Molecular Diagnosis & Therapy最新文献

{"title":"Diagnostic Utility of a 90-Gene Expression Assay (Canhelp-Origin) for Patients with Metastatic Cancer with an Unclear or Unknown Diagnosis.","authors":"Peng Qi, Yifeng Sun, Yue Pang, Jing Liu, Xu Cai, Shenglin Huang, Qinghua Xu, Qifeng Wang, Xiaoyan Zhou","doi":"10.1007/s40291-024-00746-6","DOIUrl":"https://doi.org/10.1007/s40291-024-00746-6","url":null,"abstract":"<p><strong>Background: </strong>Metastatic cancers with unclear or unknown origins pose significant challenges in diagnosis and management, frequently leading to suboptimal outcomes. Studies have demonstrated that a 90-gene expression assay is effective in predicting the primary origin and guiding the site-specific therapy to improve prognosis. This study aimed to evaluate the clinical effectiveness of a 90-gene expression assay in patients with unclear or unknown diagnoses.</p><p><strong>Methods: </strong>The study encompassed patients for whom a 90-gene expression assay was requested as part of standard care. Data on patient demographics, tumor characteristics, and clinical history were collected. The assay's performance was evaluated by comparing its predicted tumor type with the final histopathological diagnosis.</p><p><strong>Results: </strong>Among 303 cases analyzed, a 90-gene expression assay successfully identified a molecular-based tumor type for 295 (97.4%) patients. Comparison with histopathological diagnosis revealed an overall agreement of 88.5% (170/192). In patients with a single suspected primary site (n = 140), the assay confirmed the suspected diagnosis in 90.7% of cases. For those with a differential diagnosis (n = 52), the assay narrowed down the possibilities in 82.7% of cases. Moreover, in cases where the histopathology report indicated cancer of unknown primary (n = 103), the assay offered a molecular tumor type prediction with potential clinical significance.</p><p><strong>Conclusions: </strong>This study demonstrates the significant impact of a 90-gene expression assay on diagnosis and potential treatment selection for difficult-to-diagnose patients, highlighting its clinical value as a standardized molecular approach to streamline further diagnostic testing for patients with metastatic cancer of unclear or unknown origin. Further prospective study is required to assess whether employing molecular diagnostic classifiers enhances clinical outcomes in these patients.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-27","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331120","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Sensitive and Specific Droplet Digital PCR Assays for Circulating Tumor HPV DNA: Development, Validation, and Clinical Application in HPV-Associated Cancers.","authors":"Alvida Qvick, Elin Andersson, Anna Oldaeus Almerén, Max Waenerlund, Bianca Stenmark, Christina Karlsson, Mats G Karlsson, Gisela Helenius","doi":"10.1007/s40291-024-00743-9","DOIUrl":"https://doi.org/10.1007/s40291-024-00743-9","url":null,"abstract":"<p><strong>Background: </strong>Human papillomavirus (HPV) has emerged as a significant contributor to cancer incidence globally, particularly in the context of oropharyngeal squamous cell carcinoma (OPSCC) and cancer of unknown primary (HNCUP). This study aimed to develop and validate droplet digital PCR (ddPCR) assays for the detection of circulating tumor HPV DNA (ctHPV-DNA) in plasma, focusing on high-risk HPV genotypes associated with these cancers.</p><p><strong>Methods: </strong>ddPCR assays for HPV16, 18, 33, 35, 56, and 59 were developed and tested using gBlocks, HPV cell-free DNA, fragmented tumor HPV+ DNA, and plasma samples from patients with HPV+ OPSCC (n = 110) and HNCUP (n = 9).</p><p><strong>Results: </strong>Assays demonstrated robust technical sensitivity across all tested HPV genotypes. Clinical application of the assays on a cohort of patients with HPV+ OPSCC and HNCUP revealed high sensitivity (91.6%) and wide variability in ctHPV-DNA levels. Analyses revealed correlations between ctHPV-DNA levels and TNM stage and tumor viral load. The association between ctHPV-DNA and tumor viral load persisted even after adjusting for TNM stage. At posttreatment, 72.5% of samples had reached undetectable ctHPV-DNA levels. Having detectable ctHPV-DNA posttreatment was associated with a higher ctHPV-DNA level at diagnosis and higher viral load at diagnosis.