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PubMed2026

Mutational signatures in blood-brain barrier: mechanisms, computational insights, and clinical applications in precision oncology.

The blood - brain barrier (BBB) plays a central role in maintaining central nervous system (CNS) homeostasis, and its disruption is a defining feature of malignant brain tumors such as glioblastoma. Emerging evidence indicates that BBB dysfunction not only alters the tumor microenvironment but also shapes the mutational processes that drive genomic instability in CNS malignancies. This review synthesizes current understanding of the biological mechanisms linking BBB breakdown with distinct mutational signatures, including those arising from oxidative stress, hypoxia-induced replication stress, lipid peroxidation, inflammation, and metabolic reprogramming. Advances in next-generation sequencing, coupled with computational tools such as non-negative matrix factorization, Bayesian modeling, and deep learning, have enabled precise extraction of these signatures and their integration with multi-omics data. Clinically, BBB-associated mutational signatures offer significant promise for therapeutic stratification, prediction of treatment response, and noninvasive monitoring through cerebrospinal fluid - derived circulating tumor DNA. Despite these advances, challenges persist due to limited tissue accessibility, low-yield CSF samples, incomplete mechanistic models, and the lack of CNS-specific analytical frameworks. A deeper understanding of BBB-driven mutational processes, supported by improved computational approaches and integrative datasets, holds potential to advance precision oncology in neuro-oncology.

Humans↗

PubMed2025

CancerTrialMatch: a computational resource for the management of biomarker-based clinical trials at a community cancer center.

MOTIVATION: The widespread implementation of next-generation sequencing in cancer care has enabled routine use of molecular and biomarker profiling. At our cancer center, as with many others, biomarker-based clinical trials are increasingly available to oncologists as potential treatment options via molecular tumor boards. To better support this effort, we developed CancerTrialMatch, a systematic approach to capture structured clinical trial data and match patients to trials based on their disease characteristics and sequencing profiles. RESULTS: CancerTrialMatch is an open-source application designed to streamline clinical trial curation and patient trial matching, while also enabling an institution's curated trial portfolio to be distributed across the institution for easy access to providers, care teams and researchers. It facilitates curating, updating, and searching for trials through a semi-automated interface built using R Shiny, MongoDB, and Docker. While much of the trial data is retrieved via the clinicaltrials.gov Application Programming Interface, certain items like biomarkers and disease subtypes are entered manually. The user inputs disease type using the OncoTree classification, and provides relevant biomarker details, such as mutations, copy numbers, fusions, and other disease-specific markers. This resource reduces the time required for institutional trial management and helps to identify potential clinical trials for patients, ultimately supporting larger clinical trial enrollment and enhancing the clinical application of precision oncology. AVAILABILITY AND IMPLEMENTATION: CancerTrialMatch was implemented and tested on Windows 11 (64-bit, 32 GB RAM) using WSL2 with Ubuntu 22.04. Docker 27.0.3 and Docker Compose 2.28.1 were used to build images and containers. Users can build it by cloning the repo and following the README instructions and supplemental file (cancertrialmatchsupplemental.pdf) . The source code and example data are available in GitHub and Figshare at https://github.com/AveraSD/CancerTrialMatch and 10.6084/m9.figshare.28447367 respectively.

Humans↗

PubMed2025

SPARKI: a tool for the statistical analysis of pathogen identification results.

MOTIVATION: Many pathogen identification and microbiome analysis tools have been developed in recent years, with Kraken 2 being one of the most popular. While tools downstream of Kraken 2 can assist in the interpretation of its outputs, a statistical framework to assess the likelihood that a taxon/organism is present in a single sample alongside an automated end-to-end analysis pipeline has not yet been fully implemented. RESULTS: Here, we introduce SPARKI, an R package that performs statistical analysis of Kraken 2 outputs and aids in the identification of pathogens present in next-generation sequencing samples. SPARKI adds to the field by bringing a probabilistic view to Kraken 2 data, serving as a discovery tool and complementing other methods such as KrakenTools, Bracken, and Pavian. AVAILABILITY AND IMPLEMENTATION: SPARKI code is available on GitHub at https://github.com/team113sanger/sparki. SPARKI is also part of an end-to-end pathogen identification pipeline, sparki-nf, which is available at https://github.com/team113sanger/sparki-nf. An additional pipeline for further exploration and validation of SPARKI results is also available at https://github.com/team113sanger/map-to-genome.

