Variability In Treatment Response Research Articles

Fibroblast Activation Protein Inhibitor-Based Radionuclide Therapies: Current Status and Future Directions.

Metastatic malignancies have limited management strategies and variable treatment responses. Cancer cells develop beside and depend on the complex tumor microenvironment. Cancer-associated fibroblasts, with their complex interaction with tumor and immune cells, are involved in various steps of tumorigenesis, such as growth, invasion, metastasis, and treatment resistance. Prooncogenic cancer-associated fibroblasts emerged as attractive therapeutic targets. However, clinical trials have achieved suboptimal success. Fibroblast activation protein (FAP) inhibitor-based molecular imaging has shown encouraging results in cancer diagnosis, making them innovative targets for FAP inhibitor-based radionuclide therapies. This review summarizes the results of preclinical and clinical FAP-based radionuclide therapies. We will describe advances and FAP molecule modification in this novel therapy, as well as its dosimetry, safety profile, and efficacy. This summary may guide future research directions and optimize clinical decision-making in this emerging field.

In vitro and in vivo susceptibility to sulfadiazine and pyrimethamine of Toxoplasma gondii strains isolated from Brazilian free wild birds

Little is known about the existence of drug-resistant Toxoplasma gondii strains and their possible impact on clinic outcomes. To expand our knowledge about the existence of natural variations on drug susceptibility of T. gondii strains in Brazil, we evaluated the in vitro and in vivo susceptibility to sulfadiazine (SDZ) and pyrimethamine (PYR) of three atypical strains (Wild2, Wild3, and Wild4) isolated from free-living wild birds. In vitro susceptibility assay showed that the three strains were equally susceptible to SDZ and PYR but variations in the susceptibility were observed to SDZ plus PYR treatment. Variations in the proliferation rates in vitro and spontaneous conversion to bradyzoites were also accessed for all strains. Wild2 showed a lower cystogenesis capacity compared to Wild3 and Wild4. The in vivo analysis showed that while Wild3 was highly susceptible to all SDZ and PYR doses, and their combination, Wild2 and Wild4 showed low susceptibility to the lower doses of SDZ or PYR. Interestingly, Wild2 presented low susceptibility to the higher doses of SDZ, PYR and their combination. Our results suggest that the variability in treatment response by T. gondii isolates could possibly be related not only to drug resistance but also to the strain cystogenesis capacity.

An Atypical Presentation of Immune-mediated, Demyelinating Polyneuropathy with Multiple Antibodies to Nerve and Myelin Proteins Following SARS-CoV2 mRNA Vaccination (P10-5.009)

<h3>Objective:</h3> This case describes an atypical demyelinating polyneuropathy temporally associated with SARS-CoV2 mRNA vaccination and characterized by the presence of multiple co-existing autoantibodies. <h3>Background:</h3> A 62-year-old woman developed distal, symmetric upper and lower extremity sensorimotor impairments and areflexia three weeks after SARS-CoV2 booster vaccination (Pfizer-BioNTech). Initial cerebrospinal fluid analysis demonstrated cytoalbuminologic dissociation (protein 76mg/dL). Intravenous immunoglobulin (IVIg) (2 gm/kg total) was prescribed. The patient’s symptoms and signs resolved. Asymmetric, proximal appendicular weakness, distal appendicular sensory loss, gait impairment, and areflexia reoccurred approximately one week later. Plasma exchange (PLEX) was completed, resulting in marked clinical improvement. Clinical worsening again reoccurred in the weeks following PLEX completion. Electrodiagnostic and serologic studies were obtained. Immunomodulatory therapies were escalated with IVIg (repeat 2 gm/kg), corticosteroid, and rituximab therapies prescribed. Sustained symptom improvement was evidenced. <h3>Design/Methods:</h3> Case report with literature review. <h3>Results:</h3> Nerve conduction and electromyography studies demonstrated absent F-waves, prolonged distal motor latencies, and reduced recruitment of normal motor units consistent with a demyelinating polyneuropathy. Ga1NAc-GD1a IgG, beta-tubulin IgG, and neurofascin-155 IgG antibodies were detected in serum samples obtained prior to IVIg therapy (Washington University Neuromuscular Laboratory Demyelinating Neuropathy Panel). <h3>Conclusions:</h3> The patient’s clinical syndrome was ultimately consistent with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). The asymmetric pattern of weakness, robust initial treatment response(s), and severe fluctuations were atypical for classical CIDP, but consistent with demyelinating disease marked by specific autoantibodies. Uniquely, Ga1NAc-GD1a IgG, beta-tubulin IgG, and neurofascin-155 IgG antibodies were identified. Antibodies against axons and myelin proteins have been recently reported in patients with acute and chronic demyelinating polyneuropathies. Antibodies to neurofascin isoforms, anti-tubulin and Ga1NAc-GD1a can result in severe phenotypes with variable treatment responses, including robust treatment response to B-cell targeted therapies. To our knowledge, this is a novel case due to multiple co-existing, potentially pathogenic, autoantibodies. A possible immune-mediated mechanism precipitated by SARS-CoV2 vaccination requires further investigation. <b>Disclosure:</b> Dr. Saban has nothing to disclose. Dr. Leech has nothing to disclose. Dr. Carlson has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Medscape. Dr. Carlson has received research support from Horizon Therapeutics. Dr. Carlson has a non-compensated relationship as a Health Service Subcommittee Member with American Academy of Neurology that is relevant to AAN interests or activities. Dr. Sauer has nothing to disclose. The institution of Dr. Ragole has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion Pharmaceuticals. The institution of Dr. Ragole has received personal compensation in the range of $500-$4,999 for serving as a Consultant for UCB. Dr. Ragole has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion Pharmaceuticals. The institution of Dr. Ragole has received research support from Alexion Pharmaceuticals.

