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.

MRI of secondary changes in the thalamus following a cerebral infarct.

We investigated acute secondary degeneration in the thalamus following a cerebral infarct in 21 patients with an infarct in the territory of the middle cerebral artery, using serial MRI at various time after the stroke. Secondary degeneration in the ventral nuclei of the thalamus was seen as regions of slightly low signal on proton-density and/or T2-weighted images, mostly obtained a few weeks after the onset. An area of slightly high signal was observed in the dorsomedial nucleus of the thalamus on T2-weighted images about 6 weeks after the onset. Damage to the superior and anterior thalamic radiation caused degeneration in the ventral and dorsomedial nucleus, respectively. Thus, the time of detection and the abnormalities seen on MRI in secondary degeneration vary depending upon which area of the thalamus is involved. The mechanism underlying the degeneration is therefore also likely to differ in these areas.

Dissecting aneurysms at the A1 segment of the anterior cerebral artery--two case reports.

Two rare cases of dissections which involve the anterior cerebral artery (ACA) are reported. A 58-year-old woman presented with a ruptured dissecting aneurysm manifesting as sudden onset of severe headache and consciousness disturbance followed by aphasia, right hemiparesis, paresis of the left lower extremity, and choreoathetotic movements of the upper arms and face. Computed tomography and angiography revealed subarachnoid hemorrhage due to a dissecting aneurysm at the left A1 segment. The dissecting aneurysm was trapped surgically on the day of onset. Her neurological deficits disappeared within a month. A 39-year-old woman experienced continuous dull headache from the day before onset, and then suffered right hemiparesis. Magnetic resonance (MR) imaging revealed cerebral infarction at the left globus pallidus. Angiography and MR imaging revealed a dissecting aneurysm at the left A1 segment and occlusion of the left Heubner's artery. She received conservative treatment and her neurological findings were improved. Dissections or dissecting aneurysms involving the ACA can be classified into three types: Extension of a dissection to the ACA from the internal carotid artery, dissection at the A1 segment, and dissection at the A2-A4 segments. These types of dissection have distinct uniform clinical features.

Platelets expressing P-selectin and platelet-derived microparticles in stored platelet concentrates bind to PSGL-1 on filtrated leukocytes.

The levels of interleukin-6 and platelet-derived microparticles (PMPs) were measured in the blood of 137 patients with side effects from platelet concentrate (PC) transfusion with leukocyte removal filtration, P-selectin-expressing platelet and PMPs in stored PC before and after the filtration, and filtered leukocytes positive for P-selectin glycoprotein ligand-1. The side effects, which were observed in 203 transfusions for 84 patients with hematologic disease and 53 patients with nonhematologic disease with no significant difference between the two groups, included urticaria (75.9%), erythema (18.7%), and fever (17.2%), but no anaphylactic reactions. The levels of interleukin-6 and PMP correlated in both groups, and were significantly higher in the hematologic disease group than in the nonhematologic disease group. The level of PMP, but not interleukin-6, was significantly higher for patients testing positive for allergic reaction than for those testing negative. In the stored PC prior to filtration, the level of interleukin-6 was normal. The level of P-selectin-expressing platelets and PMPs was elevated before filtration, but was significantly lower after filtration. Taken together, the results suggest that PMP is involved in the generation of transfusion reactions, and indicate that both platelets and PMP displaying P-selectin bind to P-selectin glycoprotein ligand-1 of leukocytes retained by the leukocyte filter.

A transparent sheath for endoscopic surgery and its application in surgical evacuation of spontaneous intracerebral hematomas. Technical note.

