Immune marker expression and prognosis of early breast cancer expressing HER3.

INTRODUCTION: There is a strong rationale for targeting HER3, as HER3 contributes to tumorigenesis and treatment resistance. However, the prognostic role of HER3 and their association with immunoregulatory protein expression has not been established. METHODS: The main objective of this study was to investigate the prognostic role of HER3 expression and identify immunoregulatory marker expression according to HER3 status. HER3 expression and 10 immunoregulatory protein (PD-1/PD-L1/PD-L2/IDO/TIM-3/OX40/OX40L/B7-H2/B7-H3/B7-H4) expression was identified in 320 stage I-III breast cancer patients who received curative surgery at Seoul National University Hospital in 2008. The median follow-up duration was 88.8 months. Criteria for HER3 IHC was adopted from HER2 IHC score and only those with 3 + was considered positive. RESULTS: Among 320 patients, 213 (67.2 %) had luminal A disease, 30 (9.5 %) had luminal B disease, 28 (8.8 %) had HER2-positive disease, and 46 (14.5 %) had triple negative disease. HER3 expression was shown in 153 patients (47.8 %). Tumors with HER3-expression had more immunogenic tumor microenvironment compared to HER3-negative tumor. In addition, patients with HER3 expression had favorable 5-year relapse free survival compared to HER3-negative patients (5-year RFS 92.5 % vs. 85.2 %, p = 0.038). However, in the multivariate analysis, HER3 expression was not a prognostic factor, but expression of immunoregulatory protein was a prognostic factor. CONCLUSIONS: This study identified immunoregulatory protein expression according to HER3 status in breast cancer patients. As tumor with HER3 expression have more immunogenic microenvironment, investigating combination treatment of HER3 targeting agent and immunotherapy in HER3 expressing breast cancer may be promising.

Immunomodulatory effects of trastuzumab deruxtecan through the cGAS-STING pathway in gastric cancer cells.

Although the efficacy of trastuzumab deruxtecan (T-DXd) against HER2-positive gastric cancers (GCs) has driven its clinical application, the precise mechanisms governing its immunomodulatory role remain unclear. In this study, we examined the immune-related mechanisms of action of T-DXd in GC cells. T-DXd exhibited potent antitumor effects in GC cells across diverse HER2 expression levels by inducing DNA damage and apoptosis. Activation of the DNA damage response by T-DXd led to increased PD-L1 expression. RNA-Seq analysis revealed that T-DXd modulated immune-related pathways, resulting in the upregulation of genes associated with inflammation and IFN signaling. Importantly, T-DXd activated the cGAS-STING pathway, inducing an IFN-I response in HER2-positive GC cells. Furthermore, T-DXd activated dendritic cells via the cancer cell-intrinsic cGAS-STING-IFN axis and enhanced PBMC-mediated tumor cell killing by activating CD8+ T cells. These findings provide valuable insights into the role of the cytosolic DNA sensing pathway in the action of T-DXd and offer a compelling rationale for combining T-DXd with immune checkpoint blockade therapies in GC treatment.

Clinicopathologic and molecular characterization of stages II-IV gastric cancer with Claudin 18.2 expression.

