An atlas of cells in the human tonsil.

Palatine tonsils are secondary lymphoid organs (SLOs) representing the first line of immunological defense against inhaled or ingested pathogens. We generated an atlas of the human tonsil composed of >556,000 cells profiled across five different data modalities, including single-cell transcriptome, epigenome, proteome, and immune repertoire sequencing, as well as spatial transcriptomics. This census identified 121 cell types and states, defined developmental trajectories, and enabled an understanding of the functional units of the tonsil. Exemplarily, we stratified myeloid slan-like subtypes, established a BCL6 enhancer as locally active in follicle-associated T and B cells, and identified SIX5 as putative transcriptional regulator of plasma cell maturation. Analyses of a validation cohort confirmed the presence, annotation, and markers of tonsillar cell types and provided evidence of age-related compositional shifts. We demonstrate the value of this resource by annotating cells from B cell-derived mantle cell lymphomas, linking transcriptional heterogeneity to normal B cell differentiation states of the human tonsil.

Iron silicate perovskite and postperovskite in the deep lower mantle.

Ferromagnesian silicates are the dominant constituents of the Earth's mantle, which comprise more than 80% of our planet by volume. To interpret the low shear-velocity anomalies in the lower mantle, we need to construct a reliable transformation diagram of ferromagnesian silicates over a wide pressure-temperature (P-T) range. While MgSiO3 in the perovskite structure has been extensively studied due to its dominance on Earth, phase transformations of iron silicates under the lower mantle conditions remain unresolved. In this study, we have obtained an iron silicate phase in the perovskite (Pv) structure using synthetic fayalite (Fe2SiO4) as the starting material under P-T conditions of the lower mantle. Chemical analyses revealed an unexpectedly high Fe/Si ratio of 1.72(3) for the Pv phase in coexistence with metallic iron particles, indicating incorporation of about 25 mol% Fe2O3 in the Pv phase with an approximate chemical formula (Fe2+0.75Fe3+0.25)(Fe3+0.25Si0.75)O3. We further obtained an iron silicate phase in the postperovskite (PPv) structure above 95 GPa. The calculated curves of compressional (VP) and shear velocity (VS) of iron silicate Pv and PPv as a function of pressure are nearly parallel to those of MgSiO3, respectively. To the best of our knowledge, the iron silicate Pv and PPv are the densest phases among all the reported silicates stable at P-T conditions of the lower mantle. The high ferric iron content in the silicate phase and the spin-crossover of ferric iron at the Si-site above ~55 GPa should be taken into account in order to interpret the seismic observations. Our results would provide crucial information for constraining the geophysical and geochemical models of the lower mantle.

Gondwanan flood basalts linked seismically to plume-induced lithosphere instability.

Delamination of the continental lithospheric mantle is well recorded beneath several continents. However, the fate of the removed continental lithosphere has been rarely noted, unlike subducted slabs reasonably well imaged in the upper and mid mantle. Beneath former Gondwana, recent seismic tomographic models indicate the presence of at least 5 horizontal fast-wavespeed anomalies at ~600 km depths that do not appear to be related to slab subduction, including fast structures in locations consistent with delamination associated with the Paraná Flood Basalt event at ~134 Ma and the Deccan Traps event at ~66 Ma. These fast-wavespeed anomalies often lie above broad slow seismic wavespeed trunks at 500 to 700 km depths beneath former Gondwana, with slow wavespeed anomalies branching around them. Numerical experiments indicate that delaminated lithosphere tends to stagnate in the transition zone and mid-mantle above a mantle plume where it shapes subsequent plume upwelling. For hot plumes, the melt volume generated during plume-influenced delamination can easily reach ~2 to 4 × 106 km3, consistent with the basalt eruption volume at the Deccan Traps. This seismic and numerical evidence suggests that observed high-wavespeed mid-mantle anomalies beneath the locations of former flood basalts are delaminated fragments of former continental lithosphere, and that lithospheric delamination events in the presence of subcontinental plumes induced several of the continental flood basalts associated with the multiple breakup stages of Gondwanaland. Continued upwelling in these plumes can also have entrained subcontinental lithosphere in the mid-mantle to bring its distinctive geochemical signal to the modern mid-ocean spreading centers that surround southern and western Africa.

