Predictive Biomarkers Research Articles

Therapy response prediction of focal cortex stimulation based on clinical parameters: a multicentre, non-interventional study protocol

IntroductionA novel focal cortex stimulation (FCS) device has recently received approval in Europe for patients with focal drug-resistant epilepsy (DRE). After 6 months of stimulation, 17 of 32 patients achieved...

MAGI3 enhances sensitivity to sunitinib in renal cell carcinoma by suppressing the MAS/ERK axis and serves as a prognostic marker

Clear cell renal cell carcinoma (ccRCC) exhibits considerable heterogeneity, with approximately 25% of localized cases susceptible to relapse, highlighting the challenge of the absence of reliable predictive biomarkers for personalized treatment. Meanwhile, metastatic renal cell carcinoma is characterized by unfavorable survival rates, and although Sunitinib offers partial benefits, the clinical advantages are often constrained by drug resistance and adverse side effects. Here, MAGI3 was associate with ccRCC progression, as identified through comprehensive bioinformatics analysis of clinical datasets. A low level of MAGI3 emerged as a high-risk factor for ccRCC, indicating its potential as a prognostic marker. Individuals with MAGI3 expression in middle-to-low levels displayed a significantly poorer survival rate, indicating a need for additional treatment even in the early stages of ccRCC. Furthermore, patients with MAGI3 expression in middle-to-high levels exhibited increased sensitivity to Sunitinib compared to those with lower MAGI3 levels, suggesting that individuals with MAGI3 expression at middle levels may potentially benefit from Sunitinib treatment even in the early stages of ccRCC. Through its interaction with the MAS receptor, MAGI3 has been identified as a regulator of cell proliferation and a determinant of Sunitinib resistance in ccRCC, operating via the Ang-(1-7)/MAS/ERK axis. The loss of MAGI3 expression in ccRCC patients activated the ERK signaling pathway, contributing to both cancer progression and Sunitinib resistance. Therefore, our study not only highlight MAGI3’s pivotal role in ccRCC progression and Sunitinib resistance, but also reinforces MAGI3’s prospective value as a predictive marker.

Early circulating tumor DNA changes predict outcomes in head and neck cancer patients under re-radiotherapy.

Local recurrence after radiotherapy is common in locally advanced head and neck cancer (HNC) patients. Re-irradiation can improve local disease control, but disease progression remains frequent. Hence, predictive biomarkers are needed to adapt treatment intensity to the patient's individual risk. We quantified circulating tumor DNA (ctDNA) in sequential plasma samples and correlated ctDNA levels with disease outcome. Ninety four longitudinal plasma samples from 16 locally advanced HNC patients and 57 healthy donors were collected at re-radiotherapy baseline, after 5 and 10 radiation fractions, at irradiation end, and at routine follow-up visits. Plasma DNA was subjected to low coverage whole genome sequencing for copy number variation (CNV) profiling to quantify ctDNA burden. CNV-based ctDNA burden was detected in 8/16 patients and 25/94 plasma samples. Ten additional ctDNA-positive samples were identified by tracking patient-specific CNVs found in earlier sequential plasma samples. ctDNA-positivity after 5 and 10 radiation fractions (both: log-rank, p = .050) as well as at the end of irradiation correlated with short progression-free survival (log-rank, p = .006). Moreover, a pronounced decrease of ctDNA toward re-radiotherapy termination was associated with worse treatment outcome (log-rank, p = .005). Dynamic ctDNA tracking in serial plasma beyond re-radiotherapy reflected treatment response and imminent disease progression. In five patients, molecular progression was detected prior to tumor progression based on clinical imaging. Our findings emphasize that quantifying ctDNA during re-radiotherapy may contribute to disease monitoring and personalization of adjuvant treatment, follow-up intervals, and dose prescription.

