Prospective non-interventional BELOVA/BGOG-ov16 study on safety of frontline bevacizumab in elderly patients with FIGO stage IV ovarian cancer: a study of the Belgian and Luxembourg Gynaecological Oncology Group.

OBJECTIVE: Because elderly patients with ovarian cancer are underrepresented in randomized studies, this study aimed to expand our knowledge on the safety and effectiveness of frontline treatment with bevacizumab in combination with standard carboplatin and paclitaxel chemotherapy in patients aged 70 years and older with a diagnosis of Federation of Gynecology and Obstetrics (FIGO) stage IV ovarian cancer in routine clinical practice in Belgium. METHODS: Patients aged 70 years and older with FIGO stage IV ovarian cancer were included in a multicenter, non-interventional prospective studyto evaluate the safety and effectiveness of treatment with bevacizumab in combination with frontline carboplatin and paclitaxel chemotherapy. Comprehensive geriatric assessments were performed at baseline and during treatment. RESULTS: The most frequently reported adverse events for bevacizumab were hypertension (55%), epistaxis (32%) and proteinuria (21%). The Kaplan-Meier estimate of progression-free survival was 14.5 months. The results of the comprehensive geriatric assessments during treatment indicated a slight improvement in the geriatric eight health status screening tool score for general health status and the mini-nutritional assessment score for nutritional status. The median change from baseline score was close to zero for the instruments measuring independency, activity of daily living and instrumental activities of daily living, and for the mobility-tiredness test measuring self-perceived fatigue. CONCLUSIONS: No new safety signals were registered in this study in patients aged 70 years and older treated with bevacizumab and frontline carboplatin and paclitaxel for FIGO stage IV ovarian cancer. Elderly patients should not be excluded from treatment for advanced ovarian cancer based on age alone. EU PAS REGISTER: ENCEPP/SDPP/13849. CLINICALTRIALSGOV IDENTIFIER: NCT02393898.

A systematic review of psychosocial explanations for the relationship between socioeconomic status and body mass index.

A negative association between socioeconomic status (SES) and levels of overweight/obesity is consistently found in high- and middle-income countries. Yet, there is little conclusive evidence about the mechanisms driving this association. In this systematic review, we discuss and compare the results of 22 studies that examine the role of psychosocial mediators in the association between SES and BMI in diverse population samples. These include factors related to resources and constraints in one's external neighborhood, social resources, and psychological factors such as stress. The findings support theoretical models indicating that SES is related to BMI partially through environmental and psychological factors. Importantly, SES often remains a significant predictor of weight status, indicating the importance of also addressing structural antecedents in order to improve health among lower SES populations. We thoroughly discuss the quality and limitations of current study designs and mediation testing and provide recommendations for future research.

Age-Associated B Cells with Proinflammatory Characteristics Are Expanded in a Proportion of Multiple Sclerosis Patients.

Immune aging occurs in the elderly and in autoimmune diseases. Recently, IgD-CD27- (double negative, DN) and CD21-CD11c+ (CD21low) B cells were described as age-associated B cells with proinflammatory characteristics. This study investigated the prevalence and functional characteristics of DN and CD21low B cells in multiple sclerosis (MS) patients. Using flow cytometry, we demonstrated a higher proportion of MS patients younger than 60 y with peripheral expansions of DN (8/41) and CD21low (9/41) B cells compared with age-matched healthy donors (1/33 and 2/33, respectively), which indicates an increase in age-associated B cells in MS patients. The majority of DN B cells had an IgG+ memory phenotype, whereas CD21low B cells consisted of a mixed population of CD27- naive, CD27+ memory, IgG+, and IgM+ cells. DN B cells showed similar (MS patients) or increased (healthy donors) MHC-II expression as class-switched memory B cells and intermediate costimulatory molecule expression between naive and class-switched memory B cells, indicating their potential to induce (proinflammatory) T cell responses. Further, DN B cells produced proinflammatory and cytotoxic cytokines following ex vivo stimulation. Increased frequencies of DN and CD21low B cells were found in the cerebrospinal fluid of MS patients compared with paired peripheral blood. In conclusion, a proportion of MS patients showed increased peripheral expansions of age-associated B cells. DN and CD21low B cell frequencies were further increased in MS cerebrospinal fluid. These cells could contribute to inflammation by induction of T cell responses and the production of proinflammatory cytokines.

