CIS Patients Research Articles

The relationship between optic nerve sheath diameter and demographic and clinical findings in patients diagnosed with clinically isolated syndrome

Aim: This study aimed to assess optic nerve sheath diameter (ONSD) levels in patients diagnosed with clinically isolated syndrome (CIS) who were being followed in the demyelinating diseases clinic, as well as to examine their relationship with demographic characteristics and clinical findings. Material and Methods: In this cross-sectional prospective study, 14 patients diagnosed with CIS who underwent lumbar puncture for specific cerebrospinal fluid (CSF) analysis were included between January 2024 and August 2024. The ONSD were measured by transorbital sonography. All patients' demographic characteristics, clinical parameters (CSF protein, CSF albumin, serum albumin, immunoglobulin G index, and vitamin D) were recorded. Results: The patients had a mean age of 39.4 ± 12.8 years, and the majority were women. Oligoclonal bands were positive in all patients. The mean disease duration was 23.5 ± 7.6 days. The ONSD measurements for all patients ranged between 3.1 and 5.9 mm in the sagittal and axial planes of both eyes. There was a strong negative correlation between ONSD levels and age, diseases duration, CSF protein, CSF albumin, serum albumin, and immunoglobulin G index. Conclusion: This study demonstrated a significant relationship between ONSD and various clinical and laboratory parameters in patients diagnosed with CIS. These findings suggest that ONSD may serve as a valuable, non-invasive marker in assessing disease severity and progression in CIS patients.

Progression predictors of clinically isolated syndrome to multiple sclerosis: A prospective study in China

ObjectivesClinically isolated syndrome (CIS) is a preclinical phase of multiple sclerosis (MS). The progression rate of CIS to clinical definite MS (CDMS) varies significantly across different populations, and identifying predictors of progression is crucial for early diagnosis and treatment. We aimed to investigate predictors of progression from CIS to CDMS in a Chinese cohort. MethodsA single-center cohort study was conducted with newly diagnosed patients with CIS in China between 2018 and 2021. All patients underwent a comprehensive clinical evaluation, including neurological examination, magnetic resonance imaging, and laboratory tests. Follow-up assessments were conducted at regular intervals to monitor disease progression. Progression to CDMS was defined according to the 2017 McDonald criteria. Age, sex, Expanded Disability Status Scale (EDSS) score, number of patients with magnetic resonance imaging gadolinium-enhancing (Gd+) lesions, T2 lesions and Gd+ lesions count, CSF cell count, CSF total protein, CSF and serum neurofilament light chain (NfL), progranulin (PGRN) and Th17-related cytokines (IL-6, IL-17, IL-21, IL-22, IL-23 and TGF-β) were measured for association with risk of progression to CDMS. ResultsA total of 96 CIS patients were recruited in the study. During the at least 24 months follow-up period, 57 (59.38 %) CIS patients progressed to CDMS, while 39 (40.62 %) patients without progression remained stable as CIS. Multivariate analysis revealed that younger age at onset (OR= 43.43, 95 % CI= 1.76–1071.68, p<0.021), higher CSF elevated protein (OR=58.64, 95 % CI=2.72–1264.51, p=0.009), higher CSF NfL levels (OR= 97.00, 95 % CI= 4.68–2012.99, p=0.003) and higher CSF IL-23 levels (OR= 412.02, 95 % CI=6.56–25869.60, p=0.004) were associated with high risk of progression to CDMS. ConclusionYounger age at onset, elevated CSF NfL, IL-23 and protein levels might be progression predictors of CIS to CDMS in Chinese population.

Diagnostic Utility of Free Kappa Light Chain Index in Egyptian Multiple Sclerosis Patients

Abstract Background Multiple sclerosis (MS) is a chronic autoimmune-mediated demyelinating disease of the central nervous system (CNS) that is usually associated with varying degrees of progressive disability. Free Kappa light chain (FKLC) has attracted growing attention as a significant diagnostic marker of MS. Aim of the Work The aim of this work was to study the diagnostic utility of free kappa light chain index in a sample of Egyptian MS patients versus IgG oligo clonal bands (OCBs) in CSF and serum in an attempt to throw light on a new simpler non subjective potential diagnostic marker in MS. Patients and Methods This was a case control study of MS patients carried at Ain Shams University Hospitals during the period from January 2021 till January 2022. Subjects included in this study were 30 patients with symptoms suggestive of MS yet undiagnosed and 20 controls, on the basis of their MRI findings, clinical presentation and according to the revised McDonald criteria 2017. Accordingly, patients were diagnosed as MS including 4 CIS patients, 18 RRMS patients and 3 PPMS patients and non-MS including 2 NMO patients, 1 ADEM patient, 1 APS and 1 SLE patient. They were 8 males and 22 female patients, their age ranged from 20 to 40 years old with mean 30.13 ± 6.85 SD. The control group included 5 males and 15 females; their ages ranged from 20 to 40 years with mean 30.13 ± 6.85 SD. Results We found a statistically significantly higher FKLC index and FKLC IF among MS patients in comparison to both control and non-MS group. it could be used for diagnosis of MS with a diagnostic sensitivity of 100 % and a diagnostic specificity of 100 %. Conclusion The significant association between FKLC index and MS led us to conclude FKLC index can be used as a promising diagnostic marker of MS.

