[Pharmacological characteristics and clinical outcomes of Epcoritamab (recombinant) (Epkinly® subcutaneous injection ) for malignant lymphoma].

The prognosis of patients with B-cell non-Hodgkin lymphoma (B-NHL) has improved with the use of anti-CD20 based immunochemotherapy. However, management of relapsed or refractory disease remains a challenge, indicating a high unmet need for novel treatments. Epcoritamab (recombinant) is a humanized immunoglobulin G1 (IgG1) bispecific antibody that simultaneously binds to CD3 on T cells and CD20 on B cells or tumor cells inducing T-cell mediated cytotoxicity against CD20-positive B cells. It demonstrated consistent cytotoxic effects in B-cell lymphoma cell line-derived xenograft models, patient-derived xenograft models, and cynomolgus monkey studies. Pharmacological studies in cynomolgus monkeys showed peak plasma concentrations of cytokines were lower with subcutaneous versus intravenous administration. To reduce the risk of cytokine release syndrome (CRS) and improve convenience, Epcoritamab has been developed as a subcutaneous formulation.To further reduce the risk of CRS, clinical trials utilized a priming dose and incremental dose increases. In Phase I/II overseas trials with relapsed, progressive, or refractory B-NHL patients, the recommended Phase II trial dose was determined based on safety, efficacy, and pharmacokinetic model simulation results. The Phase II dose-expansion part demonstrated the efficacy and high tolerability of epcoritamab monotherapy at the recommended dose. Similar efficacy and tolerability were observed in Japanese Phase I/II trials in relapsed or refractory B-NHL patients. Based on these results, epcoritamab received the approval in September 2023 for the treatment of "relapsed or refractory large B-cell lymphoma (DLBCL, HGBCL, PMBCL)" and "relapsed or refractory follicular lymphoma (Grade 3B)" in Japan.

A systematic literature review of prognostic factors in patients with HR+/HER2- advanced breast cancer in Japan.

BACKGROUND: Breast cancer is the most prevalent cancer in women in Japan and the fifth in mortality. This systematic review summarized the evidence for prognostic factors for patients with HR+/HER2- advanced and metastatic breast cancer in Japan. METHODS: MEDLINE and EMBASE were searched with keywords 'breast neoplasms' AND 'Japan' AND 'advanced' or equivalent, and Japan Medical Abstract Society database with 'breast cancer' AND 'advanced/metastatic' for publications from January 2010 to October 2019. ASCO, ESMO, ABC4 abstracts and WHO website were hand searched. The endpoints of interest were overall survival, progression-free survival, tumour response and post-progression survival. Factors were evaluated based on the consistency in direction and the strength (hazard ratios) of association. RESULTS: Searches identified 4530 publications, of which 27 were eligible. All were observational studies. Among the endpoints, overall survival was the most commonly assessed (n = 22) and evaluated further. Ki-67 expression, progesterone receptor expression status, tumour grade and lymph node metastases were consistently associated with poor overall survival in univariate analysis but not in multivariate analysis. Short disease-free interval, the number of metastatic organs and liver metastasis were consistently associated with poor overall survival in both of univariate and multivariate analysis. The association was strong for liver metastasis (hazard ratio ≥2.8 in the majority of studies) and moderate for disease-free interval and the number of metastatic organs (hazard ratio 1.3-2.8 in the majority of studies). CONCLUSIONS: Disease-free interval, the number of metastatic organs and liver metastasis were identified as independent prognostic factors for overall survival. These findings may help clinical decision-making to improve outcomes in patients with HR+/HER2- advanced and metastatic breast cancer.

Large-Scale Cortical Networks for Hierarchical Prediction and Prediction Error in the Primate Brain.

