Prognostic significance of the BAALC isoform pattern and CEBPA mutations in pediatric acute myeloid leukemia with normal karyotype: a study by the Japanese Childhood AML Cooperative Study Group

High BAALC (brain and acute leukemia, cytoplasmic) gene expression may indicate an adverse prognosis for adults who have acute myeloid leukemia (AML) and a normal karyotype, but its prognostic significance for pediatric AML cases is unclear. Whether different BAALC isoform patterns are of prognostic significance is also unclear. Newly diagnosed AML patients with normal karyotype who were treated by the Japanese Childhood AML Cooperative Treatment Protocol AML 99 were analyzed in terms of their BAALC expression levels (n = 29), BAALC isoforms (n = 29), and CEBPA mutations (n = 49). Eleven and 18 patients exhibited high and low BAALC expression, respectively, but these groups did not differ significantly in terms of overall survival (54.6 vs. 61.1%, P = 0.55) or event-free survival (61.4 vs. 50.0%, P = 0.82). Three of these 29 patients (10.3%) expressed the exon 1-5-6-8 BAALC isoform along with the expected 1-6-8 isoform and had adverse clinical outcomes. Novel CEBPA mutations were also identified in four of 49 patients (8.2%). All four patients have maintained complete remission for at least 5 years. Thus, 1-5-6-8 isoform expression may be associated with an adverse prognosis in pediatric AML with normal karyotype. CEBPA mutations may indicate a favorable prognosis.     

Disease-associated mutations in CIAS1 induce cathepsin B-dependent rapid cell death of human THP-1 monocytic cells

Mutations in the cold-induced autoinflammatory syndrome 1 (CIAS1) gene are associated with a spectrum of autoinflammatory diseases, including familial cold autoinflammatory syndrome, Muckle-Wells syndrome, and chronic infantile neurologic, cutaneous, articular syndrome, also known as neonatal-onset multisystem inflammatory disease. CIAS1 encodes cryopyrin, a protein that localizes to the cytosol and functions as pattern recognition receptor. Cryopyrin also participates in nuclear factor-kappaB regulation and caspase-1-mediated maturation of interleukin 10. In this study, we showed that disease-associated mutations in CIAS1 induced rapid cell death of THP-1 monocytic cells. The features of cell death, including 7-AAD staining, the presence of cellular edema, and early membrane damage resulting in lactate dehydrogenase (LDH) release, indicated that it was more likely to be necrosis than apoptosis, and was effectively blocked with the cathepsin B-specific inhibitor CA-074-Me. CA-074-Me also suppressed induced by disease-associated mutation lysosomal leakage and mitochondrial damage. In addition, R837, a recently identified activator of cryopyrin-associated inflammasomes, induced cell death in wild type CIAS1-transfected THP-1 cells. These results indicated that monocytes undergo rapid cell death in a cathepsin B-dependent manner upon activation of cryopyrin, which is also a specific phenomenon induced by disease-associated mutation of CIAS1.     

Sarcomatous hepatocellular carcinoma without previous anticancer therapy

Sarcomatous hepatocellular carcinoma is a rare neoplasm of the liver. A 79-year-old man with a liver tumor was admitted to our hospital. Enhanced computed tomography and magnetic resonance imaging revealed a cystlike lesion, whereas abdominal ultrasonography revealed a solid tumor. The patient underwent medial segmentectomy of the liver for the presumptive diagnosis of atypical hepatocellular carcinoma. Microscopically, the tumor was diagnosed as hepatocellular carcinoma with sarcomatous change. Although anticancer therapy is presumed to be a cause of sarcomatous change in hepatocellular carcinoma, some cases in which patients had not previously undergone anticancer therapy have been reported. Here we report a case of sarcomatous hepatocellular carcinoma without previous anticancer therapy and present a review of the literature.     

Increased number of CD16CD56 NK cells in peripheral blood mononuclear cells after allogeneic cord blood transplantation

In the present study, we investigated subpopulations of natural killer (NK) cells and the expression of stimulatory and inhibitory NK receptors after adult blood and bone marrow transplantation (BBMT) and cord blood transplantation (CBT). There were significant increases in CD16⁺CD56^dim cell proportion and in absolute number in peripheral blood mononuclear cells (PBMC) during a period of 4–9 months after CBT compared with these in normal PBMC, cord blood (CB), and in PBMC after BBMT. Also, increased numbers of CD16⁺CD56^dim NK cells were sustained in some patients until 4 years after CBT. This CD16⁺CD56^dim cell subset after CBT exhibited decreased expression of NKG2A compared with that in CB and increased expression of NKG2C. Purified CD16⁺CD56^dim cells from patients 8–9 months after CBT exhibited significantly higher levels of cytolytic activity against K562 than did purified CD16⁺CD56^bright cells and also whole PBMC. The CD16⁺CD56^dim cell subset with a high level of cytolytic activity significantly increased after CBT, and these cells may be responsible for NK cell–mediated immunity after CBT.     

