Estimation of malignant potential of GI stromal tumors by contrast-enhanced harmonic EUS (with videos).

BACKGROUND: Contrast-enhanced harmonic EUS (CEH-EUS) is a new sonographic technique that uses US contrast agents and depicts intratumoral vessels in real time. OBJECTIVE: To evaluate whether assessment of tumor vascularity by CEH-EUS can predict the preoperative malignancy risk of GI stromal tumors (GISTs). DESIGN: Prospective study to observe GIST vascularity. SETTING: Kinki University School of Medicine. PATIENTS: Between June 2007 and September 2009, 76 consecutive patients suspected of having subepithelial lesions underwent CEH-EUS. INTERVENTION: CEH-EUS was performed by using a prototype echoendoscope in an extended pure harmonic detection mode. MAIN OUTCOME MEASUREMENTS: Resected GIST specimens in 29 patients who underwent surgical resection were divided into high-grade (n=16) and low-grade (n=13) malignancy groups based on mitotic activity. The abilities of EUS-guided FNA and CEH-EUS to diagnose the malignant potential were compared. The sensitivities with which contrast-enhanced multidetector CT, power-Doppler EUS, and CEH-EUS detected intratumoral vessels in high-grade malignancy GISTs also were compared. RESULTS: CEH-EUS identified irregular vessels and thereby predicted GIST malignancies with a sensitivity, specificity, and accuracy of 100%, 63%, and 83%, respectively. Diagnosis of high-grade malignancy GISTs by EUS-guided FNA had a sensitivity, specificity, and accuracy of 63%, 92%, and 81%, respectively. Contrast-enhanced multidetector CT, power-Doppler EUS, and CEH-EUS detected intratumoral vessels in high-grade malignancy GISTs with sensitivities of 31%, 63%, and 100%, respectively (P<.05). LIMITATIONS: A single center was involved in this study. CONCLUSIONS: CEH-EUS successfully visualized intratumoral vessels and may play an important role in predicting the malignancy risk of GISTs.

Evaluation of parametrial spread in endometrial carcinoma.

OBJECTIVE: To evaluate the detailed clinicopathologic characteristics of parametrial spread in uterine endometrial cancer. METHODS: We retrospectively identified 334 individuals with uterine endometrial cancer who had undergone radical hysterectomy between 1988 and 2007. Parametrial spread was determined by histopathological analysis of surgically resected specimens. RESULTS: Twenty-eight (8.4%) individuals had histopathologically confirmed parametrial spread, and lymphatic or blood vessel invasion (22 cases) was the most frequently observed type of parametrial spread; direct invasion to parametrial connective tissue (five cases) or cardinal lymph node metastasis (four cases) were less frequently observed. Parametrial spread occurred not only in individuals with cervical involvement but also in individuals with more than half myometrial invasion, retroperitoneal (pelvic, paraaortic, or both), lymph node metastasis, ovarian metastasis, positive peritoneal cytology results, and lymphovascular space invasion. Twenty-six individuals (92.9%) with parametrial spread showed more than one of these histopathological factors (median number of factors 3, range 1-6); the other two individuals had lymphovascular space invasion alone. In 10 individuals with parametrial spread (35.7%), the condition recurred during the median follow-up period of 49 months, and initial recurrence was observed in the lung in six individuals (60.0%). Although the long-term prognosis for those with parametrial spread was significantly poorer than that of those without parametrial spread, both among all individuals (P<.001) and among individuals with International Federation of Gynecology and Obstetrics stage III (P<.05), multivariate analysis showed that parametrial spread was not an independent prognostic factor for uterine endometrial cancer. CONCLUSION: Parametrial spread cannot be predicted by cervical involvement alone but may be predicted by various lymphovascular space invasion-related histopathologic factors. Further, parametrial spread may not be an independent prognostic factor in individuals with uterine endometrial cancer. LEVEL OF EVIDENCE: III.

Prospective comparative study of the EUS guided 25-gauge FNA needle with the 19-gauge Trucut needle and 22-gauge FNA needle in patients with solid pancreatic masses.

