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Methotrexate-associated lymphoproliferative disorders (MTX-LPDs) with diffuse large B-cell lymphoma (DLBCL) pathology present with high rates of spontaneous regression after methotrexate (MTX) termination, especially in Epstein-Barr virus-encoded RNA (EBER)-positive cases. DLBCL with adrenal involvement is known for an extremely dismal prognosis. However, the prognosis of adrenal DLBCL in the context of MTX-LPD is unknown. We herein report two EBER-positive adrenal DLBCL MTX-LPD patients who achieved long-term remissions of 22 and 40 months with MTX termination alone. Both patients are doing well with no relapse at the time of reporting. Unlike adrenal DLBCL in general, adrenal involvement may not be a poor prognostic factor when restricted to DLBCL MTX-LPDs.

Chemotherapy for hemodialysis (HD) patients is a challenging situation because HD patients are generally frail, and the pharmacokinetics and pharmacodynamics of most chemotherapeutics in HD patients are unknown. We report a classical Hodgkin lymphoma (cHL) patient successfully treated with 34 courses of brentuximab vedotin (BV) monotherapy, of which 30 courses were carried out during HD. Although grade 2 peripheral sensory neuropathy and one occasion of febrile neutropenia were observed, treatment was well-tolerated overall and effective. This is the first report of successful BV administration in a cHL patient on HD, and also the first to report efficacy and safety of extended courses of BV in an HD patient. Treatment options for cHL in the HD patient are limited, and extended courses of BV monotherapy may be an optimal treatment approach for some patients.

The Wnt/β-catenin signaling pathway plays a key role in development and carcinogenesis. Although some target genes of this signaling have been identified in various tissues and neoplasms, the comprehensive understanding of the target genes and their roles in the development of human cancer, including hepatoma and colorectal cancer remain to be fully elucidated. In this study, we searched for genes regulated by the Wnt signaling in liver cancer using HuH-7 hepatoma cells. A comparison of the expression profiles between cells expressing an active form of mutant β-catenin and cells expressing enhanced green fluorescent protein (EGFP) identified seven genes upregulated by the mutant β-catenin gene (CTNNB1). Among the seven genes, we focused in this study on ODAM, odontogenic, ameloblast associated, as a novel target gene. Interestingly, its expression was frequently upregulated in hepatocellular carcinoma, colorectal adenocarcinoma, and hepatoblastoma. We additionally identified a distant enhancer region that was associated with the β-catenin/TCF7L2 complex. Further analyses revealed that ODAM plays an important role in the regulation of the cell cycle, DNA synthesis, and cell proliferation. These data may be useful for clarification of the main molecular mechanism(s) underlying these cancers.

Previous studies have shown that HIV-infected individuals were less susceptible to chronic gastritis and Helicobacter pylori infection. Th1 and Th17 cells are important components of the immune res...

Langerhans cell histiocytosis (LCH) is a rare disease primarily occurring in children, and commonly involves the bone and skin; gastrointestinal tract involvement is notably rare. The incidence and significance of gastrointestinal lesions in adult LCH are unclear; thus, we aimed to investigate adult Japanese cases of LCH and clarify the features of gastrointestinal involvement. We gathered clinical information on 43 Japanese cases of adult LCH and analyzed patient backgrounds, affected organs, features of the gastrointestinal lesions, and the clinical courses. Thirteen patients underwent endoscopic examinations: an upper gastrointestinal endoscopy alone in 5, lower gastrointestinal endoscopy alone in 3, and both in 5 patients. A gastric lesion (one case), colonic lesion (one case), and both gastric and rectal lesions (one case) were detected. The three cases of gastrointestinal involvement also exhibited nongastrointestinal multisystem LCH lesions and showed no gastrointestinal symptoms or increased uptake on positron emission tomography. Endoscopy revealed small erosions without specific features; histological examinations were required for diagnosis. These three cases were treated with chemotherapy, comprising vinblastine/prednisolone, methotrexate, and daily 6-mercaptopurine, for 36 weeks; in two cases, the clinical condition remained stable for several years post-treatment. One case showed recurrence 1 year 7 months after treatment, and chemotherapy was re-administered. No case with single-system disease exhibited gastrointestinal involvement. Although gastrointestinal LCH lesions are rare, they were more common than expected in our cases of multisystem LCH. However, these lesions were relatively small and did not affect the patients’ clinical courses.

Nivolumab, an antibody against human programmed cell death 1 (PD-1), enhances pre-existing immune responses and has antitumor activity. However, it may also cause undesirable immune-related adverse events (irAEs), such as anti-PD-1-related colitis. In addition, Nivolumab can worsen pre-existing autoimmune diseases. Ulcerative colitis (UC) is a chronic inflammatory disease of the colon. Its exact cause is unknown, but it may involve the dysregulation of the mucosal immune response. Thus, it is of great interest whether nivolumab can affect UC activity. This is the first report of a patient with epipharyngeal carcinoma and ulcerative colitis who was confirmed to have been safely treated with nivolumab based on autopsy findings.

Clinicopathological parameters derived from initial transurethral resection of bladder tumor (TUR-Bt) have limitations in predicting tumor progression in bladder cancer. Reduced folate carrier 1 (RFC1) and equilibrative nucleoside transporter 1 (ENT1) are solute carrier (SLC) transporters supporting cellular uptake of endogenous bioactive substances and anti-cancer drugs. The aim of this study was to elucidate the role of SLC transporters in bladder cancer and investigate the potential of RFC1 and ENT1 expression as immunohistochemical markers for high-grade malignancy. We compared T-stage with the immunohistochemical expression of RFC1 and ENT1 and other clinicopathological parameters; moreover, we also used multiple logistic regression model to assess relative contributions for T-stage in bladder cancer (n=130). Concurrently, 57 TUR-Bt-derived imprint cytological samples were stained to evaluate the implication of cytological analysis. Elevated expression levels of RFC1 and ENT1 were significantly correlated with higher T-stage (p < .0001) and efficiently predicted tumor progression, compared with other clinicopathological parameters (RFC1, p = .0325; ENT1, p = .0171). Independent variables of optimal model for predicting T-stage were gender, age, histological grade, expression levels of RFC1 and ENT1. Cytological analysis was consistent with immunostained-tissue data. We reveal RFC1 and ENT1 as potential immunohistocytochemical markers for high-grade malignancy in bladder cancer.

