Clinical Validation of Artificial Intelligence-Powered PD-L1 Tumor Proportion Score Interpretation for Immune Checkpoint Inhibitor Response Prediction in Non-Small Cell Lung Cancer.

PURPOSE: Evaluation of PD-L1 tumor proportion score (TPS) by pathologists has been very impactful but is limited by factors such as intraobserver/interobserver bias and intratumor heterogeneity. We developed an artificial intelligence (AI)-powered analyzer to assess TPS for the prediction of immune checkpoint inhibitor (ICI) response in advanced non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: The AI analyzer was trained with 393,565 tumor cells annotated by board-certified pathologists for PD-L1 expression in 802 whole-slide images (WSIs) stained by 22C3 pharmDx immunohistochemistry. The clinical performance of the analyzer was validated in an external cohort of 430 WSIs from patients with NSCLC. Three pathologists performed annotations of this external cohort, and their consensus TPS was compared with AI-based TPS. RESULTS: In comparing PD-L1 TPS assessed by AI analyzer and by pathologists, a significant positive correlation was observed (Spearman coefficient = 0.925; P < .001). The concordance of TPS between AI analyzer and pathologists according to TPS ≥50%, 1%-49%, and <1% was 85.7%, 89.3%, and 52.4%, respectively. In median progression-free survival (PFS), AI-based TPS predicted prognosis in the TPS 1%-49% or TPS <1% group better than the pathologist's reading, with the TPS ≥50% group as a reference (hazard ratio [HR], 1.49 [95% CI, 1.19 to 1.86] v HR, 1.36 [95% CI, 1.08 to 1.71] for TPS 1%-49% group, and HR, 2.38 [95% CI, 1.69 to 3.35] v HR, 1.62 [95% CI, 1.23 to 2.13] for TPS <1% group). CONCLUSION: PD-L1 TPS assessed by AI analyzer correlates with that of pathologists, with clinical performance also being comparable when referenced to PFS. The AI model can accurately predict tumor response and PFS of ICI in advanced NSCLC via assessment of PD-L1 TPS.

Combination of acalabrutinib with lenalidomide and rituximab in relapsed/refractory aggressive B-cell non-Hodgkin lymphoma: a single-arm phase II trial.

Potential synergism between Bruton's tyrosine kinase (BTK) inhibitor and lenalidomide in treating aggressive B-cell lymphoma has been suggested. Here, the authors report a single-arm phase II clinical trial of combination of acalabrutinib, lenalidomide and rituximab (R2A) in patients with aggressive relapsed/refractory aggressive (R/R) B-cell non-Hodgkin lymphoma (NHL). The primary endpoint of this study is objective response rate (ORR), and the secondary endpoints are complete remission (CR) rate, duration of response (DoR), progression-free survival (PFS) and overall survival (OS). A total of 66 patients are enrolled mostly with diffuse large B-cell lymphoma. The ORR is 54.5% and CR rate is 31.8% meeting the primary end point. The median DoR is 12.9 months, and 1-year PFS and OS rate is 33.1% and 67.5% respectively. Adverse events (AE) are manageable with the most frequent AE being neutropenia (31.8%). Patients with MYD88 mutations, subtypes known for NF-κB activation, and high BTK expression by immunohistochemistry respond well. Overall, these results show a significant efficacy of the R2A regimen in patients with aggressive R/R B-cell NHL, with exploratory biomarkers suggesting potential associations with response. (ClinicalTrials.gov 51 identifier: NCT04094142).

Clinical Activity of TGF-ß Inhibitor Vactosertib in Combination with Imatinib in Desmoid Tumors: A Multicenter Phase Ib/II Study.

