Suboptimal Treatment Response Research Articles

Anti-rheumatic property and physiological safety of KMU-11342 in in vitro and in vivo models

Rheumatoid arthritis (RA) is a chronic, systemic inflammatory disorder characterized by joint destruction due to synovial hypertrophy and the infiltration of inflammatory cells. Despite substantial progress in RA treatment, challenges persist, including suboptimal treatment responses and adverse effects associated with current therapies. This study investigates the anti-rheumatic capabilities of the newly identified multi-protein kinase inhibitor, KMU-11342, aiming to develop innovative agents targeting RA. In this study, we synthesized the novel multi-protein kinase inhibitor KMU-11342, based on indolin-2-one. We assessed its cardiac electrophysiological safety using the Langendorff system in rat hearts and evaluated its toxicity in zebrafish in vivo. Additionally, we examined the anti-rheumatic effects of KMU-11342 on human rheumatoid arthritis fibroblast-like synoviocytes (RA-FLS), THP-1 cells, and osteoclastogenesis in RAW264.7 cells. KMU-11342 demonstrated the ability to inhibit LPS-induced chemokine inhibition and the upregulation of pro-inflammatory cytokines, cyclooxygenase-2, inducible nitric oxide synthase, p-IKKα/β, p-NF-κB p65, and the nuclear translocation of NF-κB p65 in RA-FLS. It effectively suppressed the upregulation of NLR family pyrin domain containing 3 (NLRP3) and caspase-1 cleavage. Furthermore, KMU-11342 hindered the activation of osteoclast differentiation factors such as RANKL-induced TRAP, cathepsin K, NFATc-1, and c-Fos in RAW264.7 cells. KMU-11342 mitigates LPS-mediated inflammatory responses in THP-1 cells by inhibiting the activation of NLRP3 inflammasome. Notably, KMU-11342 exhibited minimal cytotoxicity in vivo and electrophysiological cardiotoxicity ex vivo. Consequently, KMU-11342 holds promise for development as a therapeutic agent in RA treatment.

Response to Comments on "Increasing Enzyme Mannose-6-Phosphate Levels but Not Miglustat Coadministration Enhances the Efficacy of Enzyme Replacement Therapy in Pompe Mice".

We thank Dr. Weimer and her colleagues for their comments related to our recent work (Anding et al., 2023) and are grateful for the opportunity to further discuss the importance of efficient lysosomal targeting of enzyme-replacement therapies (ERT) for the treatment of Pompe disease. Patients with Pompe disease have mutations in the gene that encodes for acid α glucosidase (GAA), a lysosomal enzyme necessary for the breakdown of glycogen. The first-generation ERT, alglucosidase alfa, provides a lifesaving therapy for the severe form of the disease (infantile onset Pompe disease) and improves or stabilizes respiratory and motor function in patients with less severe disease (late onset Pompe disease). Despite these gains, significant unmet need remains, particularly in patients who display respiratory and motor decline following years of treatment. Poor tissue uptake and lysosomal targeting via inefficient binding of the cation-independent mannose-6-phosphate (M6P) receptor (CIMPR) in skeletal muscle contributed to this suboptimal treatment response, prompting the development of new ERTs with increased levels of M6P.

Disulfidptosis in head and neck squamous carcinoma: Integrative bioinformatic and in-vitro analysis.

Head and neck squamous carcinoma (HNSC) is a prevalent global malignancy with limited treatment options, which necessitates the development of novel therapeutic strategies. Disulfidptosis, a recently discovered and unique cell death pathway, may offer promise as a treatment target in HNSC. We identified disulfidptosis-related genes (DRGs) using multiple algorithms and developed a prognostic model based on a disulfidptosis-related gene index (DRGI). The model's predictive accuracy was assessed by ROC-AUC, and patients were stratified by risk scores. We investigated the tumor immune microenvironment, immune responses, tumorigenesis pathways, and chemotherapy sensitivity (IC50). We also constructed a diagnostic model using 20 machine-learning algorithms and validated PCBP2 expression through RT-qPCR and western blot. We developed a 12-DRG DRGI prognostic model, classifying patients into high- and low-risk groups, with the high-risk group experiencing poorer clinical outcomes. Notable differences in tumor immune microenvironment and chemosensitivity were observed, with reduced immune activity and suboptimal treatment responses in the high-risk group. Advanced machine learning and in-vitro experiments supported DRGI's potential as a reliable HNSC diagnostic biomarker. We established a novel DRGI-based prognostic and diagnostic model for HNSC, exploring its tumor immune microenvironment implications, and offering valuable insights for future research and clinical trials.

