ABSTRACT As the treatment paradigm for Waldenström macroglobulinemia (WM) continues to evolve, the debate surrounding the prioritization of depth of response versus disease control as therapeutic goals gains significant relevance. However, the impact of depth of response from fixed‐duration therapy on overall survival (OS) was unclear. This multicenter study evaluated the prognostic impact of depth of response using a landmark survival analysis. A total of 440 patients with WM treated with frontline fixed‐duration regimens were included. Attaining a major response (MaR) was associated with superior outcomes, including significantly longer OS. The estimated 5‐year PFS rates for patients with MaR at 6 months versus not were 50% versus 32%, respectively, p < 0.001, and the estimated 5‐year OS rates for patients with MaR at 6 months versus not were 89% versus 70%, respectively, p < 0.001. In a multivariable analysis, MaR at 6 months was independently associated with superior PFS (HR 0.66, p = 0.007) and OS (HR 0.28, p < 0.001). Similar results were seen when considering deeper responses (CR + VGPR vs. PR). Depth of response at 6 months is an important prognostic marker in WM and an independent predictor of PFS and OS. These results support its utilization as a suitable endpoint in clinical studies in WM.
ABSTRACT Nodal follicular helper T‐cell ( T FH ) lymphoma of the angioimmunoblastic (AITL) subtype has a dismal prognosis. Using whole‐exome sequencing ( n = 124), transcriptomic ( n = 78), and methylation ( n = 40) analysis, we identified recurrent mutations in known epigenetic drivers ( TET2, DNMT3A, IDH2 R172 ) and novel ones ( TET3, KMT2D ). TET2, IDH2 R172 , DNMT3A co‐mutated AITLs had poor prognosis ( p < 0.0001). Genes regulating T‐cell receptor (TCR) signaling ( CD28, PLCG1, VAV1 , FYN ) or activation ( RHOA G17V ) or regulators of the PI3K‐pathway (PIK(3)C members, PTEN, PHLPP1, PHLPP2 ) were mutated. CD28 mutation/fusion was associated with poor prognosis ( p = 0.02). WES of purified, neoplastic T‐cell (CD3 + PD1 + ) demonstrated high concordance with whole tumor biopsies and validated the presence of TET2 and DNMT3A in tumor and non‐lymphoid cells, but other mutations ( CD28 , RHOA G17V , IDH2 R172 , PLCG1 ) in neoplastic cells. Integrated DNA‐methylation and mRNA expression analysis revealed epigenetic alterations in genes regulating TCR, cytokines, PI3K‐signaling, and apoptosis. RNA‐seq analysis identified fusion transcripts regulating TCR‐activation (8%), revealed a restricted TCR‐repertoire (α = 87%, β = 72%), and showed the presence of Epstein–Barr virus transcriptome (73%). GEP demonstrated the association of B‐cells or dendritic cells in the tumor milieu with prognosis ( p < 0.01). RNA‐seq and WES analysis of 12 AITL‐patient‐derived‐xenografts (PDX) showed that bi‐allelic TET2 and DNMT3A mutations or sub‐clonal mutations ( PLCG1, PHLPP2 ) propagated in sequential passages, and gene signatures related to T FH and T CM (central‐memory) were well‐maintained through passages. Gene expression signatures associated with late PDX passages (3rd–5th) were enriched with proliferation and metabolic reprogramming‐related genes and predicted prognosis in an independent AITL series. Low PHLPP2 mRNA expression predicted poor prognosis ( p = 0.05) and engineered PHLPP2 or TET2 loss in CD4 + T‐cells showed enhanced PI(3)K activation, thus uncovering a therapeutic target for clinical trials.
A clinical pathway for differentiating TAFRO from HLH when a cytokine storm is identified, using ferritin, C‐reactive protein, and soluble CD25.
ABSTRACT Leigh syndrome, a severe neurological disorder is commonly caused by homozygous or bi‐allelic pathogenic variants in the SURF1 gene. SURF1 deficiency leads to dysfunction of Cytochrome C Oxidase (COX) activity, which is crucial for mitochondrial oxidative phosphorylation. Understanding COX activity's correlation with disease severity is essential for developing SURF1 Leigh Syndrome biomarkers. This study assesses the disease burden in SURF1 Leigh Syndrome and evaluates COX activity as a treatment biomarker. We reviewed records and questionnaires from 17 individuals, classifying them into phenotypic and genotypic groups. We compared COX activity assays in patient fibroblasts to age‐matched controls, clinical data, and neuroimaging findings. Patient COX activity was at most 50% of controls, averaging 32% ( p < 0.001). Common clinical features included brainstem abnormalities (93.3%), motor regression (92.3%), bi‐allelic heterozygous SURF1 variants (88.2%), and delayed growth/development (35.7%). Homozygous and heterozygous nonsense/frameshift variants showed more severe phenotypes ( p = 0.008) and more MRI abnormalities ( p = 0.005). Significant COX activity reduction is linked to SURF1 Leigh Syndrome, with genotype influencing disease severity. Clinical and neuroimaging correlations show potential for prognostic indicators. This study lays the groundwork for future research and clinical application of COX activity as a SURF1 Leigh Syndrome biomarker.