Enhanced mortality prediction in pediatric sepsis using NGAL: A comparison with PRISM III scores in critical care settings

Sepsis is a critical condition that disrupts metabolic, physiological, and immune functions, often resulting in severe complications such as multi-organ failure and increased mortality. Neutrophil gelatinase-associated lipocalin (NGAL) has emerged as a promising biomarker for infection and inflammation, offering potential advantages for early mortality prediction. This study compared the predictive value of serum NGAL levels with pediatric risk of mortality III (PRISM III) scores in critically ill pediatric patients with sepsis. A prospective cohort study was conducted at a tertiary hospital from September 2022 to March 2023, involving 75 pediatric patients diagnosed with sepsis, septic shock, or multi-organ dysfunction syndrome (MODS), along with 25 healthy controls. Serum NGAL levels were measured within the first hour of PICU admission and analyzed alongside PRISM III scores to evaluate their correlation with mortality and sepsis severity. The results demonstrated that serum NGAL levels were significantly elevated in septic patients compared to controls, with the highest levels observed in those with MODS. NGAL showed greater sensitivity and specificity for predicting mortality than PRISM III scores, with ROC curve analysis revealing that NGAL levels > 599 mg/ml were strongly associated with increased mortality risk (sensitivity 70.4% and specificity 50%). Multivariate analysis confirmed NGAL as an independent predictor of mortality, outperforming PRISM III scores in identifying severe cases.Conclusion: Serum NGAL is a valuable biomarker for early prediction of mortality and sepsis severity in pediatric patients, providing faster and more accurate assessments than PRISM III scores. Its integration into clinical practice may enhance decision-making in pediatric critical care settings, allowing for timely interventions and improved patient outcomes.What is Known:• Pediatric risk of mortality III (Prism III) scores is widely used to predict sepsis severity and mortality in pediatric intensive care units, but requiring 12-24 hours to complete. Neutrophil is an established biomarker for inflammation and infection with a potentially anti-pathological value in the neutrophil gelatinus-lipocalin (NGAL) sepsis.What is New:• Serum NGAL levels, PICU is measured within the first hour of entry, prism III score in pediatric patients in predicting mortality and severity of sepsis. > An NGAL cutoff of 599 mg/mL is significantly associated with mortality risk, which provides a rapid, independent and more immediate immunity tool for important care decision making.

Single-cell RNA sequencing identifies molecular biomarkers predicting late progression to CDK4/6 inhibition in patients with HR+/HER2- metastatic breast cancer

BackgroundCyclin-dependent kinase 4/6 inhibitors (CDK4/6is) in combination with endocrine therapy are the standard treatment for patients with hormone receptor–positive, HER2–negative metastatic breast cancer (mBC). Despite the efficacy of CDK4/6is, intrinsic resistance occurs in approximately one-third of patients, highlighting the need for reliable predictive biomarkers.MethodsSingle-cell RNA sequencing analyzed metastatic tumors from HR+/HER2- mBC patients pre-CDK4/6i treatment at baseline (BL) and/or at disease progression. BL samples were from CDK4/6i responders (median progression-free survival [mPFS] = 25.5 months), while progressors were categorized as early-progressors (EP, mPFS = 3 months) and late-progressors (LP, mPFS = 11 months). Metastatic sites included liver, pleural effusions, ascites, and bone. InferCNV distinguished tumor cells, and functional analysis utilized the Molecular Signatures Database.ResultsLP tumors displayed enhanced Myc, EMT, TNF-α, and inflammatory pathways compared to those EP tumors. Samples from BL and LP responders showed increased tumor-infiltrating CD8+ T cells and natural killer (NK) cells compared to EP non-responders. Notably, despite a high frequency of CD8+ T cells in responding tumors, a functional analysis revealed significant upregulation of genes associated with stress and apoptosis in proliferative CD4+ and CD8+ T cells in BL tumors compared to in EP and LP tumors. These genes, including HSP90 and HSPA8, are linked to resistance to PD1/PD-L1 immune checkpoint inhibitors. A ligand-receptor analysis showed enhanced interactions associated with inhibitory T-cell proliferation (SPP1-CD44) and suppression of immune activity (MDK-NCL) in LP tumors. Longitudinal biopsies consistently revealed dynamic NK cell expansion and enhanced cytotoxic T cell activity, alongside upregulation of immune activity inhibition, in LP tumors compared to in BL tumors. Notably, the predictive biomarker panel from BL tumor cells was validated in 2 independent cohorts, where it consistently predicted a significant improvement in mPFS duration in signature-high versus -low groups.ConclusionThis study underscores the significance of molecular biomarkers in predicting clinical outcomes to CDK4/6i. Tumor-infiltration CD8+ T and NK cells may also serve as baseline predictors. These insights pave the way for optimizing therapeutic strategies based on microenvironment-specific changes, providing a personalized and effective approach for managing HR+/HER2- mBC and improving patient outcomes.

