Markers Of Treatment Response Research Articles

Blood-Brain Barrier Disruption and Perivascular Spaces in Small Vessel Disease and Neurodegenerative Diseases: A Review on MRI Methods and Insights.

Perivascular spaces (PVS) and blood-brain barrier (BBB) disruption are two key features of cerebral small vessel disease (cSVD) and neurodegenerative diseases that have been linked to cognitive impairment and are involved in the cerebral waste clearance system. Magnetic resonance imaging (MRI) offers the possibility to study these pathophysiological processes noninvasively in vivo. This educational review provides an overview of the MRI techniques used to assess PVS functionality and BBB disruption. MRI-visible PVS can be scored on structural images by either (subjectively) counting or (automatically) delineating the PVS. We highlight emerging (diffusion) techniques to measure proxies of perivascular fluid and its movement, which may provide a more comprehensive understanding of the role of PVS in diseases. For the measurement of BBB disruption, we explain the most commonly used MRI technique, dynamic contrast-enhanced (DCE) MRI, as well as a more recently developed technique based on arterial spin labeling (ASL). DCE MRI and ASL are thought to measure complementary characteristics of the BBB. Furthermore, we describe clinical studies that have utilized these MRI techniques in cSVD and neurodegenerative diseases, particularly Alzheimer's disease (AD). These studies demonstrate the role of PVS and BBB dysfunction in these diseases and provide insight into the large overlap, but also into the differences between cSVD and AD. Overall, MRI techniques may provide valuable insights into the pathophysiological mechanisms underlying these diseases and have the potential to be used as markers for disease progression and treatment response. LEVEL OF EVIDENCE: 3 TECHNICAL EFFICACY: Stage 2.

Eosinophilic esophagitis—from definition to therapy

SummaryEosinophilic esophagitis (EoE) is a chronic immune-mediated disorder that is characterized clinically by symptoms of esophageal dysfunction and histologically by a dense eosinophilic inflammation of the esophagus. This article provides an overview of the current knowledge in the field of EoE. EoE has seen significant progress in its understanding, including its definition, clinical presentation, diagnosis, and treatment. Consensus criteria have been established for diagnosing EoE, with symptoms commonly including dysphagia, food impaction, and reflux-like symptoms. Diagnosis involves clinical evaluation, endoscopy, and histological assessment. Therapeutic strategies for EoE aim to alleviate symptoms, induce and maintain remission, and prevent complications. These strategies include dietary modifications, pharmacotherapy, and endoscopic interventions. Treatment choice depends on disease severity, patient preferences, and comorbidities. Despite progress, challenges persist in EoE management. Long-term outcomes and optimal treatment duration are still under investigation. Research efforts focus on identifying predictive markers for treatment response and developing personalized approaches. In conclusion, EoE is a chronic, progressive and recurrent disease with various clinical manifestations and treatment options. Improved understanding has led to better diagnostic criteria and therapeutic strategies. However, further research is necessary to enhance our understanding of disease pathogenesis, refine treatment algorithms, and optimize long-term outcomes for individuals with EoE.

Point-of-Care Intestinal Ultrasound in Pediatric Inflammatory Bowel Disease.

Intestinal ultrasound (IUS) is an emerging non-invasive point-of-care tool utilized by pediatric gastroenterologists for accurately detecting and monitoring inflammatory bowel disease (IBD) activity. In this article, we reviewed the evidence supporting and technique to perform IUS for children with IBD. IUS technique can visualize the colon from the distal sigmoid until the cecum and the terminal ileum without the need for bowel preparation, fasting, or sedation in children with IBD. IUS has been shown to be accurate to endoscopy in children with ulcerative colitis and Crohn's disease. IUS may be the most accurate biomarker to follow as a marker of treatment response that is predictive of endoscopic outcomes in children with IBD. Multiple studies have demonstrated that IUS can be performed at the point-of-care for IBD activity assessment in children. Recent studies have demonstrated the accuracy of IUS to endoscopy and magnetic resonance enterography with an ability to be repeated as a monitor of treatment response for tight control monitoring.

