Shunsuke Hatta

Paraneoplastic Pemphigus Associated with B-cell Chronic Lymphocytic Leukemia Treated with Ibrutinib and Rituximab

Paraneoplastic pemphigus (PNP) is a severe autoimmune blistering disease associated with an underlying malignancy, and its prognosis is poor. We herein report the first patient with B-cell chronic lymphocytic leukemia/small lymphocytic lymphoma (B-CLL/SLL)-associated PNP successfully treated with the Brutons tyrosine kinase inhibitor ibrutinib and rituximab. Although his PNP lesions did not improve with ibrutinib monotherapy, the combination of ibrutinib and rituximab was effective against B-CLL/SLL-associated PNP. This case suggests that ibrutinib plus rituximab may be a potent therapeutic option for B-CLL/SLL-associated PNP that is hard to control with ibrutinib alone.

A defined culture method enabling the establishment of ring sideroblasts from induced pluripotent cells of X-linked sideroblastic anemia

Congenital sideroblastic anemia is an inherited anemia characterized by the presence of bone marrow ring sideroblasts.[1][1] To date, several causative genes, mostly related to iron and heme metabolism in erythroid cells, have been considered critical for the formation of ring sideroblasts.[1][1]

Dynamics of absorption, metabolism, and excretion of 5-aminolevulinic acid in human intestinal Caco-2 cells

5-Aminolevulinic acid (ALA) is a precursor for the biosynthesis of porphyrins and heme. Although the oral administration of ALA has been widely applied in clinical settings, the dynamics of its absorption, metabolism, and excretion within enterocytes remain unknown. In this study, after enterocytic differentiation, Caco-2 cells were incubated with 200 µM ALA and/or 100 µM sodium ferrous citrate (SFC) for up to 72 h. Both ALA and the combination of ALA and SFC promoted the synthesis of heme, without affecting the expression of genes involved in intestinal iron transport, such as DMT1 and FPN. The enhanced heme synthesis in Caco-2 cells was more pronounced under the effect of the combination of ALA and SFC than under the effect of ALA alone, as reflected by the induced expression of heme oxygenase 1 (HO-1), as well as a reduced protein level of the transcriptional corepressor Bach1. Chromatin immunoprecipitation analysis confirmed Bach1 chromatin occupancy at the enhancer regions of HO-1, which were significantly decreased by the addition of ALA and SFC. Finally, Transwell culture of Caco-2 cells suggested that the administered ALA to the intestinal lumen was partially transported into vasolateral space. These findings enhance our understanding of the absorption and metabolism of ALA in enterocytes, which could aid in the development of a treatment strategy for various conditions such as anemia.

Anaplastic multiple myeloma: possible limitations of conventional chemotherapy for long-term remission