Treatment Response Variation in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease presenting as Acute Disseminated Encephalomyelitis: Two Case Illustrations. (P13-5.029)

<h3>Objective:</h3> Present two fairly distinct presentations of Myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) <h3>Background:</h3> MOGAD is an inflammatory demyelinating disease of the central nervous system. MOG is a highly immunogenic part of the outermost lamellae of the myelin sheath. MOGAD incidence is 3.4 per one million person-years, three times higher in children versus adults, with equal gender distribution. <h3>Design/Methods:</h3> Data collected primarily through chart review <h3>Results:</h3> We present an 18-year-old female with recent resolved upper respiratory infection who presented with fever, headache, and left hemiparesis, with rapid progression to quadriparesis, urinary retention, and encephalopathy. The hospital course involved autonomic dysfunction, prolonged intubation requiring tracheostomy and gastrostomy. Cerebrospinal fluid (CSF) showed pleocytosis, normal biochemical parameters with a positive MOG titer (1:40). Magnetic resonance imaging (MRI) showed extensive cervicothoracic T2 hyperintensity and brain multifocal T2 hyperintensities. Treatment included high dose steroids and Intravenous Immunoglobulin (IVIG) with recovery to baseline mentation and antigravity limb movements by discharge over two weeks. A 22-year-old male presented with progressive lower extremity paresthesia and weakness over six weeks. CSF demonstrated pleocytosis, normal glucose and elevated protein, oligoclonal bands and MOG antibody. MRI revealed multiple subcortical T2-hyperintense lesions and enhancing mid-cervical and lower thoracic lesions. Treatment with intravenous corticosteroids resulted in minor improvement with discharge on steroid taper and azathioprine. Patient’s disease progressed with a fluctuating course requiring two readmissions with bilateral upper extremity weakness, right optic neuritis, urinary sphincteric dysfunction with neuro-radiologic worsening. Treatment through multiple admissions included intravenous steroids, IVIG, plasmapheresis, Mycophenolate mofetil, and Rituximab with minimal improvement, symptom recurrence and progression of multifocal lesions. <h3>Conclusions:</h3> MOGAD has variable presentations like optic neuritis, transverse myelitis, or acute disseminated encephalomyelitis (ADEM), with or without encephalopathy. We present two rare cases of ADEM admitted within weeks of each other but distinct in severity and treatment responses, without any identifiable factors affecting clinical outcomes. <b>Disclosure:</b> Dr. Banerjee has nothing to disclose. Dr. Cabral Frade has nothing to disclose. Dr. Lobaina has nothing to disclose. Dr. Brown has nothing to disclose. Dr. Narvaez Caicedo has nothing to disclose. Dr. Kamal Mamoud Elnaeem has nothing to disclose. Sandeep Bhatt has nothing to disclose. Dr. Wu has nothing to disclose. Dr. Bhardwaj has nothing to disclose. Dr. Dabi has nothing to disclose.

