Invasive breast cancer: a significant correlation between histological types and molecular subgroups.

INTRODUCTION: The special types of breast cancer seem to have not only distinct morphological features but also distinct biological features. MATERIALS AND METHODS: Women diagnosed with a first primary invasive breast cancer in the 2004-2005 period were identified through Tuscan Cancer Registry. Information on age, tumor size, lymph node status, histological type and grade, hormonal receptors, HER2 immunohistochemical expression were collected. Five subtypes were defined: luminal A, luminal B HER2+, luminal B HER2-, triple negative, and HER2 positive. The association between the histological type and molecular subgroups was assessed by a Fisher's exact test, and a multinomial logistic regression model was used. RESULTS: Out of 1,487 patients, 34 % were luminal A subtype, 25 % luminal B HER2-, 11 % luminal B HER2+, 19 % triple negative, and 10.2 % HER2+; 58.5 % of cancers were ductal NOS types. With luminal A as reference, histological types distribution was significantly different between the subgroups. Mucinous, tubular, and cribriform histotypes were found among luminal A cancers more than in other subgroups; all medullary carcinomas were triple negative cancers. Pathological stage at diagnosis was more advanced, and histological grade was lower among subgroups other than luminal A. CONCLUSIONS: Significant association between breast cancer histotypes and molecular subgroups was found.

Biological characteristics of interval cancers: a role for biomarkers in the breast cancer screening.

INTRODUCTION: In a population-based screening program, a percentage of tumors remain undetected; these tumors comprise a heterogeneous group, and they are more likely to have adverse prognostic features. The aim of this study was to identify differences in biological characteristics of screen-detected versus interval breast cancers in a population-based screening program according to molecular subtypes. MATERIALS AND METHODS: We analyzed the population-based data from a long-running screening program in the area of Florence. Data on screening history and on age, T and N status, grade, histotype, hormonal status and Ki-67 and HER2 expression were retrieved. Subtypes of breast cancer were defined on the expression of ER, PR, Ki-67 and HER2: luminal A if ER/PR+, HER2- and Ki67 <14 %, luminal B (HER2 negative) if ER/PR+, HER2- and Ki67 ≥14 %, luminal B (HER2 positive) if ER/PR+ and HER2+, triple negative if ER/PR-and HER2-, HER2 positive if ER/PR- and HER2+. Association between molecular subtypes and mode of detection will be evaluated by a logistic regression model adjusted for the potential confounding variables. RESULTS: Information about biomarkers was known for 277 cases, 211 screening-detected and 66 interval cancers. Among interval cases, the triple-negative cancers were more represented than luminal A (OR = 3.52; CI, 1.112-11.13; p = 0.0319), while the proportion of HER2+ was quite similar (OR = 1.57; p = 0.4709). CONCLUSION: Although made on a small number of cases, our results suggest a difference in distribution of molecular subtypes according to mode detection, confirming the results of earlier studies.

Reward unpredictability inside and outside of a task context as a determinant of the responses of tonically active neurons in the monkey striatum.

Tonically active neurons (TANs) in the monkey striatum are involved in detecting motivationally relevant stimuli. We recently provided evidence that the timing of conditioned stimuli strongly influences the responsiveness of TANs, the source of which is likely to be the monkey's previous experience with particular temporal regularities in sequential task events. To extend these findings, we investigated the relationship of TAN responses to a primary liquid reward, the timing of which is more or less predictable to the monkey either outside of a task or during instrumental task performance. Reward predictability was indexed by the timing characteristics of the mouth movements. The responsiveness of TANs to reward increased with the range and variability of time periods before reward, notably when the liquid was delivered outside of a task. A change in the temporal order of events in a task context produced an increase of response to reward, suggesting an influence of the predicted nature of the event in addition to its time of occurrence. By contrast, we observed no substantial changes in neuronal activity at the expected time of reward when this event failed to occur, suggesting that these neurons do not appear to carry information about an error in reward prediction. These results demonstrate that TANs constitute a neuronal system that is involved in detecting unpredicted reward events, irrespective of the specific behavioral situation in which such events occur. The responses influenced by stimulus prediction may constitute a neuronal basis for the notion that striatal processing is crucial for habit learning.