BACKGROUND: Claudin 18.2 (CLDN18.2) is a promising target for targeted therapies in gastric cancer (GC). This study investigated the prevalence of CLDN18.2 expression in patients with stages II-IV GC or gastroesophageal junction (GEJ) adenocarcinoma and its correlation with clinicopathologic features and other crucial GC biomarkers. METHODS: We enrolled 1000 patients diagnosed with stages II-IV GC after surgical treatment. Immunohistochemistry for CLDN18 (43-14A clone), PD-L1 (22C3 pharmDx), HER2, and FGFR2 was performed. CLDN18.2 positivity was defined as moderate-to-strong (2+/3+) membranous staining in ≥75% of tumor cells. CLDN18.2 expression was compared with biomarker expression, Epstein-Barr virus (EBV) association and microsatellite instability status, and clinicopathologic features. RESULT: CLDN18.2 was positive in 34.4% of the patients. CLDN18.2 positivity was significantly higher in the middle and upper thirds than in the lower third gastric location (P < .001), but there was no correlation with age, sex, or stage (P > .05). CLDN18.2 positivity was rare (2.8%) in mucinous adenocarcinoma but frequent (90.9%) in a majority of gastric carcinomas with lymphoid stroma. CLDN18.2 positivity was higher in EBV-associated (P < .001) and PD-L1-positive (PD-L1 CPS ≥ 5) GC (P = .014) but lower in HER2 positive GC (P = .005). CLDN18.2 positivity was not significantly associated with overall survival and disease-free survival. CONCLUSION: This study provides a comprehensive evaluation of CLDN18.2 status and its correlation with the clinicopathologic characteristics of patients with stages II-IV GC in Korea and with crucial biomarkers. It may be valuable for guiding future drug development, expanding treatment options, and ultimately improving patient outcomes in GC.

Harnessing Institutionally Developed Clinical Targeted Sequencing to Improve Patient Survival in Breast Cancer: A Seven-Year Experience.

Purpose: Considering the high disease burden and unique features of Asian patients with breast cancer (BC), it is essential to have a comprehensive view of genetic characteristics in this population. An institutional targeted sequencing platform was developed through the Korea Research-Driven Hospitals project and was incorporated into clinical practice. This study explores the use of targeted next-generation sequencing (NGS) and its outcomes in patients with advanced/metastatic BC in the real world. Materials and Methods: We reviewed the results of NGS tests administered to BC patients using a customized sequencing platform - FiRST Cancer Panel (FCP) - over seven years. We systematically described clinical translation of FCP for precise diagnostics, personalized therapeutic strategies, and unraveling disease pathogenesis. Results: NGS tests were conducted on 548 samples from 522 patients with BC. 97.6% of tested samples harbored at least one pathogenic alteration. The common alterations included mutations in TP53(56.2%), PIK3CA(31.2%), GATA3(13.8%), BRCA2(10.2%), and amplifications of CCND1(10.8%), FGF19(10.0%), and ERBB2(9.5%). NGS analysis of ERBB2 amplification correlated well with HER2 immunohistochemistry and in situ hybridization. RNA panel analyses found potentially actionable and prognostic fusion genes. FCP effectively screened for potentially germline pathogenic/likely pathogenic mutation. 10.3% of BC patients received matched therapy guided by NGS, resulting in a significant overall survival advantage (p=0.022), especially for metastatic BCs. . Conclusion: Clinical NGS provided multifaceted benefits, deepening our understanding of the disease, improving diagnostic precision, and paving the way for targeted therapies. The concrete advantages of FCP highlight the importance of multi-gene testing for BC, especially for metastatic conditions.

Differential effects of desvenlafaxine on hot flashes in women with breast cancer taking tamoxifen: a randomized controlled trial.

Hot flashes (HF) are a common adverse event of prolonged tamoxifen use in women with estrogen receptor-positive breast cancer, impacting psychiatric health and quality of life. While desvenlafaxine does not interact with tamoxifen, its efficacy and safety in breast cancer patients remain unstudied. This phase 3, four-week, multi-center, three-arm, parallel-group, randomized, double-blind, placebo-controlled trial investigated the efficacy and safety of desvenlafaxine for treating HF in women with breast cancer taking tamoxifen, assessing potential differential effects in patients with psychiatric and inflammatory conditions. Between December 2017 and February 2019, 57 women aged 19 or older, regularly taking tamoxifen as adjuvant therapy, experiencing moderate-to-severe HFs for more than a month, were randomized to receive desvenlafaxine 50 mg/day (D-50), desvenlafaxine 100 mg/day (D-100), or placebo for four weeks. The primary endpoint was the change rate in HF scores over four weeks, with adverse events as a secondary endpoint. Both desvenlafaxine arms demonstrated greater HF score reductions compared to placebo: D-50 (2.20 points/week, 95% CI: 0.71, 3.68) and D-100 (2.34 points/week, 95% CI: 0.92, 3.76). Notably, D-50 arm showed significantly greater efficacy in patients with depression or elevated inflammation. Desvenlafaxine offers an effective and safe treatment regimen for HF in women with breast cancer taking tamoxifen. The presence of depression and inflammation may guide optimal desvenlafaxine dosing. (Trial Registration: ClinicalTrials.gov Identifier: NCT02819921).