Study of Effect of NB-UVB on Serum and Tissue Levels of CXCL9 in Vitiligenous Patients

Abstract Background CXCL 9 is a chemokine of Th1 which plays a significant role in the development of vitiligo. NB-UVB is an effective modality for treatment of vitiligo. Objective To finding whether NB-UVB can affect serum and tissue CXCL9 level or not. Patients and Methods The present study included 20 patients suffering from non-segmental vitiligo and 20 age- and sex- matched healthy controls, their age ranged from 18 to 65 years old, they were recruited from the outpatient clinic of Dermatology and Andrology Department in Ain Shams University Hospital during the period from May 2019 till December 2019. Results We evaluated disease severity by assessment of body surface area (BSA) of vitiligo disease in patients with calculation of VES score before NB-UVB and to evaluate patient improvement after treatment with NB-UVB we recalculated VES score after NB-UVB and calculated VES plus score. There was significant decrease in the surface area of the disease after treatment with NB-UVB than before. Conclusion The present study provides clinical data to support the role of CXCL9 in vitiligo particularly during the activity of the disease. Also our findings draw our attention to CXCL9 not only as a marker of disease activity, but also potentially as a marker of treatment response. So, targeting the IFN-γ-chemokine axis might be an effective treatment strategy.

Promising Marker for Treatment Response in Prostate Cancer

Promising Marker for Treatment Response in Prostate Cancer

Changes in cerebral connectivity and brain tissue pulsations with the antidepressant response to an equimolar mixture of oxygen and nitrous oxide: an MRI and ultrasound study.

Nitrous oxide (N2O) has recently emerged as a potential fast-acting antidepressant but the cerebral mechanisms involved in this effect remain speculative. We hypothesized that the antidepressant response to an Equimolar Mixture of Oxygen and Nitrous Oxide (EMONO) would be associated with changes in cerebral connectivity and brain tissue pulsations (BTP). Thirty participants (20 with a major depressive episode resistant to at least one antidepressant and 10 healthy controls-HC, aged 25-50, only females) were exposed to a 1-h single session of EMONO and followed for 1 week. We defined response as a reduction of at least 50% in the MADRS score 1 week after exposure. Cerebral connectivity of the Anterior Cingulate Cortex (ACC), using ROI-based resting state fMRI, and BTP, using ultrasound Tissue Pulsatility Imaging, were compared before and rapidly after exposure (as well as during exposure for BTP) among HC, non-responders and responders. We conducted analyses to compare group × time, group, and time effects. Nine (45%) depressed participants were considered responders and eleven (55%) non-responders. In responders, we observed a significant reduction in the connectivity of the subgenual ACC with the precuneus. Connectivity of the supracallosal ACC with the mid-cingulate also significantly decreased after exposure in HC and in non-responders. BTP significantly increased in the three groups between baseline and gas exposure, but the increase in BTP within the first 10 min was only significant in responders. We found that a single session of EMONO can rapidly modify the functional connectivity in the subgenual ACC-precuneus, nodes within the default mode network, in depressed participants responders to EMONO. In addition, larger increases in BTP, associated with a significant rise in cerebral blood flow, appear to promote the antidepressant response, possibly by facilitating optimal drug delivery to the brain. Our study identified potential cerebral mechanisms related to the antidepressant response of N2O, as well as potential markers for treatment response with this fast-acting antidepressant.

Approach-avoidance biases to self-harm cues in young people with self-harm

BackgroundThe urge to self-harm can be likened to craving in addictive behaviours. However, it remains unclear whether cognitive mechanisms involved in craving, such as attentional biases to cues, also underpin the urge to self-harm. MethodsA Dot Probe Task was used to investigate attentional biases to self-harm cues in young people aged 16–25 with self-harm. Cues were shown for either 0.2 s or 2 s. Dot Probe Task performance in the Self-harm group (N = 50) was compared with age-matched Healthy Controls (N = 50) and age- and negative-affect (Depression Anxiety Stress Scale-21) matched controls with no self-harm (N = 50). ResultsThe Self-harm group showed significantly greater avoidance of self-harm cues than Healthy Controls at 2 s. The Negative Affect group showed significantly less difficulty disengaging from self-harm cues than the Self-harm group and Healthy Controls at 2 s. There were no between-group differences in attentional bias at 0.2 s. LimitationsStudy limitations that may affect attentional biases in the Self-harm group include not measuring indicators of recovery and recruiting only from the community potentially missing more severe self-harm presentations in clinical settings. ConclusionsAvoidance of self-harm cues in young people with self-harm may reflect conflict around self-harm behaviour, consistent with ambivalence models of craving. An ability to disengage from self-harm cues may be a protective factor in young people with higher levels of negative affect who do not self-harm. Whether these attentional biases represent a quantifiable marker of treatment response or susceptibility to relapse in individuals with self-harm remains an area for future investigation.

