Is the evidence of the Supreme Court Ruling of gefitinib litigation in Japan scientific?

BACKGROUND: Plaintiffs of the gefitinib (Iressa) lawsuits in Japan started in 2004 were defeated in the Supreme Court in 2013. The Court judged it was not possible to foresee the outbreak of deaths caused by interstitial pneumonia due to gefitinib from death cases before approval of this drug. OBJECTIVE: We attempted to verify validity of this judgment. METHODS: We estimated the 95% confidence interval (CI) of the proportion of onset and death cases among 23 onset and 13 death cases occurring from "within 1 week" to "within 4 weeks" from clinical data before approval of this drug using data admitted to the Court. RESULTS: For death cases, all of the upper limits of the 95% CI exceeded 50% within 1-4 weeks. This fact suggested that the cases of acute interstitial pneumonia were included in the clinical trial before the approval of gefitinib. CONCLUSION: It was possible to foresee the outbreak of death cases after drug approval. This conclusion showed the Court's ruling was not reasonable and was unscientific.

Negative predictive value of multiparametric MRI for prostate cancer detection: outcome of 5-year follow-up in men with negative findings on initial MRI studies.

OBJECTIVE: To assess the clinical negative predictive value (NPV) of multiparametric MRI (mp-MRI) for prostate cancer in a 5-year follow-up. MATERIALS AND METHODS: One hundred ninety-three men suspected of harboring prostate cancer with negative MRI findings were included. Patients with positive transrectal ultrasound (TRUS)-guided biopsy findings were defined as false-negative. Patients with negative initial TRUS-guided biopsy findings were followed up and only patients with negative findings by digital rectal examination, MRI, and repeat biopsy and no increase in PSA at 5-year follow-up were defined as "clinically negative". The clinical NPV of mp-MRI was calculated. For quantitative analysis, mean signal intensity on T2-weighted images and the mean apparent diffusion coefficient value on ADC maps of the initial MRI studies were compared between peripheral-zone (PZ) cancer and the normal PZ based on pathologic maps of patients who had undergone radical prostatectomy. RESULTS: The clinical NPV of mp-MRI was 89.6% for significant prostate cancer. Small cancers, prostatitis, and benign prostatic hypertrophy masking prostate cancer returned false-negative results. Quantitative analysis showed that there was no significant difference between PZ cancer and the normal PZ. CONCLUSION: The mp-MRI revealed a high clinical NPV and is a useful tool to rule out clinically significant prostate cancer before biopsy.

Reduction in radiation and contrast medium dose via optimization of low-kilovoltage CT protocols using a hybrid iterative reconstruction algorithm at 256-slice body CT: phantom study and clinical correlation.

AIM: To optimize low-kilovoltage (kV) computed tomography (CT) protocols using a hybrid iterative reconstruction (HIR) algorithm at 256-detector-row body CT. MATERIALS AND METHODS: Based on preliminary phantom studies, three different tube voltage protocols with an equal contrast-to-noise ratio (CNR) were developed. They were a conventional 120 kV protocol with filtered back-projection (FBP), an 80 kV protocol with HIR (a 160% increase in the tube current-time product and a 40% reduction in the contrast medium dose), and a 100 kV protocol with HIR (a 20% reduction in the tube current-time product and the contrast medium dose). The clinical study included 70 patients (34 women, 36 men; mean age 70.5 ± 9.1 years, range 44-92 years) who had undergone CT at 120 kV a mean of 148 ± 137 days before undergoing low kV contrast-enhanced body CT (80 kV with HIR, n = 35; 100 kV with HIR, n = 35). The estimated effective radiation dose (ED), image noise, and CNR were calculated and the visual image quality was scored on a four-point scale. RESULTS: Mean ED was 12.3, 8.4, and 15.4 mSv for the 80, 100, and 120 kV protocol, respectively, and significantly lower using the low kV protocols. There was no significant difference in the image noise and CNR between the low kV protocols with HIR and the 120 kV protocol with FBP, or in the visual scores among the three protocols. CONCLUSION: Without ensuing image-quality degradation, the radiation and contrast medium dose can be reduced with optimal contrast-enhanced CT protocols using a low kV technique and an HIR algorithm.

