Prognostic impact of clinical factors for immune checkpoint inhibitor with or without chemotherapy in older patients with non-small cell lung cancer and PD-L1 TPS ≥ 50.

Introduction: The proportion of older patients diagnosed with advanced-stage non-small cell lung cancer (NSCLC) has been increasing. Immune checkpoint inhibitor (ICI) monotherapy (MONO) and combination therapy of ICI and chemotherapy (COMBO) are standard treatments for patients with NSCLC and programmed cell death ligand-1 (PD-L1) tumor proportion scores (TPS) ≥ 50%. However, evidence from the clinical trials specifically for older patients is limited. Thus, it is unclear which older patients benefit more from COMBO than MONO. Methods: We retrospectively analyzed 199 older NSCLC patients of Eastern Cooperative Oncology Group performance status (ECOG PS) 0-1 and PD-L1 TPS ≥ 50% who were treated with MONO or COMBO. We analyzed the association between treatment outcomes and baseline patient characteristics in each group, using propensity score matching. Results: Of the 199 patients, 131 received MONO, and 68 received COMBO. The median overall survival (OS; MONO: 25.2 vs. COMBO: 42.2 months, P = 0.116) and median progression-free survival (PFS; 10.9 vs. 11.8 months, P = 0.231) did not significantly differ between MONO and COMBO group. In the MONO group, OS was significantly shorter in patients without smoking history compared to those with smoking history [HR for smoking history against non-smoking history: 0.36 (95% CI: 0.16-0.78), P = 0.010]. In the COMBO group, OS was significantly shorter in patients with PS 1 than those with PS 0 [HR for PS 0 against PS 1: 3.84 (95% CI: 1.44-10.20), P = 0.007] and for patients with squamous cell carcinoma (SQ) compared to non-squamous cell carcinoma (non-SQ) [HR for SQ against non-SQ: 0.17 (95% CI: 0.06-0.44), P < 0.001]. For patients with ECOG PS 0 (OS: 26.1 months vs. not reached, P = 0.0031, PFS: 6.5 vs. 21.7 months, P = 0.0436) or non-SQ (OS: 23.8 months vs. not reached, P = 0.0038, PFS: 10.9 vs. 17.3 months, P = 0.0383), PFS and OS were significantly longer in the COMBO group. Conclusions: ECOG PS and histological type should be considered when choosing MONO or COMBO treatment in older patients with NSCLC and PD-L1 TPS ≥ 50%.

Efficacy and Safety of Docetaxel plus Ramucirumab for Patients with Pretreated Advanced or Recurrent Non-small Cell Lung Cancer: Focus on Older Patients.

BACKGROUND: Combination therapy with docetaxel (DTX) and ramucirumab (RAM) has been used as a second-line treatment for advanced or recurrent lung cancer. However, there is insufficient evidence regarding the safety of angiogenesis inhibitors in older patients. OBJECTIVE: This multicenter retrospective study aimed to investigate the efficacy and safety of second-line treatment regimens in older patients with advanced or recurrent non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: We retrospectively analyzed 145 patients aged ≥ 70 years with advanced or recurrent NSCLC treated with second-line chemotherapy after platinum-based therapy between April 1, 2016, and March 31, 2021. Patients were subdivided into the DTX + RAM (n = 38) and single-agent (n = 107) groups. RESULTS: The median time to treatment failure was 6.3 months (95% confidence interval [CI] 3.6-9.6) in the DTX + RAM group and 2.3 months (95% CI 1.7-3.0) in the single-agent group (p < 0.01). The median overall survival was 15.9 months (95% CI 12.3-Not Achieved) in the DTX + RAM group and 9.4 months (95% CI 6.9-15.1) in the single-agent group (p = 0.01). Grade ≥ 3 adverse events frequency was not significantly different between the two groups, except for edema. Patients in the DTX + RAM group who did not discontinue treatment owing to adverse events exhibited the most favorable prognosis. CONCLUSIONS: These findings suggest that the DTX + RAM combination is an effective second-line therapy for older patients with advanced or recurrent NSCLC, offering favorable efficacy without treatment discontinuation owing to adverse events.