Multi-omics profiling of CSF from spinal muscular atrophy type 3 patients after nusinersen treatment: a 2-year follow-up multicenter retrospective study

Spinal muscular atrophy (SMA) is a neurodegenerative disorder caused by mutations in the SMN1 gene resulting in reduced levels of the SMN protein. Nusinersen, the first antisense oligonucleotide (ASO) approved for SMA treatment, binds to the SMN2 gene, paralogue to SMN1, and mediates the translation of a functional SMN protein. Here, we used longitudinal high-resolution mass spectrometry (MS) to assess both global proteome and metabolome in cerebrospinal fluid (CSF) from ten SMA type 3 patients, with the aim of identifying novel readouts of pharmacodynamic/response to treatment and predictive markers of treatment response. Patients had a median age of 33.5 [29.5; 38.25] years, and 80% of them were ambulant at time of the enrolment, with a median HFMSE score of 37.5 [25.75; 50.75]. Untargeted CSF proteome and metabolome were measured using high-resolution MS (nLC-HRMS) on CSF samples obtained before treatment (T0) and after 2 years of follow-up (T22). A total of 26 proteins were found to be differentially expressed between T0 and T22 upon VSN normalization and LIMMA differential analysis, accounting for paired replica. Notably, key markers of the insulin-growth factor signaling pathway were upregulated after treatment together with selective modulation of key transcription regulators. Using CombiROC multimarker signature analysis, we suggest that detecting a reduction of SEMA6A and an increase of COL1A2 and GRIA4 might reflect therapeutic efficacy of nusinersen. Longitudinal metabolome profiling, analyzed with paired t-Test, showed a significant shift for some aminoacid utilization induced by treatment, whereas other metabolites were largely unchanged. Together, these data suggest perturbation upon nusinersen treatment still sustained after 22 months of follow-up and confirm the utility of CSF multi-omic profiling as pharmacodynamic biomarker for SMA type 3. Nonetheless, validation studies are needed to confirm this evidence in a larger sample size and to further dissect combined markers of response to treatment.

Using Normalized Carcinoembryonic Antigen and Carbohydrate Antigen 19 to Predict and Monitor the Efficacy of Neoadjuvant Chemotherapy in Locally Advanced Gastric Cancer.

We conducted a retrospective analysis to determine values of CEA and CA19-9 prior to NACT (pre-NACT) and after NACT (post-NACT) in 399 patients with locally advanced gastric cancer (LAGC) who received intended NACT and surgery. Among the 399 patients who underwent NACT plus surgery, 132 patients (33.1%) had elevated pre-NACT CEA/CA19-9 values. Furthermore, either pre-NACT or post-NACT CEA /CA19-9 levels were significantly associated with prognosis (p = 0.0023) compared to patients with non-elevated levels. Moreover, among the patients, a significant proportion (73/132, 55.3%) achieved normalized CEA/CA19-9 following NACT, which is a strong marker of a favorable treatment response and survival benefits. In addition, the patients with normalized CEA/CA19-9 also had a prolonged survival compared to those who underwent surgery first (p = 0.0140), which may be attributed to the clearance of micro-metastatic foci. Additionally, the magnitude of CEA/CA19-9 changes did not exhibit a statistically significant prognostic value. Normalization of CEA/CA19-9 is a strong biomarker for the effectiveness of treatment, and can thus be exploited to prolong the long-term survival of patients with LAGC.

Clinical Significance of Evaluation of Monocytic Receptors in Patients with Hepatitis C Virus Infection.

