Transarterial Radioembolization for Hepatocellular Carcinoma with Major Vascular Invasion: A Nationwide Propensity Score-Matched Analysis with Target Trial Emulation.

PURPOSE: To examine National Cancer Database (NCDB) data to comparatively evaluate overall survival (OS) between patients undergoing transarterial radioembolization (TARE) and those undergoing systemic therapy for hepatocellular carcinoma with major vascular invasion (HCC-MVI). METHODS: One thousand five hundred fourteen patients with HCC-MVI undergoing first-line TARE or systemic therapy were identified from the NCDB. OS was compared using propensity score-matched Cox regression and landmark analysis. Efficacy was also compared within a target trial framework. RESULTS: TARE usage doubled between 2010 and 2015. Intervals before treatment were longer for TARE than for systemic therapy (mean [median], 66.5 [60] days vs 46.8 (35) days, respectively, P < .0001). In propensity-score-matched and landmark-time-adjusted analyses, TARE was found to be associated with a hazard ratio of 0.74 (95 % CI, 0.60-0.91; P = .005) and median OS of 7.1 months (95 % CI, 5.0-10.5) versus 4.9 months (95 % CI, 3.9-6.5) for systemically treated patients. In an emulated target trial involving 236 patients with unilobular HCC-MVI, a low number of comorbidities, creatinine levels <2.0 mg/dL, bilirubin levels <2.0 mg/dL, and international normalized ratio <1.7, TARE was found to be associated with a hazard ratio of 0.57 (95 % CI, 0.39-0.83; P = .004) and a median OS of 12.9 months (95 % CI, 7.6-19.2) versus 6.5 months (95 % CI, 3.6-11.1) for the systemic therapy arm. CONCLUSIONS: In propensity-score-matched analyses involving pragmatic and target trial HCC-MVI cohorts, TARE was found to be associated with significant survival benefits compared with systemic therapy. Although not a substitute for prospective trials, these findings suggest that the increasing use of TARE for HCC-MVI is accompanied by improved OS. Further trials of TARE in patients with HCC-MVI are needed, especially to compare with newer systemic therapies.

Factors and Survival Implications associated with biopsy of hepatocellular carcinoma.

BACKGROUND: Hepatocellular carcinoma (HCC) is one of the few cancers that can be diagnosed based on imaging findings alone. The factors associated with the decision to perform a biopsy and the clinical impact have not been previously studied. METHODS: We collected data of patients diagnosed with HCC between 2004 and 2015 from the National Cancer Database. We assessed associations between biopsy and survival with demographic and clinical factors. RESULTS: We included 160,507 patients. The median age was 62 (40-90), 74.1% were male and 74.9% were white. Over the 12-year period, 47.7% (76,524/160,517) underwent a biopsy. Factors associated with a biopsy were black race, older age, presence of metastatic disease, larger tumor size, and treatment at a community cancer center. Factors associated with increased mortality were older age, higher comorbidity index, larger tumor size, presence of metastatic disease, higher AFP and elevated bilirubin. There was a significant decreased use of biopsy over successive years (2007-2015). After adjusting for prognostic factors, biopsy had no significant impact on survival HR 1.01 (95%CI 1.00-1.03. p = 0.07). CONCLUSIONS: A significant number of patients underwent a biopsy. Performing a biopsy did not have a significant impact on survival.

PET/CT with 18F Fluorocholine as an Imaging Biomarker for Chronic Liver Disease: A Preliminary Radiopathologic Correspondence Study in Patients with Liver Cancer.

