Frequent Relapses Research Articles

Enhancing T cell cytotoxicity in multiple myeloma with bispecific αPD-L1 × αCD3 T cell engager-armed T cells and low-dose bortezomib therapy.

Multiple myeloma (MM) is an incurable plasma cell malignancy characterized by frequent relapse due to acquired treatment resistance, underscoring the need for innovative therapies, particularly for relapsed cases. This study explores the effects of low-dose bortezomib (BTZ) on programmed death ligand 1 (PD-L1) expression in MM cell lines and its potential to enhance T cell-mediated anti-tumor responses. Utilizing this PD-L1 upregulation, we employed bispecific αPD-L1 × αCD3 T cell engager-armed T cells (BATs) to block PD-L1 signaling and activate T cells. Flow cytometry confirmed that BATs selectively bound CD3 on T cells and PD-L1 on cancer cells, inducing T cell activation and proliferation without directly affecting cancer cell viability. BATs' cytotoxic activity was evaluated in MM cell lines with or without BTZ-induced PD-L1 expression. While KMS-12-PE cells showed no significant response, BATs significantly increased cell death in L363 cells, with further enhancement by BTZ. In RPMI-8226 cells, BATs demonstrated robust cytotoxicity, further amplified by BTZ. These results suggest that BATs, particularly in combination with BTZ, represent a promising strategy for treating MM, including bortezomib-resistant cases.

Targeting NF-kappaB-inducing kinase shapes B-cell homeostasis in myasthenia gravis

BackgroundB cell immune dysregulation plays a critical role in myasthenia gravis (MG). However, targeted B-cell therapy such as rituximab may result in long-term peripheral B cell clearance and allow for the survival of plasma cells, contributing to frequent infections and relapses. Therefore, we aimed to identify potential novel therapeutic targets that preserve part of B cell function while inhibiting antibody-secreting cells (ASCs).MethodsThe transcriptome of sorted CD19+B cells obtained from MG patients in active and remission state was performed by RNA sequencing. The hallmark gene NF-kappaB-inducing kinase (NIK/MAP3K14) associated with NF-κB and TNF signaling was identified, and the expression levels of NIK in CD19+B cells, CD4+T cells and serum from new-onset MG patients and controls were validated by flow cytometry, qPCR and ELISA. In vitro and in vivo, the effects of NIK inhibitor (B022) on the function of CD19+B cells and CD4+T cells were detected under the MG PBMCs, sorted B cells and experimental autoimmune MG (EAMG) rat model, respectively.ResultsThe expression levels of NIK were upregulated in CD19+B cells, CD4+T cells and serum from new-onset MG patients. Notably, increased serum NIK levels were positively correlated with disease severity and decreased with disease remission. NIK inhibitor B022 significantly reduced B-cell activation, proliferation, ASCs differentiation and pathogenic function, as well as CD4+T cell activation and Th17 cells differentiation in vitro. Intraperitoneal injection of B022 ameliorated the severity of EAMG rats, and reduced proportion of pathogenic B and T cell subsets, antibody levels and postsynaptic membrane damage.ConclusionsTargeting NIK with small molecule kinase inhibitors can effectively shape B cell homeostasis, and exhibit protective effects in the EAMG rat model, which may be an effective novel treatment strategy for MG.

XPO1/Exportin-1 in Acute Myelogenous Leukemia; Biology and Therapeutic Targeting

Exportin 1 is responsible for the export of hundreds of proteins, several RNA species and ribosomal components from the nucleus to the cytoplasm. Several transported proteins are important for regulation of cell proliferation and survival both in normal and malignant cells. We review the biological importance and the possibility of therapeutic targeting of Exportin 1 in acute myeloid leukemia (AML). Exportin 1 levels can be increased in human primary AML cells, and even exportin inhibition as monotherapy seems to have an antileukemic effect. The results from Phase I/II studies also suggest that exportin inhibition can be combined with conventional chemotherapy, including intensive induction and consolidation therapy possibly followed by allogeneic stem cell transplantation as well as AML-stabilizing therapy in elderly/unfit patients with hypomethylating agents. However, the risk of severe toxicity needs to be further evaluated; hematological toxicity is common together with constitutional side effects, electrolyte disturbances, and gastrointestinal toxicity. A recent randomized study of intensive chemotherapy with and without the Exportin inhibitor selinexor in elderly patients showed reduced survival in the selinexor arm; this was due to a high frequency of relapse and severe infections during neutropenia. Experimental studies suggest that Exportin 1 inhibition can be combined with other forms of targeted therapy. Thus, Exportin 1 inhibition should still be regarded as a promising strategy for AML treatment, but future studies should focus on the risk of toxicity when combined with conventional chemotherapy, especially in elderly/unfit patients, combinations with targeted therapies, identification of patient subsets (AML is a heterogeneous disease) with high susceptibility, and the possible use of less toxic next-generation Exportin 1 inhibitors.

