Clinicopathological and prognostic significance of BCL2, BCL6, MYC, and IRF4 copy number gains and translocations in follicular lymphoma: a study by FISH analysis.

BCL2 translocation is the genetic hallmark of follicular lymphoma (FL). Besides BCL2 translocation, copy number (CN) gains and translocations of BCL6, MYC, and IRF4 have also been detected in FL, but there is little information regarding their prognostic significance. This retrospective study used fluorescence in situ hybridization (FISH) to analyze BCL2, BCL6, MYC, and IRF4 translocations and CN gains in 105 FL cases. Genetic translocations were detected for BCL2 (n = 64; 72.7%), BCL6 (n = 14; 15.9%), and MYC (n = 2; 2.3%); no case showed IRF4 translocation. Overall, 23 (26.1%), 30 (34.1%), 12 (13.8%), and 10 (11.0%) cases showed CN gains in BCL2, BCL6, MYC, and IRF4, respectively. BCL6 CN gain was a prognostic factor for worse overall survival, demonstrating a trend toward significance in multivariate analysis (HR =8.769, p = 0.056). BCL6 CN gain in FL might be associated with aggressive biologic behavior.

Clinical and Prognostic Significances of Cytokeratin 19 and KIT Expression in Surgically Resectable Pancreatic Neuroendocrine Tumors.

BACKGROUND: Pancreatic neuroendocrine tumors (PanNETs) are malignant endocrine neoplasms that present diverse clinical behaviors. Therefore, identification of biomarkers of PanNETs is important for stratification of the prognosis of PanNET patients. Recently, cytokeratin 19 (CK19) and KIT expression were reported to have prognostic significance in PanNET patients. METHODS: To identify their prognostic significance, CK19 and KIT protein expression were assessed in 182 surgically resected PanNETs and compared with clinicopathologic factors. RESULTS: Of 182 PanNETs cases, CK19 and KIT expression was noted in 97 (53.3%) and 16 (8.8%) cases, respectively. PanNET patients with CK19 expression had larger tumors (p=.006), higher World Health Organization (WHO) grade (p=.002) and pT classification (p<.001), increased distant metastasis (p=.004), and lymphovascular (p=.012) and perineural (p=.019) invasion. Similarly, those with KIT expression had larger tumors (p=.030), higher WHO grade (p=.001), advanced pT classification (p<.001), distant metastasis (p=.001), and lymphovascular invasion (p=.014). The 5-year survival rate for PanNET patients with KIT expression was significantly lower (62%) than that of patients without KIT expression (77%, p=.011), as determined by univariate but not by multivariate analyses. CONCLUSIONS: CK19 and KIT expression correlate with higher metastatic potential and advanced disease stage, and KIT expression is associated with worse survival in PanNET patients.

Primary Squamous Cell Carcinoma of the Upper Genital Tract: Utility of p16(INK4a) Expression and HPV DNA Status in its Differential Diagnosis from Extended Cervical Squamous Cell Carcinoma.

BACKGROUND: Primary squamous cell carcinoma (SCC) of the upper genital tract, including the endometrium, fallopian tubes, and ovaries, is extremely rare. It must be distinguished from the mucosal extension of primary cervical SCC because determination of the primary tumor site is important for tumor staging. However, patients with SCC of the fallopian tubes or ovarian surface have often undergone prior hysterectomy with inadequate examination of the cervix, making it difficult to determine the primary site. METHODS: We compared histologic findings, p16(INK4a) expression, and human papillomavirus (HPV) DNA status in four patients with primary SCC of the upper genital tract and five patients with primary cervical SCC extending to the mucosa of the upper genital tract. RESULTS: All five SCCs of cervical origin showed strong expression of p16(INK4a), whereas all four SCCs of the upper genital tract were negative, although one showed weak focal staining. Three of the five cervical SCCs were positive for HPV16 DNA, whereas all four primary SCCs of the upper genital tract were negative for HPV DNA. CONCLUSIONS: Although a thorough histological examination is important, immunonegativity for p16(INK4a) and negative for HPV DNA may be useful adjuncts in determining primary SCCs of the upper genital tract.

