Tumor FDG Uptake Research Articles

Abstract 4947: Inhibition of Rapamycin induced AKT activation elicits differential anti-tumor response in head and neck cancers.

Abstract The PI3K/AKT/mTOR pathway is an important signaling axis that is perturbed in majority of cancers. Biomarkers such as pS6RP, GLUT1 and tumor FDG uptake are being evaluated in patient stratification for mTOR pathway inhibitors. In the absence of a clear understanding of the underlying mechanisms in tumor signaling, the biomarker strategy for patient stratification is of limited use. Here, we show that no discernible correlation exists between FDG uptake and the corresponding Ki67, GLUT1, pS6RP expression in tumor biopsies from Head and Neck Cancer (HNC) patients. Correlation between GLUT1 and pS6RP levels in tumors was observed but elevated pS6RP was noticed even in the absence of concomitant AKT activation, suggesting other downstream molecules of PI3K/AKT and/or other pathways upstream of mTOR, are active in these tumors. Using an ex-vivo platform, we identified putative responders to Rapamycin, an mTOR inhibitor in these tumors. However, Rapamycin did not induce anti-tumor effect in the majority of tumors with activated mTOR, potentially attributable to the observation that Rapamycin induces feedback activation of AKT. Accordingly, treatment of these tumors with an AKT inhibitor and Rapamycin uniformly resulted in abrogation of mTOR inhibition induced AKT activation in all tumors but failed to induce anti-tumor response in a subset. Phosphoproteomic profiling of tumors resistant to dual AKT/mTOR inhibitors revealed differential activation of multiple pathways involved in proliferation and survival. Collectively, our data suggest that in addition to biomarker based segregation, functional assessment of patient tumor prior to treatment with mTOR/AKT inhibitors might be useful for patient stratification. Citation Format: Padhma Radhakrishnan, Ulaganathan Baraneedharan, Muthu Dhandapani, Allen Thyakumar, Dency Pinto, Arun Prasath, Ayyappan Velu, A Kamal, Nilesh Brijwani, Rohini Nair, R Basavaraja, Misti Jain, Saravanan Thiyagarajan, Biswanath Majumder, Mallik Sundaram, Prasad Narayanan, Vikram D. Kekatpure, Pradip K. Majumder. Inhibition of Rapamycin induced AKT activation elicits differential anti-tumor response in head and neck cancers. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4947. doi:10.1158/1538-7445.AM2013-4947

Abstract 3363: Pharmacodynamic (PD) assessment of drug activity in tumor tissue from patients (pts) enrolled in a Phase I study of MEHD7945A (MEHD), a first-in-class HER3/EGFR dual action antibody, in pts with locally advanced or metastatic epithelial tumors.

Abstract Background Members of the human epidermal growth factor receptor (HER) family of oncogenes are often co-expressed and heterodimerized, suggesting that simultaneous blockade of multiple HER family receptors may be more effective than targeting single receptors. MEHD is a dual-action human IgG1 antibody that can bivalently bind to HER3 and EGFR and block ligand binding to either. FDG-PET imaging is a recognized method of assessing PD modulation with EGFR inhibitors in the clinic. HER3 and EGFR signaling via the MAPK and PI3K pathways can be monitored in tissue by examining phosphorylation of downstream markers. Methods A Phase 1, multicenter, open-label study was conducted to evaluate the safety, pharmacokinetics, and anti-tumor activity of MEHD administered intravenously every 2 weeks at doses ranging from 1 to 30 mg/kg during escalation (n=30), and at 14 mg/kg during expansion (n=36). FDG-PET scans and optional tumor biopsies (bxs) were obtained at baseline and cycle 2, day 2 (C2D2). Tumor bxs were evaluated by immunohistochemistry (IHC) for S235/236-p-S6, T246-p-PRAS40, and T202/Y204-p-MAPK. EGFR and KRAS mutation (mt) status was determined by PCR. Paired frozen bxs were utilized for exploratory assessment by reverse-phase protein arrays (see Penuel et al. abstract). Results Evidence of PD modulation by imaging or IHC was observed in 14 pts including 7 CRC (KRAS mt-2, wt-5), 3 NSCLC, 2 SCCHN, 1 ovarian, and 1 anal cancer. Tumor FDG-uptake was decreased by at least 20%, indicating a partial metabolic response (PMR), in 9/56 evaluated pts (16%). Tumor bxs were obtained at baseline and C2D2 from 32 pts (12 escalation, 20 expansion). Sufficient viable tumor for IHC was present in both bxs from 17/32 evaluated pts. IHC signal was decreased for one or more of the 3 markers in the C2D2 bxs of 6/17 pts (35%), 5 CRC (KRAS mt-2, wt-3), 1 NSCLC. Best response by CT-RECIST includes PR in 2 patients with SCCHN, both with PMR and both tumors expressing high heregulin, with duration of response of 10 and 12+ months. Conclusions Evidence of PD modulation is demonstrated by a PMR rate of 16% and reduced pathway activity by IHC in 35% of pts with evaluable biopsies. These data suggest MEHD is biologically active in pts and downregulates intracellular signaling activity consistent with HER3 and/or EGFR inhibition in tumor tissue and is further supported by evidence of anti-tumor activity. Phase II studies in SCCHN and CRC are ongoing. Citation Format: Dejan Juric, Rodrigo Dienstmann, Andres Cervantes, Manuel Hidalgo, Wells Messersmith, George Blumenschein, Jose Baselga, Josep Tabernero, Desamparados Roda, Antonio Calles, Antonio Jimeno, Lukas Amler, Howard Stern, Sandra Sanabria, Elicia Penuel, Andrea Pirzkall. Pharmacodynamic (PD) assessment of drug activity in tumor tissue from patients (pts) enrolled in a Phase I study of MEHD7945A (MEHD), a first-in-class HER3/EGFR dual action antibody, in pts with locally advanced or metastatic epithelial tumors. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3363. doi:10.1158/1538-7445.AM2013-3363