Purpose To determine the relationship between hepatic uptake at preoperative fluorine 18 (18F) fluorocholine combined positron emission tomography (PET) and computed tomography (CT) and the histopathologic features of chronic liver disease in patients with Child-Pugh class A or B disease who are undergoing hepatic resection for liver cancer. Materials and Methods Forty-eight patients with resectable liver tumors underwent preoperative 18F fluorocholine PET/CT. Mean liver standardized uptake value (SUVmean) measurements were obtained from PET images, while histologic indexes of inflammation and fibrosis were applied to nontumor liver tissue from resection specimens. Effects of histopathologic features on liver SUVmean were examined with analysis of variance. Results Liver SUVmean ranged from 4.3 to 11.6, correlating significantly with Knodell histologic activity index (ρ = -0.81, P < .001) and several clinical indexes of liver disease severity. Liver SUVmean also differed significantly across groups stratified by necroinflammatory severity and Metavir fibrosis stage (P < . 001). The area under the receiver operating characteristic curve for 18F fluorocholine PET/CT detecting Metavir fibrosis stage F1 or higher was 0.89 ± 0.05, with an odds-ratio of 3.03 (95% confidence interval: 1.59, 5.88) and sensitivity and specificity of 82% and 93%, respectively. Conclusion Correlations found in patients undergoing hepatic resection for liver cancer between liver 18F fluorocholine uptake and histopathologic indexes of liver fibrosis and inflammation support the use of 18F fluorocholine PET/CT as a potential imaging biomarker for chronic liver disease. © RSNA, 2018.

Liver Transplantation vs Partial Hepatectomy for Stage T2 Multifocal Hepatocellular Carcinoma <3 cm Without Vascular Invasion: A Propensity Score-Matched Survival Analysis.

BACKGROUND: Multifocal hepatocellular carcinoma (HCC) differs biologically and immunologically from single-nodule HCC. Asian and European guidelines consider liver transplantation (LT) and partial hepatectomy (PH) as effective for T2 multifocal HCC, with preference toward LT, but few US studies compare these treatments directly. This propensity score-based observational study uses an established national cancer outcomes registry to compare overall survival in patients undergoing PH and LT for multifocal HCC. STUDY DESIGN: Data from the 2020 National Cancer Database were obtained on patients who underwent LT or PH for multifocal stage 2 HCC within Milan criteria and without vascular invasion. Propensity score matching and Cox regression analysis was applied to evaluate overall survival in an observational cohort balanced by age, sex, treatment facility type, treatment year, prothrombin time, α-fetoprotein, comorbidity burden, liver fibrosis severity, and pretreatment creatinine and bilirubin levels. RESULTS: Of 21,248 T2 HCC patients identified, 6,744 had multifocal tumors with largest tumor diameter <3 cm without major vascular invasion, with 1,267 and 181 having undergone LT and PH, respectively. Propensity score-matched Cox regression analysis associated LT with a hazard ratio of 0.39 (95% CI 0.30 to 0.50) relative to PH. Landmark analyses to account for a longer interval to LT demonstrated survival benefits of similar magnitude. CONCLUSIONS: Although early-stage HCC can be effectively treated with either LT or PH, propensity score-matched analysis comparatively shows a survival benefit for LT in patients with multifocal HCC who are within the Milan criteria.

Target Trial Emulation: A Design Tool for Cancer Clinical Trials.

PURPOSE: To apply target trial emulation to explore the potential impact of eligibility criteria on the primary outcome of a randomized controlled trial. METHODS: Simulations of a real-world explanatory trial of transarterial radioembolization for advanced unresectable hepatocellular carcinoma with portal vein invasion were performed to examine the effects of cohort specification on survival outcomes and patient sample size. Simulations comprised 24 different permutations of the trial varied on three disease nonspecific eligibility parameters. Treatment and control arms for these emulated trials were drawn from the National Cancer Database and matched by treatment propensity. Target trial emulation served as the causal framework for this analysis, allowing the architecture of a true controlled experiment to address forms of bias routinely encountered in comparative effectiveness studies involving real-world observational data. RESULTS: Twenty-four propensity score-matched cohorts comprising a wider clinical spectrum of patients than specified by the original target trial were successfully generated using the National Cancer Database. The arms for each of the emulated trials demonstrated exchangeability across all eligibility criteria and other clinical covariates. Significant treatment benefits were associated with only a narrow range of eligibility criteria, indicating that the original target trial was well specified. CONCLUSION: The impact of patient selection on treatment outcomes can be studied using target trial emulation. This analytical framework can furthermore serve to leverage existing real-world data to inform the task of cohort specification for a randomized controlled trial, facilitating a more data-driven approach for this important step in clinical trial design.

Beta-catenin activation and immunotherapy resistance in hepatocellular carcinoma: mechanisms and biomarkers.