Antiproliferation of HeLa cells by 3,4,5-trihydroxy-N-[2-p-tolylethyl]-benzamide is associated with induction of DNA damage and inhibition of DNA replication.

The compound 3,4,5-trihydroxy-N-[2-p-tolylethyl]-benzamide (THTEB) is one of the derivatives of tyrosol, which is p-tyrosol combined with gallic acid by an amide bond. In this study, THTEB displayed a significant antiproliferative effect on human cervical carcinoma (HeLa) cells. Cell cycle analysis revealed that THTEB could arrest HeLa cells in the S phase with a concomitant decrease in the cells' G0/G1 and G2/M phases. According to the [3H]thymidine incorporation assay results, we found that THTEB could inhibit DNA replication, which suggests that THTEB-induced S phase arrest might be the direct result of blocked DNA synthesis. However, THTEB had very weak effect on replication protein A (RPA)'s ssDNA binding activity and the topoisomerase I (topo I)-mediated DNA relaxation activity, signifying that RPA and topo I were not the main target molecules in the inhibition of DNA replication. Furthermore, by using alkaline single-cell gel electrophoresis (comet assay), we found severe DNA damage caused by THTEB. In conclusion, these results suggest that THTEB could induce tumor cell antiproliferation correlated with DNA damage and DNA replication inhibition, but the target molecule of THTEB remains elusive.

Cytotoxicity of p-tyrosol and its derivatives may correlate with the inhibition of DNA replication initiation.

p-Tyrosol is a phenolic compound present in different dietary sources that can exert mild antioxidant properties based on in vitro and in vivo studies. In our study, two p-tyrosol derivatives (p-tyrosyl gallate and p-tyrosyl acetate) were synthesized and compared together with p-tyrosol and gallic acid for their cytotoxic activities on human cancer cells. p-Tyrosyl gallate had the most potent cytotoxicity and the major cytotoxic mechanism of its action was studied. We found that in HeLa cells, p-tyrosyl gallate can effectively induce cell cycle arrest during S phase and inhibited in vitro simian virus (SV40 DNA) replication. In addition, p-tyrosyl gallate can inhibit three important functional replication proteins (topoisomerase I, RPA and pol alpha-primase), especially pol alpha-primase. These results suggest that p-tyrosyl gallate-induced cell cycle arrest during S phase correlates with the inhibition of DNA replication. Pol alpha-primase may be the main target molecule. Taken together, we suggest that p-tyrosyl gallate is a strong anticancer drug candidate that warrants further investigation.

Synthetic tyrosyl gallate derivatives as potent melanin formation inhibitors.

Three tyrosyl gallate derivatives (1-3) with variable hydroxyl substituent at the aromatic ring of tyrosol were synthesized and evaluated as potent inhibitors on tyrosinase activity and melanin formation in melan-a cells. Among three tyrosyl gallate derivatives, 4-hydroxyphenethyl 3,4,5-trihydroxybenote (1) (IC(50)=4.93 microM), 3-hydroxyphenethyl 3,4,5-trihydroxybenote (2) (IC(50)=15.21 microM), and 2-hydroxyphenethyl 3,4,5-trihydroxybenote (3) (IC(50)=14.50 microM) exhibited significant inhibitory effect on tyrosinase activity. Compound 1 was the most active compound, though it did not show the inhibitory effect on melanin formation in melan-a cells. However, compounds 2 (IC(50)=8.94 microM) and 3 (IC(50)=13.67 microM) significantly suppressed the cellular melanin formation without cytotoxicity. This study shows that the position of hydroxyl substituent at the aromatic ring of tyrosol plays an important role in the intracellular regulation of melanin formation in cell-based assay system.