Tumor Metabolic Activity Research Articles

WE‐E‐BRE‐12: Tumor Microenvironment Dynamics Following Radiation

Purpose:This work aims to understand the radiation‐induced interplay between tumor oxygenation and metabolic activity. These dynamics can potentially serve as biomarkers in assessing treatment response allowing for patient‐specific adaptive radiotherapy.Methods:Using patient‐derived xenografts of head and neck cancer we assessed tumor oxygenation via fiber‐optic probe monitored hemoglobin saturation and Blood Oxygen Level Dependent (BOLD) MRI. Measurements were taken before and after a 10 Gy dose of radiation. Changes in metabolic activity were measured via Fluorescence Lifetime IMaging (FLIM) with the appropriate controls following a 10 Gy dose of radiation. FLIM can non‐invasively monitor changes in fluorescence in response to the microenvironment including being able to detect free and bound states of the intrinsically fluorescent metabolite NADH (Nicotinamide Adenine Dinucleotide). With this information FLIM can accurately quantify the metabolic state of cells that have been radiated. To model the observed changes, a two‐compartment, source‐sink simulation relating hemoglobin saturation and metabolic activity was performed using MATLAB.Results:Hemoglobin saturation as measured by interstitial probe and BOLD‐MRI decreased by 30% within 15 minutes following radiation. FLIM demonstrated a decrease in the mean fluorescence lifetime of NADH by 100 ps following 10 Gy indicating a shift towards glycolytic pathways. Simulation of radiation‐induced alterations in tumor oxygenation demonstrated that these changes can be the result of changes in either vasculature or metabolic activity.Conclusion:Radiation induces significant changes in hemoglobin saturation and metabolic activity. These alterations occur on time scales approximately the duration of common radiation treatments. Further understanding these dynamics has important implications with regard to improvement of therapy and biomarkers of treatment response.

Prognosis Related to Metastatic Burden Measured by 18F-Fluorocholine PET/CT in Castration-Resistant Prostate Cancer

This study investigated the prognostic significance of metabolically active tumor volume (MATV) measurements applied to (18)F-fluorocholine PET/CT in castration-resistant prostate cancer (CRPC). (18)F-fluorocholine PET/CT imaging was performed on 30 patients with CRPC. Metastatic disease was quantified on the basis of maximum standardized uptake value (SUV(max)), MATV, and total lesion activity (TLA = MATV × 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. Net MATV ranged from 0.12 cm(3) to 1,543.9 cm(3) (median, 52.6 cm(3)). 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 SUV(max) 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 SUV(max) (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 SUV(max) (log-rank P = 0.0223). Metastatic prostate cancer detected by (18)F-fluorocholine PET/CT can be quantified on the basis of volumetric measurements of tumor metabolic activity. The prognostic value of (18)F-fluorocholine PET/CT may stem from this capacity to assess whole-body tumor burden. With further clinical validation, (18)F-fluorocholine PET-based indices of global disease activity and mortality risk could prove useful in patient-individualized treatment of CRPC.

Impact of Enzalutamide Administration on Primary Prostate Cancer Volume: A Metabolic Evaluation by Choline Positron Emission Tomography in Castration-Resistant Prostate Cancer Patients

BackgroundEnzalutamide is active in advanced castration-resistant prostate cancer (CRPC) patients, in whom it has shown to be able to increase survival. We report the enzalutamide effect on primary prostate tumors, assessed by changes of metabolic tumor activity detected by 18F-fluorocholine-positron emission tomography/computerized tomography (18F-FCH PET/CT). Patients and MethodsWe treated 31 patients with pretreated metastatic CRPC in an enzalutamide named-patient program. All patients were initially evaluated and then followed up by means of repeated 18F-FCH PET/CT examinations. We identified most radiotracer-avid lesions, which were defined as specific regions of interest (ROIs): for each ROI we defined the maximum radiotracer standardized uptake value (SUVmax) and the threshold-based volume of interest (VOI) with a cutoff SUV value ≥ 2.5. In the 12 patients who did not receive a radical treatment for localized disease, the prostate was also considered an ROI. ResultsThe baseline prostate median SUVmax of 7.25 showed reductions of 25% (P = .012) and 43% (P = .009) after 3 and 7 months of enzalutamide treatment, respectively. The baseline median prostate VOI of 12.73 cm3 showed a reduction of 73% (P = .002) at 3 months and a reduction of 90% (P = .005) at 7 months. ConclusionIn addition to the metabolic changes of metastatic lesions observed with enzalutamide in CRPC patients, our data have shown significant volume reductions of the primary tumors according to 18F-FCH PET/CT evaluation. These results could suggest the potential of enzalutamide therapy for localized prostate cancer.

Molecular targeting radiotherapy with cyclo-RGDFK(C) peptides conjugated to 177Lu-labeled gold nanoparticles in tumor-bearing mice.

