Markers Of Treatment Response Research Articles

Phosphorylated neurofilament heavy chain in cerebrospinal fluid and plasma as a Nusinersen treatment response marker in childhood-onset SMA individuals from Serbia.

Biomarkers capable of reflecting disease onset and short- and long-term therapeutic effects in individuals with spinal muscular atrophy (SMA) are still an unmet need and phosphorylated neurofilament heavy chain (pNF-H) holds significant promise. We conducted a longitudinal prospective study to evaluate pNF-H levels in the cerebrospinal fluid (CSF) and plasma of 29 individuals with childhood-onset SMA treated with Nuinersen (SMA type 1: n = 6, 2: n = 17, 3: n = 6). pNF-H levels before and during treatment were compared with the levels of controls (n = 22), patients with Duchenne muscular dystrophy (n = 17), myotonic dystrophy type 1 (n = 11), untreated SMA individuals with chronic type 3 disease (n = 8), and children with presymptomatic SMA (n = 3). SMA type 1 showed the highest mean CSF pNF-H levels before treatment initiation. All Nusinersen-treated individuals (types 1, 2, and 3) showed significantly elevated mean baseline CSF pNF-H compared to controls, which inversely correlated with age at disease onset, age at first dose, disease duration and the initial CHOP INTEND result (SMA type 1 and 2). During 22 months of treatment, CSF pNF-H levels declined during loading doses, stabilizing at reduced levels from the initial maintenance dose in all individuals. Baseline plasma pNF-H levels in type 1 and 2 SMA were significantly increased compared to other cohorts and decreased notably in type 1 after 2 months of treatment and type 2 after 14 months. Conversely, SMA type 3, characterized by lower baseline pNF-H levels, did not show significant fluctuations in plasma pNF-H levels after 14 months of treatment. Our findings suggest that CSF pNF-H levels in untreated SMA individuals are significantly higher than in controls and that monitoring of CSF pNF-H levels may serve as an indicator of rapid short-term treatment response in childhood-onset SMA individuals, irrespective of the subtype of the disease, while also suggesting its potential for assessing long-term suppression of neurodegeneration. Plasma pNF-H may serve as an appropriate outcome measure for disease progression and/or response to treatment in types 1 and 2 but not in type 3. Presymptomatic infants with SMA may show elevated pNF-H levels, confirming early neuronal degeneration.

Advanced neuroimaging techniques to explore the effects of motor and cognitive rehabilitation in multiple sclerosis.

Progress in magnetic resonance imaging (MRI) technology and analyses is improving our comprehension of multiple sclerosis (MS) pathophysiology. These advancements, which enable the evaluation of atrophy, microstructural tissue abnormalities, and functional plasticity, are broadening our insights into the effectiveness and working mechanisms of motor and cognitive rehabilitative treatments. This narrative review with selected studies discusses findings derived from the application of advanced MRI techniques to evaluate structural and functional neuroplasticity modifications underlying the effects of motor and cognitive rehabilitative treatments in people with MS (PwMS). Current applications as outcome measure in longitudinal trials and observational studies, their interpretation and possible pitfalls and limitations in their use are covered. Finally, we examine how the use of these techniques could evolve in the future to improve monitoring of motor and cognitive rehabilitative treatments. Despite substantial variability in study design and participant characteristics in rehabilitative studies for PwMS, improvements in motor and cognitive functions accompanied by structural and functional brain modifications induced by rehabilitation can be observed. However, significant enhancements to refine rehabilitation strategies are needed. Future studies in this field should strive to implement standardized methodologies regarding MRI acquisition and processing, possibly integrating multimodal measures. This will help identifying relevant markers of treatment response in PwMS, thus improving the use of rehabilitative interventions at individual level. The combination of motor and cognitive strategies, longer periods of treatment, as well as adequate follow-up assessments will contribute to enhance the quality of evidence in support of their routine use.

Developing and Validating Marker of Treatment Response for Subcallosal Cingulate Deep Brain Stimulation

Developing and Validating Marker of Treatment Response for Subcallosal Cingulate Deep Brain Stimulation

Prior psychiatric morbidity and differential psychopharmacological treatment patterns: Exploring the heterogeneity of bipolar disorder in a nationwide study of 9594 patients.