Abstract 4020: Donor-dependent anti-tumoral efficacy of human CD19 CAR T cells in a leukemic xenograft mouse model

Abstract The recent advances in cellular immunotherapies have revolutionized the treatment options for hematological malignancies. Among others, genetically engineered T cells to express chimeric antigen receptors targeting CD19 have shown clinical success in patients with B cell malignancies. However, depending on the study design only one to two thirds of the patients experience a complete response upon CD19 CAR T cells treatment. Antigen escape, immune suppressive microenvironment, CAR T cell dysfunction as well as lack of CAR T cell persistence have been discussed to be reasons for the lack of sustained therapy response. Well established models for the preclinical evaluation of cellular therapies are needed for the evaluation of next generation CAR T cells as well as novel combination therapies. Here, we describe a xenograft animal model of human acute lymphoblastic leukemia (NALM-6 cells) with a suboptimal treatment response to human CD19 CAR T cells from three different donors. First, the activation status and memory phenotype of the CAR T cells from the different donors was characterized by flow cytometry and the anti-tumoral efficacy of the CD19 CAR T cells was evaluated in an in vitro co-culture killing assay using luciferase expressing NALM-6 cells. Next, CD19 CAR T cells from three donors were injected in NALM-6_luc tumor bearing animals. The tumor growth was monitored by bioluminescence imaging and the phenotype of the transferred CAR T cells was checked by flow cytometry. The frequency of memory T cells differed between the donors whereas the T cells from all donors exhibited all low expression of activation markers. In vitro, all three donors showed high and comparable anti-tumoral killing efficacy independent of their memory status. In vivo, CD19 CAR T cells from all three donors delayed the tumor growth significantly although none of the animals had a complete remission. In line with the individual memory status of the CAR T cells prior to infusion, there were slight differences in the kinetics of the anti-tumoral response. The flow cytometric analysis revealed that the transferred CAR T cells were almost absent in the peripheral blood and spleen whereas for individual animals tumor cells and highly activated CAR T cells were detectable in the bone marrow of the animals. In summary, the NALM-6_luc xenograft model is a value tool for evaluating next generation cellular therapies and novel combination strategies to overcome the current limitations of cellular therapies. Citation Format: Philipp Metzger, Carla N. Castro, Jonas F. Hummel, Maria Silvia Roman Azcona, Dinu Antony, Claudio Mussolino, Daniel Zurr, Swetlana Adamsky, Holger Weber. Donor-dependent anti-tumoral efficacy of human CD19 CAR T cells in a leukemic xenograft mouse model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4020.

Rituximab Resistance in Glomerular Diseases: A GlomCon Mini Review

Resistance to rituximab B-cell depletion therapy is a clinically pertinent adverse sequela, which can have significant implications for the treatment of immune-mediated glomerular diseases. The true incidence of rituximab resistance remains unknown, however, it is an increasingly recognized treatment complication. Resistance typically presents with suboptimal treatment response, rapid B-cell reconstitution, and a relapsing disease course. While the diverse mechanisms resulting in rituximab resistance are ongoing topics of research, both primary and secondary mechanisms have been identified as key catalysts.The emergence of human anti-chimeric antibodies (HACA) is a major cause of secondary resistance to rituximab therapy and typically appears following repeated drug exposure. Frequently, HACA develop in the setting of underlying autoimmune disease and contribute to poor B-cell depletion, reduced rituximab therapeutic efficacy, and enhanced drug clearance.The clinical challenge of rituximab resistance necessitates heightened awareness among clinicians. Screening for HACA should be considered in individuals with poor clinical response to rituximab, more rapid B-cell reconstitution, and relapsing disease. Detection of HACA may guide treatment alterations, including addition of further immunosuppressive therapy and transitioning to a humanized B-cell depleting monoclonal antibody.

PERSISTENCE WHILE ON LABELED MAINTENANCE DOSE AMONG ADVANCED THERAPY-EXPERIENCED PATIENTS WITH ULCERATIVE COLITIS INITIATED ON USTEKINUMAB OR ADALIMUMAB

