Treatment Response Criteria Research Articles

International expert guidance for defining and monitoring small bowel strictures in Crohn's disease on intestinal ultrasound: a consensus statement

Diagnostic imaging using CT enterography, magnetic resonance enterography, and intestinal ultrasound are important tools in evaluating stricturing Crohn's disease. Definitions of strictures have been developed for CT enterography and magnetic resonance enterography. However, expert recommendations for definitions and treatment response of strictures on intestinal ultrasound are not available. The aim of this study was to standardise definitions, diagnosis, and treatment response criteria in small bowel stricturing Crohn's disease on intestinal ultrasound. Using modified RAND-University of California Los Angeles Appropriateness Method, a diverse expert panel of 13 gastroenterologists, seven radiologists, and two patient representatives was assembled. A total of 466 statements on definitions and response to therapy of stricturing Crohn's disease on intestinal ultrasound were generated from a systematic review and from expert opinion, with subsequent rating for appropriateness. Two rounds of voting with an interposed survey result discussion were performed. Statements were classified as inappropriate, uncertain, or appropriate based on the median panel rating and degree of disagreement. Appropriateness was rated using a nine-point Likert scale (1 being inappropriate, 9 being highly appropriate). A naive or anastomotic small bowel Crohn's disease stricture on intestinal ultrasound is defined by the combination of bowel wall thickening, luminal narrowing, and pre-stenotic dilation. Bowel wall thickness is defined as being more than 3 mm. Luminal narrowing is defined as either a luminal diameter reduction of more than 50% in the narrowest area and relative to a normal adjacent bowel loop, or a luminal diameter of less than 1 cm. Pre-stenotic dilation is defined as more than 2·5 cm or an increase in bowel diameter relative to a normal adjacent bowel loop. Definitions for grading hyperaemia, inflammatory fat, wall stratification, intestinal ultrasound machine technical parameters, and image acquisition were also devised. Treatment response of strictures was defined as reduction in stricture length, bowel wall thickening, luminal narrowing, pre-stenotic dilation, and motility abnormalities. To our knowledge, this is the first intestinal ultrasound appropriateness rating exercise conducted for defining, diagnosing, and measuring response to therapy in small bowel stricturing Crohn's disease and informs future clinical use and intestinal ultrasound index development for clinical trials. Leona M and Harry B Helmsley Charitable Trust.

Long-Term Kidney Outcome of Lupus Nephritis by Renal Response Status

IntroductionLimited evidence exists that clinical trial treatment response criteria predict long-term outcomes in Asian patients with lupus nephritis (LN). MethodsThis retrospective analysis of prospectively collected data from the Hong Kong Queen Mary Hospital Cohort categorized adults with biopsy-proven LN (Class III, IV, V, or mixed [III±V, IV±V]) after standard treatment for 2 years (2Y) post biopsy and immunosuppression induction according to modified primary efficacy renal response (mPERR: estimated glomerular filtration rate [eGFR] ≥60 ml/min/1.73 m2 or ≤20% below biopsy value AND urine protein:creatinine ratio [uPCR] ≤0.7) and modified complete renal response (mCRR; eGFR ≥90 ml/min/1.73 m2 or ≤10% below biopsy value AND uPCR ≤0.5). Associations between 2Y mPERR/mCRR status and long-term kidney survival and mild chronic kidney disease (CKD) or worse (Stage ≥3) were assessed. ResultsOf the 176 Chinese patients, 64.2% achieved mPERR and 43.8% achieved mCRR at 2Y post biopsy. After mean follow-up of 15.3 years, significantly higher proportions of mPERR and mCRR responders versus non-responders achieved long-term kidney survival (mPERR: 85.8% vs 71.4%; p=0.029; mCRR: 92.2% vs 71.7%; p<0.001). mPERR and mCRR achievement was associated with adjusted risk reductions for kidney non-survival of 60% (p=0.034) and 86% (p<0.001), respectively. Adjusted risk for mild CKD or worse (Stage ≥3) was 82% (p=0.013) and 87% (p=0.012) lower for mPERR and mCRR responders, respectively, versus non-responders. ConclusionsIn Chinese patients with LN, mPERR and mCRR at 2Y post biopsy predict superior long-term kidney outcomes and lower CKD progression risk.

The epigenetic determinants for systemic juvenile idiopathic arthritis phenotyping and treatment response

