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Focal adhesion kinase (FAK) is implicated in cancer cell survival, proliferation and migration. Expression of FAK expression is elevated and associated with tumor progression and metastasis in various tumors, including hepatocellular carcinoma (HCC). Increased 14-3-3 expression is shown to be a potential prognostic factor to predict higher risk of distant metastasis and worse overall survival in HCC. The aim of this study is to investigate whether FAK is associated or regulated by 14-3-3 to modulate tumor progression in HCC. In this study, 114 primary HCC tumors including 34 matched metastatic tumors were subjected to immunohistochemistry analysis of FAK and 14-3-3 expression. Overexpression of FAK was significantly associated with increased risk of extrahepatic metastasis (p=0.027) and reduced 5-year overall survival rate (p=0.017). A significant correlation of FAK and 14-3-3 expression was observed in primary tumor (p<0.001) and also metastatic tumors. Furthermore, overexpression of 14-3-3 induced FAK expression and promoter activity which were determined by Western blotting analysis and luciferase-reporter assay. Moreover, 14-3-3 enhanced NFκB activation and increased nuclear translocation of NFκB. Results from chromatin immunoprecipitation assay revealed that 14-3-3 induced NFκB binding on FAK promoter region. These findings suggest that FAK expression is correlated with and upregulated by 14-3-3 via activation of NFκB. Target to suppress or inactivate FAK alone, or combine with 14-3-3 is thus considered as the potential therapeutic strategy for preventing HCC tumor progression.

14-3-3β is implicated in cell survival, proliferation, migration, and tumor growth; however, its clinical relevance in tumor progression and metastasis have never been elucidated. To evaluate the clinical significance of 14-3-3β, we analyzed the association of 14-3-3β expression and clinicopathologic characteristics in primary and subsequent metastatic tumors of hepatocellular carcinoma patients. 14-3-3β was expressed abundantly in 40 of 55 (70.7%) primary tumors. Increased 14-3-3β expression in primary tumors predicted a higher 5-year cumulative incidence of subsequent extrahepatic metastasis, and multivariate analysis revealed 14-3-3β overexpression was an independent risk factor for extrahepatic metastasis. Patients with increased 14-3-3β expression in primary tumors had worse 5-year overall survival rates, and 14-3-3β overexpression was an independent prognostic factor on Cox regression analysis. Furthermore, stably overexpressed 14-3-3β enhanced hepatocellular carcinoma cell migration and proliferation and increased anchorage-independent cell growth. In addition, in vivostudy in a nude-mice model showed tumor formation significantly increased with 14-3-3β overexpression. In conclusion, this is the first report to show that increased 14-3-3β expression is associated with subsequent extrahepatic metastasis and worse survival rates, as well as cancer progression of hepatocellular carcinoma. Thus, 14-3-3β may be a novel prognostic biomarker and therapeutic target in hepatocellular carcinoma.

Focal adhesion kinase (FAK) has been implicated in tumorigenesis in various cancers; however, it remains unclear how FAK participates in tumor malignancy in vivo. This study seeks to understand the role of FAK activation in gastric cancer progression. Using immunohistochemical staining and Western blotting, we found that pY397 FAK, an autophosphorylation site on FAK activation, was abundant in the cancerous tissues of 21 of 59 patients with gastric carcinomas. We attempted to correlate clinicopathological parameters, including histological types, TNM staging, and cancer recurrence, with the expression of FAK and pY397 FAK in cancerous tissues. Intriguingly, patients with higher levels of pY397 FAK displayed higher incidences of gastric cancer recurrence after surgery and poor 5-year recurrence-free survival. Furthermore, multivariate analyses showed that pY397 FAK was an independent predictor of gastric cancer recurrence. As a result, expression of pY397 FAK is a significant prognostic factor for the recurrence of gastric cancer. Additionally, in vitrostudies showed that overexpression of Y397F, a dominant-negative mutant of FAK, in AGS human gastric carcinoma cells impaired cell migration, invasion, and proliferation compared with cells overexpressing wild-type FAK. Thus, activation of FAK through autophosphorylation at Tyr397 leads to the progression of gastric carcinomas by promoting cell migration, invasion, and proliferation. Collectively, our results have provided valuable insights for the development of novel diagnoses and therapeutic targets for gastric cancer treatments.