Individuals with bipolar disorders (BD) have heterogenic pre-onset illness courses and responses to treatment. The pattern of illness preceding the diagnosis of BD may be a marker of future treatment response. Here, we examined associations between psychiatric morbidity preceding the diagnosis of BD and pharmacological treatment patterns in the 2 years following diagnosis. In this register-based study, we included all patients with a diagnosis of BD attending Danish Psychiatric Services between January 1, 2012 and December 31, 2016. We examined the association between a diagnosis of substance use disorder, psychosis (other than schizophrenia or schizoaffective disorder), unipolar depression, anxiety/OCD, PTSD, personality disorder, or ADHD preceding BD and pharmacological treatment patterns following the diagnosis of BD (lithium, valproate, lamotrigine, antidepressants, olanzapine, risperidone, and quetiapine) via multivariable Cox proportional hazards regression adjusted for age, sex, and year of BD diagnosis. We included 9594 patients with a median age of 39 years, 58% of whom were female. Antidepressants, quetiapine, and lamotrigine were the most commonly used medications in BD and were all linked to prior depressive illness and female sex. Lithium was used among patients with less diagnostic heterogeneity preceding BD, while valproate was more likely to be used for patients with prior substance use disorder or ADHD. The pharmacological treatment of BD is linked to psychiatric morbidity preceding its diagnosis. Assuming that these associations reflect well-informed clinical decisions, this knowledge may inform future clinical trials by taking participants' prior morbidity into account in treatment allocation.

One size does not fit all: notable individual variation in brain activity correlates of antidepressant treatment response.

To date, no robust electroencephalography (EEG) markers of antidepressant treatment response have been identified. Variable findings may arise from the use of group analyses, which neglect individual variation. Using a combination of group and single-participant analyses, we explored individual variability in EEG characteristics of treatment response. Resting-state EEG data and Montgomery-Åsberg Depression Rating Scale (MADRS) symptom scores were collected from 43 patients with depression before, at 1 and 12 weeks of pharmacotherapy. Partial least squares (PLS) was used to: 1) identify group differences in EEG connectivity (weighted phase lag index) and complexity (multiscale entropy) between eventual medication responders and non-responders, and 2) determine whether group patterns could be identified in individual patients. Responders showed decreased alpha and increased beta connectivity, and early, widespread decreases in complexity over treatment. Non-responders showed an opposite connectivity pattern, and later, spatially confined decreases in complexity. Thus, as in previous studies, our group analyses identified significant differences between groups of patients with different treatment outcomes. These group-level EEG characteristics were only identified in ~40-60% of individual patients, as assessed quantitatively by correlating the spatiotemporal brain patterns between groups and individual results, and by independent raters through visualization. Our single-participant analyses suggest that substantial individual variation exists, and needs to be considered when investigating characteristics of antidepressant treatment response for potential clinical applicability. https://clinicaltrials.gov, identifier NCT00519428.

Clinical Utility of Circulating Tumor DNA in Patients With Advanced KRASG12C-Mutated NSCLC Treated With Sotorasib

IntroductionFor patients with KRASG12C-mutated NSCLC who are treated with sotorasib, there is a lack of biomarkers to guide treatment decisions. We therefore investigated the clinical utility of pretreatment and on-treatment circulating tumor DNA (ctDNA) and treatment-emergent alterations on disease progression. MethodsPatients with KRASG12C-mutated NSCLC treated with sotorasib were prospectively enrolled in our biomarker study (NCT05221372). Plasma samples were collected before sotorasib treatment, at first-response evaluation and at disease progression. The TruSight Oncology 500 panel was used for ctDNA and variant allele frequency analysis. Tumor response and progression-free survival were assessed per Response Evaluation Criteria in Solid Tumors version 1.1. ResultsPretreatment KRASG12C ctDNA was detected in 50 of 66 patients (76%). Patients with detectable KRASG12C had inferior progression-free survival (hazard ratio [HR] 2.13 [95% confidence interval [CI]: 1.06–4.30], p = 0.031) and overall survival (HR 2.61 [95% CI: 1.16–5.91], p = 0.017). At first-response evaluation (n = 40), 29 patients (73%) had a molecular response. Molecular nonresponders had inferior overall survival (HR 3.58 [95% CI: 1.65–7.74], p = 0.00059). The disease control rate was significantly higher in those with a molecular response (97% versus 64%, p = 0.015). KRAS amplifications were identified as recurrent treatment-emergent alterations. ConclusionsOur data suggest detectable pretreatment KRASG12C ctDNA as a marker for poor prognosis and on-treatment ctDNA clearance as a marker for treatment response. We identified KRAS amplifications as a potential recurring resistance mechanism to sotorasib. Identifying patients with superior prognosis could aid in optimizing time of treatment initiation, and identifying patients at risk of early progression could allow for earlier treatment decisions.