BACKGROUND AND STUDY AIMS: The aim of this prospective study was to compare fine-needle aspiration guided by endoscopic ultrasonography (EUS-FNA) using 25-gauge and 22-gauge needles with the EUS-guided 19-gauge Trucut needle biopsy (EUS-TNB) in patients with solid pancreatic mass. PATIENTS AND METHODS: Twenty-four consecutive patients with pancreatic mass underwent biopsies by both EUS-FNA and EUS-TNB. Three needles were compared with respect to technical success rate, tissue size obtained, overall diagnostic accuracy and accuracy for histological and cytological diagnosis. RESULTS: The 25-gauge EUS-FNA was technically easier and obtained superior overall diagnostic accuracy than the 22-gauge and Trucut needles, especially in lesions of the pancreas head and uncinate process. Overall accuracy for the 25-gauge, 22-gauge and Trucut needle was 91.7%, 79.7% and 54.1%, respectively. Accuracy for cytological diagnosis irrespective the site of lesions with 25-gauge, 22-gauge and Trucut needles was 91.7%, 75.0%, and 45.8%, respectively. For uncinate masses, it was 100%, 33.3%, and 0.0%, respectively. These differences were significant. Among technically successful patients, the accuracy for histological diagnosis using the 25-gauge was significantly inferior (P < 0.05) to 22-gauge and Trucut needles and the rates were 45.8%, 78.9% and 83.3%. CONCLUSIONS: The 25-gauge FNA needle was significantly superior in terms of technical success rate and overall diagnostic accuracy, especially for the head and uncinate lesions, compared to the 22-gauge and Trucut needles and could be considered 'the best choice needle for cytological diagnosis' of solid pancreatic lesions. If histological diagnosis is required, the 22-gauge FNA needle and Trucut needle may be advantageous for use in head/uncinate and body/tail lesions, respectively.

Elevated serum ALT levels during pegylated interferon monotherapy may be caused by hepatic iron overload.

OBJECTIVE: Persistently elevated serum alanine aminotransferase (ALT) levels have been observed in chronic hepatitis C (CHC) patients during pegylated interferon (PEG-IFN) therapy. We investigated whether elevated serum ALT levels during PEG-IFN therapy are associated with iron overload. METHODS: Sixty-three CHC patients treated with PEG-IFNalpha-2a monotherapy were evaluated. The associations between elevated serum ALT levels (> or =70 IU/l) were investigated before and 24 weeks after therapy. We classified patients as follows: patients with no elevated serum ALT levels (group NE: n = 35), patients with elevated serum ALT levels (group E: n = 28), and patients with no elevated serum ALT level and negative HCV RNA (group NE-: n = 24), and patients with elevated serum ALT level and negative HCV RNA (group E-: n = 19). We also compared total iron score (TIS) and fibrosis stage in liver specimens obtained before and during therapy from 3 patients with elevated serum ALT levels. RESULTS: Serum ferritin levels were significantly increased after 24 weeks compared to baseline levels in group E (218 +/- 273 vs. 438 +/- 308 ng/ml; p < 0.0001) and group E- (146 +/- 152 vs. 410 +/- 291 ng/ml; p < 0.0001). Serum ALT and ferritin levels were significantly correlated after 24 weeks. The liver specimens revealed that TIS and fibrosis progressed during therapy. CONCLUSION: Our findings suggest that the elevation in serum ALT levels during therapy is caused by iron overload which may be induced by PEG-IFNalpha-2a.

Sequential occurrence of non-small cell and small cell lung cancer with the same EGFR mutation.

We report a case of small cell lung cancer (SCLC) developing after prolonged treatment (more than 2 years) for primary adenocarcinoma of the lung, and we show that both the SCLC and non-small cell lung cancer (NSCLC) tissues obtained from the same site share the same deletion in exon 19 of EGFR. This case suggests that the activating EGFR mutations may confer the pathogenesis of a subset of SCLC.

Regulatory failure of serum prohepcidin levels in patients with hepatitis C.

BACKGROUND/AIMS: Elevated serum ferritin and hepatic iron concentrations are frequently observed in chronic hepatitis C (CHC), which may be related to hepcidin. Because the role of hepcidin in CHC patients remains unknown, we aimed in this study to generate some information about hepcidin in CHC. METHODS: To determine whether serum hepcidin correlates with markers of iron status in patients with viral hepatitis, we measured serum prohepcidin levels in patients with hepatitis C virus (HCV) and hepatitis B virus (HBV) infection and in healthy controls. RESULTS: Serum prohepcidin and ferritin levels were negatively correlated (r=-0.182, P=0.037) in HCV patients and positively correlated in HBV patients and in healthy controls. The total iron scores in liver specimens from HCV patients were also negatively correlated (r=-0.403, P=0.013). Serum prohepcidin levels in patients with liver cirrhosis (LC) were significantly lower than in patients with chronic hepatitis (CH). In both CH and LC patients, serum prohepcidin levels were significantly lower in HCV patients than in HBV patients. CONCLUSION: Failure of homeostatic regulation of serum prohepcidin concentrations may be induced by HCV infection, resulting in elevation of serum ferritin levels, which leads to the progression of liver injury by iron overload in CHC patients.

