Unresponsive Group Research Articles

Real-world evidence of avatrombopag for the treatment of immune thrombocytopenia intolerant or ineffective to eltrombopag/hetrombopag.

Due to the limited real-world research on the application of avatrombopag (AVA) for immune thrombocytopenia (ITP) in China, we evaluated the effectiveness and safety of AVA in clinical practice. We included 121 adult ITP patients treated with AVA across three medical centres. Based on the reasons for choosing AVA, these patients were divided into eltrombopag (ELT)/hetrombopag (HET) intolerance group (IG), and ELT/HET unresponsive group (UG). Compared with UG, more patients in IG had a history of liver disease and received fewer treatments before AVA. Amongst all patients, 83% had platelet response (≥30 × 109/L) after AVA and 62% achieved complete response (≥100 × 109/L, CR). Sixty-two percent in IG and 56% in UG were able to discontinue more than one concomitant ITP medication. A total of 17 patients underwent multiple switches of thrombopoietin receptor agonists (TPO-RAs), resulting in an 88% platelet response rate. Sixty-three patients discontinued AVA, 27% were due to unaffordability. AVA was well tolerated in most patients. In the ITP population, AVA proved effective and safe, particularly in patients intolerant or unresponsive to ELT/HET. Patients benefited from TPO-RAs switches, particularly those undergoing multiple switches. However, many patients struggled with the long-term financial burden of AVA.

Fat-suppression T2 relaxation time and water fraction predict response to intravenous glucocorticoid therapy for thyroid-associated ophthalmopathy.

To investigate the value of fat-suppression (FS) T2 relaxation time (T2RT) derived from FS T2 mapping and water fraction (WF) derived from T2 IDEAL to predict the treatment response to intravenous glucocorticoids (IVGC) in patients with thyroid-associated ophthalmopathy (TAO) based on texture analysis. In this study, 89 patients clinically diagnosed with active and moderate-to-severe TAO were enroled (responsive group, 48 patients; unresponsive group, 41 patients). The baseline clinical characteristics and texture features were compared between the two groups. Multivariate analysis was performed to identify the independent predictors of treatment response to IVGC. ROC analysis and the DeLong test were used to assess and compare the predictive performance of different models. The responsive group exhibited significantly shorter disease duration and higher 90th percentile of FS T2RT and kurtosis of WF in the extraocular muscle (EOM) and 95th percentile of WF in the orbital fat (OF) than the unresponsive group. Model 2 (disease duration + WF; AUC, 0.816) and model 3 (disease duration + FS T2RT + WF; AUC, 0.823) demonstrated superior predictive efficacy compared to model 1 (disease duration + FS T2RT; AUC, 0.756), while there was no significant difference between models 2 and 3. The orbital tissues of responders exhibited more oedema and heterogeneity. Furthermore, OF is as valuable as EOM for assessing the therapeutic efficacy of IVGC. Finally, WF derived from T2 IDEAL processed by texture analysis can provide valuable information for predicting the treatment response to IVGC in patients with active and moderate-to-severe TAO. The texture features of FS T2RT and WF are different between responders and non-responders, which can be the predictive tool for treatment response to IVGC. Texture analysis can be used for predicting response to IVGC in TAO patients. TAO patients responsive to IVGC show more oedema and heterogeneity in the orbital tissues. WF from T2 IDEAL is a tool to predict the therapeutic response of TAO.

Multi-index comprehensive evaluation of the efficacy and response mechanism of immunotherapy in non-small cell lung cancer.

This research conducted multi-index comprehensive evaluations of the immunotherapeutic efficacy and response in non-small cell lung cancer (NSCLC). Forty-five patients with epidermal growth factor receptor (EGFR)/anaplastic lymphoma kinase (ALK) wild-type advanced NSCLC who received immunotherapy were included. Immunohistochemistry was adopted to detect the expression levels of programmed death ligand 1 (PD-L1) with X-ray cross-complementing protein 1 (XRCC1) and excision repair cross-complementing group 1 (ERCC1) proteins in tumor tissues. Flow cytometry was utilized to measure the levels of T-cell subsets in peripheral blood before and after treatment. PCR-RELP method was employed to evaluate XRCC1 and ERCC1 gene polymorphisms in peripheral blood. According to the treatment effect, patients evaluated as complete response (CR), partial response (PR), and stable disease (SD) were categorized into the immune response group, and patients evaluated as progressive disease (PD) were categorized into the immune unresponsive group. The correlation between PD-L1 protein expression, XRCC1 and ERCC1 protein expression, gene polymorphisms, T-cell subpopulation levels, and treatment efficacy was analyzed. The therapeutic efficacy of patients with positive PD-L1 expression was better than that of patients with negative PD-L1 expression (P < 0.05). After treatment, peripheral blood CD3+ and CD4+ cell levels and Thl/Th2 cell levels were higher and CD8+ T cells were lower in the immune response group than in the immune unresponsive group (P < 0.05). Among the patients in the immune response group, peripheral blood CD3+ and CD4+ cell levels were higher and CD8+ T cells were lower in patients with positive PD-L1 expression than in patients with negative PD-L1 expression (P < 0.05). In the XRCC1 gene, the proportion of patients in the immune response group carrying the Arg/Trp + Trp/Trp genotype was higher than that of patients in the immune unresponsive group (P < 0.05). In the ERCC1 gene, the proportion of patients in the immune response group carrying the C/T + T/T genotype was higher than that of patients in the immune unresponsive group (P < 0.05). The positive expression rates of XRCC1 and ERCC1 in patients in the immune unresponsive group were higher than those in the immune response group (P < 0.05). PD-L1 protein expression, XRCC1 and ERCC1 protein expression, and gene polymorphisms are associated with immunotherapy outcome in EGFR/ALK wild-type advanced NSCLC patients, and may be biological indicators for predicting immunotherapy outcome in EGFR/ALK wild-type advanced NSCLC patients.

