Potential Biomarkers Of Response Research Articles

Anti-amyloid therapy and cerebral blood flow changes on Magnetic Resonance Imaging: a potential longitudinal biomarker of treatment response?

Amyloid-targeting therapy has recently become widely available in the U.S. for the treatment of patients with symptomatic mild Alzheimer's disease (AD). At present, there are no biomarkers that have been clinical validated to assess treatment response in routine clinical practice; longitudinal amyloid PET could play a role but is not cost effective. This report presents a case series of six patients with AD, whose amyloid positivity was confirmed by PET or CSF biomarkers, who underwent baseline and longitudinal arterial spin-labeling magnetic resonance imaging (ASL-MR) as part of FDA-mandated, clinical standard-of-care, non-contrast MR monitoring to assess for amyloid-related imaging abnormalities (ARIA). We and others have previously reported that ASL-MR can screen for neurodegenerative disease, as a proxy for FDG-PET, and can be easily added on as a cost-effective, repeatable method to monitor post-therapy changes. This series highlights varied cerebral blood flow (CBF) changes in response to lecanemab therapy. For instance, Cases 1, 3, and 5 showed increased CBF after multiple infusions, with subjective cognitive improvement in Case 1 and improved MoCA scores in Case 3. Case 2 showed improved CBF initially before the 5th infusion, but this returned to baseline on the subsequent study, with no cognitive improvement over the course of therapy. Cases 4 and 6 have demonstrated no significant changes in regional CBF thus far on therapy, with cognitive decline in Case 4. This case series underscores the potential utility of ASL-MR as an adjunct sequence to current imaging protocols to monitor treatment response to anti-amyloid therapy.ABBREVIATIONS: ASL-MR= arterial spin-labeling magnetic resonance imaging; MRI= magnetic resonance imaging; CBF= cerebral blood flow; AD= Alzheimer's disease; PET= positron emission tomography; CSF= cerebrospinal fluid; FDG= fluorodeoxyglucose.

Atezolizumab plus bevacizumab in patients with unresectable or metastatic mucosal melanoma: 3-year survival update and multi-omics analysis.

Atezolizumab plus bevacizumab has shown promising efficacy in advanced mucosal melanoma in the multi-centre phase II study. This report updates 3-year survival outcomes and multi-omics analysis to identify potential response biomarkers. Forty-three intention-to-treat (ITT) patients received intravenous administration of atezolizumab and bevacizumab every 3 weeks. Available samples underwent whole exome sequencing, transcriptome sequencing and targeted bisulphite sequencing to assess correlations with clinical outcomes. With a median follow-up of 40.3 months, the median overall survival (mOS) was 23.7 months (95% confidence interval [CI], 15.1-34), and the 3-year OS rate was 28.7% (95% CI, 17.6%-46.8%). Patients with upper site melanoma exhibited longer progression-free survival (PFS), higher tumour neoantigen burden (TNB) and greater copy number variations (CNVs) burden compared to those with lower site melanoma. NRAS mutations were associated with enhanced angiogenesis, with five of six patients achieving partial response. Inflammatory cell infiltration, angiogenic status and activation of the SMAD2 and p38 MAPK pathways may be prognostic indicators. This 3-year updated analysis confirms the sustained efficacy of atezolizumab in combination of bevacizumab in patients with advanced mucosal melanoma. Inflammatory cell infiltration and angiogenic status were associated with therapeutic response. Furthermore, mucosal melanoma of upper site and NRAS mutation appear to be good predictors of response to immune checkpoint inhibitor and anti-angiogenic combination treatment. Targeting SMAD2 and p38 MAPK pathways may further improve the outcome of mucosal melanoma. 3-year follow-up study confirmed the therapeutic efficacy of atezolizumab combined with bevacizumab Tumors in the upper site and NRAS mutations are more sensitive to treatment Inflammatory cell infiltration, angiogenic status, and activation of the SMAD2 and p38 MAPK pathways may be prognostic indicators.

Effects on Multimodal Connectivity Patterns in Female Schizophrenia During 8 Weeks of Antipsychotic Treatment.