Monocytes in hepatitis C virus (HCV) infection play a critical role in chronic liver inflammation and fibrosis. We studied circulating monocytes and monocyte receptors in patients with HCV infection who were naive to treatment and those who received direct acting antiviral therapy and achieved sustained virological response. CD64+ CCR2+ (M1-like) and CD206+ CD163+ CX3CR1+ (M2-like) monocyte numbers and receptor expression were evaluated by flow cytometry. Higher expression of the monocyte chemokine receptor CCR2 predicted the severity of liver fibrosis, independent of successful treatment and viral clearance (R2 = 0.235, p = 0.002), whereas monocyte CX3CR1 expression was lower in both treated and untreated patients compared with controls (p = 0.011). The expression of the scavenger receptor CD163 was lower in patients with successful treatment (p = 0.005), supporting its role as a marker of treatment response. CD64+ CCR2+ (M1-like) and CD206+ CD163+ CX3CR1+ (M2-like) monocyte numbers were not altered with fibrosis progression or treatment response. Our findings reflect the diverse functions of monocytes in liver inflammation, fibrosis, and therapy. However, HCV clearance did not lead to complete monocyte reconstitution. Targeting monocytes and their chemokine receptors bears therapeutic potential to reduce liver fibrosis and improve disease outcome.

Chemo Markers as Biomarkers in Septic Shock: A Comprehensive Review of Their Utility and Clinical Applications.

Sepsis is a life-threatening condition characterized by a dysregulated host response to infection, often leading to septic shock. Early diagnosis and prompt intervention are crucial for improving patient outcomes. Chemo markers, which are measurable biological substances associated with the pathophysiology of septic shock, have emerged as potential biomarkers for the identification, risk stratification, and management of this condition. This comprehensive review aims to thoroughly evaluate the utility and clinical applications of chemo markers in septic shock. The review begins by discussing the criteria for ideal chemo markers, including specificity, sensitivity, dynamic range, stability, non-invasiveness, and prognostic value. These characteristics ensure accurate diagnosis, early detection, effective monitoring, and prediction of clinical outcomes. Furthermore, the review explores the role of chemo markers in monitoring treatment response and disease progression, highlighting their ability to serve as objective indicators for assessing the effectiveness of interventions and making timely adjustments in management strategies. Moreover, the prognostic value of chemo markers in predicting outcomes is discussed, emphasizing their association with mortality, hospital stays, and the development of complications. Integration of chemo markers into prognostic models or scoring systems enhances risk stratification and informs therapeutic decisions. The review also delves into recent advances in chemo marker research and technology, emphasizing the potential for discovering novel chemo markers with enhanced diagnostic and prognostic capabilities. It highlights the use of high-throughput proteomics, genomics, and transcriptomics in identifying specific molecular signatures associated with septic shock. This contributes to a deeper understanding of the complex immune and inflammatory responses involved. In conclusion, chemo markers have emerged as valuable biomarkers in septic shock, offering potential utility in diagnosis, risk stratification, treatment monitoring, and prediction of outcomes. Continued research, validation, and integration into clinical practice are necessary to fully realize their potential in improving patient care and outcomes in septic shock.

Diffusion-Weighted MRI for Treatment Response Assessment in Osteoblastic Metastases-A Repeatability Study.

The apparent diffusion coefficient (ADC) is a candidate marker of treatment response in osteoblastic metastases that are not evaluable by morphologic imaging. However, it is unclear whether the ADC meets the basic requirement for reliable treatment response evaluation, namely a low variance of repeated measurements in relation to the differences found between viable and nonviable metastases. The present study addresses this question by analyzing repeated in vivo ADCmedian measurements of 65 osteoblastic metastases in nine patients, as well as phantom measurements. PSMA-PET served as a surrogate for bone metastasis viability. Measures quantifying repeatability were calculated and differences in mean ADC values according to PSMA-PET status were examined. The relative repeatability coefficient %RC of ADCmedian measurements was 5.8% and 12.9% for phantom and in vivo measurements, respectively. ADCmedian values of bone metastases ranged from 595×10-6mm2/s to 2090×10-6mm2/s with an average of 63% higher values in nonviable metastases compared with viable metastases (p < 0.001). ADC shows a small repeatability coefficient in relation to the difference in ADC values between viable and nonviable metastases. Therefore, ADC measurements fulfill the technical prerequisite for reliable treatment response evaluation in osteoblastic metastases.