PURPOSE: The study was to determine the activity and safety of the TGF-ß inhibitor vactosertib in combination with imatinib in patients with desmoid tumors. PATIENTS AND METHODS: In this investigator-initiated, open-label, multicenter, phase Ib/II trial, patients with desmoid tumors not amenable to locoregional therapies (surgery and/or radiotherapy) or with disease progression following at least one treatment were enrolled. Participants were administered 400 mg imatinib daily in combination with vactosertib (5 days on and 2 days off, twice a day) every 28 days. In phase Ib, the vactosertib dose was set at 100 mg (level -1) and 200 mg (level 1) to determine the recommended phase II dose (RP2D). Phase II assessed the efficacy, with the primary endpoint being progression-free rate (PFR) at 16 weeks. RESULTS: No dose-limiting toxicities were observed during phase Ib; therefore RP2D was defined at doses of 400 mg imatinib daily in combination with 200 mg vactosertib. Of the 27 patients evaluated, 7 (25.9%) achieved a confirmed partial response and 19 (70.4%) were stable. The PFR at 16 weeks and 1 year were 96.3% and 81.0%, respectively. Most toxicities were mild to moderate myalgia (n = 10, 37%), anemia (n = 10, 37%), and nausea (n = 9, 33.3%). Common grade 3 to 4 toxicities included neutropenia (n = 6, 22.2%) and anemia (n = 5, 18.5%). CONCLUSIONS: The vactosertib and imatinib combination was well tolerated, with promising clinical activity in patients with progressive, locally advanced desmoid tumors. This is the first study investigating a novel target agent, a TGF-ß inhibitor, in this rare and difficult-to-treat desmoid tumor.

Case Series of Soft Tissue Sarcoma Patients with Brain Metastasis with Implications from Genomic and Transcriptomic Analysis.

PURPOSE: Brain metastasis rarely occurs in soft tissue sarcoma (STS). Here, we present five cases of STS with brain metastases with genetic profiles. MATERIALS AND METHODS: We included five patients from Seoul National University Hospital who were diagnosed with STS with metastasis to the brain. Tissue from the brain metastasis along with that from the primary site or other metastases were used for DNA and RNA sequencing to identify genetic profiles. Gene expression profiles were compared with sarcoma samples from The Cancer Genome Atlas. RESULTS: The overall survival after diagnosis of brain metastasis ranged from 2.2 to 34.3 months. Comparison of mutational profiles between brain metastases and matched primary or other metastatic samples showed similar profiles. In two patients, copy number variation profiles between brain metastasis and other tumors showed several differences including MYCL, JUN, MYC, and DDR2 amplification. Gene ontology analysis showed that the group of genes significantly highly expressed in the brain metastasis samples was enriched in the G-protein coupled receptor activity, structural constituent of chromatin, protein heterodimerization activity, and binding of DNA, RNA, and protein. Gene set enrichment analysis showed enrichment in the pathway of neuroactive ligand-receptor interaction and systemic lupus erythematosus. CONCLUSION: The five patients had variable ranges of clinical courses and outcomes. Genomic and transcriptomic analysis of STS with brain metastasis implicates possible involvement of complex expression modification and epigenetic changes rather than the addition of single driver gene alteration.

Fertility Preservation in Young Women With Breast Cancer: A Review.

Fertility preservation is a major concern in young patients diagnosed with breast cancer and planning to receive multimodality treatment, including gonadotoxic chemotherapy with or without age-related decline through long-term endocrine therapy. Most breast cancer patients undergo multimodality treatments; many short-term and long-term side effects arise during these therapies. One of the most detrimental side effects is reduced fertility due to gonadotoxic treatments with resultant psychosocial stress. Cryopreservation of oocytes, embryos, and ovarian tissue are currently available fertility preservation methods for these patients. As an adjunct to these methods, in vitro maturation or gonadotropin-releasing hormone agonist could also be considered. It is also essential to communicate well with patients in the decision-making process on fertility preservation. It is essential to refer patients diagnosed with breast cancer on time to fertility specialists for individualized treatment, which may lead to desirable outcomes. To do so, a multimodal team-based approach and in-depth discussion on the treatment of breast cancer and fertility preservation is crucial. This review aims to summarize infertility risk related to currently available breast cancer treatment, options for fertility preservation and its details, barriers to oncofertility counseling, and psychosocial issues.

Efficacy improvement in searching MEDLINE database using a novel PubMed visual analytic system: EEEvis.