Respective abnormal structural connectivity (SC) and functional connectivity (FC) have been reported in individuals with schizophrenia. However, transmodal associations between SC and FC following antipsychotic treatment, especially in female schizophrenia, remain unclear. We hypothesized that increased SC-FC coupling may be found in female schizophrenia, and could be normalized after antipsychotic treatment. Sixty-four female drug-naïve patients with first-diagnosed schizophrenia treated with antipsychotic drugs for 8 weeks, and 55 female healthy controls (HCs) were enrolled. Magnetic resonance imaging (MRI) data were collected from HCs at baseline and from patients at baseline and after treatment. SC and FC were analyzed by network-based statistics, calculating nonzero SC-FC coupling of the whole brain and altered connectivity following treatment. Finally, an Elastic-net logistic regression analysis was employed to establish a predictive model for evaluating the clinical efficacy treatment. At baseline, female schizophrenia patients exhibited abnormal SC in cortico-cortical, frontal-limbic, frontal-striatal, limbic-striatal, and limbic-cerebellar connectivity compared to HCs, while FC showed no abnormalities. Following treatment, cortico-cortical, frontal-limbic, frontal-striatal, limbic-striatal, temporal-cerebellar, and limbic-cerebellar connectivity were altered in both SC and FC. Additionally, SC-FC coupling of altered connectivity was higher in patients at baseline than in HC, trending toward normalization after treatment. Furthermore, identified FC or/and SC predicted changes in psychopathological symptoms and cognitive impairment among female schizophrenia following treatment. SC-FC coupling may be a potential predictive biomarker of treatment response. Cortico-cortical, frontal-limbic, frontal-striatal, limbic-striatal, temporal-cerebellar, and limbic-cerebellar could represent major targets for antipsychotic drugs in female schizophrenia.

Brolucizumab for the Treatment of Diabetic Macular Edema: An Optical Coherence Tomography-Based Analysis.

Objectives: The objectives of this study were to evaluate the structural and functional outcomes after the loading phase with brolucizumab in switched patients with diabetic macular edema (DME) and to identify potential predictive biomarkers of treatment response. Methods: A total of 28 eyes with DME, switched to brolucizumab, were retrospectively reviewed. Main outcomes during the follow-up period, up to 6 weeks after the fifth injection, included changes in best-corrected visual acuity (BCVA), central subfield thickness (CST), macular volume, subfoveal choroidal thickness, intraretinal and subretinal fluid (IRF and SRF), cyst dimension including maximal horizontal cyst diameter (MHCD), maximal vertical cyst diameter (MVCD), width-to-height ratio (WHR), foveal avascular zone (FAZ) dimension, and vessel density (VD). Results: At the last follow-up, BCVA was significantly improved (p = 0.003). Significant reduction of CST was demonstrated after each injection time point (p < 0.05), and a dry macula was detected in 64.3% of patients at the last follow-up. The WHR was 1.23 ± 0.46, and a negative correlation to final CST (p < 0.0001) was found. In FAZ and VD analysis, no significant variation was detected. At the last disease activity assessment, the treatment regimen was q12 in 64% of patients. Conclusions: Brolucizumab leads to anatomical and functional improvements in switched eyes affected by DME. WHR may represent a predictive biomarker of treatment response.

Pathogenic mitochondrial DNA variants are associated with response to anti-VEGF therapy in ovarian cancer PDX models

BackgroundMitochondrial DNA (mtDNA) pathogenic variants have been reported in several solid tumors including ovarian cancer (OC), the most lethal gynecologic malignancy, and raised interest as they potentially induce mitochondrial dysfunction and rewiring of cellular metabolism. Despite advances in recent years, functional characterization of mtDNA variants in cancer and their possible modulation of drug response remain largely uncharted.MethodsHere, we characterized mtDNA variants in OC patient derived xenografts (PDX) and investigated their impact on cancer cells at multiple levels.ResultsGenetic analysis revealed that mtDNA variants predicted as pathogenic, mainly involving complex I and IV genes, were present in all but one PDX (n = 20) at different levels of heteroplasmy, including 7 PDXs with homoplasmic variants. Functional analyses demonstrated that pathogenic mtDNA variants impacted on respiratory complexes activity and subunits abundance as well as on mitochondrial morphology. Moreover, PDX cells bearing homoplasmic mtDNA variants behaved as glucose-addicted and could barely survive glucose starvation in vitro. RNA-seq analysis indicated that mtDNA mutated (heteroplasmy > 50%) PDXs were endowed with upregulated glycolysis and other pathways connected with cancer metabolism. These findings led us to investigate whether pathogenic mtDNA variants correlated with response to anti-VEGF therapy, since the latter was shown to reduce glucose availability in tumors. Strikingly, PDXs bearing homoplasmic pathogenic mtDNA variants associated with improved survival upon anti-VEGF treatment in mice, compared with mtDNA wild type or low heteroplasmy PDXs.ConclusionsThese results hint at mtDNA variants as potential biomarkers of response to antiangiogenic drugs.