Software↗

PubMed2025

Chrom-Sig: de-noising 1D genomic profiles by signal processing methods.

MOTIVATION: Modern genomic research is driven by next-generation sequencing experiments such as ChIP-seq, CUT&Tag, and CUT&RUN that generate coverage files for transcription factor binding, as well as ATAC-seq that yield coverage files for chromatin accessibility. Due to the inherent technical noise present in the experimental protocols, researchers need statistically rigorous and computationally efficient methods to extract true biological signal from a mixture of signal and noise. However, existing approaches are often computationally demanding or require input or spike-in controls. RESULTS: We developed Chrom-Sig, a Python package to quickly de-noise 1D genomic coverage tracks by computing the empirical null distribution without prior assumptions or experimental controls. When tested on 19 ChIP-seq, CUT&RUN, ATAC-seq, and snATAC-seq datasets, Chrom-Sig can effectively decompose the data into signal and noise components. Notably, Chrom-Sig performs de-noising and peak calling in 1-2 h using around 20 GB of memory. The de-noised signal corroborates with biologically meaningful results: CTCF CUT&RUN data retained a high percentage of peaks overlapping CTCF binding motifs, while ATAC-seq and RNA Polymerase II data were enriched in enhancers and promoters. We envision Chrom-Sig to be a versatile and general tool for current and future genomic technologies. AVAILABILITY AND IMPLEMENTATION: Chrom-Sig is publicly available on GitHub (https://github.com/minjikimlab/chromsig) and Zenodo (doi: 10.5281/zenodo.17488772) under the MIT licence.

Genomics↗

PubMed2026

CholeraSeq: a comprehensive genomic pipeline for cholera surveillance and near real-time outbreak investigation.

SUMMARY: Next Generation Sequencing is widely deployed in cholera-endemic regions, yet an end-to-end reproducible pipeline that unifies read QC, filtering, reference mapping, variant calling/annotation, recombination screening, and extraction of parsimony informative sites/variant codons, phylogenetic inference for downstream phylodynamic and epidemiological analyses have been lacking, slowing outbreak investigation and public health response. CholeraSeq is a high-throughput genomics pipeline for cholera genomic surveillance. It ingests consensus genomes, short read sequence data, draft assemblies, and scales seamlessly from local to cloud environments. To accelerate epidemiological context placement of new outbreak strains, we provide a curated ready-to-use core genome alignment compiled from public data, enabling flexible, fast, integration of new samples for outbreak investigations. AVAILABILITY AND IMPLEMENTATION: CholeraSeq is freely available on the GitHub platform https://github.com/CERI-KRISP/CholeraSeq. CholeraSeq is implemented in Nextflow with a modular design building upon the nf-core community standards.

Cholera↗

PubMed2026

Spitz tumours: Current insights and challenges in diagnosis and management.

Spitz tumours are a distinct subtype of melanocytic lesions composed of epithelioid and/or spindled cells. They comprise Spitz naevi (SN), atypical Spitz tumours/Spitz melanocytoma (AST), and Spitz melanoma (SM). According to the 5th WHO Classification, SM is defined by the co-occurrence of spitzoid morphology and a Spitz-defining genomic alteration, typically a kinase fusion or HRAS mutation, making it a molecularly distinct entity. Molecularly confirmed SM is exceedingly rare, usually occurs in younger adults, and appears to demonstrate a more favorable clinical course than spitzoid melanoma driven by BRAF or NRAS mutations, although robust comparative data remain limited. Dermoscopy may raise clinical suspicion based on characteristic patterns and remains an important first-line diagnostic tool; however, it cannot reliably distinguish AST from SM. In addition, Spitz tumours may exhibit overlapping histopathological features, further complicating their differentiation. In particular, the distinction between ASTs and SMs is often challenging. Immunohistochemical and molecular analyses, particularly next-generation sequencing (NGS), play a crucial role in resolving diagnostically challenging Spitz tumours and in differentiating true Spitz tumours from their morphological mimics. Furthermore, NGS contributes to improved risk stratification and has revealed high-risk genomic alterations associated with progression. Increased application of molecular techniques is expected to refine prognostic assessment and support individualized management strategies.

Journal Article↗

PubMed2025

Chromosome-Level Assembly and Annotation of the Grey Reef Shark (Carcharhinus amblyrhynchos) Genome.