PubMed is the most extensively used database and search engine in the biomedical and healthcare fields. However, users could experience several difficulties in acquiring their target papers facing massive numbers of search results, especially in their unfamiliar fields. Therefore, we developed a novel user interface for PubMed and conducted three steps of study: step A, a preliminary user survey with 76 medical experts regarding the current usability for the biomedical literature search task at PubMed; step B is implementing EEEvis, a novel interactive visual analytic system for the search task; step C, a randomized user study comparing PubMed and EEEvis. First, we conducted a Google survey of 76 medical experts regarding the unmet needs of PubMed and the user requirements for a novel search interface. According to the data of preliminary Google survey, we implemented a novel interactive visual analytic system for biomedical literature search. This EEEvis provides enhanced literature data analysis functions including (1) an overview of the bibliographic features including publication date, citation count, and impact factors, (2) an overview of the co-authorship network, and (3) interactive sorting, filtering, and highlighting. In the randomized user study of 24 medical experts, the search speed of EEEvis was not inferior to PubMed in the time to reach the first article (median difference 3 sec, 95% CI -2.1 to 8.5, P = 0.535) nor in the search completion time (median difference 8 sec, 95% CI -4.7 to 19.1, P = 0.771). However, 22 participants (91.7%) responded that they are willing to use EEEvis as their first choice for a biomedical literature search task, and 21 participants (87.5%) answered the bibliographic sorting and filtering functionalities of EEEvis as a major advantage. EEEvis could be a supplementary interface for PubMed that can enhance the user experience in the search for biomedical literature.

Therapeutic Implications of TGF-ß Pathway in Desmoid Tumor Based on Comprehensive Molecular Profiling and Clinicopathological Properties.

(1) Background: Desmoid tumors have a relatively high local failure rate after primary treatment using surgery and/or radiotherapy. Moreover, desmoid tumors recur at the primary site for many patients. An effective therapeutic strategy for the desmoid tumor is needed to maintain quality of life and prolong survival. (2) Method: First of all, we collected desmoid tumor tissues and investigated the status of protein expression for beta-catenin and alpha-SMA through immunohistochemistry. Then, we performed targeted sequencing and whole RNA sequencing. To compare the data with other cancer types, we used NGS data from sarcoma patients at Yonsei Cancer Center (YCC-sarcoma cohort, n = 48) and The Cancer Genome Atlas (TCGA, n = 9235). Secondly, we established the novel patient-derived preclinical models (n = 2) for the validation of treatment strategy. The same gene alteration of primary tissue was demonstrated. (3) Results: We discovered specific gene sets related to the TGF-ß signaling pathway. Moreover, we selected the combination treatment comprising TGF-ß inhibitor, vactosertib, and imatinib. In screening for the anti-proliferation effect, the combination treatment of TGF-ß inhibitor was more effective for tumor suppression than monotherapy. (4) Conclusion: We found preclinical indications that TGF-ß inhibitors could prove useful as a potential treatment for patients with desmoid tumors. Moreover, we could find some examples in clinical trials.

Tumor-infiltrating lymphocyte enrichment predicted by CT radiomics analysis is associated with clinical outcomes of non-small cell lung cancer patients receiving immune checkpoint inhibitors.

