Predictors Of Poor Treatment Response Research Articles

Utilizing the Systemic Immune-Inflammation Index and Blood-Based Biomarkers in Association with Treatment Responsiveness amongst Patients with Treatment-Resistant Bipolar Depression.

(1) Background: Inflammation is associated with depressive illness and treatment resistance. This study assessed a novel inflammatory index, the Systemic Immune-Inflammation Index (SII), in patients diagnosed with treatment-resistant bipolar depression (TRBDD) before and after treatment with escitalopram (ESC) and celecoxib (CBX) add-on or ESC and placebo (PBO), and compared them to healthy control (HC) subjects. (2) Methods: This is a secondary biological analysis from a double-blind randomized placebo-controlled trial of CBX augmentation in TRBDD. Our subsample with available complete blood count (CBC) data included 52 TRBDD subjects, randomized into an ESC + CBX, (n = 29), an ESC + PBO arm (n = 23), and an HC group (n = 32). SII was calculated from the CBC with differential (SII = platelets x neutrophils/lymphocytes) at baseline and end of treatment (8 weeks). Blood inflammation biomarkers, growth factors, and kynurenine metabolites were determined at both timepoints. Depressive symptom severity was the primary outcome, using the HAMD-17 rating scale score to quantitate treatment response and remission rates. (3) Results: Baseline SII did not discriminate TRBDD from HC, nor was it associated with HAMD-17 score at any timepoint, although it was significantly associated with lower baseline VEGF (p = 0.011) and higher week 8 levels of IL1-β (p = 0.03) and CRP (p = 0.048). Post-treatment HAMD-17 was not independently predicted using baseline SII unless an interaction with age was present (p = 0.003 was included), even after relevant adjustments. A similar effect was seen with baseline neutrophils. (4) Conclusions: While SII was not an independent predictor of treatment outcome, elevated baseline SII was a predictor of poor treatment response amongst older patients with TRBDD.

Dynamic processes in behavioral activation therapy for anhedonic adolescents: Modeling common and patient-specific relations.

Behavioral activation (BA) is a brief intervention for depression encouraging gradual and systematic re-engagement with rewarding activities and behaviors. Given this treatment focus, BA may be particularly beneficial for adolescents with prominent anhedonia, a predictor of poor treatment response and common residual symptom. We applied group iterative multiple model estimation (GIMME) to ecological momentary assessment (EMA) treatment data to investigate common and person-specific processes during BA for anhedonic adolescents. Thirty-nine adolescents (Mage = 15.7 years old, 67% female, 81% White) with elevated anhedonia (Snaith-Hamilton Pleasure Scale) were enrolled in a 12-week BA trial, with weekly anhedonia assessments. EMA surveys were triggered every other week (2-3 surveys per day) throughout treatment assessing current positive affect (PA) and negative affect (NA), engagement in pleasurable activities and social interactions, anticipatory pleasure, rumination, and recent pleasurable and stressful experiences. A multilevel model revealed significant decreases in anhedonia, t(25.5) = -4.76, p < .001, over the 12-week trial. GIMME results indicated substantial heterogeneity in variable networks across patients. PA was the variable with the greatest number (22% of all paths vs. 11% for NA) of predictive paths to other symptoms (i.e., highest out-degree). Higher PA (but not NA) out-degree was associated with greater anhedonia improvement, t(25.8) = -2.22, p = .035. Results revealed substantial heterogeneity in variable relations across patients, which may obscure the search for common processes of change in BA. PA may be a particularly important treatment target for anhedonic adolescents in BA. (PsycInfo Database Record (c) 2023 APA, all rights reserved).

Clinical Course of Adult FSGS and Minimal Change Disease in North American and Japanese Cohorts.

Regional differences in presentation and clinical course of nephrotic syndrome (NS) have not been studied well because few studies directly compared the data from different intercontinental regions. We included adult nephrotic patients with Focal Segmental Glomerulosclerosis (FSGS) and Minimal Change Disease (MCD) who received immunosuppressive therapy (IST) in a North American (NEPTUNE, n=89) or Japanese (N-KDR, n=288) cohort. Baseline characteristics and rates of complete remission (CR) were compared. Factors associated with time to CR were evaluated by Cox regression models. NEPTUNE cases had more FSGS (53.9 vs. 17.0%) and family history of kidney disease (35.2 vs. 3.2%). N-KDR cases were older (median 56 vs. 43 years) and demonstrated greater levels of UPCR (7.73 vs. 6.65) and hypoalbuminemia (1.6 vs. 2.2 mg/dL). N-KDR cases showed higher proportion of CR (overall: 89.2 vs. 62.9%; FSGS: 67.3 vs. 43.7%; MCD: 93.7 vs. 85.4%). A multivariable model showed that FSGS (vs. MCD: HR=0.28, 95%CI 0.20-0.41), systolic blood pressure (per 10 mmHg: HR=0.93, 95%CI 0.86-0.99) and eGFR (per 10 mL/min/1.73m2: HR=1.16, 95%CI 1.09-1.24) were associated with time to CR. There were significant interactions in patient age (p=0.004) and eGFR (p=0.001) between the cohorts. The North American cohort had more FSGS and more frequent family history. Japanese patients showed more severe NS with better response to IST. FSGS, hypertension and lower eGFR were shared predictors of poor treatment response. Identifying shared and unique features across geographically diverse populations may help uncover biologically relevant subgroups, improve prediction of disease course and better design future multi-national clinical trials.

