Standigm ASK™: knowledge graph and artificial intelligence platform applied to target discovery in idiopathic pulmonary fibrosis.

Standigm ASK™ revolutionizes healthcare by addressing the critical challenge of identifying pivotal target genes in disease mechanisms-a fundamental aspect of drug development success. Standigm ASK™ integrates a unique combination of a heterogeneous knowledge graph (KG) database and an attention-based neural network model, providing interpretable subgraph evidence. Empowering users through an interactive interface, Standigm ASK™ facilitates the exploration of predicted results. Applying Standigm ASK™ to idiopathic pulmonary fibrosis (IPF), a complex lung disease, we focused on genes (AMFR, MDFIC and NR5A2) identified through KG evidence. In vitro experiments demonstrated their relevance, as TGFß treatment induced gene expression changes associated with epithelial-mesenchymal transition characteristics. Gene knockdown reversed these changes, identifying AMFR, MDFIC and NR5A2 as potential therapeutic targets for IPF. In summary, Standigm ASK™ emerges as an innovative KG and artificial intelligence platform driving insights in drug target discovery, exemplified by the identification and validation of therapeutic targets for IPF.

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.

Mutations of TP53 and genes related to homologous recombination repair in breast cancer with germline BRCA1/2 mutations.

BACKGROUND: Germline mutations of breast cancer susceptibility gene BRCA1 and BRCA2 (gBRCA1/2) are associated with elevated risk of breast cancer in young women in Asia. BRCA1 and BRCA2 proteins contribute to genomic stability through homologous recombination (HR)-mediated double-strand DNA break repair in cooperation with other HR-related proteins. In this study, we analyzed the targeted sequencing data of Korean breast cancer patients with gBRCA1/2 mutations to investigate the alterations in HR-related genes and their clinical implications. MATERIALS AND METHODS: Data of the breast cancer patients with pathogenic gBRCA1/2 mutations and qualified targeted next-generation sequencing, SNUH FiRST cancer panel, were analyzed. Single nucleotide polymorphisms, small insertions, and deletions were analyzed with functional annotations using ANNOVAR. HR-related genes were defined as ABL1, ATM, ATR, BARD1, BRCA1, BRCA2, CDKN1A, CDKN2A, CHEK1, CHEK2, FANCA, FANCD2, FANCG, FANCI, FANCL, KDR, MUTYH, PALB2, POLE, POLQ, RAD50, RAD51, RAD51D, RAD54L, and TP53. Mismatch-repair genes were MLH1, MSH2, and MSH6. Clinical data were analyzed with cox proportional hazard models and survival analyses. RESULTS: Fifty-five Korean breast cancer patients with known gBRCA1/2 mutations and qualified targeted NGS data were analyzed. Ethnically distinct mutations in gBRCA1/2 genes were noted, with higher frequencies of Val1833Ser (14.8%), Glu1210Arg (11.1%), and Tyr130Ter (11.1%) in gBRCA1 and Arg2494Ter (25.0%) and Lys467Ter (14.3%) in gBRCA2. Considering subtypes, gBRCA1 mutations were associated with triple-negative breast cancers (TNBC), while gBRCA2 mutations were more likely hormone receptor-positive breast cancers. At least one missense mutation of HR-related genes was observed in 44 cases (80.0%). The most frequently co-mutated gene was TP53 (38.1%). In patients with gBRCA1/2 mutations, however, genetic variations of TP53 occurred in locations different from the known hotspots of those with sporadic breast cancers. The patients with both gBRCA1/2 and TP53 mutations were more likely to have TNBC, high Ki-67 values, and increased genetic mutations, especially of HR-related genes. Survival benefit was observed in the TP53 mutants of patients with gBRCA2 mutations, compared to those with TP53 wild types. CONCLUSION: Our study showed genetic heterogeneity of breast cancer patients with gBRCA1 and gBRCA2 mutations in the Korean populations. Further studies on precision medicine are needed for tailored treatments of patients with genetic diversity among different ethnic groups.