Background: Enrichment of tumor-infiltrating lymphocytes (TIL) in the tumor microenvironment (TME) is a reliable biomarker of immune checkpoint inhibitors (ICI) in non-small cell lung cancer (NSCLC). Phenotyping through computed tomography (CT) radiomics has the overcome the limitations of tissue-based assessment, including for TIL analysis. Here, we assess TIL enrichment objectively using an artificial intelligence-powered TIL analysis in hematoxylin and eosin (H&E) image and analyze its association with quantitative radiomic features (RFs). Clinical significance of the selected RFs is then validated in the independent NSCLC patients who received ICI. Methods: In the training cohort containing both tumor tissue samples and corresponding CT images obtained within 1 month, we extracted 86 RFs from the CT images. The TIL enrichment score (TILes) was defined as the fraction of tissue area with high intra-tumoral or stromal TIL density divided by the whole TME area, as measured on an H&E slide. From the corresponding CT images, the least absolute shrinkage and selection operator model was then developed using features that were significantly associated with TIL enrichment. The CT model was applied to CT images from the validation cohort, which included NSCLC patients who received ICI monotherapy. Results: A total of 220 NSCLC samples were included in the training cohort. After filtering the RFs, two features, gray level variance (coefficient 1.71 x 10-3) and large area low gray level emphasis (coefficient -2.48 x 10-5), were included in the model. The two features were both computed from the size-zone matrix, which has strength in reflecting intralesional texture heterogeneity. In the validation cohort, the patients with high predicted TILes (≥ median) had significantly prolonged progression-free survival compared to those with low predicted TILes (median 4.0 months [95% CI 2.2-5.7] versus 2.1 months [95% CI 1.6-3.1], p = 0.002). Patients who experienced a response to ICI or stable disease with ICI had higher predicted TILes compared with the patients who experienced progressive disease as the best response (p = 0.001, p = 0.036, respectively). Predicted TILes was significantly associated with progression-free survival independent of PD-L1 status. Conclusions: In this CT radiomics model, predicted TILes was significantly associated with ICI outcomes in NSCLC patients. Analyzing TME through radiomics may overcome the limitations of tissue-based analysis and assist clinical decisions regarding ICI.

Programmed death-ligand 1 expression level as a predictor of EGFR tyrosine kinase inhibitor efficacy in lung adenocarcinoma.

BACKGROUND: The main objective of this study was to investigate the impact of programmed death-ligand 1 (PD-L1) expression on the efficacy of epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKI) in patients with advanced non-small cell lung cancer (NSCLC). METHODS: This study analyzed 108 patients with NSCLC who had received EGFR-TKI as first-line systemic treatment at Seoul National University Bundang Hospital and Seoul National University Hospital between December 2012 and October 2018. The National Cancer Center Research Institute (NCCRI) and The Cancer Genome Atlas (TCGA) datasets were analyzed to investigate the mechanisms underlying EGFR-TKI-resistance in tumors with high PD-L1 expression. RESULTS: Among the 108 patients, 55, 37, and 16 had negative (PD-L1 Tumor proportion score <1%), weak (1-49%), and strong (≥50%) PD-L1 expression, respectively. Patients with strong PD-L1 expression had significantly shorter median progression-free survival (PFS; 7.07 months) than patients with weak (14.73 months, P<0.001) or negative (12.70 months, P=0.001) PD-L1 expression. After adjustment for covariates by Cox regression, PD-L1 expression remained a significant indicator of adverse prognosis. In EGFR-TKI-refractory patients, the frequency of T790M mutation and the PFS following treatment with third-generation EGFR-TKI and PD-1 antibody were similar in the three groups. TCGA and NCCRI database analysis showed that high PD-L1 expression in EGFR-mutated NSCLCs correlated with IL-6/JAK/STAT3 signaling and high MUC16 mutation frequency. CONCLUSIONS: Strong PD-L1 expression in tumors might be a surrogate indicator of poor response to first-line EGFR-TKIs in NSCLC patients with sensitizing EGFR mutations, and may reflect a de novo resistance mechanism involving JAK-STAT signaling.

Real-World Clinical Outcomes and Prognostic Factors for Patients with Advanced Angiosarcoma who Received Systemic Treatment.

PURPOSE: Angiosarcoma is a highly aggressive mesenchymal tumor. Although systemic chemotherapy is often considered for the inoperable or metastatic angiosarcoma, the outcome of such treatment is unsatisfactory and poorly delineated. MATERIALS AND METHODS: We reviewed electronic medical records of 75 patients with angiosarcoma who were treated with systemic chemotherapy for inoperable or metastatic disease. Patients were classified as having liver involvement if they had either primary or metastatic hepatic lesions. RESULTS: Among the patients evaluated, 51 patients (68%) were male and 24 patients (32%) had primary cutaneous angiosarcoma. Liver involvement was present in 28 patients (37.3%). A total of 59 patients received first-line weekly paclitaxel (wPac) and showed an objective response rate (ORR) of 23.7% (n=14), a median progression-free survival (mPFS) of 4.0 months (95% confidence interval [CI], 3.0 to 6.1), and a median overall survival (mOS) of 10.2 months (95% CI, 7.0 to 14.6). Among patients without liver involvement, patients receiving wPac (n=35) had significantly prolonged mPFS (5.8 months vs. 3.2 months, respectively; p=0.014) with a tendency for prolonged mOS (13.8 months vs. 11.6 months, respectively; p=0.13) than those receiving other regimens (n=12). A total of 24 patients received second- or later-line pazopanib monotherapy and showed an ORR of 16.7% (n=4), a mPFS of 2.4 months (95% CI, 1.8 to 4.3) and a mOS of 5.4 months (95% CI, 3.5 to not available). CONCLUSION: Treatment with first-line wPac and later-line pazopanib seems to provide survival benefit, especially for patients with advanced angiosarcoma without liver involvement.