Effect of Neutrophil to Lymphocyte ratio on antidepressant treatment response: moderating effect of sex and mediating effect of Hippocampal volumes.

IntroductionIn recent years much focus has been put on the role of immune/inflammatory alterations in affecting Major Depression (MDD) development and antidepressant efficacy. Neutrophil-to-lymphocyte ratio (NLR) is an inexpensive inflammatory marker shown to be elevated in depressed patients, with large population studies reporting this effect only in women. However, its relation to treatment response is much less clear. Reduced hippocampal volumes (HV) are among the few consistent brain structural predictors of poor treatment response, and they have been shown to be influenced by inflammatory status.ObjectivesTo investigate the effect of NLR on treatment response in MDD patients, testing a possible moderating role of sex. To investigate the effect of NLR on HV and test a possible mediating role of the latter in the relation between NLR and treatment response.MethodsOur study was performed on a sample of 120 MDD inpatients suffering from a non psychotic depressive episode (F=78; M=42). Depression severity was assessed via the Hamilton Depression Rating Scale (HDRS), both at admission and discharge; as a measure of treatment response, delta HDRS was calculated subtracting the two scores. NLR was calculated for each subject. Patients underwent 3T MRI acquisition and bilateral HV were estimated.ResultsWe found a significant moderating effect of sex on the relationship between NLR and Delta HDRS (p &lt; 0.001): a negative relation was found in women (p &lt; 0.001) and a positive one in men (p = 0.042). NLR was found to negatively affect left HV in the whole sample (p = 0.027) and in women (p = 0.038). A positive effect on Delta HDRS was found for both left (p = 0.038) and right (p = 0.027) HV. Finally, we found a significant indirect effect of NLR values on Delta HDRS through left HV in women (95% BCa CI [- 0.948, -0.017]); the direct effect of NLR on Delta HDRS also remained significant (p = 0.002).ConclusionsSex was found to moderate the relation between NLR and treatment response. The detrimental effect in women is in line with previous reports linking inflammation to hampered antidepressant effect; the positive one in men is more surprising: however, the only studies to date on the effect of NLR on antidepressant efficacy report a positive effect in patients with psychotic depression. In women we found NLR to affect treatment response partially through its effect on left HV, providing a possible, albeit incomplete, mechanistic explanation of the effect of inflammatory status on antidepressant efficacy.Disclosure of InterestNone Declared

Chemotherapy induces ACE2 expression in breast cancer via the ROS-AKT-HIF-1α signaling pathway: a potential prognostic marker for breast cancer patients receiving chemotherapy

BackgroundAngiotensin-converting enzyme 2 (ACE2) is a key enzyme of the renin-angiotensin system and a well-known functional receptor for the entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells. The COVID-19 pandemic has brought ACE2 into the spotlight, and ACE2 expression in tumors and its relationship with SARS-COV-2 infection and prognosis of cancer patients have received extensive attention. However, the association between ACE2 expression and tumor therapy and prognosis, especially in breast cancer, remains ambiguous and requires further investigation. We have previously reported that ACE2 is elevated in drug-resistant breast cancer cells, but the exact function of ACE2 in drug resistance and progression of this malignant disease has not been explored.MethodsThe expression of ACE2 and HIF-1α in parental and drug-resistant breast cancer cells under normoxic and hypoxic conditions was analyzed by Western blot and qRT-PCR methods. The protein levels of ACE2 in plasma samples from breast cancer patients were examined by ELISA. The relationship between ACE2 expression and breast cancer treatment and prognosis was analyzed using clinical specimens and public databases. The reactive oxygen species (ROS) levels in breast cancer cells were measured by using a fluorescent probe. Small interfering RNAs (siRNAs) or lentivirus-mediated shRNA was used to silence ACE2 and HIF-1α expression in cellular models. The effect of ACE2 knockdown on drug resistance in breast cancer was determined by Cell Counting Kit 8 (CCK-8)-based assay, colony formation assay, apoptosis and EdU assay.ResultsACE2 expression is relatively low in breast cancer cells, but increases rapidly and specifically after exposure to anticancer drugs, and remains high after resistance is acquired. Mechanistically, chemotherapeutic agents increase ACE2 expression in breast cancer cells by inducing intracellular ROS production, and increased ROS levels enhance AKT phosphorylation and subsequently increase HIF-1α expression, which in turn upregulates ACE2 expression. Although ACE2 levels in plasma and cancer tissues are lower in breast cancer patients compared with healthy controls, elevated ACE2 in patients after chemotherapy is a predictor of poor treatment response and an unfavorable prognostic factor for survival in breast cancer patients.ConclusionACE2 is a gene in breast cancer cells that responds rapidly to chemotherapeutic agents through the ROS-AKT-HIF-1α axis. Elevated ACE2 modulates the sensitivity of breast cancer cells to anticancer drugs by optimizing the balance of intracellular ROS. Moreover, increased ACE2 is not only a predictor of poor response to chemotherapy, but is also associated with a worse prognosis in breast cancer patients. Thus, our findings provide novel insights into the spatiotemporal differences in the function of ACE2 in the initiation and progression of breast cancer.

