Jian Q. Yu

Biodistribution and Radiation Dosimetry of the Integrin Marker 18F-RGD-K5 Determined from Whole-Body PET/CT in Monkeys and Humans

2-((2S,5R,8S,11S)-5-benzyl-8-(4-((2S,3R,4R,5R,6S)-6-((2-(4-(3-18F-fluoropropyl)-1H-1,2,3-triazol-1-yl)acetamido)methyl)-3,4,5-trihydroxytetrahydro-2H-pyran-2-carboxamido)butyl)-11-(3-guanidinopropyl)-3,6,9,12,15-pentaoxo-1,4,7,10,13-pentaazacyclopentadecan-2-yl)acetic acid (18F-RGD-K5) has been developed as an αvβ3 integrin marker for PET. The purpose of this study was to determine the biodistribution and estimate the radiation dose from 18F-RGD-K5 using whole-body PET/CT scans in monkeys and humans. Methods: Successive whole-body PET/CT scans were obtained after intravenous injection of 18F-RGD-K5 in 3 rhesus monkeys (167 ± 19 MBq) and 4 healthy humans (583 ± 78 MBq). In humans, blood samples were collected between the PET/CT scans, and stability of 18F-RGD-K5 was assessed. Urine was also collected between the scans, to determine the total activity excreted in urine. The PET scans were analyzed to determine the radiotracer uptake in different organs. OLINDA/EXM software was used to calculate human radiation doses based on human and monkey biodistributions. Results: 18F-RGD-K5 was metabolically stable in human blood up to 90 min after injection, and it cleared rapidly from the blood pool, with a 12-min half-time. For both monkeys and humans, increased 18F-RGD-K5 uptake was observed in the kidneys, bladder, liver, and gallbladder, with mean standardized uptake values at 1 h after injection for humans being approximately 20, 50, 4, and 10, respectively. For human biodistribution data, the calculated effective dose was 31 ± 1 μSv/MBq, and the urinary bladder wall had the highest absorbed dose at 376 ± 19 μGy/MBq using the 4.8-h bladder-voiding model. With the 1-h voiding model, these doses reduced to 15 ± 1 μSv/MBq for the effective dose and 103 ± 4 μGy/MBq for the absorbed dose in the urinary bladder wall. For a typical injected activity of 555 MBq, the effective dose would be 17.2 ± 0.6 mSv for the 4.8-h model, reducing to 8.3 ± 0.4 mSv for the 1-h model. For monkey biodistribution data, the effective dose to humans would be 22.2 ± 2.4 mSv for the 4.8-h model and 12.8 ± 0.2 mSv for the 1-h model. Conclusion: The biodistribution profile of 18F-RGD-K5 in monkeys and humans was similar, with increased uptake in the bladder, liver, and kidneys. There was rapid clearance of 18F-RGD-K5 through the renal system. The urinary bladder wall received the highest radiation dose and was deemed the critical organ. Both whole-body effective dose and bladder dose can be reduced by more frequent voiding. 18F-RGD-K5 can be used safely for imaging αvβ3 integrin expression in humans.

Use of Molecular Imaging to Predict Clinical Outcome in Patients With Rectal Cancer After Preoperative Chemotherapy and Radiation

PURPOSEnTo correlate changes in 2-deoxy-2-[18F]fluoro-d-glucose (18-FDG) positron emission tomography (PET) (18-FDG-PET) uptake with response and disease-free survival with combined modality neoadjuvant therapy in patients with locally advanced rectal cancer.nnnMETHODS AND MATERIALSnCharts were reviewed for consecutive patients with ultrasound-staged T3x to T4Nx or TxN1 rectal adenocarcinoma who underwent preoperative chemoradiation therapy at Fox Chase Cancer Center (FCCC) or Robert H. Lurie Comprehensive Cancer Center of Northwestern University with 18-FDG-PET scanning before and after combined-modality neoadjuvant chemoradiation therapy . The maximum standardized uptake value (SUV) was measured from the tumor before and 3 to 4 weeks after completion of chemoradiation therapy preoperatively. Logistic regression was used to analyze the association of pretreatment SUV, posttreatment SUV, and % SUV decrease on pathologic complete response (pCR), and a Cox model was fitted to analyze disease-free survival.nnnRESULTSnA total of 53 patients (FCCC, n = 41, RLCCC, n = 12) underwent pre- and postchemoradiation PET scanning between September 2000 and June 2006. The pCR rate was 31%. Univariate analysis revealed that % SUV decrease showed a marginally trend in predicting pCR (p = 0.08). In the multivariable analysis, posttreatment SUV was shown a predictor of pCR (p = 0.07), but the test results did not reach statistical significance. None of the investigated variables were predictive of disease-free survival.nnnCONCLUSIONSnA trend was observed for % SUV decrease and posttreatment SUV predicting pCR in patients with rectal cancer treated with preoperative chemoradiation therapy. Further prospective study with a larger sample size is warranted to better characterize the role of 18-FDG-PET for response prediction in patients with rectal cancer.

