Biomarkers Of Treatment Response Research Articles

The association between neuroendocrine/glucose metabolism and clinical outcomes and disease course in different clinical states of bipolar disorders.

The treatment of bipolar disorder (BD) remains challenging. The study evaluated the impact of the hypothalamic-pituitary-adrenal (HPA) axis/hypothalamic-pituitary-thyroid (HPT) axis and glucose metabolism on the clinical outcomes in patients with bipolar depression (BD-D) and manic bipolar (BD-M) disorders. The research design involved a longitudinal prospective study. A total of 500 BD patients aged between 18 and 65 years treated in 15 hospitals located in Western China were enrolled in the study. The Young Mania Rating Scale (YMRS) and Montgomery and Asberg Depression Rating Scale (MADRS) were used to assess the BD symptoms. An effective treatment response was defined as a reduction in the symptom score of more than 25% after 12 weeks of treatment. The score of symptoms was correlated with the homeostatic model assessment of insulin resistance (HOMA-IR) index, the HPA axis hormone levels (adrenocorticotropic hormone (ACTH) and cortisol), and the HPT axis hormone levels (thyroid stimulating hormone (TSH), triiodothyronine (T3), thyroxine (T4), free triiodothyronine (fT3), and free thyroxine (fT4)). In the BD-M group, the YMRS was positively correlated with baseline T4 (r = 0.349, p = 0.010) and fT4 (r = 0.335, p = 0.013) and negatively correlated with fasting insulin (r = -0.289, p = 0.013). The pre-treatment HOMA-IR was significantly correlated with adverse course (p = 0.045, OR = 0.728). In the BD-D group, the baseline MADRS was significantly positively correlated with baseline fT3 (r = 0.223, p = 0.032) and fT4 (r = 0.315, p = 0.002), while baseline T3 (p = 0.032, OR = 5.071) was significantly positively related to treatment response. The HPT axis and glucose metabolism were closely associated with clinical outcomes at 12 weeks in both BD-D and BD-M groups. If confirmed in further longitudinal studies, monitoring T3 in BD-D patients and HOMA-IR for BD-M could be used as potential treatment response biomarkers.

Prospective Evaluation of Circulating Tumor DNA using Next Generation Sequencing as a Biomarker during Neoadjuvant Chemotherapy in Localized Pancreatic Cancer.

In this prospective study, we aim to characterize the prognostic value of circulating tumor DNA (ctDNA) by next-generation-sequencing (NGS) in patients undergoing neoadjuvant chemotherapy (NAC) for pancreatic ductal adenocarcinoma (PDAC). Circulating tumor DNA is a promising blood-based biomarker that is prognostic in several malignancies. Detection of ctDNA by NGS may provide insights regarding the mutational profiles in PDAC to help guide clinical decisions for patients in a potentially curative setting. However, the utility of ctDNA as a biomarker in localized PDAC remains unclear. Patients with localized PDAC were enrolled in a prospective study at Northwestern Medicine between October 2020 and October 2022. Blood samples were collected to perform targeted tumor agnostic NGS utilizing the Tempus x|F 105 gene panel at three timepoints: pre-therapy (at diagnosis), post-NAC, and after local therapy, including surgery. The relationship between ctDNA detection and CA19-9, and the prognostic significance of ctDNA detection were analyzed. 56 patients were included in the analysis. ctDNA was detectable in 48% at diagnosis, 33% post-NAC, and 41% after local therapy. After completion of NAC, patients with detectable ctDNA had higher CA19-9 levels versus those without (78.4 vs. 30.0, P=0.02). The presence of baseline ctDNA was associated with a CA19-9 response; those without ctDNA had a significant CA19-9 response following NAC (109.0U/mL vs. 31.5U/mL; P=0.01), while those with ctDNA present at diagnosis did not (198.1U/mL vs. 113.8U/mL; P=0.77). In patients treated with NAC, the presence of KRAS ctDNA at diagnosis was associated with and independently predicted worse progression-free-survival. This report demonstrates the prognostic value of ctDNA analysis with NGS in localized PDAC. NGS ctDNA is a biomarker of treatment response to NAC. KRAS ctDNA at diagnosis independently predicts worse survival in patients treated with NAC.

Des-gamma-carboxy prothrombin (DCP) as a biomarker for treatment response in hepatocellular carcinoma.