Comparing Three Different Anti-Programmed Death-Ligand 1 Antibodies in Immunohistochemical Evaluation of Combined Chemoimmunotherapy Response in Patients With NSCLC: A Prospective Study.

Introduction: Multiple programmed death-ligand 1 (PD-L1) immunohistochemistry assays performed using different antibodies including DAKO 22C3, DAKO 28-8, and Ventana SP142 PD-L1-predictive markers for response to various immune checkpoint inhibitors in NSCLC-have been approved in several countries. The differences in multiple PD-L1 immunohistochemistry assay results in predicting the therapeutic response to combined chemoimmunotherapy in patients with NSCLC remain unclear. Methods: In this multicenter prospective observational study, we monitored 70 patients with advanced NSCLC treated with combined chemoimmunotherapy at 10 institutions in Japan. The expression of PD-L1 in pretreatment tumors was evaluated using the 22C3, 28-8, and SP142 assays in all patients. Results: The PD-L1 level in tumor cells determined using the 22C3 assay was the highest among the three assays performed with different antibodies. According to the 22C3 assay results, the PD-L1 tumor proportion score greater than or equal to 50% group had a significantly longer progression-free survival period than the PD-L1 tumor proportion score less than 50% group. Nevertheless, the other assays did not reveal remarkable differences in the objective response rate or progression-free survival. Conclusions: In our study, PD-L1 expression determined using the 22C3 assay was more correlated with the therapeutic response of patients with NSCLC treated with combined chemoimmunotherapy than that determined using the 28-8 and SP142 assays. Therefore, the 22C3 assay may be useful for clinical decision-making for patients with NSCLC treated with combined chemoimmunotherapy. Trial registration number: UMIN 000043958.

Association of Geriatric Nutritional Risk Index With Adverse Event and Treatment Duration in Adjuvant Chemotherapy for Patients With Colorectal Cancer.

BACKGROUND/AIM: In recent years, the Geriatric Nutritional Risk Index (GNRI) has been reported as a predictor of prognosis in many patients with cancer. This study investigated the association of preoperative GNRI with the occurrence of adverse events and duration of treatment with capecitabine plus oxaliplatin (CAPOX), a postoperative adjuvant chemotherapy, in 59 patients with colorectal cancer from September 2019 to April 2022. PATIENTS AND METHODS: A cut-off value of 100.9 was used to categorize patients into high and low GNRI groups. RESULTS: The incidence of grade ≥2 leukopenia (p=0.03), and all grades peripheral neuropathy (p=0.04) were significantly more frequent in the low GNRI group. Analysis of factors influencing treatment duration by univariate and multivariate Cox regression proportional hazards models showed a significant difference in GNRI (p=0.0097). CONCLUSION: GNRI, a nutritional indicator assessed before the start of treatment, influences the occurrence of adverse events and duration of treatment with CAPOX as adjuvant chemotherapy. To complete CAPOX therapy, preoperatively, it is important to assess the patients' nutritional status using the GNRI and to actively intervene in nutritional therapy.

Association of Geriatric Nutritional Risk Index With Immune Checkpoint Inhibitor Treatment Duration and Adverse Events in Lung Cancer.