Differences in severity of chemotherapy-induced nausea and vomiting between neoadjuvant and adjuvant chemotherapy in patients with breast cancer: analysis of data from two prospective observational studies.

PURPOSE: We assessed the differences in chemotherapy-induced nausea and vomiting (CINV) severity in patients with breast cancer, receiving neoadjuvant chemotherapy (NAC) and adjuvant chemotherapy (AC). METHODS: CINV severity in patients on anthracycline-based NAC (n = 203) and AC (n = 79) was assessed at baseline (C0) and after the first and fourth chemotherapy using a 10-point Likert scale. Group-by-time interaction term was used to evaluate the effect of the group on changes in CIN (cCIN) and CIV (cCIV) from C0 to the follow-up periods (C1, C4). If insignificant, group effects were analyzed without the interaction term. Subgroup analysis was performed based on age 50. In statistical analyses, sociodemographic and clinical variables that differed between groups were adjusted for. RESULTS: The effect of group by follow-up period was not significant in cCIN and cCIV. The AC group showed a significantly higher change in the severity of cCIN compared to the NAC group (estimated mean = 1.133, 95% CI = 0.104-2.161, p = 0.031), but there was no difference in cCIV. In those ≤ 50 years, significant differences in cCIN severity (estimated mean = 1.294, 95% CI = 0.103-2.484, p = 0.033) were observed, but not in cCIV. In those > 50 years, neither cCIN nor cCIV differed significantly between groups. CONCLUSIONS: NAC in breast cancer patients showed less severe CIN than adjuvant chemotherapy AC, but not in those over 50. Clinicians should recognize that the severity of CIN may vary across different chemotherapy settings and adjust their management accordingly. TRIAL REGISTRATION: The clinical trial registration ( www. CLINICALTRIALS: gov ) numbers were NCT01887925 (the registration date is from June 20, 2013, to November 27, 2015) and NCT02011815 (the registration date is from December 10, 2013, to September 22, 2019).

Pragmatic nationwide master observational trial based on genomic alterations in advanced solid tumors: KOrean Precision Medicine Networking Group Study of MOlecular profiling guided therapy based on genomic alterations in advanced Solid tumors (KOSMOS)-II study protocol KCSG AL-22-09.

BACKGROUND: Next-generation sequencing (NGS) has been introduced to many Korean institutions to support molecular diagnostics in cancer since 2017, when it became eligible for reimbursement by the National Health Insurance Service. However, the uptake of molecularly guided treatment (MGT) based on NGS results has been limited because of stringent regulations regarding prescriptions outside of approved indications, a lack of clinical trial opportunities, and limited access to molecular tumor boards (MTB) at most institutions. The KOSMOS-II study was designed to demonstrate the feasibility and effectiveness of MGT, informed by MTBs, using a nationwide precision medicine platform. METHODS: The KOSMOS-II trial is a large-scale nationwide master observational study. It involves a framework for screening patients with metastatic solid tumors for actionable genetic alterations based on local NGS testing. It recommends MGT through a remote and centralized MTB meeting held biweekly. MGT can include one of the following options: Tier 1, the therapeutic use of investigational drugs targeting genetic alterations such as ALK, EGFR, ERBB2, BRAF, FH, ROS1, and RET, or those with high tumor mutational burden; Tier 2, comprising drugs with approved indications or those permitted for treatment outside of the indications approved by the Health Insurance Review and Assessment Service of Korea; Tier 3, involving clinical trials matching the genetic alterations recommended by the MTB. Given the anticipated proportion of patients receiving MGT in the range of 50% ± 3.25%, this study aims to enroll 1,000 patients. Patients must have progressed to one or more lines of therapy and undergone NGS before enrollment. DISCUSSION: This pragmatic master protocol provides a mass-screening platform for rare genetic alterations and high-quality real-world data. Collateral clinical trials, translational studies, and clinico-genomic databases will contribute to generating evidence for drug repositioning and the development of new biomarkers. TRIAL REGISTRATION: NCT05525858.