Gene editing using engineered nucleases frequently produces on- and off-target indels in hematopoietic stem cells (HSCs). Gene-edited HSC cultures thus contain genetically heterogenous populations, the majority of which either do not carry the desired edit or harbor unwanted mutations. In consequence, transplanting edited HSCs carries the risks of suboptimal efficiency and of unwanted mutations in the graft. Here, we present an approach for expanding gene-edited HSCs at clonal density, allowing for genetic profiling of individual clones before transplantation. We achieved this by developing a defined, polymer-based expansion system and identifying long-term expanding clones within the CD201+CD150+CD48-c-Kit+Sca-1+Lin- population of pre-cultured HSCs. Using the Prkdcscid immunodeficiency model, we demonstrate that we can expand and profile edited HSC clones to check for desired and unintended modifications. Transplantation of Prkdc-corrected HSCs rescued the immunodeficient phenotype. Our ex vivo-manipulation platform establishes a novel paradigm to control genetic heterogeneity in HSC gene editing and therapy.

People living with HIV (PLWH) face greater risks of developing non-AIDS-defining cancers (NADCs) than the general population; however, the underlying mechanisms remain elusive. The tumor microenvironment plays a significant role in the carcinogenesis of colorectal cancer (CRC), an NADC. We studied this carcinogenesis in PLWH by determining inflammatory phenotypes and assessing PD-1/PD-L1 expression in premalignant CRC stages of colon adenomas in HIV-positive and HIV-negative patients.We obtained polyp specimens from 22 HIV-positive and 61 HIV-negative participants treated with colonoscopy and polyp excision. We analyzed adenomas from 33 HIV-positive and 99 HIV-negative patients by immunohistochemistry using anti-CD4, anti-CD8, anti-FoxP3, and anti-CD163 antibodies. Additionally, we analyzed the expression levels of immune checkpoint proteins. We also evaluated the correlation between cell infiltration and blood cell counts.HIV-positive participants had fewer infiltrating CD4Immune surveillance dysfunction owing to decreased CD4

Clonal hematopoiesis of indeterminate potential (CHIP) is an age-associated phenomenon characterized by clonal expansion of blood cells harboring somatic mutations in hematopoietic genes, including DNMT3A, TET2, and ASXL1. Clinical evidence suggests that CHIP is highly prevalent and associated with poor prognosis in solid-tumor patients. However, whether blood cells with CHIP mutations play a causal role in promoting the development of solid tumors remained unclear. Using conditional knock-in mice that express CHIP-associated mutant Asxl1 (Asxl1-MT), we showed that expression of Asxl1-MT in T cells, but not in myeloid cells, promoted solid-tumor progression in syngeneic transplantation models. We also demonstrated that Asxl1-MT-expressing blood cells accelerated the development of spontaneous mammary tumors induced by MMTV-PyMT. Intratumor analysis of the mammary tumors revealed the reduced T-cell infiltration at tumor sites and programmed death receptor-1 (PD-1) upregulation in CD8

This investigator-initiated, phase 2, single-arm trial primarily assessed the efficacy of G47∆, a triple-mutated, third-generation oncolytic herpes simplex virus type 1, in 19 adult patients with residual or recurrent, supratentorial glioblastoma after radiation therapy and temozolomide (UMIN-CTR Clinical Trial Registry UMIN000015995). G47Δ was administered intratumorally and repeatedly for up to six doses. The primary endpoint of 1-yr survival rate after G47∆ initiation was 84.2% (95% confidence interval, 60.4–96.6; 16 of 19). The prespecified endpoint was met and the trial was terminated early. Regarding secondary endpoints, the median overall survival was 20.2 (16.8–23.6) months after G47∆ initiation and 28.8 (20.1–37.5) months from the initial surgery. The most common G47∆-related adverse event was fever (17 of 19) followed by vomiting, nausea, lymphocytopenia and leukopenia. On magnetic resonance imaging, enlargement of and contrast-enhancement clearing within the target lesion repeatedly occurred after each G47∆ administration, which was characteristic to this therapy. Thus, the best overall response in 2 yr was partial response in one patient and stable disease in 18 patients. Biopsies revealed increasing numbers of tumor-infiltrating CD4+/CD8+ lymphocytes and persistent low numbers of Foxp3+ cells. This study showed a survival benefit and good safety profile, which led to the approval of G47∆ as the first oncolytic virus product in Japan.

Other iatrogenic immunodeficiency-associated lymphoproliferative disorders (OIIA-LPDs) occur in patients receiving immunosuppressive drugs for autoimmune diseases; however, their clinicopathological and genetic features remain unknown. In the present study, we analysed 67 patients with OIIA-LPDs, including 36 with diffuse large B-cell lymphoma (DLBCL)-type and 19 with Hodgkin lymphoma (HL)-type. After discontinuation of immunosuppressive drugs, regression without relapse was achieved in 22 of 58 patients. Spontaneous regression was associated with Epstein-Barr virus positivity in DLBCL-type (P = 0·013). The 2-year overall survival and progression-free survival (PFS) at a median follow-up of 32·4 months were 92·7% and 72·1% respectively. Furthermore, a significant difference in the 2-year PFS was seen between patients with DLBCL-type and HL-type OIIA-LPDs (81·0% vs. 40·9% respectively, P = 0·021). In targeted sequencing of 47 genes in tumour-derived DNA from 20 DLBCL-type OIIA-LPD samples, histone-lysine N-methyltransferase 2D (KMT2D; eight, 40%) and tumour necrosis factor receptor superfamily member 14 (TNFRSF14; six, 30%) were the most frequently mutated genes. TNF alpha-induced protein 3 (TNFAIP3) mutations were present in four patients (20%) with DLBCL-type OIIA-LPD. Cases with DLBCL-type OIIA-LPD harbouring TNFAIP3 mutations had shorter PFS and required early initiation of first chemotherapy. There were no significant factors for spontaneous regression or response rates according to the presence of mutations. Overall, OIIA-LPDs, especially DLBCL-types, showed favourable prognoses.

Myelofibrosis (MF) can occur due to a wide variety of causes including malignant lymphoma. We report a case of splenic marginal zone lymphoma complicated by MF mimicking primary myelofibrosis (PMF). The JAK2, CALR and MPL mutations are detected in more than 90% of PMF cases, and when detected, the diagnosis of PMF is usually straight forward. Mutational analysis should be done in all cases of MF, and in triple-negative cases, an exhaustive investigation of other causes of MF should be carried out before a diagnosis of triple-negative PMF is rendered.

