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6 recordsLinked to original sources
PubMed2026

Randomized phase 2 trial of CPX-351 vs. CLAG-M (cladribine, cytarabine, G-CSF, and mitoxantrone) for medically unfit adults with acute myeloid leukemia or other high-grade myeloid neoplasms.

Even with new drugs available, how best to treat unfit adults with acute myeloid leukemia (AML) remains uncertain. In a previous trial in such patients, we found high-dose cytarabine-based therapy with CLAG-M yielded higher response rates but no more toxicity than lower-intensity therapy with dose-attenuated CLAG-M. Here, we conducted a single-institution phase 2 trial (NCT04195945) randomizing 60 adults with untreated AML and medical unfitness with Treatment-Related Mortality (TRM) score of ≥13.1 (68% with ECOG performance status 3-4) 1:1 to standard-dose CPX-351 or CLAG-M. Primary endpoint was 3-month overall survival (OS); key secondary endpoints included overall response rate, rate of measurable residual disease (MRD) negativity, toxicity/mortality rates, and survival estimates. Only CLAG-M met the primary endpoint of ≥63% 3-month OS (70% vs. 60%; P = 0.41), and CLAG-M therapy was associated with a non-significantly higher complete remission (CR) plus CR with incomplete hematologic recovery rate (73% vs. 47%, P = 0.064). Nonetheless, there was no statistically significant difference in relapse-free survival following CLAG-M vs. CPX-351 (median 37.6 vs. 19.9 months; P = 0.80) or OS (median 10.5 vs. 5.8 months; P = 0.76). In patients with proliferative disease, however, OS following CLAG-M was longer (median 18.5 vs. 3.9 months; P = 0.02) suggesting a role for intensive therapy in this patient subset.

Adult↗
PubMed2022

Suppression of trinucleotide repeat expansion in spermatogenic cells in Huntington's disease.

Trinucleotide repeats (TNRs) are dispersed throughout the human genome. About 20 loci are related to human diseases, such as Huntington's disease (HD). A larger TNR instability is predominantly observed in the paternal germ cells in some TNR disorders. Suppressing the expansion during spermatogenesis can provide a unique opportunity to end the vicious cycle of genetic anticipation. Here, using an in vitro differentiation method to derive advanced spermatogenic cells, we investigated the efficacy of two therapeutic agents, araC (cytarabine) and aspirin, on stabilizing TNRs in spermatogenic cells. Two WT patient-derived induced pluripotent stem cell (iPSC) lines and two HD hiPSC lines, with 44 Q and 180 Q, were differentiated into spermatogonial stem cell-like cells (SSCLCs). Both HD cell lines showed CAG tract expansion in SSCLC. When treated with araC and aspirin, HD1 showed moderate but not statistically significant stabilization of TNR. In HD2, 10 nM of aspirin and araC showed significant stabilization of TNR. All cell lines showed increased DNA damage response (DDR) gene expression in SSCLCs while more genes were significantly induced in HD SSCLC. In HD1, araC and aspirin treatment showed general suppression of DNA damage response genes. In HD2, only FAN1, OGG1, and PCNA showed significant suppression. When the methylation profile of HD cells was analyzed, FAN1 and OGG1 showed significant hypermethylation after the aspirin and araC treatment in SSCLC compared to the control. This study underscores the utility of our in vitro spermatogenesis model to study and develop therapies for TNR disorders such as HD.

Male↗
PubMed2026

Consolidation Therapy Based on Mutation Clearance in Acute Myeloid Leukemia.

BACKGROUND: Optimal consolidation therapy for patients with intermediate-risk acute myeloid leukemia (AML) in first complete remission (CR1) is controversial. Retrospective studies have suggested that the clearance of leukemia-associated mutations (LAMs) in CR1 may predict lower relapse risk and better outcomes with high-dose cytarabine (HiDAC) consolidation. We tested this hypothesis prospectively. METHODS: We performed a phase II, multicenter study of intermediate-risk, transplant-eligible, de novo AML in patients 18-60 years of age who achieved a complete remission (CR) or CR with incomplete count recovery (CRi) after induction therapy. Tumor and normal whole-exome sequencing was performed at presentation to identify somatic LAMs (median ∼30 LAMs/patient). In remission marrow samples, LAM variant allele frequencies (VAFs) were then remeasured using a VAF cutoff of less than 2.5% to define clearance. Patients who met this LAM clearance threshold received HiDAC consolidation, whereas those with persistent LAMs (VAF ≥2.5%) were recommended to undergo allogeneic hematopoietic cell transplantation. The primary endpoint compared relapse-free survival (RFS) of intermediate-risk patients with complete LAM clearance to historical cohorts with intermediate-risk AML who received HiDAC-based regimens in CR1. To account for an unplanned interim assessment, the significance threshold for the primary analysis was 0.01. RESULTS: Among 100 patients who were evaluated, intermediate-risk patients who cleared all LAMs in CR1 (n=33) had a median RFS of 33.1 months (95% confidence interval, 11.7-NA) compared to a median RFS of 11.7 months in the historical cohort (n=239; 95% confidence interval, 9.9-15.6, P=0.015). CONCLUSIONS: Among patients with intermediate-risk AML, clearance of LAMs after induction, followed by HiDAC consolidation in CR1, was associated with longer RFS compared with similarly treated historical controls. Although this result did not meet the prespecified threshold for statistical significance, the reported association sets the stage for a randomized trial to further evaluate this strategy. (ClinicalTrials.gov number, NCT02756962.).