</p><p><strong>Conclusion: </strong>The findings underscore the potential of ctHPV-DNA as a biomarker for monitoring HPV+ cancers and offer insights into tumor dynamics. Implementation of these assays in clinical practice could enhance no-invasive treatment monitoring and recurrence detection in HPV-associated cancers.</p><p><strong>Clinical trials: </strong>NCT05904327.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-26","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142331121","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Molecular Therapeutics in Development to Treat Alzheimer's Disease.","authors":"Maria Carmela Tartaglia, Martin Ingelsson","doi":"10.1007/s40291-024-00738-6","DOIUrl":"https://doi.org/10.1007/s40291-024-00738-6","url":null,"abstract":"<p><p>Until recently, only symptomatic therapies, in the form of acetylcholine esterase inhibitors and NMDA-receptor antagonists, have been available for the treatment of Alzheimer's disease. However, advancements in our understanding of the amyloid cascade hypothesis have led to a development of disease-modifying therapeutic strategies. These include immunotherapies based on an infusion of monoclonal antibodies against amyloid-β, three of which have been approved for the treatment of Alzheimer's disease in the USA (one of them, lecanemab, has also been approved in several other countries). They all lead to a dramatic reduction of amyloid plaques in the brain, whereas their clinical effects have been more limited. Moreover, they can all lead to side effects in the form of amyloid-related imaging abnormalities. Ongoing developments aim at facilitating their administration, further improving their effects and reducing the risk for amyloid-related imaging abnormalities. Moreover, a number of anti-tau immunotherapies are in clinical trials, but none has so far shown any robust effects on symptoms or pathology. Another line of development is represented by gene therapy. To date, only antisense oligonucleotides against amyloid precursor protein/amyloid-β and tau have reached the clinical trial stage but a variety of gene editing strategies, such as clustered regularly interspaced short palindromic repeats/Cas9-mediated non-homologous end joining, base editing, and prime editing, have all shown promise on preclinical disease models. In addition, a number of other pharmacological compounds targeting a multitude of biochemical processes, believed to be centrally involved in Alzheimer's disease, are currently being evaluated in clinical trials. This article delves into current and future perspectives on the treatment of Alzheimer's disease, with an emphasis on immunotherapeutic and gene therapeutic strategies.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-24","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142308929","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Evaluation of the Oncomine Comprehensive Assay Plus NGS Panel and the OncoScan CNV Assay for Homologous Recombination Deficiency Detection.","authors":"Lone Schejbel, Tim Svenstrup Poulsen, Lau Kræsing Vestergaard, Ib Jarle Christensen, Estrid Høgdall","doi":"10.1007/s40291-024-00745-7","DOIUrl":"https://doi.org/10.1007/s40291-024-00745-7","url":null,"abstract":"<p><strong>Introduction: </strong>Testing for homologous recombination deficiency (HRD) as a biomarker in relation to poly (ADP-ribose) polymerase inhibitor (PARPi) treatment in ovarian cancer is done by sequencing of the BRCA1/2 genes and/or by assessing a genomic instability signature. Here we present data obtained with two different methods for genomic instability testing: the Oncomine™ Comprehensive Assay Plus (OCA Plus) NGS panel and the OncoScan CNV assay.</p><p><strong>Methods: </strong>The retrospective analytical study included 80 ovarian cancer samples of patients previously referred to clinical Myriad testing (reference cohort), and 50 ovarian cancer samples from patients collected as part of the Pelvic Mass study. OCA Plus NGS libraries were sequenced with the Ion S5™XL Sequencer and analyzed with the Ion Reporter™ Software v5.20 for calculation of the genomic instability metric (GIM). In addition, all samples were tested with the OncoScan CNV FFPE Assay and analyzed with a previously published R-algorithm for generation of an in-house genomic instability score (in-house GIS).