Impact of preoperative 18F-FDG PET/CT on survival of resected mono-metastatic non-small cell lung cancer.

OBJECTIVES: Surgery has been available for the treatment of mono-metastatic, non-small cell lung cancer (NSCLC) and promising overall survival was observed in some retrospective studies with selected patients. This study investigated whether the preoperative 18-fluorodeoxyglucose positron emission tomography/computed tomography ((18)F-FDG-PET/CT) scan influences survival in this patient group. Furthermore we tried to identify other prognostic factors associated with survival and aimed to clarify if synchronous metastases are different from metachronous disease. METHODS: Between 1994 and 2012, 181 patients underwent resection for solitary metastases. Sixty-six patients underwent surgery after an initial FDG-PET/CT scan, whereas 115 patients underwent conventional preoperative staging by a spiral CT scan. RESULTS: The overall 5-year survival rate was 38.8%. The 5-year survival rates after preoperative evaluation by FDG-PET/CT and by conventional CT were 58% and 33%, respectively (p=0.01). A higher 5-year survival rate was observed in patients without thoracic lymph node involvement (pN0: 44% vs. pN1-3: 33%, p=0.028). In patients with a solitary pulmonary metastasis, we observed a 5-year survival rate of 45.7%, whereas in patients with extrapulmonary metastases, the 5-year survival rate was 27.1% (p=0.001). In patients with a locally limited primary lung cancer according to the pT descriptor, we observed a 5-year survival rate of 53.1%, whereas in patients with a pT>1 descriptor, the 5-year survival rate was 33.6% (p=0.016). By multivariate analyses, we showed that preoperative FDG-PET/CT evaluation, no thoracic lymph node metastases, and sole pulmonary metastatic disease were favorable predictors of survival, whereas the time of metastasis (synchronous vs. metachronous) and maximum standardized uptake value was not. CONCLUSIONS: We conclude that resection of the primary tumor and metastasectomy for mono-metastatic NSCLC can be performed after a comprehensive evaluation with FDG-PET/CT. N-stage and the site of the oligometastases have a significant influence on overall survival.

Biodistribution and efficacy of [131I]A33scFv::CDy, a recombinant antibody-enzyme protein for colon cancer.

In antibody-directed enzyme-prodrug therapy (ADEPT), an antibody-bound enzyme localizes to tumor tissue, where it selectively converts a subsequently administered non-toxic prodrug into a cytotoxic drug. A33scFv::CDy is a bifunctional fusion construct comprising a single chain antibody against the gpA33 antigen and the prodrug-converting enzyme cytosine deaminase. gpA33 is highly and homogeneously expressed in >95% of all colorectal cancers. Here we describe the biodistribution and tumor-targeting capacity of 131I labeled A33scFv::CDy. 131I labeling of A33scFv::CDy was performed by the chloramine-T method, and the properties of the resulting [131I]A33scFv::CDy conjugate were determined in vivo and in vitro, including biodistribution studies in nude mice bearing human LIM1215 colon carcinoma xenografts. The [131I]A33scFv::CDy conjugate bound specifically to colorectal cancer cells in vitro with KD = 15.8 nM as determined by a saturation assay. in vivo, the tumor uptake of [131I]A33scFv::CDy peaked at 87% injected dose/g 47 h post injection. Normal tissue uptake was low, and activity in blood was lower than in tumor at all time-points studied (6-92 h). The tumor-to-blood ratio increased over time with a maximum of 8.1 at 67 h post injection. [131I]A33scFv::CDy thus shows a biodistribution that makes it attractive for both radioimmunotherapy (RIT) and ADEPT. Preliminary therapeutic experiments showed a significant reduction of tumor size in mice treated with the A33scFv::CDy-5-fluorocytosine/5-fluorouracil ADEPT system. This work demonstrates the feasibility of ADEPT and RIT based on the A33scFv::CDy recombinant construct.

