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To evaluate the extracranial venous anatomy with contrast-enhanced MR venogram (CE-MRV) in patients without multiple sclerosis (MS), and assess the prevalence of various venous anomalies such as asymmetry and stenosis in this population.We prospectively recruited 100 patients without MS, aged 18-60 years, referred for contrast-enhanced MRI. They underwent additional CE-MRV from skull base to mediastinum on a 3T scanner. Exclusion criteria included prior neck radiation, neck surgery, neck/mediastinal masses or significant cardiac or pulmonary disease. Two neuroradiologists independently evaluated the studies to document asymmetry and stenosis in the jugular veins and prominence of collateral veins.Asymmetry of internal jugular veins (IJVs) was found in 75 % of subjects. Both observers found stenosis in the IJVs with fair agreement. Most stenoses were located in the upper IJV segments. Asymmetrical vertebral veins and prominence of extracranial collateral veins, in particular the external jugular veins, was not uncommon.It is common to have stenoses and asymmetry of the IJVs as well as prominence of the collateral veins of the neck in patients without MS. These findings are in contrast to prior reports suggesting collateral venous drainage is rare except in MS patients.• The venous anatomy of the neck in patients without MS demonstrates multiple variants • Asymmetry and stenoses of the internal jugular veins are common • Collateral neck veins are not uncommon in patients without MS • These findings do not support the theory of chronic cerebrospinal venous insufficiency • MR venography is a useful imaging modality for assessing venous anatomy.

The purpose of this study was to evaluate the safety, dosimetry, and apparent receptor occupancy (RO) of [(64)Cu]DOTA-patritumab, a radiolabeled monoclonal antibody directed against HER3/ERBB3 in subjects with advanced solid tumors.Dosimetry subjects (n = 5) received [(64)Cu]DOTA-patritumab and underwent positron emission tomography (PET)/X-ray computed tomography (CT) at 3, 24, and 48 h. Evaluable RO subjects (n = 3 out of 6) received [(64)Cu]DOTA-patritumab at day 1 and day 8 (after 9.0 mg/kg patritumab) followed by PET/CT at 24 h post-injection. Endpoints included safety, tumor uptake, and efficacy.The tumor SUVmax (± SD) was 5.6 ± 4.5, 3.3 ± 1.7, and 3.0 ± 1.1 at 3, 24, and 48 h in dosimetry subjects. The effective dose and critical organ dose (liver) averaged 0.044 ± 0.008 mSv/MBq and 0.46 ± 0.086 mGy/MBq, respectively. In RO subjects, tumor-to-blood ratio decreased from 1.00 ± 0.32 at baseline to 0.57 ± 0.17 after stable patritumab, corresponding to a RO of 42.1 ± 3.[(64)Cu]DOTA-patritumab was safe. These limited results suggest that this PET-based method can be used to determine tumor-apparent RO.

This study aimed to determine the maximum-tolerated dose and dose-limiting toxicities of pegylated liposomal doxorubicin (PLD) in combination with temsirolimus (T) in patients with refractory solid tumors. Using a standard “3+3” dose escalation design, 23 patients were enrolled in three dosing cohorts in this phase I study. The starting dose level was PLD at 30 mg/m2 every 4 weeks and T at 20 mg weekly. Pharmacokinetics (PK) of doxorubicin were evaluated for patients in the expansion cohort. The most common treatment-related adverse events of all grades were mucositis/stomatitis (69.6 %), anorexia (52.2 %), thrombocytopenia (52.2 %), and fatigue (47.8 %). The recommended doses of this combination for phase II studies are 25 mg/m2 PLD and 25 mg T. PK analyses suggested increased exposure of doxorubicin in this combination regimen compared to doxorubicin administered as a single agent, possibly due to PK drug interactions. Out of 18 patients evaluable for a treatment response, two had partial responses (PR) (breast cancer and hepatocellular carcinoma) and six had stable disease (SD). Two patients remained on treatment for more than 1 year. The combination of PLD and T is tolerable, and the treatment resulted in clinical benefit. The combination regimen should be further explored in appropriate tumor types. Electronic supplementary material The online version of this article (doi:10.1007/s00280-014-2493-x) contains supplementary material, which is available to authorized users.

