale de ces tumeurs solides limitent actuellement l'efficacité des CAR-T cells. De nouvelles stratégies sont recherchées pour contrer ces obstacles thérapeutiques.

[Acute and chronic graft-versus-host disease after allogeneic hematopoietic stem cell transplantation]. / Maladie du greffon contre l'hôte aiguë et chronique après allogreffe de cellules souches hématopoïétiques.

Acute and/or chronic graft-versus-host disease (GVHD) is a serious complication after allogeneic hematopoietic stem cell transplantation (alloHSCT). It is a multisystemic inflammatory and/or fibrotic disease that occurs when the immune cells derived from the graft (and therefore originating from the donor) recognize recipient's healthy tissues as foreign and react against them. Acute GVHD is one of the main causes of non-relapse mortality after alloHSCT. Chronic GVHD can be very disabling in its severe form and can also be responsible for late mortality, mainly due to long-term immune deficiency and opportunistic infections. In contrast, GVHD can be associated with certain beneficial effects in patients transplanted for hematological malignancies, through simultaneous «graft versus tumour¼ positive effects. Therefore, one of the challenges of alloHSCT is the prevention and treatment of severe forms of GVHD without losing the beneficial anti-tumour effects of the graft.

: La maladie du greffon contre l'hôte («greffe-versus-hôte¼, GVH) aiguë et/ou chronique est une complication sérieuse de l'allogreffe de cellules souches hématopoïétiques (CSH). Elle correspond à des manifestations inflammatoires et/ou fibrotiques multisystémiques qui se produisent lorsque les cellules immunitaires dérivées de la greffe (et donc originaires du donneur) reconnaissent les tissus sains du receveur comme étrangers et réagissent contre eux. La GVH aiguë est l'une des principales causes de mortalité hors rechute post-greffe. La GVH chronique peut être très invalidante dans sa forme sévère et peut également être responsable d'une mortalité tardive, principalement due à un déficit immunitaire à long terme et à des infections opportunistes. À l'opposé, la GVH est associée à certains effets bénéfiques chez les patients transplantés pour des hémopathies malignes, par les effets simultanés favorables du «greffon contre la tumeur¼. Par conséquent, l'un des défis de l'allogreffe de CSH est la prévention et le traitement des formes sévères de GVH, sans perdre les effets bénéfiques anti-tumoraux du greffon.

[Cellular immunotherapy at the University Hospital of Liege : advances, challenges and prospects]. / Immunothérapie cellulaire au CHU de Liège : avancées, défis et perspectives.

Cellular immunotherapy consists in using the cells of the immune system as a therapeutic weapon. In this constantly evolving field, the therapeutic strategies developed at the University Hospital of Liege are hematopoietic stem cell transplantation, mesenchymal stromal cells and targeted therapy with CAR-T cells (Chimeric Antigen Receptor T cells). The first two modalities represent a form of non-targeted cell therapy that has been developed over the past decades. While hematopoietic stem cell transplantation is established as the reference treatment for many hematological diseases, mesenchymal stromal cells are still under investigation in various pathologies (notably Crohn's disease, organ transplantation, COVID-19 and pulmonary fibrosis). By contrast, CAR-T cells represent a recently developed and extremely promising targeted immunotherapy. This therapeutic approach has already revolutionized the treatment of B-cell lymphopathies, and has the potential to do the same for many other diseases in the near future.

L'immunothérapie cellulaire consiste en l'utilisation de cellules du système immunitaire comme arme thérapeutique. Dans ce domaine en évolution constante, les stratégies thérapeutiques développées au CHU de Liège sont la greffe de cellules souches hématopoïétiques, les cellules stromales mésenchymateuses et la thérapie ciblée par cellules CAR-T («Chimeric Antigen Receptor T cells¼). Les deux premières approches représentent une forme de thérapie cellulaire non ciblée, développées depuis de nombreuses années. Si la greffe de cellules souches hématopoïétiques est établie comme le traitement de référence de nombreuses hémopathies, les cellules stromales mésenchymateuses sont, quant à elles, toujours à l'étude dans diverses pathologies (notamment maladie de Crohn, transplantation d'organes, COVID-19 et fibrose pulmonaire). À l'opposé, les cellules CAR-T représentent une immunothérapie ciblée, développée récemment et extrêmement prometteuse. Cette modalité thérapeutique a déjà révolutionné le traitement des lymphopathies B, et elle possède le potentiel d'en faire de même pour de nombreuses autres pathologies dans un avenir proche.

