Phase II study of brigatinib in patients with ROS1 fusion-positive non-small-cell lung cancer: the Barossa study.

BACKGROUND: Brigatinib is a next-generation tyrosine kinase inhibitor (TKI) targeting ALK and ROS1. The Barossa study is a multicenter, phase II basket study of brigatinib in patients with ROS1-rearranged solid tumors. ROS1 TKI-naive patients with ROS1-rearranged non-small-cell lung cancer (NSCLC) were enrolled in cohort 1, and ROS1-rearranged NSCLC patients treated previously with crizotinib were enrolled in cohort 2. Patients with ROS1-rearranged solid tumors other than NSCLC were enrolled in cohort 3. PATIENTS AND METHODS: Eligible patients received brigatinib at the dose of 180 mg once daily with a 7-day lead-in period at 90 mg. The primary endpoint was the objective response rate (RECIST 1.1) assessed by independent central review in cohorts 1 and 2. RESULTS: Between July 2019 and June 2021, 51 patients were enrolled into the study. Of the 51, 47 patients had ROS1-rearranged NSCLC; 28 and 19 of these patients were enrolled in cohort 1 and cohort 2, respectively. The remaining four patients had other ROS1-rearranged solid tumors, including rectal, brain, and pancreas tumor in one patient each, and primary unknown tumor in one patient. The confirmed objective response rate was 71.4% [95% confidence interval (CI) 51.3% to 86.8%] in cohort 1 (TKI-naive NSCLC patients) and 31.6% (95% CI 12.6% to 56.6%) in cohort 2 (NSCLC patients treated previously with crizotinib). The median progression-free survival was 12.0 months (95% CI 5.5-22.9 months) in cohort 1 and 7.3 months (95% CI 1.3-17.5 months) in cohort 2. None of the patients in cohort 3 showed any treatment response. Pneumonitis was observed in 9.8% of all the patients. CONCLUSIONS: Brigatinib was effective in TKI-naive patients with ROS1-rearranged NSCLC. The safety profile of brigatinib was consistent with that reported from previous studies.

γ-Secretase inhibitor enhances antitumour effect of radiation in Notch-expressing lung cancer.

BACKGROUND: Notch receptor has an important role in both development and cancer. We previously reported that inhibition of the Notch3 by γ-secretase inhibitor (GSI) induces apoptosis and suppresses tumour proliferation in non-small-cell lung cancer. Although radiation is reported to induce Notch activation, little is known about the relationship between radiation and Notch pathway. METHODS: We examined the effect of combining GSI and radiation at different dosing in three Notch expressing lung cancer cell lines. The cytotoxic effect of GSI and radiation was evaluated using MTT assay and clonogenic assay in vitro and xenograft models. Expressions of Notch pathway, mitogen-activated protein kinase (MAPK) pathway and Bcl-2 family proteins were investigated using western blot analysis. RESULTS: We discovered that the antitumour effect of combining GSI and radiation was dependent on treatment schedule. γ-Secretase inhibitor administration after radiation had the greatest growth inhibition of lung cancer in vitro and in vivo. We showed that the combination induced apoptosis of lung cancer cell lines through the regulation of MAPK and Bcl-2 family proteins. Furthermore, activation of Notch after radiation was ameliorated by GSI administration, suggesting that treatment with GSI prevents Notch-induced radiation resistance. CONCLUSION: Notch has an important role in lung cancer. Treatment with GSI after radiation can significantly enhance radiation-mediated tumour cytotoxicity.

The effects of age on maintenance of intense neuromuscular block with rocuronium.