Outcome measures in Behçet syndrome

Disease assessment has been challenging in Behçet syndrome due to the heterogeneous disease course and multiorgan involvement with variable treatment response. There have been several recent improvements regarding outcome measures including development of a Core Set of Domains for Behçet syndrome and novel instruments for assessing specific organs and overall damage. This review focuses on the current state of outcome measures in Behçet syndrome, unmet needs, and a research agenda towards the development of standardized and validated outcome measure instruments.

Machine Learning to Predict Response to Ranibizumab in Neovascular Age-Related Macular Degeneration

Neovascular age-related macular degeneration (nAMD) shows variable treatment response to intravitreal anti-VEGF. This analysis compared the potential of different artificial intelligence (AI)-based machine learning models using OCT and clinical variables to accurately predict at baseline the best-corrected visual acuity (BCVA) at 9 months in response to ranibizumab in patients with nAMD. Retrospective analysis. Baseline and imaging data from patients with subfoveal choroidal neovascularization secondary to age-related macular dengeration. Baseline data from 502 study eyes from the HARBOR (NCT00891735) prospective clinical trial (monthly ranibizumab 0.5 and 2.0 mg arms) were pooled; 432 baseline OCT volume scans were included in the analysis. Seven models, based on baseline quantitative OCT features (Least absolute shrinkage and selection operator [Lasso] OCT minimum [min], Lasso OCT 1 standard error [SE]); on quantitative OCT features and clinical variables at baseline (Lasso min, Lasso 1SE, CatBoost, RF [random forest]); or on baseline OCT images only (deep learning [DL] model), were systematically compared with a benchmark linear model of baseline age and BCVA. Quantitative OCT features were derived by a DL segmentation model on the volume images, including retinal layer volumes and thicknesses, and retinal fluid biomarkers, including statistics on fluid volume and distribution. Prognostic ability of the models was evaluated using coefficient of determination (R2) and median absolute error (MAE; letters). In the first cross-validation split, mean R2 (MAE) of the Lasso min, Lasso 1SE, CatBoost, and RF models was 0.46 (7.87), 0.42 (8.43), 0.45 (7.75), and 0.43 (7.60), respectively. These models ranked higher than or similar to the benchmark model (mean R2, 0.41; mean MAE, 8.20 letters) and better than OCT-only models (mean R2: Lasso OCT min, 0.20; Lasso OCT 1SE, 0.16; DL, 0.34). The Lasso min model was selected for detailed analysis; mean R2 (MAE) of the Lasso min and benchmark models for 1000 repeated cross-validation splits were 0.46 (7.7) and 0.42 (8.0), respectively. Machine learning models based on AI-segmented OCT features and clinical variables at baseline may predict future response to ranibizumab treatment in patients with nAMD. However, further developments will be needed to realize the clinical utility of such AI-based tools. Proprietary or commercial disclosure may be found after the references.

Abstract 859: Simulations of tumor heterogeneity impact on treatment response using a mechanistic model of EGFR-mutant lung adenocarcinoma