Preoperative chemosensitivity testing as Predictor of Treatment benefit in Adjuvant stage III colon cancer (PePiTA): Protocol of a prospective BGDO (Belgian Group for Digestive Oncology) multicentric study

BackgroundSurgery is a curative treatment for patients with locally advanced colon cancer, but recurrences are frequent for those with stage III disease. FOLFOX adjuvant chemotherapy has been shown to improve recurrence-free survival and overall survival by more than 20% and is nowadays considered a standard of care. However, the vast majority of patients will not benefit from receiving cytotoxic drugs because they have either already been cured by surgery or because their tumor cells are resistant to the chemotherapy, for which predictive factors are still not available.Identifying which patients are unlikely to respond to adjuvant chemotherapy from among those who are eligible for such treatment would be a major step towards treatment personalization. It would spare such patients from unnecessary toxicities and would improve the allocation of societal healthcare resources.Methods/designPePiTA is a prospective, multicenter, non-randomised trial built on the hypothesis that preoperative chemosensitivity testing using FDG-PET/CT before and after one course of FOLFOX can identify the patients who are unlikely to benefit from 6 months of adjuvant FOLFOX treatment for stage III colon cancer.The study’s primary objective is to examine the ability of PET/CT-assessed tumor FDG uptake after one course of preoperative chemotherapy to predict the outcome of adjuvant therapy, as measured by 3-year disease-free survival.Secondary objectives are to examine the predictive value of changes in PET/CT-assessed tumor FDG uptake on overall survival, to define the best cut-off value of FDG uptake for predicting treatment outcome, and to analyse the cost-effectiveness of such preoperative chemo-sensitivity testing.At study planning, exploratory translational research objectives were 1) to assess the predictive value of circulating tumor cells for disease-free survival, 2) to examine the predictive value of single nucleotide polymorphisms for disease-free survival with respect to genes related either to toxicity or to drug targets, 3) to assess genomic rearrangements associated with response or resistance to FOLFOX treatment, 4) to identify an immunologic signature associated with metabolic tumor response to FOLFOX therapy and, finally, 5) to create a bank of frozen tumor samples for future studies.DiscussionPePiTA is the first study to use the primitive tumor chemosensitivity assessed by metabolic imaging as a guidance for adjuvant therapy in colon cancer. It could pave the way for tailoring the treatment and avoiding useless toxicities for the patients and inadequate expenses for the society. It could also give an interesting insight into tumoral heterogeneity, resistance to chemotherapy, genetic predisposants to oxaliplatin toxicity and immune response to cancer.EudraCT number2009-011445-13Trial registrationClinicalTrials.gov number, NCT00994864

The clinical value of tumor FDG uptake for predicting axillary lymph node metastasis in breast cancer with clinically negative axillary lymph nodes

The aim of this study was to evaluate the clinical value of 18F-fluorodeoxyglucose (FDG) uptake and the clinicopathological or immunohistochemical findings of the primary tumor to predict axillary lymph node (ALN) metastasis in breast cancer with clinically negative ALN. This study retrospectively enrolled 104 women (49.43 ± 9.9 years) having breast cancer with clinically negative ALN using all types of preoperative imaging modalities including ultrasonography, FDG positron emission tomography, and magnetic resonance imaging. All cases of breast cancer in this study were proven as invasive ductal carcinoma with ≥1 cm in size. The final diagnosis of ALN status was confirmed by permanent pathology after operation. Among 104 breast cancers with clinically negative ALN, 21 breast cancers (20.2 %) were proven to have ALN metastasis. The ROC curve analysis showed that the best cut-off value of SUVmax for identifying ALN metastasis was 9.8 with 33.3 % sensitivity and 92.8 % specificity (AUC = 0.656; p = 0.027). The multivariable analysis revealed that primary tumors with SUVmax >9.8 (p = 0.011) and D2-40 positivity (p = 0.027) were independently associated with ALN metastasis with odds ratios of 5.516 (CI 1.475-20.6333) and 3.409 (CI 1.154-10.072), respectively. Our study demonstrates that the incidence of ALN metastasis in even rigorously clinically evaluated breast cancer without suspiciously positive ALN is still not negligible, and while a high SUVmax of the primary tumor may be associated with a higher incidence of ALN metastasis in breast cancer with clinically negative ALN, a low SUVmax does not exclude ALN metastasis.