BackgroundDetermining the role of epigenetics in systemic juvenile idiopathic arthritis (SJIA) provides an opportunity to explore previously unrecognized disease pathways and new therapeutic targets.AimWe aimed to identify the clinical significance of microRNAs (miRNA-26a, miRNA-223) in SJIA.Materials and methodsThis cross-sectional study was conducted on a group of children with SJIA attending to pediatric rheumatology clinic, at Mansoura University Children’s Hospital (MUCH) from December 2021 to November 2022. Patient demographics, and clinical, and laboratory data were collected with the measurement of microRNAs by quantitative real-time PCR. The Mann–Whitney, Kruskal–Wallis, and Spearman correlation tests were used for variable comparison and correlations, besides the receiver operating characteristic (ROC) curve for microRNAs disease activity and treatment non-response discrimination.ResultsForty patients were included in the study. On comparison of miRNA-26a, and miRNA-223 levels to the clinical, assessment measures, and laboratory features, miRNA-26a was statistically higher in cases with systemic manifestations versus those without. Similarly, it was higher in children who did not fulfill the Wallace criteria for inactive disease and the American College of Rheumatology (ACR) 70 criteria for treatment response. Meanwhile, miRNA-223 was not statistically different between cases regarding the studied parameters. The best cut-off value for systemic juvenile arthritis disease activity score-10 (sJADAS-10) and the ability of miRNA-26a, and miRNA-223 to discriminate disease activity and treatment non-response were determined by the (ROC) curve.ConclusionThe significant association of miRNA-26a with SJIA features points out that this molecule may be preferentially assessed in SJIA disease activity and treatment non-response discrimination.

Clinical Associations of E148Q Heterozygosity: What to Expect From E148Q?

The exact effects of MEFV variants on inflammation are still under investigation, and reports on variants of unknown significance, particularly the E148Q variant, have been conflicting. Therefore, this study aims to investigate patients exhibiting E148Q heterozygosity, focusing on diagnoses and disease courses to assist physicians in interpreting the variant. Data of pediatric patients presenting to the Pediatric Rheumatology clinic between November 2016 and September 2023, exhibiting only E148Q heterozygosity in MEFV gene analysis, were extracted. Patients who were lost before 9 months of follow-up have been excluded to ensure the completion of initial diagnostic tests and evaluations. Among the 119 patients with E148Q variant, the diagnoses were as follows: healthy, 51.3%; IgA vasculitis, 10.1%; Familial Mediterranean Fever (FMF), 7.6%; Periodic fever, Aphtous stomatitis, Pharyngitis, Adenitis (PFAPA), 6.7%; and other diagnoses, 19.3%. IgA vasculitis patients experienced articular, gastrointestinal, and renal involvement at rates of 91.7%, 58.3%, and 16.7%, respectively. Complete response, partial response, and no response to colchicine were 37.5%, 12.5%, and 50%, respectively, in PFAPA patients. All FMF patients responded to colchicine treatment resulting in reduced mean FMF episode counts in 6 months from 3.22 ± 0.92 to 0.56 ± 0.52. The E148Q variant may amplify inflammation and modify disease courses. Patients with the E148Q variant experiencing typical FMF episodes should receive colchicine, but clinicians should exercise caution regarding alternative diagnoses. Additionally, the E148Q variant may increase acute phase reactants and disease severity in IgA vasculitis. However, to reach definitive conclusions on its treatment-modifying role in PFAPA, universal diagnosis and treatment response criteria should be adopted.

Insulin resistance, clinical presentation and resistance to selective serotonin and noradrenaline reuptake inhibitors in major depressive disorder

BackgroundThe understanding of mechanisms underlying non-response to antidepressants is limited. The latest data highlights the role of insulin resistance (IR) in major depressive disorder (MDD) pathophysiology, presentation, and treatment efficacy. This work aimed to assess IR in MDD and explore the relationships between IR, MDD presentation and non-response to selective serotonin and noradrenaline reuptake inhibitors (SNRI).Methods67 MDD individuals: 36 responsive (MDD T[+]), 31 non-responsive (MDD T[−]) to SNRI and 30 healthy controls were recruited. The treatment response criteria were: Clinical Global Impression Scale-Improvement score of 1 or 2 after ≥ 8 weeks of treatment. Participants were assessed by physician and self-report tools measuring depression, anhedonia, anxiety, bipolarity, sleep quality. Blood samples were collected to assess fasting glucose and insulin levels and calculate HOMA-IR (homeostasis model assessment of insulin resistance).ResultsMDD T[-] vs. MDD T[+] had significantly higher body mass index, insulin levels, and HOMA-IR. MDD T[-] presented higher levels of depressed mood, appetite/weight changes, loss of interest, energy, overall depressive symptoms, and sleep impairment; some evaluations suggested higher anhedonia and anxiety in MDD T[-] vs. MDD T[+]. Insulin and IR were weakly but significantly correlated with the severity of psychomotor symptoms, energy level, thoughts of death/suicide, self-criticism, appetite/weight, depressed mood symptoms, sleep problems. IR was weakly but significantly correlated with anhedonia.ConclusionIR appears to be linked to depressive symptoms characteristic of the “metabolic” MDD subtype, such as psychomotor changes, energy level, anhedonia, sleep problems, appetite/weight changes, state and trait anxiety, sleep quality, and non-response to SNRI.

