Browse Articles

Clinical utility and safety of LMA Gastro™ in ASA III–IV patients with chronic liver disease undergoing upper gastrointestinal endoscopy: A prospective observational study

Spatial fibroblast niches define Crohn’s fistulae

Abstract Crohn’s disease often presents with fistulae, abnormal tunnels that connect the intestine to the skin or other organs. Despite their profound effect on morbidity, the molecular basis of fistula formation remains unclear, largely owing to the challenge of capturing intact fistula tracts and their inherent heterogeneity 1–3 . Here we construct a subcellular-resolution spatial atlas of 68 intestinal fistulae spanning diverse anatomical locations. We describe fistula-associated epithelial, immune and stromal cell states, revealing abnormal zonation of growth factors and morphogens linked to establishment of tunnelling anatomy. We identify fistula-associated stromal (FAS) fibroblasts, which are assembled in concentric layers: a proliferative, lumen-adjacent zone beneath neutrophil and macrophage-rich granulation tissue, an active lesion core of FAS cells and a quiescent, pro-fibrotic outer zone. We examine the architecture of the extracellular matrix in the fistula tract and demonstrate that FAS populations associate with distinct collagen structures, exhibiting properties ranging from proliferation, migration and extracellular matrix remodelling to dense collagen deposition and fibrosis. We define niches supporting epithelialization of fistula tunnels and a FAS-like population that is detected at the base of ulcers in non-penetrating Crohn’s disease. Our study demonstrates that common molecular pathways and cellular niches underpin fistulae across intestinal locations, revealing the cellular protagonists of fistula establishment and persistence. This resource will inform the development of model systems and interventions to mitigate aberrant fibroblast activity while preserving their regenerative properties in Crohn’s disease.

Convergent genome evolution shaped the emergence of terrestrial animals

Abstract The challenges associated with the transition of life from water to land are profound 1 , yet they have been met in many distinct animal lineages 2–5 . These constitute a series of independent evolutionary experiments from which we can decipher the role of contingency versus convergence in the adaptation of animal genomes. Here we compare 154 genomes from 21 animal phyla and their outgroups to reconstruct the protein-coding content of the ancestral genomes linked to 11 animal terrestrialization events, and to produce a timescale of terrestrialization. We uncover distinct patterns of gene gain and loss underlying each transition to land, but similar biological functions emerged recurrently pointing to specific adaptations as key to life on land. We show that semi-terrestrial species evolved convergent functional patterns, in contrast with fully terrestrial lineages that followed different paths to land. Our timeline supports three temporal windows of land colonization by animals during the last 487 million years, each associated with specific ecological contexts. Although each lineage exhibits distinct adaptations, there is strong evidence of convergent genome evolution across the animal kingdom suggesting that, in large part, adaptation to life on land is predictable, linking genes to ecosystems.

Blood protein thwarts deadly fungal disease

Decay of driver mutations shapes the landscape of intestinal transformation

Abstract Colorectal cancer (CRC) has traditionally been thought to develop through stepwise mutation of the APC tumour suppressor and other driver genes, coupled with expansion of positively selected clones. However, recent publications show that many premalignant lesions comprise multiple clones expressing different mutant APC proteins 1–4 . Here, by mediating transformation on different mouse backgrounds containing mutations in Kras or other common CRC driver genes, we establish that the presence of diverse priming events in the normal mouse intestinal epithelium can change the transformation and clonal-selection landscape, permitting the fixation of strong driver mutations in Apc and Ctnnb1 that are otherwise lost due to negative selection. These findings, combined with our demonstration of mutational patterns consistent with similar priming events in human CRC, suggest that the order in which driver mutations occur in intestinal epithelium can determine whether clones are positively or negatively selected and can shape subsequent tumour development.

Octopus-inspired ‘synthetic skin’ changes colour and texture on demand

Climate change shifts the North Pacific storm track polewards

ML-DS 2018 TRIAL

Multiselective RAS(ON) inhibition targets oncogenic RAS and overcomes RAS-mediated resistance to FLT3i and BCL2i in AML

Abstract Aberrant activation of RAS/MAPK signaling limits the clinical efficacy of several targeted therapies in acute myeloid leukemia (AML). In FMS-like tyrosine kinase-3 (FLT3)-mutant AML, the selection of clones harboring heterogeneous RAS mutations drives resistance to FLT3 inhibitors (FLT3i). RAS activation is also associated with resistance to other AML targeted therapies, such as the B-cell lymphoma 2 inhibitor venetoclax. Despite the critical need to inhibit RAS/MAPK signaling in AML, no targeted therapies have demonstrated a clinical benefit in RAS-driven AML. To address this unmet need, we investigated the preclinical activity of RMC-7977, a multiselective inhibitor of GTP-bound active (RAS[ON]) isoforms of mutant and wild-type RAS in AML models. RMC-7977 exhibited potent antiproliferative and proapoptotic activity across AML cell lines with MAPK-activating signaling mutations. In cell line models with acquired FLT3i resistance because of secondary RAS mutations, treatment with RMC-7977 restored sensitivity to FLT3i. Similarly, RMC-7977 effectively reversed resistance to venetoclax in RAS-addicted cell line models with both RAS wild-type and mutant genetic backgrounds. In murine patient-derived xenograft models of RAS-mutant AML, RMC-7977 was well tolerated and significantly suppressed leukemic burden in combination with gilteritinib or venetoclax. Our findings strongly support clinical investigation of broad-spectrum RAS(ON) inhibition in AML to treat and potentially prevent drug resistance because of activated RAS signaling.

