SPECT/CT Imaging of hNIS - Expression after Intravenous Delivery of an Oncolytic Adenovirus and I-131

Peer reviewe

Increasing amount of ¹²³I⁻ accumulates in the tumor over time showing progressive virus replication and increasing tumor hNIS-expression.

<p>(<b>a</b>) SPECT/CT image (sagittal section) showing ¹²³I⁻ accumulation into tumor in the lungs of a mouse treated intravenously with Ad5/3-hTERT-hNIS and intraperitoneally with ¹³¹I⁻. (<b>b</b>) Control mouse treated with ¹³¹I⁻ only shows no ¹²³I⁻ -accumulation in the lungs on the course of the treatment. (<b>c</b>) Transverse section of the lungs of the mouse shown in (<b>a</b>) shows accumulation of ¹²³I⁻ into the tumor on the third treatment week. (<b>d</b>) Transverse section of lungs of the mouse shown in (<b>b</b>) shows no accumulation of ¹²³I⁻ into the tumor on the third treatment week. The crossing point of red lines indicates tumor localization.</p

Number of mice positive for uptake of the imaging isotope ¹²³I at the tumor.

<p>The total number of mice analyzed at each time point is given in parentheses. Day indicates the day after first intravenous virus injection. -, not analyzed.</p

SPECT/CT is sensitive for detecting endogenous NIS- and hNIS-expression.

<p>Mice were given Ad5/3-hTERT-hNIS or diluent and ¹²³I⁻ intravenously for SPECT-scanning. After the SPECT/CT-scan, mice received ¹³¹I⁻ or PBS intraperitoneally. The iodide uptakes were calculated weekly and normalized to the injected dose of ¹²³I⁻. (<b>a</b>) Individual tumor uptake of ¹²³I⁻ (the imaging isotope) in Ad5/3-hTERT-hNIS and Ad5/3-hTERT-hNIS+¹³¹I⁻ -treated mice. All mice received ¹²³I⁻ for evaluation of iodide uptake by SPECT. Mice in the latter group also received ¹³¹I⁻ right after the SPECT imaging for therapeutic purposes. Solid grey line, background level in the absence of Ad5/3-hTERT-hNIS; dotted grey lines, ± SD of background. (<b>b</b>) ¹²³I⁻ uptake in the thyroids. Results are expressed as %ID/mm³×1000 ± SD.</p

hNIS-expression in prostate cancer cells.

<p>(<b>a</b>) Cells were infected with 10 vp of Ad5/3-hTERT-hNIS (lanes 1 and 3) or control virus Ad5/3-hTERT-Δgp19K (lanes 2 and 4). hNIS-RNA -expression was assayed 24 h (lanes 1 and 2) and 48 h (lanes 3 and 4) later by RT-PCR. ß-actin served as an internal control. (<b>b</b>) ¹²⁵I uptake in prostate cancer cells infected in triplicates with 10 vp of Ad5/3-hTERT-hNIS or Ad5/3-hTERT-Δgp19K. The capability of the cells to concentrate iodide was assessed at 24 h and 48 h after infection. Student's t-test was used for statistical analyses, *p<0.05, **p<0.01, ***p<0.001 as compared to uninfected cells. Bars represent SD.</p

In vivo iodide uptake and efficacy.

<p>(<b>a</b>) Tumor uptake of ¹²³I⁻ 0.5 h, 2 h and 13 h after i.v. administration of ¹²³I⁻. The tumors were injected twice with hTERT-viruses 24 h and 48 h prior to radioiodide. 1, Mock-injected tumor; 2, Ad5/3-hTERT-Δgp19K-injected tumor; 3 and 4, Ad5/3-hTERT-hNIS-injected tumors. (<b>b</b>) Ad5/3-hTERT-hNIS significantly prolongs the survival of mice bearing intra pulmonary PC-3MM2 tumors. Mice received 5×10¹⁰ vp of Ad5/3-hTERT-hNIS or diluent intravenously. Next day, the mice were injected intraperitoneally with ¹³¹I⁻. The treatments were repeated once a week for a total of three weeks. Pairwise comparisons with the logrank test were used to compare survival curves, **p<0.01, ***p<0.001 as compared to mock-treated mice. (<b>c</b>) Biodistribution of ¹³¹I⁻ in mice 48 h after the first intravenous Ad5/3-hTERT-hNIS-injection and 24 h after first radioiodide-injection. Bars represent SD.</p

Oncolytic potency of Ad5/3-hTERT-hNIS.