To date less than 5% of shark species have nuclear reference genomes, despite next-generation sequencing advances. Particularly for threatened shark species, there is a lack of reliable genomes which are crucial in facilitating research and conservation applications. We assembled the first nuclear reference genome of the endangered grey reef shark (Carcharhinus amblyrhynchos) using long-read PacBio HiFi and Omni-C sequencing to reach chromosome-level contiguity (36 pseudochromosomes; 2.9 Gbp) and high completeness (94% complete BUSCOs). BRAKER3 annotated 16,505 protein-coding genes after masking repetitive elements which accounted for 59% of the genome. We identified potential X and Y sex chromosomes on pseudochromosomes 36 and 57, respectively. The quality and completeness of the draft genome of C. amblyrhynchos will enable researchers to investigate genetic variations and adaptations specific to this species as well as across other Carcharhinus spp., opening new venues for comparative genomics and advancing conservation genetic applications.

Animals↗

PubMed2026

Financing and health system capacity for precision medicine in Asia: a six country landscape analysis.

BACKGROUND: Precision medicine (PM) adoption is accelerating across Asia, but implementation remains uneven due to differences in financing, infrastructure, governance, and health-system readiness. OBJECTIVES: To examine how six Asian countries (Singapore, South Korea, China, Malaysia, Thailand, and Indonesia) adopt, finance, and integrate PM technologies, and identify common implementation patterns and challenges. METHODS: A landscape review of peer-reviewed literature, government publications, and HTA reports (2010-2026) was conducted, supplemented by stakeholder consultations. PM applications were grouped into public health screening (hereditary breast and ovarian cancer [HBOC] and familial hypercholesterolemia [FH] cascade testing), next-generation sequencing (NGS) applications (rare diseases, oncology, pharmacogenomics), and AI-enabled PM. Evidence was synthesized across access, awareness, reimbursement, and implementation. RESULTS: Public health genomic screening demonstrated the highest implementation readiness, followed by precision oncology, while rare disease diagnostics remained infrastructure-dependent and pharmacogenomics and AI-enabled PM platforms were at earlier stages. Four readiness profiles emerged: highly aligned systems; reimbursement-constrained systems with strong governance and infrastructure; systems strengthening governance, public financing and infrastructure; and strategy-led systems expanding implementation through pilot programs and referral centers. CONCLUSIONS: PM implementation across Asia remains heterogeneous. The identified readiness profiles highlight governance, financing, and infrastructure priorities for sustainable and equitable PM diffusion.

Asia↗

PubMed2026

Maternal genetic variants associated with aneuploid conception: a narrative review.

BACKGROUND: Human aneuploid conception, a leading cause of infertility, pregnancy loss, and congenital disorders (e.g. Down's syndrome), arises from errors in chromosome segregation during oocyte meiosis or embryonic mitosis. While advanced maternal age is a well-established risk factor, significant inter-individual variation exists among younger women, suggesting a substantial role for maternal genetic determinants. OBJECTIVE AND RATIONALE: This review summarizes the identified maternal genetic variants associated with aneuploid conceptions and highlights directions for future research. SEARCH METHODS: We systematically searched PubMed, Embase, and the Cochrane Library (up to 12 January 2026), using key terms related to maternal genetics, genetic variants, aneuploidy, and pregnancy. Inclusion criteria were human studies, genetic confirmation of aneuploidy (in oocytes/embryos/products of conception/fetal cells), maternal variants (rare single-nucleotide variations, single-nucleotide polymorphisms, and small indels [≤50 bp]), and English-language publications. Exclusion criteria were non-human studies, structural/non-aneuploid numerical abnormalities, paternal factors, and conference abstracts. Extracted data items included study identifiers, population characteristics, variant details, detection methods, clinical phenotypes, type and origin of aneuploidy, pathogenicity or effect assessment, and gene inclusion in currently commercially available infertility next-generation sequencing (NGS) panels. Rare variants were classified per American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG/AMP) guidelines, whereas common variants were evaluated based on effect estimates and functional validation. Study quality was appraised using a modified Newcastle-Ottawa Scale. Supplementary searches explored associations between the identified genes and a broader range of reproductive phenotypes. OUTCOMES: From 28 studies covering the broad clinical spectrum of aneuploid pregnancies (including embryo arrest, implantation failure, pregnancy loss, hydatidiform mole, and fetal aneuploidy), we identified maternal variants associated with aneuploid conceptions. These were functionally categorized into meiotic recombination, spindle dynamics, checkpoint enforcement, and the maternal-to-zygotic transition. Among them, variants in several genes are supported by higher-quality evidence, including likely pathogenic rare variants in KIF18A, ELL3, and CEP120, as well as common variants in PLK4 and CCDC66. Although some identified genes (HFM1, MCM9, MEI1, BUB1B, NLRP2, NLRP7, and TLE6) are included in commercial infertility NGS panels, their direct association with aneuploidy requires further validation. WIDER IMPLICATIONS: This review proposes that 'aneuploidy predisposition' constitutes a critical, mechanism-driven dimension for the genetic diagnosis of infertility, complementing phenotype-based frameworks. This approach would best serve women with unexplained infertility and a normal karyotype who have either a history of recurrent aneuploidy or heterogeneous reproductive phenotypes across different cycles. Adopting this perspective refines clinical genetic testing paradigms and underscores the need to prioritize artificial intelligence-enhanced clinico-genomic association studies and develop polygenic risk models integrated with clinical factors. PROSPERO REGISTRATION NUMBER: CRD42025636217.