Pan-cancer methylation analysis reveals an inverse correlation of tumor immunogenicity with methylation aberrancy.

Tumor immunogenicity is driven by various genomic and transcriptomic factors but the association with the overall status of methylation aberrancy is not well established. We analyzed The Cancer Genome Atlas pan-cancer database to investigate whether the overall methylation aberrancy links to the immune evasion of tumor. We created the definitions of hypermethylation burden, hypomethylation burden and methylation burden to establish the values that represent the degree of methylation aberrancy from human methylation 450 K array data. Both hypermethylation burden and hypomethylation burden significantly correlated with global methylation level as well as methylation subtypes defined in previous literatures. Then we evaluated whether methylation burden correlates with tumor immunogenicity and found that methylation burden showed a significant negative correlation with cytolytic activity score, which represent cytotoxic T cell activity, in pan-cancer (Spearman rho = - 0.37, p < 0.001) and 30 of 33 individual cancer types. Furthermore, this correlation was independent of mutation burden and chromosomal instability in multivariate regression analysis. We validated the findings in the external cohorts and outcomes of patients who were treated with immune checkpoint inhibitors, which showed that high methylation burden group had significantly poor progression-free survival (Hazard ratio 1.74, p = 0.038). Overall, the degree of methylation aberrancy negatively correlated with tumor immunogenicity. These findings emphasize the importance of methylation aberrancy for tumors to evade immune surveillance and warrant further development of methylation biomarker.

In vivo vocal fold augmentation using an injectable polyethylene glycol hydrogel based on click chemistry.

It is important to focus on urgent needs in clinics and develop optimal materials. For successful augmentation of vocal folds, the ideal filler should be injectable through a syringe, and should stably maintain its volume for a long time without toxicity. To achieve these criteria, a click chemistry-based PEG (polyethylene glycol) hydrogel was developed and applied for vocal fold augmentation in vivo. The PEG hydrogel enables fast gelation in vivo after injection and provides long-term stability. Azide- and dibenzocyclooctyne (DBCO)-modified 4-arm PEG were cross-linked by chemical conjugation via click chemistry and yielded gelation within several minutes. After subcutaneous injection into mice and rats, the PEG hydrogel showed higher stability after 1 month compared to the traditionally used calcium hydroxyapatite-carboxymethyl cellulose (CaHA-CMC) filler. In rabbit models with vocal fold paralysis, the PEG hydrogel stably fixed the paralyzed vocal fold in 4 months and minimized the glottic gap. It was an improved therapeutic result compared to CaHA-CMC, demonstrating the potential of a click chemistry-based PEG hydrogel for vocal fold therapy.

Clinical and Genomic Characteristics of Adult Diffuse Midline Glioma.