Abstract BACKGROUND Persistence on biologics in ulcerative colitis (UC) is a useful real-world treatment performance measure particularly important in advanced therapy (ADT)-experienced patients. Dose escalation on biologics is an indicator of suboptimal treatment response associated with higher biologic costs. This study compared persistence while on labeled maintenance dose among ADT-experienced patients with UC initiated on ustekinumab or adalimumab. METHODS Adults with UC initiated on ustekinumab or adalimumab (index date: 10/21/2019-03/02/2022) were selected from the IQVIA PharMetrics® Plus database. Patients were ADT-experienced (i.e., ≥1 claim for a non-index UC-indicated ADT agent) and without other auto-immune diseases in the 12-month baseline period. Cohorts were balanced on baseline characteristics using inverse probability of treatment weights. Persistence while on the labeled maintenance dose was defined as (1) no gaps between days of therapy supply (ustekinumab, >120 days; adalimumab, >60 days); (2) absence of any dose change relative to the maintenance dose per US label. Composite endpoints of being persistent while corticosteroid-free (<14 consecutive days of corticosteroid supply after day 90 post-index) and persistent while on monotherapy (no immunomodulators or non-index ADT) were also assessed. Endpoints were assessed from the maintenance phase start until the earliest of discontinuation (event), corticosteroid use (event), immunomodulator, non-index advanced therapy use (event), dose change (censored), 12 months follow-up or data end (censored) using weighted Kaplan-Meier analyses and Cox proportional hazards models. RESULTS Weighted cohorts included 693 ustekinumab and 294 adalimumab patients (Fig. 1). At 12 months after the maintenance phase start, 88.7% and 65.8% of the ustekinumab versus adalimumab cohort were persistent while on the labeled maintenance dose with persistence 4.77 times higher in the ustekinumab cohort (p-value:<0.001; Fig. 2a). Further, 55.7% and 44.6% of the ustekinumab versus adalimumab cohort were persistent and corticosteroid-free while on the labeled maintenance dose; persistence was 1.48 times higher in the ustekinumab cohort (p-value:0.002; Fig. 2b). Finally, 77.2% and 47.3% of the ustekinumab versus adalimumab cohort were persistent and on monotherapy while on the labeled maintenance dose; persistence was 3.29 times higher in the ustekinumab cohort (p-value:<0.001; Fig. 2c). CONCLUSIONS ADT-experienced patients with UC treated with ustekinumab were significantly more persistent while on the labeled maintenance dose, including persistent while corticosteroid-free and while on monotherapy versus patients treated with adalimumab. Findings may help inform treatment strategies for ADT-experienced patients with UC. Figure 1 Selected baseline characteristics in weighted ustekinumab and adalimumab cohorts Figure 2 Persistence while on US labelled dose among weighted ustekinumab and adalimumab cohorts: a) persistent on index biologic, b) persistent and corticosteroid-free, c) persistent and on monotherapy

P808 Use of intestinal ultrasound influences the proportion of suboptimally controlled patients: IBD Podcast Study results

Abstract Background The IBD-PODCAST study estimates the proportion of patients with Crohn’s disease (CD) and ulcerative colitis (UC) with suboptimal disease control (DC) in a real-world setting. Intestinal ultrasound (IUS) is recommended in international guidelines as a non-invasive tool to assess disease activity and to guide therapeutic decisions in IBD. It is easy to use, inexpensive, can be repeatedly used without limitations and provides an opportunity for immediate patient interaction. The aim of this descriptive analysis was to assess the impact of IUS on the proportion of suboptimal DC in this cohort. Methods IBD PODCAST was a non-interventional, cross-sectional, multi-center study conducted across 103 sites in 10 countries. Criteria for suboptimal DC were based on STRIDE-II. Retrospective data on the frequency of imaging (i.e. endoscopies, MRI/MRE/CT and IUS) in the 12 months prior to assessment were collected. We compared clinical decision making, subjective evaluation of DC by patients and physicians and objective criteria of suboptimal DC at the time of assessment (i.e. index) in patients with (i.e. CD+IUS12, UC+IUS12) and without IUS (CD-IUS, UC-IUS) in the past 12 months. Results 2185 patients (CD: n=1108, UC n=1077) with a mean age (SD) of 44.0 (14.8) years and mean disease duration (SD) of 12.4 (9.2) years were included (52.2% male). Imaging was performed in 43.1% (n=477) of CD and 44.6% (n=480) of UC patients within 12 months prior to index. Endoscopy accounted for 77.6% and 88.8%, MRI/MRE/CT for 21.0% and 6.7%, and IUS for 19% (n=89/477) and 16% (n=77/480) of patients with CD and UC, respectively. The proportion of patients with signs of active inflammation at index was higher in patients where IUS was used (CD+IUS12: 34% vs CD-IUS: 9.5%; UC+IUS12: 22.6% vs UC-IUS: 15.3%; Table 1). For UC only, numerically more patients with parameters indicating clinically active disease at index were further monitored or had their treatment adjusted, when IUS was used within the past 12 months. (UC+IUS12: 58.6% vs UC-IUS: 50.7%). Despite the high number of patients with suboptimal DC based on objective criteria, the use of IUS minorly improved the alignment of subjective evaluation of suboptimal DC between the patient and physician, and only in UC (UC+IUS12: 37.5% vs UC-IUS: 32.7%; Fig 1). Conclusion Only a minority of patients underwent IUS in this cohort. Yet, this non-invasive tool may be useful if used more frequently. Consistent with others, IUS could aid in holistic disease monitoring for the detection of suboptimal treatment response, clinical decision making and the opportunity for alignment with patients on treatment targets.

Comorbid treatment of traumatic brain injury and mental health disorders.