BACKGROUND/AIM: Compared to conventional cytotoxic anticancer agent-based therapy, treatment with immune checkpoint inhibitors (ICI) significantly prolongs overall survival. The Geriatric Nutritional Risk Index (GNRI) has been used as a new prognostic indicator in cancer. As nutritional status is associated with prognosis and indicates treatment response, we investigated the effect of the pretreatment GNRI on the (1) occurrence of ICI-induced immune-related adverse events (ir-AE) and (2) association with time to treatment failure (TTF) in ICI monotherapy for lung cancer. PATIENTS AND METHODS: In this study, 127 patients with lung cancer who were treated with ICI monotherapy were retrospectively enrolled. Based on a cutoff value of 92 for the GNRI, we investigated intergroup differences in the occurrence of adverse events and their association with TTF in the High-GNRI (≥92) and Low-GNRI (<92) groups. For intergroup comparisons, we used the Student's t-test, Welch's t-test, Fisher's direct probability test, and Mann-Whitney's U-test, and factors with p<0.05 in the intergroup comparison were extracted as explanatory variables. RESULTS: Based on the pretreatment GNRI, the median TTF was 5.1 months (95%CI=2.4-7.9 months) in the High-GNRI group and 2.3 months (95%CI=1.6-3.1 months) in the Low-GNRI group, with the High-GNRI group having a significantly longer TTF (p<0.01). The incidence of skin rash (p=0.0129) and pruritus (p<0.01) was significantly higher in the High-GNRI group. CONCLUSION: Pretreatment GNRI influences the continuation of ICI monotherapy. The High-GNRI group demonstrated a significantly higher frequency of skin lesions, which may have influenced the prolongation of TTF.

Chemoimmunotherapy Versus Pembrolizumab as a First-Line Treatment for Patients with Advanced Non-small Cell Lung Cancer and High PD-L1 Expression: Focus on the Role of Performance Status.

BACKGROUND: Immune checkpoint inhibitor (ICI) monotherapy and ICI plus chemotherapy are approved first-line treatments for patients with non-small cell lung cancer (NSCLC) expressing high levels of programmed cell death-ligand 1 (PD-L1). However, appropriate treatment for patients showing high PD-L1 expression and poor performance status (PS) is not well defined. OBJECTIVE: The aim of this study was to identify a treatment option that is better for these patients in a real-world setting. PATIENTS AND METHODS: A total of 425 patients with NSCLC and high PD-L1 expression were included retrospectively. All patients received either pembrolizumab monotherapy or ICI plus chemotherapy as the first-line treatment. Patients were subdivided into good (PS score 0 or 1; n = 354) and poor PS groups (PS score 2 or 3; n = 71). Early progressive disease (PD) was defined as PD within 3 months of ICI-based therapy initiation. RESULTS: The good PS group had significantly longer progression-free survival (PFS) and overall survival (OS) than the poor PS group upon ICI-based therapy administration. In the poor PS group, no significant difference was observed in PFS and OS between pembrolizumab monotherapy and ICI plus chemotherapy. In the good PS group, pembrolizumab monotherapy, PD-L1 50-89%, and liver metastasis were associated with early PD, as determined using multivariate logistic regression analyses. However, in the poor PS group, the multivariate logistic regression analyses did not show an association between pembrolizumab monotherapy and early PD. CONCLUSIONS: In patients with NSCLC exhibiting poor PS and high PD-L1 expression, ICI plus chemotherapy did not confer PFS or OS benefit compared with pembrolizumab monotherapy.

Mapping information flow between the inferotemporal and prefrontal cortices via neural oscillations in memory retrieval and maintenance.

Interaction between the inferotemporal (ITC) and prefrontal (PFC) cortices is critical for retrieving information from memory and maintaining it in working memory. Neural oscillations provide a mechanism for communication between brain regions. However, it remains unknown how information flow via neural oscillations is functionally organized in these cortices during these processes. In this study, we apply Granger causality analysis to electrocorticographic signals from both cortices of monkeys performing visual association tasks to map information flow. Our results reveal regions within the ITC where information flow to and from the PFC increases via specific frequency oscillations to form clusters during memory retrieval and maintenance. Theta-band information flow in both directions increases in similar regions in both cortices, suggesting reciprocal information exchange in those regions. These findings suggest that specific subregions function as nodes in the memory information-processing network between the ITC and the PFC.

Concomitant Proton Pump Inhibitor Use With Pembrolizumab Monotherapy vs Immune Checkpoint Inhibitor Plus Chemotherapy in Patients With Non-Small Cell Lung Cancer.