Influence of the predicted time of stimuli eliciting movements on responses of tonically active neurons in the monkey striatum.

Changes in activity of tonically active neurons of the primate striatum are determined both by the behavioural significance of stimuli and the context in which stimuli are presented. We investigated how the responses of these neurons are modified by the temporal predictability of stimuli eliciting learned behavioural reactions. Single neurons were recorded from the caudate nucleus and putamen of two macaque monkeys performing a visual reaction time task under conditions in which the timing of the trigger stimulus was made more or less predictable. The monkeys' ability to predict the trigger onset was assessed by measuring arm movement reaction times and saccadic ocular reactions. Of 171 neurons responding to the unsignalled presentation of the trigger stimulus, 32% lost their response when an instruction cue preceded the trigger by a highly practised 1.5 s interval, and the response reappeared when this interval was varied randomly from 1 to 2.5 s or prolonged to 3 or 4. 5 s. Although 43% of the neurons remained responsive irrespective of task condition, the responses were stronger with longer intervals than with the accustomed 1.5 s interval. In addition, a number of neurons responding to the instruction lost their response when the trigger appeared more distant from the instruction. These findings demonstrate that neuronal responses to a movement-triggering signal become more numerous and pronounced when the degree of temporal predictability of that signal was decreased. We conclude that tonic striatal neurons are sensitive to temporal aspects of stimulus prediction.

Tonically active neurons in the monkey striatum do not preferentially respond to appetitive stimuli.

The tonically active neurons in the monkey striatum respond to stimuli presented during the performance of appetitively motivated behavior. To test whether these neurons are selectively responsive to the appetitive properties of stimuli, we studied their responsiveness to three different stimuli presented in an unsignalled manner to monkeys not performing any behavioral tasks: (1) an appetitive liquid, eliciting licking movements; (2) an aversive air puff directed towards the face, eliciting eyelid closure and facial movements; (3) a neutral sound, eliciting no overt behavioral reactions. The great majority of the tonic striatal neurons tested in two monkeys showed pronounced responses to the delivery of liquid (338 of 388 neurons, 87%) or the onset of the air puff stimulus (168 of 204, 82%). In contrast, few neurons (15 of 68, 22%) were modulated by the sound. The majority (80%) of the neurons tested with appetitive and aversive stimuli (n=189) responded to both types of stimulus. The characteristics of neuronal responses to the liquid were generally not similar to those described for the air puff in terms of response pattern and response duration. This suggests the existence of differences in the encoding of the affective significance of stimuli. It is concluded that tonic striatal neurons might function to differentiate stimuli that are important to the animal from those that are not, regardless of the specific motivational attributes of relevant stimuli.

Influence of predictive information on responses of tonically active neurons in the monkey striatum.

Influence of predictive information on responses of tonically active neurons in the monkey striatum. J. Neurophysiol. 80: 3341-3344, 1998. We investigated how the expectation of a signal of behavioral significance influences the activity of tonically active neurons in the striatum of two monkeys performing a simple reaction time task under two conditions, an uncued condition in which the trigger stimulus occurred randomly in time and a cued condition in which the same trigger was preceded by an instruction stimulus serving as a predictive signal for the forthcoming signal eliciting an immediate behavioral reaction. Both monkeys benefited from the presence of the instruction stimulus to reduce their reaction time, suggesting an increased ability to predict the trigger onset during cued trials compared with uncued trials. A majority of neurons (199/272, 73%) showed a phasic reduction in activity after the onset of the trigger stimulus in the uncued condition, whereas only 38% responded to the same stimulus when it was preceded by the instruction. Furthermore, magnitudes of trigger responses in the uncued condition were significantly higher than in the cued condition. Fifty-seven percent of the neurons responded to the instruction stimulus, and one-half of the neurons losing their response to the trigger in the cued condition responded to the instruction stimulus. These findings suggest that responses of tonic striatal neurons to a trigger stimulus for movement were influenced by predictive information.

