A Dual Marker for Monitoring MDR-TB Treatment: Host-Derived miRNAs and M. tuberculosis-Derived RNA Sequences in Serum

BackgroundIn the absence of a late marker of treatment failure or relapse in MDR-TB patients, biomarkers based on host-miRNAs coupled with M. tuberculosis-RNAs evaluated in extracellular vesicles (EVs) are an alternative follow-up for MDR-TB disease. Characterization of EVs cargo to identify differentially expressed miRNAs before and after treatment, and to identify M. tuberculosis-derived RNA in serum EVs from resistant TB patients.MethodsEVs were isolated from serum of 26 drug-resistant TB (DR-TB) patients and 16 healthy subjects. Differential expression of miRNAs in pooled exosomes from both untreated and treated patients was assessed and individually validated at different time points during treatment. In addition, M. tuberculosis RNA was amplified in the same samples by qPCR.ResultsA multivariate analysis using miR-let-7e-5p, -197-3p and -223-3p were found to be a more sensitive discriminator between healthy individuals and those with TB for both DR-TB (AUC= 0.96, 95%, CI=0.907-1) and MDR-TB groups (AUC= 0.95, 95%, CI= 0.89-1). Upregulation of miR-let-7e-5p were observed at the time of M. tuberculosis negative culture T(3-5) for MDR-TB group or for long-term T(9-15) for MDR-TB group without diabetes (T2DM). A second pathogen-based marker based on 30kDa and 5KST sequences was detected in 33% of the MDR-TB patients after the intensive phase of treatment. The miR-let7e-5p is a candidate biomarker for long-term monitoring of treatment for the group of MDR-TB without T2DM. A dual marker of host-derived miR-let7e-5p and M. tuberculosis-derived RNA for monitoring-TB treatment based in serum EVs.ConclusionA dual marker consisting of host-derived miR-let7e-5p and M. tuberculosis-derived RNA, could be an indicator of treatment failure or relapse time after treatment was completed.

Time To Relapse of Severe Acute Malnutrition And Its Determinants Among Children Treated In The Health Posts of Hadiya Zone, Southern Ethiopia.

Back ground: In developing countries including Ethiopia, children under five years old are likely to suffer from repeated bouts of SAM. There is lack of study that documented time to relapse of SAM and its determinants. Objective: This study aimed to identify time of relapse and its determinants among children discharged after treatment for SAM in health facilities of Hadiya Zone, South, Ethiopia Methods: An institution based retrospective cohort study was carried out from data spanning from 2014/2015 to 2019/2020. After checking all the assumptions, multivariable CPH model was fitted to isolate independent determinants of time to relapse. All tests were two sided and statistical significance at P values <0.05. Result: The mean(±SD) time for relapse of SAM among under five children was 22(±9.9) weeks from discharge to relapse time. On multivariable CPH model, the hazard of relapse for SAM was significantly higher for children who had edema (AHR =2.02 ,95%, CI: 1.17-3.50), age of 6-11 months (AHR = 5.2, 95%, CI:1.95-13.87), had discharge low MUAC (AHR = 12,95%, CI: 7.90-19.52)Concussion: The finding showed that children discharged from SAM are likely to have relapse in 3 weeks.

Use of Disease-Modifying Therapies in Pediatric Relapsing-Remitting Multiple Sclerosis in the United Kingdom

ObjectivesTo compare the real-world effectiveness of newer disease-modifying therapies (DMTs) vs injectables in children with relapsing-remitting multiple sclerosis (RRMS).MethodsIn this retrospective, multicenter study, from the UK Childhood Inflammatory Demyelination Network, we identified children with RRMS receiving DMTs from January 2012 to December 2018. Clinical and paraclinical data were retrieved from the medical records. Annualized relapse rates (ARRs) before and on treatment, time to relapse, time to new MRI lesions, and change in Expanded Disability Status Scale (EDSS) score were calculated.ResultsOf 103 children treated with DMTs, followed up for 3.8 years, relapses on treatment were recorded in 53/89 (59.5%) on injectables vs 8/54 (15%) on newer DMTs. The ARR was reduced from 1.9 to 1.1 on injectables (p < 0.001) vs 1.6 to 0.3 on newer DMTs (p = 0.002). New MRI lesions occurred in 77/89 (86.5%) of patients on injectables vs 26/54 (47%) on newer DMTs (p = 0.0001). Children on newer DMTs showed longer time to relapse, time to switch treatment, and time to new radiologic activity than patients on injectables (log-rank p < 0.01). After adjustment for potential confounders, multivariable analysis showed that injectables were associated with 12-fold increased risk of clinical relapse (adjusted hazard ratio [HR] = 12.12, 95% CI = 1.64–89.87, p = 0.015) and a 2-fold increased risk of new radiologic activity (adjusted HR = 2.78, 95% CI = 1.08–7.13, p = 0.034) compared with newer DMTs. At 2 years from treatment initiation, 38/103 (37%) patients had MRI activity in the absence of clinical relapses. The EDSS score did not change during the follow-up, and only 2 patients had cognitive impairment.ConclusionNewer DMTs were associated with a lower risk of clinical and radiologic relapses in patients compared with injectables. Our study adds weight to the argument for an imminent shift in practice toward the use of newer, more efficacious DMTs in the first instance.Classification of EvidenceThis study provides Class IV evidence that newer DMTs (oral or infusions) are superior to injectables (interferon beta/glatiramer acetate) in reducing both clinical relapses and radiologic activity in children with RRMS.