PURPOSE: The treatment outcomes and genomic profiles of diffuse midline glioma (DMG) in adult patients are rarely characterized. We performed a retrospective study to evaluate the clinicogenomic profiles of adult patients with brain DMG. MATERIALS AND METHODS: Patients aged ≥ 18 years diagnosed with brain DMG at Seoul National University Hospital were included. The clinicopathological parameters, treatment outcomes, survival, and genomic profiles using 82-gene targeted next-generation sequencing (NGS) were analyzed. The 6-month progression-free survival (PFS6) after radiotherapy and overall survival (OS) were evaluated. RESULTS: Thirty-three patients with H3-mutant brain DMG were identified. The median OS from diagnosis was 21.8 months (95% confidence interval [CI], 13.2 to not available [NA]) and involvement of the ponto-medullary area tended to have poor OS (median OS, 20.4 months [95% CI, 9.3 to NA] vs. 43.6 months [95% CI, 18.2 to NA]; p=0.07). Twenty-four patients (72.7%) received radiotherapy with or without temozolomide. The PFS6 rate was 83.3% (n=20). Patients without progression at 6 months showed significantly prolonged OS compared with those with progression at 6 months (median OS, 24.9 months [95% CI, 20.4 to NA] vs. 10.8 months [95% CI, 4.0 to NA]; p=0.02, respectively). Targeted NGS was performed in 13 patients with DMG, among whom nine (69.2%) harbored concurrent TP53 mutation. Two patients (DMG14 and DMG23) with PIK3CAR38S+E545K and KRASG12A mutations received matched therapies. Patient DMG14 received sirolimus with a PFS of 8.4 months. CONCLUSION: PFS6 after radiotherapy was associated with prolonged survival in adult patients with DMG. Genome-based matched therapy may be an encouraging approach for progressive adult patients with DMG.

Tumor immune profiles noninvasively estimated by FDG PET with deep learning correlate with immunotherapy response in lung adenocarcinoma.

Rationale: The clinical application of biomarkers reflecting tumor immune microenvironment is hurdled by the invasiveness of obtaining tissues despite its importance in immunotherapy. We developed a deep learning-based biomarker which noninvasively estimates a tumor immune profile with fluorodeoxyglucose positron emission tomography (FDG-PET) in lung adenocarcinoma (LUAD). Methods: A deep learning model to predict cytolytic activity score (CytAct) using semi-automatically segmented tumors on FDG-PET trained by a publicly available dataset paired with tissue RNA sequencing (n = 93). This model was validated in two independent cohorts of LUAD: SNUH (n = 43) and The Cancer Genome Atlas (TCGA) cohort (n = 16). The model was applied to the immune checkpoint blockade (ICB) cohort, which consists of patients with metastatic LUAD who underwent ICB treatment (n = 29). Results: The predicted CytAct showed a positive correlation with CytAct of RNA sequencing in validation cohorts (Spearman rho = 0.32, p = 0.04 in SNUH cohort; spearman rho = 0.47, p = 0.07 in TCGA cohort). In ICB cohort, the higher predicted CytAct of individual lesion was associated with more decrement in tumor size after ICB treatment (Spearman rho = -0.54, p < 0.001). Higher minimum predicted CytAct in each patient associated with significantly prolonged progression free survival and overall survival (Hazard ratio 0.25, p = 0.001 and 0.18, p = 0.004, respectively). In patients with multiple lesions, ICB responders had significantly lower variance of predicted CytActs (p = 0.005). Conclusion: The deep learning model that predicts CytAct using FDG-PET of LUAD was validated in independent cohorts. Our approach may be used to noninvasively assess an immune profile and predict outcomes of LUAD patients treated with ICB.

Design and Characterization of Phosphatidylcholine-Based Solid Dispersions of Aprepitant for Enhanced Solubility and Dissolution.

This study aimed to improve the solubility and dissolution of aprepitant, a drug with poor aqueous solubility, using a phosphatidylcholine (PC)-based solid dispersion system. When fabricating the PC-based solid dispersion, we employed mesoporous microparticles, as an adsorbent, and disintegrants to improve the sticky nature of PC and dissolution of aprepitant, respectively. The solid dispersions were prepared by a solvent evaporation technique and characterized by Fourier transform infrared spectroscopy (FTIR), differential scanning calorimetry, and X-ray powder diffraction. The FTIR results showed that aprepitant interacted with the PC carrier by both hydrogen bonds and van der Waals forces that can also be observed in the interaction between aprepitant and polymer carriers. The solid dispersions fabricated with only PC were not sufficient to convert the crystallinity of aprepitant to an amorphous state, whereas the formulations that included adsorbent and disintegrant successfully changed that of aprepitant to an amorphous state. Both the solubility and dissolution of aprepitant were considerably enhanced in the PC-based solid dispersions containing adsorbent and disintegrant compared with those of pure aprepitant and polymer-based solid dispersions. Therefore, these results suggest that our PC-based solid dispersion system is a promising alternative to conventional formulations for poorly water-soluble drugs, such as aprepitant.