The authors advocate the use of a transparent sheath for guiding an endoscope, a simple and unique tool for endoscopic surgery, and describe preliminary results of its application in the evacuation of hypertensive intracerebral hematomas. This sheath is a 10-cm-long tube made of clear acrylic plastic, which greatly improves visualization of the surgical field through a 2.7-mm nonangled endoscope inserted within. Between April 1997 and December 1998, the authors performed endoscopic evacuation of intracerebral hematomas by using this sheath inserted into the patients' heads through a burr hole. In nine consecutive cases in which the hematoma was larger than 40 ml in volume, nearly complete evacuation (86-100%) of the lesion was achieved without complication. Excellent visualization of the border between the brain parenchyma and the hematoma facilitated accurate intraoperative orientation, and also allowed easy identification of the bleeding point. Thus, this combination of sheath and endoscope achieves both minimal invasiveness and the maximum extent of hematoma removal with secure hemostasis. This tool will reduce the inherent disadvantage of endoscopic procedures and may expand their application in other areas of neurosurgical management.

[A study on methamphetamine psychosis in a psychiatric clinic--comparison of acute and chronic-type cases].

This study compares patients with acute methamphetamine psychosis to those with chronic methamphetamine psychosis and it investigates how the two groups differ in terms of psychosomatic findings, social background, and so on. The subjects consisted of 100 outpatients diagnosed at our clinic as having methamphetamine-induced psychosis over a period of sixteen years (1979 to 1995). Of these patients, 73 were of the acute type (currently using the drug or totally abstinent for less than 3 months), and 27 were of the chronic type (totally abstinent from the drug from 2 to 38 years). Psychosomatic Findings Ninety five patients (68 acute-type and 27 chronic-type) were classified into six clinical clusters, depending on which of the following states was dominant: paranoid-hallucinatory state, schizophrenia-like state, short-tempered and impulsive state, manic-depression-like state, neurosis-like state, and permanent-encephalopathic state. In the clinical cluster of paranoid-hallucinatory state, all 32 patients were of the acute-type. On the other hand, of those patients in the clinical cluster of neurosis-like state, the majority (N = 25) were of the chronic-type. Social Background The social background of 99 patients (72 acute-type and 27 chronic-type) was investigated under the three headings of: gangsters, criminal records and broken families. Of 19 patients who are gangsters, 18 cases were acute and the remaining case was chronic. Of 64 patients with criminal records, 51 were acute and 13 were chronic. Of 24 patients who come from broken families, 20 were acute and 4 were chronic. In all of these three items, the rate of acute-type patients was significantly higher than that of chronic-type patients. Based on the results obtained, the medical treatment and the prognosis of the patients, the author refers to preventive measures for stimulant-drug abuse.

Clinical features of progressive lacunar infarction--retrospective analysis of patients with motor syndromes.

The clinical features of progressive lacunar infarction were analyzed in 20 patients with lacunar infarction. Seven of the 20 patients experienced paresis progression and the remaining 13 patients had a stable course. The mean age of progressive lacunar infarction patients (78.6 +/- 4.30 yrs) was significantly higher than that of stable lacunar infarction patients (65.1 +/- 7.68 yrs) (p < 0.01). Patients presenting with pure motor stroke were more likely to have progressive stroke (7/13) than those presenting with sensorimotor stroke (0/7) (p < 0.05). Paresis aggravation began on Day 1 and ceased on Day 2 in most patients. Progressive paresis began to improve after reaching the nadir. Hemiparesis was only slightly worse after 1 month compared with that on admission. Older patients are more likely to have a progressive course. Paresis progression in lacunar patients does not preclude the possibility of recovery and is not necessarily associated with a poor prognosis.

High cervical chordoma--case report.

A 42-year-old male presented with a high cervical chordoma detected at an early stage and manifesting only as neck pains. Serial cervical roentgenograms over 8 years confirmed the slow growth character of this malignant tumor. Computed tomography and magnetic resonance imaging provided clear visualization of the tumor localized in the anterior aspect of the C-2 vertebral body. The tumor was totally removed through a transoral approach. Early diagnosis of vertebral chordoma is difficult due to the slow growth character and insidiousness of initial symptoms, but meticulous examination of serial roentgenograms, followed by neuroimaging, can achieve early detection of cervical chordoma.

Intracranial vertebral artery dissections: clinical, radiological features, and surgical considerations.

