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Noriaki Sunaga,1,2 Kyoichi Kaira2,31Oncology Center, Gunma University Hospital, 2Department of Medicine and Molecular Science, 3Department of Oncology Clinical Development, Gunma University Graduate School of Medicine, Gunma, JapanAbstract: Epiregulin (EREG) belongs to the ErbB family of ligands. EREG binds to EGFR and ErbB4 receptor and stimulates homodimers of EGFR and ErbB4 in addition to all possible heterodimeric ErbB complexes, resulting in the activation of downstream signaling pathways. EREG is overexpressed in various human cancers and has been implicated in tumor progression and metastasis. Oncogenic activation of the MEK/ERK pathway plays a central role in the regulation of EREG expression. Non-small-cell lung cancers (NSCLCs) harboring KRAS, BRAF, or EGFR mutations overexpress EREG, and abrogation of such mutations or inhibition of MEK or ERK downregulates the expression of EREG. Elevated EREG expression in NSCLC is associated with aggressive tumor phenotypes and unfavorable prognosis, especially in oncogenic KRAS-driven lung adenocarcinomas. The finding that attenuation of EREG inhibits cell growth and induces apoptosis in KRAS-mutant and EREG-overexpressing NSCLC cell lines suggests that targeting EREG might be a treatment option for KRAS-mutant NSCLC, although further studies are necessary to elucidate its therapeutic value. These observations suggest that oncogenic mutations in the EGFR, KRAS, or BRAF genes induce EREG upregulation through the activation of MEK/ERK pathway in NSCLC cells, whereas overproduced EREG stimulates the EGFR/ErbB receptors and activates multiple downstream signaling pathways, leading to tumor progression and metastasis of these oncogene-driven NSCLCs. This paper reviews the current understanding of the oncogenic role of EREG and highlights its potential as a therapeutic target for NSCLC.Keywords: epiregulin, NSCLC, KRAS mutation, therapeutic target

The efficacy of first-line chemoradiotherapy for overall survival (OS) might be confounded by the subsequent treatments in patients with locally advanced non-small cell lung cancer (NSCLC). In this study, we assessed the associations of progression-free survival (PFS) and post-progression survival (PPS) with OS after chemoradiotherapy for locally advanced NSCLC using patient-level data.

Objective: L-[3-(18)F]-alpha-methyltyrosine ((18)F-FAMT) is an amino-acid tracer for positron emission tomography (PET), with uptake related to overexpression of L-type amino-acid transporter 1 and proliferative activity in tumour cells. This study evaluated the diagnostic performance of (18)F-FAMT PET compared with 2-[(18)F]-fluoro-2-deoxy-D-glucose ((18)F-FDG) PET in patients with multiple myeloma (MM). Methods: Eleven patients with MM (newly diagnosed, n = 3; relapsed after treatment, n = 8) underwent whole-body (18)F-FAMT and (18)F-FDG PET within a 2-week interval. Magnetic resonance imaging (MRI) of the spine was also performed to assess patterns of bone marrow infiltration. Tracer uptake was semi-quantitatively evaluated using maximal standardized uptake value (SUV(max)). Mean SUV was also determined for normal bone marrow and the aortic arch as mediastinal background SUV to calculate lesion-to-bone marrow (L/B) and lesion-to-mediastinum (L/M) ratios, respectively. Those values were statistically compared using Student's t test. Results: In 8 patients showing focal infiltration on MRI, 34 FDG-avid bone lesions were identified, with each showing increased FAMT uptake. Mean SUV(max) and L/B ratio of FDG (3.1 ± 1.2 and 3.3 ± 1.9, respectively) were significantly higher than those of FAMT (2.0 ± 1.0 and 2.6 ± 1.1, respectively; p < 0.05 each). In contrast, the L/M ratio of FDG showed no significant difference to that of FAMT (2.2 ± 1.0 and 2.4 ± 1.2, respectively; p = 0.3). Conclusions: Clear (18)F-FAMT PET uptake was seen in most (18)F-FDG-avid lesions among patients with MM, and an equivalent semi-quantitative value was obtained using L/M ratio. Our preliminary data suggest that (18)F-FAMT PET provides a useful imaging modality for detecting active myelomatous lesions. [ABSTRACT FROM AUTHOR]