COGNITIVE IMPAIRMENT IN DIFFERENT CLINICAL FORMS OF MULTIPLE SCLEROSIS

Purpose: The aim of the study is to investigate cognitive impairment (CI) in patients with different clinical forms of Multiple Sclerosis (MS) and to propose a suitable cognitive evaluation based on available tools for diagnosis and monitoring purposes. Materials and Methods: The following tests were used: Paced Auditory Serial Addition Test (PASAT), Symbol Digit Modalities Test (SDMT), Brief Visuospatial Memory Test-Revised (BVMT-R), Expanded Disability Status Scale (EDSS) and Magnetic Resonance Tomography 1.5Т (МRТ) in 60 consecutive patients; 22 were with first demyelination episode and 38 with MS. The control group of 40 healthy persons matched for sex, age and years of education. The follow-up period is three years. Results: The average screening values of PASAT, SDMT, BVSMT-R are considerably lower (р&lt;0.05) in MS patients compared to the controls and CIS patients. Point's number in the progressive forms in comparison with RRMS is reliably smaller. There was no significant difference in results between SPMS and PPMS patients at screening (р&gt;0.05). In the 3rd year, there is a significant cognitive progression in all studied groups and for all tests (р&lt;0.05). Conclusion: The use of a neuropsychological screening test is a valuable method for registering CI in patients with relapsing-remitting course, as well as in patients with a progressive course of the disease. We recommend the SDMT for screening annual follow-up because it is easy to apply, validate and reliably report the progression of CI. In patients with visual disturbances and with arm weakness, it is better to use PASAT, taking into account the level of education and depression.

A paclitaxel-hyaluronan conjugate (ONCOFID-P-B™) in patients with BCG-unresponsive carcinoma in situ of the bladder: a dynamic assessment of the tumor microenvironment

BackgroundThe intravesical instillation of the paclitaxel-hyaluronan conjugate ONCOFID-P-B™ in patients with bacillus Calmette-Guérin (BCG)-unresponsive bladder carcinoma in situ (CIS; NCT04798703 phase I study), induced 75 and 40% of complete response (CR) after 12 weeks of intensive phase and 12 months of maintenance phase, respectively. The aim of this study was to provide a detailed description of the tumor microenvironment (TME) of ONCOFID-P-B™-treated BCG-unresponsive bladder CIS patients enrolled in the NCT04798703 phase I study, in order to identify predictive biomarkers of response.MethodsThe composition and spatial interactions of tumor-infiltrating immune cells and the expression of the most relevant hyaluronic acid (HA) receptors on cancer cells, were analyzed in biopsies from the 20 patients enrolled in the NCT04798703 phase I study collected before starting ONCOFID-P-B™ therapy (baseline), and after the intensive and the maintenance phases. Clinical data were correlated with cell densities, cell distribution and cell interactions. Associations between immune populations or HA receptors expression and outcome were analyzed using univariate Cox regression and log-rank analysis.ResultsIn baseline biopsies, patients achieving CR after the intensive phase had a lower density of intra-tumoral CD8+ cytotoxic T lymphocytes (CTL), but also fewer interactions between CTL and macrophages or T-regulatory cells, as compared to non-responders (NR). NR expressed higher levels of the HA receptors CD44v6, ICAM-1 and RHAMM. The intra-tumoral macrophage density was positively correlated with the expression of the pro-metastatic and aggressive variant CD44v6, and the combined score of intra-tumoral macrophage density and CD44v6 expression had an AUC of 0.85 (95% CI 0.68–1.00) for patient response prediction.ConclusionsThe clinical response to ONCOFID-P-B™ in bladder CIS likely relies on several components of the TME, and the combined evaluation of intra-tumoral macrophages density and CD44v6 expression is a potentially new predictive biomarker for patient response. Overall, our data allow to advance a potential rationale for combinatorial treatments targeting the immune infiltrate such as immune checkpoint inhibitors, to make bladder CIS more responsive to ONCOFID-P-B™ treatment.

Left atrial stiffness in young patients with cryptogenic stroke: insights from the SECRETO-study

