Comparison of genomic alterations in Epstein-Barr virus-positive and Epstein-Barr virus-negative diffuse large B-cell lymphoma.

BACKGROUND: Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV-posDLBCL) is an aggressive B-cell lymphoma that often presents similar morphological and immune phenotype features to that of EBV-negative DLBCL (EBV-negDLBCL). AIMS AND METHODS: To better understand their difference in genomic landscape, we performed whole-exome sequencing (WES) of EBV-posDLBCL and EBV-negDLBCL. RESULTS: This analysis revealed a new mutational signature 17 (unknown) and signature 29 (smoking) in EBV-posDLBCL as well as a specific mutational signature 24 (associated with aflatoxin) in EBV-negDLBCL. Compared with EBV-negDLBCL, more somatic copy number alterations (CNAs) and deletions were detected in EBV-posDLBCL (p = 0.01). The most frequent CNAs specifically detected in EBV-posDLBCL were gains at 9p24.1 (PDL1 and JAK2), 8q22.2-q24.23 (DEPTOR and MYC), and 7q31.31-q32.2 (MET), which were validated in additional EBV-posDLBCL cases. Overall, 53.7% (22/41) and 62.9% (22/35) of the cases expressed PD-L1 and c-MET, respectively, in neoplastic cells, whereas only 15.4% (4/26) expressed c-MYC. Neoplastic c-MET expression was positively correlated with PD-L1 (p < 0.001) and MYC expression (p = 0.016). However, EBV-posDLBCL cases did not show any differences in overall survival between PD-L1-, c-MET-, or c-MYC-positive and -negative cases or between age-related groups. Analysis of the association between somatic mutation load and EBV status showed no difference in the distribution of tumor mutant burden between the two lymphomas (p = 0.41). Recurrent mutations in EBV-posDLBCL implicated several genes, including DCAF8L1, KLF2, and NOL9, while in EBV-negDLBCL, ANK2, BPTF, and CNIH3 were more frequently mutated. Additionally, PIM1 is the most altered gene in all the WES-detected cases. CONCLUSIONS: Our results confirm that genomic alteration differs significantly between EBV-posDLBCL and EBV-negDLBCL, and reveal new genetic alterations in EBV-posDLBCL. The positive correlation of c-MET and PD-L1/c-Myc expression may be involved in the pathogenesis of EBV-posDLBCL, which is should be explored prospectively in trials involving MET-directed therapies.

EBV+ nodal T/NK-cell lymphoma associated with clonal hematopoiesis and structural variations of the viral genome.

ABSTRACT: Epstein-Barr virus (EBV)-positive (EBV+) nodal T- and natural killer (NK)-cell lymphoma is a peripheral T-cell lymphoma (EBV+ nPTCL) that presents as a primary nodal disease with T-cell phenotype and EBV-harboring tumor cells. To date, the genetic aspect of EBV+ nPTCL has not been fully investigated. In this study, whole-exome and/or whole-genome sequencing was performed on 22 cases of EBV+ nPTCL. TET2 (68%) and DNMT3A (32%) were observed to be the most frequently mutated genes whose presence was associated with poor overall survival (P = .004). The RHOA p.Gly17Val mutation was identified in 2 patients who had TET2 and/or DNMT3A mutations. In 4 patients with TET2/DNMT3A alterations, blood cell-rich tissues (the bone marrow [BM] or spleen) were available as paired normal samples. Of 4 cases, 3 had at least 1 identical TET2/DNMT3A mutation in the BM or spleen. Additionally, the whole part of the EBV genome was sequenced and structural variations (SVs) were found frequent among the EBV genomes (63%). The most frequently identified type of SV was deletion. In 1 patient, 4 pieces of human chromosome 9, including programmed death-ligand 1 gene (PD-L1) were identified to be tandemly incorporated into the EBV genome. The 3' untranslated region of PD-L1 was truncated, causing a high-level of PD-L1 protein expression. Overall, the frequent TET2 and DNMT3A mutations in EBV+ nPTCL seem to be closely associated with clonal hematopoiesis and, together with the EBV genome deletions, may contribute to the pathogenesis of this intractable lymphoma.

Transcriptome Analysis Reveals Enhancement of Cardiogenesis-Related Signaling Pathways by S-nitroso-N-pivaloyl-D-penicillamine (SNPiP): Implications for Improved Diastolic Function and Cardiac Performance.