Humans↗

PubMed2025

Clinical and molecular landscape of metastatic extramammary Paget's disease.

BACKGROUND: Extramammary Paget's disease (EMPD) is a rare malignancy without established systemic therapy. EMPD shares molecular features with breast cancer, such as human epidermal growth factor receptor 2 (HER2) and hormone receptor (HR) expression, but their clinical relevance remains unclear. MATERIALS AND METHODS: Tumors from 20 metastatic invasive EMPD cases were analyzed for molecular and biological features. Genomic features, transcriptomic profiles, and HER2 and HR expression status were investigated using immunohistochemistry, fluorescence in situ hybridization, and targeted-genome next-generation sequencing and nCounter BC360 panels. Metastatic breast cancer samples were used as a comparison to clarify metastatic EMPD's clinical relevance. RESULTS: Estrogen receptor expression was observed in 45% of EMPD tumors, while only 10% expressed progesterone receptor. HER2 was overexpressed in 30% of cases, and HER2-directed therapies were durably effective. Among 8 patients with NGS data, 63% (5/8) harbored oncogenic ERBB2 alterations independent of HER2 expression. BC360 profiling revealed biological differences between EMPD and breast cancer, particularly poor biological compatibility for HR-positive tumors. Immune profiling showed that a subset of EMPD tumors exhibited CD8+ T-cell signatures and PD-1/PD-L1 gene expression comparable to triple-negative breast cancer. The median overall survival was 22.1 months (95% CI, 12.0-42.2), with 16 patients (80%) treated with systemic therapy, including anti-HER2 therapy, hormonal therapy, or cytotoxic therapies based on their molecular features. CONCLUSIONS: This study highlights the unique molecular and biological features of metastatic EMPD, emphasizing the need for tailored treatment approaches. This information should be used to guide future clinical strategies for metastatic EMPD.

Humans↗

PubMed2026

A phase II study to evaluate the efficacy of commercially available molecularly matched targeted therapies in the second-line setting.

BACKGROUND: Initial studies have shown improved outcomes in patients receiving cancer therapies matched to their molecular alterations. To improve the chances of finding a therapeutic match for patients, this study evaluated the preliminary antitumor activity of 3 commercially available multitargeted agents in the United States, regorafenib, afatinib, and cabozantinib. METHODS: In this phase II trial, patients who did not benefit from first-line treatment for non-small cell lung cancer (NSCLC), upper aerodigestive tract cancers, non-colon gastrointestinal cancers, and urothelial carcinoma underwent next-generation sequencing to identify actionable genomic alterations. Eligible patients, based on identified mutations deemed treatable by regorafenib, cabozantinib, or afatinib, were enrolled to receive matched targeted therapies. Outcomes were monitored via Response Evaluation Criteria in Solid Tumors criteria, with dose modifications per National Cancer Institute Common Terminology Criteria for Adverse Events, v4.03 guidelines for adverse events (AEs). RESULTS: One hundred patients with metastatic cancers were enrolled across tumor types. Median treatment durations were 12 weeks (regorafenib), 10.7 weeks (afatinib), and 24.1 weeks (cabozantinib). The overall objective response rate was 7.0%, with 1 complete response and 8 partial responses. The clinical benefit rate, including responses and stable disease >6 months, was 16.0%. Median progression-free survival ranged from 1.9 months for urothelial carcinoma to 3.2 months for NSCLC. Toxicities were common for all medications; for regorafenib, 90.7% of patients had AEs (50% Grade 3/4); for afatinib, 86% of patients had AEs (54% Grade 3/4); for cabozantinib, 100% of patients had AEs (36% Grade 3/4). The most common AEs were diarrhea, fatigue, nausea, decreased appetite, and stomatitis. CONCLUSIONS: Regorafenib, afatinib, and cabozantinib had modest effects when used as molecularly matched targeted therapies in patients with NSCLC, upper aerodigestive tract cancers, non-colon gastrointestinal cancers, and urothelial carcinoma in the second-line setting. Future research could examine more precise matching of therapies to genomic alterations and evaluate combination therapies.