According to predictive-coding theory, cortical areas continuously generate and update predictions of sensory inputs at different hierarchical levels and emit prediction errors when the predicted and actual inputs differ. However, predictions and prediction errors are simultaneous and interdependent processes, making it difficult to disentangle their constituent neural network organization. Here, we test the theory by using high-density electrocorticography (ECoG) in monkeys during an auditory "local-global" paradigm in which the temporal regularities of the stimuli were controlled at two hierarchical levels. We decomposed the broadband data and identified lower- and higher-level prediction-error signals in early auditory cortex and anterior temporal cortex, respectively, and a prediction-update signal sent from prefrontal cortex back to temporal cortex. The prediction-error and prediction-update signals were transmitted via γ (>40 Hz) and α/ß (<30 Hz) oscillations, respectively. Our findings provide strong support for hierarchical predictive coding and outline how it is dynamically implemented using distinct cortical areas and frequencies.

Facilitative effect of repetitive presentation of one stimulus on cortical responses to other stimuli in macaque monkeys--a possible neural mechanism for mismatch negativity.

The event-related potential 'mismatch negativity' (MMN) is an indicator of a perceiver's ability to detect deviations in sensory signal streams. MMN and its homologue in animals, mismatch activity (MMA), are differential neural responses to a repeatedly presented stimulus and a subsequent deviant stimulus (oddball). Because neural mechanisms underlying MMN and MMA remain unclear, there is a controversy as to whether MMN and MMA arise solely from stimulus-specific adaptation (SSA), in which the response to a stimulus cumulatively attenuates with its repetitive presentation. To address this issue, we used electrocorticography and the auditory roving-oddball paradigm in two awake macaque monkeys. We examined the effect of stimulus repetition number on MMA and on responses to repeated stimuli and oddballs across the cerebral cortex in the time-frequency domain. As the repetition number increased, MMA spread across the temporal, frontal and parietal cortices, and each electrode yielded a larger MMA. Surprisingly, this increment in MMA largely depended on response augmentation to the oddball rather than on SSA to the repeated stimulus. Following sufficient repetition, the oddball evoked a spectral power increment in some electrodes on the frontal cortex that had shown no power increase to the stimuli with less or no preceding repetition. We thereby revealed that repetitive presentation of one stimulus not only leads to SSA but also facilitates the cortical response to oddballs involving a wide range of cortical regions. This facilitative effect might underlie the generation of MMN-like scalp potentials in macaques that potentially shares similar neural mechanisms with MMN in humans.

Frequency-dependent spatiotemporal profiles of visual responses recorded with subdural ECoG electrodes in awake monkeys: Differences between high- and low-frequency activity.

Electrocorticography (ECoG) constitutes a powerful and promising neural recording modality in humans and animals. ECoG signals are often decomposed into several frequency bands, among which the so-called high-gamma band (80-250Hz) has been proposed to reflect local cortical functions near the cortical surface below the ECoG electrodes. It is typically assumed that the lower the frequency bands, the lower the spatial resolution of the signals; thus, there is not much to gain by analyzing the event-related changes of the ECoG signals in the lower-frequency bands. However, differences across frequency bands have not been systematically investigated. To address this issue, we recorded ECoG activity from two awake monkeys performing a retinotopic mapping task. We characterized the spatiotemporal profiles of the visual responses in the time-frequency domain. We defined the preferred spatial position, receptive field (RF), and response latencies of band-limited power (BLP) (i.e., alpha [3.9-11.7Hz], beta [15.6-23.4Hz], low [30-80Hz] and high [80-250Hz] gamma) for each electrode and compared them across bands and time-domain visual evoked potentials (VEPs). At the population level, we found that the spatial preferences were comparable across bands and VEPs. The high-gamma power showed a smaller RF than the other bands and VEPs. The response latencies for the alpha band were always longer than the latencies for the other bands and fastest in VEPs. Comparing the response profiles in both space and time for each cortical region (V1, V4+, and TEO/TE) revealed regional idiosyncrasies. Although the latencies of visual responses in the beta, low-, and high-gamma bands were almost identical in V1 and V4+, beta and low-gamma BLP occurred about 17ms earlier than high-gamma power in TEO/TE. Furthermore, TEO/TE exhibited a unique pattern in the spatial response profile: the alpha and high-gamma responses tended to prefer the foveal regions, whereas the beta and low-gamma responses preferred the peripheral visual fields with larger RFs. This suggests that neurons in TEO/TE first receive less selective spatial information via beta and low-gamma BLP but later receive more fine-tuned spatial foveal information via high-gamma power. This result is consistent with a hypothesis previously proposed by Nakamura et al. (1993) that states that visual processing in TEO/TE starts with coarse-grained information, which primes subsequent fine-grained information. Collectively, our results demonstrate that ECoG can be a potent tool for investigating the nature of the neural computations in each cortical region that cannot be fully understood by measuring only the spiking activity, through the incorporation of the knowledge of the spatiotemporal characteristics across all frequency bands.

