Tohru Iseki

Human herpesvirus‐6 encephalitis after bone marrow transplantation: magnetic resonance imaging could identify the involved sites of encephalitis

To the Editor: Human herpesvirus-6 (HHV-6) is a causative virus of exanthema subitum in early childhood (1). After primary infection, HHV-6 persists latently in salivary glands, lymph nodes and peripheral blood (2) and can be reactivated under the conditions of immunosuppression. In transplant recipients, HHV-6 can be an important pathogen causing various complications (3). However, only a few cases of HHV-6 encephalitis after bone marrow transplantation have been reported (4,s). Here, we describe a case of HHV-6 encephalitis developed after bone marrow transplantation, in which the involved sites were detected by magnetic resonance imaging (MRI). In August 1993, a 21-yr-old woman was presented to Chiba University Hospital with chronic myelogenous leukemia. She was treated with alpha-interferon but it was discontinued due to psychological symptoms after 2 months. She was then treated with hydroxyurea and was maintained in chronic phase. Two yr later she underwent bone marrow transplantation from an HLA phenoidentical unrelated donor with a mismatch in the HLA Class I1 subtype DRB1. Busulfan and cyclophosphamide were administered for the conditioning regimen, and short-methotrexate and cyclosporine for GVHD prophylaxis. Daily 200 mg/m2 of aciclovir every 8 h from d -3 to d 14 and biweekly 200 mg/kg of anti-cytomegalovirus antibody hightiter gamma-globulin were administered to prevent viral infection. On d 26, she developed disturbance of short-term memory and personality change with a refractory fever above 40°C. On d 29 she suddenly fell into a coma, and generalized tonic-clonic seizures occurred. There were no significant abnormalities in blood gas or electrolytes. Electroencephalogram revealed bursts of sharp waves on a background of slow waves indicating epilepsy. Lumbar puncture on d 29 demonstrated high intracranial pressure and cerebrospinal fluid analysis revealed 8 white cells/@ (100% lymphocytes). The protein, glucose and chloride levels were within normal range. Polymerase chain reaction (PCR) analysis of the cerebrospinal fluid (CSF) demonstrated HHV-6-DNA. DNA of herpes simplex type 1, cytomegalovirus and Epstein-Barr virus were not detected. Although cranial computed tomography (CT) on d 29 was normal, MRI on d 32 showed edema with petechial hemorrhage in the bilateral medial temporal lobes (Fig. 1). She was treated with diazepam and phenytoin for epilepsy and with gamma-globulin for viral infection. The patient then developed severe acute GVHD and died of respiratory failure with mycotic pneumonia. Neuroinvasion is a notable feature of HHV-6. Encephalitis caused by HHV-6 has been well documented in exanthema subitum and HHV-6 has been detected in the CSF of patients complicated with febrile convulsions (6). Recently, 2 encephalitis cases after bone marrow transplants have been reported (4, 5) . Drobyski et al. examined autopsy specimens of the hippocampus from a patient showing temporal symptoms, such as shortterm memory loss, and determined HHV-6 infection using immunohistochemical method (4). Mookerjee et al. demonstrated HHV-6 DNA using PCR methods from CSF of a patient complicated with encephalitis (5 ) . In both cases, radiological findings (CT and MRI) could not detect any abnormalities. In our case, CT showed no abnormal findings but MRI demonstrated edema on the medial temporal lobe, including the limbic system. Short-term memory loss suggested disease involvement in the limbic system. MRI changes in HHV6 encephalitis have been reported in nontransplanted children. Kamei et al. demonstrated T2prolongation of disease sites at an early stage, like the present case which showed atrophy later (7). MRI could have the potential diagnostic value to identify the involved sites in encephalitis patients.

Reactivation of Hepatitis B Virus in Hematopoietic Stem Cell Transplant Recipients in Japan: Efficacy of Nucleos(t)ide Analogues for Prevention and Treatment