Enhancement on CT for preoperative diagnosis of metastatic lymph nodes in thyroid cancer: a comparison across experience levels.

OBJECTIVES: To investigate the diagnostic performance and interobserver agreement of quantitative CT parameters indicating strong lymph node (LN) enhancement in differentiated thyroid cancer (DTC), comparing them with qualitative analysis by radiologists of varying experience. MATERIALS AND METHODS: This study included 463 LNs from 399 patients with DTC. Three radiologists independently analyzed strong LN enhancement on CT. Qualitative analysis of strong enhancement was defined as LN cortex showing greater enhancement than adjacent muscles on the arterial phase. Quantitative analysis included the mean attenuation value (MAV) of LN on arterial phase (LNA) and venous phase (LNV), LNA normalized to the common carotid artery (NAVCCA), internal jugular vein (NAVIJV), and sternocleidomastoid muscle (NAVSCM), attenuation difference [AD; (LNA - MAVSCM)], and relative washout ratio [((LNA - LNV)/LNA) × 100]. The interobserver agreement and diagnostic performance of the quantitative and qualitative analyses were evaluated. RESULTS: Interobserver agreement was excellent for all quantitative CT parameters (ICC, 0.83-0.94) and substantial for qualitative assessment (κ = 0.61). All CT parameters except for LNV showed good diagnostic performance for metastatic LNs (AUC, 0.81-0.85). NAVCCA (0.85, 95% CI: 0.8-0.9) and AD (0.85, 95% CI: 0.81-0.89) had the highest AUCs. All quantitative parameters except for NAVIJV had significantly higher AUCs than qualitative assessments by inexperienced radiologists, with no significant difference from assessments by an experienced radiologist. CONCLUSION: Quantitative assessment of LN enhancement on arterial phase CT showed higher interobserver agreement and AUC values than qualitative analysis by inexperienced radiologists, supporting the need for a standardized quantitative CT parameter-based model for determining strong LN enhancement. CLINICAL RELEVANCE STATEMENT: When assessing strong LN enhancement in DTC, quantitative CT parameters indicating strong enhancement can improve interobserver agreement, regardless of experience level. Therefore, the development of a standardized diagnostic model based on quantitative CT parameters might be necessary. KEY POINTS: Accurate preoperative assessment of LN metastasis in thyroid cancer is crucial. Quantitative CT parameters indicating strong LN enhancement demonstrated excellent interobserver agreement and good diagnostic performance. Quantitative assessment of contrast enhancement offers a more objective model for the identification of metastatic LNs.

PWN: enhanced random walk on a warped network for disease target prioritization.

BACKGROUND: Extracting meaningful information from unbiased high-throughput data has been a challenge in diverse areas. Specifically, in the early stages of drug discovery, a considerable amount of data was generated to understand disease biology when identifying disease targets. Several random walk-based approaches have been applied to solve this problem, but they still have limitations. Therefore, we suggest a new method that enhances the effectiveness of high-throughput data analysis with random walks. RESULTS: We developed a new random walk-based algorithm named prioritization with a warped network (PWN), which employs a warped network to achieve enhanced performance. Network warping is based on both internal and external features: graph curvature and prior knowledge. CONCLUSIONS: We showed that these compositive features synergistically increased the resulting performance when applied to random walk algorithms, which led to PWN consistently achieving the best performance among several other known methods. Furthermore, we performed subsequent experiments to analyze the characteristics of PWN.

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.

Selection Criteria for Completion Thyroidectomy in Follicular Thyroid Carcinoma Using Primary Tumor Size and TERT Promoter Mutational Status.

