A short washout period from fingolimod to anti-CD20 therapy is safe and decreases the risk of reactivation.

The frequency of switches between Disease Modifying Therapies (DMTs) in Multiple Sclerosis (MS) has increased considerably over previous years. Between fingolimod and anti-CD20 therapies, a 1-month washout period is usually recommended. However, disease reactivations are frequent after fingolimod (Fg) cessation. Using a retrospective observational monocentric exposed/non-exposed cohort study, we investigated the efficacy and the safety of a shorter washout period (WP) between Fg and anti-CD20. We compared two groups: 25 patients with a short WP (<21 days) and 20 patients with a longer WP (>21 days). We observed no reactivation during WP in patients with a short WP against a relapse in 55% of patients in the longer group. Moreover, clinical and biological safety was excellent. Based on these findings, we recommend a shorter WP between fingolimod and anti-CD20 therapies in MS.

[On the use of corticosteroids for critically ill patients with SARS-CoV-2 interstitial pneumonia]. / La corticothérapie chez le patient critique atteint d'une pneumopathie interstitielle à SARS-CoV-2.

The health crisis caused by SARS-Cov2 continues to question the scientific community on an effective treatment to combat the disease. To do this, understanding the pathophysiology is a key element of the research. Although the use of corticosteroids is debated, recent publications on pathogenesis and histologic pattern allow us to consider their use on a different way. Through these two case reports, it seemed interesting to take stock of the most recent data in the literature and on the potential interest of the corticotherapy in specific critically ill patient's cases.

La crise sanitaire provoquée par le SARS-CoV-2 n'a de cesse de questionner la communauté scientifique sur un traitement efficace pour combattre la maladie. La compréhension de la physiopathologie constitue un élément clé de la recherche. Bien que l'utilisation des corticoïdes soit débattue, des publications récentes sur la pathogenèse et l'analyse anatomopathologique nous permettent d'envisager leur utilisation avec un autre angle d'approche. À travers ces deux cas cliniques, il nous semblait intéressant de faire le point sur les données les plus récentes de la littérature sur l'intérêt de la corticothérapie chez le patient critique atteint par la COVID-19.

[Lithium toxicity after bariatric surgery]. / Intoxication au lithium après chirurgie bariatrique.

Since many years a correlation between neuropsychiatric disorders and eating disorders resulting in obesity is well established. According to different studies, 1.2 - 4 % of patients scheduled for bariatric surgery are taking lithium as a mood stabilizer treatment for bipolar disorder. We are presenting a case of lithium toxicity after vertical sleeve gastrectomy surgery in a 40 years-old female. The patient developed severe neurological and renal signs needing an intensive care unit admission and continuous veno-venous hemodiafiltration. A literature review provides insights into physiological and pharmacokinetics changes that could contribute to lithium poisoning after bariatric surgery. This article illustrates the need for closer monitoring of lithium serum levels following bariatric surgery and presents guidance in managing lithium therapy during perioperative period based on experts' opinion.

Une corrélation entre troubles neuropsychiatriques et troubles alimentaires est maintenant établie depuis plusieurs années. Selon les études, 1,2 à 4% des patients éligibles pour une chirurgie bariatrique ont un traitement chronique comprenant du lithium (1-3). Nous rapportons le cas d'une patiente de 40 ans qui développe une intoxication au lithium dans le décours d'une «sleeve¼ - gastrectomie avec des signes neurologiques et rénaux sévères nécessitant sa prise en charge aux soins intensifs avec hémodiafiltration continue veino-veineuse. Nous détaillons les modifications physiologiques et pharmacocinétiques susceptibles d'induire un surdosage en lithium après une telle chirurgie. Nous revoyons enfin les recommandations concernant la prise en charge de l'intoxication au lithium ainsi que les mesures préventives péri-opératoires afin d'éviter une telle situation.

Sepsis of the hip due to pressure sore in spinal cord injured patients: advocacy for a one-stage surgical procedure.

