[Current Status and Issues in Drug Development for Rare Cancers].

Since 1993, the"R & D Promotion System for Orphan Drugs and Orphan Medical Devices"has been in operation to support the development of orphan drugs in Japan. Various supportive measures are in place for indications that target less than 50,000 patients, have high medical needs and high probability of successful development(which means regulatory approval). However, recently a trend was observed that the designation for orphan drugs occurred most often in late phase of development, because clinical data for late stage clinical studies were required to show the high probability of successful regulatory approval. The Ministry of Health, Labour and Welfare are trying to make efforts to expand the orphan drug designation, and have made the decision to include the related expenses will be included in the FY 2023 budget request. It is expected that the expansion of orphan drug designation will lead to promote drug development in rare disease area. On the other hand, fundamental reform is considered necessary for this system. Among the approved anti-cancer drugs that obtained orphan designation in the U. S. and EU as of 2020, there are 24 drugs that have not been approved in Japan. Of these, there are at least 16 drugs approved in either China, Taiwan, and South Korea. From viewpoint of development pathway of an orphan drug, participation in a multi-regional clinical trial(MRCT)is useful, but there are cases that Japan cannot join MRCT in time due to the requirement of Japanese safety data prior to the participation. In that case, it is impossible to conduct a separate clinical trial to obtain Japan regulatory approval due to very limited patients(eg several to several tens of Ultra-Orphan). A review system that allows earlier patient access is desired.

The speed of context integration in the visual cortex.

The observation of figure-ground selectivity in neurons of the visual cortex shows that these neurons can be influenced by the image context far beyond the classical receptive field. To clarify the nature of the context integration mechanism, we studied the latencies of neural edge signals, comparing the emergence of context-dependent definition of border ownership with the onset of local edge definition (contrast polarity; stereoscopic depth order). Single-neuron activity was recorded in areas V1 and V2 of Macaca mulatta under behaviorally induced fixation. Whereas local edge definition emerged immediately (<13 ms) after the edge onset response, the context-dependent signal was delayed by about 30 ms. To see if the context influence was mediated by horizontal fibers within cortex, we measured the latencies of border ownership signals for two conditions in which the relevant context information was located at different distances from the receptive field and compared the latency difference with the difference predicted from horizontal signal propagation. The prediction was based on the increase in cortical distance, computed from the mapping of the test stimuli in the cortex, and the known conduction velocities of horizontal fibers. The measured latencies increased with cortical distance, but much less than predicted by the horizontal propagation hypothesis. Probability calculations showed that an explanation of the context influence by horizontal signal propagation alone is highly unlikely, whereas mechanisms involving back projections from other extrastriate areas are plausible.

Surround modulation in visual cortex can predict border-ownership selectivity: psychophysical study of border-ownership-dependent tilt aftereffect.

Recent physiological studies revealed that neurons in the macaque visual cortex encode the direction of a figure along a contour (border ownership, BO). Although their cortical mechanisms have not been clarified, a computational model for BO has suggested that surround modulation in early vision can play an important role. Here we examined psychophysically how the strength of BO-dependent tilt aftereffect (BO-TAE) is modulated by a stimulus outside the adapted location in relation to the strength of surround modulation reported in physiological experiments. The results showed systematic change of the strength of BO-TAE, depending on the difference in orientation and spatial frequency between the bars placed outside and at the adapted location, indicating a crucial role of surround modulation in the neural mechanism underlying BO selectivity.

Figure-ground mechanisms provide structure for selective attention.

Attention depends on figure-ground organization: figures draw attention, whereas shapes of the ground tend to be ignored. Recent research has revealed mechanisms for figure-ground organization in the visual cortex, but how these mechanisms relate to the attention process remains unclear. Here we show that the influences of figure-ground organization and volitional (top-down) attention converge in single neurons of area V2 in Macaca mulatta. Although we found assignment of border ownership for attended and for ignored figures, attentional modulation was stronger when the attended figure was located on the neuron's preferred side of border ownership. When the border between two overlapping figures was placed in the receptive field, responses depended on the side of attention, and enhancement was generally found on the neuron's preferred side of border ownership. This correlation suggests that the neural network that creates figure-ground organization also provides the interface for the top-down selection process.

Border-ownership-dependent tilt aftereffect in incomplete figures.

A recent physiological finding of neural coding for border ownership (BO) that defines the direction of a figure with respect to the border has provided a possible basis for figure-ground segregation. To explore the underlying neural mechanisms of BO, we investigated stimulus configurations that activate BO circuitry through psychophysical investigation of the BO-dependent tilt aftereffect (BO-TAE). Specifically, we examined robustness of the border ownership signal by determining whether the BO-TAE is observed when gestalt factors are broken. The results showed significant BO-TAEs even when a global shape was not explicitly given due to the ambiguity of the contour, suggesting a contour-independent mechanism for BO coding.

Integration of auditory and visual communication information in the primate ventrolateral prefrontal cortex.

The integration of auditory and visual stimuli is crucial for recognizing objects, communicating effectively, and navigating through our complex world. Although the frontal lobes are involved in memory, communication, and language, there has been no evidence that the integration of communication information occurs at the single-cell level in the frontal lobes. Here, we show that neurons in the macaque ventrolateral prefrontal cortex (VLPFC) integrate audiovisual communication stimuli. The multisensory interactions included both enhancement and suppression of a predominantly auditory or a predominantly visual response, although multisensory suppression was the more common mode of response. The multisensory neurons were distributed across the VLPFC and within previously identified unimodal auditory and visual regions (O'Scalaidhe et al., 1997; Romanski and Goldman-Rakic, 2002). Thus, our study demonstrates, for the first time, that single prefrontal neurons integrate communication information from the auditory and visual domains, suggesting that these neurons are an important node in the cortical network responsible for communication.

Prior experience of rotation is not required for recognizing objects seen from different angles.

An object viewed from different angles can be recognized and distinguished from similar distractors after the viewer has had experience watching it rotate. It has been assumed that as an observer watches the rotation, separate representations of individual views become associated with one another. However, we show here that once monkeys learned to discriminate individual views of objects, they were able to recognize objects across rotations up to 60 degrees , even though there had been no opportunity to learn the association between different views. Our results suggest that object recognition across small or medium changes in viewing angle depends on features common to similar views of objects.