Effect of loss of heterozygosity of the c-kit gene on prognosis after hepatectomy for metastatic liver gastrointestinal stromal tumors

The authors have previously reported that loss of heterozygosity (LOH) of the c-kit gene could be responsible for the gain in high proliferative activity in some gastrointestinal stromal tumors (GIST), resulting in enhanced metastatic potential. In the present study, an attempt was made to identify the factors that might predict the postoperative prognosis of patients with metastatic liver GIST. The clinicopathologic or genetic features of resected liver GIST in 14 patients who had undergone a hepatectomy for metachronous liver metastases and who had not received adjuvant imatinib treatment were examined. LOH of the c-kit gene was observed in seven of 12 metastatic liver GIST (58.3%), of which DNA suitable for testing could be extracted. Ten patients had recurrence after hepatectomy and four had none. The median post-recurrent disease-free survival (PRDFS) after hepatectomy was 27.5 months (range 8–104). The tumor-specific PRDFS was examined using clinicopathologic features, c-kit mutation and LOH of the c-kit gene. No single clinicopathologic or genetic finding was significantly associated with PRDFS. However, patients with 'Ki67 labeling index <5% and LOH(–)' had a significantly longer PRDFS than those with 'Ki67 ≥5% or LOH(+)' ( P =  0.032), and there was no correlation between the presence of LOH of the c-kit gene and the Ki67 labeling index. LOH of the c-kit gene in metastatic liver seems to be a common event, and LOH of the c-kit gene in resected liver GIST may be a helpful factor in the prediction of the post-recurrent prognosis of patients with liver metastasis. ( Cancer Sci 2007; 98: 1734–1739)     

Pyogenic liver abscess after choledochoduodenostomy for biliary obstruction caused by autoimmune pancreatitis

INTRODUCTION The differentiation of autoimmune pancreatitis (AIP) from pancreatic cancer is sometimes difficult because these diseases share many clinical features[1]. When pancreatic cancer cannot be ruled out, laparotomy or pancreatic resection may be p…     

Clinicocytopathology of breast cancers with a ring-like appearance on ultrasonography and/or magnetic resonance imaging

On breast cancer imaging some cancers have an anechoic or high-echoic zone in the tumor on ultrasonography and ring-shaped enhancement on contrast-enhanced magnetic resonance imaging (MRI) with high intensity in the central area of the tumor on T2-weighted imaging, necessitating their differentiation from benign disease. Thus, nine breast cancers with a ring-like appearance on imaging were analyzed on cytopathology. Histologically the cancer cells of these lesions showing a ring-like appearance were located in the periphery of the tumor, with a central hypocellular zone. Five such lesions with a thick, doughnut-like appearance were identified as cancers with acellular zones (CAC), and four lesions with a thinner, rim-like appearance as matrix-producing carcinomas (MPC). The percentage ratio of the cancer-zone width to the tumor diameter was 26.4 ± 7.8 and 8.0 ± 3.2 (mean ± SD), respectively ( P = 0.003). Cytologically, highly atypical, naked-nucleus cells were observed in eight of the nine cancers. In two MPC and three CAC, cartilage matrix and amorphous material, respectively, were observed in the background. In summary, the present series of breast cancers having a ring appearance on imaging did not have uniform cytopathological features. They were classified as MPC or CAC, and cytology was useful in their diagnosis and differentiation in some cases.     

The influence of uremic serum on interleukin-1beta and interleukin-1 receptor antagonist production by peripheral blood mononuclear cells

We investigated whether or not uremic serum has an influence on IL-1beta and IL-1Ra production by normal peripheral blood mononuclear cells (PBMC). Four groups of subjects were divided into healthy controls and non-dialyzed patients with chronic renal failure (CRF), patients undergoing continuous ambulatory peritoneal dialysis (CAPD) and hemodialysis (HD) patients. We examined cytokine concentrations and cytokine production by PBMC from a normal subject at the density of 2.5 x 10(6) cells/mL incubated with 25% serum in the medium and serum containing polymyxin-B or lipopolysaccharides (LPS). IL-1Ra concentrations in the serum of the uremic groups were significantly higher than those of the controls. In IL-1beta production by PBMC in medium with both serum and serum containing polymyxin-B, these values in the uremic groups were significantly higher than in the controls. In IL-1Ra production with serum containing polymyxin-B, these values in the uremic groups were significantly higher than in the controls. In contrast, in IL-1Ra production by PBMC in medium with serum containing LPS, these values in the uremic groups were significantly lower than in the controls. It was concluded that uremic serum not only contains nonendotoxemic cytokine-inducing substances, but also shows impaired cytokine production by PBMC in response to LPS.     