P0160 Vitamin D and FGF-19 in patients with Inflammatory Bowel Disease

Abstract Background Vitamin D (vit. D) has pleiotropic effects, and in recent years, its role in regulating the immune response has been widely discussed. Patients with IBD tend to have lower vit. D levels, and this may be associated with more frequent relapses, increased need for surgical interventions, and a slower response to antibody treatments. Methods An observational study was conducted at the Gastroenterology Department of UH "Saint Ivan Rilski," Sofia, Bulgaria, involving 47 patients with ulcerative colitis (UC) and 55 with Crohn’s disease (CD). We evaluated serum vit. D, laboratory markers, Fibroblast growth factor-19 (FGF-19) levels. Results Patients with IBD were equally distributed between females (49%) and males (51%). Subnormal vit. D levels were observed in 94% of patients with CD and in 98% of those with UC. This contrasts with the general Bulgarian population, where 76% have lower levels [1]. The mean serum value in patients with IBD was 40 nmol/L, which is insufficient. Vit. D was found to vary depending on treatment. IBD receiving corticosteroids or immunosuppressants had lower levels compared to those treated with biologic agents. The difference was a 13% decrease in CD and 10% in UC. This may be attributed to the inhibitory effects of corticosteroids on vit. D metabolism or the restricted sun exposure when taking azathioprine. The evaluated data revealed that vit. D had a statistically significant inverse correlation with laboratory markers such as C-reactive protein (CRP) (P = 0.0018, r = -0.351), leukocytes (P = 0.0069, r = -0.2661), erythrocyte sedimentation rate (P = 0.0022, r = -0.2992), thrombocytes (P = 0.0083, r = -0.2600), and the neutrophil-to-lymphocyte ratio (NLR) (P = 0.0011, r = -0.3175) and in UC fecal calprotectin (P= 0.0025, r= -0.4025) [2]. Serum FGF-19 levels were evaluated in all IBD and were lower in 8 patients with CD, with a mean level of 20 pg/mL. Six of them had ileocolitis and two had terminal ileitis, which is associated with probable bile acid malabsorption. In other studies was found that patients have bile acid diarrhea with levels of 60pg/mL [3,4]. Statistically significant correlation was observed between FGF-19 and vit. D levels (P = 0.232, r = 0.2836). Conclusion Patients with IBD tend to have insufficient levels of vit. D, due to corticosteroid treatment, reduced sun exposure while taking azathioprine. The role of vit. D in inflammation is worth discussing, as it may have a potential effect on inflammatory markers. In CD is a higher risk of bile acid diarrhea in terminal ileitis or ileocolitis. Serum FGF-19 concentrations in CD may be dependent on vit. D. It is also possible that bile acid diarrhea could be affected by vit. D status.

Impact of cuproptosis in gliomas pathogenesis with targeting options.