Humans↗

PubMed2025

Amplicon-based analyses of single-nucleotide polymorphisms reveal the genetic structure of a forest insect baculovirus.

Amplicon-based next-generation sequencing (aNGS) is a powerful tool in diagnostics and genetic studies. We developed an aNGS approach to study the population structure of the Lymantria dispar multiple nucleopolyhedrovirus (LdMNPV), a specific pathogen of the spongy moth Lymantria dispar, a devastating lepidopteran pest in European, Asian, and American deciduous forests. Naturally occurring pathogens, such as LdMNPV, are frequently reported to cause epizootics and a rapid decline of insect pest populations. DNA samples of pooled LdMNPV-infected larvae from forest regions in Northern Bavaria (Germany) were subjected to whole genome sequencing (WGS) and aNGS optimization. Then, five marker regions were identified in the genome of LdMNPV for PCR amplification, covering 21 highly specific single-nucleotide polymorphism (SNP) positions that enabled comprehensive analysis at the intra- and intersample levels. These markers were used in aNGS analyses of 70 single larvae collected in 12 forest sites, followed by SNP-based hierarchical clustering on principal components (HCPC). This approach identified three LdMNPV population clusters consisting of homogenous (pure) and heterogeneous (mixed) LdMNPV samples. To explain the genetic variability within each sample, a model based on linear optimization was developed and validated by comparing the predictions from aNGS and WGS data. The analyses showed that LdMNPV from Bavarian forests carried genetic variants highly similar to those present in the commercial product Gypchek®, developed for biocontrol. The distribution of genetic characteristics showed some trends of geographic and temporal prevalence, which are indicative of short-distance and long-distance transmission. The aNGS approach offers a fast, cost-effective, and comprehensive insight into the natural population structure of LdMNPV.

insects↗

PubMed2026

USP6-FISH Negative Nodular Fasciitis: Benign Impostor of the Orbit.

Nodular fasciitis (NF) is a benign, rapidly growing myofibroblastic proliferation that can closely mimic sarcoma clinically, radiographically, and histologically, posing a significant diagnostic challenge. We report a case of an 11-year-old boy presenting with a painless but progressively enlarging periorbital mass initially suspected to be a dermoid cyst. Although his ultrasound was reassuring, MRI showed an enhancing lesion concerning for neoplasm, prompting surgical excision. Histopathologic evaluation revealed spindle-cell proliferation within a myxoid stroma consistent with NF. However, the USP6 fluorescence in situ hybridization analysis was negative. Further genomic analysis identified a rare USP6-PAFAH1B1 fusion. This case highlights a diagnostically challenging subset of NF in which conventional USP6 fluorescence in situ hybridization testing may be negative, necessitating next-generation sequencing for a definitive diagnosis. Increased awareness of NF and its clinical, histologic, genetic, and radiographic presentation is essential to avoid misdiagnosis and to guide appropriate management.

Journal Article↗

PubMed2026

NF2-related Schwannomatosis Diagnosed Before and After 30 Years of Age: Differences in Disease Presentation and Rates of Positive Genetic Testing.

