Chiung-Ru Lai

Clinical, virologic, and pathologic significance of elevated serum alpha-fetoprotein levels in patients with chronic hepatitis C.

Elevated serum alpha-fetoprotein (AFP) in patients with chronic hepatitis C is not uncommonly seen, but the pathogenesis of this phenomenon remains unclear. The aims of this study were to assess the prevalence of elevated serum AFP in patients with chronic hepatitis C and to evaluate the clinical, virologic, and histopathologic significance of this phenomenon. One hundred and fifteen Chinese patients with a histologic diagnosis of chronic hepatitis C were enrolled. None had evidence of hepatocellular carcinoma by image study at enrollment and for at least 2 years follow-up. Of the 115 patients, 33 (29%) had elevated serum AFP (more than 12 ng/mL). There was a significantly lower mean serum albumin (4.0 ± 0.1 vs. 4.3 ± 0.1 gm/dL, p <0.001) and higher mean scores for periportal necroinflammation (3.3 ± 0.3 vs. 2.3 ± 0.2, p = 0.007) and fibrosis (2.3 ± 0.2 vs. 1.1 ± 0.1, p < 0.001) in patients with elevated serum AFP when compared with patients without elevated serum AFP. Patients with elevated serum AFP had significantly more incidences of genotype 1b infection when compared with patients without elevated serum AFP (77% vs. 51%, p = 0.021). Mean serum hepatitis C virus (HCV) RNA titer showed no significant difference between the two groups. Multivariate logistic regression analysis showed that as serum albumin of less than 4.2 gm/dL, a histology fibrotic score of more than 3, and HCV genotype 1b infection were significantly independent predictors associated with elevated serum AFP. In conclusion, elevated serum AFP levels were significantly correlated with lower serum albumin levels, advanced fibrosis/cirrhosis, and genotype 1b infection in patients with chronic hepatitis C.

Fibrosis and AST to platelet ratio index predict post-operative prognosis for solitary small hepatitis B-related hepatocellular carcinoma

PurposeAlthough advanced liver fibrosis is crucial in the development of hepatocellular carcinoma (HCC) for patients with chronic hepatitis B, whether it is associated with the recurrence of HCC after resection remains obscure. This study was aimed to compare the outcomes for patients with minimal or advanced fibrosis in solitary small hepatitis B virus (HBV)-related HCC.MethodsThis study enrolled 76 patients with small (<5xa0cm) solitary HBV-related HCC who underwent resection. The outcomes of patients with minimal and advanced fibrosis in non-tumor areas were compared. Serum markers were tested to assess the stage of hepatic fibrosis and to predict prognosis.ResultsFourteen patients with an Ishak fibrosis score of 0 or 1 were defined as having minimal fibrosis; the remaining 62 patients were defined as having advanced fibrosis. During a follow-up period of 77.0xa0±xa050.7xa0months, 41 patients died. The overall survival rate was significantly higher (Pxa0=xa00.018) and recurrence rate was lower (Pxa0=xa00.018) for patients in the minimal fibrosis group. Aspartate aminotransferase–platelet ratio index (APRI) exhibited the most reliable discriminative ability for predicting advanced fibrosis. The overall survival rate was significantly higher (Pxa0=xa00.003) and recurrence rate was lower (Pxa0=xa00.005) for patients with an APRI of 0.47 or less.ConclusionsFor patients with solitary small HBV-related HCC who underwent resection, minimal fibrosis is associated with a lower incidence of recurrence and with better survival. APRI could serve as a reliable marker for assessing hepatic fibrosis and predicting survival.

Periostin in tumor microenvironment is associated with poor prognosis and platinum resistance in epithelial ovarian carcinoma

The interplay between tumor microenvironment and cancer that causes chemoresistance remains unclear. By analyzing public available microarray datasets, we identified that periostin (POSTN) was overexpressed in cancer stroma in epithelial ovarian cancer (EOC) patients. Immunohistochemistry analysis showed overexpression of stromal POSTN is a powerful independent poor prognostic predictor for EOC patients. Furthermore, patients with high levels of stromal POSTN tend to have higher percentage of cisplatin resistance compared to those with low levels of stromal POSTN. Moreover, we found POSTN treatment can induce cisplatin resistant and activate AKT pathway in A2780 cells in vitro. Inhibition of AKT activity by AKT inhibitor MK-2206 abolished POSTN-induced AKT activation and cisplatin resistance in vitro. Taken together, we found high POSTN expression in cancer microenvironment is correlated with poor prognosis in EOC patients and associated with platinum resistance. The effect of POSTN in cancer stroma cells may activate AKT pathway in tumor and AKT inhibitor can be beneficial to augment the efficacy of existing cancer therapeutics.

Comparative analysis of noninvasive models to predict early liver fibrosis in hepatitis B e Antigen-negative Chronic Hepatitis B.

