[Long-term survival analysis of 1 367 patients treated with radical nephrectomy from a single center].

Objective: To report the long-term survival of renal cell carcinoma (RCC) patients treated with radical nephrectomy in Sun Yat-sen University Cancer Center. Methods: We retrospectively analyzed the clinical, pathological and follow-up records of 1 367 non-metastatic RCC patients treated with radical nephrectomy from 1999 to 2020 in this center. The primary endpoint of this study was overall survival rate. Survival curves were estimated using the Kaplan-Meier method, and group differences were compared through Log-rank test. Univariate and multivariate Cox analysis were fit to determine the clinical and pathological features associated with overall survival rate. Results: A total of 1 367 patients treated with radical nephrectomy with complete follow-up data were included in the study. The median follow-up time was 52.6 months, and 1 100 patients survived and 267 died, with the median time to overall survival not yet reached. The 5-year and 10-year overall survival rates were 82.8% and 74.9%, respectively. The 5-year and 10-year overall survival rates of Leibovich low-risk patients were 93.3% and 88.2%, respectively; of Leibovich intermediate-risk patients were 82.2% and 72.3%, respectively; and of Leibovich high-risk patients were 50.5% and 30.2%, respectively. There were significant differences in the long-term survival among the three groups (P<0.001). The 10-year overall survival rates for patients with pT1, pT2, pT3 and pT4 RCC were 83.2%, 73.6%, 55.0% and 31.4%, respectively. There were significant differences among pT1, pT2, pT3 and pT4 patients(P<0.001). The 5-year and 10-year overall survival rates of patients with lymph node metastasis were 48.5% and 35.6%, respectively, and those of patients without lymph node metastasis were 85.1% and 77.5%, respectively. There was significant difference in the long-term survival between patients with lymph node metastasis and without lymph node metastasis. The 10-year overall survival rate was 96.2% for nuclear Grade 1, 81.6% for nuclear Grade 2, 60.5% for nuclear Grade 3, and 43.4% for nuclear Grade 4 patients. The difference was statistically significant. There was no significant difference in the long-term survival between patients with localized renal cancer (pT1-2N0M0) who underwent open surgery and minimally invasive surgery (10-year overall survival rate 80.5% vs 85.6%, P=0.160). Multivariate Cox analysis showed that age≥55 years (HR=2.11, 95% CI: 1.50-2.96, P<0.001), T stage(T3+ T4 vs T1a: HR=2.37, 95% CI: 1.26-4.46, P=0.008), local lymph node metastasis (HR=3.04, 95%CI: 1.81-5.09, P<0.001), nuclear grade (G3-G4 vs G1: HR=4.21, 95%CI: 1.51-11.75, P=0.006), tumor necrosis (HR=1.66, 95% CI: 1.17-2.37, P=0.005), sarcomatoid differentiation (HR=2.39, 95% CI: 1.31-4.35, P=0.005) and BMI≥24kg/m(2) (HR=0.56, 95%CI: 0.39-0.80, P=0.001) were independent factors affecting long-term survival after radical nephrectomy. Conclusions: The long-term survival of radical nephrectomy in patients with renal cell carcinoma is satisfactory. Advanced age, higher pathological stage and grade, tumor necrosis and sarcomatoid differentiation were the main adverse factors affecting the prognosis of patients. Higher body mass index was a protective factor for the prognosis of patients.

[Establishment and validation of a novel nomogram to predict overall survival after radical nephrectomy].

