Markers Of Treatment Response Research Articles

Preliminary Results from a Phase 1b Dose De-Escalation Stage of Abnl-Marro 001: An International MDS/MPN Working Group Study

Background: Myelodysplastic/Myeloproliferative neoplasms (MDS/MPN) represent a group of rare hematologic malignancies, distinguished by their concurrent dysplastic and proliferative features. Patients with these neoplasms have an increased risk of acute leukemia transformation and often present with extramedullary and constitutional symptoms. The only approved therapies for MDS/MPNs are hydroxyurea, decitabine (oral decitabine/cedazuridine and parenteral decitabine) or azacitidine (parenteral) for pts with CMML. Given the rarity and the heterogeneity of MDS/MPNs, prospective studies focusing specifically on MDS/MPN have been uncommon, and refining treatment strategies has been difficult. ABNL-MARRO ( A Basket study of Nove l therapy for untreated MDS/MPN and Relapsed/ Refractory Overlap Syndromes) is an international cooperative effort that leverages the expertise of the MDS/MPN International Working Group (IWG) and provides a framework for collaborative studies around the world to advance treatment of MDS/MPN and to explore clinical and pathologic markers of disease severity, prognosis, and treatment response (Moyo TK et.al BMC Cancer. 2022). Methods: ABNL-MARRO 001 (AM-001) is an open-label, phase 1b/2 study testing the treatment combination of ASTX727 (days 1-5), a fixed dose oral combination pill containing 35 mg of the DNMTi decitabine (DEC) and 100 mg of the cytidine deaminase inhibitor cedazuridine (CED), together with a series of active agents in myeloid disease (see Figure 1a) for MDS/MPN. In arm A, ASTX727 is combined with itacitinib 300 mg (days 1-28), a selective JAK1 inhibitor in newly diagnosed and relapsed/refractory (R/R) pts. Here we report results from the 3+3 dose de-escalation phase 1b portion used to determine the recommended Phase 2 dose (RP2D) in arm A. Dose-limiting toxicities (DLTs) were assessed in cycle 1. Disease response was assessed by the MDS/MPN IWG response criteria (Savona et.al., Blood. 2015). Results: Seven patients were enrolled with a median age 75 (range 32-82) years with newly diagnosed (4 pts) or R/R (3 pts) MDS/MPN. Three patients had CMML, 2 had MDS/MPN-U, and 2 had refractory MDS/MPN RST. One patient was not DLT evaluable given severe disease-induced cytopenia, and was not included in the assessment (patient 4 in Figure 1b). The majority of pts experienced a treatment-emergent adverse event (TEAE) of any grade; the most common (≥30% of pts) were thrombocytopenia (50%), neutropenia (30%), and constipation (30%); 50% of pts experienced a Grade ≥3 TEAE; the most common was neutropenia (30%). No DLTs were reported, and these AEs were consistent with what has been reported in the use of ASTX727 (Savona et al. Blood. 2022). One patient achieved a CR, and two additional patients had the best overall response of optimal marrow response after receiving 6 cycles of treatment. All patients are alive with a median follow-up of 12 months (range 6-17 months). The clinical responses and time-on-treatment of all pts in phase 1b are summarized in Figure 1b. Summary/Conclusion: Based on the preliminary results of the phase 1b study, the dosing schedule of 35 mg DEC / 100 mg CED daily for 5 days in combination with itacitinib 300 mg daily for 28 days was selected as the RP2D as it balanced clinical efficacy with an acceptable and manageable safety profile. This regimen and dose are being utilized in a 28-day cycle in the ongoing global, multi-center phase 2 study (NCT04061421).

Precision medicine in inflammatory bowel disease.

Inflammatory bowel disease (IBD) is an incurable disease characterized by remission-relapse cycles throughout its course. Both Crohn's disease (CD) and ulcerative colitis (UC), the two main forms of IBD, exhibit tendency to develop complications and substantial heterogeneity in terms of frequency and severity of relapse, thus posing great challenges to the clinical management for IBD. Current treatment strategies are effective in different ways in induction and maintenance therapies for IBD. Recent advances in studies of genetics, pharmacogenetics, proteomics and microbiome provide a strong driving force for identifying molecular markers of prognosis and treatment response, which should help clinicians manage IBD patients more effectively, and then, improve clinical outcomes and reduce treatment costs of patients. In this review, we summarize and discuss precision medicine in IBD, focusing on predictive markers of disease course and treatment response, and monitoring indices during therapeutic drug monitoring.