Gliomas constitute the most prevalent primary central nervous system tumors, often characterized by complex metabolic profile, genomic instability, and aggressiveness, leading to frequent relapse and high mortality rates. Traditional treatments are commonly ineffective because of gliomas increased heterogeneity, invasive characteristics and resistance to chemotherapy. Among several pathways affecting cellular homeostasis, cuproptosis has recently emerged as a novel type of programmed cell death, triggered by accumulation of copper ions. Although the precise molecular mechanisms of cuproptosis are not fully elucidated, there is evidence that copper ions can target mitochondrial lipoylated proteins, disrupting the tricarboxylic acid cycle and electron transport chain, thus leading to deregulated mitochondrial metabolism, protein aggregation and cell death. Of importance, altered expression of copper transporters and abnormally high intracellular copper levels have been observed in several cancer types, including gliomas, contributing to tumor growth and metastasis. Furthermore, a range of prognostic models incorporating cuproptosis-related genes and lncRNAs have been proposed and are currently under clinical validation. Drugs modulating cuproptosis or interfering with copper-binding proteins are under development, causing metabolic failure and cell death, thus offering potential new avenues for glioma diagnosis and therapy. In this article, we explore the role of copper metabolism in gliomas and the potential synergistic effects of cuproptosis-based treatments with current therapies, in effective targeting of tumor progression and chemoresistance.

Ekspresi Emosi dari Keluarga yang Memiliki Pasien Penyakit Skizofrenia

Schizophrenia is a syndrome characterized by a disturbance in an individual's behavior that makes the individual's behavior strange. Individuals will also experience delusions, hallucinations and emotions. This study aims to analyze the expression of emotions of families who have family members with schizophrenia. Then also to find out the dynamics and impact on the family. This research is a qualitative research with literature review method by collecting and analyzing relevant articles published from 2014-2024. The form of article collection uses the Google Scholar database. Based on the source of the article, the results obtained show that the emotional expression of the family of schizophrenia patients can affect the frequency of relapse in patients. High emotional expression in patients such as excessive criticism and hostile behavior can cause intense relapse in patients. While low emotional expression and providing more support to patients can reduce the frequency of relapse and improve the recovery process in schizophrenia patients. This study focuses on the importance of emotional management in families and providing more support as an effort to care for schizophrenic patients

Host-microbe multi-omics and succinotype profiling have prognostic value for future relapse in patients with inflammatory bowel disease

ABSTRACT Crohn’s disease (CD) and ulcerative colitis (UC) are chronic relapsing inflammatory bowel disorders (IBD), the pathogenesis of which is uncertain but includes genetic susceptibility factors, immune-mediated tissue injury and environmental influences, most of which appear to act via the gut microbiome. We hypothesized that host-microbe alterations could be used to prognostically stratify patients experiencing relapses up to four years after endoscopy. We therefore examined multiple omics data, including published and new datasets, generated from paired inflamed and non-inflamed mucosal biopsies from 142 patients with IBD (54 CD; 88 UC) and from 34 control (non-diseased) biopsies. The relapse-predictive potential of 16S rRNA gene and transcript amplicons (standing and active microbiota) were investigated along with host transcriptomics, epigenomics and genetics. While standard single-omics analysis could not distinguish between patients who relapsed and those that remained in remission within four years of colonoscopy, we did find an association between the number of flares and a patient’s succinotype. Our multi-omics machine learning approach was also able to predict relapse when combining features from the microbiome and human host. Therefore multi-omics, rather than single omics, better predicts relapse within 4 years of colonoscopy, while a patient’s succinotype is associated with a higher frequency of relapses.

Unveiling Pediatric Neurosarcoidosis Mimicking Central Nervous System Tuberculosis: Diagnostic Challenges.

Neurosarcoidosis is a rare chronic inflammatory disease affecting the nervous system. Owing to its varying manifestations that can mimic other central nervous system infectious or autoimmune diseases, and scarcity of literature, it proves to be a challenging diagnosis. We report two cases of possible neurosarcoidosis in the pediatric age group. Our first patient presented to us with seizures at the age of 13 years, whereas our second patient presented with headaches and vomiting at the age of 10 years. Both patients had elevated cerebrospinal fluid protein levels and leptomeningeal enhancement on magnetic resonance imaging (MRI); however, one patient also had a pituitary lesion. Tests for tuberculosis were negative for both. One of the 2 patients exhibited normal angiotensin-converting enzyme levels at the start of symptoms but later showed raised angiotensin-converting enzyme levels. His diagnosis was delayed as he was treated initially for central nervous system infections. His disease course showed frequent relapses with varying clinical symptoms. After trying steroids and different immunosuppressive agents, he was given a rituximab infusion, and he went into remission. Our cases contribute to the literature for addressing diagnostic and management challenges in children with neurosarcoidosis.