Objective: To establish a nomogram prognostic model for predicting the 5-, 10-, and 15-year overall survival (OS) of non-metastatic renal cell carcinoma patients managed with radical nephrectomy (RN), compare the modelled results with the results of pure pathologic staging, the Karakiewicz nomogram and the Mayo Clinic Stage, Size, Grade, and Necrosis (SSIGN) score commonly used in foreign countries, and stratify the patients into different prognostic risk subgroups. Methods: A total of 1 246 non-metastatic renal cell carcinoma patients managed with RN in Sun Yat-sen University Cancer Center (SYSUCC) from 1999 to 2020 were retrospectively analyzed. Multivariate Cox regression analysis was used to screen the variables that influence the prognosis for nomogram establishment, and the bootstrap random sampling was used for internal validation. The time-receiver operating characteristic curve (ROC), the calibration curve and the clinical decision curve analysis (DCA) were applied to evaluate the nomogram. The prediction efficacy of the nomogram and that of the pure pathologic staging, the Karakiewicz nomogram and the SSIGN score was compared through the area under the curve (AUC). Finally, patients were stratified into different risk subgroups according to our nomogram scores. Results: A total of 1 246 patients managed with RN were enrolled in this study. Multivariate Cox regression analysis showed that age, smoking history, pathological nuclear grade, sarcomatoid differentiation, tumor necrosis and pathological T and N stages were independent prognostic factors for RN patients (all P<0.05). A nomogram model named SYSUCC based on these factors was built to predict the 5-, 10-, and 15-year survival rate of the participating patients. In the bootstrap random sampling with 1 000 iterations, all these factors occurred for more than 800 times as independent predictors. The Harrell's concordance index (C-index) of SYSUCC was higher compared with pure pathological staging [0.770 (95% CI: 0.716-0.823) vs 0.674 (95% CI: 0.621-0.728)]. The calibration curve showed that the survival rate as predicted by the SYSUCC model simulated the actual rate, while the clinical DCA showed that the SYSUCC nomogram has a benefit in certain probability ranges. In the ROC analysis that included 857 patients with detailed pathological nuclear stages, the nomogram had a larger AUC (5-/10-year AUC: 0.823/0.804) and better discriminating ability than pure pathological staging (5-/10-year AUC: 0.701/0.658), Karakiewicz nomogram (5-/10-year AUC: 0.772/0.734) and SSIGN score (5-/10-year AUC: 0.792/0.750) in predicting the 5-/10-year OS of RN patients (all P<0.05). In addition, the AUC of the SYSUCC nomogram for predicting the 15-year OS (0.820) was larger than that of the SSIGN score (0.709), and there was no statistical difference (P<0.05) between the SYSUCC nomogram, pure pathological staging (0.773) and the Karakiewicz nomogram (0.826). The calibration curve was close to the standard curve, which indicated that the model has good predictive performance. Finally, patients were stratified into low-, intermediate-, and high-risk subgroups (738, 379 and 129, respectively) according to the SYSUCC nomogram scores, among whom patients in intermediate- and high-risk subgroups had a worse OS than patients in the low-risk subgroup (intermediate-risk group vs. low-risk group: HR=4.33, 95% CI: 3.22-5.81, P<0.001; high-risk group vs low-risk group: HR=11.95, 95% CI: 8.29-17.24, P<0.001), and the high-risk subgroup had a worse OS than the intermediate-risk group (HR=2.63, 95% CI: 1.88-3.68, P<0.001). Conclusions: Age, smoking history, pathological nuclear grade, sarcomatoid differentiation, tumor necrosis and pathological stage were independent prognostic factors for non-metastasis renal cell carcinoma patients after RN. The SYSUCC nomogram based on these independent prognostic factors can better predict the 5-, 10-, and 15-year OS than pure pathological staging, the Karakiewicz nomogram and the SSIGN score of patients after RN. In addition, the SYSUCC nomogram has good discrimination, agreement, risk stratification and clinical application potential.

Lower Relative Contribution of Positive Family History to Colorectal Cancer Risk with Increasing Age: A Systematic Review and Meta-Analysis of 9.28 Million Individuals.