Abstract Funding Acknowledgements Type of funding sources: Public grant(s) – National budget only. Main funding source(s): Finnish Medical Foundation. DC recieves funding from Helse Vest Background Cryptogenic ischemic stroke (CIS) in young adults is an increasing health issue with potentially different etiologies than stroke at older age. Low left atrial (LA) reservoir strain (LASr) is a predictor of both recurrent stroke and subclinical cerebral infarct in older populations. LASr and LA stiffness have not yet been explored in young CIS patients. Purpose To assess LA stiffness and associated factors in patients experiencing CIS before the age of 50 years. Methods In the prospective, multi-center SECRETO (Searching for Explanations for Cryptogenic Stroke in the Young: Revealing the Triggers, Causes, and Outcome) study, patients aged 18–49 years with first-ever imaging-proven CIS underwent echocardiography within 2 weeks after admission. LA volumes were measured at end-diastole (minimum) and end-systole (maximum) and LA strain assessed as LASr and contractile strain. LA stiffness was derived from the ratio: mitral peak E-wave velocity divided by the mitral annular e’ velocity (E/e´) / LASr and classified as increased for age if ≥ 0.22. Systemic arterial compliance (SAC) was calculated as the left ventricular Doppler stroke volume divided by pulse pressure. Results Among 146 CIS patients (mean age 39 ± 8 years, 45% women, 34% normal weight), LA stiffness was increased in 34% of patients and more often in overweight and obese patients with low SAC (p&amp;lt;0.001, Figure 1A). Patients with high LA stiffness for age had larger minimum LA volumes and LV mass, and lower LA ejection fraction (EF) and LA contractile strain (p&amp;lt;0.001, Figure 1B). In multivariate regression analysis, increased LA stiffness was independently associated with higher age and body mass index, and lower LA EF and SAC after adjustment for sex and LV EF. In subsequent models, replacing LA EF with LA volume, increased LA stiffness was associated with larger minimum LA volume (p&amp;lt;0.001), but not maximum LA volume. Conclusion LA stiffness is increased in one-third of young patients with CIS, reflecting in part the cardiac remodeling induced by increased body mass index, reduced SAC, and ageing. This provides mechanistic insights into the link between these risk factors and the occurrence of CIS in young patients.

Relationship Between Sexual Orientation, Gender Identity, and Mental Health and Substance Use Disorder Disparities Among Federally Qualified Health Center Adult Patients: A Cross-Sectional Study

Sexual and gender minorities (SGMs) are at increased risk of adverse physical and mental health outcomes. Federally qualified health centers (FQHCs) provide healthcare to underserved and vulnerable populations to address socioeconomic health disparities. This study aims to explore whether SGM adult patients at a large, multisite FQHC in Connecticut, USA, are more likely than heterosexual, cisgender (cis) patients to have indications or diagnoses of depression, suicidal thoughts, and/or substance use disorders (SUDs) in their medical charts. We used retrospective data from the electronic health records of FQHC patients with a medical visit between April 2016 and June 2019 who had sexual orientation and gender identity documented in their chart. In addition to demographic variables, the extracted data included patients’ most recent Patient Health Questionnaire-9 and diagnostic codes for depression, suicidal thoughts, and SUDs. We conducted hierarchical logistic regressions and generalized linear and latent mixed models to answer our research questions. In comparison to heterosexual and cis patients, SGM patients had significantly higher odds of reporting severe depression, any depression, and/or suicidal thoughts. Compared to heterosexual women, sexual minority women were more likely to have an SUD in their medical chart. Bisexual men had higher odds of cannabis use disorder compared to heterosexual men. Compared to cis women, transgender women had higher odds of alcohol and opioid use disorders and having one or more SUDs. This study provides evidence of mental health and substance use disparities experienced by SGM patients at FQHCs.

Gender-Affirming Care for Cisgender People.

Gender-affirming care is almost exclusively discussed in connection with transgender medicine. However, this article argues that such care predominates among cisgender patients, people whose gender identity matches their sex assigned at birth. To advance this argument, we trace historical shifts in transgender medicine since the 1950s to identify central components of "gender-affirming care" that distinguish it from previous therapeutic models, such as "sex reassignment." Next, we sketch two historical cases-reconstructive mammoplasty and testicular implants-to show how cisgender patients offered justifications grounded in authenticity and gender affirmation that closely mirror rationales supporting gender-affirming care for transgender people. The comparison exposes significant disparities in contemporary health policy regarding care for cis and trans patients. We consider two possible objections to the analogy we draw, but ultimately argue that these disparities are rooted in "trans exceptionalism" that produces demonstrable harm..

Correlation between Lpa, APO-A, APO-B, and Stenosis of Middle Cerebral Artery in Patients with Cerebral Ischemic Stroke.

Ischemic stroke (CIS) is characterized by a high incidence, disability, and mortality. Numerous studies have demonstrated that intracranial arterial stenosis is an important pathological basis of CIS, and its main cause is atherosclerosis. Dyslipidemia is an important risk factor for atherosclerosis. Lysophosphatidic acid (Lpa), apolipoprotein -A(APO-A), and apolipoprotein -B(APO-B) proved to be significantly correlated with the severity of coronary artery disease. This study retrospectively collected the case data of 186 patients with CIS treated from May 2020 to May 2022 and explored the correlation between Lpa, APO-A, APO-B, and middle cerebral artery (MCA) stenosis in CIS patients.

Final clinical results of pivotal trial of IL-15RαFc superagonist N-803 with BCG in BCG-unresponsive CIS and papillary nonmuscle-invasive bladder cancer (NMIBC).

