Baseline Positron Emission Tomography Research Articles

Impact of 18 f-Fluoro-Deoxyglucose Positron Emission Tomography Imaging in the Management of Mantle Cell Lymphoma

Impact of 18 F-fluoro-deoxyglucose positron emission tomography (PET) imaging has become increasingly important in recent years in the management of patients with malignant lymphomas and is recommended for the staging and response to treatment assessment of both diffuse large B-cell and Hodgkin's lymphoma. Few data on the relevance of PET in the management of patients with mantle cell lymphoma (MCL) are available so far. Then, we retrospectively investigated the PET value for initial staging, interim response and predicting outcome in patients with MCL treated in two French institutions (Dijon University Hospital and the Centre Leon Berard, Lyon).From 2004 to 2013, a total of 61 de novo MCL patients assessed by PET were included. For each patient, were collected at baseline, the whole body SUVmax site, the presence of a bone marrow (BM) uptake, total metabolic tumour volume (TMTV) and total tumour glycolysis (TLG). The interim PET response after 3 or 4 cycles of induction treatment was assessed using the Deauville score and the quantitative variation of SUV between the baseline PET and the PET performed after 4 cycles of immunochemotherapy (ΔSUV).Patient's median age was 64 years [38 - 84]. At diagnosis, 92% presented a disseminated disease (stage III-IV). Mean MCL International Prognostic Index (MIPI) was 6.09 [5.89 - 6.29]. All patients received a first-line induction treatment. Twenty-eight (46%) received an autologous stem cell transplantation as consolidation treatment and 10 (16%) a rituximab maintenance. The baseline FDG uptake intensity was low (median SUVmax: 6.93 [2.5 - 25]) leading to consider that baseline PET was informative and suitable for a further PET reassessment in 40 (93%) patients. 72% of the patients with an informative baseline PET, had a SUVmax < 10 making the metabolic quantitative analyses (TMTV, TLG, ΔSUV) uninformative. Among the 46 (75%) patients with histologically proven BM involvement, only 14% of them had BM FDG uptake. After 3 to 4 cycles of induction treatment, 27 (75%) patients achieved a negative PET. With a median follow up of 27 months, a shorter PFS was related to a disseminated disease (stage III-IV) on the basis of baseline PET (2y-PFS: 47% vs 80% p = 0.03) and an insufficient interim metabolic response according to the Deauville score (score ≥ 4) (16% vs 64% p<0.01). However, in multivariate analysis, using the MIPI, the stage and the interim PET response as covariates, only a score of Deauville ≥ 4 (p = 0.0018, HR = 32.6 IC 95% [3.7 - 286.82]) and a MIPI>=6 (p = 0.04, HR = 7.1 IC 95% [1.1 - 46]) retained an independent negative impact on PFS.FDG avidity of LCM is usually low. PET underestimates BM involvement at diagnosis in 86 % of patients, compared with cytological and histological techniques, and has no independent prognostic value. The interim metabolic response assessed using the Deauville criteria is a prognosis factor independent from MIPI in patients with MCL. DisclosuresSalles:Calistoga Pharmaceuticals, Inc.; Celgene Corporation; Genentech, Inc.; Janssen Pharmaceutica Products, L.P.; Roche: Consultancy; Celgene Corporation; Roche and Gilead Sciences: Research Funding; Celgene Corporation; Roche: Speakers Bureau. Casasnovas:Gilead: Consultancy; Takeda: Consultancy; Roche: Consultancy, Research Funding.

Prognostic significance of PET assessment of metabolic response to therapy in oesophageal squamous cell carcinoma.

Objectives:The role of maximum standard uptake value (SUVmax) at baseline and after induction chemotherapy (CT) on positron emission tomography (PET) as an imaging biomarker has not been well established in oesophageal squamous cell carcinoma (SCC). In this retrospective analysis, we investigated the prognostic significance of various PET metrics in oesophageal SCC patients treated with induction chemotherapy followed by concurrent chemoradiotherapy (CRT).Methods:A total of 57 patients were treated with CRT; 52 patients received induction chemotherapy and 10 patients underwent surgery following CRT. Scans were independently analysed by a nuclear medicine physician blinded to patient outcome. Using region of interest analysis, SUVmax and metabolic tumour volume (MTV) were calculated for the index lesion and lymph node metastases in each patient. Kaplan–Meier analysis was used to evaluate overall survival (OS), disease-free survival (DFS), local recurrence-free survival (LRFS) and distant metastasis-free survival (DMFS). Cox proportional hazards regression was used to assess correlation between outcomes and PET metrics.Results:Median follow-up for those who are alive was 4.4 years, with a median survival for all patients of 2.9 years. The 3-year OS, DFS, DMFS and LRFS rates were 47, 40, 44 and 36%, respectively. Using a pre-established cutoff of a 35% decrease in SUVmax from baseline to post-induction PET, 3-year OS for responders (⩾35% decrease from baseline) was 64%, whereas non-responders (<35% decrease from baseline) had a 3-year OS of 15% (P=0.004).Conclusions:The pre-specified 35% decrease in SUVmax after induction chemotherapy was prognostic for OS. Baseline and post-induction PET metrics provide prognostic information for oesophageal SCC.

PET imaging evaluation of [(18)F]DBT-10, a novel radioligand specific to α7 nicotinic acetylcholine receptors, in nonhuman primates.