Duffy-null reference ranges for improved clinical care

A small step yet one giant leap for cGVHD biomarkers

High-risk genomic consensus validation for patients with newly diagnosed multiple myeloma using next-generation sequencing

Abstract The prognostic heterogeneity of multiple myeloma is mainly driven by the genomic features of myeloma cells. The International Myeloma Society (IMS)/International Myeloma Working Group (IMWG) recently proposed a high-risk (HR) genomic model to have a consensus definition of genomic risk. We performed next-generation sequencing in the form of a panel on samples from 6528 patients with newly diagnosed multiple myeloma (NDMM) and 1583 patients at first relapse between 2019 and 2024. We observed that 22.4% of patients at diagnosis and 36.7% of patients at first relapse were classified as high risk according to the Consensus Genomic Staging. Clinical data were available for 2695 patients at diagnosis. After a median follow-up of 35 months, the median progression-free survival (PFS) was 30 months for patients with HR NDMM and 51 months for standard-risk (SR) patients (P< .0001). The HR cytogenetic criteria from the Revised- International Staging System score were not able to differentiate between HR and SR patients based on the IMS/IMWG genomic subgroups. Looking at each criterion independently, we found that the presence of del(17p), TP53 mutation, biallelic del(1p32), or the combination of intermediate-risk cytogenetics (gain 1q, del(1p32), t(4;14), t(14;16), t(14;20)) significantly reduced the PFS when compared with SR patients. Moreover, patients with several cumulating criteria had an even worse prognosis. Among SR patients, classified according to the genomic definition with normal creatinine, the median PFS for those with high β2-microglobulin was not significantly different from that of patients with normal β2-microglobulin level. This study validated the IMS/IMWG genomic definition of HR myeloma in a large cohort of patients diagnosed from 2019 onwards.

Distinct biological subtypes of chronic GVHD after pediatric hematopoietic cell transplantation

Abstract Chronic graft-versus-host-disease (cGVHD) is the primary nonrelapse limitation to a successful hematopoietic cell transplantation and is largely treated as a single biological entity. We hypothesized that there exist different biological subtypes of cGVHD. Using the Applied Biomarkers of Late Effects of Childhood Cancer (ABLE) network database, which is derived from the largest pediatric cGVHD cohort worldwide, we applied clustering analysis to subtype patients with cGVHD from the ABLE1.0 and 2.0 studies (51 patients with cGVHD and 158 with non-cGVHD). We found 3 distinct cGVHD subtypes: cGVHD-1 was characterized by an effector memory T-cell, cytotoxic natural killer cell, and early precursor B-cell predominant pattern; cGVHD-2 was phosphatidylcholine, cytokine, and plasma cell predominant; and cGVHD-3 had more naïve CD4+ T cells and naïve regulatory T cells, had later onset, and was the only subtype with measurable T-cell receptor excision circles. We partially replicated these subtypes using metabolomic data from a separate pediatric cohort of the Children’s Oncology Group trial ASCT0031 (33 patients with cGVHD and 39 with non-cGVHD). Furthermore, cGVHD-1 was associated with serotherapy (predominantly antithymocyte globulin) exposure, and cGVHD-3 was associated with receiving peripheral blood stem cells from donors, total body irradiation, and no previous acute GVHD. cGVHD-2 was associated with liver involvement and cGVHD-2 and -3 with de novo cGVHD. Overall, none of the subtypes were closely associated with organ involvement. Contrasting each subtype against patients with non-cGVHD, the 3 subtypes shared common markers, all of which were used in our previous cGVHD diagnostic classifier. These findings suggest the presence of distinct biological subtypes of cGVHD that may help guide therapeutic strategies.

CPX-351 in Down syndrome–associated myeloid leukemia: results and prognostic factors from the phase 3 ML-DS 2018 trial