Barriers to remission from child and adolescent anxiety disorders following extensive treatment: An exploratory study

Although treatments for child and adolescent (hereafter, children) anxiety show good efficacy, a significant proportion of children do not remit, even 12 months after receiving treatment. Barriers to treatment responsiveness among chronically anxious children is not well studied. The current study evaluated barriers and predictors of poor treatment response among a small sample of children who reached the third step in a three-stage stepped-care intervention. Stepped-care involved low-intensity CBT, followed by standard CBT if required, and subsequently high intensity CBT if still warranted. Children moved to the next step of stepped-care if requested by their caregiver following feedback of clinical status and symptom change by their therapist. From the initial sample of 139 children entering step 1, 26 (18.7%) children provided data in the third step and were assessed approximately 12 months following their baseline assessment. Several baseline constructs and treatment engagement measures were completed both quantitatively and qualitatively. At the end of Step 3, 14 of 26 (54%) participants had not remitted from their primary disorder and 19 (77%) were not remitted from all anxiety disorders. Non-remission was associated with baseline measures of higher primary disorder severity, fewer anxiety disorders, higher child self-reported social anxiety and total difficulties, and poorer mood. Therapy factors associated with non-remission included greater avoidance, less engagement with exposure tasks, and poorer homework completion. Identifying factors that predict poor response to treatment can help to tailor intervention and improve outcomes for this very complex group of young people.

Attachment and mentalization as predictors of outcome in family therapy for adolescent anorexia nervosa

Anorexia nervosa-focussed family therapy (FT-AN) is the first-line treatment for adolescent anorexia nervosa (AN), but the predictors of poor treatment response are not well understood. The main aim of this study was to investigate the role of attachment and mentalization in predicting treatment outcome. The secondary aims of the study were to investigate therapeutic alliance at 1 month as a predictor of outcome, and to test the associations between alliance and baseline attachment and mentalization. 192 adolescents with AN and their parents were recruited as they began family therapy in out-patient specialist eating disorder services. Self-report measures of attachment, mentalization, and emotion regulation were completed at the start of treatment by adolescent patients and one of their parents. Self-reported alliance scores were collected at one month. Higher scores on the Certainty Scale of the Reflective Functioning Questionnaire, completed by parents, which indicate over-certainty about mental states, were the strongest predictor of poor outcome (Odds Ratio: 0.42, CI: 0.20–0.87). Similarly, for adolescents, higher Lack of Clarity scores on the Difficulties in Emotion Regulation Scale, representing being unclear about one’s feelings, were predictive of positive treatment outcome (OR: 1.10, CI: 1.00–1.21). Higher alliance scores at 1 month predicted positive outcome, and were associated with attachment security and mentalization. These novel findings suggest that, particularly in parents, a tendency towards excessive certainty about mental states in others may predict poor outcome in FT-AN. Further research is warranted to replicate the finding and characterise families at risk of poor outcome.

Transcutaneous electrical nerve stimulation as add-on therapy in children receiving anticholinergics and/or mirabegron for refractory daytime urinary incontinence: A retrospective cohort study.

To investigate if children with daytime urinary incontinence (DUI) and overactive bladder (OAB) refractory to standard urotherapy and medicinal treatment, would experience improvement in symptoms after add-on treatment with transcutaneous electrical nerve stimulation (TENS). Children were retrospectively enrolled from tertiary referral centers at Aarhus and Aalborg University Hospitals. All data were retrieved from the patients' journals. All children were prescribed TENS as an add-on treatment to the highest-tolerable dose of medicinal treatment in a standardized regime of 2 h a day for around 3 months. Primary endpoints were the number of wet days per week (WDPW) and incontinence episodes per day. Effect of treatment was defined as greater or equal to 50% reduction in the frequency of DUI episodes. Secondary endpoints were to establish predictive factors for the effect of treatment using logistic regression. Seventy-six children diagnosed with DUI and OAB refractory to treatment with standard urotherapy and pharmacological treatment, at the age of 5-16 years were included from February 2017 to February 2020. A reduction in WDPW (from 6.31 [5.86-6.61] to 4.27 [3.45-4.90], p < 0.05) and incontinence episodes per day (from 2.45 [1.98-2.91] to 1.43 [1.07-1.80], p < 0.05) was observed. Twelve patients became completely dry. At 6 months follow-up, seven of the 12 complete responders had relapsed while five remained dry. A history of constipation before TENS was a predictor of poor treatment response (p = 0.016). TENS as add-on to anticholinergic treatment seems effective in a number of children with treatment-refractory DUI.