We previously reported a novel compound called S-nitroso-N-pivaloyl-D-penicillamine (SNPiP), which was screened from a group of nitric oxide (NO) donor compounds with a basic chemical structure of S-nitroso-N-acetylpenicillamine (SNAP), to activate the non-neuronal acetylcholine (NNA) system. SNPiP-treated mice exhibited improved cardiac output and enhanced diastolic function, without an increase in heart rate. The NNA-activating effects included increased resilience to ischemia, modulation of energy metabolism preference, and activation of angiogenesis. Here, we performed transcriptome analysis of SNPiP-treated mice ventricles to elucidate how SNPiP exerts beneficial effects on cardiac function. A time-course study (24 and 48 h after SNPiP administration) revealed that SNPiP initially induced Wnt and cGMP-protein kinase G (PKG) signaling pathways, along with upregulation of genes involved in cardiac muscle tissue development and oxytocin signaling pathway. We also observed enrichment of glycolysis-related genes in response to SNPiP treatment, resulting in a metabolic shift from oxidative phosphorylation to glycolysis, which was suggested by reduced cardiac glucose contents while maintaining ATP levels. Additionally, SNPiP significantly upregulated atrial natriuretic peptide (ANP) and sarcolipin (SLN), which play crucial roles in calcium handling and cardiac performance. These findings suggest that SNPiP may have therapeutic potential based on the pleiotropic mechanisms elucidated in this study.

Diagnostic approach for classic Hodgkin lymphoma in small samples with an emphasis on PD-L1 expression and EBV harboring in tumor cells: a brief review from morphology to biology.

Classic Hodgkin lymphoma (CHL) was first described in 1832 by Thomas Hodgkin, and is characterized by a small number of Hodgkin and Reed-Sternberg cells in a rich inflammatory background. However, even in this modern era, due to the histological and biological overlap with CHL and other B-cell malignancies, including mediastinal grey zone lymphoma and other lymphomas accompanied by "Hodgkinoid cells", their discrimination is challenging and sometimes impossible. The complexity and ambiguity of the boundaries of CHL and its related diseases make the definition of CHL unresolved. Our group has studied the significance of PD-L1 expression and infection of Epstein-Barr virus (EBV) in the diagnosis of CHL, emphasizing their pathological role, clinical significance, and high reproducibility even in daily clinical practice. In this review, we summarize the diagnostic strategy of CHL and its histological lookalikes based on neoplastic PD-L1 expression and infection of EBV, and attempt a reappraisal of the definition of CHL.

Long-term follow-up after R-High CHOP/CHASER/LEED with Auto-PBSCT in untreated mantle cell lymphoma-Final analysis of JCOG0406.

Progression-free survival after R-High CHOP/CHASER/LEED with auto-PBSCT in untreated mantle cell lymphoma in JCOG0406 study. A continuous pattern of relapse was observed.

Diagnostic Utility of STAT6 and pSTAT6 Immunohistochemistry for Distinguishing Classic Hodgkin Lymphoma and Peripheral T-Cell Lymphoma With Hodgkin and Reed-Sternberg-like Cells.

Peripheral T-cell lymphomas (PTCLs), particularly nodal lymphomas of T-follicular helper cell origin, may include Hodgkin/Reed-Sternberg (HRS)-like cells in their microenvironment. These HRS-like cells are morphologically indistinguishable from HRS cells of classic Hodgkin lymphoma (CHL). Therefore, PTCLs with HRS-like cells pose a differential diagnosis vis-à-vis CHL. A previous study reported that, in contrast to HRS cells, programmed death-ligand 1 (PD-L1) expression is rare in HRS-like cells of PTCLs and suggested that PD-L1 immunohistochemistry is useful to differentiate HRS cells and HRS-like cells. In this study, we analyzed 21 patients with PTCL with HRS-like cells and 34 patients with CHL and assessed the diagnostic utility of STAT6, pSTAT6, and pSTAT3 immunohistochemistry in distinguishing HRS cells from HRS-like cells. In addition, we also performed PD-L1 immunohistochemistry to reconfirm its utility in distinguishing the 2 diseases. Compared with HRS cells in CHLs, HRS-like cells in PTCLs showed significantly less positivity for STAT6 (9.6% vs. 70%, P <0.001), pSTAT6 (9.6% vs. 70%, P <0.001), and PD-L1 (9.6% vs. 85%, P <0.001). Thus, we reconfirmed the diagnostic utility of PD-L1 immunohistochemistry in distinguishing CHLs from PTCLs with HRS-like cells. In contrast, both HRS-like and HRS cells were highly associated with pSTAT3 expression, with no significant difference in positive cell frequency (86% vs. 91%, P =0.66). On the basis of these findings, we conclude that, in addition to PD-L1, STAT6 and pSTAT6 immunohistochemistry are helpful diagnostic tools to distinguish CHLs from PTCLs with HRS-like cells.