Importance: Immune checkpoint inhibitor (ICI) monotherapy with pembrolizumab and ICI plus chemotherapy have been approved as first-line treatments for non-small cell lung cancer (NSCLC) for patients with a programmed cell death ligand-1 (PD-L1) tumor proportion score (TPS) of 50% or more, but the choice between these 2 therapeutic options is unclear. Objective: To clarify the association of a history of concurrent medication use with treatment outcomes for ICIs with or without chemotherapy in patients with NSCLC with a high PD-L1 TPS and to determine whether these clinical histories are biomarkers for appropriate treatment selection. Design, Setting, and Participants: This retrospective, multicenter cohort study at 13 hospitals in Japan included patients with advanced NSCLC with a PD-L1 TPS of 50% or more who had received pembrolizumab ICI monotherapy or ICI plus chemotherapy as the initial treatment between March 2017 and December 2020. The median (IQR) follow-up duration was 18.5 (9.2-31.2) months. Data were analyzed from April 2022 through May 2023. Exposure: ICI monotherapy with pembrolizumab or ICI plus chemotherapy as first-line treatment. Main Outcomes and Measures: The primary analysis was the association of treatment outcomes with baseline patient characteristics, including concomitant drug history, after propensity score matching. Cox proportional hazard models were used to determine the associations of patient characteristics with survival outcomes. Logistic regression analysis was used to determine the association of concomitant medication history with treatment outcomes and other patient characteristics. Results: A total of 425 patients with NSCLC were enrolled in the study including 271 patients (median [range] age, 72 [43-90] years; 215 [79%] men) who were treated with pembrolizumab monotherapy as the first-line treatment and 154 patients (median [range] age, 69 [36-86] years; 121 [79%] men) who were treated with ICI plus chemotherapy as the first-line treatment. In multivariable analysis, a history of proton pump inhibitor (PPI) use was independently associated with shorter progression-free survival (PFS) in the pembrolizumab monotherapy group (hazard ratio [HR], 1.38; 95% CI, 1.00-1.91; P = .048), but not in the ICI plus chemotherapy group. In patients with a PPI history, both the median (IQR) PFS (19.3 [9.0 to not reached] months vs 5.7 [2.4 to 15.2] months; HR, 0.38; 95% CI, 0.20-0.72; P = .002) and the median (IQR) overall survival (not reached [9.0 months to not reached) vs 18.4 [10.5 to 50.0] months; HR, 0.43; 95% CI, 0.20-0.92; P = .03) were significantly longer in the ICI plus chemotherapy group than in the pembrolizumab monotherapy group. In patients without a history of PPI use, both the median (IQR) PFS (18.8 months [6.6 months to not reached] vs 10.6 months [2.7 months to not reached]; HR, 0.81; 95% CI, 0.56-1.17; P = .26) and the median (IQR) overall survival (not reached [12.6 months to not reached] vs 29.9 [13.3 to 54.3] months, HR, 0.75; 95% CI, 0.48-1.18; P = .21) did not differ between groups. Conclusions and Relevance: This cohort study found that a history of PPI use could be an important clinical factor in treatment decision-making for patients with NSCLC with a PD-L1 TPS of 50% or more.

TTF-1 Expression and Clinical Outcomes of Combined Chemoimmunotherapy in Patients With Advanced Lung Adenocarcinoma: A Prospective Observational Study.

Introduction: Lung adenocarcinoma with negative TTF-1 expression is believed to be a poor prognostic factor for certain systemic treatments. Nevertheless, the impact of TTF-1 expression on combined chemoimmunotherapy remains unclear. We aimed to investigate the relationship between tumor TTF-1 expression and the efficacy of combined chemoimmunotherapy in patients with advanced lung adenocarcinoma. Methods: This multicenter prospective observational study included 58 patients with advanced lung adenocarcinoma treated with combined chemoimmunotherapy across 10 institutions in Japan. The expression of TTF-1 in pretreatment tumors was determined using immunohistochemistry. Results: The objective response rate of combined chemoimmunotherapy was significantly higher in TTF-1-positive groups than in TTF-1-negative groups (p = 0.02). The median progression-free survival (PFS) and overall survival were significantly longer in TTF-1-positive groups than in TTF-1-negative groups (10.9 versus 5.0 mo; p = 0.01). Multivariate analysis revealed that TTF-1 expression was an independent favorable prognostic factor for PFS. Moreover, TTF-1 expression in patients with lung adenocarcinoma is significantly associated with programmed death-ligand 1 expression (p = 0.003). The TTF-1-positive group with programmed death-ligand 1 tumor proportion score greater than or equal to 50% had a significantly longer PFS than the other groups (p = 0.02). Conclusions: TTF-1 positivity is associated with better clinical outcomes in patients with advanced lung adenocarcinoma treated with combined chemoimmunotherapy.