Mismatch negativity in common marmosets: Whole-cortical recordings with multi-channel electrocorticograms.

Mismatch negativity (MMN) is a component of event-related potentials (ERPs) evoked by violations of regularity in sensory stimulus-series in humans. Recently, the MMN has received attention as a clinical and translatable biomarker of psychiatric disorders such as schizophrenia, and for the development animal models of these psychiatric disorders. In this study, we investigated the generation of MMN in common marmosets, which are an important non-human primate model with genetic manipulability. We recorded the electrocorticograms (ECoGs) from two common marmosets with epidurally implanted electrodes covering a wide range of cortical regions. ECoG recordings were conducted in a passive listening condition with a roving oddball paradigm. We compared the ERPs evoked by repeatedly presented standard stimuli and those evoked by the deviant stimuli. Significant differences in the ERPs were observed in several cortical areas. In particular, deviant stimuli elicited larger negative activity than standard stimuli in the temporal area. In addition, the latency and polarity of the activity were comparable to human MMNs. This is thus the first report of MMN-like activity in common marmosets. Our findings have the potential to advance future gene-manipulation studies that aim to establish non-human primate models of schizophrenia.

Residual attention guidance in blindsight monkeys watching complex natural scenes.

Patients with damage to primary visual cortex (V1) demonstrate residual performance on laboratory visual tasks despite denial of conscious seeing (blindsight) [1]. After a period of recovery, which suggests a role for plasticity [2], visual sensitivity higher than chance is observed in humans and monkeys for simple luminance-defined stimuli, grating stimuli, moving gratings, and other stimuli [3-7]. Some residual cognitive processes including bottom-up attention and spatial memory have also been demonstrated [8-10]. To date, little is known about blindsight with natural stimuli and spontaneous visual behavior. In particular, is orienting attention toward salient stimuli during free viewing still possible? We used a computational saliency map model to analyze spontaneous eye movements of monkeys with blindsight from unilateral ablation of V1. Despite general deficits in gaze allocation, monkeys were significantly attracted to salient stimuli. The contribution of orientation features to salience was nearly abolished, whereas contributions of motion, intensity, and color features were preserved. Control experiments employing laboratory stimuli confirmed the free-viewing finding that lesioned monkeys retained color sensitivity. Our results show that attention guidance over complex natural scenes is preserved in the absence of V1, thereby directly challenging theories and models that crucially depend on V1 to compute the low-level visual features that guide attention.

Contribution of the retino-tectal pathway to visually guided saccades after lesion of the primary visual cortex in monkeys.

