Kohei Okada

TLR2-dependent induction of IL-10 and Foxp3+ CD25+ CD4+ regulatory T cells prevents effective anti-tumor immunity induced by Pam2 lipopeptides in vivo.

16 S-[2,3-bis(palmitoyl)propyl]cysteine (Pam2) lipopeptides act as toll-like receptor (TLR)2/6 ligands and activate natural killer (NK) cells and dendritic cells (DCs) to produce inflammatory cytokines and cytotoxic NK activity in vitro. However, in this study, we found that systemic injection of Pam2 lipopeptides was not effective for the suppression of NK-sensitive B16 melanomas in vivo. When we investigated the immune suppressive mechanisms, systemic injection of Pam2 lipopeptides induced IL-10 in a TLR2-dependent manner. The Pam2 lipopeptides increased the frequencies of Foxp3+CD4+ regulatory T (T reg) cells in a TLR2- and IL-10- dependent manner. The T reg cells from Pam2-lipopeptide injected mice maintained suppressor activity. Pam2 lipopeptides, plus the depletion of T reg with an anti-CD25 monoclonal antibody, improved tumor growth compared with Pam2 lipopeptides alone. In conclusion, our data suggested that systemic treatment of Pam2 lipopeptides promoted IL-10 production and T reg function, which suppressed the effective induction of anti-tumor immunity in vivo. It is necessary to develop an adjuvant that does not promote IL-10 and T reg function in vivo for the future establishment of an anti-cancer vaccine.

HB Vaccination in the Prevention of Viral Reactivation in Allogeneic Hematopoietic Stem Cell Transplantation Recipients with Previous HBV Infection

Hepatitis B virus (HBV)-reverse seroconversion (RS) following allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a frequent late-onset complication in recipients with previous HBV infection. We followed 38 allo-HSCT recipients with previous HBV infection, and conducted posttransplant HB vaccine intervention in 13 recipients. First, we followed the recipients without any intervention (historic control) until 2003; hence, we commenced HB vaccination. Out of the patients who underwent transplantation after 2003, 13 recipients were immunized by a standard three-dose regimen after immunosuppressant cessation (vaccine group), whereas 12 recipients were observed without any intervention (nonvaccine group). Eight of the 13 historic control group recipients and 3 of the 12 nonvaccine group recipients, but none of the 13 vaccine group recipients, suffered HBV-RS. Cumulative risks of HBV-RS at 3 years post-HSCT in the historic control, nonvaccine and vaccine groups were 41%, 39%, and 0% respectively (P=.022). We therefore conclude that intervention with HB vaccines is significantly effective in preventing post-HSCT HBV-RS.

Reduced intensity conditioning regimen with fludarabine, busulfan, and low-dose TBI (Flu-BU2-TBI): clinical efficacy in high-risk patients.

Reduced intensity conditioning (RIC) regimens are widely used in allogeneic stem cell transplantation (SCT). In this study, we retrospectively investigated the clinical outcomes of RIC with fludarabine (Flu; 180 mg/m2), intravenous busulfan (BU; 6.4 mg/kg) or oral BU (8 mg/kg), and low‐dose total body irradiation (TBI; 4 Gy) (Flu‐BU2‐TBI) in 66 patients (median age: 54.5 years) with various hematological malignancies. Thirty‐eight patients (58%) were high‐risk patients (median age: 56 years). The overall survival rate at 2 years of the high‐risk patients was 64.5%, which was comparable to the survival rate of 70.9% in standard‐risk patients (P = 0.68). The relapse rates at 2 years in the standard‐risk and high‐risk patients were 16 and 28%, respectively, and day 100 treatment‐related mortality rates were 0 and 6%, respectively. The Flu‐BU2‐TBI regimen for high‐risk patients showed therapeutic effects equivalent to those for standard‐risk patients and favorable outcomes compared with those of other previous RIC regimens. Am. J. Hematol., 2010.

Allogeneic hematopoietic stem cell transplantation following reduced-intensity conditioning for mycosis fungoides and Sezary syndrome.

Advanced‐stage mycosis fungoides and Sezary syndrome (MF/SS) have a poor prognosis. Allogeneic hematopoietic stem cell transplantation (HSCT), particularly using a reduced‐intensity conditioning (RIC) regimen, is a promising treatment for advanced‐stage MF/SS. We performed RIC‐HSCT in nine patients with advanced MF/SS. With a median follow‐up period of 954 days after HSCT, the estimated 3‐year overall survival was 85.7% (95% confidence interval, 33.4–97.9%) with no non‐relapse mortality. Five patients relapsed after RIC‐HSCT; however, in four patients whose relapse was detected only from the skin, persistent complete response was achieved in one patient, and the disease was manageable in other three patients by the tapering of immunosuppressants and donor lymphocyte infusion, suggesting that graft‐versus‐lymphoma effect and ‘down‐staging’ effect from advanced stage to early stage by HSCT improve the prognosis of advanced‐stage MF/SS. These results suggest that RIC‐HSCT is an effective treatment for advanced MF/SS. Copyright