Prognostic Significance of miRNA Subtypes in Melanoma: A Survival Analysis and Correlation with Treatment Response Across Patient Stages.

Melanoma remains a leading cause of skin cancer mortality despite advancements in targeted therapies and immunotherapies. MicroRNAs (miRNAs) have emerged as potential biomarkers for cancer prognosis and treatment response. This study aims to analyze survival outcomes according to various miRNA subtypes, assess the association between specific miRNAs and treatment response, and include patient staging to evaluate their prognostic significance. A retrospective cohort study was conducted on 90 patients from the Pius Brinzeu County Emergency Clinical Hospital, Timisoara, between 2019 and 2022. The cohort included 45 patients with advanced-stage melanoma and 45 with benign nevi. miRNA expression levels were quantified using the miRNeasy Kit and the Human Cancer PathwayFinder miScript miRNA PCR Array. Survival analysis was performed using the Kaplan-Meier method, and Cox proportional hazards models were used to assess the impact of miRNA expression on survival. Logistic regression analyzed the association between miRNA markers and treatment response, adjusting for patient staging. Elevated levels of hsa-miR-200a-3p and hsa-miR-335-5p were significantly associated with poorer overall survival (p < 0.01), particularly in stage III and IV patients. Conversely, higher expression of hsa-miR-451a correlated with improved survival rates (p = 0.02). Patients with increased hsa-miR-29b-3p expression showed a better response to immunotherapy (OR = 2.35, 95% CI: 1.15-4.79). Multivariate analysis confirmed that miRNA expression levels and patient staging were independent predictors of survival and treatment response. Specific miRNA subtypes are significant prognostic markers in melanoma, influencing survival outcomes and treatment responses across different patient stages. Incorporating miRNA profiling into clinical practice could enhance personalized treatment strategies and improve patient prognoses.

Phase II study of MEK inhibitor trametinib alone and in combination with AKT inhibitor GSK2141795/uprosertib in patients with metastatic triple negative breast cancer.

While MEK inhibitors demonstrated activity in metastatic triple negative breast cancer (mTNBC) preclinical studies, preclinical, and clinical studies implicate rapid development of resistance limiting clinical benefit. The purpose of this study was to determine response rate for Trametinib alone and in combination with Uprosertib in patients with mTNBC previously treated with chemotherapy. This was an open-label, two-part, phase II, single-arm, multicenter study. Patients first received Trametinib monotherapy (2mg daily; Part I) then at progression transitioned to Trametinib (1.5mg) plus Uprosertib (50mg; Part II). Between October 2013 and January 2017, 37 patients were enrolled to Part I. Subsequently, 19 patients entered Part II. Of the 37 patients receiving Trametinib monotherapy, 2 patients achieved partial response (PR) for an ORR of 5.4% (2/37) and an additional 6/37 (16.2%) achieved stable disease (SD). The clinical benefit rate (PR+SD) for patients receiving monotherapy was 21.6% (8/37). Of the 19 patients in Part II, 3 patients achieved PR for an ORR to Part II of 15.8% (3/19) and an additional 3 achieved SD. Median progression-free survival (PFS) was 7.7 weeks for Part I and 7.8 weeks for Part II. Circulating tumor DNA (ctDNA) clearance at C2D1 of Trametinib monotherapy was associated with improved PFS and overall survival. In patients with mTNBC, Trametinib monotherapy demonstrated limited efficacy and addition of Uprosertib was associated with numerically greater objective responses but no difference in PFS. Translational analyses suggest ctDNA clearance as a potential early biomarker of response.

Tumor Suppressor miR-34a: Potential Biomarker of TACE Response in HCC.

