Daniel Appelbaum

FDG‐PET as a predictive biomarker for therapy with everolimus in metastatic renal cell cancer

The mTOR (mammalian target of rapamycin) inhibitor, everolimus, affects tumor growth by targeting cellular metabolic proliferation pathways and delays renal cell carcinoma (RCC) progression. Preclinical evidence suggests that baseline elevated tumor glucose metabolism as quantified by FDG‐PET ([18F] fluorodeoxy‐glucose positron emission tomography) may predict antitumor activity. Metastatic RCC (mRCC) patients refractory to vascular endothelial growth factor (VEGF) pathway inhibition were treated with standard dose everolimus. FDG‐PET scans were obtained at baseline and 2 weeks; serial computed tomography (CT) scans were obtained at baseline and every 8 weeks. Maximum standardized uptake value (SUVmax) of the most FDG avid lesion, average SUVmax of all measured lesions and their corresponding 2‐week relative changes were examined for association with 8‐week change in tumor size. A total of 63 patients were enrolled; 50 were evaluable for the primary endpoint of which 48 had both PET scans. Patient characteristics included the following: 36 (72%) clear cell histology and median age 59 (range: 37–80). Median pre‐ and 2‐week treatment average SUVmax were 6.6 (1–17.9) and 4.2 (1–13.9), respectively. Response evaluation criteria in solid tumors (RECIST)‐based measurements demonstrated an average change in tumor burden of 0.2% (−32.7% to 35.9%) at 8 weeks. Relative change in average SUVmax was the best predictor of change in tumor burden (all evaluable P = 0.01; clear cell subtype P = 0.02), with modest correlation. Baseline average SUVmax was correlated with overall survival and progression‐free survival (PFS) (P = 0.023; 0.020), but not with change in tumor burden. Everolimus therapy decreased SUVs on follow‐up PET scans in mRCC patients, but changes were only modestly correlated with changes in tumor size. Thus, clinical use of FDG‐PET‐based biomarkers is challenged by high variability.

Positron emission tomography (PET) used to image subclinical inflammation associated with ulcerative colitis (UC) in remission.

Background: Positron emission tomography (PET) using 18‐fluorodeoxyglucose (18‐FDG) is a noninvasive, functional imaging modality most often used to assess cancer. The aim of this study was to perform PET/computed tomography (CT) on patients with quiescent ulcerative colitis (UC) to understand the limits of this technology for assessing inflammatory activity. Methods: We identified patients diagnosed with UC in a strictly defined remission state. PET/CT was performed in standard fashion, using approximately 10 mCi of 18‐FDG with a 60‐minute uptake delay. Uptake in each of 4 colonic segments (recto‐sigmoid [r‐s], descending, transverse, and ascending), and distal small bowel were scored on a 3‐point scale (0 = no uptake or uptake ≤liver; 1 = uptake somewhat >liver; 2 = uptake much greater than liver). Results: Ten patients participated in this study, 6 male. Eight had pancolitis, 1 had extensive colitis, and 1 had procto‐sigmoiditis, with a median disease duration was 32 years. A PET scan was performed mean 37 days after endoscopy. Six patients had no increased 18‐FDG uptake, 3 had increased uptake in the r‐s region, 1 patient with r‐s uptake also had ascending colon uptake, and 1 had ileal uptake with no colonic signal. Conclusions: In this study, PET demonstrated inflammatory activity in the colon despite negative endoscopic, histologic, and symptom assessment. This has important implications in the understanding of UC disease quiescence. Further exploration of this highly sensitive modality should be performed.

The utility of FDG-PET for assessing outcomes in oligometastatic cancer patients treated with stereotactic body radiotherapy: a cohort study

