Positron emission tomography imaging of the 18-kDa translocator protein (TSPO) with [18F]FEMPA in Alzheimer's disease patients and control subjects.

PURPOSE: Imaging of the 18-kDa translocator protein (TSPO) is a potential tool for examining microglial activation and neuroinflammation in early Alzheimer's disease (AD). [(18)F]FEMPA is a novel high-affinity second-generation TSPO radioligand that has displayed suitable pharmacokinetic properties in preclinical studies. The aims of this study were to quantify the binding of [(18)F]FEMPA to TSPO in AD patients and controls and to investigate whether higher [(18)F]FEMPA binding in AD patients than in controls could be detected in vivo. METHODS: Ten AD patients (five men, five women; age 66.9 ± 7.3 years; MMSE score 25.5 ± 2.5) and seven controls (three men, four women; age 63.7 ± 7.2 years, MMSE score 29.3 ± 1.0) were studied using [(18)F]FEMPA at Turku (13 subjects) and at Karolinska Institutet (4 subjects). The in vitro binding affinity for TSPO was assessed using PBR28 in a competition assay with [(3)H]PK11195 in seven controls and eight AD patients. Cortical and subcortical regions of interest were examined. Quantification was performed using a two-tissue compartment model (2TCM) and Logan graphical analysis (GA). The outcome measure was the total distribution volume (V T). Repeated measures analysis of variance was used to assess the effect of group and TSPO binding status on V T. RESULTS: Five AD patients and four controls were high-affinity binders (HABs). Three AD patients and three controls were mixed-affinity binders. V T estimated with Logan GA was significantly correlated with V T estimated with the 2TCM in both controls (r = 0.97) and AD patients (r = 0.98) and was selected for the final analysis. Significantly higher V T was found in the medial temporal cortex in AD patients than in controls (p = 0.044) if the TSPO binding status was entered as a covariate. If only HABs were included, significantly higher V T was found in the medial and lateral temporal cortex, posterior cingulate, caudate, putamen, thalamus and cerebellum in AD patients than in controls (p < 0.05). CONCLUSION: [(18)F]FEMPA seems to be a suitable radioligand for detecting increased TSPO binding in AD patients if their binding status is taken into account.

First-in-Human Dose-Escalation Study of Cyclin-Dependent Kinase 9 Inhibitor VIP152 in Patients with Advanced Malignancies Shows Early Signs of Clinical Efficacy.

PURPOSE: To report on the first-in-human phase I study of VIP152 (NCT02635672), a potent and highly selective cyclin-dependent kinase 9 (CDK9) inhibitor. PATIENTS AND METHODS: Adults with solid tumors or aggressive non-Hodgkin lymphoma who were refractory to or had exhausted all available therapies received VIP152 monotherapy as a 30-minute intravenous, once-weekly infusion, as escalating doses (5, 10, 15, 22.5, or 30 mg in 21-day cycles) until the MTD was determined. RESULTS: Thirty-seven patients received ≥ 1 VIP152 dose, with 30 mg identified as the MTD based on dose-limiting toxicity of grade 3/4 neutropenia. The most common adverse events were nausea and vomiting (75.7% and 56.8%, respectively), all of grade 1/2 severity. Of the most common events, grade 3/4 events occurring in > 1 patient were neutropenia (22%), anemia (11%), abdominal pain (8%), increased alkaline phosphatase (8%), and hyponatremia (8%). Day 1 exposure for the MTD exceeded the predicted minimum therapeutic exposure and reproducibly achieved maximal pathway modulation; no accumulation occurred after multiple doses. Seven of 30 patients with solid tumors had stable disease (including 9.5 and 16.8 months in individual patients with pancreatic cancer and salivary gland cancer, respectively), and 2 of 7 patients with high-grade B-cell lymphoma with MYC and BCL2/BCL6 translocations (HGL) achieved durable complete metabolic remission (ongoing at study discontinuation, after 3.7 and 2.3 years of treatment). CONCLUSIONS: VIP152 monotherapy, administered intravenously once weekly, demonstrated a favorable safety profile and evidence of clinical benefit in patients with advanced HGL and solid tumors.