OBJECTIVE: Characterize pathogenic variants, rates of mosaicism, genetic testing yield, and disease severity among patients with NF2-related schwannomatosis dichotomized by diagnosis before or after the age of 30. STUDY DESIGN: Retrospective analysis. SETTING: Tertiary referral center multidisciplinary NF2 clinic from 2021 to 2024. PATIENTS: Patients with NF2-related schwannomatosis. INTERVENTION: Next-generation sequencing. MAIN OUTCOME MEASURE: Rates of mosaicism, genetic testing rates and yield, and overall disease severity by tumor burden. RESULTS: From 2021 to 2024, there were 32 patients ≥30 years of age and 39 patients diagnosed at younger ages. Patients diagnosed ≥30 years exhibited decreased likelihood of receiving genetic testing (53% vs. 85%; P =0.009) and decreased genetic yield (defined as identification of a pathogenic genetic variant in those undergoing testing; 65% vs. 85%; P =0.20). Both age groups demonstrated similar rates of pathogenic variant type with loss-of-function being the predominant variant detected in 73% vs. 67%, for ≥30 vs. <30 years of age; P =0.90. Those ≥30 years harbored fewer number of average anatomic regions involved by tumor (2.3 vs. 3.4; P <0.001) and decreased total number of tumors (7 vs. 12; P <0.001). CONCLUSIONS: Patients diagnosed with NF2-related schwannomatosis at age ≥30 years exhibited reduced disease severity compared with those diagnosed at a younger age despite harboring similar distributions of genetic pathogenic variants inclusive of loss-of-function pathogenic variants. These observations emphasize the importance of considering patient age in addition to genetic testing for diagnostic framing tailored to patients' biology and clinical context to optimize care in the setting of NF2-related schwannomatosis.

Humans↗

PubMed2026

An Aspergillus luchuensis isolated from a patient with hemoptysis insights from a comprehensive genome-based analysis: Case report.

RATIONALE: Asp luchuensis, a member of the A niger group, is widely used in food fermentation and rarely causes invasive pulmonary aspergillosis (IPA) in humans. Clinical cases of IPA induced by this strain are extremely scarce, and its genomic characteristics, virulence profiles, and pathogenic mechanisms remain poorly understood, resulting in insufficient clinical recognition of its invasive infection potential. PATIENT CONCERNS: A 57-year-old immunocompetent non-neutropenic male patient with a long-term smoking and drinking history presented with unexplained severe cough and massive hemoptysis (approximately100 mL) without other typical infectious symptoms. DIAGNOSES: Combined with chest computed tomography (CT) inflammatory lesions, positive galactomannan test, fungal PCR and metagenomic next-generation sequencing results, the patient was definitively diagnosed with probable A luchuensis-induced IPA. Genomic and transcriptomic analyses confirmed the pathogen as a variant A luchuensis strain with 3 key hypervirulence genes, highly active mitochondrial energy metabolism, and no specific antifungal resistance genes. INTERVENTIONS: The patient received standardized intravenous antifungal combination therapy with voriconazole and amphotericin B after confirmed diagnosis. OUTCOMES: The patient's cough and hemoptysis were significantly relieved after 10 days of treatment, with stable vital signs and no adverse drug reactions or disease progression. LESSONS: A luchuensis possesses strong invasive pathogenicity and can trigger IPA even in non-neutropenic immunocompetent individuals. Negative conventional microbial tests cannot exclude its infection, and mNGS is a reliable diagnostic tool. This strain is susceptible to routine antifungal drugs, and clinicians should raise awareness of atypical Asp species-induced invasive pulmonary infections.

Humans↗

PubMed2026

Mast cell leukemia with complex genomic alterations in an elderly patient with prior hematologic and solid malignancies: a case report.

