Multimodality therapy using brachytherapy for caval tumor of hepatocellular carcinoma

BACKGROUND/AIMS: Hepatocellular carcinoma (HCC) invading the inferior vena cava will expose patients to a risk of sudden death. Effective therapeutic approaches have not been established for caval tumor. This pilot study was conducted to evaluate the feasibility, safety, and clinical efficacy of multimodality therapy using endovascular brachytherapy with iridium-192 for caval tumor. METHODOLOGY: Six consecutive patients underwent endovascular high-dose-rate brachytherapy. An iridium-192 source was placed adjacent to the caval tumor through a vascular sheath introduced via the femoral vein. The total dose of brachytherapy ranged from 10 to 14Gy (5-7Gy per fraction). Hepatic arterial infusion chemotherapy was used in combination in all patients and external-beam radiotherapy was performed in 5 patients. RESULTS: Endovascular brachytherapy was technically successful in all patients. There were no complications related to brachytherapy. The median period of follow-up was 14.5 months (range, 3-29 months). Complete response and partial response were achieved in 2 (33%) and 4 (67%) patients, respectively. The 1- and 2-year survival rates were 50% and 17%, respectively, with a median survival of 14 months. CONCLUSIONS: Multimodality therapy using endovascular brachytherapy was a feasible, safe, and effective treatment for patients with advanced HCC invading the inferior vena cava.     

Multiple Granulocytic Sarcomas in Essential Thrombocythemia

A 59-year-old woman was diagnosed with essential thrombocythemia in 1988 and had been treated with hydroxyurea, mitobronitol, busulfan, and ranimustine, in that order. Hepatosplenomegaly, low-grade fever, and body weight loss manifested, and a few blasts were noted in the peripheral blood studied in March 2002. A biopsied specimen of the bone marrow showed myelofibrosis but not a leukemia in August 2004. An abnormal karyotype with der(1; 13) appeared for the first time. She was treated with low-dose prednisolone. In January 2005, she experienced left hip joint pain, and magnetic resonance scanning showed a tumoral lesion in the femoral head. Histological diagnosis of the biopsied mass revealed that it was a granulocytic sarcoma, and radiotherapy was performed. In April 2005, bone scintigraphy showed multiple lesions. She became febrile and red blood cell transfusion-dependent with hepatosplenomegaly and a small number of circulating blasts. Intravenous cytarabine (low dose) and etoposide relieved the fever and hepatosplenomegaly; however, she developed a pathologic fracture of the right humerus. An additional karyotypic abnormality (7q22 deletion) was noted. She subsequently died of infection. Granulocytic sarcoma is very rare in essential thrombocythemia, and this patient may be the first reported case of essential thrombocythemia that developed multiple lesions and a pathologic fracture without transformation to overt leukemia.     

The novel roles of liver for compensation of insulin resistance in human growth hormone transgenic rats

Chronic excess of GH is known to cause hyperinsulinemia and insulin resistance. We developed human GH transgenic (TG) rats, which were characterized by high plasma levels of human GH and IGF-I. These TG rats showed higher levels of plasma insulin, compared with control littermates, whereas plasma glucose concentrations were normal. Insulin-dependent glucose uptake into adipocytes and muscle was impaired, suggesting that these rats developed insulin resistance. In contrast, insulin-independent glucose uptake into hepatocytes from TG rats was significantly increased, and glycogen and lipid levels in livers of TG rats were remarkably high. Because the role of liver in GH-induced insulin resistance is poorly understood, we studied insulin signaling at early stages and insulin action in liver and primary cultures of hepatocytes prepared from TG rats. There was no difference in insulin receptor kinase activity induced by insulin between TG and control rats; however, insulin-dependent insulin receptor substrate-2 tyrosine phosphorylation, glycogen synthase activation, and expression of enzymes that induce lipid synthesis were potentiated in hepatocytes of TG rats. These results suggest that impairment of insulin-dependent glucose uptake by GH excess in adipose tissue and muscle is compensated by up-regulation of glucose uptake in liver and that potentiation of insulin signaling through insulin receptor substrate-2 in liver experiencing GH excess causes an increase in glycogen and lipid synthesis from incorporated glucose, resulting in accumulation of glycogen and lipids in liver. This novel mechanism explains normalization of plasma glucose levels at least in part in a GH excess model.     

Six adult cases of respiratory complications caused by pandemic 2009 influenza A (H1N1) compared to seasonal influenza

The first case in Japan of 2009 pandemic influenza A (H1N1) was reported in May, with pediatric hospitalization exceeding that of adults. We evaluated six adults hospitalized for 2009 H1N1 respiratory complications and compared the pandemic to seasonal influenza. Hospitalization was due to aggravated asthma in four of the six, two of whom had simultaneous pneumonia probably virus-caused, and two cases of bacterial pneumonia. Among the three seasons examined, the number of adults increased slightly but the hospitalization rate was low in 2009-2010. Respiratory complications such as viral pneumonia were not seen outside of 2009-2010. Attention should therefore be paid to respiratory complications in adults with pandemic 2009 influenza A (H1N1) virus.     