Peptides based on the cyclic Arg-Gly-Asp (RGD) sequence have been designed to antagonize the function of alpha(v)beta(3) integrin, thereby inhibiting angiogenesis. The conjugation of RGD peptides to radiolabeled gold nanoparticles (AuNP) produces biocompatible and stable multimeric systems with target-specific molecular recognition. The aim of this research was to evaluate the therapeutic response of 177Lu-AuNP-RGD in athymic mice bearing alpha(v)beta(3)-integrin-positive C6 gliomas and compare it with that of 177Lu-AuNP or 177Lu-RGD. The radiation absorbed dose, metabolic activity (SUV, [18F]fluor-deoxy-glucose-microPET/CT), histological characteristics and VEGF gene expression (by real-time polymerase chain reaction) in tumor tissues following treatment with 177Lu-AuNP-RGD, 177Lu-AuNP or 177Lu-RGD were assessed. Of the radiopharmaceuticals evaluated, 1177Lu-AuNP-RGD delivered the highest tumor radiation absorbed dose (63.8 +/- 7.9 Gy). These results correlated with the observed therapeutic response, in which 177Lu-AuNP-RGD significantly (p < 0.05) induced less tumor progression, less tumor metabolic activity, fewer intratumoral vessels and less VEGF gene expression than the other radiopharmaceuticals, a consequence of high tumor retention and a combination of molecular targeting therapy (multimeric RGD system) and radiotherapy (177Lu). There was a low uptake in non-target organs and no induction of renal toxicity. 177Lu-labeled gold nanoparticles conjugated to cyclo-RGDfK(C) demonstrate properties suitable for use as an agent for molecular targeting radiotherapy.

Utility of 18F-FDG PET/CT in follow-up of patients with low-grade serous carcinoma of the ovary

ObjectiveOvarian low-grade serous carcinoma (LGSC) is a rare and indolent tumor. The utility of 18F-FDG PET/CT in monitoring patients with LGSC has not been established. We assessed the accuracy and clinical impact of 18F-FDG PET/CT in patients with ovarian LGSC after initial treatment. MethodsA retrospective analysis was performed on patients with ovarian LGSC who had undergone 18F-FDG PET/CT scans during follow-up after primary treatment. The impact of 18F-FDG PET/CT on the management plan was assessed. The sensitivity, specificity, and accuracy of 18F-FDG PET/CT findings in the detection of recurrence were calculated. Total lesion glycolysis (TLG) was determined to assess metabolic activity of tumors. Potential prognostic factors for disease-free and overall survival after recurrence were assessed. ResultsForty-eight patients were included in the analysis, 39 with recurrent disease and 9 without recurrence. A total of 91 18F-FDG PET/CT scans were performed, and 30% of these (27/91) had an impact on the management plan. Sensitivity, specificity, and accuracy in the detection of LGSC recurrence were 94%, 100%, and 97%, respectively, for 18F-FDG PET/CT; 89%, 95%, and 93%,respectively, for CT; and 68%, 89%, and 73%, respectively, for serum CA-125. There was no significant difference in sensitivity between PET/CT and CT. Survival after recurrence was poorer in patients with a TLG value greater than 67.7g. Conclusions18F-FDG PET/CT may provide useful information during the follow-up of patients with LGSC after initial treatment. TLG may be a predictor of survival after recurrence.

Biodistribution and Radiation Dosimetry of Deuterium-Substituted 18F-Fluoromethyl-[1, 2-2H4]Choline in Healthy Volunteers

(11)C-choline and (18)F-fluoromethylcholine ((18)F-FCH) have been used in patients to study tumor metabolic activity in vivo; however, both radiotracers are readily oxidized to respective betaine analogs, with metabolites detectable in plasma soon after injection of the radiotracer. A more metabolically stable FCH analog, (18)F-fluoromethyl-[1,2-(2)H4]choline ((18)F-D4-FCH), based on the deuterium isotope effect, has been developed. We report the safety, biodistribution, and internal radiation dosimetry profiles of (18)F-D4-FCH in 8 healthy human volunteers. (18)F-D4-FCH was intravenously administered as a bolus injection (mean ± SD, 161 ± 2.17 MBq; range, 156-163 MBq) to 8 healthy volunteers (4 men, 4 women). Whole-body (vertex to mid thigh) PET/CT scans were acquired at 6 time points, up to 4 h after tracer injection. Serial whole-blood, plasma, and urine samples were collected for radioactivity measurement and plasma radiotracer metabolites. Tissue (18)F radioactivities were determined from quantitative analysis of the images, and time-activity curves were generated. The total numbers of disintegrations in each organ normalized to injected activity (residence times) were calculated as the area under the curve of the time-activity curve normalized to injected activities and standard organ volumes. Dosimetry calculations were performed using OLINDA/EXM 1.1. The injection of (18)F-D4-FCH was well tolerated in all subjects, with no radiotracer-related serious adverse event reported. The mean effective dose averaged over both men and women (± SD) was estimated to be 0.025 ± 0.004 (men, 0.022 ± 0.002; women, 0.027 ± 0.002) mSv/MBq. The 5 organs receiving the highest absorbed dose (mGy/MBq) were the kidneys (0.106 ± 0.03), liver (0.094 ± 0.03), pancreas (0.066 ± 0.01), urinary bladder wall (0.047 ± 0.02), and adrenals (0.046 ± 0.01). Elimination was through the renal and hepatic systems. (18)F-D4-FCH is a safe PET radiotracer with a dosimetry profile comparable to other common (18)F PET tracers. These data support the further development of (18)F-D4-FCH for clinical imaging of choline metabolism.