Multimodality registration without a dedicated multimodality scanner.

Multimodality scanners that allow the acquisition of both functional and structural image sets on a single system have recently become available for animal research use. Although the resultant registered functional/structural image sets can greatly enhance the interpretability of the functional data, the cost of multimodality systems can be prohibitive, and they are often limited to two modalities, which generally do not include magnetic resonance imaging. Using a thin plastic wrap to immobilize and fix a mouse or other small animal atop a removable bed, we are able to calculate registrations between all combinations of four different small animal imaging scanners (positron emission tomography, single-photon emission computed tomography, magnetic resonance, and computed tomography [CT]) at our disposal, effectively equivalent to a quadruple-modality scanner. A comparison of serially acquired CT images, with intervening acquisitions on other scanners, demonstrates the ability of the proposed procedures to maintain the rigidity of an anesthetized mouse during transport between scanners. Movement of the bony structures of the mouse was estimated to be 0.62 mm. Soft tissue movement was predominantly the result of the filling (or emptying) of the urinary bladder and thus largely constrained to this region. Phantom studies estimate the registration errors for all registration types to be less than 0.5 mm. Functional images using tracers targeted to known structures verify the accuracy of the functional to structural registrations. The procedures are easy to perform and produce robust and accurate results that rival those of dedicated multimodality scanners, but with more flexible registration combinations and while avoiding the expense and redundancy of multimodality systems.

Pretargeted radioimmunotherapy with a single-chain antibody/streptavidin construct and radiolabeled DOTA-biotin: strategies for reduction of the renal dose.

UNLABELLED: Multistep immune targeting holds great promise for radioimmunodiagnosis and therapy of cancer. Pretargeting of the tetrameric single-chain, variable-fragment streptavidin construct of the tetrameric monoclonal antibody CC49 with subsequent administration of radiolabeled 1,4,7,10-tetraazacyclododecane-N,N',N'',N'''-tetraacetic acid (DOTA)-biotin has yielded promising results in TAG-72-expressing tumor xenograft models. A potential limitation of this approach, however, has been high and prolonged renal uptake of radioactivity. The objective of the current study, therefore, was to evaluate the reduction of kidney uptake of radiolabeled DOTA-biotin achieved by each of 4 different methods. METHODS: A human pancreatic adenocarcinoma xenograft model (HPAC) in nude mice was used. The animals were intravenously injected with the antibody-streptavidin construct and a synthetic clearing agent (biotinylated N-acetyl-galactosamine) 24 and 4 h, respectively, before the administration of (67)Ga-DOTA-biotin. For reduction of the renal uptake, different groups of mice were treated with streptavidin saturated with biotin, with several administrations of lysine or colchicine or with a succinylated antibody-streptavidin construct (resulting in a decreased electrical charge). All animals were sacrificed 24 h after injection of the (67)Ga-DOTA-biotin for biodistribution and quantitative autoradiography (QAR) studies and selected animals underwent microSPECT/microCT studies. RESULTS: There was marked targeting of the radiolabeled DOTA-biotin to tumor in all groups except in negative-control animals. Only succinylation of the scFv-CC49-streptavidin fusion protein significantly reduced ( approximately 30%) kidney uptake without affecting tumor activity. QAR corroborated these results and demonstrated that radiolabeled DOTA-biotin localized selectively in the renal cortex. Among the other experimental groups, there was no change in kidney uptake of the radiolabeled biotin. CONCLUSION: In contrast to directly labeled antibodies and antibody fragments, administration of the negatively charged amino acid lysine was largely ineffective in pretargeting strategies with a single-chain-immuno-streptavidin fusion protein. Succinylation of the scFv-CC49-streptavidin construct, on the other hand, reduces kidney uptake of subsequently administered radiolabeled biotin, presumably by inhibiting reuptake of the fusion protein in the proximal renal tubules, and, therefore, could significantly reduce renal doses and improve therapeutic indices associated with multistep immune targeting approaches to radioimmunotherapy.