Procoagulant Phospholipid Dependent Clotting Time: A New Tool for the Identification of Multiple Myeloma Patients at Risk Poor Treatment Response

Background: Research has long focused on the implications of platelet, endothelial cell and blood coagulation activation in the risk of venous thromboembolism in patients with multiple myeloma (MM). Given the pivotal role of the malignant cell in coagulation activation we studied the association between biomarkers of hypercoagulability and cancer cell activity.Aim: Using data from the prospective, longitudinal observational study ROADMAP-MM CAT (PROspective Risk Assessment anD bioMArkers of hyPercoagulability for the identification of patients with Multiple Myeloma at risk for Cancer Associated Thrombosis) we aimed to identify biomarkers of cellular and plasma hypercoagulability that play a role in determining response to the anti-myeloma treatment.Methods: Newly diagnosed patients with MM were enrolled. Patients on anticoagulant treatment were excluded. A standardized clinical research form (CRF) was completed at enrollment (T0) and at 3 months post treatment initiation (T1). Blood samples were collected at the same time points. Procoagulant phospholipid-dependent clotting time (Procoag-PPL®), tissue factor activity (TFa), thrombomodulin activity (TMa), factor VIIa, factor V (FV), antithrombin (AT), fibrin monomers (FM) and D-Dimers were measured with respective assays from Diagnostica Stago (Asnieres, France) on a STA-R® analyzer (Diagnostica Stago). Plasma levels of P-Selectin and heparanase were measured with ELISA Kits from Cusabio Biotech (from CliniSciencies, France) and R&D Systems (Lille France), respectively. Samples of platelet-poor plasma (PPP) were assessed for thrombin generation (TG) with the TF 5pMPPP-Reagent® on Calibrated Automated Thrombogram (Stago, France). The control group (CG) consisted of 30 healthy age and sex-matched individuals.Results. A total of 100 treatment naïve MM patients were enrolled. Median age was 66.5±12.0 (37-88) years and 54% of the population was male. Disease stage was distributed as follows: 24.3% ISS-I, 20.4% ISS II and 55.3% ISS-III. Bortezomib-based therapy was given to 64.1% of the patients, thalidomide based in 6.8% and lenalidomide-based in 24.3%. Median time to follow up was 11.5 months. There were 16 deaths overall and mortality rate was 162/1000 person-years (median time of death since diagnosis 4.5 months, range 1-9 months). At T1, patients with stable disease (n=8) and progressive disease (n=14) were classified as non-responders. A total of 78 patients achieved at least a partial response and were classified as responders. Compared to controls at T0, MM patients showed significantly increased levels of TFa, D-Dimers and FM and significantly shorter Procoag-PPL clotting time. P-selectin levels were significantly decreased and heparanase levels significantly increased. FVIIa, FV and AT were not significantly different between patients and controls. MM patients showed significantly increased lag-time and ttPeak and significantly lower Peak, ETP and MRI as compared to the control group. TFa and D-dimer levels decreased significantly 3 months post treatment initiation (T1) whereas TMa and AT significantly decreased. At T1 thrombin generation was further attenuated (lower ETP and Peak, prolongation of ttPeak and lower MRI). Univariate analysis demonstrated that among the studied biomarkers only short PPL-ct was associated with a significantly increased risk of no response to treatment. The area under the curve (AUC) in a plot of PPL-ct against no response to treatment (receiver operator curve analysis) was 0.7 (p=0.01).Conclusion. The prospective ROADMAP-CAT multiple myeloma study demonstrates for the first time that among a large number of hypercoagulability biomarkers assessed in newly diagnosed treatment-naïve MM patients, PPL-ct, that reflects the amount of procoagulant microparticles present in plasma, is a significant predictor of poor treatment response. A prospective trial is required to evaluate the potential role of this biomarker in anti-myeloma treatment optimization. [Display omitted] DisclosuresTerpos:Amgen: Honoraria, Other: SC member, Research Funding; Takeda: Honoraria, Other: SC member, Research Funding; Genesis/Celgene: Honoraria, Other: DMC member, Research Funding; Janssen: Honoraria, Research Funding; BMS: Honoraria; Abbvie: Honoraria; GSK: Honoraria. Garderet:Takeda: Honoraria; Amgen: Honoraria.

Biomarkers of treatment response in patients with progressive multiple sclerosis treated with high-dose pharmaceutical-grade biotin (MD1003).

BackgroundHigh‐dose pharmaceutical‐grade biotin (MD1003) has positive effects on disability in progressive multiple sclerosis (PMS), but its mechanism of action remains unclear. The objective of our study was to quantify the effect of MD1003 in patients with PMS, using clinical response, plasma neurofilament light chain (pNfL) levels, and brain (BV) or cervical spinal cord volume (CSCV).Materials and methodsForty‐eight patients with PMS newly treated with MD1003 were followed during one year. Patients were assessed clinically using the Expanded Disability Status Scale (EDSS), the nine‐hole peg test (9HPT), and the 25‐foot walk time (25FWT). CSCV was quantified using CORDIAL software and BV using SIENA or SIENAX. We measured pNfL level using SIMOA at several time points. Bayesian linear and logistic regressions were used to evaluate potential prognostic factors.ResultsTreatment response, defined as a significant decrease of EDSS, 25FWT, or 9HPT at 1 year, was observed in 13 patients (27%). A gain of volume was noted in 7/24 patients for brain and in 10/19 patients for cervical spinal cord. The strongest predictors of poor treatment response were a high pNfL level at MD1003 onset (OR 0.96; 95% CI [0.91; 1]), high age at MS onset (OR 0.95; 95% CI [0.89; 1.01]), and an increase in brain lesion load during MD1003 treatment (OR 0.81; 95% CI [0.55; 1.05]).ConclusionsMD1003 treatment was associated with clinical, BV, and CSCV improvement at 1 year. The correlation between the levels of pNfL at baseline, the age at multiple sclerosis onset, and a treatment response at M12 is consistent with a better effect in less disabled patients.