Expression of glucose transporter-1 and aquaporin-4 in the cerebral cortex of stroke-prone spontaneously hypertensive rats in relation to the blood-brain barrier function.

BACKGROUND: Cerebral edema is an important initial event in cases of stroke among humans. Although hypertension is a major risk factor for endothelial injury, the precise mechanisms regulating brain microvascular changes are still unknown. To elucidate the pathogenesis of increases in vascular permeability in the cerebral cortex, we investigated the expression of glucose transporter-1 (GLUT-1) in endothelial cells and aquaporin-4 (AQP4) in astrocytes in relation to blood-brain barrier (BBB) function. METHODS: Using male stroke-prone spontaneously hypertensive rats (SHRSP) and normotensive Wistar-Kyoto rats (WKY), the particular localization of both GLUT-1 and AQP4 was investigated by immunohistochemistry. Quantitative changes in these molecules were examined by Western blot analysis in these rats at 6 weeks and 20 weeks of age. Furthermore, to investigate the expression of these molecules at the mRNA level, reverse transcriptase-polymerase chain reaction (RT-PCR) analysis was carried out using 20-week-old SHRSP and age-matched WKY. RESULTS: We confirmed the localization of GLUT-1 in endothelial cells and that of AQP4 in the end feet of astrocytes around microvessels, as determined by electron immunohistochemistry. No significant differences were found in the expression of these molecules in rats at 6 weeks of age, whereas GLUT-1 expression was lower, but that of AQP4 was higher, in SHRSP after the establishment of hypertension. Furthermore, GLUT-1 mRNA expression was lower in SHRSP, and AQP4 mRNA expression was also lower in SHRSP than in WKY at 20 weeks of age. CONCLUSIONS: These results indicate that AQP4 may play a much more important role in BBB function than GLUT-1, and thereby also in water distribution in the cerebral cortex of SHRSP with severe hypertension.

Prophylactic effects of an N- and L-type Ca2+ antagonist, cilnidipine, against cardiac hypertrophy and dysfunction in stroke-prone, spontaneously hypertensive rats.

To clarify the beneficial effects of cilnidipine, an L- and N-type calcium channel blocker, which were clinically observed against diastolic dysfunction in hypertrophied hearts of hypertensive patients, we investigated the effects of cilnidipine on cardiac remodeling and enhanced gene expression in stroke-prone, spontaneously hypertensive rats in comparison with that of captopril, a well-known angiotensin-converting enzyme inhibitor, at threshold doses with little blood pressure lowering effect. The expression of type III collagen and beta/alpha-myosin heavy chain as well as transforming growth factor-beta, and basic fibroblast growth factor were suppressed by both treatments, indicating the prevention or amelioration of cardiac dysfunction. Such beneficial effects were much more intense with cilnidipine treatment than in captopril. These results indicate that Ca2+ is a key factor in the pathogenesis of cardiac remodeling in hypertension. One possible beneficial effect of cilnidipine in the prevention of cardiac dysfunction may be due to the decreased amount of growth factors such as transforming growth factor-beta and basic fibroblast growth factor via direct action for Ca2+ influx and also via inhibition of local renin-angiotensin system in the myocardium.

Effect of basic fibroblast growth factor on cultured rat neural stem cell in three-dimensional collagen gel.

OBJECTIVES: The effect of growth factors on the three-dimensional culture of neural stem cells has not been reported. We studied the effect of basic fibroblast growth factor (bFGF) on cultured rat neural stem cells in a three-dimensional culture. METHODS: We cultured rat neural stem cells in collagen gel matrix for three-dimensional culture and examined the effect of bFGF under such culture conditions. RESULTS: After 4 days culture, the cell density in the bFGF treatment group was 12 times that of the non-treatment group, reaching a significantly high value. In the bFGF treatment group, microtubule associate protein (MAP)-2-positive cell aggregation occurred, although in the bFGF non-treatment group there was no MAP-2-positive cell aggregation and few of the cells were sparsely distributed. Also, in the bFGF treatment group, MAP-2-positive cell aggregation had a luminal structure similar to neural rosettes. There was elongation of MAP-2-positive neurites from the cell aggregation to the circumference in the bFGF treatment group. DISCUSSION: bFGF is known to induce the proliferation, but not the differentiation of neural stem cells in two-dimensional cultures. However, in the three-dimensional culture, bFGF induced both the proliferation and differentiation of neural stem cells. The three-dimensional culture is, therefore, considered a useful method for predicting the response of neural stem cells to cytokines or biologically active substances in vivo.