Quantitative Three-Dimensional Assessment of the Pharmacokinetic Parameters of Intra- and Peri-tumoural Tissues on Breast Dynamic Contrast-Enhanced Magnetic Resonance Imaging.

We aimed to assess the feasibility of three-dimensional (3D) segmentation and to investigate whether semi-quantitative dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters are associated with traditional prognostic factors for breast cancer. In addition, we evaluated whether both intra-tumoural and peri-tumoural DCE parameters can differentiate the breast cancers that are more aggressive from those that are less aggressive. Consecutive patients with newly diagnosed invasive breast cancer and structural breast MRI (3.0 T) were included after informed consent. Fifty-six patients (mean age, 57 years) with mass lesions of > 7 mm in diameter were included. A semi-automatic image post-processing algorithm was developed to measure 3D pharmacokinetic information from the DCE-MRI images. The kinetic parameters were extracted from time-signal curves, and the absolute tissue contrast agent concentrations were calculated with a reference tissue model. Markedly, higher intra-tumoural and peri-tumoural tissue concentrations of contrast agent were found in high-grade tumours (n = 44) compared to low-grade tumours (n = 12) at every time point (P = 0.006-0.040), providing positive predictive values of 90.6-92.6% in the classification of high-grade tumours. The intra-tumoural and peri-tumoural signal enhancement ratios correlated with tumour grade, size, and Ki67 activity. The intra-observer reproducibility was excellent. We developed a model to measure the 3D intensity data of breast cancers. Low- and high-grade tumours differed in their intra-tumoural and peri-tumoural enhancement characteristics. We anticipate that pharmacokinetic parameters will be increasingly used as imaging biomarkers to model and predict tumour behavior, prognoses, and responses to treatment.

A multiparametric classification system for lesions detected by breast magnetic resonance imaging.

BACKGROUND: To validate a new categorisation scheme for suspicious breast lesions according to the well-defined Breast Imaging Reporting and Data System (BI-RADS) magnetic resonance imaging (MRI) lexicon descriptors, apparent diffusion coefficients (ADC), T2-weighted signal intensity (SI), and kinetic curve assessment categories. METHODS: The MRI descriptors and ADC were analysed in 697 lesions detected in 499 subjects. The descriptors were classified into Minor, Intermediate, and Major findings, and were divided into the BI-RADS subcategories 3, 4A, 4B, 4C, and 5 according to the number of descriptors. Positive predictive values (PPV) were calculated for each descriptor. The descriptors were then fitted into a multinomial logistic regression model to determine the odds ratio for a malignant diagnosis. The PPV were measured for the new categories and compared with the assigned PPV of the BI-RADS descriptors. RESULTS: The PPV for MRI descriptors ranged from 17.9%-100%. Of the 697 lesions assessed, 19 (2.7 %) were categorized as BI-RADS 3, 27 (3.9 %) as 4A, 53 (7.6 %) as 4B, 174 (25.0 %) as 4C, and 424 (60.8 %) as 5. None of the subjects in BI-RADS category 3 had a malignant diagnosis. The PPV for malignancy increased progressively with increasing BI-RADS category (4A, 11.1 %; 4B, 28.3 %; 4C, 64.4 %; 5, 94.8 %). All descriptor groups were significant in the logistic regression model. CONCLUSIONS: This study shows that using BI-RADS MRI descriptors together with ADC and T2-weighted SI in a multiparametric classification system can yield an applicable categorisation of lesions with PPV values within the recommended ranges for BI-RADS categories.

Clinical and microarray analysis of breast cancers of all subtypes from two prospective preoperative chemotherapy studies.