Responses of tonically discharging neurons in the monkey striatum to primary rewards delivered during different behavioral states.

In the primate striatum, the tonically discharging neurons respond to conditioned stimuli associated with reward. We investigated whether these neurons respond to the reward itself and how changes in the behavioral context in which the reward is delivered might influence their responsiveness. A total of 286 neurons in the caudate nucleus and putamen were studied in two awake macaque monkeys while liquid reward was delivered in three behavioral situations: (1) an instrumental task, in which reward was delivered upon execution of a visually triggered arm movement; (2) a classically conditioned task, in which reward was delivered 1 s after a visual signal; (3) a free reward situation, in which reward was delivered at irregular time intervals outside of any conditioning task. The monkeys' uncertainty about the time at which reward will be delivered was assessed by monitoring their mouth movements. A larger proportion of neurons responsive to reward was observed in the free reward situation (86%) than in the classically conditioned (57%) and instrumental tasks (37%). Among the neurons tested in all situations (n = 78), 24% responded to reward regardless of the situation and 65% in only one or two situations. Responses selective for one particular situation occurred exclusively in the free reward situation. When the reward was delivered immediately after the visual signal in the classically conditioned task, most of the neurons reduced or completely lost their responses to reward, and other neurons remained responsive. Conversely, neuronal responses invariably persisted when reward was delivered later than 1 s after the visual signal. This is the first report that tonic striatal neurons might display responses directly to primary rewards. The neuronal responses were strongly influenced by the behavioral context in which the animals received the reward. An important factor appears to be the timing of reward. These neurons might therefore contribute to a general aspect of behavioral reactivity of the subject to relevant stimuli.

Responses of tonically discharging neurons in monkey striatum to visual stimuli presented under passive conditions and during task performance.

To test whether the responsiveness of tonically discharging neurons from monkey striatum is dependent on the motor or rewarding features of the conditioned stimuli, we studied the responses of these neurons to visual stimuli presented under two behavioral conditions: during an operant task in which the stimulus triggered a movement to obtain a reward, and in a non-performing state in which the stimulus was consistently followed by a reward outside of a task. Most of the neurons tested (110/158) responded to the stimuli presented in both conditions, while a relatively small number of neurons (35/158) showed selective responses in one or other of the conditions. A gradual disappearance of neuronal responses occurred in the passive state when presenting a stimulus which was never followed by reward. These results provide evidence that tonic striatal neurons may be involved in detecting stimuli predicting reward, regardless of the behavioral contingency of those stimuli.

Interactive multiplanar reformation of conventional two-dimensional MR images.

In this report, we describe a new application for three-dimensional computer image processing that can provide for improved depiction of anatomical structures on routine nonvolumetric magnetic resonance (MR) examinations. The technique can be applied to standard two-dimensional MR images of the brain, spine, musculoskeletal system, and body including those obtained with relatively thick slices and with an intersection gap. This report demonstrates use of the reformation technique to establish retrospectively the symmetry in bilateral structures that were displayed out of alignment due to suboptimal patient positioning or patient motion during image acquisition and to improve the depiction of anatomical structures that were oriented out of the plane of original image acquisition. This method can be performed interactively in near real time, requires no increase in patient examination time, and has potential application throughout the body.

Quantitative behavioral study of the acute and long-term effects of two-stage bilateral 6-OHDA-induced lesions of the nigrostriatal dopaminergic system in monkeys.