4508 Background: Patients with NMIBC CIS unresponsive to BCG have limited treatment options. N-803 (Anktiva) is a mutant IL-15-based immunostimulatory fusion protein complex (IL15RaFc) that promotes proliferation and activation of natural killer (NK) cells and CD8+ T cells, but not regulatory T cells. Phase 1b data in BCG-naïve patients with NMIBC demonstrate that intravesical administration of N-803 with BCG induced complete response in all patients, without recurrences for the study duration of 24 months. Pembrolizumab was approved in 2020 with a 41% complete response (CR) rate in a single arm phase 2 trial of 96 patients. We report data on 160 subjects from an open-label, 3 cohort multicenter study (QUILT 3.032) of intravesical BCG plus N-803 in patients with BCG-unresponsive high-grade NMIBC (NCT03022825). Methods: All treated patients received intravesical N-803 plus BCG, consistent with the standard induction/maintenance treatment schedule. The primary endpoint for Cohort A (CIS) is incidence of CR of CIS at any time. The primary endpoint for Cohort B (Papillary) is disease-free rate (DFS) at 12 months. Results: To date, we enrolled 160 patients (83 CIS, 77 Papillary). In the overall population, median age is 72.3 years, 81% male, with mean number of prior TURBT = 4. Median number of prior BCG doses = 12. CIS patients have a CR rate of 71% (59/83), with a mediation duration of CR of 24.1 months in responders; 91% avoided cystectomy and 96% 24 month bladder cancer specific progression free survival (defined as progression to MIBC). Papillary patients have a 57% 12 month DFS rate, 48% 24 month DFS rate, and 95% avoided cystectomy. Median time to cystectomy in responders (N = 4) is 12.9 months versus 7.8 in non-responders (N = 8) for a 5.1 month delay in cystectomy. PK data shows no systemic levels of N-803; activity is confined to the bladder. Low grade treatment related AEs (grade 1-2) include dysuria (22%), pollakiurua (19%), hematuria (18%), fatigue (16%), and urgency (12%), all other AEs were seen at 7% or less. No treatment related grade 4 or 5 AE were seen. No SAE's were considered treatment related. No immune related SAE's have been seen. Conclusions: In 160 patients with BCG-unresponsive NMIBC, there is a 99% bladder cancer specific overall survival at 2 years. In CIS patients 71% CR rate with 24.1 months median duration of response, and 53% DFS rate at 18 months in Papillary disease. Cystectomy was avoided in over 90% of patients with 2 years of follow-up. The efficacy and safety profile of N-803+BCG exceeds that of other available intravesical and systemic options for BCG-unresponsive NMIBC. Clinical trial information: NCT03022825.

PLLBA-01 FINAL CLINICAL RESULTS OF PIVOTAL TRIAL OF IL-15RΑFC SUPERAGONIST N-803 WITH BCG IN BCG-UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC) CIS AND PAPILLARY COHORTS

You have accessJournal of UrologyCME1 May 2022PLLBA-01 FINAL CLINICAL RESULTS OF PIVOTAL TRIAL OF IL-15RΑFC SUPERAGONIST N-803 WITH BCG IN BCG-UNRESPONSIVE NON-MUSCLE INVASIVE BLADDER CANCER (NMIBC) CIS AND PAPILLARY COHORTS Sam Chang, Karim Chamie, Mark Hidalgo, Eugene Kramolowsky, Wade Sexton, Sandeep Reddy, and Patrick Soon-Shiong Sam ChangSam Chang More articles by this author , Karim ChamieKarim Chamie More articles by this author , Mark HidalgoMark Hidalgo More articles by this author , Eugene KramolowskyEugene Kramolowsky More articles by this author , Wade SextonWade Sexton More articles by this author , Sandeep ReddySandeep Reddy More articles by this author , and Patrick Soon-ShiongPatrick Soon-Shiong More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002671.01AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Patients with NMIBC CIS unresponsive to BCG have limited treatment options. N-803 (Anktiva) is a mutant IL-15-based immunostimulatory fusion protein complex (IL15RaFc) that promotes proliferation and activation of natural killer (NK) cells and CD8+ T cells, but not regulatory T cells. Phase 1b data in BCG-naïve patients with NMIBC demonstrate that intravesical N-803 with BCG induced complete response in all patients, without recurrences for the study duration of 24 months. An open-label, 3 cohort multicenter study (QUILT 3.032) of intravesical BCG plus N-803 in patients with BCG-unresponsive high-grade NMIBC (NCT03022825) was opened. We report data on 160 subjects. METHODS: All treated patients received intravesical N-803 plus BCG, consistent with the standard induction/maintenance treatment schedule. The primary endpoint for Cohort A (CIS) is incidence of complete response (CR) of CIS at any time. The primary endpoint for Cohort B (Papillary) is disease-free rate (DFS) at 12 months. RESULTS: To date, 83 patients have enrolled in cohort A, 77 in Cohort B. In the overall population, median age is 72.3 years, 81% male, with mean number of prior TURBT=4. Median number of prior BCG doses = 12. CIS patients have a CR rate of 71% (59/83), with a mediation duration of CR of 24.1 months in responders; 91% avoided cystectomy and 96% 24 month bladder cancer specific progression free survival (defined as progression to MIBC). Papillary patients have a 57% 12 month DFS rate, 48% 24 month DFS rate, and 95% avoided cystectomy. Median time to cystectomy in responders (N=4) is 12.9 months versus 7.8 in non-responders (N=8) for a 5.1 month delay in cystectomy. PK data shows no systemic levels of N-803; thus activity is confined to the bladder. Low grade treatment related AEs (grade 1-2) include dysuria (22%), pollakiurua (19%), hematuria (18%), fatigue (16%), and urgency (12%), all other AEs were seen at 7% or less. No treatment related grade 4 or 5 AE were seen. No treatment emergent SAE's were considered treatment related. No immune related SAE's have been seen. Final data will be presented at AUA. CONCLUSIONS: In 160 patients with BCG-unresponsive NMIBC, there is a 99% bladder cancer specific overall survival at 2 years. In CIS patients 71% CR rate with 24.1 months median duration of response and 96% absence of progression to MIBC at 24 months. 53% DFS rate at 18 months in Papillary disease, N-803+BCG efficacy and safety profile exceeds other available intravesical and systemic options. Source of Funding: ImmunityBio © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e1047 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Sam Chang More articles by this author Karim Chamie More articles by this author Mark Hidalgo More articles by this author Eugene Kramolowsky More articles by this author Wade Sexton More articles by this author Sandeep Reddy More articles by this author Patrick Soon-Shiong More articles by this author Expand All Advertisement PDF DownloadLoading ...