Recent Trends in PET Image Interpretations Using Volumetric and Texture-based Quantification Methods in Nuclear Oncology.

Image quantification studies in positron emission tomography/computed tomography (PET/CT) are of immense importance in the diagnosis and follow-up of variety of cancers. In this review we have described the current image quantification methodologies employed in (18)F-fluorodeoxyglucose ((18)F-FDG) PET in major oncological conditions with particular emphasis on tumor heterogeneity studies. We have described various quantitative parameters being used in PET image analysis. The main contemporary methodology is to measure tumor metabolic activity; however, analysis of other image-related parameters is also increasing. Primarily, we have identified the existing role of tumor heterogeneity studies in major cancers using (18)F-FDG PET. We have also described some newer radiopharmaceuticals other than (18)F-FDG being studied/used in the management of these cancers. Tumor heterogeneity studies are being performed in almost all major oncological conditions using (18)F-FDG PET. The role of these studies is very promising in the management of these conditions.

Safety, Pharmacokinetics, Pharmacodynamics, and Antitumor Activity of Dalantercept, an Activin Receptor–like Kinase-1 Ligand Trap, in Patients with Advanced Cancer

The angiogenesis inhibitor dalantercept (formerly ACE-041) is a soluble form of activin receptor-like kinase-1 (ALK1) that prevents activation of endogenous ALK1 by bone morphogenetic protein-9 (BMP9) and BMP10 and exhibits antitumor activity in preclinical models. This first-in-human study of dalantercept evaluated its safety, tolerability, pharmacokinetics, pharmacodynamics, and antitumor activity in adults with advanced solid tumors. Patients in dose-escalating cohorts received dalantercept subcutaneously at one of seven dose levels (0.1-4.8 mg/kg) every 3 weeks until disease progression. Patients in an expansion cohort received dalantercept at 0.8 or 1.6 mg/kg every 3 weeks until disease progression. In 37 patients receiving dalantercept, the most common treatment-related adverse events were peripheral edema, fatigue, and anemia. Edema and fluid retention were dose-limiting toxicities and responded to diuretic therapy. No clinically significant, treatment-related hypertension, proteinuria, gross hemorrhage, or gastrointestinal perforations were observed. One patient with refractory squamous cell cancer of the head and neck had a partial response, and 13 patients had stable disease according to RECISTv1.1, eight of whom had prolonged periods (≥12 weeks) of stable disease. Correlative pharmacodynamic markers included tumor metabolic activity and tumor blood flow, which decreased from baseline in 63% and 82% of evaluable patients, respectively, and telangiectasia in eight patients. Dalantercept was well-tolerated at doses up to 1.6 mg/kg, with a safety profile distinct from inhibitors of the VEGF pathway. Dalantercept displayed promising antitumor activity in patients with advanced refractory cancer, and multiple phase II studies are underway.

Dynamic Metabolic Changes during the First 3 Months after90Y-Ibritumomab Tiuxetan Radioimmunotherapy

Objective. To elucidate the time course of tumor metabolism during the first 3 months after 90Y-ibritumomab tiuxetan radioimmunotherapy (RIT) in patients with refractory malignant lymphoma. Materials and Methods. Seven patients with recurrent follicular lymphoma underwent FDG-PET imaging before and after 1-, 4-, and 12-week RIT with 90Y-ibritumomab tiuxetan. Tumor metabolic activity on FDG-PET scans was assessed as the maximum standard uptake value (SUVmax). Results. Decrease in metabolism was detected 1 week after RIT. In the most decreased lesion, SUVmax decreased to 20% of the baseline value during the first week. Most lesions continued to decrease for up to 4 weeks. Some lesions showed increased metabolism from 4 to 12 weeks, while the level of FDG accumulations at 12 weeks was still lower than the baseline. Conclusions. Tumor response to RIT could be observed as early as 1 week after the administration of RIT. After tumor activity decreases, the metabolism may increase at least between 4 and 12 weeks. It suggests that the metabolic changes should be carefully evaluated during this period.