STUDY DESIGN: Retrospective study reporting characteristics and management of septic arthritis of the hip due to pressure sores in spinal cord-injured patients. OBJECTIVES: To describe clinical and biological data of septic arthritis of the hip and its treating management. SETTING: The database of the regional SCI referral center, Nantes, France. METHODS: We retrospectively collected data from 33 cases of septic arthritis of the hip in the medical files of 26 patients. RESULTS: We analyzed 33 cases of septic arthritis of the hip treated in one French referent center for spinal cord-injured patients from January 1988 to December 2009. Most patients had a thoracic complete paraplegia and nearly two-third (17 out of 26) had no systematic follow-up. In 25 out of 33 cases, the septic arthritis of the hip was due to a trochanteric pressure sore. The causal pressure sore was most frequently associated with a persistent drainage. The standard radiological examination led to the diagnosis in 30 cases and, in 7 questionable cases, magnetic resonance imaging was more contributory. Surgery always consisted of a wide carcinological-like excision and of a subtrochanteric proximal femoral resection including both greater and lesser trochanters. A musculocutaneous flap was realized for all cases and the choice of the muscle depended on the localization of the causal pressure sore but also of the remaining choices, as most of the patients had already undergone a prior surgery. An antibiotic treatment was adapted to multiple samples during surgery. CONCLUSION: We do advocate for a one-stage procedure including a subtrochanteric proximal femoral resection and a musculocutaneous flap.

Multimodal assessment improves neuroprognosis performance in clinically unresponsive critical-care patients with brain injury.

Accurately predicting functional outcomes for unresponsive patients with acute brain injury is a medical, scientific and ethical challenge. This prospective study assesses how a multimodal approach combining various numbers of behavioral, neuroimaging and electrophysiological markers affects the performance of outcome predictions. We analyzed data from 349 patients admitted to a tertiary neurointensive care unit between 2009 and 2021, categorizing prognoses as good, uncertain or poor, and compared these predictions with observed outcomes using the Glasgow Outcome Scale-Extended (GOS-E, levels ranging from 1 to 8, with higher levels indicating better outcomes). After excluding cases with life-sustaining therapy withdrawal to mitigate the self-fulfilling prophecy bias, our findings reveal that a good prognosis, compared with a poor or uncertain one, is associated with better one-year functional outcomes (common odds ratio (95% CI) for higher GOS-E: OR = 14.57 (5.70-40.32), P < 0.001; and 2.9 (1.56-5.45), P < 0.001, respectively). Moreover, increasing the number of assessment modalities decreased uncertainty (OR = 0.35 (0.21-0.59), P < 0.001) and improved prognostic accuracy (OR = 2.72 (1.18-6.47), P = 0.011). Our results underscore the value of multimodal assessment in refining neuroprognostic precision, thereby offering a robust foundation for clinical decision-making processes for acutely brain-injured patients. ClinicalTrials.gov registration: NCT04534777 .

[Eyebrow reconstruction]. / Ophriopoïèse.

The eyebrow is an essential anatomical area, from a social point of view, so its reconstruction, in case of skin defect, must be as meticulous as possible, with the less residual sequela. Capillary density extremely varies from one person to another and the different methods of restoration of this area should absolutely take this into consideration. We are going to review the various techniques of reconstruction, according to the sex and the surface to cover.

Evidence for the involvement of endothelial cell integrin alphaVbeta3 in the disruption of the tumor vasculature induced by TNF and IFN-gamma.

Administration of tumor necrosis factor (TNF) and gamma interferon (IFN-gamma) to melanoma patients causes selective disruption of the tumor vasculature but the mechanism of this disruption is unknown. Here we report that exposure of human endothelial cells to TNF and IFN-gamma results in a reduced activation of integrin alphaVbeta3, an adhesion receptor that plays a key role in tumor angiogenesis, leading to a decreased alphaVbeta3-dependent endothelial cell adhesion and survival. Detachment and apoptosis of angiogenic endothelial cells was demonstrated in vivo in melanoma metastases of patients treated with TNF and IFN-gamma. These results implicate integrin alphaVbeta3 in the anti-vascular activity of TNF and IFN-gamma and demonstrate a new mechanism by which cytokines control cell adhesion.

Microglia-neuron interaction at nodes of Ranvier depends on neuronal activity through potassium release and contributes to remyelination.