Identification of Atuveciclib (BAY†1143572), the First Highly Selective, Clinical PTEFb/CDK9 Inhibitor for the Treatment of Cancer.

Selective inhibition of exclusively transcription-regulating PTEFb/CDK9 is a promising new approach in cancer therapy. Starting from lead compound BAY-958, lead optimization efforts strictly focusing on kinase selectivity, physicochemical and DMPK properties finally led to the identification of the orally available clinical candidate atuveciclib (BAY 1143572). Structurally characterized by an unusual benzyl sulfoximine group, BAY 1143572 exhibited the best overall profile in vitro and in vivo, including high efficacy and good tolerability in xenograft models in mice and rats. BAY 1143572 is the first potent and highly selective PTEFb/CDK9 inhibitor to enter clinical trials for the treatment of cancer.

Parametric Binding Images of the TSPO Ligand 18F-DPA-714.

18F-labeled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide (DPA-714) is a radioligand for the 18-kDa translocator protein. The purpose of the present study was to identify the best method for generating quantitative parametric images of 18F-DPA-714 binding. METHODS: Ninety-minute dynamic 18F-DPA-714 PET scans with full arterial sampling from 6 healthy subjects and 9 Alzheimer disease (AD) patients were used. Plasma-input-based Logan graphical analysis and spectral analysis were used to generate parametric volume of distribution (VT) images. Five versions of Ichise, reference Logan, and 2 basis function implementations (receptor parametric mapping and simplified reference tissue model 2 [SRTM2]) of SRTM, all using gray matter cerebellum as the reference region, were applied to generate nondisplaceable binding potential (BPND) images. RESULTS: Plasma-input Logan analysis (r2 = 0.99; slope, 0.88) and spectral analysis (r2 = 0.99, slope, 0.93) generated estimates of VT that correlated well with values obtained using nonlinear regression. BPND values generated using SRTM2 (r2 = 0.83; slope, 0.95) and reference Logan analysis (r2 = 0.88; slope, 1.01) correlated well with nonlinear regression-based estimates. CONCLUSION: Both Logan analysis and spectral analysis can be used to obtain quantitatively accurate VT images of 18F-DPA-714. In addition, SRTM2 and reference Logan analysis can provide accurate BPND images. These parametric images could be used for voxel-based comparisons.

Dosimetry and first clinical evaluation of the new 18F-radiolabeled bombesin analogue BAY 864367 in patients with prostate cancer.

UNLABELLED: The aim of this first-in-man study was to demonstrate the feasibility, safety, and tolerability, as well as provide dosimetric data and evaluate the imaging properties, of the bombesin analogue BAY 864367 for PET/CT in a small group of patients with primary and recurrent prostate cancer (PCa). METHODS: Ten patients with biopsy-proven PCa (5 with primary PCa and 5 with prostate-specific antigen recurrence after radical prostatectomy) were prospectively selected for this exploratory clinical trial with BAY 864367, a new (18)F-labeled bombesin analogue. PET scans were assessed at 6 time points, up to 110 min after intravenous administration of 302 ± 11 MBq of BAY 864367. Imaging results were compared with (18)F-fluorocholine PET/CT scans. Dosimetry was calculated using the OLINDA/EXM software. RESULTS: Three of 5 patients with primary disease showed positive tumor delineation in the prostate, and 2 of 5 patients with biochemical relapse showed a lesion suggestive of recurrence on the BAY 864367 scan. Tumor-to-background ratio averaged 12.9 ± 7.0. The ratio of malignant prostate tissue to normal prostate tissue was 4.4 ± 0.6 in 3 patients with tracer uptake in the primary PCa. Mean effective dose was 4.3 ± 0.3 mSv/patient (range, 3.7-4.9 mSv). CONCLUSION: BAY 864367, a novel (18)F-labeled bombesin tracer, was successfully investigated in a first-in-man clinical trial of PCa and showed favorable dosimetric values. Additionally, the application was safe and well tolerated. The tracer delineated tumors in a subset of patients, demonstrating the potential of gastrin-releasing-peptide receptor imaging.

Quantification of [18F]DPA-714 binding in the human brain: initial studies in healthy controls and Alzheimer's disease patients.

