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2.  Metabolic positron emission tomography imaging of cancer: Pairing lipid metabolism with glycolysis 
World Journal of Radiology  2016;8(11):851-856.
The limitations of fluorine-18 fluorodeoxy-D-glucose (FDG) in detecting some cancers has prompted a longstanding search for other positron emission tomography (PET) tracers to complement the imaging of glycolysis in oncology, with much attention paid to lipogenesis based on observations that the production of various lipid and lipid-containing compounds is increased in most cancers. Radiolabeled analogs of choline and acetate have now been used as oncologic PET probes for over a decade, showing convincingly improved detection sensitivity over FDG for certain cancers. However, neither choline nor acetate have been thoroughly validated as lipogenic biomarkers, and while acetyl-CoA produced from acetate is used in de-novo lipogenesis to synthesize fatty acids, acetate is also consumed by various other synthetic and metabolic pathways, with recent experimental observations challenging the assumption that lipogenesis is its predominant role in all cancers. Since tumors detected by acetate PET are also frequently detected by choline PET, imaging of choline metabolism might serve as an alternative albeit indirect marker of lipogenesis, particularly if the fatty acids produced in cancer cells are mainly destined for membrane synthesis through incorporation into phosphatidylcholines. Aerobic glycolysis may or may not coincide with changes in lipid metabolism, resulting in combinatorial metabolic phenotypes that may have different prognostic or therapeutic implications. Consequently, PET imaging using dual metabolic tracers, in addition to being diagnostically superior to imaging with individual tracers, could eventually play a greater role in supporting precision medicine, as efforts to develop small-molecule metabolic pathway inhibitors are coming to fruition. To prepare for this advent, clinical and translational studies of metabolic PET tracers must go beyond simply estimating tracer diagnostic utility, and aim to uncover potential therapeutic avenues associated with these metabolic alterations.
doi:10.4329/wjr.v8.i11.851
PMCID: PMC5120244  PMID: 27928466
Glycolysis; Lipogenesis; Fatty acid metabolism; Positron emission tomography; Choline; Acetate; Cancer; Prostate cancer; Hepatocellular carcinoma
3.  Joint analysis of multiple high-dimensional data types using sparse matrix approximations of rank-1 with applications to ovarian and liver cancer 
BioData Mining  2016;9:24.
Background
Technological advances enable the cost-effective acquisition of Multi-Modal Data Sets (MMDS) composed of measurements for multiple, high-dimensional data types obtained from a common set of bio-samples. The joint analysis of the data matrices associated with the different data types of a MMDS should provide a more focused view of the biology underlying complex diseases such as cancer that would not be apparent from the analysis of a single data type alone. As multi-modal data rapidly accumulate in research laboratories and public databases such as The Cancer Genome Atlas (TCGA), the translation of such data into clinically actionable knowledge has been slowed by the lack of computational tools capable of analyzing MMDSs. Here, we describe the Joint Analysis of Many Matrices by ITeration (JAMMIT) algorithm that jointly analyzes the data matrices of a MMDS using sparse matrix approximations of rank-1.
Methods
The JAMMIT algorithm jointly approximates an arbitrary number of data matrices by rank-1 outer-products composed of “sparse” left-singular vectors (eigen-arrays) that are unique to each matrix and a right-singular vector (eigen-signal) that is common to all the matrices. The non-zero coefficients of the eigen-arrays identify small subsets of variables for each data type (i.e., signatures) that in aggregate, or individually, best explain a dominant eigen-signal defined on the columns of the data matrices. The approximation is specified by a single “sparsity” parameter that is selected based on false discovery rate estimated by permutation testing. Multiple signals of interest in a given MDDS are sequentially detected and modeled by iterating JAMMIT on “residual” data matrices that result from a given sparse approximation.
Results
We show that JAMMIT outperforms other joint analysis algorithms in the detection of multiple signatures embedded in simulated MDDS. On real multimodal data for ovarian and liver cancer we show that JAMMIT identified multi-modal signatures that were clinically informative and enriched for cancer-related biology.
Conclusions
Sparse matrix approximations of rank-1 provide a simple yet effective means of jointly reducing multiple, big data types to a small subset of variables that characterize important clinical and/or biological attributes of the bio-samples from which the data were acquired.