</p><p><strong>Results: </strong>The OCA Plus assay had a concordance to the reference of 89% on samples with a tumor fraction ≥ 30% (auto-calculated or via molecular estimation). A total of 15 samples in the reference cohort had a calculated tumor fraction < 30% in the OCA Plus assay. In these, the concordance to reference was only 60%. For the OncoScan CNV in-house GIS a local cutoff point of ≥ 50 was calculated. This gave a concordance to the reference of 85%, with 91% of the samples in the reference cohort passing quality control (QC) on tumor fraction. Both assays had a high sensitivity for the detection of genomic instability in samples with pathogenic or likely pathogenic BRCA1/2 mutations, with 12/13 being GIM positive (OCA Plus assay) and 13/13 being in-house GIS positive (OncoScan CNV assay).</p><p><strong>Conclusions: </strong>The OCA Plus assay and the OncoScan CNV assay show a high but not complete concordance to reference standard homologous recombination deficiency (HRD) detection. The main reason for QC failure or non-concordance in our study was a low tumor fraction estimated in the assay, despite the selection of material by a pathologist with an inclusion criterion of > 30% tumor. QC steps should include careful tumor content evaluation, and results on samples with < 30% tumor should not be reported.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142299497","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Diagnosis of Lung Cancer Through Exhaled Breath: A Comprehensive Study.","authors":"Elina Gashimova, Azamat Temerdashev, Dmitry Perunov, Vladimir Porkhanov, Igor Polyakov","doi":"10.1007/s40291-024-00744-8","DOIUrl":"https://doi.org/10.1007/s40291-024-00744-8","url":null,"abstract":"<p><strong>Objectives: </strong>Exhaled breath analysis is an attractive lung cancer diagnostic tool. However, various factors that are not related to the disease status, comorbidities, and other diseases must be considered to obtain a reliable diagnostic model.</p><p><strong>Methods: </strong>Exhaled breath samples from 646 individuals including 273 patients with lung cancer (LC), 90 patients with cancer of other localizations (OC), 150 patients with noncancer lung diseases (NLD), and 133 healthy controls (HC) were analyzed using gas chromatography-mass spectrometry (GC-MS). The samples were collected in Tedlar bags. Volatile organic compounds (VOCs) were preconcentrated on Tenax TA sorbent tubes with subsequent two-stage thermal desorption followed by GC-MS analysis. The influence of age, gender, smoking status, time since last food consumption, and comorbidities on exhaled breath were evaluated. Also, the effect of histology, TNM, tumor localization, treatment status, and the presence of a tumor on VOC profile of patients with lung cancer were assessed. Intergroup statistics were estimated, diagnostic models were created using artificial neural networks (ANNs) and gradient boosted decision trees (GBDTs).</p><p><strong>Results: </strong>Smoking status and food consumption affect exhaled breath VOC profile: benzene, ethylbenzene, toluene, 1,3-pentadiene 1,4-pentadiene acetonitrile, and some ratios are significantly different in exhaled breath of smokers and nonsmokers; the ratios 2,3-butandione/2-pentanone, 2,3-butandione/dimethylsulfide, and 2-butanone/2-pentanone are affected by time since last food consumption. Exhaled breath of LC is affected by the form of the disease and comorbidities. One-pentanol and 2-butanone were different in exhaled breath of patients with various tumor localization; 2-butanone was different in exhaled breath of patients before and during treatment. Diabetes as a comorbidity affects the pentanal level in exhaled breath; obesity affects the ratios of 2,3-butanedione/dimethylsulfide and 2-butanone/isoprene. Sensitivity and specificity of diagnostic models aimed to discriminate LC and HC, OC, and NLD were 78.7% and 51.0%, 62.2% and 53.4%, and 60.4% and 58.0%, respectively. HC and patients, regardless of the disease, can be classified with sensitivity of 76.6% and specificity of 68.2%.