Fluorine-18 labelled N,N-diethyl-2-(2-[4-(2-fluoroethoxy)phenyl]-5,7-dimethylpyrazolo[1,5-α]pyrimidine-3-yl)acetamide ([(18)F]DPA-714) binds to the 18-kDa translocator protein (TSPO) with high affinity. The aim of this initial methodological study was to develop a plasma input tracer kinetic model for quantification of [(18)F]DPA-714 binding in healthy subjects and Alzheimer's disease (AD) patients, and to provide a preliminary assessment whether there is a disease-related signal. Ten AD patients and six healthy subjects underwent a dynamic positron emission tomography (PET) study along with arterial sampling and a scan protocol of 150 minutes after administration of 250 ± 10 MBq [(18)F]DPA-714. The model that provided the best fits to tissue time activity curves (TACs) was selected based on Akaike Information Criterion and F-test. The reversible two tissue compartment plasma input model with blood volume parameter was the preferred model for quantification of [(18)F]DPA-714 kinetics, irrespective of scan duration, volume of interest, and underlying volume of distribution (VT). Simplified reference tissue model (SRTM)-derived binding potential (BPND) using cerebellar gray matter as reference tissue correlated well with plasma input-based distribution volume ratio (DVR). These data suggest that [(18)F]DPA-714 cannot be used for separating individual AD patients from healthy subjects, but further studies including TSPO binding status are needed to substantiate these findings.

Plasma pharmacokinetics, whole-body distribution, metabolism, and radiation dosimetry of 68Ga bombesin antagonist BAY 86-7548 in healthy men.

UNLABELLED: This first-in-human study investigated the safety, tolerability, metabolism, pharmacokinetics, biodistribution, and radiation dosimetry of (68)Ga-bombesin antagonist (68)Ga-DOTA-4-amino-1-carboxymethylpiperidine-d-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 (BAY 86-7548). METHODS: Five healthy men underwent dynamic whole-body PET/CT after an intravenous injection of BAY 86-7548 (138 ± 5 MBq). Besides total radioactivity, plasma samples were analyzed by radio-high-performance liquid chromatography for metabolism of the tracer. Dosimetry was calculated using the OLINDA/EXM software. RESULTS: Three radioactive plasma metabolites were detected. The proportion of unchanged BAY 86-7548 decreased from 92% ± 9% at 1 min after injection to 19% ± 2% at 65 min. The organs with the highest absorbed doses were the urinary bladder wall (0.62 mSv/MBq) and the pancreas (0.51 mSv/MBq). The mean effective dose was 0.051 mSv/MBq. BAY 86-7548 was well tolerated by all subjects. CONCLUSION: Intravenously injected BAY 86-7548 is safe, and rapid metabolism is demonstrated. A 150-MBq injection of BAY 86-7548 results in an effective dose of 7.7 mSv, which could be reduced to 5.7 mSv with frequent bladder voids.

In vivo imaging of prostate cancer using [68Ga]-labeled bombesin analog BAY86-7548.

PURPOSE: A novel [(68)Ga]-labeled DOTA-4-amino-1-carboxymethyl-piperidine-D-Phe-Gln-Trp-Ala-Val-Gly-His-Sta-Leu-NH2 peptide (BAY86-7548) having high affinity to bombesin receptor subtype II to detect primary and metastatic prostate carcinoma using positron emission tomography/computed tomography (PET/CT) was synthesized and evaluated for prostate cancer. EXPERIMENTAL DESIGN: In this first human study with BAY86-7548, 14 men scheduled for radical prostatectomy (n = 11) or with biochemical recurrence after surgery or hormonal therapy (n = 3) were enrolled. The patients received an intravenous injection of BAY86-7548 followed by over 60-minute dynamic imaging of prostate gland (n = 10) and/or subsequent whole-body imaging (n = 14). The visual assessment of PET/CT images included evaluation of intraprostatic (12 subsextants) and pelvic nodal uptake of BAY86-7548 in 11 surgical patients and detection of potential metastatic foci in all patients. In patients with biochemical recurrence, results were compared with those of either [(11)C]-acetate (n = 2) or [(18)F]-fluoromethylcholine (n = 1) PET/CT. RESULTS: We found a sensitivity, specificity, and accuracy of 88%, 81% and 83%, respectively, for detection of primary PCa and sensitivity of 70% for metastatic lymph nodes using histology as gold standard. BAY86-7548 correctly detected local recurrence in prostate bed and showed nodal relapse in accordance with [(11)C]-acetate PET/CT in 2 patients with biochemical relapse. In the third hormone refractory patient, BAY86-7548 failed to show multiple bone metastases evident on [(18)F]-fluoromethylcholine PET/CT. CONCLUSION: BAY86-7548 PET/CT is a promising molecular imaging technique for detecting intraprostatic prostate cancer.