BACKGROUND: Increasing age is associated with a longer duration of action of neuromuscular block. The aim of this study was to determine the influence of ageing on the recovery of the post-tetanic count (PTC) from rocuronium-induced neuromuscular block. METHODS: Twenty-two younger (20-60 years) and 22 older (> 70 years) patients were enrolled in this study. After induction of anaesthesia with fentanyl and propofol, all patients initially received 1 mg/kg rocuronium and neuromuscular block were evaluated by contractions of the adductor pollicis muscle to ulnar nerve train-of-four stimulation using an acceleromyograph. Subsequently, intense rocuronium-induced block was determined every 6 min using the PTC during 1.0-1.5% sevoflurane and remifentanil anaesthesia. When the first response to the PTC stimulus was detected, 0.2 mg/kg rocuronium was additionally administered, and again, spontaneous recovery of neuromuscular function was monitored until the first response to the PTC reappeared. RESULTS: Median values (range) of the times from the administration of 1 mg/kg and 0.2 mg/kg rocuronium until recovery of the first detectable PTC were significantly longer in the older [51.0 (27-100) min, P < 0.0001 and 30.0 (12-66) min, P = 0.0036, respectively] than the younger patients [31.5 (21-45) min and 18.0 (12-36) min, respectively]. CONCLUSION: The times from rocuronium injection to reappearance of the first response to PTC stimulation are approximately twofold longer and more variable in older than younger patients. Hence, the dosing interval of rocuronium should be adjusted using neuromuscular monitoring when maintaining intense neuromuscular block, especially in older patients.

Correlation between cardiac output and reversibility of rocuronium-induced moderate neuromuscular block with sugammadex.

BACKGROUND: The aim of this study was to evaluate the correlation between cardiac output (CO) and reversibility of rocuronium-induced moderate neuromuscular block with sugammadex in elderly patients. METHODS: Fifty elderly (≥ 65 years) patients were enrolled in this study. During 1.0-1.5% end-tidal sevoflurane and remifentanil anaesthesia, contraction of the adductor pollicis muscle in response to ulnar nerve stimulation was acceleromyographically quantified. All patients initially received 1 mg/kg rocuronium followed by 0.2 mg/kg whenever the second twitch T2 of the train-of-four (TOF) response reappeared. CO was measured throughout the study using a FloTrac™/Vigileo™ monitor. After completion of surgery and at the reappearance of T2, the time required for a bolus dose of 2 mg/kg sugammadex to facilitate recovery to a TOF ratio of 0.9 was recorded, and its correlation with CO was analysed. RESULTS: Adequate recovery of neuromuscular block was achieved after sugammadex in all patients. Mean CO at the time of reversal with sugammadex was 5.3 l/min (1.3), and recovery time to a TOF ratio of 0.9 was 173.4 s (54.8). A statistically significant inverse correlation was seen between the time to recovery to a TOF ratio of 0.9 and CO [reversal time (s) = -27.7·CO + 298.7, R(2) = 0.461, P < 0.0001]. CONCLUSIONS: The time to reach a TOF ratio of 0.9 following sugammadex is dependent on CO in elderly patients.

Notch3 cooperates with the EGFR pathway to modulate apoptosis through the induction of bim.

Notch signaling is a highly conserved pathway important for normal embryonic development and cancer. We previously demonstrated a role for Notch3 in lung cancer pathogenesis. Notch3 inhibition resulted in tumor apoptosis and growth suppression. In vitro, these effects were enhanced when the epidermal growth factor receptor (EGFR) pathway was also inhibited, suggesting significant cross-talk between the two pathways. How Notch3 and epidermal growth factor receptor-mitogen-activated protein kinase (EGFR-MAPK) pathways cooperate in modulating apoptosis is not yet known. In this study, we provide evidence that Notch3 regulates Bim, a BH-3-only protein, via MAPK signaling. Furthermore, loss of Bim expression prevents tumor apoptosis induced by Notch3 inhibition. Using gamma-secretase inhibitor and erlotinib in a xenograft model, Bim induction and tumor inhibition were observed to be enhanced compared with either agent alone, consistent with our previous observation of significant synergism between Notch and EGFR-ras-MAPK signaling. Thus, our data support the hypothesis that Notch3 not only has a crucial role in lung cancer through regulating apoptosis, but also cooperates with the EGFR-MAPK pathway in modulating Bim.

MR tractography for the evaluation of functional recovery from lenticulostriate infarcts.