The Emory Healthcare Veterans Program (EHVP) is a multidisciplinary intensive outpatient treatment program for post-9/11 veterans and service members with invisible wounds, including posttraumatic stress disorder (PTSD), traumatic brain injury (TBI), substance use disorders (SUD), and other anxiety- and depression-related disorders. This article reviews the EHVP. The different treatment tracks that provide integrated and comprehensive treatment are highlighted along with a review of the standard, adjunctive, and auxiliary services that complement individualized treatment plans. This review particularly emphasizes the adjunctive neurorehabilitation service offered to veterans and service members with a TBI history and the EVHP data that indicate large reductions in PTSD and depression symptoms across treatment tracks that are maintained across 12 months follow up. Finally, there is a discussion of possible suboptimal treatment response and the pilot programs related to different treatment augmentation strategies being deploying to ensure optimal treatment response for all. Published data indicate that the two-week intensive outpatient program is an effective treatment program for a variety of complex presentations of PTSD, TBI, SUD, and other anxiety- and depression-related disorders in veterans and active duty service members.

Ghosal Hematodiaphyseal Dysplasia: Implications of Late Diagnosis and Unusual Presentation in Adults

Ghosal Hematodiaphyseal Dysplasia (GHDD) is a rare autosomal recessive disorder characterized by bone modeling failure, resulting in thickening of bone cortices with predominant diaphyseal involvement and responsive anemia to steroids. Late diagnosis of GHDD in adulthood can lead to significant morbidity and suboptimal response to steroids. Moreover, GHDD often mimics more common hematological disorders like myelodysplastic syndrome and myelofibrosis, leading to treatments such as transfusions, splenectomy, and hematopoietic stem cell transplantation. Early diagnosis is critical to enable the patient to receive the appropriate treatment. We present a case series of three Indian patients from different families with genetically proven GHDD. Despite experiencing symptoms from early childhood, all patients were diagnosed in adulthood. None of them were born out of a consanguineous marriage . Two of them, aged 43 and 56, are the oldest reported GHDD patients to date. They initiated steroid treatment in their 5th and 6th decades of life, respectively. Unlike previously reported cases, these two patients required additional drugs like Thalidomide along with steroids, and their response to treatment was not as rapid. The first patient, a 43-year-old male, had a history of anemia since childhood and became transfusion dependent after 15 years of age. He developed bicytopenia and later pancytopenia with hypocellular bone marrow , along with splenohepatomegaly and extramedullary hematopoiesis in the paravertebral and presacral areas, a novel finding in GHDD cases. Whole exome sequencing revealed a missense mutation in the TBXA2 gene. The second patient, a 56-year-old male, had a history of anemia since childhood and underwent splenectomy at 46 due to massive splenomegaly and transfusion dependency. However, his transfusion dependency persisted, and bone marrow biopsy suggested myelofibrosis. However he was negativefor myeloid mutations including JAK2. Subsequently, genetic testing revealed a homozygous missense mutation in the TBXAS1 gene. He also developed paraplegia and bladder incontinence, attributed to extramedullary hematopoiesis, which improved with steroid treatment The third patient a 23 year old man with history of anemia, lower limb tenderness and ecchymosis at 14 months of age. Evaluation then had shown hyperostosis of diaphysis of long bones of lower limbs with sparing of metaphysis and bicytopenia. Was on regular transfusions till 9 years. Re-evaluation with bone marrow studies at 9 years revealed a varying cellular marrow with dysplastic megakaryocytes and diagnosed as pediatric myelodysplatic syndrome ,He was on steroids till 13 years and he did not require further transfusions.He stopped steroids for 1 year following which there was a fall in Hb levels and recurrence of pain in both lower limbs with inability to squat. In view of history of steroid responsive anemia and thickening of diaphysis in X-rays GHDD was suspected and confirmed by genetic testing. He was restarted on steroids and there was a good response to steroids within 4 week with normalisation of hemoglobin levels . Late diagnosis of GHDD in adulthood can lead to severe complications and suboptimal treatment response. These cases highlight the importance of early diagnosis to prevent unnecessary interventions and improve patient outcomes. Unusual presentations, like extramedullary hematopoiesis, can further complicate the diagnostic process. Clinicians should maintain a high index of suspicion for GHDD in cases of refractory anemia or myelofibrosis-like features, especially in adults with an earlier history of anemia. Early recognition and appropriate management are crucial to mitigate morbidity and improve patients' quality of life

Cytogenetic risk explored within an electronic patient reported outcomes (ePROs) remote symptom monitoring platform among patients with acute myelogenous leukemia (AML).