Chronic inhibition of standing behaviour alters baroreceptor reflex function in rats.

AIM: To investigate whether daily orthostatic stress during development is an important factor affecting arterial baroreceptor reflex function, we examined the effect of chronic inhibition of upright standing behaviour on the baroreceptor reflex function in rats. METHODS: Upright standing behaviour was chronically inhibited during the developmental period between 3 and 8 weeks of age in Sprague-Dawley rats and heart rate (HR) and aortic nerve activity in response to increased and decreased mean arterial pressure (MAP) was measured after the treatment period. RESULTS: The baroreceptor cardiac gain in the rats grown without standing behaviour was significantly lower than the control rats grown in a normal commercial cage (1.0 +/- 0.1 beats min(-1) mmHg(-1) vs. 1.6 +/- 0.2 beats min(-1) mmHg(-1), P < 0.05). The range of HR change in the MAP-HR functional curve was also lowered by chronic inhibition of orthostatic behaviour (56.2 +/- 5.9 beats min(-1)) compared with that of the control rats (76.8 +/- 6.9 beats min(-1), P < 0.05). However the aortic afferent function remained normal after the treatment period, indicating that the attenuated baroreceptor reflex function may be due to other mechanisms involving functional alterations in the cardiovascular centres, efferents and/or peripheral organs. Body weight and adrenal weight were not affected by the inhibition of orthostatic behaviour, suggesting that the animals were not exposed to specific stress by this treatment. CONCLUSION: These results indicate that active haemodynamic changes induced by orthostatic behaviour are an important factor for setting the basal level of reflex function during development. Moreover, our experimental model may be useful for studying mechanisms of attenuated baroreceptor reflex observed after exposure to a chronic inactive condition.

Detection of Pb-LIII edge XANES spectra of urban atmospheric particles combined with simple acid extraction.

Pb-LIII edge XANES spectra of atmospheric particles are directly obtained by fluorescent XAFS spectroscopy using a 19-element solid state detector (SSD). Particulate sample was collected on a quartz fiber filter using a high-volume air sampler, and the filter was cut into small pieces (25x25 mm). Then, surface layer of the filter piece was scaled and accumulated in order to enhance the particle density per filter unit. Use of 10 pieces of the surface layer enables the measurement of Pb-LIII edge XANES spectra on beamline BL01B1 at SPring-8, Hyogo, Japan. The shape of the Pb-LIII edge XANES spectra of the particulate sample is similar to the shapes of the spectra for PbS, PbCO(3), PbSO(4) and/or PbCl(2). Additionally, the filter sample is also divided into water-soluble, 0.1 M HCl-extractable, and residual fractions of Pb compounds by a simple acid extraction procedure. We discuss the possibility of Pb speciation in the particulate samples with combination of highly sensitive XANES spectroscopy and simple acid extraction.

Lead isotope ratios in urban road runoff.

Lead isotopic analyses of road runoff and airborne particulate matter have been carried out to elucidate sources of lead pollution at urban and suburban sites. While lead is often observed in road runoff in suspended form, suspended particle size had no relation to the lead isotopic distribution, as a result of comparison between runoff samples with total suspended solids and those with minute particles passed through a 75 microm sieve. Lead isotope ratios in airborne particulate matter in urban areas fell within a wider range than those in road runoff. Since there was little difference of the ratios between a heavy traffic-flow site and residential sites, airborne lead derived from vehicle exhaust was found to make little contribution to the contamination of road runoff. On the other hand, the ratios in road runoff at a suburban site showed the same range as those at an urban site. Lead in road runoff was therefore suggested to be produced on site by traffic related substances, such as tire wear, other than vehicle exhaust.

Effects of spaceflight on postnatal development of arterial baroreceptor reflex in rats.