Electronic supplementary material
The online version of this article (doi:10.1186/s13040-016-0103-7) contains supplementary material, which is available to authorized users.
doi:10.1186/s13040-016-0103-7
PMCID: PMC4966782  PMID: 27478503
Generalized singular value decomposition; Joint data analysis; Ovarian cancer; Hepatocellular carcinoma; The Cancer Genome Atlas; LASSO; Sparse signal detection
4.  Changes in Skeletal Tumor Activity on 18F-choline PET/CT in Patients Receiving 223Radium Radionuclide Therapy for Metastatic Prostate Cancer 
Radium-223 dichloride is an alpha-emitting radiopharmaceutical shown to prolong survival in patients with castrate-resistant prostate cancer (CRPC) and symptomatic skeletal metastases. This report describes in two patients the acute changes in bone metastatic activity detected by F-18 choline PET/CT imaging midway during treatment with radium-223 dichloride. In addition to visual and standardized uptake value analysis, changes in the whole-body tumor burden were quantified by measuring the difference in net metabolically active tumor volume (MATV) and total lesion activity (TLA) between pre- and mid-treatment PET scans. After the third dose of radium-223 dichloride, near-total disappearance of abnormal skeletal activity was observed in one case (net MATV change from 260.7 to 0.8 cc; net TLA change from 510.7 to 2.1), while a heterogeneous tumor response was observed in the other (net MATV change from 272.2 to 241.3 cc; net TLA change from 987.1 to 779.4). Corresponding normalization and persistent elevation in serum alkaline phosphatase levels were observed in these cases, respectively. Further research is needed to determine the predictive value of serial F-18 choline PET/CT imaging in patients receiving radium-223 dichloride for CRPC.
doi:10.1007/s13139-014-0314-0
PMCID: PMC4463874  PMID: 26082811
Fluorocholine; PET/CT; Castrate-resistant prostate cancer; Radium-223 dichloride
5.  Volumetric modulated arc therapy planning for primary prostate cancer with selective intraprostatic boost determined by 18F-choline PET/CT 
Objective
Evaluate expected tumor control and normal tissue toxicity for prostate volumetric modulated arc therapy (VMAT) with and without radiation boost to an intraprostatic dominant lesion (IDL) defined by 18F-fluorocholine PET/CT.
Methods
Thirty patients with localized prostate cancer underwent 18F-fluorocholine PET/CT before treatment. Two VMAT plans, plan79Gy and plan100-105Gy, were compared for each patient. The whole-prostate planning target volume (PTVprostate) was prescribed 79 Gy in both plans, however plan100-105Gy added simultaneous boost doses of 100 Gy and 105 Gy prescribed to IDLs defined by 60% and 70% of maximum prostatic uptake on 18F-fluorocholine PET (IDLsuv60% and IDLsuv70%, respectively, with IDLsuv70% nested inside IDLsuv60% to potentially enhance tumor specificity of the maximum point dose). Plan evaluations included histopathologic correspondence, isodose distributions, dose-volume histograms, tumor control probability (TCP), and normal tissue complication probability (NTCP).
Results
Planning objectives and dose constraints proved feasible in 30/30 cases. Prostate sextant histopathology was available from 28 cases, confirming that IDLsuv60% adequately covered all tumor-bearing prostate sextants in 27 cases and provided partial coverage in one case. Plan100-105Gy had significantly higher TCP than Plan79Gy across all prostate regions for α/β ratios ranging from 1.5 Gy to 10Gy (p < 0.001 each case). There were no significant differences in bladder and femoral head NTCP between plans, and slightly lower rectal NTCP (endpoint: grade 2+ late toxicity or rectal bleeding) for plan100-105Gy.
