Fatal hemophagocytic lymphohistiocytosis with intravascular large B-cell lymphoma following coronavirus disease 2019 vaccination in a patient with systemic lupus erythematosus: an intertwined case.

Hemophagocytic lymphohistiocytosis (HLH) has been recognized as a rare adverse event following the coronavirus disease 2019 (COVID-19) vaccination. We report a case of neuropsychiatric symptoms and refractory HLH in a woman with systemic lupus erythematosus (SLE) after receiving her COVID-19 vaccine treated with belimumab, later found to have intravascular large B-cell lymphoma (IVLBCL) at autopsy. A 61-year-old woman with SLE was referred to our hospital because of impaired consciousness and fever. One month prior to consulting, she received her second COVID-19 vaccine dose. Afterward, her consciousness level decreased, and she developed a high fever. She tested negative for SARS-CoV-2. Neuropsychiatric SLE was suspected; therefore, glucocorticoid pulse therapy was initiated on day 1 and 8. She had thrombocytopenia, increased serum ferritin levels and hemophagocytosis. The patient was diagnosed with HLH and treated with etoposide, dexamethasone and cyclosporine. Despite treatment, the patient died on day 75; autopsy report findings suggested IVLBCL as the underlying cause of HLH. Differentiating comorbid conditions remains difficult; however, in the case of an atypical clinical presentation, other causes should be considered. Therefore, we speculate that the COVID-19 vaccination and her autoimmune condition may have expedited IVLBCL development.

TAFRO Syndrome: A Disease Requiring Immediate Medical Attention.

TAFRO syndrome was first described in 2010, standing for thrombocytopenia, anasarca, fever, reticulin fibrosis and organomegaly. Because the lymph node histopathology of TAFRO syndrome mimics idiopathic multicentric Castleman disease (iMCD), some researchers consider TAFRO syndrome to be a subtype of iMCD. However, the clinical features of TAFRO syndrome considerably differ from those of iMCD without TAFRO. The clinical features of patients with TAFRO syndrome with or without iMCD-histopathology are similar, and these patients require an accurate diagnosis and urgent treatment. Although a histological diagnosis, including a differential diagnosis, is important, lymph node involvement in patients with TAFRO syndrome is usually modest or sometimes absent. Furthermore, a bleeding tendency due to thrombocytopenia and severe anasarca hampers performing a biopsy. Nonetheless, patients with various other disorders may manifest TAFRO syndrome-like symptoms, making the differential diagnosis in borderline cases difficult. Therefore, the establishment of precise and specific biomarkers is important.

The First Reported Case of Allogenic Hematopoietic Stem Cell Transplantation for CML Blast Phase (Monocytic Lineage) in the Tyrosine Kinase Inhibitor Era.

Chronic myeloid leukemia (CML) blast phase (monocytic lineage) is extremely rare. A 39-year-old Japanese man was diagnosed with CML blast phase (monocytic lineage). T315I mutation was positive, ponatinib was initially started, and then, allogenic hematopoietic stem cell transplantation (allo-HSCT) was performed. Seven days after allo-HSCT, hyper-acute graft-versus-host disease developed, and medial temporal lobe encephalitis emerged 24 days after allo-HSCT. He was alive for over 1 year after allo-HSCT. This is the first case report of HSCT for CML blast phase (monocytic lineage) in tyrosine kinase inhibitor era. Further cases should be documented for effective treatment regimen and analysis of clinical features.

Prognostic impacts of serum levels of C-reactive protein, albumin, and total cholesterol in patients with myelodysplastic syndromes.

Various systems for predicting the prognosis of patients with myelodysplastic syndromes (MDS) have been developed. However, associations between performance status (PS) and prognosis of MDS require further investigation. To objectively assess the impact of PS on survival, we examined laboratory findings associated with PS, including serum levels of C-reactive protein (CRP), albumin (ALB), and total cholesterol (CHOL). Patients (n = 123; male 86, female 37; median age 74 yrs.) diagnosed with MDS or myelodysplastic/myeloproliferative neoplasms at Kanazawa Medical University Hospital between 2010 and 2020 were enrolled and grouped by cutoff values determined by receiver operating characteristic analysis: 0.44 mg/dL for CRP, 4.0 g/dL for ALB, and 120 mg/dL for CHOL. The median follow-up period was 17.6 months. Kaplan-Meier analysis revealed that overall survival (OS) in the high CRP, low ALB, and low CHOL groups was significantly shorter than in the low CRP, high ALB, and high CHOL groups, respectively. Multivariable analysis revealed that elevated serum CRP was an independent prognostic risk factor independent of gender, bone marrow blast percentage, and cytogenetics.