The isovalent-substituted iron pnictide compound SrFe$_{2}$(As$_{1-x}$P$_{x}$)$_{2}$ exhibits multiple evidence for nodal superconductivity via various experimental probes, such as the penetration depth, nuclear magnetic resonance and specific heat measurements. The direct identification of the nodal superconducting (SC) gap structure is challenging, partly because the presence of nodes is not protected by symmetry but instead caused by an accidental sign change of the order parameter, and also because of the three-dimensionality of the electronic structure. We have studied the SC gaps of SrFe$_{2}$(As$_{0.65}$P$_{0.35}$)$_{2}$ in three-dimensional momentum space by synchrotron and laser-based angle-resolved photoemission spectroscopy. The three hole Fermi surfaces (FSs) at the zone center have SC gaps with different magnitudes, whereas the SC gaps of the electron FSs at the zone corner are almost isotropic and $k_{z}$-independent. We propose that the SC gap of the outer hole FS changes sign around the Z-X [($0, 0, 2\pi$)-($\pi,\pi, 2\pi$)] direction., Comment: This is a pre-print of an article published in Scientific Reports. The final authenticated version is available online at: https://doi.org/10.1038/s41598-019-52887-y

The prognosis of advanced pancreatic adenocarcinoma is still extremely poor. This study sought to determine the efficacy of, and immunological response to, peptide vaccination therapy in patients with this disease. In this multicenter randomized phase II study, patients with advanced pancreatic adenocarcinoma after gemcitabine and/or tegafur/gimeracil/oteracil were randomly assigned to 3 groups that each received a 2‐step treatment course. In Step 1, the groups received treatments of: (i) survivin 2B peptide (SVN‐2B) plus interferon‐β (IFNβ); (ii) SVN‐2B only; or (iii) placebo until the patients show progression. In Step 2, all patients who consented to participate received 4 treatments with SVN‐2B plus IFNβ. The primary endpoint was progression‐free survival (PFS) after initiation of Step 1 treatment. Secondary endpoints included immunological effects assessed by analysis of PBMCs after Step 1. Eighty‐three patients were randomly assigned to receive SVN‐2B plus IFNβ (n = 30), SVN‐2B (n = 34), or placebo (n = 19). No significant improvement in PFS was observed. Survivin 2B‐specific CTLs were found to be increased in the SVN‐2B plus IFNβ group by tetramer assay. Among patients who participated in Step 2, those who had received SVN‐2B plus IFNβ in Step 1 showed better overall survival compared with those who had received placebo in Step 1. Patients vaccinated with SVN‐2B plus IFNβ did not have improved PFS, but showed significant immunological reaction after vaccination. Subgroup analysis suggested that a longer SVN‐2B plus IFNβ vaccination protocol might confer survival benefit. (Clinical trial registration number: UMIN 000012146).

Oncolytic virotherapies have emerged as new modalities for cancer treatment. We previously reported that coxsackievirus B3 (CVB3) is a novel oncolytic virus (OV) with a strong ability to lyse human non-small cell lung cancer cells; however, its non-specific toxicity against normal cells remains to be resolved. To improve its safety profile, microRNA target sequences complementary to miR-34a/c, which is expressed preferentially in normal cells, were inserted into the 5′ UTR or 3′ UTR of the CVB3 genome. In the presence of miR-34a/c, the gene-modified CVB3 could not replicate in normal cells. We also found that the pathogenicity of CVB3 was reduced to a greater extent by targeting miR-34a than miR-34c; in addition, it was more effective to insert the target sequences into the 3′ UTR rather than the 5′ UTR of the viral genome. Ultimately, we developed a double-miR-34a targeting virus (53a-CVB) by inserting miR-34a targets in both the 5′ UTR and 3′ UTR of the virus. 53a-CVB was minimally toxic to cells in normal tissue, but maintained nearly its full oncolytic activity in mice xenografted with human lung cancer. 53a-CVB is the first miR-34-regulated OV and represents a promising platform for the development of safe and effective anti-cancer therapies., Graphical Abstract

Viral infection induces potent cellular immunity and activated intracellular signaling, which may dictate the driver events involved in immune escape and clonal selection of virus-associated cancers, including Epstein-Barr virus (EBV)-positive lymphomas. Here, we thoroughly interrogated PD-L1/PD-L2-involving somatic aberrations in 384 samples from various lymphoma subtypes using high-throughput sequencing, particularly focusing on virus-associated lymphomas. A high frequency of PD-L1/PD-L2-involving genetic aberrations was observed in EBV-positive lymphomas [33 (22%) of 148 cases], including extranodal NK/T-cell lymphoma (ENKTL, 23%), aggressive NK-cell leukemia (57%), systemic EBV-positive T-cell lymphoproliferative disorder (17%) as well as EBV-positive diffuse large B-cell lymphoma (DLBCL, 19%) and peripheral T-cell lymphoma-not otherwise specified (15%). Predominantly causing a truncation of the 3′-untranslated region, these alterations represented the most prevalent somatic lesions in ENKTL. By contrast, the frequency was much lower in EBV-negative lymphomas regardless of histology type [12 (5%) of 236 cases]. Besides PD-L1/PD-L2 alterations, EBV-positive DLBCL exhibited a genetic profile distinct from EBV-negative one, characterized by frequent TET2 and DNMT3A mutations and the paucity of CD79B, MYD88, CDKN2A, and FAS alterations. Our findings illustrate unique genetic features of EBV-associated lymphomas, also suggesting a potential role of detecting PD-L1/PD-L2-involving lesions for these lymphomas to be effectively targeted by immune checkpoint blockade.

Although classic Hodgkin's lymphoma (CHL) sometimes develops after treatment for multiple myeloma (MM), simultaneous diagnosis of both malignancies is extremely rare without previous treatment history. Here we describe a case of a 54-year-old female who complained of left cervical lymphadenopathy. Biopsy specimen from the left cervical lymph node revealed mixed-cellularity CHL. Bone marrow aspirate comprised 10.3% plasma cells. She was diagnosed with MM due to involved: uninvolved serum free light chain ratio of100. She achieved complete response for CHL after 4 cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapy along with 30 Gy of involved-field radiotherapy. Three years later, bortezomib, lenalidomide, and dexamethasone (VRd-lite) therapy was initiated for MM. Severe neutropenia during her 1st cycle prompted a dosage reduction of lenalidomide and bortezomib. Partial response was achieved after 4 cycles of VRd-lite followed by high-dose melphalan/autologous stem cell transplantation. No severe adverse events were recorded. This was followed by 4 cycles of carfilzomib, lenalidomide, and dexamethasone therapy, which resulted in complete remission. As the number of elderly people increases, multiple myeloma patients with previous history of other malignancies would increase. Our case has shown that VRd-lite therapy may be suitable for those patients.