Value of axial and coronal maximum intensity projection (MIP) images in the detection of pulmonary nodules by multislice spiral CT: comparison with axial 1-mm and 5-mm slices.

The purpose of this study was to investigate the diagnostic accuracy of non-overlapping 10-mm axial and coronal maximum intensity projections (MIP) in comparison with standard axial 1-mm and 5-mm slices in the detection of pulmonary nodules. Sixty patients with suspected nodules who underwent multislice spiral CT of the chest were evaluated. Axial 1-mm and 5-mm slices as well as non-overlapping 10-mm axial/coronal MIPs were interpreted independently by three blinded radiologists. After initial review, a retrospective consensus session was performed for agreement on final nodule counts using the axial 1-mm slices as gold standard. Small nodules of less than 5 mm in size were most accurately detected by the axial MIPs. Receiver operating characteristic (ROC) analysis of these small nodules showed that 5-mm slices were not capable of a statistically significant differentiation of nodules from other focal lesions in two observers (p=0.034 and p=0.012, respectively) whereas 1-mm slices and coronal/axial MIPs did allow a statistically significant differentiation in all observers (p<0.001). Nodules larger than 5 mm were equally well depicted with all modalities. Non-overlapping 10-mm axial MIPs improve the accuracy in the detection of small pulmonary nodules.

Minimum intensity projections of the biliary system using 16-channel multidetector computed tomography in patients with biliary obstruction: comparison with MRCP.

The objective was the evaluation of minimum intensity projections (MinIP) of 16-channel multidetector computed tomography (MDCT) data for the visualization of biliary ducts with magnetic resonance cholangiopancreatography (MRCP) as reference method. Twenty-five patients with biliary obstruction who received MDCT of the abdomen and MRCP without subsequent interventions were analysed. Coronal and axial MinIP were reconstructed from the MDCT-data. The evaluation of image quality and the quantitative comparison to MRCP was performed by two observers in consensus. The additional diagnostic value of MinIP compared with conventionally visualised MDCT was assessed by three independent observers. With MRCP as the reference method, MinIP was superior to conventional MDCT concerning the visualization of the extent of bile duct dilatation (r, 1.000 vs 0.699) and the correlation of diameter measurement (r, 0.979 vs 0.942). Subsidiary to conventional MDCT, MinIP revealed an improvement of visualization of the biliary system in 73% of cases. Concerning the additional diagnostic value, MinIP allowed for a better definition of the obstruction site in 13% of patients, and in one patient a change of diagnosis was observed. Thus, MinIP can improve the diagnostic assessment of biliary obstructions in MDCT imaging.

Sagittal alignment after anterior debridement and fusion with or without additional posterior instrumentation in the treatment of pyogenic and tuberculous spondylodiscitis.

STUDY DESIGN: A retrospective clinical study investigated patients undergoing surgery for destructive pyogenic and tuberculous spondylodiscitis. OBJECTIVE: To compare anterior debridement and bone grafting with a combined anterior and posterior procedure in terms of the physiologic alignment of the segmental sagittal spinal profile. SUMMARY OF BACKGROUND DATA: There is considerable agreement in the literature on the indications for surgical treatment of destructive spondylodiscitis. An anterior approach usually is recommended for debridement and bone grafting. Additional posterior instrumentation is applied to reduce kyphotic deformities and to prevent a correction loss. No comparison has been made so far in the literature between repositioning results obtained after surgery for destructive spondylodiscitis and physiologic segmental sagittal angles. METHODS: The surgical results of 49 patients treated by anterior debridement and bone grafting were compared with those of 22 patients who received additional posterior instrumentation. A comparison between the segmental kyphotic angles obtained and the standard values reported in the literature enabled an assessment of the segmental spinal alignment in the sagittal plane. Data were obtained from medical record review, imaging procedures, and patient follow-up examinations. RESULTS: All the subgroups submitted to a combined procedure had a greater preoperative segmental kyphosis angle than those undergoing anterior fusion alone. In marked segmental kyphotic false positioning, good postoperative repositioning was achieved by the combined procedure, and an increase in segmental kyphosis was permanently prevented. CONCLUSIONS: In single-level spondylodiscitis with no major substance loss, anterior debridement and bone grafting alone seem to be adequate, especially in the lumbar spine. Additional posterior instrumentation is indicated in multiple-level spondylodiscitis, extensive kyphotic deformity, or both.

