Citations

Abstract Background Central nervous system (CNS) involvement by mycosis fungoides (MF) is an uncommon but serious manifestation of advanced disease. Large-cell transformation (LCT) is associated with aggressive clinical behavior and increased risk of extracutaneous dissemination; however, CNS involvement remains rare and is infrequently confirmed by molecular studies. Case Presentation: We report a 77-year-old man with a 13-year history of MF who presented with progressive generalized weakness, gait instability, and weight loss. Brain magnetic resonance imaging demonstrated multiple bilateral enhancing intraparenchymal lesions concerning for primary CNS lymphoma. Cerebrospinal fluid cytology and flow cytometry were nondiagnostic. Stereotactic biopsy of a right frontal lesion revealed diffuse infiltration of brain parenchyma by large atypical lymphoid cells with a predominantly perivascular distribution. By immunohistochemistry, the lymphocytes express CD3, TCRβF1, CD30, and demonstrate diffuse p53 overexpression, complete loss of p16, and a high proliferative index (70–80%). Comparison with a prior skin biopsy which showed typical MF morphology with limited CD30 expression (< 10% of atypical lymphocytes). Polymerase chain reaction–based T-cell receptor gene rearrangement studies performed on both CNS and skin specimens demonstrated similar clonal rearrangements, confirming CNS dissemination of the original MF clone with large-cell transformation. Discussion CNS involvement in MF is rare and may occur years after the initial diagnosis, particularly in the setting of transformation. This case highlights several important features, including multifocal intraparenchymal CNS disease, nondiagnostic cerebrospinal fluid studies, and molecular confirmation of clonal relatedness between skin and CNS lesions. These findings underscore the limitations of cerebrospinal fluid-based diagnostic studies and emphasize the importance of tissue biopsy and molecular analysis in establishing the diagnosis. Conclusion We describe a rare case of MF with large-cell transformation presenting as multifocal intraparenchymal CNS disease. Molecular demonstration of identical T-cell receptor rearrangements in skin and brain lesions provided definitive evidence of metastatic dissemination. Recognition of this rare complication is essential, as new neurologic symptoms in patients with MF should prompt evaluation for CNS involvement regardless of the extent of active cutaneous disease.

CD19-directed CAR T-cells (CTL019) can produce durable remissions in chronic lymphocytic leukemia (CLL), but therapeutic success depends on whether autologous T-cells expand, persist, and retain cytotoxic function after manufacturing. Failure of CLL T-cells is often attributed to exhaustion, although many dysfunctional CLL T-cells retain inflammatory cytokine production. We tested whether this paradox reflects immunosenescence, an aging-like program defined by costimulatory loss, DNA damage, inflammatory secretion, repertoire restriction, and proliferative arrest. In response-linked preinfusion CTL019 products, nonresponders and short partial responders had higher senescence and senescence-associated secretory phenotype (SASP) programs than the functional-responder group, comprising complete responders and partial responders with transformed disease. These programs were detectable before infusion and became more prominent during manufacture in susceptible products. They tracked with weak in vivo CAR T-cell expansion and were associated with inferior survival. Serum proteomics revealed a circulating, CLL-associated SASP-like inflammatory milieu in nonresponders. Flow cytometry and T-cell receptor (TCR) profiling showed that poor responders carried CD27⁻CD28⁻ and KLRG1⁺ CD8 T-cells at apheresis, lower product CD27, and reduced product TCR diversity. Research-manufactured CAR T-cells from treatment-naïve CLL samples displayed the same state, most prominently in CD4 CAR T-cells, with SA-β-gal, p16, p53, DNA damage, depletion of less-differentiated states, and senescence-enriched transcriptomes. Under repeated CD19 stimulation, CLL-derived products reached a proliferative ceiling, and p53-high products lost cytotoxic reserve. Ibrutinib improved proliferative fitness, attenuated senescence-associated features and SASP output in paired patient and direct-exposure assays, and enhanced CAR T-cell expansion in an ibrutinib-resistant CLL model. Together, these data identify immunosenescence as a measurable and functionally consequential barrier to CAR T-cell efficacy in CLL and a candidate for therapeutic modulation.

