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We investigated the efficacy and safety of a trastuzumab biosimilar, Herzuma®, in combination with treatment of physician's choice (TPC) in patients with HER2+ metastatic breast cancer (MBC) who had failed at least two HER2 directed chemotherapies.

Sweet syndrome is a neutrophilic dermatosis occasionally associated with malignancies. Due to its rarity, the clinical features of Sweet syndrome are still unclear. Thus, we aimed to analyze clinical features, treatment, and outcomes of these patients according to associated disease. We conducted a retrospective, longitudinal cohort study from January 2000 to August 2020. We reviewed the medical records of 52 patients with Sweet syndrome. The median age of patients was 57.5 years old (range, 17-84), and 48.1% were female. Of the 52 patients analyzed, 27 patients (51.9%) had malignancy-associated Sweet syndrome. Sweet syndrome was diagnosed concurrently with (N = 8), before (N = 5), and after (N = 14) the diagnosis of malignancy. The idiopathic Sweet syndrome was most common in the non-malignancy group (56.0%). Myelodysplastic syndrome was the most common malignancy associated with Sweet syndrome (47.6%). Leukopenia (p = 0.005), anemia (p 0.001), and thrombocytopenia (p = 0.008) were significantly associated with malignancy. The majority of patients showed rapid improvement of symptoms after steroid administration. The symptoms of some patients with malignancy did not improve with steroid alone; however, their symptoms often improved when steroids were combined with a treatment for the associated malignancy. Relapse and aggravation of Sweet syndrome were common in the malignancy group. Sweet syndrome showed a broad spectrum of clinical features related to various diseases. Sweet syndrome often occurred as a paraneoplastic feature. Therefore, active systemic evaluation is needed in the first diagnosis of Sweet syndrome without clear etiology.

Background: Prognosis of patients with HER-2 positive metastatic breast cancer (MBC) has been revolutionized with the development of monoclonal antibodies targeting HER-2 and antibody-drug conjugate, but resistance to anti-HER-2 therapy is inevitable ultimately. PI3K-AKT-mTOR pathway aberration is known to be one of the key resistance mechanisms. BR18-13(KM-10A) study is a phase 2 clinical trial evaluating efficacy and safety of Herzuma® (trastuzumab biosimilar) plus Gedatolisib (dual PI3K/mTORC inhibitor) in patients with HER-2 positive MBC who progressed after multiple lines of therapy. Methods: Patients with HER-2 positive MBC with known PIK3CA pathologic mutation or amplification whose disease progressed after more than 2 HER-2 directed therapy were enrolled in the study. They received Herzuma® (8mg/kg IV for 1st cycle loading dose, and then 6mg/kg IV every 3 weeks) plus Gedatolisib (180mg on D1, 8, 15 of every 21 days). We evaluated efficacy of the combination treatment as interim analysis. The data cutoff of this interim analysis was June 8, 2021. Results: 17 patients were enrolled and followed for a median of 6.2 months. At data cutoff, 17 patients were eligible for response assessment. All patients were confirmed to have pathologic PIK3CA aberrations: 9 kinase mutations (H1047X), 5 helical mutations (E545X), 2 other point mutations, and 1 amplification. Overall, response rate was 64.7% and disease control rate was 82.4%. Eleven patients reached partial response (PR) as their best response, three were stable disease (SD), and three had progressive disease (PD). Two patients who have reached PR remain on investigational treatment until the data cutoff point, and the longest one is on treatment for 12.0 months. The median progression-free survival assessed in data cutoff time was 5.9 months. One patient ended treatment due to CNS disease progression, but her visceral metastatic lesions were decreased with experimental treatment. No fatal adverse events related to trial medication were reported. Conclusion: In this phase 2 study, Trastuzumab biosimilar plus Gedatolisib presented 64.7% of response rate with manageable toxicity in patients with HER-2 positive MBC with PIK3CA mutation. Clinical trial information: NCT03698383 Acknowledgement: this research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &Welfare, Republic of Korea (Grant number: HI17C2206). Citation Format: Ju Won Kim, Hee Kyung Ahn, Jong Gwon Choi, Yee Soo Chae, Gyeong-Won Lee, Keon Uk Park, Eunmi Lee, Sung Hoon Sim, Jee Hyun Kim, Yeon Hee Park, Miso Kim, Jin Hyun Park, Jeong Eun Kim, Han Jo Kim, Mi Sun Ahn, So Yeon Oh, Min Hwan Kim, Su-Jin Koh, Kyoung Eun Lee, Myoung Joo Kang, Jae Ho Byun, Joo Young Ha, Jung Hye Kwon, Joo Young Jung, Su Ee Lee, Inhae Park, Kyong Hwa Park. Phase II study of trastuzumab biosimilar (Herzuma®) plus gedatolisib in patients with HER-2 positive metastatic breast cancer who progressed after 2 or more HER-2 directed chemotherapy (BR 18-13, KM-10A): Interim analysis [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P5-16-03.