Microglia, the resident immune cells of the central nervous system, are key players in healthy brain homeostasis and plasticity. In neurological diseases, such as Multiple Sclerosis, activated microglia either promote tissue damage or favor neuroprotection and myelin regeneration. The mechanisms for microglia-neuron communication remain largely unkown. Here, we identify nodes of Ranvier as a direct site of interaction between microglia and axons, in both mouse and human tissues. Using dynamic imaging, we highlight the preferential interaction of microglial processes with nodes of Ranvier along myelinated fibers. We show that microglia-node interaction is modulated by neuronal activity and associated potassium release, with THIK-1 ensuring their microglial read-out. Altered axonal K+ flux following demyelination impairs the switch towards a pro-regenerative microglia phenotype and decreases remyelination rate. Taken together, these findings identify the node of Ranvier as a major site for microglia-neuron interaction, that may participate in microglia-neuron communication mediating pro-remyelinating effect of microglia after myelin injury.

SMILE: a predictive model for Scoring the severity of relapses in MultIple scLErosis.

BACKGROUND: In relapsing-remitting multiple sclerosis (RRMS), relapse severity and residual disability are difficult to predict. Nevertheless, this information is crucial both for guiding relapse treatment strategies and for informing patients. OBJECTIVE: We, therefore, developed and validated a clinical-based model for predicting the risk of residual disability at 6 months post-relapse in MS. METHODS: We used the data of 186 patients with RRMS collected during the COPOUSEP multicentre trial. The outcome was an increase of ≥ 1 EDSS point 6 months post-relapse treatment. We used logistic regression with LASSO penalization to construct the model, and bootstrap cross-validation to internally validate it. The model was externally validated with an independent retrospective French single-centre cohort of 175 patients. RESULTS: The predictive factors contained in the model were age > 40 years, shorter disease duration, EDSS increase ≥ 1.5 points at time of relapse, EDSS = 0 before relapse, proprioceptive ataxia, and absence of subjective sensory disorders. Discriminative accuracy was acceptable in both the internal (AUC 0.82, 95% CI [0.73, 0.91]) and external (AUC 0.71, 95% CI [0.62, 0.80]) validations. CONCLUSION: The predictive model we developed should prove useful for adapting therapeutic strategy of relapse and follow-up to individual patients.

High frequencies of naive Melan-A/MART-1-specific CD8(+) T cells in a large proportion of human histocompatibility leukocyte antigen (HLA)-A2 individuals.

Using fluorescent HLA-A*0201 tetramers containing the immunodominant Melan-A/MART-1 (Melan-A) tumor-associated antigen (Ag), we previously observed that metastatic lymph nodes of melanoma patients contain high numbers of Ag-experienced Melan-A-specific cytolytic T lymphocytes (CTLs). In this paper, we enumerated and characterized ex vivo Melan-A-specific cells in peripheral blood samples from both melanoma patients and healthy individuals. High frequencies (>/=1 in 2,500 CD8(+) T cells) of Melan-A-specific cells were found in 10 out of 13 patients, and, surprisingly, in 6 out of 10 healthy individuals. Virtually all Melan-A-specific cells from 6 out of 6 healthy individuals and from 7 out of 10 patients displayed a naive CD45RA(hi)/RO(-) phenotype, whereas variable proportions of Ag-experienced CD45RA(lo)/RO(+) Melan-A-specific cells were observed in the remaining 3 patients. In contrast, ex vivo influenza matrix-specific CTLs from all individuals exhibited a CD45RA(lo)/RO(+) memory phenotype as expected. Ag specificity of tetramer-sorted A2/Melan-A(+) cells from healthy individuals was confirmed after mitogen-driven expansion. Likewise, functional limiting dilution analysis and interferon gamma ELISPOT assays independently confirmed that most of the Melan-A-specific cells were not Ag experienced. Thus, it appears that high frequencies of naive Melan-A-specific CD8(+) T cells can be found in a large proportion of HLA-A*0201(+) individuals. Furthermore, as demonstrated for one patient followed over time, dramatic phenotype changes of circulating Melan-A-specific cells can occur in vivo.