B cells of multiple sclerosis patients induce autoreactive proinflammatory T cell responses.

Antibody-independent B cell functions play an important role in multiple sclerosis (MS) pathogenesis. In this study, B cell antigen presentation and costimulation in MS were studied. Peripheral blood B cells of MS patients showed increased expression of costimulatory CD86 and CD80 molecules compared with healthy controls (HC). In MS cerebrospinal fluid (CSF), 12-fold and 2-fold increases in CD86+ and CD80+ B cells, respectively, were evidenced compared with peripheral blood. Further, B cells from MS patients induced proinflammatory T cells in response to myelin basic protein (MBP). Immunomodulatory treatment restored B cell costimulatory molecule expression and caused significantly reduced B cell induced T cell responses. Together, these results demonstrate the potential of B cells from MS patients to induce autoreactive proinflammatory T cell responses. Immunomodulatory therapy abrogated this effect, emphasizing the importance of B cell antigen presentation and costimulation in MS pathology.

[Preventing decline of autonomy through the promotion of mental health: a randomized clinical trial for older adults with disabilities]. / La prévention de la perte d'autonomie par le renforcement de la santé mentale : un essai clinique à répartition aléatoire auprès des personnes âgées avec incapacités.

Among older adults with disabilities, maintaining active aging can often be compromised. However, the literature highlights a positive link between mental health and autonomy on one hand, and self-determined motivation on the other. Therefore, self-determined motivation may be improved by promoting mental health and, in the end, older adults autonomy. In this context, the « pôle bien-être autonomie ¼, a mental health promotion program, has been set up to offer activities adapted to the disabilities and needs of the elderly, hence fostering active aging. The purpose of this longitudinal study is to test the hypothesis that promoting the mental health of disabled older adults would preserve their autonomy through the development of self-determined motivation. The theoretical model was tested using structural equation modelling on data of 170 participants. A RCT was conducted between 2019 and 2021 with the same cohort. Results of the structural equation modelling support the importance of promoting mental health in maintaining active aging. Evaluation of the promotion program indicates a decrease in levels of depression, an increase in the frequency of self-determined activities and in the autonomy of beneficiaries after three months of operation. The discussion focuses on the relevance of a processual analysis of the promotion program and on new directions to maintain autonomy for seniors with disabilities.

Robotic-Assisted Pelvic Exenteration for Cervical Cancer: A Systematic Review and Novel Insights into Compartment-Based Imaging.

Background: Patients with persistent or recurrent cervical cancer, following primary treatment with concurrent chemoradiation, represent a subgroup eligible for pelvic exenteration. In light of the substantial morbidity associated with open pelvic exenterations, minimally invasive surgical techniques have been introduced. This systematic review aims to analyze and discuss the current literature on robotic-assisted pelvic exenterations in cervical cancer. In addition, novel aspects of compartment-based magnetic resonance imaging (MRI) are highlighted. Methods: This systematic review followed the PRISMA guidelines, and a comprehensive literature search on robotic-assisted pelvic exenterations in cervical cancer was conducted to assess, as main objectives, early and late postoperative complications as well as oncological outcomes. Inclusion and exclusion criteria were applied to select eligible studies. Results: Among the reported cases of robotic-assisted pelvic exenterations in cervical cancer, 79.4% are anterior pelvic exenterations. Intraoperative complications are minimal and early/late major complications averaged between 30-35%, which is lower compared to open pelvic exenterations. Oncological outcomes are similar between robotic and open pelvic exenterations. Sensitivity for locoregional invasion increases up to 93% for compartment-based MRI in colorectal cancer. A refined delineation of the seven pelvic compartments for cervical cancer is proposed here. Conclusions: Robotic-assisted pelvic exenterations have demonstrated feasibility and safety, with reduced rates of major complications compared to open surgery, while maintaining surgical efficiency and oncological outcomes. Compartment-based MRI holds promise for standardizing the selection and categorization of pelvic exenteration procedures.

Regorafenib in patients with pretreated advanced melanoma: a single-center case series.

