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PubMed | Hawaii Medical, Hamamatsu Queens Imaging Center, Sungkyunkwan University and University of Hawaii at Manoa
Type: Journal Article | Journal: Journal of nuclear medicine : official publication, Society of Nuclear Medicine | Year: 2016

Measurements of metabolically active tumor volume (MATV) can be applied to (18)F-fluorocholine PET/CT to quantify whole-body tumor burden. This study evaluated the serial application of these measurements as systemic treatment response markers and predictors of disease progression in patients with castration-resistant prostate cancer (CRPC).Forty-two patients completed sequential (18)F-fluorocholine PET/CT scans before and 1-3 mo after starting treatment for CRPC. Whole-body tumor segmentation was applied to determine net MATV from each scan. Changes in net MATV were evaluated as predictors of time to prostate-specific antigen (PSA) progression by Kaplan-Meier and proportional hazards regression analysis.Treatments consisted of chemotherapy in 16 patients, antiandrogens in 19 patients, (223)Ra-dichloride in 5 patients, and sipuleucel-T in 2 patients. A significant MATV response (defined as a 30% decrease in net MATV) was observed in 20 patients on the basis of in-treatment PET/CT performed an average of 51 d (median, 49 d) into treatment. Significantly longer times to PSA progression were observed in patients who exhibited an MATV response (418 d vs. 116 d, P = 0.0067). MATV response was associated with a hazard ratio of 0.246 (P = 0.0113) for PSA progression, which remained significant when adjusted for treatment type.Significant changes in whole-body tumor burden can be measured on (18)F-fluorocholine PET/CT over the course of contemporary treatments for CRPC. In this study, these changes were found to be predictive of PSA progression as a potential surrogate marker of treatment outcome. Because (18)F-fluorocholine PET/CT can also be used for localizing resistant tumors, this modality can potentially complement other measures of response in the precision management of advanced prostate cancer.


Kuang Y.,University of Nevada, Las Vegas | Wu L.,University of Nevada, Las Vegas | Wu L.,Guangdong Medical College | Hirata E.,Hamamatsu Queens Imaging Center | And 4 more authors.
International Journal of Radiation Oncology Biology Physics | Year: 2015

Purpose This study evaluated expected tumor control and normal tissue toxicity for prostate volumetric modulated arc therapy (VMAT) with and without radiation boosts to an intraprostatically dominant lesion (IDL), defined by 18F-choline positron emission tomography/computed tomography (PET/CT). Methods and Materials Thirty patients with localized prostate cancer underwent 18F-choline PET/CT before treatment. Two VMAT plans, plan79 Gy and plan100-105 Gy, were compared for each patient. The whole-prostate planning target volume (PTVprostate) prescription was 79 Gy in both plans, but plan100-105 Gy added simultaneous boost doses of 100 Gy and 105 Gy to the IDL, defined by 60% and 70% of maximum prostatic uptake on 18F-choline PET (IDLsuv60% and IDLsuv70%, respectively, with IDLsuv70% nested inside IDLsuv60% to potentially enhance tumor specificity of the maximum point dose). Plan evaluations included histopathological 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 of 30 cases. Prostate sextant histopathology was available for 28 cases, confirming that IDLsuv60% adequately covered all tumor-bearing prostate sextants in 27 cases and provided partial coverage in 1 case. Plan100-105 Gy had significantly higher TCP than plan79 Gy across all prostate regions for α/β ratios ranging from 1.5 Gy to 10 Gy (P<.001 for 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) was found for plan100-105 Gy. Conclusions 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 a 18F-choline PET-defined IDL. © 2015 Elsevier Inc.


PubMed | University of Hawaii at Manoa, Hamamatsu Queens Imaging Center, Oncology Research and University of Nevada, Las Vegas
Type: | Journal: Molecular imaging and biology : MIB : the official publication of the Academy of Molecular Imaging | Year: 2016

[Tumor and adjacent liver were profiled by liquid chromatography mass spectrometry, quantifying phosphatidylcholine species by mass-to-charge ratio. For clinical-radiopathologic correlation, HCC profiles were reduced to two orthogonal principal component factors (PCF1 and PCF2) accounting for 80% of total profile variation.Tissues from 31 HCC patients and 4 intrahepatic cholangiocarcinoma (ICC) patients were analyzed, revealing significantly higher levels of phosphocholine, CDP-choline, and highly saturated phosphatidylcholine species in HCC tumors relative to adjacent liver and ICC tumors. Significant loading values for PCF1 corresponded to phosphatidylcholines containing poly-unsaturated fatty acids while PCF2 corresponded only to highly saturated phosphatidylcholines. Only PCF2 correlated significantly with HCC tumor-to-liver [Most HCC tumors contain high levels of saturated phosphatidylcholines, supporting their dependence on de novo fatty acid metabolism for phospholipid membrane synthesis. While [


Lan B.Y.,Cleveland Clinic | Kwee S.A.,Hamamatsu Queens Imaging Center | Wong L.L.,University of Hawaii at Manoa
American Journal of Surgery | Year: 2012

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 role of PET in detecting hepatobiliary and pancreatic malignancies has not yet been established. The purpose of this article was 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 nonhuman subjects, case reports, and series with <5 patients. Conclusions: 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. © 2012 Elsevier Inc.