We generated dual-antigen receptor (DR) T cells from induced pluripotent stem cells (iPSCs) to mitigate tumor antigen escape. These cells were engineered to express a chimeric antigen receptor (CAR) for the antigen cell surface latent membrane protein 1 (LMP1; LMP1-CAR) and a T cell receptor directed to cell surface latent membrane protein 2 (LMP2), in association with human leucocyte antigen A24, to treat therapy-refractory Epstein-Barr virus-associated lymphomas. We introduced LMP1-CAR into iPSCs derived from LMP2-specific cytotoxic T lymphocytes (CTLs) to generate rejuvenated CTLs (rejTs) active against LMP1 and LMP2, or DRrejTs. All DRrejT-treated mice survived >100 days. Furthermore, DRrejTs rejected follow-up inocula of lymphoma cells, demonstrating that DRrejTs persisted long-term. We also demonstrated that DRrejTs targeting CD19 and LMP2 antigens exhibited a robust tumor suppressive effect and conferred a clear survival advantage. Co-operative antitumor effect and in vivo persistence, with unlimited availability of DRrejT therapy, will provide powerful and sustainable T cell immunotherapy.

Myelodysplastic syndrome (MDS) is a clonal disorder of hematopoietic stem cells (HSCs), characterized by ineffective hematopoiesis and frequent progression to leukemia. It has long remained unresolved how MDS cells, which are less proliferative, inhibit normal hematopoiesis and eventually dominate the bone marrow space. Despite several studies implicating mesenchymal stromal or stem cells (MSCs), a principal component of the HSC niche, in the inhibition of normal hematopoiesis, the molecular mechanisms underlying this process remain unclear. Here, we demonstrate that both human and mouse MDS cells perturb bone metabolism by suppressing the osteolineage differentiation of MSCs, which impairs the ability of MSCs to support normal HSCs. Enforced MSC differentiation rescues the suppressed normal hematopoiesis in both in vivo and in vitro MDS models. Intriguingly, the suppression effect is reversible and mediated by extracellular vesicles (EVs) derived from MDS cells. These findings shed light on the novel MDS EV-MSC axis in ineffective hematopoiesis.

Background Multiple myeloma (MM) is an incurable disease. The acquisition of resistance to drugs, including immunomodulatory drugs (IMiDs), has a negative effect on its prognosis. Cereblon (CRBN) is a key mediator of the bioactivities of IMiDs such as lenalidomide. Moreover, genetic alteration of CRBN is frequently detected in IMiD-resistant patients and is considered to contribute to IMiD resistance. Thus, overcoming resistance to drugs, including IMiDs, is expected to improve clinical outcomes. Here, we examined potential mechanisms of a histone deacetylase (HDAC) inhibitor and Akt inhibitor in relapsed/refractory MM patients. Methods We established lenalidomide-resistant cells by knocking down CRBN with RNAi-mediated downregulation or knocking out CRBN using CRISPR-Cas9 in MM cells. Additionally, we derived multi-drug (bortezomib, doxorubicin, or dexamethasone)-resistant cell lines and primary cells from relapsed/refractory MM patients. The effects of HDAC and Akt inhibitors on these drug-resistant MM cells were then observed with a particular focus on whether HDAC inhibitors enhance immunotherapy efficacy. We also investigated the effect of lenalidomide on CRBN-deficient cells. Results The HDAC inhibitor suppressed the growth of drug-resistant MM cell lines and enhanced the antibody-dependent cellular cytotoxicity (ADCC) of therapeutic antibodies by upregulating natural killer group 2D (NKG2D) ligands in MM cells. CRBN-deficient cells showed lenalidomide-induced upregulation of phosphorylated glycogen synthase kinase-3 (p-GSK-3) and c-Myc phosphorylation. Moreover, HDAC and Akt inhibitors downregulated c-Myc by blocking GSK-3 phosphorylation. HDAC and Akt inhibitors also exhibited synergistic cytotoxic and c-Myc-suppressive effects. The dual HDAC and PI3K inhibitor, CUDC-907, exhibited cytotoxic and immunotherapy-enhancing effects in MM cells, including multi-drug-resistant lines and primary cells from lenalidomide-resistant patients. Conclusions The combination of an HDAC and an Akt inhibitor represents a promising approach for the treatment of relapsed/refractory MM.

Previous studies have shown that HIV-infected individuals were less susceptible to chronic gastritis and

Primary effusion-based lymphoma (EBL) presents as a malignant effusion in a body cavity. The clinicopathologic features and prognosis of primary human herpesvirus 8 (HHV8)–negative EBL remain unclear. We therefore conducted a retrospective study of 95 patients with EBL, regardless of HHV8 status, in Japan. Of 69 patients with EBL tested for HHV8, a total of 64 were negative. The median age of patients with primary HHV8-negative EBL at diagnosis was 77 years (range, 57-98 years); all 58 tested patients were negative for HIV. Primary HHV8-negative EBL was most commonly diagnosed in pleural effusion (77%). Expression of at least 1 pan B-cell antigen (CD19, CD20, or CD79a) was observed in all cases. According to the Hans algorithm, 30 of the 38 evaluated patients had nongerminal center B-cell (non-GCB) tumors. Epstein-Barr virus–encoded small RNA was positive in 6 of 45 patients. In 56 of 64 HHV8-negative patients, systemic therapy was initiated within 3 months after diagnosis. Cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) or CHOP-like regimens with or without rituximab (n = 48) were the most common primary treatments. The overall response and complete response rates were 95% and 73%, respectively. Three patients did not progress without systemic treatment for a median of 24 months. With a median 25-month follow-up, the 2-year overall survival and progression-free survival rates were 84.7% and 73.8%. Sixteen patients died; 12 were lymphoma-related deaths. Thus, most EBL cases in Japan are HHV8-negative and affect elderly patients. The non-GCB subtype is predominant. Overall, primary HHV8-negative EBL exhibits a favorable prognosis after anthracycline-based chemotherapy.