Clinicopathological characteristics associated with the engraftment of patient lymphoma cells in NOG mice.

Patient-derived xenograft (PDX) mouse models are useful for deepening our understanding of the biology of malignant lymphoma; however, factors associated with the success of the PDX lymphoma model are largely unknown. We retrospectively analyzed the characteristics of 66 xenotransplantations from 65 patients. In all, 43 (65%) specimens were obtained from patients aged > 60 years, and 42 (64%) specimens were obtained at diagnosis. Specimens were obtained from patients with the following diseases: diffuse large B-cell lymphoma (n = 30), intravascular large B-cell lymphoma (n = 12), follicular lymphoma (n = 8), peripheral T-cell lymphoma (n = 7), mantle cell lymphoma (n = 2), and other (n = 7). The specimens were sourced mainly from bone marrow (n = 31, 47%) and extranodal tumors (n = 13, 20%). Engraftment was successful in 33/66 (50%) xenotransplantations. The median age of patients who provided successful specimens was significantly higher than that for unsuccessful specimens (p = 0.013). Specimens with a high proportion of tumor cells in the graft and those obtained from patients with relapsed/refractory disease showed higher tendencies toward successful engraftment. Taken together, these data suggest that tumor cells with a highly malignant potential might have a high likelihood of engraftment.

Enhanced PD-L1 expression on tumor cells in primary CD30-positive cutaneous large T-cell lymphoma: a report of lymph node lesions of four cases.

Scarce data are available regarding neoplastic PD-L1 (nPD-L1, clone SP142) expression in cutaneous T-cell lymphoma. We recently documented a possible association of increased nPD-L1 expression with tumor progression to secondary nodal involvement in two cases of CD30-positive primary cutaneous large T-cell lymphoma (PC-LTCL) (Pathol Int 2020;70:804). Notably, the nodal sites exhibited classic Hodgkin lymphoma (CHL) mimicry related to both morphology and tumor microenvironment (TME), i.e., abundant PD-L1-positive tumor-associated macrophages and low-level PD-1 expression on T-cells. Immunohistochemistry highlighted distinctly different nPD-L1 positivity between the cutaneous and nodal lesions. In the present study, we aimed to validate this unique phenomenon in a larger series of four cases with FISH and targeted-capture sequencing (targeted-seq) analysis. We retrospectively identified two more cases of CD30-positive PC-LTCL with secondary nodal involvement among all patients consecutively diagnosed between 2001-2021. All cases immunohistochemically exhibited elevated nPD-L1 expression on ≥50% of lymphoma cells in nodal tumors, clearly contrasting with the scarce nPD-L1 positivity (≤1%) in cutaneous tumors. Moreover, all nodal lesions exhibited CHL-like TME, with abundant PD-L1-positive tumor-associated macrophages and low-level PD-1 expression on T cells, although the CHL-like morphology was limited in the two original cases. None showed CD274/PD-L1 copy number alteration by FISH analysis, or structural variations of PD-L1 3'-UTR by targeted-seq analysis. These findings indicated that nPD-L1 expression is linked with tumor progression and CHL-like TME in nodal involvement of PC-LTCL. Interestingly, one autopsied case exhibited heterogeneity of nPD-L1 expression at different disease sites.

The Immunology of DLBCL.

Diffuse large B-cell lymphoma (DLBCL) is an aggressive malignancy and is the most common type of malignant lymphoid neoplasm. While some DLBCLs exhibit strong cell-autonomous survival and proliferation activity, others depend on interactions with non-malignant cells for their survival and proliferation. Recent next-generation sequencing studies have linked these interactions with the molecular classification of DLBCL. For example, germinal center B-cell-like DLBCL tends to show strong associations with follicular T cells and epigenetic regulation of immune recognition molecules, whereas activated B-cell-like DLBCL shows frequent genetic aberrations affecting the class I major histocompatibility complex. Single-cell technologies have also provided detailed information about cell-cell interactions and the cell composition of the microenvironment of DLBCL. Aging-related immunological deterioration, i.e., immunosenescence, also plays an important role in DLBCL pathogenesis, especially in Epstein-Barr virus-positive DLBCL. Moreover, DLBCL in "immune-privileged sites"-where multiple immune-modulating mechanisms exist-shows unique biological features, including frequent down-regulation of immune recognition molecules and an immune-tolerogenic tumor microenvironment. These advances in understanding the immunology of DLBCL may contribute to the development of novel therapies targeting immune systems.