Humans↗
PubMed2026

Artificial intelligence for anticancer drug discovery from natural products of macroalgae and sponges: A systematic review.

Marine natural products (MNPs) from macroalgae and marine sponges have inspired clinically important anticancer agents, including the cytarabine pharmacophore and the eribulin scaffold, while cyanobacterial dolastatin chemistry supplies the auristatin payloads of several marine-inspired antibody-drug conjugates (ADCs) such as brentuximab vedotin. Artificial intelligence (AI) methods, encompassing both classical machine learning (ML) with hand-engineered features and modern deep learning (DL) with many-layered neural networks, are increasingly supporting key decisions in natural-product anticancer drug discovery, including bioactivity prediction, target identification, absorption, distribution, metabolism, excretion and toxicity (ADMET) filtering, generative analogue design, and the selection of preclinical candidates. DL architectures relevant to this field include graph neural networks, transformer-based molecular generators, diffusion models for protein-ligand docking, and convolutional networks for mass spectrometry, while classical ML contributes interpretable fingerprint-based bioactivity models and molecular networking for dereplication. This review follows a systematic literature review methodology to organize the landscape of AI methods now applied to MNP anticancer discovery, distinguishing ML and DL approaches where relevant, situating them within the chemical context of macroalgal and sponge-derived oncology leads, and critically examining published case studies, including validation level (computational, in vitro, in vivo, clinical). The principal bottleneck for medical translation has shifted partly from algorithmic capability toward data infrastructure and experimental validation. Sparse, heterogeneous, and taxonomically biased bioactivity records limit what current models can learn and reduce the reliability of AI-prioritized candidates entering the preclinical pipeline. A roadmap is proposed that prioritizes open MNP-specific benchmarks, symbiont-aware modeling, and active learning loops with synthesizability and ADMET constraints. These AI workflows may accelerate the prioritization of marine-derived anticancer leads and support earlier, more evidence-based translational decisions in oncology drug development.

Biological Products↗
PubMed2026

Predicting bloodstream infection by plasma cell-free metagenomic sequencing: a prospective cohort study.

