Shokichi Tsukamoto

Impact of macrophage infiltration of skin lesions on survival after allogeneic stem cell transplantation: a clue to refractory graft-versus-host disease

We retrospectively reviewed 104 biopsy specimens of previously untreated skin acute graft-versus-host disease (GVHD) within 100 days after allogeneic stem cell transplantation, and analyzed the relationship between types of infiltrating cells and clinical outcomes. Counting the total number of CD8(+) T cells, CD163(+) macrophages, and CD1a(+) dendritic cells in 4 fields under original magnification x200, the infiltration of more than 200 cells of CD163(+) macrophages (many macrophages [MM]) was the only significant predictor for refractory GHVD (odds ratio, 3.79; 95% confidence interval, 1.22-11.8; P = .02). In 46 patients given steroid treatments, MM was the only significant predictor for refractory acute GVHD (odds ratio, 5.05; 95% confidence interval, 1.19-21.3; P = .03). Overall survival of patients with MM was significantly lower than that of those with an infiltration of less than 200 cells of CD163(+) macrophages. Macrophage infiltration of skin lesions could be a significant predictive factor for refractory GVHD and a poor prognosis.

Tetraspanin CD9 modulates ADAM17-mediated shedding of LR11 in leukocytes.

LR11, also known as SorLA or SORL1, is a type-I membrane protein from which a large extracellular part, soluble LR11 (sLR11), is released by proteolytic shedding on cleavage with a disintegrin and metalloproteinase 17 (ADAM17). A shedding mechanism is presumed to have a key role in the functions of LR11, but the evidence for this has not yet been demonstrated. Tetraspanin CD9 has been recently shown to regulate the ADAM17-mediated shedding of tumor necrosis factor-α and intercellular adhesion molecule-1 on the cell surface. Here, we investigated the role of CD9 on the shedding of LR11 in leukocytes. LR11 was not expressed in THP-1 monocytes, but it was expressed and released in phorbol 12-myristate 13-acetate (PMA)-induced THP-1 macrophages (PMA/THP-1). Confocal microscopy showed colocalization of LR11 and CD9 proteins on the cell surface of PMA/THP-1. Ectopic neo-expression of CD9 in CCRF-SB cells, which are LR11-positive and CD9-negative, reduced the amount of sLR11 released from the cells. In contrast, incubation of LR11-transfected THP-1 cells with neutralizing anti-CD9 monoclonal antibodies increased the amount of sLR11 released from the cells. Likewise, the PMA-stimulated release of sLR11 increased in THP-1 cells transfected with CD9-targeted shRNAs, which was negated by treatment with the metalloproteinase inhibitor GM6001. These results suggest that the tetraspanin CD9 modulates the ADAM17-mediated shedding of LR11 in various leukemia cell lines and that the association between LR11 and CD9 on the cell surface has an important role in the ADAM17-mediated shedding mechanism.

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.

LR11: a novel biomarker identified in follicular lymphoma

Follicular lymphoma (FL) is the second most frequent type of non-Hodgkin lymphoma and is incurable by combination chemotherapies (Salles & Ghesquieres, 2012). Although the Follicular Lymphoma International Prognostic Index-2 (FLIPI-2) is predictive for progression-free survival (PFS) (Federico et al, 2009), widely adapted biomarkers that are directly released from FL tumour cells have not been established to date. LR11 (also called SORL1 or SorLA) is a type I membrane protein that plays a key role in the migration of undifferentiated vascular smooth muscle cells (Jiang et al, 2008), and circulating soluble LR11 (sLR11) is a biomarker for coronary stenosis (Takahashi et al, 2010). The potent action of sLR11 is mediated by the urokinase-type plasminogen activator receptor (uPAR)/integrin-mediated activation of focal adhesion kinase (FAK)/ERK/Rac1 cascades (Ohwaki et al, 2007). LR11 is also expressed in human CD34CD38 immature haematopoietic precursors (Zhang et al, 2000), but little is known about its potential role in haematopoietic cells. We have recently found that LR11 is highly expressed in leukaemic cells and that serum sLR11 levels in acute leukaemia patients are significantly increased at diagnosis and normalize at remission (Sakai et al, 2012). Here we analysed the expression profile of LR11 in FL cells and evaluated the clinical importance of serum sLR11 levels in FL patients. Tumour specimens and serum samples were collected from 61 newly diagnosed, untreated FL patients attending Chiba University Hospital and affiliated hospitals between 2002 and 2012. Fifty-two patients (85.2%) were treated with the R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) regimen, 3 (4.9%) with irradiation only, and 6 (9.8%) were observed without treatment (see Table SI for patients’ characteristics). Paired serum samples at diagnosis and remission were obtained in 20 patients. Normal controls were serum samples collected from 75 healthy adult volunteers who had given informed consent.

Clinical significance of hemophagocytosis in BM clot sections during the peri-engraftment period following allogeneic hematopoietic SCT

The effects of macrophage activation on the outcome of allogeneic hematopoietic SCT (allo-HSCT) have yet to be fully examined. A total of 70 adult patients who received a first allo-HSCT for hematological diseases were studied. We counted the number of hemophagocytic cells in BM clot sections on day +14±7, and analyzed its impact on subsequent outcome. In all, 23 patients were diagnosed as having increased numbers of hemophagocytic cells (HP group), whereas 47 were not (non-HP group). The HP group was not associated with an increased incidence of acute or chronic GVHD, but was associated with worse hematopoietic recovery than the non-HP group. The 2-year OS for the HP group and the non-HP group was 30 and 65% (P<0.01), respectively, and 2-year non-relapse mortality was 48% and 27% (P<0.01), respectively. Multivariate analysis confirmed that the HP group was associated with a lower OS (hazard ratio (HR)=2.3; 95% confidence interval (CI), 1.0–5.4; P=0.048) and higher non-relapse mortality (HR=4.0; 95% CI, 1.6–9.9; P<0.01). The HP group had higher incidences of death due to graft failure (P<0.01) and endothelial complications, such as sinusoidal obstruction syndrome and transplant-associated microangiopathy (P=0.01). Macrophage activation is a previously unrecognized complication with negative impact on outcome of allo-HSCT.

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

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

Low-dose trimethoprim-sulfamethoxazole for Pneumocystis jiroveci pneumonia prophylaxis after allogeneic hematopoietic SCT.

Low-dose trimethoprim–sulfamethoxazole for Pneumocystis jiroveci pneumonia prophylaxis after allogeneic hematopoietic SCT