Takumi Hoshino

Discrepancy in EBV-DNA load between peripheral blood and cerebrospinal fluid in a patient with isolated CNS post-transplant lymphoproliferative disorder

Post-transplant lymphoproliferative disorder (PTLD) is a fatal complication of allogeneic hematopoietic stem cell transplantation (HSCT) that is caused by reactivation of Epstein–Barr virus (EBV). A successful approach, monitoring EBV-DNA load in peripheral blood (PB) accompanied by preemptive rituximab therapy, has recently been reported. Here, we describe a 29-year-old woman who developed isolated central nervous system (CNS) PTLD. She received HSCT against acute myelogenous leukemia from a related human leukocyte antigen-haploidentical donor, following a conditioning regimen that included antithymocyte globulin. Tacrolimus and methylprednisolone were given as prophylaxis for graft-versus-host disease. On day +172, the patient’s consciousness deteriorated. Magnetic resonance imaging showed six ring-enhanced lesions in the cerebral hemispheres. These tumors were diagnosed, via a craniotomy and tumorectomy, as PTLD. EBV-DNA load was elevated in the cerebrospinal fluid (CSF) but not detected in PB. She was treated with whole-brain irradiation and rituximab, and achieved partial remission of the tumors. This case serves as a reminder that vigilance is required regarding the development of isolated CNS PTLD; it is worth examining EBV-DNA replication in CSF for diagnosis even when the EBV-DNA load is negative in PB.

Sacroiliitis as an initial manifestation of acute myelogenous leukemia

Sacroiliitis is the most pathognomonic and earliest manifestation of ankylosing spondylitis.We herein report a 28-year-old female patient who presented with sacroiliitis as an initial manifestation of acute myelogenous leukemia (AML). She had a 3-month history of anemia and walking difficulty. Bone marrow findings revealed an increase of blasts with trilineage dysplasia. Although she was initially diagnosed with myelodysplastic syndrome (MDS), blasts rapidly increased and AML developed 1 month after the diagnosis of MDS with sacroiliitis. Induction chemotherapy failed to induce a complete remission of AML, but it did effectively treat the sacroiliitis. However, the sacroiliitis relapsed when the leukemia cells progressed thereafter. Oral corticosteroids helped ameliorate the sacroiliitis. She underwent bone marrow transplantation (BMT) from an HLA-identical sister during a nonremission period; however, the leukemic cells began to rapidly increase from day 30 after BMT. The close relationship between the occurrence of sacroiliitis and AML suggested that autoimmune sacroiliitis was a paraneoplastic phenomenon of AML in this patient. Although autoimmune disorders develop in a substantial number of MDS patients, they are rarely observed in de novo AML. No previous report has described sacroiliitis as the initial manifestation of de novo AML.

X-Linked Lymphoproliferative Disease in an Adult

X-linked lymphoproliferative disease (XLP) is an inherited immunodeficiency characterized by an extreme susceptibility to Epstein-Barr virus (EBV) infection. Patients with XLP mainly present with the 3 clinical manifestations of fulminant infectious mononucleosis, lymphoproliferative disorder, and dysgammaglobulinemia and in rare cases have aplastic anemia and lymphocytic vasculitis.The causative gene for XLP was identified asSH2D1A/DSHP/SLAM-associated protein (SAP) in 1998, and genetic analysis has been used for the definite diagnosis of XLP. Diagnosis for most patients occurs at ages younger than 10 years, and there are few adult patients. Here we describe a 23-year-old man with hypogammaglobulinemia and EBV-associated hemophagocytic lymphohistiocytosis and a diagnosis of XLP. In addition, the patient showed type 1 helper T-cell (Th1) skewing, as has been described inSap knock-out mice. Th1/Th2 imbalance in humans, as well as in mice, may play an important role in the pathogenesis of XLP.

Long-term follow-up of EBV-positive lymphoproliferative disorders in a patient with systemic lupus erythematosus

We report a woman in her early thirties with a long-term history of systemic lupus erythematosus (SLE) and prednisolone administration, who progressed to Epstein-Barr virus (EBV)-positive lymphoproliferative disorder (LPD). Treatment for SLE consisted of 1 mg/kg/ day prednisolone followed by 5 mg/day of maintenance therapy. Lymph node biopsies were performed when the patient was in her early thirties, mid-forties, and late fifties. Histologically, the initial lymph node lesion was characterized by numerous enlarged, coalescing lymphoid follicles. The second biopsy showed effacement of the follicles and expansion of the paracortical area. A polymorphous population of small- to medium-sized lymphocytes, plasma cells, and immunoblasts had diffusely infiltrated the paracortical area. In the third lymph node biopsy, fibrous collagen bands divided the epithelioid cell granulomas into nodules. There were numerous Hodgkin and Reed-Sternberg cells in the epithelioid cell granuloma. In situ hybridization demonstrated there were no EBV-infected lymphocytes in the first biopsy; however, EBER+ cells were detected in the second and third biopsy specimens. The current findings illustrate the natural progression in a patient with a long-term history of EBV+ B-cell LPD in which the immunodeficiency was caused by SLE and probably her aging, which together resulted in histological change.