Predictive value of p53 and AXL immunostaining for the efficacy of immune checkpoint inhibitor-based therapy after osimertinib treatment in patients with epidermal growth factor-mutant non-small cell lung cancer.

BACKGROUND: Current evidence indicates that immune checkpoint inhibitors (ICIs) have a limited efficacy in patients with lung cancer harboring epidermal growth factor receptor (EGFR) mutations. However, there is a lack of data on the efficacy of ICIs after osimertinib treatment, and the predictors of ICI efficacy are unclear. METHODS: We retrospectively assessed consecutive patients with EGFR-mutant NSCLC who received ICI-based therapy after osimertinib treatment at 10 institutions in Japan, between March 2016 and March 2021. Immunohistochemical staining was used to evaluate the expression of p53 and AXL. The deletions of exon 19 and the exon 21 L858R point mutation in EGFR were defined as common mutations; other mutations were defined as uncommon mutations. RESULTS: A total of 36 patients with advanced or recurrent EGFR-mutant NSCLC were analyzed. In multivariate analysis, p53 expression in tumors was an independent predictor of PFS after ICI-based therapy (p = 0.002). In patients with common EGFR mutations, high AXL expression was a predictor of shorter PFS and overall survival after ICI-based therapy (log-rank test; p = 0.04 and p = 0.02, respectively). CONCLUSION: The levels of p53 in pretreatment tumors may be a predictor of ICI-based therapy outcomes in patients with EGFR-mutant NSCLC after osimertinib treatment. High levels of AXL in tumors may also be a predictor of ICI-based therapy outcomes, specifically for patients with common EGFR mutations. Further prospective large-scale investigations on the predictors of ICI efficacy following osimertinib treatment are warranted.

Clinical impact of amrubicin monotherapy in patients with relapsed small cell lung cancer: a multicenter retrospective study.

Background: Topoisomerase is an essential enzyme for deoxyribonucleic acid replication, and its inhibitors suppress tumor progression. Amrubicin, a topoisomerase II inhibitor, is mainly used in the second-line treatment of patients with extensive-stage small cell lung cancer (ES-SCLC). However, the impact of different types of topoisomerase inhibitors for first-line chemotherapy on the efficacy of amrubicin remains unclear. In the present study, we aimed to evaluate the efficacy of second-line amrubicin in patients with relapsed SCLC who were previously treated with platinum-based chemotherapy, including topoisomerase I and II inhibitors. Methods: This study retrospectively analyzed patients with ES-SCLC who experienced recurrence and were treated with amrubicin at 22 institutions in Japan between April 2015 and November 2020. The progression-free survival of amrubicin monotherapy was investigated using the Kaplan-Meier method. Results: A total of 320 patients were enrolled in this study, with 59 (18%) receiving platinum plus topoisomerase I inhibitor irinotecan and 261 (82%) receiving platinum plus topoisomerase II inhibitor etoposide as first-line treatment. The progression-free survival of amrubicin was significantly longer in the irinotecan group than in the etoposide group (3.2 vs. 2.5 months; P=0.034). Conclusions: These results showed that different types of topoisomerase inhibitors could affect the efficacy of amrubicin monotherapy in the second-line treatment of patients with relapsed ES-SCLC.

A Real-World Analysis of Immune Checkpoint Inhibitor-Based Therapy After Osimertinib Treatment in Patients With EGFR-Mutant NSCLC.

