Joji Yamamoto

Activation of peroxisome proliferator-activated receptor δ induces fatty acid β-oxidation in skeletal muscle and attenuates metabolic syndrome

In this study, we defined the role of peroxisome proliferator-activated receptor β/δ (PPARδ) in metabolic homeostasis by using subtype selective agonists. Analysis of rat L6 myotubes treated with the PPARδ subtype-selective agonist, GW501516, by the Affymetrix oligonucleotide microarrays revealed that PPARδ controls fatty acid oxidation by regulating genes involved in fatty acid transport, β-oxidation, and mitochondrial respiration. Similar PPARδ-mediated gene activation was observed in the skeletal muscle of GW501516-treated mice. Accordingly, GW501516 treatment induced fatty acid β-oxidation in L6 myotubes as well as in mouse skeletal muscles. Administration of GW501516 to mice fed a high-fat diet ameliorated diet-induced obesity and insulin resistance, an effect accompanied by enhanced metabolic rate and fatty acid β-oxidation, proliferation of mitochondria, and a marked reduction of lipid droplets in skeletal muscles. Despite a modest body weight change relative to vehicle-treated mice, GW501516 treatment also markedly improved diabetes as revealed by the decrease in plasma glucose and blood insulin levels in genetically obese ob/ob mice. These data suggest that PPARδ is pivotal to control the program for fatty acid oxidation in the skeletal muscle, thereby ameliorating obesity and insulin resistance through its activation in obese animals.

Low-density lipoprotein receptor-related protein 5 (LRP5) is essential for normal cholesterol metabolism and glucose-induced insulin secretion

A Wnt coreceptor low-density lipoprotein receptor-related protein 5 (LRP5) plays an essential role in bone accrual and eye development. Here, we show that LRP5 is also required for normal cholesterol and glucose metabolism. The production of mice lacking LRP5 revealed that LRP5 deficiency led to increased plasma cholesterol levels in mice fed a high-fat diet, because of the decreased hepatic clearance of chylomicron remnants. In addition, when fed a normal diet, LRP5-deficient mice showed a markedly impaired glucose tolerance. The LRP5-deficient islets had a marked reduction in the levels of intracellular ATP and Ca2+ in response to glucose, and thereby glucose-induced insulin secretion was decreased. The intracellular inositol 1,4,5-trisphosphate (IP3) production in response to glucose was also reduced in LRP5−/− islets. Real-time PCR analysis revealed a marked reduction of various transcripts for genes involved in glucose sensing in LRP5−/− islets. Furthermore, exposure of LRP5+/+ islets to Wnt-3a and Wnt-5a stimulates glucose-induced insulin secretion and this stimulation was blocked by the addition of a soluble form of Wnt receptor, secreted Frizzled-related protein-1. In contrast, LRP5-deficient islets lacked the Wnt-3a-stimulated insulin secretion. These data suggest that Wnt/LRP5 signaling contributes to the glucose-induced insulin secretion in the islets.

Fasting-Induced Hypothermia and Reduced Energy Production in Mice Lacking Acetyl-CoA Synthetase 2

Acetate is activated to acetyl-CoA by acetyl-CoA synthetase 2 (AceCS2), a mitochondrial enzyme. Here, we report that the activation of acetate by AceCS2 has a specific and unique role in thermogenesis during fasting. In the skeletal muscle of fasted AceCS2(-/-) mice, ATP levels were reduced by 50% compared to AceCS2(+/+) mice. Fasted AceCS2(-/-) mice were significantly hypothermic and had reduced exercise capacity. Furthermore, when fed a low-carbohydrate diet, 4-week-old weaned AceCS2(-/-) mice also exhibited hypothermia accompanied by sustained hypoglycemia that led to a 50% mortality. Therefore, AceCS2 plays a significant role in acetate oxidation needed to generate ATP and heat. Furthermore, AceCS2(-/-) mice exhibited increased oxygen consumption and reduced weight gain on a low-carbohydrate diet. Our findings demonstrate that activation of acetate by AceCS2 plays a pivotal role in thermogenesis, especially under low-glucose or ketogenic conditions, and is crucially required for survival.