Primary and Acquired Resistance to Immunotherapy with Checkpoint Inhibitors in NSCLC: From Bedside to Bench and Back.

Immunotherapy with checkpoint inhibitors has become the cornerstone of systemic treatment for non-oncogene addicted non-small-cell lung cancer. Despite its pivotal role, a significant proportion of patients-approximately 70-85%-either exhibit primary resistance to PD-1 blockade or develop acquired resistance following an initial benefit, even in combination with chemotherapy and/or anti-CTLA-4 agents. The phenomenon of primary and acquired resistance to immunotherapy represents a critical clinical challenge, largely based on our incomplete understanding of the mechanisms of action of immunotherapy, and the resulting lack of accurate predictive biomarkers. Here, we review the definitions and explore the proposed mechanisms of primary and acquired resistance, including those related to the tumor microenvironment, systemic factors, and intrinsic tumor characteristics. We also discuss translational data on adaptive changes within tumor cells and the immune infiltrate following exposure to checkpoint inhibitors. Lastly, we offer a comprehensive overview of current and emerging therapeutic strategies designed to prevent primary resistance and counteract acquired resistance.

The prognostic value of CMR diastolic parameters in patients with cardiac light-chain amyloidosis: a retrospective analysis.

Cardiac light-chain amyloidosis (AL-CA), characterized by the accumulation of amyloid fibers in the myocardium, often results in progressive diastolic dysfunction and adverse clinical outcomes. This study aimed to explore the diastolic characteristics of AL-CA using feature tracking cardiac magnetic resonance (CMR) and determine the prognostic parameters for all-cause mortality in such patients. A total of 102 AL-CA patients who underwent CMR between January 2014 and September 2018 were retrospectively reviewed, participations were follow-up until 2021. According to the inclusion and exclusion criteria, 60 patients were ultimately included. All-cause mortality was set as the primary endpoint. Healthy subjects were selected as controls. AL-CA patients were classified as the non-survival and survival group. The baseline characteristics, as well as the CMR-derived LV diastolic strain rate and LA diastolic parameters (LA volume, phasic EF, phasic strain, and strain rate), of survivors, non-survivors, and controls were compared. The associations of diastolic parameters with clinical outcomes were assessed via Cox regression and Kaplan‒Meier analyses. At a median follow-up of 7 months (interquartile range, 2-28 months), 43 (71.6%) cases of all-cause mortality were observed. Compared with controls, non-survivors presented significantly variation for all diastolic parameters (all P < 0.05), with LA volume indexes, LSRconduit and LSRpump value significantly increased and the remaining diastolic functional values significantly decreased. Compared with survivors, non-survivors presented significantly lower LV eGLSR, eGCSR, aGLSR, and selected LA diastolic parameters, including the LA phasic ejection fraction, LA phasic longitudinal strain, and LA longitudinal reservoir strain rate (all P < 0.05); moreover, LA volume indices and LA longitudinal conduit and booster‒pump strain rate values were significantly higher in the non-survival group. Multivariate Cox regression identified LA LSR as a significant predictor of all-cause mortality (hazard ratio, 14.35; 95% CI: 1.44-142.85, p < 0.05), with an optimal cutoff of -0.28s-1 according to Kaplan‒Meier analysis. LA LSRconduit further demonstrated additive prognostic value over conventional systolic parameters, including LVEF, the LVGCS, and LV-LGE (p < 0.05). CMR-derived diastolic parameters, particularly the LA LSRconduit, have potential as predictive biomarkers for all-cause mortality in patients with AL-CA.