Conclusion
VMAT can potentially increase the likelihood of tumor control in primary prostate cancer while observing normal tissue tolerances through simultaneous delivery of a steep radiation boost to an 18F-fluorocholine PET-defined IDL.
doi:10.1016/j.ijrobp.2014.12.052
PMCID: PMC4405528  PMID: 25832692
fluorocholine; PET/CT; prostate cancer; volumetric modulated arc therapy; boost
6.  Metabolic characteristics distinguishing intrahepatic cholangiocarcinoma: a negative pilot study of 18F-fluorocholine PET/CT clarified by transcriptomic analysis 
PET using fluorine-18 fluorocholine (18F-fluorocholine) may detect malignancies that involve altered choline metabolism. While 18F-fluorocholine PET/CT has shown greater sensitivity for detecting hepatocellular carcinoma (HCC) than 18F-fluoro-D-deoxyglucose (FDG) PET/CT, it is not known whether it can also detect intrahepatic cholangiocarcinoma (ICC), a less common form of primary liver cancer. Clinical, radiographic, and histopathologic data from 5 patients with ICC and 23 patients with HCC from a diagnostic trial of liver 18F-fluorocholine PET/CT imaging were analyzed to preliminarily evaluate 18F-fluorocholine PET/CT for ICC. Imaging was correlated with whole-genome expression profiling to identify molecular pathways associated with tumor phenotypes. On PET/CT, all ICC tumors demonstrated low 18F-fluorocholine uptake with a significantly lower tumor to mean background uptake ratio than HCC tumors (0.69 vs. 1.64, p < 0.0001), but no corresponding significant difference in liver parenchyma uptake of 18F-fluorocholine between ICC and HCC patients (8.0 vs. 7.7, p = 0.74). Two ICC patients demonstrated increased tumor metabolism on FDG PET/CT, while immunohistochemical analysis of ICC tumors revealed overexpression of glucose transporter 1 (GLUT-1) and hexokinase indicating a hyper-glycolytic phenotype. Gene expression analysis revealed down-regulation of farnesoid-X-receptor and other lipid pathways in ICC relative to HCC, and up-regulation of glycolytic pathways and GLUT-1 by HIF1α. These results imply limited utility of 18F-fluorocholine in ICC, however, significant metabolic differences between ICC, HCC, and parenchymal liver tissue may still provide clues about the underlying liver pathology. Gene and protein expression analysis support hyperglycolysis as a more dominant metabolic trait of ICC.
PMCID: PMC4749506  PMID: 27069767
Cholangiocarcinoma; hepatocellular carcinoma; positron emission tomography; fluorocholine
7.  Chronic Liver Disease and the Detection of Hepatocellular Carcinoma by [18F]fluorocholine PET/CT 
Diagnostics (Basel)  2015;5(2):189-199.
Positron emission tomography (PET) using the radiopharmaceutical tracer fluorine-18 fluorocholine (FCh) can elucidate tumors based on differences in choline phospholipid metabolism between tumor and surrounding tissue. The feasibility of detecting hepatocellular carcinoma (HCC) using FCh PET has been shown despite constitutively high parenchymal choline metabolism in the liver. Since HCC frequently develops in the setting of chronic liver disease, we comparatively evaluated FCh PET/CT between cirrhotic and non-cirrhotic patients with HCC to investigate the effects of hepatic dysfunction on tumor detection and the tumor-to-background ratio (TBR) of FCh uptake. FCh PET/CT was performed prospectively in 22 consecutive patients with HCC (7 newly diagnosed, 15 previously treated). Of these 22 patients, 14 were cirrhotic and 8 non-cirrhotic. Standardized uptake value (SUV) measurements were obtained by region of interest analysis of the PET images. Tumor FCh uptake and the TBR were compared between cirrhotic and non-cirrhotic patients. Liver lesions were confirmed to be HCC by biopsy in 10 patients and by Barcelona criteria in 4 patients. There was correspondingly increased liver tumor FCh uptake in 13/14 of those patients, and iso-intense tumor FCh uptake (TBR 0.94) in one non-cirrhotic patient with newly diagnosed HCC. FCh PET/CT also showed metastatic disease without local tumor recurrence in 2 previously treated patients, and was negative in 6 treated patients without tumor recurrence by radiographic and clinical follow-up. Tumor maximum SUV ranged from 6.4 to 15.3 (mean 12.1) and liver TBR ranged from 0.94 to 2.1 (mean 1.6), with no significant differences between cirrhotic and non-cirrhotic patients (SUVmax 11.9 vs. 12.2, p = 0.83; TBR 1.71 vs. 1.51, p = 0.29). Liver parenchyma mean SUV was significantly lower in cirrhotic patients (6.4 vs. 8.7, p < 0.05). This pilot study supports the general feasibility of HCC detection by FCh PET/CT. However, a broad range of tumor FCh uptake was observed, and lower liver parenchymal uptake of FCh was noted in cirrhotic patients as compared to non-cirrhotic patients. Incorporating tissue profiling into future liver imaging trials of FCh PET may help determine the molecular basis of the observed variations in tumor and hepatic FCh uptake.