Bilateral lesions of the nigrostriatal dopaminergic system (2-stage lesions separated by 5-6 months) were induced in 3 monkeys trained to initiate forelimb-reaching movements toward a visual target. After each lesion, analysis of the task performance over several months of regular testing showed that the latency to initiate the movement was permanently prolonged in monkeys showing 90% or more striatal dopamine depletion, whereas animals with less severe depletion completely recovered the task performance. Several months after a unilateral nigrostriatal damage, a lesion on the other side produced impairments only on the side of the body contralateral to that second lesion and did not reinstate the deficits on the side previously affected by the first lesion. This suggests that the remaining intact nigrostriatal dopaminergic system may not be involved in the long-term behavioral recovery observed in monkeys with a unilateral lesion.

Extension of vessels through hepatic neoplasms: MR and CT findings.

The undisturbed extension of vessels through an area of abnormal hepatic signal intensity on magnetic resonance (MR) images or abnormal attenuation on computed tomographic (CT) scans has been used as evidence of benign focal fatty infiltration and malignant hepatic neoplasms. Five cases are described in which either portal or hepatic veins extended through a hepatic lesion without evidence of appreciable mass effect, occlusion, or displacement of the vessels. These pathologically proved malignancies included hepatic lymphoma, metastatic melanoma, and metastatic adenocarcinoma.

Chemical shift misregistration artifact: increased conspicuity following intravenous administration of gadopentetate dimeglumine.

We have observed increased conspicuity of chemical shift misregistration artifact (CSMA) associated with enhancing structures on MR images after the intravenous administration of gadopentetate dimeglumine compared with corresponding unenhanced images. In this study, we investigate the influence of gadopentetate dimeglumine administration on the conspicuity of CSMA in MR imaging of the kidneys. Nine gadopentetate-enhanced and unenhanced T1-weighted images of the kidneys were evaluated in a side-by-side fashion for the conspicuity of both the high and low signal intensity (SI) components of CSMA. A phantom study of saline in a bath of oil and increasing concentrations of gadopentetate dimeglumine in a bath of oil was performed. There was increased conspicuity of both the high and low SI components of CSMA in gadopentetate-enhanced images compared with unenhanced images in all study cases and in the phantom samples containing gadopentetate compared with the saline control. In conclusion, the administration of gadopentetate dimeglumine results in increased conspicuity of CSMA on MR images of the kidneys.

MR imaging of bone marrow lesions: relative conspicuousness on T1-weighted, fat-suppressed T2-weighted, and STIR images.

OBJECTIVE: Fat-saturation pulse sequences offer important potential advantages for depiction of bone marrow lesions on MR images. The objectives of this study were to evaluate the relative conspicuousness of bone marrow lesions on images obtained by using two of the most widely available fat-suppression techniques, short-TI inversion recovery (STIR) and fat-saturation T2-weighted imaging, and to analyze the effect of these methods on image quality. In addition, we sought to determine if either or both of these sequences provide significant advantages relative to conventional T1-weighted spin-echo images for the evaluation of bone marrow lesions. SUBJECTS AND METHODS: T1-weighted (600/15 [TR/TE]), STIR (2500/20/160 [TR/TE/TI]), and fat-saturation T2-weighted (2500/20-70) MR images were obtained with a 1.5-T system in 34 consecutive patients with suspected bone marrow lesions. The conspicuousness of 36 lesions was evaluated subjectively by three radiologists, who also evaluated the MR images for how well they showed margination and extent of the lesion, image uniformity, motion artifacts, and overall image quality. In addition, lesion contrast on these sequences was compared quantitatively by using percentage contrast measurements. RESULTS: Lesions were qualitatively equally conspicuous with all four pulse sequences. Quantitative measurements indicated that lesions were more conspicuous on fat-saturation T2-weighted and STIR images than on T1-weighted images (p < .001). Differences between the first two sequences were not significant. Factors related to image quality, including reduction in motion artifacts and image uniformity, were generally superior on T1-weighted images. CONCLUSION: T1-weighted, fat-saturation T2-weighted, and STIR sequences all provide a high degree of sensitivity for depiction of most types of bone marrow abnormalities. Although the conspicuousness of lesions is similar on fat-saturation T2-weighted and STIR images, the former sequence has several practical advantages, including acquisition of more slices per unit time and improved tissue specificity. The combination of T1-weighted and either fat-saturation T2-weighted or STIR images is highly effective for the evaluation of bone marrow lesions.