Although primary central nervous system post-transplant lymphoproliferative disorder (PCNS-PTLD) causes various symptoms depending on the tumor region, there has been no previous report of PCNS-PTLD in the cerebellopontine angle that was diagnosed due to peripheral facial nerve palsy. We herein report a case involving a 62-year-old man with PCNS-PTLD in the cerebellopontine angle who was diagnosed due to peripheral facial nerve palsy. The reduction of immunosuppressive therapy, whole-brain radiotherapy, intrathecal chemotherapy, and rituximab were effective in treating this patient. Physicians should therefore be mindful that PCNS-PTLD can cause peripheral facial nerve palsy in renal transplant recipients.

Epstein-Barr virus (EBV) reactivation causes serious diseases in immunocompromised hosts, such as acquired immunodeficiency syndrome (AIDS). We report on a case of plasmablastic lymphoma (PBL) with hemophagocytic lymphohistiocytosis (HLH).A-53-year-old Japanese man was diagnosed with PBL and AIDS. In addition to combined antiretroviral therapy, HyperCVAD (cyclophosphamide, doxorubicin, vincristine, prednisone)/high-dose methotrexate + cytarabine was initiated immediately. Partial remission was attained with chemotherapy. However, the patient developed HLH and died despite intensive therapy. Autopsy findings suggested that PBL was controlled, and immunosuppression appeared to cause fatal infection. The patient showed high titers of EBV viral-capsid antigen (VCA)-IgG (1:2560) on PBL diagnosis and high EBV-DNA levels throughout the clinical course. Moreover, EBV-DNA was detected in the fraction of CD8-positive cells, which strongly supports the pathogenesis of EBV-associated HLH.Our report highlights the importance of EBV control in patients with EBV-positive AIDS lymphoma. EBV not only behaves as the etiologic pathogen of PBL but also can be a trigger of HLH, the fatal complication. Careful follow-up of the EBV status should be performed, and if needed, preemptive anti-EBV therapy should also be considered to prevent EBV-associated complications such as HLH.

Patient: Male, 27 Final Diagnosis: Secondary syphilis Symptoms: Fever • loss of appetite • neck mass • night sweats • weight loss Medication: Oral amoxicillin Clinical Procedure: Lymph node biopsy Specialty: Infectious Diseases Objective: Challenging differential diagnosis Background: Syphilis is a sexually transmitted disease caused by the pathogen Treponema pallidum. Prevalence continues to rise, especially among men who have sex with men (MSM). Due to changes in patterns of sexual activity, manifestations of the disease are highly variable. Case Report: A 27-year-old male visited the hospital for a low-grade fever and tender 5-cm mass in the right side of his neck. His right tonsil was swollen and covered with a white coating. Levofloxacin was prescribed, but ineffective. The patient’s levels of liver function enzymes increased gradually. Systemic magnetic resonance imaging (MRI) revealed bilateral cervical lymphadenopathy with right predominance, a right pulmonary nodule, and a periportal lymph node, suggestive of malignant lymphoma. However, a biopsy of the right cervical lymph node showed nonspecific inflammation. Preoperative rapid plasma reagin (RPR) and T. pallidum latex agglutination (TPLA) tests were positive. The patient was MSM and reported oral sex with many sexual partners. A diagnosis of secondary syphilis was made. Oral amoxicillin was effective, and all symptoms other than periportal lymph node resolved. Conclusions: Tonsillitis, cervical lymphadenopathy, and lung lesions can be manifestations of secondary syphilis. A detailed history, pathology, and serology are crucial for diagnosis.

Splicing factor mutations are characteristic of myelodysplastic syndromes (MDS) and related myeloid neoplasms and implicated in their pathogenesis, but their roles in the development of MDS have not been fully elucidated. In the present study, we investigated the consequence of mutant Srsf2 expression using newly generated Vav1-Cre-mediated conditional knockin mice. Mice carrying a heterozygous Srsf2 P95H mutation showed significantly reduced numbers of hematopoietic stem and progenitor cells (HSPCs) and differentiation defects both in the steady-state condition and transplantation settings. Srsf2-mutated hematopoietic stem cells (HSCs) showed impaired long-term reconstitution compared with control mice in competitive repopulation assays. Although the Srsf2 mutant mice did not develop MDS under the steady-state condition, when their stem cells were transplanted into lethally irradiated mice, the recipients developed anemia, leukopenia, and erythroid dysplasia, which suggests the role of replicative stress in the development of an MDS-like phenotype in Srsf2-mutated mice. RNA sequencing of the Srsf2-mutated HSPCs revealed a number of abnormal splicing events and differentially expressed genes, including several potential targets implicated in the pathogenesis of hematopoietic malignancies, such as Csf3r, Fyn, Gnas, Nsd1, Hnrnpa2b1, and Trp53bp1 Among the mutant Srsf2-associated splicing events, most commonly observed were the enhanced inclusion and/or exclusion of cassette exons, which were caused by the altered consensus motifs for the recognition of exonic splicing enhancers. Our findings suggest that the mutant Srsf2 leads to a compromised HSC function by causing abnormal RNA splicing and expression, contributing to the deregulated hematopoiesis that recapitulates the MDS phenotypes, possibly as a result of additional genetic and/or environmental insults.

Aims Indolent T-lymphoblastic proliferation (iT-LBP) is a non-clonal benign condition showing extrathymic proliferation of T-lymphoblasts positive for CD3, CD4, CD8, and TdT. Isolated iT-LBP has been observed, but the majority of iT-LBP have been seen in conjunction with other disorders including Castleman disease, hepatocellular carcinoma, follicular dendritic cell tumors, angioimmunoblastic T-cell lymphoma, myasthenia gravis, and acinic cell carcinoma (ACC). The clinical course of iT-LBP is indolent, and no therapy is usually required. A major concern is misdiagnosis for T-lymphoblastic lymphoma, and a correct diagnosis of iT-LBP often requires not only pathological analysis but also a cautious monitoring of the clinical course. The aim of this report is to broaden knowledge of this yet not well recognized entity to pathologists and physicians Methods and Results We report a case of iT-LBP concomitant to ACC, along with a literature review of all 14 cases of iT-LBP reported to date Conclusions iT-LBP should always be considered as a differential diagnosis of T-lymphoblastic lymphoma as the two disorders show extremely resembling traits. This article is protected by copyright. All rights reserved.