BACKGROUND: A stepwise surgical approach with hemithyroidectomy and completion thyroidectomy was used to achieve definite characterization of follicular thyroid carcinoma (FTC). Choosing appropriate candidates for completion thyroidectomy has been controversial. OBJECTIVE: The aim of this study was to clarify the selection criteria for completion thyroidectomy using telomerase reverse transcriptase (TERT) promoter mutation. METHODS: A total of 87 FTC patients who had information about TERT promoter mutation from August 1995 to November 2020 were investigated. The cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each of the World Health Organization (WHO) 2017 classifications were calculated. RESULTS: Of the 87 patients, 8 (9.2%) had initial distant metastasis and 15 (17.2%) had persistent disease or developed structural recurrence. The threshold diameter for initial distant metastasis, disease recurrence, and cancer-specific death was 2 cm in minimally invasive FTC (MI-FTC) with mutant TERT (M-TERT) and in encapsulated angioinvasive FTC (EA-FTC) with M-TERT, while that in MI-FTC with wild-type TERT (WT-TERT) and EA-FTC with WT-TERT was 4 cm. The cumulative risk of initial distant metastasis, disease recurrence, and cancer-specific death according to primary tumor size in each WHO 2017 classification was significantly different only in patients with WT-TERT (p = 0.001, p = 0.019, and p = 0.005, respectively). CONCLUSIONS: The data suggest 2 cm as a critical threshold diameter for performance of completion thyroidectomy in MI-FTC with M-TERT and EA-FTC with M-TERT. TERT promoter mutational status can help select candidates for completion thyroidectomy.

Limitations of fine-needle aspiration and core needle biopsies in the diagnosis of tall cell variant of papillary thyroid carcinoma.

BACKGROUND: The tall cell variant papillary thyroid carcinoma (TCV-PTC) shows aggressive behaviour. Thus far, the diagnosis of TCV-PTC can only be confirmed using the postoperative specimen. This study aims to evaluate whether fine-needle aspiration (FNA) or core needle biopsy (CNB) could diagnose TCV-PTC preoperatively. METHODS: This is a retrospective cohort study. We included adult patients diagnosed with TCV-PTC or PTC with tall cell features (TCF) at final surgical pathology between January 2015 and December 2018. Preoperative histology was reviewed for six cytomorphologic features suggesting TCV-PTC in FNA or the percentage of tall cells in the CNB specimen. The postoperative pathology was also reviewed to confirm the percentage of tall cells. RESULTS: A total of 119 patients were included in this study; 35 (29%) patients with PTC with TCF served as controls. The most frequent cytomorphological feature in FNA samples of TCV-PTC was tall columnar cells, including single tombstone-like cells (70%). Among 43 TCV-PTC evaluated by FNA, 3 FNA (7%) revealed the absence of any of the six cytomorphologic features suggesting TCV-PTC. When we defined 30% of tall cells in CNB specimens as a cutoff suggesting TCV-PTC, only 16 (41%) TCV-PTCs could be preoperatively detected, and 3 (7%) TCV-PTCs did not have any tall cells. The proportion of tall cells was not associated with the postoperative percentage of tall cells. CONCLUSION: Both cytomorphologic features in FNA and the percentage of tall cells in CNB present limitations for use as accurate preoperative diagnostic tools of TCV-PTC.

Prognostic role of tumor subtype and germline BRCA mutation in advanced breast cancer patients treated with palbociclib plus endocrine therapy.