External validation of the IAIHG autoimmune hepatitis response criteria in a multicentric real-world cohort

The goal of treatment in autoimmune hepatitis (AIH) is induction of remission to prevent the development of liver fibrosis, cirrhosis, and its related complications. Various definitions of treatment response and remission have been used. The International Autoimmune Hepatitis Group (IAIHG) recently defined consensus criteria for treatment response. We aimed to validate the IAIHG response criteria in our cohort and establish correlations with survival endpoints. We performed a retrospective, multicentric cohort study in one tertiary and seven secondary care centres in Belgium. Eligible patients were at least 18 years of age at data collection and were diagnosed with AIH by a simplified IAIHG score of ≥6. Complete biochemical response (CBR) was defined according to the IAIHG consensus criteria as normalisation of transaminases and serum IgG within the first 6 months of treatment. The primary endpoint was liver-related survival - defined as freedom from liver-related death or liver transplantation. Secondary endpoints were overall mortality and transplant-free survival. Outcomes were compared between patients attaining CBR and those with insufficient response. Biochemical response status could be determined in 200 patients with AIH: CBR was achieved in 128 (64.0%) individuals. Patients not achieving CBR more frequently presented with cirrhosis on initial histology (22.2% vs. 10.9%, p= 0.036). Liver-related mortality or liver transplantation as a primary outcome occurred in 26 patients (13.0%). Patients achieving CBR exhibited superior liver-related (hazard ratio 0.118; 95% CI 0.052-0.267; p <0.0001) and overall (hazard ratio 0.253; 95% CI 0.111-0.572; p= 0.0003) survival. We externally validated the IAIHG consensus criteria for CBR and confirmed their correlation with survival endpoints in a multicentric, real-world cohort. Patients with AIH achieving CBR as an intermediate endpoint have significantly superior liver-related and overall survival. Corticosteroids remain the cornerstone of treatment to induce remission of disease activity in autoimmune hepatitis (AIH), and the majority of patients require long-term corticosteroid treatment to achieve sustained remission. Definitions of response to treatment have varied over the years, and consistently used intermediate endpoints are needed to facilitate advancements in non-corticosteroid treatment for autoimmune hepatitis. The International Autoimmune Hepatitis Group (IAIHG) defined consensus criteria on endpoints in the treatment of AIH, for which further external validation is needed. Here, we demonstrate the usefulness of the IAIHG consensus criteria and corroborate their correlation to primary endpoints, such as liver-related survival and native liver survival in a multicentric, real-world setting. The design of future studies can rely on the IAIHG consensus criteria as intermediate endpoints.

Irreversible Electroporation as a Valid Treatment Option for Hepatic Epithelioid Hemangioendothelioma: An International Multicenter Experience

PurposeHepatic epithelioid hemangioendothelioma (HEHE) is a rare tumor with currently no established standard of care. This international multicenter retrospective study assesses the use of percutaneous irreversible electroporation (IRE) as an ablative tool to treat HEHE and provides a clinical overview of the current management and role of IRE in HEHE treatment.Material and MethodsBetween 2017 and 2023, 14 patients with 47 HEHE tumors were treated with percutaneous IRE using CT-scan guidance in 23 procedures. Baseline patient and tumor characteristics were evaluated. Primary outcome measures included safety and effectiveness, analyzed using Common Terminology Criteria for Adverse Events (CTCAE) and treatment response by mRECIST criteria. Secondary outcome measures included technical success, post-treatment tumor sizes and length of hospital stay. Technical success was defined as complete ablation with an adequate ablative margin (intentional tumor free ablation margin > 5 mm).ResultsIRE treatment resulted in technical success in all tumors. Following a median follow-up of 15 months, 30 tumors demonstrated a complete response according to mRECIST criteria. The average tumor size pre-treatment was 25.8 mm, accompanied by an average reduction in tumor size by 7.5 mm. In 38 out of 47 tumors, there was no evidence of local recurrence. In nine tumors, residual tumor was present. There were no cases of progressive disease. Median length of hospital stay was one day. Only one grade 3 CTCAE event occurred, a pneumothorax requiring chest tube placement.ConclusionThe current study provides evidence that IRE is a safe and efficacious minimally invasive treatment option for HEHE.Graphical

Sequential Acute Courses of Transcranial Magnetic Stimulation in Major Depressive Disorder: A Retrospective Analysis in a Veteran Cohort

BackgroundRepetitive transcranial magnetic stimulation (TMS) is now widely accepted as an effective non-pharmacologic treatment for treatment-resistant depression. However, whether repeated acute TMS courses can recapture the antidepressant effects of the initial acute course is still an open question, especially in the Veteran population. We present here a retrospective analysis of a specialty clinic within the Veteran Affairs Hospital System to help address this question. AimsFollowing an acute treatment course of TMS, we sought to determine the treatment response of a subsequent TMS course. We hypothesized that those who responded to an initial acute TMS course would respond in a similar manner to a subsequent treatment course. Methods116 cases referred for evaluation for TMS between September 2017 to April 2021 were reviewed. 63 Veterans completed at least one acute course of TMS and 12 completed at least two courses and met inclusion criteria for this review. 6 met criteria for treatment response in the first course, while the other 6 were initial treatment nonresponders. Symptoms were evaluated via self-reported scales at baseline and weekly throughout treatment. Clinical response to subsequent treatment (>50% symptom reduction as measured by the PHQ-9) was compared to initial treatment response. ResultsOf the initial treatment responders (n = 6), all six responded to a second acute course, with an 85.3% symptom reduction. Of the initial treatment nonresponders (n = 6), three responded to a second acute course. No adverse events were reported in those who completed a second course, and the Veterans tolerated the treatment well. ConclusionsOur findings support the growing understanding that a second acute TMS treatment course for treatment-resistant depression is safe, well-tolerated, and effective in initial responders and some non-responders. Despite multiple confounders in a naturalistic setting, robust initial treatment response was sustained in a second acute course. Low power limits generalizability, and larger powered, prospective studies are needed.