We retrospectively reviewed 413 recipients with hematologic malignancies who underwent hematopoietic stem cell transplantation (HSCT) between June 1986 and March 2013. Recipients with antibody to hepatitis B core antigen (anti-HBc) and/or to hepatitis B surface antigen (anti-HBs) were regarded as experiencing previous hepatitis B virus (HBV) infection. Clinical data of these recipients were reviewed from medical records. We defined ≥1 log IU/mL increase in serum HBV DNA from nadir as HBV reactivation in hepatitis B surface antigen (HBsAg)-positive recipients, and also defined ≥1 log IU/mL increase or re-appearance of HBV DNA and/or HBsAg as HBV reactivation in HBsAg-negative recipients. In 5 HBsAg-positive recipients, 2 recipients initially not administered with nucleos(t)ide analogues (NUCs) experienced HBV reactivation, but finally all 5 were successfully controlled with NUCs. HBV reactivation was observed in 11 (2.7%) of 408 HBsAg-negative recipients; 8 of these were treated with NUCs, and fortunately none developed acute liver failure. In 5 (6.0%) of 83 anti-HBc and/or anti-HBs-positive recipients, HBV reactivation occurred. None of 157 (0%) recipients without HBsAg, anti-HBs or anti-HBc experienced HBV reactivation. In HSCT recipients, HBV reactivation is a common event in HBsAg-positive recipients, or in HBsAg-negative recipients with anti-HBc and/or anti-HBs. Further attention should be paid to HSCT recipients with previous exposure to HBV.

Significance of parathyroid hormone-related protein as a factor stimulating bone resorption and causing hypercalcemia in myeloma

Elevated levels of parathyroid hormone‐related protein (PTHrP) in hypercalcemic myeloma patients were demonstrated in recent reports, suggesting that PTHrP behaves as a humoral mediator of hypercalcemia in myeloma. Herein we describe a hypercalcemic myeloma patient with a high serum PTHrP level. Moreover, the PTHrP level in the supernatant of bone marrow aspirates was about two‐fold of that in serum. Reverve transcriptase‐polymerase chain reaction analysis showed PTHrP m‐RNA in bone marrow containing myeloma cells. After chemotherapy, the concentrations of calcium and PTHrP decreased and PTHrP mRNA in bone marrow became undetectable. We conclude that PTHrP released by myeloma cells acted as the main bone resorption stimulating factor in this case. Am. J. Hematol. 59:168–170, 1998.

Changes in serum erythropoietin and the reticulocyte count during chemotherapy for leukemias

Abstract:u2002 We serially determined serum erythropoietin (Epo) and the reticulocyte count in patients with various types of leukemia during chemotherapy. Serum Epo increased soon after the initiation of chemotherapy and decreased after the termination of therapy irrespective of the types of leukemia or treatment regimen. However, it did not stay at low level but fluctuated. The reticulocyte count, on the other hand, showed a transient rise while serum Epo level descended. The value of serum Epo when increased was higher than the value expected from hemoglobin concentration; this finding was similar to that in aplastic anemia. These results suggest that myelosuppression is a major factor for the increase in serum Epo level during leukemia chemotherapy.

Severe hyponatremia caused by syndrome of inappropriate secretion of antidiuretic hormone developed as initial manifestation of human herpesvirus‐6–associated acute limbic encephalitis after unrelated bone marrow transplantation

Severe hyponatremia is a critical electrolyte abnormality in allogeneic stem cell transplantation (allo‐SCT) recipients and >50% of cases of severe hyponatremia are caused by the syndrome of inappropriate secretion of antidiuretic hormone (SIADH). Here, we present a patient with rapidly progressive severe hyponatremia as an initial sign and symptom of human herpesvirus‐6–associated post‐transplantation acute limbic encephalitis (HHV‐6 PALE) after allo‐SCT. A 45‐year‐old woman with acute lymphoblastic leukemia received unrelated bone marrow transplantation from a one locus‐mismatched donor at the DR locus. On day 21, she developed a generalized seizure and loss of consciousness with severe hyponatremia, elevated serum antidiuretic hormone (ADH), and decreased serum osmolality. A high titer of HHV‐6 DNA was detected in cerebrospinal fluid. Treatment with foscarnet sodium and hypertonic saline was started with improvement of neurological condition within several days. Although an elevated serum ADH, low serum osmolality, and high urinary osmolality persisted for 2 months, she had no other recurrent symptoms of encephalitis. Our experience suggests that hyponatremia accompanied by SIADH should be recognized as a prodromal or concomitant manifestation of HHV‐6 PALE, and close monitoring of serum sodium levels in high‐risk patients for HHV‐6 PALE is necessary for immediate diagnosis and treatment initiation.