BACKGROUND: We aimed to analyse clinical and gene expression profiles to predict pathologic complete response and disease-free survival using two consecutive, prospective, preoperative chemotherapy trial cohorts. METHODS: Clinicopathological and gene expression data were evaluated in a cohort from two consecutive phase II preoperative studies that included patients with stage IIA-IIIC breast cancer of all subtypes. Analysed specimens were obtained before preoperative chemotherapy, and cDNA microarray analyses were performed using the Affymetrix Gene Chip U133 plus 2.0. RESULTS: Between December 2005 and December 2010, 122 patients were analysed. The pathologic complete response rate was significantly higher in HER2+ and HR-/HER2- cancers. Age, pathologic complete response, HR-/HER2- status, and lymph node positivity (⩾4) were significant poor prognostic factors for disease-free survival. For the cDNA microarray analyses, sufficient tumour samples were available from 78 of the 107 patients (73%). An 8-gene signature predictive of pathologic complete response and a 17-gene signature predictive of prognosis were identified. Patients were categorised into low-risk (n=45) and high-risk groups (n=33) (HR 70.0, P=0.004). CONCLUSIONS: This study yielded preliminary data on the expression of specific genes predicting pathologic complete response and disease-free survival in a cohort of chemonaïve breast cancer patients. Further validation may distinguish those who would benefit most from perioperative chemotherapy as well as those needing further intervention.

Sudden onset of sleep due to hypothalamic lesions in neuromyelitis optica spectrum disorder positive for anti-aquaporin-4 antibody.

We report a patient with neuromyelitis optica spectrum disorders who presented with sudden onset of sleep as the sole manifestation. Magnetic resonance imaging investigation revealed lesions in the hypothalamus bilaterally, which vanished completely after methylprednisolone pulse therapy.

Muscle metabolism in patients with polymyositis simultaneously evaluated by using 31P-magnetic resonance spectroscopy and near-infrared spectroscopy.

Simultaneous measurements of muscle energy metabolism using (31)P-magnetic resonance spectroscopy ((31)P-MRS) and the kinetics of muscular oxygen metabolism using near-infrared spectroscopy (NIRS) were conducted in polymyositis (PM) patients. The subjects were 12 PM patients (age 45 +/- 12 years) and 12 normal controls (age 41 +/- 12 years). The muscle phosphocreatine (PCr) index and intracellular pH (pHi) were determined with (31)P-MRS and the changes in intramuscular oxygenated (oxy-Hb), deoxygenated (deoxy-Hb), and total haemoglobin (total Hb) were evaluated with NIRS . The pHi and PCr index before steroid therapy in PM patients were significantly lower during exercise than in normal controls, and their recovery was statistically significantly delayed compared with the controls. The pattern of changes in NIRS over time before steroid therapy in PM patients differed from that in normal controls. There were smaller changes in deoxy-Hb and oxy-Hb during exercise, and total Hb decreased during exercise. In contrast, the kinetics of muscular metabolism after steroid therapy showed changes similar to those seen in normal controls. Simultaneous (31)P-MRS and NIRS measurements to determine the kinetics of muscular metabolism are expected to be useful as a noninvasive approach for the evaluation of treatment effects in PM patients.

Salivary bisphenol-A levels detected by ELISA after restoration with composite resin.

Bisphenol-A diglycidylether methacrylate (Bis-GMA), which is synthesized from bisphenol-A (BPA), a compound with exogenous endocrine disrupter action, is widely used as a dental material. During clinical filling with sealants and composite resins, the compounds are solidified by polymerization and then used. However, it has been noted that unpolymerized monomers may become dissolved in saliva. In this study using a competitive ELISA system, we investigated the changes in the BPA concentration in saliva after restoration with composite resins. Commercial composite resins from nine companies were tested. Mixed saliva was collected from 21 subjects. Based on the dynamics of salivary BPA detected by this ELISA system, we concluded that several tens to 100 ng/ml of BPA were contained in saliva after filling teeth with composite resin but that sufficient gargling can remove it from the oral cavity. Our data suggest that sufficient gargling after treatment is important for risk management.

[Experimental retinal branch vein occlusion. 4. Pathological changes in the middle and late stage].

Retinal branch vein occlusion in macaca monkeys (Macaca irus) was produced by dye laser photocoagulation, and observed histopathologically from five days to one year after photocoagulation. Ten days later, retinal edema and hemorrhage observed at an early stage gradually decreased. Two weeks later, capillary bed closure areas were observed in fluorescein angiography. The capillary closure was not reversible when disturbance of the retinal circulation continued for more than three or four days after photocoagulation. Three months later, dry retina was observed in the capillary bed closure areas. One year later, the retina was severely degenerated and thinned. In these retinal areas, capillary lumens observed microscopically were occluded by cellular components. Sheathing of large veins was observed in these retinal areas. The walls of these large veins were thick and fell into hyaline degeneration. Their lumens were narrowed or obstructed. During the period of observation, retinal neovascularization was not observed.