Biliary tract cancers are rare, with a poor patient prognosis. Leptin and programmed death-ligand 1 (PD-L1) influence CD8Immunohistochemistry for leptin signaling-related proteins (leptin, leptin receptor, pSTAT3, extracellular-regulated kinase, mammalian target of rapamycin), PD-L1, CD8, and FOXP3 and in situ hybridization for Epstein-Barr virus-encoded small RNAs were performed in 147 cases of surgically-resected biliary tract cancers.Immune cell PD-L1-positivity, tumor size 3 cm, adjuvant chemotherapy, no recurrence, and early-stage tumors were correlated with better 5-year survival in the tumoral PD-L1The prognostic implication of the variables may depend upon tumoral protein expression and the anatomical site. Immune cell PD-L1-positivity and the administration of adjuvant chemotherapy may indicate the favorable survival of patients with surgically-resected biliary tract cancers, specifically, in the tumoral PD-L1

To investigate the difference in time-to-fusion between two sets of interbody fusion criteria (absence of peri-graft radiolucency vs. trabecular bone bridging), and to determine the effect of osteoporosis on time-to-fusion.This retrospective study enrolled 79 patients treated for degenerative disease with one-level transforaminal lumbar interbody fusion from February 2012 to December 2018, and who had both pre- and post-operative CTs. Patients were divided into osteoporosis, osteopenia, and normal groups based on L1 vertebral body attenuation values in pre-operative CT with cutoff of 90 Hounsfield units (HU) and 120 HU. The osteoporosis, osteopenia, and normal groups included 36 patients (mean age: 69.9 years; 8 men and 28 women), 18 patients (mean age: 62.6 years; 7 men and 11 women), and 25 patients (mean age: 56.6 years; 15 men and 10 women), respectively. Fusion was assessed annually on post-operative CT images using absence of peri-graft radiolucency and trabecular bone bridging criteria. Time-to-fusion was estimated using the Kaplan-Meier method, and differences between the groups were examined using the log-rank test. Cox proportional hazards regression was performed.Time-to-fusion took significantly longer in the osteoporosis group in both fusion criteria (0.5 years in normal vs. 2 years in osteopenia vs. 3 years in osteoporosis for absence of peri-graft radiolucency; p = 0.003, and 3 years vs. 4 years vs. 5 years for trabecular bone bridging; p = 0.001). Only osteoporosis grouping was independent risk factor for slow trabecular bone fusion (hazard ratio:0.339; p = 0.003).The median time to fusion was significantly longer when using trabecular bone bridging criteria than absence of peri-graft radiolucency criteria.

Herein, a water-accelerated, N-heterocyclic carbene (NHC)-catalyzed aza-Michael addition reaction was reported to access β-aminosulfonyl fluorides, which are key hubs of the sulfur(VI) fluoride exchange (SuFEx) reaction. As a crucial reaction medium, water considerably enhanced the reaction rate with excellent chemo- and site-selectivity (up to99 : 1) compared to conventional solvents. In addition, the late-stage ligation of bioactive molecules with the aliphatic β-amino SuFEx hub was demonstrated. Mechanistic studies on experimental, analytical, and computational approaches support noncovalent activation over NHC catalysis "on-water".

β-Sulfido sulfonyl fluoride and its derivatives have been gaining attention recently in the fields of medicinal chemistry and material science. The conventional method for the synthesis of functionalized alkyl sulfonyl fluorides requires several chemical transformations. Therefore, a direct establishment of such chemical structures remains challenging, and an efficient catalytic approach is highly desired. Herein a significant "on-water" hydrophobic amplification was achieved, enabling a high-turnover catalytic thia-Michael addition to produce unprecedented β-arylated-β-sulfido sulfonyl fluorides. Amounts as low as 100 ppm (0.01 mol %) of the phosphazene superbase were sufficient to successfully catalyze the reaction with excellent chemo-/site-selectivity and with optimal functional group tolerance. Several β-arylated ethene sulfonyl fluorides were converted into thia-Michael adducts up to99 % yields. The mild conditions, high turnover, neutral pH, and scalability of the sustainable catalytic process benefit the preparation of potential pharmaceuticals (e. g., polyisoprenylated methylated protein methyl esterase inhibitors) and organic materials (e. g., electrolyte additives).

A tetrasubstituted carbon atom connected by three sp3 or sp2-carbons with single nitrogen, i.e., the α-tertiary amine (ATA) functional group, is an essential structure of diverse naturally occurring alkaloids and pharmaceuticals. The synthetic approach toward ATA structures is intricate, therefore, a straightforward catalytic method has remained a substantial challenge. Here we show an efficient water-accelerated organocatalytic method to directly access ATA incorporating homoallylic amine structures by exploiting readily accessible general ketones as useful starting material. The synergistic action of a hydrophobic Brønsted acid in combination with a squaramide hydrogen-bonding donor under aqueous condition enabled the facile formation of the desired moiety. The developed exceptionally mild but powerful system facilitated a broad substrate scope, and enabled efficient multi-gram scalability.

