The prognostic impact of FLT3-ITD, NPM1 and CEBPa in cytogenetically intermediate-risk AML after first relapse.

We evaluated the impact of FLT3-ITD, NPM1 mutations, and double mutant CEBPa (dmCEBPa) on overall survival (OS) after relapse in patients with cytogenetically intermediate-risk acute myeloid leukemia (AML) who were treated with chemotherapy alone in the first remission (CR1). Patients aged 16-65 years diagnosed with cytogenetically intermediate-risk AML, and who achieved CR1 were included. We retrospectively analyzed FLT3-ITD, NPM1 mutations and CEBPa using samples obtained at diagnosis, which therefore did not affect the therapeutic decisions. Among 235 patients who had achieved CR1, 152 relapsed, and 52% of them achieved second CR. The rate of achieving second CR was significantly higher (85%) in those with dmCEBPa. Patients with FLT3-ITD had significantly worse OS after relapse than those without (19% vs 41%, p = 0.002), while OS was comparable between patients with and without NPM1 mutations (37% vs 34%, p = 0.309). Patients with dmCEBPa had improved OS than those without (61% vs 32%, p = 0.006). By multivariate analysis, FLT3-ITD was independently associated with worse OS after relapse [hazard ratio (HR) 1.99, 95% CI 1.27-3.12, p = 0.003], and dmCEBPa with improved OS (HR 0.40, 95% CI 0.17-0.93, p = 0.033). Our data show that screening for these mutations at diagnosis is useful for facilitating effective therapeutic decision-making even after relapse.

Timely Diagnosis and Successful Treatment of Intravascular Large B-Cell Lymphoma in an Elderly Patient with Poor Performance Status.

BACKGROUND Intravascular large B-cell lymphoma (IVLBCL) is a rare type of extranodal large B-cell lymphoma characterized by involvement of lymphoma cells in the lumina of small blood vessels in various organs. Although many studies have claimed that timely diagnosis and early initiation of chemotherapy are important, the literature on the successful treatment of IVLBCL in elderly patients over the age of 80 years is scarce. CASE REPORT An 82-year-old man presented with abnormal elevation of lactate dehydrogenase at 1605 IU/L and altered mental status, which manifested as forgetfulness, abnormal behavior, and worsening performance status for 2 days. There was no evidence of lymphadenopathy or skin lesions, but a computed tomography scan of the chest showed bilateral diffuse ground-glass opacities. With a primary consideration of IVLBCL, random skin biopsy and transbronchial lung biopsy were performed. Immediately after the pathologic findings on hematoxylin-eosin staining alone revealed abnormal large cells in the small vessels, chemotherapy with cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP) at half the usual dose was started; later on, immunostaining revealed CD20 expression in the abnormal lymphoid cells. Immediately after CHOP administration, his mental and physical symptoms rapidly resolved. After 8 cycles of dose-reduced CHOP with rituximab, he remained free from disease progression 2 years after the diagnosis. CONCLUSIONS We presented a case of successful early chemotherapy for IVLBCL in an elderly patient with poor performance status. Early chemotherapy with CHOP, even before obtaining a definitive diagnosis based on immunostaining, may contribute to good outcomes.

ANCA-associated vasculitis with dual ANCA positivity in coexistence with mixed connective tissue disease.

We here report a rare case of dual antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis (AAV) in a 38-year-old Japanese woman previously diagnosed with mixed connective tissue disease. The patient was found to be positive for myeloperoxidase- and proteinase 3-ANCA, and was diagnosed with AAV following admission to hospital with fervescence, polyarthralgia, purpura, and asymmetric numbness of the extremities. Examination of her genetic background revealed that she carried HLA-DR9, which confers risk of both diseases in Japanese populations.

Hypocholesterolemia in patients with polycythemia vera.