Anti-PLA2R Antibody Levels and Clinical Risk Factors for Treatment Nonresponse in Membranous Nephropathy.

The 2021 Kidney Disease Improving Global Outcomes (KDIGO) guidelines recommend following anti-phospholipase A2 receptor (PLA2R) antibody levels as a marker of treatment response in membranous nephropathy; however, the optimal timing to evaluate antibody levels and how to combine them with other clinical variables are currently unknown. We used a cohort of 85 patients from the Membranous Nephropathy Trial Of Rituximab (MENTOR) with anti-PLA2R antibodies ≥14 RU/ml to identify risk factors for not experiencing proteinuria remission after 12 months of treatment with cyclosporine or rituximab. Three landmark times were considered: at baseline and after 3 and 6 months of treatment. Logistic regression model performance was evaluated using C-statistics and model fit (Akaike information criterion [AIC], R 2 ). The model at baseline that best predicted no remission included anti-PLA2R antibodies >323 RU/ml and creatinine clearance; the best model after 3 months included the change from baseline in both antibody and albumin levels; and the best model after 6 months included antibody levels >14 RU/ml, creatinine clearance, and the change from baseline in albumin. Compared with the model at baseline, the model at 3 months had better model fit (AIC 70.9 versus 96.4, R 2 51.8% versus 30.1%) and higher C-statistic (0.93 versus 0.83, P = 0.008). The model at 6 months had no difference in performance compared with the model at 3 months (AIC 68.6, R 2 53.0%, C-statistic 0.94, P = 0.67). In patients with membranous nephropathy treated with cyclosporine or rituximab in the MENTOR trial, we found that the optimal method to evaluate risk factors for the probability of treatment response was to use anti-PLA2R antibody levels combined with albumin levels after 3 months of treatment, which was significantly better than using antibody levels alone or risk factor evaluation at baseline, with no added benefit of waiting until 6 months of treatment. This article contains a podcast at https://dts.podtrac.com/redirect.mp3/www.asn-online.org/media/podcast/CJASN/2023_10_09_CJN0000000000000237.mp3.

Sex matters: acute functional connectivity changes as markers of remission in late-life depression differ by sex.

The efficacy of antidepressant treatment in late-life is modest, a problem magnified by an aging population and increased prevalence of depression. Understanding the neurobiological mechanisms of treatment response in late-life depression (LLD) is imperative. Despite established sex differences in depression and neural circuits, sex differences associated with fMRI markers of antidepressant treatment response are underexplored. In this analysis, we assess the role of sex on the relationship of acute functional connectivity changes with treatment response in LLD. Resting state fMRI scans were collected at baseline and day one of SSRI/SNRI treatment for 80 LLD participants. One-day changes in functional connectivity (differential connectivity) were related to remission status after 12 weeks. Sex differences in differential connectivity profiles that distinguished remitters from non-remitters were assessed. A random forest classifier was used to predict the remission status with models containing various combinations of demographic, clinical, symptomatological, and connectivity measures. Model performance was assessed with area under the curve, and variable importance was assessed with permutation importance. The differential connectivity profile associated with remission status differed significantly by sex. We observed evidence for a difference in one-day connectivity changes between remitters and non-remitters in males but not females. Additionally, prediction of remission was significantly improved in male-only and female-only models over pooled models. Predictions of treatment outcome based on early changes in functional connectivity show marked differences between sexes and should be considered in future MR-based treatment decision-making algorithms.