The PET-Derived Tumor-to-Liver Standard Uptake Ratio (SUV TLR ) Is Superior to Tumor SUVmax in Predicting Tumor Response and Survival After Chemoradiotherapy in Patients With Locally Advanced Esophageal Cancer.

Background: The maximum standardized uptake values (SUVmax) derived from 18F-fluorodeoxy-glucose positron emission tomography/computed tomography (18F-FDG PET/CT) have some well-known shortcomings in predicting treatment response and prognosis in oncology. The standardized SUVmax with an appropriate reference background may overcome this problem in some instances. This study explored the prognostic value of the tumor-to-liver SUVmax ratio (SUVTLR) and the tumor-to-blood pool SUVmax ratio (SUVTBR) in predicting the objective response (OR) and overall survival (OS) in patients with locally advanced esophageal cancer after concurrent chemoradiotherapy (CCRT).Methods: We retrospectively analyzed 128 newly diagnosed esophageal squamous cell carcinoma (ESCC) patients who were treated with CCRT. The SUVmax of primary tumor, SUVTLR, SUVTBR and clinicopathologic features data were analyzed. Univariate and multivariate analyses were used to determine the predictors of tumor response. Survival analysis was performed using the Kaplan–Meier method and Cox proportional hazards model.Results: Receiver operating characteristic (ROC) curve analysis demonstrated that SUVTLR was superior to SUVmax and SUVTBR in predicting treatment response. Univariate and multivariate analyses revealed that advanced tumor stage (hazard ratio [HR] = 9.67; 95% CI: 1.15-81.28; P = 0.037) and high SUVTLR (HR = 21.92; 95% CI: 2.26-212.96; P = 0.008) were independent predictors of poor treatment response. Cox regression analysis showed that good clinical tumor response (p < 0.014, HR =0.501; 95% CI: 0.288–0.871) was a favorable independent predictive factor for OS, while an advanced tumor stage (p = 0.018, HR = 1.796; 95% CI: 1.107-2.915) and a high SUVTLR (p < 0.002, HR = 2.660; 95% CI: 1.425–4.967) were prognostic factors for poor OS. The median OS of patients in the low SUVTLR and high SUVTLR groups was 13.47 vs. 19.30 months, respectively.Conclusions: PET-derived SUVTLR is superior to tumor SUVmax and SUVTBR in predicting treatment response and overall survival in patients with ESCC undergoing CCRT. High SUVTLR was an independent predictor of poor treatment response and shorter overall survival.

Influence of smoking and obesity on treatment response in patients with axial spondyloarthritis: a systematic literature review.

To assess whether smoking and obesity are predictors of poor treatment response in patients with axial spondyloarthritis (axSpA). A systematic literature review was performed by searching in MEDLINE and EMBASE up to June 2019 with a strategy based on the PICO approach: Population: patients with axSpA; Intervention or exposure: smoking or obesity; Comparison: non-smokers (for smoking) and normal-weight individuals (for obesity); and Outcome: any response criteria currently validated for axSpA. The 2009 Oxford Centre for Evidence-based Medicine levels were used for assessing the studies quality. Out of 1873 references retrieved, 46 studies were selected for full-text review and 12 for data extraction: six stratified patients by smoking and six by obesity. All were longitudinal observational studies, except one, which was cross-sectional. Overall, these studies included 5291 patients (3917 for smoking and 1333 for obesity), and all these patients were on anti-tumor necrosis factor (anti-TNF) therapy. The quality of evidence was graded as level 2b except that from the cross-sectional study which was graded level 4. For smoking, the evidence found is inconsistent: two studies finding negative effects in response to anti-TNF while the other four found no differences in clinical response to this therapy. Regarding obesity, the evidence is more consistent: five of the six studies describing a negative influence in response to anti-TNF. According to the scientific evidence in patients with axSpA, obesity is associated with a more unsatisfactory response to anti-TNF therapy. A poorer response in smokers has yet to be demonstrated. Key Points • Identifying predictors of treatment response in axSpA, especially those that are modifiable, is relevant. • Obesity increases the risk of poorer response to anti-TNF agents in patients with axSpA. • Scientific evidence for smoking habit as a predictor of treatment response in axSpA is inconclusive.

Age of Diagnosis and Comorbid PLMD Predict Poor Response of REM Behavior Disorder to Clonazepam.