490 A CTS team approach to Gold Nanorod (GNR) Theranostics in Adoptive Cell Therapy (ACT)

OBJECTIVES/GOALS: The objective ofthis study is to use GNR technology to track immune cells infiltrating malignant brain tumors that are delivered as part of a novel immunotherapeutic strategy. We seek to implement this new platform to elucidate the underlying mechanisms of therapeutic benefit from ACT via correlation between biodistribution and efficacy. METHODS/STUDY POPULATION: Utilizing the inherent two-photon luminescent signal of GNRs, we will identify uptake and phenotype of lineage negative hematopoietic stem cells (HSCs) in vitro. HSCs will be isolated from the bone marrow of 6-week-old C57bl/6 female mice. Following isolation, HSCs will be co-cultured with varying concentrations of GNRs in DMEM w/o sodium pyruvate for 24 hours, tested for viability, and images to quantify uptake and identify phenotyping. CT contrast of our novel Iodine-capped PEGylated gold nanorods will be confirmed through microCT and biodistribution of HSCs at time points after injection will be identified via CT visualizationin vivo. RESULTS/ANTICIPATED RESULTS: We expect that increased GNR signaling 24 hours post-transplant in the tumors of glioma-bearing mice will be positively correlated with long term survival following ACT. Published data from our labs have revealed that CCR2+ lineage-negative HSCs significantly accumulate in tumor of glioma-bearing mice12. Importantly, CCR2+ lineage-negative HSCs promote differentiation to dendritic cells in the tumor, increase antitumor T cell responses mediated by cross-priming and cross-presentation, and improve efficacy of immune checkpoint inhibition12. Given that HSCs are important in mediating immunotherapy efficacy, we seek to correlate the accumulation of GNR signaling within the tumor as a marker of treatment response. DISCUSSION/SIGNIFICANCE: Adoptively transferred cells have been imaged using numerous published methods. While promising to the field of immunotherapy, these methods lack significant clinical validation. GNRs have not been used to study hematopoietic stem cells in the context of ACT and brain malignancies. Our research is poised to address this gap.

(653) - Heart Rate Variability (HRV) as a Marker of Treatment Response in PAH

(653) - Heart Rate Variability (HRV) as a Marker of Treatment Response in PAH

Psychomotor retardation: What about the partial responders to magnetic transcranial stimulation in treatment resistant depression ?

ObjectivePsychomotor retardation is a core clinical component of Major Depressive Disorder responsible for disability and is known as a treatment response marker of biological treatments for depression. Our objective was to describe cognitive and motoric measures changes during a treatment by repetitive Transcranial Magnetic Stimulation (rTMS) within the THETAD-DEP trial for treatment-resistant depression (TRD), and compare those performances at the end of treatment and one month after between responders (>50% improvement on MADRS score), partial responders (25–50%) and non-reponders (no clinically relevant improvement). Our secondary aim was to investigate baseline psychomotor performances associated with non-response and response even partial. MethodsFifty-four patients with treatment-resistant unipolar depression and treated by either high frequency 10 Hz rTMS or iTBS for 4 weeks (20 sessions) underwent assessment including French Retardation Rating Scale for Depression (ERD), Verbal Fluency test, and Trail Making Test A. before, just after treatment and one month later. Results20 patients were responders (R, 21 partial responders (PR) and 13 non-responders (NR). rTMS treatment improved psychomotor performances in the R and PR groups unlike NR patients whose psychomotor performance was not enhanced by treatment. At baseline, participants, later identified as partial responders, showed significantly higher performances than non-responders. ConclusionHigher cognitivo-motor performances at baseline may be associated with clinical improvement after rTMS treatment. This work highlights the value of objective psychomotor testing for the identification of rTMS responders and partial responders, and thus may be useful for patient selection and protocol individualization such as treatment continuation for early partial responders.