Stenotrophomonas maltophilia infection during allogeneic hematopoietic stem cell transplantation: a single‐center experience

To examine risk factors for Stenotrophomonas maltophilia (S. maltophilia) infection during allogeneic hematopoietic stem cell transplantation (allo‐HSCT), we retrospectively analyzed 259 patients who underwent allo‐HSCT. Not only S. maltophilia infection but also S. maltophilia colonization was associated with mortality during allo‐HSCT. Among 52 episodes in 39 patients in whom S. maltophilia was detected, documented infection developed in 33 episodes (25 patients). The onset of S. maltophilia infection in the period from the conditioning regimen to engraftment was associated with a high mortality rate. Breakthrough S. maltophilia infection developed in 24% of the patients during prophylactic administration of fluoroquinolones, to which S. maltophilia is sensitive. Reinsertion of a central venous catheter (CVC) immediately after removal was suggested to be a risk for persistent S. maltophilia infection in the period of neutropenia. Our results indicated that (i) onset of S. maltophilia infection in the period from the conditioning therapy to engraftment and (ii) removal and immediate reinsertion of a CVC as treatment after the onset of S. maltophilia infection are possible risk factors for S. maltophilia‐related mortality during allo‐HSCT.

The 8p11 myeloproliferative syndrome owing to rare FGFR1OP2-FGFR1 fusion

To the Editor: The 8p11 myeloproliferative syndrome (EMS) is an aggressive neoplasm associated with chromosomal abnormalities involving the fibroblast growth factor receptor 1 (FGFR1) tyrosine kinase gene on chromosome 8p11–12. A 43-yr-old man was referred owing to progressive lymphoadenopathy and eosinophilia. Laboratory data showed an elevated white blood cell count with a markedly elevated eosinophil count and no circulatory blast (WBC: 36.5 · 10 ⁄L, eosinophils: 19.5%). The lactate dehydrogenase level was elevated (LDH 478 U ⁄L). Biopsy of a cervical lymph node revealed T-cell lymphoblastic lymphoma. Bone marrow aspiration revealed hypercellular marrow with markedly increased eosinophils (Fig. 1A). Chromosome analyses of the bone marrow and lymph node specimen were both initially interpreted as 46,XY [20]. Because of the unique presentation of concurrent T-cell lymphoblastic lymphoma and eosinophilia, we were suspected that the patient had a cryptic FGFR1 abnormality despite the normal karyotype. To confirm cryptic cytogenetic abnormality, we sent a sample for spectral karyotype fluorescence in situ hybridisation (SKY-FISH) analysis (SRL, Tokyo, Japan). SKYFISH revealed an obvious chromosomal abnormality, which could read 46,XY,t(8;12)(p11;p12) [5] (Fig. 1B). A literature search revealed one previous report with an

Regimen-Related Mucosal Injury of the Gut Increased the Incidence of CMV Disease after Allogeneic Bone Marrow Transplantation

Cytomegalovirus (CMV) infection is 1 of the major causes of morbidity in patients undergoing allogeneic stem cell transplantation (allo-SCT). The incidences of CMV antigenemia and CMV disease in 43 patients who received allogeneic bone marrow transplantation (BMT) using a reduced-intensity conditioning (RIC) regimen, which mainly consisted of fludarabine (Flu), busulfan (Bu), and total body irradiation (TBI), were compared with those in 68 patients who received a myeloablative conditioning (MAC) regimen, and risk factors for CMV antigenemia and CMV disease were identified. Before engraftment, grade 3-4 mucosal injury because of the conditioning regimen was significantly decreased in RIC patients (stomatitis: P = .02; diarrhea: P < .01). Rate of engraftment, incidences of acute graft-versus-host disease (aGVHD), and rate of corticosteroid administration were not different in RIC patients and MAC patients. Although the incidences of CMV antigenemia were not significantly different in RIC patients and MAC patients (64.1% versus 57.8%, log rank, P = .59), the incidence of CMV disease was significantly decreased in RIC patients (5.4% versus 20.3%, log rank, P = .04). CMV seropositivity in the patients (P < .01) and corticosteroid administration (P < .01) were revealed by multivariate analysis to be significant risk factors for CMV antigenemia. Grade II-IV aGVHD (P = .02) and grade 3-4 diarrhea before engraftment (P = .04) were revealed to be risk factors for CMV disease. The present study is the first study to show that severe diarrhea before engraftment is a significant risk factor for CMV disease. In summary, risk of CMV disease was significantly decreased in patients without severe mucosal injury of the gut because of the conditioning regimen before engraftment.

