Sustained Responders Research Articles

Clinical Implications of NT-proBNP trajectory following Sacubitril/Valsartan initiation

Abstract Introduction Serum N-terminal pro–B-type natriuretic peptide (NT-proBNP) values after initiating Sacubitril/Valsartan is considered as a favorable prognostic factor, and widely used for risk stratification in patients with heart failure (HF). However, the relationship between the trajectory of serially measured NT-proBNP values and cardiovascular events in patients with HF who are treated with Sacubitril/Valsartan remains uncertain. Purpose This study aimed to reveal the prognostic association of an NT-proBNP trajectory after initiating Sacubitril/Valsartan and subsequent cardiovascular outcomes. Methods and Results A Japanese nationwide multicenter study was conducted on HF patients who initiated Sacubitril/Valsartan. Out of the 995 patients enrolled, we excluded 561 patients who were undergoing assessment of BNP or who lacked a complete set of NT-proBNP measurement. Finally, 434 patients included this study, and were divided into three groups based on NT-proBNP trajectory as follows; the ‘sustained-responder’ group (n = 129, 30%) : which exhibited a reduction of NT-proBNP by ≥10% at 1 month and further reduction of ≥10% at 3 months; and the ‘transient-responder’ group (n = 161, 37%), with ≥10% reduction at 1 month but not at 3 months; and the ‘non-responder’ group (n = 144, 33%), which did not achieve ≥10% reduction at 1 month. The mean age was 68 years, with females comprising 29%. In the ‘sustained-responder’ group, the age was significantly younger, and the duration of heart failure was significantly shorter. There were no significant differences in the mean systolic blood pressure, mean Sacubitril/Valsartan dose at each measurement points among the 3 groups. During follow-up of 456 (IQR, 371-549) days, the primary endpoint, which was either cardiovascular death or hospitalization of HF occurred in 78 of 434 patients (18%). The Kaplan-Meier analysis showed that the ‘sustained responder’ group experienced significantly lower event rate among the 3 groups (Log-rank p<.001). Additionally, an analysis that set a landmark time at 3 months post-initiation of Sacubitril/Valsartan showed that the ‘sustained-responder’ group experienced significantly fewer events than the ‘transient-responder’ group (Log-rank p=0.039) (Figure.1). Also, the ‘sustained responder’ was observed to have a better prognosis in a subgroup with LVEF<50%, but not in patients with LVEF ≥50%. (p value for interaction=0.035) (Figure.2). Conclusions This study revealed that sustained reduction of NT-proBNP was associated with a reduced risk of cardiovascular death or hospitalization for HF. The periodic NT-proBNP monitoring and the patterns of NT-proBNP during treatment with Sacubitril/Valsartan may be helpful in optimizing HF therapy and understanding the prognosis of HF.Figure.1Figure.2

Very-high-molecular-weight vs high-molecular-weight hyaluronic acid injections show long-term sustained benefits in the treatment of osteoarthritis of the knee: a 15-year Indian cohort study

IntroductionLack of confidence in intra-articular hyaluronic acid injections for osteoarthritis (OA) may result from conflicting guidelines and pooling of results for different molecular weight products. ObjectivesThe objectives were to determine responder rates to injections of very-high-molecular-weight hyaluronic acid (VHMW-HA) vs high-molecular-weight hyaluronic acid (HMW-HA) for knee OA and treatment efficacy measured by the interval between follow-up injections. MethodsA retrospective analysis of a 15-year cohort from a single center. Inclusion criteria: adults with Kellgren-Lawrence Grade III or IV knee OA treated with hyaluronic acid injections. Subjects were stratified into 2 groups based on the molecular weight of the hyaluronic acid. Outcome measures were responder rates with improvement in Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) scores of >30% from baseline vs nonresponders; those with a response lasting >6 months after each injection were considered sustained responders. ResultsIn total, 2037 (female 1467 [72.02%] and male 570 [27.98%]) patients were treated. The overall primary responder rate was 73.44% (1496). VHMW-HA had significantly higher primary responders (75.21% vs 70.22%, P = .015) and significantly lower nonresponders (24.79% vs 29.78%, P = .015). As a subset of primary responders, the sustained responders had greater responses with VHMW-HA vs HMW-HA (85.54% vs 67.06%, P < .0001) and lower dropouts (14.46% vs 32.94%, P < .0001). The average interval between the first and the third injections was longer for VHMW-HA vs HMW-HA—5.67 vs 1.95 years (P < .0001). ConclusionsAbout 73.44% of subjects responded to treatment with intra-articular hyaluronic acid. The sustained response was greater in VHMW-HA vs HMW-HA and VHMW-HA has a longer duration of effect than HMW-HA.

757P Sustained long-term responders to niraparib maintenance in recurrent platinum-sensitive high-grade ovarian cancer (PSROC): A subanalysis of the GEICO-88R study

757P Sustained long-term responders to niraparib maintenance in recurrent platinum-sensitive high-grade ovarian cancer (PSROC): A subanalysis of the GEICO-88R study

Leveraging interindividual variability in threat conditioning of inbred mice to model trait anxiety.