Melanoma patients failing all approved treatment options have a poor prognosis. The antimelanoma activity of regorafenib (REGO), a multitargeted kinase inhibitor, has not been investigated in this patient population. The objective response rate and safety of REGO treatment in advanced melanoma patients was investigated retrospectively. Twenty-seven patients received REGO treatment. All patients had progressed on anti-programmed cell death protein 1 (PD-1) and anti-cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) checkpoint inhibition and BRAF/MEK inhibitors (in case of a BRAF V600 mutation). REGO was administered in continuous dosing and combined (upfront or sequentially) with nivolumab ( n  = 5), trametinib ( n  = 8), binimetinib ( n  = 2), encorafenib ( n  = 1), dabrafenib/trametinib ( n  = 9), or encorafenib/binimetinib ( n  = 7). The best overall response was partial response (PR) in five patients (18.5%) and stable disease in three patients (11.1%). Three of seven (42.8%) BRAF V600mut patients treated with REGO in combination with BRAF/MEK inhibitors obtained a PR (including regression of brain metastases in all three patients). In addition, PR was documented in a BRAF V600mut patient treated with REGO plus anti-PD-1, and a NRASQ61mut patient treated with REGO plus a MEK inhibitor. Common grade 3-4 treatment-related adverse events included arterial hypertension ( n  = 7), elevated transaminase levels ( n  = 5), abdominal pain ( n  = 3), colitis ( n  = 2), anorexia ( n  = 1), diarrhea ( n  = 1), fever ( n  = 1), duodenal perforation ( n  = 1), and colonic bleeding ( n  = 1). Median progression-free survival was 11.0 weeks (95% confidence interval, 7.1-14.9); median overall survival was 23.1 weeks (95% confidence interval, 13.0-33.3). REGO has a manageable safety profile in advanced melanoma patients, in monotherapy as well as combined with BRAF/MEK inhibitors or PD-1 blocking monoclonal antibodies. The triplet combination of REGO with BRAF/MEK inhibitors appears most active, particularly in the BRAF V600mut patients.

Socioeconomic status and social anxiety: attentional control as a key missing variable?

BACKGROUND AND OBJECTIVES: The aim was to examine the role of attentional control as a psychological factor involved in socioeconomic status-related mental health differences, and specifically in social anxiety. Based on the literature on socioeconomic status differences in cognitive abilities and attentional control theory, we hypothesized that attentional control would account for the relation between socioeconomic status and social anxiety. We tested this hypothesis in an integrative model also including trait anxiety and subjective socioeconomic status. DESIGN: Cross-sectional. METHOD: Online, 439 French adults were recruited via social media. They completed self-reported measures of attentional control, objective socioeconomic status, subjective socioeconomic status, social anxiety, and trait anxiety. RESULTS: Using Structural Equation Modelling, findings showed a positive association between objective (but not subjective) socioeconomic status and attentional control, which in turn was related to social anxiety. Exploratory analyses showed that only income, as objective socioeconomic status indicator, was associated with attentional control. CONCLUSIONS: The current study is the first to support that low socioeconomic status individuals report less attentional control and more social anxiety symptoms. This suggests that attentional control is a psychological factor involved in social anxiety inequalities.

Robotic surgery in early and advanced ovarian cancer: Case selection for surgical staging and interval debulking surgery.

OBJECTIVE: During the last decade several case series have been published on robotic surgery in early and advanced stage ovarian cancer. Although most studies lack a significant oncological follow-up, more importantly criteria for patient selection for both robotic surgical staging (R-SS) and robotic interval debulking surgery (R-IDS) are not well defined. The objective of this study was to assess the surgical and oncological outcomes, using well-defined selection criteria, between robotic and open surgery in early and advanced stage ovarian cancer. STUDY DESIGN: Single-center retrospective case cohort study including 96 ovarian cancer patients. For early stage ovarian cancer, patients were selected for R-SS after laparoscopic salpingo-oophorectomy of a suspicious adnexal mass. For advanced stage ovarian cancer, only patients receiving neoadjuvant chemotherapy and IDS were included in the study. Exclusion criteria were the presence of residual peritoneal disease after NACT and/or patients requiring additional complex surgical procedures. RESULTS: For early stage ovarian cancer, similar median operative times were seen between R-SS and open surgical staging (O-SS), 132 min and 120 min respectively. Pelvic/para-aortic lymph node yield was similar between R-SS and O-SS, 22/11 nodes and 18/8 nodes respectively. Surgical upstaging occurred in 11.5% in the R-SS group and in 27.6% in the O-SS group. In advanced stage ovarian cancer, the BMI was significantly higher in the R-IDS group compared to the O-IDS group (27.8 vs 23.5; p =.006). The median follow was 52 months in the R-IDS group and 31 months in the O-IDS group. Recurrent disease occurred in 42.9% of the R-IDS group and in 45% of the O-IDS group. The length of hospitalization was significantly longer in the O-SS and O-IDS group (p <.00001). CONCLUSION: Patients with clinically early stage ovarian cancer, confirmed after laparoscopic removal of a suspicious adnexal mass, are candidates for R-SS whilst maintaining similar surgical and oncological outcome measures as O-SS. In advanced ovarian cancer, suitable candidates for R-IDS are those who receive NACT with good response and no residual peritoneal disease, especially in patients with a high BMI, but large prospective randomized trials with well-defined criteria are needed.