Castleman disease and TAFRO syndrome.

Although Castleman disease was first described in 1956, this disease includes various conditions, including unicentric Castleman disease with hyaline vascular histology, human herpesvirus-8 (HHV-8) related multicentric Castleman disease, idiopathic multicentric Castleman disease, and mimics of Castleman disease associated with other conditions. To date, Castleman disease remains incompletely understood due to its rareness and difficulties in clinical and pathological diagnosis. TAFRO syndrome was reported in Japan in 2010. Because lymph node histology is similar in patients with TAFRO syndrome and Castleman disease, TAFRO syndrome is described as a related disorder of Castleman disease. Clinically, however, these conditions differ markedly. Although elevated interleukin-6 (IL-6) expression is characteristic of Castleman disease, increased expression of IL-6 may occur in patients with other diseases, making elevated IL-6 unsuitable for differential diagnosis. Further understanding of these disorders requires the identification of novel disease-specific biomarkers. This review article therefore outlines the characteristics of Castleman disease and TAFRO syndrome.

DPP8 is a novel therapeutic target for multiple myeloma.

Dipeptidyl peptidases (DPPs) are proteolytic enzymes that are ideal therapeutic targets in human diseases. Indeed, DPP4 inhibitors are widely used in clinical practice as anti-diabetic agents. In this paper, we show that DPP4 inhibitors also induced cell death in multiple human myeloma cells. Among five DPP4 inhibitors, only two of them, vildagliptin and saxagliptin, exhibited apparent cytotoxic effects on myeloma cell lines, without any difference in suppression of DPP4 activity. As these two DPP4 inhibitors are known to have off-target effects against DPP8/9, we employed the specific DPP8/9 inhibitor 1G244. 1G244 demonstrated anti-myeloma effects on several cell lines and CD138+ cells from patients as well as in murine xenograft model. Through siRNA silencing approach, we further confirmed that DPP8 but not DPP9 is a key molecule in inducing cell death induced by DPP8/9 inhibition. In fact, the expression of DPP8 in CD38+ cells from myeloma patients was higher than that of healthy volunteers. DPP8/9 inhibition induced apoptosis, as evidenced by activated form of PARP, caspases-3 and was suppressed by the pan-caspase inhibitor Z-VAD-FMK. Taken together, these results indicate that DPP8 is a novel therapeutic target for myeloma treatment.

Serum soluble interleukin-2 receptor levels for screening for malignant lymphomas and differential diagnosis from other conditions.

The serum soluble interleukin 2 receptor (sIL2R) level is elevated in patients with most types of lymphoid neoplasms, and is also elevated in patients with solid tumors or reactive conditions, such as severe inflammation. To evaluate the diagnostic significance of sIL2R levels for the screening and differential diagnosis of lymphomas, data from 248 consecutive adult patients with suspected lymphoma were retrospectively analyzed in order to determine its diagnostic characteristics and the clinical parameters that affect diagnosis. In 133 patients with aggressive or indolent lymphomas or related neoplasms, the sIL2R level was higher (median: 920 U/ml, standard deviation: 7,312 U/ml) compared with that of 115 patients with other diagnoses (median: 520 U/ml, standard deviation: 727 U/ml), including solid tumors, infection, inflammation, and others. When the cutoff value of sIL2R was 1,104 U/ml, the specificity was 80%, at which point lymphoma was suspected. When the threshold levels were increased from 1,500 to 2,000 U/ml, the specificity increased from 87 to 93%, with the positive likelihood ratio increasing from 2.99 to 4.97, strongly suggesting the diagnosis of lymphoma. The receiver operating characteristic curve for prediction of lymphoma by sIL2R revealed that the area under the curve was 0.695. The curve was nearest to the left corner of the plot when the threshold was 1,946 U/ml; at this point, the sensitivity, specificity and positive likelihood ratio were 35%, 93% and 5.06, respectively. Multivariate analysis demonstrated that an age >46 years and lactate dehydrogenase level >173 U/l appeared to increase the risk of malignant lymphoma diagnosis. Although sIL2R appears to be a less specific marker for the screening of lymphomas, its detection at higher levels strongly suggests the diagnosis of lymphomas. Therefore, sIL2R may be more useful compared with any other parameter for lymphoma diagnosis, provided other false-positive conditions are taken into consideration.