Primary prevention of post-molar gestational trophoblastic neoplasia in high-risk complete hydatidiform mole: A single-dose prophylactic actinomycin D, associated with uterine evacuation - a long retrospective cohort study.

To evaluate the efficacy of actinomycin D (ActD) as prophylactic chemotherapy (P-chem) in patients with high-risk complete hydatidiform mole (Hr-CHM) on progression to gestational trophoblastic neoplasia (GTN). From 1996 to 2023, 426 Hr-CHMs were selected in a cohort of 1623 patients with gestational trophoblastic disease (GTD). From 1996 to 2023, 290 patients with Hr-CHMs received a single bolus dose of Act-D at the time of uterine evacuation (Hr-CHM P-chem group); 136 with the same risk factors did not receive P-chem (Hr-CHM control group). The variables assessed in post-molar GTN were incidence and morbidity considering hCG serum level at diagnosis, relapse frequency, hysterectomy rates. Post-molar GTN was diagnosed in 19% of the patients with Hr-CHM P-Chem (55/290) and in 39.7% of the patients in the Hr-CHM control group (54/136) (P<0.001). The relative risk of developing post-molar GTN decreased by 52% (RR=0.48; 95% CI: 0.35-0.66; P<0.001), with a number needed to treat (NNT) of 5. Patients in the P-chem group had a lower hCG serum level (P=0.007), lower risk of recurrence (P=0.001) and lower risk of hysterectomy (P=0.04), with no effect on time to GTN diagnosis (P=0.09), first line chemotherapy response (P=0.50) and time to remission (P=0.72). A single bolus dose of Act-D (1.25mg/m2) given as P-chem during uterine evacuation in patients with Hr-CHM may safely prevent the incidence of post-molar GTN and reduce the morbidity associated with GTN. This prophylactic approach can be adopted at any trophoblastic disease center (TDC).

Quantitative susceptibility mapping is more sensitive and specific than phase imaging in detecting chronic active multiple sclerosis lesion rims: pathological validation

Abstract Quantitative susceptibility mapping and phase imaging are used to identify multiple sclerosis lesions with paramagnetic rims that slowly expand over time, and are associated with earlier progression to disability, decreased brain volume, and increased frequency of clinical relapse. However, the presence of iron-laden microglia/macrophages at the lesion rim and demyelination within the lesion both contribute to phase and quantitative susceptibility mapping images. Therefore, simultaneous pathological validation is needed to assess accuracies in identifying iron-positive lesions. MRI was performed on fifteen multiple sclerosis brain slabs; thirty-two lesions of interest were processed for myelin, iron, and microglial markers. Three experienced readers classified lesions as rim positive or negative on quantitative susceptibility mapping and phase; these classifications were compared with Perls’ stain as the gold standard. All ten of the quantitative susceptibility mapping-positive lesions had iron-positive rims on histology. Of the sixteen phase-positive lesions, only ten had iron-positive rims on histology. Using Perls’ stain as the ground truth, the positive predictive value was 100% for quantitative susceptibility mapping and 63% for phase; the negative predictive value was 95% for quantitative susceptibility mapping and 94% for phase. Post-mortem imaging results demonstrate that quantitative susceptibility mapping is a more reliable indicator of an iron-positive rim compared to phase imaging.

Heat shock protein 70 levels in children with nephrotic syndrome.