Antilipolytic drug boosts glucose metabolism in prostate cancer

The antilipolytic drug Acipimox reduces free fatty acid (FFA) levels in the blood stream. We examined the effect of reduced FFAs on glucose metabolism in androgen-dependent (CWR22Rv1) and androgen-independent (PC3) prostate cancer (PCa) xenografts. Subcutaneous tumors were produced in nude mice by injection of PC3 and CWR22Rv1 PCa cells. The mice were divided into two groups (Acipimox vs. controls). Acipimox (50mg/kg) was administered by oral gavage 1h before injection of tracers. 1h after i.v. co-injection of 8.2MBq (222 ± 6.0 μCi) (18)F-FDG and~0.0037 MBq (0.1 μCi) (14)C-acetate, (18)F-FDG imaging was performed using a small-animal PET scanner. Counting rates in reconstructed images were converted to activity concentrations. Quantification was obtained by region-of-interest analysis using dedicated software. The mice were euthanized, and blood samples and organs were harvested. (18)F radioactivity was measured in a calibrated γ-counter using a dynamic counting window and decay correction. (14)C radioactivity was determined by liquid scintillation counting using external standard quench corrections. Counts were converted into activity, and percentage of the injected dose per gram (%ID/g) tissue was calculated. FDG biodistribution data in mice with PC3 xenografts demonstrated doubled average %ID/g tumor tissue after administration of Acipimox compared to controls (7.21 ± 1.93 vs. 3.59 ± 1.35, P=0.02). Tumor-to-organ ratios were generally higher in mice treated with Acipimox. This was supported by PET imaging data, both semi-quantitatively (mean tumor FDG uptake) and visually (tumor-to-background ratios). In mice with CWR22Rv1 xenografts there was no effect of Acipimox on FDG uptake, either in biodistribution or PET imaging. (14)C-acetate uptake was unaffected in PC3 and CWR22Rv1 xenografts. In mice with PC3 PCa xenografts, acute administration of Acipimox increases tumor uptake of (18)F-FDG with general improvements in tumor-to-background ratios. Data indicate that administration of Acipimox prior to (18)F-FDG PET scans has potential to improve sensitivity and specificity in patients with castration-resistant advanced PCa.

Regional PET/CT after water gastric inflation for evaluating loco-regional disease of gastric cancer

ObjectiveWe aimed to improve diagnostic accuracy of 18F-fluoro-2-deoxyglucose (FDG) PET/CT for gastric cancer with water gastric inflation. Materials and methods44 gastric cancer patients (M:F=30:14, age±std=62.1±14.5y) were enrolled before surgery. Fifty minutes after injection of FDG (0.14mCi/kg body weight), whole body PET/CT was performed first and then regional PET/CT over gastric area was obtained 80min post FDG injection after water gastric inflation. Diagnostic accuracies for loco-regional lesions were compared between whole body and regional PET/CT. Results48 primary tumors (23 EGC and 25 AGC) and 348 LN stations (61 metastatic and 287 benign) in 44 patients were investigated. Primary tumor sensitivity of whole body PET/CT (50%=24/48) was significantly improved by regional PET/CT (75%=36/48, p<0.005). Sensitivity of whole body PET/CT (24.6%=15/61) for LN metastasis was also significantly improved by regional PET/CT (36.1%=22/61, p<0.01), whereas specificity of whole body PET/CT (99.3%=285/287) was not compromised by regional PET/CT (98.3%=282/287, p>0.05). Higher primary tumor FDG uptake in regional PET/CT indicated shorter progress-free survival (p=0.0003). ConclusionDiagnostic accuracy of whole body PET/CT for loco-regional disease of gastric cancer could be significantly improved by regional PET/CT after water gastric inflation and prognosis could be effectively predicted by primary tumor FDG uptake in regional PET/CT.

