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1.  Viral hepatitis markers in liver tissue in relation to serostatus in hepatocellular carcinoma 
Hepatocellular carcinoma (HCC) incidence is rising in the United States. Hepatitis B virus (HBV) and hepatitis C virus (HCV) are major causes of HCC. Hepatitis infection in HCC patients is generally diagnosed by serology, which is not always consistent with the presence of HBV and HCV in the liver. The relationship of liver viral status to serostatus in hepatocarcinogenesis is not fully understood.
HBV and HCV were evaluated in formalin-fixed paraffin-embedded liver tissue specimens in a retrospective study of 61 U.S. HCC cases of known serologic status. HBV DNA and HCV RNA were detected by PCR, RT-PCR and pyrosequencing, and HBsAg and HBcAg were evaluated by immunohistochemistry.
Viral markers were detected in the liver tissue of 25 of 61 (41%) HCC cases. Tissue viral and serologic status were discordant in 27 (44%) cases, including those with apparent “occult” infection. Specifically, HBV DNA was detected in tissue of 4 of 39 (10%) serum HBsAg (−) cases, including 1 anti-HCV(+) case; and HCV RNA was detected in tissue of 3 of 42 (7%) anti-HCV seronegative cases, including 2 with serologic evidence of HBV.
Viral hepatitis, including HBV-HCV coinfection, may be unrecognized in up to 17% of HCC patients when based on serology alone. Further research is needed to understand the clinical significance of viral makers in liver tissue of HCC patients in the absence of serologic indices.
The contribution of HBV and HCV to the rising incidence of HCC in the United States may be underestimated.
PMCID: PMC3818344  PMID: 23983238
hepatitis; HBV; HCV; occult; hepatocellular carcinoma
2.  Positron Emission Tomography (PET) in Hepatobiliary and Pancreatic Malignancies - A Review 
American journal of surgery  2012;204(2):232-241.
The prognosis for hepatobiliary and pancreatic malignancies is dismal. Surgery remains the primary curative option but unresectable disease is often discovered during operative exploration. Positron emission tomography (PET) provides unique biological information different from current imaging modalities. The purpose of this paper is to review the literature on the use of PET in hepatobiliary and pancreatic malignancies
We performed an extensive search on PubMed, using PET and hepatocellular, pancreatic, gallbladder, and cholangiocarcinoma as keywords, excluding articles not written in English or on non-human subjects, case reports, and series with <5 patients.
Although PET has shown usefulness in the diagnosis of certain cancers, current literature cautions against the use of PET for determining malignant potential of primary liver and pancreatic lesions. Literature on PET more strongly supports clinical roles for restaging of hepatobiliary and pancreatic malignancies, and for identifying metastatic disease.
The role of PET in detecting hepatobiliary and pancreatic malignancies has not yet been clearly defined. This article surveys the literature on the use of PET in identifying hepatobiliary and pancreatic malignancies.
PMCID: PMC3454495  PMID: 22464445
3.  Healthcare Disparities in Asians and Pacific Islanders with hepatocellular cancer 
American journal of surgery  2012;203(6):726-732.
Hawaii has the highest incidence of hepatocellular cancer (HCC) in the U.S. and the largest proportion of Asian/Pacific Islanders(PI). HCC studies generally combine these groups into one ethnicity and we sought to examine differences between Asian/PI subpopulations.
Demographic, clinical, and treatment data for 617 HCC cases ( 420 Asian, 114 white, and 83 PI patients) were reviewed. Main outcome measures included HCC screening and liver transplant.
Asian/PI subgroups had significantly more immigrants and age was different between groups. Compared to Whites, the PI and Filipinos had less HCC screening and liver transplants, fewer met Milan criteria and a smaller proportion of those with Milan criteria actually underwent transplant.
There were significant differences in risk factors, clinical presentation, treatment and access to care between Asian, PI and White patients with HCC. Future HCC studies may benefit from differentiating subgroups within Asian/PI populations to better focus these efforts.
PMCID: PMC3524307  PMID: 22227170
hepatocellular cancer; screening; liver transplant
4.  Elucidating the Landscape of Aberrant DNA Methylation in Hepatocellular Carcinoma 
PLoS ONE  2013;8(2):e55761.