Evaluation of genetic risk, its clinical manifestation and disease management based on 18 susceptibility gene markers among West-Slavonic patients with sarcoidosis

Sarcoidosis is a heterogenous, multisystemic inflammatory disease that primarily affects lungs. In this study, we multiplex genotyped 18 single-nucleotide polymorphisms (SNPs) to replicate the findings from previous genome-wide association studies (GWAS) and candidate gene studies, and extended analyses to different clinical manifestations (Löfgren’s syndrome and chest X-ray [CXR] stages) including treatment response among West-Slavonic subjects (564 sarcoidosis patients and 301 healthy controls). We confirm the replication (with Bonferroni's correction) of ANXA11 rs1049550 as protective variant for sarcoidosis (odds ratio [OR] = 0.71, p = 1.33 × 10−3), non-LS (OR = 0.66, p = 2.71 × 10−4) and CXR stages 2–4 (OR = 0.62, p = 7.48 × 10−5) compared to controls in West-Slavonic population. We also validate the association of risk variants C6orf10 rs3129927 (OR = 2.61, p = 2.60 × 10−8), TNFA rs1800629 (OR = 1.56, p = 6.65 × 10−4), ATF6B rs3130288 (OR = 2.75, p = 1.06 × 10−9) and HLA-DQA1 rs2187668 (OR = 1.74, p = 8.83 × 10−4) with sarcoidosis compared to controls. For sub-phenotypes compared to controls, risk variants C6orf10 rs3129927 (OR = 5.35, p = 1.07 × 10−12), TNFA rs1800629 (OR = 2.66, p = 5.94 × 10−7), ATF6B rs3130288 (OR = 5.24, p = 5.21 × 10−13), LRRC16A rs9295661 (OR = 2.97, p = 4.29 × 10−4), HLA-DQA1 rs2187668 (OR = 3.14, p = 1.09 × 10−6) and HLA-DRA rs3135394 (OR = 5.23, p = 8.25 × 10−13) were associated with LS while C6orf10 rs3129927 (OR = 1.96, p = 4.27 × 10−4) and ATF6B rs3130288 (OR = 2.15, p = 3.36 × 10−5) were associated with non-LS. For CXR stages compared to controls, C6orf10 rs3129927 (OR = 3.67, p = 3.63 × 10−11), TNFA rs1800629 (OR = 1.84, p = 1.32 × 10−4), ATF6B rs3129927 (OR = 3.63, p = 1.82 × 10−11), HLA-DQA1 rs2187668 (OR = 2.13, p = 9.59 × 10−5) and HLA-DRA rs3135394 (OR = 3.42, p = 3.45 × 10−10) were risk variants for early CXR stages 0–1 while C6orf10 rs3129927 (OR = 1.99, p = 5.51 × 10−4), ATF6B rs3129927 (OR = 2.23, p = 3.52 × 10−5) and HLA-DRA rs3135394 (OR = 1.85, p = 2.00 × 10−3) were risk variants for advanced CXR stages 2–4. The present findings nominate gene variants as plausible prognostic markers for clinical phenotypes, treatment response and disease resolution/progression and may form the basis for establishing genotype–phenotype relationships in patients with sarcoidosis among West-Slavonic population.

Basement membrane proteins in extracellular matrix characterize NF1 neurofibroma development and response to MEK inhibitor.

Neurofibromatosis Type 1 (NF1) is one of the most common tumor-predisposing genetic disorders. Neurofibromas are NF1-associated benign tumors. A hallmark feature of neurofibromas is an abundant collagen-rich extracellular matrix (ECM) that constitutes >50% of the tumor dry weight. However, little is known about the mechanism underlying ECM deposition during neurofibroma development and treatment response. We performed a systematic investigation of ECM enrichment during plexiform neurofibroma (pNF) development, and identified basement membrane (BM) proteins, rather than major collagen isoforms, as the most upregulated ECM component. Following MEK inhibitor treatment, the ECM profile displayed an overall down-regulation signature, suggesting ECM reduction as a therapeutic benefit of MEK inhibition. Through these proteomic studies, TGF-β1 signaling was identified as playing a role in ECM dynamics. Indeed, TGF-β1 overexpression promoted pNF progression in vivo. Furthermore, by integrating single-cell RNA-sequencing, we found that immune cells including macrophages and T cells produce TGF-β1 to induce Schwann cells to produce and deposit BM proteins for ECM remodeling. Following Nf1 loss, neoplastic Schwann cells further increased BM protein deposition in response to TGF-β1. Our data delineate the regulation governing ECM dynamics in pNF and suggest that BM proteins could serve as markers for disease diagnosis and treatment response.