Anaplastic multiple myeloma (AMM) is a very rare morphological subtype of multiple myeloma, which has been reported only sporadically, mostly in case reports (1-3). The clinical course of AMM is highly aggressive and the disease has an extremely poor prognosis, which is considerably different from that of conventional myeloma. Some patients are diagnosed with AMM at disease onset, whereas others can develop anaplastic transformation during the course of conventional plasma cell myeloma. AMM can present as multiple extramedullary tumors (3). Pathologically, the pleomorphic multinucleated morphology of AMM can mimic multinucleated carcinoma (4). Due to its rarity, however, a therapeutic strategy for AMM remains to be established. A 63-year-old woman with severe lumbago and right upper limb pain for longer than 1 week was referred to us because of thrombocytopenia, high serum lactic dehydrogenase (LDH) level, and a mass on the right brachial plexus found by magnetic resonance imaging (MRI). The patient’s general condition was very poor, with severe pain and easy fatigability. She was afebrile and her vital signs were normal. There was no lymphadenopathy or hepatosplenomegaly. The complete blood count indicated thrombocytopenia (38000/μL) without anemia (hemoglobin, 12.2 g/dL). The white blood cell count (8600/μL) was normal, with a normal differentiation count (69% neutrophils, 18% lymphocytes, 9% monocytes, 3% eosinophils, and 1% metamyelocytes); there were no atypical lymphocytes, plasma cells, or blasts. Biochemical analysis revealed an extremely high serum LDH level (16200 IU/L) and mild elevation of the serum transaminase level (asparagine transaminase, 226 IU/L; alanine transaminase, 88 IU/L). The alkaline phosphatase level was within the normal range. LDH subclass analysis demonstrated the predominance of LDH2 (39%) and LDH3 (44%). Renal function was normal (serum creatinine, 0.74 mg/dL) with normal findings on urinalysis. Serum levels of uric acid (8.8 mg/dL) and inorganic phosphate (6.3 mg/dL) were elevated, but there were no abnormalities in other electrolytes. Serum total protein (6.6 g/dL) and albumin (4.5 g/dL) levels were normal. Coagulation tests revealed only slight elevation of fibrin degenerative products. Elevated levels of serum ferritin (3338 ng/mL), soluble interleukin-2 receptor (625 U/mL), and beta-2 microglobulin (2.5 mg/L) were also observed. Immunoelectrophoresis of serum and urine detected monoclonal IgD-lambda protein and Bence-Jones protein (BJP) subtypes. Serum IgG, IgA, IgM, and IgD levels were 395, 16, 7, and 197.3 mg/dL, respectively. Serum free light chain analysis indicated deviation of the kappa/ lambda ratio (kappa-chain, 1.4 mg/L; lambda-chain, 2150 mg/L). The patient was negative for anti-human immunodeficiency virus (HIV) antibody. Elevation of the Epstein–Barr virus DNA titer in peripheral blood was not observed. Bone marrow aspiration resulted in dry tap. However, biopsy revealed nodular aggregation of atypical large cells that had basophilic cytoplasm and euchromatic nuclei (Figure 1); on flow cytometry and immunohistochemical analysis, they were CD3–, CD4–, CD7+, CD10–, CD13+, CD20–, CD30–, CD33+, CD56–, CD79a–, IgG–, IgM–, IgA–, Igκ–, Igλ+, c-myc+, MPO+, and MUM1+ (Figure 1). CD38 was weakly positive and CD138 was negative. The Ki-67 labeling index was very high (95%). Epstein–Barr virus-encoded RNA was not detected by in situ hybridization. G-banding analysis revealed a complex karyotype, including duplication of the 14q32 locus (Table 1). Fluorescence in situ hybridization demonstrated no fusion signals of IgG/Myc, IgH/MAF, IgH/ FGFR3, or IgH/CCND1, and no split signal of Myc. Strong uptake of fluorodeoxyglucose (FDG) in systemic bones without bone destruction and around the right brachial plexus was observed on positron emission tomography combined with computed tomography (PET/CT) (Figure 2). There was no lymphadenopathy or hepatosplenomegaly. Magnetic resonance imaging detected infiltrating lesions around the right brachial plexus. The clinicopathological findings described above indicated atypical plasma cell dyscrasia with extreme clinical aggressiveness, features markedly different from those of conventional plasma cell myeloma, and considered to be included within the concept of AMM. We initially administered high-dose dexamethasone, which resulted in partial relief of pain, improvement of general status, and reduction of serum LDH to some extent. Thereafter, the anti-lymphoma EPOCH regimen (etoposide, doxorubicin hydrochloride, vincristine, prednisolone, and cyclophosphamide) was started. Further transient elevation of LDH was observed, but there were no signs of tumor lysis syndrome or disseminated intravascular coagulopathy. After 3 weeks, serum LDH and IgD levels had significantly decreased and abnormal cells were not detected in the bone marrow, suggesting that the EPOCH regimen was highly effective. After a total of four courses of EPOCH, a significant reduction in systemic bone FDG uptake was noted on PET/CT. Thereafter, Anaplastic multiple myeloma: possible limitations of conventional chemotherapy for long-term remission

Successful Treatment of Aggressive Mature B-cell Lymphoma Mimicking Immune Thrombocytopenic Purpura

A 55-year-old woman suffered from hemorrhagic tendency. She had severe thrombocytopenia without any hematological or coagulatory abnormalities, and a bone marrow examination revealed an increased number of megakaryocytes without any abnormal cells or blasts. No lymphadenopathy or hepatosplenomegaly was observed on computed tomography. She was initially diagnosed with immune thrombocytopenic purpura (ITP). None of the treatments administered for ITP produced a response. However, abnormal cells were eventually found during the third bone marrow examination. The pathological diagnosis was mature B-cell lymphoma. Rituximab-containing chemotherapy produced a marked increase in the patients platelet count, and her lymphoma went into complete remission.