Predicting Pathological Response to Neoadjuvant Chemoradiotherapy in Locally Advanced Rectal Cancer Using 18FDG-PET/CT

BackgroundPathologic complete response (pCR) after neoadjuvant chemoradiation (CRT) has been observed in 15–30% of patients with locally advanced rectal cancer (LARC). The objective of this study was to determine whether PET/CT can predict pCR and disease-free survival in patients receiving CRT with LARC.MethodsThis is a retrospective review of patients with EUS-staged T3–T4, Nxa0+xa0rectal tumors treated with CRT, who underwent pre/post-treatment PET/CT from 2002–2009. All patients were treated with CRT and surgical resection. Standardized uptake value (SUV) of each tumor was recorded. Logistic regression was used to analyze the association of pre-CRT SUV, post-CRT SUV, %SUV change, and time between CRT and surgery, compared with pCR. Kaplan–Meier estimation evaluated significant predictors of survival.ResultsSeventy patients (age 62xa0years; 42M:28F) with preoperative stage T3 (nxa0=xa061) and T4 (nxa0=xa09) underwent pre- and post-CRT PET/CT followed by surgery. The pCR rate was 26%. Median pre-CRT SUV was 10.8, whereas the median post-CRT SUV was 4 (Pxa0=xa00.001). Patients with pCR had a lower median post-CRT SUV compared with those without (2.7 vs. 4.5, Pxa0=xa00.01). Median SUV decrease was 63% (7.5–95.5%) and predicted pCR (Pxa0=xa00.002). Patients with a pCR had a greater time interval between CRT and surgery (median, 58 vs. 50xa0days) than those without (Pxa0=xa00.02). Patients with post-CRT SUVxa0<xa04 had a lower recurrence compared with those without (Pxa0=xa00.03). Patients with SUV decrease ≥63% had improved overall survival at median follow-up of 40xa0months than those without (Pxa0=xa00.006).ConclusionsPET/CT can predict response to CRT in patients with LARC. Posttreatment SUV, %SUV decrease, and greater time from CRT to surgery correlate with pCR. Post-CRT, SUVxa0<xa04, and SUV decrease ≥63% were predictive of recurrence-free and overall survival.

Biodistribution and radiation dosimetry of the hypoxia marker 18F-HX4 in monkeys and humans determined by using whole-body PET/CT.

Objectives 18F-HX4 is a novel positron emission tomography (PET) tracer for imaging hypoxia. The purpose of this study was to determine the biodistribution and estimate the radiation dose of 18F-HX4 using whole-body PET/computed tomography (CT) scans in monkeys and humans. MethodsSuccessive whole-body PET/CT scans were done after the injection of 18F-HX4 in four healthy humans (422±142 MBq) and in three rhesus monkeys (189±3 MBq). Biodistribution was determined from PET images and organ doses were estimated using OLINDA/EXM software. ResultsThe bladder, liver, and kidneys showed the highest percentage of the injected radioactivity for humans and monkeys. For humans, approximately 45% of the activity is eliminated by bladder voiding in 3.6 h, and for monkeys 60% is in the bladder content after 3 h. The critical organ is the urinary bladder wall with the highest absorbed radiation dose of 415±18 (monkeys) and 299±38 &mgr;Gy/MBq (humans), in the 4.8-h bladder voiding interval model. The average value of effective dose for the adult male was estimated at 42±4.2 &mgr;Sv/MBq from monkey data and 27±2 &mgr;Sv/MBq from human data. ConclusionBladder, kidneys, and liver have the highest uptake of injected 18F-HX4 activity for both monkeys and humans. The urinary bladder wall receives the highest dose of 18F-HX4 and is the critical organ. Thus, patients should be encouraged to maintain adequate hydration and void frequently. The effective dose of 18F-HX4 is comparable with that of other 18F-based imaging agents.