Nagase and Inoue et al. generated a novel Asxl1 mutant mouse model to mimic clonal hematopoiesis and myelodysplastic syndromes caused by ASXL1 mutations and elucidated the effects of mutant versus wild-type ASXL1 on hematopoiesis, gene expression, and chromatin state., Additional sex combs like 1 (ASXL1) is frequently mutated in myeloid malignancies and clonal hematopoiesis of indeterminate potential (CHIP). Although loss of ASXL1 promotes hematopoietic transformation, there is growing evidence that ASXL1 mutations might confer an alteration of function. In this study, we identify that physiological expression of a C-terminal truncated Asxl1 mutant in vivo using conditional knock-in (KI) results in myeloid skewing, age-dependent anemia, thrombocytosis, and morphological dysplasia. Although expression of mutant Asxl1 altered the functions of hematopoietic stem cells (HSCs), it maintained their survival in competitive transplantation assays and increased susceptibility to leukemic transformation by co-occurring RUNX1 mutation or viral insertional mutagenesis. KI mice displayed substantial reductions in H3K4me3 and H2AK119Ub without significant reductions in H3K27me3, distinct from the effects of Asxl1 loss. Chromatin immunoprecipitation followed by next-generation sequencing analysis demonstrated opposing effects of wild-type and mutant Asxl1 on H3K4me3. These findings reveal that ASXL1 mutations confer HSCs with an altered epigenome and increase susceptibility for leukemic transformation, presenting a novel model for CHIP.

Lymphomatoid granulomatosis (LYG) is a rare Epstein-Barr virus-associated systemic angiocentric and angiodestructive lymphoproliferative disorder. It commonly involves the lungs and can also affect the skin, liver, kidney, and central nervous system. It can rarely occur in the spine, however, the details are unclear. We performed a systematic review of published cases (including our 1 case) of spinal LYG. We performed a systematic search of studies in English on spinal LYG, focusing on its clinical features, imaging, and treatments, according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses guidelines on the PubMed database. We identified 14 patients from the literature. We also found 1 case of isolated cervical LYG (grade 3) who was treated with steroid and radiation therapy for the spinal lesion after pathologic diagnosis. We performed a pooled analysis of these 15 cases. The mean age was 43.4 years, and 13 of the 15 patients were male. Brain lesions were present in 11 of 12 intramedullary spinal lesions, and only 1 was an isolated spinal LYG case. Regarding the diagnostic methods, 1 case was not described. Of the 14 cases described, 12 patients underwent biopsies (7 brain, 4 lung, and 1 spinal cord lesion) and 2 underwent surgical removal for an extramedullary lesion. In the overall prognosis from a mean follow-up period of 21.6 months, 4 patients died despite several treatments. Spinal LYG, particularly isolated spinal LYG, is rare. Thus further accumulation of cases may be necessary to better understand its characteristics.

Summary Generation of hematopoietic stem cells (HSCs) from pluripotent stem cells (PSCs) could potentially provide unlimited HSCs for clinical transplantation, a curative treatment for numerous blood diseases. However, to date, bona fide HSC generation has been largely unsuccessful in vitro. We have previously described proof of concept for in vivo HSC generation from PSCs via teratoma formation. However, our first-generation system was complex and the output low. Here, we further optimize this technology and demonstrate the following: (1) simplified HSC generation using transcription factor overexpression; (2) improved HSC output using c-Kit-deficient host mice, and (3) that teratomas can be transplanted and cryopreserved. We demonstrate that overexpression of Gfi1b, c-Fos, and Gata2, previously reported to transdifferentiate fibroblasts into hematopoietic progenitors in vitro, can induce long-term HSC formation in vivo. Our in vivo system provides a useful platform to investigate new strategies and re-evaluate existing strategies to generate HSCs and study HSC development., Graphical Abstract, Highlights • iPSC overexpressing Gfi1b, c-Fos, and Gata2 (GFG) form HSC-producing teratomas • Hemogenic endothelial-like and peripheral blood cells emerge in GFG teratomas • Depletion of host HSCs promotes expansion of long-term, transplantable HSCs • Teratomas can be cryopreserved and transplanted, Tsukada et al. demonstrate that teratomas formed in vivo by Gfi1b-, c-Fos-, and Gata2-overexpressing iPSCs give rise to functional, long-term HSCs. Teratoma-derived HSCs and hematopoietic cells were detected in peripheral blood, expanded to the bone marrow after depletion of host HSCs, and showed successful engraftment in serial transplantation assays. This work underscores the importance of evaluating differentiation strategies in vivo.

Islet transplantation is an established therapy for diabetes. We have previously shown that rat pancreata can be created from rat pluripotent stem cells (PSCs) in mice through interspecies blastocyst complementation. Although they were functional and composed of rat-derived cells, the resulting pancreata were of mouse size, rendering them insufficient for isolating the numbers of islets required to treat diabetes in a rat model. Here, by performing the reverse experiment, injecting mouse PSCs into Pdx-1-deficient rat blastocysts, we generated rat-sized pancreata composed of mouse-PSC-derived cells. Islets subsequently prepared from these mouse-rat chimaeric pancreata were transplanted into mice with streptozotocin-induced diabetes. The transplanted islets successfully normalized and maintained host blood glucose levels for over 370 days in the absence of immunosuppression (excluding the first 5 days after transplant). These data provide proof-of-principle evidence for the therapeutic potential of PSC-derived islets generated by blastocyst complementation in a xenogeneic host.

A 48-year-old man was admitted due to marked leukocytosis. Bone marrow examinations resulted in a diagnosis of Philadelphia (Ph) chromosome-positive chronic myeloid leukemia. One month later, massive muscle and bone invasion by leukemic cells was detected. After induction chemotherapy, he complained of a headache and visual loss, which was caused by a leukemic infiltration in the central nervous system. After temporary remission in response to chemotherapy, the disease relapsed in the form of an intracranial tumor. The unusual t(14;22)(q24;q11.2) translocation of the Ph-chromosome and the significant increase in monocytes observed might have contributed to the unique and aggressive clinical course.