</p><p><strong>Conclusions: </strong>The models created to diagnose lung cancer can also classify OC and NLD as patients with lung cancer. Additionally, the influence of comorbidities and factors not related to the disease status must be considered before the creation of diagnostic models to avoid false results.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-19","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142299596","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Tumour Marker Expression in Head and Neck Malignancies to Identify Potential Targets for Intraoperative Molecular Near-Infrared Imaging","authors":"Lorraine J. Lauwerends, Bo E. Zweedijk, Hidde A. Galema, Lisanne K. A. Neijenhuis, Neeltje G. Dekker-Ensink, Robert J. Baatenburg de Jong, Cornelis Verhoef, Shadhvi S. Bhairosingh, Peter J. K. Kuppen, Alexander L. Vahrmeijer, Tessa M. van Ginhoven, Senada Koljenović, Sjors A. Koppes, Denise E. Hilling, Stijn Keereweer","doi":"10.1007/s40291-024-00742-w","DOIUrl":"https://doi.org/10.1007/s40291-024-00742-w","url":null,"abstract":"<h3 data-test=\"abstract-sub-heading\">Background</h3><p>Oral and laryngeal squamous cell carcinoma (OSCC and LSCC) and papillary thyroid carcinoma (PTC) are common head and neck cancers (HNCs) typically treated surgically. Challenges in tumour delineation often lead to inadequate resection margins in OSCC and LSCC, and missed multifocality in PTC. Fluorescence imaging (FLI) using near-infrared tumour-targeting tracers may improve intraoperative identification of malignancy, facilitating precise excision. This study evaluates six potential FLI targets in OSCC, LSCC and PTC.</p><h3 data-test=\"abstract-sub-heading\">Materials and methods</h3><p>Immunohistochemical staining was performed on OSCC (<i>n</i> = 20), LSCC (<i>n</i> = 10) and PTC (<i>n</i> = 10), assessing CEA, c-Met, EpCAM, EGFR, integrin αvβ6 and VEGF-α. Expression was scored (0–12) using the total immunostaining score (TIS) system, and categorized into absent (TIS 0), low (TIS 1–5), moderate (TIS 6–8) or high (TIS 9–12).</p><h3 data-test=\"abstract-sub-heading\">Results</h3><p>Integrin αvβ6 showed significant overexpression in OSCC (TIS: 12; <i>p</i> &lt; 0.001) and LSCC (TIS: 8; <i>p</i> = 0.002), with 80% of OSCC and 90% of LSCC exhibiting moderate-high expression. Similarly, EGFR expression was moderate-high in most OSCC (87.5%; TIS: 8) and universally high in LSCC (100%; TIS: 12). In PTC, EGFR and VEGF-α expressions were low-moderate, but significantly higher than in healthy tissue (TIS: 6; <i>p</i> &lt; 0.006).</p><h3 data-test=\"abstract-sub-heading\">Conclusion</h3><p>This study highlights integrin αvβ6 and EGFR as viable FLI targets in OSCC and LSCC, especially integrin αvβ6 for tumour margin delineation. In PTC, despite lower expressions, the significant overexpression of VEGF-α, c-MET, and EGFR suggests their potential as FLI targets. Our findings support the development of tumour-targeted FLI tracers to improve surgical precision in HNC.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":null,"pages":null},"PeriodicalIF":4.0,"publicationDate":"2024-09-09","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"142190172","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Gene Therapies in Clinical Development to Treat Retinal Disorders.","authors":"Michelle E McClements, Maram E A Abdalla Elsayed, Lauren Major, Cristina Martinez-Fernandez de la Camara, Robert E MacLaren","doi":"10.1007/s40291-024-00722-0","DOIUrl":"10.1007/s40291-024-00722-0","url":null,"abstract":"<p><p>Gene therapies have emerged as promising treatments in clinical development for various retinal disorders, offering hope to patients with inherited degenerative eye conditions. Several gene therapies have already shown remarkable success in clinical trials, with significant improvements observed in visual acuity and the preservation of retinal function. A multitude of gene therapies have now been delivered safely in human clinical trials for a wide range of inherited retinal disorders but there are some gaps in the reported trial data. Some of the most exciting treatment options are not under peer review and information is only available in press release form. Whilst many trials appear