PMCID string | Title string | Sentences string |
|---|---|---|
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | E Representative case (patient 166) showing MES marker positivity prior to relapse. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | At diagnosis adrenal tumor with MYCN amplification and multiple bone metastases and bone marrow infiltration; patient suffered a relapse one month after completion of SIOPEN/HR-NBL1 treatment and died 20 months later from disease. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Bone marrow samples assessed by RT-qPCR-ADRN and RT-qPCR-MES (normalized mRNA expression left y-axis) and AIPF (given as % DTCs, right y-axis) per timepoint (x-axis). |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | DE = diagnosis, RE1 = mid-induction chemotherapy, RE2 = end of induction therapy, RE3 = surgery, RE4 = before stem cell transplantation, RE5 = before immunotherapy, RES6 = mid-immunotherapy, RE7 = at end of immunotherapy Mesenchymal markers identify MRD in adrenergic negative and AIPF negative bone marrow liquid biopsies prior to relapse. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | A Contribution of mesenchymal mRNA RT-qPCR-markers (RT-qPCR-MES),RT-qPCR-ADRN, AIPF and cytomorphology (CM)/histology. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Venn diagram shows samples positive for at least one technology. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Each circle represents positive results of one technique. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | N = 395 samples analyzed by all techniques; N = 273 samples positive by ≥ 1 technique. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | B MES-positive samples by RT-qPCR-MES. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Level of infiltration according to AIPF (y-axis; given as % DTCs) and RT-qPCR-ARDN (x-axis; given as % relative to neuroblastoma cell lines IMR32) (n = 107; Spearman correlation = 0.59, 95% CI 0.33–0.77; p < 0.001 of samples positive for both techniques (n = 38). |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | C Level of infiltration by AIPF (y-axis; given as % DTCs) versus MES-positivity (x-axis). |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Box plots represent 10–90 percentiles, line shows median. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Heatmap represents number of negative and positive cases. * |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | = 0.0377. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | D Level of infiltration by RT-qPCR-ADRN (y-axis; given as % relative to neuroblastoma cell line IMR32) versus MES-positivity (x-axis). |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Box plots represent 10–90 percentiles, line shows median. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Heatmap represents number of negative and positive cases. ** |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | = 0.0029. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | E Representative case (patient 166) showing MES marker positivity prior to relapse. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | At diagnosis adrenal tumor with MYCN amplification and multiple bone metastases and bone marrow infiltration; patient suffered a relapse one month after completion of SIOPEN/HR-NBL1 treatment and died 20 months later from disease. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Bone marrow samples assessed by RT-qPCR-ADRN and RT-qPCR-MES (normalized mRNA expression left y-axis) and AIPF (given as % DTCs, right y-axis) per timepoint (x-axis). |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | DE = diagnosis, RE1 = mid-induction chemotherapy, RE2 = end of induction therapy, RE3 = surgery, RE4 = before stem cell transplantation, RE5 = before immunotherapy, RES6 = mid-immunotherapy, RE7 = at end of immunotherapy When considering only discordant pairs, the number of samples positive for the combination but CM/histology was 10.7 times higher (95% CI, 6.3–18.2) than the number of samples positive by CM/histology alone (Table 3), demonstrating that the combined test is superior to the current standard-of-care, CM/histology. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Of the 37 samples exclusively positive for MES mRNAs and negative by the other techniques, fourteen cases were from Dutch patients for which 12/14 plasma samples were available. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | In all twelve samples we detected hypermethylated RASSF1A DNA, a marker for neuroblastoma for which our group previously designed a droplet digital PCR assay . |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | We further investigated eight samples from patients carrying a MYCN amplification in tumor cells which were RT-qPCR-MESAIPF (five RT-qPCR-ADRN, three -ADRN); however, using MYCN iFISH, no cells with MYCN amplification were detectable. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | For 38 cases positive for AIPF, RT-qPCR-MES and -ADRN, tumor cell infiltration covered a range of 1 DTC in 5.30 million to 2.23 million DTCs in 2.48 million MNCs according to AIPF and 0.0001–341% (relative to IMR32) according to RT-qPCR, and correlated well (Fig. 4B). |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | There was a slightly higher tumor cell infiltration detectable in bone marrow-positive compared to those negative for MES mRNAs, as determined by AIPF (the number of investigated MNCs did not differ between MES and MES) and RT-qPCR-ADRN (Fig. 4C & D and Supplemental Fig. 4C). |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | This indicates that RT-qPCR-MES shows lower sensitivity, yet might identify MRD in an additional set of samples. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Interestingly, in patients with serially collected samples along multi-modal treatment and follow-up, signals often alternated between different techniques. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | This is exemplified by patient 166 and others, who showed an initial increase of MES mRNAs and delayed clearance upon induction chemotherapy, with an early increase of MES mRNA POSTN prior to relapse (Fig. 4E and Supplemental Fig. 5A-C). |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Sensitive bone marrow MRD detection is crucial for evaluating therapy response, monitoring disease progression, and early relapse detection, helping to identify patients who may benefit from alternative treatments. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Additionally, assessing tumor cell state plasticity and the abundance of immunotherapy targets is essential for accurately evaluating immunotherapy efficacy. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | In this prospective study, we address these needs using multi-modal, high-sensitivity MRD techniques in 509 samples obtained from 108 patients. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | We show that (1) performing all three high-sensitivity analyses, i.e. AIPF, RT-qPCR-ADRN and -MES on the same bone marrow specimen, alongside standard-of-care assessments, is feasible in an international multicenter setting; (2) multi-modal analysis is more effective at detecting bone marrow MRD than the current standard of care, with low tumor cell burden detected by RT-qPCR-ADRN more frequently and less frequently by AIPF; (3) bone marrow disease is present on both sides when DTC infiltration is high (e.g., at diagnosis). |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | In MRD settings during and post-treatment, more frequently only one side is affected; (4) AIPF and RT-qPCR are complementary approaches for high-sensitivity MRD detection and characterizing of tumor cell phenotypes and therapeutic targets; and (5) RT-qPCR-MES shows lower sensitivity but may identify MRD in an additional subset of samples. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Notably, in a patient with initially high MES markers, these markers showed delayed clearance post-induction chemotherapy and an early increase before relapse. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | We have previously demonstrated the superior sensitivity of mRNA- and DTC-based bone marrow MRD detection techniques. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | RT-qPCR-based testing of bone marrow and peripheral blood neuroblastoma patients is a robust and highly sensitive method for detecting residual disease [19, 31–34, 36–40, 54, 55]. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Stutterheim, et al. reported RT-qPCR positivity in 31% (5/16) of bone marrow GD2-immunocytology samples and Hartomo, et al. reported RT-qPCR positivity in 48% (30/63) of bone marrow-cytology samples . |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | We have further shown in 345 patients that molecular detection of MRD by RT-qPCR was more sensitive and had higher prognostic value than GD2-immunocytology for neuroblastoma BM infiltration . |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | In contrast, AIPF can detect up to one tumor cell per million cells and provides a more automated and objective alternative to manual CM or immunocytology assessment based solely on GD2 . |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | AIPF has been compared against flow cytometry and cytomorphology in a study by Schriegel, et al. involving 369 bone marrow aspirates . |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | In the latter study, AIPF was demonstrated to be the single most sensitive method for the detection of bone marrow involvement in neuroblastoma . |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Furthermore, at end of induction chemotherapy, DTC-positivity by AIPF was significantly associated with event-free survival and cumulative incidence of relapse in a study of 180 patients (personal communication). |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | In the prospective study described here, we combined these complementary techniques, i.e. RT-qPCR-ADRN, AIPF and RT-qPCR-MES, to evaluate their effectiveness in detecting MRD across 509 bone marrow aspirates from 108 patients in a multicenter setting. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Our findings indicate that multicenter exchange is feasible within a clinically relevant six-day turnaround time. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Despite differences in treatment protocols (NCT01704716, NCT01704716) and cut-offs for CM assessment , and differences in mean cell counts (3.80 million (range 130,000–7.97 million) for Austrian and 1.95 million (range 237,000–5.00 million) for Dutch samples) no major differences in results were observed between Austrian and Dutch samples compared to aggregated results. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | This underlines the ability to perform high-sensitivity analyses from small bone marrow volumes in an international setting and demonstrates the robustness of the techniques, paving the way for standardized MRD detection across clinical settings. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | This standardization is important for the ongoing European SIOPEN High-Risk Neuroblastoma 2 (HR-NBL2) trial (NCT04221035), ensuring accurate and timely diagnosis. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Moreover, in our study, RT-qPCR-ADRN emerges as the most sensitive method for MRD detection. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | It is important to emphasize that AIPF uniquely identified certain samples not detected by RT-qPCR, suggesting that AIPF provides complementary information by enabling direct visualization and genetic verification of disseminated tumor cells, thereby offering insights into tumor cell morphology and immunotherapy marker expression that molecular methods alone cannot provide. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | As AIPF quantifies actual cells while RT-qPCR measures transcripts, a strong correlation between the techniques is evident when tumor cell infiltration is high, i.e., at diagnosis and at an event. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Our findings confirm previous observations that PHOX2B sensitivity is most evident in samples with low tumor infiltration, such as bone marrow samples during treatment . |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Notably, bone marrow infiltration levels detected by AIPF and RT-qPCR decreased during treatment and increased at relapse, reinforcing the potential of these methods response monitoring and early relapse, as well as highlighting the importance of serial sampling. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Future studies should explore their association in treatment response as predictive value for survival. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | While our study did not recommend a reduction of bilateral BM sampling, the sensitivity of AIPF and RT-qPCR suggests unilateral sampling at diagnosis may suffice for initial bone marrow disease assessment. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | This could reduce patient burden and costs, with bilateral sampling reserved for follow-up when tumor cell infiltration is lower. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Future studies should explore this approach. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Our results also facilitate implementation as clinical decision-making tools for detecting molecular relapse, crucial for timely intervention. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Prospective trials are currently underway to validate the use of RT-qPCR-ADRN as a diagnostic tool in blood liquid biopsies to determine imminent molecular relapse early. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Beyond MRD detection, understanding therapy suitability is essential. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Recent studies highlight distinct vulnerabilities of MES and ADRN neuroblastoma phenotypes. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | MES cells exhibit in vitro, more resistant to chemotherapeutics, retinoic acid, and ALK inhibition , drugs that are applied in current first- and second-line treatment protocols for patients with neuroblastoma . |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | In contrast, NOTCH pathway downregulation adversely affects MES cell survival in vitro and in vivo . |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Our study shows that MES and ADRN phenotypes fluctuate during therapy, with MES-related mRNAs increasing before relapse in a patient with metastatic disease and slow induction therapy response. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | This corroborates previous work by our group in a retrospective cohort (95 bone marrow samples from 38 patients), where MES mRNA-expression increased in 18/27 patients during induction, while ADRN mRNA-expression initially decreased but was elevated at relapse in 9/12 patients . |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Interestingly, MES-related mRNAs were detected in the absence of detectable ADRN mRNAs or DTCs in patients who did not relapse. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Future research should determine whether these findings indicate MES tumor cells or other mesenchymal-like processes are triggered or induced by therapy or fibrosis which can result in tumor cell senescence . |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Monitoring the appearance of MES cells can provide insights into treatment response and potential resistance. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Tools that accurately detect and characterize these phenotypes are useful for tailoring treatment plans to individual patients. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Therapies targeting MES-neuroblastoma may benefit from such monitoring, although wider prospective studies are needed to validate these findings. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Anti-GD2 immunotherapy is a critical treatment for high-risk neuroblastoma and other cancers . |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Our study shows that GD2 and other immunotherapy targets can be monitored and quantified using AIPF and advanced image-based multiplexed approaches. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Anti-GD2 therapy, after successful trials in relapsed/refractory patients , is transitioning to frontline treatment as part of chemo-immunotherapy. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Flow cytometry has been successfully used in 41 bone marrow specimens from 25 patients to determine GD2 levels on DTCs at diagnosis and relapse when tumor cells are abundant . |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | We demonstrate that GD2 can be detected even when tumor cells are extremely rare, e.g. during treatment. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Measuring GD2 and other immunotherapy targets (e.g., NCAM, L1CAM, GPC-2) in therapy-resistant cells is essential for assessing treatment efficacy and making informed clinical decisions. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | AIPF, as one of the few ISO-certified tests for GD2 detection, will be integral in multi-modal diagnostic workflows as antibody and CAR-T cell-based immunotherapies gain traction in neuroblastoma [25, 26, 28, 66–69] and other cancers, such as Ewing sarcoma and melanoma , highlighting the broader applicability of these monitoring techniques. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Limitations of this study include the following aspects: First, this study is well-powered for technical comparison and proof-of-principle demonstration, however, clinical relevance of the combined test in detecting treatment response, early relapse, or evaluating its predictive or prognostic power cannot be determined. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Its clinical relevance is currently being assessed prospectively in the SIOPEN frontline trial HR-NBL2 (NCT04221035) and other trials enrolling patients with high-risk neuroblastoma. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | A second limitation is the current clinical practice for collecting bone marrow aspirates, which mandates using the first drop of aspirates for smear preparation to assess cytomorphology . |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Consequently, bone marrow samples used for RT-qPCR and AIPF are more diluted with blood, potentially explaining why sixteen samples were positive by CM/histology only. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | Lastly, AIPF is highly robust in detecting GD2 and CD56 on tumor cells, particularly when combined with iFISH, which includes adequate positive and negative controls in each analysis run. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | However, detecting tumor cells negative for both markers remains challenging and will require techniques with carefully designed, highly multiplexed marker panels, such as imaging mass cytometry or flow cytometry. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | For clinical application it will be important to carefully design such marker panels and develop in future prospective studies cost-effective lab tests for highly sensitive methods such as RT-qPCR, AIPF, and multiparameter flow cytometry. |
PMC12317575 | Sensitive detection of minimal residual disease and immunotherapy targets by multi-modal bone marrow analysis in high-risk neuroblastoma – a multi-center study | In conclusion, our study highlights the importance of advanced multi-modal MRD detection techniques, monitoring tumor phenotype switches, and assessing immunotherapy targets to improve patient outcomes in neuroblastoma and other cancers. |
PMC12602814 | LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer's Disease Cell Models | Alzheimer's disease (AD) leads to a progressive loss of cognitive abilities and memory. |
PMC12602814 | LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer's Disease Cell Models | A critical factor now recognized as driving AD pathology is neuroinflammation—inflammation occurring in the nervous system, which contributes to neuronal harm and communication breakdowns. |
PMC12602814 | LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer's Disease Cell Models | our research investigated the specific effects of neuroinflammation on neuronal signaling pathways. |
PMC12602814 | LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer's Disease Cell Models | In this study, we primarily employed the SH-SY5Y neuroblastoma cell line as an in vitro neuronal model to investigate inflammatory responses relevant to AD etiology, alongside supplementary observations in primary neurons and 3D spheroids for comparative analysis. |
PMC12602814 | LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer's Disease Cell Models | Our analysis focused on modifications of key molecules, including the neuroprotective protein Brain-Derived Neurotrophic Factor (BDNF), pro-inflammatory cytokines such as IL-6 and TNF-α, and crucial regulatory kinases. |
PMC12602814 | LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer's Disease Cell Models | Our results demonstrated that LPS treatment dramatically lowered the vitality and decreased BDNF levels in the SH-SY5Y cells. |
PMC12602814 | LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer's Disease Cell Models | Furthermore, we observed a considerable elevation in the pro-inflammatory cytokines IL-6 and TNF-α, coupled with elevated levels of COX-2 and iNOS. |
PMC12602814 | LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer's Disease Cell Models | Gene expression data validated that LPS treatment altered the expression of essential signaling kinases (Protein Kinase A (PKA), Protein Kinase B (AKT), and Mitogen-Activated Protein Kinase (MAPK)). |
PMC12602814 | LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer's Disease Cell Models | Our first comparative analysis revealed that 3D spheroid cultures may elicit more pronounced inflammatory responses than standard 2D cultures; nevertheless, our detailed investigation primarily focused on the SH-SY5Y model. |
PMC12602814 | LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer's Disease Cell Models | This study revealed that LPS-induced neuroinflammation affects neuronal signaling in vitro, thereby revealing a relationship between inflammation and neuronal dysfunction in cellular models of neuroinflammation. |
PMC12602814 | LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer's Disease Cell Models | These findings highlight pathways that may be relevant to AD pathophysiology; however, further in vivo studies are necessary to demonstrate their translational relevance to humans. |
PMC12602814 | LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer's Disease Cell Models | This graphical abstract illustrates how LPS-induced neuroinflammation disrupts neurotrophic signaling and kinase activity in Alzheimer's models. |
PMC12602814 | LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer's Disease Cell Models | It highlights the involvement of SH-SY5Y cells, primary neurons, and 3D spheroids in inflammatory cascades that lead to oxidative stress, BDNF suppression, and synaptic dysfunction, offering insights into potential therapeutic targets. |
PMC12602814 | LPS-Induced Neuroinflammation Disrupts Brain-Derived Neurotrophic Factor and Kinase Pathways in Alzheimer's Disease Cell Models | AD is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and synaptic malfunction. |
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