Background: Prognosis of patients with HER-2 positive metastatic breast cancer (MBC) has been revolutionized with the development of dual antibodies targeting HER-2 and antibody-drug conjugate, but resistance to anti-HER-2 therapy is inevitable ultimately. PI3K-AKT-mTOR pathway aberration is known to be one of the resistance mechanisms. This randomized phase 2 pilot study evaluated safety and efficacy of Herzuma® (trastuzumab biosimilar) plus Gedatolisib (dual PI3K/mTORC inhibitor) in patients with HER-2 positive MBC who progressed after multiple lines of therapy. Methods: Patients with HER-2 positive MBC with known PIK3CA pathologic mutation or amplification whose disease progressed after more than two HER-2 directed therapy were enrolled in the study. They received Herzuma® (8mg/kg IV for 1st cycle loading dose, and then 6mg/kg IV every 3 weeks) plus Gedatolisib (180mg on D1, 8, 15 of every 21 days). We evaluated efficacy of the combination treatment as interim analysis. The data cutoff of this interim analysis was Aug 4, 2020. Results: As a pilot study, 15 patients were enrolled and followed for a median of 2.3 months. At data cutoff, 11 patients were eligible for response assessment. All patients were confirmed to have pathologic PIK3CA aberrations: H1047R, H1047L, E542Q, E542K, E453K, N345K, and PIK3CA amplification. Five patients reached partial response (PR) as their best response, three were stable disease (SD), and three had progressive disease (PD). All patients who have reached PR remain on investigational treatment at the data cutoff point, and the longest one is on treatment for 7.8 months. One of the SD patients ended treatment due to disease progression, and the other two have been undergoing treatment. Overall, response rate was 45.5% and disease control rate was 72.7%. No fatal adverse events related to trial medication were reported. Conclusion: In this phase 2 pilot study, Trastuzumab biosimilar plus Gedatolisib presented 45.5% of response rate with manageable toxicity in patients with HER-2 positive MBC with PIK3CA aberration. Clinical trial information: NCT03698383 Acknowledgement: this research was supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health &Welfare, Republic of Korea (Grant number: HI17C2206). Citation Format: Ju Won Kim, Hee Kyung Ahn, Jong Gwon Choi, Yee Soo Chae, Gyeong Won Lee, Keon Uk Park, Eun Mi Lee, Sung Hoon Sim, Jee Hyun Kim, Yeon Hee Park, Mi So Kim, Jin Hyun Park, Jeong Eun Kim, Han Jo Kim, Mi Sun Ahn, So Yeon Oh, Min Hwan Kim, Su-Jin Koh, Kyoung Eun Lee, Myoung Joo Kang, Jae Ho Byun, Joo young Ha, Jung Hye Kwon, Joo Young Jung, Su Ee Lee, In Hae Park, Kyong Hwa Park. Phase II pilot study of trastuzumab biosimilar (herzuma®) plus gedatolisib in patients with HER-2 positive metastatic breast cancer who progressed after 2 or more HER-2 directed chemotherapy [KM-10A/KCSG18-13 interim analysis] [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS11-39.

Purpose The 21-gene recurrence score (RS) assay is currently used for predicting chemotherapeutic benefits for hormone receptor-positive (HR +) early-stage breast cancer patients without consideration regarding racial differences in that predictive value. This study aimed at demonstrating racial differences in the predictive values of the 21-gene RS assay. Methods The study cohort was selected from the Surveillance, Epidemiology, and End Results (SEER) database. Breast cancer-specific mortality (BCSM) was compared between patients who received chemotherapy (the “CTx group”) and those who did not (the “no CTx group”) to estimate the predictive value of the assay. This comparison was repeated for each racial group. Results Among 88,498 T1 − 2N0 HR + breast cancer patients who had results of 21-gene RS, 13,123 patients had RS > 25, which included 10,697 Whites, 1282 Blacks, and 1,144 Asian Americans/Pacific Islanders (AAPIs). Chemotherapy was administered to 8364 patients (63.4%). The adjusted hazard ratio for BCSM in the CTx group (vs. no CTx group) was 0.734 (95% confidence interval [CI] 0.588–0.917) in Whites, 0.748 (95% CI 0.428–1.307) in Blacks, and 1.343 (95% CI 0.558–3.233) in AAPIs. No subgroup within patients with RS > 25 among non-White women showed a significant predictive value of the 21-gene RS assay, except for Black women with grade 3 tumors. Conclusion The predictive value of the 21-gene RS assay for assessing chemotherapy benefit was validated in White women based on the SEER database, although the predictive value was not warranted in non-White women.