The moderating role of socioeconomic status on the relationship between teacher social support and sense of belonging to school.

BACKGROUND: Teacher social support (TSS) has been identified as one of the most important factors of success and well-being for students. Yet, there is a gap in the literature regarding the impact of students' socioeconomic status (SES) on their perceptions of TSS, and whether SES may impact the strength of the relationship between teacher social support and students' sense of belonging to school (SBS). AIMS: In this preregistered study, we aimed at filling this gap by testing the moderating role of SES on the TSS-SBS link, along with the direct associations between these variables. SAMPLE: We used data from the French sample of the Programme for International Student Assessment 2018 (PISA; N = 6308). METHODS: TSS was primarily assessed as a latent construct based on three indicators provided by PISA: teacher support, teacher emotional support and teacher feedback. Regarding SES, we primarily focused on family wealth possessions and parents' highest level of education. RESULTS: Using structural equation modelling, findings confirmed that the TSS-SBS link was stronger for high-SES than low-SES students. We also found a negative association between teacher support and SES. Importantly, preregistered additional analyses highlight that findings depend on the SES and TSS indicators considered. CONCLUSIONS: Findings support the importance of SES effect on students' perceptions of their interactions with teachers and the extent to which they perceive they belong to the school. The implications and limitations of this research are discussed.

Case report: a robotic-vaginal approach for total vaginectomy and hysterectomy with pelvic sentinel lymph node dissection in primary vaginal melanoma: a 10-step technique and literature review.

Introduction: Primary vaginal melanoma is extremely rare, has a poor prognosis, and occurs mostly in elderly women. The diagnosis is based on histology and immunohistochemistry of a biopsy. Given the rarity of vaginal melanoma, no standardized treatment guidelines are established; however, surgery is the primary treatment modality in the absence of metastatic disease. Most reports in the literature are retrospective single cases, case series, and population-based studies. The open surgical approach is the main modality reported. Here, we report for the first time a 10-step combined robotic-vaginal technique, with en bloc resection of the uterus and total vagina, for treating clinically early-stage primary vaginal melanoma. In addition, the patient in our case underwent a robotic pelvic bilateral sentinel lymph node dissection. The literature on the surgical approach for vaginal melanoma is reviewed. Case presentation: A 73-year-old woman was referred to our tertiary cancer center and was clinically staged according to the 2009 International Federation of Gynaecology and Obstetrics (FIGO) staging for vaginal cancer as FIGO-stage I (cT1bN0M0) and according to the American Joint Committee on Cancer (AJCC) for (cutaneous) Melanoma Staging as clinical stage IB. Preoperative imaging with magnetic resonance imaging, FDG-positron emission tomography-computed tomography, and ultrasound of the groins did not reveal any adenopathy nor metastases. The patient was planned for a combined vaginal and robotic en bloc total vaginectomy and hysterectomy, as well as a pelvic bilateral sentinel lymph node dissection. Results: The surgical procedure was performed in 10 steps described in this case report. The pathology revealed free surgical margins and negative test results for all sentinel lymph nodes. The postoperative recovery process was uneventful, and the patient was discharged on day 5. Conclusion: The main surgical approach reported for primary early-stage vaginal melanoma is open surgery. A minimally invasive surgical approach, described here as a combined vaginal-robotic en bloc total vaginectomy and hysterectomy, for the surgical treatment of early-stage vaginal melanoma enables precise dissection, low surgical morbidity, and fast recovery for the patient.

Primary leiomyosarcoma of the uterine cervix: an unusual case and critical appraisal.