Background: Positron emission tomography (PET) with fluorine-18-fluorodeoxyglucose ((18)F-FDG) has been studied in thymic epithelial tumors. We evaluated the usefulness of (18)F-FDG PET for monitoring after treatment in unresectable thymic epithelial tumors. Method: Twelve patients with unresectable/metastatic thymic epithelial tumors underwent PET study with (18)F-FDG before and after chemotherapy or radiotherapy. Response and survival were analyzed according to the ratio of the peak standardized uptake value (SUV) of the tumor to the mean SUV of the mediastinum (T/M ratio). Results: Partial response (PR) evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) was noted in 4 (33%) of 12 patients, and partial metabolic response (PMR) was observed in 6 (50%) of 12 patients. PR was observed in 4 of 6 patients with PMR. In 6 patients with any response, the T/M ratio at post-treatment was significantly lower than at baseline (p = 0.0017). In 6 patients with stable disease (SD), stable metabolic disease (SMD) was observed in 5 by use of (18)F-FDG PET. No statistically significant difference of (18)F-FDG uptake between at baseline and post-therapy was observed in 6 patients with SD (p = 0.4157) and SMD (p = 0.8419). Although the overall survival after treatment showed no statistically significant difference between PMR and SMD or progressive metabolic disease in the whole group of patients including thymoma, a statistically significant difference in the overall survival was observed between 5 patients with PMR and 5 patients with non-PMR (p = 0.0280). Conclusion: Our preliminary study suggests that (18)F-FDG PET is useful for monitoring response and outcome after treatment in unresectable thymic epithelial tumors. [ABSTRACT FROM AUTHOR]

Background. The effects of first-line chemoradiotherapy on overall survival (OS) may be confounded by subsequent lines of therapy in patients with limited-stage disease small cell lung cancer (LD-SCLC). Therefore, we aimed to determine the relationships between progression-free survival (PFS), post-progression survival (PPS) and OS after first-line chemoradiotherapy in LD-SCLC patients.

Background: Policies, such as stay home, bubbling, and stay with your community, recommending that individuals reduce contact with diverse communities, including families and schools, have been introduced to mitigate the spread of the COVID-19 pandemic. However, these policies are violated if individuals from various communities gather, which is a latent risk in a real society where people move among various unreported communities., Objective: We aimed to create a physical index to assess the possibility of contact between individuals from diverse communities, which serves as an indicator of the potential risk of SARS-CoV-2 spread when considered and combined with existing indices., Methods: Moving direction entropy (MDE), which quantifies the diversity of moving directions of individuals in each local region, is proposed as an index to evaluate a region's risk of contact of individuals from diverse communities. MDE was computed for each inland municipality in Tokyo using mobility data collected from smartphones before and during the COVID-19 pandemic. To validate the hypothesis that the impact of intercommunity contact on infection expansion becomes larger for a virus with larger infectivity, we compared the correlations of the expansion of infectious diseases with indices, including MDE and the densities of supermarkets, restaurants, etc. In addition, we analyzed the temporal changes in MDE in municipalities., Results: This study had 4 important findings. First, the MDE values for local regions showed significant invariance between different periods according to the Spearman rank correlation coefficient (>0.9). Second, MDE was found to correlate with the rate of infection cases of COVID-19 among local populations in 53 inland regions (average of 0.76 during the period of expansion). The density of restaurants had a similar correlation with COVID-19. The correlation between MDE and the rate of infection was smaller for influenza than for COVID-19, and tended to be even smaller for sexually transmitted diseases (order of infectivity). These findings support the hypothesis. Third, the spread of COVID-19 was accelerated in regions with high-rank MDE values compared to those with high-rank restaurant densities during and after the period of the governmental declaration of emergency (P<.001). Fourth, the MDE values tended to be high and increased during the pandemic period in regions where influx or daytime movement was present. A possible explanation for the third and fourth findings is that policymakers and living people have been overlooking MDE., Conclusions: We recommend monitoring the regional values of MDE to reduce the risk of infection spread. To aid in this monitoring, we present a method to create a heatmap of MDE values, thereby drawing public attention to behaviors that facilitate contact between communities during a highly infectious disease pandemic., (©Yukio Ohsawa, Yi Sun, Kaira Sekiguchi, Sae Kondo, Tomohide Maekawa, Morihito Takita, Tetsuya Tanimoto, Masahiro Kami. Originally published in JMIR Public Health and Surveillance (https://publichealth.jmir.org), 21.08.2024.)