Successful treatment of refractory donor lymphocyte infusion‐induced immune‐mediated pancytopenia with rituximab

A 6‐year‐old male with chronic granulomatous disease, who was transplanted with bone marrow and exhibited increasing mixed chimerism, subsequently received two donor lymphocyte infusions (DLI). Two weeks after the second DLI, the patient developed acute graft‐versus‐host disease (GVHD) and progressive pancytopenia that was associated with autoantibody production. Conventional treatment did not improve the pancytopenia. However, administration of Rituximab (RTX) (375 mg/m²/week for four consecutive weeks) resulted in a rapid resolution of the pancytopenia. The patient achieved full donor chimerism without GVHD symptoms. RTX can be valuable for managing immune‐mediated cytopenias that arise after DLI and are refractory to conventional therapies. Pediatr Blood Cancer 2010;54:329–331. © 2009 Wiley‐Liss, Inc.     

Serial changes in negative T wave on electrocardiogram in acute pulmonary thromboembolism

A negative T wave is frequently observed in precordial ECG leads in patients with acute pulmonary thromboembolism. We investigated the clinical significance of negative T wave in 15 patients with acute pulmonary thromboembolism who were treated with thrombolytic agents by measuring the mean pulmonary artery pressure and ratio of right to left ventricular end-diastolic diameter using echocardiography and ECG. The study included only patients with massive acute pulmonary thromboembolism of a mean age of 65+/-9.7 years (+/-SD). A negative T wave was observed on admission in 10 patients but was later detected in 14 of the 15 patients. The mean amplitude of the negative T wave increased within 1 week then decreased after thrombolytic treatment. The peak negative amplitude of the T wave was observed from 1 to 7 days (mean, 2.6+/-1.8 days) and disappeared afterwards. During this period, improvements in both the mean pulmonary artery pressure (37.8+/-11.2 to 19.1+/-6.7 mmHg) and the ratio of right to left ventricular end-diastolic diameter (0.97+/-0.16 to 0.51+/-0.13) were noted in all patients. Our results suggest that an increase in the amplitude of negative T wave in precordial leads after thrombolytic therapy in patients with massive acute pulmonary thromboembolism reflects improvement in cardiopulmonary hemodynamics.     

Total removal of infected pacemaker lead with cardiopulmonary bypass; report of a case

The incidence of infection after pacemaker implant has been reported to occur rarely but it's one of the severe complication. Pacemaker lead sometimes imbedded in the right atrial and ventricular wall, and it seemed to be difficult to remove the pacemaker lead by closed techniques. The optimal treatment is total removal generator and pacing lead, therefore, it is necessary to remove with cardiopulmonary bypass. Septicemia caused by infections retained pacemaker lead developed in an 87-year-old man. Following antibiotic therapy, the lead was successfully removed by cardiotomy on cardiopulmonary bypass. Total removal with cardiopulmonary bypass would be recommended.     

Inhibition of leukemic cell growth by a novel anti-cancer drug (GUT-70) from calophyllum brasiliense that acts by induction of apoptosis

During our search for cancer chemopreventing compounds derived from plant sources, we discovered that the natural product GUT-70, isolated from the stem bark of Calophyllum brasiliense collected in Brazil, significantly inhibits the growth of leukemic cells. GUT-70, characterized as a tricyclic coumarin, 5-methoxy-2,2-dimethyl-6-(2-methyl-1-oxo-2-butenyl) -10-propyl-2H,8H-benzo[1,2-b;3,4-b']dipyran-8-one (C(23)H(26)O(5)), inhibited all 6 human leukemic cell lines evaluated, including the P-glycoprotein overexpressing cell line, in a concentration and time-dependent manner with IC(50) values from 2-5 microM. Furthermore, GUT-70 did not inhibit colony formation by normal hematopoietic progenitors up to 30 microM and also did not inhibit the proliferation of normal human hepatocytes up to 30 microM. GUT-70 activated the caspase 2, 3, 8 and 9, and induced the apoptosis in leukemic cells, which was inhibited by caspase inhibitors. GUT-70 induced anti-leukemic effects independent of the p53-p2l(WAFl/CIP1) pathway and increased the overall expression of p27(KIP1) and p57(KIP2), to stop the cell cycle at the G(1)/S transition. Thus, a novel anti-cancer drug, GUT-70 isolated from the stem bark of C. brasiliense induces caspase-mediated and p53-independent apoptosis to overcome multidrug resistance and may become a potent leukemia therapeutics.     

Slit ventricle syndrome after cyst-peritoneal shunting for temporal arachnoid cyst in children--a clinical entity difficult to detect on neuroimaging study

Slit ventricle syndrome, known to occur from malfunction of the shunt procedure for hydrocephalus, is reported after cyst-peritoneal shunt for temporal arachnoid cyst. Two children aged 12 and 10 years, who underwent cyst-peritoneal shunting for a large temporal arachnoid cyst at the age of 10 and 5 years, respectively, recently experienced several episodes of severe headache. Prior to admission, repeated CT scans did not reveal any morphological change in either of these two patients. Evidence of high intracranial pressure by lumbar tap revealed shunt malfunction. Both patients became free of neurological complaints and deficits after shunt revision. Despite elevated intracranial pressure due to shunt malfunction, neuroimaging studies showed no morphological changes in slit ventricle syndrome. Delay in both the diagnosis and prompt treatment may result in complete loss of visual acuity and even death. It is important to suspect this complication in patients with persistent elevated intracranial pressure symptoms and signs after any shunting procedure, regardless of unchanged neuroimaging studies. Once this is suspected, lumbar tap may be necessary and the choice of treatment is shunt revision.