Symptomatic cardiac toxicity is predicted by dosimetric and patient factors rather than changes in 18F-FDG PET determination of myocardial activity after chemoradiotherapy for esophageal cancer☆

PURPOSEnTo determine factors associated with symptomatic cardiac toxicity in patients with esophageal cancer treated with chemoradiotherapy.nnnMATERIAL AND METHODSnWe retrospectively evaluated 102 patients treated with chemoradiotherapy for locally advanced esophageal cancer. Our primary endpoint was symptomatic cardiac toxicity. Radiation dosimetry, patient demographic factors, and myocardial changes seen on (18)F-FDG PET were correlated with subsequent cardiac toxicity. Cardiac toxicity measured by RTOG and CTCAE v3.0 criteria was identified by chart review.nnnRESULTSnDuring the follow up period, 12 patients were identified with treatment related cardiac toxicity, 6 of which were symptomatic. The mean heart V20 (79.7% vs. 67.2%, p=0.05), V30 (75.8% vs. 61.9%, p=0.04), and V40 (69.2% vs. 53.8%, p=0.03) were significantly higher in patients with symptomatic cardiac toxicity than those without. We found the threshold for symptomatic cardiac toxicity to be a V20, V30 and V40 above 70%, 65% and 60%, respectively. There was no correlation between change myocardial SUV on PET and cardiac toxicity, however, a greater proportion of women suffered symptomatic cardiac toxicity compared to men (p=0.005).nnnCONCLUSIONSnA correlation did not exist between percent change in myocardial SUV and cardiac toxicity. Patients with symptomatic cardiac toxicity received significantly greater mean V20, 30 and 40 values to the heart compared to asymptomatic patients. These data need validation in a larger independent data set.

Evaluation of the Anti-HER2 C6.5 Diabody as a PET Radiotracer to Monitor HER2 status and Predict Response to Trastuzumab Treatment

Purpose: The rapid tumor targeting and pharmacokinetic properties of engineered antibodies make them potentially suitable for use in imaging strategies to predict and monitor response to targeted therapies. This study aims to evaluate C6.5 diabody (C6.5db), a noncovalent anti-HER2 single-chain Fv dimer, as a radiotracer for predicting response to HER2-targeted therapies such as trastuzumab. Experimental Design: Immunodeficient mice bearing established HER2-positive tumor xenografts were injected with radioiodinated C6.5db and imaged by PET/CT. Radiotracer biodistribution was quantified by biopsied tumor and normal tissues. Potential competition between trastuzumab and C6.5db was examined in vitro by flow cytometry and coimmunoprecipitations. Results: Biodistribution analysis of mice bearing xenografts with varying HER2 density revealed that the tumor uptake of 125I-C6.5db correlates with HER2 tumor density. In vitro competition experiments suggest that the C6.5db targets an epitope on HER2 that is distinct from that bound by trastuzumab. Treatment of mice affected with SK-OV-3 tumor with trastuzumab for 3 days caused a 42% (P = 0.002) decrease in tumor uptake of 125I-C6.5db. This is consistent with a dramatic decrease in the tumor PET signal of 124I-C6.5db after trastuzumab treatment. Furthermore, mice affected with BT-474 tumor showed an approximately 60% decrease (P = 0.0026) in C6.5db uptake after 6 days of trastuzumab treatment. Immunohistochemistry of excised xenograft sections and in vitro flow cytometry revealed that the decreased C6.5db uptake on trastuzumab treatment is not associated with HER2 downregulation. Conclusions: These studies suggest that 124I-C6.5db–based imaging can be used to evaluate HER2 levels as a predictor of response to HER2-directed therapies. Clin Cancer Res; 17(6); 1509–20. ©2010 AACR.

Findings of intramediastinal gossypiboma with F-18 FDG PET in a melanoma patient.

FDG PET/CT scan was performed to evaluate recurrence in an asymptomatic 64-year-old man with a history of melanoma in the left posterior ear. PET/CT images showed an intense ring-shaped area of FDG activity in the posterior mediastinum in a large posterior mediastinal mass. However, further evaluation indicated that this activity was caused by an intramediastinal gossypiboma after coronary artery bypass graft surgery 4 years before the PET/CT scan.

Biodistribution and Radiation Dosimetry of the Carbonic Anhydrase IX Imaging Agent [18 F]VM4-037 Determined from PET/CT Scans in Healthy Volunteers