Effect of NAT2, GSTM1 and CYP2E1 genetic polymorphisms on plasma concentration of isoniazid and its metabolites in patients with tuberculosis, and the assessment of exposure-response relationships.

Objectives: Isoniazid is a key drug in the chemotherapy of tuberculosis (TB), however, interindividual variability in pharmacokinetic parameters and drug plasma levels may affect drug responses including drug induced hepatotoxicity. The current study investigated the relationships between isoniazid exposure and isoniazid metabolism-related genetic factors in the context of occurrence of drug induced hepatotoxicity and TB treatment outcomes. Methods: Demographic characteristics and clinical information were collected in a prospective TB cohort study in Latvia (N = 34). Time to sputum culture conversion (tSCC) was used as a treatment response marker. Blood plasma concentrations of isoniazid (INH) and its metabolites acetylisoniazid (AcINH) and isonicotinic acid (INA) were determined at three time points (pre-dose (0h), 2h and 6h after drug intake) using liquid chromatography-tandem mass spectrometry. Genetic variations of three key INH-metabolizing enzymes (NAT2, CYP2E1, and GSTM1) were investigated by application PCR- and Next-generation sequencing-based methods. Depending on variables, group comparisons were performed by Student's t-test, one-way ANOVA, Mann-Whitney-Wilcoxon, and Kruskal-Wallis tests. Pearson correlation coefficient was calculated for the pairs of normally distributed variables; model with rank transformations were used for non-normally distributed variables. Time-to-event analysis was performed to analyze the tSCC data. The cumulative probability of tSCC was obtained using Kaplan-Meier estimators. Cox proportional hazards models were fitted to estimate hazard rate ratios of successful tSCC. Results: High TB treatment success rate (94.1%) was achieved despite the variability in INH exposure. Clinical and demographic factors were not associated with either tSCC, hepatotoxicity, or INH pharmacokinetics parameters. Correlations between plasma concentrations of INH and its metabolites were NAT2 phenotype-dependent, while GSTM1 genetic variants did not showed any effects. CYP2E1*6 (T > A) allelic variant was associated with INH pharmacokinetic parameters. Decreased level of AcINH was associated with hepatotoxicity, while decreased values of INA/INH and AcINH/INH were associated with month two sputum culture positivity. Conclusion: Our findings suggest that CYP2E1, but not GSTM1, significantly affects the INH pharmacokinetics along with NAT2. AcINH plasma level could serve as a biomarker for INH-related hepatotoxicity, and the inclusion of INH metabolite screening in TB therapeutic drug monitoring could be beneficial in clinical studies for determination of optimal dosing strategies.

Abstract 4157: Combining hyperpolarized magnetic resonance and positron emission tomography to interrogate prostate cancer metabolism