PURPOSE: Palbociclib is a cyclin-dependent kinase 4 and 6 inhibitor which shows promising effect in hormone receptor-positive breast cancer. The purpose of this study is to evaluate the real-world efficacy and toxicity of palbociclib plus endocrine therapy. METHODS: This is a retrospective study performed in two tertiary referral hospitals in Korea. Advanced breast cancer patients who were treated with 1st-line palbociclib plus endocrine therapy were enrolled. RESULTS: A total of 216 patients were included between August 2016 and May 2019. Median age was 56 (29-89) years old and 75 patients (34.7%) were premenopausal. Median progression-free survival (PFS) was 33.0 months [95% confidence interval (CI) 24.7 to 41.3] and objective response rate was 59.3%. Luminal B patients had shorter PFS (33.0 months vs. Not reached, p = 0.019) and tendency of lower ORR (58.3 vs. 62.0%, p = 0.19) compared to luminal A patients. Multivariate analysis revealed luminal B (adjusted hazard ratio 1.90, p = 0.038) and germline BRCA mutation (adjusted hazard ratio 5.57, p = 0.002) as an independent poor prognostic factor for PFS. The most common grade 3 or 4 adverse event was neutropenia (86.7%). CONCLUSION: The efficacy and toxicity of palbociclib in the real world were comparable to those of clinical trials. In addition, palbociclib with endocrine therapy was an effective treatment option for young patients. Luminal B and germline BRCA mutation were associated with inferior outcome.

Prognosis of Patients with 1-4 cm Papillary Thyroid Cancer Who Underwent Lobectomy: Focus on Gross Extrathyroidal Extension Invading Only the Strap Muscles.

BACKGROUND: This study was designed to evaluate the prognostic implication of gross extrathyroidal extension (ETE) invading the strap muscles after thyroid lobectomy in patients with 1-4 cm papillary thyroid cancer (PTC). METHODS: This retrospective cohort study included patients with 1-4 cm PTC who underwent thyroid lobectomy from 2005 to 2012. Overall, 595 patients were enrolled after excluding patients with aggressive variants of PTC, gross ETE into a major neck structure, and lateral cervical lymph node (LN) metastasis. We evaluated the risk factors for structural recurrence after lobectomy in 1-4 cm PTC. RESULTS: Seventy-eight patients (13.1%) had gross ETE invading only the strap muscles. During the median follow-up period of 7.7 years, structural recurrence was confirmed in 35 patients (5.9%). The presence of gross ETE was an independent risk factor for structural recurrence (hazard ratio 2.54, 95% confidence interval 1.19-5.44; p = 0.016). Subgroup analysis of patients with gross ETE showed that 11 and 47 patients had low- and intermediate-risk LN metastasis, respectively. A significant difference in recurrence-free survival was observed according to the degree of cervical LN metastasis (p = 0.03). Those without LN metastasis or low-risk LNs had a 75% lower risk of recurrence when compared with those with both gross ETE and intermediate-risk LNs. CONCLUSION: Gross ETE and intermediate-risk cervical LN metastasis were associated with a significantly high risk of recurrence after lobectomy in patients with 1-4 cm PTC. Completion thyroidectomy would be considered in this subgroup of patients but not in all patients with gross ETE invading only the strap muscles.

Do posttraumatic stress symptoms predict trajectories of sleep disturbance and fatigue in patients with breast cancer? A parallel-process latent growth model.

OBJECTIVE: Using a parallel-process latent growth model (LGM), this study examined whether posttraumatic stress symptoms (PTSS) are associated with the trajectory of sleep disturbance (SD) and fatigue and whether the SD trajectory mediates the PTSS-fatigue relationship. METHODS: Data were from 215 patients with breast cancer recruited from a tertiary hospital in South Korea. A self-report survey was administered at four time points during the course of adjuvant chemotherapy. RESULTS: The mean age of the participants was 46.69 (SD = 9.08) and the majority was at stage I and the average months since diagnosis was 1.33 (SD = 1.43). Unconditional parallel-process LGM indicated that SD and fatigue were positively associated with each other, both in terms of initial status and growth rate. Then, the conditional parallel-process LGM with baseline PTSS (i.e., avoidance, intrusion, and hyperarousal) as predictors were examined and anxiety, depressive symptoms and chronotype were entered as covariates in the model. Results indicated that a higher initial status and faster growth of SD were associated with a faster increase in fatigue. Greater baseline hyperarousal was directly related to a higher initial status and a slower increase in SD, and higher initial fatigue. Furthermore, a higher hyperarousal was associated with a greater initial SD, which was related to a faster increase in fatigue. Additionally, the late chronotype was related to a faster increase in fatigue through its impact on the initial SD. CONCLUSIONS: The detrimental impact of hyperarousal on the SD trajectory and fatigue suggests the need to intervene in PTSS and SD early and throughout the course of cancer treatments to prevent fatigue.