Background Liquid-based cytology (LBC) has achieved great success in cytological diagnosis of various cancers when compared with conventional smear methods. However, its application in diagnosing nasopharyngeal carcinoma (NPC) has never been studied.Methods Eighty-four consecutive patients who underwent nasopharyngeal biopsy for suspicious NPC or a nasopharyngeal mass under nasopharyngoscopy were enrolled in this prospective study. Brush samples were taken from the same site before punch biopsy and processed with the Thin Prep test.Results The adequacy, accuracy, sensitivity, specificity, false-negative rate, and false-positive rate of LBC in diagnosing NPC were 92.9% (78 of 84), 93.6% (73 of 78), 84.2% (16 of 19), 96.6% (57 of 59), 15.8% (three of 19), and 3.4% (two of 25), respectively. There were four inadequate specimens from patients with NPC and two inadequate ones from those without NPC.Conclusions Our study showed that the adequacy, accuracy, sensitivity, specificity, and diagnostic rate of LBC were equivalent to those using conventional smear methods. Although the diagnostic rate of NPC was lower using brush cytology than by punch biopsy, further improvements in the sampling technique could make brushing cytology a potential tool for NPC screening.

ABSTRACTTo evaluate a commercialized in situ hybridization (ISH) assay for detecting human papillomavirus (HPV) DNA, we compared the ability of a new ISH probe, Inform HPV III (Ventana Medical Systems, Tucson, AZ), to that of PCR assays to detect HPV DNA in cervical tissue specimens with normal cervix (20 cases), cervical intraepithelial neoplasia (CIN; CIN 1, 27 cases; CIN 2, 28 cases; and CIN 3, 33 cases), and cervical carcinoma (29 cases). General HPV DNA was detected using consensus primer-mediated PCR assays. HPV genotyping was performed by using EasyChip HPV blot (King Car Yuan Shan Institute, I-Lan, Taiwan). HPV16 integration status (E2/E6 ratio) was determined by using quantitative real-time PCR. Our findings showed that the ISH and PCR had fair to good agreements in detecting HPV DNA across all CIN categories without significant differences (Kappa coefficient, 0.34 to 0.63; P= 0.13 to 1.0). However, ISH detected significantly fewer HPV-positive cases in carcinoma than PCR did (Kappa coefficient, 0.2; P= 0.03). Eleven cases with ISH-PCR+results had HPV types that can be detected by Inform HPV III. Five carcinoma cases with ISH-PCR+results showed a significantly higher level of integrated HPV16 (P= 0.008) than did the ISH+cases. As a consequence, lower copy numbers of episomal HPV16 in carcinoma might be the cause for the false-negative ISH results. Although the punctate signal pattern of HPV significantly increased with the severity of disease (Ptrend = 0.01), no significant difference in the HPV16 integration status was observed between the cases with a punctate signal only and the cases with mixed punctate and diffuse signals (P= 0.4). In conclusion, ISH using the Inform HPV III probe seems comparable to PCR for detecting HPV DNA in cervical tissue with CINs. False-negative ISH results appear to be associated with the lower copy numbers of the episomal HPV16 but not with the ability of the Inform HPV III probe to detect specific HPV types. In addition, signal patterns, especially a mixed punctate and diffuse pattern of HPV, cannot be reliably used to predict viral integration status.