To determine the long-term prognostic role of hormone receptor subtype in breast cancer using surveillance, epidemiology, and end results (SEER) database. Data of 810,587 female operable invasive breast cancer patients from SEER database with a mean follow-up period of 94.2 months (range, 0–311 months) were analyzed. Hormone receptor subtype was classified into four groups based on estrogen receptor (ER) and progesterone receptor (PR) statuses: ER(+)/PR(+), ER(+)/PR(−), ER(−)/PR(+), and ER(−)/PR(−). Numbers of subjects with ER(+)/PR(+), ER(+)/PR(−), ER(−)/PR(+), ER(−)/PR(−), and unknown were 496,279 (61.2%), 86,858 (10.7%), 11,545 (1.4%), 135,441 (16.7%), and 80,464 (9.9%), respectively. The ER(+)/PR(+) subtype showed the best breast-cancer-specific survival, followed by ER(+)/PR(−), ER(−)/PR(+), and ER(−)/PR(−) subtypes in the respective order (all p

Background In locally advanced or metastatic biliary tract cancer (BTC), second-line chemotherapy is challenging after progression from first-line gemcitabine/cisplatin. This study evaluated whether irinotecan/5-fluorouracil (5-FU; mFOLFIRI) was superior to oxaliplatin/5-FU (mFOLFOX) as a second-line treatment in BTC. Patients and methods Patients diagnosed with BTC with disease progression after prior gemcitabine/cisplatin were randomised (1:1) to either mFOLFOX (control arm) or mFOLFIRI (experimental arm). Randomisation was stratified by tumour location (intrahepatic versus extrahepatic versus gallbladder versus ampulla of Vater) and ECOG performance status (0, 1 versus 2). The primary endpoint was the overall survival (OS) rate at 6 months. Results In total, 120 patients were enrolled and 118 patients were randomised (mFOLFOX n = 59, mFOLFIRI n = 59). The baseline characteristics were well balanced between the two arms. The tumour location was intrahepatic bile duct in 48 patients (40.7%), extrahepatic bile duct in 29 patients (24.6%), gallbladder in 35 patients (29.7%) and ampulla of Vater in 6 patients (5.1%). At a median follow-up duration of 25.8 months, the 6-month OS rate was 54.1% in mFOLFOX and 44.1% in mFOLFIRI (p = 0.677). The median OS was 6.3 months (95% CI, 4.4–8.2) in mFOLFOX and 5.7 months (95% CI, 4.7–6.7) in mFOLFIRI (p = 0.677). The median progression-free survival was 2.8 months (95% CI, 2.3–3.3) in mFOLFOX and 2.1 months (95% CI, 1.1–3.1) in mFOLFIRI (p = 0.974). Of the 101 evaluable patients, the objective response rate and disease control rate were 5.9% and 66.7% in mFOLFOX and 4.0% and 64.0% in mFOLFIRI (p = 0.663 and p = 0.778, respectively). Peripheral neuropathy (37.5% versus 5.2%) and thrombocytopenia (35.7% versus 15.5%) in mFOLFOX and vomiting (19.0% versus 1.8%) and cholangitis (10.3% versus 0.0%) in mFOLFIRI occurred more frequently. No chemotherapy-related death was reported. Conclusion In the second-line treatment of BTC, mFOLFIRI was not superior to mFOLFOX. However, mFOLFIRI was tolerable and showed comparable efficacy to mFOLFOX. Adverse events were different between the two arms. ClinicalTrials.gov Identifier NCT03464968

We aimed to compare the health-related quality of life and health behaviors of acute leukemia (AL) survivors with that of the general population from two cohorts. AL survivors (n = 149) completed a set of questionnaires to evaluate quality of life, mental status, and health behaviors. AL survivors had more physical and mental difficulties (problems with usual activities, 15% vs. 5%, p

Background/Aims The role of [18F]-f luorodeoxyglucose positron emission tomography-computed tomography (PET/CT) in patients with diffuse large B-cell lymphoma (DLBCL) in first remission is unclear. Methods Medical costs within the first 3 years of treatment completion and clinical outcomes of 118 patients with DLBCL in first remission with and without surveillance PET/CT (PET/CT [+] group [n = 76] and PET/CT [–] group [n = 42], respectively) were retrospectively analyzed. Results In a propensity matched cohort with adjustment for International Prognostic Index risk and relapse, the PET/CT (+) group was shown to have similar medical costs as the PET/CT (–) group. Relapse-free survival (RFS) and overall survival (OS) were comparable between the two groups (median RFS not reached [NR] for both groups, p = 0.133; median OS NR, p = 0.542). Among 76 patients with surveillance PET/CT, 31 (40.8%) had findings suggestive of recurrence and 16 of these (51.6%) were later confirmed to have recurrent disease. Fifteen patients (48.4%) were confirmed to not have recurrence after follow-up CT or PET/CT evaluation (n = 10) and biopsy (n = 4). None of the patients with negative PET/CT findings had disease recurrence. Sensitivity, specificity, positive predictive value, and negative predictive value of PET/CT for detection of recurrence were 1, 0.75, 0.52, and 1, respectively. Conclusions Surveillance PET/CT resulted in similar clinical outcomes and medical costs compared to no surveillance PET/CT. Approximately half of patients with PET/CT findings of recurrence had no recurrence after follow-up imaging and biopsy, which would not have been carried out if PET/CT had not been performed in the first place.