Inhibition of Rapamycin-Induced AKT Activation Elicits Differential Antitumor Response in Head and Neck Cancers

The PI3K/AKT/mTOR pathway is an important signaling axis that is perturbed in majority of cancers. Biomarkers such as pS6RP, GLUT1, and tumor FDG uptake are being evaluated in patient stratification for mTOR pathway inhibitors. In the absence of a clear understanding of the underlying mechanisms in tumor signaling, the biomarker strategy for patient stratification is of limited use. Here, we show that no discernible correlation exists between FDG uptake and the corresponding Ki67, GLUT1, pS6RP expression in tumor biopsies from patients with head and neck cancer. Correlation between GLUT1 and pS6RP levels in tumors was observed but elevated pS6RP was noticed even in the absence of concomitant AKT activation, suggesting that other downstream molecules of PI3K/AKT and/or other pathways upstream of mTOR are active in these tumors. Using an ex vivo platform, we identified putative responders to rapamycin, an mTOR inhibitor in these tumors. However, rapamycin did not induce antitumor effect in the majority of tumors with activated mTOR, potentially attributable to the observation that rapamycin induces feedback activation of AKT. Accordingly, treatment of these tumors with an AKT inhibitor and rapamycin uniformly resulted in abrogation of mTOR inhibition-induced AKT activation in all tumors but failed to induce antitumor response in a subset. Phosphoproteomic profiling of tumors resistant to dual AKT/mTOR inhibitors revealed differential activation of multiple pathways involved in proliferation and survival. Collectively, our results suggest that, in addition to biomarker-based segregation, functional assessment of a patient's tumor before treatment with mTOR/AKT inhibitors may be useful for patient stratification.

18 F]FDG-PET imaging is an early non-invasive pharmacodynamic biomarker for a first-in-class dual MEK/Raf inhibitor, RO5126766 (CH5126766), in preclinical xenograft models

BackgroundPositron emission tomography (PET) with [2-18 F]-2-fluoro-2-deoxy-D-glucose ([18 F]FDG-PET) was acquired at multiple time-points a) to monitor the early response to RO5126766 (CH5126766) in xenograft models b) to evaluate non-invasive small animal [18 F]FDG-PET imaging as a biomarker for MEK inhibitors for translation into dose-finding studies in cancer patients and c) to explore the underlying mechanism related to FDG uptake in tumors treated with RO5126766.Methods[18 F]FDG uptake was studied in HCT116 (K-ras), COLO205 (B-raf) mutants and COLO320DM (wild type) xenografts from day 0 to 3 of RO5126766 treatment using a microPET Focus 120 and complemented with in vitro incubations, ex-vivo phosphor imaging and immunohistochemical (IHC) analyses.ResultsIn the HCT116 (K-ras) and COLO205 (B-raf) mutant xenografts, significant decreases in [18 F]FDG uptake were detected in vivo on day 1 with 0.3 mg/kg and ex vivo on day 3 with 0.1 mg/kg RO5126766. [18 F]FDG changes correlated with decreases in tumor cells proliferation (Ki-67) and with changes in expression levels of GLUT1. No effects were observed in drug resistant COLO320DM cells. The cellular fractionation and Western blotting analyses suggested that the change of [18 F]FDG uptake associated with RO5126766 is due to translocation of GLUT1 from membrane to cytosol, similar to the results reported in the literature with EGFR tyrosine kinase inhibitors, which also target the MAPK pathway.ConclusionsRO5126766 inhibition resulted in a rapid time - and dose - dependent decline in [18 F]FDG uptake in both mutant xenografts. These results strongly resemble the clinical observations obtained with MEK/Raf inhibitors support the use of preclinical [18 F]FDG-PET as a translational tool for decision support in preclinical and early clinical development of MEK inhibitors.

Correlations between F-18 FDG PET/CT and pathological findings in soft tissue lesions

To evaluate the correlations between F-18 FDG uptake imaged with PET/CT and pathological findings in soft tissue lesions. Fifty-four soft tissue lesions in 47 patients were evaluated. The correlations between the degree of FDG uptake, pathological type and grade, and MRI signal intensity and/or enhancement pattern were evaluated. Tumor FDG uptake was quantified by the maximum standardized uptake value (SUVmax). Thirty-one lesions were malignant and twenty-three lesions were benign. The difference between SUVmax in the malignant and benign groups was statistically significant (p<0.001). Malignant myxoid lesions and well differentiated liposarcoma showed low FDG uptake. Benign neurogenic lesions showed low FDG uptake while malignant neurogenic tumors showed high FDG uptake, and the difference between SUVmax in the benign and malignant lesions was statistically significant (p<0.001). In a neurofibromatosis type-1 patient who had multiple neurogenic tumors, FDG-PET/CT could distinguish malignant peripheral nerve sheath tumors from other benign lesions with similar MRI findings. FDG-PET/CT is useful for differentiating malignant from benign soft tissue lesions, but malignant soft tissue lesions may show various patterns on FDG-PET, and MRI may be helpful for a differential diagnosis.