Extracellular pH, lactate, and a hypothesis for NADH-associated proton dynamics in tumor cells

Event Abstract Back to Event Extracellular pH, lactate, and a hypothesis for NADH-associated proton dynamics in tumor cells Angela M. Otto1* and Cornelia Janzon2 1 Technische Universitaet Muenchen, Institute of Medical Engineering (IMETUM), Germany 2 Klinikum Leverkusen, Abteilung Onkologie/Haematologie, Germany Background and aim. The microenvironment of tumor cells is characterized by a gradual deprivation of nutrients and oxygen, an accumulation of lactate, and increased acidification. The question is how variable combinations of these components change tumor cell growth and metabolic activity in quantitative terms. The aim here is to investigate how extracellular lactate and pH affect this metabolic activity under limiting nutrient conditions. Methods. The breast cancer cell line MCF-7 was cultivated in “low growth” medium (DMEM with reduced FCS, containing tumor-relevant concentrations of glucose, glutamine as well as lactate, and set at different pH (6.6 – 7.4) for up to 4 days. Growth was determined by cell count. The WST-assay was used as a measure of plasma membrane NADH-oxidase activity (1). The activities of pyruvate kinase and lactate dehydrogenase (LDH) in cell lysates were measured by the kinetics of NADH-based changes in absorption. Lactate production was determined in cell culture supernatants using LDH activity as a read out. Results. At pH 7.4 with combinations of variable glucose concentrations and 0.1 mM glutamine, tumor cell growth was low, but the activity of NADH oxidase activity markedly increased at 2.5. mM glucose. Pyruvate kinase activity was also increased, while LDH activity remained 2-3-fold lower than that of pyruvate kinase. The inhibition of mitochondrial respiration by rotenone transiently increased NADH oxidase activity further. Lactate (25 mM) further increased NADH oxidase activity, but enhanced growth only at limiting conditions. At an acidic pH (6.6), these tumor cells become virtually independent of glucose and glutamine levels for both growth and the metabolic parameters tested. The culture medium of such cells contained only 7% of the lactic acid measured for cultures at pH 7.4, suggesting attenuated lactate release. Conclusions / Discussion. Extracellular pH has a differential effect on the replenishment of NAD+ from NADH produced by glycolysis. This is not solely accomplished by LDH, but may also involve plasma membrane NADH oxidase activity. Furthermore, lactate may be converted to pyruvate and support the TCA-cycle, thereby enhancing mitochondrial NADH levels. The resistance of NADH oxidase activity to rotenone suggests that reduction equivalents, along with the respective protons, are shuttled from the mitochondria to the cytosol. A hypothesis is proposed to explain the changes in plasma membrane NADH oxidase activity with respect to glycolysis and the tricarbonic acid cycle. Acknowledgements Part of this work was supported by the German Research Council (DFG). References (1) Berridge, M.V. and Tan, A.S. (1998) Trans-plasma membrane electron transport: A cellular assay for NADH- and NADPH-oxidase based on extracellular, superoxide-mediated reduction of the sulfonated tetrazolium salt WST-1. Protoplasma, 205:74-82. Keywords: Tumor Cells, Cultured, nutrient deprivation, Glucose, Glutamine, extracellular pH, tumor cell metabolism, Pyruvate Kinase, Lactate Dehydrogenases, extracellular lactate, NADH-oxidase, cell growth analysis Conference: 4th Annual Meeting of the International Society of Proton Dynamics in Cancer, Garching, Germany, 10 Oct - 12 Oct, 2013. Presentation Type: Abstract Topic: 4. pH and energy metabolism Citation: Otto AM and Janzon C (2014). Extracellular pH, lactate, and a hypothesis for NADH-associated proton dynamics in tumor cells. Front. Pharmacol. Conference Abstract: 4th Annual Meeting of the International Society of Proton Dynamics in Cancer. doi: 10.3389/conf.fphar.2014.61.00031 Copyright: The abstracts in this collection have not been subject to any Frontiers peer review or checks, and are not endorsed by Frontiers. They are made available through the Frontiers publishing platform as a service to conference organizers and presenters. The copyright in the individual abstracts is owned by the author of each abstract or his/her employer unless otherwise stated. Each abstract, as well as the collection of abstracts, are published under a Creative Commons CC-BY 4.0 (attribution) licence (https://creativecommons.org/licenses/by/4.0/) and may thus be reproduced, translated, adapted and be the subject of derivative works provided the authors and Frontiers are attributed. For Frontiers’ terms and conditions please see https://www.frontiersin.org/legal/terms-and-conditions. Received: 17 Dec 2013; Published Online: 07 Feb 2014. * Correspondence: Dr. Angela M Otto, Technische Universitaet Muenchen, Institute of Medical Engineering (IMETUM), Garching, 85748, Germany, otto@tum.de Login Required This action requires you to be registered with Frontiers and logged in. To register or login click here. Abstract Info Abstract The Authors in Frontiers Angela M Otto Cornelia Janzon Google Angela M Otto Cornelia Janzon Google Scholar Angela M Otto Cornelia Janzon PubMed Angela M Otto Cornelia Janzon Related Article in Frontiers Google Scholar PubMed Abstract Close Back to top Javascript is disabled. Please enable Javascript in your browser settings in order to see all the content on this page.