Previous studies have shown the therapeutic effects of clonazepam for rapid eye movement sleep behavior disorder (RBD), but they had several limitations such as the lack of clear definition of treatment outcomes and little information about adjuvant therapy. The aims of this study were to evaluate the treatment outcomes with clonazepam and to explore possible determinants of treatment response. We performed a retrospective medical chart review of 171 patients with RBD. All the participants underwent overnight polysomnography and completed questionnaires. The positive treatment response was defined as the absence of disruptive behaviors causing sleep-related injuries during the last year of follow-up. Among the 171 patients presented with disruptive behaviors, 155 (90.6%) experienced positive treatment responses. Of the responders, 18 (11.6%) received adjunctive medication due to insufficient therapeutic effect of clonazepam monotherapy. After adjusted analysis, an earlier age of diagnosis (odds ratio [OR] = 0.74, 95% confidence interval [CI] = 0.64-0.86, P < .001) and comorbid periodic limb movement during sleep (OR = 4.96, 95% CI = 1.05-23.33, P = .043) were related to poor treatment response. Clinicians should recognize the predictors of poor treatment response and consider combination therapy for better prevention of sleep-related injuries in those who show unsatisfactory responses to clonazepam monotherapy.

Efficacy and safety of ustekinumab in real clinical practice. Retrospective multicentre study. ARAINF cohort

Introduction Ustekinumab, a monoclonal antibody that blocks interleukins 12/23, has proven in clinical trials its efficacy in inducing and maintaining clinical remission of Crohn's disease (CD). Its effectiveness and safety in actual clinical practice is less known and may differ from trials. Objective To evaluate its effectiveness and safety in clinical practice (intravenous induction pattern essentially), such as induction and over the long term, in patients with CD refractory to biological treatment. Material and methods Multicentre retrospective analysis (6 hospitals in Aragon), which includes all patients (N=69) with CD undergoing treatment with ustekinumab (either with intravenous or subcutaneous induction), who had at least 16 weeks of follow-up. The clinical response or remission has been evaluated at weeks 16, 24, 32 and 48 using the Harvey-Bradshaw index. Results A total of 69 patients have been included, mean age 42 years, 54% men. A percentage of 89.86 (95% CI [0.805, 0.949]) of the patients presented clinical improvement at week 16 (15.95% remission, 73.92% response). In the subsequent follow-up, this response has been maintained. Age (OR 0.95, P=.028) and smoking habits (OR 0.19, P=.027) have been identified by an ordinal regression model as predictors of poor treatment response while the need for biological change due to adverse effect (OR 96, P=.00017) and due to loss of secondary response (OR 7.07, P=.034) have been predictors of good response. No serious adverse effects have been reported that forced them to stop taking ustekinumab. Conclusion Ustekinumab is effective and safe in real clinical practice to achieve induction and maintenance of the response in patients with refractory CD. Tobacco and age have been shown to be predictors of poor response, while the indication for adverse effect to previous biological and for loss of secondary response has been shown to be predictors of good response.

Eficacia y seguridad de ustekinumab en la práctica clínica real. Estudio multicéntrico retrospectivo. Cohorte ARAINF

IntroductionUstekinumab, a monoclonal antibody that blocks interleukins 12/23, has proven in clinical trials its efficacy in inducing and maintaining clinical remission of Crohn's disease (CD). Its effectiveness and safety in actual clinical practice is less known and may differ from trials. ObjectiveTo evaluate its effectiveness and safety in clinical practice (intravenous induction pattern essentially), such as induction and over the long term, in patients with CD refractory to biological treatment. Material and methodsMulticentre retrospective analysis (6 hospitals in Aragón), which includes all patients (N=69) with CD undergoing treatment with ustekinumab (either with intravenous or subcutaneous induction), who had at least 16 weeks of follow-up. The clinical response or remission has been evaluated at weeks 16, 24, 32 and 48 using the Harvey-Bradshaw index. ResultsA total of 69 patients have been included, mean age 42 years, 54% men. A percentage of 89.86 (95% CI [0.805, 0.949]) of the patients presented clinical improvement at week 16 (15.95% remission, 73.92% response). In the subsequent follow-up, this response has been maintained. Age (OR 0.95, P=.028) and smoking habits (OR 0.19, P=.027) have been identified by an ordinal regression model as predictors of poor treatment response while the need for biological change due to adverse effect (OR 96, P=.00017) and due to loss of secondary response (OR 7.07, P=.034) have been predictors of good response. No serious adverse effects have been reported that forced them to stop taking ustekinumab. ConclusionUstekinumab is effective and safe in real clinical practice to achieve induction and maintenance of the response in patients with refractory CD. Tobacco and age have been shown to be predictors of poor response, while the indication for adverse effect to previous biological and for loss of secondary response has been shown to be predictors of good response.

