Analysis of Response and Progression Patterns of Tyrosine Kinase Inhibitors in Recurrent or Metastatic Adenoid Cystic Carcinoma: A Post Hoc Analysis of Two KCSG Phase II Trials.

Purpose: In this study, we evaluated 66 patients diagnosed with adenoid cystic carcinoma (ACC) enrolled in two Korean Cancer Study Group trials to investigate the response and progression patterns in recurrent and/or metastatic ACC treated with vascular endothelial growth factor receptor tyrosine kinase inhibitors (VEGFR-TKIs). Materials and Methods: We evaluated 66 patients diagnosed with ACC who were enrolled in the Korean Cancer Study Group trials. The tumor measurements, clinical data, treatment outcomes, and progression patterns of therapy were analyzed. Results: In the 66 patients (53 receiving axitinib and 13 receiving nintedanib), the disease control rate was 61%, and 3 patients achieved partial response. The median follow-up, median progression-free survival (PFS), overall survival, and 6-month PFS rate were 27.6, 12.4, and 18.1 months and 62.1%, respectively. Among 42 patients who experienced progression, 27 (64.3%) showed target lesion progression. Bone metastasis was an independent poor prognostic factor. Conclusion: Overall, most patients demonstrated stable disease with prolonged PFS; however, prominent target lesion progression occurred in some patients. Thus, PFS may capture VEGFR-TKI efficacy better than the objective response rate.

Efficacy and Safety of Alogliptin-Pioglitazone Combination for Type 2 Diabetes Mellitus Poorly Controlled with Metformin: A Multicenter, Double-Blind Randomized Trial.

Background: Guidelines for switching to triple combination therapy directly after monotherapy failure are limited. This study investigated the efficacy, long-term sustainability, and safety of either mono or dual add-on therapy using alogliptin and pioglitazone for patients with type 2 diabetes mellitus (T2DM) who did not achieve their target glycemic range with metformin monotherapy. Methods: The Practical Evidence of Antidiabetic Combination Therapy in Korea (PEAK) was a multicenter, placebo-controlled, double-blind, randomized trial. A total of 214 participants were randomized to receive alogliptin+pioglitazone (Alo+Pio group, n=70), alogliptin (Alo group, n=75), or pioglitazone (Pio group, n=69). The primary outcome was the difference in glycosylated hemoglobin (HbA1c) levels between the three groups at baseline to 24 weeks. For durability, the achievement of HbA1c levels <7% and <6.5% was compared in each group. The number of adverse events was investigated for safety. Results: After 24 weeks of treatment, the change of HbA1c in the Alo+Pio, Alo, and Pio groups were -1.38%±0.08%, -1.03%±0.08%, and -0.84%±0.08%, respectively. The Alo+Pio group had significantly lower HbA1c levels than the other groups (P=0.0063, P<0.0001) and had a higher proportion of patients with target HbA1c achievement. In addition, insulin sensitivity and ß-cell function, lipid profiles, and other metabolic indicators were also improved. There were no significant safety issues in patients treated with triple combination therapy. Conclusion: Early combination triple therapy showed better efficacy and durability than the single add-on (dual) therapy. Therefore, combination therapy with metformin, alogliptin, and pioglitazone is a valuable early treatment option for T2DM poorly controlled with metformin monotherapy.

Predictors for emergency readmission in patients with ureteral calculi: a focus on pain management and stone location.

