Real world predictors of response and 24-month survival in high-grade TP53-mutated myeloid neoplasms.

Current therapies for high-grade TP53-mutated myeloid neoplasms (≥10% blasts) do not offer a meaningful survival benefit except allogeneic stem cell transplantation in the minority who achieve a complete response to first line therapy (CR1). To identify reliable pre-therapy predictors of complete response to first-line therapy (CR1) and outcomes, we assembled a cohort of 242 individuals with TP53-mutated myeloid neoplasms and ≥10% blasts with well-annotated clinical, molecular and pathology data. Key outcomes examined were CR1 & 24-month survival (OS24). In this elderly cohort (median age 68.2 years) with 74.0% receiving frontline non-intensive regimens (hypomethylating agents +/- venetoclax), the overall cohort CR1 rate was 25.6% (50/195). We additionally identified several pre-therapy factors predictive of inferior CR1 including male gender (P = 0.026), ≥2 autosomal monosomies (P < 0.001), -17/17p (P = 0.011), multi-hit TP53 allelic state (P < 0.001) and CUX1 co-alterations (P = 0.010). In univariable analysis of the entire cohort, inferior OS24 was predicated by ≥2 monosomies (P = 0.004), TP53 VAF > 25% (P = 0.002), TP53 splice junction mutations (P = 0.007) and antecedent treated myeloid neoplasm (P = 0.001). In addition, mutations/deletions in CUX1, U2AF1, EZH2, TET2, CBL, or KRAS ('EPI6' signature) predicted inferior OS24 (HR = 2.0 [1.5-2.8]; P < 0.0001). In a subgroup analysis of HMA +/-Ven treated individuals (N = 144), TP53 VAF and monosomies did not impact OS24. A risk score for HMA +/-Ven treated individuals incorporating three pre-therapy predictors including TP53 splice junction mutations, EPI6 and antecedent treated myeloid neoplasm stratified 3 prognostic distinct groups: intermediate, intermediate-poor, and poor with significantly different median (12.8, 6.0, 4.3 months) and 24-month (20.9%, 5.7%, 0.5%) survival (P < 0.0001). For the first time, in a seemingly monolithic high-risk cohort, our data identifies several baseline factors that predict response and 24-month survival.

Decoupling 1D and 2D features of 2D sp-nanoribbons-the megatom model.

The dependence of the electron energy band gap on the width of ansp-nanoribbon is investigated using a generalization of the 1D tight binding model for a chain of atoms. Within the proposed generalization, small linear atomic formations along lines perpendicular to the 2D ribbon axis are modeled as single large atoms calledmegatomswhose properties depend on the type, the size and the atomic conformation. Replacement of a 1D chain of atoms by that of the megatoms is accompanied by the incorporation of zeroth order 2D features into the 1D model approximation of the nanoribbon. We use this model to investigate the oscillating band gap of ansp-nanoribbon in terms of the ribbon's width. Results are presented for the width dependence of the energy gap of the zig-zag Si2BN nanoribbons.

Magnetism versus band-gap relationship in diluted magnetic semiconductors: megatom impurity behavior of the magnetic dopant complexes.

An analysis ofab initionumerical results obtained for the total energy of diluted magnetic semiconductors (DMSs) doped with dopant formations of various structural and spin conformations consisting of 2-4 3D transition metal (TM atoms) has revealed that a dopant formation acts as large impurity atom i.e., as amegatom, in a reverse analogy to the process of the adsorption ofsp-atoms onto metallic surfaces. As a result, thed-orbitals of the magnetic dopant formation (themegatom) become hybridized with thesp-bands of the host anions thus creating a number of impurity states which are reflected in the changes of the band gap of the DMS establishing an implicit relationship between the band gap and magnetism. Additional findings also indicate that: (i) the total magnetic momentMtot(α)and the band gapegap(α)which characterize a DMS with a dopant formation in spin conformation (α) do not vary independently from each other but instead form one composite system parameter. (ii) The per dopant-pair magnetic interactions in dopant formations consisting of more than two dopants are smaller than those obtained for an isolated dopant-pair. These are demonstrated with results obtained for GaN doped with 3D-TM dopant formations.