Background Cardiac involvement by extranodal natural killer/T-cell lymphoma (ENKTL) and aggressive NK-cell leukaemia (ANKL) is exceedingly rare and presents with heterogeneous manifestations, often leading to diagnostic uncertainty and delay. We contribute three additional biopsy- or autopsy-proven cases and place them in the context of a literature review of previously reported cases classified according to the 5th edition of the World Health Organization (WHO) Classification of Hematolymphoid Tumors. Case series Three men (ages 58–72) presented with diverse cardiac manifestations. A 72-year-old with progressive dyspnoea and cardiogenic shock had cMRI findings interpreted as myocarditis on an infiltrative substrate; endomyocardial biopsy confirmed cardiac infiltration by ENKTL. Despite brentuximab vedotin (BV)-based therapy he died shortly thereafter. A 60-year-old with encephalopathy, biventricular dysfunction, and widespread nodal/multiorgan disease had nodal pathology consistent with EBV-negative ANKL according to the criteria of the 5th edition of the WHO Classification of Hematolymphoid Tumors; he declined chemotherapy and died within six days, with autopsy confirming multiorgan (including myocardial and bone marrow) infiltration. A 58-year-old with prior sinonasal ENKTL treated with four cycles of SMILE developed a new right atrial mass one month later; the mass was diagnosed by cMRI/PET-CT concordance and an extracardiac (EBUS-lung) tissue confirmation of the same recurrence. BV followed by gemcitabine/oxaliplatin failed to control progression and he died approximately one month after cardiac spread. Across cases, CD56 was positive in all, EBER in two, and CD30 was expressed variably. Conclusions Cardiac ENKTL/ANKL is a rapidly fatal entity with protean features. Multimodal imaging aids early recognition and tissue targeting, but definitive diagnosis rests on tissue confirmation. L-asparaginase-based chemotherapy remains the treatment backbone; CD30- and PD-L1-guided agents such as BV, PD-1 blockade, and daratumumab may offer transient control after biomarker-guided selection but lack randomized data in cardiac disease. Across the reported experience, survival after cardiac involvement was uniformly short, typically days to a few months. Our three cases add to this literature by illustrating the diversity of cardiac presentations, the variable CD30 expression relevant to brentuximab vedotin use, and the contribution of multimodal imaging to diagnosis. Findings from our series and the pooled literature are descriptive rather than constituting a formal survival analysis, and underscore the need for earlier diagnosis and prospective investigation.

ABSTRACT We report a case of a 71‐year‐old female with acute myeloid leukemia (AML), treated with chemotherapy and hematopoietic stem cell transplant (HSCT), who developed a clonally related non‐Langerhans cell histiocytosis (NLCH). She presented with pink papules on the mid‐upper cutaneous lip and thighs 3 months following HSCT. Skin biopsies revealed a dermal proliferation of cells with eosinophilic cytoplasm. Immunohistochemistry (IHC) studies demonstrated positivity for CD68, CD163, BRAF, cyclin D1, and Factor XIIIa and negativity for CD1a, S100, MPO, and CD20. Next‐generation sequencing (NGS) with a comprehensive myeloid panel revealed corresponding pathogenic mutations to her AML, including BCOR Q176fs*40, IDH1 R132C, and TP53 Y163N, and an additional BRAF V600E mutation. Additional mutations in DNMT3A and KMT2A associated with her AML were not identified. These findings supported the diagnosis of NLCH sharing a clonal origin with the patient's AML. Work up demonstrated isolated cutaneous involvement without AML relapse; therefore, the skin lesions were treated with shave excision, topical tacrolimus 0.1% ointment, and topical clobetasol 0.05% cream without further systemic treatment. The acquired BRAF V600E mutation illustrates the potential for divergent myeloid differentiation and likely explains the emergence of a clonal NLCH after successful AML treatment. Genetic analysis in NLCH can establish clonality with associated hematologic malignancies, uncover actionable mutations, and guide treatment.