Multicenter phase II study of bendamustine for relapsed or refractory indolent B‐cell non‐Hodgkin lymphoma and mantle cell lymphoma

Bendamustine is a unique cytotoxic agent that has demonstrated efficacy in the treatment of indolent B‐cell non‐Hodgkin lymphomas (B‐NHLs). In this multicenter phase II trial, the efficacy and safety of bendamustine were evaluated in Japanese patients with relapsed or refractory indolent B‐NHL or mantle‐cell lymphoma (MCL). Patients received bendamustine (120 mg/m2) on days 1–2 of a 21‐day cycle, for up to six cycles. The primary endpoint was the overall response rate (ORR) as assessed by an extramural committee according to International Workshop Response Criteria (IWRC). Secondary endpoints included complete response (CR) rate, ORR according to Revised Response Criteria (revised RC), progression‐free survival (PFS), and safety. Fifty‐eight patients with indolent B‐NHL and 11 with MCL were enrolled. By IWRC, bendamustine produced an ORR of 91% (95% confidence interval [CI], 82–97%; 90% and 100% in patients with indolent B‐NHL and MCL, respectively), with a CR rate of 67% (95% CI, 54–78%). ORR and CR rates according to revised RC were 93% (95% CI, 84–98%) and 57% (95% CI, 44–68%), respectively. After a median follow‐up of 12.6 months, median PFS had not been reached. Estimated PFS rates at 1 year were 70% and 90% among indolent B‐NHL and MCL patients, respectively. Bendamustine was generally well tolerated. Reversible myelosuppression, including grade 3/4 leukopenia (65%) and neutropenia (72%), was the most clinically significant toxicity observed. Common non‐hematologic toxicities included mild gastrointestinal events and fatigue. These results demonstrate the high efficacy and tolerability of single‐agent bendamustine in relapsed patients with indolent B‐NHL or MCL histologies. (ClinicalTrials.gov ID: NCT00612183). (Cancer Sci 2010;)

Successful treatment with bortezomib and thalidomide for POEMS syndrome.

Dear Editor, A 60-year-old female patient was admitted to our hospital because of progressive pleural effusion. Physical examination revealed lymphadenopathy in the neck, axillary, and inguinal regions, edema of the lower extremities, skin changes such as hyperpigmentation and hypertrichosis, and distal weakness and paresthesias in extremities. She was unable to walk. A computed tomography scan showed multiple lymphadenopathy, osteosclerotic lesions on ribs, thoracic vertebrae, ilium and sacrum, massive pleural effusion, and mild splenomegaly with ascites. A positron-emission tomography (PET) scan revealed increased accumulation of [F] fluorodeoxyglucose in the osteosclerotic lesions. Immunoglobulin levels were normal, but serum monoclonal IgG λ protein was detected by immunoelectrophoresis. Bone marrow aspiration showed no increase of plasma cells. Biopsy of an osteosclerotic lesion in the rib was compatible with plasma cell neoplasm with λ light-chain restriction. Her serum vascular endothelial growth factor (VEGF) level was elevated at 378 pg/ml (normal range, <38 pg/ml). Endocrinological tests showed hypothyroidism and hyperprolactinemia. Nerve conduction studies demonstrated severe sensorimotor polyneuropathy. The diagnosis of polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome was made [1]. The autologous transplant was not planned because of poor performance status and progressive pleural effusion and ascites. The patient was initially treated with high dose dexamethasone, and then, MP regimen (melphalan and prednisolone), but her conditions rapidly deteriorated. We decided to use bortezomib because this agent has been reported to inhibit the secretion of VEGFwhich is the dominant-driving cytokine in POEMS syndrome [2], and there have been three case reports of POEMS syndrome successfully treated with bortezomib-based regimen (Table 1) [3–5]. Bortezomib was started at a dosage of 1.3 mg/m on days 1, 4, 8, and 11 of a 21-day cycle. After the second cycle, her extravascular volume overload dramatically improved, and the serum VEGF level decreased to 54 pg/ml. On a PET scan after 3 cycles of bortezomib, no abnormal uptake of tracer was seen. Bortezomib was reduced to 1.3 mg/m on days 1 and 8 for grade 3 diarrhea from the fourth cycle, which became manageable with this dose reduction. Although her conditions significantly improved and the serum VEGF level further decreased to 41 pg/ml, fluid retention and serum monoclonal protein was still present. We then added thalidomide at 100 mg/day to bortezomib from the sixth cycle, because several reports have suggested that thalidomide is effective for POEMS syndrome [6–9]. After the addition of thalidomide, pleural effusion and ascites completely disappeared, and serum monoclonal protein did not become detectable by immunofixation. Peripheral neuropathy is a common side effect of bortezomib and thalidomide, but symptoms of polyneuropathy improved gradually, and she was able to walk with equipment, suggesting the benefit of these drugs exceed the risk of those neurotoxicities, consistent with previous reports [3–9]. Administration of bortezomib was H. Ohguchi (*) : R. Ohba :Y. Onishi :N. Fukuhara :Y. Okitsu : J. Yamamoto :K. Ishizawa :H. Harigae Department of Hematology and Rheumatology, Tohoku University Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan e-mail: ohguchi@med.tohoku.ac.jp

