Diffuse Large B-Cell Lymphomas: From Morphology to Genomic Profiling

Diffuse large B-cell lymphoma (DLBCL) is the most common type of non-Hodgkin lymphoma in the western world. The classification of these lymphomas has been and continues to be one of the most challenging aspects of this entity. DLBCLs are clinically and morphologically very heterogeneous diseases presenting a barrier to successfully developing adequate classification systems with significant clinical, prognostic and therapeutic relevance. Recent gene expression profiling and next-generation sequencing advances have improved our understanding of the disease. This review will present an up-to-date overview of traditional and modern classification systems in DLBLC, emphasizing newly proposed subgroups based on integrating gene expression profiling and sequencing data

Vacuolization of hematopoietic precursors: an enigma with multiple etiologies

Cytoplasmic vacuoles in precursors can be seen in a number of clinical settings, including copper deficiency, zinc toxicity, alcohol abuse, antibiotic treatment, myelodysplasia, and VEXAS syndrome. Gurnari et al asked how common VEXAS syndrome is in patients whose bone marrow aspirates show this distinctive feature, finding 2 diagnoses of VEXAS among 24 cases with vacuoles

Histone H4 acetylation by immunohistochemistry and prognosis in newly diagnosed adult acute lymphoblastic leukemia (ALL) patients

Background: Histone deacetylase (HDAC) inhibitors are a novel anti-tumor therapy. To determine whether HDAC inhibitors may be useful in the treatment of adult acute lymphoblastic leukemia (ALL), we examined the acetylation of histone H4 by immunohistochemistry in newly diagnosed ALL patients and evaluated the impact of acetylation on complete remission (CR) rate, relapse-free survival (RFS), and overall survival (OS). Methods: Patients >= 18 years of age and an available diagnostic bone marrow biopsy were evaluated. Cox proportional hazards analysis was used to identify univariate and multivariate correlates of CR, RFS, and OS. The variables histone H4 acetylation (positive or negative), white blood count, cytogenetic (CG) risk group (CALGB criteria), and age were used in multivariate analysis. Results: On multivariate analysis, histone acetylation was associated with a trend towards an improved OS (for all CG risk groups) (HR = 0.51, p = 0.09). In patients without poor risk CG, there was an impressive association between the presence of histone acetylation and an improved CR rate (OR 3.43, p = 0.035), RFS (HR 0.07, p = 0.005), and OS (HR 0.24, p = 0.007). This association remained statistically significant in multivariate analysis. Conclusions: These data provide a rationale for the design of novel regimens incorporating HDAC inhibitors in ALL

Star Formation Laws and Efficiencies across 80 Nearby Galaxies

We measure empirical relationships between the local star formation rate (SFR) and properties of the star-forming molecular gas on 1.5 kpc scales across 80 nearby galaxies. These relationships, commonly referred to as "star formation laws," aim at predicting the local SFR surface density from various combinations of molecular gas surface density, galactic orbital time, molecular cloud free-fall time, and the interstellar medium dynamical equilibrium pressure. Leveraging a multiwavelength database built for the PHANGS survey, we measure these quantities consistently across all galaxies and quantify systematic uncertainties stemming from choices of SFR calibrations and the CO-to-H$_2$ conversion factors. The star formation laws we examine show 0.3-0.4 dex of intrinsic scatter, among which the molecular Kennicutt-Schmidt relation shows a $\sim$10% larger scatter than the other three. The slope of this relation ranges $\beta\approx0.9{-}1.2$, implying that the molecular gas depletion time remains roughly constant across the environments probed in our sample. The other relations have shallower slopes ($\beta\approx0.6{-}1.0$), suggesting that the star formation efficiency (SFE) per orbital time, the SFE per free-fall time, and the pressure-to-SFR surface density ratio (i.e., the feedback yield) may vary systematically with local molecular gas and SFR surface densities. Last but not least, the shapes of the star formation laws depend sensitively on methodological choices. Different choices of SFR calibrations can introduce systematic uncertainties of at least 10-15% in the star formation law slopes and 0.15-0.25 dex in their normalization, while the CO-to-H$_2$ conversion factors can additionally produce uncertainties of 20-25% for the slope and 0.10-0.20 dex for the normalization.Comment: 10 pages main text + 2 appendices. ApJL in press. Data products available at https://www.canfar.net/storage/list/phangs/RELEASES/Sun_etal_2023 . Slides summarizing key results can be found at https://www.dropbox.com/s/5gsegexeo9n0t05/Sun_et_PHANGS_2023.pptx?dl=

The Physical Drivers and Observational Tracers of CO-to-H2 Conversion Factor Variations in Nearby Barred Galaxy Centers