P060 Multi-targeted therapy better in achieving a complete response in Lupus Nephritis: A systematic review and meta-analysis

Abstract Background/Aims Overall management of SLE and Lupus Nephritis (LN) has significantly improved over the last four decades. Recently great therapeutic strides have been made in management of LN using newer agents alone or combination of older therapies. With the availability of increased number of options choosing the optimal treatment regimen for LN has become challenging. Identifying the treatment regimen most effective in achieving complete response while minimizing adverse events is crucial for improving patient outcomes. We performed a systematic review and meta-analysis of clinical trials to explore optimal treatment regimen for LN. Methods The systematic review and meta-analysis were performed using the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The literature search was conducted using public databases, such as the Cochrane Library, Web of Science and PubMed. Only randomized controlled clinical trials with either active comparator or placebo arms were included. Studies were excluded if they were retrospective, with no comparative drug arm, or less than 20 subjects per treatment response arm. Due to lack of agreed upon outcome measures, complete response (CR) and partial response (PR) criteria were determined as per the definition used by individual studies. Severe adverse reaction (SAE) frequencies were determined for each study for safety evaluation. Publication bias was detected by using funnel plots. Forest plots were used to summarize data, generate frequencies, odds ratio (OR), relative risks (RR) and corresponding 95% confidence intervals (CI) for each subgroup. Heterogeneity was evaluated using the I2 statistic, and labelled as low (25%), moderate (50%) and high (75%). All analyses were performed using R Statistical Software meta package (v4.2.1; R Core Team 2022). Results 31 eligible studies comprising 5495 SLE patients were included in analyses, the study characteristic features are shown in Table 1. Overall significant OR for achieving CR was reported by 10 studies (Figure 1). The highest effect was reported from study by Bao et.al using a combination of tacrolimus(TAC) and mycophenolate mofetil (MMF) compared to cyclophosphamide (CYC) (OR = 10.5, 95% CI 2.27; 48.76), another study using TAC+MMF combo reported OR = 2.49, 95% CI 1.59;3.88. The study by Ginzler et.al reported OR = 5.06 (95% CI 1.6:16.02) in favor of using MMF. Studies using CYC, voclosporin + MMF, and belimumab also reported significant OR for achieving CR. Data for the frequency of SAE were available in 22 studies. The frequency of SAE was not significantly different between treatments arms (OR: 1.07, 95%CI: 0.93-1.23, p &amp;gt; 0.05) Conclusion Our meta-analysis suggests multi-target treatment strategies, by adding calcineurin inhibitors to MMF may be better for achieving complete response in LN. Furthermore, using this combination treatment did not seem to increase the risk of side effects. Heterogenous treatment response criteria and variable comparator arms were major limiting factors of this study. Disclosure O. Pamuk: None. B. Shaikh: None. S. Khan: None. S. Abi Doumeth: None. S. Hasni: None.

Deep transcranial magnetic stimulation for adolescents with treatment-resistant depression: A preliminary dose-finding study exploring safety and clinical effectiveness

BackgroundTranscranial magnetic stimulation (TMS) is an intervention for treatment-resistant depression (TRD) that modulates neural activity. Deep TMS (dTMS) can target not only cortical but also deeper limbic structures implicated in depression. Although TMS has demonstrated safety in adolescents, dTMS has yet to be applied to adolescent TRD. Objective/hypothesisThis pilot study evaluated the safety, tolerability, and clinical effects of dTMS in adolescents with TRD. We hypothesized dTMS would be safe, tolerable, and efficacious for adolescent TRD. Methods15 adolescents with TRD (Age, years: M = 16.4, SD = 1.42) completed a six-week daily dTMS protocol targeting the left dorsolateral prefrontal cortex (BrainsWay H1 coil, 30 sessions, 10 Hz, 3.6 s train duration, 20s inter-train interval, 55 trains; 1980 total pulses per session, 80 % to 120 % of motor threshold). Participants completed clinical, safety, and neurocognitive assessments before and after treatment. The primary outcome was depression symptom severity measured by the Children's Depression Rating Scale-Revised (CDRS-R). Results14 out of 15 participants completed the dTMS treatments. One participant experienced a convulsive syncope; the other participants only experienced mild side effects (e.g., headaches). There were no serious adverse events and minimal to no change in cognitive performance. Depression symptom severity significantly improved pre- to post-treatment and decreased to a clinically significant degree after 10 treatment sessions. Six participants met criteria for treatment response. LimitationsMain limitations include a small sample size and open-label design. ConclusionsThese findings provide preliminary evidence that dTMS may be tolerable and associated with clinical improvement in adolescent TRD.