Purpose[18u2009F]VM4-037 has been developed as a positron emission tomography (PET) imaging marker to detect carbonic anhydrase IX (CA-IX) overexpression and is being investigated for use as a surrogate marker for tissue hypoxia. The purpose of this study was to determine the biodistribution and estimate the radiation dose from [18u2009F]VM4-037 using whole-body PET/CT scans in healthy human volunteers.ProceduresSuccessive whole-body PET/CT scans were performed after intravenous injection of [18u2009F]VM4-037 in four healthy humans. The radiotracer uptakes in different organs were determined from the analysis of the PET scans. Human radiation doses were estimated using OLINDA/EXM software.ResultsHigh uptake of [18u2009F]VM4-037 was observed in the liver and kidneys, with little clearance of activity during the study period, with mean standardized uptake values of ~35 in liver and ~22 in kidneys at ~1xa0h after injection. The estimated effective dose was 28u2009±u20091xa0μSv/MBq and the absorbed doses for the kidneys and liver were 273u2009±u200931 and 240u2009±u200968xa0μGy/MBq, respectively, for the adult male phantom. Hence, the effective dose would be 10u2009±u20090.5xa0mSv for the anticipated injected activity of 370xa0MBq, and the kidney and liver doses would be 101u2009±u200911 and 89u2009±u200925xa0mGy, respectively.Conclusions[18u2009F]VM4-037 displayed very high uptake in the liver and kidneys with little clearance of activity during the study period, resulting in these organs receiving the highest radiation doses among all bodily organs. Though the effective dose and the organ doses are within the limits considered as safe, the enhanced uptake of [18u2009F]VM4-037 in the kidneys and liver will make the compound unsuitable for imaging overexpression of CA-IX in those two organs. However, the tracer may be suitable for imaging overexpression of CA-IX in lesions in other regions of the body such as in the lungs or head and neck region.

The Role of Qualitative and Quantitative Analysis of F18-FDG Positron Emission Tomography in Predicting Pathologic Response Following Chemoradiotherapy in Patients with Esophageal Carcinoma

ObjectiveThe aim of this study was to determine if a qualitative and quantitative assessment of pre- and post-chemoradiotherapy (CRT) F18-FDG PET scans of esophageal cancer patients could predict for residual disease in esophagectomy specimens.MethodsWe retrospectively reviewed the records of esophageal cancer patients who had undergone CRT at a single institution. Analysis was limited to esophagectomy patients with both pre- and post-CRT F18-FDG PET scans. The maximum standardized uptake value (SUV), location, and measured length of esophagus with increased F18-FDG uptake were obtained from the PET scan before and 3–4xa0weeks following CRT (preoperatively). The pattern of F18-FDG uptake was qualitatively assigned a category of diffuse, focal, or diffuse with focal component.ResultsFifty-seven patients with localized esophageal carcinoma underwent F18-FDG PET/CT scans as part of their initial staging and post-CRT restaging workup, followed by esophagectomy. The pathologic complete response (pCR) rate was 25xa0%. The presence of a focal component on post-CRT PET predicted residual disease on univariate analysis (86xa0% vs. 64xa0%), and achieved significance when controlling for SUV and presence of diabetes on MVA (ORu2009=u20095.59, pu2009=u20090.028). There was no significant relationship between pre- or post-CRT SUV, tumor histology, or length of increased F18-FDG uptake and presence of residual disease. SUV and focality did not interact significantly to predict residual disease.ConclusionsQualitative but not quantitative PET imaging can help predict increased likelihood of residual tumor in esophageal cancer patients following CRT; however, it is not sensitive enough to solely rule out the presence of residual disease. Additional investigation with a larger cohort of patients is warranted.

Potential role of 124 I-girentuximab in the presurgical diagnosis of clear-cell renal cell cancer

Renal cell carcinoma (RCC) is a biologically heterogeneous disease, with many small renal masses (SRMs) exhibiting an indolent natural history, while others progress more rapidly to become life-threatening. Existing multiphase contrast-enhanced imaging methods, such as computed tomography or magnetic resonance imaging, cannot definitively distinguish between benign and malignant solid tumors or identify histologic subtype, and early results of molecular imaging studies (positron emission tomography [PET]) in the evaluation of SRMs have not improved on these established modalities. Alternative molecular markers/agents recognizing aberrant cellular pathways of cellular oxidative metabolism, DNA synthesis, and tumor hypoxia tracers are currently under development and investigation for RCC assessment, but to date none are yet clinically applicable or available. In contrast, immuno-PET offers highly selective binding to cancer-specific antigens, and might identify radiographically recognizable and distinct molecular targets. A phase I proof-of-concept study first demonstrated the ability of immuno-PET to discriminate between clear-cell RCC (ccRCC) and non-ccRCC, utilizing a chimeric monoclonal antibody to carbonic anhydrase IX (cG250, girentuximab) labeled with 124I (124I-girentuximab PET); the study examined patients with renal masses who subsequently underwent standard surgical resection. A follow-up phase III multicenter trial confirmed that 124I-cG250-PET can accurately and noninvasively identify ccRCC with high sensitivity (86%), specificity (87%), and positive predictive value (95%). In the challenge to appropriately match treatment of an incidentally identified SRM to its biological potential, this highly accurate and histologically specific molecular imaging modality demonstrates the ability of imaging to provide clinically important preoperative diagnostic information, which can result in optimal and personalized therapy.