The need for students to learn science, technology, engineering, and mathematics (STEM) has increased steadily, while student motivation in this area continues to fall behind. We investigated the effects of science utility value intervention in increasing the science motivation (i.e., interest in science, appreciation of the role of science in future careers, and intention to engage in science-related activities) of Korean 5th and 6th graders. The usefulness of science for attaining the personal and communal goals inherent to various non-STEM careers was emphasized and internalized through classroom activities including postcard writing. At the end of the semester, students in the experimental group (n = 219) perceived greater personal and communal utility in science than those from the control group (n = 197). This enhanced perception of science utility led to greater interest, a higher likelihood of cognitively connecting science to future careers, and the willingness to engage in scientific activities.

Background MG1113 is a human monoclonal antibody of tissue factor pathway inhibitor (TFPI) under development for prophylaxis for hemophilia patients with or without inhibitors against factor VIII products, which have been used for the treatment of hemophilia. Because TFPI is a negative regulator in the extrinsic coagulation pathway, neutralization of TFPI function by MG1113 can potentially increase coagulation activity by bypassing the intrinsic coagulation pathway, which factor VIII activates. Objectives This study aims to determine the correlation between pharmacokinetics (PK) and pharmacodynamics (PD) after administering MG1113 to monkeys and to predict the PK and PD of MG1113 in humans by the Target-Mediated Drug Disposition (TMDD) model using the results from monkeys. Methods The PK profile of MG1113 and the PD effect on the free TFPI level were evaluated after intravenous (IV) and subcutaneous (SC) administrations of MG1113 (2.5, 5, and 10 mg/kg) to male cynomolgus monkeys. After setting up the PK/PD model on monkeys, PK parameters on humans were calculated using allometric scaling, and then clinically effective doses were predicted applying the TMDD model. Results and conclusions MG1113 showed nonlinear PK after both IV and SC administrations at the dosing range from 2.5 to10 mg/kg. The concentrations of MG1113 versus TFPI could be characterized a dose-response relationship using a TMDD model. The TMDD modeling and simulation built in this study were used to simulate various dosage regimens of MG1113 to apply to the first-in-human study design, and moreover expected to be referred to establish the dose for further clinical trials.

439 Background: Standard first-line treatment for advanced biliary tract cancer (BTC) with gemcitabine plus cisplatin confers only modest benefits (objective response rate [ORR], 26%; Valle et al. N Engl J Med 2010;362:1273-1281) and patient prognosis is poor. Therefore, new first-line strategies are urgently required. Human epidermal growth factor receptor (HER) tyrosine kinases are commonly overexpressed in BTC. Varlitinib is a reversible small molecule pan-HER inhibitor. Methods: This was a multicentre, phase 1B/2 study in patients with advanced BTC who had not received prior systemic therapy. Using a modified 3+3+3 escalation design in phase 1B, patients received oral varlitinib twice daily (BID) every day (starting dose 200 mg BID) plus gemcitabine/cisplatin on Days 1 and 8 in a 3-week cycle. The primary objective was to determine the maximum tolerated dose (MTD) and safety profile of varlitinib in combination with gemcitabine plus cisplatin. Patients were evaluable for MTD if they had varlitinib treatment compliance of ≥80% and received 2 doses of chemotherapy in Cycle 1, or if they experienced a dose-limiting toxicity (DLT) in Cycle 1. Preliminary efficacy was a secondary objective. Results: Overall, 23 patients were enrolled in Korea (3 sites), Singapore (1 site), and Taiwan (1 site). Patient characteristics at baseline: male, 52%; median (range) age, 66 (47-82) years; ECOG PS, 0 (43%)/ 1 (57%); primary tumor site, intrahepatic bile duct (43%)/ extrahepatic bile duct (22%)/ gallbladder (22%)/ ampulla of Vater (13%). In total, 11 and 12 patients were included in the varlitinib 200 mg and 300 mg cohorts, of whom 9 and 7 were evaluable for MTD, respectively. DLTs were observed in 2 patients in the 200 mg cohort. Prior to study termination, the 300 mg dose was being assessed with 1 patient experiencing a DLT. In the overall population (n = 23), 36% of patients in the 200 mg cohort and 67% in the 300 mg cohort had at least one grade ≥3 treatment-related adverse event. Grade ≥3 treatment-related investigations abnormalities and blood and lymphatic system disorders were reported in 27% and 18% of patients in the 200 mg cohort, and 25% and 25% of those in the 300 mg cohort, respectively. Among all 23 patients, 8 had a partial response and 12 had stable disease for ≥12 weeks, giving an ORR of 35% and a disease control rate of 87%. The median (Q1-Q3) duration of objective response was 4.0 (2.8-11.0) months. At the time of analysis, 17 patients had progression events and 6 were censored. The median (Q1-Q3) progression-free survival was 6.8 (5.1-10.7) months. Conclusions: Varlitinib combined with gemcitabine plus cisplatin was well tolerated and associated with preliminary anti-tumor activity in patients with treatment-naïve advanced BTC. Clinical trial information: NCT02992340.