Hepatocellular carcinoma (HCC) is one of the most common cancers and frequently presents with an advanced disease at diagnosis. There is only limited knowledge of genome-scale methylation changes in HCC.
Methods and Findings
We performed genome-wide methylation profiling in a total of 47 samples including 27 HCC and 20 adjacent normal liver tissues using the Illumina HumanMethylation450 BeadChip. We focused on differential methylation patterns in the promoter CpG islands as well as in various less studied genomic regions such as those surrounding the CpG islands, i.e. shores and shelves. Of the 485,577 loci studied, significant differential methylation (DM) was observed between HCC and adjacent normal tissues at 62,692 loci or 13% (p<1.03e-07). Of them, 61,058 loci (97%) were hypomethylated and most of these loci were located in the intergenic regions (43%) or gene bodies (33%). Our analysis also identified 10,775 differentially methylated (DM) loci (17% out of 62,692 loci) located in or surrounding the gene promoters, 4% of which reside in known Differentially Methylated Regions (DMRs) including reprogramming specific DMRs and cancer specific DMRs, while the rest (10,315) involving 4,106 genes could be potential new HCC DMR loci. Interestingly, the promoter-related DM loci occurred twice as frequently in the shores than in the actual CpG islands. We further characterized 982 DM loci in the promoter CpG islands to evaluate their potential biological function and found that the methylation changes could have effect on the signaling networks of Cellular development, Gene expression and Cell death (p = 1.0e-38), with BMP4, CDKN2A, GSTP1, and NFATC1 on the top of the gene list.
Substantial changes of DNA methylation at a genome-wide level were observed in HCC. Understanding epigenetic changes in HCC will help to elucidate the pathogenesis and may eventually lead to identification of molecular markers for liver cancer diagnosis, treatment and prognosis.
PMCID: PMC3577824  PMID: 23437062
5.  Choline Kinase Alpha and Hexokinase-2 Protein Expression in Hepatocellular Carcinoma: Association with Survival 
PLoS ONE  2012;7(10):e46591.
Hexokinase-2 (HK2) and more recently choline kinase alpha (CKA) expression has been correlated with clinical outcomes in several major cancers. This study examines the protein expression of HK2 and CKA in hepatocellular carcinoma (HCC) in association with patient survival and other clinicopathologic parameters.
Immunohistochemical analysis for HK2 and CKA expression was performed on a tissue microarray of 157 HCC tumor samples. Results were analyzed in relation to clinicopathologic data from Surveillance, Epidemiology, and End-Results Program registries. Mortality rates were assessed by Kaplan-Meier estimates and compared using log-rank tests. Predictors of overall survival were assessed using proportional hazards regression. RESULTS: Immunohistochemical expression of HK2 and CKA was detected in 71 (45%) and 55 (35%) tumor samples, respectively. Differences in tumor HK2 expression were associated with tumor grade (p = 0.008) and cancer stage (p = 0.001), while CKA expression differed significantly only across cancer stage (p = 0.048). Increased mortality was associated with tumor HK2 expression (p = 0.003) as well as CKA expression (p = 0.03) with hazard ratios of 1.86 (95% confidence interval (CI) 1.23–2.83) and 1.59 (95% CI 1.04–2.41), respectively. Similar effects on overall survival were noted in a subset analysis of early stage (I and II) HCC. Tumor HK2 expression, but not CKA expression, remained a significant predictor of survival in multivariable analyses.
HK2 and CKA expression may have biologic and prognostic significance in HCC, with tumor HK2 expression being a potential independent predictor of survival.
PMCID: PMC3465336  PMID: 23071593
6.  Detection of recurrent prostate cancer with 18F-fluorocholine PET/CT in relation to PSA level at the time of imaging 
Annals of Nuclear Medicine  2012;26(6):501-507.
To evaluate fluorine-18 fluorocholine (FCH) PET/CT for the detection of recurrent prostate cancer in relation to prostate-specific antigen (PSA) level.