Constraining Earth's nonlinear mantle viscosity using plate-boundary resolving global inversions.

Variable viscosity in Earth's mantle exerts a fundamental control on mantle convection and plate tectonics, yet rigorously constraining the underlying parameters has remained a challenge. Inverse methods have not been sufficiently robust to handle the severe viscosity gradients and nonlinearities (arising from dislocation creep and plastic failure) while simultaneously resolving the megathrust and bending slabs globally. Using global plate motions as constraints, we overcome these challenges by combining a scalable nonlinear Stokes solver that resolves the key tectonic features with an adjoint-based Bayesian approach. Assuming plate cooling, variations in the thickness of continental lithosphere, slabs, and broad scale lower mantle structure as well as a constant grain size through the bulk of the upper mantle, a good fit to global plate motions is found with a nonlinear upper mantle stress exponent of 2.43 [Formula: see text] 0.25 (mean [Formula: see text] SD). A relatively low yield stress of 151 [Formula: see text] 19 MPa is required for slabs to bend during subduction and transmit a slab pull that generates asymmetrical subduction. The recovered long-term strength of megathrusts (plate interfaces) varies between different subduction zones, with South America having a larger strength and Vanuatu and Central America having lower values with important implications for the stresses driving megathrust earthquakes.

Mineral carbonation of peridotite fueled by magmatic degassing and melt impregnation in an oceanic transform fault.

Most of the geologic CO2 entering Earth's atmosphere and oceans is emitted along plate margins. While C-cycling at mid-ocean ridges and subduction zones has been studied for decades, little attention has been paid to degassing of magmatic CO2 and mineral carbonation of mantle rocks in oceanic transform faults. We studied the formation of soapstone (magnesite-talc rock) and other magnesite-bearing assemblages during mineral carbonation of mantle peridotite in the St. Paul's transform fault, equatorial Atlantic. Clumped carbonate thermometry of soapstone yields a formation (or equilibration) temperature of 147 ± 13 °C which, based on thermodynamic constraints, suggests that CO2(aq) concentrations of the hydrothermal fluid were at least an order of magnitude higher than in seawater. The association of magnesite with apatite in veins, magnesite with a δ13C of -3.40 ± 0.04‰, and the enrichment of CO2 in hydrothermal fluids point to magmatic degassing and melt-impregnation as the main source of CO2. Melt-rock interaction related to gas-rich alkali olivine basalt volcanism near the St. Paul's Rocks archipelago is manifested in systematic changes in peridotite compositions, notably a strong enrichment in incompatible elements with decreasing MgO/SiO2. These findings reveal a previously undocumented aspect of the geologic carbon cycle in one of the largest oceanic transform faults: Fueled by magmatism in or below the root zone of the transform fault and subsequent degassing, the fault constitutes a conduit for CO2-rich hydrothermal fluids, while carbonation of peridotite represents a vast sink for the emitted CO2.

Vestiges of impact-driven three-phase mixing in the chemistry and structure of Earth's mantle.

Highly siderophile elements (HSEs; namely Ru, Rh, Pd, Re, Os, Ir, Pt, and Au) in Earth's mantle require the addition of metals after the formation of Earth's core. Early, large collisions have the potential to deliver metals, but the details of their mixing with Earth's mantle remain unresolved. As a large projectile disrupts and penetrates Earth's mantle, a fraction of its metallic core may directly merge with Earth's core. Ensuing gravitational instabilities remove the remaining projectile's core stranded in Earth's mantle, leaving the latter deprived of HSEs. Here, we propose a framework that can efficiently retain the metallic components during large impacts. The mechanism is based on the ubiquitous presence of a partially molten region in the mantle beneath an impact-generated magma ocean, and it involves rapid three-phase flow with solid silicate, molten silicate, and liquid metal as well as long-term mixing by mantle convection. In addition, large low-shear-velocity provinces in the lower mantle may originate from compositional heterogeneities resulting from the proposed three-phase flow during high-energy collisions.