Song M.-A.,University of Hawaii at Manoa | Song M.-A.,Ohio State University | Kwee S.A.,University of Hawaii at Manoa | Kwee S.A.,Hamamatsu Queens Imaging Center | And 6 more authors.
Epigenetics | Year: 2016

ABSTRACT: Hepatocellular carcinoma (HCC) incidence has steadily increased in the US over the past 30 years. Our understanding of epigenetic regulation in HCC is still limited, especially the impact of hepatitis B virus (HBV) or hepatitis C virus (HCV) infection on aberrant DNA methylation. We performed genome-wide DNA methylation profiling in 33 fresh frozen tumor samples, including 10 HBV-HCC, 13 HCV-HCC, and 10 non-infected (NIV-HCC) using the Illumina HumanMethylation450 BeadChip. Gene expression profiling was also performed using the Illumina whole-genome DASL HT Assay. Biological influences and gene networks of the differentially-methylated (DM) CpG loci were predicted using the Ingenuity Pathway Analysis. Genome-wide methylation analysis identified 7, 26, and 98 DM loci between HBV-HCC vs. HCV-HCC, HBV-HCC vs. NIV-HCC, and HCV-HCC vs. NIV-HCC, respectively, at P < 5 × 10−5 for each. Overall, the DM loci were highly enriched for enhancers (48%), promoters (37%), or CpG islands and surrounding regions (37%). Most DM loci were hypermethylated in HCV-HCC compared to HBV-HCC or NIV-HCC. The DM loci were associated with a variety of biological functions including Cell Morphology (HBV-HCC vs. NIV-HCC), Cell Death/ Survival (HBV-HCC vs. NIV-HCC), or Cellular Growth and Proliferation (HCV-HCC vs. NIV-HCC). A subset of the DM loci were correlated (either positively or negatively) with their gene expression or associated with alcohol consumption, BMI, cirrhosis, diabetes, and cigarette smoking. Our findings of differential methylation by viral infection lend insights into the potential effects of viral infection on the epigenetic regulation and further the development and progression of HCC. © 2016 Taylor & Francis Group, LLC.


Kwee S.A.,Punchbowl | Kwee S.A.,University of Hawaii at Manoa | Lim J.,Punchbowl | Lim J.,Hamamatsu Queens Imaging Center | And 4 more authors.
Journal of Nuclear Medicine | Year: 2014

This study investigated the prognostic significance of metabolically active tumor volume (MATV) measurements applied to 18F-fluorocholine PET/CT in castration-resistant prostate cancer (CRPC). Methods: 18F- fluorocholine PET/CT imaging was performed on 30 patients with CRPC. Metastatic disease was quantified on the basis of maximum standardized uptake value (SUVmax), MATV, and total lesion activity (TLA = MATV x mean standardized uptake value). Tumor burden indices derived from whole-body summation of PET tumor volume measurements (i.e., 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 1,543.9 cm3 (median, 52.6 cm3). Net TLA ranged from 0.40 to 6,688.7 g (median, 225.1 g). Prostate-specific antigen 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 mo (range, 6-38 mo). On Cox regression analyses, overall survival had a significant association with net MATV (P = 0.0068), net TLA (P = 0.0072), and highest lesion SUVmax (P = 0.0173) and a borderline association with prostate-specific antigen 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). Conclusion: Metastatic prostate cancer detected by 18F- fluorocholine PET/CT can be quantified on the basis of volumetric measurements of tumor metabolic activity. The prognostic value of 18F- fluorocholine PET/CT may stem from this capacity to assess whole-body tumor burden. With further clinical validation, 18F-fluorocholine PET-based indices of global disease activity and mortality risk could prove useful in patient-individualized treatment of CRPC. Copyright © 2014 by the Society of Nuclear Medicine and Molecular Imaging, Inc.


Song M.-A.,University of Hawaii at Manoa | Tiirikainen M.,University of Hawaii at Manoa | Kwee S.,University of Hawaii at Manoa | Kwee S.,Hamamatsu Queens Imaging Center | And 3 more authors.
PLoS ONE | Year: 2013

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. © 2013 Song et al.


PubMed | Hamamatsu Queens Imaging Center
Type: Clinical Trial | Journal: Annals of nuclear medicine | Year: 2012

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.

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