The association between sex hormones and bone mineral density in US females

Osteoporosis and osteoporosis-related fractures exhibits a higher prevalence among females, particularly those aged 50 and above, implying a potential association between sex hormones and bone mineral density (BMD). However, the precise role of sex hormones in BMD remains elusive. Meanwhile, estradiol-to-testosterone ratio (E2/T ratio) or testosterone-to-estradiol ratio (T/E2 ratio) is a new biomarker of sex hormone milieu. We investigated whether sex hormones, E2/T ratio and T/E2 ratio were associated with BMD or fractures risk in US females. This study is a cross-sectional study, and the data sourced from the National Health and Nutrition Examination Survey (NHANES) 2013–2014 cycle. This study primarily focuses on females aged 50 and above, employing weighted multivariate linear regression, restricted cubic spline (RCS) model to examine the association between sex hormones and BMD or FRAX scores. We included 1,012 females. Testosterone was not associated with BMD or fracture risk. Increasing estradiol and E2/T ratio were positively correlated with BMD and negatively correlated with osteoporosis-related fractures risk, while increasing T/E2 ratio was negatively correlated with BMD and increased risk of osteoporosis-related fractures. The T/E2 ratio showed better specificity for predicting low BMD compared to estradiol alone. These findings suggest that hormonal ratios can serve as predictive biomarkers for osteoporosis and fractures. This study highlights the potential of E2/T and T/E2 ratios as biomarkers for assessing osteoporosis risk in postmenopausal women. Incorporating these ratios into clinical practice could improve early diagnosis and risk stratification for osteoporosis-related fractures. Future longitudinal studies are needed to confirm these findings and further explore the causal relationships between sex hormones and bone health.

Soluble CD14 and IL-12p70 on early ART predict HIV load setpoint after treatment interruption.

After analytical treatment interruption (ATI), viral rebound occurs in most people with HIV. The time to viral rebound (TTVR) is likely determined by the properties of the viral reservoir as well as the anti-viral immune response. Soluble biomarkers of immune activation may be predictive of TTVR and plasma viral load (pVL) setpoint after ATI. The objective of this study is to identify these soluble biomarkers. A retrospective biomarker analysis of the Primo-SHM trial who were treated 24 or 60 weeks during early HIV infection. Thirty-five biomarkers were measured at ATI in 65 participants. Association between biomarkers and reservoir size, TTVR and pVL at setpoint was assessed. SCD14 correlated to pVL setpoint (B = 0.598; p = 0.004) and lower levels of IL-12p70 to a higher level of pVL setpoint (B = -0.448; p = 0.04). SCD163 correlated to levels of total HIV-DNA (B = 0.413; p = 0.007). An increased pVL setpoint was associated with higher sCD14 and lower IL12-p70 at ATI and increased total HIV-DNA was associated with higher sCD163 at ATI. SCD14 and sCD163 are biomarkers of monocyte activation, while IL12-p70, produced by monocytes, is essential for inducing Th1 responses. This underscores the relation between immune activation and diminished immune control of HIV. Our findings indicate that sCD14 and IL-12p70 could serve as predictive biomarkers for favorable outcomes in cure interventions.

A multicentre implementation trial of an Artificial Intelligence-driven biomarker to inform Shared decisions for androgen deprivation therapy in men undergoing prostate radiotherapy: the ASTuTE protocol