Baseline Severity and Disease Duration Can Predict the Response to Allergen-specific Immunotherapy in Allergic Rhinitis.

Allergen-specific immunotherapy (AIT) has confirmed its efficacy in improving the symptoms of allergic rhinitis. However, no reliable biomarkers have been identified to predict the efficacy of AIT were found. We aimed to find clinical and immunological markers to predict efficacy in children after 2 years of sublingual immunotherapy (SLIT). A total of 285 children diagnosed with allergic rhinitis were recruited. The clinical efficacy was evaluated by comparing endpoint and baseline symptom and medication scores (SMS). Baseline clinical and immunological markers (serum total and specific immunoglobulin [Ig]E) and their correlation with clinical efficacy were analyzed. Of the 285 children recruited, 249 completed the 2-year SLIT program. After 2 years of SLIT, 68.3% of the children showed a significant response. Children in the Remarkable Response Group had the highest baseline SMS and most extended disease duration, followed by the Effective Relief and Unresponsive Group. Correlation analysis demonstrated that SMS improvement was positively correlated with baseline SMS (r=0.67) and disease duration (r=0.35). SMS improvement was not correlated with age, body mass index, total or specific IgE levels, or their ratios. Our results show that baseline SMS and disease duration can predict the efficacy of SLIT. Our study can guide the selection of suitable candidates for SLIT.

Real-World Evidence of Avatrombopag for the Treatment of Immune Thrombocytopenia Intolerant or Ineffective to Eltrombopag/Hetrombopag

Abstract Objectives: Thrombopoietin receptor agonists (TPO-RA) have dramatically changed the treatment landscape for immune thrombocytopenia (ITP). Although avatrombopag has been confirmed to achieve platelet response for chronic ITP in clinical trials, and it has no hepatotoxicity unlike eltrombopag or hetrombopag, there is still a lack of real-world research on the application of avatrombopag in Chinese ITP patients. Here, we aimed to evaluate the effect and safety of avatrombopag in ITP treatment in a real-world clinical practice. Methods: In this retrospective analysis, we enrolled consecutive cohorts of 50 adult ITP patients who received avatrombopag in two centers from January 2021 to March 2023. The median duration of follow-up of these patients was 16.5 months (range from 3.8 to 25.4 months). Results: The median age of patients was 44 years when they received the treatment of avatrombopag, and 42% of them were males. Most patients (n=45) had a persistent (3-12 months) or chronic course (more than 12 months) of ITP. The patients in our study were heavily treated, who received a median of 4 kinds of ITP treatment prior to avatrombopag. The baseline TPO levels was 88.1 (110.2±84.5) pg/ml. Based on the reasons for choosing avatrombopag, these patients were divided into eltrombopag/hetrombopag intolerance group (IG, n=14) and eltrombopag/hetrombopag unresponsive group (UG, n=36). The reasons for choosing avatrombopag in IG included active hepatitis B (n=4), hepatic insufficiency before using TPO-RA (n= 6), autoimmune hepatitis (n=1), hepatic lesion after using eltrombopag (n=2), and myelofibrosis after using eltrombopag (n=1). Compared with UG, more patients had a history of liver disease (active Hepatitis B and autoimmune liver diseases, P=0.003). The median platelet count before avatrombopag was 9 × 10 9/L. The median duration of avatrombopag treatment was 12 weeks and the median weekly dose of avatrombopag was 140 mg. Among the total cohort, platelet response (platelet count ≥30 × 10 9 /L) was achieved in 44/50 (88%) and complete platelet response (platelet count ≥100 × 10 9 /L) was seen in 35/50 patients (70%) after using avatrombopag. The median time of platelets rising above 30 × 10 9 /L was 7 days, while it was 8 days when platelet count exceeded 50 × 10 9 /L. Nearly half patients (47%) were able to discontinue more than 1 concomitant ITP medication after avatrombopag treatment. Besides, most patients (74%) in our study tapered off or withdrew steroids. There were no significant differences in baseline platelet count, 30-day response rate, the maximum effective dose of avatrombopag and duration of avatrombopag between IG and UG. So far, 19 patients achieved platelet response were still taking avatrombopag, and 58% of them maintained platelet count above 100× 10 9 /L. Meanwhile, 31 patients discontinued avatrombopag.The reasons for withdrawal of drug included adverse events (n=2), sustained remission in ITP (n=8), no/lose response to avatrombopag (n=10), and unablity to afford the cost consistently (n=11). Avatrombopag was well tolerated in most patients, even those suffered from hepatic insufficiency and/or myelofibrosis after other TPO-RA. However, two cases had thrombosis and two patients reported mild fatigue. Conclusion: In the ITP population, avatrombopag was effective and safe, especially for those intolerant or ineffective to eltrombopag/hetrombopag. However, most patients with ITP were not able to afford the long-term usage of avatrombopag in China.