349 Background: Patients with AML and poor-risk cytogenetic abnormalities often have suboptimal treatment response and poor long-term survival, Electronic Patient Reported Outcomes (ePROs) integration into routine oncology practice have been shown to improve patient time on therapy, survival, and resource utilization. This study explores the use of an ePRO platform to explore differences in treatment experience and ePRO compliance in patients with AML and poor and other-risk cytogenetics. Methods: Adult patients with AML undergoing treatment were enrolled in the Carevive remote symptom monitoring (RSM) platform between March 1, 2021 and April 20, 2023. Patients received baseline and weekly surveys to assess patient-reported symptom burden, physical function, overall health, and survey compliance throughout treatment. Baseline characteristics included age, sex, race, frailty status (modified Geriatric Assessment, CARE survey item, and/or self-reported activity level), comorbidities, and social determinants of health. Symptoms (derived from the PRO-CTCAE), physical function (PROMIS 4a), and quality of life (QoL) (EORTC QLQ-C30, items #29-30) were assessed weekly. Results were stratified by poor vs. other cytogenetic risk. As this was an exploratory study, statistical significance was not reported. Results: Of a total of 124 patients, 47 (38%) had poor-risk and 77 (62%) had other-risk disease by cytogenetics. Weekly survey compliance was comparable (68% vs 69%), and median age was 66 (range 35-88) and 69 (range 21-88), respectively. About 50% of all patients were male, 76% were White, and 69% had ≥1 comorbidity. Patients with other-risk were younger with 40% fewer comorbidities (mean 0.95, median 0, range 0-5) than patients with poor cytogenetic risk (mean 1.36, median 1, range 0-5). Overall symptoms were reported 12% more frequently among patients with other risk (1.49 symptoms per patient-week) compared to patients with poor risk (1.33 symptoms per patient-week). Fatigue was reported by 20% of patients across all patient-weeks for both risk groups; shortness of breath was reported 6% and 10% across all patient-weeks for poor and other risk groups, respectively. Although baseline treatment bother was 17% higher for poor risk patients, over time, QoL and treatment bother were comparable between both groups, and physical function was directionally higher. Conclusions: This study illustrates the feasibility of using remote symptom monitoring for evaluating patients with poor vs. other cytogenetic risk in routine care, with relatively high survey compliance in a real-world setting. Despite poor prognostic status, the experience of poor cytogenetic risk patients was comparable to other cytogenetic risk patients and reported directionally lower levels of symptom burden and higher levels of function over time.

59 Neuropsychiatric Clustering of Veterans with TBI: The Link Between Neuropsychological Test Validity and Somatic Post-Concussive Symptoms

Objective:There is a wide variability in the neuropsychiatric presentation of mild traumatic brain injury (mTBI), and accurate diagnosis and treatment is complicated by within-condition heterogeneity and overlapping symptoms of common comorbidities (e.g., PTSD). Such diagnostic complexities can obfuscate clinical decision-making and lead to suboptimal treatment response. In contrast to traditional diagnostic categories, person-centered analysis methods create data-derived groupings wherein individuals within a cluster are similar and individuals across clusters are different. The current study sought to apply clustering to dimensional emotional and neuropsychological features in treatment-seeking Veterans with mTBI, with the goal of identifying more precise, homogeneous clinical profiles.Participants and Methods:Study participants were 190 Veterans with mTBI history participating in a clinical neuropsychological assessment of cognitive complaints (Mean age: 34.38, 89.6% male, average years of education: 13.14). Participants completed a diagnostic interview, neuropsychological tests, and symptom questionnaires (NBSI, PCL, BDI, BAI, AUDIT, PSQI). To identify clusters of similar neuropsychiatric presentations, we first conducted dimension reduction on data from the cognitive tests and self-report measures using principal components analysis. Second, cluster analysis and cluster validation was performed on the resultant principal components (R: kmeans, clusterboot, clusterValid) to find homogeneous subgroups of participants.Results:The clinical data was best represented by principal components reflecting anxious arousal, depressive cognitions, somatic post-concussive symptoms, reexperiencing and avoidance symptoms, and objective cognitive deficits. Cluster analysis using bootstrapping and cluster validity indices (e.g., Silhouette width, Dunn index) indicated that a 6-subgroup solution was optimal (subgroups were labeled Group A-Group F). Group A was characterized by moderate levels across all dimension scores. Group B was characterized by elevated somatic post-concussive symptoms and cognitive deficits. Group C was characterized by intact cognitive performance and low somatic post concussive symptoms. Group D was characterized by elevated depressive cognitions. Group E was characterized by high anxious arousal but low depressive cognitions and reexperiencing and avoidance. Group F was characterized by elevated reexperiencing and avoidance. The subgroups did not differ statistically on any demographic items, such as years of education, age, or gender. However, there were statistically significant differences across groups in performance validity failure (x2(10) = 27.17, p=.002); Group B showed the highest rate of failure.Conclusions:Results demonstrate that phenotypically similar subgroups of individuals can be identified within treatment-seeking Veterans with mTBI. Data suggest that somatic post-concussive symptoms may be linked to cognitive deficits, however the rate of validity failure indicates that neuropsychological test scores may not reflect true cognitive ability. In contrast to prior studies that treat mTBI as a unitary construct that accounts for symptoms, our data suggest that a nuanced evaluation yields vastly diverse clinical presentations. Cluster analytic frameworks hold promise for better assessment and treatment planning for Veterans, as both patients and their treating clinicians would be greatly served by the ability to use common clinical assessment tools to better identify a given individual’s clinical needs. A critical next step is to validate subgroups using novel samples and data sources (e.g., neurobiology, genetics) and to determine if these subgroupings can be effectively utilized to personalize treatment assignment.