Positron emission tomography (PET) radioligands specific to α7 nicotinic acetylcholine receptors (nAChRs) afford in vivo imaging of this receptor for neuropathologies such as Alzheimer's disease, schizophrenia, and substance abuse. This work aims to characterize the kinetic properties of an α7-nAChR-specific radioligand, 7-(1,4-diazabicyclo[3.2.2]nonan-4-yl)-2-[(18)F]-fluorodibenzo[b,d]thiophene 5,5-dioxide ([(18)F]DBT-10), in nonhuman primates. [(18)F]DBT-10 was produced via nucleophilic substitution of the nitro-precursor. Four Macaca mulatta subjects were imaged with [(18)F]DBT-10 PET, with measurement of [(18)F]DBT-10 parent concentrations and metabolism in arterial plasma. Baseline PET scans were acquired for all subjects. Following one scan, ex vivo analysis of brain tissue was performed to inspect for radiolabeled metabolites in brain. Three blocking scans with 0.69 and 1.24 mg/kg of the α7-nAChR-specific ligand ASEM were also acquired to assess dose-dependent blockade of [(18)F]DBT-10 binding. Kinetic analysis of PET data was performed using the metabolite-corrected input function to calculate the parent fraction corrected total distribution volume (V T/f P). [(18)F]DBT-10 was produced within 90 min at high specific activities of 428 ± 436 GBq/μmol at end of synthesis. Metabolism of [(18)F]DBT-10 varied across subjects, stabilizing by 120 min post-injection at parent fractions of 15-55%. Uptake of [(18)F]DBT-10 in brain occurred rapidly, reaching peak standardized uptake values (SUVs) of 2.9-3.7 within 30 min. The plasma-free fraction was 18.8 ± 3.4%. No evidence for radiolabeled [(18)F]DBT-10 metabolites was found in ex vivo brain tissue samples. Kinetic analysis of PET data was best described by the two-tissue compartment model. Estimated V T/f P values were 193-376 ml/cm(3) across regions, with regional rank order of thalamus > frontal cortex > striatum > hippocampus > occipital cortex > cerebellum > pons. Dose-dependent blockade of [(18)F]DBT-10 binding by structural analog ASEM was observed throughout the brain, and occupancy plots yielded a V ND/f P estimate of 20 ± 16 ml/cm(3). These results demonstrate suitable kinetic properties of [(18)F]DBT-10 for in vivo quantification of α7-nAChR binding in nonhuman primates.

Initial Standardized Uptake Value of Positron Emission Tomography Influences the Prognosis of Patients with Localized Gastric Adenocarcinoma Treated Preoperatively

Background: In patients with localized gastric adenocarcinoma (LGAC) who receive preoperative therapy, tools to predict response or prognosticate outcome before therapy are lacking. We used initial standardized uptake value (iSUV) of positron emission tomography (PET) to evaluate its association with overall survival (OS). Methods: We identified 60 patients with confirmed LGAC who were treated with preoperative chemoradiation and had a baseline PET in addition to other routine staging. Fisher's exact test and Wilcoxon's rank sum test were used to determine the association between iSUV and other variables, and the log-rank test and Cox proportional hazards model were used for survival analysis. Results: The median iSUV was 6 (range, 0-28). The presence of signet ring cells in pretreatment biopsies correlated highly with low iSUV (≤6; p = 0.0017). Patients with a high iSUV (>6) had a longer OS compared to those with a low iSUV (≤6; p = 0.0344). iSUV was not an independent predictor (p = 0.12); however, the risk of death was reduced for patients with an iSUV >6 (hazard ratio = 0.26). Conclusion: Our novel findings show that among LGAC patients treated with preoperative chemoradiation and surgery, those with a high iSUV have longer OS than patients with a low iSUV. iSUV appears to have a predictive role in patients with LGAC when treated with preoperative chemoradiation.

Prognostic Value of Preradiotherapy 18F-FDG PET/CT Volumetrics in Limited-Stage Small-Cell Lung Cancer

BackgroundWhether 18F-fludeoxyglucose positron emission tomography (PET)/computed tomography (CT) metrics predict outcome in limited-stage (LS) small-cell lung cancer (SCLC) has not been well established; most previous reports have only analyzed maximal standardized uptake values (SUVmax). We investigated multiple pretreatment PET metrics, including SUVmax, mean SUV (SUVmean), total lesion glycolysis, and metabolic tumor volume (MTV) in LS-SCLC patients undergoing chemoradiotherapy (CRT) and correlated them with survival and disease control outcomes. Patients and MethodsAll patients received platinum-based chemotherapy and a median radiation dose of 45 Gy. Kaplan-Meier and competing-risks analyses were performed to assess the prognostic value of PET metrics with respect to overall survival (OS), distant failure (DF), disease-free survival (DFS), and locoregional failure (LRF). Univariate and multivariate analyses were performed to account for the effect of other clinical factors on outcomes. ResultsA total of 120 patients with LS-SCLC had analyzable pre-CRT PET/CTs. The median follow up was 34 months. Median OS was 26.9 months. OS was 53.2% at 2 years and 33.1% at 5 years. SUVmax, SUVmean, MTV, and total lesion glycolysis of the primary tumor were not significantly associated with OS, LRF, and DFS on univariate analysis. MTV was significantly associated with DF (P = .024) on univariate but not multivariate analysis. ConclusionThis is the largest reported series to date evaluating the prognostic value of baseline PET metrics in LS-SCLC. Neither SUVmax nor other analyzed PET metrics demonstrated significant correlation with OS or LRF. MTV was correlated with DF and DFS, but this association was no longer significant after adjustment for other clinical factors. This analysis suggests that pretreatment PET scans, even with the use of advanced metrics, do not have independent prognostic value for outcomes in LS-SCLC patients after CRT.

Dissociable rate-dependent effects of oral methylphenidate on impulsivity and D2/3 receptor availability in the striatum.

We have previously shown that impulsivity in rats is linked to decreased dopamine D2/3 receptor availability in the ventral striatum. In the present study, we investigated, using longitudinal positron emission tomography (PET), the effects of orally administered methylphenidate (MPH), a first-line treatment for attention deficit hyperactivity disorder, on D2/3 receptor availability in the dorsal and ventral striatum and related these changes to impulsivity. Rats were screened for impulsive behavior on a five-choice serial reaction time task. After a baseline PET scan with the D2/3 ligand [(18)F]fallypride, rats received 6 mg/kg MPH, orally, twice each day for 28 d. Rats were then reassessed for impulsivity and underwent a second [(18)F]fallypride PET scan. Before MPH treatment, we found that D2/3 receptor availability was significantly decreased in the left but not the right ventral striatum of high-impulse (HI) rats compared with low-impulse (LI) rats. MPH treatment increased impulsivity in LI rats, and modulated impulsivity and D2/3 receptor availability in the dorsal and ventral striatum of HI rats through inverse relationships with baseline levels of impulsivity and D2/3 receptor availability, respectively. However, we found no relationship between the effects of MPH on impulsivity and D2/3 receptor availability in any of the striatal subregions investigated. These findings indicate that trait-like impulsivity is associated with decreased D2/3 receptor availability in the left ventral striatum, and that stimulant drugs modulate impulsivity and striatal D2/3 receptor availability through independent mechanisms.