An association between auditory responsiveness of children and duration of entertainment screen time in the early years of life

Objective To examine whether the responsiveness of young children to simple sounds was associated with entertainment screen time (EST), opportunities for social interaction, and social and communication skills. Design Parents completed a questionnaire covering, for years one and two, the number of times the child met with other children; the number of words the child spoke; and the daily amount of EST. Social, attention and communication skills were assessed. Study sample Participants were 118 children, aged 15 to 46 months. They were initially assessed behaviourally using simple sounds. Children who responded to such sounds were denoted the Responsive group. Children who did not were assessed using familiar songs and denoted the Unresponsive group. Results The two groups did not differ significantly in mean age or the number of opportunities to meet other children. The Unresponsive group had significantly fewer words than the Responsive group at 12 and 24 months and had significantly higher EST than the Responsive group for years 1 and 2. The Unresponsive group showed lower social, attention and communication skills than the Responsive group. Conclusions High EST was associated with poorer auditory and social skills. Hence, it may be wise to limit the EST of young children.

Determination of predictive factors for the clinical cure rate of endometritis in Holstein dairy cows

Endometritis is one of the most common disorders that negatively influence reproductive performance in dairy cows. The purpose of this study was to determine the predictive factors of the clinical cure of endometritis. A total of 700 Holstein dairy cows were examined for signs of clinical endometritis between 30 and 40 days in milk (the first examination in the time of clean test). A total of 131 cows with clinical endometritis were assigned for treatment. Cytological examination, reagent test strips, and characteristics of reproductive organs were evaluated at the time of treatment (the first examination) and two weeks after the treatment (the second examination: for evaluation of response to treatment of endometritis). After evaluation of treatment, cows were grouped into the responsive (n=56) and unresponsive (n=75) to treatment. Percentages of non-degenerated neutrophil (NDN), degenerated neutrophil (DN), total neutrophils and leukocyte esterase activity were significantly higher (P&lt;0.05) in the unresponsive cows than those of responsive ones to treatment at the second examinations. Moreover, the nitrate test was significantly higher in the unresponsive group than the responsive group at the first examination. However, protein concentration and percentages of lymphocyte cells were significantly higher in the unresponsive animals than the responsive cows at the first and second stages of examination (P&lt;0.05). Increasing of lymphocytes percentage, protein concentration, and nitrate test at the first stage of examination in the unresponsive cows showed more sever of inflammatory conditions and uterine infection in the unresponsive cows. Evaluation of these factors can predict the clinical cure of endometritis in dairy cows.

Association of SCN1A Gene Polymorphism with Phenytoin Response in Patients with Epilepsy: Relevance of Stratification by the History of Febrile Seizure

AIM: The SCN1A gene encodes the NaV1.1 sodium channel in the central nervous system that serves as the target for phenytoin. Our study aimed to investigate the association of SCN1A polymorphism (SNP rs3812718) with phenytoin response. MATERIALS AND METHODS: A total of 120 epileptic patients who had received phenytoin for at least 1 year were enrolled in the study and genotyped using the TaqMan assay. They were classified into phenytoin-responsive (n = 62) and phenytoin unresponsive groups (n = 58). Patients were also stratified according to the history of febrile seizure (24 in the febrile seizure subgroup; 96 patients in the no history of febrile seizure subgroup) and epilepsy etiology (47 in idiopathic; 73 in the symptomatic + cryptogenic subgroup). RESULTS: The frequency of AA (19% vs. 11.3%) and AG genotypes (43.1% vs. 40.3%) was found to be more frequent in phenytoin unresponsive. GG genotypes dominated in the phenytoin responsive group (37.9% vs. 48.4%) but were not statistically significant (p &gt; 0.05). We identified two variables associated with phenytoin response: the etiology of epilepsy (p = 0.012) and history of febrile seizure (0.014). A significant positive association between the rs3812718 genotype and phenytoin response was found when patients were stratified by a history of febrile seizures. In patients without a history of febrile seizures, the AA genotype had a higher risk of phenytoin unresponsiveness than the GG genotype (p = 0.048; OR 3.73, 95% CI: 1.01–13.78). CONCLUSION: There was no significant association between the rs3812718 polymorphism and phenytoin responsiveness in patients with epilepsy. In the patients without a history of febrile seizure subgroup, AA increased the risk of phenytoin unresponsiveness compared to the GG genotype.