Early predictors of poor treatment response in patients with schizophrenia treated with atypical antipsychotics

BackgroundThe aims of this study were to explore the relationship between early reduction in psychotic symptoms and the ultimate response in patients with schizophrenia treated by atypical antipsychotics, and to determine the best time to switch or maitain the regimen. We also explore the possible predictors for the clinical response.MethodsOne hundred eleven inpatients with acutely exacerbated schizophrenia were randomized to give optimal therapy of olanzapine, risperidone, and paliperidone in one-week run-in period and 12 weeks’ intervention. All participants were assessed using Positive and Negative Syndrome Scale (PANSS). Early Response, defined as reduction of 25% in PANSS score, was examined at weeks 1, 2, 3, 4 and 8, and these ratings were used to predict ultimate response (25% PANSS reduction) at week 12. We hypothesized that early treatment response at Week 1 or 2 could predict Week 12’s treatment outcome.ResultsThe early treatment response at Week 2 had a greater negative prediction value (NPV, 93.6%) than did the response at Week 1 (NPV, 69.7%), Week 3 (NPV, 91.5%), Week 4 (NPV, 90.7%) and Week 8 (NPV, 87.2%). The positive predictive value became more acceptable (65%) until Week 4. There was no any other potential predictors, including types of antipsychotics medication and treatment dosage, were associated with ultimate response in this study.ConclusionThe treatment non-response at Week 2 optimally predicted the ultimate (Week 12) non-response, in terms of negative predictive value (NPV). These finding suggests that the revision of treatment strategy should be considered t if patients with schizophrenia was not responsive to them after 2 weeks’ treatment, and for those who are responders at Week 2, another two weeks are needed to further evaluate whether they will be continuously responsive.Trial registrationNCT03730857 at ClinicalTrial.gov. Date of registration: 30/Oct/2018.

In Newly Diagnosed Multiple Myeloma Patients, Longer Procoagulant Phospholipid-Dependent Clotting Time, Higher Levels of P-Selectin, D-Dimers and Thrombin Generation Peak Are Associated with Increased Risk of Resistance to Treatment: Results of the Prospective Roadmap-MM Study

Background:Despite an increasing number of approved therapies, multiple myeloma (MM) remains an incurable disease with frequent drug resistsance. Resistance-mediating alterations are preexisting in early disease, and it is the selective pressure of antitumor therapy that promotes their clonal expansion from baseline tumor heterogeneity. Cross-talk between monoclonal plasma cells, platelets and endothelial cells enhances hypercoagulability. The prospective, longitudinal observational study ROADMAP-MM CAT (PROspective Risk Assessment anD bioMArkers of hyPercoagulability for the identification of patients with Multiple Myeloma at risk for Cancer Associated Thrombosis) was designed to explore alternative strategies for the development of risk stratification tools in patients with MM. Aim: We explored cellular and plasma hypercoagulability in newly diagnosed chemotherapy naïve MM (NDMM) patients to identify relevant biomarkers that can be used to classify patients at high risk of resistance to anti-myeloma treatment. Methods: Symptomatic NDMM were enrolled. Patients on anticoagulant treatment were excluded from the study. Study end-point was response to treatment at 3 months (T1) according the the International Myeloma Working Group response criteria. “Resistance to antimyeloma treatment” was defined as progressive disease (PD), stable disease (SD) or minor response (MR) at 3 months post treatment initiation. Blood samples were collected at inclusion. Procoagulant phospholipid-dependent clotting time (Procoag-PPL®), tissue factor activity (TFa), thrombomodulin activity (TMa), factor VIIa, factor V (FV), antithrombin (AT), fibrin monomers (FM) and D-Dimers were measured with respective assays from Diagnostica Stago (Asnieres, France) on a STA-R® analyzer (Diagnostica Stago). Plasma levels of P-Selectin and heparanase were measured with ELISA Kits from Cusabio Biotech (from CliniSciencies, France) and R&D Systems (Lille France), respectively. Samples of platelet-poor plasma (PPP) were assessed for thrombin generation (TG) with the TF 5 pM PPP-Reagent® on Calibrated Automated Thrombogram (Stago, France). Univariate logistic regression analysis examined the associations between biomarkers and treatment resistance. The cut-off values for studied biomarkers were selected based on ROC analysis. Results A total of 144 patients were enrolled (age 66.0±12.0 yrs; 53% male). Distribution of disease stage was as follows: 32% ISS I, 23% ISS II, 45% ISS III. Bone disease was present in 71% of patients and 19% of patients had high risk cytogenetic lesions. Proteasome inhibitor (PI) based therapy was given to 64% of patients, immunomodulatory drug (IMiD) based therapy in 32% and 4% received other regimens. At 3 months, 64% of patients showed treatment “resistance”. At the univariate logistic regression “resistance to treatment” was associated with longer Procoag-PPL (32.4% in patients with Procoag-PPL ≥41.7 sec vs. 12.3% in patients with Procoag-PPL <41.7 sec; OR=3.41, 95%CI: 1.45-8.03, p=0.005), higher levels of D-dimers (36.0% in patients with D-dimers ≥1.44 μg/ml vs. 14.9% in patients with D-dimers <1.44 μg/ml; OR=3.21, 95%CI: 1.43-7.22, p=0.005) and higher Peak in the thrombogram (28.1% in patients with Peak ≥181.66 nM vs. 12.5% in patients with Peak <181.66 nM; OR=2.73, 95%CI: 1.03-7.23, p=0.043). On the other hand, PD/SD/MR rate was inversely associated with P-selectin levels (14.5% in patients with ≥23477 pg/ml vs. 42.3% in patients with P-selectin <23477 pg/ml; OR=0.23, 95%CI: 0.08-0.65, p=0.005). Conclusion. The prospective ROADMAP-CAT multiple myeloma study demonstrates for the first time that biomarkers of hypercoagulablity may also be useful to identify patients likely to display resistance to treatment. Among a large number of hypercoagulability biomarkers PPL-ct, that reflects the amount of procoagulant microparticles present in plasma, thrombin generation and the levels P-Selectine and D-Dimers were found to be significant predictors of poor treatment response. A prospective trial is required to evaluate the potential role of these biomarkers in anti-myeloma treatment optimization. DisclosuresTerpos:Novartis: Honoraria; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Genesis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Patents & Royalties; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Grant, Research Funding. Dimopoulos:Celgene: Honoraria; Takeda: Honoraria; Bristol-Myers Squibb: Honoraria; Janssen: Honoraria; Amgen: Honoraria.