Abstract Background: There is an unmet clinical need for imaging biomarkers to distinguish indolent from aggressive prostate cancer (PCa). Many advanced and aggressive PCa patients receiving anti-androgens (enzalutamide) develop resistance. It is hypothesized that dysregulated cell metabolism is a key driver for PCa progression and therapy resistance. Two pathways commonly involved in PCa are glycolysis and fatty acid metabolism. Therefore, metabolic imaging and metabolomics were performed on enzalutamide sensitive/resistant, Androgen Receptor dependent (AR+) and AR independent (AR-) patient derived xenograft (PDX) tumors. To interrogate both pathways, [1-13C]-pyruvate hyperpolarized magnetic resonance spectroscopy (HP-MRS) and [18F]-fluorodeoxyglucose positron emission tomography (18F-FDG) for glycolysis, and [18F]-fluoro-pivalic acid positron emission tomography (18F-FPIA) for fatty acid metabolism were employed. 1H Nuclear Magnetic Resonance (NMR) spectroscopy and liquid chromatography with tandem mass spectrometry (LC-MS-MS) were employed for validation purposes. Methods: [1-13C]-labeled pyruvic acid was hyperpolarized using a DNP HyperSense polarizer following standard protocol. Anatomical MRI and 13C-MRS were obtained on different PCa PDX mouse models at two different time points using a Bruker 7T scanner. The PDX models included AR+ enzalutamide sensitive (183-A, 180-30), AR+ enzalutamide resistant (274-4), and AR- (144-4, 114-B). The time points imaged were before and after 7 days of treatment with enzalutamide. 1H-NMR spectroscopy was performed on extracted tissue. Simultaneously, 18F-FPIA-PET imaging were acquired on the same models on an Albira trimodal PET station. Results: The dynamic metabolic flux ratio, lactate-to-pyruvate (Lac/Pyr) was determined in vivo and used as a treatment response marker. The Lac/Pyr ratios were significantly higher in resistant tumors compared to sensitive tumors (p<0.01). The enzalutamide sensitive group had a lower Lac/Pyr ratio after treatment, while the enzalutamide resistant group had a higher Lac/Pyr ratio. After treatment, there was also a decrease in [18F]-FDG uptake, corresponding to the HP-MRS data. This was expected as both Pyruvate and [18F]-FDG interrogate the glycolytic pathway. As for the fatty acid metabolic imaging, PET imaging also revealed that [18F]-FPIA is transported into the tumors, and we are currently exploring how its uptake varies between AR (+/-) PCa-PDX tumors and enzalutamide resistant/sensitive models. Ex vivo NMR and mass spectrometry-based metabolomics validated the in vivo HP-MRS data with higher lactate levels in drug resistant tumors. Conclusion: Combining HP-MRS and PET presents an exciting opportunity to realize imaging-based personalized medicine in different AR (+/-) PCa-PDX preclinical models by interrogating glycolysis and fatty acid oxidation pathways. Citation Format: Muxin Wang, José S. Enriquez, Prasanta Dutta, Jenny Han, Peter Shepherd, Daniel Frigo, Federica Pisaneschi, Pratip K. Bhattacharya. Combining hyperpolarized magnetic resonance and positron emission tomography to interrogate prostate cancer metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 4157.

Association Between Mood Disorder Severity, Treatment Response and Systemic Inflammatory Markers: Exploring the Role of NLR, PLR, MLR, and SII

Association Between Mood Disorder Severity, Treatment Response and Systemic Inflammatory Markers: Exploring the Role of NLR, PLR, MLR, and SII

Use of multiple pharmacodynamic measures to deconstruct the Nix-TB regimen in a short-course murine model of tuberculosis.

A major challenge for tuberculosis (TB) drug development is to prioritize promising combination regimens from a large and growing number of possibilities. This includes demonstrating individual drug contributions to the activity of higher-order combinations. A BALB/c mouse TB infection model was used to evaluate the contributions of each drug and pairwise combination in the clinically relevant Nix-TB regimen [bedaquiline-pretomanid-linezolid (BPaL)] during the first 3 weeks of treatment at human equivalent doses. The rRNA synthesis (RS) ratio, an exploratory pharmacodynamic (PD) marker of ongoing Mycobacterium tuberculosis rRNA synthesis, together with solid culture CFU counts and liquid culture time to positivity (TTP) were used as PD markers of treatment response in lung tissue; and their time-course profiles were mathematically modeled using rate equations with pharmacologically interpretable parameters. Antimicrobial interactions were quantified using Bliss independence and Isserlis formulas. Subadditive (or antagonistic) and additive effects on bacillary load, assessed by CFU and TTP, were found for bedaquiline-pretomanid and linezolid-containing pairs, respectively. In contrast, subadditive and additive effects on rRNA synthesis were found for pretomanid-linezolid and bedaquiline-containing pairs, respectively. Additionally, accurate predictions of the response to BPaL for all three PD markers were made using only the single-drug and pairwise effects together with an assumption of negligible three-way drug interactions. The results represent an experimental and PD modeling approach aimed at reducing combinatorial complexity and improving the cost-effectiveness of in vivo systems for preclinical TB regimen development.