A DNA methylation signature discriminates between excellent and non-response to lithium in patients with bipolar disorder type 1.

Lithium (Li) is the cornerstone maintenance treatment for bipolar disorders (BD), but response rates are highly variable. To date, no clinical or biological marker is available to reliably define eligibility criteria for a maintenance treatment with Li. We examined whether the prophylactic response to Li (assessed retrospectively) is associated with distinct blood DNA methylation profiles. Bisulfite-treated total blood DNA samples from individuals with BD type 1 (15 excellent-responders (LiERs) versus 11 non-responders (LiNRs)) were used for targeted enrichment of CpG rich genomic regions followed by high-resolution next-generation sequencing to identify differentially methylated regions (DMRs). After controlling for potential confounders we identified 111 DMRs that significantly differ between LiERs and LiNRs with a significant enrichment in neuronal cell components. Logistic regression and receiver operating curves identified a combination of 7 DMRs with a good discriminatory power for response to Li (Area Under the Curve 0.806). Annotated genes associated with these DMRs include Eukaryotic Translation Initiation Factor 2B Subunit Epsilon (EIF2B5), Von Willebrand Factor A Domain Containing 5B2 (VWA5B2), Ral GTPase Activating Protein Catalytic Alpha Subunit 1 (RALGAPA1). Although preliminary and deserving replication, these results suggest that biomarkers of response to Li may be identified through peripheral epigenetic measures.

Distinctive role of integrin-mediated adhesion in TNF-induced PKB/Akt and NF-kappaB activation and endothelial cell survival.

Tumor necrosis factor (TNF) is a pro-inflammatory cytokine exerting pleiotropic effects on endothelial cells. Depending on the vascular context it can induce endothelial cell activation and survival or death. The microenvironmental cues determining whether endothelial cells will survive or die, however, have remained elusive. Here we report that integrin ligation acts permissive for TNF-induced protein kinase B (PKB/Akt) but not nuclear factor (NF)-kappaB activation. Concomitant activation of PKB/Akt and NF-kappaB is essential for the survival of endothelial cells exposed to TNF. Active PKB/Akt strengthens integrin-dependent endothelial cell adhesion, whereas disruption of actin stress fibers abolishes the protective effect of PKB/Akt. Integrin-mediated adhesion also represses TNF-induced JNK activation, but JNK activity is not required for cell death. The alphaVbeta3/alphaVbeta5 integrin inhibitor EMD121974 sensitizes endothelial cells to TNF-dependent cytotoxicity and active PKB/Akt attenuates this effect. Interferon gamma synergistically enhanced TNF-induced endothelial cell death in all conditions tested. Taken together, these observations reveal a novel permissive role for integrins in TNF-induced PKB/Akt activation and prevention of TNF-induced death distinct of NF-kappaB, and implicate the actin cytoskeleton in PKB/Akt-mediated cell survival. The sensitizing effect of EMD121974 on TNF cytotoxicity may open new perspectives to the therapeutic use of TNF as anticancer agent.

p53 status correlates with histopathological response in patients with soft tissue sarcomas treated using isolated limb perfusion with TNF-alpha and melphalan.

BACKGROUND: Recombinant tumor necrosis factor-alpha (TNF-alpha) combined to melphalan is clinically administered through isolated limb perfusion (ILP) for regionally advanced soft tissue sarcomas of the limbs. In preclinical studies, wild-type p53 gene is involved in the regulation of cytotoxic action of TNF-alpha and loss of p53 function contributes to the resistance of tumour cells to TNF-alpha. The relationship between p53 status and response to TNF-alpha and melphalan in patients undergoing ILP is unknown. PATIENTS AND METHODS: We studied 110 cases of unresectable limbs sarcomas treated by ILP. Immunohistochemistry was carried out using DO7mAb, which reacts with an antigenic determinant from the N-terminal region of both the wild-type and mutant forms of the p53 protein, and PAb1620mAb, which reacts with the 1620 epitope characteristic of the wild-type native conformation of the p53 protein. The immunohistochemistry data were then correlated with various clinical parameters. RESULTS: P53DO7 was found expressed at high levels in 28 patients, whereas PAb1620 was negative in 20. The tumours with poor histological response to ILP with TNF-alpha and melphalan showed significantly higher levels of p53-mutated protein. CONCLUSIONS: Our results might be a clue to a role of p53 protein status in TNF-alpha and melphalan response in clinical use.