Artificial intelligence-driven drug repositioning uncovers efavirenz as a modulator of α-synuclein propagation: Implications in Parkinson's disease.

Parkinson's disease (PD) is a complex neurodegenerative disorder with an unclear etiology. Despite significant research efforts, developing disease-modifying treatments for PD remains a major unmet medical need. Notably, drug repositioning is becoming an increasingly attractive direction in drug discovery, and computational approaches offer a relatively quick and resource-saving method for identifying testable hypotheses that promote drug repositioning. We used an artificial intelligence (AI)-based drug repositioning strategy to screen an extensive compound library and identify potential therapeutic agents for PD. Our AI-driven analysis revealed that efavirenz and nevirapine, approved for treating human immunodeficiency virus infection, had distinct profiles, suggesting their potential effects on PD pathophysiology. Among these, efavirenz attenuated α-synuclein (α-syn) propagation and associated neuroinflammation in the brain of preformed α-syn fibrils-injected A53T α-syn Tg mice and α-syn propagation and associated behavioral changes in the C. elegans BiFC model. Through in-depth molecular investigations, we found that efavirenz can modulate cholesterol metabolism and mitigate α-syn propagation, a key pathological feature implicated in PD progression by regulating CYP46A1. This study opens new avenues for further investigation into the mechanisms underlying PD pathology and the exploration of additional drug candidates using advanced computational methodologies.

Comparison of atezolizumab plus bevacizumab and lenvatinib for hepatocellular carcinoma with portal vein tumor thrombosis.

BACKGROUND/AIM: Atezolizumab plus bevacizumab and lenvatinib are currently available as first-line therapy for the treatment of unresectable hepatocellular carcinoma (HCC). However, comparative efficacy studies are still limited. This study aimed to investigate the effectiveness of these treatments in HCC patients with portal vein tumor thrombosis (PVTT). METHODS: We retrospectively included patients who received either atezolizumab plus bevacizumab or lenvatinib as first-line systemic therapy for HCC with PVTT. Primary endpoint was overall survival (OS), and secondary endpoints included progressionfree survival (PFS) and disease control rate (DCR) determined by response evaluation criteria in solid tumors, version 1.1. RESULTS: A total of 52 patients were included: 30 received atezolizumab plus bevacizumab and 22 received lenvatinib. The median follow-up duration was 6.4 months (interquartile range, 3.9-9.8). The median OS was 10.8 months (95% confidence interval [CI], 5.7 to not estimated) with atezolizumab plus bevacizumab and 5.8 months (95% CI, 4.8 to not estimated) with lenvatinib (P=0.26 by log-rank test). There was no statistically significant difference in OS (adjusted hazard ratio [aHR], 0.71; 95% CI, 0.34-1.49; P=0.37). The median PFS was similar (P=0.63 by log-rank test), with 4.1 months (95% CI, 3.3-7.7) for atezolizumab plus bevacizumab and 4.3 months (95% CI, 2.6-5.8) for lenvatinib (aHR, 0.93; 95% CI, 0.51-1.69; P=0.80). HRs were similar after inverse probability treatment weighting. The DCRs were 23.3% and 18.2% in patients receiving atezolizumab plus bevacizumab and lenvatinib, respectively (P=0.74). CONCLUSION: The effectiveness of atezolizumab plus bevacizumab and lenvatinib was comparable for the treatment of HCC with PVTT.