Resting-State fMRI in Predicting Response to Treatment With SSRIs in First-Episode, Drug-Naive Patients With Major Depressive Disorder.

ObjectiveFor major depressive disorder (MDD), there has been a lack of neuroimaging markers of efficacy of pharmacological treatment. In this study, we aimed to explore the neuroimaging mechanisms in patients with first-episode MDD and identify markers that predict the efficacy of 5-hydroxytryptamine reuptake inhibitors (SSRIs) with the use of resting-state brain imaging technology.MethodsA total of 101 patients with first-episode MDD and 53 normal controls were finally included in this study. Based on the reduction rate of the score of Hamilton Depression Rating Scale (HAMD-17) during the 2-week SSRI treatment, 31 patients were assigned into the unresponsive group and 32 were assigned into the responsive group. The brain function was compared between patients with MDD and normal controls, and the diagnostic value of brain function was analyzed. With brain regions showing differences between patients with MDD and normal controls as a mask, and the brain function between the responsive and unresponsive groups were compared. Correlations between brain function the HAMD-17 score reduction rate during the 2-week SSRI treatment were analyzed.ResultsCompared to normal controls, patients with MDD showed increased ReHo in the left parahippocampal gyrus and right parahippocampal gyrus, decreased ReHo in the right middle occipital gyrus, and decreased functional connectivity between the right and left parahippocampal gyri, right middle occipital gyrus and middle temporal gyrus. Receiver operator characteristic (ROC) curve analysis showed that the area under the curve (AUC) was 0.544 (95% CI: 0.445–0.644) for ReHo and 0.822 (95% CI: 0.734–0.909) for functional connectivity. Logistic regression pooling of the differences in ReHo mean time series with the functional connectivity mean time series was performed for the ROC curve analysis, which showed an AUC of 0.832 (95% CI: 0.752–0.911). Compared to the responsive group, the unresponsive group showed elevated ReHo in the right parahippocampal gyrus and lower functional connectivity in the middle temporal gyrus. We also found that the ReHo value was negatively correlated with the HAMD-17 score reduction after 2 weeks of SSRI treatment.ConclusionAltered resting-state brain function in some regions might be a neurobiological marker for the diagnosis of MDD, and ReHo values are expected to be predictors of patient response to treatment with SSRIs.Clinical Trial Registration[http://www.chictr.org.cn/], identifier [ChiCTR1900028722].

T2 -Weighted MR Imaging-Derived Radiomics for Pretreatment Determination of Therapeutic Response to Glucocorticoid in Patients With Thyroid-Associated Ophthalmopathy: Comparison With Semiquantitative Evaluation.

MR imaging has been applied to determine therapeutic response to glucocorticoid (GC) before treatment in thyroid-associated ophthalmopathy (TAO), while the performance was still poor. To investigate the value of T2 -weighted imaging (T2 WI)-derived radiomics for pretreatment determination of therapeutic response to GC in TAO patients, and compare its diagnostic performance with that of semiquantitative parameters. Retrospective. A total of 110 patients (49 ± 12 years; male/female, n=48/62; responsive/unresponsive, n=62/48), divided into training (n=78) and validation (n=32) cohorts. 3.0 T, T2 -weighted fast spin echo. W.C. and H.H. (6 and 10 years of experience, respectively) performed the measurements. Maximum, mean, and minimum signal intensity ratios (SIRs) of extraocular muscle (EOM) bellies were collected to construct a semiquantitative imaging model. Radiomics features from volumes of interest covering EOM bellies were extracted and three machine learning-based (logistic regression [LR]; decision tree [DT]; support vector machine [SVM]) models were built. The diagnostic performances of models were evaluated using receiver operating characteristic curve analyses, and compared using DeLong test. Two-sided P < 0.05 was considered statistically significant. The responsive group showed higher minimum signal intensity ratio (SIRmin ) of EOMs than the unresponsive group (training: 1.46 ± 0.34 vs. 1.18 ± 0.39; validation: 1.44 ± 0.33 vs. 1.19 ± 0.20). In both cohorts, LR-based radiomics model demonstrated good diagnostic performance (area under the curve [AUC]=0.968, 0.916), followed by DT-based (AUC=0.933, 0.857) and SVM-based models (AUC=0.919, 0.855). All three radiomics models outperformed semiquantitative imaging model (SIRmin : AUC=0.805) in training cohort. In validation cohort, only LR-based radiomics model outperformed that of SIRmin (AUC=0.745). The nomogram integrating LR-based radiomics signature and disease duration further elevated the diagnostic performance in validation cohort (AUC: 0.952 vs. 0.916, P=0.063). T2 WI-derived radiomics of EOMs, together with disease duration, provides a promising noninvasive approach for determining therapeutic response before GC administration in TAO patients. 3 TECHNICAL EFFICACY: Stage 4.