Polycythemia vera (PV) is characterized by low serum total cholesterol despite its association with vascular events such as myocardial and cerebral infarction. Serum cholesterol level has not been used as a diagnostic criterion for PV since the 2008 revision of the WHO classification. Therefore, we revisited the relationship between serum lipid profile, including total cholesterol level, and erythrocytosis. The medical records of 34 erythrocytosis patients (hemoglobin : men, > 18.5 g/dL ; women, > 16.5 g/dL) collected between August 2005 and December 2011 were reviewed for age, gender, and lipid profiles. The diagnoses of PV and non-PV erythrocytosis were confirmed and the in vitro efflux of cholesterol into plasma in whole blood examined. The serum levels of total cholesterol, low-density-lipoprotein cholesterol (LDL-Ch), and apolipoproteins A1 and B were lower in PV than in non-PV patients. The in vitro release of cholesterol into the plasma was greater in PV patients than in non-PV and non-polycythemic subjects. Serum total cholesterol, LDL-Ch, and apolipoproteins A1 and B levels are lower in patients with PV than in those with non-PV erythrocytosis. The hypocholesterolemia associated with PV may be attributable to the sequestration of circulating cholesterol into the increased number of erythrocytes.

Relationship between clotting activity and phosphatidylserine expression on erythrocyte membranes in polycythemia vera patients with the JAK2 V617F mutation.

INTRODUCTION: Polycythemia vera (PV) accompanies the clinical course of thrombosis. Phosphatidylserine (PS) expression on the plasma membrane has been known to be one of place where the coagulation system activates. We studied the relationship between clotting factor activity and PS expression on the erythrocyte membrane in patients with erythrocytosis. METHODS: The coagulation test and PS expression in 23 patients with erythrocytosis were measured. PS expression was determined indirectly by measuring annexin V binding to erythrocytes using fluorescence activated cell sorter analysis (FACS). RESULTS: The activity of clotting factors (II, V, VII, VIII, von Willebrand factor, IX, X) was significantly lower in PV than in the mutation-negative erythrocytosis. There was a significant correlation between reduced activity of clotting factors such as V, X, and IX and increased PS expression of the erythrocyte membrane. CONCLUSION: Increased expression of PS on the erythrocyte membrane may reduce the activities of clotting factors in PV patients with JAK2 V617F mutation.

[Low-titer cold agglutinin disease following Salmonella gastroenteritis].

We encountered a patient with cold agglutinin disease (CAD) that worsened after Salmonella gastroenteritis. A 52-year-old male complained pain in the left fingers with cyanosis and was admitted in a local hospital. After treatment for ischemia, he demonstrated diarrhea with fever. Because of progressive anemia, he was referred to our hospital. Salmonella gastroenteritis was diagnosed based on the results of microbiological examination. Severe hemolysis was noted at admission, and Coombs test was positive (IgG-, C3d+). Cold agglutinin titer was elevated (x256). There were no findings of malignancy or infection demonstrating CA. A diagnosis of CAD with Salmonella gastroenteritis was made. Because spherocytosis was noted during admission, we measured the mean channel fluorescence (MCF) of eosin-5-maleimide (EMA) in erythrocytes from patients. MCF of EMA of the patient's erythrocytes was similar to that of normal subjects. Therefore, we concluded that coexisting hereditary spherocytosis was unlikely. We also examined the in vitro hemolytic effect of Salmonella infection on his blood and on blood from normal subjects. Treatment with Salmonella enteritidis isolated from this patient was found to induce hemolysis in the patient's blood, but not in blood from a normal subject. Moreover, treatment with Salmonella increased the titer of cold agglutinin in vitro. These data suggested that Salmonella infection might worsen hemolysis in CAD.

Losartan potassium/hydrochlorothiazide (Preminent®) and hyponatremia: case series of 40 patients.