Efficacy of Combination Docetaxel and Nintedanib in Advanced Non-Small Cell Lung Cancer in Thailand: A Multicenter Study

IntroductionThe mainstay systemic treatment for non-oncogenic addictive advanced stage non-small cell lung cancer is chemotherapy. Anti-angiogenic agents are additive compounds that enhance disease control and lead to improvement of overall survival benefit. Recently PD-(L)1 blockage, a checkpoint inhibitor, has been adopted as another line of treatment. A sequential strategy to enhance the efficacy of combination docetaxel and nintedanib after immunotherapy, correlated with genomic mutation, has been explored.MethodA retrospective cohort study of 56 patients from 8 centers in Thailand who received combination docetaxel and nintedanib via the Thai nintedanib Named Patient Use program was conducted. Demographic characteristics, treatment details, and treatment responses were retrieved from medical records.ResultsThe majority of patients were male (62.5%) with adenocarcinoma subtype (88%). Thirty-five percent had sensitizing EGFR mutation. Combination docetaxel and nintedanib was given as second to fourth line of treatment. Median PFS of docetaxel/nintedanib was 5.6 months [95% CI 4.8-6.9]. Median OS of the entire cohort was 22.5 months [95% CI 20.2-31.1]. Among them, only four patients received this combination after immunotherapy which limited the validity of efficacy analysis. Median PFS of those four patients was 7.9 months [range 5.2-9.1] which was slightly higher than the remaining cohort (median PFS 4.5 months, 95% CI: 4.0-6.0, p-value 0.09). Among the adenocarcinoma subtype, a relapse-time of platinum-doublet chemotherapy of more than 6 months was solely indicated as a benefit of combination docetaxel/nintedanib treatment compared to the relapse-time of platinum-doublet chemotherapy of less than 6 months by multivariate HR of PFS 0.32 [95% CI: 0.14-0.68, p-value 0.003].ConclusionCombination docetaxel and nintedanib provided more benefit in relapse-time of platinum-doublet chemotherapy of more than 6 months in advanced stage adenocarcinoma lung cancer. Neither EGFR nor ALK alteration influenced the outcome of treatment.

Injectable Versus Oral First-Line Disease-Modifying Therapies: Results from the Italian MS Register

The current study aims to compare injectable and oral first-line disease-modifying therapies (DMTs) for time to first relapse, time to confirmed disability progression (CDP), and time to discontinuation using a cohort of relapsing remitting multiple sclerosis (RRMS) patients, with data extracted from the Italian MS Register. This multicenter, observational, retrospectively acquired, and propensity-adjusted cohort study utilized RRMS-naïve patients from the Italian MS Register who started either injectable or oral first-line DMTs between January 1, 2010, and December 31, 2017, to evaluate the impact on disability outcomes in patients. Enrolled patients were divided into two groups, namely the injectable group (IG) and the oral group (OG). Of a cohort of 11,416 patients, 4602 were enrolled (3919 in the IG and 683 in the OG). The IG had a higher rate of women (67.3% vs 63.4%, p < 0.05) and a lower mean age (36.1 ± 10.9 vs 38.9 ± 11.8, p < 0.001). The event time to first relapse demonstrated a lower risk in the OG (HR = 0.58; CI 95% 0.48–0.72, p < 0.001). However, no differences were found between the two groups with respect to the risk of CDP (HR = 0.94; CI 95% 0.76–1.29, p = 0.941), while a lower risk of DMT was found in the OG (HR = 0.72; CI 95% 0.58–0.88, p = 0.002) for the event time to discontinuation. Real-world data from the Italian MS Register suggests that first-line oral DMTs are associated with a lower risk of experiencing a new relapse and of therapy discontinuation compared to injectable DMTs.