T2 Mapping with and without Fat-Suppression to Predict Treatment Response to Intravenous Glucocorticoid Therapy for Thyroid-Associated Ophthalmopathy.

ObjectiveTo evaluate the performance of baseline clinical characteristics and pretherapeutic histogram parameters derived from T2 mapping of the extraocular muscles (EOMs) in the prediction of treatment response to intravenous glucocorticoid (IVGC) therapy for active and moderate-to-severe thyroid-associated ophthalmopathy (TAO) and to investigate the effect of fat-suppression (FS) in T2 mapping in this prediction.Materials and MethodsA total of 79 patients clinically diagnosed with active, moderate-to-severe TAO (47 female, 32 male; mean age ± standard deviation, 46.1 ± 10 years), including 43 patients with a total of 86 orbits in the responsive group and 36 patients with a total of 72 orbits in the unresponsive group, were enrolled. Baseline clinical characteristics and pretherapeutic histogram parameters derived from T2 mapping with FS (i.e., FS T2 mapping) or without FS (i.e., conventional T2 mapping) of EOMs were compared between the two groups. Independent predictors of treatment response to IVGC were identified using multivariable analysis. Receiver operating characteristic (ROC) curve analysis was performed to evaluate the predictive performance of the prediction models. Differences between the models were examined using the DeLong test.ResultsCompared to the unresponsive group, the responsive group had a shorter disease duration, lower kurtosis (FS-kurtosis), lower standard deviation, larger 75th, 90th, and 95th (FS-95th) T2 relaxation times in FS mapping and lower kurtosis in conventional T2 mapping. Multivariable analysis revealed that disease duration, FS-95th percentile, and FS-kurtosis were independent predictors of treatment response. The combined model, integrating all identified predictors, had an optimized area under the ROC curve of 0.797, 88.4% sensitivity, and 62.5% specificity, which were significantly superior to those of the imaging model (p = 0.013).ConclusionAn integrated combination of disease duration, FS-95th percentile, and FS-kurtosis was a potential predictor of treatment response to IVGC in patients with active and moderate-to-severe TAO. FS T2 mapping was superior to conventional T2 mapping in terms of prediction.

Clinical and electroencephalogram characteristics and treatment outcomes in children with benign epilepsy and centrotemporal spikes.

BACKGROUNDEpilepsy is a syndrome characterized by transient, rigid, paroxysmal, and repetitive central nervous system dysfunction. Prevention, control, and improvement of cognitive and behavioral dysfunction are of great significance for improving the patients’ intellectual development and quality of life. Electroencephalograms (EEG) can predict an accelerated decline in cognitive function.AIMTo determine the clinical and EEG characteristics and treatment results of benign epilepsy in spiking children.METHODSA total of 106 cases of benign epilepsy in children with myocardial spines treated at our hospital from January 2017 to January 2020 were selected. Differences in clinical data and EGG characteristics between treatment-effective/-ineffective patients were analyzed, and children’s intellectual development before and after treatment evaluated using the Gesell Development Diagnostic Scale.RESULTSEEG showed that the discharge proportion in the awake and sleep periods was 66.04%, and the peak/peak discharge was mainly single-sided, accounting for 81.13%, while the discharge generalization accounted for 31.13%. There was no significant difference in any of these variables between sexes and ages (P > 0.05). The proportion of patients with early onset (< 5 years old) and seizure frequency > 3 times/half a year was 40.00% and 60.00%, respectively; the incidence rate and seizure frequency in the younger age group (< 5 years old) were significantly higher than those in the treatment-effective group (P < 0.05), while the discharge index was significantly lower than that in the treatment-effective group (P < 0.05). The discharge index was negatively correlated with fine motor skill and language development (r = -0.274 and -0.247, respectively; P < 0.05), but not with the rest (P > 0.05). Logistic regression analysis showed that low age onset (< 5 years old) and seizure frequency were the factors affecting ineffective-treatment of benign epilepsy in children (odds ratio = 11.304 and 5.784, respectively; P < 0.05). The discharge index of the responsive group after treatment was significantly lower than that of the unresponsive group (P < 0.05). However, there was no significant difference between groups after treatment in gross and fine motor skills, adaptability, language, and personal social development (P > 0.05).CONCLUSIONThe EEG of children with benign epilepsy due to spinal wave in central time zone has characteristic changes, and the therapeutic effect is influenced by age of onset and attack frequency.