We reviewed 24 patients with intracranial vertebral artery dissections treated during the last 12 years. Sixteen patients were admitted with subarachnoid hemorrhage (SAH) and 8 did not have SAH. The mean age at the time of onset was 50.0 years. Male preponderance was noted. Among 21 patients with acute onset, 6 (29%) experienced prodromal neck pain and 3 (60%) of 5 SAH patients showed nuchal stiffness when examined within 6 hours of onset. The preoperative angiographical findings were uniform in SAH cases in contrast to the varied angiographical findings seen in non-SAH cases. So-called pearl and string sign was observed in most SAH cases, but the "string" was often so short and wide that the term "constriction" appeared more suitable. From intraoperative observations, the angiographical point of constriction seemed to represent the proximal or distal end of dissection. As for treatment, 19 patients underwent 20 surgeries. Trapping was performed in eight surgeries, base clipping was performed in five, and proximal clipping was performed in seven. Both trapping and base clipping prevented further bleeding, but trapping was associated with a high rate of postoperative lower cranial nerve palsy. Postoperative neurological complications were less frequent after proximal clipping, but subsequent postoperative bleeding occurred in one patient treated by this technique. The overall long-term outcome in the surgically treated cases in our series was favorable, but most patients suffered from various degrees of uncomfortable dysphagia or hoarseness for some period after surgery. It was also noted that, in half of the disabled cases, the major disability was attributable to lower cranial nerve palsy and respiratory troubles that developed postoperatively.

Nonsurgical treatment of unruptured intracranial vertebral artery dissection with serial follow-up angiography.

The question of whether unruptured intracranial vertebral artery dissections should be treated surgically or nonsurgically still remains unresolved. In this study, six consecutive patients with intracranial vertebral artery dissection presenting with brain-stem ischemia without subarachnoid hemorrhage (SAH) were treated non-surgically with control of blood pressure and bed rest, and five received follow-up review with serial angiography. No further progression of dissection or associated SAH occurred in any of the cases, and all patients returned to their previous lifestyles. In the serial angiograms in five patients, the findings continued to change during the first few months after onset. Four cases ultimately showed "angiographic cure," while fusiform aneurysmal dilatation of the affected vessel persisted in one case. In one patient, arterial dissection was visualized on the second angiogram despite negative initial angiographic findings. These results indicate that intracranial vertebral artery dissection presenting without SAH can be treated nonsurgically, with careful angiographic follow-up monitoring. Persistent aneurysmal dilatation as a sequela of arterial dissection seemed to form a subgroup of fusiform aneurysms of the posterior circulation. These aneurysms may be prone to late bleeding and may require surgical treatment.

Magnetic resonance imaging study of intracranial vertebrobasilar artery dissections.

BACKGROUND AND PURPOSE: The purpose of this study is to demonstrate the magnetic resonance features of intracranial vertebrobasilar artery dissections and to determine the potential and limitations of magnetic resonance imaging in their diagnosis. METHODS: We studied five consecutive patients with angiographically verified intracranial vertebrobasilar artery dissection with magnetic resonance imaging (0.5 T) in regard to the shapes of the intramural hematoma and the chronological change of its signal intensity. We also estimated the sensitivity of magnetic resonance imaging for diagnosing dissection. RESULTS: We observed intramural hematoma in four patients on the first magnetic resonance scan and in all five patients during the course of the study. The shapes of the intramural hematomas were curvilinear, crescentic, "bamboo-cut," "band-like," and spotty. The intensity of the intramural hematoma varied according to its age. On the T1-weighted and the proton images, the intramural hematomas appeared isointense to slightly hyperintense in the first few days and became hyperintense thereafter. The intramural hematomas became isointense or unrecognizable 2 months after onset. The T1-weighted image and the proton images were superior to the T2-weighted image in demonstrating the intramural hematomas. CONCLUSIONS: Magnetic resonance imaging is a sensitive tool for diagnosing intracranial vertebrobasilar artery dissection, particularly in the subacute to early chronic stage. Magnetic resonance imaging is complementary to angiography in that it can directly visualize intramural hematomas.

Intradural, purely extramedullary hemangioblastoma of the spinal cord--case report.