Psychiatric symptoms mediate the effect of resilience on health-related quality of life in patients with breast cancer: Longitudinal examination.

OBJECTIVE: Patients with breast cancer receiving neoadjuvant chemotherapy are at increased risk of poor health-related quality of life (HRQOL). This study examined clinical caseness on depression and anxiety mediate the relationship between resilience and HRQOL in patients with breast cancer. METHODS: A total of 193 patients with breast cancer undergoing neoadjuvant chemotherapy completed questionnaires including the Connor-Davidson Resilience Scale, Hospital Anxiety and Depression Scale (HADS), and Functional Assessment of Cancer Therapy-Breast before the first session (T0), before the start of the last session (T1), and 6 months after the end (T2) of chemotherapy. Mediation analyses using a bootstrapping method was performed. RESULTS: The indirect effect (IE) through T1 depression was significant (IE through depression = 0.043, 95% confidence interval [CI] [0.002-0.090]), while IE through T1 anxiety was not significant (IE through anxiety = 0.037, 95% CI [-0.010-0.097]) in the association between T0 resilience and T2 HRQOL. CONCLUSIONS: Clinical caseness on HADS depression subscale during chemotherapy was a mediating factor of the relationship between resilience before chemotherapy and HRQOL after chemotherapy in patients with breast cancer receiving neoadjuvant chemotherapy. Depression during chemotherapy in patients with breast cancer may be a target symptom of screening and intervention to maintain the HRQOL after chemotherapy. Also, patients with low resilience are more likely to develop depression during chemotherapy, and clinicians should carefully monitor whether depression occurs in these patients with low resilience.

Risk factors for metastasis in indeterminate lymph nodes in preoperative patients with thyroid cancer.

OBJECTIVES: To investigate the relevance of clinical and sonographic features as indicators of metastasis in indeterminate lymph node (LN), to determine possible indications for fine-needle aspiration (FNA). METHODS: Consecutive patients who underwent US-guided FNA for sonographic indeterminate LNs from differentiated thyroid carcinoma between January 2014 and December 2018 were retrospectively reviewed. Indeterminate LNs were defined as LNs which had neither an echogenic hilum nor hilar vascularity in the absence of any suspicious finding in accordance with the Korean Society of Thyroid Radiology (KSThR) guidelines. Univariate and multivariate logistic regression analyses were performed to identify significant risk factors related to malignancy of indeterminate LNs. RESULTS: Of the 236 LNs in 212 patients enrolled in this study, 67 LNs (28.3%) were metastatic. The multivariate logistic regression analysis showed that the long diameter of LNs has a negative association with metastasis in indeterminate LNs and the sonographic features of extrathyroidal extension (ETE) and nonparallel orientation of the primary tumor are associated with metastasis in indeterminate LNs. The sensitivity and positive predictive value were increased when FNA was performed for LNs with primary tumors showing ETE or nonparallel orientation than when FNA was performed for LNs larger than 5 mm (59.7% and 40.4% vs. 11.94% and 15.69%). CONCLUSIONS: The size of LNs has a negative association with metastasis in indeterminate LNs. Performing FNA for indeterminate LNs in patients whose primary tumor shows ETE or a nonparallel orientation can improve the diagnostic performance and decrease the rate of unnecessary FNA. KEY POINTS: • The size of lymph nodes was negatively related to the risk of metastasis in indeterminate lymph nodes. • Extrathyroidal extension and a nonparallel orientation of the primary tumor were suggested as sonographic features predicting metastasis in indeterminate lymph nodes. • The routine practice of FNA for large indeterminate lymph nodes detected during preoperative evaluation of thyroid cancer should be discouraged.