OBJECTIVES: Existing algorithms predicting the risk of colorectal cancer (CRC) assign a fixed score for family history of CRC. Whether the increased CRC risk attributed to family history of CRC was higher in younger patients remains inconclusive. We examined the risk of CRC associated with family history of CRC in first-degree relative (FDR) according to the age of index subjects (<40 vs. ≥40; <50 vs. ≥50; and <60 vs. ≥60 years). METHODS: Ovid Medline, EMBASE, and gray literature from the reference lists of all identified studies were searched from their inception to March 2017. We included case-control/cohort studies that investigated the relationship between family history of CRC in FDR and prevalence of CRC. Two reviewers independently selected articles according to the PRISMA guideline. A random effects meta-analysis pooled relative risks (RR). RESULTS: We analyzed 9.28 million subjects from 63 studies. A family history of CRC in FDR confers a higher risk of CRC (RR = 1.76, 95% CI = 1.57-1.97, p < 0.001). This increased risk was higher in younger individuals (RR = 3.29, 95% CI = 1.67-6.49 for <40 years versus RR = 1.42, 95% CI = 1.24-1.62 for ≥40 years, p = 0.017; RR = 2.81, 95% CI = 1.94-4.07 for <50 years versus RR = 1.47, 95% CI = 1.28-1.69 for ≥50 years, p = 0.001). No publication bias was identified, and the findings are robust in subgroup analyses. CONCLUSIONS: The increase in relative risk of CRC attributed to family history was found to be higher in younger individuals. Family history of CRC could be assigned a higher score for younger subjects in CRC risk prediction algorithms. Future studies should examine if such approach may improve their predictive capability.

[Recombinant human tumor necrosis factor receptor type â ¡-IgG Fc fusion protein for treatment of occupational medicamentosa-like dermatitis induced by trichloroethylene].

Objective: To investigate the efficacy and safety of the recombinant human tumor necrosis factor receptor Ⅱ-IgG Fc fusion protein (rhTNFR: Fc, etanercept) for the treatment of occupational medicamentosa-like dermatitis induced by trichloroethylene (OMLDT) . Methods: In September 2011 to February 2016, 12 patients with OMLDT were treated with etanercept 25 mg, subcutaneous injection, twice per week, doubling of first dose. The course of treatment was 6 weeks. The drug eruption area and severity index (DASI) score, the proportion of patients achieving a 50%, 75% and 90% reduction in DASI (DASI50, DASI75, DASI90) and the serum level of TNF-α were used to assess the efficacy at different times. Adverse reactions were also recorded and evaluated. The results were statistically analyzed by nonparametric Friedman test and repetitive measurement ANOVA using the software SPSS19.0. Results: After 4 weeks treatment, the DASI score decreased form 56.33±7.02 to 0.50±0.91 (P<0.01) . The DASI50, DASI75 and DASI90 were all increased to 12 (100%) . The serum level of TNF-α decreased form (43.74±41.62) pg/ml to (3.03±0.47) pg/ml (P<0.01) . Statistically significant difference was observed from the above indexes. There were no adverse reactions in clinical application. Conclusion: Recombinant human tumor necrosis factor receptor Ⅱ-IgG Fc fusion protein may be a safe and effective drug in the treatment of OMLDT.

The Association between Distal Findings and Proximal Colorectal Neoplasia: A Systematic Review and Meta-Analysis.

OBJECTIVES: Whether screening participants with distal hyperplastic polyps (HPs) detected by flexible sigmoidoscopy (FS) should be followed by subsequent colonoscopy is controversial. We evaluated the association between distal HPs and proximal neoplasia (PN)/advanced proximal neoplasia (APN) in asymptomatic, average-risk patients. METHODS: We searched Ovid Medline, EMBASE, and the Cochrane Library from inception to 30 June 2016 and included all screening studies that examined the relationship between different distal findings and PN/APN. Data were independently extracted by two reviewers with disagreements resolved by a third reviewer. We pooled absolute risks and odds ratios (ORs) with a random effects meta-analysis. Seven subgroup analyses were performed according to study characteristics. Heterogeneity was characterized with the I2 statistics. RESULTS: We analyzed 28 studies (104,961 subjects). When compared with normal distal findings, distal HP was not associated with PN (OR=1.16, 95% confidence interval (CI)=0.89-1.51, P=0.14, I2=40%) or APN (OR=1.09, 95% CI=0.87-1.36, P=0.39, I2=5%), while subjects with distal non-advanced or advanced adenoma had higher odds of PN/APN. Higher odds of PN/APN were observed for more severe distal lesions. Weaker association between distal and proximal findings was noticed in studies with higher quality, larger sample size, population-based design, and more stringent endoscopy quality-control measures. The Egger's regression tests showed all P>0.05. CONCLUSIONS: Distal HP is not associated with PN/APN in asymptomatic screening population when compared with normal distal findings. Hence, the presence of distal HP alone detected by FS does not automatically indicate colonoscopy referral for all screening participants, as other risk factors of PN/APN should be considered.