BACKGROUND: The management of patients with ureteral calculi in the emergency department (ED) remains challenging due to high revisit rates. PURPOSE: To identify predictors of revisits among patients with ureteral calculi in the ED. DESIGN, SETTING, AND PARTICIPANTS: Data from patients who presented at a tertiary academic hospital in Seoul, Republic of Korea, between February 2018 and December 2019, were analyzed retrospectively. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Variables, including the respiratory rate (RR), estimated glomerular filtration rate (eGFR), duration of pain, number of analgesic doses, location of ureteral calculi, and ED length of stay (LOS) were examined using logistic regression. We also examined some additional variables included in the STONE and CHOKAI scoring systems to examine their association with revisit. RESULTS: Significant predictors of revisits included the number of analgesic doses and the location of ureteral calculi. Patients who required multiple analgesic doses or those with proximal or mid-ureteral calculi were more likely to revisit the ED. Although the STONE and CHOKAI scores could predict uncomplicated ureteral calculi, we found that the CHOKAI score is a valuable tool for predicting the likelihood of patient revisits (p = 0.021). CONCLUSIONS: Effective pain management and consideration of calculi location are important for predicting patient revisits. More research is required to validate findings, develop precise predictive models, and empower tailored care for high-risk patients. In patients with ureteral calculi in the ED, the number of analgesics given and stone location predict return visits. Proximal ureteral calculi on CT may require early urologic intervention to prevent pain-related revisits.

Effects of an Electronic Medical Records-Linked Diabetes Self-Management System on Treatment Targets in Real Clinical Practice: Retrospective, Observational Cohort Study.

Background: This study evaluated the effects of a mobile diabetes management program called "iCareD" (College of Medicine, The Catholic University of Korea) which was integrated into the hospital's electronic medical records system to minimize the workload of the healthcare team in the real clinical practice setting. Methods: In this retrospective observational study, we recruited 308 patients. We categorized these patients based on their compliance regarding their use of the iCareD program at home; compliance was determined through self-monitored blood glucose inputs and message subscription rates. We analyzed changes in the ABC (hemoglobin A1c, blood pressure, and low-density lipoprotein cholesterol) levels from the baseline to 12 months thereafter, based on the patients' iCareD usage patterns. Results: The patients comprised 92 (30%) non-users, 170 (55%) poor-compliance users, and 46 (15%) good-compliance users; the ABC target achievement rate showed prominent changes in good-compliance groups from baseline to 12 months (10.9% vs. 23.9%, P<0.05), whereas no significant changes were observed for poor-compliance users and non-users (13.5% vs. 18.8%, P=0.106; 20.7% vs. 14.1%, P=0.201; respectively). Conclusion: Implementing the iCareD can improve the ABC levels of patients with diabetes with minimal efforts of the healthcare team in real clinical settings. However, the improvement of patients' compliance concerning the use of the system without the vigorous intervention of the healthcare team needs to be solved in the future.

Automated Detection and Segmentation of Bone Metastases on Spine MRI Using U-Net: A Multicenter Study.

OBJECTIVE: To develop and evaluate a deep learning model for automated segmentation and detection of bone metastasis on spinal MRI. MATERIALS AND METHODS: We included whole spine MRI scans of adult patients with bone metastasis: 662 MRI series from 302 patients (63.5 ± 11.5 years; male:female, 151:151) from three study centers obtained between January 2015 and August 2021 for training and internal testing (random split into 536 and 126 series, respectively) and 49 MRI series from 20 patients (65.9 ± 11.5 years; male:female, 11:9) from another center obtained between January 2018 and August 2020 for external testing. Three sagittal MRI sequences, including non-contrast T1-weighted image (T1), contrast-enhanced T1-weighted Dixon fat-only image (FO), and contrast-enhanced fat-suppressed T1-weighted image (CE), were used. Seven models trained using the 2D and 3D U-Nets were developed with different combinations (T1, FO, CE, T1 + FO, T1 + CE, FO + CE, and T1 + FO + CE). The segmentation performance was evaluated using Dice coefficient, pixel-wise recall, and pixel-wise precision. The detection performance was analyzed using per-lesion sensitivity and a free-response receiver operating characteristic curve. The performance of the model was compared with that of five radiologists using the external test set. RESULTS: The 2D U-Net T1 + CE model exhibited superior segmentation performance in the external test compared to the other models, with a Dice coefficient of 0.699 and pixel-wise recall of 0.653. The T1 + CE model achieved per-lesion sensitivities of 0.828 (497/600) and 0.857 (150/175) for metastases in the internal and external tests, respectively. The radiologists demonstrated a mean per-lesion sensitivity of 0.746 and a mean per-lesion positive predictive value of 0.701 in the external test. CONCLUSION: The deep learning models proposed for automated segmentation and detection of bone metastases on spinal MRI demonstrated high diagnostic performance.