TACE induces variable systemic effects by producing factors that promote inflammation, oncogenesis, and angiogenesis. Here we compare concentrations of microRNAs (miR-21, miR-210 and miR-34a) and vascular endothelial growth factor (VEGF) in hepatocellular carcinoma (HCC) patients undergoing TACE with degradable (DSM) and nondegradable (DEB) particles and potential use of these biomarker changes for prediction of patient outcomes. Overall, 52 patients with HCC treated with DSM TACE (24 patients) and DEB TACE (28 patients) were included in this prospective study. Concentrations of studied biomarkers were measured from blood plasma preprocedurally, immediately (< 90min) postprocedurally, and 24-h after TACE. Levels were compared between DSM and DEB TACE and correlated with treatment response six and 12months after the first TACE. Both DSM and DEB TACE elevated plasma levels of miR-21, miR-34a, and miR-210 at 24h post-procedure compared to baseline levels (FC 1.25-4.0). MiR-34a elevation immediately after TACE was significantly associated with nonprogressive disease compared to those with progressive disease at both sixmonths (FCa: p = 0.014) and 12months (FCa: p = 0.029) post-TACE. No significant biomarker changes were found between the embolization particle groups. However, VEGF levels showed a decrease only in the DSM TACE group (FC24: p = < 0.001). Embolization particle type did not significantly impact miRNA or VEGF changes post-TACE. However, miR-34a elevation immediately after the procedure predicts better patient outcome and may prove useful as a biomarkers for the monitoring of clinical outcomes. Level 3 Prospective cohort study.

The tumor suppressor SALL2 opposes chemotherapeutic resistance in breast cancer.

Chemotherapy continues to be the primary treatment for certain types of breast cancer. However, despite an initial positive response to chemotherapeutic agents, the development of resistance is inevitable. The exact molecular mechanisms underlying this phenomenon remain unclear. In this research, a significant downregulation of SALL2 expression was observed in chemo-resistant breast cancer, which was attributed to promoter methylation. Decreased SALL2 expression correlated significantly with poorer relapse-free survival in chemotherapy-treated patients with breast cancer. Functionally, SALL2 silencing induced a stem cell-like phenotype in breast cancer cells, fostering resistance to cisplatin both in vitro and in vivo. This resistance was mediated, at least in part, through the transcriptional regulation of BTG2, a negative regulator of stemness, achieved by direct binding to its promoter regions. These findings underscore the critical role of SALL2 in modulating cisplatin response and propose SALL2 as a potential prognostic biomarker for chemotherapy response in breast cancer.

Proteomic Analysis of Biomarkers Predicting Treatment Response in Patients with Head and Neck Cancers.

Head and neck cancers (HNCs) are the sixth most commonly diagnosed cancer and the eighth leading cause of cancer-related mortality worldwide, with squamous cell carcinoma being the most prevalent type. The global incidence of HNCs is steadily increasing, projected to rise by approximately 30% per year by 2030, a trend observed in both developed and undeveloped countries. This study involved serum proteomic profiling to identify predictive clinical biomarkers in cancer patients undergoing chemoradiotherapy (CRT). Fifteen HNC patients at Tikur Anbessa Specialized Hospital, Radiotherapy (RT) center in Addis Ababa were enrolled. Serum samples were collected before and after RT, and patients were classified as responders (R) or non-responders (NR). Protein concentrations in the serum were determined using the Bradford assay, followed by nano-HPLC-MS/MS for protein profiling. Progenesis QI for proteomics identified 55 differentially expressed proteins (DEPs) between R and NR, with a significance of p < 0.05 and a fold-change (FC) ≥ 1.5. The top five-up-regulated proteins included MAD1L1, PSMC2, TRIM29, C5, and SERPING1, while the top five-down-regulated proteins were RYR1, HEY2, HIF1A, TF, and CNN3. Notably, about 16.4% of the DEPs were involved in cellular responses to DNA damage from cancer treatments, encompassing proteins related to deoxyribonucleic acid (DNA) damage sensing, checkpoint activation, DNA repair, and apoptosis/cell cycle regulation. The analysis of the relative abundance of ten proteins with high confidence scores identified three DEPs: ADIPOQ, HEY2, and FUT10 as potential predictive biomarkers for treatment response. This study highlighted the identification of three potential predictive biomarkers-ADIPOQ, HEY2, and FUT10-through serum proteomic profiling in HNC patients undergoing RT, emphasizing their significance in predicting treatment response.