OBJECTIVE: To evaluate the anatomic and clinical relationship between the lenticulostriate artery (LSA) territory and the corticospinal tract (CST) in patients with acute infarcts in this territory using MR tractography. METHODS: Thirteen consecutive patients who presented with acute infarcts in the LSA territory and who also had undergone an MRI study within 3 days after symptom onset were studied. Visualization of the CST was achieved by postprocessing the acquired diffusion tensor imaging data. To classify lesion location, the LSA territory was divided into four subsegments, the boundaries of which were drawn by axial and coronal planes crossing through the foramen of Monro. Infarct volume and extent of CST involvement were measured and compared with neurologic findings. RESULTS: All of the infarcts were located in the posterior segment. All of the depicted CSTs crossed the LSA territory only at the posterosuperior quadrant. The extent of CST involvement within the infarcts was correlated with the severity of the patient's motor deficit (p < 0.01) and with the clinical outcome (p < 0.05). CONCLUSIONS: The corticospinal tracts (CSTs) crossed the lenticulostriate artery territory exclusively at the posterosuperior quadrant, and the degree of CST involvement within the infarcts was directly related to stroke severity and functional recovery.

Decrease in cortical benzodiazepine receptors in symptomatic patients with leukoaraiosis: a positron emission tomography study.

BACKGROUND AND PURPOSE: [11C]flumazenil (FMZ), a ligand that selectively binds to the central benzodiazepine receptor in the neuronal membrane, is useful for evaluating neuronal viability in a positron emission tomography (PET) scan. Using this ligand, we investigated whether there was a correlation between neuronal integrity in various brain structures and dementia in patients with leukoaraiosis. METHODS: Twelve patients with extensive leukoaraiosis on magnetic resonance imaging were divided into groups of patients with or without dementia. Based on a 2-compartment, 2-parameter model that included metabolite-corrected arterial input and PET-measured cerebral radioactivity, the distribution volume of FMZ (FMZ-V(d)) was calculated in various regions of interest by nonlinear curve fitting. Additionally, tracer kinetic analysis was applied for voxel-by-voxel quantification of FMZ-V(d), and data analysis was performed by statistical parametric mapping. RESULTS: The presence of dementia was associated with a reduced FMZ-V(d) in widespread areas of the cerebral cortex, including the bilateral frontopolar and frontal/insular areas, the left temporo-occipital border areas, and the left marginal cortical areas. CONCLUSIONS: Differences in neuronal integrity in the cerebral cortex might determine whether patients with leukoaraiosis become symptomatic or not.

2-(2'-Hydroxyphenyl)benzene sulfinate desulfinase from the thermophilic desulfurizing bacterium Paenibacillus sp. strain A11-2: purification and characterization.

2-(2'-Hydroxyphenyl)benzene sulfinate (HPBSi) desulfinase (TdsB), which catalyzes the final step of desulfurization of dibenzothiophene (DBT), was purified from a thermophilic DBT- and benzothiophene (BT)-desulfurizing bacterium: Paenibacillus sp. strain A11-2. The molecular mass of the purified enzyme was 31 kDa and 39 kDa by gel filtration and sodium dodecyl sulfate polyacrylamide gel electrophoresis, respectively, suggesting a monomeric structure. The optimal temperature and pH for the reaction involving TdsB was 55 degrees C and the enzyme was more resistant to heat treatment than DszB, a counterpart purified from Rhodococcus erythropolis. The optimum pH for TdsB activity was pH 8. TdsB converted HPBSi to 2-hydroxybiphenyl (2-HBP) and sulfite stoichiometrically. The Km and kcat values for HPBSi were 0.33 mM and 0.32 s(-1), respectively. TdsB was inactivated by SH reagents such as p-chloromercuribenzoic acid and 5,5'-dithio-bis-2-nitrobenzoic acid, but was not inhibited by chelating reagents such as EDTA and o-phenanthroline. TdsB was also inhibited by o-hydroxystyrene, the final desulfurized product of BT. However, 2-HBP and its derivatives showed only a weak inhibitory effect. TdsB desulfurized 2-(2'-hydroxyphenyl)ethen-1-sulfinate to yield o-hydroxystyrene, but DszB could not. A site-directed mutagenesis study revealed the cysteine residue at position 17 to be essential to the catalytic activity of TdsB.

Purification and characterization of the monooxygenase catalyzing sulfur-atom specific oxidation of dibenzothiophene and benzothiophene from the thermophilic bacterium Paenibacillus sp. strain A11-2.