Prognosis of a second clinical event from baseline MRI in patients with a CIS: a multicenter study using a machine learning approach

To predict the occurrence of a second clinical event in patients with a CIS suggestive of MS, from baseline magnetic resonance imaging (MRI), by means of a pattern recognition approach. Two hundred sixty-six patients with a CIS were recruited from four participating centers. Over a follow-up of 3years, 130 patients had a second clinical episode and 136 did not. Grey matter and white matter T1-hypointensities masks segmented from 3D T1-weighted images acquired on 3T scanners were used as features for the classification approach. Differences between CIS that remained CIS and those that developed a second event were assessed at a global level and at a regional level, arranging the regions according to their contribution to the classification model. All classification metrics were around or even below 50% for both global and regional approaches. Accuracies did not change when T1-hypointensity maps were added to the model; just the specificity was increased up to 80%. Among the 30 regions with the largest contribution, 26 were grey matter and 4 were white matter regions. For grey matter, regions contributing showed either a larger or a smaller volume in the group of patients that remained CIS, compared to those with a second event. The volume of T1-hypointensities was always larger for the group that presented a second event. Prediction of a second clinical event in CIS patients from baseline MRI seems to present a highly heterogeneous pattern, leading to very low classification accuracies. Adding the T1-hypointensity maps does not seem to improve the accuracy of the classification model.

Predictive Value of Apelin and Vaspin on Hemorrhagic Transformation in Patients with Acute Ischemic Stroke after Intravenous Thrombolysis and Analysis of Related Factors.

Background Acute ischemic stroke (CIS) is a high-risk condition among the elderly, and intravenous thrombolytic therapy (ITT) is the most effective means for it. However, ITT is prone to induce hemorrhagic transformation (HT) that further threatens the life and health of patients. As paramount substances in cardiovascular and cerebrovascular diseases, adipocyte factor (Apelin) and serine protease inhibitor (Vaspin) are strongly bound up with CIS. Objective To analyze the predictive significance of Apelin and Vaspin on HT in CIS patients after ITT and offer effective reference to HT prevention in the future. Methods A total of 109 CIS patients treated with intravenous thrombolysis (IT) in two hospitals between June 2017 and February 2018 were enrolled. Among them, 48 patients who suffered HT after therapy were assigned to the research group (Res group) and the other 61 patients who did not suffer it after therapy were assigned to the control group (Con group). Serum Apelin, Vaspin, inflammatory factors, and oxidative stress levels were quantified, and receiver operating characteristic (ROC) curves were drawn for analyzing the predictive value of Apelin and Vaspin on HT after ITT and their associations with inflammatory factors and oxidative stress. CIS patients who suffered HT were followed up for 3 years for prognostic significance analysis of Apelin and Vaspin. Results After ITT, the Res group showed lower Apelin and Vaspin levels than the Con group (all P < 0.05), and patients with a higher HT grade had lower Apelin and Vaspin levels (all P < 0.05). The joint detection of Apelin and Vaspin showed a sensitivity of 77.08% and a specificity of 73.77% for forecasting HT in CIS patients after thrombolytic therapy (all P < 0.001). In addition, after thrombolytic therapy, the Res group presented higher levels of interleukin-1β (IL-1β) and IL-6 as well as malondialdehyde (MDA) than the Con group, and the levels had negative associations with Apelin and Vaspin (all P < 0.05). The Res group showed a lower superoxide dismutase (SOD) level than the Con group, and the level presented a positive association with Apelin and Vaspin (all P < 0.05). According to Logistic analysis, IL-1β, IL-6, and MDA were independent risk factors for HT in CIS patients after IT, while Apelin, Vaspin, and SOD were independent protective factors (all P < 0.05). According to the follow-up results, Apelin and Vaspin demonstrated excellent value in forecasting the death of patients with both CIS and HT (P < 0.05), and their lower levels indicate a higher risk of death (all P < 0.05). Conclusion Apelin and Vaspin can help effectively forecast the occurrence of HT in CIS patients after ITT as independent protective factors of HT, so they are of a high clinical application value.