Rostral Anterior Cingulate Cortex Oscillatory Power Indexes Treatment-Resistance to Multiple Therapies in Major Depressive Disorder

Introduction: High rostral anterior cingulate cortex (rACC) activity is proposed as a nonspecific prognostic marker for treatment response in major depressive disorder, independent of treatment modality. However, other studies report a negative association between baseline high rACC activation and treatment response. Interestingly, these contradictory findings were also found when focusing on oscillatory markers, specifically rACC-theta power. An explanation could be that rACC-theta activity dynamically changes according to number of previous treatment attempts and thus is mediated by level of treatment-resistance. Methods: Primarily, we analyzed differences in rACC- and frontal-theta activity in large national cross-sectional samples representing various levels of treatment-resistance and resistance to multimodal treatments in depressed patients (psychotherapy [n = 175], antidepressant medication [AD; n = 106], repetitive transcranial magnetic stimulation [rTMS; n = 196], and electroconvulsive therapy [ECT; n = 41]), and the respective difference between remitters and non-remitters. For exploratory purposes, we also investigated other frequency bands (delta, alpha, beta, gamma). Results: rACC-theta activity was higher (p < 0.001) in the more resistant rTMS and ECT patients relative to the less resistant psychotherapy and AD patients (psychotherapy-rTMS: d = 0.315; AD-rTMS: d = 0.320; psychotherapy-ECT: d = 1.031; AD-ECT: d = 1.034), with no difference between psychotherapy and AD patients. This association was even more pronounced after controlling for frontal-theta. Post hoc analyses also yielded effects for delta, beta, and gamma bands. Conclusion: Our findings suggest that by factoring in degree of treatment-resistance during interpretation of the rACC-theta biomarker, its usefulness in treatment selection and prognosis could potentially be improved substantially in future real-world practice. Future research should however also investigate specificity of the theta band.

Cardiac [99mTc]Tc-hydroxydiphosphonate uptake on bone scintigraphy in patients with hereditary transthyretin amyloidosis: an early follow-up marker?

PurposeThere is a need for early quantitative markers of potential treatment response in patients with hereditary transthyretin (ATTRv) amyloidosis to guide therapy. This study aims to evaluate changes in cardiac tracer uptake on bone scintigraphy in ATTRv amyloidosis patients on different treatments.MethodsIn this retrospective cohort study, outcomes of 20 patients treated with the transthyretin (TTR) gene silencer patisiran were compared to 12 patients treated with a TTR-stabilizer. Changes in NYHA class, cardiac biomarkers in serum, wall thickness, and diastolic parameters on echocardiography and NYHA class during treatment were evaluated.ResultsMedian heart/whole-body (H/WB) ratio on bone scintigraphy decreased from 4.84 [4.00 to 5.31] to 4.16 [3.66 to 4.81] (p < .001) in patients treated with patisiran for 29 [15–34] months. No changes in the other follow-up parameters were observed. In patients treated with a TTR-stabilizer for 24 [20 to 30] months, H/WB ratio increased from 4.46 [3.24 to 5.13] to 4.96 [ 3.39 to 5.80] (p = .010), and troponin T increased from 19.5 [9.3 to 34.0] ng/L to 20.0 [11.8 to 47.8] ng/L (p = .025). All other parameters did not change during treatment with a TTR-stabilizer.ConclusionA change in cardiac tracer uptake on bone scintigraphy may be an early marker of treatment-specific response or disease progression in ATTRv amyloidosis patients.