547 Background: Causes of variable disease response to first-line treatment with atezolizumab/bevacizumab (atezo/bev) in hepatocellular carcinoma (HCC) patients remain unclear. Identifying tumor markers that predict treatment efficacy may help raise clinical suspicion for early disease progression. The role of des-gamma-carboxy prothrombin (DCP) is not well established in Hepatitis B Virus (HBV) non-endemic areas. This study aimed to investigate DCP as a predictive biomarker of atezo/bev treatment response in HCC patients. Methods: This single-center retrospective analysis evaluated DCP and radiographic response in HCC patients who received atezo/bev in the first-line setting. DCP was measured at the time of best response evaluation and compared to day one of atezo/bev initiation. Elevated DCP was defined by >=7.5 ng/mL. DCP response was defined as a decrease of >=50% at response assessment compared with baseline. Treatment response was evaluated based on imaging modalities including computed tomography and/or magnetic resonance imaging. Objective response rate (ORR) was defined as the percentage of patients with complete response (CR) and partial response (PR). Disease control rate (DCR) was defined as the percentage of patients with CR, PR, and stable disease (SD). No Response (NR) was defined as the percentage of patients with SD and PD. Comparisons of treatment effects were performed using two-tailed Fisher Exact Probability Test. Results: A total of 53 HCC patients treated with atezo/bev as first-line therapy were included. The best treatment responses according to radiographic evaluation were as follows: CR 3.8%, PR 22.6%, SD 52.8%, and PD 20.8%, respectively. Patients with DCP response had ORR of 69% (odds ratio, 15.75; 95% CI, 3.50-70.9; P=.0002) and DCR of 100% ( P=.047). Patients with >=50% increase in DCP at response evaluation compared to day one of treatment had ORR of 4.5% and NR of 95% ( P=.0035). On day one of treatment, 70% of patients had an elevated DCP. There was no difference between elevated DCP vs non-elevated DCP on day one of treatment and ORR. Conclusions: This study found that DCP has utility in predicting response to atezo/bev for HCC patients in HBV non-endemic areas. Further studies are needed to confirm findings and evaluate the prognostic implications of DCP in HBV non-endemic areas.

An online rectal cancer tumoroid biorepository: A resource to facilitate multimodal data integration.

159 Background: Advancing genetic and computational technologies have increased the complexity and quantity of data available in the field of rectal cancer research. As such, there is a need for a centralized source of data to aid and organize current research efforts. To this end, our team has created a unique online biorepository of rectal cancer tumoroids which may serve as a resource for a community of researchers. Methods: The rectal cancer tumoroid biorepository was created in cBioPortal in 2015. Organoids were derived from patient tumor samples (tumoroids). These samples represented multiple treatment timepoints and included primary, recurrent, and metastatic tumors. These tumoroids were further analyzed by various assays such as MSK-IMPACT and IC50 (to fluorouracil, FOLFOX, and FOLFIRI) to obtain patient-specific genomic and chemosensitivity data. A tumoroid profile was then created in cBioPortal for each sample. Clinical information was collected by chart review and annotated into the tumoroid profiles using the unique features of cBioPortal. These included interactive filters and graphical depictions of patient demographics, clinical and pathologic staging, treatment course, clinical response, overall survival, and disease-free survival. Results were organized in an intuitive visual display for convenient analysis. Novel features such as chemosensitivity plots and an interactive patient timeline were incorporated as well. Results: In total, 401 rectal cancer tumoroids have been derived from 177 unique patients. Approximately 32% of the tumoroids were from patients 50 years or younger, and 63% of patients have a treatment naïve sample in our repository. Ten percent of tumoroids were derived from T1-T2 tumors, 56% from T3 tumors, and 17% from T4 tumors. Additionally, 14% of tumoroids were derived from primary tumor recurrences while 6% were derived from metastases. Of the 78% of tumoroids with completely annotated clinical data, 8% were MSI-H, 11% were clinical complete responders, and 5.5% were pathologic complete responders. Lastly, complete IC50 data with clinical correlates has been established for 20% of tumoroids. These data show that tumoroids with a high sensitivity to chemotherapy (FOLFOX) correlated with a 3.3-fold increase in clinical complete response rates in the corresponding patients (p=0.0263). Conclusions: Integrating histopathological, clinicogenomic, and tumoroid response data, this expanding online resource provides a platform to identify valid biomarkers for patient treatment response. This publicly available biorepository built within cBioPortal is intuitive and flexible to accommodate and organize a wide range of data and has the potential to serve as an important resource in rectal cancer research.