Although there has been a surge in reports on coronavirus disease 2019 (COVID-19), the clinical signs and findings associated with fatal outcomes have rarely been studied. This systematic review and meta-analysis aimed to investigate the clinical, laboratory, and radiologic features associated with mortality in COVID-19. A comprehensive search was performed using PubMed, Embase, Web of Science, and other databases including government sources, for articles and reports published until May 1, 2020. We extracted the number of events (mortality and non-mortality) from case series and case-control and cross-sectional studies. Hazard ratios (HR) of each finding were extracted from studies with time-to-outcome analysis. In total, 23 studies met the inclusion criteria. Of them, 18 studies were case-control, cross-sectional, and case series study. Whereas, only 5 studies included time-to-outcome analysis. Male sex, age over 80 years, dyspnea, cardiovascular disease, chronic kidney disease, increased troponin I level, acute respiratory distress syndrome, acute kidney injury, and need of invasive mechanical ventilation were significantly associated with mortality. The identification of patients at higher risk of mortality has an utmost importance to achieve better treatment outcomes. The findings from our study may aid the prioritization in times of severe shortages of medical resources. Further studies analyzing diverse demographic and geographic populations are needed to generalize the findings from this study.

Purpose We aimed to investigate the clinicopathologic factors associated with distant metastasis (DM) and post-recurrence overall survival (OS) after salvage treatments for isolated locoregional recurrence (ILRR) of breast cancer and identify long-term surviving patients for providing a more personalized therapy. Methods We analyzed 125 patients who underwent salvage local treatments for ILRR after initial curative breast surgery. Results Fifty-two (41.6%) patients experienced secondary recurrence or disease progression, of which 20 (38.5%) experienced a secondary locoregional recurrence and 40 (76.9%) experienced DM as the first site of failure. In multivariate analysis of distant metastasis free survival (DMFS) and post-recurrence OS, the initial pN2-3 stage, a disease-free interval of < 36 months, and non-curative resection for recurrent disease were independently poor prognosticators. The score for patients stratified according to the number of risk factors increased from 0 to 3; the corresponding 5-year DMFS rates were 91.4%, 53.0%, 35.9%, and 0% and the 5-year OS rates were 97.3%, 70.4%, 32.7%, and 25.0%, respectively (p < 0.001). Systemic chemotherapy reduced DM in patients with a score of 2-3, but it did not in those with a score of 0-1. Conclusion Our collective stratification can help with prognosis prediction for ILRR of breast cancer. Depending on the DM risk of patients, the potential combination of systemic therapy should be discussed further.

We developed an asymmetrically porous membrane with a leaf-stacked structure (LSS membrane; top with nanosized pores and bulk/bottom with leaf-stacked structure) via immersion-precipitation using polycarprolactone (PCL)/Pluronic F127 mixture solution (in tetraglycol). The bone morphogenetic protein-2 (BMP-2) is immobilized on the pore surfaces of the LSS membrane by immersing the membrane in the BMP-2 solution. The BMP-2 loaded in the LSS membrane is continuously released for 38 days (without additional modifications of the matrix) to improve osteogenic differentiation of cells and new bone formation (carvarial defect rat model). The leaf-stacked structure is recognized to be a physical stimulus for bone regeneration, and the stimulation effect is comparable to that of continuously released BMP-2. Moreover, we observe the combined effect of BMP-2 and the leaf-stacked structure for bone healing. Thus, we suggest that the BMP-2-immobilized LSS membrane may be a candidate as a bioactive guided bone regeneration (GBR) membrane for clinical applications, due to the use of clinically acceptable biomaterials and fabrication procedures as well as effective osteogenic differentiation and bone regeneration.

eEyes is an integrated aid system for people with low vision. eEyes is a wearable device that can be attached to glasses, which consists of a wearable unit and a self-developed standalone computing unit. eEyes employed Natural User Interface (NUI) technology such as user's hand gesture recognition. An eEyes user can interact with eEyes through static hand gestures (open hand, pointing, v sign, etc.). eEyes's hand gesture recognition technology was developed using on skin-color-based hand gesture recognition techniques. This NUI technology on eEyes provides users with enhanced usability for using eEyes's services. eEyes's capabilities can be also applied to other fields such as mobile VR and AR interactions.

Radiation-induced cavernous malformations (RICMs) are most commonly reported in young patients who have previously received radiotherapy. Here, we report a case of a patient with a germ cell tumor who was treated with whole brain radiotherapy (WBRT) and then incidentally found to have numerous RICMs. A 31-year-old male visited the hospital for a testicular mass. On examination, he was diagnosed with a mixed germ cell tumor with lung/brain metastases. The patient underwent a left orchiectomy and received 4 cycles of chemotherapy. He was then treated with WBRT for residual lesions in the brain and a wedge resection for the lung metastasis. Four years later, approximately 250-300 RICMs were incidentally observed in a follow-up brain image. Because the patient had not noticed any symptoms and the RICMs were small in size, he was not treated. To our knowledge, this is the first reported case of numerous (approximately 250-300) RICMs in a germ cell tumor patient after WBRT. Herein, we report details of this case and discuss the typical clinical features of RICM.

