Sustained MRD Negativity Might Predict Successful Maintenance Discontinuation in Patients with Transplant-Eligible NDMM

Background: Multiple myeloma is still an uncurable plasma cell malignancy. Maintenance plays an important role in the MM therapy for decreasing the probability of disease progression. However, prolonged maintenance therapy inevitably brings economic burdens and toxicities to the patients and families. Minimal residual disease (MRD) directed maintenance discontinuation might balance the disease progression and the toxicities. This study aimed to compare the risk of disease progression after maintenance discontinuation between transplant-eligible patients with and without achieving sustained MRD negativity for at least 2 years since post-induction. Methods: One hundred and fifty-seven consecutive patients with newly diagnosed multiple myeloma who had received bortezomib based induction and subsequent single autologous stem cell transplant (ASCT) between 2008 and 2018 in our institute were enrolled. Patients discontinued maintenance was identified during regular follow-up. These patients were then follow-up every 6-12 months until disease progression. Results: Twenty-five patients discontinued their maintenance therapy at the median of 29.3 months post-transplant because of intolerability. For these 25 patients, the median age was 50 years old (range 35-68), and 19 (76%) were male and 6 (24%) were female. The frequencies of IgG, IgA, IgD and light-chain-only subtype of MM were 6 (24.0 %), 7 (28.0 %), 1 (4.0 %) and 11 (44.0 %) patients, respectively. There were 10 (40.0 %), 7 (28.0 %), 8 (32.0 %) patients with ISS stages of 1, 2, and 3, respectively. High-risk iFISH was defined as 17p deletion-positive and/or t (4;14)-positive and/or t (14;16)-positive. Fifteen (60.0 %), four (16.0 %) and six (24.0 %) patients had high-risk, standard-risk and missing iFISH, respectively. With the median follow-up time of 25.4 months after discontinuation, the cumulative disease progression rate was 35%±11% at 2 years after discontinuation (Fig1). Among the 16 patients who had received MRD monitoring since post-induction and thereafter every 3-6 months, 9 achieved sustained MRD negativity since post-induction and maintained for at least 2 years after the transplant. None of these 9 patients had disease progression. No significant difference on age, sex, ISS staging, LDH level and high-risk cytogenetic rate was found between patients with and without sustained MRD negativity. The log-rank analysis showed that patients achieving sustained MRD negativity for at least 2 years since post-induction had significantly lower 2-year disease progression rate after maintenance discontinuation (0% vs. 78.6±17.8%, median time to PD since discontinuation were not reached vs. 14.3 months, as shown in Fig 2). Conclusion: sustained MRD negativity since post-induction and maintained at least 2 years after transplant might predict successful maintenance discontinuation in patients with transplant-eligible NDMM. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Correlation between leukocyte phenotypes and prognosis of amyotrophic lateral sclerosis: a longitudinal cohort study

Background: Immune response changes have been reported in amyotrophic lateral sclerosis (ALS), but their clinical relevance remains undetermined. Therefore, we aim to evaluate the relationships between blood leukocyte subpopulations and prognosis of ALS.<br />Methods: A longitudinal cohort of 288 ALS patients with up to 5 years of follow-up during 2015-2020 were recruited at the only tertiary referral center for ALS in Stockholm, Sweden. Routine differential leukocyte counts, and determination of lymphocyte subpopulations including an extended T cell panel with flow cytometry, collected at diagnosis and at regular intervals thereafter. The primary outcome was risk of death (alternatively use of invasive ventilation) after diagnosis of ALS. The secondary outcomes included repeatedly measured functional status - through Amyotrophic Lateral Sclerosis Functional Rating Scale-revised (ALSFRS-R) score and disease progression rate. Cox model was used to evaluate the associations between leukocytes and risk of death. Generalized estimating equation model (GEE) was used to assess the correlation between leukocytes and ALSFRS-R score<br />and disease progression rate.<br />Results: The counts of leukocytes, neutrophils and monocytes increased gradually over time since diagnosis and were negatively correlated with ALSFRS-R score, but not associated with risk of death or disease progression rate. Focusing on lymphocyte subpopulations, increasing counts of natural killer (NK) cells (HR=0.61, 95% CI= [0.42-0.88] per SD increase) and proportions of Th2-diffrentiated CD4+ central memory (CM) T cells (HR=0.64, 95% CI= [0.48-0.85] per SD increase) were correlated with a lower risk of death. Increasing proportions of CD4+ effector memory cells re-expressing CD45RA (EMRA) T cells (HR=1.39, 95% CI= [1.01-1.92] per SD increase) and CD8+ T cells (HR=1.38, 95% CI= [1.03-1.86] per SD increase) were associated with a higher risk of death. None of the lymphocyte subpopulations was correlated with ALSFRS-R score or disease progression rate.<br />Conclusion: Our findings suggest a dual role of immune responses in ALS prognosis, where neutrophils and monocytes primarily reflect functional status whereas NK cells and different T lymphocyte populations act as prognostic markers for survival.