Potential biomarkers for treatment response in advanced non-pancreatic neuroendocrine tumors.

599 Background: Well-differentiated NETs are highly vascular and hence, inhibition of angiogenesis is of interest. VEGF, a key molecule in promoting angiogenesis, has also been shown to promote an immunosuppressive tumor microenvironment. Nintedanib, an oral inhibitor of FGFR1–3, VEGFR1–3 and PDGFRA, has previously been evaluated in a phase II clinical trial in well-differentiated, non-pancreatic NETs, where 83% of the evaluable patients were progression-free at 16 weeks and median PFS was 11 months. In preclinical studies, nintedanib has been shown to increase PD-L1 expression in tumor cells, which then results in improved outcomes with immune checkpoint inhibition. There are multiple indicators of T-cell exhaustion, including PD-L1 and LAG-3. LAG-3+ T-cells have been found to correlate with poor response to treatment in neuroendocrine neoplasms. Given these findings, this study evaluates serum VEGF and LAG-3 expression to determine potential biomarkers of response in patients treated with nintedanib. Methods: 27 sets of paired samples collected at baseline and 8-weeks post treatment with nintedanib, from clinical trial NCT02399215 were used for this study. With IRB approval, we tested for serum VEGFa and serum LAG-3 using Luminex test kits: HCKP1-11K-01 (LAG-3) and HCYTA-60K-01 (VEGFa). We compared the baseline, 8-week, and percentage change in serum VEGF and serum LAG-3 levels with Rd Cd8+ pAkt+ T-cells (activated cytotoxic T-cells) as a marker of immune activation, Rd CD25+ pAkt+ T-cells (regulatory T-cells) as a marker of immune suppression, and PFS. Results: The median VEGF levels at baseline and 8-weeks were 10.50 pg/mL and 11.90 pg/mL respectively. The median LAG-3 level at baseline and 8-weeks were 59000 pg/mL and 62900 pg/mL respectively. Higher VEGFa levels in the post-treatment samples were associated with poorer progression free survival (HR= 1.009, 95% HR CI: [0.999, 1.019], with P= 0.0760). Higher levels of VEGF at baseline were also associated with lower numbers of Rd CD8+ pAkt + cells (Pearson coefficient = -0.42, p-value 0.04) at baseline. Increased baseline CD25+ pAkt+ levels were positively correlated with percent change in serum LAG-3 levels between baseline and post-treatment samples. (Pearson Co-efficient: 0.45; p=value: 0.02). Conclusions: Elevated serum VEGFa levels at 8-weeks post treatment correlated with lower PFS. Serum VEGFa level is a potential indicator of effector T-cell suppression, as evidenced by low number of activated cytotoxic T-cells in patients with higher VEGFa levels at baseline. Higher baseline regulatory T-cells were associated with a greater increase in serum LAG-3 levels, suggesting that serum LAG-3 may be an indicator of an immunosuppressive tumor microenvironment.

Urine Mast Cell Mediators in the Evaluation and Diagnosis of Mast Cell Activation Syndrome.

Mast cell activation syndrome is defined by severe, episodic, and recurrent symptoms induced by mast cell mediators with objective measurement of increase in biomarkers of mast cell activation and treatment response with mast cell therapies. Increase in serum tryptase from baseline during a mast cell activation episode is currently the most accepted biomarker measurement of mast cell release. However, during symptomatic episodes, serum tryptase can be difficult to obtain as it is a venipuncture procedure. Other objective measures of mast cell activation are needed to complement serum tryptase. Urine mast cell mediators can be collected at home and are non-invasive tests. There is emerging evidence for the utility of urine mast cell mediators including histamine, cysteinyl leukotrienes, and prostaglandins in the diagnosis of mast cell activation syndrome. In this review, clinically available urine mast cell mediators will be discussed including N-methylhistamine, leukotriene E4, and 2,3-dinor-11beta-prostaglandin F2 alpha. We discuss the rationale for the use of these urine mast cell mediators and examine the studies analyzing their performance for identifying mast cell activation.

Neurofilament light protein as a biomarker for spinal muscular atrophy: a review and reference ranges.