Factor X heterozygous mutation in a patient with potential risk of bleeding: A case report.

RATIONALE: Factor X (FX) deficiency is a rare autosomal recessive bleeding disorder. The majority of patients carry a missense mutation in F10, and patients with bleeding disorders are either homozygous or compound heterozygous for F10. Nonsense mutations are exceptionally rare, and a heterozygous nonsense mutation is not considered to cause bleeding disorders. PATIENT CONCERNS: A 35-year-old Japanese female with an incidental hemorrhage after gynecologic polypectomy was referred to our hospital. DIAGNOSES: Following differential diagnostic workup, including cross-mixing test, congenital FX deficiency was strongly suspected. INTERVENTION: Coagulation tests and mutation analyses were conducted for the patient and her parents. OUTCOMES: Mutation analysis revealed that she carried a heterozygous nonsense mutation in F10. Pedigree analysis revealed that the mutation was inherited from her mother although there was no familial history of bleeding or hemostatic disturbance. LESSONS: Hemostatic disturbance may occur even in a patient with heterozygous F10. Because heterozygous nonsense mutation in F10 is expected to be hidden in an apparently healthy population, as observed in our patient, unexpected hemostatic disturbance may occur, particularly during the use of direct oral anticoagulant (DOAC)-targeting factor Xa for thrombotic diseases. FX activity should be evaluated before prescribing DOACs to patients.

Spontaneous Remission of Diffuse Large B Cell Lymphoma in the Stomach and the Continuation of Remission for 10 Years.

According to the literature, spontaneous remission of aggressive lymphomas is extremely rare; gastric non-Hodgkin lymphomas, such as mucosa-associated lymphoid tissue lymphomas, often regress due to Helicobacter pylori treatment or no progression, even in a watch-and-wait strategy. Although spontaneous remission of diffuse large B cell lymphomas in the stomach was very rarely reported, the follow-up periods of the cases of spontaneous remission are within 2 years and most cases are likely to relapse after the first remission. Here, we report that a diffuse large B cell lymphoma in the stomach showed spontaneous remission within 2 months after the initial diagnosis and the remission is still continuing for 10 years without any specific treatments against this aggressive lymphoma.

Hepatic Sinusoidal Obstruction Syndrome Induced by Non-transplant Chemotherapy for Non-Hodgkin Lymphoma.

Hepatic sinusoidal obstruction syndrome (SOS), a serious complication that mainly occurs after hematopoietic-stem cell transplantation (HSCT), is caused by damage to the sinusoidal endothelial cells after the obstruction of the sinusoid. Recently, hepatic SOS was reported to occur after non-HSCT chemotherapies. This report describes a patient who experienced hepatic SOS after non-HSCT chemotherapy for non-Hodgkin lymphoma. A liver biopsy showed the slight dilatation of the hepatic sinusoid, which may be indicative of hepatic SOS. Hepatic SOS should be included in the differential diagnosis of patients with severe liver injury following the administration of chemotherapy regimens that are toxic to the vascular endothelial cells.

Modeling mesothelioma utilizing human mesothelial cells reveals involvement of phospholipase-C beta 4 in YAP-active mesothelioma cell proliferation.