[Recanalization of venule following experimental retinal branch vein occlusion].

Retinal branch vein occlusion was experimentally produced in monkey (macaca irus) by dye laser photocoagulation. Venous dilatation, retinal edema and punctate hemorrhages were the ophthalmoscopic changes immediately after the occurrence of venous occlusion by photocoagulation. Fluorescein angiography revealed delay of retinal circulation and dye leakage from these venules. Fluorescein angiography on the 2nd day revealed caliber irregularities in the venules distal to the photocoagulated points. Histopathologically, thrombus formation and partial defect of the endothelial cells were observed in the venules in the areas which showed recovery with immature endothelial cells on the 4th day. Young endothelial cells proliferating along the endothelial basement membrane, which remained around the thrombi, and recanalization were observed on the 7th day. These results reveals a process of recanalization in the thrombogenous retinal venous occlusion.

[Retinal degeneration after intravitreal injection of ornithine. 2. Late change after administration].

The influence of intravitreal injection of a small amount of l-ornithine hydrochloride in monkey eyes has been investigated morphologically. In a previous paper, the author demonstrated that acute selective damage was caused in the retinal pigment epithelium (RPE) by ornithine. This paper will demonstrate retinal degeneration at the late stage by intravitreal injection of ornithine. At one year after administration, sharply demarcated chorioretinal atrophy was seen ophthalmoscopically from the equator to the peripheral retina. These areas corresponded to those where RPE became necrosis at early stage following administration of ornithine. Histopathologically, the photoreceptor cells, RPE, and choriocapillaris disappeared completely in these areas, and the inner retina was directly contact with the Bruch membrane with the proliferating Müller fibers. On the other hand at the posterior pole, the photoreceptor cells, RPE, and the choriocapillaris maintained intact. This study demonstrated that necrosis of RPE by intravitreal injection of ornithine leads to complete loss of the visual cells and choriocapillaris, at the late stage.

[Experimental retinal branch vein occlusion].

Experimental retinal branch vein occlusion in monkeys (macaca irus) were produced by yellow wavelength (577nm) dye laser photocoagulation. The clinical sequence was observed in terms of the structural and ultrastructural findings occurring during the natural history of experimental branch vein occlusion, particularly in the early stage. Immediately after the occlusion, venous dilatation and retinal edema and hemorrhage appeared. Extravascular leakage of dye in fluorescein angiography and hemorrhage appeared from small venules at an early stage. Leakage from the larger vessels was observed later. Opening of the intercellular junctional complexes, which signifies breakdown of the blood-retinal barrier was detected by electron microscopy. Subsequently degenerative or necrotic changes in endothelial cells appeared with the formation of intravascular thrombi and extravascular leakage of blood components appeared from these vessels.

Biosensor system for continuous flow determination of enzyme activities. II. Simultaneous determination of plural enzyme activities.

A biosensor system for continuous flow determination of plural enzyme activities was prepared from the combination of two pyruvate sensors, a prereactor and a flow cell. This system was applied to the simultaneous determination of lactic dehydrogenase (LDH) and glutamic-pyruvic transaminase (GPT) activities in the same sample. These enzyme activities can be determined by measuring pyruvate produced by the enzyme reactions as follows. The amount of pyruvic acid can also be determined from the amount of oxygen consumed upon oxidation of pyruvic acid by pyruvate oxidase. (Formula: see text). Therefore, both of the detectors for the determination of lactic dehydrogenase and glutamic-pyruvic transaminase activities were prepared from the combination of a pyruvate oxidase membrane and an oxygen electrode. Pyruvate oxidase was covalently immobilized on a membrane prepared from cellulose triacetate. A linear relation was obtained between the output current and LDH or GPT activities in the range of 50 to 3,600 IU l-1 or 6 to 1,000 IU l-1, respectively. Each assay of these enzyme activities was completed within 15 min. The results obtained had a precision of ca. 4%. The sensor was stable for more than 25 days at 5 degrees C.

[Experimental retinal branch vein occlusion].