Codoping induced enhanced ferromagnetism in diluted magnetic semiconductors.

The experimentally observedd0-magnetism and its subsequent attribution to the presence of structural and topological defects has opened the way for engineering the magnetic properties of diluted magnetic semiconductors (DMSs) and transition metal oxides (TMOs). Doping and codoping constitute the most commonly used processes (either experimentally or theoretically) for developing and studying this type of defect-induced magnetism. The focus of the present review is to highlight the basic features of the defect magnetism which have been observed over diverse systems, while emphasizing the local, holistic and synergistic response of the host materials to their doping and investigating their role in the development of the magnetic coupling (MC) that is developed among the magnetic dopants.Ab initiocomputational results elucidate the local aspects of the MC (charge and spin transfers between dopants and their first nearest neighboring anion ligands) and their relation with holistic processes which are reflected in the band structure, and the shifts of both thed- andp-band centers of the doped material (compared to the undoped one). In view of these results the MC between the magnetic dopants is framed within the newly proposed successive spin polarization and the defect-induced defect-mediated models. The similarities found in the magnetic characteristics between the codoped DMSs/TMOs and the magnetic multilayer systems lends further support to these models which introduce new contributions to the MC that are competitive with the existing classical ones (superexchange, double exchange,s-d&p-dcouplings etc).

High temperature stability, metallic character and bonding of the Si2BN planar structure.

The family of monolayered Si2BN structures constitute a new class of 2D materials exhibiting metallic character with remarkable stability. Topologically, these structures are very similar to graphene, forming a slightly distorted honeycomb lattice generated by a union of two basic motifs with AA and AB stacking. In the present work we study in detail the structural and electronic properties of these structures in order to understand the factors which are responsible for their structural differences as well as those which are responsible for their metallic behavior and bonding. Their high temperature stability is demonstrated by the calculations of finite temperature phonon modes which show no negative contributions up to and beyond 1000 K. Presence of the negative thermal expansion coefficient, a common feature of one-atom thick 2D structures, is also seen. Comparison of the two motifs reveal the main structural differences to be the differences in their bond angles, which are affected by the third nearest neighbor interactions ofcis-transtype. On the other hand, the electronic properties of these two structures are very similar, including the charge transfers occurring between orbitals and between atoms. Their metallicity is mainly due to thepzorbitals of Si with a minor contribution from thepzorbitals of B, while the contribution from thepzorbitals of N atoms is negligible. There is almost no contributions from the Npzelectrons to the energy states near the Fermi level, and they form a band well below it. I.e., thepzelectrons of N are localized mostly at the N atoms and therefore cannot be considered as mobile electrons of thepzcloud. Moreover, we show that due to the relative positions in the energy axis of the atomic energies of thepzorbitals of B, N and Si atoms, the density of states (DOS) of Si2BN can be considered qualitatively as a combination of the DOS of planar hexagonal BN (h-BN) and hypothetically planar silicene (ph-Si). As a result, the Si2BN behaves electronically at the Fermi level as slightly perturbed ph-Si, having very similar electronic properties as silicene, but with the advantage of having kinetic stability in planar form. As for the bonding, the Si-Si bonds are covalent, while theπback donation mechanism occurs for the B-N bonding, in accordance with the B-N bonding in h-BN.

Estimation ofsp-dexchange constants revisited.