Introduction: The use of immune checkpoint inhibitors (ICIs) with chemotherapy has increased the survival of patients with advanced NSCLC. Nevertheless, the efficacy of ICI treatment for NSCLC with EGFR mutations is limited. Previous studies have not evaluated the efficacy of ICI treatment after osimertinib treatment in real-world settings. Methods: This study performed a retrospective analysis of the association between clinical characteristics and ICI efficacy in patients with EGFR-mutant NSCLC treated with ICIs after osimertinib treatment at 12 institutions in Japan from March 2016 to March 2021. Results: Among 80 patients with EGFR-mutant lung cancer, 42 received ICI monotherapy and 38 received chemoimmunotherapy. In the chemoimmunotherapy group, the progression-free survival (PFS) was significantly longer in the group that exhibited PFS more than 10 months with osimertinib than in the group that exhibited PFS less than or equal to 10 months with osimertinib (8.4 mo versus 3.8 mo, p = 0.026). Nevertheless, there was no significant difference in PFS in the ICI monotherapy group (1.7 mo versus 1.5 mo, p = 0.45). Regardless of the EGFR mutation subtype, PFS of osimertinib treatment was a predictor of the PFS of chemoimmunotherapy (exon 19 deletion mutation: p = 0.03 and exon 21 L858R mutation: p = 0.001). Conclusions: The PFS of osimertinib might be a predictor of PFS of chemoimmunotherapy in patients with EGFR-mutant NSCLC. Further clinical investigations on the predictors of efficacy of administering ICIs after osimertinib treatment are required.

Pembrolizumab monotherapy for untreated PD-L1-Positive non-small cell lung cancer in the elderly or those with poor performance status: A prospective observational study.

Objectives: We investigated the efficacy and safety of pembrolizumab monotherapy as first-line treatment for poor Eastern Cooperative Oncology Group performance status (PS) and elderly patients with programmed cell death-ligand 1 (PD-L1)-positive advanced non-small cell lung cancer (NSCLC). We also investigated clinical prognostic factors for the efficacy of pembrolizumab monotherapy, based on patient characteristics. Materials and methods: In this prospective observational study, PS-2 and elderly NSCLC patients with PD-L1 tumor proportion score (TPS) ≥1% who received first-line pembrolizumab monotherapy, from October 2019 to March 2021, at 10 institutions in Japan were enrolled. Patients judged eligible by their physicians for combined chemotherapy and PD-1/PD-L1 inhibitors as first-line treatment were excluded. Clinicopathological characteristics and adverse events were investigated for correlation with clinical outcomes. Results: Forty patients were enrolled in the study. The median progression-free survival (PFS) of patients with PS 2 and those aged ≥ 75 years were 4.4 (95% confidence interval [CI]: 0.9-14.4) months and 5.3 (95% CI 2.9-9.4) months, respectively. The median overall survival (OS) of patients with PS 2 and those aged ≥ 75 years were 11.6 (95% CI: 1.4-not evaluable [NE]) months and 11.6 (95% CI 7.4-18.1) months, respectively. Immune-related adverse events (irAEs) were observed in 19 patients; 6 patients had severe irAEs of Common Terminology Criteria for Adverse Events (CTCAE) Grade 3 or higher. Patients who achieved stable disease or better, had a statistically significant increase in PFS (p < 0.001) and OS (p < 0.001). In the multivariate analysis, the acquisition of disease control with pembrolizumab monotherapy was an independent prognostic factor for PFS and OS. Conclusion: Pembrolizumab monotherapy was relatively effective and tolerable as a first-line treatment for patients with PD-L1-positive advanced NSCLC who had poor PS or were elderly. Our results suggest that disease control might be an independent prognostic factor for PFS and OS in this population. (UMIN000044052 https://center6.umin.ac.jp/cgi-open-bin/ctr_e/ctr_view.cgi?recptno=R000050176).

Prediction-Related Frontal-Temporal Network for Omission Mismatch Activity in the Macaque Monkey.