Blood Pb levels are associated with prostate cancer prevalence among general adult males: Linking National Cancer Registry (2002-2017) and KNHANES (2008-2017) databases of Korea.

BACKGROUND: Exposure to heavy metals may increase the risk of developing prostate cancer. However, these observations are often inconsistent and not based on clinically diagnosed cases. OBJECTIVE: To investigate the association of lead (Pb), cadmium (Cd), and mercury (Hg) exposure with clinically determined prostate cancer cases among adult males in South Korea. METHODS: Metal biomonitoring data and cancer information from the general Korean population were extracted by linking National Cancer Center (NCC) cancer registration data (2002-2017) with Korea National Health and Nutrition Examination Survey (KNHANES) data (2008-2017). Among them, 46 prostate cancer cases (designated as 'all-prostate'), including 25 diagnosed after heavy metal measurement (designated as 'post-prostate'), and 93 matching controls were chosen. Logistic regression analysis was used to calculate the odds ratios (ORs) and 95% confidence intervals (CIs) between the heavy metal levels and prostate cancer. RESULTS: Post-prostate patients exhibited higher blood Pb levels than controls (median 3.1 µg/dL vs. 2.38 µg/dL, p = 0.01). For all-prostate cancer, the OR of prostate cancer increased by 2.04-fold for every doubling of Pb levels (95% CI = 1.08-3.87, p = 0.03). The OR was also significantly elevated when comparing the third quartile (Q3) to the lowest quartile (Q1), with ORs ranging from 3.38 to 7.95, depending on model (p < 0.05). Blood Pb levels maintained a positive association with inconsistent significance for post-prostate cancer patients. For Cd and Hg, no statistically significant association was established. SIGNIFICANCE: By linking two national health databases for the first time, we constructed an unbiased database of prostate cancer cases and matching controls. We found that blood Pb concentrations were associated with the risk of prostate cancer in Korean men at the current level of exposure.

Pemetrexed plus vinorelbine versus vinorelbine monotherapy in patients with metastatic breast cancer (KCSG-BR15-17): A randomized, open-label, multicenter, phase II trial.

INTRODUCTION: Metastatic breast cancer refractory to anthracycline and taxanes often shows rapid progression. The development of effective and tolerable combination regimens for these patients is needed. This phase II trial investigated the efficacy of pemetrexed plus vinorelbine in patients with metastatic breast cancer. METHODS: This randomized, open-label, phase II trial was conducted in 17 centers in Korea. Patients with advanced breast cancer who had previously been treated with anthracyclines and taxanes were randomly assigned in a 1:1 ratio to receive either vinorelbine or pemetrexed plus vinorelbine. Randomization was stratified by prior capecitabine treatment and hormone receptor status. The primary endpoint was investigator-assessed progression-free survival (PFS). Secondary endpoints included the objective response rate, overall survival, safety, and quality of life. RESULTS: Between March 2017 and August 2019, a total of 125 patients were enrolled. After a median follow-up duration of 14.1 months, 118 progression events and 88 death events had occurred. Sixty-two patients were assigned to the pemetrexed plus vinorelbine arm, and 63 were assigned to the vinorelbine arm. Pemetrexed plus vinorelbine significantly prolonged PFS compared to vinorelbine (5.7 vs. 1.5 months, p < 0.001). The combination arm had higher disease control rate (76.8% vs. 45.9%, p = 0.001) and a tendency toward longer overall survival (16.8 vs. 10.5 months, p = 0.102). Anemia was more frequent in the pemetrexed plus vinorelbine arm per cycle compared with vinorelbine (7.9% vs. 1.9%, p < 0.001), but there was no difference in the incidence of grade 3-4 neutropenia per cycle between the pemetrexed plus vinorelbine arm and the vinorelbine single arm (14.7% vs. 19.5%, p = 0.066). CONCLUSIONS: This phase II study showed that pemetrexed plus vinorelbine led to a longer PFS than vinorelbine. Adverse events of pemetrexed plus vinorelbine were generally manageable.