Spinal muscular atrophy (SMA) is the leading genetic cause of infant mortality, characterized by progressive neuromuscular degeneration resulting from mutations in the survival motor neuron (SMN1) gene. The availability of disease-modifying therapies for SMA therapies highlights the pressing need for easily accessible and cost-effective blood biomarkers to monitor treatment response and for better disease management. Additionally, the wide implementation of newborn genetic screening programs in Western countries enables presymptomatic diagnosis of SMA and immediate treatment administration. However, the absence of monitoring and prognostic blood biomarkers for neurodegeneration in SMA hinders effective disease management. Neurofilament light protein (NfL) is a promising biomarker of neuroaxonal damage in SMA and reflects disease progression in children with SMA undergoing treatment. Recently, the European Medicines Agency issued a letter of support endorsing the potential utilization of NfL as a biomarker of pediatric neurological diseases, including SMA. Within this review, we comprehensively assess the potential applications of NfL as a monitoring biomarker for disease severity and treatment response in pediatric-onset SMA. We provide reference ranges for normal levels of serum based NfL in neurologically healthy children aged 0-18 years. These reference ranges enable accurate interpretation of NfL levels in children and can accelerate the implementation of NfL into clinical practice.

Cortical glutamate, Glx, and total N-acetylaspartate: potential biomarkers of repetitive transcranial magnetic stimulation treatment response and outcomes in major depression

Repetitive transcranial magnetic stimulation (rTMS) is an effective treatment for individuals with major depressive disorder (MDD) who have not improved with standard therapies. However, only 30–45% of patients respond to rTMS. Predicting response to rTMS will benefit both patients and providers in terms of prescribing and targeting treatment for maximum efficacy and directing resources, as individuals with lower likelihood of response could be redirected to more suitable treatment alternatives. In this exploratory study, our goal was to use proton magnetic resonance spectroscopy to examine how glutamate (Glu), Glx, and total N-acetylaspartate (tNAA) predict post-rTMS changes in overall MDD severity and symptoms, and treatment response. Metabolites were measured in a right dorsal anterior cingulate cortex voxel prior to a standard course of 10 Hz rTMS to the left DLPFC in 25 individuals with MDD. MDD severity and symptoms were evaluated via the Inventory of Depression Symptomatology Self-Report (IDS-SR). rTMS response was defined as ≥50% change in full-scale IDS-SR scores post treatment. Percent change in IDS-SR symptom domains were evaluated using principal component analysis and established subscales. Generalized linear and logistic regression models were used to evaluate the relationship between baseline Glu, Glx, and tNAA and outcomes while controlling for age and sex. Participants with baseline Glu and Glx levels in the lower range had greater percent change in full scale IDS-SR scores post-treatment (p < 0.001), as did tNAA (p = 0.007). Low glutamatergic metabolite levels also predicted greater percent change in mood/cognition symptoms (p ≤ 0.001). Low-range Glu, Glx, and tNAA were associated with greater improvement on the immuno-metabolic subscale (p ≤ 0.003). Baseline Glu predicted rTMS responder status (p = 0.025) and had an area under the receiving operating characteristic curve of 0.81 (p = 0.009), demonstrating excellent discriminative ability. Baseline Glu, Glx, and tNAA significantly predicted MDD improvement after rTMS; preliminary evidence also demonstrates metabolite association with symptom subdomain improvement post-rTMS. This work provides feasibility for a personalized medicine approach to rTMS treatment selection, with individuals with Glu levels in the lower range potentially being the best candidates.

Liquid Biopsies for Monitoring Medulloblastoma: Circulating Tumor DNA as a Biomarker for Disease Progression and Treatment Response.