Sensory prediction is considered an important element of mismatch negativity (MMN) whose reduction is well known in patients with schizophrenia. Omission MMN is a variant of the MMN which is elicited by the absence of a tone previously sequentially presented. Omission MMN can eliminate the effects of sound differences in typical oddball paradigms and affords the opportunity to identify prediction-related signals in the brain. Auditory predictions are thought to reflect bottom-up and top-down processing within hierarchically organized auditory areas. However, the communications between the various subregions of the auditory cortex and the prefrontal cortex that generate and communicate sensory prediction-related signals remain poorly understood. To explore how the frontal and temporal cortices communicate for the generation and propagation of such signals, we investigated the response in the omission paradigm using electrocorticogram (ECoG) electrodes implanted in the temporal, lateral prefrontal, and orbitofrontal cortices of macaque monkeys. We recorded ECoG data from three monkeys during the omission paradigm and examined the functional connectivity between the temporal and frontal cortices by calculating phase-locking values (PLVs). This revealed that theta- (4-8 Hz), alpha- (8-12 Hz), and low-beta- (12-25 Hz) band synchronization increased at tone onset between the higher auditory cortex and the frontal pole where an early omission response was observed in the event-related potential (ERP). These synchronizations were absent when the tone was omitted. Conversely, low-beta-band (12-25 Hz) oscillation then became stronger for tone omission than for tone presentation approximately 200 ms after tone onset. The results suggest that auditory input is propagated to the frontal pole via the higher auditory cortex and that a reciprocal network may be involved in the generation of auditory prediction and prediction error. As impairments of prediction may underlie MMN reduction in patients with schizophrenia, an aberrant hierarchical temporal-frontal network might be related to this pathological condition.

Decoding distributed oscillatory signals driven by memory and perception in the prefrontal cortex.

Sensory perception and memory recall generate different conscious experiences. Although externally and internally driven neural activities signifying the same perceptual content overlap in the sensory cortex, their distribution in the prefrontal cortex (PFC), an area implicated in both perception and memory, remains elusive. Here, we test whether the local spatial configurations and frequencies of neural oscillations driven by perception and memory recall overlap in the macaque PFC using high-density electrocorticography and multivariate pattern analysis. We find that dynamically changing oscillatory signals distributed across the PFC in the delta-, theta-, alpha-, and beta-band ranges carry significant, but mutually different, information predicting the same feature of memory-recalled internal targets and passively perceived external objects. These findings suggest that the frequency-specific distribution of oscillatory neural signals in the PFC serves cortical signatures responsible for distinguishing between different types of cognition driven by external perception and internal memory.

Mental construction of object symbols from meaningless elements by Japanese macaques (Macaca fuscata).

When writing an object's name, humans mentally construct its spelling. This capacity critically depends on use of the dual-structured linguistic system, in which meaningful words are represented by combinations of meaningless letters. Here we search for the evolutionary origin of this capacity in primates by designing dual-structured bigram symbol systems where different combinations of meaningless elements represent different objects. Initially, we trained Japanese macaques (Macaca fuscata) in an object-bigram symbolization task and in a visually-guided bigram construction task. Subsequently, we conducted a probe test using a symbolic bigram construction task. From the initial trial of the probe test, the Japanese macaques could sequentially choose the two elements of a bigram that was not actually seen but signified by a visually presented object. Moreover, the animals' spontaneous choice order bias, developed through the visually-guided bigram construction learning, was immediately generalized to the symbolic bigram construction test. Learning of dual-structured symbols by the macaques possibly indicates pre-linguistic adaptations for the ability of mentally constructing symbols in the common ancestors of humans and Old World monkeys.

Theory of mind tested by implicit false belief: a simple and full-fledged mental state attribution.

About 40 years have passed since 'theory of mind (ToM)' research started. The false-belief test is used as a litmus test for ToM ability. The implicit false-belief test has renewed views of ToM in several disciplines, including psychology, psychiatry, and neuroscience. Many important questions have been considered via the paradigm of implicit false belief. We recently addressed the phylogenetic and physiological aspects of ToM using a version of this paradigm combined with the chemogenetic technique on Old World monkeys. We sought to create animal models for autism that exhibit behavioral phenotypes similar to human symptoms. The simultaneous manipulation of neural circuits and assessments of changes in phenotypes can help identify the causal neural substrate of ToM.