Trait anxiety is a major risk factor for stress-induced and anxiety disorders in humans. However, animal models accounting for the interindividual variability in stress vulnerability are largely lacking. Moreover, the pervasive bias of using mostly male animals in preclinical studies poorly reflects the increased prevalence of psychiatric disorders in women. Using the threat imminence continuum theory, we designed and validated an auditory aversive conditioning-based pipeline in both female and male mice. We operationalised trait anxiety by harnessing the naturally occurring variability of defensive freezing responses combined with a model-based clustering strategy. While sustained freezing during prolonged retrieval sessions was identified as an anxiety-endophenotype biomarker in both sexes, females were consistently associated with an increased freezing response. RNA-sequencing of CeA, BLA, ACC, and BNST revealed massive differences in phasic and sustained responders' transcriptomes, correlating with transcriptomic signatures of psychiatric disorders, particularly post-traumatic stress disorder (PTSD). Moreover, we detected significant alterations in the excitation/inhibition balance of principal neurons in the lateral amygdala. These findings provide compelling evidence that trait anxiety in inbred mice can be leveraged to develop translationally relevant preclinical models to investigate mechanisms of stress susceptibility in a sex-specific manner.

Factors contributing to the clinical effectiveness of imeglimin monotherapy in Japanese patients with type 2 diabetes mellitus.

To investigate the effect of patient characteristics on imeglimin effectiveness in Japanese patients with type 2 diabetes mellitus. Data were pooled from two randomized, placebo-controlled, 24-week, double-blind studies of imeglimin monotherapy in Japanese adults with type 2 diabetes mellitus, with the proportion of responders (glycated hemoglobin [HbA1c] < 7.0%) and sustained responders (i.e., achieved and maintained response) in the imeglimin 1,000 mg twice daily group calculated at each visit. Patient factors significantly (P < 0.05) correlated with response were explored through multivariate logistic regression. Subgroup analyses compared the efficacy of imeglimin in patients with a HbA1c improvement less than or equal to -0.3% (early responders) versus greater than -0.3% (early non-responders) at week 4. A total of 38.0% of imeglimin-treated patients and 7.2% of placebo-treated patients were responders (P < 0.001, number needed to treat = 4). The proportion of sustained responders at weeks 4, 8, 12, 16 and 20 was 10.6, 19.0, 24.0, 25.7 and 29.1%, respectively (>70% of responders at each visit). Improvements in HbA1c and fasting glucose were significantly greater in early responders versus early non-responders from week 4; between-group differences remained significant to week 24. Older age (odds ratio 1.09, 95% confidence interval 1.04-1.14; P < 0.001); treatment-naïve status vs previous treatment (odds ratio 3.70, 95% confidence interval 1.55-8.82; P = 0.003), and lower baseline HbA1c (odds ratio 0.06, 95% confidence interval 0.02-0.16; P < 0.001) predicted response. A significantly higher proportion of patients receiving imeglimin 1,000 mg twice daily monotherapy were responders versus placebo. Most (>70%) were sustained responders, suggesting that response is fairly predictable. Older age, treatment-naïve status and early treatment response significantly predicted imeglimin effectiveness.

Myeloid Derived Suppressor Cell Kinetics in Peripheral Blood Correlate with Efficacy and Toxicity of CAR T Cell Therapy in Relapsed or Refractory B Cell Lymphoma