Repeatability of deuterium metabolic imaging of healthy volunteers at 3 T

BackgroundMagnetic resonance (MR) imaging of deuterated glucose, termed deuterium metabolic imaging (DMI), is emerging as a biomarker of pathway-specific glucose metabolism in tumors. DMI is being studied as a useful marker of treatment response in a scan-rescan scenario. This study aims to evaluate the repeatability of brain DMI.MethodsA repeatability study was performed in healthy volunteers from December 2022 to March 2023. The participants consumed 75 g of [6,6′­2H2]glucose. The delivery of 2H-glucose to the brain and its conversion to 2H-glutamine + glutamate, 2H-lactate, and 2H-water DMI was imaged at baseline and at 30, 70, and 120 min. DMI was performed using MR spectroscopic imaging on a 3-T system equipped with a 1H/2H-tuned head coil. Coefficients of variation (CoV) were computed for estimation of repeatability and between-subject variability. In a set of exploratory analyses, the variability effects of region, processing, and normalization were estimated.ResultsSix male participants were recruited, aged 34 ± 6.5 years (mean ± standard deviation). There was 42 ± 2.7 days between sessions. Whole-brain levels of glutamine + glutamate, lactate, and glucose increased to 3.22 ± 0.4 mM, 1.55 ± 0.3 mM, and 3 ± 0.7 mM, respectively. The best signal-to-noise ratio and repeatability was obtained at the 120-min timepoint. Here, the within-subject whole-brain CoVs were -10% for all metabolites, while the between-subject CoVs were -20%.ConclusionsDMI of glucose and its downstream metabolites is feasible and repeatable on a clinical 3 T system.Trial registrationClinicalTrials.gov, NCT05402566, registered the 25th of May 2022.Relevance statementBrain deuterium metabolic imaging of healthy volunteers is repeatable and feasible at clinical field strengths, enabling the study of shifts in tumor metabolism associated with treatment response.Key points• Deuterium metabolic imaging is an emerging tumor biomarker with unknown repeatability. • The repeatability of deuterium metabolic imaging is on par with FDG-PET. • The study of deuterium metabolic imaging in clinical populations is feasible.Graphical

Treatment response and clinical event-free survival in autoimmune hepatitis: A Canadian multicentre cohort study

We sought to identify predictors of outcome for people living with autoimmune hepatitis (AIH). We evaluated the clinical course of people with AIH across 11 Canadian centres. Biochemical changes were analysed using linear mixed-effect and logistic regression. Clinical outcome was dynamically modelled using time-varying Cox proportional hazard modelling and landmark analysis. In 691 patients (median age 49 years, 75.4% female), with a median follow-up of 6 years (25th-75th percentile, 2.5-11), 118 clinical events occurred. Alanine aminotransferase (ALT) normalisation occurred in 63.8% of the cohort by 12-months. Older age at diagnosis (odd ratio [OR] 1.19, 95% CI 1.06-1.35) and female sex (OR 1.94, 95% CI 1.18-3.19) were associated with ALT normalisation at 6 months, whilst baseline cirrhosis status was associated with reduced chance of normalisation at 12 months (OR 0.52, 95% CI 0.33-0.82). Baseline total bilirubin, aminotransferases, and immunoglobulin G (IgG) values, as well as initial prednisone dose, did not predict average ALT reduction. At baseline, older age (hazard ratio [HR] 1.25, 95% CI 1.12-1.40), cirrhosis at diagnosis (HR 3.67, 95% CI 2.48-5.43), and elevated baseline total bilirubin (HR 1.36, 95% CI 1.17-1.58) increased risk of clinical events. Prolonged elevations in ALT (HR 1.07, 95% CI 1.00-1.13) and aspartate aminotransferase (HR 1.13, 95% CI 1.06-1.21), but not IgG (HR 1.01, 95% CI 0.95-1.07), were associated with higher risk of clinical events. Higher ALT at 6 months was associated with worse clinical event-free survival. In people living with AIH, sustained elevated aminotransferase values, but not IgG, are associated with poorer long-term outcomes. Biochemical response and long-term survival are not associated with starting prednisone dose. Using clinical data from multiple Canadian liver clinics treating autoimmune hepatitis (AIH), we evaluate treatment response and clinical outcomes. For the first time, we apply mixed-effect and time-varying survival statistical methods to rigorously examine treatment response and the impact of fluctuating liver biochemistry on clinical event-free survival. Key to the study impact, our data is 'real-world', represents a diverse population across Canada, uses continuous measurements over follow-up, and our findings help inform risk stratification of patients. We provide evidence for treating clinicians, as well as those developing and evaluating new therapies, to seek evidence of good treatment response by keeping aminotransferase activity values within the reference range. Our results challenge the role of IgG as a marker of treatment response and if normalisation of IgG should remain an important part of the definition of biochemical remission. Our analysis further highlights that baseline markers of disease severity may not prognosticate early treatment response. Additionally, the initial prednisone dose may be less relevant for achieving aminotransferase normalisation. This is important for patients and treating clinicians given the relevance and importance of side-effects of treatment for patients.