Clinical applications of TNF-alpha in cancer.

High-dose TNF-alpha plus chemotherapy, with or without IFN-gamma, can be safely administered regionally through isolated limb perfusion. This procedure produced between 70% and 80% complete remission in cases of in transit melanoma metastases and between 25% and 36% complete remission in cases of inextirpable soft-tissue sarcomas. Dual targeting is involved; TNF-alpha and IFN-gamma induce apoptosis of angiogenic endothelium, while melphalan induces apoptosis of tumour cells.

Sentinel lymph node involvement and a high Breslow index are independent factors of risk for early relapse of melanoma.

AIM: The clinical relevance of sentinel lymph node (SLN) analysis was evaluated prospectively and compared with other known risk factors of relapse in early stage melanoma. METHODS: Surgery was guided by lymphoscintigraphy, blue dye and gamma probe detection. SLN were analysed by haematoxylin eosin (HE) histochemistry and multimarker immunohistochemistry (IHC). Disease free survival (DFS) was evaluated with Kaplan-Meier plots according to different parameters and Cox analyses of variance. RESULTS: From 210 patients a total of 381 SLN were excised. Lymphoscintigraphy identified all excised SLN with only 2 false positive lymphatic lakes. Fifty patients (24%) had tumour positive SLN. With a mean follow-up of 31.3 months, 29 tumour recurrences were observed, 19 (38%) in 50 SLN positive and 10 (6%) in 160 SLN negative patients. Strong predictive factors for early relapse (p < 0.0005) were SLN positivity and a high Breslow index. CONCLUSION: SLN tumour positivity is an independent factor of high risk for early relapse with a higher power of discrimination than the Breslow index.

Sunscreen use and duration of sun exposure: a double-blind, randomized trial.

BACKGROUND: In epidemiologic studies, sunscreen use is associated with increased risk of cutaneous melanoma, basal cell skin cancer, and higher numbers of nevi. It has been proposed that sunscreens may encourage prolonged sun exposure because they delay sunburn occurrence. We examined whether, under habitual conditions of sunscreen use, the sun-protection factor (SPF) had an influence on sun-exposure duration. METHODS: Before the 1997 summer holidays, we randomly assigned 87 French and Swiss participants who were 18-24 years of age to receive an SPF 10 or an SPF 30 sunscreen. Neither medical personnel nor study participants were aware of their sunscreen assignment. Participants were asked to complete daily records of their sun exposure. To avoid influencing the recreational sun-exposure habits of the study participants, no recommendation was made about sun exposure or sun protection. Furthermore, participants were told that the trial end point was the number of pigmented skin lesions before and after the holidays. One subject was lost to follow-up. All statistical tests were two-sided. RESULTS: The SPF 10 (n = 44) and SPF 30 (n = 42) groups had equivalent mean holiday durations (19.4 days versus 20.2 days) and mean quantities of sunscreen used (72.3 g versus 71.6 g). The mean cumulative sun exposures for the two groups were 58.2 hours and 72.6 hours, respectively (P =.011). The mean daily durations of sunbathing were 2.6 and 3.1 hours, respectively (P =.0013), and, for outdoor activities, they were 3.6 and 3.8 hours, respectively (P =.62). There was no difference in sunburn experience between the two groups. CONCLUSIONS: Use of higher SPF sunscreen seems to increase the duration of recreational sun exposure of young white Europeans.

A simple and accurate new method for cytostatics dosimetry in isolation perfusion of the limbs based on exchangeable blood volume determination.