Prediction of Treatment Effect of SLE-ITP Patients Based on Cost-Sensitive Neural Network and Variational Autoencoder.

The aim of the study was to examine the factors influencing the therapeutic effect of patients with systemic lupus erythematosus combined with immune thrombocytopenia (SLE-ITP) and develop a prediction model to predict the therapeutic effect of SLE-ITP. Three hundred twenty-four SLE-ITP patients were retrieved from the electronic health record database of SLE patients in Jiangsu Province according to the latest treatment response criteria for ITP. We adopted the Cox model based on the least absolute shrinkage and selection operator to explore the impact factors affecting patient therapeutic effect, and we developed neural network model to predict therapeutic effect, and in prediction model, cost-sensitivity was introduced to address data category imbalance, and variational autoencoder was used to achieve data augmentation. The performance of each model was evaluated by accuracy and the area under the receiver operator curve. The results showed that B-lymphocyte count, H-cholesterol level, complement-3 level, anticardiolipin antibody, and so on could be used as predictors of SLE-ITP curative effect, and abnormal levels of alanine transaminase, immunoglobulin A, and apolipoprotein B predicted adverse treatment response. The neural network treatment effect prediction model based on cost-sensitivity and variational autoencoder was better than the traditional classifiers, with an overall accuracy rate closed to 0.9 and a specificity of more than 0.9, which was useful for clinical practice to identify patients at risk of ineffective treatment response and to achieve better individualized management. By predicting the curative effect of SLE-ITP, the severity of patients can be determined, and then the best treatment strategy can be planned to avoid ineffective treatment.

Spectral CT vs. diffusion-weighted imaging for the quantitative prediction of pathologic response to neoadjuvant chemotherapy in locally advanced gastric cancer.

To compare the performance of spectral CT and diffusion-weighted imaging (DWI) for predicting pathologic response after neoadjuvant chemotherapy (NAC) in locally advanced gastric cancer (LAGC). This was a retrospective analysis drawn from a prospective dataset. Sixty-five patients who underwent baseline concurrent triple-phase enhanced spectral CT and DWI-MRI and standard NAC plus radical gastrectomy were enrolled, and those with poor images were excluded. The tumor regression grade (TRG) was the reference standard, and patients were classified as responders (TRG 0 + 1) or non-responders (TRG 2 + 3). Quantitative iodine concentration (IC), normalized IC (nIC), and apparent diffusion coefficient (ADC) were measured by placing a freehand region of interest manually on the maximal two-dimensional plane. Their differences between responders and non-responders were compared. The performances of significant parameters were evaluated by the receiver operating characteristic analysis. The correlations between parameters and TRG status were explored through Spearman correlation coefficient test. Kaplan-Meier survival analysis was adopted to analyze their relationship with patient survival. nICDP and ADC were associated with the TRG and yielded comparable performances for predicting TRG categories, with area under the curve (AUC) of 0.674 and 0.673, respectively. Their combination achieved a significantly increased AUC of 0.770 (p ; 0.05) and was associated with patient disease-free survival, with hazard ratio of 2.508 (1.043-6.029). Spectral CT and DWI were equally useful imaging techniques for predicting pathologic response to NAC in LAGC. The combination of nICDP and ADC gained significant incremental benefits and was related to patient disease-free survival. Spectral CT and DWI-based quantitative measurements are effective markers for predicting the pathologic regression outcomes of locally advanced gastric cancer patients after neoadjuvant chemotherapy. • The pathologic tumor regression grade, the standard criteria for treatment response after neoadjuvant chemotherapy in gastric cancer patients, is difficult to predict early. • The quantitative parameters of normalized iodine concentration at delay phase and apparent diffusion coefficients were correlated with pathologic response; their combination demonstrated incremental benefits and was associated with patient disease-free survival. • Spectral CT and DWI are equally useful imaging modalities for predicting tumor regression grade after neoadjuvant chemotherapy in patients with locally advanced gastric cancer.

Longitudinal outcomes of a therapist-supported digital mental health intervention for depression and anxiety symptoms: A retrospective cohort study.

This study examined treatment outcomes (depression and anxiety symptoms) up to 24 months after completion of a therapist-supported digital mental health intervention (DMHI). The sample consisted of 380 participants who participated in an eight-week DMHI from February 6, 2017 to May 20, 2019. Participants reported depression and anxiety symptoms at eight timepoints from baseline to 24 months. Mixed-effects modelling was used to investigate symptom changes over time. The proportion of participants meeting criteria for treatment response, clinically significant change, and remission of depression and anxiety symptoms were calculated, including proportions demonstrating each outcome sustained up to each timepoint. Multivariate analyses yielded statistically significant reductions in depression (β = -5.40) and anxiety (β = -3.31) symptoms from baseline to end of treatment (8 weeks). Symptom levels remained significantly reduced from baseline through 24 months. The proportion of participants meeting criteria for clinical treatment outcomes remained constant over 24 months, although there were linear decreases in the proportions experiencing sustained clinical outcomes. Treatment gains were made for depression and anxiety symptoms at the end of treatment and up to 24 months. Future studies should determine the feasibility of integrating post-treatment programmes into DMHIs to address symptom deterioration.