CARD9 mutation linked to Corynespora cassiicola infection in a Chinese patient.

Corynespora cassiicola is a plant pathogen associated with leaf-spotting disease. The fungus has been found on diverse substrates: leaves, stems and roots of plants; nematode cysts and human skin. It rarely causes human infections. Here we report one case of subcutaneous phaeohyphomycosis caused by C. cassiicola with prominent tissue necrosis in a woman. All of her clinical features pointed towards a genetic linkage. Hence, whole-exome sequencing and Sanger sequencing were performed on this patient. One mutation of CARD9 was detected.

Potential modulation on P-glycoprotein and CYP3A by soymilk and miso: in vivo and ex-vivo studies.

P-glycoprotein (P-gp) and CYP3A4 both play very important roles in drug bioavailability, resistance and interactions. Our in vitro studies indicated that P-gp function was activated by many isoflavones. This study investigated the in vivo effects of soymilk and miso, isoflavone-rich soy foods, on P-gp and CYP3A by tracing the pharmacokinetics of cyclosporine (CSP), a probe drug of P-gp. Rats were orally administered CSP with and without soymilk or miso. A specific monoclonal fluorescence polarisation immunoassay was used to determine the blood concentration of CSP. The results showed that soymilk and miso significantly decreased the C(max) of CSP by 64.5% and 78.3%, and reduced the AUC(0-540) by 64.9% and 78.3%, respectively. Mechanism studies revealed that the activities of P-gp and CYP3A4 were induced by soymilk and miso. In conclusion, ingestion of soymilk and miso significantly activated the functions of P-gp and CYP3A.

Individually tailored screening of breast cancer with genes, tumour phenotypes, clinical attributes, and conventional risk factors.

BACKGROUND: We demonstrated how to comprehensively translate the existing and updated scientific evidence on genomic discovery, tumour phenotype, clinical features, and conventional risk factors in association with breast cancer to facilitate individually tailored screening for breast cancer. METHODS: We proposed an individual-risk-score-based approach that translates state-of-the-art scientific evidence into the initiators and promoters affecting onset and subsequent progression of breast tumour underpinning a novel multi-variable three-state temporal natural history model. We applied such a quantitative approach to a population-based Taiwanese women periodical screening cohort. RESULTS: Risk prediction for pre-clinical detectable and clinical-detected breast cancer was made by the two risk scores to stratify the underlying population to assess the optimal age to begin screening and the inter-screening interval for each category and to ascertain which high-risk group requires an alternative image technique. The risk-score-based approach significantly reduced the interval cancer rate as a percentage of the expected rate in the absence of screening by 30% and also reduced 8.2% false positive cases compared with triennial universal screening. CONCLUSION: We developed a novel quantitative approach following the principle of translational research to provide a roadmap with state-of-the-art genomic discovery and clinical parameters to facilitate individually tailored breast cancer screening.

Atypical ductal hyperplasia of the breast diagnosed by ultrasonographically guided core needle biopsy.