Role of Blood Neurofilaments in the Prognosis of Amyotrophic Lateral Sclerosis: A Meta-Analysis

Background: Neurofilaments in cerebrospinal fluid (CSF) and in blood are considered promising biomarkers of amyotrophic lateral sclerosis (ALS) because their levels can be significantly increased in patients with ALS. However, the roles of neurofilaments, especially blood neurofilaments, in the prognosis of ALS are inconsistent. We performed a meta-analysis to explore the prognostic roles of blood neurofilaments in ALS patients.Methods: We searched all relevant studies on the relationship between blood neurofilament levels and the prognosis of ALS patients in PubMed, Embase, Scopus, and Web of Science before February 2, 2021. The quality of the included articles was assessed using the Quality in Prognosis Studies (QUIPS) scale, and R (version 4.02) was used for statistical analysis.Results: Fourteen articles were selected, covering 1,619 ALS patients. The results showed that higher blood neurofilament light chain (NfL) levels in ALS patients were associated with a higher risk of death [medium vs. low NfL level: HR = 2.43, 95% CI (1.34–4.39), p &lt; 0.01; high vs. low NfL level: HR = 4.51, 95% CI (2.45–8.32), p &lt; 0.01]. There was a positive correlation between blood phosphorylated neurofilament heavy chain (pNfH) levels and risk of death in ALS patients [HR = 1.87, 95% CI (1.35–2.59), p &lt; 0.01]. The levels of NfL and pNfH in blood positively correlated with disease progression rate (DPR) of ALS patients [NfL: summary r = 0.53, 95% CI (0.45–0.60), p &lt; 0.01; pNfH: summary r = 0.51, 95% CI (0.24–0.71), p &lt; 0.01].Conclusion: The blood neurofilament levels can predict the prognosis of ALS patients; specifically, higher levels of blood neurofilaments are associated with a greater risk of death.

Multiple sclerosis progression and galanin receptor GALR2: is there evidence for a link?

BACKGROUND: Given the recently proposed role of the rare galanin receptor-2 (GALR2) genes missense mutation (SNP rs61745847) in the etiology of MS, we genotyped rs61745847 in a group of MS patients that was enriched with an unfavorable disease course cases. MATERIALS AND METHODS: Our study cohort consisted of 100 MS patients selected based on their progressive course, high disease progression rate and pediatric onset. To determine the nucleotide sequence of GALR2 gene fragment, surrounding the rs61745847 area, Sanger sequencing of PCR amplicons was performed. RESULTS: No homozygous rs61745847 carrier was found in our cohort, and the region of exon 2 surrounding rs61745847 completely coincided with the reference sequence (Gene Bank NC_000017.11). In agreement with previously published data on Canadian and Brazilian populations of patients, our study of a Russian cohort confirmed the rarity of the rs61745847 variant, including among patients with rapidly progressive MS. CONCLUSIONS: Thus, although structural changes in the GALR2 gene associated with rs61745847 may play a significant role in individual patients carrying this rare mutation, it is unlikely that such changes determine an unfavorable disease course of MS in general.