Mesotheliomas are frequently characterized by disruption of Hippo pathway due to deletion and/or mutation in genes, such as neurofibromin 2 ( NF2 ). Hippo disruption attenuates yes-associated protein (YAP) phosphorylation allowing YAP to translocate to the nucleus and regulate gene expression. The role of disrupted Hippo pathway in maintenance of established mesotheliomas has been extensively investigated using cell lines; however, its involvement in development of human mesothelioma has not been explored much. Here, we employed immortalized human mesothelial cells to disrupt Hippo pathway. YAP phosphorylation was reduced on NF2 knockdown and the cells exhibited altered growth in vitro , developing tumors when transplanted into nude mice. Similar results were obtained from enforced expression of wild-type or constitutively active (S127A) YAP, indicating the crucial role of activated YAP in the transformation of mesothelial cells. Gene expression analysis comparing control- and YAP-transduced immortalized human mesothelial cells revealed phospholipase-C beta 4 ( PLCB4 ) to be among the genes highly upregulated by YAP. PLCB4 was upregulated by YAP in immortalized human mesothelial cells and downregulated on YAP knockdown in Hippo-disrupted mesothelioma cell lines. PLCB4 knockdown attenuated the growth of YAP-transduced immortalized mesothelial cells and YAP-active, but not YAP-nonactive, mesothelioma cell lines. Our model system thus provides a versatile tool to investigate the mechanisms underlying mesothelioma development. We suggest that PLCB4 may be an attractive drug target for the treatment of mesothelioma.

Molecular characterization of chronic-type adult T-cell leukemia/lymphoma.

Adult T-cell leukemia/lymphoma (ATL) is a human T-cell leukemia virus type-1-induced neoplasm with four clinical subtypes: acute, lymphoma, chronic, and smoldering. Although the chronic type is regarded as indolent ATL, about half of the cases progress to acute-type ATL. The molecular pathogenesis of acute transformation in chronic-type ATL is only partially understood. In an effort to determine the molecular pathogeneses of ATL, and especially the molecular mechanism of acute transformation, oligo-array comparative genomic hybridization and comprehensive gene expression profiling were applied to 27 and 35 cases of chronic and acute type ATL, respectively. The genomic profile of the chronic type was nearly identical to that of acute-type ATL, although more genomic alterations characteristic of acute-type ATL were observed. Among the genomic alterations frequently observed in acute-type ATL, the loss of CDKN2A, which is involved in cell-cycle deregulation, was especially characteristic of acute-type ATL compared with chronic-type ATL. Furthermore, we found that genomic alteration of CD58, which is implicated in escape from the immunosurveillance mechanism, is more frequently observed in acute-type ATL than in the chronic-type. Interestingly, the chronic-type cases with cell-cycle deregulation and disruption of immunosurveillance mechanism were associated with earlier progression to acute-type ATL. These findings suggested that cell-cycle deregulation and the immune escape mechanism play important roles in acute transformation of the chronic type and indicated that these alterations are good predictive markers for chronic-type ATL.

Clonal heterogeneity of lymphoid malignancies correlates with poor prognosis.

Clonal heterogeneity in lymphoid malignancies has been recently reported in adult T-cell lymphoma/leukemia, peripheral T-cell lymphoma, not otherwise specified, and mantle cell lymphoma. Our analysis was extended to other types of lymphoma including marginal zone lymphoma, follicular lymphoma and diffuse large B-cell lymphoma. To determine the presence of clonal heterogeneity, 332 cases were examined using array comparative genomic hybridization analysis. Results showed that incidence of clonal heterogeneity varied from 25% to 69% among different types of lymphoma. Survival analysis revealed that mantle cell lymphoma and diffuse large B-cell lymphoma with clonal heterogeneity showed significantly poorer prognosis, and that clonal heterogeneity was confirmed as an independent predictor of poor prognosis for both types of lymphoma. Interestingly, 8q24.1 (MYC) gain, 9p21.3 (CDKN2A/2B) loss and 17p13 (TP53, ATP1B2, SAT2, SHBG) loss were recurrent genomic lesions among various types of lymphoma with clonal heterogeneity, suggesting at least in part that alterations of these genes may play a role in clonal heterogeneity.

Generation of mouse models of lymphoid neoplasm using retroviral gene transduction of in vitro-induced germinal center B and T cells.

Evidence is accumulating that hematologic malignancies develop following acquisition of multiple genetic changes. Despite providing many insights into the way by which given genetic changes contribute to the development of disease, the generation of animal models is often laborious. We show a simplified method that allows the retroviral transduction of genes of interest into mouse B or T cells, thus leading to the rapid generation of models of lymphoid neoplasm in mice. Specifically, germinal center B cells induced in vitro from naive mouse B cells and infected with retroviruses for Myc and Bcl2 rapidly developed a neoplasm of immunoglobulin-expressing mature B cells in transplanted mice. Likewise, T cells induced in vitro from immature hematopoietic cells and infected with retroviruses for Myc, Bcl2, and Ccnd1 rapidly developed CD4(+)CD8(-) and CD4(+)CD8(+) T cell neoplasm in transplanted mice. These findings support the use of our simplified method as a versatile tool for lymphoma research.