BackgroundStudies suggest that patients with metastases limited in number and destination organ benefit from metastasis-directed therapy. Stereotactic body radiotherapy (SBRT) is commonly used for metastasis directed therapy in this group. However, the characterization of PET response following SBRT is unknown in this population. We analyzed our cohort of patients to describe the PET response following SBRT.MethodsPatients enrolled on a prospective dose escalation trial of SBRT to all known sites of metastatic disease were reviewed to select patients with pre- and post-therapy PET scans. Response to SBRT was characterized on PET imaging based on standard PET response criteria and compared to CT based RECIST criteria for each treated lesion.Results31 patients had PET and CT data available before and after treatment for analysis in this study. In total, 58 lesions were treated (19 lung, 11 osseous, 11 nodal, 9 liver, 6 adrenal and 2 soft tissue metastases). Median follow-up was 14 months (range: 3–41). Median time to first post-therapy PET was 1.2 months (range; 0.5-4.1). On initial post-therapy PET evaluation, 96% (56/58) of treated metastases responded to therapy. 60% (35/58) had a complete response (CR) on PET and 36% (21/58) had a partial response (PR). Of 22 patients with stable disease (SD) on initial CT scan, 13 had CR on PET, 8 had PR, and one had SD. Of 21 metastases with PET PR, 38% became CR, 52% remained PR, and 10% had progressive disease on follow-up PET. 10/35 lesions (29%) with an initial PET CR progressed on follow-up PET scan with median time to progression of 4.11 months (range: 2.75-9.56). Higher radiation dose correlated with long-term PET response.ConclusionsPET response to SBRT enables characterization of metastatic response in tumors non-measurable by CT. Increasing radiation dose is associated with prolonged complete response on PET.

Interobserver variability among measurements of the maximum and mean standardized uptake values on 18F-FDG PET/CT and measurements of tumor size on diagnostic CT in patients with pulmonary tumors

Background: 18F-fluoro-2-deoxyglucose positron emission tomography (18F-FDG PET) imaging has been shown to be an accurate method for diagnosing pulmonary lesions, and the standardized uptake value (SUV) has been shown to be useful in differentiating benign from malignant lesions. Purpose: To survey the interobserver variability of SUVmax and SUVmean measurements on 18F-FDG PET/CT scans and compare them with tumor size measurements on diagnostic CT scans in the same group of patients with focal pulmonary lesions. Material and Methods: Forty-three pulmonary nodules were measured on both 18F-FDG PET/CT and diagnostic chest CT examinations. Four independent readers measured the SUVmax and SUVmean of the 18F-FDG PET images, and the unidimensional nodule size of the diagnostic CT scans (UDCT) in all nodules. The region of interest (ROI) for the SUV measurements was drawn manually around each tumor on all consecutive slices that contained the nodule. The interobserver reliability and variability, represented by the intraclass correlation coefficient (ICC) and coefficient of variation (COV), respectively, were compared among the three parameters. The correlation between the SUVmax and SUVmean was also analyzed. Results: There was 100% agreement in the SUVmax measurements among the 4 readers in the 43 pulmonary tumors. The ICCs for the SUVmax, SUVmean, and UDCT by the four readers were 1.00, 0.97, and 0.97, respectively. The root-mean-square values of the COVs for the SUVmax, SUVmean, and UDCT by the four readers were 0%, 13.56%, and 11.03%, respectively. There was a high correlation observed between the SUVmax and SUVmean (Pearsons r=0.958; P <0.01). Conclusion: This study has shown that the SUVmax of lung nodules can be calculated without any interobserver variation. These findings indicate that SUVmax is a more valuable parameter than the SUVmean or UDCT for the evaluation of therapeutic effects of chemotherapy or radiation therapy on serial studies.

A new PET/CT volumetric prognostic index for non-small cell lung cancer

OBJECTIVES Whole-body metabolic tumor volume (MTVWB) has been shown of prognostic value for non-small cell lung cancer (NSCLC) beyond that of TNM stage, age, gender, performance status, and treatment selection. The current TNM staging system does not incorporate tumor volumetric information. We propose a new PET/CT volumetric prognostic (PVP) index that combines the prognostic value of MTVWB and TNM stage. MATERIALS AND METHODS Based on 328 consecutive NSCLC patients with a baseline PET/CT scan before treatment, from which MTVWB was measured semi-automatically, we estimated hazard ratios (HRs) for ln(MTVWB) and TNM stage from a Cox proportional hazard regression model that consisted of only ln(MTVWB) and TNM stage as prognostic variables of overall survival. We used the regression coefficients, which gave rise to the HRs, as weights to formulate the PET/CT volumetric prognostic (PVP) index. We also compared the prognostic value of the PVP index against that of TNM stage alone and ln(MTVWB) alone with univariate and multivariate survival analyses and C-statistics. RESULTS Univariate analysis C-statistic for the PVP index (C=0.71) was statistically significantly greater than those for TNM stage alone (C=0.67, p<0.01) and for ln(MTVWB) alone (C=0.69, p=0.033). Multivariate analyses showed that the PVP index yielded significantly greater discriminatory power (C=0.74) than similar models based on either TNM stage (C=0.72, p<0.01) or ln(MTVWB) (C=0.73, p<0.01). Lower values of the PVP index were associated with significantly better overall survival (adjusted HR=2.70, 95%CI [2.16, 3.37]). CONCLUSION The PVP index provides a practical means for clinicians to combine the prognostic value of MTVWB and TNM stage and offers significantly better prognostic accuracy for overall survival of NSCLC patients than the current TNM staging system or metabolic tumor burden alone.