Mutations involving CTNNB1, the gene encoding beta-catenin, and other molecular alterations that affect the Wnt/beta-catenin signaling pathway are exceptionally common in hepatocellular carcinoma. Several of these alterations have also been associated with scarcity of immune cells in the tumor microenvironment and poor clinical response to immune checkpoint inhibitor therapy. In light of these associations, tumor biomarkers of beta-catenin status could have the potential to serve as clinical predictors of immunotherapy outcome. This editorial review article summarizes recent pre-clinical and clinical research pertaining to associations between beta-catenin activation and diminished anti-tumor immunity. Potential non-invasive biomarkers that may provide a window into this oncogenic mechanism of immune evasion are also presented and discussed.

Phospholipids are A Potentially Important Source of Tissue Biomarkers for Hepatocellular Carcinoma: Results of a Pilot Study Involving Targeted Metabolomics.

BACKGROUND: Hepatocellular carcinoma (HCC) pathogenesis involves the alteration of multiple liver-specific metabolic pathways. We systematically profiled cancer- and liver-related classes of metabolites in HCC and adjacent liver tissues and applied supervised machine learning to compare their potential yield for HCC biomarkers. METHODS: Tumor and corresponding liver tissue samples were profiled as follows: Bile acids by ultra-performance liquid chromatography (LC) coupled to tandem mass spectrometry (MS), phospholipids by LC-MS/MS, and other small molecules including free fatty acids by gas chromatography-time of flight MS. The overall classification performance of metabolomic signatures derived by support vector machine (SVM) and random forests machine learning algorithms was then compared across classes of metabolite. RESULTS: For each metabolite class, there was a plateau in classification performance with signatures of 10 metabolites. Phospholipid signatures consistently showed the highest discrimination for HCC followed by signatures derived from small molecules, free fatty acids, and bile acids with area under the receiver operating characteristic curve (AUC) values of 0.963, 0.934, 0.895, 0.695, respectively, for SVM-generated signatures comprised of 10 metabolites. Similar classification performance patterns were observed with signatures derived by random forests. CONCLUSION: Membrane phospholipids are a promising source of tissue biomarkers for discriminating between HCC tumor and liver tissue.

Transcriptomics Associates Molecular Features with 18F-Fluorocholine PET/CT Imaging Phenotype and Its Potential Relationship to Survival in Hepatocellular Carcinoma.

Studies involving transcriptomics have revealed multiple molecular subtypes of hepatocellular carcinoma (HCC). Positron emission tomography/computed tomography (PET/CT) has also identified distinct molecular imaging subtypes, including those with increased and decreased choline metabolism as measured by the tissue uptake of the radiopharmaceutical 18F-fluorocholine. Gene signatures reflecting the molecular heterogeneity of HCC may identify the biological and clinical significance of these imaging subtypes. In this study, 41 patients underwent 18F-fluorocholine PET/CT, followed by tumor resection and gene expression profiling. Over- and underexpressed components of previously published gene signatures were evaluated for enrichment between tumors with high and low 18F-fluorocholine uptake using gene set analysis. Significant gene sets were enumerated by FDR based on phenotype permutation. Associations with overall survival were analyzed by univariate and multivariate proportional hazards regression. Ten gene sets related to HCC were significantly associated with high tumor 18F-fluorocholine uptake at FDR q < 0.05, including those from three different clinical molecular classification systems and two prognostic signatures for HCC that showed predictive value in the study cohort. Tumor avidity for 18F-fluorocholine was associated with favorable characteristics based on these signatures with lower mortality based on survival analysis (HR 0.36; 95% confidence interval, 0.14-0.95). Tumors demonstrating high 18F-fluorocholine uptake were also enriched for genes involved in oxidative phosphorylation, fatty acid metabolism, peroxisome, bile acid metabolism, xenobiotic metabolism, and adipogenesis. These results provide a pathobiological framework to further evaluate 18F-fluorocholine PET/CT as a molecular and prognostic classifier in HCC. SIGNIFICANCE: A pathobiological framework for HCC brings together multiple prognostically relevant gene signatures via convergence with 18F-fluorocholine PET/CT imaging phenotype.

Clinical and molecular sub-classification of hepatocellular carcinoma relative to alpha-fetoprotein level in an Asia-Pacific island cohort.