INTRODUCTION: Mast cell leukemia (MCL) is the rarest and most aggressive variant of systemic mastocytosis (approximately 1% of cases), with a median survival of under 2 years. Diagnosis requires ≥20% atypical mast cells in the marrow aspirate, and the disease frequently overlaps with myeloid neoplasms. CASE PRESENTATION: An 86-year-old man with paranasal sinus diffuse large B-cell lymphoma in remission since 2017 after R-CHOP and methotrexate, and prostate adenocarcinoma treated in 2019, presented with acute pancytopenia, presumed to represent lymphoma relapse. Serum tryptase exceeded 11 999 ng/mL; the aspirate showed 20% pleomorphic mast cells (CD117+, weak CD25, CD2-), confirming aleukemic MCL. Formal CMML criteria could not be confirmed due to the unavailability of monocyte differential data; however, the findings raised suspicion for an associated myeloid neoplasm, with SM with an associated hematological neoplasm remaining an alternative classification. Karyotyping was normal; next-generation sequencing revealed pathogenic variants in TP53, RB1, DAXX, ASXL1, TET2, and SRSF2, and a rare extracellular-domain KIT p.D419del. He declined inpatient midostaurin, deteriorated rapidly, and died 2 weeks later. CLINICAL DISCUSSION: This case illustrates a therapy-related MCL (plausible but unconfirmed given the non-leukemogenic profile of methotrexate and the focal nature of prostate stereotactic body radiation therapy) with a suspected associated myeloid neoplasm and complex pathogenic mutations. The KIT p.D419del extracellular domain variant is a rare non-D816V mutation; the canonical D816V was not detected on NGS, though the presence of a low-variant allele fraction D816V cannot be fully excluded due to assay sensitivity. Despite midostaurin, the disease remained aggressive. CONCLUSION: Persistent unexplained cytopenias warrant heightened suspicion of MCL, and comprehensive genomic profiling clarifies diagnosis, distinguishes overlapping myeloid disease, and informs prognosis in this aggressive, refractory neoplasm.

case report↗

PubMed2026

Hepatocellular Carcinoma With JAK1 Mutations Harbors Distinct Histologic Features and Specific Mutational Hotspots in an Asian Cohort.

The pathogenesis and clinicopathological features of hepatocellular carcinoma (HCC) harboring JAK1 mutation have not been reported. Sixty inflammatory hepatocellular adenoma-like HCCs (IHA-like HCCs) and 16 IHAs were analyzed using targeted next-generation sequencing. Nearly all IHA-like HCCs (n=59, 98%) showed positive SAA/CRP expression. Genetic alterations of the JAK/STAT pathway were detected in 35 (58%) IHA-like HCCs, encompassing mutations in JAK1 (n=22), STAT3 (n=8), and IL6ST (n=5). Nine (56%) IHAs harbored mutations in STAT3 (n=3), IL6ST (n=4), GNAS (n=1), and FRK (n=1). All the mutations occurred in a mutually exclusive manner. JAK1 mutations were frequent (22/60, 37%) in IHA-like HCCs. JAK1-mutated IHA-like HCCs displayed distinctive cytologic characteristics, including abundant eosinophilic cytoplasm, vesicular chromatin, and prominent central nucleoli. Recurrent hotspot JAK1 mutations were identified at S703, S729, and L910. Surveillance for JAK1 mutations in the HCC genomics of other cohorts also revealed recurrent mutations at S703, S729, and L910. In particular, the S703 and S729 mutations were strongly associated with the features of Asian ethnicity, presence of chronic viral hepatitis, and hepatic fibrosis/cirrhosis. In conclusion, JAK1 mutations were frequent in HCC with IHA-like morphology in an Asian cohort. JAK1 mutation exhibited recurrent and specific hotspot mutations at S703, S729, and L910 in HCC. Patients diagnosed with JAK1-mutated HCC may be eligible for JAK-targeted molecular therapy.

JAK therapeutics↗

PubMed2025

Robot-Assisted Stereotactic Aspiration of a Parietal Brain Abscess With Metagenomic Identification of Fusobacterium nucleatum.

Robot-assisted stereotactic aspiration offers a minimally invasive approach to brain abscesses near the eloquent cortex. We report a rare case of a left parietal abscess caused by Fusobacterium nucleatum in an immunocompetent adult, managed successfully with this approach. The patient, a 52-year-old man, presented with right-sided limb numbness. MRI and contrast-enhanced CT revealed a cystic, ring-enhancing lesion with diffusion restriction in the left parietal lobe. Despite empiric broad-spectrum antibiotics, neurological deterioration occurred due to progressive mass effect. Robot-assisted stereotactic aspiration enabled single-stage, precise drainage of the abscess. Metagenomic next-generation sequencing identified F. nucleatum , prompting adjustment of antibiotics to ceftriaxone plus metronidazole, followed by metronidazole monotherapy. The patient improved clinically, and a 6-month MRI confirmed complete resolution, underscoring the precision of robotic stereotaxy for eloquent-region abscesses and highlighting the diagnostic value of metagenomic sequencing in detecting anaerobic pathogens.

Humans↗