Leiomyosarcomas of the uterine cervix are rare, mostly occurring in perimenopausal women. Diagnosis is based on pathology and immunohistochemistry. Surgery with a total abdominal hysterectomy and bilateral salpingo-oophorectomy remains the standard. A female patient in her 60s presented with heavy postmenopausal bleeding. Vaginal ultrasound scan and magnetic resonance imaging showed a large strongly vascularized cervical mass with features suspicious of sarcomatous degeneration. Positron Emission Tomography-Computed Tomography (PET-CT) did not reveal any evidence of metastases nor lymphadenopathy, but presence of right hydronephrosis. An abdominal hysterectomy with bilateral salpingo-oophorectomy, and end-to-end anastomosis of the right ureter, was performed. Pathology showed an International Federation of Gynecology and Obstetrics (FIGO)-stage 1B leiomyosarcoma of the uterine cervix. No adjuvant treatment was given. Adjuvant radiotherapy reduces the risk of recurrence but no survival impact. The benefit of adjuvant chemotherapy is questionable given the lack of randomized trials. Multidisciplinary research concerning molecular alterations of the disease is required to determine optimal management strategies with potential novel molecular therapies.

"Learning a Way of Thinking"-World Café on Clinical Reasoning in Nursing and Midwifery Education and Practice across Five European Union Countries.

Clinical reasoning is a key attribute of nursing and midwifery professionals. As a part of the Erasmus plus project, we designed a study with the aim of exploring the understanding of clinical reasoning as a concept, experiences of teaching clinical reasoning and practices related to using clinical reasoning in nursing and midwifery. A qualitative study was carried out using the World Café method, involving 44 participants from five European countries. The participants represented diverse professional backgrounds, including nurses, midwives and lecturers. Our analytical approach was based on a thematic analysis. We categorized the data into three main categories, namely, "Spiral of thinking", "The learning and teaching of a way of thinking" and "Clinical reasoning in real life", all under an overarching theme, "Learning a way of thinking". This study highlighted areas of learning and teaching which can be improved in current nursing and midwifery education. Furthermore, it identified barriers, facilitators and practices from five European countries which can be used in the further development of nursing and midwifery curricula and courses with the aim of enhancing clinical reasoning competence and ultimately improving patient care.

Robotic Staging of Cervical Cancer With Simultaneous Detection of Primary Pelvic and Secondary Para-Aortic Sentinel Lymph Nodes: Reproducibility in a First Case Series.

Objective: Discrepancies exist among international guidelines on the surgical staging of para-aortic lymph nodes in locally advanced cervical cancer (LACC), varying from considering a para-aortic lymph node dissection, at least up to the inferior mesenteric artery, to a complete para-aortic lymph node dissection. In this study, we aim to assess the reproducibility of our recently reported robotic technique using indocyanine green for identifying besides primary pelvic sentinel lymph nodes (SLNs), secondary para-aortic SLNs in a first case-cohort of cervical cancer patients. Methods: A retrospective case series of LACC patients with/without suspicious pelvic lymph nodes (LNs) on imaging (including two patients with an additional suspicious para-aortic LN) is reported. All patients underwent a robotic pelvic SLN and para-aortic sentinel/nonsentinel LN dissection using the da Vinci Xi platform. Indocyanine green was used as a fluorescent tracer, at a concentration of 1.9 mg/mL, and injected as 0.5 mL in each quadrant of the cervix. Results: In a total of 10 cases, primary pelvic SLNs (90% bilateral) with subsequent secondary para-aortic SLNs were identified in all cases. Lower para-aortic SLNs were present in all cases, and upper para-aortic SLNs were found in 9 out of 10 cases. The mean age of the cervical cancer patients was 49.8 years (SD ± 6.89), and the mean body mass index (BMI; kg/m2) was 23.96 (SD ± 4.60). The median total operative time was 105.5 min (range: 89-141 min). The mean numbers of primary pelvic SLNs and secondary lower and upper para-aortic SLNs were 3.10 (SD ± 1.10), 2.90 (SD ± 0.74), and 2.30 (SD ± 1.57), respectively. The median number of total para-aortic LNs (PALNs) dissected per patient was 11.5. Six patients had positive primary pelvic SLNs, and two had secondary positive para-aortic SLNs. The nonsentinel para-aortic LNs were negative in all cases. There were no intra- or postoperative complications. Conclusion: Our preliminary experience demonstrates the reproducibility of identifying, besides primary pelvic SLNs, secondary lower and upper para-aortic SLNs during robotic staging in LACC. A surgical approach limiting a complete para-aortic LN dissection could reduce the potential risks and morbidity associated with this procedure. To determine the sensitivity and negative predictive value of this new surgical approach, and whether the lower para-aortic SLNs under the inferior mesenteric artery are representative of the whole para-aortic region, large prospective observational studies are needed in LACC and/or those with suspicious pelvic LNs but apparent normal para-aortic LNs on imaging.