AIM: It has been reported that spaceflight attenuates the arterial baroreceptor reflex. As this reflex function changes dramatically during postnatal development, we hypothesized that space flight depresses the developmental changes of the reflex system. To test this hypothesis, we evaluated the baroreceptor reflex function in rats, which were exposed to a microgravity environment on a space shuttle 9-25 days after birth. METHODS: Baroreceptor reflex sensitivity and the afferent sensitivity were evaluated by measuring heart rate (HR) and aortic nerve activity (ANA) changes in response to an increase in mean arterial pressure (MBP) derived by phenylephrine injection (20-50 microg kg(-1)) under urethane-anaesthesia. RESULTS: Baroreceptor reflex sensitivity (% change of HR/% change of MBP) was lower in the flight group (FLT: -0.19 +/- 0.04, n = 4) than either the asynchronous ground control group (AGC: -0.47 +/- 0.06, n = 6, P < 0.01) or the vivarium group (VIV: -0.41 +/- 0.07, n = 6, P < 0.05). This was similar to the differences of the afferent sensitivity (% change of ANA/% change of MBP) between FLT (2.07 +/- 0.30) and the control groups (AGC: 2.71 +/- 0.22, n.s.; VIV: 3.00 +/- 0.32, P < 0.05). At the end of 30 days of recovery under normal gravity conditions, however, there were no significant group differences in these parameters. conclusion: These results suggest that the space environment attenuates the postnatal development of the arterial baroreceptor reflex function in rats, which may be partially because of a depression of the postnatal development of the baroreceptor afferents. These functional alterations, however, recover to their normal level on re-exposure to the Earth's gravity.

Spaceflight alters the fiber composition of the aortic nerve in the developing rat.

Hydrostatic pressure gradients due to the gravitational force in blood vessels disappear under conditions of microgravity during spaceflight, and the ability of the baroreceptor reflex to control arterial pressure and blood distribution may be altered. We hypothesized, on the basis of the results obtained in our previous experiments using the head-down tilt method in rats and rabbits, that the range of increase in arterial pressure caused by animal behavior narrows under conditions of microgravity, affecting the development of high-threshold unmyelinated fibers in the rat aortic nerve which sends signals from baroreceptors located in the aortic wall to the reflex center. We verified this hypothesis using 9-day-old rat neonates housed with their dams for 16 days on the space shuttle Columbia in outer space (STS-90, Neurolab Mission). Age-matched neonatal rats with the dams remained on the ground as controls. After breeding was carried out in the three experimental groups (FLT, spaceflight; AGC, asynchronous ground control; VIV, vivarium ground control), specimens of the 25-day-old rats were excised and five left aortic nerves in each group were examined by electron microscopy. The number of aortic unmyelinated fibers was significantly less in the FLT group than in each ground control (mean+/-S.D.; 139+/-37 in the FLT, 207+/-36 in the AGC, 283+/-121 in the VIV; P<0.05), which may be related to the weakness of the baroreceptor reflex under conditions of microgravity in space. This result may contribute to understanding of the several cardiovascular issues which occur under microgravity and after reexposure to gravity in human.

Interleukin-5 transgenic mice show augmented resistance to Angiostrongylus costaricensis infection.

To determine the possible role of eosinophils in Angiostrongylus costaricensis infection, both interleukin-5 (IL-5) transgenic (Tg) and non-transgenic (non-Tg) C3H/HeN mice were infected with A. costaricensis third-stage larvae. IL-5 Tg mice demonstrated greater resistance than non-Tg mice to A. costaricensis, as shown by lower adult worm recovery, smaller adults, fewer eggs in the intestinal wall and fewer larvae passed in the feces. Both mice showed similar antigen-specific IgA and IgGI antibody responses, although IgA was more prominent than IgG1. Egg deposition and inflammatory responses in the intestinal walls were milder in IL-5 Tg mice than in non-Tg mice. The eggs with developed larvae, deposited in the intestinal walls of IL-5 Tg mice, were surrounded by numerous degranulating eosinophils and sometimes with Splendore-Hoeppli deposits. The data suggest that eosinophils are involved in the resistance of the mouse during primary infection with A. costaricensis.