Current methods for cytostatic dosimetry in isolation perfusion of the limbs are based on either limb tissue volume (LTV) or body weight. None of them take into account the actual blood volume intra- and extracorporal, including even the blood leakage if any, in which the pharmacokinetics take place. The present study describes a method which allows the assessment of the actual exchangeable blood volume. The latter is calculated by a formula based on three hematocrit measurements. Thirty-one cases entered the study. Exchangeable limb blood volume representing the limb vascular bed was found to average 340 +/- 148 (SD) ml for upper limb perfusion and 768 +/- 279 and 621 +/- 454 ml for iliac and femoropopliteal perfusion, respectively. There was a good correlation between exchangeable limb blood volume and limb tissue volume (LTV, r = 0.7), a poor one with body weight (r = 0.3), and no correlation at all with body surface. Melphalan dosage was calculated per ml of blood and applied at 20 to 40 micrograms/ml. Comparison between calculated dose and concentration measured by high performance liquid chromatography showed a high correlation (r = 0.963). Since there was a correlation between exchangeable limb blood volume and LTV, it was possible to derive a conversion for melphalan dosage where 13 mg/liter corresponds to 20 micrograms/ml in upper limb perfusion and 10 mg/liter corresponds to 40 micrograms/ml in lower limb perfusion. Comparison between calculated melphalan dosage based on our method and the LTV method showed a large dispersion of values in the latter (12 to 18% coefficient of variation) while the dispersion given by the body weight-based method increased 2-fold (16 to 31% coefficient of variation). It is concluded that the present dosimetry method is the most suitable up to the present for accurate prediction of cytostatic concentration in isolation perfusion.

Naturally occurring human lymphocyte antigen-A2 restricted CD8+ T-cell response to the cancer testis antigen NY-ESO-1 in melanoma patients.

Cancer testis (CT) antigens are particularly interesting candidates for cancer vaccines. However, T-cell reactivity to CT antigens has been detected only occasionally in cancer patients, even after vaccination. A new group of CT antigens has been recently identified using the SEREX technique based on immunoscreening of tumor cDNA expression libraries with autologous sera. We have used fluorescent HLA-A2/peptide tetramers containing an optimized antigenic peptide to directly identify HLA-A2-restricted CD8+ T cells specific for the SEREX-defined CT antigen NY-ESO-1 in melanoma patients. High frequencies of NY-ESO-1-specific CD8+ T cells were readily detected in peptide-stimulated peripheral blood mononuclear cells as well as in lymphocytes infiltrating melanoma lesions from patients with measurable antibody responses to NY-ESO-1. NY-ESO-1-specific CD8+ T cells were also detectable in peptide-stimulated peripheral blood mononuclear cells from some seronegative patients. Whereas the frequencies of NY-ESO-1-specific CD8+ T cells in circulating lymphocytes were usually below the limit of detection by tetramer staining, the presence of NY-ESO-1 CD8+ T cells displaying a memory phenotype was clearly detectable ex vivo in blood from a seropositive patient over an extended period of time. These results indicate that sustained CD8+ T-cell responses to CT antigens can naturally occur both locally and systemically in melanoma patients.

An antigen-targeted approach to adoptive transfer therapy of cancer.

Previous attempts to treat human malignancies by adoptive transfer of tumor-specific CTLs have been limited by the difficulty of isolating T cells of defined antigen specificity. The recent development of MHC class I/antigenic peptide tetrameric complexes that allow direct identification of antigen-specific T cells has opened new possibilities for the isolation and in vitro expansion of tumor-specific T cells. In the present study, we have derived polyclonal monospecific cell lines from circulating Melan-A-specific CTL precursors of HLA-A*0201+ melanoma patients by combining stimulation with recently identified peptide analogues of the immunodominant epitope from the melanoma-associated antigen Melan-A with staining with fluorescent HLA-A*0201/Melan-A peptide tetramers. In vitro expansion of antigen-specific CD8+ T cells was monitored by flow cytometry with the fluorescent tetramers and anti-CD8 monoclonal antibody. This analysis revealed that Melan-A 26-35 peptide analogues were much more efficient than the parental peptides in stimulating a rapid in vitro expansion of antigen-specific CD8+ T cells. These cells were then isolated by tetramer-guided cell sorting and subsequently expanded in vitro by mitogen stimulation. The resulting polyclonal but monospecific CTLs fully cross-recognized the parental peptides and were able to efficiently lyse Melan-A-expressing tumor cells. Altogether, these results pave the way to a molecularly defined approach to antigen-specific adoptive transfer therapy of cancer.