The Complementary Prognostic Role of Baseline and Interim PET in Predicting Treatment Outcome in Advanced-Stage Hodgkin Lymphoma

INTRODUCTION: We retrospectively evaluated the contribution of the positron emission tomography (PET) combined with computed tomography (PET/CT) and contrast enhanced computed tomography (ceCT) in the staging and in the prognostication of untreated advanced Hodgkin’s lymphoma (HL).METHODS: One-hundred-sixty-two HL patients from Italian, Poland and Danish centers entered this study. Treatment consisted on ABVD with or without radiotherapy. All patients were staged at baseline with ceCT and PET/CT (PET-0) and after 2 ABVD with PET/CT (PET-2). All the ceCT and FDG/PET scans were centrally reviewed. PET-2 was reported according to the 5-point Deauville scale: score 1 to 3 considered negative and score 4-5 positive.RESULTS: Patients breakdown into (a) stage I-II; (b) III or (c) IV for CeCT and PET/CT-staged patients was as follows: 49.1%, 31.0%, 19.9% and 46.6%, 21.7%, 31.7%, respectively. ceCT and PET-0 were concordant or discordant in 117 (72.2%) and 45 (27.8%) patients, respectively. Combining the PET-0 and ceCT data we demonstrated an extra-nodal sites (ENS) in 57 (35.2%) of the 162 patients. Most (27/57) extra-nodal sites (ENS) were detected by PET-0 alone while ENS were concordantly detected by ceCT and PET-0 in other 25 cases and by ceCT alone in the remaining 5 patients. These latter three patient groups showed similar 2-y EFS rates of 62%, 83% and 56%, respectively.In patients with PET/CT-documented ENS, a pathological metabolic uptake was documented, respectively, in the BM (18 cases), lung (7 cases) and in two other parenchymal sites (2 cases). Overall, the 2 and 5-year OS and EFS for the entire patient cohort were 97.4%, 97.4% and 86.6% and 82.6%, respectively. PET-2 was positive in 40 cases (25.1%) and negative in 119 (74.84%). At univariate and multivariate analyses ENS disease and a positive PET-2 were the only variables significantly affecting the EFS rates, with a HR of 3.9 (95% CI:1.62-9.36; P=.002) and 2.9 (95% CI:1.82-4.52; P<.00001), respectively. Combining these two variables we stratified the patients in 4 risk groups with significantly different EFS rates (P<.00001). Group 1 (i.e. nodal disease and a negative PET-2) identified patients with a very favorable 3-y EFS (98%), whereas group 4 (i.e. presence of ENS disease and a positive PET-2) had a very dismal prognosis, with a 3-y EFS of 0%. Group 2 (i.e. presence of ENS and a negative PET-2) and group 3 (nodal disease and a positive PET-2) identified patients at intermediate risk. CONCLUSIONPresent findings indicate that (1) PET/CT is mandatory for baseline HL staging while CeCT is of limited value. (2) The combination of ENS and PET-2 in a integrated prognostic model was even more predictive than PET-2 alone on treatment outcome in ABVD-treated HL patients. DisclosuresNo relevant conflicts of interest to declare.

PET-CT Defined Focal Lesions at Baseline and Day 7 Predict Outcome in GEP 70 Defined High Risk Multiple Myeloma Patients

▪Introduction:Fluoro-deoxy-glucose (FDG) positron emission tomography (PET) scanning is an important state-of-the-art imaging tool in the initial workup of patients with multiple myeloma (MM). We evaluate the impact of PET focal lesions (FL) at baseline (BL), 7 days after starting induction therapy (D7) and prior to first autologous transplant (pre-ACST) in gene expression profiling (GEP 70) defined high risk (HR) multiple myeloma (MM) patients.Patients and methods:48 GEP 70 HR MM patients were treated uniformly on IRB approved protocol consisting of tandem transplants with dose reduced Mel-80-VRD-PACE (melphalan, velcade, revlimid, dexamethasone, cisplatin, adreamycin, cyclophosphamide and etoposide) and interspersed Mel-20-VTD-PACE (melphalan, velcade, thalidomide, dexamethasone, cisplatin, adreamycin, cyclophosphamide and etoposide) consolidation and VRD (velcade, revlimid, dexamethasone) maintenance. PET examinations were performed at (BL), D7 and pre-ASCT, enumerating FDG-avid FL, their SUV max and extra-medullary disease (EMD).Of the 48 GEP 70 HR patients, 39 had BL, 28 had D7 and 42 had pre-ASCT PET examinations. 20 patients had examinations at all 3 time points. At BL, there were 24 (50%) patients with B2M >5.5mg/L and 26 (54%) with albumin <3.5g/dL. Metaphase cytogenetic abnormalities were documented in 36 (75%) patients, including deletion 13/hypodiploidy in 30 (63%). EMD was present in 3 (8%) patients, 28 (58%) had diffuse SUV <= 2 (median 2.4; range 1.4 to 9.5) and 14 (29%) had FL max SUV >3.9 (median 4.6; range 1.6 to 14.4).Results:From BL, the 3-yr PFS estimate was 46% for the group with no FL and 29% for those with FL (Figure 1a). The corresponding PFS data for the D7 was 53% for no FL at D7 as opposed to 11% for those with FL (Figure 1b), and for pre-ASCT it was 34% for no FL and 33% for those with FL (Figure 1c). Joint consideration of BL and D7 landmark revealed 3-yr PFS of 54% for those with no FL at BL, compared to 40% for those with resolution of BL FL by D7 and 18% for those whose FL did not resolve (log rank p-value=0.09), confirming the significance of FL resolution.Cox regression of PFS revealed that those with FL at BL had 2.34 times the risk of progression or death compared to those with no FL at BL (p=0.075), while those with FL at D7 had 3.27 times the risk (p=0.033). Diffuse SUV and SUV max had no impact on PFS at the three time points. [Display omitted] [Display omitted] [Display omitted] Fig 1a- PFS from baseline PET Fig 1b- PFS from D7 PET Fig 1c- PFS from pre-ASCT PETConclusion:The prognosis of GEP 70 HR MM is dominantly affected by BL indicators of MM metabolism, as revealed by FDG uptake in FL. Our analysis in HR GEP70 MM patients confirms that early suppression of FL by D7 was key to improved PFS. MM patients who had absence of FL resolution from BL to D7 had poorer PFS and are candidates for early therapy change. DisclosuresMorgan:Celgene Corp: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees; Myeloma UK: Membership on an entity’s Board of Directors or advisory committees; International Myeloma Foundation: Membership on an entity’s Board of Directors or advisory committees; The Binding Site: Membership on an entity’s Board of Directors or advisory committees; MMRF: Membership on an entity’s Board of Directors or advisory committees. Zangari:Norvartis: Membership on an entity’s Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding. van Rhee:Janssen: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Millenium: Membership on an entity’s Board of Directors or advisory committees; Sanofi: Membership on an entity’s Board of Directors or advisory committees.