High-Dimensional Analysis Identifies Mechanisms of Gilteritinib Resistance in FLT3-Mutated AML

While clinical benefit has been observed with gilteritinib in patients with FLT3 mutated relapsed/refractory acute myeloid leukemia (AML), most patients relapse through mechanisms that are incompletely understood. In this study, to investigate mechanisms of gilteritinib sensitivity and resistance, we performed targeted sequencing (21 patients) and scRNASeq analysis (8 patients) of FLT3-ITD-positive AML samples obtained before and during treatment. Before treatment, co-occurring mutations were observed in 33 genes among 21 patients. Mutations in RAS pathway genes (PTPN11, KRAS, NRAS, CBL) were the most common and observed in 57% (12/21) of patients. Seven patients pretreatment already contained RAS pathway mutations, of which 6 of these mutations were maintained over the course of treatment. During treatment, 9 patients showed emerging RAS mutations, 4 of which initially presented with a different RAS pathway mutation pre-treatment. Other mutations that arose during treatment were observed in CEBPA, IDH1, SF1 and WT1; as well as CSF3R, CUX1, PLEKHG5, and XPO1, not previously identified in gilteritinib-treated patients. Mutational clonality was generally maintained over treatment in both responders and non-responders. scRNASeq revealed global gene expression differences in myeloblast populations between gilteritinib-responsive and -unresponsive patients. Previous studies in vitro have shown that bone marrow-derived hematopoietic and inflammatory cytokines/chemokines confer resistance to FLT3 inhibitors. In the unresponsive group, we observed an increase in expression of CCL5, CXCL1, CXCL2, CXCL8, FLT3, IL6R, IL3RA, and CSF2RA during gilteritinib treatment, supporting the concept from preclinical studies that AML microenvironment-mediated factors play a critical role in drug resistance. Baseline expression of the Tec kinase BMX was significantly higher in unresponsive patients (Log2FoldChange, 6.65; adjusted P value, 0.00186), and this was maintained in the expanding myeloblast populations during treatment. Previously, upregulated BMX was shown to contribute to sorafenib resistance in patients with FLT3-ITD-positive AML, through cell-nonautonomous microenvironment hypoxia-dependent effects. Further in vitro investigation confirmed gilteritinib resistance could be reversed through genetic and pharmacological manipulation of BMX. Gene module analysis showed associations between gilteritinib responsive and upregulation of genes and pathways involved in lymphocyte differentiation and myeloid leukocyte activation, including TBX21, GATA3, CD33, and LYZ. By contrast, there was association between unresponsiveness to gilteritinib and upregulation of cell-cycle, DNA, and RNA metabolic processes, including pathways involving METTL1 and DNMT3A, as well as pre-treatment expression of pathways associated with protein translation. Together, these data provide support for microenvironment-dependent escape from targeted therapy and suggest that BMX may contribute to gilteritinib resistance. High-dimensional analysis with scRNA-seq provides a deeper understanding of targets and pathways for potential therapeutic intervention to restore gilteritinib sensitivity. DisclosuresBlachly: INNATE: Consultancy, Honoraria; KITE: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria.

Clinical comorbidities correlated with a response to the cerebrospinal fluid tap test in idiopathic normal-pressure hydrocephalus

AimsThe mainstay of treatment for idiopathic normal-pressure hydrocephalus (iNPH) is spinal fluid shunting. A tap test (TT) is recommended as an indication of shunting. Patients with iNPH are often elderly and have multiple comorbidities affecting the shunting outcome. We investigated the factors affecting TT in patients with iNPH. MethodsSeventy-five patients with iNPH were admitted to our department for a TT from April 2010 to May 2021. The patients were divided into a responsive group and an unresponsive group according to the clinical outcomes after TT on the Timed Up and Go Test (TUG), Mini-Mental State Examination (MMSE), or iNPH grading scale. Factors affecting the TT were compared between the responders and nonresponders. ResultsThere were 38 patients (50.7%) in the TT responder group, and the prevalence of improvement was 82.9% in the TUG, 27.6% in the MMSE, and 76.3% in the iNPH grading scale. There were no significant differences in the vascular risk factors between the two groups. The prevalence of lumbar spondylosis, compression fracture, severe periventricular hyperintensity, deep and subcortical white matter hyperintensity (DSWMH), and old cerebral infarcts was significantly higher among the TT nonresponders. The logistic regression analysis showed that severe DSWMH and lumbar spondylosis were associated with a TT nonresponse (p < 0.001 and p = 0.003, respectively). Shunting was performed in 22 patients, 19 of whom were TT responders. ConclusionSevere DSWMH and lumbar spondylosis were associated with a poor response to the TT in iNPH patients. We should consider risk factors when selecting candidates for shunt surgery.