to have delivered good outcomes of safety, others have failed to meet primary endpoints and therefore not proceeded to phase III. Despite this, such trials have enabled researchers to learn how best to assess and monitor patient outcomes, which will guide future trials to greater success. In this review, we consider recent and ongoing clinical trials for a variety of potential retinal gene therapy treatments and discuss the positive and negative issues related to these trials. We discuss the treatment potential following clinical trials as well as the potential risks of some treatments under investigation. As these therapies continue to advance through rigorous testing and regulatory approval processes, they hold the potential to revolutionise the landscape of retinal disorder treatments, providing renewed vision and enhancing the quality of life for countless individuals worldwide.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11349810/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141494054","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Identification of Immunodominant Epitopes of Dengue Virus 2 Envelope and NS1 Proteins: Evaluating the Diagnostic Potential of a Synthetic Peptide.","authors":"Sushmita Singha, Neena Nath, Vaishali Sarma, Kangkana Barman, Gurumayum Chourajit Sharma, Lahari Saikia, Shashi Baruah","doi":"10.1007/s40291-024-00728-8","DOIUrl":"10.1007/s40291-024-00728-8","url":null,"abstract":"<p><strong>Background and objective: </strong>Dengue is a major infectious disease with potential for outbreaks and epidemics. A specific and sensitive diagnosis is a prerequisite for clinical management of the disease. We designed our study to identify epitopes on the Dengue virus (DENV) envelope (E) and non-structural protein 1 (NS1) with potential for diagnosis.</p><p><strong>Methods: </strong>Serology and immunoinformatic approaches were employed. We collected DENV-positive, DENV-negative and Japanese encephalitis virus-positive samples from collaborating hospitals in 2019 and 2022-2023. Seropositive peptides in 15-18 mer peptide arrays of E and NS1 proteins of DENV2 were determined by an indirect enzyme-linked immunosorbent assay. B-cell linear and conformational epitopes were predicted using BepiPred2.0 and ElliPro, respectively. A consensus recombinant peptide was designed, synthesised and evaluated for its diagnostic potential using patient sera.</p><p><strong>Results: </strong>Eight peptides of E protein and six peptides of NS1 protein were identified to be the most frequently recognised by Dengue-positive patients. These peptide sequences were compared with B-cell epitope regions and found to be overlapped with predicted B-cell linear and conformational epitopes. EP11 and NSP15 showed a 100% amino acid sequence overlap with B-cell epitopes. EP1 and NSP15 had 14 whereas EP28, EP31, EP60 16, NSP12 and NSP32 had more than 15 interacting interface residues with a neutralising antibody, suggesting a strength of interaction. Interestingly, potential epitopes identified were localised on the surface of proteins as visualised by PyMOL. Validation with a recombined synthetic peptide yielded 92.3% sensitivity and 91.42% specificity.</p><p><strong>Conclusions: </strong>Immunodominant regions identified by serology and computationally predicted epitopes overlapped, thereby showing the robustness of the methodology and the peptide designed for diagnosis.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141560214","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"Clinical Metagenomic Next-Generation Sequencing for Diagnosis of Central Nervous System Infections: Advances and Challenges.","authors":"LingHui David Su, Charles Y Chiu, David Gaston, Catherine A Hogan, Steve Miller, Dennis W Simon, Kiran T Thakur, Shangxin Yang, Anne Piantadosi","doi":"10.1007/s40291-024-00727-9","DOIUrl":"10.1007/s40291-024-00727-9","url":null,"abstract":"<p><p>Central nervous system (CNS) infections carry a substantial burden of morbidity and mortality worldwide, and accurate and timely diagnosis is required to optimize management. Metagenomic next-generation sequencing (mNGS) has proven to be a valuable tool in detecting pathogens in patients with suspected CNS infection. By sequencing microbial