1) Describe the kinetics of thymidine relevant to FLT PET imaging. 2) Discuss approaches to FLT image interpretation. 3) Describe studies that have tested FLT PET as a marker cancer response to treatment.

MR imaging of primary brain tumors has limited value for assessing the extent of tumor infiltration and differentiating tumor recurrence from pseudoprogression. Molecular imaging has the potential to overcome these limitations. CLR1404 is a novel alkylphosphocholine analogue characterized by preferential uptake and prolonged retention in cancer cells and cancer stem cells. Here, we report on the first-in-human use of ¹²⁴I-CLR1404 PET/CT in primary and recurrent glioma.

4 patients with low grade and 7 patients with high grade glioma were injected with 74 or 185 MBq of ¹²⁴I-CLR1404 and imaged with PET/CT at 6, 24, and 48 hrs post-infusion. The majority of patients (10/11) had suspected recurrent disease. In patients with uptake above background, tumor to background ratios (T:B) were generated and T1 MRI-Gad+ volumes, SUV threshold volumes (1.0, 1.2), and T:B ratio threshold volumes (1.6, 2.0) were segmented. In addition, T:B lesion kinetics were analyzed.

124I-CLR1404 PET demonstrated avid tumor uptake above background in 7 of 11 patients. Three low grade gliomas and one high grade did not show uptake. With clinical follow-up, two of the three low grade gliomas and the high grade glioma were shown to be pseudoprogression and not tumor recurrence. In positive patients, uptake was observed both in areas with and without Gadolinium enhancement on MRI. There was no significant uptake in normal brain. Maximum T:B ratios were 11.3±3.9 at 24 hrs (range 5.7-15.6) and 10.8±2.9 at 48 hrs (range 6.4-14.0). Average tumor volumes (in mL) were 4.6 (range 0.2-7.6) for Gad+ MRI, 59.1 (range 33.6-91.0) for PET T:B_1.6, 47.2 (range 28.8-66.3) for PET T:B_2.0, 17.4 (range 5.1-35.3) for SUV_1.0, and 12.3 (range 1.7-28.7) for SUV_1.2.

¹²⁴I-CLR1404 PET/CT successfully images glioma and demonstrates high tumor-to-background contrast and larger lesion volumes than contrast-enhanced MRI. ¹²⁴I-CLR1404 PET provides tumor-specific molecular imaging that may be valuable for the identification of tumor margin and the differentiation of treatment related changes from tumor progression.

¹²⁴I-CLR1404 PET/CT demonstrates differential, high contrast uptake as well as larger lesion volumes than CE MRI in glioma and may help distinguish treatment related changes from disease progression.

¹¹C-acetate PET/CT is useful for the detection of multiple myeloma (MM) because it was previously shown that myeloma cell lines prefer fatty acid over glucose metabolism for growth. We aim to compare the diagnostic value of ¹¹C-acetate PET/CT in relapsed MM with treatment naive MM patients.

From year 2010 to 2013, 66 MM patients were referred for 11C-acetate PET/CT: 37 relapsed (M: 23, F: 14; mean age=61.4±7.7y) and 29 newly diagnosed (M: 17, F: 12; mean age=63.1±10.6y). All patients were confirmed by trephine bone marrow biopsy. 20 subjects with normal marrow were recruited as controls (M: 12, F: 8; mean age=59.8±10.9y). Active myeloma disease was first visually assessed as having focal or diffuse pattern on PET. SUV_max of L3 was chosen as the representative site for quantitative assessment of marrow disease activity for patients with diffuse MM. ROC analysis was performed between MM and normal subjects to define the individual SUV_max_L3 cut-off values for newly diagnosed and relapsed patients with diffuse MM pattern.