Cross talk of tumor protein D52 (TPD52) with KLF9, PKCε, and MicroRNA 223 in ovarian cancer

BackgroundGynecologic cancers comprise malignancies in the female reproductive organs. Ovarian cancer ranks sixth in terms of incidence rates while seventh in terms of mortality rates. The stage at which ovarian cancer is diagnosed mainly determines the survival outcomes of patients. Various screening approaches are presently employed for diagnosing ovarian cancer; however, these techniques have low accuracy and are non-specific, resulting in high mortality rates of patients due to this disease. Hence, it is crucial to identify improved screening and diagnostic markers to overcome this cancer. This study aimed to find new biomarkers to facilitate the prognosis and diagnosis of ovarian cancer.MethodsBioinformatics approaches were used to predict the tertiary structure and cellular localization along with phylogenetic analysis of TPD52. Its molecular interactions were determined through KEGG analysis, and real-time PCR-based expression analysis was performed to assess its co-expression with another oncogenic cellular pathway (miR-223, KLF9, and PKCε) proteins in ovarian cancer.ResultsBioinformatics analysis depicted the cytoplasmic localization of TPD52 and the high conservation of its coiled-coil domains. Further study revealed that TPD52 mRNA and miRNA-223 expression was elevated, while the expression of KLF 9 and PKCε was reduced in the blood of ovarian cancer patients. Furthermore, TPD52 and miR-223 expression were upregulated in the early stages of cancer and non-metastatic cancers.ConclusionTPD52, miR-223, PKCε, and KLF9, can be used as a blood based markers for disease prognosis, metastasis, and treatment response. The study outcomes hold great potential to be translated at the clinical level after further validation on larger cohorts.

MRI graph parameters are longitudinal markers of neuronal integrity in multiple sclerosis

PurposeWe sought to determine if structural network parameters add to traditional markers of MS treatment response following immunoablation and autologous haemopoietic stem cell transplantation (IAHSCT). The post-IAHSCT paradigm afforded us the opportunity to study MS patients after relapsing biology had been effectively suppressed, enabling us to study the cortical substrate of progressive MS in a less confounded manner. MethodsIn this analysis of data from a phase 2 prospective study, associations between magnetic resonance graph parameters, N-acetylaspartate to creatine ratio (NAA/Cr), and serum neurofilament light chain (sNfL), amongst other markers, were assessed at 3 months pre-and 12 months post-IAHSCT. Correlations between graph parameter score changes and markers of brain health were calculated. Predictive factors of NAA/Cr or sNfL levels were calculated, adjusting for reference models. Model improvements were evaluated using the G2 likelihood-ratio test. Results24 patients (aged 18–38) were evaluated. Post-IAHSCT, high NAA/Cr and low sNfL (both measures of neuronal injury) were respectively associated with more favourable degree, density, clustering and path lengths, and degree, γ, and path length. Post-IAHSCT, absolute change in degree, path length and γ were associated with NAA/Cr and sNfL. Multivariate analysis demonstrated that the relative change in network parameters after IAHSCT accounted for 14% and 35% more variance in NAA/Cr and sNfL levels respectively than the reference model alone. ConclusionsCross-sectionally and longitudinally, network parameters demonstrate added utility as markers of disease severity in MS. These measures have the potential to capture cortical changes relevant to progressive non-relapsing biology in MS.

An end is in sight: a perspective on PCR as an endpoint for Chagas disease treatment trials

Novel therapies for chronic indeterminate Chagas disease (CICD) are needed, but trials are limited by the absence of tests to detect infection and early treatment efficacy. This perspective highlights the shortfalls and strengths of polymerase chain reaction (PCR) as a study endpoint for anti-parasitic drug development. Serologic reversion, the gold standard test of cure, may take decades to occur in adults and therefore is challenging as an endpoint for drug development. Use of PCR as a marker of infection and treatment response has notable limitations due to low parasitemia in CICD, fluctuations in circulating (versus tissue) parasite burden, strain differences, and assay performance. It is, however, rapidly responsive to therapy, and technological advances have improved detection of different strains and may allow for parasite quantification. Until we have more sensitive tests for parasitological clearance, PCR as a measure of treatment failure may be the best available efficacy endpoint to accelerate early development of much-needed novel therapies. Adequately designed clinical studies are needed to correlate PCR clearance with clinical outcomes and to identify novel biomarkers predictive of clinical outcomes in patients with CICD. Public-private partnerships and health authority engagement are paramount to identify feasible trial endpoints and deliver promising new drug candidates for Chagas disease.

Correlation of drug exposure and bacterial susceptibility with treatment response for Mycobacterium avium complex lung disease: protocol for a prospective observational cohort study

IntroductionThe burden of Mycobacterium avium complex (MAC) lung disease is increasing globally and treatment outcome is in general poor. Therapeutic drug monitoring has the potential to improve treatment outcome by...