Mental Health Inequalities During COVID-19 Outbreak: The Role of Financial Insecurity and Attentional Control.

The COVID-19 pandemic and subsequent lockdowns negatively impacted the mental health of populations. This impact is not equally distributed and increases existing mental health inequalities. Indeed, government restrictions and the economic consequences of the pandemic affect more the less educated and less wealthy people. However, psychological processes implicated in this increase of mental health inequalities during the COVID-19 pandemic remain unexplored. The present study (N=591) tested the role of financial insecurity and attentional control in the relation between socioeconomic status and mental health, along with the influence of trait anxiety. Based on Structural Equation Modelling, findings showed a mediation effect of financial insecurity, but not of attentional control, in the relationship between socioeconomic status and mental health. In addition, exploratory analyses suggested that financial insecurity also mediated the effect of attentional control on mental health. Results of the present research point at the importance of understanding psychological processes implicated in the effect of economic crises on mental health inequalities.

Effect of lipegfilgrastim administration as prophylaxis of chemotherapy-induced neutropenia on dose modification and incidence of neutropenic events: real-world evidence from a non-interventional study in Belgium and Luxembourg.

Objectives: This study evaluated the effect of lipegfilgrastim, a glycopegylated granulocyte-colony stimulating factor, used as primary (PP) or secondary prophylaxis (SP) on chemotherapy (CT) treatment modifications, as well as the incidence of CT-induced neutropenic events in adult patients receiving cytotoxic CT with or without biological therapy (BT) for solid and hematological tumors, in routine clinical practice. Other objectives were to characterize the population of lipegfilgrastim-treated cancer patients and safety assessment. Methods: This phase 4, prospective, observational study was conducted at 15 centers from Belgium and Luxembourg, between 2015 and 2017. Results: Of 139 patients, 82.7% had breast cancer and 54.7% were treated with dose-dense regimens. Most received lipegfilgrastim as PP (82.0%) and were at high-risk of febrile neutropenia (FN) (68.3%). FN and grade III/IV neutropenia were reported for 7.9% and 22.3% patients. Among 123 evaluated patients, CT/BT dose modifications were recorded for 33.3% (PP) and 52.4% (SP) of patients receiving lipegfilgrastim; dose reductions, followed by dose delays, were more frequent than omissions. Among 45 patients with dose modifications, FN was reported for 8.8% and 9.1% patients and grade IV neutropenia for 17.6% and 18.2% of patients when lipegfilgrastim was applied for PP and SP, respectively. Adverse events related to lipegfilgrastim occurred for 55 (39.6%) patients; bone pain and back pain were more frequent. Lipegfilgrastim-related serious adverse events were reported for 9 (6.5%) patients. Conclusion: Use of lipegfilgrastim in real-world settings resulted in limited CT dose modifications and low incidences of neutropenic events, with no new safety concerns arising.

B Cells Are Multifunctional Players in Multiple Sclerosis Pathogenesis: Insights from Therapeutic Interventions.

Multiple sclerosis (MS) is a severe disease of the central nervous system (CNS) characterized by autoimmune inflammation and neurodegeneration. Historically, damage to the CNS was thought to be mediated predominantly by activated pro-inflammatory T cells. B cell involvement in the pathogenesis of MS was solely attributed to autoantibody production. The first clues for the involvement of antibody-independent B cell functions in MS pathology came from positive results in clinical trials of the B cell-depleting treatment rituximab in patients with relapsing-remitting (RR) MS. The survival of antibody-secreting plasma cells and decrease in T cell numbers indicated the importance of other B cell functions in MS such as antigen presentation, costimulation, and cytokine production. Rituximab provided us with an example of how clinical trials can lead to new research opportunities concerning B cell biology. Moreover, analysis of the antibody-independent B cell functions in MS has gained interest since these trials. Limited information is present on the effects of current immunomodulatory therapies on B cell functions, although effects of both first-line (interferon, glatiramer acetate, dimethyl fumarate, and teriflunomide), second-line (fingolimod, natalizumab), and even third-line (monoclonal antibody therapies) treatments on B cell subtype distribution, expression of functional surface markers, and secretion of different cytokines by B cells have been studied to some extent. In this review, we summarize the effects of different MS-related treatments on B cell functions that have been described up to now in order to find new research opportunities and contribute to the understanding of the pathogenesis of MS.