An unusual, purely extramedullary hemangioblastoma of the spinal cord occurred in a 59-year-old female. Myelography revealed a filling defect at the Th6 level, and computed tomographic myelography demonstrated an extramedullary intradural isodense mass at the same level. The mass was homogeneously enhanced on postcontrast computed tomographic scans. T1-weighted magnetic resonance imaging showed an isointense mass, homogeneously enhanced by contrast medium. The tumor was removed en bloc.

Degeneration of the ipsilateral substantia nigra following cerebral infarction in the striatum.

BACKGROUND AND PURPOSE: In rats, degeneration of the ipsilateral substantia nigra occurs a few weeks after occlusion of the middle cerebral artery. The aim of this study was to clarify whether similar change is observed in stroke patients. METHODS: Eighteen patients with striatal infarction and six patients with cortical infarction in the territory of the middle cerebral artery were examined by means of sequential magnetic resonance imaging. RESULTS: In all patients with striatal infarction, T2-weighted images revealed a high-signal-intensity spot in the ipsilateral substantia nigra. Changes in the ipsilateral substantial nigra appeared at day 14 after stroke on average and then became less intense and smaller a few months after the stroke. By contrast, we observed no nigral changes in any patient with cortical infarction. CONCLUSIONS: The degenerative change in the ipsilateral substantia nigra initially found in the rat model similarly occurred in patients with striatal infarction. This remote change in the substantia nigra may represent magnetic resonance imaging detection of neuropathologic changes in this region through the striatonigral pathway.

Determination of the minimal concentrations of contact activation factors in deficient substrate plasmas required to assess accurately factor XII, factor XI, factor IX, and high molecular weight kininogen.

Using combined deficient plasmas prepared by passage of a deficient plasma over an anti-factor XI-monoclonal antibody column, we have determined the threshold concentrations of each coagulation factor of contact phase in factor-deficient substrate plasmas required to determine accurately the functional activities of factor XII, factor XI, factor IX and high molecular weight kininogen (HMWK). In order to reliably quantitate factor XI and factor IX activity levels, at least 20% factor XII and 20% factor XI, respectively, were required in the deficient substrate plasmas. In the assessment of factor XII activity, approximately 40% factor XI was required in the factor XII-deficient substrate plasma. On the other hand, only 11-12% factor XI or HMWK was required in the deficient substrate plasmas in the assessment of these two clotting factors. Our data emphasize that deficiencies of other clotting factors may reduce the apparent activity of the clotting factor in question if their concentration is rate-limiting in the clotting assay.

[Dissecting aneurysm of the posterior inferior cerebellar artery--a case report].

The authors present a case of dissecting aneurysm of the right posterior inferior cerebellar artery (PICA) in a 47-year-old female, who suffered from mild subarachnoid hemorrhage. Right vertebral angiogram showed typical "pearl and string" sign of the PICA, but we could not fully understand the condition until a surgical exposure revealed a purple sausage-like dissecting aneurysm of the PICA. The aneurysm was wrapped with muscle pieces. Postoperatively she developed Wallenberg's syndrome, but it subsided gradually. No specific disorder concerning the mural dissection was found in this patient, except for a history of mild hypertension. This case is unusual because it affected not an arterial trunk but a small branch and we could find only one other case reported in the literature. Other formerly reported cases were of arterial trunks. The intracranial dissecting aneurysm has been known as a rare cause of cerebral infarct in children and adolescents. Infants are also affected and referred to as "infantile hemiplegia". It mainly affects one of the trunk arteries and cause a severe ischemic stroke, and surgically treatable case is rare. But as the typical angiographic findings are commonly known the number of the reported cases is increasing at an accelerating rate, and some of them are being noted to need surgical treatment because they cause subarachnoid hemorrhage. We here emphasize that not only trunk arteries but also small branch arteries can develop mural dissection, leading to subarachnoid hemorrhage. Dissecting aneurysm of a smaller artery would be milder in symptom, and would give more chance for surgical intervention.(ABSTRACT TRUNCATED AT 250 WORDS)