All-trans-retinoic acid as a possible cause of acute pancreatitis even in the absence of hypertriglyceridemia

The standard therapy for patients affected by acute promyelocytic leukemia (APL) is the administration of all-trans-retinoic acid (ATRA). ATRA therapy is usually well-tolerated, but it also has the potential to induce toxicity. The most severe side effect of ATRA is retinoic acid syndrome; the next is acute pancreatitis, which is a rare but serious adverse event mostly due to hypertriglyceridemia. We herein report a patient who developed ATRA-induced acute pancreatitis without hypertriglyceridemia. A 17-year-old female presented to our hospital complaining of a 3-week history of dyspnea. Her peripheral blood counts were: Hb: 4.5 g/dL, WBC: 0.96 9 10/L with 9% blasts, and platelets: 48 9 10/L. The biochemistry findings were significant only regarding the serum lactate dehydrogenase level of 276 IU/L. A bone marrow examination revealed an abnormal cellularity, thus indicating APL, while a cytogenetic study showed the presence of t(15;17) (q22;q21). The patient was treated with ATRA for the purpose of remission induction. On the second day of ATRA treatment, she suffered acute epigastric and upper left quadrant pain, and laboratory tests showed an elevation of amylase to 7,600 IU/L (normal range: 49–136 IU/L) and lipase to 1,680 IU/L (normal range: 11–53 IU/L), with no marked increases in triglyceride (TG). Computed tomography of the abdomen revealed no abnormal findings in either the biliary ducts or pancreas. With the cessation of ATRA, the symptoms rapidly disappeared and the pancreas-derived enzyme level thereafter decreased to the normal range. The peak level of TG was only 145 mg/dL (normal range: 30–149 mg/dL) throughout the entire course. The patient was then treated with arsenic trioxide therapy without experiencing any subsequent complications, and she has since remained in complete remission for 8 months after starting the induction treatment. Four cases of acute pancreatitis associated with the use of ATRA have been described [1–4], but only one of these presented without hypertriglyceridemia, which is one of the common side effects of ATRA [4, 5]. Our case is the second such case. The pathogenesis of ATRA-induced acute pancreatitis without hypertriglyceridemia is not clear. Cytokines, such as IL-8, IL-1beta, and TNF-alpha, have been shown to be intimately involved in the inflammatory response to acute pancreatitis in general [6]. Teng et al. suggested that the increased expression of these cytokines in APL cells induced by ATRA may also play a role in the pathogenesis of ATRA-induced acute pancreatitis [4, 7]. As far as the case of Teng et al. is concerned, however, this suggestion remains controversial because of the recurrence of an elevated lipase level with a second ATRA treatment even after achieving complete remission in his case. His case rather suggests that either allergic or autoimmune mechanisms might play critical roles in the development of ATRA-induced acute pancreatitis. On the other hand, the activation of pancreatic stellate cells (PSCs) is known to be implicated in the production of pancreatic fibrosis and associated with the loss of retinol-containing fat droplets, which are stored in quiescent PSCs. Recent studies have demonstrated that retinol and its ATRA metabolites induce quiescence in activated PSCs and decreased collagen synthesis [8]. Pancreatic fibrosis, which is the process of repair after pancreatic injury, is prevented by ATRA, and then proinflammatory cytokines might be upregulated and lead to ATRA-induced acute pancreatitis. T. Hoshino (&) N. Hatsumi S. Takada T. Sakura S. Miyawaki Leukemia Research Center, Saiseikai Maebashi Hospital, Kamishinden-machi, 564-1, Maebashi, Gunma 371-0821, Japan e-mail: takumihoshino4249@yahoo.co.jp

Spontaneous remission of adult acute myeloid leukemia with t(8;16)(p11;p13)/MOZ-CBP fusion