PURPOSE: We analysed the ultrasonographic (US) features of atypical ductal hyperplasia (ADH) of the breast diagnosed by US-guided core needle biopsy (CNB) with the aim of identifying factors that affect the underestimation of ADH. MATERIALS AND METHODS: A total of 134 ADH lesions sampled by US-guided CNB were reviewed retrospectively. All lesions were evaluated for pattern, size, lesion characteristics and margins, and the corresponding surgical outcome or imaging follow-up was obtained. Each patient's clinical and radiological features were analysed to identify factors involved in ADH underestimation. RESULTS: The prevalence of malignancy in each pattern of lesions following surgical excision was 32/81 (40%) for solid masses, 14/31 (45%) for ductal patterns, 5/17 (29%) for complex cystic lesions and 2/5 (40%) for architectural distortions. Based on the results of surgical and US follow-up, none of the category 3 lesions was proven to be a malignancy. Malignancy was found in 17 (21%) of the 80 BI-RADS (Breast Imaging Reporting and Data System) category 4a lesions, 20 (74%) of the 27 category 4b lesions, 12 (92%) of the 13 category 4c lesions, and four (100%) of the four category 5 lesions. Lesions with a higher US assessment category, lacking circumscribed margins, or a mammographic finding of suspected malignancy were all significantly associated with underestimation (p < 0.05 for each). CONCLUSION: US is useful in evaluating ADH lesions and in clarifying the indication for biopsy of these lesions. Familiarity with the frequency associated with malignancy for each feature will improve the utility of US in the work-up of these breast abnormalities.

Sam68 expression and cytoplasmic localization is correlated with lymph node metastasis as well as prognosis in patients with early-stage cervical cancer.

BACKGROUND: This study was aimed at investigating the role and molecular mechanism of Sam68 in cervical cancer lymph node metastasis. MATERIALS AND METHODS: Sam68 expression profile was detected by quantitative polymerase chain reaction, western blotting and immunohistochemical staining. Short hairpin RNA interfering approach was employed to suppress endogenous Sam68 expression in cervical cancer cells to determine its role in metastasis and the possible mechanism. RESULTS: Sam68 expression in cervical cancer was significantly up-regulated at both messenger RNA and protein levels compared with that in normal cervical tissues. The high expression level of Sam68 and its cytoplasmic localization were significantly associated with risk factors including pelvic lymph node metastasis (P < 0.001), and served as independent prognostic factors for predicting shortening of the overall survival time and disease-free survival time in patients with early-stage cervical cancer. Moreover, down-regulation of Sam68 in cervical cancer cells remarkably inhibited cellular motility and invasion. In addition, down-regulation of Sam68 reversed epithelial-mesenchymal transition through inhibiting the Akt/ GSK-3ß/Snail pathway. CONCLUSION: This study demonstrated that Sam68 could induce cervical cancer lymph node metastasis through regulating epithelial-mesenchymal transition, and Sam68 expression profile possessed the potential to serve as predictors of pelvic lymph node metastasis in cervical cancer patients.

Use of RNA interference to modulate liver adenoma development in a murine model transgenic for hepatitis B virus.

Chronic hepatitis B virus (HBV) infection is closely related to the development of severe liver complications, including hepatocellular carcinoma. In previous studies, we reported that in vivo long-term HBV suppression in transgenic mice can be achieved without apparent toxicity by short hairpin RNA sequentially delivered using adeno-associated viral (AAV) vectors of different serotypes. Our goal herein was to address the clinical utility of this delivery system and, in particular, to determine whether RNA interference (RNAi) and its ability to induce long-term HBV suppression will modulate the development of HBV-associated liver pathology. As a model system, we used a unique HBV transgenic mouse model, containing a 1.3 times over length of the HBV genome, on the ICR mouse background. These transgenic mice produce high serum HBV titers comparable with human chronic HBV patients, and, importantly, manifest characteristic HBV-associated pathology, including progressive hepatocellular injury and the development of hepatocellular adenoma. Using this system, we injected animals with AAV vectors expressing either HBV-specific or a control luciferase-specific short hairpin RNA and followed animals for a total of 18 months. We report herein that AAV-mediated RNAi therapy profoundly inhibits HBV replication and gene expression, with a significant reduction in hepatic regeneration, liver enzymes and, importantly, the appearance of liver adenomas. Indeed, the therapeutic effect of RNAi correlated with the reduction in HBV titers. Our data demonstrate that appropriately designed RNAi therapy has the potential to prevent formation of HBV-associated hepatocellular adenoma.

