HSP90 inhibition leads to proteosomal degradation of activated KIT and has in vitro activity against gastrointestinal stromal tumors (GIST). BIIB021 is an oral non-ansamycin HSP90 inhibitor. We ...carried out a phase II study of BIIB021 in patients with GIST refractory to imatinib and sunitinib.
The primary end-point was metabolic partial response (mPR) as assessed by fluorodeoxyglucose positron emission tomography (FDG-PET). The secondary end-points were pharmacokinetic assessments of BIIB021 and pharmacodynamic assessments of HSP70. Twenty-three patients were treated on two schedules: 12pts received 600mg twice a week (BIW) and 11 patients received 400mg three times a week (TIW). All had prior imatinib and sunitinib but stopped >14 days before starting BIIB021.
The median age was 59 years (33–88 years), 61% male, 44% Eastern Cooperative Oncology Group 1 (ECOG1). The best response was PR by FDG-PET for five patients (3/12 at 600mg BIW and 2/9 at 400 TIW) for an overall response rate of 22%. The response duration was 25–138 days. Adverse events (AEs) were mild to moderate. The mean Cmax was 1.5µmol and the mean AUC was 2.9µmolh. Cmax >1.5µmol was associated with a decrease in standardized uptake value (SUVmax). HSP70 increased substantially following treatment.
This study met its primary end-point. BIIB021 leads to objective responses in refractory GIST patients. Pharmacodynamic studies confirmed HSP90 inhibition. Further evaluation of BIIB021 in GIST is warranted.
Purpose
The aim of our study was to investigate the efficacy of
18
F-Fluciclovine brain PET imaging in recurrent gliomas, and to compare the utility of these images to that of contrast enhanced ...magnetic resonance imaging (MRI) and to
11
C-methyl-L-methionine (
11
C-Methionine) PET imaging. We also sought to gain insight into the factors affecting the uptake of
18
F-FACBC in both tumors and normal brain, and specifically to evaluate how the uptake in these tissues varied over an extended period of time post injection.
Methods
Twenty-seven patients with recurrent or progressive primary brain tumor (based on clinical and MRI/CT data) were studied using dynamic
18
F-Fluciclovine brain imaging for up to 4 h. Of these, 16 patients also had
11
C-Methionine brain scans. Visual findings, semi-quantitative analyses and pharmacokinetic modeling of a subset of the
18
F-Fluciclovine images was conducted. The information derived from these analyses were compared to data from
11
C-Methionine and to contrast-enhanced MRI.
Results
18
F-Fluciclovine was positive for all 27 patients, whereas contrast MRI was indeterminate for three patients. Tumor
18
F-Fluciclovine SUVmax ranged from 1.5 to 10.5 (average: 4.5 ± 2.3), while
11
C-Methionine’s tumor SUVmax ranged from 2.2 to 10.2 (average: 5.0 ± 2.2). Image contrast was higher with
18
F-Fluciclovine compared to
11
C-Methionine (
p
< 0.0001). This was due to
18
F-Fluciclovine’s lower background in normal brain tissue (0.5 ± 0.2 compared to 1.3 ± 0.4 for
11
C-Methionine).
18
F-Fluciclovine uptake in both normal brain and tumors was well described by a simple one-compartment (three-parameter: V
b
,k
1
,k
2
) model. Normal brain was found to approach transient equilibrium with a half-time that varied greatly, ranging from 1.5 to 8.3 h (mean 2.7 ± 2.3 h), and achieving a consistent final distribution volume averaging 1.4 ± 0.2 ml/cc. Tumors equilibrated more rapidly (t
1/2
ranging from 4 to 148 min, average 57 ± 51 min), with an average distribution volume of 3.2 ± 1.1 ml/cc. A qualitative comparison showed that the rate of normal brain uptake of
11
C-Methionine was much faster than that of
18
F-Fluciclovine.
Conclusion
Tumor uptake of
18
F-Fluciclovine correlated well with the established brain tumor imaging agent
11
C-Methionine but provided significantly higher image contrast.
18
F-Fluciclovine may be particularly useful when the contrast MRI is non-diagnostic. Based on the data gathered, we were unable to determine whether Fluciclovine uptake was due solely to recurrent tumor or if inflammation or other processes also contributed.
The article
18
F-Fluciclovine (
18
F-FACBC) PET imaging of recurrent brain tumors written by Laure Michaud, B. J. Beattie, T. Akhurst, M. Dunphy, P. Zanzonico, R. Finn, A. Mauguen, H. Schöder, W. A. ...Weber, A. B. Lassman, R. Blasberg.