A benzothiophene (BT) and dibenzothiophene (DBT) monooxygenase (TdsC), which catalyzes the oxidation of the sulfur atoms in BT and DBT molecules, was purified from Paenibacillus sp. strain A11-2. The molecular mass of the purified enzyme and its subunit were determined to be 200 kDa and 43 kDa by gel filtration and sodium dodecyl sulfate polyacrylamide gel electrophoresis, respectively, indicating a tetrameric structure. The N-terminal amino acid sequence of the purified TdsC completely matched the amino acid sequence deduced from the nucleotide sequence of the tdsC gene reported previously [Ishii et al. (2000) Biophys Biochem Res Commun 270:81-88]. The optimal temperature and pH for the TdsC reaction were 65 degrees C and pH 9, respectively. TdsC required NADH, FMN and TdsD, a NADH-dependent FMN oxidoreductase, for its activity, as was observed for TdsA. FAD, lumiflavin and/or NADPH had some effect on the maintenance of TdsC activity. A comparison of the substrate specificity of TdsC and DszC, the homologous monooxygenase purified from Rhodococcus erythropolis strain KA2-5-1, demonstrated a contrasting pattern towards alkylated DBTs and BTs.

Biodesulfurization of benzothiophene and dibenzothiophene by a newly isolated Rhodococcus strain.

Rhodococcus sp. KT462, which can grow on either benzothiophene (BT) or dibenzothiophene (DBT) as the sole source of sulfur, was newly isolated and characterized. GC and GC-MS analyses revealed that strain KT462 has the same BT desulfurization pathway as that reported for Paenibacillus sp. A11-2 and Sinorhizobium sp. KT55. The desulfurized product of DBT produced by this strain, as well as other DBT-desulfurizing bacteria such as R. erythropolis KA2-5-1 and R. erythropolis IGTS8, was 2-hydroxybiphenyl. A resting cells study indicated that this strain was also able to degrade various alkyl derivatives of BT and DBT.

Abnormal cortical mechanisms of voluntary muscle relaxation in patients with writer's cramp: an fMRI study.

Although it is hypothesized that there is abnormal motor inhibition in patients with dystonia, the question remains as to whether the mechanism related to motor inhibition is specifically impaired. The objective of the present study was to clarify the possible abnormalities of the mechanisms underlying voluntary muscle relaxation during motor preparation and execution in patients with writer's cramp, using event-related functional MRI. Eight patients with writer's cramp and 12 age-matched control subjects participated in the study. Two motor tasks were employed as an experimental paradigm. In the relaxation task, subjects were asked to hold their right wrist in the horizontal plane by maintaining moderate contraction of wrist extensor muscles in the premotor phase; they relaxed those muscles voluntarily just once during each fMRI scanning session. In the contraction task, subjects extended the right wrist voluntarily from the same premotor state as for the relaxation task. Five axial images covering the primary sensorimotor cortex (SMC) and supplementary motor area (SMA) were obtained once every second. Activated volumes in the left SMC and the SMA were significantly reduced in patients for both muscle relaxation and contraction tasks. These data suggest that there is impaired activation in both SMC and SMA in voluntary muscle relaxation and contraction in patients with writer's cramp. This implies that abnormalities of both inhibitory and excitatory mechanisms in motor cortices might play a role in the pathophysiology of focal dystonia.

[A case of lung metastasis from colon cancer treated successfully with combined chemotherapy of CPT-11 and 5'-DFUR].

The patient was a 52-year-old woman who had sigmoid colon cancer with liver metastasis and multiple lung metastases. Resection of curability B was performed, and alternating adjuvant chemotherapy consisting of hepatic artery injection of 5-FU and systemic administration of CPT-11 was performed. Lung recurrence was found and no antitumor effect of chemotherapy was observed, so the CPT-11 which had been administered every other week was given every week in a dose of 60 mg/body, half of the original dose. Moreover, 5'-DFUR was administered in a dose of 800 mg/day every day. As a result, lung metastasis tumors were reduced markedly. Adverse events such as nausea, vomiting and depilation were mitigated, and no other toxicity was observed. The patient could thus be treated extremely safely in the outpatient clinic. This was considered to be a valuable case suggestive of the significance of combination chemotherapy of CPT-11 and 5'-DFUR and the importance of appropriate administration of CPT-11.

