Gastric carcinosarcoma presenting as a huge epigastric mass

Gastric carcinosarcoma often presents with an elevated lesion or increased thickness of the stomach wall. Histological diagnosis is achieved using conventional hematoxylin and eosin staining to confirm the coexistence of both epithelial and mesenchymal elements. We report a case of gastric carcinosarcoma presenting as a large mass in the epigastric region. Specimens obtained by endoscopic biopsy and surgical excision showed diffuse proliferation of atypical cells in sheet formation. No mucus production or glandular structures were apparent, but immunoreactivity for both epithelial and mesenchymal markers was noted. These findings led to a definitive diagnosis of gastric carcinosarcoma. Immunohistochemical analysis is useful for the early diagnosis and treatment of gastric carcinosarcoma.     

IL12RB2 and ABCA1 genes are associated with susceptibility to radiation dermatitis

PURPOSE: Severe acute radiation dermatitis is observed in approximately 5% to 10% of patients who receive whole-breast radiotherapy. Several factors, including treatment-related and patient-oriented factors, are involved in susceptibility to severe dermatitis. Genetic factors are also thought to be related to a patient's susceptibility to severe dermatitis. To elucidate genetic polymorphisms associated with a susceptibility to radiation-induced dermatitis, a large-scale single-nucleotide polymorphism (SNP) analysis using DNA samples from 156 patients with breast cancer was conducted. EXPERIMENTAL DESIGN: Patients were selected from more than 3,000 female patients with early breast cancer who received radiotherapy after undergoing breast-conserving surgery. The dermatitis group was defined as patients who developed dermatitis at a National Cancer Institute Common Toxicity Criteria grade of > or =2. For the SNP analysis, DNA samples from each patient were subjected to the genotyping of 3,144 SNPs covering 494 genes. RESULTS: SNPs that mapped to two genes, ABCA1 and IL12RB2, were associated with radiation-induced dermatitis. In the ABCA1 gene, one of these SNPs was a nonsynonymous coding SNP causing R219K (P = 0.0065). As for the IL12RB2 gene, the strongest association was observed at SNP-K (rs3790568; P = 0.0013). Using polymorphisms of both genes, the probability of severe dermatitis was estimated for each combination of genotypes. These analyses showed that individuals carrying a combination of genotypes accounting for 14.7% of the Japanese population have the highest probability of developing radiation-induced dermatitis. CONCLUSION: Our results shed light on the mechanisms responsible for radiation-induced dermatitis. These results may also contribute to the individualization of radiotherapy.     

Urinary acidification in extremely low birth weight infants

Premature infants often present metabolic acidosis without protein load in the early neonatal period, around days 4–6. In order to elucidate the cause of acidosis, we investigated urinary acidification of infants in the early neonatal period.

Urine pH, fractional excretion of HCO₃⁻ (FEHCO₃), excretion of HCO₃⁻ and NH₄⁺ of the appropriate-for-date infants were measured on days 0–2 and on days 4–6 of life.

Extremely low birth weight (ELBW) infants showed higher urine pH than more than 1500 g birth weight infants. FEHCO₃ and HCO₃⁻ excretion were of high values in ELBW infants on days 0–2, but decreased on days 4–6. Urine NH₄⁺ excretion rate was lower in ELBW infants than in birth weight more than 1000 g on days 0–2 of life and still remained at a low rate on days 4–6.

These data indicated that insufficiency of NH₄⁺ excretion is the main cause for metabolic acidosis of ELBW infants in the early neonatal period.     

Magnetoencephalographic responses to odor and non-odor by fast Fourier transformation analysis in humans

Magnetoencephalographic (MEG) responses to odor (amyl-acetate) and non-odor stimuli for 1 second were recorded in 9 healthy volunteers (right handed) with a dual 37-channel SQUID (Magnes, Bti Co.) and evaluated by fast Fourier transformation analysis, with the following results: 1. On MEG analysis, the spectral density increase in the left mid-central region at a frequency of 7 Hz was significantly greater in response to odor than in response to non-odor stimuli. This greater increase is apparently related to the presence of the odor perception mechanism in the orbital frontal area, a major center of the olfactory system. 2. Both increased and decreased spectral density areas at a frequency of 8 Hz were observed over the right hemisphere when no stimuli was compared with non-odor and no stimulus compared with odor. These changes may reflect a high level of vigilance caused by stimulation. 3. When no stimulus was compared with non-odor stimulation, a significant spectral density increase at a frequency of 11 Hz was noted. Similar trends were observed at frequencies of 11 and 12 Hz when no stimulus was compared with odor. These findings indicated increased attention in response to random presentation of odor and non-odor. 4. Significant differences at frequencies from 14 to 24 Hz were noted in the contralateral hemisphere when no stimulus was compared with odor stimuli. MEG spectral densities at 21 and 22 Hz were also noted in the contralateral hemisphere when no stimulus was compared with non-odor stimulus. These differences apparently arise from the response of the somato-sensory cortex to non-odor stimuli and amyl-acetate. Alternation of MEG spectral densities at frequencies from 14 to 17 Hz and 23 to 24 Hz in the left hemisphere was noted when no stimulus was compared with non-odor and no stimulus was compared with odor. These results appear to be related to "emotions" of pleasantness and unpleasantness evoked by non-odor and odor.     