Predictive factors for treatment response and mortality in chronic pulmonary aspergillosis.

Chronic pulmonary aspergillosis (CPA) is associated with significant mortality, and suboptimal antifungal treatment response. We describe predictive factors for treatment response and survival. We retrospectively analysed clinical, serological and radiological parameters at baseline and following antifungal treatment in patients with CPA and correlated with clinical and radiological response and survival. Fifty-nine patients were included with a mean age of 61 years. Thirty (51%) had a diagnosis of COPD. On clinical assessment at 6 months, 21 (36%) had clinically improved, 20 (34%) were clinically stable and 15 (25%) had deteriorated. Radiological improvement was observed in 30 (53%), stability in 11 (19%) and deterioration in 16 (28%). Only a lower C-reactive protein (CRP) at baseline was associated with a favourable clinical-radiological response. On univariate analysis, lower CRP, higher albumin, lower Aspergillus IgG and use of inhaled steroids were associated with lower mortality. An overall favourable response at 6 months was associated with lower mortality. Inflammatory markers and Aspergillus IgG were predictors of mortality in CPA. This suggests that mortality in CPA is driven mainly by the chronic fungal infection itself rather than the underlying disease, therefore early optimised treatment of CPA may lead to improved outcomes.

Factors Affecting Intensive Aflibercept Treatment Response in Diabetic Macular Edema: A Real-World Study.

To investigate the systemic and ocular factors that affect the response to intensive aflibercept treatment in diabetic macular edema (DME) in a real-world setting. This retrospective cohort study evaluated 30 eyes of 23 patients with DME who underwent intensive intravitreal aflibercept injections (five monthly loading doses). Treatment response was assessed by central retinal thickness (CRT) and best-corrected visual acuity (BCVA) at each monthly visit. The patients were categorized as good (<300 μm) and suboptimal (≥300 μm) responders based on CRT after the loading phase. Baseline systemic and ocular factors associated with treatment response were investigated. The mean CRT and BCVA significantly improved after five loading injections (486.87 ± 95.46 to 334.90 ± 69.47 μm and 0.51 ± 0.30 to 0.35 ± 0.25 LogMAR, respectively, all p < 0.05). During 12 months of follow-up, 16 eyes (53.33%) maintained CRT without additional treatment. Eyes with diabetes mellitus (DM) for ≥15 years, estimated glomerular filtration rate (eGFR) < 80 mL/min/1.73 m2, serum creatinine ≥ 0.95 mg/dL and potassium ≥ 4.7 mmol/L, and presence of epiretinal membrane (ERM) were more likely to have a suboptimal response to the treatment. Five monthly loading doses of intravitreal aflibercept injection provided significant anatomical and visual improvements in patients with DME. Patients with longer DM duration, lower eGFR, higher serum creatinine or potassium levels, or ERM were predisposed to a suboptimal treatment response. Individual response to intensive aflibercept treatment for DME can be predicted by these systemic and ocular risk factors.

Regional gray matter volume correlates with anxiety, apathy, and resilience in geriatric depression.

Geriatric depression (GD) is associated with significant medical comorbidity, cognitive impairment, brain atrophy, premature mortality, and suboptimal treatment response. While apathy and anxiety are common comorbidities, resilience is a protective factor. Understanding the relationships between brain morphometry, depression, and resilience in GD could inform clinical treatment. Only few studies have addressed gray matter volume (GMV) associations with mood and resilience. Forty-nine adults aged >60 years (38 women) with major depressive disorder undergoing concurrent antidepressant treatment participated in the study. Anatomical T1-weighted scans, apathy, anxiety, and resilience data were collected. Freesurfer 6.0 was used to preprocess T1-weighted images and qdec to perform voxel-wise whole-brain analyses. Partial Spearman correlations controlling for age and sex tested the associations between clinical scores, and general linear models identified clusters of associations between GMV and clinical scores, with age and sex as covariates. Cluster correction and Monte-Carlo simulations were applied (corrected alpha = 0.05). Greater depression severity was associated with greater anxiety (r = 0.53, p = 0.0001), lower resilience (r = -0.33, p = 0.03), and greater apathy (r = 0.39, p = 0.01). Greater GMV in widespread, partially overlapping clusters across the brain was associated with reduced anxiety and apathy, as well as increased resilience. Our results suggest that greater GMV in extended brain regions is a potential marker for resilience in GD, while GMV in more focal and overlapping regions may be markers for depression and anxiety. Interventions focused on improving symptoms in GD may seek to examine their effects on these brain regions.