P310 Intestinal ultrasound as a tool to assess treatment response in patients with Inflammatory Bowel Diseases

Abstract Background The assessment of treatment response in patients with Inflammatory Bowel Disease (IBD) is often based on clinical indices [Harvey Bradshaw index (HBI), Partial Mayo score (PMS)] and biomarkers [C - reactive protein (CRP)]. Intestinal ultrasound (IUS) has been proposed as a modality capable of objectively evaluating therapeutic response. We investigated the utility of the IUS as a tool to assess treatment response, as well as its association with HBI, PMS and CRP. Methods We included patients with an established diagnosis of IBD who initiated biologic agent (infliximab, adalimumab, ustekinumab, vedolizumab) or tofacitinib. Active disease on IUS was defined as an increase in bowel wall thickness (BWT) &amp;gt;3 mm in the most affected bowel segment, while the presence of a Doppler signal (CDS) in the bowel wall was also assessed. Treatment response on IUS was defined according to the International Bowel Ultrasound Group (IBUS) criteria: reduction in bowel wall thickness (in continuous measurements) &amp;gt;25% or &amp;gt;2.0 mm or &amp;gt;1.0 mm with concomitant reduction in CDS by 1 unit at week 14 ± 2 from the initiation of treatment. Results A total of 19 patients (11 men, 11 with Crohn's disease) underwent IUS at week 0 and week 14 ± 2, while CRP, HBI and PMS were calculated at the same time points. We included bio-naïve as well bio experienced patients (table 1). At week 0, 84.2% of patients exhibited clinical activity (HBI ≥5, PMS ≥2), median CRP was 24.7 mg /L (IQR 18.6-42.8) and median BWT was 7.1mm (IQR 6.5-7.6). At week 14 ± 2, 42.1% of patients remained clinically active, median CRP was 6.8 mg/L (IQR 4.6-20.7) and median BWT was 5.2 mm (IQR 4.6- 6.4). Overall 10/19 patients fulfilled the criteria of treatment response on IUS at week 14 ± 2. Clinical remission was observed in 8/10 patients who demonstrated therapeutic response on IUS and 3/9 patients who did not (p=0.07). Normalization of CRP value (&amp;lt;6mg/L) was observed in 8/10 patients who exhibited treatment response on IUS and in none of the patients who did not (p&amp;lt;0.001). Among the IUS parameters at baseline, a statistically significant difference was found only in the presence of fat wrapping between treatment responders and treatment non-responders (table 2). Finally, median CRP was 4.9 mg/L (IQR 2.6-6.2) in IUS treatment responders and 20.7 mg/L (IQR 10.5-28.5) in IUS treatment non-responders. (p&amp;lt;0.001), with median BWT being 4.7mm (IQR 3.3-5.1) and 6.4mm (IQR 6.1-6.9) respectively (p&amp;lt;0.001). Conclusion IUS represents an objective tool for evaluating treatment response in patients with IBD, which demonstrates a significant correlation with CRP but not with clinical indices of activity.

Toward Precision Medicine for Patients with Multiple Myeloma

Multiple myeloma (MM), the second most common hematologic malignancy, is a plasma cell neoplasm that arises from a precursor, monoclonal gammopathy of undetermined significance (MGUS), which may or may not be previously diagnosed. Smoldering multiple myeloma (SMM), another precursor of MM, lacks myeloma-defining events and end-organ damage that are diagnostic of MM in the appropriate clinical settings. Newly diagnosed MM (NDMM) is highly heterogeneous genetically and clinically with very variable survival outcomes ranging from a few months to over a decade. Despite this heterogeneity, treatment outcomes have improved significantly in the last two decades, with overall survival improving continuously due to novel classes of drugs approved for treating MM. However, due to the immense heterogeneity, the quest for a cure will almost certainly require individualized patient evaluation and management at every level for every factor influencing patient quality of life and survival, including most importantly determining upfront the progression risks in the precursor states and prognostic risks for progression or relapse in NDMM. Toward that goal, this paper briefly describes, including a historical perspective, current concepts, and recent advances in NDMM for students, researchers, and clinical practitioners. The topics discussed include an overview of the epidemiology, current diagnostic criteria, including for distinguishing MGUS, SMM, and MM, refractory and relapsed MM, staging and prognosis of MM, treatment response criteria, including measurable residual disease evaluation, improvements in survival, current standards for treating NDMM, and disparities and inequities in receiving care in ethnic minority populations for treatment of MM, followed by progress in evaluating the risk of progression in MGUS and SMM, and finally, the genomics of MM, SMM, and MGUS since integrating disease biology in assessing and precisely managing all risk factors and achieving equity in treating all patients would help to achieve that precision medicine goal for a cure.

Esketamine Augmentation in Treatment-Resistant Obsessive-Compulsive Disorder: A Retrospective Chart Review.

