E‐selectin targeting to visualize tumorsin vivo

Generally angiogenic factors induce the expression of E‐selectin in vascular endothelial cells in the tumors. In this study, we employed an anti‐E‐selectin monoclonal antibody to target tumors in vivo and evaluated an optical imaging reagent to visualize tumor regions. The anti‐E‐selectin antibody was conjugated on the surface of liposomes, which encapsulated the near‐infrared fluorescent substances Cy3 or Cy5.5. The liposomes efficiently recognized human umbilical vein endothelial cells only when E‐selectin was induced by angiogenic factors such as TNF‐α in vitro. Cy5.5 encapsulated into liposomes that were conjugated with an anti‐E‐selectin antibody successfully visualized Ehrlich ascites tumor cells when transplanted into mice. Thus, E‐selectin targeting with liposomes containing a near‐infrared fluorescent dye was found effective in visualizing tumors in vivo. This strategy should be extremely useful as a method to identify sentinel lymphatic nodes and angiogenic tumors as well as use for drug delivery to tumor cells. Copyright © 2010 John Wiley & Sons, Ltd.     

Comparison of laparoscopic versus open cholecystectomy in patients with cardiac valve replacement

To evaluate the benefits and safety of laparoscopic cholecystectomy (LC) in patients with cardiac valve replacement (which frequently leads to cholelithiasis), 12 patients with cholelithiasis associated with cardiac valve replacement were studied. The patients were divided into two groups, of 6 patients each, according to the type of operation performed, open cholecystectomy (OC) or LC. The postoperative course was monitored with respect to laboratory data on postoperative days (POD) 1, 3, and 7. The mean duration of operation, blood loss, days to food resumption, length of hospital stay, and morbidity were compared between the two groups. Significant differences (P < 0.05) were found between the OC and LC groups in white blood cell counts on POD 1 (12 980 ± 3040/mm³ vs 8300 ± 1590/mm³), days to food resumption (2.7 ± 0.4 days vs 1.0 ± 0.7 days), and length of postoperative stay (15.8 ± 1.0 days vs 10.8 ± 1.6 days). There were no complications in the LC group, but 1 patient in the OC group had heart failure postoperatively. Our findings indicate the efficacy and safety of LC in patients with cardiac valve replacement. Received: August 14, 2000 / Accepted: December 22, 2000     

Expression of the p38 MAPK, NF-kappaB and cyclin D1 in extramammary Paget's disease

BACKGROUND: The p38 mitogen-activated protein kinase (MAPK)/nuclear factor kappaB (NF-kappaB)/cyclin D1 signaling pathway has recently been shown to play an important part in the pathogenesis of many human tumors. However, the role of this signal transduction pathway in extramammary Paget's disease (EMPD) remains unknown. OBJECTIVE: This study was designed to investigate the expression of phosphorylated p38 MAP kinasealpha (p-p38 MAPKalpha), phosphorylated NF-kappa B p65 (p-NF-kappaB p65) and cyclin D1 proteins in EMPD and to evaluate the relationship among them. METHODS: Thirty-five tissue samples from 30 primary EMPD cases were analyzed by immunohistochemical staining in formalin-fixed, paraffin-embedded tissue sections for p-p38 MAPKalpha, p-NF-kappaB p65 and cyclin D1. RESULTS: Among the 35 specimens of EMPD, p-p38 MAPKalpha, p-NF-kappaB p65 and cyclin D1 were expressed in 30, 28 and 27, respectively. Moreover, in five metastatic lymph node specimens, all were positive for p-p38 MAPKalpha and p-NF-kappaB p65, four were positive for cyclin D1. There were significant correlations between expression of p-p38 MAPKalpha, p-NF-kappaB p65, and cyclin D1 in EMPD. CONCLUSION: This study provides evidence that p-p38 MAPKalpha, p-NF-kappaB p65, and cyclin D1 was overexpressed in EMPD, suggesting that the p38 MAPK/NF-kappaB/cyclin D1 signaling pathway might participate in the oncogenesis of EMPD.     

Influence of early cerebrospinal fluid-guided diagnosis and early high-dose corticosteroid therapy on ocular outcomes of Vogt–Koyanagi–Harada disease

PURPOSE: To evaluate the importance of early cerebrospinal fluid (CSF)-guided diagnosis and early high-dose corticosteroid therapy on the complications and visual prognosis of Vogt-Koyanagi-Harada (VKH) disease. PATIENTS AND METHODS: Charts from patients with VKH disease who had been seen at Tokyo Medical and Dental University Hospital and Miyata Eye Hospital between 1994 and 2002 were retrospectively reviewed. The patients were classified into two groups. The first group (group A) consisted of patients who had received a full work-up including CSF examination and corticosteroid pulse therapy at the acute ophthalmic stage of disease. The second group (group B) consisted of patients who were referred to us by local ophthalmologists long after the disease onset, had not had a CSF examination and had been treated with low-dose systemic corticosteroids or topical corticosteroid therapy. The ocular complications, systemic complications and visual prognosis were compared between the two groups. RESULTS: Twenty-two patients were included in group A and ten patients in group B. The initial diagnosis at the acute ophthalmic stage had been VKH disease in all patients of group A, while, in group B, the diagnosis was idiopathic uveitis in six patients (60%) initially. Frequency of recurrent uveitis and integumentary symptoms were significantly lower in group A. Intensity of sunset glow fundus was significantly more severe in group B. All eyes in group A obtained a final visual acuity of 0.8 or better, whereas 11 eyes (55%) in group B were below this level. CONCLUSIONS: The results indicate that early diagnosis, helped by CSF examination and early high-dose corticosteroid therapy, decreased the complication rate and improved the visual prognosis.     