MBRS-44. TIME, PATTERN AND OUTCOME OF MEDULLOBLASTOMA RELAPSE ARE ASSOCIATED WITH TUMOUR BIOLOGY AT DIAGNOSIS AND UPFRONT THERAPY: A COHORT STUDY

Disease relapse occurs in ~30% of children with medulloblastoma, and is fatal in the majority. We sought to establish whether clinico-molecular characteristics at diagnosis are associated with the nature of relapse, subsequent disease-course, and whether these associations could inform clinical management. We surveyed the clinical features of medulloblastoma relapse (time-to-relapse, pattern-of-relapse, time-to-death and overall outcome) in 247 centrally-reviewed patients who relapsed following standard-upfront-therapies. We related these to clinico-molecular features at diagnosis, prognostic factors, and first-line/relapse treatment. Patients who received upfront craniospinal irradiation (CSI-treated) displayed prolonged time-to-relapse compared to CSI naïve patients (p&lt;0.001). Similarly, in CSI naïve patients, CSI at relapse, alongside re-resection and desmoplastic/nodular histology, were associated with long-term survival. In CSI-treated patients, the nature of relapse was subgroup-dependent. Local-nodular relapse patterns were enriched in relapsed-MBSHH patients (p&lt;0.001), but a notable proportion (65%) also acquired distant-diffuse disease (p=0.010). MBGroup3 relapsed quickly (median 1.3 years), MBGroup4 slowly (median 2.1 years). Distant-disease was prevalent in MBGroup3 and MBGroup4 relapses (90%) but, in contrast to relapsed-MBSHH, nodular and diffuse patterns of distant-disease were observed. Furthermore, nodular disease was associated with a prolonged time-to-death post-relapse (p=0.006). Investigation of second-generation MBGroup3/4 subtypes refined our understanding of heterogeneous relapse characteristics. Subtype VIII had prolonged time-to-relapse; subtype II a rapid time-to-death. Subtypes II/III/VIII developed a significantly higher incidence of distant-disease at relapse, whereas subtypes V/VII did not. The nature of medulloblastoma relapse are biology and therapy-dependent, providing immediate translational opportunities for improved disease management through biology-directed surveillance, post-relapse prognostication and risk-stratified selection of second-line treatment.

One Single Site Clinical Study: To Evaluate the Safety and Efficacy of Immunotherapy With Autologous Dendritic Cells, Cytokine-Induced Killer Cells in Primary Hepatocellular Carcinoma Patients

Dendritic cells (DCs) and cytokine-induced killer (CIK) cells play an important role in the anti-tumor immune response. In this study, we evaluated the clinical effectiveness of DC/CIK-CD24 immunotherapies to primary hepatocellular carcinoma patients who received radical resection. 36 resected primary hepatocellular carcinoma (HCC) patients were enrolled from August 2014 to December 2015. All patients received two or four times of DC/CIK immunotherapy after radical resection. 1–4 years patients’ survival rates were evaluated during the follow-up. The 4-year survival rate of patients who received two times of immunotherapy was 47.1%, and the rate of those who received four times of immunotherapies was 52.6%. Compared to baseline, after receiving the DC/CIK-CD24 autotransfusion, the serum Treg concentration of the patients decreased, while CD3+, CD4+, CD56+ increased slightly. The adverse effect of immunotherapy was I–II° transient fever and could be tolerable. DC/CIK-CD24 immunotherapy can delay the relapse time.

Time to Relapse and Its Predictors among Children with Nephrotic Syndrome in Comprehensive Specialized Hospitals, Tigray, Ethiopia, 2019

Background. Relapse in children with nephrotic syndrome leads to a variety of complications due to prolonged treatment and potential dependency on steroids. However, there is no study conducted to determine the incidence and predictive factors of relapse for nephrotic syndrome in Ethiopia, especially in children. Thus, this study aimed to assess the incidence of relapse and its predictors among children with nephrotic syndrome in Ethiopia. Methods. A retrospective study was conducted by reviewing all charts of children with an initial diagnosis of the nephrotic syndrome in tertiary hospitals from 2011 to 2018. Charts of children with a diagnosis of steroid-resistant cases were excluded. The extraction tool was used for data collection, Epi-data manager V-4.4.2 for data entry, and Stata V-14 for cleaning and analysis. Kaplan-Meier curve, log-rank test, life table, and crude hazard ratios were used to describe the data and adjusted hazard ratios with 95% CI and P value for analysis. Median relapse time, incidence rate of relapse, and cumulative relapse probabilities at a certain time interval were computed. Bivariable and multivariate analyses were performed using the Cox proportional hazard regression to identify the factors associated with relapse. Any variable at P < 0.25 in the bivariable analysis was transferred to multivariate analysis. Then, the adjusted hazard ratio with 95% CI and P ≤ 0.05 was used to report the association and to test the statistical significance, respectively. Finally, texts, tables, and graphs were used to present the results. Results and Conclusion. Majority, 64.5% (40/66), of relapses were recorded in the first 12 months of follow-up. The incidence rate of relapse was 42.6 per 1000 child-month-observations with an overall 1454 child-month-observations and the median relapse time of 16 months. Having undernutrition [ AHR = 3.44 ; 95% CI 1.78-6.65], elevated triglyceride [ AHR = 3.37 ; 95% CI 1.04-10.90], decreased serum albumin level [ AHR = 3.51 ; 95% CI 1.81-6.80], and rural residence [ AHR = 4.00 ; 95% CI 1.49-10.76] increased the hazard of relapse. Conclusion and Recommendation. Relapse was higher in the first year of the follow-up period. Undernutrition, hypoalbuminemia, hypertriglyceridemia, and being from rural areas were independent predictors of relapse. A focused evaluation of those predictors during the initial diagnosis of the disease is compulsory.