Emerging potential of immunopeptidomics by mass spectrometry in cancer immunotherapy.

With significant advances in analytical technologies, research in the field of cancer immunotherapy, such as adoptive T cell therapy, cancer vaccine, and immune checkpoint blockade (ICB), is currently gaining tremendous momentum. Since the efficacy of cancer immunotherapy is recognized only by a minority of patients, more potent tumor-specific antigens (TSAs, also known as neoantigens) and predictive markers for treatment response are of great interest. In cancer immunity, immunopeptides, presented by human leukocyte antigen (HLA) class I, play a role as initiating mediators of immunogenicity. The latest advancement in the interdisciplinary multiomics approach has rapidly enlightened us about the identity of the "dark matter" of cancer and the associated immunopeptides. In this field, mass spectrometry (MS) is a viable option to select because of the naturally processed and actually presented TSA candidates in order to grasp the whole picture of the immunopeptidome. In the past few years the search space has been enlarged by the multiomics approach, the sensitivity of mass spectrometers has been improved, and deep/machine-learning-supported peptide search algorithms have taken immunopeptidomics to the next level. In this review, along with the introduction of key technical advancements in immunopeptidomics, the potential and further directions of immunopeptidomics will be reviewed from the perspective of cancer immunotherapy.

Predictive Markers of Treatment Response to Neoadjuvant Systemic Therapy with Dual HER2-Blockade.

In patients with human epidermal growth factor receptor 2 (HER2)-positive breast cancer, achievement of pathologic complete response (pCR) is a known prognostic indicator after neoadjuvant systemic therapy (NAST). We investigated the clinicopathological factors associated with pCR in patients with HER2-positive breast cancer treated with dual HER2-blockade. In this retrospective study, 348 patients with HER2-positive breast cancer who received NAST with docetaxel and carboplatin, combined with trastuzumab and pertuzumab (TCHP), were included. Of the 348 patients with HER2 protein expression data, 278 (79.9%) had HER2 immunochemistry (IHC) 3+. Data on tumor-infiltrating lymphocyte (TIL) levels were available for 305 patients, showing a median TIL level of 20% (IQR 5-50), among which 121 (39.7%) had high TIL levels (≥30%). Estrogen receptor (ER) status (77.9% in ER-negative vs. 47.5% in ER-positive; p < 0.001), HER2 protein expression (71.6% in IHC 3+ vs. 34.3% in IHC 2+; p < 0.001), and TIL levels (71.9% in high vs. 57.6% in low; p = 0.011) were significantly associated with the pCR rate. In addition, we observed a significant link between numerical TIL levels (per 10% increment) and the pCR rate. After adjusting other clinicopathologic factors, ER status (low expression [defined as 1-9% expression] or negative), HER2 IHC 3+ and numerical TIL levels (per 10% increment), and high TIL levels (≥30%) were found to be independent predictors of pCR. Notably, in ER-negative breast cancer, the treatment response was excellent, irrespective of HER2 expression and TIL levels. Conversely, in ER-positive cases, low ER expression, HER2 IHC 3+, and numerical TIL levels or high TIL levels emerged as independent predictors of pCR. Our results suggest that ER expression, HER2 protein expression, and TIL levels serve as valuable predictors of the treatment response to neoadjuvant TCHP.