Pharmacokinetics and enhancement patterns of macromolecular MR contrast agents with various sizes of polyamidoamine dendrimer cores.

Four macromolecular contrast agents are synthesized to visualize small vessels by MRI using generation-3 (G3D), -4 (G4D), -5 (G5D), and -6 (G6D) polyamidoamine dendrimers conjugated to chelated gadolinium (Gd). The pharmacokinetics, enhancement patterns, and the ability of these constructs to visualize fine vessels is evaluated by dynamic MRI in relationship to their size. Gd-G6D and -G5D exhibit a prolonged high vascular (ventricular) signal intensity (SI) with high ventricle-to-organ SI ratios. The initial high vascular SI with Gd-G4D decreases to a value as low as that obtained with Gd-G3D and Gd-dimeglumine-diethylenetriaminepentaacetic acid (Gd-DTPA). Gd-G5D, -G4D, and -G3D show high renal SIs, and Gd-DTPA prominently enhances the skin. Gd-G6D and -G5D present fine vasculature significantly more clearly than Gd-G3D and -DTPA (P < 0.005). As the molecular size increases, the excretion of the 153Gd-conjugates is retarded. In conclusion, Gd-G6D and -G5D are retained in the blood and present fine vessels with high quality and detail, and should be adequate for visualizing small tumor vasculature.

Micro-MR angiography of normal and intratumoral vessels in mice using dedicated intravascular MR contrast agents with high generation of polyamidoamine dendrimer core: reference to pharmacokinetic properties of dendrimer-based MR contrast agents.

Pharmacokinetic characteristics of intravascular macromolecular magnetic resonance imaging (MRI) contrast agents with polyamidoamine dendrimer cores smaller than generation-7 were previously studied in the literature. To evaluate the effects of greater hepatic uptake on the pharmacokinetics of the larger generation dendrimers, the MRI contrast agents GxD-(1B4M-Gd)(2(x+2)) were synthesized with generation-7, -8, and -9 polyamidoamine dendrimers and 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M). Their pharmacokinetic characteristics in mice were compared with that of G6D-(1B4M-Gd)(256). In biodistribution and dynamic micro-MRI studies, significantly less renal accumulation of G7D-(1B4M-Gd)(512), G8D-(1B4M-Gd)(1024), and G9D-(1B4M-Gd)(2048) was shown compared to G6D-(1B4M-Gd)(256) (P < 0.01). There was a significantly greater accumulation of G8D-(1B4M-Gd)(1024) and G9D-(1B4M-Gd)(2048) in the liver compared to G6D-(1B4M-Gd)(256) and G7D-(1B4M-Gd)(512) (P < 0.01). The highest blood retention of all dendrimer-based MRI contrast agents was exhibited by G7D-(1B4M-Gd)(512) (P < 0.01). The normal and intratumoral fine vessels of approximately 100 microm diameter were visualized in normal or tumor-bearing mice by high resolution three-dimensional-micro-MR angiographs with G7D-(1B4M-Gd)(512) and G8D-(1B4M-Gd)(1024) with good vessel-to-soft tissue contrast. In summary, increased accumulation in the liver with concomitant decreased uptake in the kidney was caused by increased molecular sizes of the dendrimer-based MRI contrast agents.

Myocardial metabolism of 123I-BMIPP during low-flow ischaemia in an experimental model: comparison with myocardial blood flow and 18F-FDG.