Idiopathic nephrotic syndrome (NS) is the most prevalent glomerular disease in children. Heat shock protein 70 (HSP70) is synthesized in response to diverse stress factors like infections and oxidative stress. We aimed to evaluate serum and urine levels of HSP70 in children with steroid-sensitive nephrotic syndrome (SSNS) and to assess changes in HSP70 levels with prednisolone treatment. Additionally, we seek to determine whether serum and urine levels of HSP70 can differentiate between frequently relapsing and infrequently relapsing cases in children with SSNS. A total of 36 patients with SSNS and 35 healthy children were included in the study. Samples were taken from all patients at four time points; before corticosteroid treatment (day 0) and on days 15, 30, and 90 after the initiation of corticosteroid treatment. Serum and urine levels of HSP70 were measured by enzyme-linked immunosorbent assay (ELISA). In the NS group before steroid treatment (day 0), urine HSP70 (uHSP70) levels and urine HSP70/creatinine (uHSP70/Cre) ratios were significantly higher (p<0.0001), whereas serum HSP70 (sHSP70) levels were lower (p=0.002), compared to the healthy group. uHSP70 levels decreased gradually during prednisolone treatment in the patient group (p<0.0001). There was no difference in terms of sHSP70, uHSP70, and uHSP70/Cre ratios between patients with frequently relapsing and infrequently relapsing. Our study demonstrates that uHSP70 levels are elevated in SSNS prior to treatment and decrease with prednisolone therapy, reflecting reduced renal stress and damage. uHSP70 may be a useful biomarker for monitoring renal damage and treatment response. Serum and urine levels of HSP70, as well as uHSP70/Cre ratios, did not differentiate between frequent and infrequent relapses.

Finding ways to correct nonspecific vaginitis in menopausal women with obesity

Objective — to increase the effectiveness of treatment of nonspecific vaginitis in menopausal women with excess body weight and obesity through long-term lifestyle modification. Materials and methods. 1178 patients aged 45—55 years were examined, including 317 with nonspecific vaginitis, who were divided into 3 study groups: with a healthy body weight, overweight and obesity. Each group was divided into three subgroups of comparison with standard therapy and three study groups that applied long-term lifestyle modification (actively and systematically used behavioral therapy, physical activity and a low-calorie diet) for 6 months. The control group consisted of 72 volunteers. Results and discussion. In the study subgroups of women who used long-term lifestyle modification, recurrences of nonspecific vaginitis were less frequent than in the corresponding comparison subgroups. Thus, after 6 months, in subgroups of women with a healthy body weight, the difference in the frequency of relapses after treatment was 40 % greater (34.2 vs 20.5 %), with excess body weight — 31.1 % (41.2 vs 28.4 %), with obesity — 29.8 % (55.1 vs 38.7 %). A significant deterioration in the state of the microbiota in menopausal patients with increased body weight and the effectiveness of the use of long-term lifestyle modification on its condition were established. It was proven that excess body weight and obesity in women negatively affected the frequency of nonspecific vaginitis, clinical picture, decreased quality of life, and frequency of relapses. Active and systematic use of behavioral therapy, physical activity, and a low-calorie diet in patients with nonspecific vaginitis in menopause had significant advantages in preventing relapses, compared to standard therapy, and in preserving and improving the quality of life of obese patients. Conclusions. Overweight and obese women are more likely than healthy women to suffer from nonspecific vaginitis, which is more severe and recurrent, accompanied by a decrease in quality of life and a disruption of the vaginal and skin biotope. After 6 months in obese postmenopausal women, the use of long-term lifestyle modification contributes to the restoration of the vaginal and skin microbiome, a decrease in the frequency of recurrences of nonspecific vaginitis and an improvement in quality of life compared with subgroups. with standard therapy. The best effect of treatment was observed in women with a healthy body weight, and the worst in the presence of obesity.

Dynamics of Clinical Manifestations and Social Functioning in Schizophrenia: A Non-interventional Observational Study of Paliperidone Palmitat Dosage Forms

BACKGROUND: Over the past seven years, the use of long-acting forms of antipsychotic medication has significantly increased in Russia. Specifically, in Moscow, from 2016 to 2021, the proportion of prescribed injectable long-acting antipsychotics had increased more than sevenfold (from 3% to 23%). Studies have shown that the correct selection of target groups for such therapy can reduce the frequency of relapses requiring hospitalization, lower the costs of inpatient care, and shift the focus of therapy from multiple drug administrations to psychosocial work. AIM: This study was aimed at evaluating changes over time in psychosocial functioning, as well as clinical and psychopathological manifestations, in patients with schizophrenia during early remission and while on therapy with different forms of paliperidone: oral paliperidone (OP), paliperidone palmitate administered once monthly (PP1M), and paliperidone palmitate administered once every three months (PP3M). METHODS: The observational study included 155 patients: 54 patients who had been treated with another second-generation antipsychotic received OP, 50 patients who had been treated with another antipsychotic received PP1M injections, and 51 patients who had been in remission for four months after treatment with PP1M received PP3M. The duration of the follow-up period was 12 months. Assessment of personal and social functioning was conducted five times: before the start of treatment, and 3, 6, 9, and 12 months later. RESULTS: Treatment in all groups led to a statistically significant reduction in the severity of positive symptoms (p 0.001). Hallucinations proved more susceptible to therapy (p 0.001), while persistent delusions showed greater treatment resistance. Significantly more patients in the PP1M and PP3M groups had completed the entire program (n=24; 48.0%, and n=30; 58.8%, respectively) compared to the OP group (n=11; 20.4%). The PP3M group demonstrated the highest treatment adherence, with the largest number of patients completing the study, and a similar rate of exacerbations or inadequate efficacy compared to the other groups. CONCLUSION: Treatment with different forms of paliperidone provides a roughly equal pace reduction in the severity of schizophrenia, including positive and negative symptoms. The PP3M group had better adherence and the highest number of patients who fully completed the study.