Positron Emission Tomography (PET) Guided Therapy of Aggressive Lymphomas – a Randomized Controlled Trial Comparing Different Treatment Approaches Based on Interim PET Results (PETAL Trial)

Introduction: The predictive value of 18-fluorodeoxyglucose PET performed after a few cycles of chemotherapy has been questioned in aggressive lymphomas. Inconsistent study results, however, may be due to procedural differences rather than an inability of the method to predict outcome. Whether changing treatment in pts. with an unfavorable interim PET (iPET) improves outcome, has not been determined in a randomized study. The PETAL trial (EudraCT 2006-001641-33, NCT00554164) was initiated to resolve these issues.Methods: Pts. aged 18 to 80 yrs. with newly diagnosed aggressive lymphomas and a positive baseline PET received 2 cycles of rituximab (R), cyclophosphamide (C), doxorubicin (H), vincristine (O) and prednisone (CHOP) followed by iPET. The conditions of iPET were strictly defined: 3-week interval between the 2nd R-CHOP cycle and iPET to avoid inflammatory reactions (Eur J Nucl Med Mol Imaging 30:682, 2003), no G-CSF after the 2nd R-CHOP cycle to avoid altered glucose biodistribution (J Nucl Med 47:950, 2006), standardized uptake value (SUV)-based PET interpretation to improve objectivity of evaluation (favorable iPET response: reduction of maximum SUV by > 66 % compared to baseline; J Nucl Med 48:1626, 2007). Pts. with CD20-positive lymphomas and a favorable iPET were randomized to receive 4 additional cycles of R-CHOP or the same treatment plus 2 extra doses of R (Part A of the trial). Pts. with an unfavorable iPET were randomized to continue standard R-CHOP for 6 additional cycles or receive 6 blocks of a more complex and more intensive protocol yielding excellent results in Burkitt and other aggressive lymphomas (Part B). Its main components were hyperfractionated alkylating agents (C, ifosfamide) and high doses of methotrexate and cytarabine, with dose reductions in pts. > 60 yrs. Other constituents were R, H, O, vindesine, etoposide and dexamethasone (Blood 120: abstr 667, 2012). R was omitted in pts. with CD20-negative lymphomas. Sample size was based on the empirically derived assumption that treatment failure after 2 yrs. (TF: progression, relapse, treatment discontinuation due to toxicity, start of alternative therapy, death of any cause) could be improved from 80 % to 90 % in Part A and from 30 % to 45 % in Part B (alpha=0.05, power=0.8). Complete remission (CR), overall survival (OS) and toxicity were secondary endpoints.Results: From 2007 to 2012 926 pts. were recruited by 57 participating oncological centers and analyzed by PET in 23 nuclear medicine institutions. With a median follow-up of 33 months 853 pts. are currently evaluable in the intent-to-treat population. 757 pts. had CD20-positive B cell lymphomas (80 % diffuse large B cell [DLBCL], 3 % primary mediastinal B cell, 8 % follicular lymphoma grade 3), 13 had CD20-negative B cell lymphomas and 83 had peripheral T cell lymphomas. Interim PET was favorable in 746 pts. (87 %) and unfavorable in 107 (13 %). It was highly predictive of outcome, time to TF being significantly higher in Part A than Part B (2-year probability: 79 % vs. 47 %; hazard ratio (HR) for B 3.4, 95 % confidence interval (CI) 2.6 – 4.6, p<0.0001; Figure). On multivariate analysis iPET response, International Prognostic Index and B vs. T cell lineage independently predicted TF. Interim PET was also predictive of OS (HR 3.9, CI 2.7 – 5.7, p<0.0001). In pts. with CD20-positive lymphomas and a favorable iPET, addition of 2 extra doses of R failed to improve TF (HR for 2 extra doses 1.2, CI 0.8 – 2.1) and all secondary endpoints. Likewise, in pts. with an unfavorable iPET response, a switch from R-CHOP to the Burkitt-type regimen showed no beneficial effect on TF (HR for Burkitt 1.6, CI 0.9 – 2.7), CR rate (50 % vs. 31 %, p=0.10) or OS (HR 1.0, CI 0.5 – 2.1). Similar results were obtained, when the analysis was restricted to DLBCL, and for covariate adjusted Cox regression of all survival endpoints. Although treatment related deaths (3 vs. 2 pts.) were comparable in both treatment arms, the Burkitt protocol was associated with more severe grade 3/4 leukopenia (84 % vs. 67 %, p=0.043), thrombocytopenia (63 % vs. 35 %, p=0.007) and mucositis (41 % vs. 12 %, p=0.002).Conclusion: Applying strict rules to the procedure and its interpretation iPET proved highly predictive of outcome in pts. with aggressive lymphomas in this large multicenter trial. Because switching to a more aggressive protocol failed to improve outcome, our results do not support a change in cytotoxic regimen in poor iPET responders. [Display omitted] [Display omitted] DisclosuresDuehrsen:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Klapper:Roche: Research Funding. Hoelzer:Amgen: Speakers Bureau; Medac: Membership on an entity’s Board of Directors or advisory committees.