BACKGROUND: Patients receiving myelosuppressive chemotherapy or haematopoietic cell transplantation are at high risk for life-threatening bloodstream infections. A novel pre-emptive treatment paradigm guided by pathogen detection before symptoms appear might reduce this risk, but no validated screening test is available. This study evaluated the sensitivity and specificity of plasma microbial cell-free DNA metagenomic sequencing (mcfDNA-Seq) for predicting bloodstream infections in children and adolescents receiving therapy for high-risk leukaemia. METHODS: In this prospective cohort study, between Aug 9, 2017, and Feb 28, 2022, leftover clinical plasma samples were prospectively collected up to once per day from patients who were younger than 25 years, receiving care for leukaemia at St Jude Children's Research Hospital (Memphis, TN, USA), and at high risk for life-threatening bloodstream infections. mcfDNA-Seq was used to identify pathogen DNA in blood samples obtained during the 7 days before to 1 day after bloodstream infection onset, and in control samples from the same population in the absence of fever or infection. The testing laboratory was masked to sample status. Primary outcomes were predictive sensitivity of mcfDNA-Seq for detecting the expected bloodstream infection pathogen during the 3 days preceding the day of bloodstream infection onset, with a prespecified favourable sensitivity of 50%, and predictive specificity of mcfDNA-Seq in control samples. Exploratory analyses comprised assessing sensitivity and specificity restricted to bacteria or common bloodstream infection pathogens, and after applying a data-derived DNA fragment concentration cutoff; estimating the predictive sensitivity on each of the 7 days before bloodstream infection onset; identifying clinical characteristics that affected predictive sensitivity or specificity; and examining the clinical relevance of additional organisms identified by mcfDNA-Seq during bloodstream infection episodes. Diagnostic sensitivity was also assessed on samples collected on the day of, or day after, diagnosis of bloodstream infection. This study is registered with ClinicalTrials.gov, NCT03226158. FINDINGS: 94 evaluable bloodstream infections occurred in 60 (38%) of 158 enrolled participants; 19 episodes were previously described in the pilot phase of this study. The predictive sensitivity of mcfDNA-Seq was 51·9% (95% CI 40·5-63·1) for all bloodstream infection episodes, 53·8% (42·2-65·2) for bacterial infection only, and 51·9% (40·5-63·1) when applying a DNA fragment concentration cutoff of 140 molecules per μL. Sensitivity was lowest at day -7 and increased daily until the day of diagnosis. Diagnostic sensitivity was 81·3% (95% CI 71·0-89·1) for all bloodstream infection episodes and 83·1% (72·9-90·7) for bacterial infections only. Predictive specificity was 82·7% (95% CI 76·0-88·2), but improved to 88·9% (83·0-93·3) for common bloodstream infection pathogens, and to 93·8% (88·9-97·0) when also applying the DNA fragment concentration cutoff. Predictive sensitivity was higher in participants with acute lymphoblastic leukaemia (adjusted odds ratio [aOR] 11·1 [1·7-74·2] vs those with acute myeloid leukaemia), and it was lower in polymicrobial infections (aOR 0·0 [0·0-0·2] vs monomicrobial Gram-positive infections). Clinical false-positive results were positively associated with gastrointestinal disturbance alone (p=0·037) or combined with recent administration of high-dose cytarabine (p=0·012). Additional organisms identified by mcfDNA-Seq that were not identified by blood culture were less likely than expected organisms to have an increasing DNA concentration during the days preceding bloodstream infection diagnosis. INTERPRETATION: mcfDNA-Seq can detect causative pathogens before the onset of some bloodstream infection episodes in profoundly immunocompromised patients. Predictive specificity might be improved by restricting results to a subgroup of relevant organisms, excluding patients with high risk of false-positive results, or applying a higher concentration cutoff. Clinical trials are needed to evaluate mcfDNA-Seq-guided pre-emptive therapy for preventing life-threatening bloodstream infections in patients with high risk. FUNDING: The National Cancer Institute, American Lebanese Syrian Associated Charities, St Jude Children's Research Hospital, and Karius.

Adolescent↗
PubMed2026

Serial CSF CA19-9 monitoring and CSF genomic profiling in ERBB2-mutant lung adenocarcinoma with leptomeningeal metastasis: a case report.

Leptomeningeal metastasis (LM) from ERBB2-mutant lung adenocarcinoma is difficult to treat and monitor because systemic disease and leptomeningeal disease may evolve discordantly. Evidence regarding cerebrospinal fluid (CSF) genomic profiling and serial CSF tumor marker monitoring in ERBB2-mutant non-small cell lung cancer with LM remains limited. We report a 48-year-old woman initially diagnosed with stage IB mucinous lung adenocarcinoma harboring an ERBB2 exon 20 p.G776delinsVC mutation. After surgery and adjuvant chemotherapy, she developed nodal recurrence and later presented with lower back pain and lower-limb numbness. LM was clinically diagnosed based on neurological symptoms, magnetic resonance imaging and CSF cytopathology. She received craniospinal irradiation, systemic therapy and subsequent intrathecal treatment. At month 33, CSF CA19-9 was markedly elevated despite no clear radiographic systemic progression. CSF next-generation sequencing(NGS) detected the same ERBB2 exon 20 p.G776delinsVC mutation as the primary lung tumor, with a higher variant allele fraction in CSF than in lung tissue.The patient subsequently received trastuzumab deruxtecan and sequential intrathecal therapy with pemetrexed, etoposide, cytarabine and pemetrexed rechallenge. Intrathecal treatment was adjusted according to serial CSF CA19-9 levels, neurological status, imaging findings, systemic disease activity and treatment-related toxicities. CSF CA19-9 was not used as a stand-alone criterion for progression or treatment modification.At the latest follow-up, she remained alive more than 36 months after the clinical diagnosis of LM. This case suggests that CSF NGS and serial CSF CA19-9 may provide further insights into disease activity within the integrated assessment of systemic and leptomeningeal disease. Their clinical applicability is still under investigation and necessitates future validation.

CA19-9↗