Pediatric brain tumors, including medulloblastoma (MB), represent a significant challenge in clinical oncology. Early diagnosis, accurate monitoring of therapeutic response, and the detection of minimal residual disease (MRD) are crucial for improving outcomes in these patients. This review aims to explore recent advancements in liquid biopsy techniques for monitoring pediatric brain tumors, with a specific focus on medulloblastoma. The primary research question is how liquid biopsy techniques can be effectively utilized for these purposes. Liquid biopsies, particularly the analysis of circulating tumor DNA (ctDNA) in cerebrospinal fluid (CSF), are investigated as promising noninvasive tools. This comprehensive review examines the components of liquid biopsies, including ctDNA, cell-free DNA (cfDNA), and microRNA (miRNA). Their applications in diagnosis, prognosis, and MRD assessment are critically assessed. The review also discusses the role of liquid biopsies in categorizing medulloblastoma subgroups, risk stratification, and the identification of therapeutic targets. Liquid biopsies have shown promising applications in the pediatric brain tumor field, particularly in medulloblastoma. They offer noninvasive means of diagnosis, monitoring treatment response, and detecting MRD. These biopsies have played a pivotal role in subgroup classification and risk stratification of medulloblastoma patients, aiding in the identification of therapeutic targets. However, challenges related to sensitivity and specificity are noted. In conclusion, this review highlights the growing importance of liquid biopsies, specifically ctDNA analysis in CSF, in pediatric brain tumor management, with a primary focus on medulloblastoma. Liquid biopsies have the potential to revolutionize patient care by enabling early diagnosis, accurate monitoring, and MRD detection. Nevertheless, further research is essential to validate their clinical utility fully. The evolving landscape of liquid biopsy applications underscores their promise in improving outcomes for pediatric brain tumor patients.

Evaluating microRNA-499 expression and serum IL-17, ACCP and PADI4 cytokine levels in rheumatoid arthritis patients undergoing anti-TNF alpha therapy

Introduction: Rheumatoid arthritis (RA) is a chronic inflammatory autoimmune disease characterized by joint inflammation and damage. While anti-TNF-alpha therapies like infliximab have revolutionized RA, treatment response varies among patients. Identifying reliable biomarkers for treatment response is crucial for optimizing therapy and patient outcomes. MicroRNA-499 has been implicated in autoimmune diseases, and IL-17 is a key mediator in RA pathogenesis. Additionally, PADI4 and ACCP are linked to RA autoimmunity. This study aimed to investigate the potential of microRNA-499 expression, serum levels of IL-17, PADI4 and ACCP as biomarkers for predicting and monitoring treatment response in RA patients undergoing anti-TNF-alpha (infliximab) therapy. Methodology: In this case-control research, blood samples from 100 Iraqi patients with RA and 100 controls were collected. RNA was extracted and the levels of miRNA499 were quantified using real-time PCR. The serum IL-17, PADI4 and ACCP levels were determined using ELISA. Patients were sub-grouped as responders and non-responders based on their responses to anti-TNF-alpha (infliximab) treatment. Results: The mean age of the patients in this study was 46.22 years. The occurrence of RA was higher in age group (31-45) years. There was a significant association between RA, smoking and BMI. miRNA-499 expression was significantly higher in RA patients versus controls (1.1 folds in patients compared to 0.52 in control group). The serum levels of IL-17, PADI4 and ACCP was significantly higher in RA patients than controls (54.3ng/L, 2.52 ng/ml and 2.15 U/ml) vs (40.35ng/ L, 1.78 ng/ml and 1.06 U/ml) respectively. Subdividing of patients showed that miRNA-499 expression and serum IL-17, PADI4 and ACCP to be significantly higher in non-responders patients than responders. Conclusion: MicroRNA-499 expression, serum levels of IL-17, PADI4 and ACCP were found to be significantly higher in RA patients compared to control group as well as in non-responding than responding patients.

Binding Folate Receptor Alpha Autoantibody Is a Biomarker for Leucovorin Treatment Response in Autism Spectrum Disorder.

Autism spectrum disorder (ASD) affects up to 1 in 36 children in the United States. It is a heterogeneous neurodevelopmental disorder with life-long consequences. Patients with ASD and folate pathway abnormalities have demonstrated improved symptoms after treatment with leucovorin (folinic acid), a reduced form of folate. However, biomarkers for treatment response have not been well investigated and clinical trials are lacking. In this retrospective analysis, a cohort of prospectively collected data from 110 consecutive ASD clinic patients [mean (SD) age: 10.5 (6.2) years; 74% male] was examined. These patients all underwent testing for folate receptor alpha autoantibodies (FRAAs) and soluble folate binding proteins (sFBPs) biomarkers and were treated with leucovorin, if appropriate. Analyses examined whether these biomarkers could predict response to leucovorin treatment as well as the severity of ASD characteristics at baseline. The social responsiveness scale (SRS), a measure of core ASD symptoms, and the aberrant behavior checklist (ABC), a measure of disruptive behavior, were collected at each clinic visit. Those positive for sFBPs had more severe ASD symptoms, and higher binding FRAA titers were associated with greater ABC irritability. Treatment with leucovorin improved most SRS subscales with higher binding FRAA titers associated with greater response. Leucovorin treatment also improved ABC irritability. These results confirm and expand on previous studies, underscore the need for biomarkers to guide treatment of folate pathways in ASD, and suggest that leucovorin may be effective for children with ASD.