[Allogeneic hematopoietic stem cell transplantation : general principles and recent progress]. / Allogreffes de cellules souches hématopoïétiques Principes généraux et progrès récents.

Hematopoietic stem cell transplantation is a potentially curative therapeutic option for many oncologic and non-oncologic hematological diseases. There is a constant evolution regarding donor choice, conditioning regimen intensity and immunosuppressive treatments, which leads to a reduction in morbidity and mortality during and after transplantation. In this article, we describe the general principles of hematopoietic stem cell transplantation and discuss the progress of global patient management after transplantation.

L'allogreffe de cellules souches hématopoïétiques constitue un traitement potentiellement curatif pour de nombreuses pathologies hématologiques cancéreuses ou non cancéreuses. Une évolution constante dans le choix du donneur, de l'intensité du conditionnement et des stratégies de traitements immunosuppresseurs, permet une réduction de la morbidité et de la mortalité durant et après la greffe. Cet article a pour but de réexpliquer les principes généraux d'une allogreffe et de discuter des nouvelles avancées et adaptations dans la prise en charge globale des patients greffés.

[Diffuse large B-cell lymphoma: a revolutionary treatment based on genetically-modified immune cells called CAR T cells]. / Le lymphome diffus à grandes cellules B : nouveau traitement révolutionnaire par des cellules immunitaires génétiquement modifiées appelées «CART cells¼.

Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of non-Hodgkin lymphoma. Firstline immunochemotherapy cures approximatively 60 % of patients. The prognosis of patients with refractory disease or with relapsed disease within the first two years after the end of treatment is highly unfavourable. Since June 2019, a new third-line treatment with CAR T cells (chimeric antigen receptor T cells) seems to completely modify the prognosis of these patients. A significant proportion of long-lasting complete responses is obtained with this revolutionary treatment. Quick specialized intervention is required for the unique side effects of this therapy.

Le lymphome B diffus à grandes cellules (LBDGC) est le type histologique de lymphome non Hodgkinien le plus fréquent. Le traitement de première ligne par immunochimiothérapie ne permet de guérir qu'environ 60 % des patients. Les patients présentant une maladie réfractaire à une première ligne de traitement ou en rechute dans les deux premières années suivant le traitement présentent un mauvais pronostic. Disponible depuis juin 2019, un nouveau traitement de 3ème ligne sous forme d'immunothérapie par CAR T cells (acronyme anglais de «chimeric antigen receptor T cells¼) semble modifier complètement le pronostic de ces patients, avec l'obtention d'une proportion importante de réponses complètes de longue durée. Les effets indésirables spécifiques liés à ce traitement demandent une prise en charge rapide et spécialisée.

Living with HIV at the time of its normalization: a routine experience for women?

To meet the objective of ending the AIDS pandemic in 2030, screening and access to antiretroviral treatments (ARV) must be extended in Africa. This in turns requires that people agree to be screened and treated. Since the beginning of the epidemic, however, the stigmatization of people persons living with HIV (PlHIV) has been a major obstacle in the battle against HIV/AIDS. Despite a substantial reduction in its prevalence over the past 20 years in Burkina Faso, its stigma remains high. The objective of this study is to characterize the local expression of stigmatization in this country towards these women to help to combat it. The method used a long-term ethnographic survey that combined observations of the setting and qualitative interviews of 40 women - both seronegative and seropositive. The results show the appearance of a sort of normalization of HIV/AIDS because the bioclinical effects of the infection are less serious and less visible than they were before ARV. The social effects of the disease nonetheless continue to constitute a threat, or at least they are so perceived by both seropositive and seronegative women. Although less visible, stigmatization persists and constrains seropositive women to use strategies to withdraw from some social spaces to protect themselves. PlHIV active in community associations play an essential role in this setting. They help women to keep their stigmata "under control" and play a role in its normalization by helping to moderate representations of HIV/AIDS and the people who have it.

Ethics of health research partnerships in Global South : PhD students in learning.

In view of the worldwide epidemic processes that require and result in simultaneous research in several countries and in an increasingly more structured scientific community, especially in countries of Global South, it is essential to establish partnerships between researchers, policy-makers, local supervisors, and communities in both the North and the South. The objectives of this essay are to: 1) present the context and issues linked to research in the framework of a North-South partnership; 2) describe the development of appropriate responses to improve consideration of ethical aspects; and 3) discuss the current role of young researchers in this era of multiple partnerships and share the observations and thoughts of PhD students in one research unit.