Allogeneic hematopoietic stem cell transplant following chemotherapy containing L-asparaginase as a promising treatment for patients with relapsed or refractory extranodal natural killer/T cell lymphoma, nasal type

The prognosis of advanced extranodal NK/T cell lymphoma (ENKTL) is poor. Allogeneic hematopoietic stem cell transplant (allo-HSCT) has been suggested to be a promising treatment for this disease, but its utility has yet to be established. Here we retrospectively analyzed five cases of ENKTL treated with allo-HSCT in our institute. After induction chemotherapy, disease status at allo-HSCT was second CR in three patients and refractory in two patients. All patients received a myeloablative conditioning regimen, and GVHD prophylaxis consisted of tacrolimus or cyclosporine with short-term methotrexate. Only one patient who received conventional induction chemotherapy developed severe complications, which needed long-term treatment, while others who received chemotherapy containing l-asparaginase did not have severe complications. There were no cases of treatment-related mortality, and all patients survived without disease for a median follow-up period of 1911 days. These results suggested that allo-HSCT following l-asparaginase-containing induction chemotherapy might improve the outcome of advanced ENKTL.

Acquired hemophilia A with sigmoid colon cancer : successful treatment with rituximab followed by sigmoidectomy

Acquired hemophilia A is a rare and potentially fatal condition of coagulopathy caused by autoantibodies against clotting factor VIII (factor VIII inhibitor). We report a case of a 63-year-old woman, who presented with a sudden onset of severe hemorrhagic tendency with exclusively prolonged activated partial thromboplastin time (APTT). She was diagnosed with acquired hemophilia A due to a decrease in factor VIII activity and a high titer of factor VIII inhibitor. Hemorrhage was well controlled by recombinant activated factor VII. Although the level of factor VIII inhibitor did not decline with prednisolone and cyclophosphamide, it became undetectable with rituximab. In parallel with controlling hemorrhage, malignancy, which may cause acquired hemophilia A, was searched for and sigmoid colon cancer was found. After the eradication of factor VIII inhibitor, surgical resection was performed uneventfully. Thereafter, acquired hemophilia A has been in complete remission without any additional therapy. The present case suggests the efficacy of rituximab for refractory acquired hemophilia A and the importance of the identification of underlying diseases that can cause acquired hemophilia A.