Risk stratification of coronary artery disease may provide a basis for selection of treatment to prevent myocardial events and to assist functional recovery. Iodine-123 (rho-iodophenyl)-3-R,S-methylpentadecanoic acid (123I-BMIPP) is a radioiodinated fatty acid analogue for single-photon emission tomographic (SPET) imaging, and several reports have demonstrated that the abnormal uptake of 123I-BMIPP is associated with wall motion abnormality and severe coronary artery stenosis. Clarification of the contribution of fatty acids to myocardial metabolism would be highly valuable in recognising this critical condition. In this study, we investigated the myocardial uptake of 123I-BMIPP under low-flow ischaemia, and compared it with the uptake of fluorine-18 fluorodeoxyglucose (18F-FDG). Using open chest dogs, the flow of the left anterior descending coronary artery was controlled using a pneumatic occluder in order to maintain a 30%-40% reduction of Doppler flow. 123I-BMIPP and 18F-FDG were injected into the left atrium after 90 min of ischaemia (protocols 1 and 3). Canine hearts were excised after 120 min of ischaemia for the measurement of radioactivity. In protocol 2, 123I-BMIPP alone was injected and hearts were excised 8 min after the injection. A time-course biopsy study was also performed at the same time (protocol 3). Wall thickening was evaluated using a wall tracker module. The uptake of 18F-FDG increased significantly in the ischaemic region (232%+/-135% vs non-ischaemic, P<0.05 in protocol 1) even on mild reduction of myocardial blood flow (MBF). The increased uptake of 18F-FDG did not correlate well with the severity of MBF. On the other hand, 123I-BMIPP uptake decreased gradually (78.9%+/-23.6%, P<0.05 in protocol 1, and 85.9%+/-24.3% in protocol 2) in the ischaemic region, specifically in the endocardium (64.0%+/-28.9%, P<0.05 in protocol 1, and 75.1%+/-28.8%, P<0.05 in protocol 2), and correlated strongly with MBF (r=0.93 in protocol 1 and r=0.97 in protocol 2) as a logarithmic function. This indicated that the abnormal uptake of 123I-BMIPP was associated not only with wall motion abnormality but also with the severity of MBF. In the biopsy study (protocol 3), the radioactivity of either 123I-BMIPP or 18F-FDG correlated well with the MBF at the time of tracer injection and was similar to post-mortem analysis. It is concluded that 18F-FDG is a valid tool for identifying ischaemic myocardium even in its earliest stages. On the other hand, 123I-BMIPP might be used to detect moderately to severely ischaemic myocardium such as hibernation, suggesting the potential value of 123I-BMIPP in the risk stratification of patients with severe coronary artery disease who require revascularisation without delay.

Tumor targeting and imaging of intraperitoneal tumors by use of antisense oligo-DNA complexed with dendrimers and/or avidin in mice.

To establish an effective nonviral gene delivery and a corresponding imaging method for i.p.-disseminated tumors, various oligonucleotide-carrier complexes were synthesized, and their in vitro and in vivo properties were examined. The 20-mer multiamino-linked oligonucleotide (oligo), synthesized as antisense against the c-erbB-2 sequence, and the 3'-biotinylated form of the same oligonucleotide (oligo-Bt) were (111)In labeled through a diethylenetriaminepentaacetic acid chelate. (111)In-oligo was mixed with generation 4 polyamidoamine dendrimer (G4) or with biotinylated G4 (G4-Bt), which are positively charged to form electrostatic complexes. (111)In-oligo/G4-Bt and (111)In-oligo-Bt were conjugated to avidin ((111)In-oligo/G4-Av and (111)In-oligo-Av, respectively). (111)In-oligo/G4, (111)In-oligo/G4-Av, (111)In-oligo-Av, and carrier-free (111)In-oligo (2.96 kBq/22.4-45.9 ng of oligo) were examined for internalization in vitro in human ovarian cancer cells (SHIN3). Biodistribution of (111)In-oligo-carrier complexes or (111)In-oligo was examined in normal (n = 4-7) or i.p. SHIN3 tumor-bearing (n = 6-10) mice 2-24 h after i.p. injection (74 kBq/125-300 ng). Scintigraphy of i.p. tumor-bearing and normal mice was performed at various times postinjection of (111)In-oligo-carrier complex or (111)In-oligo (1.85 MBq/2.2 ng). (111)In-oligo-carrier complexes bound to the tumor cells were internalized at a rate of 34-56% at 24 h. In vivo, G4, G4-Av, and Av significantly enhanced tumor delivery of (111)In-oligo [9.1, 14.5, and 24.4% of injected dose per g of tissue (ID/g) at 24 h; P < 0.05, < 0.01, and < 0.0001, respectively] compared with delivery without carrier (0.8% ID/g). Scintigrams of (111)In-oligo delivered to the i.p.-disseminated tumors by the carriers were successfully obtained. In conclusion, G4, G4-Av, and Av can effectively deliver (111)In-oligo to i.p.-disseminated tumors. (111)In-oligo-carrier complexes also have potential as tracers for imaging and monitoring of gene delivery.