Introduction. CAR T-cell therapy is potentially curative for patients with relapsed or refractory B-cell lymphoma (BCL). However, about 60% of patients fail CAR T-cell therapy. Immune-related adverse events (irAE) like cytokine release syndrome (CRS) and immune effector cell associated neurotoxicity syndrome (ICANS) occur in an inflammatory state. Myeloid-derived suppressor cells (MDSCs) expand during acute inflammation as steady-state hematopoiesis switches to emergency myelopoiesis. We hypothesized that the acute inflammatory conditions created by CAR T-cell therapy may alter MDSC kinetics and investigated MDSC expansion in the context of CAR T-cell efficacy and toxicity in BCL. Methods. Patients with BCL receiving standard-of-care CAR T-cell therapy were enrolled in a prospective sample collection study. Blood samples were collected before lymphodepletion (baseline), prior to and at early intervals after CAR T-cell infusion. Viable white blood cell (WBC) and MDSC counts were evaluated by multicolor flow cytometry. Phenotypically, MDSCs were defined as immature myeloid cells (CD11b + CD33 + HLA-DR -/low IL-4R +) and divided into monocytic (M-MDSC, CD14 +) and polymorphonuclear (PMN-MDSC, CD15 +) subsets. Clinical response was assessed by Lugano criteria at 1, 3 and 6 months. Incidence and severity of CRS and ICANS were recorded. Cell counts were analyzed by descriptive statistics and reported as mean ± standard error or fold-change from baseline. Kinetics of MDSCs in blood and correlation with clinical outcomes were evaluated by Wilcoxon matched pair signed rank t-test and Mann Whitney U-test. Results. Forty-three BCL patients (41 large BCL, 2 mantle cell lymphoma) were enrolled in the study. Median age was 64 (range 27-83), 32.6% were female. Racial and ethnic minority groups represented 14% of enrolled subjects. One patient developed grade 5 ICANS and was not evaluable for response. Thirty-seven (86%) developed leukopenia and all received granulocyte colony stimulating factor (G-CSF) starting on day 5 post-CAR T infusion. WBC count fell sharply from baseline following lymphodepletion (7.7E +05±8.6E +04 baseline vs 2.9E +05±9.2E +04/mL, p&amp;lt;0.0001) and continued to decline 2-3 days post-CAR T infusion (baseline vs 1.4E +05±2.1E +04/mL, p&amp;lt;0.0001) before returning to baseline within 1 week post-CAR T (i.e. within 3 days of G-CSF). MDSCs followed similar kinetics early on but significantly increased from baseline levels by 1-week post-CAR T (3.4E +03±5.8E +02 baseline vs 8.5E +03±1.7E +02 /mL, p&amp;lt;0.0001). This effect was mainly driven by an exuberant expansion of M-MDSC observed in 33/43 patients (median 6.1-fold increase from baseline at 1 week, range 0.5-4301). Seven patients (16.3%) had progressive disease (PD) at 1 month, 6 (13.9%) additional patients progressed at 3 months and 4 (9.3%) more progressed at 6 months after CAR T-cell infusion. M-MDSC expansion 1-week post-CAR T was only observed in 3/7 refractory patients compared with 28/35 responding patients (Fisher's exact test, p=0.0635). Patients who progressed at 3 months had poorer M-MDSC retention compared to patients with sustained response (1.7E +02±6.1E +01 PD vs 1.4E +03±2.4E +01/mL at 2-week post-infusion, p&amp;lt;0.1). Similarly, patients who progressed at 6 months had lower M-MDSC compared with sustained responders (2.0E +02±8.1E +01 PD vs 4.5E +02±1.4E +02 ml at 1-month post-infusion, p&amp;lt;0.05). Thirteen patients (30.2%) developed &amp;gt; grade 2 CRS and had lower PMN-MDSC retention rate 2-3 days post-CAR-T compared with those with no/low-grade CRS (4.4E +02±2.6E +02 vs 1.4E +03±3.9E +02/mL, p&amp;lt;0.05). Similarly, patients who had ICANS &amp;gt; grade 2 (n=14, 32.5%) had lower PMN-MDSC early retention compared to those with no or low-grade ICANS (5.0E +02±2.5E +02 vs 1.5E +03±4.1E +02/mL, p&amp;lt;0.05). Further analyses are currently underway to bridge these findings with the kinetics of CAR T-cells and T-cell repertoire post-CAR T. Conclusions. The proinflammatory milieu after CAR-T and the use of G-CSF can lead to significant expansion of M-MDSCs. Rather than an impediment to CAR T therapy, M-MDSC expansion and retention are associated with favorable clinical response and PMN-MDSC with a lower risk of developing high grades CRS or ICANS. Whether MDSCs play a mechanistic role remains to be elucidated, but they may have a role as a biomarker in predicting outcomes after CAR T-cell therapy in BCL.

Time to sustained responder status in patients with focal seizures treated with adjunctive eslicarbazepine acetate

Rapid and sustained clinical responses are critical in improving long-term outcomes in epilepsy. While a 50 % reduction from baseline in standardized seizure frequency (SSF) is often cited as a measure of clinically meaningful efficacy, sustained response (SR) is an alternative method that allows the assessment of onset and durability of the response. Time to sustained response in SSF of ≥ 50 %, ≥ 75 %, ≥ 90 %, and 100 % was assessed for pooled data from 3 similar randomized clinical trials of adjunctive eslicarbazepine acetate (ESL). Patients with focal seizures on stable doses of 1–2 antiseizure medications were randomized to placebo, ESL 800 mg/day, or ESL 1200 mg/day. SR50, SR75, SR90, and SR100 were defined as a ≥ 50 %, ≥ 75 %, ≥ 90 %, and 100 % reduction, respectively, in SSF compared to baseline occurring anytime during the 12-week maintenance period, sustained through the end of the maintenance period. Safety signals were assessed for patients with SR50 onset within the first 2 weeks of the maintenance period (early responders) and any point following the first 2 weeks (later responders). A total of 1221 patients were included in this analysis. SR50 was achieved as early as Day 1 (placebo, 4.7 %; ESL 800 mg/day, 8.8 %; ESL 1200 mg/day, 10.4 %). After 84 days, SR50 was achieved by 32.1 % of the placebo group, 46.9 % of the ESL 800 mg/day group (p = 0.0002 vs placebo), and 53.7 % of the ESL 1200 mg/day group (p < 0.0001 vs placebo). Both ESL groups demonstrated earlier SR50 onset compared with placebo (p < 0.0001). Time to SR50 onset was not statistically different between the 800 and 1200 mg/day ESL dose groups. SR75 (p = 0.0001), SR90 (p = 0.0019), and SR100 (p = 0.0014) were achieved significantly earlier in the ESL 1200 mg/day groups vs placebo. SR75 was achieved significantly earlier in the ESL 800 mg/day group vs placebo (p = 0.0188), while achievements of SR90 (p = 0.0525) and SR100 (p = 0.0540) trended toward earlier occurrence. A greater proportion of patients in the ESL groups compared to the placebo group achieved an SR50 during the maintenance period, and those patients in the ESL groups also achieved SR50 and SR75 sooner than placebo treated patients. Additionally, patients treated with the higher ESL dose achieved SR90 and SR100 sooner than those treated with placebo.