Compositional and thermal state of the lower mantle from joint 3D inversion with seismic tomography and mineral elasticity.

The compositional and thermal state of Earth's mantle provides critical constraints on the origin, evolution, and dynamics of Earth. However, the chemical composition and thermal structure of the lower mantle are still poorly understood. Particularly, the nature and origin of the two large low-shear-velocity provinces (LLSVPs) in the lowermost mantle observed from seismological studies are still debated. In this study, we inverted for the 3D chemical composition and thermal state of the lower mantle based on seismic tomography and mineral elasticity data by employing a Markov chain Monte Carlo framework. The results show a silica-enriched lower mantle with a Mg/Si ratio less than ~1.16, lower than that of the pyrolitic upper mantle (Mg/Si = 1.3). The lateral temperature distributions can be described by a Gaussian distribution with a standard deviation (SD) of 120 to 140 K at 800 to 1,600 km and the SD increases to 250 K at 2,200 km depth. However, the lateral distribution in the lowermost mantle does not follow the Gaussian distribution. We found that the velocity heterogeneities in the upper lower mantle mainly result from thermal anomalies, while those in the lowermost mantle mainly result from compositional or phase variations. The LLSVPs have higher density at the base and lower density above the depth of ~2,700 km than the ambient mantle, respectively. The LLSVPs are found to have ~500 K higher temperature, higher Bridgmanite and iron content than the ambient mantle, supporting the hypothesis that the LLSVPs may originate from an ancient basal magma ocean formed in Earth's early history.

Oceanic intraplate explosive eruptions fed directly from the mantle.

Constraining the volatile content of magmas is critical to our understanding of eruptive processes and their deep Earth cycling essential to planetary habitability [R. Dasgupta, M. M. Hirschmann, Earth Planet. Sci. Lett. 298, 1 (2010)]. Yet, much of the work thus far on magmatic volatiles has been dedicated to understanding their cycling through subduction zones. Further, studies of intraplate mafic volcanism have disproportionately focused on Hawaii [P. E. Wieser et al., Geochem. Geophys. Geosyst. 22, e2020GC009364 (2021)], making assessments of the overall role of intraplate volcanoes in the global volatile cycles a challenge. Additionally, while mafic volcanoes are the most common landform on Earth and the Solar System [C. A. Wood, J. Volcanol. Geotherm. Res. 7, 387-413 (1980)], they tend to be overlooked in favor of silicic volcanoes when it comes to their potential for explosivity. Here, we report primitive (olivine-hosted, with host Magnesium number - Mg# 78 to 88%) melt inclusion (MI) data from Fogo volcano, Cabo Verde, that suggest that oceanic intraplate silica-undersaturated explosive eruptions sample volatile-rich sources. Primitive MI (melt Mg# 70 to 71%) data suggest that these melts are oxidized (NiNiO to NiNiO+1) and very high in volatiles (up to 2 wt% CO2, 2.8 wt% H2O, 6,000 ppm S, 1,900 ppm F, and 1,100 ppm Cl) making Fogo a global endmember. Storage depths calculated from these high volatile contents also imply that magma storage at Fogo occurs at mantle depths (~20 to 30 km) and that these eruptions are fed from the mantle. Our results suggest that oceanic intraplate mafic eruptions are sustained from the mantle by high volatile concentrations inherited from their source and that deep CO2 exsolution (here up to ~800 MPa) drives their ascent and explosivity.

Carbonates and intermediate-depth seismicity: Stable and unstable shear in altered subducting plates and overlying mantle.