ABSTRACT Pathogenic variants in GNAS can cause a wide range of diseases including pseudohypoparathyroidism, pseudopseudohypoparathyroidism, McCune‐Albright syndrome, among others. The specific phenotypic features that may be seen are influenced by the variant type and location in the gene, whether it causes loss or gain of function, and whether it is germline or somatic in nature. The GNAS locus is imprinted, which also results in a parent‐of‐origin effect. Typically, germline loss of function variants on the maternal allele are associated with variable hormonal resistances, obesity, intrauterine growth restriction, and cognitive impairment. Here, we describe a mother and daughter with a unique splicing variant near exon 5 of the GNAS gene (NM_000516.5:c.432 + 5G>A), shown to cause alternative splicing through RNA sequencing (RNA‐seq), likely resulting in a loss‐of‐function effect. Segregation testing revealed that the variant arose de novo in the mother, and phasing showed it was on her paternal allele. The resultant phenotype includes a SHOX deficiency‐like disorder with Madelung deformity in the mother, and significant growth restriction with brachydactyly in the daughter, further expanding the phenotypic spectrum of GNAS inactivation disorders.
ABSTRACT The nucleosome remodeling and deacetylation (NuRD) complex is a major chromatin regulator and plays a critical role in regulating gene transcription, genome integrity, and cell cycle progression. Heterozygous variants in GATAD2B , a core NuRD component, have been reported to cause GATAD2B ‐Associated Neurodevelopmental Disorder (GAND), an autosomal dominant neurodevelopmental disorder characterized by intellectual disability, developmental delay, hypotonia, and distinctive craniofacial features. The vast majority of disease‐causing variants in GATAD2B reported to date are loss‐of‐function (nonsense, frameshift, or splice site) variants. Here, we report a 6‐year‐old male patient with profound global developmental delay and dysmorphic features, who was found to have a de novo ~97 kbp partial duplication of the GATAD2B gene. Using long‐read transcriptome and genome sequencing on the Pacific BioSciences (PacBio) platform, we show that the duplication is a tandem event whose breakpoint in the 3′ UTR of the gene causes skipping of the last exon and transcriptional read‐through. The resulting transcript contains two incomplete copies of GATAD2B , one with exons 1–10 and the other with exons 2–7, likely representing a loss‐of‐function allele. Follow‐up clinical evaluations confirmed the patient's diagnosis of GAND, ending a years‐long diagnostic odyssey for the family and highlighting an unusual mechanism of gene disruption in GATAD2B .
ABSTRACT Short stature is a common presenting feature and an important concern for families of children with Turner syndrome. In this review, we summarize the data that shaped the updated international consensus guidelines for Turner syndrome published in 2024. The natural history of growth in Turner syndrome, the safety and efficacy of recombinant human growth hormone therapy, and the alternate growth promoting agents under consideration are presented. Timely, adequate growth hormone therapy can counter growth failure in childhood, promote catch‐up growth and help many individuals with Turner syndrome attain a near‐normal adult height. However, individual responses to growth hormone treatment are highly variable and are influenced by factors such as parental heights, age, baseline height, timing of estrogen initiation and pubertal status. Shared decision making on initiation of treatment, a candid conversation regarding the modest gradual height gain resulting from growth hormone therapy, and individualization of therapeutic goals can facilitate realistic expectations of growth promoting therapy in Turner syndrome.
ABSTRACT Facilities may forgo attempting to socially house adult males due to fear of animal injury, study disruptions, and confounding data results. To leverage the potential advantages of male–female pairs, and to understand the impact on measures typically used in safety pharmacology studies, we measured activity as well as physiologic parameters in vasectomized male‐female pairs: heart rate, blood pressure, and body temperature. Seven singly housed males that were previously implanted with telemetry were vasectomized and paired with females. Data were collected before and after pairing at specific timepoints in the first study. A second study employed four nonvasectomized, singly housed males to determine if the physiologic effects observed in the first study could be due simply to the increased cage size due to pairing. Results indicated that pair‐housing with a female resulted immediately in a significant increase in blood pressure, body temperature, and heart rate. Over the course of a week of being paired, the males showed a significant decline in blood pressure; body temperature remained elevated, though at a lower level than during the immediate response. The second study suggested that increased cage size alone could not account for the immediate results in Experiment 1, inasmuch as no effects were found on our measures. Although the sample sizes for the studies were small, we discuss how our results are similar to, and differ from, previous studies, as well as the clinical significance and welfare implications. This information may be useful in designing long‐term studies using sexually mature males while providing stable social support to animals.