In Vivo Assessment of Ovarian Tumor Response to Tyrosine Kinase Inhibitor Pazopanib by Using Hyperpolarized 13C-Pyruvate MR Spectroscopy and 18F-FDG PET/CT Imaging in a Mouse Model.

Purpose To assess in a mouse model whether early or late components of glucose metabolism, exemplified by fluorine 18 (18F) fluorodeoxyglucose (FDG) positron emission tomography (PET) and hyperpolarized carbon 13 (13C)-pyruvate magnetic resonance (MR) spectroscopy, can serve as indicators of response in ovarian cancer to multityrosine kinase inhibitor pazopanib. Materials and Methods In this Animal Care and Use Committee approved study, 17 days after the injection of 2 × 106 human ovarian SKOV3 tumors cells into 14 female nude mice, treatment with vehicle or pazopanib (2.5 mg per mouse peroral every other day) was initiated. Longitudinal T2-weighted MR imaging, dynamic MR spectroscopy of hyperpolarized pyruvate, and 18F-FDG PET/computed tomographic (CT) imaging were performed before treatment, 2 days after treatment, and 2 weeks after treatment. Results Pazopanib inhibited ovarian tumor growth compared with control (0.054 g ± 0.041 vs 0.223 g ± 0.112, respectively; six mice were treated with pazopanib and seven were control mice; P < .05). Significantly higher pyruvate-to-lactate conversion (lactate/pyruvate + lactate ratio) was found 2 days after treatment with pazopanib than before treatment (0.46 ± 0.07 vs 0.31 ± 0.14, respectively; P < .05; six tumors after treatment, seven tumors before treatment). This was not observed with the control group or with 18F-FDG PET/CT imaging. Conclusion The findings suggest that hyperpolarized 13C-pyruvate MR spectroscopy may serve as an early indicator of response to tyrosine kinase (angiogenesis) inhibitors such as pazopanib in ovarian cancer even when 18F-FDG PET/CT does not indicate a response. © RSNA, 2017 Online supplemental material is available for this article.

Feasibility of a reduced field-of-view diffusion-weighted (rFOV) sequence in assessment of myometrial invasion in patients with clinical FIGO stage I endometrial cancer.

PURPOSE: To compare the clinical usefulness of reduced field-of-view diffusion-weighted imaging (rFOV) with other imaging techniques in determining the depth of myometrial invasion (DMI) in endometrial cancer. MATERIALS AND METHODS: In this prospective study we reviewed 3T magnetic resonance images of 51 patients with clinical Stage I endometrial cancer who underwent total abdominal hysterectomy with bilateral salphingoopherectomy within 3 days after imaging. rFOV with apparent diffusion coefficient reconstruction was obtained in three standard planes followed by sagittal T2 -weighted (T2 WI) images and 3D dynamic T1 -weighted and contrast-enhanced imaging (DCE MRI). Two radiologists with expertise in imaging gynecologic cancers evaluated images independently. The DMI was recorded on imaging and correlated with surgical pathology results. Sensitivity, specificity, positive predictive value, negative predictive value, and accuracy for DMI were calculated (<50% vs. >50%). RESULTS: Compared with sagittal T2 WI + DCE MRI, rFOV imaging yielded greater specificity (82.2% vs. 90.0%, positive predictive value (42.8% vs. 60.0%), and accuracy (84.0% vs. 92%) for DMI determined by reader 1 and greater the sensitivity (83.3% vs. 100%) for DMI determined by reader 2. The error of measurement of DMI as a continuous variable in millimeters did not differ significantly between the rFOV and pathology results (P < 0.21). However, there was a statistically significant difference for the DMI measured on the dynamic sequence. The DMI on DCE was greater than that seen on pathology at P = 0.02. CONCLUSION: rFOV can be used to assess DMI in clinical Stage I endometrial cancer.

Noninvasive assessment of gene transfer and expression by in vivo functional and morphologic imaging in a rabbit tumor model.

PURPOSE: To evaluate the importance of morphology in quantifying expression after in vivo gene transfer and to compare gene expression after intra-arterial (IA) and intra-tumoral (IT) delivery of adenovirus expressing a SSTR2-based reporter gene in a large animal tumor model. MATERIALS AND METHODS: Tumor directed IA or IT delivery of adenovirus containing a human somatostatin receptor type 2A (Ad-CMV-HA-SSTR2A) gene chimera or control adenovirus (Ad-CMV-GFP) was performed in VX2 tumors growing in both rabbit thighs. Three days later, ¹¹¹In-octreotide was administered intravenously after CT imaging using a clinical scanner. ¹¹¹In-octreotide uptake in tumors was evaluated the following day using a clinical gamma-camera. Gene expression was normalized to tumor weight with and without necrosis. This procedure was repeated on nine additional rabbits to investigate longitudinal gene expression both 5 days and 2 weeks after adenovirus delivery. CT images were used to evaluate tumor morphology and excised tissue samples were analyzed to determine ¹¹¹In-octreotide biodistribution ex vivo. RESULTS: VX2 tumors infected with Ad-CMV-HA-SSTR2 had greater ¹¹¹In-octreotide uptake than with control virus (P<0.05). Intra-arterial and intra-tumoral routes resulted in similar levels of gene expression. Longitudinally, expression appeared to wane at 2 weeks versus 5 days after delivery. Areas of necrosis did not demonstrate significant uptake ex vivo. Morphology identified areas of necrosis on contrast enhanced CT and upon excluding necrosis, in vivo biodistribution analysis resulted in greater percent injected dose per gram (P<0.01) and corresponded better with ex vivo biodistribution(r = 0.72, P<0.01, Coefficient of the x-variable = .72) at 2 weeks than without excluding necrosis (P<0.01). CONCLUSION: Tumor specificity and high transgene expression can be achieved in tumors via both tumor directed intra-arterial and intra-tumoral delivery in a large animal tumor model. Using clinical machines, morphologic imaging contributes to functional imaging for quantifying SSTR2-based reporter expression in vivo.