Background: Patritumab (P) is a HER3-specific human mAB that promotes receptor downregulation, inhibits ligand binding and tumor growth in xenografts models, and is safe in humans. The radioisotope 64Cu conjugated with P with a DOTA chelate, was confirmed by mass spectrometry and stable in serum for 24-hours. A microPET study in a mouse model (BxPC3) revealed significant tumor uptake of 64Cu-DOTA-patritumab (64Cu-DOTA-P) and uptake blockage (>50%) with co-injection of unlabeled P. Clinically administering 64Cu-DOTA-P could identify serum concentrations needed for maximal receptor occupancy. Methods: This Phase 1 study evaluated the safety, dosimetry (Cohort 1) and HER3 receptor occupancy (Cohort 2) of escalating doses of GMP generated intravenously administered 64Cu-DOTA-P in subjects with HER3+, solid tumors. Cohort 1 subjects received 64Cu-DOTA-P (8-15 mCi) on D1, then PET/CT scans at 3, 24, and 48 hours (± 3 hours). Sequential PET/CT scans and time integrated organ activity concentrations were used to compute organ residence times and radiation doses. Cohort 2 subjects received 64Cu-DOTA-P on D1 (tracer only) and D8 (tracer after 9.0 mg/kg of P), each followed by PET/CT scans at 24 hours (± 3 hours). Receptor occupancy was measured by: 1) tracer tumor “uptake” at D1 versus D8; and 2) D1 “uptake” versus tumoral HER3 expression with validated IHC (membrane H-Score). After dosimetry and receptor occupancy studies, subjects received P (18.0 mg/kg loading, then 9.0 mg/kg Q3 weeks) were followed for safety and had PK samples collected. Results: Eleven subjects (mean age 61.7) were evaluated. In Cohort 1 (n=5), the mean tumor uptake (SUV ± SD) at 3, 24 and 48 hours was 5.6 (± 4.5), 3.2 (±1.7), and 2.9 (±1.1), respectively. The mean tumor uptake (Tumor-To-Muscle Uptake Ratio [T/M] ± SD) at 3, 24 and 48 hours was 3.0 (± 2.1), 2.1 (±1.2), and 1.6 (±0.5), respectively. The tracer localized primarily in the blood pool and liver, with modest uptake in tumors. The average effective dose was 0.16 ± 0.016 rem/mCi with largest tracer uptake in the liver (1.61 ± 0.30 rad/mCi). In Cohort 2 (n=6), the mean SUV uptake of 64Cu-DOTA-P after administration of unlabeled P was 3.4 (± 1.1) baseline and 4.1 (± 1.3) after 24 hours (p>NS). T/Ms were 1.6 (± 0.6) and 2.8 (± 1.7), respectively. No correlation existed between SUV, T/M, and HER3 H-Score. After D1 injection, tracer signal was detected primarily in the liver. Following D8 co-injection with unlabeled P, tracer signal was higher in the circulation and unchanged in the tumor. Common AEs were diarrhea (27%); and dizziness, fatigue, headache, hypertension, and weight loss (18% each). Conclusions: 64Cu -DOTA-P administration is safe and feasible in humans. This study was unable to determine HER3 receptor occupancy. Possible reasons include lower tumor HER3 expression versus xenografts, tracer liver accumulation, and target internalization. A modified design should be considered for future studies. Citation Format: Albert C. Lockhart, Yongjian Liu, Farrokh Dehdashti, Richard Laforest, Joel Picus, Andrea Wang-Gillam, Lauren Trull, Stefanie Belanger, Madhuri Desai, Jeanne Mendell, Syed Mahmood, Barry A. Siegel, Michael J. Welch. A phase 1 evaluation of 64Cu-DOTA-patritumab to assess dosimetry, receptor occupancy, and safety in advanced solid tumors. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5443. doi:10.1158/1538-7445.AM2014-5443