Aim: Increased serum alpha-fetoprotein (AFP) levels are associated with specific molecular sub-classes of hepatocellular carcinoma (HCC), supporting AFP as a predictive or therapeutic biomarker for precision treatment of this disease. Considering recent efforts to validate HCC molecular classification systems across different populations, we applied existing signature-based classification templates to Hawaii cohorts and examined whether associations between HCC molecular sub-class, AFP levels, and clinical features found elsewhere can also be found in Hawaii, a region with a unique demographic and risk factor profile for HCC. Methods: Whole-genome expression profiling was performed on HCC tumors collected from 40 patients following partial hepatectomy. Tumors underwent transcriptome-based categorization into 3 molecular sub-classes (S1, S2, and S3). Patient groups based on molecular sub-class and AFP level were then compared with regards to clinical features and survival. Differences associated with AFP level and other clinical parameters were also examined at the gene signature level by gene set enrichment analysis. Results: Statistically confident (false discovery rate < 0.05) sub-classifications were made in 98% (39/40) of tumors. Patient sub-groups differed significantly with regards to serum AFP level, with significantly lower levels in the S3 sub-group as compared to S1 (P = 0.048) and S2 (P = 0.010). Serum AFP > 400 ng/mL predicted significant tumor enrichment for genes corresponding to MYC target activation, high cell proliferation, poor clinical prognosis, and the S2 sub-class. AFP > 400 ng/mL and non-S3 tumor classification were found to be significant predictors of overall survival. Conclusion: Distinct sub-classes of HCC associated with different molecular features and survival outcomes can be detected with statistical confidence in a Pacific Island cohort. Molecular classification signatures and other predictive markers for HCC that are valid for all patient populations are needed to support multi-center efforts to develop targeted therapies for HCC.

Gender differences in hepatocellular cancer: disparities in nonalcoholic fatty liver disease/steatohepatitis and liver transplantation.

AIM: Worldwide, hepatocellular cancer (HCC) is the fourth leading cause of cancer death and occurs 3 times more commonly in males than females. Current surveillance practices do not fully address gender differences in HCC. METHODS: Clinical characteristics and survival were compared between males and females using a prospectively collected database of HCC patients. RESULTS: In a cohort of 1206 patients, 307 (25%) were female who presented with older age, more non-alcoholic fatty liver disease/steatohepatitis (NAFLD/NASH), family history of HCC, and hypertension. Males (75%) were more likely to use alcohol and cigarettes. Females were more likely to undergo HCC surveillance, have smaller tumor size at diagnosis, and less vascular involvement. Males who met Milan criteria were more likely to undergo liver transplant than women who met the criteria. Median/mean survival was similar between the genders. Multivariate analysis showed that NAFLD/NASH was predictive of mortality for both males and females, age and smoking were predictive of mortality for males, and transplant was predictive of survival for males. CONCLUSION: Gender differences in HCC appear related to both behavioral risk factors and biologic factors. Older females with HCC have more NAFLD/NASH and may be overlooked by current surveillance guidelines. These gender disparities may lend support to future studies of gender-based HCC screening.

Cancer imaging with fluorine-18-labeled choline derivatives.

The choline transporter and choline kinase enzyme frequently are overexpressed in malignancy. Therefore, positron-emitter-labeled compounds derived from choline have the potential to serve as oncologic probes for positron emission tomography. The fluorine-18 ((18)F)-labeled choline derivative fluorocholine (FCH) in particular has demonstrated potential utility for imaging of a variety of neoplasms, including those of the breast, prostate, liver, and brain. The pharmacokinetics of FCH and other choline tracers allow for whole-body imaging within minutes of injection while still achieving high tumor-to-background contrast in most organs, including the brain. These features, along with the possibility of imaging malignancies that have proved elusive with the use of (18)F-fluorodeoxyglucose positron emission tomography support further clinical investigations of (18)F-labeled choline tracers.

Soft Tissue Response on 18F-Fluorocholine PET/CT in Metastatic Castrate-Resistant Prostate Cancer Treated With 223Ra-Dichloride: A Possible Abscopal Effect?