Abstract Introduction Epidermal growth factor receptor (EGFR) mutations occur in about 40% of Asian and 13-25% of Western patients with lung adenocarcinoma (LUAD) [1,2]. EGFR tyrosine kinase inhibitors (TKIs) have been developed to target tumors with an EGFR driver mutation. However such tumors also harbor additional mutations and genotypic alterations, which contribute to the variability in treatment response. Overall, intratumor heterogeneity is a dynamic source of therapeutic resistance. Here, we assessed the impact of tumor mutational profile on inter-patient treatment response variability by using a mechanistic model of late stage EGFR-mutant LUAD [3]. Methods We developed in the jinko platform a knowledge-based model of late stage EGFR-mutant LUAD, whose parameters each hold a pathophysiology-related meaning. Indeed, causality between disease-related biological phenomena is inherent to the mechanistic knowledge-based model, easing the biological interpretation of the impact of parameter values on model outcomes, which is highly valuable in the context of uncommon populations. To explore the impact of tumor heterogeneity, tumors are implemented with distinct subpopulations of cancer cells, called subclones. Each subclone is defined by a set of mutations and a corresponding proliferating phenotype. A virtual population representative of real world EGFR-mutant LUAD patients was developed to reproduce the variability observed between and within patients’ tumors for the modeled mutations. A physiologically-based pharmacokinetics model of a TKI drug, integrating a mechanistic modeling of the drug’s mechanism of action, is connected to the disease model. Results After simulating a clinical trial on a virtual population in the jinko platform using the developed model, we were able to follow the proliferating phenotype of each cancer subclone over time, as well as the overall evolution of the tumor size of each patient. The model reproduced the emergence of treatment-resistant subclones on EGFR TKI therapy. Modeling tumor size evolution throughout the clinical trial enabled computing the patients’ time to progression as clinical outcome, based on the RECIST 1.1 criteria, and generating corresponding survival curves. Stratification of virtual patients according to their tumor mutations allowed us to pinpoint key mutations that negatively impacted treatment response. Conclusion Modeling and simulation can help understanding how intratumor heterogeneity affects cancer evolution and drives resistance to treatment. Clinical trial simulations using knowledge-based models of disease and treatment provide relevant additional tools to help clinicians in exploring new hypotheses, providing treatment guidance and supporting therapeutic innovation.

The clinical relevance of dupilumab serum concentration in patients with atopic dermatitis: a two-center prospective cohort study

BackgroundDupilumab is prescribed in one dosage across adult atopic dermatitis patients. Differences in drug exposure may explain variation in treatment response.ObjectiveInvestigating the clinical relevance of dupilumab serum concentration in atopic dermatitis in real-world practice.MethodsIn two centers (Netherlands, UK), adults treated with dupilumab for atopic dermatitis were evaluated for effectiveness and safety pretreatment and at 2, 12, 24, and 48 weeks; trough serum samples were analyzed for dupilumab concentration at corresponding time points.ResultsIn 149 patients, median dupilumab levels during follow-up ranged from 57.4 to 72.4 μg/mL. Levels showed high inter-patient and low intra-patient variability. No correlation was found between levels and ΔEASI. At 2 weeks, levels of ≥64.1 μg/mL predict EASI ≤7 at 24 weeks (specificity:100%, sensitivity:60%; p = .022). At 12 weeks, ≤32.7 μg/mL predicts EASI >7 at 24 weeks (sensitivity:95%, specificity:26%; p = .011). Inverse correlations were found between baseline EASI and levels at 2, 12, and 24 weeks (r = −0.25 to 0.36; p ≤ .023). Low levels were particularly observed in patients with adverse events, treatment interval deviation, and discontinuation.ConclusionAt the on-label dosage, the measured range of dupilumab levels does not seem to yield differences in treatment effectiveness. However, disease activity does seem to influence dupilumab levels - higher baseline disease activity results in lower levels at follow-up.

Immunomics analysis of rheumatoid arthritis identified precursor dendritic cells as a key cell subset of treatment resistance

ObjectivesLittle is known about the immunology underlying variable treatment response in rheumatoid arthritis (RA). We performed large-scale transcriptome analyses of peripheral blood immune cell subsets to identify immune cells that...

Cluster headache polygenetic risk and known functional variants of CYP3A4 are not associated with treatment response.

The response to cluster headache treatments has a high interindividual variation. To date, treatment response has only been assessed by a candidate gene approach and no investigations into metabolic pathways have been performed. Our aim was to investigate the association between the polygenetic risk of cluster headache and treatment response to first-line cluster headache treatments as well as known functional variants of CYP3A4 and the response to verapamil. Further, it was aimed to replicate previous single nucleotide polymorphisms found to be associated with treatment response in cluster headache and/or migraine. In, 508 cluster headache patients diagnosed according to the International Classification of Headache Disorders were genotyped and participated in a semi-structured interview to evaluate treatment response. Polygenetic risk scores were calculated by the effect retrieved from a meta-analysis of the latest two genome-wide association studies on cluster headache. Inferior treatment response to oxygen, triptans and verapamil is associated with chronicity of cluster headache were confirmed but no evidence was found that a response could be predicted by a high genetic risk of cluster headache. Likewise, verapamil response was not associated with functional variants of CYP3A4. No support of the genetic variants previously reported to be associated with treatment response to triptans or verapamil was found. The clinically relevant variation in treatment response for cluster headache was not influenced by genetic factors in the present study.