For the detection of focal MM, 11C-acetate PET/CT had a detection sensitivity of relapsed MM (31/33: 93.9%) comparable to that of newly diagnosed MM (15/16: 93.8%). For diffuse MM, the ROC-defined thresholds of SUV_max_L3 were 3.78 and 3.80 (AUC=0.97 vs 0.97) in relapsed and newly diagnosed groups, respectively. At these thresholds, 11C-acetate PET/CT had a slightly better sensitivity for detection of diffuse MM in the relapsed group (22/25: 88.0%) than newly diagnosed group (22/27: 81.5%). The average marrow activity in relapsed group was higher than that of newly diagnosed group (SUV_max_L3=6.57±3.59 vs 5.10±1.78, P=0.065), suggesting that relapsed MM patients had more severe marrow infiltration. The overall detection sensitivity of focal and/or diffuse MM disease by 11C-acetate PET/CT was also slightly better in relapsed (34/37: 91.9%) than in newly diagnosed MM (24/29: 82.8%) patients.

¹¹C-acetate PET/CT is sensitive for detection of both relapsed and newly diagnosed MM. It has even better diagnostic performance in relapsed patients with diffuse MM pattern, which is the group of MM patients known to have the greatest diagnostic challenge.

In addition to its high detection sensitivity in newly diagnosed MM, ¹¹C-acetate PET/CT is also sensitive in assessment of MM relapse, hence with potential to suggest when to re-initiate treatment.

1) To identify the advantages of F-18 NaF PET/CT imaging in oncology. 2) To understand the importance of a standardized imaging protocol. 3) To become comfortable differentiating benign from malignant lesions on F-18 NaF PET/CT.

F-18 NaF PET/CT has been shown to have higher sensitivity and specificity than planar 99m-Tc MDP bone scanning in several small studies. The concomitant acquisition of anatomic images permits immediate correlation of any abnormal findings. Additionally, F-18 NaF PET/CT bone imaging can be quantitated, allowing bone disease to be "measureable", increasing its utility therapy monitoring. When a consistent F-18 NaF uptake period is used, the SUV values are highly reproducible, and due to the high extraction fraction, high quality images can be obtained with a radiation dose exposure similar to that of Tc-99m MDP (including the low dose CT scan). This presentation will discuss the benefits and challenges of F-18 NaF PET/CT in oncology.

This study compared C11-Acetate (CA) positron emission tomography (PET/CT) and F18 Sodium Fluoride (F18-NaF) PET bone imaging for the detection of skeletal metastasis in men with biochemically recurrent PCa.

Men with PCa previously having had definitive therapy demonstrating a rising PSAs were evaluated retrospectively. CA PET/CT studies where performed and F18-NaF PET performed within 2 months was compared. Imaging studies were reviewed for the presence/absence of skeletal lesions, and for concordance in the number of detected lesions. Detection rates of soft tissue lesions was also evaluated on the CA PET studies in relation to the presence/absence of skeletal lesions. PSA kinetics were evaluated.

183 studies (men age 45 - 88) met our criteria for image review. PSA ranged from 0.5 - 148 (median 2.5). CA PET detected skeletal lesions in 59 (32%) of studies, whereas F18-NaF PET detected lesions in 75 (41%). In 22 studies, CA PET and F18-NaF where concordant, demonstrating a solitary bony lesion in 14 and multiple bony lesions in 7. 57 studies were discordant. F18-NaF PET demonstrated lesions not seen on CA PET in 36 (20%) studies (median PSA 3.05, median PSA doubling time[dt] 4 months). CA PET found bony lesions in 14 studies (8%) not present on the F18-NaF studies. In 7 studies there were non-specific findings on the F18-NaF study that where negative on the CA PET and therefor felt to be benign. In studies positive for bony lesions, CA PET additionally identified soft tissue lesions in 31 (17%) studies. In 78 (42%) studies CA PET identified soft tissue lesions when no bone lesions where found on either CA PET or F18-NaF (median PSA 2.36, median PSAdt 5 months). These lesions were found to be in the pelvis in 61 (33%), extrapelvic regions in 6 (3%) and involving both pelvic and extrapelvic soft tissue sites in 11 (6%).

CA PET and F18-NaF PET are useful and appear complimentary for the detection of skeletal metastasis in patients with biochemical recurrence of PCa, but do show discordance in their detection rates. CA PET also detected soft tissue lesions in most patients negative for bone lesions. PSA kinetics do not appear to help select one imaging study over the other.

