Retrospective geometric correlation of MR, CT, and PET images

Magnetic resonance imaging, computed tomographic, and positron emission tomographic studies of the brain provide complementary information, and many patients undergo more than one of these studies during the course of their diagnostic workup and treatment. A new technique for quantitative geometric correlation of such studies makes it possible to create integrated multimodality images by mapping features from one image onto an image obtained with another modality. The coordinate transformation between any pair of images is found by a semiautomatic algorithm for matching models of the patient's external surface as depicted in the two data sets. The resultant hybrid images, which combine complementary features of different studies, are often more useful for diagnosis and treatment planning than are the original single-modality images. The algorithm can also be used for spatial registration of baseline studies with follow-up images created with the same modality, which allows tracking of a lesion to detect subtle interval changes in size and shape. This technique can be applied to images acquired in routine clinical practice, since it is completely retrospective and does not necessitate special positioning or landmarking of the patient.     

Amelioration of hypoxic and hypoglycemic damage to cerebral endothelial cells

Induction of the 70 kDa heat shock protein (HSP70) by hypoxia and/or hypoglycemia and the effects of prior heat shock on injury owing to hypoxia and/or hypoglycemia were studied in rat cerebral endothelial cells. Hypoxia and/or hypoglycemia treatment resulted in increased expression of HSP70 only when such treatment was sufficient to cause detectable injury and when the initial treatment was followed by exposure of the cells to 24 h of normoxia and normoglycemia. Heat shock induced 24 h prior to treatment with 48 h of hypoxia slightly reduced endothelial cell damage as measured by fraction of lactate dehydrogenase release (10% decrease in injury). There was a more dramatic effect of prior heat shock on the moderate damage produced by 12 h of combined hypoxia and hypoglycemia (45% decrease), whereas the severe damage produced by 24 h of hypoxia and hypoglycemia was decreased by prior heat shock by only 16%. These results indicate that the hypoxia and hypoglycemia occurring in conjunction with ischemia are more likely to result in heat shock protein expression when there is injury to the tissue. Furthermore, heat shock protects cerebral endothelial cells from hypoxia and hypoglycemia either by slowing the initial development of injury or by delaying the onset of injury.     

Measurement of regional cerebral blood flow in the dog using ultrafast computed tomography. Experimental validation

The applicability, feasibility, reproducibility, and accuracy of the method of measuring regional cerebral blood flow using ultrafast computed tomography were evaluated in 25 dogs under varying physiological and pathophysiological conditions. Regional cerebral blood flow values were 75.6 +/- 29.4 ml/100 g/min (mean +/- standard deviation) for the hemisphere, 68.4 +/- 28.2 ml/100 g/min for the basal ganglia, 41.2 +/- 15.0 ml/100 g/min for the internal capsule, and 80.8 +/- 37.2 ml/100 g/min for the neocortex. Measurements made 10 minutes apart were significantly (p less than 0.05) correlated. Simultaneous measurements of regional cerebral blood flow by the microsphere and ultrafast computed tomography methods showed a significant (p less than 0.05) correlation for the hemisphere (r = 0.95), basal ganglia (r = 0.95), and neocortex (r = 0.94) but not for the internal capsule (r = 0.51). Microsphere and ultrafast computed tomography regional cerebral blood flow values were also in agreement in radiation-damaged brain with appreciable blood-brain barrier breakdown, and the two methods demonstrated similar responsiveness of regional cerebral blood flow to alterations in arterial carbon dioxide tension. The accuracy and sensitivity of the ultrafast computed tomography technique suggests that it affords a useful new tool for studying normal and abnormal regional cerebral blood flow.     

Immune cytolytic activity is associated with reduced intra-tumoral genetic heterogeneity and with better clinical outcomes in triple negative breast cancer

Evaluation of the functional aspects if the tumor immune microenvironment (TIME), such as the recently introduced cytolytic activity score (CYT) index have been under the spotlight in cancer research; however, clinical relevance of immune cell killing activity in breast cancer has never been analyzed in large patient cohorts. We hypothesized that CYT reflects the immune activity of TIME and can predict patient survival. A total of 7533 breast cancer patients were analyzed as both discovery and validation cohorts. We found that high CYT was associated with advanced histological grade and triple-negative breast cancer (TNBC). High CYT in tumors was significantly associated with better survival in TNBC, but unexpectedly, not in other breast cancer subtypes. High CYT TNBC included both favorable immune-related, as well as unfavorable (suppressive) inflammation-related gene sets, and characterized by high infiltration with T cells and B cells. High CYT TNBC was associated with high homologous recombination deficiency and low somatic copy number alteration score and less mutant allele tumor heterogeneity, but not with tumor mutation burden (TMB). Although CYT was not associated with pathological complete response after neoadjuvant chemotherapy, it was significantly associated with high expression of multiple immune checkpoint molecules. In conclusion, CYT of TNBC is associated with enhanced anti-cancer immunity, less intra-tumoral heterogeneity, and with better survival.     