Metabolic Activity on [18F]-Fluorodeoxyglucose-Positron Emission Tomography/Computed Tomography and Glucose Transporter-1 Expression Might Predict Clinical Outcomes in Patients With Limited Disease Small-Cell Lung Cancer Who Receive Concurrent Chemoradiation

BackgroundLimited disease small-cell lung cancer responds well to concurrent chemoradiation therapy (CCRT), but shows high relapse rate and short RFS. We aimed to evaluate tumor metabolic activities measured using FDG-PET as a prognostic factor and analyze its relationships with markers of tumor biologic behavior. Patients and MethodsForty-one LD-SCLC patients receiving 4 cycles of EP (etoposide 120 mg/m2, days 1-3; cisplatin 60 mg/m2, day 1), 2 cycles of EP (etoposide 130 mg/m2, days 1-3; cisplatin 30 mg/m2, day 1)-CCRT were enrolled. Maximum standardized uptake value (SUV; SUVmax) of primary tumor was revised with SUV of liver (SUVlivermax). Differences between pre-, posttreatment average SUV uptake of primary tumor, and intrathoracic lymph nodes were presented as ΔSUVliveravg. Thirty-one tumor biopsy specimens were immunostained for GLUT-1, Bcl-2, and HIF-1α. ResultsThe median overall survival (OS), and RFS were 13.7 and 10.4 months, respectively. In multivariate analysis, pretreatment lactate dehydrogenase (LDH) and ΔSUVliveravg correlated with RFS (hazard ratio [HR], 2.8, P = .043; HR, 0.3, P = .004). Sex, LDH, objective tumor metabolic response, and SUVlivermax correlated with OS (HR, 12.1, P = .006; HR, 3.7, P = .037; HR, 10.1, P = .008; and HR, 0.2, P = .014, respectively). High GLUT-1 positivity (> 75%), and LDH level (> 400 U/L) correlated with better objective response rate (P = .012) and HIF-1α immunoreactivity score (P = .029). ConclusionΔSUVliveravg and GLUT-1 expression might predict RFS and ORR in patients with LD-SCLC treated with definitive CCRT.

Automated Cosegmentation of Tumor Volume and Metabolic Activity Using PET-CT in Non-Small Cell Lung Cancer (NSCLC)

Purpose/Objective(s): This study presents a novel computer-aided, automatic contouring (co-segmentation) gross target volume (GTV) that integrates tumor boundaries on both PET and CT through a globally optimal graph-based algorithm. Metabolic TV (MTV) was developed by integration of co-segmented tumor boundaries and metabolic activities as a tumor response metric. Materials/Methods: Records of 649 lung cancer patients were reviewed. Patients with stage III/IV NSCLC who received chemotherapy and lung radiation and had PET-CT imaging for simulation and PET-CT/CT at 2-4 months follow-up post-radiation were included. A total of 19 patients fulfilled the criteria. Post-treatment residual GTV (post-GTV) was retrospectively contoured by physician. A co-segmented GTV was generated on pretreatment PET-CT. MTV was defined as co-segmented GTV times mean SUV. As tumor response metrics, co-segmented GTV, co-segmented MTV, and mean SUV were generated on pretreatment dataset and tested for correlation with a pre-treatment, physician contoured GTV (pre-GTV) that was used as a ground truth for comparison. Their correlations with physician’s contour were measured using spearman’s correlation coefficient. Linear regression was used to evaluate if the different metric was predictive of post-GTV. Tumor response after chemoradiation therapy was measured using preand post-GTV. Results: Co-segmented GTV and MTV significantly correlated with pre-GTV (p < 0.001). Co-segmented GTV (p < 0.0001), co-segmented MTV (p Z 0.0009), pre-GTV (p < 0.0001) significantly correlated with post-GTV. No significant correlation was found in mean SUV (p Z 0.74). The overall averaged tumor response rate after chemoradiation therapy in 2-4 months is 69.5% +/-19.2%. Squamous cell histology responded better by 20% compared to adenocarcinoma. Tumor response pattern was modeled as post-GTV Z 10.0 + 0.4*pre-GTV (R Z 0.68). Conclusions: Co-segmented GTV and MTV present significant correlations with physician’s manual contouring, showing potential as a tumor response evaluation tool for large scale clinical trials and daily clinical practice. Average local tumor response in 2-4 months for advanced stage NSCLC after chemoradiation therapy was 69.5%. Author Disclosure: H. Li: None. J. Bai: None. T. Abu Hejle: None. X. Wu: None. S. Bhatia: None. Y. Kim: None.