BackgroundAndrogen deprivation therapy (ADT) improves outcomes in men undergoing definitive radiotherapy for prostate cancer but carries significant toxicities. Clinical parameters alone are insufficient to accurately identify patients who will derive the most benefit, highlighting the need for improved patient selection tools to minimize unnecessary exposure to ADT’s side effects while ensuring optimal oncological outcomes. The ArteraAI Prostate Test, incorporating a multimodal artificial intelligence (MMAI)-driven digital histopathology-based biomarker, offers prognostic and predictive information to aid in this selection. However, its clinical utility in real-world settings has yet to be measured prospectively.MethodsThis multicentre implementation trial aims to collect real-world data on the use of the previously validated Artera MMAI-driven prognostic and predictive biomarkers in men with intermediate-risk prostate cancer undergoing curative radiotherapy. The prognostic biomarker estimates the 10-year risk of metastasis, while the predictive biomarker determines the likely benefit from short-term ADT (ST-ADT). A total of 800 participants considering ST-ADT in conjunction with curative radiotherapy will be recruited from multiple Australian centers. Eligible patients with intermediate-risk prostate cancer, as defined by the National Comprehensive Cancer Network, will be asked to participate. The primary endpoint is the percentage of patients for whom testing led to a change in the shared ST-ADT recommendation, analyzed using descriptive statistics and McNemar’s test comparing recommendations before and after biomarker testing. Secondary endpoints include the impact on quality of life and 5-year disease control, assessed through linkage with the Prostate Cancer Outcomes Registry. The sample size will be re-evaluated at an interim analysis after 200 patients.DiscussionASTuTE will determine the impact of a novel prognostic and predictive biomarker on shared decision-making in the short term, and both quality of life and disease control in the medium term. If the biomarker demonstrates a significant impact on treatment decisions, it could lead to more personalized treatment strategies for men with intermediate-risk prostate cancer, potentially reducing overtreatment and improving quality of life. A potential limitation is the variability in clinical practice across different centers inherent in real-world studies.Trial RegistrationAustralian New Zealand Clinical Trials Registry, ACTRN12623000713695p. Registered 5 July 2023.

Clinical efficacy and therapy response prediction of neoadjuvant dalpiciclib plus letrozole in postmenopausal patients with HR+/HER2- stage II-III breast cancer (DARLING 01): a single-arm, open-label, exploratory study

BackgroundHormone receptor-positive/human epidermal growth factor receptor 2-negative (HR+/HER2-) breast cancer is the most common subtype of breast cancer, yet its response to traditional chemotherapy remains limited, posing a challenge in achieving optimal therapeutic outcomes. In this study, we aimed to evaluate the clinical efficacy and safety of dalpiciclib, a novel CDK4/6 inhibitor, combined with letrozole as neoadjuvant therapy (NAT) in postmenopausal patients with HR+/HER2- stage II-III breast cancer. Additionally, we explored potential predictive biomarkers for treatment response using gene analysis.MethodsThis single-arm, open-label, exploratory phase II trial involved 35 postmenopausal women with HR+/HER2- breast cancer (ClinicalTrials.gov identifier NCT05512780). Patients received four cycles of dalpiciclib (125 mg/day for 3 weeks, followed by 1 week off) plus continuous letrozole (2.5 mg/day). The primary endpoint was objective response rate (ORR), and secondary endpoints included changes in Ki-67 expression, complete cell cycle arrest (CCCA) rate, residual cancer burden (RCB), and safety profiles. Gene expression profiling and least absolute shrinkage and selection operator (LASSO) regression were conducted to identify biomarkers predictive of response to NAT.ResultsAmong the 35 enrolled patients, 31 completed the full treatment course. Of the 29 patients with evaluable response data after 4 cycles, 16 achieved partial response (PR), resulting in an ORR of 55.2%. Following two weeks of treatment, the mean Ki-67 expression significantly decreased from a baseline of 17.5–1.8%, and CCCA was observed in 75% of patients. Grade ≥ 3 treatment-emergent adverse events (TEAEs) were mainly decreased neutrophil count (45.7%), with a median duration of 3 days. The NAT predictive model, developed using gene expression analysis and clinicopathological factors, achieved an area under the curve (AUC) of 0.928, indicating that TFRC, SCUBE2, and MMP11A could serve as novel predictive biomarkers for response to NAT.ConclusionsDalpiciclib combined with letrozole demonstrated promising antitumor activity and an acceptable safety profile in postmenopausal patients with HR+/HER2- breast cancer. The identification of TFRC, SCUBE2, and MMP11A as predictive biomarkers provides insights into the potential for personalized neoadjuvant treatment strategies.