Fullerene derivatives as inhibitors of the SARS-CoV-2 main protease.

COVID-19 is an ongoing worldwide pandemic. Even today, there is a need for the development of effective therapeutic agents. SARS-CoV-2 is known as the causative virus of COVID-19, and its main protease is one of the enzymes essential for its growth and is considered a drug discovery target. In this study, we evaluated the inhibitory activities of a variety of fullerene derivatives, including newly synthesized derivatives, against the main protease of SARS-CoV-2. As a result, the malonic acid-type fullerene derivatives showed the strongest inhibitory activity.

Case-based similar image retrieval for weakly annotated large histopathological images of malignant lymphoma using deep metric learning.

In the present study, we propose a novel case-based similar image retrieval (SIR) method for hematoxylin and eosin (H&E) stained histopathological images of malignant lymphoma. When a whole slide image (WSI) is used as an input query, it is desirable to be able to retrieve similar cases by focusing on image patches in pathologically important regions such as tumor cells. To address this problem, we employ attention-based multiple instance learning, which enables us to focus on tumor-specific regions when the similarity between cases is computed. Moreover, we employ contrastive distance metric learning to incorporate immunohistochemical (IHC) staining patterns as useful supervised information for defining appropriate similarity between heterogeneous malignant lymphoma cases. In the experiment with 249 malignant lymphoma patients, we confirmed that the proposed method exhibited higher evaluation measures than the baseline case-based SIR methods. Furthermore, the subjective evaluation by pathologists revealed that our similarity measure using IHC staining patterns is appropriate for representing the similarity of H&E stained tissue images for malignant lymphoma.

New concepts in EBV-associated B, T, and NK cell lymphoproliferative disorders.

EBV-associated lymphoproliferative disorders (LPD) include conditions of B, T, and NK cell derivation with a wide clinicopathological spectrum ranging from indolent, self-limiting, and localized conditions to highly aggressive lymphomas. Since the 2016 World Health Organization (WHO) lymphoma classification, progress has been made in understanding the biology of the EBV-associated LPDs. The diagnostic criteria of EBV+ mucocutaneous ulcer and lymphomatoid granulomatosis have been refined, and a new category of EBV-positive polymorphic B cell LPD was introduced to encompass the full spectrum of EBV-driven B cell disorders. The differential diagnosis of these conditions is challenging. This report will present criteria to assist the pathologist in diagnosis. Within the group of EBV-associated T and NK cell lymphomas, a new provisional entity is recognized, namely, primary nodal EBV+ T or NK cell lymphoma. The EBV + T and NK cell LPDs in children have undergone major revisions. In contrast to the 2016 WHO classification, now four major distinct groups are recognized: hydroa vacciniforme (HV) LPD, severe mosquito bite allergy, chronic active EBV (CAEBV) disease, and systemic EBV-positive T cell lymphoma of childhood. Two forms of HV LPD are recognized: the classic and the systemic forms with different epidemiology, clinical presentation, and prognosis. The subclassification of PTLD, not all of which are EBV-positive, remains unaltered from the 2016 WHO classification. This review article summarizes the conclusions and the recommendations of the Clinical Advisory Committee (CAC), which are summarized in the International Consensus Classification of Mature Lymphoid Neoplasms.

Randomized phase III study of high-dose methotrexate and whole-brain radiotherapy with/without temozolomide for newly diagnosed primary CNS lymphoma: JCOG1114C.