Phase II trial of atezolizumab in BCG-unresponsive non-muscle invasive bladder cancer: SWOG S1605 (NCT #02844816).

4541 Background: Radical cystectomy (RC) is the standard of care for patients with BCG-unresponsive high risk non-muscle invasive bladder cancer (NMIBC), but many patients are unfit for surgery or elect bladder preservation. This trial was designed to evaluate the activity of atezolizumab in BCG-unresponsive high risk NMIBC. Methods: This single arm phase II registration trial testing systemic atezolizumab (1200 mg IV) every 3 weeks for one year aimed to enroll 135 (70 CIS and 65 non-CIS) eligible patients with histologically proven BCG-unresponsive high risk NMIBC who were unfit for or declined RC. Here we report the 18 month results for all eligible patients who received at least one protocol treatment. The co-primary endpoints were pathological complete response (CR) rate at 6 months in patients with CIS (reported at ASCO 2020), and event-free survival (EFS) in all patients at 18 months using Kaplan-Meier methods (KM), conditional on a positive CIS response rate. A sample size of 135 evaluable patients provided 93% statistical power for detecting a 30% 18-month EFS rate versus 20% using a one-sided alpha = 0.05. EFS in the subset with Ta/T1 disease and duration of response in CIS patients were secondary endpoints. Results: 172 patients were enrolled, 166 received at least one dose of atezolizumab and are included in the safety analysis, and, of those, 128 were eligible and included in the efficacy analysis. As previously reported, 20 (27%) out of 74 patients with CIS attained a pathologic CR at 6 months. The KM estimate of 12 month (actual 11.9 mo) duration of response after 6 month CR for CIS patients was 54% (95% CI 30%, 78%) and the median duration of response was 16.5 months. The KM EFS rate at 18 months in 74 patients with CIS was 17% (90% CI 9%, 25%). The 18 month KM EFS rate in the overall population of 128 patients with Ta, T1 and CIS was 29% (90% CI 22%, 36%). The 18 month actuarial EFS rate in 54 patients with Ta/T1 disease was 45% (90% CI 34, 57%). Any possibly or probably treatment-related adverse event (TRAE) was observed in 142 out of 166 (86%) patients who received any atezolizumab regardless of eligibilty. The most frequent TRAEs were fatigue 72 (43%), diarrhea 34 (20%), and anemia 38 (23%). Grade 3-5 TRAEs occurred in 28 (17%) patients, including rash in 4 (2%), hyponatremia in 4 (2%), hypertension in 3 (2%) and elevated liver function tests in 3 (2%). There were two treatment-related deaths (sepsis and respiratory failure due to myasthenia gravis). Conclusions: The observed response of atezolizumab at 6 and 18 months in patients with BCG-unresponsive CIS suggests that this could be a valuable treatment to address a critical unmet need in this patient population. The 18 month EFS in patients with Ta/T1 disease suggests activity in this patient subset. This trial provided no new safety concerns. Funding: NIH/NCI grants: CA180888, CA180819, CA180820, CA180821, CA180863 and in part by Genentech. Clinical trial information: NCT02844816.

Profiling CIS progression and stability using RNA-seq single-cell analysis in peripheral blood mononuclear cells

Abstract Objective: To use single-cell mRNA analyses to identify immune cell profiles in CIS patients associated with a higher risk of developing an MS relapse or new central nervous system (CNS) disease activity on brain MRI. Methods: Cryopreserved peripheral blood mononuclear cells were collected at study entry and six months from six CIS participants in the ITN020AI STAyCIS trial of atorvastatin. Three participants met the primary endpoint defined as ≥ 3 new T2 lesions on MRI or an MS relapse within 12 months, while the other three did not. RNA from about 10,000 PBMC per sample were identified at the single-cell level using the 10X Genomics Chromium platform and analyzed using Cell Ranger software. Seurat R software package was used for downstream analysis. Results: 31 clusters of differentially expressed genes were assigned as specific cell types; baseline frequencies of clusters enriched &amp;gt;2-fold for macrophage, NK, NKT, CD4+ T cell, and B cell markers were associated with disparate outcomes at six months. Several clusters of B cells, CD4+ and CD8+ T cells were expanded from baseline at six months in participants with CNS disease activity at that time point, while no notable changes were observed in those with stable disease. Conclusion: Our results show varied frequencies of innate and adaptive leukocyte populations in participants with disparate clinical outcomes, suggesting a predictive biomarker for aggressive early intervention. Expanded clusters of CD4+ and CD8+ T cells and B cells in blood at the time of disease activity may identify biomarkers leading to acute demyelination. Follow-up studies are underway to increase sample size and incorporate protein data to better define cell subtypes associated with disparate outcomes in the STAyCIS trial.