The Role of JAK-STAT-SOCS1 Axis in Tumorigenesis, Malignant Progression and Lymphatic Metastasis of Penile Cancer.

Background: To uncover the potential significance of JAK-STAT-SOCS1 axis in penile cancer, our study was the pioneer in exploring the altered expression processes of JAK-STAT-SOCS1 axis in tumorigenesis, malignant progression and lymphatic metastasis of penile cancer. Methods: In current study, the comprehensive analysis of JAK-STAT-SOCS1 axis in penile cancer was analyzed via multiple analysis approaches based on GSE196978 data, single-cell data (6 cancer samples) and bulk RNA data (7 cancer samples and 7 metastasis lymph nodes). Results: Our study observed an altered molecular expression of JAK-STAT-SOCS1 axis during three different stages of penile cancer, from tumorigenesis to malignant progression to lymphatic metastasis. STAT4 was an important dominant molecule in penile cancer, which mediated the immunosuppressive tumor microenvironment by driving the apoptosis of cytotoxic T cell and was also a valuable biomarker of immune checkpoint inhibitor treatment response. Conclusions: Our findings revealed that the complexity of JAK-STAT-SOCS1 axis and the predominant role of STAT4 in penile cancer, which can mediate tumorigenesis, malignant progression, and lymphatic metastasis. This insight provided valuable information for developing precise treatment strategies for patients with penile cancer.

Proteomics provides insights into the theranostic potential of extracellular vesicles.

Extracellular vesicles (EVs) encompass a diverse range of membranous structures derived from cells, including exosomes and microvesicles. These vesicles are present in biological fluids and play vital roles in various physiological and pathological processes. They facilitate intercellular communication by enabling the exchange of proteins, lipids, and genetic material between cells. Understanding the cellular processes that govern EV biology is essential for unraveling their physiological and pathological functions and their potential clinical applications. Despite significant advancements in EV research in recent years, there is still much to learn about these vesicles. The advent of improved mass spectrometry (MS)-based techniques has allowed for a deeper characterization of EV protein composition, providing valuable insights into their roles in different physiological and pathological conditions. In this chapter, we provide an overview of proteomics studies conducted to identify the protein contents of EVs, which contribute to their therapeutic and pathological features. We also provided evidence on the potential of EV proteome contents as biomarkers for early disease diagnosis, progression, and treatment response, as well as factors that influence their composition. Additionally, we discuss the available databases containing information on EV proteome contents, and finally, we highlight the need for further research to pave the way toward their utilization in clinical settings.

Association between several immune response-related genes and the effectiveness of biological treatments in patients with moderate-to-severe psoriasis.

Biological therapies are safer and more effective against psoriasis than conventional treatments. Even so, 30-50% of psoriatic patients show an inadequate response, which is associated with individual genetic heterogeneity. Pharmacogenetic studies have identified several single nucleotide polymorphisms (SNPs) as possible predictive and prognostic biomarkers for psoriasis treatment response. The objective of this study was to determine the link between several SNPs and the clinical response to biological therapies in patients with moderate-severe psoriasis. A set of 21 SNPs related to psoriasis and/or other immunological diseases were selected and analysed from salivary samples of patients (n = 88). Treatment effectiveness and patient improvement was assessed clinically through Relative Psoriasis Area and Severity Index (PASI), also called 'PASI response', as well as absolute PASI. Associations between SNPs and PASI factors were assessed at 3 and 12 months for every treatment category of IL-17, IL-23, IL-12&23 and TNF-α inhibitors. Multivariate correlation analysis and Fisher's exact test were used to analyse the relationship between SNPs and therapy outcomes. Several SNPs located in the TLR2, TLR5, TIRAP, HLA-C, IL12B, SLC12A8, TNFAIP3 and PGLYRP4 genes demonstrated association with increased short and long-term therapy-effectiveness rates. Most patients achieved values of PASI response ≥75 or absolute PASI<1, regardless of the biological treatment administered. In conclusion, we demonstrate a relationship between different SNPs and both short- and especially long-term effectiveness of biological treatment in terms of PASI. These polymorphisms may be used as predictive markers of treatment response in patients with moderate-to-severe psoriasis, providing personalized treatment.

