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Purpose: NK012 is a polymeric micelle formulation of SN-38, the active metabolite of irinotecan. We evaluated the efficacy and safety of NK012 in Japanese patients with unresectable metastatic colorectal cancer., Methods: We conducted a multicenter open-label phase II trial of NK012 monotherapy in 58 patients who had been treated with an oxaliplatin-based chemotherapy regimen (group A: 53 patients with UGT1A1 genotype -/-, *6/-, or *28/-; group B: 5 patients with UGT1A1 genotype *6/*28 or *6/*6). The primary endpoint was the response rate (RR). Initial doses of 28 and 18 mg/m 2 for group A and group B, respectively, were administered intravenously over 30 min, and these doses were subsequently administered every 3 weeks. Group A was evaluated as the primary efficacy population, while group B was evaluated for reference., Results: In group A, the RR was 3.8%, and the median progression-free survival and overall survival were 3.30 months and 15.03 months, respectively. In both groups, the most common grade ≥ 3 adverse drug reaction (ADR) was neutropenia and the incidence of grade ≥ 3 diarrhea was low or zero. In group A, 17 serious ADRs were observed in 10 patients (17%); all improved or recovered. In group B, no serious ADRs were observed. No treatment-related deaths were reported in either group., Conclusions: NK012 monotherapy yielded an RR similar to the RR of irinotecan monotherapy that was reported in the phase III EPIC trial (4.2%), and the incidence of grade ≥ 3 diarrhea was low. Based on the incidence and severity of febrile neutropenia and grade ≥ 3 neutropenia, the initial dose of NK012 28 mg/m 2 may be too high for colorectal cancer patients who have previously been treated with an oxaliplatin-based chemotherapy regimen.

Objective Multiple myeloma (MM) is the second most common hematological cancer. An attempt to treat MM using a topoisomerase I inhibitor was made based on our previous non-clinical studies suggesting the usefulness of an SN-38 derivative. Our aim was to conduct a phase I/II study of NK012, a micelle-forming SN-38 conjugate, in patients with relapsed/refractory multiple myeloma (RRMM). Methods NK012 was administered at doses of 12-24 mg/m 2 and the safety, pharmacokinetics and preliminary efficacy were evaluated. Results Neutropenia was the most common grade 3 or 4 adverse drug reaction. Grade 4 neutropenia accounted for the majority of dose-limiting toxicities and only appeared at a dose of 24 mg/m 2 . The maximum concentrations and the area under the concentration-time curves from time zero to infinity for both NK012 and its active metabolite SN-38 increased in a dose-dependent manner. The best overall response was stable disease, which was achieved in 12 out of 16 patients. Conclusion The recommended dose of NK012 monotherapy for RRMM patients was concluded to be 20 mg/m 2 . However, this phase I/II study was terminated at the end of the phase I stage because no patients showed an objective response. Additional clinical studies of combination therapy with NK012 and other agents are warranted.

The stimulus-preceding negativity (SPN) is an event-related potential that reflects emotional and perceptual anticipation. The SPN is characterized by a right hemisphere preponderance in amplitude, and previous studies suggest that activity in the insular cortex might contribute to the amplitude of the SPN. Although the insula might contribute to the SPN's occurrence, the exact role of the insula in the pattern of SPN right hemisphere dominance remains unclear. In the present study, we manipulated task difficulty and brain activation was measured using event-related fMRI, to examine the relationship between insula functioning and the right hemisphere preponderance of the SPN. Twenty-three participants performed a time estimation task, in which they had to press a button when they thought a predetermined time had elapsed. Three seconds after pressing the button, a feedback stimulus was presented, informing subjects as to whether their response was correct, too early, or too late. There were four experimental conditions: easy, moderate, difficult, and no feedback. The fMRI results showed significantly increased activation in the bilateral insular cortex during the pre-feedback anticipation phase, in which the subjects prepare to pay attention to the occurrence of feedback stimuli. In addition, in the Difficult-Easy and Difficult-Moderate contrasts, significantly increased activations of the right anterior insula were demonstrated, suggesting the possibility that this area does underlie the SPN right hemisphere preponderance. Because the right anterior insula is related to awareness of viscerosensory information, the SPN right hemisphere preponderance might itself be related to the awareness of interoceptive information that precedes feedback stimuli.

For real-time 3D visualization of respiratory organ motion for MRI-guided therapy, a new adaptive 4D MR imaging method based on navigator echo and multiple gating windows was developed. This method was designed to acquire a time series of volumetric 3D images of a cyclically moving organ, enabling therapy to be guided by synchronizing the 4D image with the actual organ motion in real time. The proposed method was implemented in an open-configuration 0.5T clinical MR scanner. To evaluate the feasibility and determine optimal imaging conditions, studies were conducted with a phantom, volunteers, and a patient. In the phantom study the root mean square (RMS) position error in the 4D image of the cyclically moving phantom was 1.9 mm and the imaging time was approximately 10 min when the 4D image had six frames. In the patient study, 4D images were successfully acquired under clinical conditions and a liver tumor was discriminated in the series of frames. The image quality was affected by the relations among the encoding direction, the slice orientation, and the direction of motion of the target organ. In conclusion, this study has shown that the proposed method is feasible and capable of providing a real-time dynamic 3D atlas for surgical navigation with sufficient accuracy and image quality., ((c) 2008 Wiley-Liss, Inc.)