Potential Prognostic Protein Biomarkers in Tears From Noninfectious Uveitis Patients Under Biologic Treatment as a Prelude to Personalized Medicine.

Adalimumab (ADA) is a systemic biological treatment option approved for the treatment of noninfectious uveitis (NIU); however, up to 40% of patients do not respond to the drug, either in a primary or secondary manner. Here, we evaluated the proteomic profile of patients with NIU who fail to ADA to identify proteins implicated in intraocular inflammation, as well as potential biomarkers for treatment response and novel therapeutic targets. Cross-sectional observational study of patients with NIU under ADA treatment for six or more months. Tears were collected with microcapillary tubes and protein analyzed by data-independent acquisition/sequential window acquisition of all theoretical mass spectra. Differentially expressed proteins (DEPs) were defined based on the fold change between their expression in nonresponders (NR) and responders (R). Protein network and gene ontology analysis were performed. The χ2 test for trend and receiver operating characteristic (ROC) curves were used to evaluate potential biomarkers of treatment response. Twenty-nine DEPs, 14 upregulated and 15 downregulated, were detected in NR. These proteins were mainly related to enhanced neutrophil effector functions and redox imbalance. ROC analysis identified defensin-1,3 (DEF-1,3), biotinidase, and ATP-binding cassette transporter A1 as potential biomarkers for treatment response. This is the first study on a clinical cohort of patients with noninfectious uveitis that identifies tear proteins related to neutrophil hyperactivation as drivers of the persistent intraocular inflammation observed in NR to ADA and provides evidence that targeting interleukin 6, Janus kinases, or the complement cascade could be potential alternative therapeutic strategies in these patients. Our results indicate the potential of high-throughput proteomics to provide insights into the underlying pathological mechanisms of persistent intraocular inflammation observed in patients who do not adequately respond to anti-TNF treatment and the value of tear proteomics as a tool for personalized medicine.

CTIM-32. PHASE I/II STUDY OF STEREOTACTIC RADIOSURGERY WITH CONCURRENT OLAPARIB FOLLOWED BY ADJUVANT DURVALUMAB AND PHYSICIAN’S CHOICE SYSTEMIC THERAPY IN SUBJECTS WITH BREAST CANCER BRAIN METASTASES (SOLARA)

Abstract BACKGROUND Despite progress in the treatment of brain metastasis for HER2+ breast cancer, outcomes for patients with HER2-negative breast cancer brain metastases remain poor. Preclinical studies show inhibitors of poly(ADP-ribose) polymerase (PARP) are effective in combination with radiation therapy as a DNA damage response inhibitor. Triple-negative breast cancer (TNBC) has higher rates of homologous recombination deficiency compared to other subtypes, and together with HER2-negative, BRCA-mutated breast cancer would be particularly sensitive to PARP inhibition. PARP inhibition has also demonstrated promising efficacy combined with immunotherapy in patients with germline BRCA-mutant and metastatic TNBC in clinical trials. In addition, immunotherapy with stereotactic radiosurgery (SRS) is associated with favorable intracranial control and survival in patients with brain metastases. We hypothesize that this biologically-driven combination will enhance local control of SRS-treated brain metastases through synergy with PARP inhibition, while controlling micrometastatic disease via potentiation of the immune response. METHODS We are conducting a multi-institution, Phase I/II trial of SRS plus olaparib, followed by durvalumab (with physician’s choice systemic therapy), for patients with TNBC (any BRCA status) or HER2-negative with BRCA-mutated (germline or somatic) breast cancer brain metastases [NCT04711824]. A total of 41 patients are planned for enrollment at 8 sites. The primary objectives are to evaluate safety and tolerability (Phase I) and determine intracranial disease control at 6 months (Phase II). Secondary objectives include assessing intracranial and global progression-free survival, overall survival, and intracranial and extracranial response rate. Exploratory objectives will assess potential biomarkers of treatment response, including changes in circulating tumor cells and DNA in blood and cerebrospinal fluid, germline and tumor mutations in DNA repair pathway genes, and PD-L1 expression, as well as quality of life and patient-reported outcomes. As of May 2024, phase I has been completed without dose-limiting toxicity, and phase II is currently enrolling. Funding/drug provision from AstraZeneca.