Impact of IL-12B Genetic Variants on Antiviral Treatment Response among Hepatitis B Patients in Pakistan

HBV is a continuous major global health concern. Genetic factors of hosts are known to play a role in HBV infection outcomes. This study aimed to reveal the association of IL-12b 3′ UTR variant rs3212227 in HBV patients. Genotyping was performed using ARMS-PCR to detect IL-12b rs3212227 polymorphism. The patients were categorized into groups based on their response to the antiviral therapy. Group I: non-sustained virological response (NSR); Group II: sustained virological responders (SVR); and Group III: HBV-positive fresh cases. ALT levels were measured to evaluate liver function, and viral load was determined to evaluate viral infectivity among the study groups. The variant genotype CC was found to be significantly associated with the non-sustained virological response to the antiviral therapy (with a p-value of 0.0117; OR = 2.914; RR = 1.556). It was also determined that the genotype CC was the most prevalent genotype among both genders in the NSR group. Viral load was found to be 6-fold higher in Group III compared to Group I and Group II. The results suggest that genotype CC is the most prevalent genotype in the NSR groups, and it is associated with a poor response to antiviral therapy in Pakistani patients with HBV infection.

Plecanatide Improves Symptoms of Irritable Bowel Syndrome with Constipation: Results of an Integrated Efficacy and Safety Analysis of Two Phase 3 Trials.

Patients with irritable bowel syndrome with constipation (IBS-C) experience abdominal pain with altered bowel movements. Plecanatide is indicated as IBS-C treatment in adults. This integrated analysis further characterizes plecanatide efficacy and safety in IBS-C. Data pooled from 2 identically designed phase 3 trials included adults with IBS-C randomized to plecanatide 3 mg or 6 mg, or placebo once daily for 12 weeks. A daily diary recorded stool frequency/symptoms, with abdominal pain, bloating, cramping, discomfort, fullness, and straining intensity individually rated. Overall response (primary endpoint) was defined as ≥30% improvement from baseline in average worst abdominal pain severity and increase of ≥1 complete spontaneous bowel movement, during same week (composite), for ≥6 of 12 weeks. Secondary endpoints included sustained response (overall response, plus meeting weekly composite criteria during ≥2 of last 4 treatment weeks) and changes from baseline in individual symptoms. Safety assessments included adverse event monitoring. Overall, 2176 patients (74.0% female; mean [SD] age, 43.5 [14.1] years) were included in efficacy analyses (plecanatide 3 mg [n = 724], 6 mg [n = 723], placebo [n = 729]). A significantly greater percentage of patients achieved overall response with plecanatide 3 mg (25.6%) and 6 mg (26.7%) versus placebo (16.0%; both P < 0.001 vs placebo). A significantly greater percentage of patients were sustained responders with plecanatide 3 mg (24.3%) and 6 mg (25.6%) versus placebo (15.6%; both P < 0.001 vs placebo). Significant improvements from baseline in abdominal discomfort, abdominal fullness, abdominal pain, bloating, and cramping occurred as early as Week 1 (Week 2 for abdominal pain) with plecanatide and were maintained through Week 12 versus placebo. Diarrhea, the most common adverse event, occurred in 4.3% (3 mg), 4.0% (6 mg) and 1.0% (placebo) of patients, leading to study discontinuation in 1.2%, 1.4%, and 0 patients, respectively. Plecanatide is safe and effective for treating global and individual IBS-C symptoms.

#5821 CLINICALLY MEANINGFUL IMPROVEMENT IN QUALITY OF LIFE ACCOMPANIES ITCH RELIEF IN PATIENTS WITH CHRONIC KIDNEY DISEASE ASSOCIATED PRURITUS

Abstract Background and Aims The impairing effect of chronic kidney disease-associated pruritus (CKD-aP) on the quality of life (QoL) of patients undergoing haemodialysis (HD) is well-established. The aim of this post-hoc analysis was to assess the impact of itch relief on QoL, as measured by the 5-D itch scale, in patients with CKD-aP enrolled in the Phase 3 KALM-1 and -2 clinical trials. This study also aimed to confirm the use of ≥5-point reduction in 5-D itch scale total score as a threshold for clinically meaningful improvement in itch-related QoL, by comparing to notable improvement on the Patients’ Global Impression of Change (PGI-C) scale. Method Data were pooled from 851 patients with moderate-to-severe CKD-aP undergoing HD in the KALM-1 and -2 trials testing difelikefalin vs placebo. Sustained responders were defined as patients who achieved a ≥3-point improvement in the weekly mean 24-hour Worst Itching Intensity Numerical Rating Scale [WI-NRS] score at Week 12 of the study, whereas non-sustained responders were defined as patients that reported a ≥3-point improvement in any week of the study but not at Week 12. Improvements in QoL, as measured by the mean change in 5-D itch scale total score from baseline to Week 12, were compared in sustained responders vs non-sustained responders. Data were analysed by ANCOVA multiple imputation, with a missing-at-random assumption. The mean change in 5-D itch scale total score was analysed in relation to patients’ reporting on the five categories of the PGI-C scale. Results In pooled analysis, 305 patients undergoing HD with CKD-aP qualified as sustained responders, whereas 128 patients were non-responders. Reduction in 5-D itch scale total score over 12 weeks was significantly higher in sustained responders compared with non-sustained responders (least squares [LS] mean ±standard error; –7.1±0.2 vs –4.0±0.3, LS mean difference –3.0±0.3, p&amp;lt;0.001) (Figure 1). Greater reductions in 5-D itch scale total score were observed in patients reporting more substantial improvements in PGI-C. Specifically, patients reporting much, or very much, improvement in PGI-C scored ≥5-point reduction on the 5-D itch scale (mean ±standard error; –5.3±0.2 and –8.2±0.3, respectively) (Figure 2). Conclusion This study observed a greater improvement in QoL, as measured by the 5-D itch scale total score, in patients with CKD-aP who reported a clinically meaningful reduction in itch, as measured by WI-NRS, at Week 12. These results also support the use of ≥5-point reduction in the 5-D itch scale total score as a threshold for clinically meaningful improvement in the QoL of patients with CKD-aP. As only sustained responders exceeded this threshold, these data suggest that continued treatment of itch may be necessary to maximally improve QoL in these patients.