Short-term modulation of the ipsilateral primary sensory cortex by nociceptive interference revealed by SEPs

We studied the modulation of the topographic arrangement of the human ipsilateral primary somatosensory cortex following interference of nociceptive stimuli by means of dipole source analysis. Multichannel somatosensory evoked potentials were obtained by electrical stimulation of digits 1 and 5 of the left hand before, during and after the application of pain to digits 2-4 of the right hand. The primary cortical response of the SEP (N20) was obtained for dipole localization of the representation of the primary sensory cortex receiving input from digits 1 to 5. The 3D-distance between these sides was calculated for further analysis. To account for possible attentional effects recordings were performed while simultaneously to this intervention subjects were asked to turn their attention to the right or left hand in a pseudorandom order. The application of pain induced an expansion of the 3D-distance between digits 1 and 5. Focusing attention to the stimulated limb or the site of the intervention did not yield to an additional effect. Our results provide further evidence for the presence of a quickly adapting interaction between primary somatosensory areas of both hemispheres following an interference of nociceptive stimulation in SEPs. This modifying process is probably mediated by interhemispheric and intercortical connections leading to hyperexcitability of the primary sensory cortex contralateral to that receiving nociceptive input. Spatial attention does not seem to have an impact on this kind of short-term intercortical plasticity.     

Sleep stage dependant changes of the high-frequency part of the somatosensory evoked potentials at the thalamus and cortex.

OBJECTIVES: It is known that the high-frequency oscillations (above 400 Hz) of the somatosensory evoked potentials (SEPs) diminish during sleep while the N20 persists (Neurology 38 (1988) 64; Electroenceph clin Neurophysiol 70 (1988) 126; Electroenceph clin Neurophysiol 100 (1996) 189). We investigated possible differential effects of sleep on the 600 Hz SEPs at the thalamus and cortex. METHODS: SEPs from 10 subjects were recorded using 64 channels following electric stimulation at the wrist during awake state and sleep stages II, IV and REM. Dipole source analysis was applied to separate brain-stem, thalamic and cortical activity in the low-frequency (20-450 Hz) and the high-frequency (450-750 Hz) part of the signal. RESULTS: The low-frequency SEPs showed a non-significant increase of the latency of the N20 and a bifid change of the waveform in 3 subjects. The high-frequency SEPs showed a significant decrease of their amplitude at the level of the thalamus and cortex but not at the brain-stem. This decrease in amplitude at the thalamus and cortex were significantly correlated. There was no effect on the latency of the signal. In addition, at the cortex, differential effects on early and late parts of the 600 Hz oscillations were found by time-frequency analysis using a wavelet transformation. CONCLUSIONS: Sleep dependent decrease of the high-frequency SEPs were first observed at the thalamus pointing to the known function of the reticular thalamic nucleus regulating arousal. The results presented here provide further evidence for a thalamic origin of the 600 Hz oscillations. In addition, on the basis of the differential effects on early (up to the N20 peak) and late (between 20 and 25 ms) parts of the signal, at least one intracortical generator of these oscillations is proposed. In general, the high-frequency SEPs (600 Hz oscillations) are supposed to reflect activity of a somatosensory arousal system.     

Evaluation of BRCA1 and BRCA2 mutations and risk-prediction models in a typical Asian country (Malaysia) with a relatively low incidence of breast cancer

Introduction

The cost of genetic testing and the limited knowledge about the BRCA1 and BRCA2 genes in different ethnic groups has limited its availability in medium- and low-resource countries, including Malaysia. In addition, the applicability of many risk-assessment tools, such as the Manchester Scoring System and BOADICEA (Breast and Ovarian Analysis of Disease Incidence and Carrier Estimation Algorithm) which were developed based on mutation rates observed primarily in Caucasian populations using data from multiplex families, and in populations where the rate of breast cancer is higher, has not been widely tested in Asia or in Asians living elsewhere. Here, we report the results of genetic testing for mutations in the BRCA1 or BRCA2 genes in a series of families with breast cancer in the multi-ethnic population (Malay, Chinese and Indian) of Malaysia.

Method

A total of 187 breast cancer patients with either early-onset breast cancer (at age ≤ 40 years) or a personal and/or family history of breast or ovarian cancer were comprehensively tested by full sequencing of both BRCA1 and BRCA2. Two algorithms to predict the presence of mutations, the Manchester Scoring System and BOADICEA, were evaluated.

Results

Twenty-seven deleterious mutations were detected (14 in BRCA1 and 13 in BRCA2), only one of which was found in two unrelated individuals (BRCA2 490 delCT). In addition, 47 variants of uncertain clinical significance were identified (16 in BRCA1 and 31 in BRCA2). Notably, many mutations are novel (13 of the 30 BRCA1 mutations and 24 of the 44 BRCA2). We report that while there were an equal proportion of BRCA1 and BRCA2 mutations in the Chinese population in our study, there were significantly more BRCA2 mutations among the Malays. In addition, we show that the predictive power of the BOADICEA risk-prediction model and the Manchester Scoring System was significantly better for BRCA1 than BRCA2, but that the overall sensitivity, specificity and positive-predictive value was lower in this population than has been previously reported in Caucasian populations.

Conclusion

Our study underscores the need for larger collaborative studies among non-Caucasian populations to validate the role of genetic testing and the use of risk-prediction models in ensuring that the other populations in the world may also benefit from the genomics and genetics era.