Pre-therapeutic dosimetry and biodistribution of 86Y-DOTA-Phe1-Tyr3-octreotide versus 111In-pentetreotide in patients with advanced neuroendocrine tumours.

PURPOSE: For the internal radiotherapy of neuroendocrine tumours, the somatostatin analogue DOTATOC labelled with 90Y is frequently used [90Y-DOTA-Phe1-Tyr3)-octreotide (SMT487-OctreoTher)]. Radiation exposure to the kidneys is critical in this therapy as it may result in renal failure. The aim of this study was to compare cumulative organ and tumour doses based upon dosimetric data acquired with the chemically identical 86Y-DOTA-Phe1-Tyr3-octreotide (considered as the gold standard) and the commercially available 111In-pentetreotide. METHODS: The cumulative organ and tumour doses for the therapeutic administration of 13.32 GBq 90Y-DOTA-Phe1-Tyr3-octreotide (three cycles, each of 4.44 GBq) were estimated based on the MIRD concept (MIRDOSE 3.1 and IMEDOSE). Patients with a cumulative kidney dose exceeding 27 Gy had to be excluded from subsequent therapy with 90Y-DOTA-Phe1-Tyr3-octreotide, in accordance with the directives of the German radiation protection authorities. RESULTS: The range of doses (mGy/MBq 90Y-DOTA-Phe1-Tyr3-octreotide) for kidneys, spleen, liver and tumour masses was 0.6-2.8, 1.5-4.2, 0.3-1.3 and 2.1-29.5 (86Y-DOTA-Phe1-Tyr3-octreotide), respectively, versus 1.3-3.0, 1.8-4.4, 0.2-0.8 and 1.4-19.7 (111In-pentetreotide), with wide inter-subject variability. Despite renal protection with amino acid infusions, estimated cumulative kidney doses in two patients exceeded 27 Gy. CONCLUSION: Compared with 86Y-DOTA-Phe1-Tyr3-octreotide, dosimetry with 111In-pentetreotide overestimated doses to kidneys and spleen, whereas the radiation dose to the tumour-free liver was underestimated. However, both dosimetric approaches detected the two patients with an exceptionally high radiation burden to the kidneys that carried a potential risk of renal failure following radionuclide therapy.

Detection of recurrent oral squamous cell carcinoma by [18F]-2-fluorodeoxyglucose-positron emission tomography: implications for prognosis and patient management.

BACKGROUND: Patients with recurrent oral squamous cell carcinoma (OSCC) have a dismal prognosis and represent a therapeutic challenge. A positron emission tomography (PET) scan with [(18)F]-2-fluorodeoxyglucose ([(18)F]FDG) can improve early cancer detection. The current study evaluates the prognostic value of [(18)F]FDG-PET scan in patients with recurrent OSCC. METHODS: The authors studied 97 patients with previously resected OSCC who were restaged by PET scanning. Of the 97 patients, 64 had no evidence of clinical disease and 33 were suspected of having disease by imaging, clinical findings, or pathologic evaluation. The median follow-up period was 35.4 months after a PET scan. The end points included disease recurrence, a disease recurrence-free period 6 months after a PET scan, or death. RESULTS: The overall sensitivity of a PET scan did not exceed 90% and its specificity varied from 67% for local disease recurrence/second primaries to 99% for lymph node metastasis. Increased [(18)F]FDG uptake predicted increased hazard of death (hazard ratio: 6.83; P = 0.00034) and proved to be a highly predictive marker of disease status. A significant association was established for incremental standardized uptake values and 3-year patient survival (P=0.0089), indicating that intense glucose metabolism in the tumor is a negative marker of survival in recurrent OSCC. Overall, survival was longer in patients with a negative rather than a positive PET scan (P < 0.00001). CONCLUSIONS: PET scanning was found to be highly valuable for diagnosing OSCC recurrence in a postoperative setting. It provided prognostic information and played an important role in patient counseling and management.