DNA methylation in small lung adenocarcinoma with bronchioloalveolar carcinoma components

We examined the methylation status in 100 specimens of lung adenocarcinomas measuring 2 cm or less and with bronchioloalveolar carcinoma (BAC) components (Noguchi types A–C) and then compared the methylation status between noninvasive tumors (Noguchi type A or B) and invasive tumors (Noguchi type C). Methylation-specific PCR was used to determine the methylation statuses of p16^INK4a, RASSF1A, CDH13, RARβ, and Cyclin D2. The methylation index that was regarded as representing the degree of methylation was calculated. We also determined the mutational statuses of EGFR exons 19 and 21 using a PCR-based method. A multivariate analysis showed that the aberrant methylation of p16^INK4a, RASSF1A, and CDH13 was significantly more frequent in invasive tumors than in noninvasive tumors [p16^INK4a, 36.5% versus (vs.) 8.3%, P = 0.0023; RASSF1A, 46.2% vs. 14.6%, P = 0.0012; CDH13, 42.3% vs. 10.4%, P = 0.0006]. The methylation index was significantly higher in invasive tumors than in noninvasive tumors (P = 0.004). The methylation of p16^INK4a was significantly more frequent in EGFR wild-type tumors than in EGFR mutant tumors (P = 0.021). Our results indicate the involvement of epigenetic alterations in the progression of adenocarcinoma with BAC components.     

No increase of breast cancer incidence in Japanese women who received hormone replacement therapy: overview of a case-control study of breast cancer risk in Japan

Hormone replacement therapy (HRT) has been considered one of the main risk factors for breast cancer. Studies demonstrating the relationship between HRT and breast cancer incidence were conducted in Western countries and the target populations were mainly Caucasians. Since the Women’s Health Initiatives demonstrated that HRT increased the risk of breast cancer with statistical significance, the number of HRT users in the United States has dramatically decreased. A recent case-control study has investigated the relationship between HRT and breast cancer in Japan, and here we review the results of this study to compare any discrepancy in breast cancer risk between Japanese and Western populations. For this case-control study, at seven institutions, women between the ages of 45 through 69 years, with histologically confirmed breast cancer, were selected as the case group. An age-adjusted control group was selected, using hospital-based data, including records of those screened for lung, gastrointestinal, and gynecological cancer. Questionnaires were administered, and items questioned included various factors related to the incidence of breast cancer: age at diagnosis, body mass index (BMI), smoking habit, age at menopause, birth history, number of births, number of children, history of breast feeding, familial background, and menopausal status. In total, 6183 samples (98.4% of the estimated samples) were put into the database. Data from 276 samples were excluded due to ineligibility. Finally, 5861 samples (3434 cases and 2427 controls) were analyzed. In 3316 cases, 164 (5.0%) patients received hormone-replacement therapy (HRT); on the other hand, 253 (10.7%) of 2355 controls received HRT. The odds ratio was 0.432 (95% confidence intervals [CI], 0.352–0.53), and there was a significantly negative correlation between HRT use and breast cancer. The risk factors in Japanese women showed similar profiles to those in women in Western countries. However, we did find some different profiles of breast cancer risk in the Japanese women. Changing of lifestyle may increase breast cancer risk in Japan.     

beta-Catenin mutation and its nuclear localization are confirmed to be frequent causes of Wnt signaling pathway activation in pilomatricomas

BACKGROUND: beta-Catenin has been shown to play an important role in the formation of hair follicle-related tumors, including pilomatricomas. Several investigators have shown that beta-catenin gene mutation is observed in pilomatricomas. However, the relationship between the pattern of beta-catenin localization in the cell and beta-catenin gene mutation is still controversial. OBJECTIVES: This work was performed to determine the frequency of beta-catenin nuclear localization in pilomatricoma, the relationship between the pattern of beta-catenin localization and beta-catenin mutation, and the involvement of APC mutation. METHODS: Typical 32 pilomatricomas were examined for beta-catenin expression by immunostaining. Genomic DNA was extracted, amplified and sequenced from 23 pilomaticomas with nuclear beta-catenin staining and 4 pilomaticomas without nuclear beta-catenin staining. Mutations of beta-catenin gene were confirmed by subcloning assay and restriction endonuclease assay. RESULTS: Using immunostaining, we found that 81% (26/32) of pilomatricomas displayed nuclear beta-catenin staining in basophilic cells. Sequence analysis revealed that 61% (14/23) contained mutations in exon 3 of beta-catenin. However, no mutations were detected in 4 pilomaticomas without beta-catenin nuclear staining. Detected mutations were adjacent to or abolished well-known regulatory phosphorylation sites of beta-catenin. APC gene mutations were not detected in 27 pilomatricomas with/without beta-catenin nuclear staining. CONCLUSIONS: These results confirmed that beta-catenin mutation and its nuclear localization are frequent causes of Wnt signaling pathway activation and suggested that beta-catenin activation mutations contribute to tumorigenesis of pilomatricomas.