Ethanol ablation for the treatment of thyroglossal duct cysts: follow-up results for longer than 2 years.

OBJECTIVES: To evaluate the long-term efficacy and safety of ethanol ablation (EA) for the treatment of thyroglossal duct cysts (TGDCs). METHODS: This retrospective study included 81 consecutive patients diagnosed with and treated for symptomatic TGDCs at two institutions between Jan 2008 and Oct 2018. Preprocedural evaluation included US assessment with calculation of the TGDC volume. EA was performed under US guidance using 99% ethanol. Post-treatment follow-up was scheduled within 3 months, 6 months, and then annually. Immediate success was defined as a volume reduction ratio (VRR; ratio of the volume difference after EA to the initial TGDC volume) > 50% within 3 months. Long-term success was defined as VRR > 50% or resolution or improvement of cosmetic problems and symptoms without recurrence at last follow-up. RESULTS: Seventy-seven patients underwent EA, and outcomes were assessed in 68 patients with available follow-up data. The immediate success rate of the first EA was 81% (55/68), with a mean VRR within 3 months of 73% ± 31%. One patient (1.5%, 1/68) developed wound inflammation after the first EA. Forty-two patients were followed up for longer than 2 years. For the median follow-up of 69 months (range, 24-131 months), the long-term success rate was 83% (35/42), with a mean VRR at last follow-up of 81% ± 35%. No patients developed malignancy from the ablated TGDCs. CONCLUSIONS: EA for treatment of TGDCs achieved acceptable rates of immediate and long-term efficacy with a low complication rate, and can be considered as a first-line treatment for the management of TGDCs. KEY POINTS: • The immediate success rate of EA for the treatment of TGDCs was 81% (55/68), with a mean VRR within 3 months of 73% ± 31%. • For the median follow-up of 69 months (range, 24-131 months), the long-term success rate was 83% (35/42), with a mean VRR at last follow-up of 81% ± 35%. • No patients developed malignancy from the ablated TGDCs but one patient (1.5%, 1/68) developed wound inflammation after the first EA.

Sonographic assessment of minor extrathyroidal extension of papillary thyroid microcarcinoma involving the posterior thyroid capsule.

OBJECTIVES: This study aimed to determine sonographic features and clinical significance of minor extrathyroidal extension (ETE) to the posterior thyroid capsule in papillary thyroid microcarcinoma (PTMC) patients. METHODS: We retrospectively reviewed the records of 506 PTMC patients consisting of 151 patients with minor ETE and 355 patients without ETE. Significant clinicoradiologic features associated with ETE were identified by logistic regression analyses. The diagnostic performance of sonographic features, including the presence of capsular abutment, capsular abutment degree (< 25%, 25-50%, ≥ 50%), and protrusion, were assessed for the diagnosis of posterior minor ETE. Interobserver agreement was calculated. RESULTS: PTMC patients with posterior minor ETE were more likely to have lymphovascular invasion and lateral neck lymph node metastasis (OR = 2.636, 95%CI: 1.754, 3.963 and OR = 2.897, 95%CI: 1.069, 7.848). Regarding the diagnostic performance, the capsular abutment yielded the highest sensitivity (81.5%), followed by ≥ 25% abutment, protrusion, and ≥ 50% abutment (57.0%, 21.9%, and 4.6%, respectively), with similar levels of diagnostic accuracy (71.3-75.1%). The specificity was highest for the sonographic feature of ≥ 50% abutment (99.7%), followed by protrusion, ≥ 25% abutment, and capsular abutment (97.8%, 82.0%, and 68.7%, respectively). Abutment assessment had a moderate interobserver agreement (K = 0.705), and abutment degree and protrusion assessment had a fair and slight interobserver agreement (K = 0.553 and 0.287). CONCLUSIONS: Sonographic features of posterior capsular abutment are sensitive and reliable for diagnosis of posterior minor ETE and are associated with lymphovascular invasion and lateral neck lymph node metastasis in PTMC patients. The assessment of posterior minor ETE is important for considering candidates for active surveillance among PTMC patients. KEY POINTS: • PTMC patients with posterior minor ETE were more likely to have lymphovascular invasion and lateral neck lymph node metastasis. • Sonographic features of posterior capsular abutment are sensitive and reliable for the diagnosis of posterior minor ETE. • The assessment of posterior minor ETE is important for considering candidates for active surveillance among PTMC patients.