We present a new computational method for estimating thesp-dexchange constant,Jeffsp-d, applicable to transition metal doped diluted magnetic semiconductors, transition metal oxides, and 2D- and 3D- dichalcogenides. The proposed method is based on results describing the variation of the magnetic features of a doped system with the variation of its magnetization density (M). The results forJeffsp-d(M)obtained with the proposed method are compared with the corresponding results,Jeffsp-d(ΔEVBM), obtained from estimations of the spin electron orbital splitting, ΔEVBM, at the valence band maximum (VBM). The latter is estimated in two ways; either directly from plots of the band structure calculations or by calculating the energy difference between the band-centers of the spin-up and spin-down electron density of states of the doped systems. Despite the inherent drawbacks in these two estimation methods for ΔEVBM, they lead to equivalent results and the correspondingJeffsp-d(ΔEVBM)are in good agreement with theJeffsp-d(M)ones.Ab initioresults obtained for the 2D-MoS2doped with 3d-series transition metals are presented to demonstrate the validity and applicability of the proposed computational schemes for obtainingJeffsp-d. The proposed methods can be utilized as useful tools in the search of new materials for spintronics and valleytronics applications.

Goodenough-Kanamori rules applied to wurtzite crystals.

Goodenough-Kanamori (GK) criteria have provided a significant contribution to our understanding of the importance of the symmetry and the electron orbital characteristics in the development of the magnetic superexchange coupling [antiferromagnetic (AFM) or ferromagnetic (FM)] applied primarily to systems with bond angles of 180° and 90°. In the present work, we quantify and apply the GK criteria to wurtzite systems. Our approach is based on calculations of (i) the spin electron densities of the anions which are first nearest neighbors (1nn) to the magnetic dopants and, (ii) the generalized exchange integrals which are derived by investigating the electronic properties of the systems under a magnetization density constraint. We demonstrate that the magnetization constraint can be used as a probe in investigating the magnetic properties of the materials under magnetization constraints. Our results indicate that the GK criteria applied to diluted magnetic semiconductors and transition metal oxides of wurtzite structures always lead to a FM coupling between two 1nn dopants of the same type. This is justified by ab initio calculations obtained for ZnO and GaN doped with 3d-transition metal dopants.

Diagnostic utility of STAT6YE361 expression in classical Hodgkin lymphoma and related entities.

Although the distinction of classical Hodgkin lymphoma from nodular lymphocyte predominant Hodgkin lymphoma using morphology and immunostains is straightforward in most instances, occasional cases pose diagnostic challenge. We sought to determine the utility of the novel YE361 STAT6 rabbit monoclonal antibody in Hodgkin lymphoma and diagnostically challenging B- and T-cell non-Hodgkin lymphoma entities with Hodgkin-like features. Cases from seven institutions included: 57 classical Hodgkin lymphomas (31% EBV+), 34 nodular lymphocyte predominant Hodgkin lymphomas, 34 mimicking B- and T-cell non-Hodgkin lymphomas, and 7 reactive lymphoproliferations. After review of histology, STAT6YE361 immunostaining was performed. The intensity and spatial localization of immunopositivity was assessed in neoplastic cells. Additional FISH for programmed death ligand-1 (PD-L1) was performed in one patient in paired treatment-naive and relapse biopsy tissues. Two STAT6YE361 immunopositive cases were examined by whole-exome sequencing after flow sorting to assess mutations in STAT6 pathway genes. Most classical Hodgkin lymphomas showed nuclear staining for STAT6YE361 [46/57 cases (80%)] on Hodgkin cells. Staining was exclusively nuclear in a minority [12/46 (26%)], while dual nuclear and cytoplasmic localization was more common [34/46 (74%)]. In contrast, all nodular lymphocyte predominant Hodgkin lymphomas [0/34 (0%)] were negative for nuclear STAT6YE361 staining on the lymphocyte predominant cells. Within B- and T-cell non-Hodgkin lymphomas, nuclear STAT6YE361 was seen in: B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, and in primary mediastinal large B-cell lymphoma. Strong PD-L1 gene amplification was noted in the paired cHL and relapse B-cell lymphoma unclassifiable with features intermediate between diffuse large B-cell lymphoma and classical Hodgkin lymphoma, although STAT6YE361 was negative in both biopsies. Whole-exome sequencing identified mutations in B2M, XPO1, and ITPKB as well CISHP213L (in the STAT pathway) in one classical Hodgkin lymphoma patient positive for nuclear STAT6YE361 although no underlying STAT6 mutations were observed in either sample examined. STAT6YE361 nuclear staining has 100% positive predictive value and 85.7% negative predictive value in confirming or excluding classical Hodgkin lymphoma diagnosis in the distinction from nodular lymphocyte predominant Hodgkin lymphoma and other benign and malignant entities.