BAFF as a predictive marker for treatment response in immune thrombocytopenia patients

Abstract Background Immune thrombocytopenic purpura (ITP) is a hematological autoimmune bleeding disorder that characterized by isolated thrombocytopenia (platelet count &lt;100 × 109/L) with unclear pathophysiology due to contribution of many cytokines, one of them is B-cell activating factor (BAFF) which affect both B-cell and T-cell activation and survival. Objectives This work aimed to study serum BAFF levels in the Egyptian ITP patients, and the relation between its level and response to steroid therapy, as well its value as a predictive marker for steroid response in ITP patients. Patients and methods 90 subjects were recruited, and divided into 45 patients with primary ITP, and 45 healthy subjects. Serum BAFF was estimated using the ELISA technique. Results BAFF level was significantly higher in the ITP patients than in the control group. Serum BAFF level was significantly higher in newly diagnosed ITP cases and steroids-resistant ITP cases. BAFF was negatively correlated with platelet count, while MPV, PDW, and LDH were positively correlated, BAFF level at a cut-off 201.01 pg/ml is a good predictive for steroid resistance in ITP cases. Conclusion BAFF could be a good inexpensive helper to determine the response to steroid treatment in ITP cases.

Pattern Analysis of Daily Lesion Volume Trajectories for Early Prediction of Glioblastoma Progression During MR-Linac Radiotherapy

Distinguishing between true progression (TP) and pseudoprogression (PP) post-radiotherapy (RT) is of paramount importance for treatment management of patients with glioblastoma (GBM). MR-Linac systems allow for daily monitoring of tumor changes throughout the course of RT. We hypothesized that the patterns of tumor volume change during RT may enable early prediction of treatment response. Using an IRB-approved prospective cohort of GBM patients undergoing 30 fractions of chemoRT to 60 Gy on a 0.35T MR-Linac, tumor/edema (tumor lesion) regions of interest (ROI) were contoured on daily T2-weighted treatment set-up scans. The obtained tumor lesion (TL) volume changes during treatment were smoothed with a moving average Gaussian window over time. Non-negative Matrix Factorization (NMF) was applied to the data matrix D (N x F), containing the trajectories in its rows for each patient, where N is the number of patients analyzed and F is the number of fractions. NMF represents D as a linear combination of three temporal (hidden) patterns and their weights in each individual trajectory. The same analysis was performed for ΔD, containing the changes in volumes with reference to the first fraction. The calculated weights were scaled in [0, 1], expressed as probabilities (by ℓ1-normalization) and used as features in Linear Discriminant Analysis (LDA). The LDA model was trained to differentiate between no progression (NP), PP and TP, and assessed by leave-one-subject-out cross-validation. Thirty-six patients were screened for inclusion: 9 were excluded due to no T2 lesion (resection cavity only). Of the remaining 27 GBM patients analyzed, 10 had no tumor growth on first post-RT diagnostic MRI, 6 were determined to have PP based on regression or long-term stability of findings, and 11 had TP due to continued progression of disease past 6 months, rapid patient death from disease, or tissue sampling showing active malignancy. With the use of only 2 features, LDA achieved an overall accuracy of 70.4% classifying correctly: 6 (60%), 4 (67%), and 9 (82%) patients with NP, PP, and TP, respectively. The temporal NMF patterns (monotonous decrease, rapid increase during the third part of the treatment, etc.) indicate that there is enough signal to classify patients' response based on the pattern tumor volume changes during RT. We identified tumor dynamics' patterns during RT, indicative of differential behavior of tumor growth between TP and PP. Although with a limited number of patients, these initial results suggest that tumor volume changes during treatment may provide early markers of treatment response. This could allow physicians to adapt/intensify treatment in real time for poorly responding patients. Next steps include automating the process of real-time tumor volume monitoring by incorporating a deep learning solution for automatic volume delineation on daily treatment set-up scans.

Feasibility of circulating tumor DNA as a marker for treatment response and prognosis in in BRCA non-mutated patients with platinum-sensitive recurrent ovarian cancer (OPEB-01) (011)

Feasibility of circulating tumor DNA as a marker for treatment response and prognosis in in BRCA non-mutated patients with platinum-sensitive recurrent ovarian cancer (OPEB-01) (011)

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.