A prognostic baseline blood biomarker and tumor growth kinetics integrated model in paclitaxel/platinum treated advanced non-small cell lung cancer patients.

Paclitaxel/platinum chemotherapy, the backbone of standard first-line treatment of advanced non-small cell lung cancer (NSCLC), exhibits high interpatient variability in treatment response and high toxicity burden. Baseline blood biomarker concentrations and tumor size (sum of diameters) at week 8 relative to baseline (RS8) are widely investigated prognostic factors. However, joint analysis of data on demographic/clinical characteristics, blood biomarker levels, and chemotherapy exposure-driven early tumor response for improved prediction of overall survival (OS) is clinically not established. We developed a Weibull time-to-event model to predict OS, leveraging data from 365 patients receiving paclitaxel/platinum combination chemotherapyonceeverythreeweeks for ≤six cycles. A developed tumor growth inhibition model, combining linear tumor growth and first-order paclitaxel area under the concentration-time curve-induced tumor decay, was used to derive individual RS8. The median model-derived RS8 in all patients was a 20.0% tumor size reduction (rangefrom -78% to +15%). Whereas baseline carcinoembryonic antigen, cytokeratin fragments, and thyroid stimulating hormone levels were not significantly associated with OS in a subset of 221 patients, and lactate dehydrogenase, interleukin-6 and neutrophil-to-lymphocyte ratio levels were significant only in univariate analyses (p value < 0.05); C-reactive protein (CRP) in combination with RS8 most significantly affected OS (p value < 0.01). Compared to the median population OS of 11.3months, OS was 128% longer at the 5th percentile levels of both covariates and 60% shorter at their 95th percentiles levels. The combined paclitaxel exposure-driven RS8 and baseline blood CRP concentrations enables early individual prognostic predictions for different paclitaxel dosing regimens, forming the basis for treatment decision and optimizing paclitaxel/platinum-based advanced NSCLC chemotherapy.

Unique microbial profile identified in patients with gastric cancer with pathologic response to neoadjuvant chemotherapy.

458 Background: Microbial dysbiosis has been shown to be associated with the pathogenesis of gastric cancer (GC). However, the relationship between the GC microbiome and response to systemic therapy, such as neoadjuvant chemotherapy (NAC), is largely unknown. This study aims to explore changes in the microbiome after neoadjuvant chemotherapy, by analyzing the microbial profile of patients who received NAC and comparing differences among those with varied pathologic response to therapy. Methods: A microbiome bioinformatics pipeline using multiple next generation sequencing platforms was developed and used for analysis. GC tissue from patients who received NAC (n=101) and those who did not (n=85) were acquired at the time of surgical resection. Shannon alpha diversity plot and enrichment analyses by odds ratio were used to compare the microbial differences of the treatment cohorts. The microbial profiles of patients with pathologic response to NAC (&gt;20% response) were characterized. Results: Of patients who received NAC, 66 (65.3%) experienced a greater than 20% response to NAC, and 35 (34.6%) demonstrated a 20% or lower response. Patients with a pathologic response to NAC were enriched for Rhizobium, Streptomyces, Comamonas, Sphingomonas, Micrococcus, Mycobacterium, Thauera, Hyphomicrobium, and Sinorhizobium (OR&gt;4). There were no statistically significant differences in alpha diversity (p&gt;0.05). Conclusions: Our results demonstrate that patients with a greater than 20% pathologic response to NAC have a distinct microbial enrichment compared to those with a poor pathologic response. Given the variable NAC treatment responses in GC, understanding unique microbial signatures in tumors will provide the landscape to explore key microbial contributors to GC NAC treatment response that may improve our understanding of treatment response variability among patients. [Table: see text]

2/1 dose schedule of sunitinib is superior than the 4/2 regimen for the first-line therapy of clear cell metastatic renal cell carcinoma - An Indian experience.