Positivity of oligoclonal bands in the cerebrospinal fluid predisposed to metabolic changes and rearrangement of inhibitory/excitatory neurotransmitters in subcortical brain structures in multiple sclerosis

BackgroundThe latest diagnostic criteria for multiple sclerosis (MS) have revitalized the role of oligoclonal bands synthesis in the cerebrospinal fluid (CSF-OCB). This study identifies predictors of CSF-OCB-positivity among in vivo metabolic markers in the subcortical gray/white matter in MS patients after their first episode (CIS) and in patients with relapsing-remitting course (RRMS). MethodsThe study enrolled 13 CIS and 23 RRMS patients. Metabolism was evaluated using Mescher-Garwood-edited proton-magnetic resonance spectroscopy on a 3T MR scanner. In addition to N-acetyl-aspartate (tNAA), myoinositol (mIns), and choline- and creatine compounds (tCho, tCr) were also evaluated γ-aminobutyric acid (GABA) and glutamate-glutamine (Glx) ratios. ResultsCSF-OCB-positivity was found in 76.9% of CIS and 78.2% of RRMS patients. GABA and Glx ratios in putamen and corpus callosum strongly determined CSF-OCB-positive CIS patients. Other essential predictors of CSF-OCB-positive CIS were mIns and Glx ratios in the putamen, and tCho/tNAA in the corpus callosum. In RRMS, GABA ratios in the right thalamus and Glx ratios in the left hippocampus strongly predicted CSF-OCB-positive patients. tCho/tNAA and tNAA/tCr in the left hippocampus were also identified as essential predictors of CSF-OCB-positive RRMS patients. ConclusionThis is the first in vivo evidence of GABA-Glx rearrangement in CSF-OCB-positive patients since its early stages of MS.

A Systematic Review of Outcome Reporting, Definition and Measurement Heterogeneity in Non-Muscle Invasive Bladder Cancer Effectiveness Trials of Adjuvant, Prophylactic Treatment After Transurethral Resection.

Heterogenous outcome reporting in non-muscle-invasive bladder cancer (NMIBC) effectiveness trials of adjuvant treatment after transurethral resection (TURBT) has been noted in systematic reviews (SRs). This hinders comparing results across trials, combining them in meta-analyses, and evidence-based decision-making for patients and clinicians. We aimed to systematically review the extent of reporting and definition heterogeneity. We included randomized controlled trials (RCTs) identified from SRs comparing adjuvant treatments after TURBT or TURBT alone in patients with NMIBC (with or without carcinoma in situ) published between 2000-2020. Abstracts and full texts were screened independently by two reviewers. Data were extracted by one reviewer and checked by another. We screened 807 abstracts; from 15 SRs, 57 RCTs were included. Verbatim outcome names were coded to standard outcome names and organised using the Williamson and Clarke taxonomy. Recurrence (98%), progression (74%), treatment response (in CIS studies) (40%), and adverse events (77%) were frequently reported across studies. However, overall (33%) and cancer-specific (33%) survival, treatment completion (17%) and treatment change (37%) were less often reported. Quality of Life (3%) and economic outcomes (2%) were rarely reported. Heterogeneity was evident throughout, particularly in the definitions of progression and recurrence, and how CIS patients were handled in the analysis of studies with predominantly papillary patients, highlighting further issues with the definition of recurrence and progression vs treatment response for CIS patients. Data reporting was also inconsistent, with some trials reporting event rates at various time-points and others reporting time-to-event with or without Hazard Ratios. Adverse events were inconsistently reported. QoL data was absent in most trials. Heterogenous outcome reporting is evident in NMIBC effectiveness trials. This has profound implications for meta-analyses, SRs and evidence-based treatment decisions. A core outcome set is required to reduce heterogeneity. This systematic review found inconsistencies in outcome definitions and reporting, pointing out the urgent need for a core outcome set to help improve evidence-based treatment decisions.

CSF oligoclonal band frequency in a Cuban cohort of patients with multiple sclerosis. comparison with Latin American countries and association with latitude

Background. The diagnostic sensitivity of CSF specific oligoclonal bands (OCBs) in multiple sclerosis (MS), using state of the art methods, has been clearly established to be over 95% in patients with a predominantly Caucasian background. This is not the case for other geographical regions, where reports of OCB prevalence can be much lower, and a relationship between OCB frequency and latitude has been suggested. Objective. The aim of the present study was to assess the frequency of OCBs in a cohort of MS patients evaluated at the Institute of Neurology and Neurosurgery (Havana, Cuba), and to review the scientific literature in order to investigate the possible relationship between OCB status and latitude in the region of Latin America. Methods. Fifty-three patients (47 with definite MS and 6 with clinically isolated syndrome – CIS) were included. Isoelectric focusing (IEF) with IgG immunoblotting for OCB analyses, was performed placing paired CSF and serum samples in the same analytical run. PubMed, Scielo and Google Scholar were searched for papers containing information concerning CSF OCB status (employing isoelectric focusing with IgG immunoblotting) in patients with definite MS in Latin America and the Caribbean. Results. In Cuban patients with definite MS, an OCB prevalence of 87% was observed, while the frequency in CIS patients was lower (67%). The prevailing pattern was that of OCBs restricted to the CSF (type 2), which was observed in 71% of definite MS patients and in all CIS patients with intrathecal IgG synthesis. OCB prevalence was slightly lower, but very close to that reported in Caucasian populations. Comparison with other Latin American countries revealed a significant correlation between OCB prevalence and latitude. Conclusions. A prevalence of CSF restricted OCBs of 87% was observed in definite MS patients, a frequency which was slightly lower, but similar to that reported in Caucasian populations. The analysis of OCB frequency in Latin American countries revealed a possible relationship between OCB prevalence and latitude, but this must be further investigated in more countries and larger samples of patients.