Bone Marrow Fibrosis Is Associated with Non-Response to CD19 CAR-T Therapy

Background: Despite the use of CD19-directed CAR-T cell therapy (CAR19) for treatment of relapsed/refractory (R/R) B-acute lymphoblastic leukemia (B-ALL), we cannot predict patient response before infusion. While CAR19 therapies show high complete remission (CR) rates, 15% of patients do not respond (NR), while others eventually relapse (REL). The B-ALL tumor microenvironment may impact efficacy of CAR T cell therapy. We evaluated whether pre-infusion bone marrow biopsy (BMB) parameters predict response to CAR-T cell therapy. Methods: Patients treated with CAR19 for R/R B-ALL from 2012-2021 at the Children's Hospital of Philadelphia were identified. BMBs from pre-CAR and 28 days post-CAR timepoints were evaluated. RNA sequencing-based gene expression profiling was performed (EdgeSeq Whole Transcriptome Panel, HTG Diagnostics). Differential expression (DE) was assessed by DESeq2 in HTG Reveal software. Pathway analysis was done using Metascape. BMBs were evaluated with reticulin special stain and CD3 immunostaining and quantified by expert scoring and digital image analysis. Modified Bauermeister scale ≥ 2 was considered severe fibrosis. Sustained Responders (SR) were defined as patients who did not relapse after achieving CAR19-mediated CR. 63 cases of primary and relapsed B-ALL were stained with CD3 and reticulin to determine baseline variation in fibrosis and CD3 infiltration before any immunotherapy. Results: DE and pathway enrichment analysis of NR and SR pre-CAR infusion samples showed significant NR up-regulation of genes in Skeletal System (p < 0.001) and Connective Tissue Development (p < 0.001), Epithelial to Mesenchymal Transition (p < 0.001), and ECM Structural Constituent (p < 0.001) pathways. Cytokine signaling was not significantly different between groups. Several fibrosis-associated genes, TGFB3 (5.67x, p = 0.009), PRELP (19.26x, p = 0.001), EGR1 (4.85x, p = 0.005), and DUSP1 (4.51x, p = 0.009), were among the ten most significantly upregulated genes. NRs also demonstrated the highest levels of pre-CAR fibrosis. 76% of NRs had a fibrosis score ≥ 2 compared to 56.7% for CRs and 46.7% for REL, and a higher average fibrosis score (2.23), compared to CR (1.46), SR (1.59), and REL (1.47) groups (p = 0.00776, p = 0.03, p = 0.00999, respectively; Mann-Whitney U-Test, two-tailed). CD3 staining was inversely correlated to reticulin fibrosis. Among non-immunotherapy treated patients, 70.3% of primary and 55.6% of relapsed cases had severe fibrosis, while 51.9% of primary and 77.8% of relapsed cases lacked CD3 infiltration. Fibrosis was higher in hyperdiploid, hypodiploid, iAMP21, PAX5-rearranged, and complex genetic subtypes of B-ALL, while CD3 infiltration was lower in PAX5-rearranged, MLL, TCF3-PBX1 and relapsed subtypes of B-ALL. Conclusions We describe for the first time the association between bone marrow fibrosis and response to CAR19 therapy in B-ALL. ECM and Connective Tissue Development pathway expression in NRs exceeds that of both their treatment-responsive peers, as well as expected physiological expression of bone growth/remodeling. Moreover, severe fibrosis and diminished lymphocytic infiltrates were noted in high-risk genetic subtypes of B-ALL even before administration of any immunotherapy. As such, up-regulated fibrosis-associated genes such as PRELP, EGR1, DUSP1, and TGFB3 could be targeted to improve response to CAR19 therapy. Additionally, reticulin staining is a widely available assay that could be used to assess fibrosis in bone marrow biopsies and serve as a useful heuristic tool in predicting the likelihood of therapy success. Ultimately, evaluation of pre-CAR infusion fibrosis levels in conjunction with other molecular and morphological markers may allow for more informed decision making, targeted therapeutic plan development, and patient outcome optimization in R/R B-ALL. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Age and Gender are Predictors for Occult Hepatitis C in Egyptian Sustained Responders to Directly Acting Antivirals