Characterization of tumor heterogeneity using dynamic contrast enhanced CT and FDG-PET in non-small cell lung cancer

PurposeDynamic contrast-enhanced CT (DCE-CT) quantifies vasculature properties of tumors, whereas static FDG-PET/CT defines metabolic activity. Both imaging modalities are capable of showing intra-tumor heterogeneity. We investigated differences in vasculature properties within primary non-small cell lung cancer (NSCLC) tumors measured by DCE-CT and metabolic activity from FDG-PET/CT. MethodsThirty three NSCLC patients were analyzed prior to treatment. FDG-PET/CT and DCE-CT were co-registered. The tumor was delineated and metabolic activity was segmented on the FDG-PET/CT in two regions: low (<50% maximum SUV) and high (⩾50% maximum SUV) metabolic uptake. Blood flow, blood volume and permeability were calculated using a maximum slope, deconvolution algorithm and a Patlak model. Correlations were assessed between perfusion parameters for the regions of interest. ResultsDCE-CT provided additional information on vasculature and tumor heterogeneity that was not correlated to metabolic tumor activity. There was no significant difference between low and high metabolic active regions for any of the DCE-CT parameters. Furthermore, only moderate correlations between maximum SUV and DCE-CT parameters were observed. ConclusionsNo direct correlation was observed between FDG-uptake and parameters extracted from DCE-CT. DCE-CT may provide complementary information to the characterization of primary NSCLC tumors over FDG-PET/CT imaging.

A Single-institution Retrospective Cases Series of Childhood Undifferentiated Embryonal Liver Sarcoma (UELS)

Undifferentiated embryonal liver sarcoma (UELS) makes up 9% to 15% of all malignant liver tumors in children. UELS is characteristically diagnosed between the ages of 6 and 10 years and presents with abdominal pain, vomiting, and an abdominal mass. There is currently no standardized treatment for UELS except attempt at complete surgical resection. There have been only about 150 cases of UELS reported in the literature all with historically poor overall survival of <37.5% at 5 years. This report is one of the largest single-institution reports of UELS consisting of 5 patients over 2 decades. The purpose of this study is to characterize presentation and to report treatment success in UELS in children, adolescents, and young adults and the use of liver transplantation and, lastly, to suggest a use of positron emission tomography/computed tomography (PET/CT) in monitoring of this disease process. We conducted an Institutional Review Board-approved retrospective chart review. Data were collected from UELS patients younger than 21 years seen at the University of California Los Angeles over the past 20 years (January 2001 to September 2011). Descriptive analysis was conducted including multiple parameters of patient demographics, tumor characteristics, treatment modalities, and morbidity and mortality. Five patients with UELS were identified. Patients initially presented with fever, abdominal pain, or nausea. Ages ranged from 10 to 19 years old (median age 13 y old), and there was a 4:1 male-to-female predominance. Tumor size ranged from 6 to 22 cm in largest diameter. One patient presented with metastatic disease to the lungs and heart and 1 patient recurred 2 years from diagnosis with bilateral paraspinal masses. Treatment included local control surgery with neoadjuvant and adjuvant chemotherapy with an anthracycline/alkylating agent combination. One patient with recurrent and refractory disease achieved local control with an orthotopic liver transplantation (OLT). Metastatic disease was controlled with surgery and radiation therapy. 18-Fluorodeoxyglucose PET/CT was a useful imaging tool for judging response to therapy with complete loss of metabolic activity in tumor after neoadjuvant chemotherapy in 2 representative cases. Although follow-up is short for some patients, overall survival in these 5 patients was 100% with follow-up ranging from 21 to 68 months. Disease-free survival ranged from 8 to 46 months with no patients with residual disease. UELS is an aggressive high-grade primary liver sarcoma with high metastatic potential. This report represents one of the largest single-institution studies of UELS. Using multimodality therapy, patients have achieved 100% overall survival even in the setting of extensive disease, metastases, and recurrence. In cases of unresectable primary tumor or recurrent and refractory disease isolated to the liver, OLT is a potential therapeutic option. We report success with adjuvant chemotherapy and complete surgical resection with OLT as an alternative in unresectable or refractory cases. We also suggest a possible utility of PET/CT in monitoring treatment response in this disease.

Pulsed Versus Conventional Radiation Therapy in Combination With Temozolomide in a Murine Orthotopic Model of Glioblastoma Multiforme