Differential diagnosis of small round cervical lymph nodes: comparison of power Doppler US with contrast-enhanced CT and pathologic results.

PURPOSE: The purpose of this study was to differentiate reactive small round lymph nodes (SRLNs) from metastases by power Doppler ultrasonography (PD-US) and contrast-enhanced CT (CE-CT). MATERIALS AND METHODS: Both PD-US and CE-CT were performed in 99 cervical lymph nodes (LNs) with a maximum diameter of 1.5 cm or smaller and maximum longitudinal/transverse ratio of 1.5 or smaller in 76 patients with head and neck cancer. At pathologic examinations, 45 were reactive and 54 were metastatic LNs. The vascular patterns on PD-US were classified as hilar, avascular, peripheral, and miscellaneous vascular patterns. The enhancement patterns on CE-CT were classified as homogeneous, heterogeneous, and ring enhancement. RESULTS: On PD-US, the hilar pattern was more frequently associated with benignancy (91%) and the peripheral, miscellaneous vascular pattern with malignancy (91%). The avascular pattern included both benign (58%) and malignant (42%) LNs. On PD-US, accuracy was 85%. On CE-CT, ring enhancement showed metastasis (100%), and these LNs showed avascular or peripheral patterns on PD-US. On CE-CT, accuracy was 77%. When information on CE-CT results was added to PD-US results, the accuracy rate increased significantly, to 94% (p=0.01). CONCLUSION: Vascular patterns evaluated with PD-US and enhancement patterns on CE-CT can characterize SRLNs. For an avascular pattern on PD-US, information on CE-CT results can significantly increase the accuracy of characterization.

MR imaging of the anterior cruciate ligament: value of thin slice direct oblique coronal technique.

PURPOSE: The value of the thin slice direct oblique coronal technique, which is parallel to the anterior cruciate ligament (ACL), was assessed in the evaluation of ACL injury in comparison with conventional oblique sagittal and coronal images. MATERIAL AND METHODS: A thin slice direct oblique coronal technique was developed and applied clinically to 62 patients after conventional oblique sagittal and coronal images had been obtained. MR images of these 62 patients (24 with tears and 38 without tears) with an arthroscopic correlation were evaluated by three radiologists who were unaware of the arthroscopic results. The diagnostic accuracy of these new images was compared with that of oblique sagittal and coronal images by ROC analysis. RESULTS: Conventional oblique sagittal and coronal images for the diagnosis of ACL tears revealed accuracies of 82%, 84%, and 84%, sensitivities of 92%, 92%, and 96% and specificities of 76%, 79%, and 76% for the three reviewers, respectively. On thin slice direct oblique coronal images, specificities of 97%, 97%, and 97%, sensitivities of 96%, 96%, and 96%, and accuracies of 97%, 97%, and 97% were obtained, respectively. Diagnostic ability was significantly better with direct oblique coronal images (mean area under the ROC curve [Az]=0.99) than with conventional oblique sagittal and coronal images (Az=0.91) (p<0.05). CONCLUSION: The addition of thin slice direct oblique coronal images significantly improved specificity and accuracy in the diagnosis of ACL tears.

Fast breath-hold T2-weighted MRI of the kidney by means of half-Fourier single-shot turbo spin echo: comparison with high resolution turbo spin echo sequence.