FDG-PET/CT findings of a metastatic pituitary tumor

Abstract The authors report the fluorodeoxyglucose (FDG)-positron emission tomography(PET)/computed tomography (CT) findings of a rare case of growth hormone-secreting pituitary carcinoma with multiple metastatic lesions to the skeleton. A 31-year-old male had presented with acromegaly and had received transsphenoidal resection of a pituitary tumor and adjuvant radiotherapy. However, the tumor recurred with local invasions and the patient underwent more resections and adjuvant chemotherapy. Several months later, the patient developed rising levels of insulin-like growth factor 1 and whole-body FDG-PET/CT scanning revealed multiple hypermetabolic lesions throughout the skeleton compatible with metastasis.

Clinical utility of temporal subtraction images in successive whole-body bone scans: Evaluation in a prospective clinical study

In order to aid radiologists’ routine work for interpreting bone scan images, we developed a computerized method for temporal subtraction (TS) images which can highlight interval changes between successive whole-body bone scans, and we performed a prospective clinical study for evaluating the clinical utility of the TS images. We developed a TS image server which includes an automated image-retrieval system, an automated image-conversion system, an automated TS image-producing system, a computer interface for displaying and evaluating TS images with five subjective scales, and an automated data-archiving system. In this study, the radiologist could revise his/her report after reviewing the TS images if the findings on the TS image were confirmed retrospectively on our clinical picture archiving and communication system. We had 256 consenting patients of whom 143 had two or more whole-body bone scans available for TS images. In total, we obtained TS images successfully in 292 (96.1%) pairs and failed to produce TS images in 12 pairs. Among the 292 TS studies used for diagnosis, TS images were considered as “extremely beneficial” or “somewhat beneficial” in 247 (84.6%) pairs, as “no utility” in 44 pairs, and as “somewhat detrimental” in only one pair. There was no TS image for any pairs that was considered “extremely detrimental.” In addition, the radiologists changed their initial reported impression in 18 pairs (6.2%). The benefit to the radiologist of using TS images in the routine interpretation of successive whole-body bone scans was significant, with negligible detrimental effects.

Delayed 99mTc-labeled erythrocyte scintigraphy in patients with lower gastrointestinal tract hemorrhage: effect of positive findings on clinical management.

RATIONALE AND OBJECTIVES This study was performed to determine whether the results of delayed technetium 99m (99mTc)-labeled erythrocyte scintigraphy for lower gastrointestinal tract hemorrhage resulted in different clinical management and outcome from that in cases in which the results of initial scintigraphy were negative or equivocal. MATERIALS AND METHODS The authors retrospectively reviewed all 398 99mTc-labeled erythrocyte scintigraphic studies obtained emergently for lower gastrointestinal tract hemorrhage at their institution between January 1, 1994, and December 7, 2001. Of 67 patients who underwent delayed studies, 37 had positive findings (average delay, 18.4 hours; range, 6-25 hours) and 30 had negative findings (average delay, 20.1 hours; range, 8-26 hours). Clinical management and outcome were compared between these two groups with respect to duration of hospitalization, volume of blood transfusion, mortality, and the percentage who were treated conservatively or referred for angiography, endoscopy, and/or surgery. RESULTS Patients with positive delayed studies were referred more frequently for angiography than those with negative studies (35% vs 0%, P < .01). There were no significant differences between patients with positive findings and patients with negative findings with respect to mortality (8% vs 0%, P < .32), transfusion requirements (5.6 vs 3.2 units, P < .20), hospitalization (9.5 vs 6.1 days, P < .11), the percentage treated conservatively (35% vs 37%, P < .90), or the percentages referred for endoscopy (49% vs 60%, P < .50) or for surgery (24% vs 17%, P < .64). CONCLUSION Positive findings at delayed scintigraphy resulted in increased referrals for angiography but had no other effect on clinical course or outcome of lower gastrointestinal tract hemorrhage.