BIOM-36. DETECTION OF CIRCULATING TUMOR DNA (CTDNA) IN CEREBROSPINAL FLUID (CSF) IN PATIENTS WITH GLIOBLASTOMA TREATED IN PHASE I CLINICAL TRIAL

Abstract BACKGROUND As circulating tumor DNA (ctDNA) has been shown to be a source of tumor-specific biomarkers, liquid biopsy has emerged as a novel noninvasive tool in diagnosis, disease monitoring and treatment selection in several solid tumors. However, its use in brain tumors remains challenging because ctDNA is commonly not detected in blood. Thus, CSF (cerebrospinal fluid) has emerged as a potential source of ctDNA in the context of brain tumors. PATIENTS AND METHODS We prospectively evaluated the detection of ctDNA in CSF (CSF-ctDNA) +/- blood of patients with pre-treated MTAP-deleted glioblastoma, currently treated in a phase I clinical trial evaluating PRMT5 inhibitors. We did CSF samples at C2D15 and at progression, after patient’s oral and written consent. CSF was collected by lumbar puncture and analyzed with a panel of 35 genes including IDH1-2, TERT promoter and EGFR. Blood was collected, synchronously with CSF, by peripheral veinous punction and analyzed with the Foundation One Liquid CDx panel. RESULTS Between January and April 2024, five patients were included. All of them undergone initial surgical resection and received at least one previous systemic treatment associated with radiotherapy. At least one somatic mutation was identified in each patient, including EGFR amplification in 2/5 patients (40%). CSF was not available at baseline. One patient provided CSF only at progression. Four patients provided CSF at C2D15 on treatment, and among them, one patient was also collected at progression. At data cut-off, one patient was still on treatment. We identified a detectable level of CSF-ctDNA in only one patient with occipital tumor localization, with detection of EGFR amplification known at diagnosis. Synchronous blood analysis showed only clonal hematopoiesis variants. CONCLUSION We showed in this small cohort of patients that detection of CSF-ctDNA is technically feasible. The type of panel used might be optimized for this population especially to monitor patients as a potential surrogate biomarker for treatment response.

MicroRNAs as potential biomarkers of response to modified Atkins diet in treatment of adults with drug-resistant epilepsy: A proof-of-concept study

BackgroundAccurate predictors of response to modified Atkins diet (MAD) are needed. MicroRNAs are potential biomarkers in epilepsy. This study aimed to explore the value of circulating miR-146a, miR-155, miR-22, miR-21 and miR-134 levels in predicting response to MAD. MethodsPatients who completed 3 months of MAD were selected from a prospective cohort of adults with DRE followed in a specialized MAD outpatient clinic. Patients were classified as responders if any reduction in seizure frequency at follow-up, calculated through seizure-calendars). The >50 % seizure reduction cut-off was also explored. Qualitative benefits in seizures and cognition were analysed. Blood samples were collected prior to initiate MAD and microRNAs were quantified by qRT-PCR. ResultsThirty-nine patients were included (56 %males, mean age=33.1±8.5yo, 62 %focal epilepsies, 59 %structural aetiology): 20(51 %) were responders [mean reduction in seizure frequency=54 %(17–100 %); 10 had ≥50 % reduction]; 25(64 %) reported qualitative benefit in seizures and 21(54 %) reported cognitive benefits. At pre-treatment baseline, a panel combining serum levels of all studied microRNAs predicted seizure reduction (AUC=0.839, p<0.0001), qualitative benefit in seizures (AUC=0.683, p=0.048) and in cognition (AUC=0.751, p<0.01) at 3months. miR-146a was the only significant microRNA when evaluated in isolation. There was no statistical correlation in the biomarkers when a ≥50 % seizure reduction was compared to <50 %. ConclusionsA panel combining pre-treatment serum levels of miR-146a, miR-155, miR-134, miR-21 and miR-22 predicted any reduction in seizures with MAD in adults with DRE at 3months. This panel may be a promising biomarker and a useful tool in the selection of patients.