A model for intermediate-depth earthquakes of subduction zones is evaluated based on shear localization, shear heating, and runaway creep within thin carbonate layers in an altered downgoing oceanic plate and the overlying mantle wedge. Thermal shear instabilities in carbonate lenses add to potential mechanisms for intermediate-depth seismicity, which are based on serpentine dehydration and embrittlement of altered slabs or viscous shear instabilities in narrow fine-grained olivine shear zones. Peridotites in subducting plates and the overlying mantle wedge may be altered by reactions with CO2-bearing fluids sourced from seawater or the deep mantle, to form carbonate minerals, in addition to hydrous silicates. Effective viscosities of magnesian carbonates are higher than those for antigorite serpentine and they are markedly lower than those for H2O-saturated olivine. However, magnesian carbonates may extend to greater mantle depths than hydrous silicates at temperatures and pressures of subduction zones. Strain rates within altered downgoing mantle peridotites may be localized within carbonated layers following slab dehydration. A simple model of shear heating and temperature-sensitive creep of carbonate horizons, based on experimentally determined creep laws, predicts conditions of stable and unstable shear with strain rates up to 10/s, comparable to seismic velocities of frictional fault surfaces. Applied to intermediate-depth earthquakes of the Tonga subduction zone and the double Wadati-Benioff zone of NE Japan, this mechanism provides an alternative to the generation of earthquakes by dehydration embrittlement, beyond the stability of antigorite serpentine in subduction zones.

Pharmacological reprogramming of zebrafish lateral line supporting cells to a migratory progenitor state.

In the zebrafish lateral line, non-sensory supporting cells readily re-enter the cell cycle to generate new hair cells and supporting cells during homeostatic maintenance and following damage to hair cells. This contrasts with supporting cells from mammalian vestibular and auditory sensory epithelia which rarely re-enter the cell cycle, and hence loss of hair cells results in permanent sensory deficit. Lateral line supporting cells are derived from multipotent progenitor cells that migrate down the trunk midline as a primordium and are deposited to differentiate into a neuromast. We have found that we can revert zebrafish support cells back to a migratory progenitor state by pharmacologically altering the signaling environment to mimic that of the migratory primordium, with active Wnt signaling and repressed FGF signaling. The reverted supporting cells migrate anteriorly and posteriorly along the horizontal myoseptum and will re-epithelialize to form an increased number of neuromasts along the midline when the pharmacological agents are removed. These data demonstrate that supporting cells can be readily reprogrammed to a migratory multipotent progenitor state that can form new sensory neuromasts, which has important implications for our understanding of how the lateral line system matures and expands in fish and also suggest avenues for returning mammalian supporting cells back to a proliferative state.

Accretion of the cratonic mantle lithosphere via massive regional relamination.

Continental, orogenic, and oceanic lithospheric mantle embeds sizeable parcels of exotic cratonic lithospheric mantle (CLM) derived from distant, unrelated sources. This hints that CLM recycling into the mantle and its eventual upwelling and relamination at the base of younger plates contribute to the complex structure of the growing lithosphere. Here, we use numerical modeling to investigate the fate and survival of recycled CLM in the ambient mantle and test the viability of CLM relamination under Hadean to present-day mantle temperature conditions and its role in early lithosphere evolution. We show that the foundered CLM is partially mixed and homogenized in the ambient mantle; then, as thermal negative buoyancy vanishes, its long-lasting compositional buoyancy drives upwelling, relaminating unrelated growing lithospheric plates and contributing to differentiation under cratonic, orogenic, and oceanic regions. Parts of the CLM remain in the mantle as diffused depleted heterogeneities at multiple scales, which can survive for billions of years. Relamination is maximized for high depletion degrees and mantle temperatures compatible with the early Earth, leading to the upwelling and underplating of large volumes of foundered CLM, a process we name massive regional relamination (MRR). MRR explains the complex source, age, and depletion heterogeneities found in ancient cratonic lithospheric mantle, suggesting this may have been a key component of the construction of continents in the early Earth.