ABSTRACT Aims Metabolic dysfunction‐associated steatotic liver disease (MASLD) is increasingly linked to cognitive decline, yet the hepatic factors associated with imaging‐derived neurovascular coupling (NVC) remain unclear. This study aimed to investigate whether liver stiffness or liver fat content was more closely associated with resting‐state CBF‐ReHo surrogate measures. Materials and Methods A total of 130 participants including 98 MASLD patients and 32 age‐ and education‐matched healthy controls (HCs) underwent clinical assessment, neuropsychological testing, and multi‐modal MRI. Liver stiffness and fat content were quantified using MR elastography (MRE) and MRI‐proton density fat fraction (PDFF). Imaging‐derived NVC was assessed using global cerebral blood flow (CBF)‐regional homogeneity (ReHo) coupling and voxel‐wise CBF/ReHo ratios, interpreted as resting‐state surrogates rather than direct stimulus‐evoked NVC. Multivariable regression and exploratory mediation analyses were employed. Results Compared to HCs and patients with lower liver stiffness (MASLD_low), those with higher liver stiffness (MASLD_high) showed reduced global CBF‐ReHo coupling and altered CBF/ReHo ratios, primarily localized to the bilateral superior temporal pole/superior temporal gyrus (TPOsup). In multivariable regression, liver stiffness remained independently associated with TPOsup CBF/ReHo ratios ( p < 0.001). Exploratory mediation analysis showed a statistically significant indirect association between hepatocellular injury markers and TPOsup CBF/ReHo ratios involving MRE‐derived liver stiffness (95% CI: 0.0795–0.2790). Conclusions Within this cohort and the observed PDFF range, MRE‐derived liver stiffness was more closely associated with imaging‐derived NVC surrogate measures than liver fat content in MASLD. These findings are hypothesis‐generating and require validation in longitudinal studies.

ABSTRACT As a principal metabolite of ginsenosides, compound K (CK) exhibits remarkable antioxidant, anti‐inflammatory, antidiabetic, and anticancer bioactivities. However, CK is naturally scarce in ginseng and its industrial application is limited by the lack of efficient deglycosylating enzymes for large‐scale CK bioproduction. Here, we report a synthetic biology‐driven approach for high‐yield CK production via recombinant β‐glycosidase‐mediated bioconversion of the polar ginsenoside Rb1. The β‑glycosidase‐encoding gene was introduced into Escherichia coli BL21 (DE3), and the resulting engineered strain produced 2.1 g/L β‑glycosidase in shake flasks and 10.1 g/L in a 5‐L fermentor. The crude β‐glycosidase exhibited excellent enzymatic activity; at a concentration of 1.5 g/L, it converted 95% of the Rb1 substrate (initial concentration 10 g/L) to CK within 4 h. In vitro studies demonstrated CK's high cytocompatibility and potent anti‐aging effects, including suppression of reactive oxygen species ( via upregulation of superoxide dismutase, catalase, and glutathione peroxidase), enhanced collagen I, Ⅲ and elastin synthesis, and matrix metalloproteinase‐1 inhibition. These findings highlight CK as a promising candidate for anti‐wrinkle formulations, supported by the feasibility of scalable bioproduction.

Abstract Background Cardiac magnetic resonance elastography (MRE) allows the non-invasive quantification of myocardial stiffness, but long-interval reproducibility data at 3.0 T single-frequency 140-Hz remain limited. Purpose To evaluate the short- and long-interval reproducibility of 3.0 T cardiac MRE for left ventricular (LV) myocardial stiffness across healthy volunteers and patients with conditions associated with elevated myocardial stiffness. Materials and Methods This prospective single-center study included 69 participants: 60 healthy volunteers and 9 with cardiovascular disease (6 with aortic stenosis and 3 with long-standing hypertension). All participants underwent baseline cardiac MRE (scanner: Signa Premier 3.0 T, GE Healthcare, driver: Resoundant), an immediate short-interval rescan (SIR) within 5 minutes, and a long-interval rescan (LIR) after approximately 1 month. Left ventricular myocardial stiffness and octahedral shear strain signal-to-noise ratio were measured independently by 2 readers. Reproducibility was assessed using Bland-Altman analysis, intraclass correlation coefficients (ICCs), within-subject coefficient of variation, standard error of measurement, and smallest detectable change at the 95% confidence (SDC95) level. Results Baseline LV myocardial stiffness was higher in the disease group than in healthy volunteers, 11.73 ± 1.01 kPa and 7.80 ± 0.70 kPa (mean ± SD; P &lt; .001), respectively. Inter-reader agreement was excellent across all timepoints, with ICCs of 0.970 at baseline (95% CI, 0.953-0.982), 0.966 for SIR (95% CI, 0.945-0.979), and 0.962 for LIR (95% CI, 0.939-0.976). Within-reader scan-rescan reproducibility was also excellent. For Reader 1, stiffness ICC was 0.979 for the SIR (95% CI, 0.966-0.987) and 0.957 for the LIR (95% CI, 0.932-0.973), with SDC95 values of 0.616 kPa (95% CI, 0.528-0.741) and 0.869 kPa (95% CI, 0.744-1.044), respectively. Reader 2 showed excellent reproducibility, with ICCs ≤0.943. Conclusions 3D single-frequency 140-Hz cardiac MRE at 3.0 T provides excellent short- and long-interval reproducibility for LV myocardial stiffness quantification. The SDC95 values may help distinguish true longitudinal stiffness changes from measurement variability.