Small-animal PET demonstrates brain metabolic change after using bevacizumab in a rat model of cerebral ischemic injury.

To evaluate the effect of bevacizumab on cerebral ischemia, we used 2-deoxy-2-(18)F-fluoro-D-glucose ((18)F-FDG) small-animal positron emission tomography (PET) in the middle cerebral artery occlusion (MCAO) rat model. After baseline neurologic function tests and PET studies, MCAO Sprague-Dawley rats received bevacizumab or normal saline (controls). Weekly PET imaging and neurologic function tests showed that the (18)F-FDG accumulation in the bevacizumab group was similar to that in the controls during the first 2 weeks, but lower than in controls at weeks 3 and 4. However, no difference was found in neurological scores between the groups. The number of von Willebrand factor-positive cells in the bevacizumab group was lower than that in controls. The expression of vascular endothelial growth factor was higher than in controls at week 4. These results suggested that bevacizumab does not influence functional recovery in this model of cerebral ischemia during a 4-week period, but inhibits vascular formation and metabolic recovery, which may be considered in cancer patients with a recent ischemic stroke.

Prognostic Significance Of FDG-PET Metrics In Esophageal Squamous Cell Carcinoma

Fluorodeoxyglucose (FDG) avidity as measured by the maximum standard uptake value (SUV) at baseline and after induction chemotherapy (CT) on positron emission tomography (PET) imaging has been shown to be prognostic in patients with esophageal adenocarcinoma; however, the role of FDG PET in esophageal squamous cell carcinoma (SCC) has not been well established. We investigated the prognostic significance of various FDG metrics in a cohort of esophageal SCC patients treated with chemoradiation (CRT). We identified 58 esophageal SCC patients with fully analyzable FDG-PET data at baseline, post-induction CT and post-CRT. All patients received concurrent CRT, of which 53 patients also received induction CT and 11 patients underwent surgery following CRT. Median radiation dose was 5040 cGy (range 5040-5600 cGy). All scans were independently analyzed by a nuclear medicine physician blinded to patient outcome. Using region of interest analysis, max and mean standardized uptake value (SUVmax, SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were calculated for the index lesion and nodes in each patient. Kaplan-Meier analysis was used to evaluate overall survival (OS), disease free survival (DFS), local recurrence free survival (LRFS), and distant metastasis free survival (DMFS). The log-rank test was used to assess correlation between outcomes and FDG-PET metrics. Median follow-up was 3.8 years, with median survival for all patients of 2.9 years. The 3-year OS, DFS, DMFS, and LRFS rates were 49%, 47%, 43%, and 42%, respectively. Using a pre-established cutoff of a 35% decrease in SUVmax from baseline to post-induction PET, 3 yr OS for responders (≥ 35% decrease from baseline) was 52%, whereas nonresponders (< 35% decrease from baseline) had a 3 yr OS of 21% (p = 0.046). Baseline SUVmax, SUVpeak, MTV, and TLG were significantly associated with OS, LRFS, DFS, and DMFS. On post-induction PET, SUVmax, SUVpeak, MTV, and TLG were significantly associated with OS, LRFS, DMFS, and DFS. After completion of CRT, only SUVmax was prognostic for OS, while only SUVmax and TLG were prognostic for DMFS. Baseline and post-induction PET metrics were most prognostic in patients with esophageal SCC. Our data confirms a 35% decrease in SUVmax after induction CT, as established in the adenocarcinoma literature, is also a significant predictor of OS in esophageal SCC patients. This analysis demonstrates that in addition to SUVmax, volumetric PET metrics may also be useful in predicting outcomes.Oral Scientific Abstract 12; TableHazard Ratio for significant PET-metrics based on clinical outcomesHazard Ratio for OS (p-value)Hazard Ratio for DFS (p-value)Hazard Ratio for DMFS (p-value)Hazard Ratio for LRFS (p-value)Baseline SUVmax1.105 (p < 0.001)1.089 (p = 0.002)1.131 (p < 0.001)1.089 (p < 0.001)Post Induction CT SUVmax1.111 (p < 0.001)1.105 (p = 0.001)1.131 (p < 0.001)1.082 (p = 0.004)Post-CRT SUVmax1.161 (p = 0.049)Not Significant1.174 (p = 0.023)Not SignificantBaseline SUVpeak1.115 (p < 0.001)1.115 (p < 0.001)1.152 (p < 0.001)1.095 (p = 0.001)Post Induction CT SUVpeak1.171 (p < 0.001)1.146 (p = 0.003)1.182 (p < 0.001)1.122 (p = 0.005)Baseline MTV1.018 (p = 0.002)1.016 (p = 0.009)1.023 (p < 0.001)1.014 (p = 0.012)Post Induction CT MTV1.02 (p = 0.001)1.017 (p = 0.015)1.024 (p < 0.001)1.015 (p = 0.014)Baseline TLG1.001 (p = 0.021)1.001 (p = 0.023)1.002 (p = 0.001)1.001 (p = 0.044)Post Induction CT TLG1.002 (p = 0.003)1.002 (p = 0.034)1.002 (p = 0.001) and 1.015 (p = 0.043) for Post-CRT TLG1.001 (p = 0.024) Open table in a new tab

Phase II study of first-line 131I-rituximab radioimmunotherapy in follicular non-Hodgkin lymphoma and prognostic 18F-fluorodeoxyglucose positron emission tomography

First-line 131I-anti-CD20 radioimmunotherapy of indolent non-Hodgkin lymphoma (NHL) achieves durable remission with low toxicity. The phase II INITIAL study comprised 68 patients with follicular NHL followed up to 7 years (median 4 years) after outpatient 131I-rituximab radioimmunotherapy (RIT) in conjunction with rituximab, followed by maintenance therapy for 1 year. Baseline and 3-month 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) imaging, analyzed according to Deauville criteria, was used to evaluate response and predict prognosis. The overall response rate at 3 months was 99%, with 88% achieving Deauville category 1–3. These satisfactory responders did not reach median time-to-next-treatment, versus a median of 29 months for a category 4–5 response (p < 0.0001). Grade IV hematological toxicity (9%) was self-limited without clinical sequelae. 131I-rituximab radioimmunotherapy in newly diagnosed, advanced stage, symptomatic follicular NHL is an effective, practical and affordable alternative to existing conventional chemotherapies, with lower toxicity and durable remissions. Response assessment at 3 months by 18F-FDG PET Deauville five-point scale permits prognostic stratification.