Basaltic reservoirs in the Earth's mantle transition zone.

The formation and preservation of compositional heterogeneities inside the Earth affect mantle convection patterns globally and control the long-term evolution of geochemical reservoirs. However, the distribution, nature, and size of reservoirs in the Earth's mantle are poorly constrained. Here, we invert measurements of travel times and amplitudes of seismic waves interacting with mineralogical phase transitions at 400-700-km depth to obtain global probabilistic maps of temperature and bulk composition. We find large basalt-rich pools (up to 60% basalt fraction) surrounding the Pacific Ocean, which we relate to the segregation of oceanic crust from slabs that have been subducted since the Mesozoic. Segregation of oceanic crust from initially cold and stiff slabs may be facilitated by the presence of a weak hydrated layer in the slab or by weakening upon mineralogical transition due to grain-size reduction.

The mud-dwelling clam Meretrix petechialis secretes endogenously synthesized erythromycin.

Although lacking an adaptive immune system and often living in habitats with dense and diverse bacterial populations, marine invertebrates thrive in the presence of potentially challenging microbial pathogens. However, the mechanisms underlying this resistance remain largely unexplored and promise to reveal novel strategies of microbial resistance. Here, we provide evidence that a mud-dwelling clam, Meretrix petechialis, synthesizes, stores, and secretes the antibiotic erythromycin. Liquid chromatography coupled with mass spectrometry, immunocytochemistry, fluorescence in situ hybridization, RNA interference, and enzyme-linked immunosorbent assay revealed that this potent macrolide antimicrobial, thought to be synthesized only by microorganisms, is produced by specific mucus-rich cells beneath the clam's mantle epithelium, which interfaces directly with the bacteria-rich environment. The antibacterial activity was confirmed by bacteriostatic assay. Genetic, ontogenetic, phylogenetic and genomic evidence, including genotypic segregation ratios in a family of full siblings, gene expression in clam larvae, phylogenetic tree, and synteny conservation in the related genome region further revealed that the genes responsible for erythromycin production are of animal origin. The detection of this antibiotic in another clam species showed that the production of this macrolide is not exclusive to M. petechialis and may be a common strategy among marine invertebrates. The finding of erythromycin production by a marine invertebrate offers a striking example of convergent evolution in secondary metabolite synthesis between the animal and bacterial domains. These findings open the possibility of engineering-animal tissues for the localized production of an antibacterial secondary metabolite.

Superhydrous aluminous silica phases as major water hosts in high-temperature lower mantle.

Water transported by subducted oceanic plates changes mineral and rock properties at high pressures and temperatures, affecting the dynamics and evolution of the Earth's interior. Although geochemical observations imply that water should be stored in the lower mantle, the limited amounts of water incorporation in pyrolitic lower-mantle minerals suggest that water in the lower mantle may be stored in the basaltic fragments of subducted slabs. Here, we performed multianvil experiments to investigate the stability and water solubility of aluminous stishovite and CaCl2-structured silica, referred to as poststishovite, in the SiO2-Al2O3-H2O systems at 24 to 28 GPa and 1,000 to 2,000 °C, representing the pressure-temperature conditions of cold subducting slabs to hot upwelling plumes in the top lower mantle. The results indicate that both alumina and water contents in these silica minerals increase with increasing temperature under hydrous conditions due to the strong Al3+-H+ charge coupling substitution, resulting in the storage of water up to 1.1 wt %. The increase of water solubility in these hydrous aluminous silica phases at high temperatures is opposite of that of other nominally anhydrous minerals and of the stability of the hydrous minerals. This feature prevents the releasing of water from the subducting slabs and enhances the transport water into the deep lower mantle, allowing significant amounts of water storage in the high-temperature lower mantle and circulating water between the upper mantle and the lower mantle through subduction and plume upwelling. The shallower depths of midmantle seismic scatterers than expected from the pure SiO2 stishovite-poststishovite transition pressure support this scenario.