#3418 DISAPPEARANCE OF GLOMERULAR C3 DEPOSITION MIGHT BE A PROGNOSTIC MARKER IN MEMBRANOUS NEPHROPATHY AFTER TREATMENT

Abstract Background and Aims Membranous nephropathy (MN) is the most common cause of nephrotic syndrome (NS) in adults. In about 80% is primary and remaining 20% are secondary due to medications or other diseases. Treatment of primary MN remains controversial, and the prognosis is still difficult to predict despite the introduction of anti phospholipase A2 receptor (PLA2R) antibody. We evaluated pathological changes for predicting prognosis in patients of MN after methyprednisolone (MPD) pulse therapy. Method We performed 1,649 renal biopsies at the OPD during last 9 years, of which 31 subjects were MN. We performed follow up biopsy who showed normal urinary findings after treatment with MPD pulse therapy in 11 subjects of MN. Indications of the initial biopsy in MN were oral steroid resistant NS (9 subjects), massive proteinuria associated with hematuria (2 subjects). Among the 11 subjects of MN, 3 subjects were lupus nephritis (LN), 8 subjects were primary MN. One cycle of MPD consist of 10-20 mg/kg (max 1.0 g)/day for 3 consecutive days, performing every 10 to 14 days. Mean MPD pulse therapy were done 13 cycles Results Among the 11 cases of MN, male to female ratio was 6 to 5. Age distribution from 1 year old to 61years old (mean 40.8 y/o), Mean spot urine protein to creatinine before treatment was 4,182.5 mg/g and 189.4 mg/g after treatment. 9 subjects showed glomerular C3 deposition were noted at the initial biopsy and 2 subjects showed no C3 deposition. After treatment glomerular C3 deposition were disappeared in 8 subjects, and showed no relapse during 5.3 years follow up. However, 3 subjects who showed glomerular C3 deposition were lupus nephritis, relapsed during follow up period. Conclusion MPD pulse therapy might be still promising therapeutic modality in conventional oral steroid resistant MN. Although further larger number of studies are mandatory, disappearance of glomerular C3 deposition might be a prognostic marker for treatment response, instead of disappearance of proteinuria in MN.

Effect of an artificial intelligence–powered programmed death-ligand 1 combined positive score analyzer in urothelial cancer on inter-observer and inter-site variability.

e13546 Background: Programmed death-ligand 1 (PD-L1) is a predictive marker for immune checkpoint inhibitors treatment response in urothelial carcinoma (UC). The combined positive score (CPS) is a representative method to evaluate the expression level of PD-L1 in UC. However, inter-observer and inter-institute variations can disrupt accurate CPS evaluation. The purpose of this study is to assess the role of an artificial intelligence (AI)-powered PD-L1 CPS analyzer on UC in reducing inter-observer and inter-institute variability. Methods: Lunit SCOPE PD-L1 CPS was developed with 4.94 x 105 tumor cells and 4.17 x 105 immune cells from 360 PD-L1 stained whole-slide images (WSIs) of UC from multiple institutions. The algorithm consisted of tissue area segmentation and cell detection AI models. The AI models calculated the CPS by detecting tumor cells over the tumor area and immune cells over the tumor and adjacent area. Three uropathologists from different university hospitals evaluated the CPS classification (≥10 or &lt;10) of 543 PD-L1 stained WSIs of UC from each hospital. The result with concordant CPS classification of each slide across ≥ 2 pathologists was considered the consensus. Each pathologist revisited to evaluate WSIs by referencing the AI model inference, after a washout period, if there was a discrepancy between the pathologist and the AI model. Results: Of 543 WSIs, 446 (82.1%) were classified as the same CPS subgroup by all three uropathologists. Also, pathologists had a high degree of concordance with the consensus in WSIs from their own hospitals. They re-evaluated 64, 73, and 75 WSIs with AI assistance, respectively, and changed the CPS classification for 47, 48, and 48 WSIs. After re-evaluation with AI assistance, three uropathologists agreed on the same CPS classification in 510 WSIs (93.9%). The overall percentage agreement (OPA) of each pathologist with the consensus increased from 95.0%, 94.8%, and 92.3% to 98.7%, 98.3%, and 96.9% after AI assistance, and the OPA for WSIs of other institutions increased more compared to the OPA for WSIs of their own hospital. Conclusions: This study shows that an AI-powered PD-L1 CPS analyzer in UC can reduce inter-observer and inter-site variability. This result suggests that the AI model will help evaluate CPS in UC more accurately and reduce variation in situations where pathologists analyze WSIs from unfamiliar institutions.[Table: see text]