The augment of regulatory T cells undermines the efficacy of anti-PD-L1 treatment in cervical cancer

BackgroundImmune checkpoint inhibitors have aroused great expectation of tumor eradication. However, the effect of anti-PD-L1 treatment for cervical cancer is unsatisfactory and the underlying antagonist to anti-PD-L1 efficacy is remained to be studied. Here, we investigated the anti-tumor effect of anti-PD-L1 treatment in cervical tumor model and identified the antagonist to the therapeutic efficacy of anti-PD-L1 treatment.ResultsWe found that PD-L1 exhibited a moderate expression in both cervical tumor cell lines and clinical samples compared to other tumor types and the para-tumor tissue respectively. Interestingly, our results showed that the anti-PD-L1 treated mice were dichotomously divided into responsive and unresponsive group after five cycles of anti-PD-L1 treatment although all the mice had the same genome background. In addition, the unresponsive tumors showed less tumor necrosis area and higher immunosuppression activity induced by regulatory T cells (Tregs) population than the responsive ones. Furthermore, we found that anti-PD-L1 treatment autonomously upregulated Tregs proliferation and frequency in multiple immune organs, and, most importantly, Tregs depletion significantly depressed the tumor growth rate and tumor weight compared with either anti-PD-L1 or anti-CD25 treatment alone. Finally, we observed that the upregulating effector CD8+ T cell is associated with the better therapeutic effect of anti-PD-L1 therapy post Tregs depletion.ConclusionsAnti-PD-L1 treatment upregulates Tregs frequency and proliferation in tumor model, and the depletion of Tregs may be a useful adjuvant strategy for anti-PD-L1 therapy of cervical cancer.

Prediction of treatment response to intravenous glucocorticoid in patients with thyroid-associated ophthalmopathy using T2 mapping and T2 IDEAL

PurposeTo investigate the performance of combined T2 mapping and T2 iterative decomposition of water and fat with echo asymmetry and least-squares estimation (IDEAL) in orbital tissues to predict the therapeutic efficacy of intravenous glucocorticoids (IVGCs) for active and moderate-to-severe thyroid-associated ophthalmopathy (TAO). MethodSixty-three active and moderate-to-severe TAO patients (responsive group, n = 35; unresponsive group, n = 28) who underwent orbital MRI before receiving IVGCs were retrospectively enrolled. Baseline clinical characteristics and imaging parameters were analyzed and compared between the two groups of different therapeutic efficacy. Binary logistic regression analysis was conducted to determine the independent predictors, the predictive performance of which was evaluated using receiver operating characteristic curve analysis. ResultsThe mean T2 relaxation time of extraocular muscle (EOM-T2RTmean) (P = 0.001), maximum T2RT of EOM (EOM-T2RTmax) (P = 0.001), mean water fraction of EOM (EOM-WFmean) (P < 0.001), maximum WF of EOM (EOM-WFmax) (P < 0.001) and exophthalmos (P = 0.007) were significantly higher in the responsive group than in the unresponsive group. EOM-T2RTmean (P < 0.001) and EOM-WFmax (P < 0.001) were determined as independent predictors for responsive patients with TAO in the multivariable analysis. Combining EOM-T2RTmean ≥ 77.1 and EOM-WFmax ≥ 91.52 demonstrated optimal efficiency for prediction (area under the curve = 0.844) and optimal predictive sensitivity (77.1%). Setting EOM-WFmax ≥ 91.52 achieved the optimal predictive specificity (89.3%). ConclusionsPretherapeutic quantitative measurements, based on combining T2 mapping and T2 IDEAL in orbital tissues, are valuable for predicting IVGC treatment response in active and moderate-to-severe TAO. EOM-T2RTmean and EOM-WFmax may become promising IVGC treatment response predictors.

Relationship of Serum Cytokine Profile to Steroid Resistance in Demyelinating Neurologic Illnesses

Background and Purpose: Corticosteroids form main stay of treatment of autoimmune neurological diseases. Immunotherapy with Intravenous Immunoglobulin, Plasmapheresis, biological agents like Rituximab, Infliximab, etanarcept are also used for treatment of patients who are resistant to steroid treatment and in severe cases. This study was aimed to elicit the relationship between serum cytokine levels and steroid resistance which is important for early commencement of other medications. Methods: The serum samples of patients who presented with autoimmune neurological diseases were collected and cytokine levels were estimated. The cytokine profile of patients who responded well to steroid treatment was compared with that of steroid nonresponders. Results: The steroid unresponsive group had significantly higher serum Interferon gamma and IL-13 levels than steroid unresponsive group. Conclusion: when patients present with high serum levels of IL-13 and Interferon Gamma they should be considered for prompt escalation of immunomodulatory therapy.

Baseline Volumetric T2 Relaxation Time Histogram Analysis: Can It Be Used to Predict the Response to Intravenous Methylprednisolone Therapy in Patients With Thyroid-Associated Ophthalmopathy?