Two patients with castrate-resistant prostate cancer and symptomatic skeletal metastases underwent F-fluorocholine PET/CT prior to treatment with Ra-dichloride to reveal additional active lesions in the prostate gland and lymph nodes. Subsequent scans performed at the midpoint and end of Ra-dichloride therapy showed resolution of this soft tissue activity alongside declining bone lesion activity. Concomitant increases in plasma interleukin 6 were detected, suggesting that immune system activation may have mediated the soft tissue response. Abscopal effects usually encountered with external beam radiotherapy may also be occurring with Ra-dichloride therapy.

Late recurrence of hepatocellular carcinoma after liver transplantation.

AIMS: Hepatocellular carcinoma (HCC) is the third leading cause of cancer deaths worldwide and liver transplant (LT) prolongs survival. However, 15-20% will experience recurrent HCC, most occurring within 2 years of LT. HCC patients with late recurrences (>5 years after LT) may have distinctive clinical/biological characteristics. METHODS: A retrospective review was conducted of 88 patients who underwent LT for HCC between 1993-2015, analyzing demographics, clinical factors, explant pathology, and outcome. RESULTS: Median follow-up was 6.4 years. HCC recurred in 15 (17.0%) patients with mean time to recurrence of 3.96 +/- 3.99 years. Five patients recurred >5 years post-LT. All late recurrences involved males in their 50s, recurring at 8.5 years on average. Recurrences occurred in chest wall (2), liver (2), lung (2), bone (1) and pelvis (1), with multifocal involvement in 2 patients. Four patients died within 18 months of late recurrence. The fifth patient is alive after ablation of liver recurrence and treatment with sorafenib and everolimus. CONCLUSIONS: One-third of post-LT patients with recurrent HCC experienced late recurrence. Although the sample size makes it difficult to identify significant risk factors, this study highlights the importance of long-term follow up and need for biomarkers to identify patients at risk for late recurrences.

[18F]Fluorocholine PET/CT Imaging of Liver Cancer: Radiopathologic Correlation with Tissue Phospholipid Profiling.

PURPOSE: [18F]fluorocholine PET/CT can detect hepatocellular carcinoma (HCC) based on imaging the initial steps of phosphatidylcholine synthesis. To relate the diagnostic performance of [18F]fluorocholine positron emission tomography (PET)/x-ray computed tomography (CT) to the phospholipid composition of liver tumors, radiopathologic correspondence was performed in patients with early-stage liver cancer who had undergone [18F]fluorocholine PET/CT before tumor resection. PROCEDURES: 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. RESULTS: 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 [18F]fluorocholine uptake ratio (ρ = 0.59, p < 0.0005). Sensitivity for all tumors based on an abnormal [18F]fluorocholine uptake ratio was 93 % while sensitivity for HCC based on increased tumor [18F]fluorocholine uptake was 84 %, with lower levels of highly saturated phosphatidylcholines in tumors showing low [18F]fluorocholine uptake. CONCLUSION: Most HCC tumors contain high levels of saturated phosphatidylcholines, supporting their dependence on de novo fatty acid metabolism for phospholipid membrane synthesis. While [18F]fluorocholine PET/CT can serve to identify these lipogenic tumors, its imperfect diagnostic sensitivity implies metabolic heterogeneity across HCC and a weaker lipogenic phenotype in some tumors.

Pitfalls in surveillance for hepatocellular carcinoma: How successful is it in the real world?

BACKGROUND/AIMS: Surveillance for hepatocellular carcinoma (HCC) with ultrasound in high-risk populations is generally believed to improve opportunities for treatment. However, tumors are still missed due to various factors. This study explores success versus failure of HCC surveillance. METHODS: This is a retrospective study of 1,125 HCC cases. Categories considered for successful detection were largest tumor ≤3.0 cm, single tumors ≤3.0 cm and ≤2.0 cm, and adherence to Milan criteria. Examined factors were age <60 years, gender, rural residence, body-mass index (BMI), hepatitis infection, smoking, diabetes, hyperlipidemia, cirrhosis, ascites, and Model for End-Stage Liver Disease <10. RESULTS: HCC was found on surveillance in 257 patients with a mean tumor size of 3.17 cm; multiple tumors were seen in 28% of cases, bilateral tumors in 7.4%, and vascular invasion in 3.7%. Surveillance was successful in 61.5% of cases involving a largest tumor ≤3.0 cm, with BMI ≥35 negatively affecting detection (odds ratio [OR] 0.28, P=0.014) and cirrhosis positively affecting detection (OR 2.31, P=0.036). Ultrasound detected 19.1% of single tumors ≤2.0 cm with ascites improving the detection rate (OR 3.89, P=0.001). Finally, adherence to Milan criteria occurred in 75.1% of cases, revealing negative associations with diabetes (OR 0.48, P=0.044 and male gender (OR 0.49, P=0.08). CONCLUSIONS: Although surveillance is recommended for HCC, not all surveillance ultrasound are ideal. Tumor detection can depend on gender, BMI, diabetes, cirrhosis, and ascites and is achieved in 19.1-75% of cases depending on the definition of success. Closer follow-up or additional imaging might be necessary for some patient subgroups.