Attenuated cardioprotection by ischemic preconditioning in coronary stenosed heart and its restoration by carvedilol

OBJECTIVE: Infarct size (IS) reduction by ischemic preconditioning (IPC) has been assessed in the heart in which coronary stenosis (CS)-induced chronic ischemia was not present. The aim of this study is to assess whether and how IS reduction by IPC is modified in the heart in which CS has occurred, and how further therapeutics, if any, modify it. METHODS: We assessed the IS produced by a 30-minute acute coronary occlusion and a 24-hour reperfusion (COR) in rat hearts in which CS had developed for 1-12 weeks. Modifications of IS by IPC and the mitochondrial KATP channel (mitoKATP) opener and blocker, and the effects of daily beta-blocker treatment with carvedilol on them, were also assessed. Myocardial protein kinase C (PKC)-epsilon activities in the risk areas were measured by Western blotting. RESULTS: One to 4 weeks after CS induction, myocardial PKC-epsilon was activated in the risk area of CS even without IPC, but such CS-induced PKC activation as well as that by IPC was attenuated 8-12 weeks after CS. The IS reductions by the mitoKATP opener as well as by IPC were attenuated 8-12 and 4-12 weeks after CS, respectively. Daily carvedilol treatment after inducing CS restored the malfunctioning PKC-mitoKATP signal cascade and the attenuated IPC and mitoKATP effect on IS. CONCLUSION: CS activates the PKC-mitoKATP signal cascade, mimicking the IPC effect, whereas this cardioprotective effect is attenuated late after CS via their downregulation. Restoration of these changes may be a novel mechanism for cardioprotection by carvedilol in the CS-induced ischemic heart.     

Membrane potential of rat ventricular myocytes responds to axial stretch in phase, amplitude and speed-dependent manners

OBJECTIVE: To elucidate the interdependence between the mechanical state of the myocardium and its electrical activity, previous studies have been performed at the cellular level. However, the information to date has been limited by the technical difficulties associated with stretching single myocytes. METHODS: We solved this problem by combining two techniques, namely a carbon fiber technique for stretching rat myocytes with wide ranges of amplitude and speed, and ratiometric measurement of a fluorescent indicator (di8-ANEPPS) for evaluating the membrane potential in the non-contact mode. RESULTS: During systole, stretching caused depolarization that prolonged the action potential duration without affecting the peak amplitude, but the effect was only significant in the late phase. Application of a stretch to quiescent myocytes depolarized the membrane potential in amplitude- and speed-dependent manners, but the response was suppressed by cytochalasin D treatment, suggesting participation of the cytoskeleton in the mechanotransduction mechanism. Finally, ion replacement experiments revealed that although Na+ was the dominant charge carrier for large amplitude stretches, Ca2+ permeation was involved in small amplitude stretches, suggesting amplitude-dependent ion selectivity. CONCLUSIONS: Application of axial stretching to rat ventricular myocytes changed the membrane potential in phase-, amplitude- and speed-dependent manners. Amplitude may also modulate the ion selectivity of stretch-activated channels.     