Repair-assisted damage detection as a potential predictive biomarker for immunotherapy response in ovarian cancer

Repair-assisted damage detection as a potential predictive biomarker for immunotherapy response in ovarian cancer

The intra-tumoral microbiome as a potential biomarker of response to external beam radiation therapy in cervical cancer

BackgroundWe aimed to determine the potential predictive value of the intra-tumoral microbiome as a marker of the response to external beam radiation therapy (EBRT) in cervical cancer (CC).MethodsA prospective longitudinal trial of 36 CC patients receiving pelvic radiotherapy was designed to investigate microbial characteristic signatures and diversity (alpha and beta) of multiple sites (tumor, vaginal, gut, urethral, and oral) in the superior response (SR) and inferior response (IR) groups of CC patients by 16S rRNA sequencing. Utilized the least absolute shrinkage and selection operator (LASSO) logistic regression method to analyze clinicopathological factors that potentially influenced the efficacy of EBRT. LEfSe analysis highlighted the microbiome features that best distinguished the categorized patient samples. Selected parameters were validated with Spearman correlation analysis, receiver operating characteristic (ROC) area under the curve (AUC) analysis and Kaplan-Meier survival analysis.ResultsFirstly, in our cohort, LASSO logistic regression analysis revealed no association between clinicopathological factors and EBRT efficacy. Subsequently, we employed 16S rRNA sequencing to compare microbiome differences across multiple sites and their correlations with major clinicopathological factors. We discovered that the intra-tumoral microbiome was independent of clinicopathologic features and represented the most direct and reliable reflection of the microbial differences between the SR and IR groups. We found lower alpha diversity in the tumor microbiome of SR group and identified the most relevant microbiome taxa (Bifidobacteriaceae, Beijerinckiaceae, and Orbaceae) associated with the efficacy of the response to EBRT in CC patients. We then conducted ROC analysis, finding that specific microbial taxa had an AUC of 0.831 (95% CI, 0.667–0.995), indicating the potential of these taxa as biomarkers for predicting EBRT efficacy. Kaplan-Meier survival analysis showed a better prognosis for patients with lower alpha diversity and higher relative abundance of Bifidobacteriaceae.ConclusionsOur data suggested that intra-tumoral specific microbiome taxa and lower alpha diversity may play an important role in the CC patient sensitivity to EBRT and offer novel potential biomarkers for predicting the response to EBRT efficacy.

Altered Expression of Neuroplasticity-Related Genes in Alcohol Addiction and Treatment.

Alcohol use disorder's complexity arises from genetic and environmental factors, with alcohol metabolism genes and neurotransmitter pathways being critical. This study aims to analyze synaptic plasticity gene expression changes in individuals with AUD in order to study their contribution to AUD development and to identify potential biomarkers of treatment response. RNA was extracted from whole peripheral blood (20 patients, 10 healthy controls), before and after treatment (Qiagen AllPrep RNA/DNA Mini Kit), and the gene expression of 84 genes related to neuroplasticity was studied using the RT2 Profiler for Human Synaptic Plasticity RT-PCR Array (PAHS-126ZA, Qiagen), comparing AUD patients to control and responders to non-responders. The potential prognostic/predictive biomarkers were searched using machine learning models. A total of 35 dysregulated genes were found in AUD patients. EPHB2, EGR, and AKT1 were increased, while TIMP1, NCAM1, and GRM2 were decreased. Responders showed distinct gene expression profiles at baseline. After treatment, the expression of 57 genes was normalized, while NCAM1, GRM2, and BDNF showed the most significant recovery. EGR4, INHBA, and NCAM1 emerged as potential biomarkers to predict treatment success. These results indicate that gene profiles in peripheral blood can serve as prognostic markers for the prognosis and treatment of AUD, although further validation is required.

Secreted Apoe rewires melanoma cell state vulnerability to ferroptosis.

A major therapeutic barrier in melanoma is the coexistence of diverse cellular states marked by distinct metabolic traits. Transitioning from a proliferative to an invasive melanoma phenotype is coupled with increased ferroptosis vulnerability. However, the regulatory circuits controlling ferroptosis susceptibility across melanoma cell states are unknown. In this work, we identified Apolipoprotein E (APOE) as the top lipid-metabolism gene segregating the melanoma MITFhigh/AXLlow proliferative/ferroptosis-resistant from MITFlow/AXLhigh invasive/ferroptosis-sensitive state. Mechanistically, ApoE secreted by the MITFhigh/AXLlow cells protects the invasive phenotype from ferroptosis-inducing agents by reducing the content of peroxidation-prone polyunsaturated fatty acids and boosting GPX4 levels both in vitro and in vivo. Whole-exome sequencing indicates that APOEhigh expression in patients with melanoma is associated with resistance to ferroptosis, regardless of APOE germline status. In aggregate, we found a ferroptosis-resistance mechanism between melanoma cell states relying on secreted ApoE and APOEhigh expression as a potential biomarker for poor ferroptosis response in melanoma.