Clinical Significance of 18F-fluorodeoxyglucose Positron Emission Tomography in Superficial Esophageal Squamous Cell Carcinoma

To assess the clinical usefulness and significance of (18)F-fluorodeoxyglucose positron emission tomography (FDG-PET) in superficial esophageal squamous cell carcinoma (ESCC). We examined FDG-PET for 80 consecutive patients with superficial ESCC without neoadjuvant treatment. Fifty-seven patients underwent radical esophagectomy, and 23 patients received endoscopic resection. The FDG uptake index was evaluated with clinicopathological findings, and glucose transporter 1 (Glut-1) expression in primary tumors was examined immunohistochemically. The FDG uptake in primary tumors correlated with histology, depth of tumor invasion, lymph node metastasis, lymphatic invasion, vascular invasion, and Glut-1 expression. All patients with more than 4.4 maximum standardized uptake value (SUVmax) had deeper invasion of submucosa. Among 16 patients with lymph node metastasis, only two were found to have lymph node metastasis. FDG uptake, depth of tumor invasion, lymph node metastasis, and histology were found to be prognostic factors, and histology was an independent prognostic factor. In FDG uptake-positive patients, depth of tumor invasion and histology were prognostic factors. FDG-PET is useful for diagnosing tumors with deeper invasion of submucosa and is helpful in making decisions regarding endoscopic treatment for superficial ESCC. Patients with FDG uptake-positive disease, deeper invasion of submucosa, poorly differentiated tumor, and poor prognosis should receive multimodal treatment.

Feasibility of perfusion CT technique integrated into conventional 18FDG/PET-CT studies in lung cancer patients: clinical staging and functional information in a single study

To assess the additional functional vascular information and the relationship between perfusion measurements and glucose metabolism (SUVmax) obtained by including a perfusion CT study in a whole-body contrast-enhanced PET/CT protocol in primary lung cancer lesions. Enrolled in this prospective study were 34 consecutive patients with a biopsy-proven diagnosis of lung cancer who were referred for contrast-enhanced PET/CT staging. This prospective study was approved by our institutional review board, and informed consent was obtained from all patients. Perfusion CT was performed with the following parameters: 80 kV, 200 mAs, 30 scans during intravenous injection of 50 ml contrast agent, flow rate 5 ml/s. Another bolus of contrast medium (3.5 ml/s, 80 ml, 60-s delay) was administered to ensure a full diagnostic contrast-enhanced CT scan for clinical staging. The perfusion CT data were used to calculate a range of tumour vascularity parameters (blood flow, blood volume and mean transit time), and tumour FDG uptake (SUVmax) was used as a metabolic indicator. Quantitative and functional parameters were compared and in relation to location, histology and tumour size. The nonparametric Kruskal-Wallis rank sum test was used for statistical analysis. A cut-off value of 3 cm was used according to the TNM classification to discriminate between T1 and T2 tumours (i.e. T1b vs. T2a). There were significant perfusion differences (lower blood volumes and higher mean transit time) between tumours with diameter >30 mm and tumours with diameter <30 mm (p < 0.05; blood volume 5.6 vs. 7.1 ml/100 g, mean transit time 8.6 vs. 3.9 s, respectively). Also there was a trend for blood flow to be lower in larger lesions (p < 0.053; blood flow 153.1 vs. 98.3 ml/100 g tissue/min). Significant inverse correlations (linear regression) were found between blood volume and SUVmax in tumours with diameter >30 mm in diameter. Perfusion CT combined with PET/CT is feasible technique that may provide additional functional information about vascularity and tumour aggressiveness as a result of lower perfusion and higher metabolism shown by larger lesions.

Diagnostic performance of fluorodeoxyglucose-positron emission tomography/computed tomography combined with ultrasonography-guided fine needle aspiration cytology for identifying axillary lymph node status in patients with breast cancer

AimThe aim of this study was to assess the diagnostic performance of fluorodeoxyglucose-positron emission tomography/computed tomography (FDG-PET/CT) in combination with ultrasonography-guided fine needle aspiration cytology (US-guided FNAC) for the preoperative diagnosis of axillary lymph node (ALN) metastases in patients with breast cancer. Materials and methodsA total of 318 patients with breast cancer were recruited retrospectively. Some of the cases that underwent neoadjuvant chemotherapy (NAC) were included. The sensitivity and specificity of FDG-PET/CT were calculated. We assessed the relationship between the combined results for US-guided FNAC with FDG-PET/CT and the pathological ALN status. ResultsA total of 271 patients underwent FDG-PET/CT. Of these patients, 41 underwent US-guided FNAC. The sensitivity and the specificity of FDG-PET/CT for the cases without NAC were 18.5%, 97.1%, respectively. The sensitivity in cases with NAC was 68.2%. As a whole, the sensitivity was 40.8%.ALN metastasis was detected using US-guided FNAC in a case with a negative FDG uptake in the ALN. The T stage was T2 in the case and the FDG uptake at the primary site was poor. ConclusionFDG-PET/CT has a good specificity for ALN metastasis, although its sensitivity is limited, especially in early-stage cases. In cases with a negative FDG uptake in the ALN, US-guided FNAC may play a role in the detection of lymph node metastasis when the primary tumor size is large and the FDG uptake in the primary tumor is low.