S100A9+ MDSC and TAM-mediated EGFR-TKI resistance in lung adenocarcinoma: the role of RELB.

BackgroundMonocytic myeloid-derived suppressor cells (MDSCs), particularly the S100A9+ subset, has been shown initial clinical relevance. However, its role in EGFR-mutated lung adenocarcinoma, especially to EGFR-tyrosine kinase inhibitor (EGFR-TKI) is not clear. In a clinical setting of EGFR mutated lung adenocarcinoma, a role of the MDSC apart from T cell suppression was also investigated.ResultsBlood monocytic S100A9+ MDSC counts were higher in lung cancer patients than healthy donors, and were associated with poor treatment response and shorter progression-free survival (PFS). S100A9+ MDSCs in PBMC were well correlated to tumor infiltrating CD68+ and S100A9+ cells, suggesting an origin of TAMs. Patient’s MDMs, mostly from S100A9+ MDSC, similar to primary alveolar macrophages from patients, both expressed S100A9 and CD206, attenuated EGFR-TKI cytotoxicity. Microarray analysis identified up-regulation of the RELB signaling genes, confirmed by Western blotting and functionally by RELB knockdown.ConclusionsIn conclusion, blood S100A9+ MDSC is a predictor of poor treatment response to EGFR-TKI, possibly via its derived TAMs through activation of the non-canonical NF-κB RELB pathway.MethodsPatients with activating EGFR mutation lung adenocarcinoma receiving first line EGFR TKIs were prospectively enrolled. Peripheral blood mononuclear cells (PBMCs) were collected for MDSCs analysis and for monocyte-derived macrophages (MDMs) and stored tissue for TAM analysis by IHC. A transwell co-culture system of MDMs/macrophages and H827 cells was used to detect the effect of macrophages on H827 and microarray analysis to explore the underlying molecular mechanisms, functionally confirmed by RNA interference.

Executive Dysfunction Predicts Treatment Response to Neuroplasticity-Based Computerized Cognitive Remediation (nCCR-GD) in Elderly Patients with Major Depression

Executive dysfunction (ED) is a predictor of poor treatment response of late-life depression to pharmacotherapy. In response to the consistency of these findings, we designed neuroplasticity-based computerized cognitive remediation (nCCR-GD) intervention to target and improve ED in patients who failed to remit with antidepressant treatment. This study tests the hypothesis that ED at baseline will predict favorable treatment response to nCCR-GD. 11 elderly patients with treatment-resistant major depression were treated with a 30-hour, 4-week, unblinded, nCCR-GD treatment trial. Neuropsychological performance was assessed at baseline and after treatment ceased. ED at baseline was associated with greater reduction in Montgomery-Asberg Depression Rating Scale score over the 4-week treatment β = -0.74, F(2,8) = 10.85, p = 0.009, R(2) = 0.55. ED predicts favorable treatment response to nCCR-GD in older adults suffering from major depression resistant to antidepressants. This finding is opposed to studies testing pharmacotherapy where ED predicts poorer treatment response.

Early in-session predictors of response to trauma-focused cognitive therapy for posttraumatic stress disorder

Trauma-focused cognitive behaviour therapy is effective in treating posttraumatic stress disorder but non-response rates range between 25% and 50%. Results of previous research on patient characteristics predicting outcome are inconsistent and mainly focused on demographic and diagnostic variables. This study examined whether behavioural predictors of poor treatment response can be observed in early sessions. It was predicted that greater patient perseveration, lower expression of thoughts and feelings and weaker therapeutic alliance would be associated with poorer outcomes. We also explored the relationships of patient behaviours with therapeutic alliance and the efficiency and competence of treatment delivery. Audio or video recordings of the initial treatment sessions of 58 patients who had shown either good (n = 34) or poor response (n = 24) to cognitive therapy for PTSD (CT-PTSD, Ehlers & Clark, 2000) were blindly coded for patient perseveration, expression of thoughts and feelings, therapeutic alliance, efficiency and competency of treatment delivery and therapist competence. Poor responders showed more perseveration and less expression of thoughts and feelings in the initial session. Patient perseveration and low expression of thoughts and feelings were associated with poorer therapeutic alliance and compromised treatment delivery. Patients with these behavioural characteristics may benefit from additional treatment strategies. Limitations of the study and implications for clinical practice are discussed.