Age and Gender are Predictors for Occult Hepatitis C in Egyptian Sustained Responders to Directly Acting Antivirals

An observational, non-interventional study for the follow-up of patients with amyloidosis who received miridesap followed by dezamizumab in a phase 1 study

BackgroundMiridesap depletes circulating serum amyloid P (SAP) and dezamizumab (anti-SAP monoclonal antibody) targets SAP on amyloid deposits, triggering amyloid removal. In a phase 1, first-in-human study (FIHS), progressive amyloid removal was observed in some patients after ≤ 3 cycles of miridesap/dezamizumab.MethodsThis observational, non-interventional study in patients who received miridesap/dezamizumab during the FIHS (planned follow-up: 5 years) evaluated response to treatment based on routine assessments of disease status and key organ function. In a post hoc analysis, patients responding to treatment in the FIHS during follow-up were identified as responders and further categorized as sustained or declining responders.ResultsIn the FIHS, 17/23 patients were treatment responders. Of these patients, seven (immunoglobulin light chain [AL], n = 6; serum amyloid A, n = 1) were considered sustained responders and ten (fibrinogen-a alpha chain [AFib], n = 5; AL, n = 4; apolipoprotein A-I, n = 1) were considered declining responders. We primarily present responder patient-level data for functional, cardiac, laboratory and imaging assessments conducted during the follow-up period, with non-responder data presented as supplementary.ConclusionNo further development of miridesap/dezamizumab is planned in amyloidosis. However, long-term follow-up of these patients may provide insight into whether active removal of amyloid deposits has an impact on disease progression.Trial registrationClinicalTrials.gov, NCT01777243. Registered 28 January 2013, https://clinicaltrials.gov/ct2/show/study/NCT01777243.

Kinetics in HBsAg after Stopping Entecavir or Tenofovir in Patients with Virological Relapse but Not Clinical Relapse.

This study investigated the kinetics in HBsAg and the HBsAg loss rate after entecavir or tenofovir disoproxil fumarate (TDF) cessation in patients with chronic hepatitis B (CHB) who achieved virological suppression after virological relapse without clinical relapse. A total 504 HBeAg-negative, non-cirrhotic patients who previously received entecavir or TDF with post-treatment and who were followed up for at least 30 months were included. Of the 504 patients, 128 achieved sustained virological suppression (Group I), and 81 experienced virological relapse without clinical relapse. Of the 81 patients, 52 had intermittent or persistent HBV DNA > 2000 IU/mL (Group II), and 29 achieved persistent virological suppression (HBV DNA < 2000 IU/mL) for at least 1.5 years (Group III) after virological relapse. A generalized estimating equations analysis showed that Groups I and III experienced larger off-treatment HBsAg declines than Group II (both, p < 0.001). The post-treatment HBsAg declines of Group I and Group III were similar (p = 0.414). A multivariate analysis showed that there were no differences in the HBsAg change and HBsAg decline (p = 0.920 and 0.886, respectively) or HBsAg loss rate (p = 0.192) between Group I and Group III. The patients who achieved persistent viral suppression after HBV relapse without clinical relapse have a similar decline in HBsAg and the HBsAg loss rate as the sustained responders.

Lidocaine infusions for refractory chronic migraine: a retrospective analysis

IntroductionPatients with refractory chronic migraine have poor quality of life. Intravenous infusions are indicated to rapidly ‘break the cycle’ of pain. Lidocaine infusions may be effective but evidence is limited.MethodsThe...

The CANOVA Study Real-World Evidence of Biologic Treatments in Moderate-Severe Psoriasis in Italy: A Gender Perspective.

Background:In psoriasis, several studies have indicated sex differences in clinical characteristics, type of treatment, and outcomes. A higher impact of psoriasis on quality of life (QoL) and a lower treatment satisfaction have been reported in women by different authors.Objectives:This article reports the results of a post hoc gender analysis of CANOVA study, aimed at assessing 16/24/52-week effectiveness of biologics in patients with moderate-severe plaque psoriasis.Materials and Methods:CANOVA was a real-world, multicenter, noninterventional, retro-prospective study conducted in 17 Italian hospital dermatology clinics.Results:Of the 669 eligible patients, 63.8% were men. Demographic and baseline characteristics and duration of disease were rather homogeneous between sexes. Slightly more women had been treated with biologics (50.4% vs. 46.5%) and had received ≥2 biologic treatment lines (17.2% vs. 12.4%) before study treatment. The most frequently used biologics were secukinumab, ustekinumab, adalimumab, and ixekizumab in both sexes. At 6 months, Psoriasis Area Severity Index (PASI) 75/90/100 responders were 90.8%/72.3%/45.3% of men and 89.2%/76.6%/48.2% of women. Sustained PASI responders were 79.5% of men and 75.9% of women. Treatment satisfaction was significantly lower in women at enrolment for all subscales, and was still lower at 6 months, no longer significantly. Gender distribution in Dermatology Life Quality Index total score classes showed a significantly greater effect of psoriasis on QoL in women, both at enrolment and at the 6-month follow-up.Conclusions:In conclusion, this gender analysis confirms in both genders the efficacy of biologics in psoriasis. However, women reported a greater impact of the disease on QoL and lower treatment satisfaction.