Obstructive sleep apnoea syndrome, plasma adiponectin levels, and insulin resistance

OBJECTIVE: To investigate whether sleep-disordered breathing and/or plasma adiponectin levels are associated with insulin resistance independent of obesity or fat distribution in obstructive sleep apnoea syndrome (OSAS). DESIGN: Cross-sectional clinical study. PATIENTS: Two-hundred and thirteen Japanese patients with OSAS aged 27-80 years were divided into three groups: 30 with mild OSAS [apnoea-hypopnoea index (AHI) = 10.3 +/- 0.9 episodes/h, minimum oxygen saturation (min SpO2) = 87.3 +/- 0.9%], 98 with moderate OSAS (AHI = 28.9 +/- 0.6 episodes/h, min SpO2 = 82.1 +/- 0.7%), and 85 with severe OSAS (AHI = 68.1 +/- 2.8 episodes/h, min SpO2 = 72.3 +/- 1.6%). Twenty-one patients undergoing diabetic treatments (two mild, nine moderate and 10 severe) were excluded from the assessment of insulin resistance and plasma adiponectin measurements. MEASUREMENTS: Fat distribution [evaluated according to visceral (V) and subcutaneous (S) fat areas using computed tomography scanning at the umbilical level], blood pressure, metabolic parameters and hormones including insulin and adiponectin were measured. After full polysomnography, venous blood was collected between 0600 and 0700 h. RESULTS: Severe OSAS patients were more hypertensive than mild and moderate OSAS. Fasting plasma glucose (FPG) and fasting plasma insulin and homeostasis model assessment of insulin resistance (HOMA-IR) levels were all higher in severe OSAS than mild and moderate OSAS patients. HOMA-IR was correlated not only with obesity [body mass index (BMI), V and S areas] but also with apnoea (AHI, min SpO2 and desaturation time). Additionally, HOMA-IR was correlated positively with haemoglobin (Hb)A1c, systolic (SBP) and diastolic blood pressure (DBP), triglycerides and free fatty acids (FFA), and negatively with high density lipoprotein (HDL)-cholesterol, suggesting that insulin resistance is a key component of the metabolic syndrome in OSAS. Plasma adiponectin levels were not different between mild, moderate and severe OSAS groups. Plasma adiponectin levels were correlated with HOMA-IR and V area, but not AHI or min SpO2. Stepwise multiple regression analysis, however, revealed that BMI, AHI and plasma adiponectin were independently associated with HOMA-IR. CONCLUSION: Sleep-disordered breathing was associated with insulin resistance independent of obesity. Although plasma adiponectin was also an independent determinant of HOMA-IR in OSAS patients, plasma adiponectin was more closely related to obesity than to sleep apnoea. Although treatment of sleep-disordered breathing with nasal continuous positive airway pressure reportedly improves insulin sensitivity, our findings suggest that treatment of obesity is also essential in ameliorating insulin resistance at least through increased plasma adiponectin levels in OSAS.     

Estrogen receptor-beta gene disruption potentiates estrogen-inducible aggression but not sexual behaviour in male mice

Aggressive behaviour of gonadally intact male mice is increased by estrogen receptor (ER)-beta gene disruption, whereas sexual behaviour remains unchanged. The elevated aggression levels following ER-beta gene disruption is pronounced during repeated aggression tests in young animals and the first aggression test in adults. In the present study, the roles of ER-beta activation in the regulation of aggressive and sexual behaviour were investigated in gonadectomized ER-beta knockout (betaERKO) and wild-type (WT) male mice treated with various doses of estrogen. Overall, estradiol benzoate (EB) treatment induced higher levels of aggression in betaERKO mice than in WT mice. In WT mice, the levels of aggression induced by EB were highest in the lowest-dose (2.5 microg/day) group and gradually decreased in higher-dosage groups. On the other hand, equally high levels of aggressive behaviour were induced by all three doses of EB in betaERKO mice. A marked genotype difference in dose responses is inferred, such that the ER-alpha-mediated facilitatory action of estrogen is more pronounced at lower and physiological doses and the ER-beta-mediated inhibitory action is only unveiled at higher doses of estrogen. In contrast to aggression, the levels of sexual behaviour induced by EB were not different between betaERKO and WT at either dose of EB (2.5 and 12.5 microg/day) examined. These findings support the notion that ER-beta activation may exert an attenuating action on male aggression induced by estrogen through ER-alpha-mediated brain mechanisms, whereas its effect on male sexual behaviour is relatively small.