Sunitinib remains the first-line treatment for favorable risk metastatic clear cell renal cell cancer (mccRCC). It was conventionally given in the 4/2 schedule; however, toxicity necessitated trying the 2/1 regimen. Regional variations in treatment response and toxicity are known, and there is no data from the Indian subcontinent about the outcomes of the alternative dosing schedule. Clinical records of all consecutive adult patients who received sunitinib as first-line therapy for histologically proven mccRCC following cytoreductive nephrectomy from 2010-2018 were reviewed. The primary objective was to determine the progression-free survival (PFS), and the secondary objectives were to evaluate the response rate (objective response rate and clinical benefit rate), toxicity, and overall survival. A list of variables having a biologically plausible association with outcome was drawn and multivariate inverse probability treatment weights (IPTW) analysis was done to determine the absolute effect size of dosing schedules on PFS in terms of "average treatment effect on the treated" and "potential outcome mean." We found 2/1 schedule to be independently associated with higher PFS on IPTW analysis such that if every patient in the subpopulation received sunitinib by the 2/1 schedule, the average time to progression was estimated to be higher by 6.1 months than the 4/2 schedule. We also found 2/1 group to have a lower incidence than the 4/2 group for nearly all ≥ grade 3 adverse effects. Other secondary outcomes were comparable between both treatment groups. Sunitinib should be given via the 2/1 schedule in Indian patients.

Total tau in cerebrospinal fluid detects treatment responders among spinal muscular atrophy types 1-3 patients treated with nusinersen.

Considering the substantial variability in treatment response across patients with spinal muscular atrophy (SMA), reliable markers for monitoring response to therapy and predicting treatment responders need to be identified. The study aimed to determine if measured concentrations of disease biomarkers (total tau protein, neurofilament light chain, and S100B protein) correlate with the duration of nusinersen treatment and with scores obtained using functional scales for the assessment of motor abilities. A total of 30 subjects with SMA treated with nusinersen between 2017 and 2021 at the Department of Pediatrics, University Hospital Centre Zagreb, Croatia, were included in this study. Cerebrospinal fluid (CSF) samples were collected by lumbar puncture prior to intrathecal application of nusinersen. Protein concentrations in CSF samples were determined by enzyme-linked immunosorbent assay in 26 subjects. The motor functions were assessed using functional motor scales. The main finding was significantly decreased total tau correlating with the number of nusinersen doses and motor improvement in the first 18-24 months of treatment (in all SMA patients and SMA type 1 patients). Neurofilament light chain and S100B were not significantly changed after administration of nusinersen. The measurement of total tau concentration in CSF is a reliable index for monitoring the biomarker and clinical response to nusinersen therapy in patients with SMA.

Clinical Determinants of Childhood Onset Systemic Lupus Erythematosus among Early and Peri-Adolescent Age Groups.

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease that is associated with significant morbidity and mortality. SLE disproportionately affects women and minorities. Childhood-onset SLE (cSLE) in particular tends to be more aggressive than adult-onset SLE. Despite substantial improvements in the treatment of cSLE, there is significant variability in treatment responses and long-term outcomes. Furthermore, there is a paucity of studies involving cSLE, and in particular, cSLE among different age groups. The aim of this study was to test the hypothesis that an early-onset cSLE cohort would demonstrate unique characteristics with distinctive clinical and laboratory features at disease onset. We specifically investigated whether clinical, epidemiological, or serological factors are differentially associated with early- and late-onset cSLE. This could have direct impact on clinical management with the goal of improving outcomes and quality of life for children with SLE. Our study was conducted at a large tertiary center. We included 213 subjects seen at our pediatric rheumatology clinic aged 4-17 years. Epidemiologic, clinical phenotype, disease severity, serology, treatment, and outcome data were compared between subjects with cSLE onset prior to 10 years of age (early-onset disease, n = 43) and those with cSLE onset greater than 10 years of age (peri-adolescent disease, n = 170). We compared clinical features between early- and peri-adolescent onset cSLE in order to investigate the association between age at disease onset of cSLE and clinical disease expression and outcomes. Of the 213 subjects with cSLE in our study, 43 subjects had early-onset disease (age 2 to ≤9 years) and 170 patients had peri-adolescent onset disease. We found that early-onset cSLE was associated with a higher prevalence of positive anti-dsDNA antibody at cSLE diagnosis, higher anti-dsDNA antibody titer at cSLE diagnosis, rash, and azathioprine use (p &lt; 0.001, p = 0.004, p = 0.011, and p = 0.008, respectively). In contrast, we found that peri-adolescent onset cSLE (≥10 years of age) was associated with worse disease activity (SLEDAI range 0-24) (p &lt; 0.001), higher SLICC at diagnosis (p &lt; 0.001), as well as a higher rate of mycophenolate mofetil and hydroxychloroquine use (p = 0.003 and p &lt; 0.001, respectively). There were no significant differences in the prevalence of neuropsychiatric symptoms or the development of Class IV/Class V lupus nephritis between the early-onset and peri-adolescent groups.