Abstract Myeloid leukemia of Down syndrome (ML-DS) is associated with an excellent prognosis but high treatment-related toxicity and mortality. The Phase 3 Clinical Trial for CPX-351 in ML-DS 2018 aimed to maintain the excellent event-free survival (EFS) achieved in the previous ML-DS 2006 trial while reducing the treatment intensity. Intensity-reduced induction and reinduction therapy with cytarabine and idarubicin with or without etoposide was replaced with CPX-351 (66 U/m2 on 3 days in course 1 and on 2 days in course 2). Risk stratification was based on flow cytometric measurable residual disease (MRD) after first induction. High-risk patients received high-dose cytarabine (3 g/m2 per 12 hour) in consolidation; standard-risk patients received cytarabine at a dose of 1 g/m2 per 12 hour. A total of 35 patients were enrolled until the trial was halted because of an unexpectedly high relapse rate. A per-protocol interim analysis revealed a significantly lower 24-month EFS when compared with the ML-DS 2006 trial (69% vs 90%; P< .001). In contrast with previous studies, most patients who relapsed responded to salvage therapy, leading to a comparable 24-month overall survival of 88% (vs 92%; P = .612). CPX-351 demonstrated a favorable toxicity profile with no treatment-related mortality. Positive MRD by error-corrected GATA1 next-generation sequencing, the presence of trisomy 8 or a complex karyotype were associated with an increased risk for relapse. In conclusion, replacing intensity-reduced induction therapy with CPX-351 in ML-DS led to a significantly lower EFS, highlighting the need for dose optimization to balance the efficacy and toxicity in this sensitive patient population. This trial was registered at https://www.clinicaltrialsregister.eu as EudraCT #2018-002988-25.

Elevated serum erythropoietin level in JAK2+ polycythemia vera with small vessel Budd-Chiari syndrome

Jellyfish sleep like humans — even though they don’t have brains

Patient-reported outcomes: a Polaris for POLARIX

miR-aculous effects for hemophilic arthropathy

PROs vs clinician-reported adverse events in a large clinical trial: findings from the phase 3 POLARIX study

Abstract Diffuse large B-cell lymphoma (DLBCL) poses a challenge in hematology given its varied symptoms, and the complex interplay between disease and treatment effects on health-related quality of life (HRQoL). The phase 3 POLARIX study demonstrated superior progression-free survival and a similar safety profile with polatuzumab vedotin plus rituximab, cyclophosphamide, doxorubicin, and prednisone (Pola-R-CHP) vs R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) in patients with previously untreated DLBCL. Here, we evaluate HRQoL through patient-reported outcome (PRO) instruments to fully characterize the patient experience in the POLARIX study. Changes from baseline in HRQoL, lymphoma symptoms, and gastrointestinal (GI) symptoms were assessed, as well as incidence and severity of common symptoms by PROs vs clinician-reported adverse events (AEs). Baseline characteristics of PRO-evaluable patients (N = 874) were consistent. Comparison between PROs and clinician-reported AEs revealed a notable discordance; patients generally reported a higher incidence of symptoms than clinicians, emphasizing the need for patient-centric tools to accurately capture the patient experience. Both treatments exhibited rapid and sustained improvements in HRQoL and lymphoma symptoms, with the most substantial improvements seen in global health status/QoL, lymphoma symptoms, fatigue, role, emotional, and social functioning. GI symptoms (diarrhea, constipation, nausea, and vomiting) were generally similar between treatment arms and returned to baseline levels after treatment completion. These HRQoL data underscore the complementarity of PROs, as an adjunct to clinician-reported AEs, in evaluating the efficacy and tolerability of new treatments, including Pola-R-CHP, which may represent a new benchmark for patient-reported HRQoL in previously untreated DLBCL. This trial was registered at www.clinicaltrials.gov as NCT03274492.

Multinational assessment of absolute neutrophil counts and white blood cell counts among healthy Duffy-null adults

Abstract Laboratory reference intervals must reflect population diversity for accurate medical decisions. The Duffy-null variant lowers absolute neutrophil counts (ANC), but existing dedicated reference intervals are based on a single African American cohort. The impact across other ethnic groups and regions remains unclear, and no white blood cell count (WBC) intervals exist for Duffy-null individuals. This study aimed to establish and compare Duffy-null ANC and WBC reference intervals across 4 continents. A cross-sectional study was conducted assessing healthy Duffy-null individuals from dedicated cohorts (blood donors in Namibia, Saudi Arabia, and the United Kingdom; primary care patients in the United States) and biobanks (participants from the United Kingdom and the United States). Among 8018 participants (880 from dedicated cohorts and 7138 from biobanks), novel ANC and WBC reference intervals were established (Namibia [ANC, 820/μL to 6370/μL; WBC, 2.51 × 109/L to 9.85 × 109/L]; Saudi Arabia [ANC, 1140/μL to 5290/μL; WBC, 3.72 × 109/L to 10.71 × 109/L]; United Kingdom (ANC, 1185/μL to 5462/μL; WBC, 3.1 × 109/L to 8.8 × 109/L]; the United States [ANC, 1210/μL to 5390/μL; WBC, 3.00 × 109/L to 9.66 × 109/L]), with no significant differences between cohorts. Institutional reference intervals misclassified 27.9% (Namibia), 50.9% (Saudi Arabia), 26.0% (United Kingdom), and 21.7% (the United States) as neutropenic. Biobank analyses confirmed no significant difference in ANC between Black and non-Black Duffy-null participants. Duffy-null individuals consistently exhibit lower ANC and WBC across ethnic groups and regions. Current reference intervals overlook this variation, risking misdiagnosis and health inequities. Implementing Duffy-specific reference intervals is essential for equitable and accurate clinical decisions worldwide.