The CO-to-H$_2$ conversion factor (\alpha_\rm{CO}) is central to measuring the amount and properties of molecular gas. It is known to vary with environmental conditions, and previous studies have revealed lower \alpha_\rm{CO} in the centers of some barred galaxies on kpc scales. To unveil the physical drivers of such variations, we obtained ALMA Band 3, 6, and 7 observations toward the inner 2 kpc of NGC 3627 and NGC 4321 tracing $^{12}$CO, $^{13}$CO, and C$^{18}$O lines on 100 pc scales. Our multi-line modeling and Bayesian likelihood analysis of these datasets reveal variations of molecular gas density, temperature, optical depth, and velocity dispersion, which are among the key drivers of \alpha_\rm{CO}. The central 300 pc nuclei in both galaxies show strong enhancement of temperature T_\rm{k}>100 K and density n_\rm{H_2}>10^3 cm$^{-3}$. Assuming a CO-to-H$_2$ abundance of $3\times10^{-4}$, we derive 4-15 times lower \alpha_\rm{CO} than the Galactic value across our maps, which agrees well with previous kpc-scale measurements. Combining the results with our previous work on NGC 3351, we find a strong correlation of \alpha_\rm{CO} with low-J $^{12}$CO optical depths (\tau_\rm{CO}), as well as an anti-correlation with T_\rm{k}. The \tau_\rm{CO} correlation explains most of the \alpha_\rm{CO} variation in the three galaxy centers, whereas changes in T_\rm{k} influence \alpha_\rm{CO} to second order. Overall, the observed line width and $^{12}$CO/$^{13}$CO 2-1 line ratio correlate with \tau_\rm{CO} variation in these centers, and thus they are useful observational indicators for \alpha_\rm{CO} variation. We also test current simulation-based \alpha_\rm{CO} prescriptions and find a systematic overprediction, which likely originates from the mismatch of gas conditions between our data and the simulations.Comment: Accepted for publication in ApJ; 30 pages of main text + 3 appendice

Stratifying diffuse large B-cell lymphoma patients treated with chemoimmunotherapy: GCB/non-GCB by immunohistochemistry is still a robust and feasible marker

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of aggressive lymphomas that can be classified into three molecular subtypes by gene expression profiling (GEP): GCB, ABC and unclassified. Immunohistochemistry-based cell of origin (COO) classification, as a surrogate for GEP, using three available immunohistochemical algorithms was evaluated in TMA-arranged tissue samples from 297 patients with de novo DLBCL treated by chemoimmunotherapy (R-CHOP and R-CHOP-like regimens). Additionally, the prognostic impacts of MYC, BCL2, IRF4 and BCL6 abnormalities detected by FISH, the relationship between the immunohistochemical COO classification and the immunohistochemical expression of MYC, BCL2 and pSTAT3 proteins and clinical data were evaluated. In our series, non-GCB DLBCL patients had significantly worse progression-free survival (PFS) and overall survival (OS), as calculated using the Choi, Visco-Young and Hans algorithms, indicating that any of these algorithms would be appropriate for identifying patients who require alternative therapies to R-CHOP. Whilst MYC abnormalities had no impact on clinical outcome in the non-GCB subtype, those patients with isolated MYC rearrangements and a GCB-DLBCL phenotype had worse PFS and therefore might benefit from novel treatment approaches

The genetic landscape of immune-competent and HIV lymphoma

This journal supplement is Proceedings of the 13th International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICMAOI)Open Access JournalBurkitt lymphoma (BL) and diffuse large B cell lymphoma (DLBCL) are aggressive forms of lymphoma in adults and demonstrate overlapping morphology, immunophenotype and clinical behavior. The risk of developing these tumors increases ten to hundred-fold in the setting of HIV infection. The genetic causes and the role of specific mutations, especially in the setting of HIV, are largely unknown. The decoding of the human genome and the advent of high-throughput sequencing have provided rich opportunities for the comprehensive identification of the genetic causes of cancer. In order to comprehensively identify genes that are recurrently mutated in immune-competent DLBCL and BL, we obtained a total of 92 cases of DLBCLs and 40 cases of BL. These cases were compared to a set of 5 DLBCLs and BL tumors derived from patients with HIV. The DLBCL cases were divided into a discovery set (N=34) and …link_to_OA_fulltextThe 13th International Conference on Malignancies in AIDS and Other Acquired Immunodeficiencies (ICAMAOI), Bethesda, MD., 7-8 November 2011. In Infectious Agents and Cancer, 2011, v. 7 suppl. 1, article no. O