Successful Cord Blood Stem Cell Transplantation for Primary Cutaneous CD8-positive Aggressive Epidermotropic Cytotoxic T-cell Lymphoma Complicated with Cerebral Infiltration

A 16-year-old boy, who had been initially examined for bilateral blepharedema and slight eruption, presented with rapidly deteriorating symptoms in associating with headache and consciousness disturbance. He was diagnosed to have primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (PCAE-CTL) by a biopsy of the skin and brain. After whole-brain radiation and some courses of chemotherapy, cord blood transplantation was performed with myeloablative conditioning. After transplantation, the cerebral dysfunction gradually improved. Disease remission was confirmed by the disappearance of any abnormal findings on electroencephalogram and magnetic resonance imaging. PCAE-CTL is reported to be an extremely aggressive disease with a poor prognosis, but the timely performance of cord blood transplantation is considered to be a promising treatment strategy.

γδ T cell clonal proliferation early after PD-1 blockade

Dear Editor, A recent study showed that programmed death 1 (PD-1) suppresses not only T cell-mediated immune responses but also overactivated T cell receptor (TCR) signaling, and its blockade can potentially promote T cell lymphomagenesis [1]. However, T cell lymphoma triggered by PD-1 inhibitors has not been reported previously. Recently, we encountered a case of secondary hepatosplenic T cell lymphoma (HSTCL) that developed early after PD-1 blockade therapy. A 73-year-old man had been diagnosed with classical Hodgkin lymphoma (HL), mixed cellularity type, 2 years previously. He received nivolumab treatment (3 mg/kg every 2 weeks) for HL that relapsed after standard chemotherapy and brentuximab vedotin treatment. After two doses of nivolumab, the patient presented with high-grade fever, general fatigue, and bleeding tendency. Laboratory investigation showed acute-onset pancytopenia (white blood cell count, 1.0 × 10/μL; hemoglobin level, 9.2 g/dL; reticulocyte count, 0.5%; and platelet count, 47 × 10/μL) with increased serum levels of lactic dehydrogenase (12,313 IU/L) and ferritin ( 2 6 6 , 8 0 0 μ g / L ) s u g g e s t i n g h emop h a g o c y t i c lymphohistiocytosis. Disseminated intravascular coagulation was also noted. Epstein–Barr virus (EBV) DNA levels in the peripheral blood were not elevated, and the patient showed neither infections nor autoimmune diseases. Whole-body computed tomography showed that the HL lesions had decreased in size compared to before nivolumab treatment. Bone marrow examination revealed clonal proliferation of atypical lymphocytes (Fig. 1a) that exhibited TCR-γδ restriction on flow cytometric analysis. Moreover, monoclonal rearrangements of the TCR-γ and TCR-δ genes were detected (Fig. 1b). Chromosomal examination showed abnormalities o f 46 ,XY,add (17 ) (p13 ) [19 /20 ] /46 , idem ,de r (1 ) t (1:3)(p34:p13)[1/20]. Bone marrow biopsy specimen showed massive infiltration of neoplastic lymphoid cells, which were immunohistochemically positive for CD3, TIA-1, and granzyme B, but negative for CD4, CD5, CD8, CD10, CD20, CD30, CD79a, and EBV-encoded RNA on in situ hybridization. Despite intensive treatment, the patient’s condition deteriorated rapidly, and he died 2 months after initiation of nivolumab. Autopsy showed massive infiltration of T cell lymphoma into the bone marrow, liver, and spleen. These findings were consistent with HSTCL, a rare subtype of extranodal T cell lymphoma. HSTCL has been reported in patients undergoing kidney transplantation or with a prior history of Crohn’s disease, systemic lupus, rheumatoid arthritis, or malaria [2–4], suggesting that HSTCL is associated with immune dysregulation and chronic antigen stimulation. These reports also included two cases of HSTCL with a history of HL [2, 3]. An experimental model suggested that CD30 molecules, characteristic of Hodgkin–Reed–Sternberg cells, can potentially trigger clonal proliferation of γδ T cells [5]. In our case, blockade of PD-1 may have accelerated γδ T cell clonal proliferation occurring during prolonged HL-associated inflammation. Another point of note in this case was that the neoplastic cells atypically showed expression of granzyme B with TIA1, although HSTCLs usually have a non-activated cytotoxic phenotype without granzyme B expression [3]. We assumed that overactivated T cell-mediated immune responses triggered by PD-1 inhibitor led to the patient’s severe inflammatory condition and aggressive clinical course. PD-1 blockade is a promising therapeutic approach for refractory * Yasushi Onishi yonishi@med.tohoku.ac.jp