Metabolomics-based predictive biomarkers of oral cancer and its severity in human patients from North India using saliva.

Oral squamous cell carcinoma (OSCC) is frequently the outcome of oral submucous fibrosis (OSMF), a common possibly premalignant disease. In our study, a cohort of 50 patients with OSCC and OSMF, along with 50 healthy controls, was analyzed to identify significant metabolic differences between the patient and control groups through multivariate statistical analysis using NMR-based metabolomics in saliva samples. The 2D scatter plot of PC1 versus PC2 scores clearly show a distinction between the groups, with the principal component analysis (PCA) explaining 24.6% of the variance. Partial least-squares discriminant analysis (PLS-DA) demonstrated R2 and Q2 values of 0.94 and 0.90, respectively, indicating a robust model fit. A total of 20 distinct metabolites were identified, including 5 that were up-regulated and 5 that were down-regulated. Univariate ROC curve analysis identified nine salivary metabolites with AUC values exceeding 0.70, including acetone, tryptophan, 5-aminopentanoic acid, betaine, aspartic acid, ethanol, acetoacetate, adipic acid, and citrate. Notably, the distinct presence of three metabolites-acetone, tryptophan, and 5-aminopentanoic acid-yielded AUC values of 0.98123, 0.95358, and 0.91506, respectively. The refined statistical model was subjected to metabolic pathway analysis, revealing interconnected pathways. We were also able to predict the severity of the disease, specifically distinguishing between stage I and stage II OSCC. This differentiation was highlighted by the PCA score plot, which explained 28.6% of the variance. These results were further confirmed by PLS-DA. These insights pave the way for early diagnosis and predicting severity in patients with oral cancer, which will enable better management of the disease.

DYNC2H1 mutation as a potential predictive biomarker for immune checkpoint inhibitor efficacy in NSCLC and melanoma.

Dynein cytoplasmic 2 heavy chain 1 (DYNC2H1) is reported to play a potential role in cancer immunotherapy. However, the association between DYNC2H1 mutation and the clinical benefit of immunotherapy in non-small cell lung cancer (NSCLC) and melanoma remains to be elucidated. We collected data from three public immune checkpoint inhibitor (ICI)-treated NSCLC cohorts (n = 137 in total) and seven ICI-treated melanoma cohorts (n = 418 in total) to explore the potential of DYNC2H1 mutation as a predictive biomarker. The clinical outcomes, including the objective response rate (ORR) and progression-free survival (PFS), of patients with DYNC2H1 mutations are significantly better than those of patients with wild-type DYNC2H1. Multivariate Cox regression analysis confirmed that DYNC2H1 mutation was an independent predictive factor for ICI efficacy in NSCLC and melanoma. In addition, DYNC2H1 mutation exhibited no prognostic value for NSCLC or melanoma. Tumour mutational burden (TMB) and tumour neoantigen burden (TNB) were significantly higher in patients with DYNC2H1 mutation than in those with wild-type DYNC2H1 in both NSCLC and melanoma cohort. The analysis of immune-related genes and immune cell enrichment revealed an association between DYNC2H1 mutation and increased immune infiltration, revealing a potential mechanism underlying the predictive role of DYNC2H1 mutation in immunotherapy efficacy. In conclusion, DYNC2H1 mutation serves as a predictive biomarker of ICI efficacy in NSCLC and melanoma.

Circulating tumor DNA in muscle-invasive bladder cancer: A systematic review.