Assessment of dyspepsia in the era of endoscopic ultrasonography

Dyspepsia is one of the commonest indications for referral to gastroenterology and endoscopy assessment. It includes a wide range of differential diagnosis and variety of pathologies that needs further assessment in depth. Initial evaluation should focus on the identification and treatment of potential causes of symptoms such as peptic ulcer disease and medication side effects but also on recognizing those at risk for more serious conditions such as cancer or premalignant lesions. Dyspepsia is common in clinical practice with frequent relapses that often requires multiple investigations to assess intraluminal and extraluminal aetiologies. The basic gastroscopy represents a widely used tool for dyspepsia assessment for specific indications. Endoscopic ultrasonography (EUS), introduced into gastroenterological diagnostics more than 20 years ago, has undergone extensive evaluation of its diagnostic capability, probably to a larger extent than most other endoscopic and other imaging techniques in gastroenterology. The introduction of EUS in the recent era added the benefit of better visualization, assessment of layers and lesions and sampling for histological and pathological guidance. In this article, we aim to review the diagnostic yield in different causes of dyspepsia. We will also shed some light on role of EUS in staging of specific causes of dyspepsia including gastric, pancreatic, biliary and subepithelial lesions.

CHRONIC RECURRENT HERPETIC STOMATITIS: STRATEGIES FOR COMPREHENSIVE PATIENT’S EXAMINATION

Introduction. This research paper highlights the diagnosis and treatment of patients with chronic recurrent herpetic stomatitis, a condition caused by herpes simplex virus type 1. This disease is marked by frequent relapses, often triggered by stress, illness, or dental procedures. The aim of this study is to assess the effectiveness of using questionnaires and modern diagnostic tests to improve the accuracy of diagnosis and treatment outcomes. Subjects and materials. A total of 40 patients aged 20 to 45 were evaluated using a questionnaire and an initial clinical assessment. Recurrences were confirmed in 67.5% of the patients, with four individuals exhibiting clinical manifestations of the disease at the time of examination. Additional laboratory tests were prescribed for those presenting symptoms of chronic recurrent herpetic stomatitis. These tests included a complete blood count, IgG testing for herpes simplex virus, vitamin D level assessment, and a biochemical blood analysis focusing on liver function. Patients were also referred to relevant specialists, including an internist, a neurologist, and an infectious disease expert. Results. Based on the laboratory results, personalized treatment plans were developed, which included Valtrex (an antiviral medication), essential phospholipids, Ibuprofen (as needed), and local diode laser therapy. This approach yielded positive results, with patients reporting reduced itching and pain, and noticeable healing beginning as early as the fourth day of treatment. The author concludes that stress is a significant factor contributing to the recurrence of herpetic stomatitis. The use of advanced diagnostic techniques, such as immunological tests with molecular markers (including polymerase chain reaction, immunofluorescence methods, and enzyme-linked immunosorbent assays), enables highly accurate detection of the virus’s activity. Furthermore, a comprehensive patient history and questionnaire can help refine treatment strategies and enhance prevention efforts through the application of the latest physiotherapeutic methods.

Optimizing Drug Selection in Children with Multiple Sclerosis: What Do We Know and What Remains Unanswered?