PCa recurrence after definitive treatment occurs in up to 40% of patients. Conventional imaging is of limited value in detection in early biochemical recurrence, thereby limiting treatment options.

To associate NaF PET findings for first bone metastases with PSA values and kinetics in patients with biochemical recurrence in the post-prostatectomy setting.

All NaF PET scans that were performed at USC between 2010 and 2104 were queried to find patients who had undergone radical prostatectomy. We excluded patients who had known metastatic disease at the time of NaF PET to obtain a cohort of patients for whom NaF PET was being used to determine first osseous metastases. The electronic medical records of the patients were then reviewed to extract information on PSA at the time of NaF PET, PSA kinetics, pathologic features of the prostatectomy specimen, as well as other radiologic studies performed to validate the NaF PET findings.

56 patients met our inclusion criteria; of which, 11 (19.6%) had positive NaF PET scans. The average PSA for patients with a positive NaF PET was 6.25 ng/mL (range 0.04- 30.38 ng/mL). There were 14 patients who had imaging studies with PSA values below 0.2ng/mL; 3 of those patients (21%) had positive scans.. The average PSA velocity of patients with positive NaF PET was 0.34 ng/ml/mo (range 0.02 to 2.25 ng/ml/mo), the average PSA doubling-time amongst the patients with positive scans was 9.92 months (range 1.22 - 36.32 months). Of those with positive NaF PET scans, 4 had other imaging modalities that confirmed the existence of bone abnormalities and all 11 were treated for progression of disease based on the findings of the NaF PET scans.

NAF PET detected first osseous metastatic disease in 19.6% of patients with PSA relapse in this population of patients. The test was able to detect early metastatic disease in 3 of 14 patients with PSA values <= 0.2ng/mL.

NaF PET has the ability to detect early prostate cancer bone metastases in the post-prostatectomy setting. (This work was done with grant support from Dr. Jadvar's NIH/NCI Grant R01-CA111613).

1) Review the major biological targets that may be useful for imaging in prostate cancer. 2) Understand the need for tailoring the imaging technique to the particular clinical phase of disease. 3) Analyze the current evidence with the potential utility of PET with various radiotracers in the imaging evaluation of prostate cancer.

Recent advances in the fundamental understanding of the complex biology of prostate cancer have provided increasing number of potential targets for imaging and treatment. In this presentation, I review the experience with a number of major PET radiotracers for potential use in the imaging evaluation of men with prostate cancer.

The ⁶⁸Ga-labelled PSMA (prostate specific membrane antigen) ligand is a highly promising tracer for imaging of recurrent prostate cancer (PC). The aim of the study was to compare this novel tracer with the standard ¹¹C-Choline based PET/CT.

42 patients with suspected PC relapse underwent a PET/CT 5 min p.i. of 615±26 MBq 11C-Choline and 60 min p.i. of 157±16 MBq 68Ga-HBED-CC-PSMA. The examinations were performed on the same day. 39 patients had a biochemical relapse after prostatectomy and/or radiotherapy (mean PSA 8.3 ng/ml, range 0.3-64 ng/ml, median 3.3 ng/ml), 3 patients had a primary staging. Suspicious lesions were evaluated visually and semiquantitatively (mean SUV, standard uptake value and T/B, tumor to blood ratio).

In 36/42 patients, at least one lesion suspicious for cancer could be detected using 68Ga-PSMA (detection rate 85.7%), while at least one lesion could be found by 11C-Choline in 34/42 patients (detection rate 81.0%). In five patients no lesion was found in both methods. Twelve patients had local recurrences, whereof 11/12 relapses were detected by both methods. One local relapse was not detected by 68Ga-PSMA. In 1/3 patients with primary staging the tumor could not be detected by either of the tracers. In 28 patients suspicious lymph nodes (LN) were detected. 89% of these patients had at least one PSMA-positive LN, 89% of them had at least one Choline-positive LN. Among all 98 suspicious LN, 86 were PSMA-positive and 80 were Choline-positive. 18 LN were PSMA-positive only, 12 were Choline-positive only. Mean size of the LN which could only be detected by PSMA was 8±3 mm. SUV mean and T/B ratio of the LN was clearly higher using 68Ga-PSMA (15.3±14) than using 11C-Choline (4.4±2). Bone metastases were found in 14 patients, the number of detected lesions as well as tracer uptake was clearly higher using 68Ga-PSMA (SUV mean 11.4±8.4 vs 6±3.2). In one patient bone metastases were only dertected with 68Ga-PSMA PET. In only 8/14 patients, bone metastases could be detected in CT.