PURPOSE: The value of the fast half-Fourier single-shot turbo spin echo (HASTE) sequence in T2-weighted MRI of the kidney was evaluated as a substitute for the conventional turbo spin echo (TSE) sequence. METHOD: Forty-five patients with suspected abnormalities of the kidney underwent MRI with a 1.5 T system. Breath-hold HASTE and respiratory-triggered TSE sequences were performed. Qualitative and quantitative analyses were performed for comparison of these sequences. RESULTS: The signal-to-noise ratio (SNR) with HASTE was higher than that with TSE. The lesion-to-kidney contrast-to-noise ratio for solid masses with HASTE was almost equal to that with TSE. For cystic masses, the CNR with HASTE was significantly higher than that with TSE (p < 0.05). Respiratory and chemical shift artifacts were significantly smaller on HASTE than on TSE (p < 0.01). However, the blurring artifact was higher on HASTE than on TSE (p = 0.01). CONCLUSION: The HASTE sequence generates high contrast images and is free of motion and chemical shift artifacts, with much better time efficacy. The sequence provides comparable diagnostic information to TSE sequences.

[Global harmonization in the care and use of laboratory animals for the space life science research].

Space researches are supported with the international space agencies, NASA and NASDA. Animal experiments on the space life science must conform to the NIH policies and the NASA guide for the care and use of laboratory animals. The goal of the NIH policies is to promote the humane care of animals used biomedical and behavioral research, teaching, and testing. In each institute, the Institutional Animal Care and Use Committee (IACUC) plays an important role in conformity with NIH policies. The IACUC is charged with developing, recommending and monitoring NIH/NASA (ARC and KSC) policies, guides and rules relating to animal acquisition, care and use. In ARC and KSC, investigators will be responsible only for activities directly related to the conduct of their animal experiments. Even if researchers have protocols of the space science in Japan, the animal experiment should be carried out under the global harmonized conditions in accordance with NIH policies and NASA guides.

Time-dependent change in baroreflex control capacity of arterial pressure by pentobarbital anesthesia in rabbits.

The present study is designed to investigate the time-dependent effect of pentobarbital anesthesia on the baroreflex arterial pressure (AP) control system in rabbits. The overall AP control capacity of the baroreflex system was assessed with mean arterial pressure (MAP) responses to the rapid mild hemorrhage (2 ml/kg body weight) and an overall open-loop gain (G) of the system. The G value was determined by means of the following formula: G = delta API/delta APS-1, where delta APl is an immediate MAP fall and delta APS a steady-state fall after the rapid hemorrhage. Prior to the experiment, two catheters for AP measurement and hemorrhage were chronically in-dwelt in the aortic arch via the left subclavian and left common carotid arteries, respectively. Control mean arterial pressure averaged for 30 sec before the rapid hemorrhage (CMAP), delta API and delta APS significantly increased and reached the maximal value at 14 min (CAMP: p < 0.01) and 28 min (delta API: p < 0.01 and delta APS: p < 0.01) after the intravenous injection of sodium pentobarbital in a 25.0 mg/kg dose, respectively. These values gradually decreased in the course of time and tended to recover to near the preanesthetic level at 77-98 min after the anesthesia. The G value significantly decreased from 7.3 in the conscious state to 1.5 at 28 min after the anesthesia (p < 0.001), gradually increased with lapse of time and recovered to near the preanesthetic level at 77-98 min after the anesthesia. No significant difference in G was observed between in the conscious and anesthetized states beyond 70 min after the anesthesia (p > 0.05). These findings suggest that pentobarbital sodium exerts a time-dependent inhibitory effect on the baroreflex system but does not significantly affect the overall AP control capacity of the baroreflex system itself at least 70 min after the intravenous administration at a dose of 25.0 mg/kg.

Improved tissue characterization of focal liver lesions with ferumoxide-enhanced T1 and T2-weighted MR imaging.