The Impact of Mental Practice on Motor Function in Patients With Stroke: A Systematic Review and Meta-analysis.

Mental practice (MP), the cognitive rehearsal of physical activities without overt movements, has recently emerged as a promising rehabilitation method for patients with stroke. This paper presents a systematic review and meta-analysis critically evaluating the existing evidence to offer a comprehensive estimate of the overall effect of MP on motor function in stroke patients. A systematic search of 3 international databases (PubMed, Embase, and the Cochrane Library) was conducted for randomized controlled trials. We finally selected 31 randomized clinical trials and conducted meta-analysis to determine the effectiveness of MP on motor recovery of upper extremity, upper extremity function, activities of daily living, and gait velocity in stroke patients. The results of the systematic reviews showed that MP combined with conventional therapy has a positive impact on improving upper extremity motor function, with a moderate quality of evidence. However, the beneficial effect of MP on gait velocity was not demonstrated. It is recommended to treat with MP in addition to conventional rehabilitation therapy to improve the motor outcome of stroke depending on the patient's condition (Recommendation level: Conditional Recommend Evidence certainty: Moderate).

Cerebrospinal fluid flow artifact reduction with deep learning to optimize the evaluation of spinal canal stenosis on spine MRI.

PURPOSE: The aim of study was to employ the Cycle Generative Adversarial Network (CycleGAN) deep learning model to diminish the cerebrospinal fluid (CSF) flow artifacts in cervical spine MRI. We also evaluate the agreement in quantifying spinal canal stenosis. METHODS: For training model, we collected 9633 axial MR image pairs from 399 subjects. Then, additional 104 image pairs from 19 subjects were gathered for the test set. The deep learning model was developed using CycleGAN to reduce CSF flow artifacts, where T2 TSE images served as input, and T2 FFE images, known for fewer CSF flow artifacts. Post training, CycleGAN-generated images were subjected to both quantitative and qualitative evaluations for CSF artifacts. For assessing the agreement of spinal canal stenosis, four raters utilized an additional 104 pairs of original and CycleGAN-generated images, with inter-rater agreement evaluated using a weighted kappa value. RESULTS: CSF flow artifacts were reduced in the CycleGAN-generated images compared to the T2 TSE and FFE images in both quantitative and qualitative analysis. All raters concordantly displayed satisfactory estimation results when assessing spinal canal stenosis using the CycleGAN-generated images with T2 TSE images (kappa = 0.61-0.75) compared to the original FFE with T2 TSE images (kappa = 0.48-0.71). CONCLUSIONS: CycleGAN demonstrated the capability to produce images with diminished CSF flow artifacts. When paired with T2 TSE images, the CycleGAN-generated images allowed for more consistent assessment of spinal canal stenosis and exhibited agreement levels that were comparable to the combination of T2 TSE and FFE images.

Artificial intelligence-powered spatial analysis of tumor-infiltrating lymphocytes as a predictive biomarker for axitinib in adenoid cystic carcinoma.

BACKGROUND: This study analyzed the predictive value of artificial intelligence (AI)-powered tumor-infiltrating lymphocyte (TIL) analysis in recurrent or metastatic (R/M) adenoid cystic carcinoma (ACC) treated with axitinib. METHODS: Patients from a multicenter, prospective phase II trial evaluating axitinib efficacy in R/M ACC were included in this study. H&E whole-side images of archival tumor tissues were analyzed by Lunit SCOPE IO, an AI-powered spatial TIL analyzer. RESULTS: Twenty-seven patients were included in the analysis. The best response was stable disease, and the median progression-free survival (PFS) was 11.1 months (95% CI, 9.2-13.7 months). Median TIL densities in the cancer and surrounding stroma were 25.8/mm2 (IQR, 8.3-73.0) and 180.4/mm2 (IQR, 69.6-342.8), respectively. Patients with stromal TIL density >342.5/mm2 exhibited longer PFS (p = 0.012). CONCLUSIONS: Cancer and stromal area TIL infiltration were generally low in R/M ACC. Higher stromal TIL infiltration was associated with a longer PFS with axitinib treatment.