⁶⁸Ga-PSMA-PET/CT is able to detect recurrent PC with a higher detection rate compared to the standard ¹¹C-Choline PET/CT and has an improved T/B ratio. However, ⁶⁸Ga-PSMA was not able to detect all primary and metastatic sites.

⁶⁸Ga-PSMA is a new tracer for prostate cancer, promising particularly for detection of recurrence in patients with low PSA.

Since the introduction of PET-imaging with the 68Ga-labelled PSMA ligand HBED-CC, this highly promising method has rapidly spread out across many countries. There exists evidence, that this imaging method might be a significant step forward in the diagnosis of prostate cancer (PCa). The aim of this study was to evaluate the role and valence of the 68Ga-PSMA-PET/CT in the diagnosis of PCa.

We performed a retrospective analysis of 319 patients who were investigated by 68Ga-PSMA-PET/CT. Mean Gleason Score (GSC) was 7.5, median PSA level 4.6 ng/ml. Possible influence of several factors (PSA level, GSC, hormonal therapy, age, applied amount of injected tracer) were evaluated. 41 Patients were investigated by biopsy after PET/CT. Tracer uptake was measured in 901 representative tumor lesions.

In 82.8% of the patients at least one lesion indicative for PCa was detected. Current hormonal therapy had no negative influence on the detection rate. High amounts of injected tracer did not improve the probability to detect tumor suspicious lesions. Tumor detection showed a positive association with PSA level. GSC did not show an influence on tumor detection. Mean SUVmax of all tumor lesions was 13.3 ± 14.6. Only three of all histopathologically investigated lesions were false negative in PSMA-PET/CT, all others (n=304) were true negative and positive.

68Ga-PSMA-PET/CT can detect PCa with high sensitivity. In addition, the tracer is highly specific for PCa. Detection of PCa can be improved by higher PSA level. Current hormonal therapy did not influence the detection rate negatively. GSC did not show an influence on tumor detection.

Introduced in 2011, PET-imaging with the 68Ga-labelled PSMA-ligand HBED-CC has rapidly spread out across many countries. This new method of imaging is thought to be a significant step foreward in the diagnosis of recurrent prostate cancer.

1) Understand the evolution of tumor hypoxia and its biological implications. 2) Identify the mechanistic changes in tumor biology that will result in tumor resistance and poor patient outcome. 3) Learn novel ways to image tumor hypoxia with focus on FMISO PET imaging. 4) Understand the potential approaches to overcoming the negative impact of hypoxia.

The physiological microenvironment for a tumor is largely dictated by abnormal vasculature and metabolism. Many solid tumors develop areas of hypoxia during their evolution caused by unregulated cellular growth, resulting in greater demand on oxygen for energy metabolism. Hypoxia induces a cascade of changes that reflects the homeostatic attempts (highly conserved evolutionally) to maintain adequate oxygenation that may result in tumor cells to adapt by developing more aggressive survival traits; mediated by Hypoxia Inducible Factor (HIF1a) part of the cellular oxygen sensing mechanism. Hypoxic tumors are not effectively eradicated with conventional doses of radiation and show resistance to several chemotherapy drugs. Hypoxia may also result in angiogenesis (itself a marker of tumor aggressiveness) mediated by Vascular endothelial growth factor (VEGF). While angiogenesis is a frequent consequence of hypoxia, some tumors develop extensive angiogenesis without the presence of hypoxia and vice versa. Advances in PET imaging instrumentation, coupled with the development of an increasing array of novel molecular probes, provide opportunities for imaging and selection of appropriate therapies to overcome the cure limiting effects of these two fundamental aspects of tumor microenvironment. The biology of tumor microenvironment related to hypoxia and its effect on patient outcome and developments in imaging technology and novel radiotracers for hypoxia imaging with a focus on F-18 FMISO would be reviewed.Challernges and novel treatments to overcome the cure limiting ability of hypoxia will be discussed.