nucleic acids present in a patient's cerebrospinal fluid, brain tissue, or samples collected outside of the CNS, such as plasma, mNGS can detect a wide range of pathogens, including rare, unexpected, and/or fastidious organisms. Furthermore, its target-agnostic approach allows for the identification of both known and novel pathogens. This is particularly useful in cases where conventional diagnostic methods fail to provide an answer. In addition, mNGS can detect multiple microorganisms simultaneously, which is crucial in cases of mixed infections without a clear predominant pathogen. Overall, clinical mNGS testing can help expedite the diagnostic process for CNS infections, guide appropriate management decisions, and ultimately improve clinical outcomes. However, there are key challenges surrounding its use that need to be considered to fully leverage its clinical impact. For example, only a few specialized laboratories offer clinical mNGS due to the complexity of both the laboratory methods and analysis pipelines. Clinicians interpreting mNGS results must be aware of both false negatives-as mNGS is a direct detection modality and requires a sufficient amount of microbial nucleic acid to be present in the sample tested-and false positives-as mNGS detects environmental microbes and their nucleic acids, despite best practices to minimize contamination. Additionally, current costs and turnaround times limit broader implementation of clinical mNGS. Finally, there is uncertainty regarding the best practices for clinical utilization of mNGS, and further work is needed to define the optimal patient population(s), syndrome(s), and time of testing to implement clinical mNGS.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141591857","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}

{"title":"The Future of CAR T Therapeutics to Treat Autoimmune Disorders.","authors":"Ann-Christin Pecher, Luca Hensen, Claudia Lengerke, Jörg Henes","doi":"10.1007/s40291-024-00730-0","DOIUrl":"10.1007/s40291-024-00730-0","url":null,"abstract":"<p><p>The concept of chimeric antigen receptor (CAR) T cell therapy emerged from cancer immunotherapy and has been rapidly adapted and developed for the treatment of autoimmune, especially B-cell-driven, diseases since the first publication of an article featuring a patient with systemic lupus erythematosus in 2021. Phase II studies are about to start, but up to now, only case reports and small series have been published. In contrast to hemato-oncological diseases, where an aggressive response to malignant cells and long-lasting persistence of CAR T cells has been aimed at and observed in many patients, this is not the case with autoimmune diseases but might not be necessary to control disease. Future studies will focus on the optimal target but also on the optimal level of immunogenicity. The latter can be influenced by numerous modulations that affect not only cytokine release but also regulation. In addition, there are potential applications in regulatory cells such as CAR regulatory T cells (Treg). The question of toxicity reduction must also be addressed, as long-term complications such as the potential development of malignant diseases, infections, or cytopenia must be considered even more critically in the area of autoimmune diseases than is the case for patients with oncologic diseases. Alternative antibody-based therapies using the same target (e.g., CD3/CD19 bispecific targeting antibodies) have not been used in these patients and might also be considered in the future. In conclusion, CAR T cell therapy represents a promising therapeutic approach for autoimmune diseases, offering a targeted strategy to modulate immune responses and restore immune tolerance.</p>","PeriodicalId":49797,"journal":{"name":"Molecular Diagnosis & Therapy","volume":null,"pages":null},"PeriodicalIF":4.1,"publicationDate":"2024-09-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11349844/pdf/","citationCount":null,"resultStr":null,"platform":"Semanticscholar","paperid":"141793889","PeriodicalName":null,"FirstCategoryId":null,"ListUrlMain":null,"RegionNum":3,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":"OA","EPubDate":null,"PubModel":null,"JCR":null,"JCRName":null,"Score":null,"Total":0}