Physiological effect of prone positioning in mechanically ventilated SARS-CoV-2- infected patients with severe ARDS: An observational study.

Background and Aims:Mechanical ventilation in prone position was associated with a reduction in mortality and increase in arterial oxygenation in acute respiratory distress syndrome (ARDS) patients. However, physiological effects of prone position in COVID ARDS patients are unknown.Material and Methods:In this prospective observational study, data of n = 47 consecutive real time RT- PCR confirmed SARS-CoV-2-infected patients with severe ARDS were included. Respiratory mechanics and oxygenation data of recruited patients were collected before and after prone position.Results:Median (Interquartile range, IQR) age of the recruited patients was 60 (50–67) years and median (IQR) PaO2/FiO2 ratio of 61.2 (54–80) mm Hg with application of median (IQR) positive end expiratory pressure (PEEP) of 12 (10–14) cm H2O before initiation of prone position. Out of those patients, 36 (77%) were prone responders at 16 hours after prone session, evident by increase of PaO2 by at least 20 mm Hg or by 20% as compared to baseline, and 73% patients were sustained responders (after returning to supine position). Plateau airway pressure (p < 0.0001), peak airway pressure (p < 0.0001), and driving pressure (p < 0.0001) were significantly reduced in prone position, and static compliance (p = 0.001), PaO2/FiO2 ratio (p < 0.0001), PaO2 (p = 0.0002), and SpO2 (p = 0.0004) were increased at 4 hours and 16 hours since prone position and also after returning to supine position.Conclusion:In SARS-CoV-2-infected patients, mechanical ventilation in prone position is associated with improvement in lung compliance and oxygenation in almost three-fourth of the patients and persisted in supine position in more than 70% of the patients.

Electrophysiological correlates and predictors of the antidepressant response to repeated ketamine infusions in treatment-resistant depression

BackgroundSub-anesthetic ketamine doses rapidly reduce depressive symptoms, although additional investigations of the underlying neural mechanisms and the prediction of response outcomes are needed. Electroencephalographic (EEG)-derived measures have shown promise in predicting antidepressant response to a variety of treatments, and are sensitive to ketamine administration. This study examined their utility in characterizing changes in depressive symptoms following single and repeated ketamine infusions. MethodsRecordings were obtained from patients with treatment-resistant major depressive disorder (MDD) (N = 24) enrolled in a multi-phase clinical ketamine trial. During the randomized, double-blind, crossover phase (Phase 1), patients received intravenous ketamine (0.5 mg/kg) and midazolam (30 μg/kg), at least 1 week apart. For each medication, three resting, eyes-closed recordings were obtained per session (pre-infusion, immediately post-infusion, 2 h post-infusion), and changes in power (delta, theta1/2/total, alpha1/2/total, beta, gamma), alpha asymmetry, theta cordance, and theta source-localized anterior cingulate cortex activity were quantified. The relationships between ketamine-induced changes with early (Phase 1) and sustained (Phases 2,3: open-label repeated infusions) decreases in depressive symptoms (Montgomery-Åsberg Depression Rating Score, MADRS) and suicidal ideation (MADRS item 10) were examined. ResultsBoth medications decreased alpha and theta immediately post-infusion, however, only midazolam increased delta (post-infusion), and only ketamine increased gamma (immediately post- and 2 h post-infusion). Regional- and frequency-specific ketamine-induced EEG changes were related to and predictive of decreases in depressive symptoms (theta, gamma) and suicidal ideation (alpha). Early and sustained treatment responders differed at baseline in surface-level and source-localized theta. ConclusionsKetamine exerts frequency-specific changes on EEG-derived measures, which are related to depressive symptom decreases in treatment-resistant MDD and provide information regarding early and sustained individual response to ketamine.Clinical Trial Registration: ClinicalTrials.gov: Action of Ketamine in Treatment-Resistant Depression, NCT01945047

Abstract 13300: Does Mechanical Dyssynchrony in Addition to QRS Area Ensure Sustained Response to Cardiac Resynchronization Therapy?

Introduction: Judicious patient selection for CRT may further enhance treatment response. Progress has been made by using improved markers of electrical dyssynchrony and mechanical discoordination, using QRS AREA , and systolic rebound stretch of the septum (SRSsept) or systolic stretch index (SSI), respectively. Hypothesis: We hypothesize that the presence of combined electrical and mechanical dysfunction are of added benefit in predicting a sustained CRT-response. Methods: A total of 240 CRT patients were prospectively enrolled from six centers. Patients underwent standard 12-lead electrocardiography, and echocardiography, at baseline, 6 month, and 12 month follow-up. QRS AREA was derived using vectorcardiography, and SRSsept and SSI were measured using strain-analysis. Reverse remodelling was measured as the relative decrease in left ventricular end-systolic volume, indexed to body surface area (ΔLVESVi). Sustained response was defined as ≥ 15% decrease in LVESVi, at both 6 and 12 month follow-up. Presence of left bundle branch block (LBBB) was determined according to strict American Heart Association criteria. Results: QRS AREA and SRSsept were both strong, multivariably adjusted, predictors of reverse remodelling. The presence of SRSsept ≥ 2.5%, in addition to QRS AREA ≥ 120 μVs, significantly increased the extent of reverse remodelling when compared to high QRS AREA alone (ΔLVESVi 38±21 versus 22±21%). As a result, 100% of LBBB-patients and 74% of non-LBBB patients with combined electrical and mechanical dysfunction were sustained volumetric responders, as opposed to 53% and 46% with high QRS AREA alone, respectively. Conclusions: In patients with high QRS AREA , concomitant presence of high SRSsept significantly increases 6-month remodelling after CRT. Combined presence of high SRSsept and QRS AREA , but not high QRS AREA alone, is of importance in order to ensure a sustained response after CRT in LBBB patients.