Experimental retinal branch vein occlusion was produced in monkeys (macaca irus) by dye laser photocoagulation (yellow wavelength 577nm The 920 ARGON/DYE Laser System, Coherent Radiation). The Clinical process was observed based on ophthalmoscopic and fluorescein angiographic alterations which occur during the natural history of experimental branch vein occlusion. Immediately after occlusion, venous dilatation, retinal edema and punctate hemorrhage, were recognized by ophthalmoscopy, and leakage of dye from postcapillary venules, followed later by additional leakage from large veins were observed frequently by fluorescein angiography. Circulatory disturbances remained over 3-4 days, and the retinal branch vein occlusion were persisted. Ten days later, a non-perfusion area was observed by fluorescein angiography. More than 1 year later, these nonperfusion area remained.

Transition of physical fitness in wheelchair marathon competitors over several years.

Twenty eight stress tests for 14 wheelchair marathon competitors were performed to determine their physical fitness just before the Oita International wheelchair marathon since 1984. All the subjects were wheelchair-bound Japanese males and workers at Sun Industry. Oxygen consumption at the maximal workload was significantly larger than that of non-athletic paraplegics and the mean values were 35.0 +/- 4.8 ml/kg in competitors and 22.6 +/- 5.0 ml/min/kg in non-athletic paraplegics. Eight competitors had more than 2 stress tests and 6 of them had 3 tests from 1984 to 1987. The oxygen consumption at the maximal workload of their third test was very high (46.5 +/- 6.8 ml/min/kg) equal to highly trained paraplegics, and was larger than the result of the first test significantly. Their physical fitness was reduced significantly during the off season, however their physical fitness was maintained at a satisfactory higher level than that of non-athletes. This study demonstrated that individual training for wheelchair marathoners had improved the competitors' physical fitness over several years.

Physical fitness of paraplegics in full wheelchair marathon racing.

The wheelchair marathon is one of the most difficult sports for participants with much uncertainty regarding the security of the paraplegics. The physical fitness of paraplegics has been examined regularly since The Oita International Wheelchair Marathon (half marathon) was inaugurated (1981). A full marathon (42.195 km) was adopted at The 3rd Meeting (1983). The individual equations between heart rate (HR) and oxygen consumption VO2 were drawn from the preliminary test on the subjects who were expected to be among the top finishers in these races. VO2 during these races was indirectly estimated and showed a fairly low value (35.0 +/- 3.8 ml/kg/min in the full race, 32.7 +/- 6.3 ml/kg/min in the half race respectively) in comparison with able-bodied elite runners. However, the paraplegic participants had extremely high HR (171.6 +/- 20.5 beats/min, 168.1 +/- 9.8) continuously throughout the race. Though the ratio of active muscle mass of arms to legs in paraplegic athletes may approximate to near equal, paraplegic arms seem to exert physiologically and mechanically less efficient power. There were no significant differences in physical fitness between the full and the half marathon elite finishers. The cardiovascular function of paraplegic athletes may well be ranked among those of able-bodied athletes in their fitness. Full wheelchair marathon seems to be safe if it is held in an appropriate environment.

Long-term prognosis of behavior therapy in practice.

A prognosis study was carried out on 30 cases of patients treated with behavior therapy. The treatments, which took more than three years before the study, averaged four years and eight months. The results are as follows: (1) The improvement achieved by therapy was maintained or further improved in 29 cases during the post-therapeutic period of more than three years. (2) The prognosis largely depended on the grade of improvement at the end of therapy. A complete disappearance of symptoms at the end of therapy did not necessarily mean that it was a fair prognosis. (3) There was no relation between the prognosis and the length of history of illness or the situation of therapy terminated. (4) The impression is that long-term prognoses are different depending on the main symptoms.

A case of hypogonadotropic eunuchoidism associated with familiar periodic paralysis--induction of paralytic attacks by testosterone administration.

A case report was made of a 24-year-old man suffering from hypogonadotropic eunuchoidism associated with a hypokalemic type of familiar periodic paralysis. The attacks were observed only during the period of continual administration of the oil solution of 115.7 mg of testosterone enanthate and 20.0 mg of testosterone propionate, intramuscularly as a depot. From the findings on this patient, it was concluded that testosterone might possibly play a role in the occurrence of attacks in the case of periodic paralysis.