Free light chain kappa and the polyspecific immune response in MS and CIS – Application of the hyperbolic reference range for most reliable data interpretation

ObjectivesFree light chain kappa (FLC-k) in cerebrospinal fluid (CSF) is involved in intrathecal immune responses and is being investigated frequently for its diagnostic sensitivity. The objective of this study was the application and interpretation of FLC-k data in quotient diagrams with a hyperbolic reference range and to confirm the superior evaluation in comparison with another proposed reference method and cut-off values. Secondly, the performance of the FLC-k quotient diagram was analyzed in respect to MS and CIS patients and in relation to the polyspecific immune response. Materials and methodsFLC-k was analyzed in a control cohort (n = 302) and in patients with MS/CIS (n = 98) using a nephelometric FLC-k kit. The intrathecal fraction of FLC-k based on the hyperbolic reference range was calculated in comparison to various linear FLC-k indices and routine CSF parameters [oligoclonal bands (OCB), polyspecific antiviral immune response]. ResultsUsing the new hyperbolic reference range, intrathecal FLC-k synthesis was found in 20 / 302 OCB negative controls. The sensitivity in the definitive MS cohort was 100%, compared to 93% positive OCB. The linear FLC-k Index interpretation with similar sensitivity for MS, however, bares the risk for the control samples,depending on the reference range, of false positive interpretations (up to 7 at low QAlb) or false negative interpretations (up to 17/20 FLC-k positives at high QAlb). The quantitative mean intrathecal FLC-k synthesis in the CIS cohort (later MS) was even slightly higher than in initially definitive MS questioning a pathophysiological difference. A positive MRZ reaction found in 53% percent of CIS patients with intrathecal FLC-k synthesis could have allowed diagnosis of MS immediately, i.e. earlier than with the Mc Donald criteria. ConclusionsThe evaluation of FLC-k with hyperbolic reference range in quotient diagrams is superior to other analytical methods like the linear FLC-k index. We suggest a sequential CSF testing with FLC-k Reibergram evaluation, potentially followed by isoelectric focusing. With the MRZ reaction we obtain highest specificity for MS diagnosis.

Conversion of clinically isolated syndrome to multiple sclerosis: a prospective study

BackgroundMultiple sclerosis (MS) begins with an acute clinical attack (clinically isolated syndrome) in approximately 85% of patients. The conversion rate from clinically isolated syndrome to multiple sclerosis has been documented at 30% to 82% in previous studies. When an individual presents for evaluation after a single episode of inflammation of the CNS, several decisions regarding follow-up in subsequent years need to be made, including that of whether or not to start a therapy. There is, therefore, an emerging need to identify the predictive factors that anticipate conversion from CIS to MS. MethodsThis paper presents a single-center prospective longitudinal study aimed at identification of the most powerful independent predictors for conversion from CIS to MS, utilizing the 2010 McDonald MS criteria and focusing on selected demographic, clinical, radiographical (magnetic resonance imaging – MRI), cerebrospinal fluid (predominantly oligoclonal bands – OCB) and electrophysiological parameters (multimodal sensory and motor-evoked potentials – EP). Two independent outcomes meeting MS criteria are evaluated: development of second clinical relapse (clinically definite multiple sclerosis) and progression in magnetic resonance imaging (based on new MRI T2 brain and/or spinal cord lesions). CIS patients were followed clinically and MRI was repeated at one and two years within the course of a follow-up period of at least 24 months (median 27, range 24–36 months). ResultsOf the 64 CIS patients enrolled who completed at least a 2-year follow-up period (42 women and 22 men, median age 36.5, range 22–66 years), 45 (70.3%) (29 women and 16 men, median age 38; range 22–66 years) fulfilled the 2010 McDonald criteria for MS by dissemination in space (DIS) and time (DIT) over the follow-up period. Twenty-nine CIS patients converted to MS through a clinically symptomatic attack, and 16 CIS patients developed new T2 lesions on MRI, while 19 patients without progression remained stable as CIS. Confirmed among potential predictors for the conversion of CIS patients to MS were increased (>10) baseline MRI T2-hyperintense lesions (odds ratio (OR) 3.107, p = 0.046), OCB positivity (OR 5.958, p = 0.003) and subclinical EP abnormality (OR 14.400, p = 0.003). Multivariate statistical models (logistic regression and Cox proportional hazards regression models) confirmed these parameters as independent predictors of high sensitivity (84%) and acceptable specificity (63%). ConclusionIn addition to accepted predictors for the conversion of CIS to MS (i.e. baseline MRI T2 lesion load and OCB positivity), already implemented in current diagnostic criteria for MS, this study demonstrates, in addition, the high predictive value of subclinical multimodal evoked potential abnormalities.