A progesterone-receptor-positive huge retroperitoneal tumour mimics metastasis in a breast cancer patient: sarcomatoid renal cell carcinoma.

We report a rare case of breast cancer concomitant with progesterone-receptor-positive renal cell carcinoma. A 48-year-old woman was diagnosed as having infiltrating ductal carcinoma of the breast and underwent modified radical mastectomy. A synchronous retroperitoneal tumour was detected by sonography of the abdomen in a routine cancer staging. Initially, the tumour was diagnosed as a synchronous retroperitoneal metastasis by needle biopsy; further tests revealed that it was progesterone receptor-positive. The retroperitoneal tumour showed poor response to full courses of adjuvant chemotherapy for breast cancer. Subsequently, the patient underwent a radical operation that included nephrectomy. The final pathology confirmed a sarcomatoid renal cell carcinoma. The post-operative course was uneventful. The patient had no recurrence at the 1-year follow-up. In this report, accurate diagnosis and adequate treatment were discussed. An intra-abdominal tumour with progesterone receptor- (PR) positive features is usually considered to be metastatic in breast cancer patients. For breast cancer patients with a PR-positive retroperitoneal tumour, renal cell carcinoma should be differentiated from a metastatic lesion of breast cancer, even if PR-expression is rare in renal cell carcinoma. To the best of our knowledge, this is the first case of PR-positive expression in breast cancer concomitant with renal carcinoma. In clinical settings, it is challenging for the surgeon to make an accurate diagnosis and to provide prompt treatment in such cases.

A rare case of the coexistence of ovarian clear cell carcinoma, mucinous cystadenoma, and endometriosis in the same ovary.

Clear cell carcinomas and endometrioid carcinomas are associated with endometriosis. The association of clear cell carcinomas with mucinous lesions has only been reported infrequently, and with mucinous cystadenoma has been rarely reported. This is the second reported case of the coexistence of ovarian clear cell carcinoma, mucinous cystadenoma, and endometriosis in the same ovary. A 57-year-old woman presented with lower abdominal pain for three weeks. Ultrasonography revealed a 16 x 14 x 10 cm mass in the left ovary with solid and cystic components. Hysterectomy and bilateral salpingo-oophorectomy were performed. Histopathological examination of the left ovary revealed the presence of clear cell carcinoma, mucinous cystadenoma, and endometriosis. Continuity between the areas of mucinous epithelium and clear cell carcinoma were noted; this may suggest that clear cell carcinoma may arise from endometriosis or mucinous cystic tumors.

The presence of Merkel cells and CD10- and CD34-positive stromal cells compared in benign and malignant oral tumors.

BACKGROUND: To describe sequential changes in Merkel cells (MC), and CD10(+) and CD34(+) stromal cells (SC) during the transition from benign to malignant oral lesions and correlate with clinicopathologic parameters. MATERIALS AND METHODS: Changes in cytokeratin 20-positive (CK20(+)) Merkel cells, CD10(+) and CD34(+) SC were immunohistochemically examined in specimens of 28 oral verrucous carcinomas (VC), 32 squamous cell carcinomas (SCC) and 36 benign squamous lesions (BSL). Immunoreactivity and localized inflammation were measured quantitatively and/or semiquantitatively, and between-group results were statistically compared. RESULTS: The mean number of CD34(+) SC was significantly lower in VC (57.36) and SCC (33.81) than BSL (351.56, P < 0.001). However, the three tumor types had similar staining level and number of CD10(+) SC. We found a significant difference in the density of MC between BSL and VC (P < 0.001) or SCC (P < 0.001). The number of CK20(+) MC was significantly lower in highly inflamed specimens than mildly inflamed specimens (P = 0.001). CONCLUSION: CD34(+) SC and to a lesser extent MC, but not CD10(+) SC, reveal statistically different density during the transition from benign to malignant oral lesions. The correlations between the CD34(+) SC expression and squamous lesions may be associated with epithelial dysplasia and/or tumor invasion.