The clinical course of losartan potassium/hydrochlorothiazide (Preminent(®))-induced hyponatremia has not been described. We summarized 40 patients with Preminent-induced hyponatremia. The study involved 15 (37.5%) men and 25 (62.5%) women (mean age [SD], 76.4 [8.3] years; range, 55-95). Their sodium levels before Preminent administration were 139.5 (4.9) mEq/L (range, 131-145; reference range, 135-147). The duration from the day of Preminent administration to the day with the lowest sodium level was 59.3 (64.9) days (range, 2-207; median, 24). Most patients for whom this duration was <50 days exhibited progressive symptoms, whereas most of those for whom this duration was >50 days did not exhibit progressive symptoms but exhibited symptoms after fever or appetite loss. The lowest sodium value was 114.4 (8.2) mEq/L (range, 99-133). The duration from the time of Preminent discontinuation to (1) the time of early recovery and (2) the time of final recovery was 6.8 (5.5) days (range, 1-20; median, 5) and 11.6 (7.6) days (range, 2-29; median, 7.5), respectively. Of the 40 patients, 36 (90.0%) achieved full recovery, 1 (2.5%) suffered from after-effects due to central pontine myelinolysis, 1 (2.5%) died, and 2 (5.0%) were unknown. In the analysis of other adverse effects of Preminent and the same adverse effects of other three angiotensin II receptor blocker (ARB)/thiazide combinations, hyponatremia was observed as a primary adverse effect of all ARB/thiazide combinations. However, hyperesthesia dermatitis was reported as an adverse effect of Preminent only.

A Markov decision analysis of allogeneic hematopoietic cell transplantation versus chemotherapy in patients with acute myeloid leukemia in first remission.

Various prospective trials have been performed to assess the roles of allogeneic hematopoietic cell transplantation (allo-HCT) and chemotherapy in patients with acute myeloid leukemia (AML) in first complete remission (CR1). However, the results have not always been consistent, and there has been a limited evaluation of quality of life (QOL) in these postremission strategies. We performed a Markov decision analysis that enabled us to compare survival outcomes with a QOL evaluation using a database of 2029 adult AML patients who achieved CR1. The Markov decision model compared 2 strategies: allo-HCT or chemotherapy in CR1. Patients who had intermediate- or unfavorable-risk AML had a longer life expectancy when they received allo-HCT in CR1 than patients treated with chemotherapy alone. Likewise, patients who had a suitable related donor who received allo-HCT in CR1 had a longer life expectancy. The life expectancy was shortened to a greater degree by adjustment for QOL in the allo-HCT group. Nevertheless, QOL-adjusted life expectancies in most of the subgroups remained longer in the allo-HCT group than in the chemotherapy group. Our results showed that older patients with a related donor and younger patients with unfavorable cytogenetics benefited the most from allo-HCT in CR1.

Comparison of allogeneic hematopoietic cell transplantation and chemotherapy in elderly patients with non-M3 acute myelogenous leukemia in first complete remission.

The benefits of allogeneic hematopoietic cell transplantation (allo-HCT) for patients with acute myelogenous leukemia (AML) in first complete remission (CR1) have mostly been evaluated in younger patients. Although favorable outcomes of allo-HCT over chemotherapy have been reported with the use of reduced-intensity conditioning (RIC) regimens in elderly patients with AML in CR1, information is still limited, especially on the effects of cytogenetic risks and donor sources. We collected data from AML patients aged 50 to 70 years who achieved CR1, and compared the outcome in 152 patients who underwent allo-HCT in CR1 (HCT group) to that in 884 patients who were treated with chemotherapy (CTx group). The cumulative incidence of relapse in the HCT group was significantly lower than that in the CTx group (22% versus 62%). Both overall survival (OS) and relapse-free survival (RFS) were significantly improved in the HCT group (OS: 62% versus 51%, P = .012), not only in the whole population, but also in the intermediate-risk group. Among patients who had a suitable related donor, the outcomes in the HCT group were significantly better than those in the CTx group. The introduction of appropriate treatment strategies that include allo-HCT may improve the outcome in elderly patients with AML in CR1.

Thyroid hormones, their carrier proteins, and thyroid antibodies in the pleural effusion of two patients with graves' disease-induced thyrotoxicosis.