ObjectivePrediction of therapy response to intravenous methylprednisolone pulses (ivMP) is crucial for thyroid-associated ophthalmopathy (TAO). Image histograms may offer sensitive imaging biomarkers for therapy effect prediction. This study aimed to investigate whether pretherapeutic, multiparametric T2 relaxation time(T2RT) histogram features of extraocular muscles (EOMs) can be used to predict therapy response.Materials and MethodsForty-five active and moderate-severe TAO patients, who were treated with standard ivMP and underwent orbital MRI before therapy, were retrospectively included in this study. The patients were divided into responsive (n = 24, 48 eyes) and unresponsive group(n = 21, 42 eyes) according to clinical evaluation. Baseline clinical features of patients and histogram-derived T2RT parameters of the EOMs were analyzed and compared. Logistic regression model was conducted to determine independent predictors, and a histogram features nomogram was formulated for personalized prediction.ResultsResponsive group displayed lower values for 5th, 10th percentiles (P < 0.050, respectively), and higher values for 75th, 90th, and 95th percentiles, skewness, entropy, and inhomogeneity (P < 0.050, respectively) than unresponsive group. Multivariate logistic regression analysis showed that 95th percentile of >88.1 [odds ratio (OR) = 12.078; 95% confidence interval (CI) = 3.98–36.655, p < 0.001], skewness of >0.31 (OR = 3.935; 95% CI = 2.28–6.788, p < 0.001) and entropy of >3.41 (OR = 4.375; 95% CI = 2.604–7.351, p < 0.001) were independent predictors for favorable response. The nomogram integration of three independent predictors demonstrated optimal predictive efficiency, with a C-index of 0.792.ConclusionsPre-treatment volumetric T2RT histogram features of EOMs could function to predict the response to ivMP in patients with TAO. The nomogram based on histogram features facilitates the selection of patients who will derive maximal benefit from ivMP.

T2 mapping histogram at extraocular muscles for predicting the response to glucocorticoid therapy in patients with thyroid-associated ophthalmopathy

To evaluate the performance of T2 mapping histograms at the extraocular muscles (EOMs) in predicting the response to glucocorticoid therapy in the patients with active and moderate-severe thyroid-associated ophthalmopathy (TAO). Thirty active and moderate-severe TAO patients (responsive group, n=20; unresponsive group, n=10) were enrolled, and evaluated using T2 mapping before treatment. Histogram parameters (mean, median, max, min, 10th, 90th percentiles, skewness, and kurtosis) of T2 relaxation time (T2RT) at the EOMs for each orbit, and clinical variables (age, sex, disease duration, anti-thyroid treatment, smoking habit, pre-treatment thyroid function, thyrotrophin receptor antibody, diplopia presence, activity and severity scores) were collected and compared between groups. Logistic regression and receiver operating characteristic (ROC) curve analyses were used to assess the predictive value of identified independent variables for treatment response. The responsive group showed significantly shorter disease duration (p=0.003), while higher T2RTmin than unresponsive group (p<0.001). Multivariate analysis showed that T2RTmin and disease duration were independent predictors for responsive TAOs. ROC curve analyses indicated that setting a cut-off value of ≥54.3 for T2RTmin demonstrated the optimal predicting specificity for responsive TAOs (100%), while a combination of T2RTmin ≥54.3 and disease duration ≤4.5 showed optimal predicting efficiency and sensitivity (area under the curve, 0.820; sensitivity, 65%). Histogram analysis can help to exhibit the heterogeneity of T2RT at the EOMs. T2RTmin, together with disease duration may be the promising marker for predicting response to glucocorticoid therapy in the patients with active and moderate-severe TAO.

Predicting the response to glucocorticoid therapy in thyroid-associated ophthalmopathy: mobilizing structural MRI-based quantitative measurements of orbital tissues.

We aimed to evaluate the performance of structural magnetic resonance imaging (MRI)-based quantitative measurements at extraocular muscle (EOM), orbital fat (OF), and especially lacrimal gland (LG) in predicting response to glucocorticoid (GC) in patients with active and moderate-severe thyroid-associated ophthalmopathy (TAO). Forty-seven active and moderate-severe TAOs (responsive group, 29 patients and 58 eyes; unresponsive group, 18 patients and 36 eyes) were enrolled. Pretreatment MRI-based parameters of EOM, OF, and LG, and clinical factors were retrospectively collected and compared between two groups. Logistic regression and receiver operating characteristic curve analyses were used to assess the predictive value of identified independent variables. Responsive group showed significantly higher minimum signal intensity ratio of EOM (EOM-SIRmin) (p < 0.001), higher EOM-SIRmean (p = 0.034), higher LG herniation (LGH) (p = 0.019), lower OF thickness (OFT) (p = 0.017), higher LGH/OFT ratio (p = 0.001), and shorter disease duration (p = 0.004) than unresponsive group. Multivariate analysis showed that EOM-SIRmin, LGH/OFT ratio, and disease duration were independent predictors for responsive TAOs (all p < 0.05). Integration of three independent predictors demonstrated optimal predictive efficiency (area under curve, 0.829). Combining EOM-SIRmin ≥1.43 and LGH/OFT ratio ≥1.65, optimal predictive specificity (94.4%) could be obtained, while optimal predictive sensitivity (82.8%) was achieved when integrating disease duration ≤3.5 and LGH/OFT ratio ≥1.65. Structural MRI-based quantitative measurements at EOM, OF, and LG, specially EOM-SIRmin and LGH/OFT ratio, together with disease duration, may serve as promising markers to predict response to GC in patients with active and moderate-severe TAO.