Seismic detection of a deep mantle discontinuity within Mars by InSight.

Constraining the thermal and compositional state of the mantle is crucial for deciphering the formation and evolution of Mars. Mineral physics predicts that Mars' deep mantle is demarcated by a seismic discontinuity arising from the pressure-induced phase transformation of the mineral olivine to its higher-pressure polymorphs, making the depth of this boundary sensitive to both mantle temperature and composition. Here, we report on the seismic detection of a midmantle discontinuity using the data collected by NASA's InSight Mission to Mars that matches the expected depth and sharpness of the postolivine transition. In five teleseismic events, we observed triplicated P and S waves and constrained the depth of this discontinuity to be 1,006 [Formula: see text] 40 km by modeling the triplicated waveforms. From this depth range, we infer a mantle potential temperature of 1,605 [Formula: see text] 100 K, a result consistent with a crust that is 10 to 15 times more enriched in heat-producing elements than the underlying mantle. Our waveform fits to the data indicate a broad gradient across the boundary, implying that the Martian mantle is more enriched in iron compared to Earth. Through modeling of thermochemical evolution of Mars, we observe that only two out of the five proposed composition models are compatible with the observed boundary depth. Our geodynamic simulations suggest that the Martian mantle was relatively cold 4.5 Gyr ago (1,720 to 1,860 K) and are consistent with a present-day surface heat flow of 21 to 24 mW/m2.

Limited underthrusting of India below Tibet: 3He/4He analysis of thermal springs locates the mantle suture in continental collision.

During continent­continent collision, does the downgoing continental plate underplate far inboard of the collisional boundary or does it subduct steeply into the mantle, and how is this geometry manifested in the mantle flow field? We test conflicting models for these questions for Earth's archetypal continental collision forming the Himalaya and Tibetan Plateau. Air-corrected helium isotope data (3He/4He) from 225 geothermal springs (196 from our group, 29 from the literature) delineate a boundary separating a Himalayan domain of only crustal helium from a Tibetan domain with significant mantle helium. This 1,000-km-long boundary is located close to the Yarlung-Zangbo Suture (YZS) in southern Tibet from 80 to 92°E and is interpreted to overlie the "mantle suture" where cold underplated Indian lithosphere is juxtaposed at >80 km depth against a sub-Tibetan incipiently molten asthenospheric mantle wedge. In southeastern Tibet, the mantle suture lies 100 km south of the YZS, implying delamination of the mantle lithosphere from the Indian crust. This helium-isotopic boundary helps resolve multiple, mutually conflicting seismological interpretations. Our synthesis of the combined data locates the northern limit of Indian underplating beneath Tibet, where the Indian plate bends to steeper dips or breaks off beneath a (likely thin) asthenospheric wedge below Tibetan crust, thereby defining limited underthrusting for the Tibetan continental collision.

miR-17-92 cluster-BTG2 axis regulates B-cell receptor signaling in mantle cell lymphoma.

B-cell receptor (BCR) signaling is critically activated and stable for mantle cell lymphoma (MCL), but the underlying mechanism of the activated BCR signaling pathway is not clear. The pathogenic basis of miR-17-92 cluster remains unclear although the oncogenic microRNA (miRNA) miR-17-92 cluster is highly expressed in patients with MCL. We revealed that miR-17-92 cluster overexpression is partly dependent on SOX11 expression and chromatin acetylation of MIR17HG enhancer regions. Moreover, miR-17-92 cluster regulates not only cell proliferation but BCR signaling activation in MCL cell lines. To comprehensively identify miR-17-92 cluster target genes, we performed pulldown-seq, where target RNA of miRNA was captured using the biotinylated miRNA mimics and magnetic bead-coated streptavidin, and quantified using next-generation sequencing. The pulldown-seq identified novel miRNA target genes, including tumor suppressors such as BTG2 (miR-19b), CDKN2A (miR-17), SYNE1 (miR-20a), TET2 (miR-18, miR-19b, and miR-92a), TNFRSF10A (miR-92a), and TRAF3 (miR-17). Notably, the gene expression profile data of patients with MCL revealed that BTG2 expression was negatively associated with that of BCR signature genes, and low BTG2 expression was associated with poor overall survival. Moreover, BTG2 silencing in MCL cell lines significantly induced BCR signaling overactivation and cell proliferation. Our results suggest an oncogenic role of miR-17-92 cluster-activating BCR signaling throughout BTG2 deregulation in MCL. Furthermore, this may contribute to the prediction of the therapeutic efficacy and improved outcomes of MCL.