Pediatric-onset multiple sclerosis (POMS) refers to multiple sclerosis with onset before 18 years of age. It is characterized by a more inflammatory course, more frequent clinical relapses, and a greater number of magnetic resonance imaging (MRI) lesions compared with adult-onset MS (AOMS), leading to significant impacts on both disability progression and cognitive outcomes in affected individuals. Managing POMS presents distinct challenges due to the unique needs of pediatric patients and the limited number of disease-modifying therapies (DMTs) approved for pediatric use. Notably, only one therapy (fingolimod) is approved by the United States (US) Food and Drug Administration (FDA) and three (fingolimod, teriflunomide, and dimethyl fumarate) by the European Medicines Agency (EMA) for use in youth with MS. However, observational evidence identifies use of almost all agents off-label in this population. This review provides a comprehensive overview of literature supporting the use of DMTs for POMS, including evidence from observational studies. In this paper, we highlight the shift in clinical practice, which has led to increased use of high-efficacy therapies (HETs) at or near disease onset. We review emerging evidence indicating better cognitive and motor outcomes in this population with early initiation of therapy. Finally, in this paper, we provide a suggested treatment algorithm for managing POMS. We underscore the need for personalized approaches in POMS management. We identify special considerations unique to pediatric care, including attention to family dynamics, and strategies to improve medication adherence and a smooth transition to adult care. Further research on DMTs in POMS is essential to optimize outcomes and improve long-term prognosis.

Machine learning methods for spectrally-resolved imaging analysis in neuro-oncology

To reduce the frequency of relapses after surgical removal a brain tumor, it is critically important to completely remove all affected areas of the brain without disrupting the functionality of vital organs. Therefore, intraoperative differential diagnostics of micro-areas of tumor tissue with their subsequent removal or destruction is an urgent task that determines the success of the operation as a whole. Optical spectroscopy has shown its advantages over the past decade when used as a tool for intraoperative metabolic navigation. And one of the most promising options for the development of this technology is spectrally-resolved imaging. Currently, methods of spectrally-resolved imaging in diffusely reflected light have been developed, for example, mapping the degree of hemoglobin oxygen saturation, as well as fluorescence visualization systems, for both endogenous fluorophores and special fluorescent markers. These systems allow rapid analysis of tissue by the composition of chromophores and fluorophores, which allows the neurosurgeon to differentiate tumor and normal tissues, as well as functionally significant areas, during surgery. No less mandatory are the methods of using spectrally resolved visualization based on mapping characteristics obtained from Raman spectra, but due to the smaller cross-section of the process, these methods are used ex vivo, as a rule, for urgent analysis of fresh tissue samples. In this paper, we focus on both the physical foundations of such methods and a very important aspect of their application – machine learning (ML) methods for image processing and tissues’ classification.

Remission induction therapies and long-term outcomes in granulomatosis with polyangiitis and microscopic polyangiitis: real-world data from a European cohort

To explore disease characteristics, renal involvement and induction treatment strategies over the last decades and evaluate relapse rates and renal outcomes in ANCA-associated vasculitides (AAV). We retrospectively analyzed remission, relapse rates and the occurrence of the composite endpoint (comprising death and renal failure) in newly diagnosed AAV cases in four tertial referral centers in Germany and Switzerland diagnosed between 1999 and 2022. Hazard ratios were computed by Cox proportional hazard and Kaplan–Meier curves were plotted to compare therapeutic strategies after propensity-matching. In our cohort of 358 AAV patients, 203 (58.1%) were classified as granulomatosis with polyangiitis (GPA) based on the novel 2022 ACR/EULAR criteria, 139 (38.8%) as microscopic polyangiitis (MPA). The proportion of MPA cases among all AAV patients increased from 28.9% between 1999 and 2013 up to 46.7% thereafter. Cyclophosphamide (CYC) was chosen most frequently for remission induction (74.8% before 2013 and 57.3% thereafter), whereas the use of rituximab (RTX) increased from 5 to 26% within these periods. GPA patients had a higher relapse rate as compared to MPA patients (41.3% vs. 25.9%, p = 0.006). However, in AAV patients with renal involvement, renal events (i.e. end-stage kidney disease or a persistent drop in the estimated glomerular filtration rate (eGFR) below 15 ml/min/1.73 m2) occurred more frequently in MPA patients, particularly under RTX treatment as compared to matched CYC counterparts (11.8% vs. 7.5%, p = 0.011). In our cohort, GPA patients exhibited frequent relapses, advocating for a more intense and extended treatment. MPA patients had lower relapse rates, however, RTX was less effective to prevent renal endpoints in MPA as compared to CYC, highlighting the need to further investigate additional treatment strategies.