The translocation t(8;16)(p11;p13), which results in fusion of the MOZ/MYST3/KAT6A gene (8p11) and CBP/CREBBP gene (16p13), is characterized by unique morphologic and clinical findings in acute myeloid leukemia (AML), such as frequent extramedullary involvement, severe coagulation disorder, myelomonocytic differentiation, and erythrophagocytosis by the leukemic cell [1,2]. This translocation is associated with extremely poor prognosis in adults [2,3], but not in children [4]. In addition, spontaneous remissions often occur in neonates with t(8;16)(p11;p13) [3–6], whereas such remissions have not been reported in adults. We herein report an adult patient with t(8;16)(p11;p13)-AML who underwent spontaneous remission. An asymptomatic 49-year-old woman was presented for an annual checkup, at which a very high white blood cell (WBC) count of 74.9 10/L, hemoglobin level of 11.7 g/dL, and platelet count of 117 10/L were detected. Regarding the biochemistry findings, only the serum lactate dehydrogenase (LDH) level of 1575 IU/L was significant. She was referred to our hospital 3 days later. Her peripheral blood counts in our hospital indicated a WBC count of 63.2 10/L with 9% blasts, 58% immature monocytic cells, and no anemia or thrombocytopenia. There was no abnormality in coagulation test. The serum LDH level remained high (1354 IU/L). She was presented with no evidence of extramedullary disease. Six days later, however, peripheral blood analysis showed a WBC count of 4.1 10/L with normal WBC differentiation, and the serum LDH level was within the normal limits without treatment. Bone marrow aspiration revealed hypercellularity with an increased number of blasts (52.0%), which showed a monocytic appearance with heavy granulation upon dual myeloperoxidase and nonspecific esterase cytochemical staining. Erythrophagocytosis by the leukemic cells was not remarked. Flow cytometric immunophenotyping demonstrated the blast cells to be positive for CD4, CD11b, CD13, CD14, CD15, CD33, CD56, and HLA-DR and to be negative for CD34 and CD117. She was therefore diagnosed as having AML (FAB M5a). A cytogenetic analysis of the bone marrow cells revealed 46,XX,t(8;16)(p11;p13) as the sole karyotypic abnormality in 17 of 20 metaphases. RT-PCR using RNA extracted from a bone marrow sample detected several PCR products, including the MOZ-CBP type I chimeric transcript (Figure 1). The patient’s clinical condition remained good with no signs or symptoms of disseminated intravascular coagulation, so we observed the patient without chemotherapy, and surprisingly, she spontaneously underwent complete remission (CR) 7 days after diagnosis of the disease and stayed in remission. Microscopic examination of the bone marrow 4 months after diagnosis still revealed CR, cytogenetic analysis of the bone marrow cells revealed the normal karyotype and minimal residual disease (MRD) was not detected in bone marrow sample by flow cytometric immunophenotyping, however, a small amount of MOZ-CBP fusion transcript remained detectable by RTPCR. Owing to concern regarding the risk of recurrence, she received bone marrow transplantation (BMT) from an unrelated donor with an HLA-1 antigen mismatch at the HLA-DR during the remission period; the conditioning regimen consisted of a conventional dose of total body irradiation and cyclophosphamide. To prevent graft versus host disease (GVHD), tacrolimus (TAC) and short-term methotrexate were administered. Primary engraftment with neutrophils >0.5 10/L and complete donor chimerism by sex chromosome analysis were achieved on day 14 after BMT. She developed grade II acute GVHD, which subsided with administration of a corticosteroid. MOZ-CBP chimeric transcript as MRD was not detected in a bone marrow sample tested by RT-PCR; after 6 years, despite discontinuation of TAC, she completely expresses the donor chimera. The clinicobiological characteristics of t(8;16)(p11;p13) are unique, although they do resemble the characteristics of MLL-rearranged AML [1]. Erythrophagocytosis by blasts, which is highly suggestive of t(8;16)(p11;p13)-AML, was

Association between OGG1 S326C CC genotype and elevated relapse risk in acute myeloid leukemia

Recent studies have shown that tumors of relapsed acute myeloid leukemia (AML) present additional genetic mutations compared to the primary tumors. The base excision repair (BER) pathway corrects oxidatively damaged mutagenic bases and plays an important role in maintaining genetic stability. The purpose of the present study was to investigate the relationship between BER functional polymorphisms and AML relapse. We focused on five major polymorphisms: OGG1 S326C, MUTYH Q324H, APE1 D148E, XRCC1 R194W, and XRCC1 R399Q. Ninety-four adults with AML who achieved first complete remission were recruited. Genotyping was performed with the polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) method. The OGG1 S326C CC genotype (associated with lower OGG1 activity) was observed more frequently in patients with AML relapse [28.9 vs. 8.9%, odds ratio (OR) = 4.10, 95% confidence interval (CI) = 1.35–12.70, P = 0.01]. Patients with the CC genotype exhibited shorter relapse-free survival (RFS). Moreover, the TCGA database suggested that low OGG1 expression in AML cells is associated with a higher frequency of mutations. The present findings suggest that the OGG1 S326C polymorphism increased the probability of AML relapse and may be useful as a prognostic factor for AML relapse risk.

Persistence of anti-HLA antibody after cord blood transplantation engraftment in acute myelogenous leukemia: a potential marker of minimal residual disease, but not a significant factor in secondary humoral engraftment failure.

The presence of pre-transplant anti-HLA antibodies in recipients of cord blood transplantation (CBT) is associated with failed engraftment. However, only a small number of studies have reported that recipient-derived anti-HLA antibodies persist after CBT and have potential impact on the outcome. Of 61 patients who underwent HLA-mismatched CBT at Saiseikai Maebashi Hospital, three patients were identified as having anti-HLA antibodies not corresponding to HLA antigens in the transplanted CB. All patients achieved successful engraftment. However, the three patients with the pre-transplant anti-HLA antibodies not corresponding to HLA antigens in the transplanted CB continued to produce these antibodies even after engraftment; the persistence of these antibodies served as a sensitive minimal residual disease (MRD) marker. In contrast, donor HLA-specific and newly produced third party antibodies were not detectable even after relapse. The persistence of anti-HLA antibodies even after engraftment may be a potential marker for MRD, but is not a significant factor in secondary humoral engraftment failure.