Muscle impairment in MRI affect variability in treatment response to nusinersen in patients with spinal muscular atrophy type 2 and 3: A retrospective cohort study

BackgroundReal-world data have shown variability in treatment responses to nusinersen in spinal muscular atrophy (SMA). We investigated whether the magnitude of muscle impairment assessed by magnetic resonance imaging (MRI) at baseline can predict the treatment response. MethodsWe retrospectively assessed the clinical data in relevance to the thigh and pelvic MRI taken before the nusinersen treatment. A total of 16 patients with SMA types 2 and 3 (age = mean [SD]; 9.2 [4.6] year) receiving nusinersen treatment were enrolled. The T1-weighted MRI images of the pelvis and thigh were scored for muscle fatty infiltration and atrophy. The minimally clinically important difference (MCID) was considered as gaining at least 3 points of Hammersmith Functional Motor Scale-Expanded (HFMSE) from baseline. ResultsOf these 16 individuals, 14 had been treated for at least 15 months with baseline data. At 15 months, seven individuals obtained MCID in HFMSE. Baseline muscle MRI score could not differentiate the two groups; however, individuals who obtained MCID had significantly less severe scoliosis. In addition, there was a significant and negative relationship between baseline MRI score and the change of score in HFMSE after 15 months of treatment. Further, baseline Cobb angle along with MRI score also indicated the correlation to the degree of change in motor function. ConclusionThe degree of muscle damage may confer the variability in response to nusinersen in SMA types 2 and 3. Muscle MRI score along with the severity of scoliosis assessed at baseline may help to predict the motor function change.

Explore the distribution of (rs35742686, rs3892097 and rs1065852) genetic polymorphisms of cytochrome P4502D6 gene in the Moroccan population

BackgroundThe CYP2D6 gene encodes a crucial enzyme involved in the metabolic pathways of many commonly used drugs. It is a highly polymorphic gene inducing an interethnic and interindividual variability in disease susceptibility and treatment response. The aim of this study is to evaluate the frequency of the three CYP2D6 most investigated alleles (CYP2D6*3, CYP2D6*4, and CYP2D6*10 alleles) in Morocco compared to other populations.This study enrolled 321 healthy Moroccan subjects. CYP2D6 genotypes and allele frequencies were assessed using a restriction fragment length polymorphism–polymerase chain reaction genotyping method. The Principal Component Analysis (PCA) and dendrogram were conducted to evaluate genetic proximity between Moroccans and other populations depending on CYP2D6 allele frequencies.ResultsAccording to the current study, the results observed the homozygous wild type of the three studied SNPs were predominant among the Moroccan population, while 1.4% of Moroccans carried the CYP2D6*4 allele responsible for a Poor Metabolizer phenotype and associated with low enzyme activity which may induce a treatment failure. The PCA and cluster dendrogram tools revealed genetic proximity between Moroccans and Mediterranean, European and African populations, versus a distancing from Asian populations.ConclusionThe distribution of CYP2D6 polymorphisms within Morocco follows the patterns generally found among the Mediterranean, European and African populations. Furthermore, these results will help to lay a basis for clinical studies, aimed to introduce and optimize a personalized therapy in the Moroccan population.