Response to antiviral therapy in haematopoietic stem cell transplant recipients with cytomegalovirus (CMV) reactivation according to the donor CMV serological status.

Pre-emptive antiviral treatment efficiently prevents occurrence of cytomegalovirus (CMV) disease in allogeneic stem cell transplant recipients. However, successive treatment courses can be necessary. The current study was aimed at determining factors that could influence the response to antiviral treatment, in particular the donor CMV serostatus. A total of 147 consecutive CMV-seropositive recipients (R+) were included and prospectively monitored for 6 months after transplantation. Reactivation of CMV occurred in 111 patients, 61 of 78 with a CMV-positive donor (D+) and in 50 of 69 with a CMV-negative donor (D-) (p 0.45). Baseline viral loads and initial viral doubling times did not differ between D+/R+ and D-/R+. Fifteen D+/R+ and four D-/R+ had self-resolving CMV infections. A total of 92 patients received antiviral treatment and 81 (88%) had a significant decrease in CMV load under therapy. Repeated CMV episodes were observed in 67% of those and were significantly more frequent in D-/R+ than in D+/R+ (p <0001). Half-life of CMV under treatment was significantly longer in D-/R+ than in D+/R+. Treatment failure observed in eight recipients was associated with low leucocyte count at reactivation onset, and was significantly more frequent in D-/R+ (six patients) than in D+/R+ (two patients) (p <0.0001). CMV strains resistant to antivirals were found in two D-/R+. Donor CMV serostatus influenced neither CMV reactivation occurrence nor the kinetics of CMV DNA load in the early phase of CMV replication but had a significant impact on response to antiviral therapy. Virological drug-resistance remained rare.

[Allogeneic hematopoietic stem cell transplantation: what is the upper age limit?]. / Allogreffe de cellules souches hématopoïétiques chez le patient agé: jusqu' a quel age?

In the last decades, the upper age limit for allogeneic hematopoietic cell transplantation has increased from 50-60 years to 70-75 years of age, in part due to the development of allogeneic transplantation following reduced-intensity or truly nonmyeloablative conditioning. This review describes challenges and opportunities of allogeneic hematopoietic cell transplantation in the elderly.

Spontaneous pneumomediastinum caused by bleomycin-induced pneumonitis.

We report the case of a 24-yr-old woman treated for lymphoma who developed bleomycin-induced interstitial pneumonia. This interstitial pneumonia was complicated by spontaneous pneumomediastinum. Pneumomediastinum is an unfrequent side effect of high dose bleomycin-induced pneumonitis (BIP) and we describe the first case occurring with low-dose of bleomycin.

[How to explore a fever of unknown origin in adult patients?]. / Une fièvre d'origine indéterminée chez le patient adulte?

Fever of unknown origin (FUO), with more than 200 potential causes, can represent a real diagnostic challenge. For the work-up of FUO, the first step is to pay attention to each element revealed by a detailed history, a complete physical examination and by some basic diagnostic tests. These elements may constitute some clues that can guide the physician for the prescription of further appropriate diagnostic examinations and procedures. If there is no real specific clues,a pet-scan seems to be useful for the work-up of FUO.

[Chronic graft-versus-host disease: a multidisciplinary approach]. / Maladie du greffon contre l'hôt chronique: une prise en charge multidisciplinaire.

Chronic Graft-Versus-Host Disease (GVHD) is a frequent complication of allogeneic hematopoietic cell transplantation. This review article describes recent advances in the classification and treatment of chronic GVHD.

[Obsessive compulsive disorder (OCD)]. / Trouble obsessionnel-compulsif (TOC).

Obsessive compulsive disorder (OCD) is a frequent and disabling psychic illness. Along psychiatric history, several etiological models have been successively hypothesized to explain the obsessive compulsive symptoms from a psychological, behavioural or biological point of view. This review aims at presenting OCD etiological models as well as describing OCD clinical and therapeutic aspects.

[Cerebral venous thrombosis (CVT)]. / ..... la thrombose veineuse cerebrale (TVC).

Cerebral venous thrombosis is a rare cause of stroke. Clinical presentation is not very specific and can be very variable. Imaging establishes the diagnosis in the majority of cases. Specially, magnetic resonance venography has high sensitivity and is presently the gold standard. Long term prognosis of cerebral venous thrombosis is generally good and few patients remain handicapped in the long term. Evolution is however unpredictable. Treatment strategies follow three axes: anti-thrombotic treatment, symptomatic measures and treatment of the cause if one is found.