A comparative study of the effect of drug hydrophobicity on nanoparticle drug delivery in vivo using two photosensitizers.

To evaluate the effect of drug hydrophobicity on nanoparticle delivery in vivo, we conducted a comparative study using different photosensitizer-loaded poly(lactic-co-glycolic acid) (PLGA) nanoparticles (NPs). Chlorin e6 (Ce6) and pheophorbide a (Pba) with similar structure but different hydrophobicity were loaded into PLGA-NPs separately. We observed release profiles and photodynamic effects in vitro from the resulting Ce6- and Pba-PLGA-NPs. After intravenous injection into SCC7 tumor-bearing mice, biodistribution and accumulation of two drugs in tumor tissue were observed by real-time fluorescence imaging. Finally, in vivo photodynamic therapy with Ce6- and Pba-PLGA-NPs provided different therapeutic results according to imaging data. The results demonstrated that drug hydrophobicity is an important factor in nanoparticle drug delivery and should be considered for efficient drug delivery in vivo.

Development of water quality criteria for arsenic to protect aquatic life based on species sensitivity distribution.

Arsenic is a hazardous environmental pollutant widely distributed globally. Arsenic toxicity is well known and it is regulated by many countries in terms of managing water quality and protecting aquatic organisms. Unfortunately, water quality criterion (WQC) to protect aquatic organisms has not been introduced in Korea yet. Thus, it is of great importance and necessity to introduce WQC to protect aquatic organisms from arsenic, as WQC play a significant role in protecting aquatic ecosystems from pollutants. Therefore, the purpose of this study is to derive arsenic water quality criterion for aquatic life in Korea. Arsenic acute toxicity tests were performed with 10 Korean native aquatic species, which belong to 7 different taxonomic groups. Based on the results of acute toxicity test and additional toxicity data from literature, the species sensitivity distribution (SSD) method was used in ecological risk assessment. The arsenic concentration of 95% protection level for aquatic life was 0.229 mg L-1 in this study. An assessment factor 3 and a background concentration 0.0004 mg L-1 were applied to the concentration value in consideration of the uncertainty of the data and the amount of arsenic natural generation. Consequently, the WQC value derived for arsenic was found to be 0.077 mg L-1. These results will serve as reference values to establish water quality criterion for the protection of aquatic life in Korea.

Clinical Application of Next-Generation Sequencing-Based Panel to BRAF Wild-Type Advanced Melanoma Identifies Key Oncogenic Alterations and Therapeutic Strategies.

Molecular profiling with next-generation sequencing (NGS) has been applied in multiple solid cancers to discover potential therapeutic targets. Here, we describe the results of a clinical NGS panel in patients with advanced melanoma. Thirty-six tumor tissues from patients with BRAF wild-type melanoma at Seoul National University Hospital (SNUH; Seoul, Republic of Korea) were collected and deep-sequenced using the SNUH FIRST-Cancer NGS panel to assess single-nucleotide variants, small insertions/deletions, copy number variations, and structural variations to estimate tumor mutation burden (TMB). We discovered 106 oncogenic alterations and most of the patients (n = 33, 92%) harbored at least one oncogenic alteration, including 2 patients who were initially diagnosed as BRAF V600E-negative but were later confirmed to be positive. Altogether, 36 samples were classified into RAS/BRAF/NF1-mutant (n = 14, 39%) or triple wild-type (n = 22, 61%) melanoma subtypes. The estimated median TMB was 8.2 mutations per Mb, ranging from 0 to 146.67 mutations per Mb. Of the 36 patients, 25 (70%) had actionable alterations with currently developed drugs, and 7 (19.4%) were enrolled in clinical trials with an RAF inhibitor, multiple receptor tyrosine kinase inhibitor, and anti-programmed cell death-1 (PD-1) antibody. TMB tended to associate with progression-free survival (PFS) of treatment with anti-PD-1/PDL-1 antibody (HR, 0.96; 95% confidence interval, 0.92-1.00; P = 0.07). High-TMB (≥13) group was associated with longer PFS than the low-TMB group (median 34.0 vs. 11.0 weeks, P = 0.04). Overall, the clinical use of a NGS panel in patients with advanced melanoma shows association with clinical outcomes and several therapeutic strategies.