Nasal IgE is a Potential Marker of Aspirin Treatment Response in Patients with N-ERD

Nasal IgE is a Potential Marker of Aspirin Treatment Response in Patients with N-ERD

Coagulation factor V in breast cancer: a p53-regulated tumor suppressor and predictive marker for treatment response to chemotherapy

BackgroundPatients with cancer are at an increased risk of developing coagulation complications, and chemotherapy treatment increases the risk. Tumor progression is closely linked to the hemostatic system. Breast cancer tumors express coagulation factor V (FV), an essential factor in blood coagulation. The functional role of FV during treatment with chemotherapy is poorly understood and was explored in this study. ObjectivesWe aimed to investigate the role of FV in breast cancer progression by exploring associations with treatment response, gene regulation, and the functional effects of FV. MethodsThe receiver operating characteristic plotter was used to explore the predictive value of FV mRNA (F5) expression for treatment with FEC (5-fluorouracil, anthracycline, and cyclophosphamide). Breast cancer cohorts were analyzed to study treatment response to FEC. The effect of chemotherapy on F5 expression, the regulation of F5, and the functional effects of FV dependent and independent of chemotherapy were studied in breast cancer cell lines. ResultsF5 tumor expression was significantly higher in responders to FEC than in nonresponders. In vitro experiments revealed that anthracycline treatment increased the expression of F5. Inhibition and knockdown of p53 reduced the anthracycline-induced F5 expression. Mutation of a p53 half-site (c.158+1541/158+1564) in a luciferase plasmid reduced luciferase activity, suggesting that p53 plays a role in regulating F5. FV overexpression increased apoptosis and reduced proliferation slightly during anthracycline treatment. ConclusionOur study identified F5 as a p53-regulated tumor suppressor candidate and a promising marker for response to chemotherapy. FV may have functional effects that are therapeutically relevant in breast cancer.

HIGH COPY NUMBER POLYMORPHISMS OF ALPHA DEFENSIN 1-3 ARE ASSOCIATED WITH THERAPEUTIC RESPONSIVENESS IN INFLAMMATORY BOWEL DISEASE

Abstract BACKGROUND AND PURPOSE Prednisolone therapy is the first choice for the treatment of acute severe ulcerative colitis (ASUC), however, the refractory case is sometimes observed. Alpha defensin 1-3 (DEFA1A3) stored in neutrophils acts as an effector factor of innate immunity. It has been reported that the copy number variation of the DEFA1A3 gene is associated with the severity of ulcerative colitis (UC). However, the impact of DEFA1A3 in response to treatment have not been fully investigated. Therefore, we aimed to clarify the relationship between the number of DEFA1A3 copies and UC prednisolone treatment response. SUBJECTS AND METHODS Patients with UC who had attended our department and related facilities and had the number of DEFA1A3 copies measured were included between 2020 and 2022. The number of DEFA1A3 copies were measured using droplet digital PCR after DNA extraction from peripheral blood mononuclear cells. Mayo score was used to determine the response to prednisolone and severity of UC. ASUC was defined as presence of more than 6 bloody stools/d along with any one of the following: pulse rate&amp;gt; 90 bpm, temperature &amp;gt; 37.8 °C, hemoglobin &amp;lt; 10.5 g/dL, and/or CRP &amp;gt; 30mg/L. Clinical background and various parameters were extracted from medical record information. RESULTS The 47 ASUC patients were included in the study. The median DEFA1A3 copy number of the patients was 9, the median DEFA1A3 copy number in ASUC was higher than that in healthy subjects. The DEFA1A3 copy number was significantly higher in the non-remission group than in the remission group after treatment with prednisolone.There were no differences in other parameters such as CRP and WBC between the two groups. CONCLUSION DEFA1A3 copy number may be a predictive marker of prednisolone treatment response.