To retrospectively compare the performance of combined 68Ga-DOTA-TATE PET/CT and stand-alone ceCT in 54 patients with NET

Patients with histologically confirmed NET and available follow-up of at least 6 months (median 12.6 months; range 6.1-23.2) were included. PET/CT and ceCT images were analyzed separately by two blinded nuclear medicine physicians and two radiologists, respectively. Finally all investigators reviewed all detected lesion together reaching a consensus-grading for PET/CT. The results were then compared to the reference standard consisting of clinical follow-up data

Regarding true positive lesions, PET/CT detected: 139 bone-lesions vs. 48 (ceCT), 106 lymph node metastases (PET/CT) vs. 71 (CT) and 26 lung lesions (PET/CT and CT each). On a patient basis, PET/CT achieved a higher sensitivity (100% vs. 47%) and specificity (89% vs. 49%) for bones than stand-alone ceCT. For lymph nodes the effect was similar (sensitivity 92% vs. 64% and specificity 83% vs. 59%). For the detection of pulmonary lesions the sensitivity was identical (100%) while specificity of PET/CT was superior to CT-alone (95% vs. 82%)

In summary, the use of Gallium-68-DOTATATE-PET-CT appears to lead to an increase in sensitivity and specificity for the detection of extra-hepatic NET metastases compared to stand-alone ceCT

use of 68Ga-DOTATATE PET/CT appears to lead to an increase in quality for the detection of extra-hepatic NET metastases compared to stand-alone ceCT

PET/CT with ⁶⁸Ga-DOTATOC has been used for detection of neuroendocrine tumors, but the optimal duration after administration of DOTATOC has not been fully investigated. The purpose of this study was to investigate whether delayed scanning at about 90-min post-injection had any clinical benefits for evaluating neuroendocrine tumors, comparing with conventional scanning at 60-min post-injection.

57 patients (M:F=25:32, mean 55 yr) who underwent DOTATOC-PET/CT scan for suspected or known neuroendocrine tumors were retrospectively evaluated. PET/CT scanning was performed twice at about 1-h and 1.5-h post-injection. For visual analysis, a 5-point grading scale (0: definitely normal - 4: definitely abnormal) was used, and lesions with grade 3 or 4 were regarded as positive. For quantitative analysis, standardized uptake values for each lesion and physiological uptake in liver were evaluated. When patients had more than five lesions (SUVs), representative 5 lesions were assessed.

Of 57 patients, 44 patients had a total of 133 lesions (83 in liver, 20 in pancreas, 10 in bone, 10 in lymph node, and 10 in others), and 13 patients were negative. In interpreting early images, there were 3 lesions with grade 3, but the remaining 130 lesions were grade 4. All 133 lesions were grade 4 in delayed images, and there were no lesions which were suspected in either scanning. The physiological uptake in liver was comparable between the two scanning (Mean±SD=5.6±1.8). SUVs and tumor-to-liver ratios of hepatic lesions were slightly higher in early scanning than in delayed scanning (SUV; 26.5±20.7 : 28.0±20.8, Tumor-to-liver ratio; 6.0±4.4 : 6.4±4.5, p<0.01), which did not affect detectability. In addition, bone and peritoneal metastases had slightly higher SUVs at delayed images as well (p<0.05), without difference of diagnostic performance. There was no significant difference in SUVs of pancreatic lesions and primary sites of midgut between the two scans.

Our preliminary data suggest that the delayed scan had no specific merits for detecting primary or metastatic neuroendocrine tumors, although it could be helpful for improving diagnostic confidence.

In DOTATOC-PET/CT, the delayed scanning at 90-min postinjection had no specific merits for detecting neuroendocrine tumors, as compared with conventional scanning at 60-min postinjection, although diagnostic confidence may be changed.