Perfusion CT assessment of tissue hemodynamics following hepatic arterial infusion of increasing doses of angiotensin II in a rabbit liver tumor model.

PURPOSE: To investigate the effects of increasing doses of angiotensin II on hepatic hemodynamics in the normal rabbit liver and in hepatic VX2 tumors by using dynamic contrast material-enhanced perfusion computed tomography (CT). MATERIALS AND METHODS: This study was approved by the institutional animal care and use committee. Solitary hepatic VX2 tumors were implanted into 12 rabbits. In each animal, perfusion CT of the liver was performed before (at baseline) and after hepatic arterial infusion of varying doses (0.1-50.0 µg/mL) of angiotensin II. Images were acquired continuously for 80 seconds after the start of the intravenous contrast material administration. Blood flow (BF), blood volume (BV), mean transit time (MTT), and capillary permeability-surface area product were calculated for the tumor and the adjacent and distant normal liver tissue. Generalized linear mixed models were used to estimate the effects of angiotensin II dose on outcome measures. RESULTS: Angiotensin II infusion increased contrast enhancement of the tumor and distal liver vessels. Tumor BF increased in a dose-dependent manner after administration of 0.5-25.0 µg/mL angiotensin II, but only the 2.5 µg/mL dose induced a significant increase in tumor BF compared with BF in the adjacent (68.0 vs 26.3 mL/min/100 g, P < .0001) and distant (68.0 vs 28.3 mL/min/100 g, P = .02) normal liver tissue. Tumor BV varied with angiotensin II dose but was greater than the BV of the adjacent and distant liver tissue at only the 2.5 µg/mL (4.8 vs 3.5 mL/100 g for adjacent liver [P < .0001], 4.8 vs 3.3 mL/100 g for distant liver [P = .0006]) and 10.0 µg/mL (4.9 vs 4.4 mL/100 g for adjacent liver [P = .007], 4.9 vs 4.3 mL/100 g for distant liver [P = .04]) doses. Tumor MTT was significantly shorter than the adjacent liver tissue MTT at angiotensin II doses of 2.5 µg/mL (9.7 vs 15.8 sec, P = .001) and 10.0 µg/mL (5.1 vs 13.2 sec, P = .007) and significantly shorter than the distant liver tissue MTT at 2.5 µg/mL only (9.7 vs 15.3 sec, P = .0006). The capillary permeability-surface area product for the tumor was higher than that for the adjacent liver tissue at the 2.5 µg/mL angiotensin II dose only (11.5 vs 8.1 mL/min/100 g, P = .01). CONCLUSION: Perfusion CT enables a mechanistic understanding of angiotensin II infusion in the liver and derivation of the optimal effective dose. The 2.5 µg/mL angiotensin II dose increases perfusion in hepatic VX2 tumors versus that in adjacent and distant normal liver tissue primarily by constricting normal distal liver vessels and in turn increasing tumor BF and BV.

In vivo functional and anatomic imaging for assessment of in vivo gene transfer.

PURPOSE: To assess whether a combination of in vivo anatomic and functional imaging can help quantify expression of somatostatin receptor type 2 (SSTR2)-based reporters after in vivo gene transfer. MATERIALS AND METHODS: All animal experiments were approved by an institutional animal care and use committee. Six nude mice bearing two subcutaneous L3.6pl (human pancreatic cancer) tumors were injected intratumorally with an adenovirus containing a human somatostatin receptor type 2 gene chimera (Ad-HA-SSTR2) or a control adenovirus containing green fluorescent protein (Ad-GFP). Two days later, magnetic resonance (MR) imaging was performed to derive tumor weight and analyze morphology. Intravenous injection of Food and Drug Administration-approved indium 111 octreotide was followed by gamma camera imaging (planar imaging and single photon emission computed tomography [SPECT]) the next day. Region-of-interest analysis followed. The procedure was also performed in six nude mice with slow-growing MDA-MB-435 (human breast carcinoma) tumors, which allowed serial imaging 3 days and 2 weeks after adenovirus injection. After imaging, excised tumor weight and biodistribution were assessed. Statistical analyses included a Student t test and linear regression. RESULTS: With both tumor types, ex vivo and image-based in vivo biodistribution demonstrated greater uptake (percentage of injected dose per gram) in tumors infected with Ad-HA-SSTR2 than in those infected with Ad-GFP (P < .05). Furthermore, in vivo and ex vivo biodistribution analysis correlated (ex vivo vs planar and MR imaging: r = 0.87, P < .05, n = 24; ex vivo vs SPECT and MR imaging: r = 0.84, P < .05, n = 24). Moreover, in vivo biodistribution distinguished greater expression at the earlier time point in MDA-MB-435 tumors infected with Ad-HA-SSTR2 from waning expression at the later time point (P < .05). CONCLUSION: A combination of in vivo functional and anatomic imaging methods can help quantify gene expression after in vivo gene transfer.