The Incidence and Severity of Downy Mildew Disease on Local Madurese Maize Crops in Sumenep district, East Java, Indonesia

In Madura island, corn is the main commodity that is widely planted with an area of 301,725 ha or about 30% of the area of maize in East Java. Madura Island has local cultivars, such as: Tambin, Talango, Guluk-guluk, Manding, and Kretek. Efforts to increase production are continuously being made, starting from improving varieties until managing plant pests. One of the main diseases in maize is downy mildew. However, information about the incidence, incidence, severity, and species that cause downy mildew in local cultivars has not been reported. So, this study aims to identify the causes of downy mildew in local cultivars of Madura and disease severity in the field. The research method is a survey on local maize centers. Sampling was done by using the diagonal sampling method. Each plant sample was observed for symptoms of disease and scoring to calculate the value of disease severity. Fungi identification was carried out by microscopic observation of the fungus. The results showed that the cause of downy mildew in Madura local maize in Sumenep Regency was P. maydis. The highest incidence, disease severity, and AUDPC value after 4 MST were found in Guluk-guluk cultivars in Padangdangan Village, but had the lowest disease progression rate values. Meanwhile, the highest rate of disease progression was found in the Manding cultivar in Mandala Village. Based on the resistance category, Talango cultivar had the best resistance when compared to other cultiva.Keywords: AUDPC, downy mildew, disease progress, Madurese maize, Peronosclerospora maydis

Relationship between Dietary Fiber Intake and the Prognosis of Amytrophic Lateral Sclerosis in Korea

The gut microbiota has been suggested as an important factor in the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS). This study aimed to investigate whether the intake of different kinds of dietary fiber was related to the disease progression rate (∆FS) and survival time. In total, 272 Korean sporadic ALS patients diagnosed according to the revised EI Escorial criteria were recruited starting in March 2011 and were followed until the occurrence of events or the end of September 2020. The events included percutaneous endoscopic gastrostomy, tracheostomy, and death. Dietary fiber intake was calculated based on a 24-h dietary recall and classified according to five major fiber-rich foods: vegetables, fruits, grains, legumes, and nuts/seeds. Among the total participants, the group with ∆FS values lower than the mean ∆FS (0.75) was noted in the highest tertiles of total and vegetable fiber intake. Participants in the highest tertile for vegetable fiber intake showed longer survival in the Kaplan–Meier analysis (p = 0.033). Notably, vegetable fiber intake was negatively correlated with pro-inflammatory cytokine (interleukin (IL)-1β, IL-6, and monocyte chemoattractant protein-1) levels in the cerebrospinal fluid. This study showed that vegetable fiber intake could influence the disease progression rate and survival time. Further clinical trials are needed to confirm whether dietary fiber supplementation improves the prognosis of ALS.

Relationship between Dietary Fiber Intake and the Prognosis of Amyotrophic Lateral Sclerosis

The gut microbiota has been suggested as an important factor in the pathogenic mechanisms of amyotrophic lateral sclerosis (ALS). This study aimed to investigate whether the intake of different kinds of dietary fiber was related to the disease progression rate (∆FS) and survival time. In total, 272 sporadic ALS patients diagnosed according to the revised EI Escorial criteria were recruited from March 2011 and were followed-up until the occurrence of events or the end of September 2020. The events included percutaneous endoscopic gastrostomy, tracheostomy, and death. Dietary fiber intake was calculated based on a 24-hour dietary recall and classified according to five major fiber-rich foods: vegetables, fruits, grains, legumes, and nuts/seeds. Among the total participants, the group with ∆FS values lower than the mean ∆FS (0.75) was noted in the highest tertiles of total and vegetable fiber intake. Participants with the highest tertile of vegetable fiber intake showed longer survival in the Kaplan&ndash;Meier analysis (p = 0.033). Notably, vegetable fiber intake was negatively correlated with pro-inflammatory cytokine (interleukin [IL]-1&beta;, IL-6, and monocyte chemoattractant protein-1) levels in the cerebrospinal fluid. This study showed that vegetable fiber intake could influence the disease progression rate and survival time. Further clinical trials are needed to confirm whether dietary fiber supplementation improves the prognosis of ALS.