Cortactin, fascin, and survivin expression associated with clinicopathological parameters in esophageal squamous cell carcinoma.

Cortactin, fascin, and survivin have been documented in several human cancers and play important roles in tumor progression. We collected 57 surgical specimens, including esophageal squamous cell carcinomas (SqCC; 7 well-differentiated, 15 moderately differentiated, and 24 poorly differentiated), 3 dysplasias, and 8 normal esophageal tissues. Tissue microarrays were constructed and the immunostaining scores for cortactin, fascin, and survivin were assessed. In 46 SqCC specimens, we examined the relationship between the expression of three biomarkers and tumor differentiation or clinical parameters. Higher immunostaining scores for cortactin, fascin, and survivin correlated positively with tumor differentiation of esophageal SqCC. Univariate survival analysis showed significantly worse prognosis in patients with high scores of cortactin (>or=290), fascin (>or=245), and survivin (score >or= 175), poor differentiation, T4 stage, positive for lymph node metastasis, and positive for distant metastasis. In multivariate survival analysis, high scores of survivin (>or=175) and poor differentiation were independent risk factors for worse prognosis. Our results demonstrated that higher expression of survivin may be related to tumor progression and it is an independent risk factor for poor survival time of esophageal SqCC. Survivin may be a good biomarker to be applied in clinic to predict the prognosis of esophageal SqCC.

Circulating levels of leptin, adiposity and breast cancer risk.

The present case-control study was to investigate the relationships of plasma leptin level and anthropometric measures of adiposity with the risk of breast cancer. Questionnaire information, anthropometric measures and blood samples were taken before treatment from 297 incident cases with breast cancer and 593 controls admitted for health examination at the Tri-Service General Hospital, Taipei, between 2004 and 2006. Plasma levels of leptin were measured by RIA. Logistic regression analysis was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for assessing the associations. Overall, higher leptin concentrations were significantly associated with an increased risk of breast cancer (OR (95% CI) for top vs bottom tertile of leptin was 1.63 (1.07-2.49), P(trend)=0.009). Waist circumference was a significant anthropometric factor for breast cancer in both pre- and postmenopausal women. Furthermore, the associations of leptin with breast cancer risk remained after adjustment for obesity indices. These results suggest that leptin may have an independent role in breast tumorigenesis. Regardless of the impact of circulating leptin, more research is needed to elucidate molecular mechanisms and local leptin levels that are critical for the development of breast cancers.

Comparative study of treatment dose plans after the refinement of Leksell Gamma Knife single-beam dose profiles.

We investigated the amplification of discrepancy when using multiple shots of the same collimator size helmet, by comparing dose plans in the Leksell GammaPlan employing the default single-beam dose profiles and the Monte Carlo generated single-beam profiles. Four collimator helmets were studied. The results show that the largest amplification of discrepancy with multiple shots was found with the 8 mm collimator because of the largest discrepancy of its single-beam dose profile. The amplification of discrepancy is significant when tumor volumes increase but insignificant when the tumor volumes are in an elongated shape. Using close shot overlapping strategy (i.e., more shots close packed together) shows no observable increase in the amplification of discrepancy. For the best quality of Leksell Gamma Knife radiosurgery, it is suggested that the single-beam dose profiles should be refined, especially the 8 mm collimator, to prevent error amplification when using multiple collimator shots.

Long-term inhibition of hepatitis B virus in transgenic mice by double-stranded adeno-associated virus 8-delivered short hairpin RNA.