Postinterventional Tumor Necrosis Predicts Recurrence-Free Long-Term Survival in Liver Transplant Patients with Advanced Hepatocellular Carcinoma on Clinical Staging

Background: There is some evidence that a subset of patients with advanced HCC on clinical staging may, nonetheless, benefit from liver transplantation. The role of pretransplant interventional bridging treatment (IBT) for identifying adequate liver transplant candidates with HCC beyond the Milan criteria is still undefined. The aim of this trial was, therefore, to evaluate the value of IBT induced tumor necrosis on recurrence-free long-term survival in liver transplant patients with advanced HCC. Furthermore, we aimed at identifying pretransplant available clinical parameters that may predict histopathological response to IBT, and thereby, be useful for selecting adequate liver transplant candidates. Patients and methods: A total of 93 patients with HCC were included in this trial. 18F-FDG positron emission tomography (PET) has been performed in all of them pre-LT, classifying patients in PET− (no increased FDG tumor uptake on PET) and PET + (increased FDG tumor uptake on PET). If being eligible, patients underwent pretransplant IBT by transarterial chemoembolization (TACE) or radiofrequency ablation (RFA). Clinical response to IBT was assessed by repeat CT scans (RECIST criteria). Macromorphologic tumor staging was based on CT/MRI. Explant livers were histopathologically examined to determine variables of macromorphology, vascular and lymphatic invasion invasion, grading and grade of post-IBT tumor necrosis. Patients with a 50%-100% tumor necrosis were defined to be histological responders, while tumor necrosis rate < 50% indicated histological non-response to IBT. The impact of clinical and histopathologic parameters on clinical outcome was evaluated in uni- and multivariate analysis. Results: Current overall follow-up is ranging between 5 and 162 months posttransplantation (mean: 64.3 ± 44.2 months). Finally, 59 liver transplant patients (63.4%) have received IBT, predominantly TACE. Overall, 21 patients developed tumor recurrence post-LT (22.6%), 11 patients in the IBT-group (18.6%) and 10 patients in the non-IBT-population (29.4%). Histologic responders had a significantly better recurrence-free survival rate after 5 years than histologic non-responders (96% versus 21%; P < 0,001). Histologic response to IBT resulted in a 5-year recurrence-free survival of 80% in Milan Out patients, which was comparable to Milan In recipients (87%), but significantly better than in histologically non-responding Milan Out recipients (0%; P < 0,001). In multivariate analysis, histologic response to IBT was identified as the only independent predictor of recurrence-free long-term survival (hazard ratio 53.3; P < 0.001). In multivariate logistic regression, pretransplant PET- status was assessed as the only independent clinical parameter predicting histologic response to IBT (odds ratio 12.4; P < 0.001). Conclusion: Data of our trial indicate that liver transplant patients with HCC should undergo pretransplant IBT, if being eligible, aiming at extended tumor necrosis. Patients with advanced HCC on clinical staging may, thereby, achieve excellent recurrence-free lomg-term survival. Pretransplant PET evaluation is useful for identifying those patients that may undergo successful IBT. This could be useful for a reasonable extension of liver transplant criteria.

Relationship between 18F-fluorodeoxyglucose uptake in primary lesions and clinicopathological characteristics of esophageal squamous cell carcinoma patients

The aim of this study, was to investigate the relationship between 18F-fluorodeoxyglucose (18F-FDG) uptake in primary tumors and the clinicopathological characteristics of esophageal squamous cell carcinoma (ESCC) patients. Patients with histopathologically diagnosed ESCC who had received a pre-therapeutic 18F-FDG positron emission tomography-computed tomography (PET-CT) scan were enrolled in the study. The maximum standardized uptake value (SUVmax) and the length of the primary tumor were measured by PET-CT. The clinical tumor-node-metastasis (TNM) stage was determined mainly by PET-CT images according to the American Joint Committee on Cancer (AJCC) staging system, 2002. A significant difference was observed in SUVmax between the length and T stage of the primary tumor (P=0.000 and P=0.017, respectively), but not in the grade of tumor differentiation (P=0.383), clinical stage (P=0.583), N staging (P=0.387), M staging (P=0.886), patient age (P= 0.752) or gender (P=0.233). There was a significant positive correlation between the SUVmax and the length of the tumor (r=0.456, P=0.000) and the depth of invasion of the primary tumor (r=0.257, P=0.006). After controlling for length, no statistically significant correlation was found between T stage and SUVmax (r=0.074, P=0.537). In conclusion, these findings suggest that tumor length influences FDG uptake in ESCC tumors, and that the T stage of the primary tumor is not significantly correlated with the SUVmax after controlling for length. However, we did not find a significant correlation between the SUVmax and primary tumor differentiation and clinical stage. These data provide important information for the management of ESCC.