Thyroid-dedicated internally-cooled wet electrode for benign thyroid nodules: experimental and clinical study.

BACKGROUND: To assess the effects of radiofrequency ablation (RFA) using an internally-cooled wet (ICW) electrode in ex vivo bovine liver and evaluate the feasibility of the ICW electrode for benign thyroid nodules. METHODS: We developed an 18-gauge ICW electrode with a microhole at the distal tip for tissue infusion of chilled (0 - 4 °C) isotonic saline (rate = 1.5 ml/min). RFA using ICW and IC electrodes were performed in bovine livers (40 pairs, 1-cm active tip, 50 W, 1-min). We compared the morphological characteristics of ablation zones and presence of carbonization. Twenty patients with benign thyroid nodules larger than 5 ml were prospectively enrolled in a clinical study and underwent ultrasound-guided RFA with ICW electrodes. Ultrasound examinations, laboratory data, and symptom and cosmetic scores were evaluated preprocedure and 1 and 6 months after the procedure. RESULTS: In the ex vivo study, the ICW achieved significantly larger ablation zones than the IC (p<.001). In the clinical study, ICW electrodes were tolerable in all patients. At last follow-up, nodule volume had decreased from 15.6 ± 12.1 ml to 4.1 ± 4.3 ml (p<.001), and the mean volume reduction ratio (VRR) was 73.3 ± 13.7% at 6.0 months follow-up. Cosmetic and symptom scores were reduced from 3.52 ± 1.03 to 2.65 ± 0.88 and 3.10 ± 2.17 to 0.85 ± 0.99 (both p<.001), respectively. After RFA, thyroid function was well preserved in all patients, and mean thyroglobulin level decreased from 36.6 ± 52.1 ng/ml to 26.9 ± 62.2 ng/ml. One patient experienced a temporary voice change that recovered within a week. CONCLUSIONS: We developed a thyroid-dedicated ICW electrode that we showed to be feasible and effective in patients with benign thyroid nodules.

A safe and sustainable bacterial cellulose nanofiber separator for lithium rechargeable batteries.

Bacterial cellulose nanofiber (BCNF) with high thermal stability produced by an ecofriendly process has emerged as a promising solution to realize safe and sustainable materials in the large-scale battery. However, an understanding of the actual thermal behavior of the BCNF in the full-cell battery has been lacking, and the yield is still limited for commercialization. Here, we report the entire process of BCNF production and battery manufacture. We systematically constructed a strain with the highest yield (31.5%) by increasing metabolic flux and improved safety by introducing a Lewis base to overcome thermochemical degradation in the battery. This report will open ways of exploiting the BCNF as a "single-layer" separator, a good alternative to the existing chemical-derived one, and thus can greatly contribute to solving the environmental and safety issues.

Morning Chronotype Decreases the Risk of Chemotherapy-Induced Peripheral Neuropathy in Women With Breast Cancer.