Data driven modeling of magnetism in dilute magnetic semiconductors: correlation between the magnetic features of diluted magnetic semiconductors and electronic properties of the constituent atoms.

We propose an efficient machine learning based approach in modeling the magnetism of diluted magnetic semiconductors (DMSs) leading to the prediction of new compounds with enhanced magnetic properties. The approach combines accurate ab initio methods with statistical tools to uncover the correlation between the magnetic features of DMSs and electronic properties of the constituent atoms to determine the underlying factors responsible for the DMS-magnetism. Taking the electronic properties of different DMS systems as descriptors to train different regression models allows us to achieve a speed up of several orders of magnitude in the search for an optimum combination of the host semiconductor and the dopants with enhanced magnetic properties. We demonstrate this by analyzing a large set of descriptors for a wide range of systems and show that only 30% of these features are more likely to contribute to this property. We also show that training regression models with the reduced set of features to predict the total magnetic moment of new candidate DMSs has reduced the mean square error by about 20% compared to the models trained using the whole set of features. Furthermore, our results indicate that the predictive power of our method can be improved even more by extending our descriptor set.

A rare case of follicular lymphoma transformed to a high-grade B-cell lymphoma in orbit.

Transformation of lymphoma is an infrequent phenomenon, and involvement of the eye as such is even uncommon. Histological transformation in patients with follicular lymphoma who were previously treated with immune-chemotherapy carry a poor outcome. Here, we illustrate such a case with aggressive histological transformation from a low-grade lymphoma.

GATA3 Immunohistochemical Staining in Hodgkin Lymphoma: Diagnostic Utility in Differentiating Classic Hodgkin Lymphoma From Nodular Lymphocyte Predominant Hodgkin Lymphoma and Other Mimicking Entities.

BACKGROUND: Classic Hodgkin lymphoma (CHL) and nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) are clinically distinct entities, with different prognostic and treatment implications. In addition, several large B-cell lymphomas and some T-cell lymphomas can mimic CHL. Differentiating these entities from CHL is crucial for ensuring appropriate therapy. GATA3 is a T-cell transcription factor involved in T-cell maturation and has been previously shown to be overexpressed in CHL cells via gene expression profiling. We investigated the utility of GATA3 immunostain in differentiating CHL from NLPHL and other mimicking entities. MATERIALS AND METHODS: We accrued 17 NLPHLs, 49 CHLs [23 nodular sclerosis (NS), 3 syncytial variants, 3 lymphocyte rich and 13 mixed cellularity types], 4 primary mediastinal large B-cell lymphomas (PMBLs), 2 Epstein-Barr virus (EBV) positive diffuse large B-cell lymphomas (DLBCLs) (EBV+LBCLs), 2 T-cell/histiocyte-rich large B-cell lymphomas (TCHRBCLs), 1 gray zone lymphoma, and 2 tissue microarrays consisting of 72 DLBCLs. One slide from each was stained with GATA3 and percent positive tumor cells and intensity of nuclear expression was semiquantitatively graded independently by 2 board certified hematopathologists. RESULTS: GATA3 was positive in 80% of CHLs. Both percent positivity and intensity of staining varied greatly. Syncytial variant of NS subtype showed the highest positivity rate (3/3; 100%), followed by NS (20/23; 87%), mixed cellularity (9/13; 70%), and lymphocyte rich (2/3; 67%). GATA3 was negative in all NLPHLs, EBV+LBCLs, TCRBCLs, and DLBCLs stained. The single gray zone lymphoma and 3/4 PMBLs were positive. CONCLUSIONS: Nuclear expression of GATA3 can be used to delineate CHL from NLPHL. GATA3 positivity effectively excludes NLPHL with 100% negative predictive value. However, as 20% of CHL can be negative for GATA3, CHL cannot be ruled out with negative GATA3. Additional findings include GATA3 positivity among PMBLs, whereas all 72 DLBCLs were negative for GATA3. This finding further highlights similarities between CHL and PMBL.