Background Portal or bridging fibrosis is an indication for antiviral treatment in patients with chronic hepatitis B (CHB). An early marker predictive of liver fibrosis in hepatitis B e antigen (HBeAg)-negative CHB patients can alert clinicians to plan for treatment before disease progression. Goals To predict early and significant liver fibrosis (Ishak score ≥2) in HBeAg-negative CHB by validating several noninvasive markers derived from CHC. Study One hundred seventy-seven consecutive treatment-naive HBeAg-negative CHB patients who underwent liver biopsy were divided into a training group (n=121) and a validation group (n=56). Factors associated with liver fibrosis were analyzed. Results Multivariate analysis identified Loks model ≥0.87, cirrhosis discriminant score greater than 4, and positive alanine aminotransferase ratio platelet score as independent factors associated with liver fibrosis in the training group. The area under the receiver operating characteristic curve revealed that Loks model was better than cirrhosis discriminant score in predicting liver fibrosis in both the training and the validation groups. In patients with hepatitis B virus DNA greater than 2000 IU/mL or greater than 20,000 IU/mL, Loks model showed equal prediction value (area under the receiver operating characteristic curve 0.709 and 0.704, respectively). Loks model could also discriminate high and low hepatitis B virus DNA loads. In general, liver biopsy can be avoided in one-third (58 of 177) of patients by Loks model. Conclusions Loks model ≥0.87 can be an early marker of liver fibrosis in HBeAg-negative CHB patients. Loks model has clinical applications not only for CHC, but also for HBeAg-negative CHB.

Clinical Significance of Atypical Glandular Cells by the 2001 Bethesda System in Cytohistologic Correlation

OBJECTIVEnTo evaluate incidence, cytology findings and pathology outcome of atypical glandular cells (AGC) in Pap smears according to the 2001 Bethesda criteria.nnnSTUDY DESIGNnFrom 103,073 consecutive Pap smears, 113 (0.1%) AGC cases were identified. Of these, 91 (80%) had adequate histologic evaluation included in this study.nnnRESULTSnAbnormal histology findings were seen in 38 patients (42%). Final pathology results revealed 14 endometrial adenocarcinomas, 5 endocervical adenocarcinomas, 1 cervical squamous cell carcinoma, 1 endometrial stromal sarcoma, 6 other malignancies, 4 endocervical adenocarcinomas in situ, 4 cases ofendometrial complex byperplasia, 1 case of endocervical glandular dysplasia and 2 cases of cervical intraepithelial neoplasia 3 with glandular involvement. Women with AGC, favor neoplasia, were more likely to have significant pathology than those with AGC, not otherwise specified, 74% vs. 33% (p = 0.002). Some characteristic background cytologic findings were also noticed in most cases of endometrial, fallopian tube and endocervical adenocarcinoma.nnnCONCLUSIONnA diagnosis of AGC is more clinically significant by the 2001 Bethesda System, especially the AGC, favor neoplastic category. Some background cytologic features are important because they are indicators of malignancy.

Impact of body mass index and viral load on liver histology in hepatitis B e antigen-negative chronic hepatitis B

BACKGROUND & AIMSnThe impact of overweight and obesity on chronic hepatitis B (CHB) is unclear. This study was to examine the relationship among body mass index, viral load and liver histology in HBeAg-negative CHB.nnnMETHODSnThe study retrospectively investigated 136 HBeAg-negative chronic hepatitis B patients who had undergone liver biopsies in Taiwan. Factors associated with significant liver histology were analyzed. Definitions of overweight and obesity for the Asian population were body mass index≥23 kg/m(2) and ≥25 kg/m(2), respectively.nnnRESULTSnThe prevalence of overweight, obesity, and type 2 diabetes mellitus in the 136 patients were 22.8%, 52.2%, and 12.5%, respectively. Multivariate analysis identified obesity, AST>40 U/L, HBV DNA>20,000IU/mL and platelet count<150 × 10(9)/L as independent factors associated with significant liver fibrosis. Similarly, overweight/obesity, ALT>80 U/L, HBV DNA>1,000,000IU/mL, and platelet count<150 × 10(9)/L were independent predictors of significant hepatic necro-inflammation. By stratification, high BMI and high viral load patients had more advanced stage and grade of liver histology.nnnCONCLUSIONSnBody mass index and HBV viral loads may have synergistic effect on disease progression in HBeAg-negative CHB. Both controlling body weight and anti-viral therapy are important in the management of CHB.

Ovarian cancers arising from endometriosis: A microenvironmental biomarker study including ER, HNF1ß, p53, PTEN, BAF250a, and COX-2