We used functional magnetic resonance imaging to investigate brain activity related to motivational function of informative feedback stimuli in a time estimation task. In that task, subjects pressed a button as a response 3 s after a cue stimulus; a visual feedback stimulus was presented 2 s after the response. In a true feedback condition, subjects received true information (informative feedback) about their time-estimation performance. In the false feedback condition, the same visual signs were used, but they were presented randomly. Therefore, they were not related to actual performance. In the 20 subjects examined, higher hemodynamic responses were identified in the insular cortex, the thalamus, and the striatum by comparing the true feedback condition to the false feedback condition. The time estimation performance and subjective score on motivation were also markedly higher in the true feedback condition. The anterior insular cortex and striatal regions are known to be involved in motivational and reward processing. Therefore, the hemodynamic responses observed in this study suggest that the motivational function of the feedback information is a crucial factor for behavioral learning; it is considered that the informative feedback might serve as an implicit reward for humans.

This study examined the effects of emotional valence on stimulus-preceding negativity (SPN) using reward and fine. A time estimation task under reward, punishment, combined, and control conditions was performed. Participants were rewarded for accurate responses in the reward condition, and were fined for incorrect estimations in the punishment condition. in the combined condition, correct responses were rewarded and incorrect responses were fined. In the control condition, neither a reward nor fine was used. Results showed a significant interaction of condition x hemisphere. The SPN at the left hemisphere was increased in the reward condition. For the punishment effect, although it evoked right hemisphere dominance, no conditional difference was apparent at the right hemisphere. These results suggest that the SPN is affected by positive emotion: The left hemisphere activation might represent a pleasant emotion accompanying monetary gain.

Aiming at real-time 3-D visualization of organ motion to navigate surgical procedures in MRI-guided surgery, a new 4-D MR imaging technique called "Adaptive 4-D Scan" has been proposed. The technique is designed to acquire a time series of volumetric 3-D images (4-D image) of cyclically moving organ, even in a low-field open-configuration MR scanner. A pre-operative 4-D image is acquired with respiratory phase parameter, which is monitored by using navigator-echo-based real-time tracking of the liver and diaphragm. During operation, the respiratory phase is again monitored in real-time, and a 3-D image, reflecting the current state of the target organ, is extracted from the pre-operative 4-D image and provided to physicians as a pseudo real-time 3-D image. We implemented Adaptive 4-D Scan into a 0.5 Tesla open-configuration clinical MRI system for intervention. Phantom and volunteer studies were performed to assess feasibility of this technique, in terms of image quality, imaging time and position accuracy of the imaged subject. A 4-D image (matrix: 256 x 128 x 10 x 8) of cyclically moving phantom was acquired in 719 s, and RMS position error between the imaged subject and the real subject was 2.3 mm, where the range of motion was 50 mm. 4-D image of the moving liver was also successfully acquired under near clinical condition. In conclusion, the study shows that the proposed method is feasible and has capability to provide real-time dynamic 3-D atlas for surgical navigation.

Twenty-one subjects underwent event-related fMRI while carrying out a simple visuomotor task in which they responded to stimuli flashed either onto the right visual field, onto the left visual field, or onto both visual fields at once. The aim of this study was to clarify areas of brain activity associated with crossed-uncrossed differences (CUD) and to investigate differences of the brain activity between CUD and redundancy gain. An intriguing brain activation related to CUD was found in the genu of the corpus callosum (CC). The sites of activation related to redundancy gain were the extrastriate cortex and the cingulate cortex. Our results suggested that CUD depended on the interhemispheric transfer via the CC, and that CUD and redundancy gain involved different brain mechanisms.

In writing to dictation, one mode of language processing is based on the knowledge of how to convert speech sounds to the corresponding letters, namely, phoneme-to-grapheme conversion (phonological mode). Little is known about the neural substrates of the phoneme-to-grapheme conversion. Our study aims to clarify the neural substrates of phoneme-to-grapheme conversion in writing to dictation using functional magnetic resonance imaging. We employed Japanese as the stimulus language because in Japanese, one phoneme is represented by one grapheme (kana) and vice versa. Functional magnetic resonance imaging revealed that the left premotor, extending into Broca's area was activated. The present results suggested that the frontal region is required for the conversion of phonemes to graphemes in writing to dictation.

MRI (magnetic resonance imaging) with 129Xe has gained much attention as a diagnostic methodology because of its affinity for lipids and possible polarization. The quantitative estimation of net detectability and stability of hyperpolarized 129Xe in the dissolved phase in vivo is valuable to the development of clinical applications. The goal of this study was to develop a stable hyperpolarized 129Xe experimental 3T system to statistically analyze the dissolved-phase 129Xe signal in the rat lungs. The polarization of 129Xe with buffer gases at the optical pumping cell was measured under adiabatic fast passage against the temperature of an oven and laser absorption at the cell. The gases were insufflated into the lungs of Sprague-Dawley rats (n = 15, 400-550 g) through an endotracheal tube under spontaneous respiration. Frequency-selective spectroscopy was performed for the gas phase and dissolved phase. We analyzed the 129Xe signal in the dissolved phase to measure the chemical shift, T2*, delay and its ratio in a rat lungs on 3T. The polarizer was able to produce polarized gas (1.1+/-0.47%, 120 cm3) hundreds of times with the laser absorption ratio (25%) kept constant at the cell. The optimal buffer gas ratio of 25-50% rendered the maximum signal in the dissolved phase. Two dominant peaks of 211.8+/-0.9 and 201.1+/-0.6 ppm were observed with a delay of 0.4+/-0.9 and 0.9+/-1.0 s from the gas phase spectra. The ratios of their average signal to that of the gas phase were 5.6+/-5.2% and 4.4+/-4.7%, respectively. The T2* of the air space in the lungs was 2.5+/-0.5 ms, which was 3.8 times shorter than that in a syringe. We developed a hyperpolarized 129Xe experimental system using a 3T MRI scanner that yields sufficient volume and polarization and quantitatively analyzed the dissolved-phase 129Xe signal in the rat lungs.