Outcomes from a pilot dose comparison study of naming therapy in aphasia

ABSTRACT Background People with aphasia vary considerably in response to aphasia treatments. Treatment dose is likely to be an important factor in understanding treatment response variability and optimising aphasia recovery; however, there is limited empirical evidence to guide dose prescription in post-stroke aphasia rehabilitation. In the present study, we used a novel approach to personalise dose prescription and explored the effect of dose on treatment response in chronic post-stroke aphasia. Aims Examine the effect of providing personalised doses of a cued picture naming treatment (Kendall et al., 2014) on acquisition and maintenance of picture naming outcomes. Method This pilot study used a multiple-baselines design with follow-up at 4- and 12-weeks with replication across four people with chronic post-stroke anomia. Prior to treatment, a comprehensive battery of cognitive and language tests was completed. Participants then undertook a period of cued picture naming treatment (45-minute sessions, five days per week for three weeks) totalling 15 sessions (11.25 hours). Participants were allocated four picture sets – one each for three treated conditions (low dose, moderate dose, and high dose) and one for an untreated control set. The number of naming opportunities provided per dose condition was calibrated against individuals’ pre-treatment picture naming accuracy and speed. Generalised linear mixed effects models were used to evaluate learning effects during treatment, maintenance of these effects, and dose-response relationships. Outcomes Participants received 99% of prescribed treatment doses (i.e., number of naming opportunities provided over the course of treatment). As anticipated, individual treatment responses varied substantially. Three participants demonstrated significantly improved picture naming accuracy on probed items during treatment, with varying response profiles by participant and dose. All participants were able to name more pictures accurately on a bespoke 298-item object picture naming test following treatment. However, no participant demonstrated significant pre-post treatment gains relative to untreated items, although one person demonstrated improved naming four weeks after treatment for items treated under the high dose condition. Dose-response relationships amongst these participants exhibited a greater number of significant results on naming probes in the high dose condition, possibly suggesting superiority of the high dose condition over lower doses of cued picture naming treatment. Conclusion Modest treatment effects and variable dose-response relationships were observed. We explore the role of dose, cognitive factors such as self-monitoring abilities, and linguistic factors such as underlying lexical-semantic and phonological processing that may have influenced treatment response in these participants. Avenues for future research are identified.

Pharmacogenomics of Cancer Pain Treatment Outcomes in Asian Populations: A Review

In advanced cancer, pain is a poor prognostic factor, significantly impacting patients' quality of life. It has been shown that up to 30% of cancer patients in Southeast Asian countries may receive inadequate analgesia from opioid therapy. This significant under-management of cancer pain is largely due to the inter-individual variability in opioid dosage and relative efficacy of available opioids, leading to unpredictable clinical responses to opioid treatment. Single nucleotide polymorphisms (SNPs) cause the variability in opioid treatment outcomes, yet their association in Asian populations remains unclear. Therefore, this review aimed to evaluate the association of SNPs with variability in opioid treatment responses in Asian populations. A literature search was conducted in Medline and Embase databases and included primary studies investigating the association of SNPs in opioid treatment outcomes, namely pharmacokinetics, opioid dose requirements, and pain control among Asian cancer patients. The results show that CYP2D6*10 has the most clinical relevance in tramadol treatment. Other SNPs such as rs7439366 (UGT2B7), rs1641025 (ABAT) and rs1718125 (P2RX7) though significant have limited pharmacogenetic implications due to insufficient evidence. OPRM1 rs1799971, COMT rs4680 and ABCB1 (rs1045642, rs1128503, and rs2032582) need to be further explored in future for relevance in Asian populations.

Differential Predictors of Response to Early Start Denver Model vs. Early Intensive Behavioral Intervention in Young Children with Autism Spectrum Disorder: A Systematic Review and Meta-Analysis.

The effectiveness of early intensive interventions for Autism Spectrum Disorder (ASD) is now well-established, but there continues to be great interindividual variability in treatment response. The purpose of this systematic review is to identify putative predictors of response to two different approaches in behavioral treatment: Early Intensive Behavioral Interventions (EIBI) and the Early Start Denver Model (ESDM). Both are based upon the foundations of Applied Behavioral Analysis (ABA), but the former is more structured and therapist-driven, while the latter is more naturalistic and child-driven. Four databases (EmBase, PubMed, Scopus and WebOfScience) were systematically screened, and an additional search was conducted in the reference lists of relevant articles. Studies were selected if participants were children with ASD aged 12-48 months at intake, receiving either EIBI or ESDM treatment. For each putative predictor, p-values from different studies were combined using Fisher's method. Thirteen studies reporting on EIBI and eleven on ESDM met the inclusion criteria. A higher IQ at intake represents the strongest predictor of positive response to EIBI, while a set of social cognitive skills, including intention to communicate, receptive and expressive language, and attention to faces, most consistently predict response to ESDM. Although more research will be necessary to reach definitive conclusions, these findings begin to shed some light on patient characteristics that are predictive of preferential response to EIBI and ESDM, and may provide clinically useful information to begin personalizing treatment.