Macaques Exhibit Implicit Gaze Bias Anticipating Others' False-Belief-Driven Actions via Medial Prefrontal Cortex.

The ability to infer others' mental states is essential to social interactions. This ability, critically evaluated by testing whether one attributes false beliefs (FBs) to others, has been considered to be uniquely hominid and to accompany the activation of a distributed brain network. We challenge the taxon specificity of this ability and identify the causal brain locus by introducing an anticipatory-looking FB paradigm combined with chemogenetic neuronal manipulation in macaque monkeys. We find spontaneous gaze bias of macaques implicitly anticipating others' FB-driven actions. Silencing of the medial prefrontal neuronal activity with inhibitory designer receptor exclusively activated by designer drugs (DREADDs) specifically eliminates the implicit gaze bias while leaving the animals' visually guided and memory-guided tracking abilities intact. Thus, neuronal activity in the medial prefrontal cortex could have a causal role in FB-attribution-like behaviors in the primate lineage, emphasizing the importance of probing the neuronal mechanisms underlying theory of mind with relevant macaque animal models.

An observational study of the epidermal growth factor receptor-tyrosine kinase inhibitor resistance mechanism in epidermal growth factor receptor gene mutation-positive non-small cell lung cancer.

Non-small cell lung cancer (NSCLC) patients with epidermal growth factor receptor (EGFR) mutation show a high response to EGFR-tyrosine kinase inhibitor (EGFR-TKI). Clinically, EGFR-positive NSCLC acquires several resistance mechanisms during EGFR-TKI treatment, such as the emergence of a secondary mutation (T790M), MET gene amplification, and transformation to small cell lung cancer. However, the mechanism of resistance to afatinib, a second-generation EGFR-TKI, remains unclear. In this study, we prospectively investigate the mechanism of resistance to afatinib using proteomic analyses.In total, 35 EGFR-positive NSCLC patients of both sexes and ≥20 years old will be included. NSCLC patients with major obstacles in major organs, such as bone marrow, heart, lung, liver, and kidney, will be excluded. Eligible patients will be administered afatinib or gefitinib until disease progression and proteomic analysis will be performed with biopsy samples before treatment and at disease progression.The primary outcome is to detect the potential predictive anomalies in proteins that can be candidates for the resistance factor of afatinib. The secondary outcome is to detect gene and protein abnormalities affecting progression-free survival, response rate, and rate of disease control in afatinib therapy.The protocol was approved by the institutional review boards of Kyoto Prefectural University of Medicine and all the participating hospitals. Written informed consent was obtained from all patients before registration, in accordance with the Declaration of Helsinki. The results of the study will be disseminated via publications in peer-reviewed journals.Trial registration number is UMIN000031013.

Locally induced neuronal synchrony precisely propagates to specific cortical areas without rhythm distortion.

Propagation of oscillatory spike firing activity at specific frequencies plays an important role in distributed cortical networks. However, there is limited evidence for how such frequency-specific signals are induced or how the signal spectra of the propagating signals are modulated during across-layer (radial) and inter-areal (tangential) neuronal interactions. To directly evaluate the direction specificity of spectral changes in a spiking cortical network, we selectively photostimulated infragranular excitatory neurons in the rat primary visual cortex (V1) at a supra-threshold level with various frequencies, and recorded local field potentials (LFPs) at the infragranular stimulation site, the cortical surface site immediately above the stimulation site in V1, and cortical surface sites outside V1. We found a significant reduction of LFP powers during radial propagation, especially at high-frequency stimulation conditions. Moreover, low-gamma-band dominant rhythms were transiently induced during radial propagation. Contrastingly, inter-areal LFP propagation, directed to specific cortical sites, accompanied no significant signal reduction nor gamma-band power induction. We propose an anisotropic mechanism for signal processing in the spiking cortical network, in which the neuronal rhythms are locally induced/modulated along the radial direction, and then propagate without distortion via intrinsic horizontal connections for spatiotemporally precise, inter-areal communication.