[The electroconvulsive therapy in 2008]. / L'électroconvulsivothérapie en 2008.

Electroconvulsive therapy (formerly called sismotherapy, electronarcosis or shock therapy) is a therapeutic tool used in several psychiatric illnesses. It consists in the induction of a generalized convulsive seizure by a transcranial electric stimulation. If it is true that this tool continues to stigmatise the collective imagination in giving rise to dread and suspicion (considered by some people as a barbarian or obsolete therapy), it is however an effective (sometimes irreplaceable) and well tolerated treatment. Over the last decades, ECT has generated renewed interest in psychiatric therapy. It constitutes today the oldest biological therapeutic tool still in use in psychiatry.

Liver mitochondrial properties from the obesity-resistant Lou/C rat.

OBJECTIVE: The first objective was to evaluate the influence of caloric intake on liver mitochondrial properties. The second objective was aimed at determining the impact of increasing fat intake on these properties. DESIGN: Lou/C rats, displaying an inborn low caloric intake and resistant to diet-induced obesity, were compared to Wistar rats fed either ad libitum or pair-fed. An additional group of Lou/C rats were allowed to increase their fat intake by adjusting their diet from a standard high carbohydrate low-fat diet to a high-fat carbohydrate-free diet. MEASUREMENTS: Hydrogen peroxide (H(2)O(2)) generation, oxygen consumption rate (J(O(2))), membrane potential (DeltaPsi), activity of respiratory chain complexes, cytochrome contents, oxidative phosphorylation efficiency (OPE) and uncoupling protein 2 (UCP2) expression were determined in liver mitochondria. RESULTS: H(2)O(2) production was higher in Lou/C than Wistar rats with glutamate/malate and/or succinate, octanoyl-carnitine, as substrates. These mitochondrial features cannot be mimicked by pair-feeding Wistar rats and remained unaltered by increasing fat intake. Enhanced H(2)O(2) production by mitochondria from Lou/C rats is due to an increased reverse electron flow through the respiratory-chain complex I and a higher medium-chain acyl-CoA dehydrogenase activity. While J(O(2)) was similar over a large range of DeltaPsi in both strains, Lou/C rats were able to sustain higher membrane potential and respiratory rate. In addition, mitochondria from Lou/C rats displayed a decrease in OPE that cannot be explained by increased expression of UCP2 but rather to a slip in proton pumping by cytochrome oxidase. CONCLUSIONS: Liver mitochondria from Lou/C rats display higher reactive oxygen species (ROS) generation but to deplete upstream electron-rich intermediates responsible for ROS generation, these animals increased intrinsic uncoupling of cytochrome oxidase. It is likely that liver mitochondrial properties allowed this strain of rat to display higher insulin sensitivity and resist diet-induced obesity.

Mitochondrial H2O2 production is reduced with acute and chronic eccentric exercise in rat skeletal muscle.

Oxidative stress with acute/chronic exercise has been so far examined using exercise involving a combination of concentric and eccentric contractions, but skeletal muscles are likely to be injured to a greater extent by pliometric contractions. In the present study, the effects of acute and chronic bouts of downhill running exercise on mitochondrial hydrogen peroxide (H2O2) generation (fluorimetric detection of a dimer with homovanillic acid in presence of horseradish peroxidase) and oxygen consumption in conjunction with antioxidant enzymes activity were examined. The results show that acute eccentric exercise was accompanied by a significantly reduced mitochondrial H2O2 production that is likely due to a decrease in complex I of the electron transport chain (ETC). On the other hand, eccentric training leads to positive adaptations, reflected by a higher citrate synthase activity and decreased mitochondrial H2O2 production. The decrease in mitochondrial H2O2 cannot be attributed to alterations in antioxidant capacities but rather to changes in mitochondrial membrane composition characterized by an increased polyunsaturated to saturated fatty acids ratio, and decreased contents in arachidonic acid and plasmalogens. These results suggest that changes in mitochondrial membrane properties with eccentric training can affect H2O2 production by muscle mitochondria. It is hypothesized that these changes resulted in a mild uncoupling sufficient to reduce electron back flow through complex I of the ETC, the major generator of reactive oxygen species by skeletal muscle mitochondria.

Skeletal muscle HSP72 and norepinephrine response to static magnetic field in rat.