We aimed to investigate the prognostic influence of primary tumor site on the survival of patients with breast cancer.Data of 63,388 patients with primary breast cancer from the Korean Breast Cancer Registry were analyzed. Primary tumor sites were classified into 5 groups: upper outer quadrant, lower outer quadrant, upper inner quadrant, lower inner quadrant (LIQ), and central portion. We analyzed overall survival (OS) and breast cancer-specific survival (BCSS) according to primary tumor site.Central portion and LIQ showed lower survival rates regarding both OS and BCSS compared with the other 3 quadrants (all P .05) and hazard ratios were 1.267 (95% CI, 1.180-1.360, P .001) and 1.215 (95% CI, 1.097-1.345, P .001), respectively. Although central portion showed more unfavorable clinicopathologic features, LIQ showed more favorable features than the other 3 quadrants. Primary tumor site was a significant factor in univariate and multivariate analyses for OS and BCSS (all P .001). For lymph node-negative patients, LIQ showed a worse OS than the other primary tumor sites in the subgroup with no chemotherapy (P .001), but that effect disappeared in the subgroup with chemotherapy (P = .058).LIQ showed a worse prognosis despite having more favorable clinicopathologic features than other tumor locations and it was more prominent for lymph node-negative patients who received no chemotherapy. The hypothesis of possible hidden internal mammary node metastasis could be suggested to play a key role in LIQ lesions.

In many Asian countries battling with the double burden of increasing noninfectious diseases on top of infectious diseases, multiple myeloma (MM) patients presenting with pleural effusion (PE) pose a great diagnostic challenge. Thus, we aimed to analyze the clinical features and practice patterns of such patients. This is a multicenter retrospective study of newly diagnosed MM patients between January 2011 and December 2015. Among 575 MM patients diagnosed during the study period, 80 (13.9%) that were associated with PE were identified and analyzed. The most common cause of PE was parapneumonic (25%), followed by reactive (18.8%). Higher CRP levels and leukocytosis were indicators of parapneumonic PE. There were 7 (8.8%) with myelomatous PE and 2 (2.5%) with tuberculosis. Fifty-six patients underwent additional examinations to determine the exact cause of effusion; 28 patients received computed tomography (CT) of the chest, 5 patients underwent thoracentesis/biopsy, and 23 patients underwent both CT and thoracentesis/biopsy. On the other hand, 24 patients did not undergo additional analyses but were treated empirically. Real-world analyses of practice patterns in MM patients with PE showed the suboptimal use of invasive procedures to determine the exact cause of PE. Since reversible causes and tuberculosis pleurisy are not uncommon, invasive procedures should be actively incorporated as needed.

Although nonalcoholic fatty liver disease (NAFLD) has been linked to breast cancer risk, the actual relationship remains unclear. Fatty liver index (FLI) is a noninvasive method for predicting NAFLD. We aimed to assess the association between FLI, a predictor of NAFLD, and breast cancer risk.Using the Korean National Health Insurance Corporation data, we reviewed 7,046,153 women who underwent biennial evaluations between 2009 and 2010. FLI was calculated using body mass index, waist circumference, triglyceride level, and gamma-glutamyl transferase level. FLI 30 ruled out hepatic steatosis, while FLI ≥ 60 indicated NAFLD. Cox regression models were used for analysis.Among the subjects, 51.8% (n = 3,606,079) were premenopausal women. In the premenopausal and postmenopausal groups, 32,145 (0.89%) and 28,103 (0.82%) women developed breast cancer, respectively (median follow-up, 7.02 years; interquartile range, 6.39-7.39 years). Mean FLI and standard deviation were lower in premenopausal women (11.24 ± 14.72 vs. 23.88 ± 19.54, P .0001). Three groups were formed according to FLI: 30 (n = 5,693,730, 80.81%), 30-60 (n = 1,031,025, 14.63%), and ≥ 60 (n = 321,398, 4.56%). FLIs of 30-60 and ≥ 60 were significantly associated with increased breast cancer risk in postmenopausal women (hazard ratio, 1.07; 95% confidence interval, 1.04-1.11; and hazard ratio, 1.11; 95% confidence interval, 1.05-1.17, respectively). No association was found in premenopausal women.High FLI, an indicator of NAFLD, could predict breast cancer in postmenopausal women.

Water enables the highly challenging enantioselective Michael addition of sterically congested β-trifluoromethyl-β-aryl- or -alkyl-substituted nitroolefins with dithiomalonates. Under on-water conditions, the reaction rates were remarkably accelerated as a result of enforced hydrophobic interactions between catalysts and reactants. Takemoto-type thiourea catalysts are very effective for this transformation, affording highly enantioenriched Michael adducts that provide simple access to chiral γ-aminobutyric acid (GABA) analogues with a β-trifluoromethylated quaternary stereocenter.