FCH PET/CT was performed in 50 patients with rising PSA levels at follow-up of primary treatment of prostate cancer (radical prostatectomy in 28, radiation therapy in 13, and brachytherapy in 9). PET detection rates were determined at various PSA thresholds and examined by receiver operating characteristic analysis.
Findings consistent with recurrent prostate cancer were noted on FCH PET/CT in 31/50 (62 %) patients, with positive findings in 17/18 (94 %), and 11/13 (85 %), 2/7 (29 %), and 1/12 (8 %) patients with PSA >4, >2–4, >0.5–2, and ≤0.5 ng/mL, respectively. These findings were indicative of local/regional recurrence in 23 cases and systemic recurrence in 8 cases, with only a single route of recurrence (i.e., either hematogenous, lymphatic, or intraprostatic) in 84 % of PET scans with positive findings. Abnormal tumor activity was detected in 88 % of patients with a PSA level of 1.1 ng/mL or higher, and in only 6 % of patients with a PSA level below this threshold value.
FCH PET/CT may serve to identify the route of tumor progression in patients with recurrent prostate cancer; however, the likelihood of tumor detection may be related to the PSA level at the time of imaging.
PMCID: PMC3400027  PMID: 22549847
Fluorocholine; Prostate cancer; Positron emission tomography
7.  Cushing’s syndrome caused by an ACTH-producing large cell neuroendocrine carcinoma of the gallbladder 
Malignancies of the gallbladder, including neuroendocrine tumors, are uncommon, mostly found incidentally after cholecystectomy and are frequently asymptomatic in the early stages, but highly fatal. Limited data is available on adrenocorticotropic hormone (ACTH)-producing neuroendocrine tumors specifically originating from the gallbladder. We report the clinical and radiographic findings, which included positron emission tomography and computed tomography, of a patient with a gallbladder mass who presented with Cushing’s syndrome. Subsequently, a diagnosis of ACTH-producing large cell neuroendocrine carcinoma of the gallbladder was made. Despite being rare and having a poor prognosis, hormone-producing neuroendocrine tumors should be part of the differential diagnosis in the approach of patients with Cushing’s syndrome.
PMCID: PMC2999155  PMID: 21160818
Adrenocorticotropic hormone; Cushing’s syndrome; Neuroendocrine; Carcinoma; Gallbladder
8.  Measurement of Circulating Cell-Free DNA in Relation to 18F-Fluorocholine PET/CT Imaging in Chemotherapy-Treated Advanced Prostate Cancer 
To examine the effects of chemotherapy on circulating cell-free DNA (cfDNA) composition in relation to investigational whole-body measurement of tumor activity by fluorine-18 fluorocholine (FCH) positron emission tomography/computed tomography (PET/CT) in hormone-refractory prostate cancer (HRPC).
Serial FCH PET/CT scans were performed in eight patients with HRPC receiving docetaxel-based chemotherapy. Corresponding serial cfDNA samples were characterized by microfluidic electrophoresis, quantified by real-time PCR, and compared with PET/CT results. Promoter methylation of two prostate cancer-associated genes, GSTP1 and RARB2, was assessed by methylation-specific PCR of bisulfite-converted cfDNA.
Plasma cfDNA concentrations increased significantly from 13.3 ng/mL at baseline to 46.8 ng/mL and 50.9 ng/mL after one and three treatment cycles, respectively (p= 0.001). GSTP1 and/or RARB2 promoter methylation was identified in all pretreatment samples. The appearance of large (200 bp–10.4 kb) cfDNA fragments was noted in posttreatment samples along with loss of methylation at GSTP1 and/or RARB2. Tumor activity on PET/CT correlated with cfDNA concentration (r=−0.50, p= 0.01). Patients meeting criteria for PET tumor response had significantly lower pretreatment cfDNA levels than those who did not (8.0 vs. 16.4 ng/mL, p= 0.03).
Chemotherapy is associated with significant changes in plasma cfDNA content and FCH PET/CT-detected tumor activity. These interrelated measures are potential candidate markers of therapeutic response in HRPC. Clin Trans Sci 2012; Volume #: 1–6
PMCID: PMC3500883  PMID: 22376260
prostate cancer; nucleic acids; epigenetics; positron emission tomography

Results 1-8 (8)