To evaluate the efficacy of pulsed low-dose radiation therapy (PLRT) combined with temozolomide (TMZ) as a novel treatment approach for radioresistant glioblastoma multiforme (GBM) in a murine model. Orthotopic U87MG hGBM tumors were established in Nu-Foxn1(nu) mice and imaged weekly using a small-animal micropositron emission tomography (PET)/computed tomography (CT) system. Tumor volume was determined from contrast-enhanced microCT images and tumor metabolic activity (SUVmax) from the F18-FDG microPET scan. Tumors were irradiated 7 to 10 days after implantation with a total dose of 14 Gy in 7 consecutive days. The daily treatment was given as a single continuous 2-Gy dose (RT) or 10 pulses of 0.2 Gy using an interpulse interval of 3 minutes (PLRT). TMZ (10 mg/kg) was given daily by oral gavage 1 hour before RT. Tumor vascularity and normal brain damage were assessed by immunohistochemistry. Radiation therapy with TMZ resulted in a significant 3- to 4-week tumor growth delay compared with controls, with PLRT+TMZ the most effective. PLRT+TMZ resulted in a larger decline in SUVmax than RT+TMZ. Significant differences in survival were evident. Treatment after PLRT+TMZ was associated with increased vascularization compared with RT+TMZ. Significantly fewer degenerating neurons were seen in normal brain after PLRT+TMZ compared with RT+TMZ. PLRT+TMZ produced superior tumor growth delay and less normal brain damage when compared with RT+TMZ. The differential effect of PLRT on vascularization may confirm new treatment avenues for GBM.

Clinical significance of VEGFR-2 and 18F-FDG PET/CT SUVmax pretreatment score in predicting the long-term outcome of patients with locally advanced rectal cancer treated with neoadjuvant therapy

Vascular endothelial growth factor receptor-2 (VEGFR-2), epidermal growth factor receptor-1 (EGFR), and cyclooxygenase-2 (COX-2) stimulate key processes involved in tumor progression and are important targets for cancer drugs. (18)F-FDG maximum standardized uptake value (SUVmax) is a marker of tumor metabolic activity. The purpose of this study was to measure SUVmax combined with VEGFR-2, EGFR and COX-2 proteins in pretreatment tumor biopsies from patients with locally advanced rectal cancer receiving intensive neoadjuvant treatment and to correlate the findings with clinical outcome. VEGFR-2, EGFR and COX-2 were measured using the immunoreactive score (IRS). SUVmax (median 8.4) was quantified in tumors with molecular overexpression (IRS ≥3 + SUVmax ≥ 8.4 indicating active tumors; SUVmax <8.4 indicating inactive tumors). The Cox proportional hazards model was used to explore associations between tumor markers, disease-free survival (DFS) and overall survival (OS). The study group comprised 38 patients with a median follow-up of 69.3 months (range 4.5 - 92 months). Multivariate analysis showed that active tumors (overexpressing VEGFR-2, high SUVmax) were associated with worse DFS (HR 4.73, 95 % CI 1.18 - 22.17; p = 0.04) and OS (HR 4.28, 95 % CI 1.04 - 20.12; p = 0.05). Active tumors overexpressing VEGFR-2 are associated with a worse overall outcome in patients with rectal cancer treated with induction chemotherapy followed by pelvic chemoradiation and surgery. The optimal diagnostic cut-off level for this novel biomarker association should be investigated. Evaluation in a clinical trial is required to determine whether selected patients could benefit from a VEGFR-targeting drug.

Translational Predictive Biomarker Analysis of the Phase 1b Sorafenib and Bevacizumab Study Expansion Cohort

Predictive biomarkers are needed to triage patients to the best therapy. We prospectively planned examination of sequential blood, biopsy, and functional imaging with which to confirm the mechanism and to identify potential predictive biomarkers in a phase Ib clinical trial expansion of patients with solid tumors receiving sorafenib/bevacizumab. The maximally tolerated doses of sorafenib at 200 mg twice daily with bevacizumab at 5 mg/kg every other week were given to biopsiable patients. Patients were randomized to receive either sorafenib or bevacizumab monotherapy for the first 28-day cycle with the second drug added with cycle 2. Biopsies, dynamic contrast-enhanced MRI, and fluorodeoxyglucose-proton emission tomography were done pre-therapy and at 2 and 6 weeks (2 weeks into combination therapy). Tumor and serum proteomics, Ras/Raf mutational analysis, and functional imaging results were examined individually and across the dataset to identify potential changes predictive of response to therapy and those that confirm the biochemical drug mechanism(s). Therapy with sorafenib/bevacizumab resulted in clinical benefit in 45% of this mixed solid tumor group. ERK activation and microvessel density were decreased with monotherapy treatment with sorafenib or bevacizumab, respectively; whereas a decreased signal over the group of total AKT, phospho(p)-VEGF receptor2, p-endothelial nitric-oxide synthase, b-RAF, and cleaved poly(ADP-ribose) polymerase was associated with earlier progression of disease. Tumor metabolic activity decreased in those patients with clinical benefits lasting longer than 4 months, and activity increased with progression of disease. Cleavage of caspase 3 and poly(ADP-ribose) polymerase was increased, and Ki67 expression decreased in patients with prolonged clinical benefits, consistent with decreased proliferation and increased apoptosis. The conglomerate analysis, incorporating pharmacodynamic and tumor biochemistry, demonstrated sorafenib/bevacizumab-targeted vascular activity in the tumor. Results suggest potential biomarkers for which changes, as a group, during early therapeutic exposure may predict clinical benefit.

Can Metabolic Activity Predict Response in Early-Stage Lung Cancer Treated with Stereotactic Body Radiation Therapy?