Localization of primary prostate cancer with dual-phase 18F-fluorocholine PET.

UNLABELLED: This study compared 18F-fluorocholine uptake in malignant and benign areas of the prostate at 2 time points to determine the suitability of delayed or dual-phase 18F-fluorocholine PET for localizing malignancy in the prostate gland. METHODS: Twenty-six men (15 newly diagnosed with prostate cancer, 2 with recurrent prostate cancer, 6 with no evidence of prostate cancer recurrence after treatment, and 3 with no history of prostate cancer) underwent dual-phase PET consisting of initial whole-body PET starting 7 min after injection of 3.3-4 MBq/kg of 18F-fluorocholine followed by 1-h delayed PET of the pelvis. Tracer uptake in the prostate on the initial and delayed images was measured on a sextant basis. Prostate biopsy or whole-prostate histologic examination after radical prostatectomy was used to classify a prostate sextant as a dominant malignant region or probable benign region. For each sextant, a retention index based on the measured maximum standardized uptake value (SUVmax) was calculated on the initial and delayed images. In 15 prostates with both benign and malignant sextants on histologic examination, a malignant-to-benign ratio of SUVmax was also calculated for each time point. RESULTS: A dominant malignant region was found in 17 subjects, and a probable benign region was found in 24 subjects. The mean SUVmax for dominant malignant regions increased significantly between initial and delayed scans, from 7.6 to 8.6 (mean retention index, +14%; 95% confidence interval, 6%-22%; P = 0.002). The mean SUVmax for probable benign regions decreased significantly between initial and delayed scans, from 4.8 to 3.9 (mean retention index, -17%; 95% confidence interval, -10% to -23%, P < 0.001). The mean malignant-to-benign ratio increased significantly, from 1.4 on the initial scan to 1.8 on the delayed scan (P = 0.003). The areas under the receiver operating characteristic curves for distinguishing dominant malignant regions from probable benign regions based on initial SUVmax, delayed SUVmax, and retention index were 0.81, 0.92, and 0.93, respectively. CONCLUSION: On dual-phase PET of the prostate, areas of malignancy consistently demonstrated stable or increasing 18F-fluorocholine uptake, whereas most areas containing benign tissue demonstrated decreasing uptake. Delayed or dual-phase imaging after injection of 18F-fluorocholine may improve the performance of 18F-fluorocholine PET for localizing malignant areas of the prostate.

Metabolic positron emission tomography imaging of cancer: Pairing lipid metabolism with glycolysis.

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.

Metabolic characteristics distinguishing intrahepatic cholangiocarcinoma: a negative pilot study of (18)F-fluorocholine PET/CT clarified by transcriptomic analysis.

PET using fluorine-18 fluorocholine ((18)F-fluorocholine) may detect malignancies that involve altered choline metabolism. While (18)F-fluorocholine PET/CT has shown greater sensitivity for detecting hepatocellular carcinoma (HCC) than (18)F-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 (18)F-fluorocholine PET/CT imaging were analyzed to preliminarily evaluate (18)F-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 (18)F-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 (18)F-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 (18)F-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.

Prediction of PSA Progression in Castration-Resistant Prostate Cancer Based on Treatment-Associated Change in Tumor Burden Quantified by 18F-Fluorocholine PET/CT.

UNLABELLED: 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). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Comparison of genome-scale DNA methylation profiles in hepatocellular carcinoma by viral status.

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.