CD26, together with cell surface adenosine deaminase, is selectively expressed on ALK-positive, but not on ALK-negative, anaplastic large cell lymphoma and Hodgkin's lymphoma

CD26/dipeptidyl peptidase IV is a cell surface antigen with multiple biological functions. Although its involvement in tumor biology has been suggested, the significance of its expression in malignant lymphoma has not been clarified in detail. This study examined the expression of CD26 and cell surface adenosine deaminase (ADA) in 42 cases of Hodgkins lymphoma (HL) and T-cell lymphoma by immunohistochemistry on frozen sections. CD26 was expressed in three of 14 cases of HL, in four of eight cases of anaplastic large cell lymphoma (ALCL), in two of nine cases of peripheral T-cell lymphoma, in one of six cases of lymphoblastic lymphoma and in none of three cases of adult T-cell lymphoma/leukemia. Expression of cell surface ADA was fully correlated with the expression of CD26 and expression of CD26/ADA in ALCL and HL was also completely correlated with the expression of p80 and epithelial membrane antigen. Of 10 CD26-positive patients, seven had fever and elevated CRP at initial diagnosis and over a median follow-up of 61 months (range, 7 – 152 months) only three survived. This study suggested that CD26 is selectively expressed on ALK-positive, but not on ALK-negative, ALCL and HL. This is also the first report to demonstrate that ADA is coexpressed with CD26 on the cell surface of malignant neoplasms in vivo.

Clinicopathological analysis of primary adrenal diffuse large B-cell lymphoma: effectiveness of rituximab-containing chemotherapy including central nervous system prophylaxis

BackgroundPrimary adrenal lymphoma (PAL) is an extremely rare subtype of extranodal non-Hodgkin’s lymphoma. Some researchers have reported some of the characteristics of PAL and its association with poor prognosis; however, the clinicopathological features of PAL remain to be elucidated.MethodsFrom 2008 to 2011 we experienced seven cases of PAL in our institutions. We retrospectively analyzed the clinical and pathological features of these patients.ResultsThe patients ranged in age from 50 to 85 years, with a median of 71 years. The overall male:female ratio was 6:1. All seven patients were diagnosed with diffuse large B-cell lymphoma (DLBCL) pathologically. Bilateral adrenal involvement was confirmed in five patients. The median largest tumor diameter at diagnosis was 58 mm. The Ki-67 index was generally high (>70%). All patients were treated with rituximab-containing chemotherapy, and central nervous system (CNS) prophylaxis was conducted for three patients. One patient with CNS involvement at the time of the diagnosis also received whole-brain radiation. The overall survival rate at two years was 57% (median follow-up; 24.8 months). It is noteworthy that the three patients who received a full course of the rituximab-containing regimen and CNS prophylaxis are currently alive without disease relapse, and that none of the seven patients died due to progression of lymphoma.ConclusionsPrimary adrenal DLBCL can be a clinically aggressive disease entity. Rituximab-containing chemotherapy combined with CNS prophylaxis could be a reasonable option for the treatment of PAL; however, analyses of more PAL cases are needed for the establishment of this strategy.

Association between BACH2 expression and clinical prognosis in diffuse large B-cell lymphoma.

BACH2, a B cell‐specific transcriptional repressor, plays a significant role in B cell maturation. Despite a number of previous studies, the clinicopathological significance of BACH2 expression in diffuse large B cell lymphoma (DLBCL) remains to be established. The present study was performed to validate the significance of BACH2 expression as a predictor of prognosis in DLBCL. A total of 94 DLBCL cases were included in the present study. All were diagnosed between 2008 and 2011, and thorough clinical and pathological investigations were possible, including immunohistochemical analysis of BACH2. Eighteen cases were selected by positive MYC gene alteration (MYC+ group) according to cytogenetic study. The remaining 76 cases were subclassified into germinal center B cell phenotype (GCB group, 38 cases) or non‐GCB phenotype (non‐GCB group, 38 cases). There were no significant differences between the two groups with regard to clinical characteristics and outcomes. In the GCB group, 21 cases were judged to have high BACH2 expression, with 19 cases in the non‐GCB group. In cases with high BACH2 expression in GCB and non‐GCB groups, the 3‐year overall survival (OS) rate was significantly shorter than that with low expression (71.7% vs 91.3%, P = 0.0256). In the MYC+ group, 15 cases had high BACH2 expression levels. Although overall the MYC+ group showed short survival time (3‐year OS 35.0%), 3 out of 4 cases with low BACH2 expression are alive without disease relapse at the time of publication of this paper. In conclusion, BACH2 expression level is a promising predictor of prognosis for DLBCL.