A broadly applicable biomimetic enantioselective decarboxylative catalytic aldol reaction of trifluoromethyl ketones with malonic acid half-thioesters (MAHTs) is described. Utilizing cinchona-based thioureas as highly efficient polyketide synthase-mimic catalysts, chiral tertiary aldols, β-trifluoromethyl-β-hydroxy thioesters, were obtained in up to 99% yield and 95% ee. Facile transformation of the thioester moiety of the aldol adducts showcases the synthetic utility of this biomimetic aldol protocol to deliver a range of chiral trifluoromethylated tertiary aldol pharmacophores.

Background Tuberculosis is associated with hypercoagulation; however, there are few reports of cases thromboembolism and tuberculosis at the same time in the real world. The purpose of this study was to report the incidence and clinical course of thromboembolism in patients diagnosed with tuberculosis. Materials and Methods We retrospectively analyzed the data of patients who were diagnosed with both tuberculosis and thromboembolism including pulmonary thromboembolism (PTE) or deep vein thrombosis (DVT) at Seoul National University Boramae Medical Center from January 2000 through March 2015. Results Among the 7905 tuberculosis patients, 49 (0.6%) exhibited PTE, DVT, or both at or after the time of tuberculosis diagnosis. All patients treated for tuberculosis started with isoniazid, ethambutol, rifampicin, and pyrazinamide. Eight patients were switched to treatment with second-line medication because of resistance or adverse events. About half of the patients (n = 21, 44.7%) had thrombosis at the time of tuberculosis diagnosis. Of 48 patients treated for thromboembolism, 36 received warfarin. A total of 20 patients improved symptom caused by thrombosis, and 10 patients were confirmed cure by image study such as computed tomography or doppler ultrasonography. Eight patients who were treated with warfarin had persistent thrombosis. Five patients (10.2%) experienced major bleeding that required hospitalization. All of these bleeding events were associated with warfarin therapy. Conclusions Careful attention to PTE/DVT is needed at the time of diagnosis of tuberculosis and during anti-tuberculosis therapy. Warfarin therapy administered with anti-tuberculosis medication requires frequent monitoring to prevent major bleeding.

In order to move mobile robots to desired locations in a minimum time, optimal control problems have to be solved; however, their analytic solutions are almost impossible to obtain due to robot nonlinear equations. This paper presents a method to get optimal control gains of mobile robots using genetic algorithms. Since the optimal control gains of mobile robots depend on the initial conditions, the initial condition range is discretized to form some grid points, and genetic algorithms are applied to provide the optimal control gains for the corresponding grid points. The optimal control gains for general initial conditions may be obtained by use of neural networks. So the optimal control gains and the corresponding grid points are used to train neural networks. The trained neural networks can supply pseudo-optimal control gains. Finally simulation studies have been conducted to verify the effectiveness of the method presented in this paper. 키워드 : 신경회로망, 유전알고리즘, 이동로봇, 최단시간, 최적제어이득

Purpose Interstitial lung disease (ILD) is a serious adverse effect of gefitinib. We examined the incidence and clinical characteristics of drug-induced ILD in Korean non-small cell lung carcinoma patients treated with gefitinib. Materials and Methods A retrospective cohort study was performed in non-small cell lung cancer (NSCLC) patients who started gefitinib treatment at Seoul National University Hospital from January 2002 through December 2011. Patients who developed new abnormal radiologic findings with respiratory symptoms after gefitinib treatment were defined as having possible adverse pulmonary reactions. The patients’ medical records were reviewed independently by investigators to identify the causes of pulmonary toxicities. Results Among the 1,114 patients evaluated, 128 patients (11.5%) developed pulmonary adverse reactions after taking gefitinib. An infectious complication occurred in 98 patients (8.8%) and 15 patients (1.3%) developed ILD. Nine of the 15 patients (60.0%) with gefitinib-induced ILD experienced a fatal clinical course that met either the Common Terminology Criteria for Adverse Events grade 4 (n=3) or grade 5 (n=6). In the multivariate analysis, a lower serum albumin level (≤ 3.0 g/dL) at baseline was significantly associated with the development of gefitinib-induced ILD (odds ratio, 3.91; 95% confidence interval, 1.20 to 12.71). Conclusion The incidence of gefitinib-induced ILD in Korean NSCLC patients was similar to that reported worldwide, but lower than values reported for Japanese population. ILD was usually a life-threatening adverse effect of gefitinib, and the development of ILD was significantly associated with a lower baseline serum albumin level.

In this paper, we strengthen the advantages of a simple PID controller as a study on the formation control of mobile robots and propose an adaptive PID controller with robust performance at the dynamics characteristics of following robot. Simulation studies show that the adaptive PID controller has better keeping constant distance and angle such as tracking performance of following robot for the formation control than a conventional PID controller. This is the proposed adaptive PID controller to change the gains is found to represent the best performance. This is able to verify that the performance of the proposed adaptive PID controller is excellent.