Antiferromagnetic successive superexchange interactions underlying ferromagnetic couplings in codoped diluted magnetic semiconductors.

Our recent works have revealed that the magnetic coupling among the magnetic codopants in diluted magnetic semiconductors and doped transition metal oxides has a strong local feature. This was attributed to successive spin polarizations induced by the codopants to their neighboring anion ligands. In the present work, we analyze and refine the successive spin polarization based magnetic coupling using results of ab initio calculations and assign the magnetic coupling among the magnetic codopants to a combination of superexchange and double-exchange interactions. In particular, it is shown that antiferromagnetic successive superexchange interactions can lead to a ferromagnetic coupling between two magnetic dopants mediated by a suitable codopant with the latter forming a ferromagnetic double exchange coupling with its first nearest neighbor anions which couple it with the magnetic cations. This is exemplified by ab initio results for the magnetic coupling of two Co-dopants in the presence of a mediated Cu codopant in the environment of various hosts, namely ZnO, GaN, GaP, TiO2, CdS and SnO2. Additional results for other codopant pairs in various hosts are also presented.

Universal features underlying the magnetism in diluted magnetic semiconductors.

Investigation of a diverse variety of wide band gap semiconductors and metal oxides that exhibit magnetism on substitutional doping has revealed the existence of universal features that relate the magnetic moment of the dopant to a number of physical properties inherent to the dopants and the hosts. The investigated materials consist of ZnO, GaN, GaP, TiO2, SnO2, Sn3N4, MoS2, ZnS and CdS doped with 3d-transition metal atoms. The primary physical properties contributing to magnetism include the orbital hybridization and charge distribution, the d-band filling, d-band center, crystal field splitting, electron pairing energy and electronegativity. These features specify the strength of the spin-polarization induced by the dopants on their first nearest neighboring anions which in turn specify the long range magnetic coupling among the dopants through successively induced spin polarizations (SSP) on neighboring dopants. The proposed local SSP process for the establishment of the magnetic coupling among the TM-dopants appears as a competitor to other classical processes (superexchange, double exchange, etc). Furthermore, these properties can be used as a set of descriptors suitable for developing statistical predictive theories for a much larger class of magnetic materials.

Peripheral T-cell lymphomas of follicular helper T-cell type frequently display an aberrant CD3(-/dim)CD4(+) population by flow cytometry: an important clue to the diagnosis of a Hodgkin lymphoma mimic.