Correlation Between Proliferation Activity, Glucose Metabolism, and Tumor Volume in Patients With Cervical Cancer, Measured by 18F-FLT-PET and 18F-FDG-PET -- Preliminary Results

PET/CT studies can provide various information related to tumor molecular activity. Glucose metabolism and proliferation are well known factors, which have a significant impact on treatment planning, treatment response and patients prognosis. The aim of the study was to compare pretreatment tumor volume, FDG, and FLT uptake in the cervix cancer tumor before radiation therapy planning.

18F‐FDG Uptake at Initial Staging of the Adrenocortical Cancers: A Diagnostic Tool but Not of Prognostic Value

Adrenocortical carcinoma (ACC) is a rare cancer for which little level evidence exists to guide management. (18)F-FDG PET ((18)F-fluorodeoxyglucose positron emission tomography) is an increasingly used diagnostic tool in patients with suspicious or indeterminate adrenal tumors. In some other solid tumors, (18)F-FDG PET may offer prognostic information that can guide optimal patient treatment. The aim of the present study was to evaluate whether preoperative (18)F-FDG PET based on SUVs assessments has a prognostic value in ACC patients. A retrospective analysis was performed in patients who underwent (18)F-FDG PET/CT for the evaluation of ACC. Inclusion criteria were an unequivocal diagnosis of ACC; all data from primary diagnosis available; (18)F-FDG PET/CT performed prior to surgery or other treatment of the primary tumor; a minimum of 6-months follow-up for surviving patients. All (18)F-FDG PET/CT procedures were reinterpreted in a blind fashion. Thirty-seven patients (23 without metastasis [M0], 14 with metastasis [M1]) fulfilled the study criteria. Median uptake values were tumor standardized uptake values (SUV)(max) = 11 (range: 3-56) and a tumor/liver SUV(max) ratio = 4.2 (range: 1.3-15). Median follow-up was 20 months. Although classic risk factors (tumoral stage, Weiss score) were associated with poor outcome, there was no correlation between primary tumor FDG uptake with overall survival (OS) and disease free survival (DFS) in M0 patients and with overall survival in M1 patients. (18)F-FDG uptake correlated inconsistently with sinister histological features, such as atypical mitoses or necrosis. At initial staging, primary tumor FDG uptake in ACC patients does not correlate with OS and DFS at 2 years. Patient prognosis and treatment strategy should not be based on uptake values.

1296P - Radical Treatment of Non-Small Cell Lung Cancer Patients with Synchronous Oligometastases: Long-Term Results of a Prospective Phase II Trial (NCT01282450)

ABSTRACT Background Stage IV non-small cell lung cancer (NSCLC) patients with oligometastases ( Methods Prospective single-arm phase II trial. Main inclusion criteria: pathological proven NSCLC stage IV with less than 5 metastases at primary diagnosis, amendable for radical local treatment (surgery or radiotherapy). The study is listed in clinicaltrials.gov number NCT01282450. Results 39 patients (18 males, 21 females) with a mean age of 62.1 ± 9.2 years, range 44-81) were analysed. 29 (74 %) had “local” stage III; 17 (44 %) brain, 7 (18 %) bone and 4 (10 %) adrenal gland metastases. 34 (87 %) had a single metastatic lesion. 37 (95 %) of patients received chemotherapy as part of their primary treatment. Median overall survival (OS) was 13.5 months (95 % CI 7.6-19.4); 1-, 2- and 3-year OS 56.4 %, 23.3 % and 17.5 %, respectively. Median progression-free survival (PFS) was 12.1 months (95 % CI 9.6-14.3); 1-year PFS was 51.3 %, both 2- and 3 year PFS 13.6 %. Only 2 patients (5 %) had a local recurrence. No patient or tumour parameter, including volume and FDG uptake was significantly correlated with OS or PFS. The treatment was well tolerated. Conclusion In this phase II study, long-term PFS was found in a subgroup of NSCLC patients with synchronous oligometastases when treated radically. Identification of this favourable subgroup before therapy is needed. Disclosure All authors have declared no conflicts of interest.

Preclinical Evaluation of a Novel c-Met Inhibitor in a Gastric Cancer Xenograft Model Using Small Animal PET

Here, we describe the efficacy of the novel small molecule c-Met inhibitor BAY 853474 in reducing tumor growth in the Hs746T gastric cancer xenograft model and tested the suitability of 2-deoxy-2-[(18)F]fluoro-D-glucose ([(18)F]FDG) versus 3'-deoxy-3'-18F-fluorothymidine ([(18)F]FLT) for response monitoring in a gastric cancer xenograft mouse model using small animal PET. The c-Met inhibitor or vehicle control was administered orally at various doses in tumor-bearing mice. Glucose uptake and proliferation was measured using PET before, 48 and 96h after the first treatment. The PET data were compared to data from tumor growth curves, autoradiography, Glut-1 and Ki-67 staining of tumor sections, and biochemical analysis of tissue probes, i.e., c-Met and ERK phosphorylation and cyclin D1 levels. BAY 853474 significantly reduces tumor growth. [(18)F]FDG uptake in Hs746T tumors was significantly reduced in the groups receiving the drug, compared with the control group. The [(18)F]FLT uptake in the tumor tissue was completely absent 96h after treatment. Autoradiographic, immunohistochemical, and biochemical analyses confirmed the PET findings. Treatment with the c-Met inhibitor did not affect body weight or glucose levels, and no adverse effects were observed in the animals. These preclinical findings suggest that clinical PET imaging is a useful tool for early response monitoring in clinical studies.