Disseminated toxoplasmosis after hematopoietic stem cell transplantation showing unusual magnetic resonance images

We herein report a patient who had disseminated toxoplasmosis after hematopoietic stem cell transplantation showing atypical clinical presentation and neuroimaging. Parkinsonism symptoms such as muscle rigidity, bradykinesia, tremor, and postural instability were initial manifestations. Magnetic resonance imaging showed diffuse symmetrical lesions of bilateral basal ganglia lacking ringed enhancement. Post‐mortem analysis revealed multiple tachyzoites of Toxoplasma gondii in the basal ganglia, mid brain, cerebellum, and cardiac muscle.

Case of peripheral T‐cell lymphoma, not otherwise specified, presenting dyshidrosis‐like eruptions as the first clinical manifestation

Dear Editor, Peripheral T-cell lymphomas (PTCL) are a heterogeneous group of disorders that compose 5–20% of non-Hodgkin lymphoma. The most common subtype is PTCL, not otherwise specified (NOS), accounting for approximately 25% of cases. Skin involvement is reported in 20% of PTCL-NOS cases, but there are few reports describing dyshidrosis-like eruptions. Herein, we describe a patient with dyshidrotic eruptions as the first clinical manifestation of PTCL-NOS. A 67-year-old Japanese man with no history of mycosis fungoides (MF) was referred to our department with a 4-week history of itchy eruptions on the whole body. Physical examination revealed dyshidrotic vesicles on the palms and soles, erythematous plaques around the ears and papules on the trunk (Fig. 1a–c). Superficial lymph nodes (cervical, axillary and inguinal) were palpable. The biopsy specimen from the dyshidrotic vesicle on the right palm showed intraepidermal bullae with dense infiltration of atypical lymphocytes into the epidermis and upper dermis (Fig. 1d,e). A biopsy specimen from a plaque around the ear showed similar findings (Fig. 1f). Immunohistochemistry of the atypical lymphocytes was positive for CD3, CD4 (focally), CD5 and CD30, whereas it was negative for CD7, CD8, CD20, Epstein–Barr virus-encoded RNA, anaplastic lymphoma kinase (ALK)-1, epithelial membrane antigen, perforin, granzyme B and TIA-1 (Fig. 1g–l). Laboratory examinations revealed elevated levels of lactase dehydrogenase (584 U/L; normal, 124–222) and soluble interleukin-2 receptor (624 U/mL; normal, 0–459). Neither antihuman T-lymphotropic virus 1 nor HIV antibodies were detected. Computed tomography (CT) revealed enlarged lymph nodes and diffuse granular shadows like acute respiratory distress syndrome on the lungs. Positron emission tomography/

Diffuse large B-cell lymphoma with a bulky mass in the cranial vault

tumor. The neurological symptoms began to improve after surgical resection of the tumor, and the patient achieved complete metabolic remission without any residual neurological symptoms after six cycles of R-CHOP (Fig. 2). However, relapse at the right thigh occurred 18 months after the diagnosis. Bone involvement of DLBCL is not rare, and is typically seen in the long bones and spine [1]. However, initial involvement of cranial vault is rare and primary cranial vault lymphoma constitutes only 0.2% of lymphoma cases. Cranial vault lymphoma is categorized as primary bone lymphoma and differs biologically from primary central nervous lymphoma. Our patient presented with a bulky mass and diverse neurologic symptoms and no evidence of central nervous system infiltration. Lymphoma, including DLBCL, should be considered in the differential diagnosis of a bulky mass of the cranial vault, and surgical decompression may be beneficial for patients with neurological symptoms. A previously healthy 65-year-old man was referred to our institute for the evaluation of a bulky mass in the cranial vault. Neurologic examination revealed right hemiplegia, aphasia, acalculia, and agraphia. [F] fluoro-2-deoxyd-glucose positron emission tomography/computed tomography (F-FDG-PET/CT) showed a bulky mass with an abnormal FDG uptake in the cranial vault accompanied by mild systemic lymphadenopathy (Fig. 1a). Surgical resection of the cranial tumor was performed for pathological examination and cranial decompression. A macroscopic examination of the surgical specimen showed that the tumor was localized in the cranial vault, and the cranial bone had been extensively lysed by the tumor without any evidence of dural invasion (Fig. 1b). The tumor was pathologically diagnosed as diffuse large B-cell lymphoma (DLBCL). Immunohistochemical analysis revealed that neoplastic cells were positive for CD20, CD79a, MUM-1, and Bcl6, and negative for CD3, CD5, and CD10, indicating further subclassification as a non-germinal center B-cell-like