To evaluate the role of circulating tumor DNA (ctDNA) as a prognostic and predictive biomarker in the perioperative management of muscle-invasive bladder cancer (MIBC). We conducted a systematic literature review using PubMed, MEDLINE, and Embase, following PRISMA guidelines. Studies from January 2013 to March 2024 were included if they examined ctDNA in MIBC patients undergoing radical cystectomy (RC) and perioperative chemotherapy or immunotherapy. Eight studies were included. ctDNA detected before RC was associated with poor recurrence-free survival and higher risk of nodal and locally advanced disease. Postoperative ctDNA levels correlated with shorter disease-free survival and higher recurrence rates. ctDNA clearance during neoadjuvant chemotherapy was predictive of treatment response. ctDNA status post-neoadjuvant immunotherapy correlated with pathological outcomes and recurrence rates. ctDNA is a promising biomarker for predicting oncological outcomes in MIBC, with potential to guide perioperative treatment decisions. Further randomized controlled trials are needed to validate these findings.

Dynamic forecasting module for chronic graft-versus-host disease progression based on a disease-associated subpopulation of B cells: a multicenter prospective study.

Predicting chronic graft-versus-host disease (cGVHD) progression has been challenging due to its dynamic nature and the lack of reliable real-time monitoring tools, necessitating substantial investments of time and financial resources for effective management. Consequently, identifying appropriate immune cell subsets or molecules as prognostic or predictive biomarkers for cGVHD is essential. Building on the pivotal role of B-cell homeostasis in cGVHD progression, we integrated spectral flow cytometry with advanced machine learning algorithms to systematically analyze the relationship between B cells and cGVHD progression. Leveraging the identification of a distinct B-cell subpopulation, we developed cGPS (cGVHD Progress Score), a user-friendly tool based on marker distribution. To validate cGPS, we conducted both retrospective and prospective multi-center studies involving 91 patients (25 non-GVHD and 66 cGVHD cases). We identified a distinct B-cell subpopulation characterized by CD27+CD86+CD20-, which can precisely distinguish cGVHD. Leveraging this discovery, we developed cGPS. The retrospective study highlighted the predictive power of cGPS, achieving an impressive area under the curve (AUC) of 0.98 for identifying non-GVHD patients prone to cGVHD and 0.88 for predicting disease progression in cGVHD patients. Notably, the prospective study highlighted cGPS's effectiveness, as it accurately predicted all instances of cGVHD development or progression within an average of three-month observation window. These findings validate cGPS as a highly effective and dynamic B cell-based tool for monitoring cGVHD progression, offering a crucial solution for prognosis and prediction of treatment effectiveness. The multicenter approach applied to both retrospective and prospective studies strengthen the reliability and adaptability of our findings. We are confident that cGPS is a highly competitive tool with great potential for clinical application. This work was supported by grants from the National Key Research and Development Program of China, Stem Cell and Translational Research (2022YFA1105000, 2022YFA1104100); the National Natural Science Foundation of China (82430050, 32130046, 82270230, 81970109); Key Research and Development Program of Guangdong Province (2023B1111050006); Guangdong Basic and Applied Basic Research Foundation (2023B1515020119); Key Scientific and Technological Program of Guangzhou City (2023B01J1002); Pioneering talents project of Guangzhou Development Zone (2021-L029); the Shenzhen Science and Technology Program (KJZD20230923114504008).

Evaluation of NANOG/HDAC1 Expression in Predicting Outcomes of BCG Therapy in Non-Muscle Invasive Bladder Cancer.

Urinary bladder cancer includes non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancer (MIBC). While patients with NMIBC have a better prognosis, NMIBC often recurs, requiring long-term surveillance and repeated treatments. Intravesical Bacillus Calmette-Guérin (BCG) therapy is standard for high-grade or recurrent NMIBC; however, 30%-50% of patients failed to respond, and the mechanisms of resistance remain unclear. To identify predictive biomarkers for response to intravesical BCG therapy, we analyzed NANOG and Histone deacetylase 1 (HDAC1) expression in 90 bladder cancer specimens from NMIBC patients treated with BCG therapy using immunohistochemistry. The correlation between NANOG and HDAC1 expression and clinical outcomes, including response to BCG therapy, was assessed. High-grade NMIBC cases showed significantly higher expression of NANOG and HDAC1 compared to low-grade cases (p < 0.05). Additionally, elevated NANOG expression in combination with HDAC1, was associated with poor response to BCG therapy and decreased lymphocyte infiltration in the tumor-microenvironment. NANOG is suggested to directly increases HDAC1 expression, which could suppress lymphocyte infiltration in the tumor microenvironment by altering immune-related gene expression. These findings suggest that the NANOG/HDAC1 axis plays a key role in predicting resistance to intravesical BCG therapy in NMIBC.