Background/aim: Granulocyte colony-stimulating factor (G-CSF)-producing neoplasms are relatively rare; however, little is known on the clinical features of G-CSF-producing lung cancer harboring activating epidermal growth factor receptor (EGFR) mutations., Case Report: A 66-year-old female was definitively diagnosed with G-CSF-producing lung cancer that was positive for EGFR mutations. She repeatedly received epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs), such as osimertinib and afatinib. However, she developed resistance to these molecular-targeting drugs within 2 to 3 months after immediate shrinkage. Thus, the patient was treated with chemoimmunotherapy including bevacizumab, and demonstrated a slight survival benefit., Conclusion: Overall, G-CSF-producing lung cancers positive for EGFR mutations were resistant to different treatment modalities. Clinicians should be attentive to the potential resistance of G-CSF-producing EGFR mutant lung cancer to EGFR-TKI therapy., Competing Interests: The Authors have no conflicts of interest., (Copyright 2024, International Institute of Anticancer Research.)

Multiple subfields of neuroscience research are beginning to incorporate astrocytes into current frameworks of understanding overall brain physiology, neuronal circuitry, and disease etiology that underlie sleep and sleep-related disorders. Astrocytes have emerged as a dynamic regulator of neuronal activity through control of extracellular space (ECS) volume and composition, both of which can vary dramatically during different levels of sleep and arousal. Astrocytes are also an attractive target of sleep research due to their prominent role in the glymphatic system, a method by which toxic metabolites generated during wakefulness are cleared away. In this review we assess the literature surrounding glial influences on fluctuations in ECS volume and composition across the sleep-wake cycle. We also examine mechanisms of astrocyte volume regulation in glymphatic solute clearance and their role in sleep and wake states. Overall, findings highlight the importance of astrocytes in sleep and sleep research., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Sriram, Carstens, Dewing and Fiacco.)

Background and Objective: Neoadjuvant chemoimmunotherapy (NACI) is the standard of care for patients with resectable non-small cell lung cancer (NSCLC). Although the pathological complete response (pCR) after NACI reportedly exceeds 20%, an optimal predictor of pCR is yet to be established. This review aims to examine the possible predictors of pCR after NACI., Methods: We identified research article published between 2018 and 2022 in English by the PubMed database. Fifty research studies were considered as relevant article, and were examined to edit information for this narrative review., Key Content and Findings: Recently, several studies have explored potential biomarkers for the pathological response after NACI. For example, 18 F-fluorodeoxyglucose positron emission tomography ( 18 F-FDG-PET) imaging, tumor microenvironment (TME), genetic alternation such as circulating tumor DNA (ctDNA), and clinical markers such as neutrophil-to-lymphocyte ratio (NLR) and smoking signature were assessed in patients with resectable NSCLC to predict the pathological response after NACI. Based on the PET response criteria, the complete metabolic response (CMR) achieved a positive predictive value (PPV) of 71.4% for predicting pCR, and the decreasing rate of post-therapy maximum standardized uptake value (SUV max ) after NACI substantially correlated with the major pathological response (MPR). TME, as a significant marker for MPR in tumor specimens, was identified as an increase in CD8 + T cells and decrease in CD3 + T cells or Foxp3 T cells. Considering blood samples, TME comprised an increase in CD4 + PD-1 + cells or natural killer cells and a decrease in CD3 + CD56 + CTLA4 + cells, total T cells, Th cells, myeloid-derived suppressor cells (MDSCs), or regulatory T cells. Although low pretreatment levels of ctDNA and undetectable ctDNA levels after NACI were markedly associated with survival, the relationship between ctDNA levels and pCR remains elusive. Moreover, the patients with a high baseline NLR had a low incidence of pCR. Heavy smoking (>40 pack-years) was favorable for predicting pathological response., Conclusions: A reduced rate of 18 F-FDG uptake post-NACI and TME-related surface markers on lymphocytes could be optimal predictors for pCR. However, the role of these pCR predictors for NACI remains poorly validated, warranting further investigations. This review focuses on predictive biomarkers for pathological response after NACI in patients with resectable NSCLC., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tlcr.amegroups.com/article/view/10.21037/tlcr-24-142/coif). The authors have no conflicts of interest to declare., (2024 Translational Lung Cancer Research. All rights reserved.)