In vivo tumor immune microenvironment phenotypes correlate with inflammation and vasculature to predict immunotherapy response

Response to immunotherapies can be variable and unpredictable. Pathology-based phenotyping of tumors into ‘hot’ and ‘cold’ is static, relying solely on T-cell infiltration in single-time single-site biopsies, resulting in suboptimal treatment response prediction. Dynamic vascular events (tumor angiogenesis, leukocyte trafficking) within tumor immune microenvironment (TiME) also influence anti-tumor immunity and treatment response. Here, we report dynamic cellular-level TiME phenotyping in vivo that combines inflammation profiles with vascular features through non-invasive reflectance confocal microscopic imaging. In skin cancer patients, we demonstrate three main TiME phenotypes that correlate with gene and protein expression, and response to toll-like receptor agonist immune-therapy. Notably, phenotypes with high inflammation associate with immunostimulatory signatures and those with high vasculature with angiogenic and endothelial anergy signatures. Moreover, phenotypes with high inflammation and low vasculature demonstrate the best treatment response. This non-invasive in vivo phenotyping approach integrating dynamic vasculature with inflammation serves as a reliable predictor of response to topical immune-therapy in patients.

Residual Disease Associated with Suboptimal Treatment Response in Patients with Psoriatic Arthritis: A Systematic Review of Real-World Evidence.

ObjectiveThis systematic literature review aimed to identify and summarise real-world observational studies reporting the type, prevalence and/or severity of residual symptoms and disease in adults with psoriatic arthritis (PsA) who have received treatment and been assessed against remission or low disease activity targets.MethodsPatients had received treatment and been assessed with treat-to-target metrics, including minimal disease activity (MDA), Disease Activity Index in PsA (DAPSA) and others. MEDLINE, Embase® and the Cochrane Database of Systematic Reviews (CDSR) were searched using search terms for PsA, treatment targets and observational studies. Screening of search results was completed by two independent reviewers; studies were included if they reported relevant residual disease outcomes in adults with PsA who had received one or more pharmacological treatments for PsA in a real-world setting. Non-observational studies were excluded. Information from included studies was extracted into a prespecified grid by a single reviewer and checked by a second reviewer.ResultsDatabase searching yielded 2328 articles, of which 42 publications (27 unique studies) were included in this systematic literature review. Twenty-three studies reported outcomes for MDA-assessed patients, and 14 studies reported outcomes for DAPSA-assessed patients. Physician- and patient-reported residual disease was less frequent and/or severe in patients reaching targets, but often not absent, including when patients achieved very low disease activity (VLDA) or remission. For example, studies reported that 0–8% patients in remission according to DAPSA (or clinical DAPSA) had > 1 tender joint, 25–39% had Psoriasis Area and Severity Index (PASI) score > 1 and 0–10% had patient-reported pain > 15. Residual disease was usually less frequent and/or severe among patients achieving MDA-assessed targets versus DAPSA-­assessed targets, especially for skin outcomes.ConclusionThe findings demonstrate a need for further optimisation of care for patients with PsA.

Efficacy and safety of cariprazine augmentation in patients treated with clozapine: a pilot study.

Cariprazine, a novel antipsychotic drug, is a partial agonist of dopamine D2/D3 receptors with preferential binding to the D3 receptor. There has been an increasing interest in cariprazine augmentation to clozapine; however, the evidence thus far has been only limited to case reports and case series. To evaluate the efficacy and safety of the augmentation of clozapine with cariprazine in patients with sub-optimal treatment response. Demographic and clinical information of the study population were collected from the electronic records and PANSS scale administered at baseline and 3 months. Tolerability and discontinuation reasons where applicable were also recorded. Ten patients (four men and six women) with a mean age of 36.5 years (range = 26-45) were included. Reasons for cariprazine initiation included inadequate treatment response, persistent negative symptoms and/or tolerability issues with clozapine or previous augmentation options. Two patients discontinued cariprazine within the first 6 weeks due to restlessness and poor response, respectively. There was a significant reduction in the median total PANSS score from baseline to 3 months (from 59 to 22.5, p < 0.05), median positive PANSS score (from 11.5 to 5.5, p < 0.05) and in the median negative PANSS score (from 15.5 to 3, p < 0.05) which correspond to a 48%, 33.8% and 65.8% mean score reduction, respectively. This is the first pilot study evaluating the effectiveness of clozapine augmentation. The preliminary evidence suggests that this may be a safe and effective practice in patients failing to adequately respond to or tolerate clozapine and/or previous augmentation strategies.

Siglec-1 expression on monocytes is associated with the interferon signature in juvenile dermatomyositis and can predict treatment response.