Use of biomarkers in clinical trials and future developments that will help identify novel biomarkers.

Engineering new solutions for therapeutic benefit in Amyotrophic Lateral Sclerosis (ALS) has proved a difficult task to accomplish. This is largely the reflection of complexities at multiple levels, that require solutions to improve cost-effectiveness and outcomes. The main obstacle related to the condition's clinical heterogeneity, chiefly the broad difference in survival observed among ALS patients, imposes large populations studies and long follow-up to evaluate any efficacy. The emerging solution is composite clinical and biological parameters enabling prognostic stratification into homogeneous phenotypes for more affordable studies. From a therapeutic development perspective, the choice of a medicinal product requires the availability of treatment-specific biomarkers of target engagement to identify off-target effects based on the compound's putative modality of action. More importantly, there are no established biomarkers of treatment response that can complement clinical outcome measures and support futility and end of treatment analyses of efficacy. Ultimately the onus rests on the development of biomarkers encompassing the unmet needs of clinical trial design, from inclusion to efficacy. These readouts of the pathological process may be used in combination with clinical and paraclinical outcome measured, significantly reducing the time and financial burden of clinical studies. Progress towards a biomarker-driven clinical trial design in ALS has been possible thanks to the accurate detection of neurofilaments and of other immunological mediators in biological fluids with the disease progression, a step change enabling the testing of novel therapeutic agents in a new clinical trial setting. However, further progress remains to be made to find treatment specific target engagement biomarkers along with readouts of treatment response that can be reliably applied to all emerging therapies and clinical studies. Here we will cover the basic notions of biomarker development in ALS clinical trials, the most crucial unanswered questions and the unmet needs in the ALS biomarkers space.

Exploring potential predictive biomarkers through historical perspectives on the evolution of systemic therapies into the emergence of neoadjuvant therapy for the treatment of hepatocellular carcinoma.

Hepatocellular carcinoma (HCC), a type of liver cancer, ranks as the sixth most prevalent cancer globally and represents the third leading cause of cancer-related deaths. Approximately half of HCC patients miss the opportunity for curative treatment and are then limited to undergoing systemic therapies. Currently, systemic therapy has entered the era of immunotherapy, particularly with the advent of immune-checkpoint inhibitors (ICIs), which have significantly enhanced outcomes for patients with advanced HCC. Neoadjuvant treatment for HCC has become a possibility-findings from the IMbrave 050 trial indicated that ICIs offer the benefit of recurrence-free survival for high-risk HCC patients post-resection or local ablation. However, only a small fraction of individuals benefit from systemic therapy. Consequently, there is an urgent need to identify predictive biomarkers for treatment response and outcome assessment. This study reviewed the historical progression of systemic therapy for HCC, highlighting notable therapeutic advancements. This study examined the development of systemic therapies involving conventional drugs and clinical trials utilized in HCC treatment, as well as potential predictive biomarkers for advanced and/or locally advanced HCC. Various studies have revealed potential biomarkers in the context of HCC treatment. These include the association of dendritic cells (DCs) with a favorable response to neoadjuvant therapy, the presence of enriched T effector cells and tertiary lymphoid structures, the identification of CD138+ plasma cells, and distinct spatial arrangements of B cells in close proximity to T cells among responders with locally advanced HCC receiving neoadjuvant cabozantinib and nivolumab treatment. Furthermore, pathological response has been associated with intratumoral cellular triads consisting of progenitor CD8+ T cells and CXCL13+ CD4+ T helper cells surrounding mature DCs in patients receiving neoadjuvant cemiplimab for resectable HCC. Despite no widely recognized predictive biomarkers for HCC individualized treatment, we believe neoadjuvant trials hold the most promise in identifying and validating them. This is because they can collect multiple samples from resectable HCC patients across stages, especially with multi-omics, bridging preclinical and clinical gaps.

An Unusual Presentation of Midline Lethal Granuloma.