Nodal follicular helper T-cell-derived lymphoproliferations (specifically the less common peripheral T-cell lymphomas of follicular type) exhibit a spectrum of histologic features that may mimic reactive hyperplasia or Hodgkin lymphoma. Even though angioimmunoblastic T-cell lymphoma and peripheral T-cell lymphoma of follicular type share a common biologic origin from follicular helper T-cells and their morphology has been well characterized, flow cytometry of peripheral T-cell lymphomas of follicular type has not been widely discussed as a tool for identifying this reactive hyperplasia/Hodgkin lymphoma mimic. We identified 10 peripheral T-cell lymphomas of follicular type with available flow cytometry data from five different institutions, including two cases with peripheral blood evaluation. For comparison, we examined flow cytometry data for 8 classical Hodgkin lymphomas (including 1 lymphocyte-rich classical Hodgkin lymphoma), 15 nodular lymphocyte predominant Hodgkin lymphomas, 15 angioimmunoblastic T-cell lymphomas, and 26 reactive nodes. Lymph node histology and flow cytometry data were reviewed, specifically for the presence of a CD3(-/dim)CD4(+) aberrant T-cell population (described in angioimmunoblastic T-cell lymphomas), besides other T-cell aberrancies. Nine of 10 (90%) peripheral T-cell lymphomas of follicular type showed a CD3(-/dim)CD4(+) T-cell population constituting 29.3% (range 7.9-62%) of all lymphocytes. Five of 10 (50%) had nodular lymphocyte predominant Hodgkin lymphoma or lymphocyte-rich classical Hodgkin lymphoma-like morphology with scattered Hodgkin-like cells that expressed CD20, CD30, CD15, and MUM1. Three cases had a nodular growth pattern and three others exhibited a perifollicular growth pattern without Hodgkin-like cells. Epstein-Barr virus was positive in 1 of 10 cases (10%). PCR analysis showed clonal T-cell receptor gamma gene rearrangement in all 10 peripheral T-cell lymphomas of follicular type. By flow cytometry, 11 of 15 (73.3%) angioimmunoblastic T-cell lymphomas showed the CD3(-/dim)CD4(+) population (mean: 19.5%, range: 3-71.8%). Using a threshold of 3% for CD3(-/dim)CD4(+) T cells, all 15 nodular lymphocyte predominant Hodgkin lymphoma controls and 8 classical Hodgkin lymphomas were negative (Mann-Whitney P=0.01, F-PTCL vs Hodgkin lymphomas), as were 25 of 26 reactive lymph nodes. The high frequency of CD3(-/dim)CD4(+) aberrant T cells is similar in angioimmunoblastic T-cell lymphomas and peripheral T-cell lymphomas of follicular type, and is a useful feature in distinguishing peripheral T-cell lymphomas of follicular type from morphologic mimics such as reactive hyperplasia or Hodgkin lymphoma.

Primary CNS T-cell Lymphomas: A Clinical, Morphologic, Immunophenotypic, and Molecular Analysis.

Primary central nervous system (CNS) lymphomas are relatively rare with the most common subtype being diffuse large B-cell lymphoma. Primary CNS T-cell lymphomas (PCNSTL) account for <5% of CNS lymphomas. We report the clinical, morphologic, immunophenotypic, and molecular characteristics of 18 PCNSTLs. Fifteen cases were classified as peripheral T-cell lymphoma, not otherwise specified, 2 of which were of γδ T-cell derivation and 1 was TCR silent; there was 1 anaplastic large cell lymphoma, ALK-positive and 2 anaplastic large cell lymphoma, ALK-negative. Median age was 58.5 years (range, 21 to 81 y), with an M:F ratio of 11:7. Imaging results showed that 15 patients had supratentorial lesions. Regardless of subtype, necrosis and perivascular cuffing of tumor cells were frequently observed (11/18 cases). CD3 was positive in all cases but 1; 10/17 were CD8-positive, and 5/17 were CD4-positive. Most cases studied had a cytotoxic phenotype with expression of TIA1 (13/15) and granzyme-B (9/13). Polymerase chain reaction analysis of T-cell receptor γ rearrangement confirmed a T-cell clone in 14 cases with adequate DNA quality. Next-generation sequencing showed somatic mutations in 36% of cases studied; 2 had >1 mutation, and none showed overlapping mutations. These included mutations in DNMT3A, KRAS, JAK3, STAT3, STAT5B, GNB1, and TET2 genes, genes implicated previously in other T-cell neoplasms. The outcome was heterogenous; 2 patients are alive without disease, 4 are alive with disease, and 6 died of disease. In conclusion, PCNSTLs are histologically and genomically heterogenous with frequent phenotypic aberrancy and a cytotoxic phenotype in most cases.