Singular cases of Alzheimer’s disease disclose new and old genetic “acquaintances”

Background Alzheimer’s disease (AD) is the most common age-related dementia. Besides its typical presentation with amnestic syndrome at onset, atypical AD cases are being increasingly recognized, often in presenile age. Objectives To provide an extensive clinical and genetic characterization of six AD patients carrying one or more singular features, including age of onset, atypical phenotype and disease progression rate. By reviewing the pertinent literature and accessing publicly available databases, we aimed to assess the frequency and the significance of the identified genetic variants. Methods Biomarkers of amyloid-β deposition and neurodegeneration were used to establish the in vivo diagnosis of probable AD, in addition to neurological and neuropsychological evaluation, extensive laboratory assays and neuroradiological data. Considering the presenile onset of the majority of the cases, we hypothesized genetically determined AD and performed extensive genetic analyses by both Sanger sequencing and next generation sequencing (NGS). Results We disclosed two known missense variants, one in PSEN1 and the other in PSEN2, and a novel silent variant in PSEN2. Most notably, we identified several additional variants in other dementia-related genes by NGS. Some of them have never been reported in any control or disease databases, representing variants unique to our cases. Conclusions This work underlines the difficulties in reaching a confident in vivo diagnosis in cases of atypical dementia. Moreover, a wider genetic analysis by NGS approach may prove to be useful in specific cases, especially when the study of the so-far known AD causative genes produces negative or conflicting results.

Multi-parametric disease dynamics study and analysis of the COVID-19 epidemic and implementation of population-wide intrusions: The Indian perspective

The outbreak of COVID-19 had spread at a deadly rate since its onset at Wuhan, China and is now spread across 216 countries and has affected more than 6 million people all over the world. The global response throughout the world has been primarily the implementation of lockdown measures, testing and contact tracing to minimise the spread of the disease. The aim of the present study was to predict the COVID-19 prevalence and disease progression rate in Indian scenario in order to provide an analysis that can shed light on comprehending the trends of the outbreak and outline an impression of the epidemiological stage for each state of a diverse country like India. In addition, the forecast of COVID-19 incidence trends of these states can help take safety measures and policy design for this epidemic in the days to come. In order to achieve the same, we have utilized an approach where we test modelling choices of the spatially unambiguous kind, proposed by the wave of infections spreading from the initial slow progression to a higher curve. We have estimated the parameters of an individual state using factors like population density and mobility. The findings can also be used to strategize the testing and quarantine processes to manipulate the spread of the disease in the future. This is especially important for a country like India that has several limitations about healthcare infrastructure, diversity in socioeconomic status, high population density, housing conditions, health care coverage that can be important determinants for the overall impact of the pandemic. The results of our 5-phase model depict a projection of the state wise infections/disease over time. The model can generate live graphs as per the change in the data values as the values are automatically being fetched from the crowd-sourced database.

Testing whether the progression of Alzheimer's disease change with the year of publication, additional design and geographical area: a modeling analysis of literature aggregate data

Background Our objective was to develop a disease progression model for cognitive decline in Alzheimer’s disease (AD) and to determine whether disease progression of AD is related to the year of publication, add-on trial design, and geographical regions. Methods Placebo-controlled randomized AD clinical trials were systemically searched in public databases. Longitudinal placebo response (mean change from baseline in the cognitive subscale of the Alzheimer’s Disease Assessment Scale [ADAS-cog]) and the corresponding demographic information were extracted to establish a disease progression model. Covariate screening and subgroup analyses were performed to identify potential factors affecting the disease progression rate. Results A total of 134 publications (140 trials) were included in this model-based meta-analysis. The typical disease progression rate was 5.82 points per year. The baseline ADAS-cog score was included in the final model using an inverse-U type function. Age was found to be negatively correlated with disease progression rate. After correcting the baseline ADAS-cog score and the age effect, no significant difference in disease progression rate was found between trials published before and after 2008, and between trials using add-on design and those that did not use add-on design. However, a significant difference was found among different trial regions. Trials in East Asian countries showed the slowest decline rate and the largest placebo effect. Conclusions Our model successfully quantified AD disease progression by integrating baseline ADAS-cog score and age as important predictors. These factors and geographic location should be considered when optimizing future trial designs and conducting indirect comparisons of clinical outcomes.