Tumor Infiltrating Lymphocytes, CAR-, and T Cell Receptor- Modified T Cells in Solid Cancer Oncology.

Adoptive cellular therapy (ACT) is a promising treatment approach aiming at enhancing T cell antitumor immune response. ACT includes tumor-infiltrating lymphocytes (TILs), chimeric antigen receptor (CAR) and T-cell receptor (TCR) gene-modified T cells. Despite a milestone achievement with CAR-T cells in hematopoietic malignancies, ACT has shown modest clinical responses in refractory solid cancers and durable responses remain limited to a minor fraction of patients. In this review, we highlight major advances, limitations and current developments of T cell therapies for solid cancers. We discuss emerging promising strategies as next-generation ACT, exploring local delivery routes to maximise efficacy and improve safety, integrating predictive biomarkers to optimize selection of patients who most likely would benefit from ACT, using combination therapy to overcome the immunosuppressive tumor microenvironment, targeting multiple tumor antigen to avoid tumor antigen escape, selection of the most potent T cell product to overcome T cell dysfunction and incorporating cutting edge new technologies, such as gene-editing to further improve anti-tumor T cell functions and reduce therapy-related toxicity. Advances made in ACT trials have move the field of immunotherapy for refractory solid cancers to a new stage, by constantly incorporating new strategies to develop next-generation therapies designed to enhance efficacy and improve safety and to allow a broaden access to a large numbers of patients.

Emerging biomarkers for CD3×CD20 bispecific antibodies in lymphoma.

Novel CD3xCD20 bispecific (BsAb) immunotherapies have entered the armamentarium for follicular lymphoma and diffuse large B-cell lymphoma based on accelerated approvals. The primary challenge in utilizing BsAbs lies in patient selection due to variable responses, unique toxicity, and health economics. To date, no validated biomarkers of therapy response exist, however data demonstrating potential clinical, imaging and biological markers relating to BsAb are growing. This review examines current prognostic and potentially predictive biomarkers and explores future directions for nuanced patient selection.

An exploratory study of new predictive biomarkers of castration resistance.

An exploratory study of new predictive biomarkers of castration resistance.

MHC class II: a predictor of outcome in melanoma treated with immune checkpoint inhibitors.

This study aimed to evaluate the predictive value of MHC class II (MHC-II) expression by melanoma cells in a large cohort of metastatic cutaneous melanoma patients treated with immune checkpoint inhibitors (ICIs). We conducted a single-center, retrospective study involving stage IV cutaneous melanoma patients who received ICI as first-line therapy. MHC-II expression in melanoma cells was quantified using dual-color anti-SOX10 and anti-MHC-II immunohistochemistry on tumor samples from 95 patients. The primary endpoint was event-free survival (EFS), with secondary endpoints including 1-year EFS, 1-year overall survival (OS), disease control rate (DCR), and the correlation between MHC-II expression and clinico-biological characteristics. The cohort had a median age of 67 years (range, 33-90), with a male-to-female ratio of 50 : 45. Thirty-three percent of patients received the ipilimumab-nivolumab combination. The median follow-up was 16.8 months. Disease progression occurred in 58 patients (61%), with a median time to progression of 4.8 months. Forty-six patients (48.4%) experienced an event within the first year, and 52 patients (54.7%) died during follow-up. MHC-II positivity was observed in ≥10% of melanoma cells in 6.3% of patients. MHC-II expression was significantly associated with 1-year EFS (P = 0.037) and DCR (P = 0.032), but not with EFS or 1-year OS. Age, phototype, and brain metastases were correlated with MHC-II expression status. Our findings suggest that MHC-II expression by melanoma cells may serve as a favorable predictive biomarker for survival in metastatic cutaneous melanoma patients treated with ICIs.