Comprehensive gene expression profiles of NK cell neoplasms identify vorinostat as an effective drug candidate.

NK cell neoplasms are lymphoid malignancies with an aggressive clinical course. In the present study, we analyzed gene expression profiling of NK cell neoplasms and attempted to identify important molecular pathways and new effective drugs. Pathway analysis of gene expression profiles suggested the important roles of the JAK-STAT pathway, NF-κB pathway or Wnt pathways in NK cell neoplasms. Notably, western blot analysis revealed that STAT3 was expressed and phosphorylated at a higher level in NK cell lines than in normal NK cells or other cell lines. These findings indicate the occurrence of JAK-STAT activation in NK cell neoplasms. Connectivity Map (CMAP) analysis of gene expression profiles identified candidate drugs against NK cell neoplasms. Among the drugs suggested by CMAP analysis, we focused on puromycin, phenoxybenzamine, LY294002, wortmannin, vorinostat and trichostatin A because they exhibited high enrichment scores. We added these drugs to NK cell lines and other cell lines. Among the drugs, vorinostat suppressed NK cell line proliferation at a significantly lower concentration compared to other cell lines. Suppression of the JAK-STAT pathway appeared to contribute to this effect. Vorinostat may be a good candidate for use in the therapy against NK cell neoplasms.

Clonal heterogeneity of mantle cell lymphoma revealed by array comparative genomic hybridization.

Mantle cell lymphoma (MCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) characterized by the translocation t(11;14)(q13;q32). This lymphoma exhibits a poor prognosis and remains incurable with standard chemotherapy approaches. Recently, we have shown that a majority of patients with acute-type adult T-cell leukemia/lymphoma (ATLL) have multiple subclones that were likely produced in lymph nodes. We investigated whether MCL has multiple subclones as identified in ATLL by high-resolution oligo-array comparative genomic hybridization (CGH). Eleven of 20 (55%) evaluable MCL cases had a log2 ratio imbalance, suggesting the existence of multiple subclones in MCL. Based on the proportion of every subclone relative to the main clone, we were able to speculate clonal evolution in each MCL case with multiple subclones. Our analysis gave new insights into the clonal heterogeneity quantitatively and accurately. Furthermore, genomic copy number alterations are not hierarchical events and not necessarily the initial or later events for cells to become MCL.

Recurrence of IgG4-related disease following treatment with rituximab.

A 54-year-old woman with suspected low-grade B-cell lymphoma of mucosa-associated lymphoid tissue type of the eyelids underwent rituximab-containing chemotherapy. She initially responded to the rituximab therapy, but later experienced two recurrences over a 3-year period. Biopsy specimens and a review of her previous histology revealed that she had had immunoglobulin G4-related disease at the initial presentation. Although IgG4-related disease seems to respond well to rituximab therapy, long-term follow up, including disease monitoring, is needed to evaluate disease remission.

Lineage-specific growth inhibition of NK cell lines by FOXO3 in association with Akt activation status.

FOXO3 and PRDM1 are located on 6q21, one of the most frequently deleted regions among natural killer (NK) cell neoplasms. We previously demonstrated that forced expression of each gene suppresses the proliferation of NK cell lines with the 6q deletion. In this study, the forced expression of FOXO3 or PRDM1 was performed in various cell lines to clarify these suppressive effects. Forced expression of PRDM1 suppressed the proliferation of not only NK cell lines, but also other broad lineage cell lines. On the other hand, forced expression of FOXO3 was only effective on NK cell lines. FOXO3 functions as a transcriptional factor when it is localized in nuclei. Akt is known to induce cytoplasmic localization of FOXO3 as a result of phosphorylation. Transduced FOXO3 was predominantly localized in nuclei of NK cell lines, while it was localized in the cytoplasm of all non-NK cell lines. NK cell lines showed significantly lower Akt activity compared to other lineage cell lines. The low Akt activity and nucleic localization of FOXO3 in NK cell neoplasms seemed to cause NK cell-specific suppression. These findings indicate the "functional lineage specificity" of FOXO3 and the possibility for NK cell-specific gene therapy with minimal unexpected effects.