Relationship between Overall Survival of Patients with Non–Small Cell Lung Cancer and Whole-Body Metabolic Tumor Burden Seen on Postsurgical Fluorodeoxyglucose PET Images

PURPOSE To test the hypothesis that whole-body metabolic tumor burden (MTBWB) on postsurgical fluorodeoxyglucose (FDG) positron emission tomographic (PET)/computed tomographic (CT) images in patients with non-small cell lung cancer (NSCLC) is associated with their overall survival (OS). MATERIALS AND METHODS The institutional review board approved this study and waived the requirement for obtaining informed consent. One hundred forty-two patients with NSCLC (69 men, 73 women; median age, 67.7 years) who underwent postsurgical FDG PET/CT were retrospectively reviewed. The whole-body metabolic tumor volume (MTVWB), whole-body total lesion glycolysis (TLGWB), and whole-body maximum standardized uptake value (SUVWBmax) were measured. OS served as the primary end point of the study. Kaplan-Meier curves and Cox regression were used to assess the association between PET/CT markers and OS. RESULTS The interobserver variability was low, as demonstrated with intraclass correlation coefficients higher than 0.94 for SUVWBmax, MTVWB, and TLGWB. When compared with those with negative postsurgical FDG PET/CT findings, a significant decrease of OS was found in patients with the presence of FDG-avid tumor on the basis of both a log-rank test (P = .001) and a univariate Cox model (hazard ratio = 2.805, P = .001). In patients with FDG-avid tumor, there was a significant association between OS and ln MTVWB (P < .001), ln TLGWB (P < .001), and ln SUVWBmax (P < .010) in either univariate or multivariate analysis, after adjusting for patient age, sex, TNM restage, and therapy after postsurgical PET/CT studies. The OS differences between the groups dichotomized by the median value of MTVWB (11.54 mL, P = .004), TLGWB (32.38 mL, P < .001), or SUVWBmax (4.93, P = .023) were significant. CONCLUSION MTBWB and tumor maximum standardized uptake at postsurgical FDG PET/CT are related to the patients OS in NSCLC, independent of age, sex, TNM restaging, and therapy after postsurgical PET/CT studies.

Evaluation of the gallbladder and cystic duct patency with gadoxetate disodium enhanced MR cholangiography: prospective comparison of patients with normal gallbladder function and acute cholecystitis.

Background Using hepatocyte-specific magnetic resonance imaging (MRI) contrast agents such as gadoxetate disodium, MRI can provide functional information regarding the patency of the cystic duct similar to hepatobiliary scintigraphy in addition to anatomic images. Purpose To describe the gadoxetate disodium enhanced MR cholangiography (GDE-MRC) findings in patients with acute cholecystitis and to compare them with findings in patients without acute cholecystitis and with normal hepatobiliary scintigraphy. Material and Methods This study was HIPAA compliant and institutional review board approved. Twenty-three patients (n = 14 diagnosed with acute calculous cholecystitis based on ultrasound [US] or computed tomography [CT]; n = 9 controls with normal hepatobiliary scintigraphy) were prospectively enrolled. All patients underwent GDE-MRC within 2 days of the US, CT, or hepatobiliary scintigraphy. GDE-MRC included axial gradient echo T1-weighted images before and 3, 10, 20, 30, and 60 min after injection of 10 mL of gadoxetate disodium. If excretion of contrast into the gallbladder was not noted at 60 min, intravenous morphine was administered (0.04 mg/kg) and images were acquired 30 min later. Results In all nine controls, gadoxetate disodium was excreted into the gallbladder within 60 min (7/9 in <30 min). Twelve out of 14 patients with acute cholecystitis completed the study. Six out of 12 (50%) patients demonstrated contrast in their gallbladder within 1 h of administration similar to the control group (2/6 in <30 min). In the remaining 6/12 patients, contrast was not present in the gallbladder within 1 h from injection. Following morphine augmentation, contrast was subsequently noted in the gallbladder in 2/6 patients. Conclusion GDE-MRC can assess the patency of the cystic duct. Delayed (>60 min) or lack of filling of the gallbladder during GDE-MRC supports the diagnosis of acute cholecystitis. However, filling of the gallbladder with contrast in <60 min does not exclude the diagnosis of acute calculous cholecystitis.