Baseline Metabolic Tumor Volume and Total Lesion Glycolysis Are Associated With Survival Outcomes in Patients With Locally Advanced Pancreatic Cancer Receiving Stereotactic Body Radiation Therapy

Although previous studies have demonstrated the prognostic value of positron emission tomography (PET) parameters in other malignancies, the role of PET in pancreatic cancer has yet to be well established. We analyzed the prognostic utility of PET for patients with locally advanced pancreatic cancer (LAPC) undergoing fractionated stereotactic body radiation therapy (SBRT). Thirty-two patients with LAPC in a prospective clinical trial received up to 3 doses of gemcitabine, followed by 33 Gy in 5 fractions of 6.6 Gy, using SBRT. All patients received a baseline PET scan prior to SBRT (pre-SBRT PET). Metabolic tumor volume (MTV), total lesion glycolysis (TLG), and maximum and peak standardized uptake values (SUVmax and SUVpeak) on pre-SBRT PET scans were calculated using custom-designed software. Disease was measured at a threshold based on the liver SUV, using the equation Livermean + [2 × Liversd]. Median values of PET parameters were used as cutoffs when assessing their prognostic potential through Cox regression analyses. Of the 32 patients, the majority were male (n=19, 59%), 65 years or older (n=21, 66%), and had tumors located in the pancreatic head (n=27, 84%). Twenty-seven patients (84%) received induction gemcitabine prior to SBRT. Median overall survival for the entire cohort was 18.8 months (95% confidence interval [CI], 15.7-22.0). An MTV of 26.8 cm(3) or greater (hazard ratio [HR] 4.46, 95% CI 1.64-5.88, P<.003) and TLG of 70.9 or greater (HR 3.08, 95% CI 1.18-8.02, P<.021) on pre-SBRT PET scan were associated with inferior overall survival on univariate analysis. Both pre-SBRT MTV (HR 5.13, 95% CI 1.19-22.21, P=.029) and TLG (HR 3.34, 95% CI 1.07-10.48, P=.038) remained independently associated with overall survival in separate multivariate analyses. Pre-SBRT MTV and TLG are potential predictive factors for overall survival in patients with LAPC and may assist in tailoring therapy.

Abstract P4-01-05: 3’-deoxy-3’-[18F]fluoro-thymidine (18F-FLT) positron emission tomography (PET): An accurate and effective tool for assessing tumor response in breast cancer

Abstract Objectives : A French multicenter study was promoted by the national French cancer federation (Unicancer R&amp;D) to assess the potential of [18F]FLT (positron emission tomography (PET) biomarker of proliferation)to manage breast cancer neoadjuvant chemotherapy (NAC). The main objective was to compare changes in tumor [18F]FLT uptake to histopathological changes induced by NAC, assuming an arrest of tumor growth related to the effectiveness of NAC. Methods : 97 patients (age 48.6 +/- 10.2 y.) were included in 13 nuclear medicine centers. All patients were eligible to anthracycline-based NAC for a de novo unifocal breast cancer (ductal n = 84, lobular = 11, other type = 2; stage II n = 75, stage III n = 21 et stage IV n = 1). 90 patients underwent a baseline PET before the onset of NAC (PET1) and a final PET after the end of NAC and before surgery (PET3). PET acquisitions were performed 60±7min after FLT injection. SUVmax (maximum standardized uptake value), SUVpeak (1 cm3 ROI including pixel max) and SUV41 (isocontour 41% of pixel max) were computed. Changes in SUV on PET3 vs PET1 were analyzed in relation to histopathological findings at the end of NAC (Sataloff criteria). Results : Tumor FLT uptake decreased markedly between TEP1 and TEP3 (SUVmax = 6.2±4.8 vs 1.3±1.2 respectively; SUVpeak = 4.6±3.2 vs 0.9±0.9; SUV41 = 3.6±2.8 vs 0.8±0.7). Total or near-total therapeutic effect (grade A) were obtained in 20 patients, more than 50% therapeutic effect but less than total or near-total effect (grade B) in 37 patients, less than 50% therapeutic effect but visible effect (grade C) in 22 patients, or no therapeutic effect (grade D) in 11 patients. SUVmax decreased dramatically (87.5%) to background levels in all patients with a complete response (grade A). Overall, changes in SUV differed depending on the type of histological response (p&amp;lt;0.01) i.e. SUVmax changes were more pronounced as pathological responses were good: 61% for grade D; 65.7% grade C and 69.8% grade B. The same results were obtained with the two other SUV types. Conclusions : Pathologic response to NAC in breast cancer can be assessed accurately by FLT. Citation Information: Cancer Res 2013;73(24 Suppl): Abstract nr P4-01-05.