<p>Prostate cancer cells were infected in triplicates with 0.01 to 100 vp/cell and the cell viability was assessed by MTS-assay. Ad5/3Luc1 is a replication-deficient adenovirus. Ad5 WT is the serotype 5 wild-type adenovirus. Ad5/3-hTERT-Δgp19K is similar to Ad5/3-hTERT-hNIS but does not contain hNIS. ***p<0.001 as compared to replication-deficient adenovirus. Bars represent SD.</p

Risk of Rupture After Intracranial Aneurysm Growth

IMPORTANCE Unruptured intracranial aneurysms not undergoing preventive endovascular or neurosurgical treatment are often monitored radiologically to detect aneurysm growth, which is associated with an increase in risk of rupture. However, the absolute risk of aneurysm rupture after detection of growth remains unclear.OBJECTIVE To determine the absolute risk of rupture of an aneurysm after detection of growth during follow-up and to develop a prediction model for rupture.DESIGN, SETTING, AND PARTICIPANTS Individual patient datawere obtained from 15 international cohorts. Patients 18 years and older who had follow-up imaging for at least 1 untreated unruptured intracranial aneurysm with growth detected at follow-up imaging and with 1 day or longer of follow-up after growth were included. Fusiform or arteriovenous malformation-related aneurysms were excluded. Of the 5166 eligible patients who had follow-up imaging for intracranial aneurysms, 4827 were excluded because no aneurysm growth was detected, and 27 were excluded because they had less than 1 day follow-up after detection of growth.EXPOSURES All included aneurysms had growth, defined as 1mmor greater increase in 1 direction at follow-up imaging.MAIN OUTCOMES AND MEASURES The primary outcomewas aneurysm rupture. The absolute risk of rupture was measured with the Kaplan-Meier estimate at 3 time points (6 months, 1 year, and 2 years) after initial growth. Cox proportional hazards regression was used to identify predictors of rupture after growth detection. RESULTS A total of 312 patients were included (223 [71%] were women; mean [SD] age, 61 [12] years) with 329 aneurysms with growth. During 864 aneurysm-years of follow-up, 25 (7.6%) of these aneurysms ruptured. The absolute risk of rupture after growth was 2.9% (95% CI, 0.9-4.9) at 6 months, 4.3%(95% CI, 1.9-6.7) at 1 year, and 6.0% (95% CI, 2.9-9.1) at 2 years. In multivariable analyses, predictors of rupture were size (7mmor larger hazard ratio, 3.1; 95% CI, 1.4-7.2), shape (irregular hazard ratio, 2.9; 95% CI, 1.3-6.5), and site (middle cerebral artery hazard ratio, 3.6; 95% CI, 0.8-16.3; anterior cerebral artery, posterior communicating artery, or posterior circulation hazard ratio, 2.8; 95% CI, 0.6-13.0). In the triple-S (size, site, shape) prediction model, the 1-year risk of rupture ranged from 2.1% to 10.6%.CONCLUSION AND RELEVANCE Within 1 year after growth detection, rupture occurred in approximately 1 of 25 aneurysms. The triple-S risk prediction model can be used to estimate absolute risk of rupture for the initial period after detection of growth.Paroxysmal Cerebral Disorder

Effects of Dexmedetomidine on motor- and somatosensory-evoked potentials in patients with thoracic spinal cord tumor: a randomized controlled trial

BACKGROUND: We hypothesized that the addition of dexmedetomidine in a clinically relevant dose to propofol-remifentanil anesthesia regimen does not exert an adverse effect on motor-evoked potentials (MEP) and somatosensory-evoked potentials (SSEP) in adult patients undergoing thoracic spinal cord tumor resection. METHODS: Seventy-one adult patients were randomized into three groups. Propofol group (n = 25): propofol-remifentanil regimenand the dosage was adjusted to maintain the bispectral index (BIS) between 40 and 50. DP adjusted group (n = 23): Dexmedetomidine (0.5 μg/kg loading dose infused over 10 min followed by a constant infusion of 0.5 μg/kg/h) was added to the propofol-remifentanil regimen and propofol was adjusted to maintain BIS between 40 and 50. DP unadjusted group (n = 23): Dexmedetomidine (administer as DP adjusted group) was added to the propofol-remifentanil regimen and propofol was not adjusted. All patients received MEP, SSEP and BIS monitoring. RESULTS: There were no significant changes in the amplitude and latency of MEP and SSEP among different groups (P > 0.05). The estimated propofol plasma concentration in DP adjusted group (2.7 ± 0.3 μg/ml) was significantly lower than in propofol group (3.1 ± 0.2 μg/ml) and DP unadjusted group (3.1 ± 0.2 μg/ml) (P = 0.000). BIS in DP unadjusted group (35 ± 5) was significantly lower than in propofol group (44 ± 3) (P = 0.000). CONCLUSIONS: The addition of dexmedetomidine to propofol-remifentanil regimen does not exert an adverse effect on MEP and SSEP monitoring in adult patients undergoing thoracic spinal cord tumor resection. TRIAL REGISTRATION: The study was registered with the Chinese Clinical Trial Registry on January 31st, 2014. The reference number was ChiCTR-TRC-14004229