BACKGROUND: The goal was to determine whether the addition of temozolomide (TMZ) to the standard treatment of high-dose methotrexate (HD-MTX) and whole-brain radiotherapy (WBRT) for primary central nervous system lymphoma (PCNSL) improves survival. METHODS: An open-label, randomized, phase III trial was conducted in Japan, enrolling immunocompetent patients aged 20-70 years with histologically confirmed, newly diagnosed PCNSL. After administration of HD-MTX, patients were randomly assigned to receive WBRT (30 Gy) ±â€…10 Gy boost (arm A) or WBRT ±â€…boost with concomitant and maintenance TMZ for 2 years (arm B). The primary endpoint was overall survival (OS). RESULTS: Between September 29, 2014 and October 15, 2018, 134 patients were enrolled, of whom 122 were randomly assigned and analyzed. At the planned interim analysis, 2-year OS was 86.8% (95% confidence interval [CI]: 72.5-94.0%) in arm A and 71.4% (56.0-82.2%) in arm B. The hazard ratio was 2.18 (95% CI: 0.95-4.98), with the predicted probability of showing the superiority of arm B at the final analysis estimated to be 1.3%. The study was terminated early due to futility. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status was measured in 115 tumors, and it was neither prognostic nor predictive of TMZ response. CONCLUSIONS: This study failed to demonstrate the benefit of concomitant and maintenance TMZ in newly diagnosed PCNSL.

Extranodal T- and NK-cell lymphomas.

Non-cutaneous extranodal NK/T cell lymphoproliferations constitute a heterogenous group of rare neoplasms, occurring primarily in the gastro-intestinal tract, nasal area, spleen, and liver. Their nomenclature refers to their usual clinical presentation and predilection for specific anatomic sites-i.e. extranodal NK/T-cell lymphoma, nasal-type, hepatosplenic T-cell lymphoma, primary intestinal T-cell lymphomas, indolent lymphoproliferative disorders of the gastrointestinal tract, and breast implant-associated anaplastic large cell lymphoma. Extranodal tissues may also be involved by T-cell leukemias, or other entities usually presenting as nodal diseases. Primary extranodal entities range from indolent to highly aggressive diseases. Here, we will review the clinicopathologic features of the pertinent entities including the recent advances in their molecular and genetic characterization, with an emphasis on the changes introduced in the 2022 International Consensus Classification of lymphoid neoplasms, and highlight the diagnostic criteria helpful to sort out the distinction with potential mimickers.

Classification and diagnostic evaluation of nodal T- and NK-cell lymphomas.

Nodal T- and NK-cell lymphomas are among the most frequent T-cell malignancies and most subtypes have aggressive clinical behavior. Evolving understanding of the biology and molecular characteristics of these lymphomas, as well as the development of new precision therapy approaches, underscores the importance of ongoing updates to the classification and diagnostic evaluation of this group of malignancies. Here, we discuss the classification of nodal T- and NK-cell lymphomas based on the 2022 International Consensus Classification of Mature Lymphoid Neoplasms (2022 ICC). Lymphomas of T-follicular helper cell origin are now grouped into a single entity, follicular helper T-cell lymphoma (TFH lymphoma), with three subtypes (angioimmunoblastic-type, follicular-type, and not otherwise specified), reflecting their common cellular origin and shared molecular and clinical characteristics. Classification of anaplastic large cell lymphoma (ALCL) remains essentially unchanged; DUSP22-rearranged cases are now considered a genetic subtype of ALK-negative ALCL. Primary nodal EBV-positive T-/NK-cell lymphoma is introduced as a new provisional entity; these cases were previously considered a variant of peripheral T-cell lymphoma, not otherwise specified (PTCL, NOS). PTCL, NOS remains a diagnosis of exclusion, with evolving molecular data indicating the presence of distinct subgroups, including PTCL-TBX21, PTCL-GATA3, and EBV-negative cytotoxic PTCLs. We also discuss diagnostic strategies to facilitate the 2022 ICC classification among nodal T- and NK-cell lymphomas and the distinction from nodal involvement by extranodal neoplasms.

Hodgkin Lymphoma: Biology and Differential Diagnostic Problem.

Hodgkin lymphomas (HLs) are lymphoid neoplasms that are morphologically defined as being composed of dysplastic cells, namely, Hodgkin and Reed-Sternberg cells, in a reactive inflammatory background. The biological nature of HLs has long been unclear; however, our understanding of HL-related genetics and tumor microenvironment interactions is rapidly expanding. For example, cell surface overexpression of programmed cell death 1 ligand 1 (CD274/PD-L1) is now considered a defining feature of an HL subset, and targeting such immune checkpoint molecules is a promising therapeutic option. Still, HLs comprise multiple disease subtypes, and some HL features may overlap with its morphological mimics, posing challenging diagnostic and therapeutic problems. In this review, we summarize the recent advances in understanding the biology of HLs, and discuss approaches to differentiating HL and its mimics.

An Update on the Pathology and Molecular Features of Hodgkin Lymphoma.