Defucosylated anti CC chemokine receptor 4 monoclonal antibody combined with immunomodulatory cytokines: a novel immunotherapy for aggressive/refractory Mycosis fungoides and Sezary syndrome.

PURPOSE: Sézary syndrome (SS) and Mycosis fungoides (MF) in the advanced stage have dismal prognoses. Because CC chemokine receptor 4 (CCR4) has an important role in the skin-homing capacity of MF/SS cells, we postulated that anti-CCR4 monoclonal antibody (mAb) could represent a novel therapeutic agent against aggressive/refractory MF/SS. EXPERIMENTAL DESIGN: The defucosylated next-generation therapeutic mAb KM2760 induces enhanced antibody-dependent cellular cytotoxicity (ADCC). Here, we assessed the therapeutic potential of this antibody against aggressive MF/SS tumor cells in vitro and in animal models in vivo. RESULTS: KM2760 induced robust ADCC by peripheral blood mononuclear cell (PBMC) from healthy controls against a MF/SS cell line as well as against primary tumor cells from patients with aggressive MF/SS. KM2760 also showed significant antitumor activity in disseminated and nondisseminated MF/SS mouse models. In addition, approximately 30% of autologous MF/SS tumor cells were killed in in vitro assays of KM2760-induced ADCC mediated by patients' PBMC after only 4 h, despite the low numbers of natural killer cells present in these PBMCs. It is also shown that ADCC induced by defucosylated therapeutic mAb can be greatly augmented by the immunomodulatory cytokines interleukin-12, IFN-alpha-2b, and IFN-gamma. CONCLUSIONS: The present study has encouraged us in the conducting of a phase I clinical trial of a completely defucosylated anti-CCR4 mAb in patients with CCR4-positive T-cell lymphomas, including aggressive MF/SS (ClinicalTrials.gov identifier: NCT00355472). In the near future, the efficacy not only of defucosylated anti-CCR4 mAb single-agent treatment but also of combination therapy with immunomodulatory cytokines will be clinically established to target aggressive/refractory MF/SS.     

Silymarin enhanced cytotoxic effect of anti-Fas agonistic antibody CH11 on A375-S2 cells

Silymarin is a polyphenolic flavonoid from milk thistle (Silybum marianum), which has anti-inflammatory, cytoprotective as well as antioxidant effects. Our previous study demonstrated that silymarin has anti-apoptotic effect against UV irradiation. In this study, we assessed the effect of silymarin on anti-Fas agonistic antibody CH11-treated human malignant melanoma, A375-S2 cells. Pretreatment with silymarin (3 × 10^- 4 mol/L) significantly induced cell apoptosis in CH11-treated A375-S2 cells. Mitochondrial transmembrane potential (ΔΨ_m) was also down-regulated by silymarin pretreatment. Caspase-8, -9, -3 and pan-caspase inhibitors partially reversed silymarin-induced apoptosis of CH11-treated cells. The expression of Fas-associated proteins with death domain (FADD), a downstream molecule of the death receptor pathway, was increased by silymarin pretreatment, followed by cleavage of procaspase-8, whose activation induced cell apoptosis. Moreover, cleavage of procaspase-3 and digestion of its substrate, the inhibitor of caspase-activated DNase (ICAD), were also increased by silymarin pretreatment. These results suggested that silymarin could also exaggerate the apoptotic effect of anti-Fas agonistic antibody CH11 on A375-S2 cells.     