CD74 is a potential biomarker predicting the response to immune checkpoint blockade

BackgroundImmune checkpoint blockade (ICB) has been improving the patient outcome in multiple cancer types. However, not all patients respond to ICB. Biomarkers are needed for selecting appropriate patients to receive ICB. CD74 is an important chaperone that regulates antigen presentation for immune response. However, the relationship between CD74 expression and ICB response remains elusive.MethodsThe unified normalized pan-cancer dataset was downloaded from the UCSC database. Wilcoxon Rank Sum Rank Tests were used to analyze the expression differences between normal and tumor samples in each tumor type. Then, the prognostic value of CD74 was determined using univariable Cox proportional hazards regression analysis. The STRING database was utilized to construct the protein-protein interaction (PPI) network of CD74 and the signal pathways were analyzed as well. The correlation of CD74 expression with immune cells and immune regulating genes was investigated in the TIMER database. The TIDE framework was utilized to evaluate the relationship between CD74 expression and the response to immunotherapy. Moreover, the localization of CD74 in the tumor immune microenvironment was verified using multiplex immunohistochemistry. Clinically annotated samples from 38 patients with esophageal cancer treated with neoadjuvant chemotherapy combined with ICB were analyzed for CD74 expression using immunohistochemistry.ResultsIn this study, we investigated the prognostic and predictive value of CD74 in different types of cancer. Compared with normal tissue, the expression of CD74 was higher in tumor tissue in various cancers. High expression of CD74 was associated with improved patient prognosis in the majority of cancers. CD74 and its interacting proteins were mainly enriched in the immune-related pathways. The expression of CD74 was significantly positively correlated with B cells, CD4 T-cells, CD8 T-cells, neutrophils, macrophages and dendritic cells. TIDE analysis showed that tumors with high CD74 expression may have better responses to immunotherapy and improved patient survival. In patients with esophageal cancer who had received ICB, higher intratumoral CD74 expression was associated with improved response to ICB.ConclusionsThe findings of this study suggest that the high expression of CD74 may be a potential predictive biomarker of response to ICB.

Phase II Trial of Gemcitabine and Nab-Paclitaxel for Recurrent Osteosarcoma with Serial Monitoring Using Liquid Biopsy: A Report from the National Pediatric Cancer Foundation.

The combination of gemcitabine and docetaxel is often used to treat patients with recurrent osteosarcoma. Nab-paclitaxel has preclinical activity against osteosarcoma and is potentially less myelosuppressive than docetaxel. We conducted a prospective multi-institutional phase II trial combining gemcitabine and nab-paclitaxel for patients aged 12 to 30 years with recurrent osteosarcoma and measurable disease. A Simon's two-stage design was used to test a 4-month progression-free survival (PFS-4) of 10% vs. 35%. Patients received nab-paclitaxel 125 mg/m2 and gemcitabine 1,000 mg/m2 weekly × 3 in 4-week cycles. Immunohistochemical analysis of archival tissue and serial assessment of circulating tumor cells (CTC) and circulating tumor DNA (ctDNA) using ultralow passage whole-genome sequencing were performed to identify potential biomarkers of response. Eighteen patients received 56 total cycles (median 2, range 1-12). Two patients (11%) experienced confirmed partial response and six (33%) received >2 cycles. The PFS-4 was 28% (95% confidence interval, 13%-59%). Six patients required dose reductions and three patients were removed due to toxicities. All 18 patients had detectable CTCs and 10 had ctDNA identified. All eight patients with MYC amplification at study entry experienced disease progression. Gemcitabine and nab-paclitaxel demonstrated similar clinical activity and toxicity compared to previous retrospective reports utilizing gemcitabine and docetaxel in patients with recurrent osteosarcoma. Serial analysis of CTC and ctDNA was feasible in this prospective multi-institution study and provides preliminary data on the use of these assays in patients with relapsed disease.