Peritumoural versus subareolar administration of technetium-99m nanocolloid for sentinel lymph node detection in breast cancer: preliminary results of a prospective intra-individual comparative study.

The scintigraphic detection of sentinel lymph nodes (SNs) in early-stage breast cancer is a widely accepted diagnostic method. However, which radiotracer administration mode should be used is still controversial. This prospective study aimed to intra-individually compare the detection rates obtained after peritumoural versus subareolar injection with regard to SN number and localisation. Fifty-one women (age, 32-76 years) with breast cancer were investigated on two consecutive days. On day 1, 140-400 MBq technetium-99m nanocolloid was injected along the peripheral tumour margins. Static lymphoscintigrams of the axilla, thorax and neck were taken in various views 1 and 19 h p.i. On day 2, 10 MBq (99m)Tc-nanocolloid was injected subareolarly in the clock position of the tumour and dynamic and static scans were performed immediately. Thereafter, 30 MBq (99m)Tc-nanocolloid was administered peri-subareolarly and lymphoscintigrams were acquired in a dynamic and static manner. In 49/51 women, the different injection techniques disclosed the identical number and location of SNs in the axilla. In seven patients, the peritumoural injection detected additional SNs in the parasternal group. Axillary SNs were detected as early as 2-15 min following subareolar injection, both in the clock position and peri-subareolarly, as compared with about 1 h after peritumoural administration. Sixteen patients showed at least one tumour-positive SN, and nine also had tumour-positive non-SNs. One patient with a tumour-negative SN, visualised concordantly by both subareolar and peritumoural administration, demonstrated two metastatic non-SNs, yielding a false-negative rate of 5.9%. In conclusion, a simple subareolar injection in the clock position is sufficient for SN detection in breast cancer, if it is accepted that parasternal lymph node detection has no therapeutic consequences.

Influence of fast lymphatic drainage on metastatic spread in cutaneous malignant melanoma: a prospective feasibility study.

The concept of sentinel lymph node biopsy in cutaneous malignant melanoma is widely established. Preoperative cutaneous lymphoscintigraphic mapping is a reliable method for identifying the nodal basins at risk of metastases in melanomas. In this prospective study we investigated the correlation between the scintigraphic appearance time and the metastatic involvement of sentinel lymph nodes. In 276 malignant melanoma patients (137 women, 139 men; age 16-93 years), dynamic and static lymphoscintigraphy was performed after strict intracutaneous application of technetium-99m nanocolloid (40-150 MBq; 0.05 ml/deposit) around the tumour or biopsy scar. Analysis of dynamic scans primarily focussed on the appearance time of sentinel lymph nodes. Sentinel lymph node visualisation 20 min as slow drainage. Fast lymphatic drainage was found in 236 patients, of whom 34 (14.4%) had sentinel lymph node metastases. Twenty-two patients showed hybrid (fast and slow) lymphatic drainage, and eight (36.4%) of them had sentinel lymph node metastases. Seven of the latter demonstrated fast lymphatic drainage, while one showed one positive sentinel lymph node with fast and another with slow drainage. The melanomas of 18 patients demonstrated exclusively slow lymphatic drainage, in all cases without sentinel lymph node metastases. This prospective study indicates that the scintigraphic appearance time of sentinel lymph nodes seems to be a clinically relevant factor for prediction of metastatic spread of cutaneous malignant melanoma. Larger numbers of patients need to be examined to truly assess the benefit of the scintigraphic appearance time compared with other predictors of sentinel lymph node tumour positivity.