BACKGROUND: The purpose of this longitudinal prospective cohort study was to investigate the role of chronotype in the incidence of chemotherapy-induced peripheral neuropathy (CIPN) among women with breast cancer. METHODS: We recruited women with breast cancer awaiting adjuvant chemotherapy, including four cycles of docetaxel. Participants reported peripheral neuropathy symptoms of numbness/tingling at the baseline, and at 4weeks after completion of chemotherapy. Candidate psychiatric factors associated with CIPN were assessed at the baseline, using the Composite Scale of Morningness, the Pittsburgh Sleep Quality Index, and the Hospital Anxiety and Depression Scale. To examine the association between chronotype and CIPN, we built logistic regression models, adjusting for demographic, clinical, and other psychiatric variables. RESULTS: Among 48 participants, 29 participants developed CIPN. The morning chronotype was inversely associated with CIPN (odds ratio, 0.06; confidence interval, 0.01-0.74; P = 0.028) after adjusting for age, BMI, education, type of operation, alcohol use, smoking, sleep quality, depression, and anxiety. CONCLUSION: Our results suggest that the morning chronotype is a protective factor against the development of CIPN in patients with breast cancer who were treated with docetaxel. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT01887925.

Characterization of Latilactobacillus curvatus MS2 isolated from Korean traditional fermented seafood and cholesterol reduction effect as synbiotics with isomalto-oligosaccharide in BALB/c mice.

This study investigated the properties of Latilactobacillus curvatus MS2 isolated from Korean traditional fermented seafood as probiotics and the effect of reducing cholesterol as a synbiotic with isomalto-oligosaccharide (IMO) in BALB/c mice. The isolated strain showed high resistance to acids and bile acids and exhibited a high DPPH scavenging capacity of 72.27 ± 0.38 %. In the intestinal adhesion test using HT-29 cells, the adhesion rate of MS2 was 17.10 ± 1.78 %, which was higher than the adhesion rate of the other investigated probiotics. MS2 showed good antimicrobial activity against food-borne pathogens, especially Staphylococcus aureus, S. epidermidis, Escherichia coli, and Vibrio vulnificus. This strain had high availability for IMO among the prebiotics of fructo-oligosaccharide, inulin and IMO. Oral administration of MS2 and IMO to BALB/c mice for 5 weeks resulted in a significant reduction in blood cholesterol levels by regulating liver lipid metabolism. These results suggest that the combination of MS2 and IMO has potential for application in functional foods.

Genomic profile of metastatic breast cancer patient-derived xenografts established using percutaneous biopsy.

BACKGROUND: Metastatic breast cancer (mBC) is a complex and life-threatening disease and although it is difficult to cure, patients can benefit from sequential anticancer treatment, including endocrine therapy, targeted therapy and cytotoxic chemotherapy. The patient-derived xenograft (PDX) model is suggested as a practical tool to predict the clinical outcome of this disease as well as to screen novel drugs. This study aimed to establish PDX models in Korean patients and analyze their genomic profiles and utility for translational research. METHODS: Percutaneous core needle biopsy or punch biopsy samples were used for xenotransplantation. Whole exome sequencing and transcriptome analysis were performed to assess the genomic and RNA expression profiles, respectively. Copy number variation and mutational burden were analyzed and compared with other metastatic breast cancer genomic results. Mutational signatures were also analyzed. The antitumor effect of an ATR inhibitor was tested in the relevant PDX model. RESULTS: Of the 151 cases studied, 40 (26%) PDX models were established. Notably, the take rate of all subtypes, including the hormone receptor-positive (HR +) subtype, exceeded 20%. The PDX model had genomic fidelity and copy number variation that represented the pattern of its donor sample. TP53, PIK3CA, ESR1, and GATA3 mutations were frequently found in our samples, with TP53 being the most frequently mutated, and the somatic mutations in these genes strengthened their frequency in the PDX model. The ESR1 mutation, CCND1 amplification, and the APOBEC signature were significant features in our HR + HER2- PDX model. Fulvestrant in combination with palbociclib showed a partial response to the relevant patient's tumor harboring the ESR1 mutation, and CCND1 amplification was found in the PDX model. AZD6738, an ATR inhibitor, delayed tumor growth in a relevant PDX model. CONCLUSIONS: Our PDX model was established using core needle biopsy samples from primary and metastatic tissues. Genomic profiles of the samples reflected their original tissue characteristics and could be used for the interpretation of clinical outcomes.