Objective Pembrolizumab plus platinum and pemetrexed (Pemb-Plt-PEM) combination therapy is an effective first-line treatment for advanced non-squamous non-small-cell lung cancer (NSCLC), regardless of programmed death ligand 1 expression. However, the effectiveness and feasibility of first-line Pemb-Plt-PEM therapy in elderly patients (≥75 years old) remain unclear. Therefore, this study investigated the safety and efficacy of first-line Pemb-Plt-PEM in elderly patients with nonsquamous NSCLC. Methods We retrospectively evaluated the data of patients ≥75 years old with non-squamous NSCLC who were treated with first-line Pemb-Plt-PEM from December 2018 to December 2020 at 10 institutes in Japan. Data on patient characteristics, efficacy of pemb-Plt-PEM therapy, and the type and severity of adverse events were reviewed. Results Thirty patients [20 men and 10 women; median age: 76 (range: 75-82) years old] were included in the analysis. The overall response rate, disease control rate, median progression-free survival (PFS), and median overall survival (OS) were 40.0%, 66.7%, and 7.5 and 24.0 months, respectively. The treatment-related deaths were caused by pneumonitis. First-line Pemb-Plt-PEM was associated with the PFS, based on the neutrophil-to-lymphocyte ratio (NLR). The PFS for low and high NLR values was 10.1 and 2.0 months, respectively. Furthermore, the sex and NLR influenced the association between Pemb-Plt-PEM and the OS. The OS for low and high NLR values was 32.8 and 2.6 months, respectively. Conclusion First-line pemb-Plt-PEM therapy is effective and feasible in elderly patients with non-squamous NSCLC.

Nivolumab plus ipilimumab showed promising efficacy in patients with metastatic non-small-cell lung cancer (NSCLC). The efficacy of the nivolumab plus ipilimumab combination regimen in NSCLC patients who relapse after durvalumab consolidation following concurrent chemoradiotherapy (CCRT) has not been determined. Between January 2021 and June 2022, clinical data were retrospectively extracted from the medical records of patients with NSCLC who received nivolumab plus ipilimumab after CCRT and durvalumab consolidation. A total of 30 patients were included in this analysis. The median number of durvalumab treatment cycles was 11. Median PFS and OS with nivolumab plus ipilimumab were 4.2 months (95% confidence interval [CI]: 0.7-7.7) and 18.5 months (95% CI: 3.5-33.5), respectively. The 6-month and 12-month PFS rates were 46.7% (95% CI: 28.8-64.5) and 36.4% (95% CI: 19.0-53.7). In multivariate analysis, a significant correlation was observed between a durvalumab treatment duration of 6 months or more and PFS ( p = 0.04) as well as OS ( p = 0.001). Grade 3 adverse events, including pneumonitis, dermatitis, and colitis, occurred in 10% of the patients. This study suggests that nivolumab plus ipilimumab is effective, especially in patients who have received durvalumab for 6 months or more, and tolerable for patients who relapsed after durvalumab following CCRT.