doi:10.3390/diagnostics5020189
PMCID: PMC4469073  PMID: 26090216
Positron Emission Tomography; hepatocellular carcinoma; fluorocholine
8.  Prognosis Related to Metastatic Burden Measured by 18F-Fluorocholine PET/CT in Castrate Resistant Prostate Cancer 
This study investigates the prognostic significance of metabolically active tumor volume (MATV) measurements applied to fluorine-18 fluorocholine (FC) PET/CT in castrate-resistant prostate cancer (CRPC).
Methods
FC PET/CT imaging was performed in 30 patients with CRPC. Metastatic disease was quantified on the basis of maximum standardized uptake value (SUVmax), MATV, and total lesion activity (TLA = MATV × mean SUV). Tumor burden indices derived from whole-body summation of PET tumor volume measurements (ie. net MATV and net TLA) were evaluated as variables in Cox regression and Kaplan-Meier survival analyses.
Results
Net MATV ranged from 0.12 cm3 to 1543.9 cm3 (median 52.6 cm3). Net TLA ranged from 0.40g to 6688.7g (median 225.1g). PSA level at the time of PET correlated significantly with net MATV (Pearson r = 0.65, p = 0.0001) and net TLA (r = 0.60, p = 0.0005) but not highest lesional SUVmax of each scan. Survivors were followed for a median 23 months (range 6 – 38 months). On Cox regression analyses, overall survival was significantly associated with net MATV (p = 0.0068), net TLA (p = 0.0072), and highest lesion SUVmax (p = 0.0173), and borderline associated with PSA level (p = 0.0458). Only net MATV and net TLA remained significant in univariate-adjusted survival analyses. Kaplan-Meier analysis demonstrated significant differences in survival between groups stratified by median net MATV (log-rank P = 0.0371), net TLA (log-rank P = 0.0371), and highest lesion SUVmax (log-rank P = 0.0223).
Conclusions
Metastatic prostate cancer detected by FC PET/CT can be quantified based on volumetric measurements of tumor metabolic activity. The prognostic value of FC PET/CT may stem from this capacity to assess whole-body tumor burden. With further clinical validation, FC PET-based indices of global disease activity and mortality risk could prove useful in patient-individualized treatment of CRPC.
doi:10.2967/jnumed.113.135194
PMCID: PMC4424048  PMID: 24676753
Castrate Resistant Prostate Cancer; Positron Emission Tomography; Fluorocholine; Survival
9.  Chronic Liver Disease and the Detection of Hepatocellular Carcinoma by [18F]fluorocholine PET/CT 
Diagnostics  2015;5(2):189-199.
Positron emission tomography (PET) using the radiopharmaceutical tracer fluorine-18 fluorocholine (FCh) can elucidate tumors based on differences in choline phospholipid metabolism between tumor and surrounding tissue. The feasibility of detecting hepatocellular carcinoma (HCC) using FCh PET has been shown despite constitutively high parenchymal choline metabolism in the liver. Since HCC frequently develops in the setting of chronic liver disease, we comparatively evaluated FCh PET/CT between cirrhotic and non-cirrhotic patients with HCC to investigate the effects of hepatic dysfunction on tumor detection and the tumor-to-background ratio (TBR) of FCh uptake. FCh PET/CT was performed prospectively in 22 consecutive patients with HCC (7 newly diagnosed, 15 previously treated). Of these 22 patients, 14 were cirrhotic and 8 non-cirrhotic. Standardized uptake value (SUV) measurements were obtained by region of interest analysis of the PET images. Tumor FCh uptake and the TBR were compared between cirrhotic and non-cirrhotic patients. Liver lesions were confirmed to be HCC by biopsy in 10 patients and by Barcelona criteria in 4 patients. There was correspondingly increased liver tumor FCh uptake in 13/14 of those patients, and iso-intense tumor FCh uptake (TBR 0.94) in one non-cirrhotic patient with newly diagnosed HCC. FCh PET/CT also showed metastatic disease without local tumor recurrence in 2 previously treated patients, and was negative in 6 treated patients without tumor recurrence by radiographic and clinical follow-up. Tumor maximum SUV ranged from 6.4 to 15.3 (mean 12.1) and liver TBR ranged from 0.94 to 2.1 (mean 1.6), with no significant differences between cirrhotic and non-cirrhotic patients (SUVmax 11.9 vs. 12.2, p = 0.83; TBR 1.71 vs. 1.51, p = 0.29). Liver parenchyma mean SUV was significantly lower in cirrhotic patients (6.4 vs. 8.7, p < 0.05). This pilot study supports the general feasibility of HCC detection by FCh PET/CT. However, a broad range of tumor FCh uptake was observed, and lower liver parenchymal uptake of FCh was noted in cirrhotic patients as compared to non-cirrhotic patients. Incorporating tissue profiling into future liver imaging trials of FCh PET may help determine the molecular basis of the observed variations in tumor and hepatic FCh uptake.