Posterior reversible encephalopathy syndrome in an adult patient with acute lymphoblastic leukemia after remission induction chemotherapy

Posterior reversible encephalopathy syndrome (PRES) has been reported in childhood leukemia patients increasingly frequently. However, the development of PRES in adult leukemia patients during chemotherapy is very rare. We present a case of PRES in an adult patient with acute lymphoblastic leukemia (ALL) after remission induction chemotherapy. A 28-year-old woman with ALL was administered remission induction chemotherapy consisting of cyclophosphamide, daunorubicin, vincristine, prednisone, and l-asparaginase. After initiation of chemotherapy, the patient developed paralytic ileus and hypertension, and on day 30, she suddenly developed generalized convulsions, loss of visual acuity, and muscle weakness in the legs. Magnetic resonance imaging findings and her signs and symptoms were typical of PRES. The symptoms gradually improved following treatment with an anticonvulsant and an antihypertensive agent, and the patient underwent allogeneic bone marrow transplantation. She has completely recovered from PRES and has been asymptomatic without leukemia relapse. During remission induction chemotherapy for ALL, PRES may be caused by multiple drugs, such as l-asparaginase, vincristine, and corticosteroids, with different mechanisms of action. PRES should be recognized as an important complication, which will occur more frequently with the increased intensity of chemotherapy for adult ALL patients.

Extramedullary blast crisis of chronic myelogenous leukemia as an initial presentation

Extramedullary blast crisis of chronic myelogenous leukemia (CML) is defined as the development of extramedullary disease caused by the infiltration of blasts regardless of proliferation of blasts in the bone marrow. The onset of extramedullary blast crisis in the newly diagnosed patients is known to be extremely rare. Here, we present a case of extramedullary blast crisis of CML as an initial presentation in a 17-year-old female presenting with pain in the left femur tumor. This case was treated successfully with dasatinib and allogeneic hematopoietic stem cell transplantation, with achievement of long-term remission.

Factors associated with the efficiency of PBSC collection in POEMS syndrome patients undergoing autologous PBSC transplantation

Factors associated with the efficiency of PBSC collection in POEMS syndrome patients undergoing autologous PBSC transplantation

Dual inhibition of EZH2 and EZH1 sensitizes PRC2-dependent tumors to proteasome inhibition

Purpose: EZH2 and EZH1, the catalytic components of polycomb repressive complex 2 (PRC2), trigger trimethylation of H3K27 (H3K27me3) to repress the transcription of target genes and are implicated in the pathogenesis of various cancers including multiple myeloma and prostate cancer. Here, we investigated the preclinical effects of UNC1999, a dual inhibitor of EZH2 and EZH1, in combination with proteasome inhibitors on multiple myeloma and prostate cancer. Experimental Design: In vitro and in vivo efficacy of UNC1999 and the combination with proteasome inhibitors was evaluated in multiple myeloma cell lines, primary patient cells, and in a xenograft model. RNA-seq and ChIP-seq were performed to uncover the targets of UNC1999 in multiple myeloma. The efficacy of the combination therapy was validated in prostate cancer cell lines. Results: Proteasome inhibitors repressed EZH2 transcription via abrogation of the RB-E2F pathway, thereby sensitizing EZH2-dependent multiple myeloma cells to EZH1 inhibition by UNC1999. Correspondingly, combination of proteasome inhibitors with UNC1999, but not with an EZH2-specific inhibitor, induced synergistic antimyeloma activity in vitro. Bortezomib combined with UNC1999 remarkably inhibited the growth of myeloma cells in vivo. Comprehensive analyses revealed several direct targets of UNC1999 including the tumor suppressor gene NR4A1. Derepression of NR4A1 by UNC1999 resulted in suppression of MYC, which was enhanced by the combination with bortezomib, suggesting the cooperative blockade of PRC2 function. Notably, this combination also exhibited strong synergy in prostate cancer cells. Conclusions: Our results identify dual inhibition of EZH2 and EZH1 together with proteasome inhibition as a promising epigenetics-based therapy for PRC2-dependent cancers. Clin Cancer Res; 23(16); 4817–30. ©2017 AACR.

Mobilization of PBSCs in poor mobilizers with POEMS syndrome using G-CSF with plerixafor

Auto-SCT has been established as an effective treatment for patients with hematological malignancies such as lymphoma or myeloma. Unfortunately, some patients fail to mobilize a sufficient number of PBSCs for transplantation. Plerixafor is the first molecule to reversibly inhibit the binding of chemokine stromal cell-derived factor-1α (SDF-1α) to its cognate receptor, CXCR4.1 Many recent reports have shown that there is a potential clinical application for plerixafor in PBSC harvesting.2, 3, 4, 5, 6