The present work was undertaken in order to investigate the noradrenergic system and skeletal muscle heat shock protein 72 (HSP72) response to static magnetic field (MF) in male rats. At thermoneutrality (25 degrees C), the exposition of rats 1 hour/day for 5 consecutive days to MF of 128 mT (m tesla) induced an increase in norepinephrine content in gastrocnemius muscle (+25%, p < 0.05) but had no effect at 67 mT (+1%, p > 0.05), indicating a stimulatory effect of sub-acute MF exposure on the noradrenergic system activity. Moreover, exposed rats to MF displayed a non-significant increase of HSP72 levels in gastrocnemius muscles (+29%, p > 0.05). The results indicate that noradrenergic systems in rat's gastrocnemius muscles are affected by MF exposure. Interestingly, sub-acute exposure insufficiency increased HSP72 levels in gastrocnemius muscles.

Age-related sensitivity to lung oxidative stress during ozone exposure.

As immature and aged rats could be more sensitive to ozone (O(3))-linked lung oxidative stress we have attempted to shed more light on age-related susceptibility to O(3) with focusing our interest on lung mitochondrial respiration, reactive oxygen species (ROS) production and lung pro/antioxidant status. For this purpose, we exposed to fresh air or O(3) (500 ppb 12 h per day, for 7 days) 3 week- (immature), 6 month- (adult) and 20 month-old rats (aged). We determined, in lung, H(2)O(2) release by mitochondria, activities of major antioxidant enzymes [superoxide dismutase (SOD), glutathione peroxidase (GPx) and catalase (CAT)], heat shock protein (HSP(72)) content and 8-oxodG and dG-HNE nDNA contents, as DNA oxidative damage markers. In adult rats we did not observe alteration of pro/antioxidant status. In contrast to adults, immature rats exposed to O(3) higher nDNA 8-oxodG content and HSP(72) and without antioxidant enzymes modification. Aged rats displayed mild uncoupled lung mitochondria, increased SOD and GPx activities, and higher 8-oxodG content after O(3) exposure. Thus, in contrast to adults, immature and aged rats displayed lung oxidative stress after O(3) exposure. Higher sensitivity of immature to O(3) was partly related to ventilatory parameters and to the absence of antioxidant enzyme response. In aged rats, the increase in cytosolic SOD and GPx activities during O(3) exposure was not sufficient to prevent the impairment in mitochondrial function and accumulation in lung 8- oxodG. Finally, we showed that mitochondria seem not to be a major source of ROS under O(3) exposure.

Metabolic and hormonal responses to exercise in the anti-obese Lou/C rats.

OBJECTIVE: Lou/C rats are a substrain of Wistar rats that exhibit a spontaneous low caloric intake and no development of obesity with age. Recently, we reported that Lou/C rats, compared to equally food-restricted Wistar counterparts, show lower resting levels of plasma glucose, epinephrine and liver glycogen. To further explore this metabolic particularity, we used exercise (swimming 60 min) as a situation of high-energy demand, to test the ability of Lou/C rats to maintain euglycemia. DESIGN: Male Lou/C rats (14-week-old) were compared to age-matched male Wistar rats fed either ad libitum (WAL) or Wistar rats whose food was chronically restricted (WFR) to the same caloric intake as the Lou/C rats. RESULTS: In spite of low liver glycogen stores ( approximately 50% of normal values), Lou/C rats were able to maintain euglycemia during exercise even though liver glycogen breakdown was blunted. The decreased use of glycogen during exercise in Lou/C rats was associated with a reduced epinephrine response compared to WFR animals. By contrast, WFR were also able to maintain euglycemia during exercise but at the expense of a significant (P<0.01) decrease in liver and muscle glycogen content. Plasma free fatty acid and glycerol concentrations were increased (P<0.01) similarly in all three groups during exercise. In a separate experiment conducted in isolated hepatocytes from 24 h fasted Lou/C and Wistar rats, it was found that gluconeogenic flux from glycerol was found to be significantly (P<0.01) higher in Lou/C than in Wistar rats (5.4+/-0.2 vs 3.7+/-0.1 micromol/min/g dry cells). Resting and exercising plasma leptin levels were also significantly (P<0.05) lower in Lou/C than in the two other groups. CONCLUSION: It is concluded that Lou/C rats have the particularity to rely spontaneously less on their liver glycogen stores to meet their energy demands during exercise while maintaining euglycemia.