INTRODUCTION: Concentrations of thyroid hormones, their carrier proteins, and thyroid antibodies in plasma have been extensively investigated, but those in pleural effusion have not. PATIENTS AND MEDTHODS: In the present study, we report, for the first time, the concentrations of thyroid hormones, their carrier proteins, and thyroid antibodies in the pleural effusion of two thyrotoxicosis patients with Graves' disease. RESULTS: The pleural effusions were transudates. The concentrations of thyroid hormone carrier proteins, such as thyroxine-binding globulin (TBG), thyroxine-binding prealbumin (TBPA), and albumin (Alb) were approximately 30-50% of the plasma. The concentrations of total triiodothyronine (TT3), total tetraiodothyronine (TT4), free triiodothyronine (FT3), and free tetraiodothyronine (FT4) were approximately 15-40%, 45-55%, 45-75%, and 80-85% of the plasma, respectively. The concentration of thyroid stimulating hormone receptor antibody (TRAb) (equal to TSH-binding inhibitory immunoglobulins%; TBII%) was approximately 90% of the plasma. CONCLUSION: If the pleural effusions were treated with diuretics, substantial quantity of thyroid hormones and thyroid antibodies in the pleural effusion may have returned to the plasma, and might exacerbate thyrotoxicosis. For patients with thyrotoxicosis and pleural effusion, thoracentesis should be considered. The present findings will contribute to the understanding and treatment of hyperthyroidism-induced pleural effusion.

A patient with DiGeorge syndrome with spina bifida and sacral myelomeningocele, who developed both hypocalcemia-induced seizure and epilepsy.

DiGeorge syndrome - a component of the 22q11 deletion syndrome - causes a disturbance in cervical neural crest migration that results in parathyroid hypoplasia. Patients can develop hypocalcemia-induced seizures. Spina bifida is caused by failure of neurulation, including a disturbance in the adhesion processes at the neurula stage. Spina bifida has been reported as a risk factor for epilepsy. We report, for the first time, the case of a patient with DiGeorge syndrome with spina bifida and sacral myelomeningocele, who developed both hypocalcemia-induced seizures and epilepsy. The patient had spina bifida and sacral myelomeningocele at birth. At the age of 13 years, he experienced a seizure for the first time. At this time, the calcium concentration was normal. An electroencephalogram (EEG) proved that the seizure was due to epilepsy. Antiepileptic medications controlled the seizure. At the age of 29, the patient's calcium concentration began to reduce. At the age of 40, hypocalcemia-induced seizure occurred. At this time, the calcium concentration was 5.5mg/dL (reference range, 8.7-10.1mg/dL). The level of intact parathyroid hormone (PTH) was 6 pg/mL (reference range, 10-65 pg/mL). Chromosomal and genetic examinations revealed a deletion of TUP-like enhancer of split gene 1 (tuple1)-the diagnostic marker of DiGeorge syndrome. Many patients with DiGeorge syndrome have cardiac anomalies; however, our patient had none. We propose that the association among DiGeorge syndrome, spina bifida, epilepsy, cardiac anomaly, 22q11, tuple1, and microdeletion inheritance should be clarified for appropriate diagnosis and treatment.

Idiopathic plasmacytic lymphadenopathy with polyclonal hypergammaglobulinemia accompanied with cutaneous involvement and renal dysfunction.

Idiopathic plasmacytic lymphadenopathy (IPL) with polyclonal hypergammaglobulinemia has been proposed as a new disease entity resembling the plasma cell type of multicentric Castleman's disease. Here, we report a case of IPL accompanied by renal failure and skin involvement. A 35-year-old man was admitted for advanced renal failure, anemia, systemic lymphadenopathy and skin rashes. Laboratory examinations indicated polyclonal hypergammaglobulinemia and elevated serum interleukin-6 (IL-6). Biopsy of a cervical lymph node revealed follicular hyperplasia with normal germinal centers, sheets of polyclonal proliferating plasma cells and the absence of marked proliferation of blood vessels in the interfollicular area. Lesions of the kidney and skin also had pathological characteristics of IPL. Following a diagnosis of IPL, corticosteroid therapy successfully improved the anemia and hypergammaglobulinemia, and serum IL-6 levels decreased to a normal range. This case may give suggestions about diagnosing and preventing the progression of complications from this disease entity.

Pregnancy-induced thrombocytopenia and TTP, and the risk of fetal death, in Upshaw-Schulman syndrome: a series of 15 pregnancies in 9 genotyped patients.