Extranodal natural killer T-cell lymphoma, nasal type (ENKTCL), is a rare form of non-Hodgkin lymphoma that is strongly related to Epstein-Barr Virus (EBV) infection and commonly presents as "midline lethal granuloma." Herein, we report a middle-aged lady who presented with a two-week history of fever, sore throat and constitutional symptoms. Intraoral examination revealed a lacerated soft palate with an ulcerated uvula. A diagnosis of ENKTCL was confirmed through deep biopsies under general anaesthesia supplemented with a positive serum EBV genome. Unfortunately, she succumbed due to disease progression with left frontal brain metastasis with concurrent pulmonary tuberculosis before treatment was completed. The recommended treatment is multimodality with L-asparaginase-containing regimes chemotherapy in an advanced stage, relapsed, or refractory ENKTCL for better outcomes. The quantification of circulating plasma EBV deoxyribonucleic acid (DNA) is helpful as the baseline of tumour load and a biomarker for monitoring treatment response and prognostication. We advocate repeated and deeper core tissue biopsies.

The Role of miRNAs in Childhood Acute Lymphoblastic Leukemia Relapse and the Associated Molecular Mechanisms.

Acute lymphoblastic leukemia (ALL) is the most common cancer in children worldwide. Although ALL patients' overall survival rates in wealthy countries currently surpass 80%, 15-20% of patients still experience relapse. The underlying mechanisms of relapse are still not fully understood, and little progress has been made in treating refractory or relapsed disease. Disease relapse and treatment failure are common causes of leukemia-related death. In ALL relapse, several gene signatures have been identified, but it is also important to study miRNAs involved in ALL relapse in an effort to avoid relapse and to achieve better survival rates since miRNAs regulate target genes that participate in signaling pathways involved in relapse, such as those related to drug resistance, survival signals, and antiapoptotic mechanisms. Several miRNAs, such as miR-24, miR-27a, miR-99/100, miR-124, miR-1225b, miR-128b, miR-142-3p, miR-155 and miR-335-3p, are valuable biomarkers for prognosis and treatment response in ALL patients. Thus, this review aimed to analyze the primary miRNAs involved in pediatric ALL relapse and explore the underlying molecular mechanisms in an effort to identify miRNAs that may be potential candidates for anti-ALL therapy soon.

A tandem DNA nanomachines-supported electrochemiluminescence assay for attomolar detection of miRNA at ambient-temperature

Differential expression profiles of miRNAs are linked with a variety of diseases and could serve as biomarkers for routine clinical diagnosis and treatment response. However, the simple, reliable, and highly sensitive quantification remains one of the major challenges in miRNA application. Here we report an ambient-temperature tandem DNA nanomachines-supported electrochemiluminescence (ECL) assay that leverages a tandem two DNA nanomachines (three-dimensional (3D) DNA walker, DNA rolling machine) and the electrochemiluminescence technique for the rapid, ultrasensitive and specific detection of miRNA-155. We demonstrate that the proposed assay is able to detect target miRNA-155 down to 0.33 aM in about 70 min. Notably, the whole procedure can be operated at room temperature since it is protein enzyme-free. It also demonstrates desirable selectivity, excellent stability, and quantitative ability for human serum miRNA-155 detection. In summary, this assay could be used as an ultrasensitive, simple, and reliable diagnostic test for miRNA.

Correlation between Topographic Vessel Density and Retinal Thickness Changes in Patients with Diabetic Macular Edema Treated with Anti-VEGF Therapy: Is It a Suitable OCTA Biomarker?

The objective of this study was to determine the correlation between topographic vessel density (VD) and retinal thickness (RT) reductions induced by vascular endothelial growth factor inhibitors (anti-VEGF) in patients with diabetic macular edema (DME) using optical coherence tomography angiography (OCTA). This was a prospective, interventional case series. VD and RT measurements were separately taken in four parafoveal subfields at baseline and after six months of treatment. This correlation was statistically assessed using Spearman's rho correlation coefficient after adjustment for multiple comparisons. The study included a total of 48 eyes in the final analysis. Mean VD decreased from baseline to month 6 (from 45.2 (±3.5) to 44.6% (±3.2) in the superficial capillary plexus and from 50 (±3.3) to 49% (±3.9) in the deep capillary plexus). Statistically significant reductions in RT were observed in all ETDRS sectors (p < 0.0001). No significant association was found between RT and VD, even when analyzing responders and non-responders separately. After six months of anti-VEGF treatment, no significant correlation was observed between the topographic VD and RT values. These findings suggest that reductions in VD values may not solely result from a reduction in microaneurysms, also being affected by the repositioning of displaced vessels due to edema and a reduction in their caliber. Therefore, VD changes may not be a suitable indirect OCTA biomarker of microaneurysm turnover and treatment response.