Responses of monkey dopamine neurons to reward and conditioned stimuli during successive steps of learning a delayed response task.

The present investigation had two aims: (1) to study responses of dopamine neurons to stimuli with attentional and motivational significance during several steps of learning a behavioral task, and (2) to study the activity of dopamine neurons during the performance of cognitive tasks known to be impaired after lesions of these neurons. Monkeys that had previously learned a simple reaction time task were trained to perform a spatial delayed response task via two intermediate tasks. During the learning of each new task, a total of 25% of 76 dopamine neurons showed phasic responses to the delivery of primary liquid reward, whereas only 9% of 163 neurons responded to this event once task performance was established. This produced an average population response during but not after learning of each task. Reward responses during learning were significantly more numerous and pronounced in area A10, as compared to areas A8 and A9. Dopamine neurons also showed phasic responses to the two conditioned stimuli. These were the instruction cue, which was the first stimulus in each trial and indicated the target of the upcoming arm movement (58% of 76 neurons during and 44% of 163 neurons after learning), and the trigger stimulus, which was a conditioned incentive stimulus predicting reward and eliciting a saccadic eye movement and an arm reaching movement (38% of neurons during and 40% after learning). None of the dopamine neurons showed sustained activity in the delay between the instruction and trigger stimuli that would resemble the activity of neurons in dopamine terminal areas, such as the striatum and frontal cortex. Thus, dopamine neurons respond phasically to alerting external stimuli with behavioral significance whose detection is crucial for learning and performing delayed response tasks. The lack of sustained activity suggests that dopamine neurons do not encode representational processes, such as working memory, expectation of external stimuli or reward, or preparation of movement. Rather, dopamine neurons are involved with transient changes of impulse activity in basic attentional and motivational processes underlying learning and cognitive behavior.

Neuronal activity in monkey ventral striatum related to the expectation of reward.

Projections from cortical and subcortical limbic structures to the basal ganglia are predominantly directed to the ventral striatum. The present study investigated how the expectation of external events with behavioral significance is reflected in the activity of ventral striatal neurons. A total of 420 neurons were studied in macaque monkeys performing in a delayed go-no-go task. Lights of different colors instructed the animal to do an arm-reaching movement or refrain from moving, respectively, when a trigger light was illuminated a few seconds later. Task performance was reinforced by liquid reward in both situations. A total of 60 ventral striatal neurons showed sustained increases of activity before the occurrence of individual task events. In 43 of these neurons, activations specifically preceded the delivery of reward, independent of the movement or no-movement reaction. In a series of additional tests, these activations were time locked to the subsequent reward, disappeared within a few trials when reward was omitted, and were temporally unrelated to mouth movements. Changes in the appetitive value of the reward liquid modified the magnitude of activations, suggesting a possible relationship to the hedonic properties of the expected event. Activations also occurred when reward was delivered in a predictable manner outside of any behavioral task. These data suggest that neurons in the ventral striatum are activated during states of expectation of individual environmental events that are predictable to the subject through its past experience. The prevalence of activations related to the expectation of reward suggests that ventral striatal neurons have access to central representations of reward and thereby participate in the processing of information underlying the motivational control of goal-directed behavior.

Neuronal activity in monkey striatum related to the expectation of predictable environmental events.