Converging evidence supports the role of the glutamate, an excitatory amino acid neurotransmitter, in the pathophysiology of obsessive-compulsive disorder (OCD). Ketamine and esketamine, both noncompetitive N -methyl- d -aspartate antagonists, have emerged as a promising medication for this psychiatric disorder, given its possible efficacy with faster onset and good tolerability. The purpose of this retrospective chart review is to evaluate whether unbiased clinical documentation supports formal clinical trials of esketamine for an OCD indication. A retrospective chart review of patients with treatment-resistant OCD receiving a single dose of esketamine (0.5mg/kg) added to standard therapy was conducted. The Yale-Brown Obsessive-Compulsive Scale and the Montgomery-Åsberg Depression Rating Scale were used to evaluate OCD and depressive symptoms respectively at baseline, 24 hours, and 7 days after esketamine administration. Descriptive statistics were used to analyze the data. Eight subjects were identified in this retrospective chart review: esketamine was administered subcutaneously in 7 and intravenously in 1. One week after infusion, 25% of the sample met criteria for treatment response and 50% for partial response. Major depressive disorder was a comorbid diagnosis in 75% of the sample and 2 of these subjects showed a positive antidepressant response. Our findings provide preliminary evidence that esketamine may reduce obsessive-compulsive symptoms in a subset of treatment-resistant OCD patients.

Trial in Progress: A Phase 1b Study of AS-1763, an Oral, Potent and Selective Noncovalent BTK Inhibitor, in Patients with Previously Treated Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma or Non-Hodgkin Lymphoma

Background: Covalent Bruton's tyrosine kinase (BTK) inhibitors such as ibrutinib are approved for treating patients with B-cell malignancies, but their long-term efficacy is limited by toxicity related to off-target kinase inhibition and acquired resistance due to BTK C481 mutation. AS-1763 is a potent, highly selective, orally available, and non-covalent BTK inhibitor, equipotent against both wild-type and C481S-mutated BTK with sub-nanomolar IC50 values (Kawahata et al. J Med Chem 2021; 64,14129-14141). In a Phase 1 single-ascending dose study in healthy volunteers, AS-1763 was well tolerated and safe at doses of 5-600 mg and achieved maximum inhibition of B cell activation at doses of 100 mg and above at 1-2 h post-dose and the duration of inhibitory effect increased with dose [Arimura et al. AACR 2022; Cancer Res 2022;82(12_Suppl)]. In preclinical studies, AS-1763 demonstrated a broad spectrum of inhibition against BTK mutations that confer resistance to other non-covalent BTK inhibitors in addition to the C481 mutation. Study Design and Methods: This study is an open-label, multi-center, Phase 1b study of oral AS-1763 in patients with advanced chronic lymphocytic leukemia (CLL)/small lymphocytic leukemia (SLL) and other B-cell non-Hodgkin lymphomas (NHLs) who have failed or are intolerant to at least two prior lines of systemic therapy. Prior therapy with a covalent BTK inhibitor is permitted; prior use of a noncovalent BTK inhibitor is excluded. This study consists of two parts, i.e., dose escalation and expansion parts. The dose escalation part will follow a 3+3 design with a starting dose of 100 mg BID. Each cycle will be 28 days. Three dose levels will be selected for dose expansion part based on a comprehensive review of data from dose escalation. The dose expansion part consists of 2 cohorts, i.e., Cohort 1 for CLL/SLL and Cohort 2 for B-cell NHL. In each cohort, the first 30 patients will be allocated to the 3 dose levels (10 patients for each), then the same provisional recommended Phase 2 Dose (RP2D) will be selected for Cohort 1 and Cohort 2 after 30 patients have enrolled in either cohort. After the provisional RP2D is selected, up to 28 patients in Cohort 1 and up to 15 patients in Cohort 2 may be treated at the provisional RP2D. In this study, up to 110 patients will be enrolled. Treatment will continue for 24 cycles or until disease progression, occurrence of unacceptable toxicity or discontinuation because of other reasons. Eligible patients include CLL/SLL, Waldenstrӧm macroglobulinemia (WM), marginal zone lymphoma (MZL), mantle cell lymphoma (MCL), and follicular lymphoma (FL). Patients with transformed disease (e.g., Richter's transformation) prior to or during screening are not eligible. Key exclusion criteria include CNS involvement by systemic lymphoma, stem cell transplant or CAR-T therapy &amp;lt;30 days, and clinically significant cardiovascular disease. The primary objective of the dose escalation part is to determine the maximum tolerated dose/dose-limiting toxicity. Key secondary endpoints include the evaluation of safety profile and tolerability, pharmacokinetics properties, and preliminary anti-tumor activity based on overall response rate (ORR) by investigator according to iwCLL 2018 for CLL, IWW6 for WM, and Lugano Treatment Response Criteria for MCL, MZL, SLL and FL. The primary objective of the dose expansion part is to assess the preliminary anti-tumor activity based on ORR by the Safety Monitoring Committee (SMC). Key secondary objectives are to investigate safety, tolerability, and pharmacokinetic profiles and to assess the preliminary antitumor activity based on ORR by investigator and best overall response, duration of response, progression-free survival and overall survival by investigator and the SMC. This trial will evaluate several key exploratory objectives including evaluation of minimal residual disease negativity, characterization of patient subsets defined by mutation status of BTK and phospholipase C gamma 2 (PLCG2), and characterize BTK and PLGC2 gene mutation before and after disease progression. Changes in the level of biomarkers such as CCL3 and CCL4 chemokines and B-cell receptor pathway signaling will be evaluated prior to, during therapy, and at time of disease progression. The RP2D will be determined based on all the data generated in the study. The study has been registered on ClinicalTrials.gov (NCT05602363).