Importance Myelin oligodendrocyte glycoprotein antibody–associated disease (MOGAD) lacks proven relapse-preventive therapies. While clinical trials are ongoing, safety data may be limited and approved drugs are costly. Studies of interleukin 6 receptor blocker (IL-6RB) in MOGAD are limited by small numbers and no comparative studies, contributing to low use. Objective To evaluate the impact of IL-6RB therapy on relapse rates in MOGAD and compare relapse frequency with intravenous immunoglobulin (IVIG). Design, Setting, and Participants This international, multicenter, retrospective cohort study (January 1, 2015, through December 31, 2025) included a historical IVIG-treated cohort of varying doses. The study took place across sites in North and South America (US, Canada, Mexico, Argentina, Brazil, Chile, Colombia, and Peru). Patients with MOGAD (n = 116, no excluded patients) who received at least 1 dose of an IL-6RB were included. These data were analyzed in January 2026. Exposures Tocilizumab or satralizumab. Main Outcomes and Measures Annualized relapse rate (ARR) during IL-6RB therapy, time to next relapse after treatment initiation, and adverse events. Outcomes were compared with the IVIG cohort using inverse probability of treatment weighting (IPTW) adjusted for age, sex, prior ARR, and concomitant therapies. Results A total of 116 patients with MOGAD (89% relapsing) receiving IL-6RB (tocilizumab, 104 [90%] and satralizumab, 12 [10%]) were included; overall, 60.3% were female, 39.7% were male, and 18% were younger than 18 years. The median (IQR) IL-6RB treatment follow-up was 1.4 (0.7-2.5) years and 23 relapses occurred during 241.8 person-years of IL-6RB therapy. The ARR decreased from 0.64 (95% CI, 0.58-0.70) for relapsing MOGAD before IL-6RB to 0.09 (95% CI, 0.06-0.14) during IL-6RB treatment (incidence rate ratio, 0.08; 95% CI, 0.04-0.16). Adverse events occurred in 58 patients (50%), most commonly mild infections, although 10 (9%) had severe infections. In the IVIG cohort (n = 59), 30 relapses occurred over 133.8 person-years (ARR, 0.22; 95% CI, 0.15-0.32). After IPTW, IL-6RB was associated with a lower hazard ratio (HR) than the group who underwent IVIG therapy less than 1 g/kg every 4 weeks (HR, 4.5; 95% CI, 2.0-9.8), with no significant difference vs the group who underwent IVIG 1 g/kg or more every 4 weeks (HR, 2.0; 95% CI, 0.8-4.5). Conclusions and Relevance In this multicenter observational cohort, IL-6RB use in MOGAD was associated with low relapse rates and a favorable safety profile, though severe infections occurred occasionally. Relapse rates were lower than the group who underwent IVIG less than 1 g/kg every 4 weeks but not significantly different from the group who underwent IVIG 1 g/kg or more every 4 weeks. This supports IL-6RB as a potential relapse-prevention therapy in MOGAD; the wide availability and relative affordability of tocilizumab may enable broad global use.