Background: The microenvironmental biomarkers of different subtypes of ovarian cancers arising from endometriosis have not been studied in Taiwan. Their expression can help in understanding the carcinogenic mechanism. Methods: Our study used immunohistochemistry to compare the expression of estrogen receptor (ER), hepatocyte nuclear factor‐1 beta (HNF1ß), p53, phosphatase and tensin homolog (PTEN), BAF250a, and cyclooxygenase‐2 (COX‐2) among 79 cases of endometriosis‐associated ovarian cancers, including 40 (50%) clear cell carcinomas (CCCs), 33 (41%) endometrioid (EM) adenocarcinomas, four (5%) serous carcinomas, one adenosquamous carcinoma, and one adenosarcoma. Results: Positive stainings for ER, HNF1ß, p53, and COX‐2 were identified in 34 (43%), 30 (38%), 10 (13%), and 44 (56%) cases. Loss of PTEN and BAF250a were noted in 29 (37%) and 37 (47%) cases. The expression of ER was reversely correlated with that of HNF1ß (rho = −0.417, p < 0.001) and correlated with p53 (rho = 0.284, p = 0.011). ER positivity was commonly identified in EM adenocarcinomas (91%), and rarely in CCCs (8%) and serous carcinoma (0%; p < 0.001). By contrast, HNF1ß expression was frequently noted in CCCs (65%) and serous carcinomas (50%), but less in EM adenocarcinoma (6%; p < 0.001). All staining results were similar between atypical endometriosis glandular epithelium and contiguous malignant parts. Only nine cases showed 10 minor differences (10/474, 2%) in ER, HNF1ß, and BAF250a. For the staining patterns of p53, COX‐2, and PTEN, there was no difference between the invasive and precursor parts. Conclusion: Our results supported the suggestion that estrogen‐dependent ovarian cancer arising from endometriosis is substantially more associated with EM adenocarcinoma than CCCs. The positive HNF1ß staining was a frequent finding in CCCs, but not in EM adenocarcinoma. The similar staining patterns of atypical endometriosis glandular cells with the invasive parts confirmed their precursor status.

Thalidomide decreases intrahepatic resistance in cirrhotic rats

Increased intrahepatic resistance (IHR) within cirrhotic liver is caused by increased endotoxemia, cytokines tumor necrosis factor-alpha (TNF-alpha), vasoconstrictor thromboxane A(2) (TXA(2)), and disrupted microvasculatures. We evaluated the effects of thalidomide-related inhibition of TNF-alpha upon the hepatic microcirculation of cirrhosis in rats. Portal venous pressure (PVP), hepatic TNF-alpha, expression of thromboxane synthase (TXS), and leukocyte common antigen (LCA) were measured in bile-duct-ligated (BDL) rats receiving 1 month of thalidomide (BDL-thalido rats). Portal perfusion pressure (PPP), IHR, and hepatic TXA(2) production were measured in the isolated liver perfusion system. Intravital microscopy was used to examine hepatic microvascular disruptions. In BDL-thalido rats, PVP, PPP, IHR, hepatic TXA(2) and TNF-alpha, hydroxyproline content, expression of TXS and LCA, and LPS-induced leukocyte recruitment were significantly decreased. Conversely, hepatic microvascular density and perfused sinusoids were significantly increased. Thalidomide decreased PVP and IHR by reducing hepatic TXA(2) and improving hepatic microvascular disruptions in rats with biliary cirrhosis.

Contribution of immunocytochemistry in routine diagnostic cytology

The authors report the experience of applying immunocytochemistry in routine cytological examination and its contribution for diagnosis during a period of 3 yr in Veterans General Hospital‐Taipei, Taiwan. From August 1991 to July 1994, the cytology laboratory received 5,762 non‐gynecologic specimens with urine excluded. Immunocytochemistry was performed selectively in problematic cases. A total of 215 stainings including 124 epithelial markers, 50 lymphoma/leukemia markers, 22 neuroglial and choroid plexus markers, seven mesenchymal markers, six melanoma markers, and six others was performed on 145 specimens consisting of 89 effusions, 28 fine‐needle aspirations, 11 cerebrospinal fluids, and 17 other specimens. Effusions were by far the most frequent specimens for immunocytochemistry and the epithelial markers were the most frequently used antibodies. The immunocytochemical results were essential in 41 specimens (28%), confirmatory in 37 (26%), and non‐contributory in 67 (46%). Essential and confirmatory results occurred in 49% of effusions (44/89), 71% of fine‐needle aspirations (20/28), 55% of cerebrospinal fluids (6/11), and 47% of other specimens (8/17). It is concluded that immunocytochemistry is proved to be a good aid for the final diagnosis of daily cytologic practices in which the fine‐needle aspiration specimens are benefitted best. Diagn Cytopathol 1996;14:221–225.

Adult Embryonal Rhabdomyosarcoma Metastatic to the Breast and Diagnosed by Fine Needle Aspiration

BACKGROUNDnMetastasis to the breast from extra-mammary malignancies is rare, but its recognition is important. A solitary metastasis must be distinguished from the primary breast cancer because the treatment and prognosis are quite different.nnnCASEnA 30-year-old female presented with a 4.0-cm, solitary, nontender mass in the upper outer quadrant of the right breast 11 months after primary surgery for maxillary sinus embryonal rhabdomyosarcoma. The cytomorphology revealed features of small round cell tumor. Immunocytochemical staining disclosed a positive reaction to vimentin and desmin and negative reaction to cytokeratin, confirming the diagnosis of rhabdomyosarcoma.nnnCONCLUSIONnFine needle aspiration with ancillary studies is essential in the diagnosis of metastatic malignancy of the breast in order to avoid unnecessary mastectomy and to implement appropriate systemic therapy.