Upshaw-Schulman syndrome (USS) is a congenital thrombotic thrombocytopenic purpura (TTP) due to mutations in the gene that encodes for ADAMTS13 (ADAMTS13), but its clinical signs may be mild or absent during childhood. We have identified 37 patients with USS (24 females, 13 males) belonging to 32 families. The nine women from six families who were diagnosed during their first pregnancy are the focus of this report. Six of the nine women had episodes of thrombocytopenia during childhood misdiagnosed as idiopathic thrombocytopenic purpura. Thrombocytopenia occurred during the second-third trimesters in each of their 15 pregnancies, with 16 babies (one twin pregnancy), often followed by TTP. Of 15 pregnancies, eight babies were stillborn or died soon after birth, and the remaining seven were all premature except one, who was born naturally following plasma infusions to the mother that had started at 8 weeks' gestation. All nine USS women had severely deficient ADAMTS13 activity. ADAMTS13 analyses demonstrated that eight women were compound heterozygotes of Y304C/G525D (2 siblings), R125VfsX6/Q1302X (2 siblings), R193W/R349C (2 siblings), I178T/Q929X, and R193W/A606P; one woman was homozygous for R193W. Only the R193W mutation has been previously reported. These observations emphasize the importance of measuring ADAMTS13 activity in the evaluation of thrombocytopenia during childhood and pregnancy.

IL-12 and IL-18 induction and subsequent NKT activation effects of the Japanese botanical medicine Juzentaihoto.

In this study, we first measured some cytokine concentrations in the serum of patients treated with Juzentaihoto (JTT). Of the cytokines measured interleukin (IL) -18 was the most prominently up-regulated cytokine in the serum of patients under long term JTT administration. We next evaluated the effects of JTT in mice, focusing especially on natural killer T (NKT) cell induction. Mice fed JTT were compared to control group ones. After sacrifice, the liver was fixed, embedded and stained. Transmission electron microscope (TEM) observations were performed. Although the mice receiving the herbal medicine had same appearance, their livers were infiltrated with massive mononuclear cells, some of which were aggregated to form clusters. Immunohistochemical staining revealed that there was abundant cytokine expression of IL-12 and IL-18 in the liver of JTT treated mice. To clarify what the key molecules that induce immunological restoration with JTT might be, we next examined in vitro lymphocyte cultures. Mononuclear cells isolated and prepared from healthy volunteers were cultured with and without JTT. Within 24 hours, JTT induced the IL-12 and IL-18 production and later (72 hours) induction of interferon (IFN)-gamma. Oral administration of JTT may induce the expression of IL-12 in the early stage, and IL-18 in the chronic stage, followed by NKT induction. Their activation, following immunological restoration could contribute to anti-tumor effects.

[A case of resection of esophageal cancer infiltrating the left main bronchus following preoperative chemo-radiotherapy and resection of metachronous lung metastasis].

We herein report a case of T4 esophageal carcinoma, which was resected after chemo-radiation therapy. In addition, the metachronous lung metastasis was also resected. A 59-year-old female with esophageal carcinoma, which invaded the left main bronchus, underwent chemo-radiation therapy (the combination of systemic chemotherapy of 5-FU/CDDP and external radiation therapy) from January 2004. After the therapy, although the imaging showed a downstaging of esophageal carcinoma, a severe esophageal stricture appeared with ingestion defective. So hyper-alimentation was performed. After the state of nutrition was improved, esophagectomy was performed on March 2004 without a complication. Histopathological study revealed that no viable cells remained. Nine months after esophagectomy, chest CT scan revealed that a solitary pulmonary tumor appeared in S6 of the right. The solitary tumor enlarged gradually. On August 2005, a surgical resection for the solitary pulmonary tumor was performed. Histopathologically, the lesion was compatible for metastasis from esophageal carcinoma. The patient is alive without recurrence more than 23 months after the last surgery.

[Posterior leukoencephalopathy syndrome presenting with bilateral ataxie optique: a case report].