Clinical insights on outcomes of corticosteroid administration in immune checkpoint inhibitor-induced pneumonitis by retrospective case series analysis.

Background: For the management of immune checkpoint inhibitor (ICI)-induced pneumonitis (ICI-pneumonitis), discontinuation of ICIs and high dose corticosteroid based on grade are generally recommended. The purpose of this study is to describe management and outcome of ICI-pneumonitis and explore what to consider when managing ICI-pneumonitis with or without corticosteroids in addition to grade. Methods: We reviewed data of 706 cancer patients who were treated with ICIs and identified radiographically proven pneumonitis. The diagnosis of ICI-pneumonitis was established after excluding alternative aetiologies either by a bronchoscopy or a thorough examination of clinical features. The evaluation of the management and outcome of pneumonitis were evaluated according to the time of corticosteroid administration. Results: ICI-pneumonitis developed in 16 patients (2.3%); nine grade 1, four grade 2 and three grade 3. Initially, 10 patients were spared from corticosteroid administration; fourpatients eventually received corticosteroid after 4 weeks of pneumonitis diagnosis due to clinical, radiographical aggravation and/or clinicians' decision. The other sixpatients never received corticosteroid and improved or remained stable radiographically. When the four and sixpatients were compared, pneumonitis grade was similar, while the latter sixpatients had a later onset from initiation of ICIs (mean 37.48 weeksvs25.45 weeks), more prior lines of chemotherapy (median 2.5 vs 1.0 lines), higher proportion of current/ex-smokers (83.3% vs 50.0%), and fewer other accompanying immune-related adverse events (50% vs 75%). Time to improvement of pneumonitis was similar between the fourpatients who received delayed corticosteroid and fivepatients who received corticosteroid within 4 weeks(3.6 vs 2.5 weeks). Conclusions: Our analyses provide clinical insights that stratification of the patients is important in managing ICI-pneumonitis. Along with ICI-pneumonitis grade, more factors associated with the outcome need to be unravelled in the future.

The efficacy of immune checkpoint inhibitors in anaplastic lymphoma kinase-positive non-small cell lung cancer.

BACKGROUND: Despite recent advances in treating non-small cell lung cancer (NSCLC) with immune checkpoint inhibitors (ICIs), their role in ALK-positive NSCLC patients is unclear. We investigated the efficacy of ICIs in patients with ALK-positive NSCLC. METHODS: Between 2011 and 2018, a total of 14 ALK-positive NSCLC patients treated with ICIs were evaluated retrospectively. Clinicopathologic features including age, PD-L1 expression, and treatment outcomes were analyzed. RNA expression level and cytolytic activity by ALK positivity were analyzed using The Cancer Genome Atlas (TCGA) and National Cancer Center Research Institute (NCCRI) data sets. RESULTS: A total of 13 patients (92.9%) received ALK inhibitors. Patients received a median of three (range 2-8) courses of therapy. The study included nine patients (64.3%) who were PD-L1-high (>50%) and four (28.6%) who were PD-L1-low (<50%). The objective response rate was 14.3% (2/14). The median progression-free survival time was 2.18 months (95% confidence interval [CI] 1.13 months-not reached [NR]). The median overall survival time was 5.67 months (95% CI 3.00 months-NR). RNA expression levels of CD274 were similar between the ALK-positive and negative groups in both TCGA and NCCRI datasets. RNA levels of CD8A in both TCGA and NCCRI data sets were nonsignificantly lower in the ALK-positive group. Cytolytic activity scores including interferon-γ-related response were lower in the ALK-positive group in the NCCRI but not TCGA dataset. CONCLUSIONS: Despite high PD-L1-positive rates, ICIs show limited efficacy in ALK-positive NSCLC. Decreased interferon-γ-related response may underlie these findings.