HER2 amplification level by in situ hybridization predicts survival outcome in advanced HER2-positive breast cancer treated with pertuzumab, trastuzumab, and docetaxel regardless of HER2 IHC results.

BACKGROUND: The role of HER2 amplification level in predicting the effectiveness of HER2-directed therapies has been established. However, its association with survival outcomes in advanced HER2-positive breast cancer treated with dual HER2-blockade remains unexplored. METHODS: This is a single-center retrospective study of patients with advanced HER2-positive breast cancer treated with first-line pertuzumab, trastuzumab, and docetaxel. The primary objective was to ascertain the relationship between treatment outcomes and the level of HER2 amplification by in situ hybridization (ISH). RESULTS: A total of 152 patients were included with a median follow-up duration of 50.0 months. Among the 78 patients who received ISH, a higher HER2/CEP17 ratio correlated significantly with longer PFS (HR 0.50, p = 0.022) and OS (HR 0.28, p = 0.014) when dichotomized by the median. A higher HER2 copy number also correlated significantly with better PFS (HR 0.35, p < 0.001) and OS (HR 0.27, p = 0.009). In multivariate analysis, the HER2/CEP17 ratio was an independent predictive factor for PFS (HR 0.66, p = 0.004) and potentially for OS (HR 0.64, p = 0.054), along with HER2 copy number (PFS HR 0.85, p = 0.004; OS HR 0.84, p = 0.049). Furthermore, the correlation between HER2 amplification level by ISH with PFS and OS was consistent across the HER2 IHC 1+/2+ and 3+ categories. CONCLUSIONS: This is the first study to report that a higher level of HER2 amplification by ISH is associated with improved PFS and OS in advanced HER2-positive breast cancer treated with dual HER2-blockade. Notably, HER2 amplification level had a predictive role regardless of IHC results. Even in patients with HER2 protein expression of 3+, treatment outcome to HER2-directed therapy was dependent on the level of HER2 gene amplification.

Longitudinal kinetics of neutralizing antibodies against circulating SARS-CoV-2 variants and estimated level of group immunity of booster-vaccinated individuals during omicron-dominated COVID-19 outbreaks in the Republic of Korea, 2022.

The coronavirus disease 2019 pandemic persisted for 3 years and is now transitioning to endemicity. We illustrated the change in group immunity induced by vaccination (monovalent vaccines) and breakthrough infections (BIs) in a healthcare worker (HCW) cohort. Five sampling points were analyzed: before the third dose and 1, 3, 5, and 8 months after the vaccination. The last two points corresponded roughly to 1 and 4 months after omicron BA.1/BA.2 BI. A semi-quantitative anti-spike binding antibody (Sab) assay and plaque reduction neutralization test (PRNT) against circulating variants were conducted. A linear regression model was utilized to deduce correlation equations. Baseline characteristics and antibody titers after the third dose were not different between 106 HCWs with or without BI (54/52). One month after the third dose, BA.1 PRNT increased with wild-type (WT), but 3 months after the third dose, it decreased more rapidly than WT PRNT. After BI, BA.1 PRNT increased robustly and waned slower than WT. A linear equation of waning kinetics was deduced between log10Sab and months, and the slope became gradual after BI. The estimated BA.5 PRNT titers at the beginning of the BA.5 outbreak were significantly higher than the BA.1 PRNT titers of the initial BA.1/BA.2 wave, which might be associated with the smaller size of the BA.5 wave. BA.1/BA.2 BI after the third dose elicited robust and broad neutralizing activity, preferentially maintaining cross-neutralizing longevity against BA.1 and BA.5. The estimated kinetics provide an overview of group immunity through the third vaccination and BA.1/BA.2 BI, correlating with the actual outbreaks. IMPORTANCE This study analyzed changes in group immunity induced by coronavirus disease 2019 (COVID-19) vaccination and BA.1/BA.2 breakthrough infections (BIs) in a healthcare worker cohort. We investigated the longitudinal kinetics of neutralizing antibodies against circulating variants and confirmed that BA.1/BA.2 BIs enhance the magnitude and durability of cross-neutralization against BA.1 and BA.5. Correlation equations between semi-quantitative anti-spike antibody and plaque reduction neutralization test titers were deduced from the measured values using a linear regression model. Based on the equations, group immunity was estimated to last up to 11 months following the third dose of the COVID-19 vaccine. The estimated group immunity suggests that the augmented immunity and flattened waning slope through BI could correlate with the overall outbreak size. Our findings could provide a better understanding to establish public health strategies against future endemicity.