Radiation response non-invasively imaged by [18F]FDG-PET predicts local tumor control and survival in advanced oral squamous cell carcinoma.

It is a major challenge to preoperatively identify patients who will profit from surgery of advanced oral cancer. In multimodality therapy, response to neoadjuvant radiation correlates to treatment success. Hence, for preoperative decisions, assessment of treatment response is required. Therefore, we analysed the prognostic significance of glucose metabolism after preoperative radiotherapy. [(18)F]FDG-PET investigations were performed for re-staging 35 patients after neoadjuvant radiotherapy (36Gy) immediately prior to tumor resection. Emission and transmission measurements were obtained and SUV's were calculated for the sites of maximum [(18)F]FDG-uptake. Subpopulations of "low" (SUV < 4) and "high" (SUV > or = 4) glucose metabolism were compared by univariate and multivariate survival analysis. 3-years survival was 80% in the "low" SUV group and 43% in the "high" SUV group. Post-irradiation [(18)F]FDG-uptake significantly predicts survival (P = 0.046) and local tumor control (P = 0.0017). High [(18)F]FDG-uptake was associated with an increased hazard of death (P = 0.037) and especially of local progress (P = 0.011) even when radical resection was performed. Thus, [(18)F]FDG-PET non invasively identified patients with poor prognosis whose indication for radical surgery has to be considered with caution.

SPET/CT image co-registration in the abdomen with a simple and cost-effective tool.

Fusion of morphology and function has been shown to improve diagnostic accuracy in many clinical circumstances. Taking this into account, a number of instruments combining computed tomography (CT) with positron emission tomography (PET) or single-photon emission tomography (SPET) are appearing on the market. The aim of this study was to evaluate a simple and cost-effective approach to generate fusion images of similar quality. For the evaluation of the proposed approach, patients with neuroendocrine abdominal tumours with liver metastases were chosen, since the exact superimposition in the abdomen is more difficult than in other regions. Five hours following the injection of 110 MBq (111)In-DTPA-octreotide, patients were fixed in a vacuum cushion (MED-TEC, Vac-Loc) and investigated with helical CT in a mid-inspiration position ( n=14). Directly following the CT, a SPET study (SPET1) of the abdominal region was performed without changing the position of the patient. A second SPET study (SPET2), 24 h p.i., was acquired after repositioning the patient in his or her individually moulded vacuum cushion. A total of nine markers suitable for imaging with CT and SPET were fixed on the cushion. Datasets were fused by means of internal landmarks (e.g. metastases or margin of abdominal organs) or by the external markers. Image fusion using external markers was fast and easy to handle compared with the use of internal landmarks. Using this technique, all lesions detectable by SPET ( n=28) appeared exactly superpositioned on the respective CT morphology by visual inspection. Image fusion of CT/SPET1 and CT/SPET2 showed a mean deviation of the external markers that in the former case was smaller than the voxel size of 4.67 mm: 4.17+/-0.61 (CT/SPET1; +/-SD) and 5.52+/-1.56 mm (CT/SPET2), respectively. Using internal landmarks, the mean deviation of the chosen landmarks was 6.47+/-1.37 and 7.78+/-1.21 mm. Vector subtraction of corresponding anatomical points of the CT and the re-sampled SPET volume datasets resulted in a similar accuracy. Vector subtraction of the metastases showed a significantly less accurate superimposition when internal landmarks were used ( P<0.001). The vacuum cushion did not affect the image quality of CT and SPET. The proposed technique is a simple and cost-effective way to generate abdominal datasets suitable for image fusion. External markers positioned on the cushion allow for a rapid and robust overlay even if no readily identifiable internal landmarks are present. This technique is, in principle, also suitable for CT/PET fusion as well as for fusions of MRI data with PET or SPET.