Abstract Targeting oxidative phosphorylation (OXPHOS) represents an attractive therapeutic strategy in acute myeloid leukemia, which exhibits exceptional dependence on mitochondrial respiration compared to normal hematopoietic cells. However, clinical attempts to exploit this vulnerability have been limited by on-target toxicity to healthy tissue. Here, we comprehensively compare the cellular consequences of inhibiting distinct nodes of the electron transport chain in AML. We demonstrate that selective inhibition of the F 1 subunit of ATP synthase with EB2023 (ammocidin A) delivers an energetic stress to AML cells without the profound redox stress that characterizes complex I inhibition, preventing NAD⁺/NADH imbalance and allowing continued TCA cycling. Further, the duration of OXPHOS inhibition is transient in nature in vivo , a finding revealed through pharmacokinetic and serial pharmacodynamic monitoring of AMPK phosphorylation accompanied by OPA1-mediated mitochondrial structural remodeling that primes AML cells for BCL2 inhibitor synergy. EB2023 in combination with venetoclax demonstrates potent anti-AML activity across cell lines and patient-derived xenograft models at doses that spare normal hematopoietic progenitors and avoid the neuropathy and sustained detrimental systemic metabolic rewiring in healthy tissues associated with prior efforts to target OXPHOS. These findings establish F 1 -selective ATP synthase inhibition as a clinically actionable therapeutic strategy in AML and establish the duration of OXPHOS inhibition as a critical and previously underappreciated determinant of therapeutic index.

Abstract Introduction Acute interstitial nephritis is an important differential diagnosis in patients with deteriorating kidney function. Diagnosis currently requires kidney biopsy, an invasive procedure associated with risks. We hypothesized that urinary T cells may serve as a non-invasive biomarker for acute interstitial nephritis. Methods A total of 320 patients undergoing clinically indicated kidney biopsy were enrolled in a discovery cohort at Charité Berlin (n = 80), an internal validation cohort at Charité (n = 100), and an external validation cohort at The First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou (n = 140). Urinary immune cells were assessed by flow cytometry. Renal T cell infiltration was evaluated by immunofluorescence in kidney biopsy specimens from the discovery and internal validation cohorts, including 16 patients with acute interstitial nephritis and 9 patients without acute interstitial nephritis. Additionally, CXCL9 was measured by ELISA in 102 urine samples from these cohorts. Results Across all cohorts, 27 patients (8.4%) were diagnosed with acute interstitial nephritis. In the discovery cohort, multiple urinary T cell subsets were increased in acute interstitial nephritis, with activated CD4 + effector memory T cells expressing CD38 and HLA-DR showing the strongest diagnostic performance. This marker outperformed urinary monocytes, eosinophils, and CXCL9 and was validated in both independent cohorts. Across all cohorts, the area under the receiver operating characteristic curve was 0.84 and increased to 0.91 after exclusion of 8 patients receiving corticosteroids. A cutoff of 211 activated CD4 + effector memory T cells per 100 mL urine yielded a sensitivity of 78% and a specificity of 81%. Urinary activated CD4 + effector memory T cell counts correlated with renal CD4 + and CD4 + CD38 + T cell infiltration in acute interstitial nephritis. Conclusions Urinary activated CD4 + effector memory T cells expressing CD38 and HLA-DR represent a promising non-invasive biomarker for the diagnosis of acute interstitial nephritis. Lay Summary Acute interstitial nephritis is a frequent cause of acute kidney injury and is usually diagnosed by kidney biopsy, an invasive procedure that carries risks. We investigated whether immune cells in urine could help identify AIN in a less invasive manner. In this multicenter study, urine samples from 320 patients undergoing kidney biopsy in Germany and China were analyzed. We found that a specific population of activated T cells was markedly increased in the urine of patients with AIN compared with patients with other kidney diseases. This urinary marker outperformed other immune cell types and the inflammatory cytokine CXCL9 and was successfully validated in independent cohorts from both Germany and China. Importantly, urinary activated T cell counts correlated with immune cell infiltration within the kidney. These findings suggest that urinary activated T cells may serve as a non-invasive biomarker to support the diagnosis of AIN and facilitate earlier clinical decision-making.