Bone Marrow Biopsy T Cell Aggregates and Cytokine Transcriptional Signatures Predict Sustained Response to CAR T-Cell Therapy in B-ALL

BackgroundCAR T-cell therapies directed against CD19 (CAR19) are used to treat relapsed/refractory (R/R) B-acute lymphoblastic leukemia (B-ALL) and show high complete remission (CR) rates compared to salvage chemotherapy. However, subsets of patients do not respond or relapse after initial CR. While previous work has demonstrated the importance of CAR T cell immunophenotype and vector integration site in long term CAR19 responders, there are currently no clinically applicable predictors of response. Given the importance of the B-ALL tumor microenvironment in mediating chemoresistance, inflammatory signaling and recruitment of immune effectors to the leukemic bone marrow, we hypothesized that the pre-CAR19 infusion bone marrow biopsy immune microenvironment may predict CAR19 responses.MethodsPatients treated with CAR19 for R/R B-ALL from 2012-2017 were retrospectively identified. Marrow core biopsies were collected immediately prior to CAR19 infusion (pre-CAR) and at one month post-infusion (post-CAR). Bone marrow biopsy slides immunohistochemically stained for CD3 were digitally scanned, analyzed algorithmically for T-cell infiltration and assessed qualitatively for interstitial T cell aggregates of >5 cells (Leica Aperio ImageScope). B-ALL involvement was determined by bone marrow aspirate counts and minimal residual disease (MRD) flow cytometry. Targeted RNA sequencing-based gene expression profiling (EdgeSeq Immuno-Oncology Panel, HTG Diagnostics) was performed on pre- and post-treatment biopsies, with differential expression assessed by DESeq2 within HTG Reveal software, and further analyses conducted using Metascape.ResultsWe identified 143 bone marrow core biopsies (84 pre-treatment, 59 post-treatment) from 84 R/R B-ALL patients treated with CAR19. Pre-CAR B-ALL marrow involvement ranged from 0-95% (median: 67.5%), and the dataset included patients with relapses occurring between 1-33 months following CAR therapy (median: 6 months).Pre-CAR CD3+ T cell aggregates were significantly increased in CAR19 Sustained Responders (SR) compared to Non-Responders (NR) (92.3% versus 50%, p=0.007) and eventual relapses (CD19+: 40%, p= 0.002 and CD19-: 61.5%, p=0.019) (Figure 1A-B). A lack of T cell aggregates in pre-CAR marrow biopsies showed a sensitivity of 45.8% and a specificity of 92.3% in distinguishing NRs and eventual relapses from SRs. In one month post-CAR marrow biopsies, T cell aggregates continued to show higher frequency in SRs compared to eventual CD19+ relapses (100% versus 42.9%, p=0.007) and NRs (50%, p=0.04).Pre-CAR marrow T cell infiltration was also significantly greater in SRs compared to NRs (2146 CD3+ T cells per biopsy versus 850, p=0.038) and eventual CD19- relapses (1086, p=0.022), and trended toward a significant increase compared to eventual CD19+ relapses (1056, p=0.063) (Figure 1C). Pre-CAR marrow T cells of < 920 per biopsy showed a sensitivity of 45.8% and a specificity of 92.3% in distinguishing NRs and relapses from SRs (Figure 1D).RNAseq differential gene expression analysis of pre-CAR marrow biopsies revealed a chemokine axis of CXCL9, CXCL13, CXCR5, CXCL5, CXCL2 and CCL1 in SR that was deficient in patients with eventual relapse (Figure 1E). By contrast, NRs and eventual relapses showed a pre-CAR transcriptional signature reflecting Th2 (IL5RA, IL13) and Th17 (IL17A, IL23R) skewing, in addition to higher IL2, IFNG and IL6 transcripts.ConclusionThese immunohistochemical and transcriptional findings support a pivotal role for the peri-infusion bone marrow microenvironment in long-term responses to CAR19 therapy in B-ALL. A deficiency of marrow T cell aggregates and marrow-infiltrating T cells pre-CAR shows high specificity in distinguishing NRs and eventual relapses from SRs to CAR19, and marrow T cell aggregates are a persistent feature of SRs at one month post-CAR infusion. SR to CAR19 is also associated with elevated marrow expression of a suite of immune chemoattractants which may enhance the ability of infused CAR T cells and other effectors to infiltrate the B-ALL microenvironment. Combined assessment of bone marrow T cell infiltrates and transcriptional profiling could be used to improve the sensitivity and specificity of predictive algorithms for responses to CAR19 therapy. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.