Previous reports on 'blindsight' have shown that some patients with lesions of the primary visual cortex (V1) could localize visual targets in their scotoma with hand and/or eye movements without visual awareness. A role of the retino-tectal pathway on residual vision has been proposed but the direct evidence for this still remains sparse. To examine this possibility, we inactivated the superior colliculus (SC) of unilateral V1-lesioned monkeys using microinjections of muscimol, and analysed the effects on visually guided saccades. Following muscimol injections into the contralesional SC, the monkeys performed the visually guided saccade task with relatively minor deficits. The effects of ipsilesional SC inactivation were more severe. After injections, the monkeys failed to localize the target within the visual field represented at the injection site on the SC map. The effects of ipsilesional SC inactivation may result from sensory deficits, motor deficits or a combination of both. To examine these possibilities, we tested the effects of SC inactivation on the motor system by investigating spontaneous saccades. After inactivation of the ipsilesional SC, spontaneous saccades toward the injection site were not abolished, suggesting that impairment of visually guided saccades following inactivation of the ipsilesional SC could not be explained solely by a motor deficit and was primarily due to a visual deficit, presumably by interfering with processing in the superficial layer. We conclude that the retino-tectal pathway plays an essential role in residual vision after V1 lesion. The results suggest that this pathway may be involved in mediating unconscious vision in blindsight patients.

Neural substrate of spatial memory in the superior colliculus after damage to the primary visual cortex.

In the primate brain, the primary visual cortex (V1) is a major source of visual information processing in the cerebral cortex, although some patients and monkeys with damage to the V1 show visually guided behaviors in the visual field affected by the damage. Until now, behaviors of the surviving brain regions after damage to V1 and their contribution to the residual visual functions remain unclear. Here, we report that the monkeys with a unilateral lesion of V1 can make not only visually guided saccades but also memory-guided saccades (MGS) into the affected visual field. Furthermore, while the monkeys were performing the MGS task, sustained activity was observed in a large fraction of the neurons in the superior colliculus ipsilateral to the lesion, which has been supposed as a key node for recovery after damage to V1. These neurons maintained the spatial information throughout the delay period regardless of whether they exhibited saccadic bursts or not, which was not the case on the intact side. Error analysis revealed that the sustained activity was correlated with monkeys' behavioral outcome. These results suggest that the ipsilesional SC might function as a neural substrate for spatial memory in the affected visual field. Our findings provide new insight into the understanding of the compensatory mechanisms after damage to V1.

Striate cortical lesions affect deliberate decision and control of saccade: implication for blindsight.

Monkeys with unilateral lesions of the primary visual cortex (V1) can make saccades to visual stimuli in their contralateral ("affected") hemifield, but their sensitivity to luminance contrast is reduced. We examined whether the effects of V1 lesions were restricted to vision or included later stages of visual-oculomotor processing. Monkeys with unilateral V1 lesions were tested with a visually guided saccade task with stimuli in various spatial positions and of various luminance contrasts. Saccades to the stimuli in the affected hemifield were compared with those to the near-threshold stimuli in the normal hemifield so that the performances of localization were similar. Scatter in the end points of saccades to the affected hemifield was much larger than that of saccades to the near-threshold stimuli in the normal hemifield. Additional analysis revealed that this was because the initial directional error was not as sufficiently compensated as it was in the normal hemifield. The distribution of saccadic reaction times in the affected hemifield tended to be narrow. We modeled the distribution of saccadic reaction times by a modified diffusion model and obtained evidence that the decision threshold for initiation of saccades to the affected hemifield was lower than that for saccades to the normal hemifield. These results suggest that the geniculostriate pathway is crucial for on-line compensatory mechanisms of saccadic control and for decision processes. We propose that these results reflect deficits in deliberate control of visual-oculomotor processing after V1 lesions, which may parallel loss of visual awareness in human blindsight patients.

Change detection and difference detection of tone duration discrimination.

An event-related potential called mismatch negativity is known to exhibit physiological evidence of sensory memory. Mismatch negativity is believed to represent complicated neuronal mechanisms in a variety of animals and in humans. We employed the auditory oddball paradigm varying sound durations and observed two types of duration mismatch negativity in anesthetized guinea pigs. One was a duration mismatch negativity whose increase in peak amplitude occurred immediately after onset of the stimulus difference in a decrement oddball paradigm. The other exhibited a peak amplitude increase closer to the offset of the longer stimulus in an increment oddball paradigm. These results demonstrated a mechanism to percept the difference of duration change and revealed the importance of the end of a stimulus for this perception.