Current human papillomavirus (HPV) DNA testing using pooled probes, although sensitive, lacks specificity in predicting the risk of high-grade cervical intraepithelial neoplasia (CIN 2/3) progression. To evaluate selected HPV genotyping, viral load, and viral integration status as potential predictive markers for CIN progression, we performed HPV genotyping in formalin-fixed, paraffin-embedded cervical tissue with cervical carcinoma (29 cases) and CINs (CIN 1, 27 cases; CIN 2, 28 cases; CIN 3, 33 cases). General HPVs were screened using consensus primers GP5+/GP6+ and PGMY09/11. HPV genotyping and viral load measurement were performed using quantitative real-time PCR for eight oncogenic HPV types (16, 18, 31, 33, 35, 45, 52, and 58). HPV 16 viral integration status was evaluated by measuring HPV 16 E2/E6 ratio. We observed that HPV DNA positivity increased in parallel with the severity of CINs and carcinoma, with 59% positivity in CIN 1, 68% in CIN 2, 76% in CIN 3, and 97% in carcinoma (P trend=0.004). The eight oncogenic HPV types were significantly associated with CIN 2/3 (81%) and carcinoma (93%) (odds ratio (OR), 15.0; 95% confidence interval (CI), 5.67–39.76; P<0.0001) compared with the unknown HPV types (OR, 2.87; 95% CI, 0.89–9.22; P=0.08). HPV 16 was the predominant oncogenic HPV type in CIN 2/3 (51%) and carcinoma (71%) and integrated significantly more frequently in carcinoma than in CIN 2/3 (P=0.004). No significant differences in viral load were observed across the disease categories. Our findings suggest that selected genotyping for the eight oncogenic HPV types might be useful in separating women with a higher risk of CIN progression from those with a minimal risk. We also conclude that the HPV 16 integration status has potential to be a marker for risk assessment of CIN progression.Modern Pathology (2007) 20, 256–266. doi:10.1038/modpathol.3800737; published online 22 December 2006

Abstract: Large cell neuroendocrine carcinoma in the ampulla of Vater is rare and very different from the common ampullary adenocarcinoma. A 59-year-old man was admitted with obstructive jaundice. Gastroendoscopy showed a swollen ampulla of Vater and pathological examination of an ampullary biopsy revealed findings of a carcinoid tumor. After endoscopic biliary drainage, he underwent pancreaticoduodenectomy. A diagnosis of large cell neuroendocrine carcinoma was confirmed by immunohistochemical examination of the resected specimen. Despite adjuvant chemotherapy with cyclophosphamide and cisplatin, liver and peritoneal metastasis developed within 5 months and he survived for only 10 months after the operation. Thus, further investigations are needed to find a more effective postoperative adjuvant chemotherapy agent to treat patients with this aggressive tumor.

A total of 29 atrophic rhinitis patients were treated by endoscopic sinus surgery between 1990 and 1995. After the surgery, a 7 to 10-day course of systematic aminoglycoside was administered. Two cases were excluded, due to later occurrence of nasal lymphoma in one patient and incompleteness of postoperative antibiotic therapy in the other. Among those included, atrophic rhinitis occurred in the absence of prior surgery in 24 patients, and the condition was secondary to a previous intranasal surgery in the other three patients. After a 1 to 6-year follow-up (mean: 63.4 months), seven patients were successfully managed without any characteristic symptom or sign of atrophic rhinitis. Another 18 patients felt improved. Only two patients did not have any improvement. The rate of improvement was 92.6%. Overall, one patient suffered from a left retrobulbar hematoma after operation. Exposed orbital fat was observed in the other patient. The orbital complication rate was therefore 7.4%. No other major complication occurred in this series. The bacteriologic, radiological, antroscopic, and pathologic findings are also included here. It is concluded that endoscopic sinus surgery in combination with adequate postoperative antibiotic therapy can significantly treat atrophic rhinitis.

We report a case of primary gastric choriocarcinoma with liver metastasis. The mixed histologic patterns included adenocarcinoma, undifferentiated carcinoma, and choriocarcinoma. Immunohistologic staining for the β-subunit of human chorionic gonadotrophin (β-HCG) showed positive results in the choriocarcinoma, adenocarcinoma, and normal mucosal gland. However, positive HCG cells were present at different intensities in the choriocarcinoma, adenocarcinoma, and normal mucosal gland. The level of HCG was significantly increased in serum. This unusual tumor probably resulted from dedifferentiation of a primary adenocarcinoma or developed directly from the mucosal glands.

An intestinal web is a rare congenital anomaly, typically reported in childhood, but often remaining asymptomatic throughout the entire life span of the individual. We report the case of a symptomatic intestinal web associated with an enteric bezoar in an adult, which to the best of our knowledge has never been documented before. A 25-year-old man presented with acute small bowel obstruction, and laparotomy revealed a stenotic area of the ileum as well as impaction of an enteric bezoar. We resected this segment of ileum and an intestinal web was subsequently found in the stenotic area. The patient recovered well and has remained asymptomatic for 3 years. Although rare, a congenital intestinal web may be a cause of adult small bowel obstruction requiring surgical resection.

Otolaryngol Head Neck Surg 2001;125:569-70.