RNA interference (RNAi) was reported to block hepatitis B virus (HBV) gene expression and replication in vitro and in vivo. However, it remains a technical challenge for RNAi-based therapy to achieve long-term and complete inhibition effects in chronic HBV infection, which presumably requires more extensive and uniform transduction of the whole infected hepatocytes. To increase the in vivo transfection efficiency in liver, we used a double-stranded adeno-associated virus 8-pseudotyped vector (dsAAV2/8) to deliver shRNA. HBV transgenic mice were used as an animal model to evaluate the inhibition effects of the RNAi-based gene therapy. A single administration of dsAAV2/8 vector, carrying HBV-specific shRNA, effectively suppressed the steady level of HBV protein, mRNA and replicative DNA in liver of HBV transgenic mice, leading to up to 2-3 log(10) decrease in HBV load in the circulation. Significant HBV suppression sustained for at least 120 days after vector administration. The therapeutic effect of shRNA was target sequence dependent and did not involve activation of interferon. These results underscore the potential for developing RNAi-based therapy by dsAAV2/8 vector to treat HBV chronic infection, and possibly other persistent liver infections as well.

Expression of the serine protease, matriptase, in breast ductal carcinoma of Chinese women: correlation with clinicopathological parameters.

Matriptase is a serine protease expressed by cells of surface epithelial origin, including epithelial breast tumor cells. Matriptase cleaves and activates proteins implicated in the progression of cancer and represents a potential prognostic and therapeutic target. The aim of this study was to examine matriptase expression in breast tumors of Chinese women and to identify its clinicopathological correlations. Immunohistochemical analysis of matriptase was performed in tissue microarrays of 251 breast tumors including 30 fibroadenomas, 59 ductal carcinomas in situ (DCIS), 38 grade I invasive ductal carcinomas (IDC), 79 grade II IDC, and 45 grade III IDC. The matriptase scores were significantly higher in the tumors than their non-tumor counterparts (178+/-12 for fibroadenoma; 275+/-11 for DCIS; 299+/-10 for grade I IDC; 251+/-10 for grade II IDC; and 314+/-11 for grade III IDC). In cases of IDC, matriptase scores were significantly correlated with tumor staging and nodal staging. Our findings demonstrate that matriptase is over-expressed in breast ductal carcinoma of Chinese women. It therefore may be a good biomarker for diagnosis and treatment of malignant breast tumors.

Increasing expression of fascin in renal cell carcinoma associated with clinicopathological parameters of aggressiveness.

AIM: To determine whether higher expression of fascin, an actin-bundling protein associated with motility, in conventional renal cell carcinoma (RCC) is associated with more advanced stages of the disease. METHODS: Immunohistochemical analysis of fascin expression was performed in tissue microarrays of 108 RCCs including 55 clear cell RCCs (CRCCs), 39 CRCCs with granular cell differentiation (GRCCs), 8 CRCCs with sarcomatoid differentiation (SRCCs) and 6 metastatic RCCs. RESULTS: The expression of fascin was undetectable in normal renal tubules of all control cases. However, among the 108 RCC cases, fascin immunoreactivity was seen on the cell membrane and cytoplasm. The average immunostaining score for fascin was 128/400 in grade I, 170/400 in grade II, 207/400 in grade III, and 323/400 in grade IV RCC. The average immunostaining score of fascin was 187/400 for stage T1, 205/400 for stage T2, 288/400 for stage T3, and 355/400 for stage T4 cases of RCCs. Higher fascin scores in RCC were significantly correlated with higher T and N stages and nuclear grade. In addition, the fascin scores in GRCC (368+/-19) and SRCC (263+/-21) were significantly higher than in CRCC (95+/-18). CONCLUSIONS: Our findings demonstrate for the first time that increased expression of fascin is associated with clinicopathological parameters of aggressiveness in patients with RCC. Fascin may be a novel biomarker for diagnosis and treatment of RCC.