Application of the albumin-bilirubin (ALBI) grade as predictive marker of atezolizumab plus bevacizumab (A+B) treatment outcomes for patients with advanced hepatocellular carcinoma (HCC): Real-world retrospective analysis at Veterans Health Administration (VHA).

4107 Background: Most clinical trials use Child-Pugh (CP) for patient selection; this subjective scale was originally developed to assess liver function in cirrhosis, thus cannot be applied to HCC patients with non-cirrhotic background. Alternatively, ALBI grade is an objective and validated prognostic system that has demonstrated improved accuracy to predict survival and liver function decline in HCC patients. Our real-world study aims to assess the ALBI grade as a predictive marker of treatment response in patients with advanced HCC who received (A+B) within the VHA. Methods: VHA patients with HCC receiving 1st line therapy with A+B were identified through EMR using ICD-9 or ICD-10 codes between 1 Jan 2007 and 31 Dec 2021. Patients were followed from their A+B initiation date through the earliest of the last VHA visit, loss to follow up, death, or end of study on Jan 31, 2023. Structured electronic health record and chart review data were retrospectively collected to determine patient baseline characteristics, treatment response, overall survival (OS), and progression-free survival. Survival rates were based on patients with at least 6 months or 1 year of time (as indicated) from A+B initiation until the chart was reviewed; patients without a scan or known date of scan were excluded from PFS calculations. The Chi-Squared test was used to compare rates. Results: 332 patients were included in the study. The median age was 67 yrs, 99% were males, 63% non-Hispanic White, 26% Black, 86% with ECOG &lt; 1, 84% had CPS class A, 16% had CPS class B and C, 56% had viral hepatitis-caused HCC, 20% had no cirrhosis present, and 60% had prior local therapies. There was a statistically significant difference in progression free survival (PFS) and over survival (OS) amongst different ALBI grades as shown. Conclusions: In our retrospective cohort, it was clear that patients with ALBI grade 1 had improved PFS and OS compared to ALBI score grade 3. Patients with ALBI score grade 2 also had a moderate response to treatment with modest OS and PFS compared to patients with ALBI score grade 3. Utilizing stratification ability ALBI grade in future clinical trials may improve prognostic power facilitating ideal patient selection. [Table: see text]

COMPARATIVE ANALYSIS OF PRICK TEST PRE AND POST SUBLINGUAL IMMUNOTHERAPY FOR ALLERGIC RHINITIS

Introduction: Allergic rhinitis is an immune-mediated reaction, the diagnosis of which can be complemented with the immediate hypersensitivity skin test using the prick test. Allergen-specific immunotherapy (AIT) is indicated for specific cases and is the only disease-modifying treatment. So far, there is not a biomarker to objectively monitor its evolution. Objectives: To compare the degree of pre- and post-sublingual immunotherapy (SLIT) skin sensitization in patients with allergic rhinitis, in order to validate the prick test as an objective measure of response to treatment. Material and methods: Observational, analytical and retrospective study, which compared, for each allergen, the skin reactions of the prick test before and after starting sublingual immunotherapy. Results: 71 patients were included. There was a reduction in skin sensitization in patients undergoing SLIT to grasses (p0.05). A positive correlation was found between the interval of skin tests and the reduction of skin sensitization to Dermatophagoides pteronyssinus. Discussion: The prick test can be considered an objective marker of response to treatment only for patients with seasonal allergic rhinitis. The present study suggests that the longer the SLIT, the greater the reduction in skin sensitization, evidencing the importance of completing the treatment for a better outcome. Conclusion: Studies are still needed to determine an objective marker of treatment response that reliably correlates with the patient’s clinical response.