Integrative analysis of risk factors for immune-related adverse events of checkpoint blockade therapy in cancer.

Immune-related adverse events (irAEs) induced by checkpoint inhibitors involve a multitude of different risk factors. Here, to interrogate the multifaceted underlying mechanisms, we compiled germline exomes and blood transcriptomes with clinical data, before and after checkpoint inhibitor treatment, from 672 patients with cancer. Overall, irAE samples showed a substantially lower contribution of neutrophils in terms of baseline and on-therapy cell counts and gene expression markers related to neutrophil function. Allelic variation of HLA-B correlated with overall irAE risk. Analysis of germline coding variants identified a nonsense mutation in an immunoglobulin superfamily protein, TMEM162. In our cohort and the Cancer Genome Atlas (TCGA) data, TMEM162 alteration was associated with higher peripheral and tumor-infiltrating B cell counts and suppression of regulatory T cells in response to therapy. We developed machine learning models for irAE prediction, validated using additional data from 169 patients. Our results provide valuable insights into risk factors of irAE and their clinical utility.

Erratum: Korean Practice Guidelines for Gastric Cancer 2022: An Evidence-based, Multidisciplinary Approach.

This corrects the article on p. 3 in vol. 23, PMID: 36750993.

Mapping the pathways of photo-induced ion migration in organic-inorganic hybrid halide perovskites.

Organic-inorganic hybrid perovskites exhibiting exceptional photovoltaic and optoelectronic properties are of fundamental and practical interest, owing to their tunability and low manufacturing cost. For practical applications, however, challenges such as material instability and the photocurrent hysteresis occurring in perovskite solar cells under light exposure need to be understood and addressed. While extensive investigations have suggested that ion migration is a plausible origin of these detrimental effects, detailed understanding of the ion migration pathways remains elusive. Here, we report the characterization of photo-induced ion migration in perovskites using in situ laser illumination inside a scanning electron microscope, coupled with secondary electron imaging, energy-dispersive X-ray spectroscopy and cathodoluminescence with varying primary electron energies. Using methylammonium lead iodide and formamidinium lead iodide as model systems, we observed photo-induced long-range migration of halide ions over hundreds of micrometers and elucidated the transport pathways of various ions both near the surface and inside the bulk of the samples, including a surprising finding of the vertical migration of lead ions. Our study provides insights into ion migration processes in perovskites that can aid perovskite material design and processing in future applications.

MECP2 duplication syndrome initially misdiagnosed as cerebral palsy: a case report.