Quantitative FDG PET/CT in the community: Experience from interpretation of outside oncologic PET/CT exams in referred cancer patients

Tertiary care institutions often deal with patients who have had a baseline positron emission tomography (PET)/computed tomography (CT) scan performed elsewhere. Little data exist regarding the quality of these PET/CT scans and whether they are fully suitable for qualitative or quantitative interpretation. We evaluated outside PET/CT scans from cancer patients referred to our institution and compared them with PET/CT scans acquired locally. This Health Insurance Portability and Accountability Act-compliant retrospective study was approved by our institutional review board. Informed consent requirements were waived. One hundred seventy recent whole-body outside PET/CT exams from many sites were digitally imported into our radiology imaging system and reviewed for key quality metrics including time from injection until imaging, availability of patient height and weight information, serum glucose level and [(18) F]fluoro-2-deoxy-D-glucose (FDG) dose. The standardised uptake value (SUV) and SUV based on lean body mass (SUL) in the liver were measured whenever possible. These were compared with 170 internal studies performed at our centre during the same period. Missing data were common in outside scans with height in 62%, weight 35%, uptake time 25%, FDG dose 28% and glucose levels in 64% of cases. In quantitatively evaluable cases, mean liver SUL, SUV, FDG dose and uptake time were much more variable in outside than in internal studies. Approximately one-third of the outside PET/CT studies submitted digitally for analysis lacked key information required to secure any quantitative imaging data. Only about a third of these studies had all necessary information available for accurate SUL determination and had acceptable quality that was comparable with locally acquired scans. This suggests that many of PET studies performed in the community cannot be relied upon to provide quantitative image data that can be applied in a different centre. Greater standardisation of oncologic PET/CT studies among different centres must still be pursued.

Positive Correlation between Baseline PET or PET/CT Findings and Clinical Parameters in Multiple Myeloma Patients

Recently, positron emission tomography (PET) has been incorporated into a series of prospective studies as a predictor of outcomes in multiple myeloma (MM), and the number of ¹⁸F-fluorodeoxuglucose (FDG)-avid focal lesions (FLs) and the intensity of tumor metabolism have been designated as important surrogate markers for predicting prognosis. Here, we compared initial clinical characteristics of MM patients with baseline PET parameters: the number of FLs and the maximum standardized uptake value (SUV_max). A total of 59 patients diagnosed with MM between August 2004 and February 2012 were reviewed. At diagnosis, 23 patients (40.0%) had ≤3 FLs, 11 patients (18.6%) 4-9 FLs, and 25 patients (42.4%) ≥10 FLs. The median SUV_max was 5.3 (range 0-24.3), and 40 patients (67.8%) showed a SUV_max >4. No clinical characteristics were significantly different between groups with a SUV_max ≤4 and a SUV_max >4. However, there were significant differences in several clinical indices between the FLs ≤3 and FLs >3 groups; elevated β₂-microglobulin, elevated lactate dehydrogenase, anemia and more advanced disease by the Durie-Salmon stage corresponded to FLs >3 at baseline PET. Adverse baseline PET findings are positively correlated with prognostically relevant clinical parameters. Regarding PET parameters, FLs are more likely to be well correlated with disease aggressiveness and pathophysiology compared to SUV_max.

Interim Positron Emission Tomography Scan Predicts Early Outcomes Of Patients With Peripheral T-Cell Lymphoma

IntroductionInterim positron emission tomography (PET) scan has shown to be useful for evaluating response in Hodgkin lymphoma. And, there has been increasing interests in using interim PET for predicting outcomes in diffuse large B-cell lymphoma. However, few data are available regarding prognostic value of interim PET in patients with peripheral T cell lymphoma (PTCL). Recently, in an attempt to standardize reporting criteria for interim PET, Deauville five-point scale (5-PS), which visually assess the uptake of lesions in comparison with background mediastinal and liver uptakes, were proposed, but this was not investigated in PTCL. Therefore, the aim of this study was to determine the prognostic role of interim PET, assessed by Deauville 5-PS, in patients with PTCL treated with systemic chemotherapy. Patients and MethodsWe consecutively enrolled newly diagnosed PTCL patients, treated with systemic chemotherapy (CHOP/CHOP-like or non-anthracycline-based) and had the baseline PET data with ³1 evaluable hypermetabolic lesion between 2006 and 2012 in two Korean institutions. Patients treated with upfront chemoradiotherapy before interim PET scan were excluded. Interim PET scan was performed after 3 cycles of chemotherapy, before 1 week of the next cycle. Interim PET response was visually assessed by 5-PS and four point or higher was regarded as positive. All PET assessment was performed by 2 nuclear medicine specialists at each institution, and the discrepancy of assessment was resolved by the agreement through discussion. ResultsA total of 35 patients was included in this analysis. The median age was 60 years (range, 31-79) and 26 (74%) were male. Histologic subtypes included were PTCL, not otherwise specified in 10 (29%), extranodal NK/T cell lymphoma in 8 (23%), angioimmunoblastic T cell lymphoma in 7 (20%), anaplastic large cell lymphoma, ALK negative in 4 (11%), and others in 6 (18%). 22 patients (63%) were presented as advanced stage disease and 9 (26%) had B symptoms. ECOG performance status was ≥ 2 in 7 (20%), serum LDH level was elevated in 16 (46%), and bone marrow was involved in 5 (14%). Thus, 14 patients (40%) were classified as high risk (≥ 2 factors) by the prognostic index for PTCL (PIT). 31 patients (89%) completed planned systemic chemotherapy ± involved-field radiotherapy and 25 (71%) achieved complete response by systemic chemotherapy. 10 patients (29%) underwent consolidative autologous stem cell transplantation (ASCT).Using 5-PS, interim PET scan was visually scored as follows; 1 point in 10 patients (29%), 2 in 6 (17%), 3 in 8 (23%), 4 in 7 (20%), and 5 in 4 (11%). Among these, 11 patients (31%) had 4 point or above were considered positive for interim PET scan. With a median follow-up of 43.4 (range, 4.3-89.8) months, progression-free survival (PFS; median, 5.2 vs 38.0 months, respectively; P=0.001) and overall survival (median, 12.6 months vs not reached, respectively; P=0.004) was significantly worse in patients with positive interim PET than those with negative results. In multivariate analysis for PFS, high risk of PIT (HR, 3.67; 95% CI, 1.13-11.99) and positive interim PET (HR, 4.02; 95% CI, 1.32-12.23) were independently associated with faster disease progression, whereas consolidation with ASCT was independent prognostic factor for better PFS (HR, 0.23; 95% CI, 0.06-0.84). ConclusionVisual assessment of interim PET scan using Deauville 5-PS appears to predict early outcomes of patients with PTCL. Patients with positive interim PET shows highly predictive of extremely poor outcomes. Therefore, our findings suggest further studies regarding early stratification based on interim PET results as a response-adapted treatment strategies in patients with PTCL are needed to improve outcomes. Disclosures:No relevant conflicts of interest to declare.