Background and Aims. We retrospectively investigated the incidence of acute graft-versus-host disease (GVHD) in the lower gastrointestinal (GI) tract and the diagnostic accuracy of endoscopy.Methods. Of 1231 patients who underwent allogeneic hematopoietic stem cell transplantation between January 2005 and December 2014, 186 of whom underwent colonoscopy and biopsy and had no cytomegalovirus infection. The endoscopic findings and histologic diagnosis from these 186 patients were retrospectively analyzed.Results. Based on the histopathological findings, 171 patients were diagnosed with GVHD, accounting for 13.9% of all transplant recipients. Useful endoscopic findings for the diagnosis of GVHD were atrophy of the ileocecal valve and villous atrophy in the terminal ileum and tortoise shell-like mucosae, edema, and low vascular permeability in the colon. Even when no mucosal abnormality was observed, the incidence of GVHD was 78.9% in the terminal ileum and 75.0% in the colon. Furthermore, patients with mucosal exfoliation, although infrequent, were all diagnosed with grade 3/4 GVHD.Conclusions. It is important to perform endoscopy proactively for the early diagnosis of GVHD, and biopsy should be performed even when no abnormality is observed. In addition, because patients with mucosal exfoliation are extremely likely to have grade 3/4 GVHD, early treatment should be initiated.

Myelodysplastic syndromes (MDS) is a clonal disorder of hematopoietic stem cells (HSCs) characterized by clonal hematopoietic stem cells (HSCs) with cytopenia, morphological abnormalities, genetic alteration, ineffective normal hematopoiesis, and frequent progression to AML. It has long remained unresolved how MDS cells, which are less proliferative, inhibit normal hematopoiesis and eventually come to dominate the bone marrow space. Despite several studies of mesenchymal stem cells (MSCs), one of the principal components of HSC niche supporting normal hematopoiesis, the molecular mechanisms underlying this process remain unclear. In this study, we examined the mechanism by which less-proliferative MDS cells outcompete normal hematopoiesis through the effects on MSCs using serially transplantable Abcg2-induced MDS/AML model we recently generated. The recipient-derived normal BM cells displayed a considerably lower colony output with markedly decreased numbers of the hematopoietic stem progenitor cells (HSPCs) . However, there were no direct effects on the colony-forming ability of the recipient HSPCs co-cultured with MDS/AML cells, indicating that MDS/AML cells inhibited hematopoiesis through alteration of bone marrow microenvironment, such as MSCs, rather than direct interaction between normal and malignant HSCs. We next analyzed histological features of BM specimens. Interestingly, bone sections from the MDS/AML mice showed a reduced trabecular bone and narrowed growth plates. Moreover, micro computed tomography (micro-CT) analysis of the femora showed a significant reduction of the trabecular bone volume in the recipient mice transplanted with the MDS/AML BM cells. We detected decreased bone formation based on the calcein double labeling, but unchanged numbers of the TRAP-positive mononuclear or multinucleated (osteoclastic) cells in the MDS/AML samples, suggesting that the reduced bone volume was caused by suppressed bone formation. The impaired bone formation was also observed in the human MDS patients in terms of lower bone volume and decreased expression of BGLAP, one of osteogenic markers. In line with the above findings, single cell qRT-PCR analyses of mouse MSCs displayed downregulation of a line of osteolineage markers, indicating that MDS/AML cells suppress bone formation through inhibiting osteolineage differentiation of MSCs. Based on the findings, we next examined if re-induction of osteolineage differentiation of the MDS/AML-derived MSCs could rescue the potential of MSCs to support normal hematopoiesis. Importantly, the number of colony-forming cells (CFCs) was significantly restored by inducing differentiation of MDS/AML-derived MSCs toward osteogenic lineage both in vitro and in vivo. These results indicate that the impairment of osteolineage differentiation is the principal cause for an impaired normal hematopoiesis in MDS/AML, and that restoring the supportive niche will be a potential therapeutic option. Since extracellular vesicles (EVs) derived from MDS/AML cells are critical mediators of intercellular communication, we examined the molecular mechanism underlying the dysfunction of MSCs via EVs. As expected, EVs from MDS/AML cells were incorporated into the normal MSCs where osteolineage marker genes were clearly downregulated, and the number of CFCs significantly decreased in the HSPCs co-cultured with MSCs treated by the MDS/AML-derived EVs. Moreover, by comprehensively analyzing microRNAs (miRNAs) enriched in EVs derived from MDS/AML cells, we identified several miRNAs that impaired the differentiation of normal MSCs. These results suggested that miRNAs in EVs derived from MDS/AML cells disrupted the hematopoietic supporting niche through suppressing an osteolineage differentiation of MSCs. Here we uncover a heretofore unrecognized mechanism of bone marrow failure in MDS via the impairment of osteolineage differentiation in MSCs. EVs from MDS cells will be an attractive therapeutic target to restore the supportive niches, such as MSCs, for the remaining normal HSCs. Figure Disclosures No relevant conflicts of interest to declare.

For electron-doped cuprates, the strong suppression of antiferromagnetic spin correlation by efficient reduction annealing by the ``protect-annealing'' method leads to superconductivity not only with lower Ce concentrations but also with higher transition temperatures. To reveal the nature of this superconducting state, we have performed angle-resolved photoemission spectroscopy measurements of protect-annealed electron-doped superconductors ${\mathrm{Pr}}_{1.3\ensuremath{-}x}{\mathrm{La}}_{0.7}{\mathrm{Ce}}_{x}{\mathrm{CuO}}_{4}$ and directly investigated the superconducting gap. The gap was found to be consistent with $d$-wave symmetry, suggesting that strong electron correlation persists and hence antiferromagnetic spin fluctuations remain a candidate that mediates Copper pairing in the protect-annealed electron-doped cuprates.

Background For the diagnosis and treatment of adult T-cell leukemia/lymphoma (ATLL) caused by human T-lymphotropic virus type 1 (HTLV-1) are required therapeutic modalities urgently. Non-human primate models for ATLL would provide a valuable information for clinical studies. We did a pilot study to establish an ATLL non-human primate model using common marmosets (Callithrix jacchus). Methods We inoculated HTLV-1-producing MT-2 cells into 9-month-old marmosets, either intraperitoneally or intravenously. We next administrated MT-2 cells into 13-month-old marmosets under cyclosporine A (CsA) treatment to promote infection. HTLV-1 infection was determined by measuring HTLV-1 antibody titer in the common marmosets. Results The HTLV-1 antibody titer increased in the intraperitoneally inoculated marmoset with or without CsA treatment, and it kept over five 5 years though proviral copy number (proviral load, PVL) remained low throughout the study. Conclusion We obtained HTLV-1 asymptomatic carriers of common marmosets by inoculating MT-2 cells.