Society of abdominal radiology survey of practice patterns in using LI-RADS treatment response criteria in the evaluation of hepatocellular carcinoma post-locoregional treatment.

To examine national trends in the adoption and use of the LI-RADS Treatment Response Algorithm. Members of the Society of Abdominal Radiology (SAR) Disease-Focused Panel (DFP) on LI-RADS Treatment Response (LR-TR) of hepatocellular carcinoma (HCC) developed a 15-question survey which was distributed to radiologists at academic and private practice institutions around the USA and Canada. The survey focused on HCC-related practice patterns as well as the adoption and use of the LR-TR algorithm. Of 122 surveys distributed, a total of 76 radiologists responded (62%). Responders were predominantly from academic centers (85%). Nearly all (96%) participate in multidisciplinary hepatic tumor boards and most (67%) have an active liver transplant program. All responders' institutions perform locoregional therapy for HCC, including radiation-based therapy (TARE and SBRT). There was a preference for use of MRI over CT for follow-up after locoregional therapy. All responders were aware of the LR-TR algorithm and nearly all (92%) used the system in routine practice. Radiologists expressed a need for more visual aids related to the LR-TR system. Multiple respondents requested additional clarity within the LR-TR algorithm regarding the evolution of post-treatment radiation changes over time. Most survey participants use the LR-TR algorithm after locoregional therapy for HCC. Future iterations of the algorithm may benefit from increased clarity regarding response after radiation-based therapies. Educational materials should include more visual aids to improve reader understanding.

Australian consensus: Treatment goals for moderate to severe psoriasis in the era of targeted therapies – Adult patients

AbstractBackgroundOver the last decade, the treatment landscape for moderate–severe psoriasis has rapidly evolved. The Australasian College of Dermatologists sought to review and update previously published treatment goals for moderate–severe psoriasis.MethodsA modified Delphi approach was used. Comprehensive literature review and guideline evaluation resulted in the development of statements and other questions to establish current clinical practices. Two rounds of anonymous voting were undertaken, with a collaborative meeting held in between to discuss areas of discordance. Overall, consensus was defined as achievement of ≥75% agreement in the range 7–9 on a 9‐point scale (1 strongly disagree; 9 strongly agree).ResultsConsensus was achieved on 26/29 statements in round 1 and a further 20 statements in round 2. There was strong agreement to expanding the classification/definition of psoriasis severity by including a choice of metrics, incorporating quality of life measures, and widening the scope of high‐impact sites. Consensus was also reached on revised treatment response criteria, which were then incorporated into a new treatment algorithm. There was discordance with the current requirement to undertake a trial with established systemic agents before accessing targeted therapy.ConclusionThe ability of new targeted treatment options to change the narrative in psoriasis patient care can only be properly realised if challenges to timely and equitable access are addressed. The proposed framework for the assessment, classification and management of moderate–severe psoriasis aligns with international recommendations. Its adoption into Australian clinical practice is hoped to improve treatment outcomes and patients' satisfaction with their care.

Percutaneous Electrical Nerve Field Stimulation for Drug-Refractory Pediatric Cyclic Vomiting Syndrome.

Cyclic vomiting syndrome (CVS) is a disabling condition frequently refractory to pharmacologic therapy. The aim of this study was to evaluate the effects of non-invasive, auricular percutaneous electrical nerve field stimulation (PENFS) as prophylactic therapy for pediatric CVS. Children 8-18 years with drug-refractory CVS were prospectively enrolled from a tertiary care CVS clinic. Subjects received 6 consecutive weeks of PENFS. CVS severity was quantified by episode frequency and duration score (range 0-25) at baseline and at extended follow-up (4-6 months after end of therapy). Response was classified as ≥50% improvement in either frequency or duration of attacks at extended follow-up. Subjects also completed validated surveys of nausea, disability and global response. 30 subjects completed the study. Median (IQR) age was 10.5 (8.5,15.5) years; 60% were female. At follow-up, 80% met criteria for treatment response with a median (IQR) response duration of 113 (61, 182) days. The frequency-duration score improved from baseline median (IQR) 12.0 (9.0, 16.0) to 3.0 (1.0, 6.0) at follow-up, p<0.0001. Median (IQR) nausea and disability scores decreased from baseline to week 6: 2.1 (1.3, 2.7) to 0.9 (0, 1.6), p=0.003 and 47.5 (41.0, 53.0) to 38.0 (16.0, 51.0), p=0.001 respectively. At end of therapy, 66% and 55% patients reported global response of at least "moderately better" and "a good deal better" respectively. There were no serious side effects. This study suggests long-term benefits of PENFS for children with CVS. PENFS improves several disabling aspects of CVS, including episode frequency, duration and functional disability.