Mutations in the X-linked methyl-CpG-binding protein 2 (MECP2) gene were first described as a cause of Rett syndrome. MECP2 duplication can cause intellectual disability, developmental delay, severe feeding difficulties, and recurrent infections. Here, we report a Korean family with MECP2 duplication syndrome, which was previously misdiagnosed as cerebral palsy. A man in his early 30 s visited our clinic with intellectual disability, speech impairment, epilepsy, and progressive spasticity. He had been previously misdiagnosed with cerebral palsy, and had received orthopedic surgeries such as musculotendinous lengthening and derotational osteotomy. After the surgeries, he received comprehensive rehabilitation. Upon carefully checking his family history, we noted that his younger brother had similar symptoms. Next-generation sequencing revealed whole exon duplication in MECP2 in both the patient and his brother; their mother also had this genetic mutation but was asymptomatic. Early diagnosis is essential for improving the success of MECP2 duplication syndrome treatment. Individuals with MECP2 duplication syndrome should be referred to specialists to manage multidisciplinary symptoms and to regularly check for complications that are common in this syndrome.

Genetic and immune microenvironment characterization of HER2-positive gastric cancer: Their association with response to trastuzumab-based treatment.

BACKGROUND: We aimed to determine the molecular and immune microenvironment characteristics of HER2-positive gastric cancer (GC) related to the patient's response to first-line trastuzumab-based treatment. METHODS: Eighty-three cases of HER2-positive advanced gastric adenocarcinoma patients treated with trastuzumab were enrolled. Targeted deep sequencing and transcriptome analysis were performed on selected 21 cases (exploration cohort) along with two post-treatment samples. The results were compared between patients progressed before 6 months (Group 2) and others (Group 1), and were validated by FISH and immunohistochemistry in total cohort. Tumor-infiltrating immune cells were evaluated using RNA sequencing data and multiplex immunohistochemistry. Progression-free survival (PFS) analysis was performed. RESULTS: Group 1 showed frequent amplification of G1/S cell cycle checkpoint-related genes and upregulated KEGG pathways related to cell proliferation. In contrast, Group 2 had more frequent EGFR, HER3, and MET amplification and higher RNA expression in immune-related KEGG pathways than Group 1. In total cohort, significant predictors of better PFS were cell cycle-related including CCNE1 amplification, Cyclin A and PLK1 overexpression, and decreased Cyclin D3 and HER3 expression (p < 0.05), or immune-related including high density of CD3- CD57+ NK cells and PD-L1 combined positive score ≥5 (p < 0.05). The best prognostic predictors were a combination of Cyclin A, Cyclin E, p21, and HER3 (p < 0.001). CONCLUSION: HER2-positive GC with favorable response to trastuzumab were characterized by cell cycle-related gene alterations and increased CD3- CD57+ NK cell infiltration. These findings would be helpful to the fine modulation of therapeutic strategies for patients with HER2-positive GC.

Recent Progress in Immunotherapy for Gastric Cancer.

Gastric cancer (GC) is the fourth leading cause of cancer-related deaths worldwide. Under the standard of care, patients with advanced GC (AGC) have a median survival time of approximately 12-15 months. With the emergence of immunotherapy as a key therapeutic strategy in medical oncology, relevant changes are expected in the systemic treatment of GC. In the phase III ATTRACTION-2 trial, nivolumab, a monoclonal anti-programmed cell death 1 (PD-1) antibody, as a third- or later-line treatment improved overall survival (OS) compared with placebo in patients with AGC. Furthermore, nivolumab in combination with 5-fluorouracil and platinum as a first-line treatment improved OS in patients with human epidermal growth factor receptor-2 (HER2)-negative AGC in the global phase III CheckMate-649 study. Another anti-PD-1 antibody, pembrolizumab, in combination with trastuzumab and cytotoxic chemotherapy as a first-line treatment, significantly improved the overall response rate in patients with HER2-positive AGC. Therefore, immune checkpoint inhibitors (ICIs) are essential components of the current treatment of GC. Subsequent treatments after ICI combination therapy, such as ICI rechallenge or combination therapy with agents having other modes of action, are being actively investigated to date. On the basis of the success of immunotherapy in the treatment of AGC, various clinical trials are underway to apply this therapeutic strategy in the perioperative and postoperative settings for patients with early GC. This review describes recent progress in immunotherapy and potential immunotherapy biomarkers for GC.