Transcriptional targeting of gene expression has been plagued by the weakness of tissue-specific promoters. Thus, to increase promoter strength while maintaining tissue specificity, we constructed a ...recombinant adenovirus containing a binary promoter system with a tumor-specific promoter (CEA; carcinoembryonic antigen) driving a transcription transactivator, which then activates a minimal promoter to express a suicide gene (HSV-tk; herpes simplex virus thymidine kinase). This ADV/binary-tk induced equal or greater cell killing in a CEA-specific manner in vitro compared with the CEA-independent killing of a vector with a constitutive viral promoter driving HSV-tk (ADV/RSV-tk). To monitor adenovirus-mediated HSV-tk gene expression in vivo, we employed noninvasive nuclear imaging using a radioiodinated nucleoside analog (((1)31)I-FIAU) serving as a substrate for HSV-tk. ((1)31)I-FIAU-derived radioactivity accumulated after intratumoral injection of ADV/binary-tk only in the area of CEA-positive tumors with significantly less spread to the adjacent liver tissue than after administration of the universally expressed ADV/RSV-tk. Both viruses exhibited similar antitumor efficacy upon injection of liver metastases. Importantly, in vivo dose escalation studies demonstrated significantly reduced toxicity after intravenous administration of ADV/binary-tk versus ADV/RSV-tk. In summary, the increased therapeutic index of this novel, amplified CEA-driven suicide gene therapy vector is a proof of principle for the powerful enhancement of a weak tissue-specific promoter for effective tumor restricted gene expression.
Aim To report a case series in which the radiological features of the subcutaneous use of calcium hydroxylapatite (CaHa) dermal fillers are described for the first time. Materials and methods Five ...patients with facial hyperattenuating hypermetabolic subcutaneous lesions were identified on 2- 18 F-fluoro-2-deoxy- d- glucose (FDG) positron-emission tomography/computed tomography (PET/CT), who gave a history of facial injections to augment physical appearance. Correlation with additional imaging studies was performed. Results All cases had subcutaneous high attenuation material on CT (range 280–700 HU), which was FDG avid on PET, with a standardized uptake value (SUV) range of 2.9–13.4. Magnetic resonance imaging (MRI) demonstrated a heterogeneous intermediate signal intensity subcutaneous lesion with enhancement post-gadolinium in one case. Conclusions CaHa dermal filler is hyperattenuating on CT, hypermetabolic on FDG-PET imaging, of intermediate signal intensity on MRI, and is a potential cause of a false-positive imaging study.
The purpose of this study is to establish and validate a methodology for estimating the standard deviation of voxels with large activity concentrations within a PET image using replicate imaging that ...is immediately available for use in the clinic. To do this, ensembles of voxels in the averaged replicate images were compared to the corresponding ensembles in images derived from summed sinograms. In addition, the replicate imaging noise estimate was compared to a noise estimate based on an ensemble of voxels within a region. To make this comparison two phantoms were used. The first phantom was a seven-chamber phantom constructed of 1 liter plastic bottles. Each chamber of this phantom was filled with a different activity concentration relative to the lowest activity concentration with ratios of 1:1, 1:1, 2:1, 2:1, 4:1, 8:1 and 16:1. The second phantom was a GE Well-Counter phantom. These phantoms were imaged and reconstructed on a GE DSTE PET/CT scanner with 2D and 3D reprojection filtered backprojection (FBP), and with 2D- and 3D-ordered subset expectation maximization (OSEM). A series of tests were applied to the resulting images that showed that the region and replicate imaging methods for estimating standard deviation were equivalent for backprojection reconstructions. Furthermore, the noise properties of the FBP algorithms allowed scaling the replicate estimates of the standard deviation by a factor of 1/square root N, where N is the number of replicate images, to obtain the standard deviation of the full data image. This was not the case for OSEM image reconstruction. Due to nonlinearity of the OSEM algorithm, the noise is shown to be both position and activity concentration dependent in such a way that no simple scaling factor can be used to extrapolate noise as a function of counts. The use of the Well-Counter phantom contributed to the development of a heuristic extrapolation of the noise as a function of radius in FBP. In addition, the signal-to-noise ratio for high uptake objects was confirmed to be higher with backprojection image reconstruction methods. These techniques were applied to several patient data sets acquired in either 2D or 3D mode, with (18)F (FLT and FDG). Images of the standard deviation and signal-to-noise ratios were constructed and the standard deviations of the tumors' uptake were determined. Finally, a radial noise extrapolation relationship deduced in this paper was applied to patient data.
Summary
Systemic AL amyloidosis (AL) is a disorder in which light chains form fibrillar deposits, leading to organ dysfunction and death. Rarely, AL has been associated with non‐Hodgkin's lymphoma ...(NHL), although this association has not been well characterized. We report a series of six patients with AL associated with NHL, primarily lymphoplasmacytic lymphoma. Organ involvement was variable, with frequent bulky lymphadenopathy and visceral cavity deposits, but no cardiac involvement. Positron emission tomography scans were negative. Bone marrow and lymph node biopsies showed a mixed population of CD20+ lymphoid and CD138+ plasma cells. Serum free light chains were elevated, and correlated with response to therapy. Immunoglobulin light chain variable region (Ig VL) germline gene use was typical for AL, reflecting previously observed correlations between germline gene use and organ tropism. Five patients received rituximab‐based therapies with two responses. Two patients underwent autologous stem cell transplantation with one complete haematological response. Four patients survive at 10–132 months from diagnosis. AL with NHL has distinctive clinical features but employs the same Ig VL gene repertoire as AL with clonal plasma cell dyscrasias. Serial serum free light chain levels are useful for tracking response to therapy. Treatments aimed at both lymphoid and plasma cell components appear warranted.
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