P497 Is mucosal healing sufficient paramater for anti-TNF discontinuation?

Background Long-term treatment with biologic therapy alongside with immunomodulators in patients with inflammatory bowel disease (IBD) can be associated with severe side effects. Nowadays, there is not a clear recommendation for de-escalation of therapy in patients on biologic treatment. The aim of the study was to evaluate relapse rate in 4 ili 2 years follow-up in patients with mucosal healing after two years of anti-TNF treatment, regardless achieved histological remission. Methods 52 patients with IBD after two years treatment with anti-TNF agents (Infliksimab (IFX) and Adalimumab (ADA)) and achieved mucosal healing, were enrolled in this retrospective study. Mayo endoscopic sub-score (0,1) and SES (&lt;2) was used to define mucosal healing in UC and CD patients, respectively. For the assessment of histological activity Nancy and Global Histologic Disease Activity Score (GHAS) were used. Histologic remission was defined by Nancy’s score ≤ 1 and GHAS ≤ 4. Data were collected for 4 years follow-up period after discontinuation of anti-TNF agents. Statistical analysis was carried out using SPSS 20.0 (Chicago, IL). Results From 52 patients 40.38% (21/52) patients had UC, and 59.61 % (31/52) had CD with an average disease duration of 11.57 (SD ± 6.28) years. Gender distribution was relatively equal, 46% men (24/52), with an average age of 40.66 (SD ± 11.15) years. All of the patients were on anti-TNF therapy and had mucosal healing at the moment of discontinuation, 55% (29/52) were on IFX, 35% (23/52) were on ADA, respectively. 48.07% (25/52), were with pathohistological remission of disease. In 4 years follow-up after anti-TNF therapy discontinuation, 59.61% (31/52) relapsed, with an estimated period of relapse time of 15.4 (SD ± 9.83) months. Using Spearman`s correlation moderate relation was revealed between histological activity and relapse (rho 0.467, p &lt; 0.001). Probability of relapse within 4 years in this group of patients with histologically active disease was higher (p &lt; 0.01, OR 2.72, 95% Cl 1.24–5.92). Conclusion Achieving both, endoscopic and histological remission, may be a good parameter in making a decision when to de-escalate anti-TNF therapy.

Decitabine Containing Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in Patients with Intermediate- and High-Risk Myelodysplastic Syndrome/Acute Myeloid Leukemia: Potential Decrease in the Incidence of Acute Graft Versus Host Disease

Objective: To evaluate the role of Decitabine in the allo-HSCT conditioning regimen for intermediate- and high-risk patients with MDS or AML. Methods:Retrospective analysis of data pertaining to 76 intermediate and high-risk patients with MDS or AML who underwent allo-HSCT between December 2005 and June 2018 at the Peking University First Hospital. Forty patients received Decitabine containing conditioning regimen before transplantation, while thirty-six patients received regimen without Decitabine. Results: Overa median follow up of 40 months(range, 1 to 155), the incidence of grade II to IV acute graft versus host disease was 12.5% in the Decitabine group and 41.7% in the non-Decitabine group (P=0.003). On multivariate analysis, Decitabine containing conditioning regimen was found to protect against grade II to IV aGVHD (HR=0.275, 95% confidence interval 0.098-0.770,P=0.014). Incidence of respiratory infection in the Decitabine and non Decitabine groups was 22.5% and 52.78%, respectively (P=0.012). No significant between group difference was observed with respect to 3-year OS, DFS, or RR (P=0.980, 0.959, and 0.837, respectively), while the median relapse time was longer in the Decitabine group [7 months (range, 2 to 12) versus 3 months (range, 2 to 4), P=0.171]. Decitabine containing conditioning showed a tendency for lower relapse rate among higher risk patients, as assessed by IPSS R; however, the between-group difference was not statistically significant (P=0.085). Conclusions: Inclusionof Decitabine in the conditioning regimen for allo-HSCT in intermediate- and high-risk patients may lower the incidence of aGVHD and respiratory infections, and contribute to longer median relapse time. Disclosures No relevant conflicts of interest to declare.