ObjectiveJDM is a rare chronic immune-mediated inflammatory disease with a predominant role for type I IFN responses. We aimed to determine the potential of Siglec-1 expression on monocytes as a novel IFN-inducible biomarker for disease activity monitoring and prediction of treatment response in patients with JDM.MethodsSiglec-1 was measured by flow cytometry on circulating monocytes of 21 newly diagnosed JDM patients before start of treatment and, for 10 of these, also during follow-up. The expression levels of five type I IFN-stimulated genes, MX1, IFI44, IFI44L, LY6E and IFIT3, were measured by RT-qPCR to determine the IFN signature and calculate an IFN score. IFN-inducible plasma proteins CXCL10 and galectin-9 were measured by multiplex immunoassay.ResultsSiglec-1 and IFN score were increased in JDM patients compared with controls and correlated with clinical disease activity. Stratification of patients by Siglec-1 expression at diagnosis identified those with high Siglec-1 expression as having a higher risk of requiring treatment intensification within the first 3 months after diagnosis (55% vs 0% of patients, P = 0.01). Siglec-1 expression strongly correlated with plasma levels of previously validated biomarkers CXCL10 (rs = 0.81, P < 0.0001) and galectin-9 (rs = 0.83, P < 0.0001), and was superior to the IFN score in predicting treatment response (area under the curve 0.87 vs 0.53, P = 0.01).ConclusionSiglec-1 on monocytes is a novel IFN-inducible biomarker in JDM that correlates with clinical disease activity and identifies patients at risk for a suboptimal treatment response. Further studies are required to validate these findings and their clinical potential.

A Real-World, Prospective, Multicenter, Single-Arm Observational Study of Duloxetine in Patients With Major Depressive Disorder or Generalized Anxiety Disorder.

Background: Suboptimal treatment response during anti-depressive treatment is fairly common with the first antidepressant (AD) choice, followed by switching to another agent in the majority of cases. However, the efficacy of this strategy over continuation of the original agent is less solidly documented in real-life studies. The aim of our present study was to ascertain the effects of switching to duloxetine following inadequate response to prior ADs on general illness severity, pain, and health-related quality of life in a large sample of major depressive disorder (MDD) and generalized anxiety disorder (GAD) patients in a prospective, real-world, multicenter, observational study.Methods: A total of 578 participants with MDD or GAD were enrolled in 58 outpatient sites in an 8-week, single-arm, open-label, flexible-dose trial with duloxetine. Severity of symptoms [with Clinical Global Impression-Severity (CGI-S) and Clinical Global Impression-Improvement (CGI-I)], severity of pain (with a Visual Analog Scale), satisfaction with current treatment, and health-related quality of life [with the three-level version of the EuroQol five-dimensional questionnaire (EQ-5D-3L)] measures were recorded at baseline and at follow-up visits 4 and 8 weeks after initiation of treatment. Data were analyzed using ANOVA and mixed linear models.Results: 565 patients completed the study and comprised the analyzed dataset. Results indicated that severity of illness significantly decreased over the 8 weeks of the study and already at 4 weeks in both patient groups. Overall quality of life and all of its subindicators also significantly improved in both patient groups and so did subjective experience of pain. Satisfaction with current treatment also significantly increased during the study period. Frequency of side effects was low. In both GAD and MDD groups, two patients dropped out of the study due to adverse effects, leading to treatment termination in four cases (0.7%).Conclusions: This 8-week, multicenter, flexible-dosing, single-arm, open-label, observational real-life study in MDD and GAD patients switched to duloxetine after inadequate response or low tolerability to other ADs showed a significant positive effect on all outcome measures, including a significant decrease in illness severity as well as significant overall symptomatic improvement, with good tolerability.

Stereotypy and spontaneous alternation in deer mice and its response to anti-adenosinergic intervention.

Repetitive behavioral phenotypes are a trait of several neuropsychiatric disorders, including obsessive-compulsive disorder (OCD). Such behaviors are typified by complex interactions between cognitive and neurobiological processes which most likely contribute to the suboptimal treatment responses often observed. To this end, exploration of the adenosinergic system may be useful, since adenosine-receptor modulation has previously shown promise to restore control over voluntary behavior and improve cognition in patients presenting with motor repetition. Here, we employed the deer mouse (Peromyscus maniculatus bairdii) model of compulsive-like behavioral persistence, seeking to investigate possible associations between stereotypic motor behavior and cognitive flexibility as measured in the T-maze continuous alternation task (T-CAT). The effect of istradefylline, a selective adenosine A2A receptor antagonist at two doses (10 and 20mgkg-1 day-1 ) on the expression of stereotypy and T-CAT performance in high (H) and non-(N) stereotypical animals, was investigated in comparison to a control intervention (six groups; n=8 or 9 per group). No correlation between H behavior and T-CAT performance was found. However, H but not N animals presented with istradefylline-sensitive spontaneous alternation and stereotypy, in that istradefylline at both doses significantly improved the spontaneous alternation scores and attenuated the stereotypical expression of H animals. Thus, evidence is presented that anti-adenosinergic drug action improves repetitive behavior and spontaneous alternation in stereotypical deer mice, putatively pointing to a shared psychobiological construct underlying naturalistic stereotypy and alterations in cognitive flexibility in deer mice.