Overexpression of hexokinase-2 in giant cell tumor of bone is associated with false positive in bone tumor on FDG-PET/CT

The aim of the current study was to evaluate the usefulness of maximum standardized uptake value (SUV(max)) in 2-deoxy-2-F(18)-fluoro-D-glucose positron emission tomography combined with computed tomography (18F-FDG-PET/CT) for preoperative differential diagnosis between benign and malignant bone tumors. Seventy-nine patients with bone tumors were examined by FDG-PET prior to histopathological diagnosis. The SUV(max) was calculated and compared between benign and malignant lesions, and among different histopathological subgroups, to identify false-positive histological subtypes. There was a statistically significant difference in the SUV(max) of benign (3.7 ± 3.3; n = 17) and malignant (5.3 ± 3.3; n = 62) bone tumors. However, receiver operating characteristic curve analysis revealed the poor accuracy of this distinction. The cut-off value was determined to be 2.6, while the value of sensitivity and specificity was calculated to be 74.2 and 64.7 %, respectively. Giant cell tumor of bone (9.0 ± 2.0; n = 5) displayed a higher SUV(max) than osteosarcoma (4.2 ± 2.3; n = 18). Immunohistochemical analysis demonstrated that markers of these cancers, hexokinase-2 (HK-2) and glucose transporter type 1 (GLUT-1), supported our findings. The poor accuracy of SUV(max) in 18F-FDG-PET/CT in distinguishing malignant from benign bone tumors was confirmed; some benign bone tumors showed high FDG uptake. Giant cell tumor of bone was a major false-positive histopathological subtype of bone tumors, showing high FDG accumulation. HK-2 contributed significantly to FDG uptake, whereas GLUT-1 appeared to play no role in FDG uptake in giant cell tumor of bone.

FDG-PET is a good biomarker of both early response and acquired resistance in BRAFV600 mutant melanomas treated with vemurafenib and the MEK inhibitor GDC-0973

BackgroundThe BRAF inhibitor, vemurafenib, has recently been approved for the treatment of metastatic melanoma in patients harboring BRAFV600 mutations. Currently, dual BRAF and MEK inhibition are ongoing in clinical trials with the goal of overcoming the acquired resistance that has unfortunately developed in some vemurafenib patients. FDG-PET measures of metabolic activity are increasingly employed as a pharmacodynamic biomarker for guiding single-agent or combination therapies by gauging initial drug response and monitoring disease progression. However, since tumors are inherently heterogeneous, investigating the effects of BRAF and MEK inhibition on FDG uptake in a panel of different melanomas could help interpret imaging outcomes.Methods18 F-FDG uptake was measured in vitro in cells with wild-type and mutant (V600) BRAF, and in melanoma cells with an acquired resistance to vemurafenib. We treated the cells with vemurafenib alone or in combination with MEK inhibitor GDC-0973. PET imaging was used in mice to measure FDG uptake in A375 melanoma xenografts and in A375 R1, a vemurafenib-resistant derivative. Histological and biochemical studies of glucose transporters, the MAPK and glycolytic pathways were also undertaken.ResultsWe demonstrate that vemurafenib is equally effective at reducing FDG uptake in cell lines harboring either heterozygous or homozygous BRAFV600 but ineffective in cells with acquired resistance or having WT BRAF status. However, combination with GDC-0973 results in a highly significant increase of efficacy and inhibition of FDG uptake across all twenty lines. Drug-induced changes in FDG uptake were associated with altered levels of membrane GLUT-1, and cell lines harboring RAS mutations displayed enhanced FDG uptake upon exposure to vemurafenib. Interestingly, we found that vemurafenib treatment in mice bearing drug-resistant A375 xenografts also induced increased FDG tumor uptake, accompanied by increases in Hif-1α, Sp1 and Ksr protein levels. Vemurafenib and GDC-0973 combination efficacy was associated with decreased levels of hexokinase II, c-RAF, Ksr and p-MEK protein.ConclusionsWe have demonstrated that 18 F-FDG-PET imaging reflects vemurafenib and GDC-0973 action across a wide range of metastatic melanomas. A delayed post-treatment increase in tumor FDG uptake should be considered carefully as it may well be an indication of acquired drug resistance.Trial registrationClinicalTrials.gov NCT01271803