doi:10.3390/diagnostics5020189
PMCID: PMC4469073  PMID: 26090216
Positron Emission Tomography; hepatocellular carcinoma; fluorocholine
10.  Viral hepatitis markers in liver tissue in relation to serostatus in hepatocellular carcinoma 
Background
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.
Methods
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.
Results
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.
Conclusions
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.
Impact
The contribution of HBV and HCV to the rising incidence of HCC in the United States may be underestimated.
doi:10.1158/1055-9965.EPI-13-0397
PMCID: PMC3818344  PMID: 23983238
hepatitis; HBV; HCV; occult; hepatocellular carcinoma
11.  Positron Emission Tomography (PET) in Hepatobiliary and Pancreatic Malignancies - A Review 
American journal of surgery  2012;204(2):232-241.
BACKGROUND
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
DATA SOURCES
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.
CONCLUSION
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.
SUMMARY
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.
doi:10.1016/j.amjsurg.2011.07.025
PMCID: PMC3454495  PMID: 22464445
12.  Healthcare Disparities in Asians and Pacific Islanders with hepatocellular cancer 
American journal of surgery  2012;203(6):726-732.
Background
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.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1016/j.amjsurg.2011.06.055
PMCID: PMC3524307  PMID: 22227170
hepatocellular cancer; screening; liver transplant
13.  Elucidating the Landscape of Aberrant DNA Methylation in Hepatocellular Carcinoma 
PLoS ONE  2013;8(2):e55761.
Background
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.
Conclusion
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.
doi:10.1371/journal.pone.0055761
PMCID: PMC3577824  PMID: 23437062
14.  Choline Kinase Alpha and Hexokinase-2 Protein Expression in Hepatocellular Carcinoma: Association with Survival 
PLoS ONE  2012;7(10):e46591.
Purpose
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.
Methods
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.
Conclusion
HK2 and CKA expression may have biologic and prognostic significance in HCC, with tumor HK2 expression being a potential independent predictor of survival.
doi:10.1371/journal.pone.0046591
PMCID: PMC3465336  PMID: 23071593
15.  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.
Purpose
To evaluate fluorine-18 fluorocholine (FCH) PET/CT for the detection of recurrent prostate cancer in relation to prostate-specific antigen (PSA) level.
Methods
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.
Results
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.
Conclusion
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.
doi:10.1007/s12149-012-0601-8
PMCID: PMC3400027  PMID: 22549847
Fluorocholine; Prostate cancer; Positron emission tomography
16.  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.
doi:10.4251/wjgo.v2.i1.56
PMCID: PMC2999155  PMID: 21160818
Adrenocorticotropic hormone; Cushing’s syndrome; Neuroendocrine; Carcinoma; Gallbladder
17.  Measurement of Circulating Cell-Free DNA in Relation to 18F-Fluorocholine PET/CT Imaging in Chemotherapy-Treated Advanced Prostate Cancer 
Abstract
Purpose:
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).
Methods:
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.
Results:
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).
Conclusions:
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
doi:10.1111/j.1752-8062.2011.00375.x
PMCID: PMC3500883  PMID: 22376260
prostate cancer; nucleic acids; epigenetics; positron emission tomography

Results 1-17 (17)