165 ISSN 1758-1966 10.2217/LMT.13.17 © 2013 Future Medicine Ltd Lung Cancer Manage. (2013) 2(3), 165–167 Lung cancer has been and continues to be a devastating disease, with projections for 2013 estimating 228,190 new cases, while 159,480 individuals will succumb to their disease [101]. Although intensive molecular studies have identified novel target therapies, such as that for ALK-mutated metastatic disease, there is relatively little new information for patients diagnosed with early-stage disease. This is especially important with the increased utilization of screening protocols to detect early-stage disease and the now relatively widespread implementation of stereotactic body radiation therapy (SBRT) for patients who are medically inoperable or elect for this promising treatment over that of more invasive therapies. With fluorodeoxyglucose-PET scanning being a part of the standard staging protocols [1], there is additional information on the metabolic activity of tumors, which, beyond diagnostic and planning purposes, is largely ignored. The question that has been asked is: can this information be used to identify a high-risk cohort that may potentially benefit from more aggressive initial therapy? This question can in part be answered by extrapolating from the surgical literature, as both modalities are often used to treat early-stage disease. In a 2010 metaanalysis sanctioned by the International Association for the Study of Lung Cancer (IASLC), the maximum standardized uptake value (SUV max ) was found to be a useful marker for predicting overall survival in definitive surgical lung cancer patients [2]. Patients who receive SBRT as therapy, however, often lack a histological diagnosis and are treated based on interval changes in radiographic and PET findings, leaving the multidisciplinary team with relatively little information about the patient’s disease compared with those with pathological findings. Because it is expected that the patients have a similar disease process, a projection from the surgical literature would indicate that SUV max may be a useful marker for patients treated with SBRT.

Metabolic characterization of inflammatory breast cancer (IBC) with baseline FDG-PET/CT: Relationship with histopathology, hormone receptor status, and pathologic response after neoadjuvant chemotherapy.

1105 Background: Higher metabolic activity on FDG-PET is associated with triple negative (TN) hormone receptor status and invasive ductal histopathology in non-IBC breast cancer. Pts with IBC and a complete pathologic response (pCR) in mastectomy tissue after neoadjuvant chemotherapy (NAC) have a better prognosis compared to pts with residual disease. The objectives were to characterize IBC on baseline FDG-PET with respect to hormone receptor status, tumor grade and to determine if baseline metabolic activity in primary or metastatic lymph nodes (LN) predicts pCR. Methods: This is an IRB-approved retrospective study of 28 pts. SUVmax of primary IBC tumor and local LN metastases were compared between (b/w) pts with pCR versus residual disease, b/w pts with different receptor status (ER, PR, HER2), and b/w pts with different grade tumors (1-3). Results: Baseline SUVmax was higher in 6 pts with TN tumors (median 12.4, range 5.4-29.3) compared with 22 pts with ER+ or PR+ or HER2+ tumors (5.0, 2.0-16.3, p=0.04). SUVmax in local LN metastases tended to be higher in TN tumors vs. others (11.2, 2.7-27.9 vs. 5.4, 2.0-15.5, p=0.06). SUVmax in primary IBC was not different based on tumor grade (p=0.26), but higher SUVmax was seen in metastatic LN in pts with grade 3 vs. 2 tumors (10.5, 2.0-27.9 vs. 4.7, 2.0-10.2, p=0.02). SUVmax of primary IBC tumor was not significantly different b/w pts with pCR (median 10.6, range 2-29.3) vs. residual disease (6.4, 2.5-13.6, p=0.36). No significant difference was seen b/w baseline SUVmax of locally metastatic LN between pts with pCR (9.0, 3.3-27.9) vs. residual disease (6.1, 2.0-16.2, p=0.13). Conclusions: Baseline metabolic activity of primary IBC tumor and locally metastatic LN did not predict pCR at mastectomy. Triple-negative receptor status is associated with higher SUVmax in primary tumor and marginally in metastatic LN suggesting a more aggressive nature. These findings are consistent with data in non-IBC breast cancer.

Measuring tumour response: RECIST 1.1 and beyond

•. Response Evaluation Criteria in Solid Tumors (RECIST) standardises the method of response assessment within oncology clinical trials, allowing for results of different clinical trials to be compared.•. RECIST is based on anatomical measurement.•. RECIST 1.1 has revised some of the criteria requirements with respect to: target lesion number and measurement, lymph node measurement and the use of non-target lesions alone for overall response assessment.•. There remain some challenges for RECIST as biological response to treatment may not always result in a reduction in tumour size.•. There is an increasing requirement to measure functional parameters such as tumour metabolic activity, cellularity and vascularisation in order to acquire adequate data to effectively assess response. Currently these do not form part of the RECIST.The Response Evaluation Criteria in Solid Tumors (RECIST) were introduced in 2000 to provide a standardised method for assessing response to treatments to enable the results of diff...