Letting the mantle out of the bag.

Mantle cell lymphoma is a rare disease that attracts the curiosity of clinicians and scientists due to its heterogeneous clinical behaviour, that can vary from indolent forms to the most aggressive presentations among non-Hodgkin lymphomas. The report by Eyre and colleagues describes the current treatment strategies available in most countries, and offers insights to clinicians for several intriguing difficult-to-treat scenarios. Commentary on: Eyre et al. Diagnosis and management of mantle cell lymphoma: a British Society for Haematology Guideline. Br J Haematol 2024;204:108-126.

Evaluation of clinical parameters and biomarkers in older, untreated mantle cell lymphoma patients receiving bendamustine-rituximab.

Mantle cell lymphoma (MCL) is clinically and biologically heterogeneous. While various prognostic features have been proposed, none currently impact therapy selection, particularly in older patients, for whom treatment is primarily dictated by age and comorbidities. Herein, we undertook a comprehensive comparison of clinicopathological features in a cohort of patients 60 years and older, uniformly treated with bendamustine and rituximab, with a median survival of >8 years. The strongest prognostic indicators in this cohort were a high-risk call by a simplified MCL international prognostic index (s-MIPI) (HR: 3.32, 95% CI: 1.65-6.68 compared to low risk), a high-risk call by MCL35 (HR: 10.34, 95% CI: 2.37-45.20 compared to low risk) and blastoid cytology (HR: 4.21, 95% CR: 1.92-9.22 compared to classic). Patients called high risk by both the s-MIPI and MCL35 had the most dismal prognosis (HR: 11.58, 95% CI: 4.10-32.72), while those with high risk by either had a moderate but clinically relevant prognosis (HR: 2.95, 95% CI: 1.49-5.82). A robust assay to assess proliferation, such as MCL35, along with stringent guidelines for cytological evaluation of MCL, in combination with MIPI, may be a strong path to risk-stratify older MCL patients in future clinical trials.

Conditional survival of younger patients with mantle cell lymphoma: Results from a randomized phase III trial of the European MCL Network.

During a fatal disease, patients often request updated information on their prognosis. After patients have already survived a certain time, conditional survival captures their future survival probability. We investigated conditional overall and failure-free survival in 473 younger mantle cell lymphoma (MCL) patients from a randomized phase III trial comparing immunochemotherapies R-CHOP and alternating R-CHOP/R-DHAP before autologous transplantation. Using conditional Kaplan-Meier method and Cox regression, we estimated subsequent survival of patients who had survived 1-8 years, considering MIPI, Ki-67, and treatment failure status. Starting at a lower level, R-CHOP patients only showed increasing subsequent survival as they survived longer (5-year conditional survival: 72% and 81% after surviving 1 and 7 years), while R-CHOP/R-DHAP patients had stable future survival over time (77% and 78%). The prognostic value of MIPI diminished after 3 years in R-CHOP patients but remained unchanged after R-CHOP/R-DHAP. Patients with treatment failure had markedly inferior survival compared with those in ongoing remission, regardless of the time survived. The longer patients remained in remission, the longer they would stay free of treatment failures. Our results enable personalized counselling for younger MCL patients by offering dynamic prognosis and underscore the importance of highly effective first-line treatment to improve survival.