Comparison of coronary microcirculation in female nurses after day-time versus night-time shifts

Nightshift work, which is known to cause mental stress and disrupt normal biological diurnal rhythms, leads to endothelial dysfunction resulting in increased risk for cardiovascular disease. This study aimed to investigate the acute effect of night-shift work on coronary microcirculation through assessment of coronary flow reserve (CFR) by transthoracic Doppler echocardiography. This study consisted of 36 women nurses who underwent transthoracic Doppler echocardiographic examinations after working a nightshift and on a regular day without previous nightshift work. Flow velocity in the distal portion of the left anterior descending coronary artery was measured at baseline and during adenosine infusion. CFR was calculated as the ratio of hyperemic to basal mean diastolic flow velocity. CFR after night work was lower than that on a regular workday (3.8 ± 0.6 vs 4.1 ± 0.6, p <0.001). Degree of decreases in CFR after night work was correlated to Framingham risk score (r = 0.35, p = 0.036). In conclusion, this study demonstrated that coronary microcirculation was impaired after nightshift work in women nurses.     

Identification and characterization of an oocyte factor required for development of porcine nuclear transfer embryos

Nuclear reprogramming of differentiated cells can be induced by oocyte factors. Despite numerous attempts, these factors and mechanisms responsible for successful reprogramming remain elusive. Here, we identify one such factor, necessary for the development of nuclear transfer embryos, using porcine oocyte extracts in which some reprogramming events are recapitulated. After incubating somatic nuclei in oocyte extracts from the metaphase II stage, the oocyte proteins that were specifically and abundantly incorporated into the nuclei were identified by mass spectrometry. Among 25 identified proteins, we especially focused on a multifunctional protein, DJ-1. DJ-1 is present at a high concentration in oocytes from the germinal vesicle stage until embryos at the four-cell stage. Inhibition of DJ-1 function compromises the development of nuclear transfer embryos but not that of fertilized embryos. Microarray analysis of nuclear transfer embryos in which DJ-1 function is inhibited shows perturbed expression of P53 pathway components. In addition, embryonic arrest of nuclear transfer embryos injected with anti-DJ-1 antibody is rescued by P53 inhibition. We conclude that DJ-1 is an oocyte factor that is required for development of nuclear transfer embryos. This study presents a means for identifying natural reprogramming factors in mammalian oocytes and a unique insight into the mechanisms underlying reprogramming by nuclear transfer.     

Selective expansion of donor‐derived regulatory T cells after allogeneic bone marrow transplantation in a patient with IPEX syndrome

IPEX syndrome is a rare and fatal disorder caused by absence of regulatory T cells (Tregs) due to congenital mutations in the Forkhead box protein 3 gene. Here, we report a patient with IPEX syndrome treated with RIC followed by allogeneic BMT from an HLA‐matched sibling donor. We could achieve engraftment and regimen‐related toxicity was well tolerated. Although the patient was in mixed chimera and the ratio of donor cells in whole peripheral blood remained relatively low, selective and sustained expansion of Tregs determined as CD4+CD25+Foxp3+ cells was observed. Improvement in clinical symptoms was correlated with expansion of donor‐derived Tregs and disappearance of anti‐villin autoantibody, which was involved in the pathogenesis of gastrointestinal symptoms in IPEX syndrome. This clinical observation suggests that donor‐derived Tregs have selective growth advantage in patients with IPEX syndrome even in mixed chimera after allogeneic BMT and contribute to the control of clinical symptoms caused by the defect of Tregs.     

Effects of aromatase inhibitors on the pathobiology of the human breast, endometrial and ovarian carcinoma

It is very important to examine the influence of inhibition of in situ estrogen production on the pathobiology of human sex steroid-dependent tumors in order to understand the clinical effects of aromatase inhibitors. We have examined the biological changes before and after aromatase inhibitor treatment in vitro (endometrial and ovarian cancer) and in vivo (breast cancer). First, we analyzed these changes using histoculture of 15 human endometrial cancers and 9 ovarian cancers. Five of the fifteen endometrial cancers and four of the nine ovarian cancers demonstrated decreased [3H]thymidine uptake or Ki67 labeling index after 14alpha-hydroxy-4-androstene-3,6,17-trione (NKS01) treatment. In ovarian cancer cases, the responsive cases tended to be associated with higher aromatase and estrogen receptor alpha (ER) expression compared with the other cases but this was not seen in the endometrial cancer cases. There were no changes in ER and aromatase expression before and after NKS01 treatment in either ovarian or endometrial cancer cases. We then studied the same primary human breast tumors before and after aminoglutethimide (AMG, n=3) and 4-hydroxyandrostenedione (4-OHA, n=3) treatment. Tumor aromatase activity increased in 3 cases and decreased or was unchanged in 3 cases but aromatase immunoreactivity in stroma and adipocytes was unaltered in 5 cases. There were no changes in the ER labeling index before or after treatment. Five of the six cases including the responsive cases tended to be associated with decreased cell proliferation or Ki67 expression and increased apoptosis when examined by the TUNEL method. These results indicate that aromatase inhibitors may exert their effects on human breast and other cancers through decreasing proliferation and increasing apoptosis, possibly without altering ER status.