The purpose of our study was to evaluate the potential value of ferumoxide-enhanced T1-weighted magnetic resonance (MR) imaging for tissue characterization of focal liver lesions when combined with T2-weighted sequences. Images were acquired within 30 minutes after the end of ferumoxide administration, when ferrite particles were not totally cleared from the intravascular compartment. Thirty-eight patients with 47 focal liver lesions underwent T1-weighted gradient-echo (TR/TE 150/4.1 msec) and T2-weighted fast spin-echo (3180-8638/90 msec) MR imaging at 1.5 T before and after intravenous administration of ferumoxides (10 micromol/kg body weight). A qualitative and quantitative analysis was performed. During the early phase after infusion of ferumoxide, blood vessels showed hypersignal intensity on T1-weighted fast low-angle shot (FLASH) images, while liver signal decreased. Hemangiomas showed both homogeneous and inhomogeneous enhancement patterns, and liver metastasis most typically showed ring enhancement. Hypervascular tumors (hepatocellular carcinomas and focal nodular hyperplasias) showed a slight degree of homogeneous enhancement. Quantitatively, the degree of enhancement and lesion-to-liver contrast on ferumoxide-enhanced images were significantly different among these tumors. Our results demonstrate that distinct enhancement patterns obtained on ferumoxide-enhanced T1-weighted MR imaging improve tissue characterization of focal liver lesions when combined with T2-weighted images.

Recording of blood pressure, heart rate and aortic nerve activity during parabolic flight in the rat via radio-telemetry.

Exposure to microgravity induces cardiovascular deconditioning characterized by orthostatic hypotension when astronauts return to the earth. In order to understand the mechanism of cardiovascular deconditioning, it is necessary to clarify the changes in hemodynamics and the cardiovascular regulation system over the period of space flight. The telemetry system applied to freely moving animals will be a useful and appropriate technique for this kind of long term study of the cardiovascular system in the conscious animal during space flight. The purpose of the present study is twofold: firstly, to observe the detailed changes of arterial pressure and heart rate (HR) during microgravity elicited by the parabolic flight in order to study the acute effect of microgravity exposure on the cardiovascular system; and secondly, to test the feasibility of the telemetry system for recording blood pressure, HR and autonomic nervous activities continuously during space flight.

Mechanical tensile properties of the aortic wall in the premature rat exposed to the microgravity environment during space flight for 16 days.

Under microgravity environment, blood shifts headward and thereafter decrease in volume to adapt to the environment, which could affect cardiovascular hemodynamics and their regulatory mechanisms. Baroreceptor sensitivity is known to be reduced in newborn animals and to gradually increase with development. The baroreceptor is a stretch receptor; therefore its function is closely related to the rheological properties and fine structure of the aortic wall in which the baroreceptor lies. The mechanical and histological properties could be altered under microgravity conditions in the process of development with change in circulatory function. In the present study, we investigated the mechanical tensile characteristics and histological structure of the aortic wall in the proximal thoracic aorta of premature rats bred in the microgravity environment of the space shuttle for 16 days.

Pancreaticobiliary ductal system: value of half-Fourier rapid acquisition with relaxation enhancement MR cholangiopancreatography for postoperative evaluation.

PURPOSE: To assess the usefulness of half-Fourier rapid acquisition with relaxation enhancement (RARE) magnetic resonance cholangiopancreatography (MRCP) for evaluation of postoperative changes in the pancreaticobiliary ductal system. MATERIALS AND METHODS: The study included 34 patients (20 men, 14 women; mean age, 65.5 years) who underwent surgery of the pancreaticobiliary ductal system. Half-Fourier RARE MRCP images were obtained after surgery. Qualitative evaluation included ratings by two observers for depiction of postoperative anatomy and for artifacts, as well as analysis of postoperative complications. Direct cholangiographic, computed tomographic, and ultrasonographic findings and 6-month follow-up results were the reference standard. Sensitivity, specificity, and accuracy were calculated for the evaluation of postsurgical complications seen at half-Fourier RARE MRCP. RESULTS: The sensitivity, specificity, and accuracy of MRCP for the evaluation of postsurgical complications were each 100% for ductal dilatation; 100%, 87%, and 89%, respectively, for choledochoenteric anastomotic stricture; 100%, 86%, and 87%, respectively, for pancreaticoenteric anastomotic stricture; 100% each for intraductal stones and anastomotic leakage; and 80%, 100%, and 94%, respectively, for cholangitis. CONCLUSION: Half-Fourier RARE MRCP is a reliable imaging technique for the evaluation of anatomy and of complications associated with a surgically altered pancreaticobiliary ductal system.