Immune checkpoint inhibitors (ICIs) have revolutionized the treatment of cancer by providing new options in addition to existing therapies. However, peptide vaccination therapies still represent an attractive approach, because of the antigen specificity. We identified survivin 2B peptide (SVN‐2B), a 9‐mer antigenic peptide encoded by survivin, and an SVN‐2B peptide vaccine‐based phase II randomized clinical trial targeting unresectable and refractory pancreatic carcinoma was undertaken. The SVN‐2B peptide vaccine did not have any statistically significant clinical benefits in that study. Therefore, we undertook an autopsy study to analyze the immune status of the pancreatic cancer lesions at the histological level. Autopsies were carried out in 13 patients who had died of pancreatic cancer, including 7 who had received SVN‐2B peptide vaccination and 6 who had not, as negative controls. The expression of immune‐related molecules was analyzed by immunohistochemical staining. Cytotoxic T lymphocytes were analyzed by tetramer staining and enzyme‐linked immunospot assay. Histological analysis revealed dense infiltration of CD8+ T cells in some lesions in patients who had received the SVN‐2B peptide vaccine. A high rate of programmed cell death ligand 1 expression in cancer cells was observed in these cases, indicating that CTLs were induced by SVN‐2B peptide vaccination and had infiltrated the lesions. The lack of a significant antitumor effect was most likely attributable to the expression of immune checkpoint molecules. These findings suggest that the combination of a tumor‐specific peptide vaccine and an ICI might be a promising approach to the treatment of pancreatic carcinoma in the future.

Previous worldwide epidemiological studies on lymphoid leukemia and/or lymphoma (LL/L) had considerable bias because of difficulty in covering all clinical departments of hospitals in a restricted area (population base). These studies may not have reflected the actual number of newly diagnosed cases (incidence) strictly, or the true LL/L subtype frequencies. We searched all cases of newly diagnosed LL/L in Miyagi Prefecture over a 5-year period, including those that were discovered as LL/L sorely after autopsy. We registered the actual number of 2098 cases in the prefecture and calculated an accurate incidence rate (17.8 per 100,000 persons). Additionally, we identified more realistic and detailed frequencies of LL/L subtypes including the leukemic phase of some lymphomas. As Miyagi Prefecture is an area in which the population dynamics are relatively stable and representative of Japan, the result of our epidemiological study can be used as the first representative index of LL/L for Japan.

Mucormycosis is an opportunistic infection occurring in immunocompromised hosts with hematological malignancies. Mortality due to mucormycosis in patients with hematological malignancies is high. However, the clinical symptoms of mucormycosis are poorly characterized, and diagnosis is difficult due to the lack of specific culture or serological markers or antigens. We present two cases in which nested polymerase chain reaction with specific primers was used in the serum of patients with hematological malignancies.

Immunohistochemistry is not only the most important tool for pathologists to establish a final diagnosis, but it can also inform decisions regarding optimal treatment methods. However, there is no universal standard notation for expressing immunohistochemical findings. For a diagnosis of malignant lymphoma, it is important to confirm the presence or absence of MYC translocation and communicate these results to a clinical audience. However, the criteria for selecting cases for fluorescence in situ hybridization (FISH) analysis to confirm MYC translocation are ill defined. We therefore devised a notation that we termed proportion of immunoreactivity/expression for immunohistochemistry (PRIME notation) based on the cellular proportion showing different antigen-antibody reactivity in immunohistochemistry (CPAR) and used it to examine the relationship between MYC translocation and the proportion of c-MYC+ lymphoma cells. We reviewed 82 cases diagnosed as diffuse large B-cell lymphoma or diffuse large B-cell lymphoma coexisting with grade 3A to 3B follicular lymphoma. The most common notation was "+/(weak)+/-" (49/82 cases [59.8%]); cases that were CPAR positive, weakly positive, and negative for tumor cells each accounted for about one-third of the total. Unexpectedly, no MYC translocation was observed by FISH in this group. Thus, FISH is not needed even if more than half of cells are c-MYC positive by PRIME notation. This is the first report describing a correspondence between immunohistochemical findings and chromosomal abnormality, reflecting findings at the protein and gene levels, respectively.

There has been no comparative clinical study focused on differences in the clinical features of Epstein-Barr virus (EBV)+ Hodgkin lymphoma (HL) between HIV-positive and -negative cases. In a nationwide survey from 511 institutions in Japan, the present study investigated 16 EBV+ HIVpositive HL patients. To further clarify their characteristics in comparison with EBV+ HIVnegative HL (n=34) in the combination antiretroviral therapy era in Japan, the present study was performed. Results indicated that EBV+ HIVpositive HL frequently occurred in a younger population compared with EBV+ HIVnegative HL (P=0.0295), and that the EBV+ HIVpositive HL group was not associated with the nodular sclerosis subtype in the population who were below the age of 40. Notably, the EBV+ HIVpositive HL group had a significantly higher frequency of extra-nodal involvement (P=0.0214), including marrow invasion. In the advanced stage, 80% of those with EBV+ HIVpositive HL did not require dose-reduction and in the majority of cases, chemotherapy was completed. There were no significant differences in the complete remission rate (P=0.1961), overall survival (P=0.200) and progression-free survival (P=0.245) between EBV+ HIVpositive HL (median observational period, 23.5 months) and EBV+ HIVnegative HL (median observational period, 64.5 months), suggesting that HIV positivity may not have a negative impact on the clinical outcome of EBV+ HL. Notably, standard chemotherapy is effective and tolerable for EBV+ HL, regardless of HIV infection.

To study development of the conceptus in xenogeneic environments, we assessed interspecies chimera formation as well as tetraploid complementation between mouse and rat. Overall contribution of donor PSC-derived cells was lower in interspecies chimeras than in intraspecies chimeras, and high donor chimerism was associated with anomalies or embryonic death. Organ to organ variation in donor chimerism was greater in interspecies chimeras than in intraspecies chimeras, suggesting species-specific affinity differences among interacting molecules necessary for organogenesis. In interspecies tetraploid complementation, embryo development was near normal until the stage of placental formation, after which no embryos survived.