Prophylaxis and treatment of influenza encephalitis in an experimental mouse model

A mouse model study using mouse brain-adapted influenza A virus was performed to establish the prophylaxis and treatment of influenza encephalitis and encephalopathy. All mice died after intranasal inoculation of the brain-adapted influenza A virus (H7N3), and the pathological findings indicated the presence of significant encephalitis. Viral antigen was also detected in the brain, both pathologically and virologically. By contrast, infected mice immunized with inactivated vaccine of the same strain did not lose weight, which is an indicator of the overall condition of the mice, and all of them survived. Similarly, antiserum treatment in the early period (0-1 day post-infection) resulted in 100% survival, and no pathological findings were observed in the brain. However, mice treated with antiserum 3 days post-infection showed encephalitis with viral antigens in both glial cells and neurocytes. Although amantadine treatment for 4 days delayed weight loss, it did not prevent death from encephalitis. These results show vaccination and early antiserum treatment to be highly effective, whereas 4-day treatment of amantadine was not very effective in treating or preventing influenza encephalitis. The life-prolonging effect of amantadine, however, suggests that use of amantadine together with other treatments may inhibit the progression of encephalitis.     

Effect of anticholesterol therapy on soluble ICAM-1 in chronic stroke patients with hyperlipidemia

OBJECTIVE: We examined the effects of drug therapy with pravastatin (P) or bezafibrate (B) and diet (D) therapy on serum lipids and soluble intercellular adhesion molecule-1 (sICAM-1) in hyperlipidemic cerebrovascular disease (CVD) patients in the chronic stage. METHODS: This study included 36 patients (28 with cerebral infarction and hyperlipidemia and eight with cerebral hemorrhage and hyperlipidemia) divided into three groups: Group P (12 patients), Group B (10 patients), and Group D (14 patients). Before and after treatment, total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), triglyceride (TG), high density lipoprotein cholesterol (HDL-C) and sICAM-1 levels were measured. RESULTS: In Group P, Group B and Group D, TC levels were decreased by 30% (p < 0.005), 21% (p < 0.01), and 21% (p < 0.001), LDL-C levels were decreased by 38% (p < 0.005), 18% (not significant), and 25% (p < 0.005) and TG levels were decreased by 27% (p < 0.05), 53% (p < 0.005) and 22% (p < 0.05), respectively. sICAM-1 levels were decreased by 20% (p < 0.005) in Group P, but were not decreased in Group B or Group D. There was no correlation between deltaTC and delta sICAM-1 (r = 0.172). CONCLUSION: Administration of pravastatin significantly reduced sICAM-1 levels, independently of its decreasing effect on TC and TG in chronic CVD patients. Pravastatin may exert anti-atherosclerotic activity via two distinct mechanisms.     

Rapid and simple determination of epoxyeicosatrienoic acids in rabbit renal artery by reversed-phase HPLC with fluorescence detection

A liquid chromatographic method with fluorescence detection coupled with a solid-phase extraction was applied to the rapid determination of epoxyeicosatrienoic acids (EETs) in the rabbit renal artery. The EETs were extracted with an acetonitrile from renal artery homogenate and concentrated by a solid-phase extraction method. The concentrated EETs were reacted directly with a 6, 7-dimethoxy-1-methyl-2 (1H)-quinoxalinone-3-propionyl-carboxylic acid (DMEQ) hydrazide and separated by a reversed-phase HPLC with eluting a combination of a step-wise and a gradient of a mixture of methanol and water. The content of EETs in the renal arteries was significantly greater in the 0.5% cholesterol fed rabbits than in control rabbits. It is suggested that hyperchlesterolemia increases the production of EETs in the rabbit renal artery.     

Bioactivation of morphine in human liver: isolation and identification of morphinone, a toxic metabolite

Morphinone, identified in the bile of guinea pigs and rats given morphine, is a reactive electrophile and has the ability to bind to glutathione (GSH) and tissue macromolecules, leading to GSH depletion and cell damage. We previously demonstrated that the livers of various animal species are capable of forming morphinone from morphine. In this study, we examined whether the human liver can produce morphinone from morphine. HPLC analysis revealed that the incubation of morphine with the 9000xg supernatant of human liver in the presence of NAD(P) and 2-mercaptoethanol (ME) gave a peak corresponding to the synthetic morphinone-ME adduct (MO-ME), which is readily formed by a nonenzymatic reaction of morphinone with ME. The reaction product was isolated and was unambiguously identified as MO-ME using FAB-MS and NMR analyses in comparison with synthetic MO-ME. The conversion of morphine to morphinone required NAD(P), and NAD was a preferred cofactor over NADP. All the 9000xg supernatants from six human livers could produce morphinone at different rates, ranging from 30 to 120 nmol/g liver/30 min with NAD at pH 7.4. The enzyme activity responsible for the formation of morphinone from morphine was mainly localized in the microsomes. The microsomal enzyme activity was inhibited by steroids, lithocholic acid and indomethacin. Among these compounds, steroids with a 17beta-hydroxyl group almost completely depressed morphinone formation. In conclusion, the metabolic pathway of morphine to morphinone, a toxic metabolite, in human was shown for the first time in in vitro experiments.