Results of the baseline positron emission tomography can customize therapy of localized esophageal adenocarcinoma patients who achieve a clinical complete response after chemoradiation

BackgroundPatients with localized esophageal adenocarcinoma (EAC) who achieve a clinical complete response (clinCR) after preoperative chemoradiation (trimodality therapy; TMT) or definitive chemoradiation (bimodality therapy; BMT) live longer than those who achieve a <clinCR (Suzuki A, Xiao LC, Hayashi Y et al. Prognostic significance of baseline positron emission tomography and importance of clinical complete response in patients with esophageal or gastroesophageal junction cancer treated with definitive chemoradiotherapy. Cancer 2011; 117: 4823–4833; Cheedella NK, Suzuki A, Xiao L et al. Association between clinical complete response and pathological complete response after preoperative chemoradiation in patients with gastroesophageal cancer: analysis in a large cohort. Ann Oncol 2013; 24: 1262–1266; Ajani JA, Correa AM, Hofstetter WL et al. Clinical parameters model for predicting pathologic complete response following preoperative chemoradiation in patients with esophageal cancer. Ann Oncol 2012; 23: 2638–2642). We hypothesized that the initial standardized uptake value (iSUV) of positron emission tomography will define novel subsets of clinCR patients. MethodsWe analyzed 323 EAC patients, from our prospective database, who achieved a clinCR. Various statistical methods were used to assess the influence of iSUV on patient outcome. ResultsThe median follow-up of 323 patients was 40.8 months [95% confidence interval (CI) 35.6–47.3 months]. Two hundred six (63.8%) patients had TMT and 117 (36.2%) had BMT. If iSUV was ≥6, TMT patients had a longer median OS (94.8 months; 95% CI 66.07–NA) than BMT patients (31.4 months; 95% CI 21.7–42.1; P ≤ 0.001). However, if iSUV was <6, the median OS of TMT and BMT patients was similar (P = 0.62). iSVU did not influence the pathologic complete response rate in TMT patients (P = 0.85). ConclusionclinCR patients with iSUV of <6 are identified as a new subset that fared equally well when treated with TMT or BMT. Future esophageal preservation strategy may be best suited for this newly identified subset of EAC patients.

Preclinical Evaluation of Biopolymer-Delivered Circulating Angiogenic Cells in a Swine Model of Hibernating Myocardium

Vasculogenic cell-based therapy combined with tissue engineering is a promising revascularization approach targeted at patients with advanced coronary artery disease, many of whom exhibit myocardial hibernation. However, to date, no experimental data have been available in this context; we therefore examined the biopolymer-supported delivery of circulating angiogenic cells using a clinically relevant swine model of hibernating myocardium. Twenty-five swine underwent placement of an ameroid constrictor on the left circumflex artery. After 2 weeks, animals underwent echocardiography, rest and stress ammonia-positron emission tomography perfusion, and fluorodeoxyglucose positron emission tomography viability scans. The following week, swine were randomized to receive intramyocardial injections of PBS control (n=10), circulating angiogenic cells (n=8), or circulating angiogenic cells+collagen-based matrix (n=7). The imaging protocol was repeated after 7 weeks. Baseline positron emission tomography myocardial blood flow and myocardial flow reserve were reduced in the left circumflex artery territory (both P<0.001), and hibernation (mismatch) was observed. At follow-up, stress myocardial blood flow had increased (P≤0.01) and hibernation decreased (P<0.01) in the cells+matrix group only. Microsphere-measured myocardial blood flow validated the perfusion results. Arteriole density and wall motion abnormalities improved in the cells+matrix group. There was also a strong trend toward an improvement in ejection fraction (P=0.07). In this preclinical swine model of ischemic and hibernating myocardium, the combined delivery of circulating angiogenic cells and a collagen-based matrix restored perfusion, reduced hibernation, and improved myocardial wall motion.

Prognostic value of metabolic metrics extracted from baseline positron emission tomography images in non-small cell lung cancer

Background. Maximum, mean and peak SUV of primary tumor at baseline FDG-PET scans, have often been found predictive for overall survival in non-small cell lung cancer (NSCLC) patients. In this study we further investigated the prognostic power of advanced metabolic metrics derived from intensity volume histograms (IVH) extracted from PET imaging. Methods. A cohort of 220 NSCLC patients (mean age, 66.6 years; 149 men, 71 women), stages I–IIIB, treated with radiotherapy with curative intent were included (NCT00522639). Each patient underwent standardized pre-treatment CT-PET imaging. Primary GTV was delineated by an experienced radiation oncologist on CT-PET images. Common PET descriptors such as maximum, mean and peak SUV, and metabolic tumor volume (MTV) were quantified. Advanced descriptors of metabolic activity were quantified by IVH. These comprised five groups of features: absolute and relative volume above relative intensity threshold (AVRI and RVRI), absolute and relative volume above absolute intensity threshold (AVAI and RVAI), and absolute intensity above relative volume threshold (AIRV). MTV was derived from the IVH curves for volumes with SUV above 2.5, 3 and 4, and of 40% and 50% maximum SUV. Univariable analysis using Cox Proportional Hazard Regression was performed for overall survival assessment. Results. Relative volume above higher SUV (80%) was an independent predictor of OS (p = 0.05). None of the possible surrogates for MTV based on volumes above SUV of 3, 40% and 50% of maximum SUV showed significant associations with OS [p (AVAI3) = 0.10, p (AVAI4) = 0.22, p (AVRI40%) = 0.15, p (AVRI50%) = 0.17]. Maximum and peak SUV (r = 0.99) revealed no prognostic value for OS [p (maximum SUV) = 0.20, p (peak SUV) = 0.22]. Conclusions. New methods using more advanced imaging features extracted from PET were analyzed. Best prognostic value for OS of NSCLC patients was found for relative portions of the tumor above higher uptakes (80% SUV).