Targets of the humoral autoimmune response in multiple sclerosis.

Multiple sclerosis (MS) is an inflammatory disorder of the central nervous system (CNS) with heterogeneous clinical, genetic and pathophysiological characteristics. The establishment of reliable biomarkers for diagnosis, prognosis and treatment of MS has therefore proven to be very difficult. During the last decades, mounting evidence has been collected for the involvement of B cells and antibodies in MS pathogenesis. A wide variety of autoantibodies has been described in MS and these autoantibodies could be useful biomarkers for MS. Since demyelination is a key component of MS pathogenesis, myelin antigens were first investigated as primary targets of autoantibodies in MS. More recently, it became evident that the humoral autoimmune response is not restricted to myelin but is much more widespread throughout the brain. Autoantibodies are formed against different CNS cell types, including neurons, oligodendrocytes and astrocytes, and even immune cells, indicating the complex heterogeneity of the disease. In this review, we give an extensive overview of the known autoantibody targets in MS, not according to the traditional subdivision of myelin and non-myelin components but according to each of the affected cell types, including the most recently described target antigens.

Compositional changes of B and T cell subtypes during fingolimod treatment in multiple sclerosis patients: a 12-month follow-up study.

BACKGROUND AND OBJECTIVE: The long term effects of fingolimod, an oral treatment for relapsing-remitting (RR) multiple sclerosis (MS), on blood circulating B and T cell subtypes in MS patients are not completely understood. This study describes for the first time the longitudinal effects of fingolimod treatment on B and T cell subtypes. Furthermore, expression of surface molecules involved in antigen presentation and costimulation during fingolimod treatment are assessed in MS patients in a 12 month follow-up study. METHODS: Using flow cytometry, B and T cell subtypes, and their expression of antigen presentation, costimulation and migration markers were measured during a 12 month follow-up in the peripheral blood of MS patients. Data of fingolimod-treated MS patients (n = 49) were compared to those from treatment-naive (n = 47) and interferon-treated (n = 27) MS patients. RESULTS: In the B cell population, we observed a decrease in the proportion of non class-switched and class-switched memory B cells (p<0.001), both implicated in MS pathogenesis, while the proportion of naive B cells was increased during fingolimod treatment in the peripheral blood (PB) of MS patients (p<0.05). The remaining T cell population, in contrast, showed elevated proportions of memory conventional and regulatory T cells (p<0.01) and declined proportions of naive conventional and regulatory cells (p<0.05). These naive T cell subtypes are main drivers of MS pathogenesis. B cell expression of CD80 and CD86 and programmed death (PD) -1 expression on circulating follicular helper T cells was increased during fingolimod follow-up (p<0.05) pointing to a potentially compensatory mechanism of the remaining circulating lymphocyte subtypes that could provide additional help during normal immune responses. CONCLUSIONS: MS patients treated with fingolimod showed a change in PB lymphocyte subtype proportions and expression of functional molecules on T and B cells, suggesting an association with the therapeutic efficacy of fingolimod.

Autoantigen induced clonal expansion in immortalized B cells from the peripheral blood of multiple sclerosis patients.

We studied Ig heavy chain (VDJ) sequences and antigen reactivity of 412 immortalized B cell lines from the peripheral blood of 10 multiple sclerosis (MS) patients, 4 clinically isolated syndrome (CIS) patients and 6 healthy controls (HCs). 78/238 (32.8%) MS and CIS B cell lines were part of 9 clonally expanded B cell populations, of which 5 were present in multiple patients. Increased VH1 gene family usage was evidenced for MS B cells, with 29.2% expressing VH1-69. Affinity maturation in MS and CIS was indicated by increased Ig VDJ mutations. Autoantibody producing B cells reactive to intracellular antigens were significantly higher in MS (25%) and CIS (28%) patients than in HCs (5%), including 3/9 expanded B cell clones. Specificity for phosphatidylcholine was observed for 1/9 B cell clones. These findings indicate clonally expanded autoreactive B cells with affinity maturation in the peripheral blood in MS and CIS.