We report a 45 years old right-handed woman who developed acute respiratory distress syndrome (ARDS) after the operation for rupture of an ovarian cyst. One week after the onset of ARDS, she presented visual disturbance and Gerstmann syndrome. MRI T2-weighted images demonstrated abnormal high intensity lesions involving the gray and white matter of the occipital lobes bilaterally extending to the parietal lobes. Based on these findings, she was diagnosed as having posterior leukoencephalopathy syndrome (PLES). Her neurologic symptoms gradually improved, however, she started to complain of difficulty in grasping a cup placed on her peripheral visual fields. Neurological examination revealed no visual disturbance, weakness or cerebellar ataxia. She could easily reach objects presented in the central visual field, however, she could not grasp objects presented peripheral visual fields, while she was looking straight ahead. This disorder was observed both in the right and left visual field, whether she used the right hand or the left hand. We thought she had ataxie optique of Garcin. She was noted to have bilateral both direct and crossed ataxie optique. Ataxie optique is characterized by disturbance in reaching objects presented in the peripheral visual field. The underlying pathophysiologic mechanism is believed to be disconnection of the fibers between the primary visual area and the angular gyrus at the parietooccipital junction. Crossed ataxie optique consisting of difficulty in reaching objects presented in the contralateral visual field believed to be caused by disconnection of crossed pathways of the corpus callosum. Ataxie optique in our patient can be explained by disconnection of both direct and crossed fibers. Ataxie optique is sometimes unrecognized by the patient. Our patient suggests that ataxie optique may well be a symptom of PLES.

[Autologous peripheral blood stem cell transplantation for Japanese multiple myeloma patients: results of a feasibility study].

A feasibility study on high-dose therapy with autologous peripheral blood stem cell transplantation (HDT/PBSCT) was performed in Japanese patients with multiple myeloma (MM). Twenty evaluable patients younger than 65 years old with stage II/III MM were enrolled in this study. Three courses of VAD were used as initial chemotherapy. High-dose etoposide or cyclophosphamide followed by G-CSF was used for PBSCH, and 1.2-89.3 (median 23.4) x 106/kg of CD34+ cells were collected. Single (11 patients) or tandem (9 patients) HDT with melphalan (MEL) 200 mg/m2 or MEL 140 mg/m2 plus TBI 10 Gy were performed. The incidence of grade 4 toxicity (COG) was 10% and treatment-related mortality was 5%. Complete response and tumor reduction of more than 75% were obtained in 4 (21%) and 16 (84%) out of 19 patients, respectively. The actuarial 3-year overall survival (OS) and event-free survival (EFS) after PBSCT/HDT were 65.6% and 22.0%, respectively. The median EFS duration was 18 months. These preliminary results indicated that HDT/PBSCT is feasible for Japanese MM patients. A prospective randomized clinical trial will be required to assess the efficacy.

Development of a liquid culture system for megakaryocyte terminal differentiation: fibrinogen promotes megakaryocytopoiesis but not thrombopoiesis.

Megakaryocyte differentiation is composed of three distinct stages: formation of erythromegakaryocytic progenitor cells, maturation of megakaryocytes and production of platelets. We have developed a liquid culture system for megakaryocyte terminal differentiation from haematopoietic stem cells into proplatelets. In this system, CD34+ cells isolated from human cord blood, differentiated to CD41+ cells, were classified either as propidium iodide (PI)+ cells (large) or PI- cells (small) by fluorescence-activated cell sorting analysis on the late-stage CD41+ cells. Transmission electron microscopy showed that the cultured small cells were morphologically identical to platelets isolated from normal peripheral blood. Moreover, the number of differentiated cells that were CD42b-positive attained an approximately 60-fold expansion over that of the primary CD34+ cells in this culture system. Furthermore, gene expression of megakaryocytopoietic transcriptional factors, GATA-1 and NF-E2, and several megakaryocytic markers such as glycoprotein (GP)IIb and thromboxane synthase was observed in the individual differentiation stage. Treatment with fibrinogen, a ligand of GPIIb/IIIa, increased the number of CD41+/PI+ cells, but treatment in the late stage suppressed CD41+/PI- cell formation, suggesting that fibrinogen promotes megakaryocytopoiesis, but not thrombopoiesis. We conclude that this liquid culture system using human CD34+ cells may be used to mimic the physiological development from haematopoietic stem cells into megakaryocytes, as well as promote subsequent thrombopoiesis.