[Temporary placement of inferior vena cava filter prior to transcatheter arterial embolization (TAE) for hepatocellular carcinoma with IVC tumor thrombus--prevention of pulmonary tumor emboli after TAE].

A 66-year-old-man with a right huge hepatocellular carcinoma (HCC) extending into both the right portal vein and the right atrium underwent transcatheter arterial embolization (TAE) via the right hepatic artery. Prior to the TAE, a temporary inferior vena cava (IVC) filter was placed suprarenally for prevention of pulmonary tumor emboli. When we replaced the temporary IVC filter with a new one 7 days after the TAE, the filter which was pulled out of the IVC captured a fragment of the tumor thrombus. A histopathological specimen demonstrated only ghost cells. The patient has been followed at our outpatient clinic without any tumor thrombus or pulmonary infarction for 13 months after this procedure.

Positive effects of polyethylene glycol conjugation to generation-4 polyamidoamine dendrimers as macromolecular MR contrast agents.

Macromolecules conjugated with polyethylene glycol (PEG) acquire more hydrophilicity, resulting in a longer half-life in circulation and lower immunogenicity. Two novel conjugates for MRI contrast agents were synthesized from a generation-4 polyamidoamine dendrimer (G4D), 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M), and one or two PEG molecules with a molecular weight of 20000 Da (PEG(2)-G4D-(1B4M-Gd)(62) (MW: 96 kD), PEG(1)-G4D-(1B4M-Gd)(63) (MW: 77 kD)). Their pharmacokinetics, excretion, and properties as vascular MRI contrast agents were evaluated and compared with those of G4D-(1B4M-Gd)(64) (MW: 57 kD). PEG(2)-G4D-(1B4M-Gd)(62) remained in the blood significantly longer and accumulated significantly less in the liver and kidney than the other two preparations (P < 0.01). Although the blood clearance was slower, PEG(2)-G4D-(1B4M-Gd)(62) was excreted more readily without renal retention than the other two preparations. In conclusion, the positive effects of PEG conjugation on a macromolecular MRI contrast agent were found to be prolonged retention in the circulation, increased excretion, and decreased accumulation in the organs.

Novel liver macromolecular MR contrast agent with a polypropylenimine diaminobutyl dendrimer core: comparison to the vascular MR contrast agent with the polyamidoamine dendrimer core.

As MRI contrast agents, more hydrophobic molecules reportedly accumulate in the liver and thus are potentially useful as liver MRI contrast agents. In this study, a generation-4 polypropylenimine diaminobutane dendrimer (DAB-Am64), which is expected to be more hydrophobic than the generation-4 polyamidoamine dendrimer (PAMAM-G4D), was used to synthesize a conjugate with 2-(p-isothiocyanatobenzyl)-6-methyl-diethylenetriaminepentaacetic acid (1B4M) [DAB-Am64-(1B4M-Gd)(64)] for complexing Gd(III) ions. This DAB conjugate quickly accumulated in the liver and its characteristics were studied and compared with those of a PAMAM conjugate [PAMAM-G4D-(1B4M-Gd)(64)], which is known to be a useful vascular MRI contrast agent, in regard to its availability as a liver MRI contrast agent. DAB-Am64-(1B4M-Gd)(64) accumulated significantly more in the liver and less in blood than PAMAM-G4D-(1B4M-Gd)(64) (P < 0.001). Contrast-enhanced MRI with DAB-Am64-(1B4M-Gd)(64) was able to homogeneously enhance liver parenchyma and visualize both portal and hepatic veins of 0.5 mm diameter in mice. In conclusion, DAB-Am64-(1B4M-Gd)(64) is a good candidate for a liver MRI contrast agent.