Short and long-term outcome of levamisole in early versus late steroid responsive nephrotic syndrome: A single centre experience.

To determine the effectiveness of Levamisole (Leva) in maintaining short-term and long-term remission in early steroid responders (ESRs) and late steroid responders (LSRs). This retrospective study on 106 cohorts, aged 2-14 years with frequent-relapsing (FR) and steroid-dependent nephrotic syndrome (SDNS) who received Leva over 10-years (2012-2023), was carried out at tertiary care centre, Karachi from January-August 2023. Patients were categorized based on steroid response during first episode of NS as ESRs if complete remission (CR) was achieved within two weeks of daily steroid and LSRs if CR achieved between two-four weeks. Leva was administered after inducing remission with daily steroid after labelling as FRNS and SDNS. Low-dose steroid was continued during Leva-therapy. Short-term outcome was assessed at completion of Leva and long-term outcome in terms of CR, relapse frequency, alternative immunosuppressive agents (ISAs) use and compliance was assessed at six, 12 and 36-months' follow-up while off levamisole therapy. Leva was used in 106 patients (male 67%) for 20.4±8months during the study period. The mean age at Leva-initiation was 6.3±3 years. Eighty-three were FRNS and 23 SDNS. ESRs were 64 and 42 were LSRs. Overall, Leva was effective in maintaining short-term CR (73%) at end of Leva and it was effective in both ESRs (75%) and LSRs (69%, p=0.51) as well as in FRNS (72%) and SDNS (74%), P=0.08). Post-Leva follow-up duration was 36±31 months. Long-term Leva was effective in both ESRs and LSRs (p=0.51). Complete remission in 22,17 and 26%; infrequent relapses in 50,40 and 5% and alternate ISAs use in 24,39 and 55% at six,12 and 36 months follow-up respectively. Levamisole was effective in maintaining short-term and long-term remission in early and late initial steroid responsive nephrotic syndrome.

Bone-Marrow-Targeted Nanocomposite Abrogates C-Myb-Survivin Cross Talk in MLL-AF9-Rearranged Acute Myeloid Leukemia in In Vitro and In Vivo Patient-Derived Xenograft Models.

The heterogeneous form of malignancy in the myeloid lineage of normal hematopoietic stem cells (HSCs) is characterized as acute myeloid leukemia (AML). The t(9;11) reciprocal translocation (p22;q23) generates MLL-AF9 oncogene, which results in myeloid-based monoblastic AML with frequent relapse and poor survival. MLL-AF9 binds with the C-Myb promoter and regulates AML onset, maintenance, and survival. The bone marrow microenvironment (BMM) protects leukemia stem cells (LSCs) from therapeutic agents, which can lead to relapsed condition. Targeting leukemia BMM can be a viable therapeutics approach for AML treatment, wherein bone homing bisphosphonate, ibandronic acid (IBD), can localize to the BMM. In order to target the BMM of AML, C-Myb siRNA was entrapped in Vitamin D nanoemulsion-functionalized with BMM-targeted IBD, which exhibited binding with ex vivo bone slices and localization into mice bone marrow. IBD functionalization and C-Myb siRNA nanotherapy enhanced the suppression of LSCs (c-Kit+) and the upregulation of myeloid differentiation markers CD11b and Gr-1 in peripheral blood and bone marrow of athymic nude mice and patient-derived xenograft models. IBD functionalization enhanced the downregulation of C-Myb and C-Myb-Survivin cross talk in bone marrow and spleen tissue responsible for AML onset, maintenance, and pathogenesis. Further C-Myb binding to Survivin promoter was abrogated by the present bone-marrow-targeted nanotherapy, signifying its translational potential for AML therapeutics.