1. This study investigated neuronal activity in the striatum preceding predictable environmental events and behavioral reactions. Monkeys performed in a delayed go-nogo task that included separate time periods during which animals expected signals of behavioral significance, prepared for execution or inhibition of arm reaching movements, and expected the delivery of reward. In the task, animals were instructed by a green light cue to perform an arm reaching movement when a trigger stimulus came on approximately 3 s later (go situation). Movement was withheld after the same trigger light when the instruction cue had been red (nogo situation). Liquid reward was delivered on correct performance in both situations. 2. A total of 1,173 neurons were studied in the striatum (caudate nucleus and putamen) of 3 animals, of which 615 (52%) showed some change in activity during task performance. This report describes how the activity of 193 task-related neurons increased in advance of at least 1 component of the task, namely the instruction cue, the trigger stimulus, or the delivery of liquid reward. These neurons were found in dorsal and anterior parts of caudate and putamen and were slightly more frequent in the proximity of the internal capsule. 3. The activity of 16 neurons increased in both go and nogo trials before the onset of the instruction and subsided shortly after this signal. These activations may be related to the expectation of the instruction as the first signal in each trial. 4. The activity of 15 neurons increased between the instruction and the trigger stimulus in both go and nogo trials. These activations may be related to the expectation of the trigger stimulus independent of an arm movement. Further 56 neurons showed sustained activations only when the instruction requested a movement reaction. Activations were absent in trials in which the movement was withheld. Twenty-one of these neurons were tested with 2 different movement targets, 5 of which showed activity related to the direction of movement. These activations may be related to the preparation of movement or expectation of the specific movement triggering signal. The activity of an additional 20 neurons was unmodulated before the trigger stimulus in movement trials but increased in the interval between the no-movement instruction and the trigger stimulus for withholding the movement. These activations may be related to the preparation of movement inhibition as specific nogo reaction.(ABSTRACT TRUNCATED AT 400 WORDS)

Responses of monkey dopamine neurons during learning of behavioral reactions.

1. Previous studies have shown that dopamine (DA) neurons respond to stimuli of behavioral significance, such as primary reward and conditioned stimuli predicting reward and eliciting behavioral reactions. The present study investigated how these responses develop and vary when the behavioral significance of stimuli changes during different stages of learning. Impulses from DA neurons were recorded with movable microelectrodes from areas A8, A9, and A10 in two awake monkeys during the successive acquisition of two behavioral tasks. Impulses of DA neurons were distinguished from other neurons by their long duration (1.8-5.0 ms) and low spontaneous frequency (0.5-7.0 imp/s). 2. In the first task, animals learned to reach in a small box in front of them when it opened visibly and audibly. Before conditioning, DA neurons were activated the first few times that the empty box opened and animals reacted with saccadic eye movements. Neuronal and behavioral responses disappeared on repeated stimulus presentation. Thus neuronal responses were related to the novelty of an unexpected stimulus eliciting orienting behavior. 3. Subsequently, the box contained a small morsel of apple in one out of six trials. Animals reacted with ocular saccades to nearly every box opening and reached out when the morsel was present. One-third of 49 neurons were phasically activated by every door opening. The response was stronger when food was present. Thus DA neurons responded simultaneously to the sight of primary food reward and to the conditioned stimulus associated with reward. 4. When the box contained a morsel of apple on every trial, animals regularly reacted with target-directed eye and arm movements, and the majority of 76 DA neurons responded to door opening. The same neurons lacked responses to a light not associated with task performance that was illuminated at the position of the food box in alternate sessions, thus demonstrating specificity for the behavioral significance of stimuli. 5. The second task employed the operant conditioning of a reaction time situation in which animals reached from a resting key toward a lever when a small light was illuminated. DA neurons lacked responses to the unconditioned light. During task acquisition lasting 2-3 days, one-half of 25 DA neurons were phasically activated when a drop of liquid reward was delivered for reinforcing the reaching movement. In contrast, neurons were not activated when reward was delivered at regular intervals (2.5-3.5 s) but a task was not performed.(ABSTRACT TRUNCATED AT 400 WORDS)