Hodgkin lymphomas (HLs) are lymphoid neoplasms derived from B cells and consist histologically of large neoplastic cells known as Hodgkin and Reed-Sternberg cells and abundant reactive bystander cells. HLs include two main types, classic HL (CHL) and nodular lymphocyte predominant HL (NLPHL). Recent molecular analyses have revealed that an immune evasion mechanism, particularly the PD-1/PD-L1 pathway, plays a key role in the development of CHL. Other highlighted key pathways in CHL are NF-κB and JAK/STAT. These advances have dramatically changed the treatment for CHL, particularly relapsed/refractory CHL. For example, PD-1 inhibitors are now widely used in relapsed/refractory CHL. Compared with CHL, NLPHL is more characterized by preserved B cell features. Overlapping morphological and molecular features between NLPHL and T-cell/histiocyte-rich large B-cell lymphoma (THRLBCL) have been reported, and biological continuity between these two entities has been highlighted. Some THRLBCLs are considered to represent progression from NLPHLs. With considerable new understanding becoming available from molecular studies in HLs, therapies and classification of HLs are continually evolving. This paper offers a summary of and update on the pathological and molecular features of HLs for a better understanding of the diseases.

PD-L1-expressing extranodal diffuse large B-cell lymphoma, NOS with and without PD-L1 3'-UTR structural variations.

Immune evasion mediated by PD-L1 plays an important role in the development of B-cell malignancies. However, PD-L1 expression is infrequently observed in tumor cells of extranodal diffuse large B-cell lymphoma, not otherwise specified (DLBCL, NOS). Other than copy number alterations, PD-L1 is aberrantly upregulated by structural variations in the 3'-UTR of PD-L1. We report four cases with PD-L1 expression on tumor cells, including two with structural variations in the 3'-UTR of PD-L1 and two without. Our report demonstrates the presence of a small number of "immune evasion-type" extranodal DLBCL, NOS cases.

Prognostic value of the Kyoto Prognostic Index in higher-risk diffuse large B-cell lymphomas treated by upfront autologous stem cell transplantation in JCOG0908 trial.

BACKGROUND: There is currently no standard prognostic model optimized for the patients with diffuse large B-cell lymphoma (DLBCL) treated with upfront intensive immunochemotherapy including autologous stem cell transplantation (ASCT). The Kyoto Prognostic Index (KPI) has been proposed as a novel prognostic model for DLBCL, which can accurately identify especially high-risk patients. In this study, we investigated the prognostic value of the KPI in JCOG0908 trial in which higher-risk DLBCL patients defined by the conventional International Prognostic Index (IPI) were treated with upfront high dose therapy followed by ASCT. METHODS: Fifty-eight patients with DLBCL, not otherwise specified, enrolled in JCOG0908 and confirmed by the central pathological review were analyzed. The Kaplan-Meier method was used to estimate the probabilities of overall survival (OS) and progression-free survival (PFS). We compared the discrimination ability of the KPI with that of the IPI. RESULTS: According to KPI, 3-year OS and PFS rates were 86.7% and 76.7% in low-intermediate, 73.3% and 60.0% in high-intermediate, and 61.5% and 46.2% in high-risk group. According to IPI, 3-year OS and PFS rates were 75.0% and 50.0% in low-intermediate, 82.9% and 74.3% in high-intermediate, and 63.6% and 54.5% in high-risk group. The concordance-indices of KPI and IPI were 0.642 and 0.580 for OS and 0.606 and 0.606 for PFS. CONCLUSIONS: The KPI may be a suitable predictor of outcome than the IPI for patients with higher-risk DLBCL treated with upfront intensive immunochemotherapy including ASCT.

Synthesis and evaluation of tofacitinib analogs designed to mitigate metabolic activation.

Tofacitinib (TFT), a JAK inhibitor used for the treatment of rheumatoid arthritis and other diseases, is associated with severe liver injury that is believed to be caused by its reactive aldehyde or epoxide metabolites. In this study, we synthesized six tofacitinib analogs designed to avoid the formation of reactive metabolites and evaluated their JAK3 inhibitory activity, metabolic stability, CYP3A time-dependent inhibition, and cytotoxicity. Our data indicated that purine analog 3, which showed little inhibition of CYP3A and cytotoxicity and inhibited JAK3 in the nanomolar range, could be a safer drug candidate than TFT. In addition, the results of the bioactivation study using TFT and its analogs suggest that the epoxide metabolite might contribute to TFT-induced CYP3A4 mechanism-based inhibition and hepatic toxicity.