A safety mechanism enables tissue-specific resistance to protein aggregation during aging in C. elegans.

During aging, proteostasis capacity declines and distinct proteins become unstable and can accumulate as protein aggregates inside and outside of cells. Both in disease and during aging, proteins selectively aggregate in certain tissues and not others. Yet, tissue-specific regulation of cytoplasmic protein aggregation remains poorly understood. Surprisingly, we found that the inhibition of 3 core protein quality control systems, namely chaperones, the proteasome, and macroautophagy, leads to lower levels of age-dependent protein aggregation in Caenorhabditis elegans pharyngeal muscles, but higher levels in body-wall muscles. We describe a novel safety mechanism that selectively targets newly synthesized proteins to suppress their aggregation and associated proteotoxicity. The safety mechanism relies on macroautophagy-independent lysosomal degradation and involves several previously uncharacterized components of the intracellular pathogen response (IPR). We propose that this protective mechanism engages an anti-aggregation machinery targeting aggregating proteins for lysosomal degradation.

Comparison of antibiotic resistance rates and outcomes among older adult patients with urinary tract infections living in long- term care hospitals and the community.

OBJECTIVE: In this study, we compared the proportion of antibiotic resistance between patients who visited the emergency department (ED) with urinary tract infection (UTI) from long-term care hospitals (LTCH), which is a type of long-term care facilities (LTCF) and the community. We assessed the resulting difference in prognosis. METHOD: Older adults who visited the ED between January and December 2019 and were diagnosed with UTI were divided into community residents and LTCH residents. We investigated the antibiotics sensitivity rates, end of therapy (EOT), and the patient's outcomes were evaluated. RESULTS: The antibiotic resistance rate was higher in LTCH residents. LTCH residents had a higher in hospital mortality rate compared to community residents. EOT was found to be longer, and admission rate and in-hospital mortality rate were also higher in LTCH residents. CONCLUSION: LTCF residents had a higher rate of antibiotic resistance and a poor prognosis.

Risk factors for deep neck infection in patients with sore throat and neck pain.

BACKGROUND: Deep neck infection (DNI) is a potentially life-threatening disease because infections spread quickly, causing se-rious complications. Therefore, more attention is needed than other neck infections, but there are many difficulties due to isolation guidelines in the period of coronavirus disease 2019 pandemic. We investigated the early predictability of DNI through patient symptoms at the first emergency department encounter. METHODS: This was a retrospective study of patients with suspected soft-tissue neck infections from January 2016 to February 2021. Symptoms were retrospectively analyzed in fever, foreign body sensation, chest discomfort/pain, submandibular pain, odynopha-gia, dysphagia, voice change, and severe pain. Furthermore, baseline characteristic data, laboratory findings, and pre-vertebral soft-tissue (PVST) thickness were evaluated. DNI and other neck infections were diagnosed through computed tomography. Logistic regression analysis was conducted to determine the independent factors for predicting DNI. RESULTS: In the 793 patients included in the study, 267 (33.7%) were diagnosed with DNI, and 526 (66.3%) were diagnosed with other soft-tissue neck infections. In the comparison between the two groups, C-reactive protein (CRP), sodium, PT (INR), foreign body sensation, chest discomfort/pain, submandibular pain, odynophagia, dysphagia, severe pain, and PVST thickness showed statisti-cally significant differences. Independent factors for predicting DNI were severe pain (odds ratio: 6.336 [3.635-11.045], p<0.001), for-eign body sensation (odds ratio: 7.384 [2.776-19.642], p<0.001), submandibular pain (odds ratio: 4.447 [2.852-6.932], p<0.001), and dysphagia (odds ratio: 52.118 [8.662-313.588], p<0.001) among symptoms and CRP (odds ratio: 1.034 [1.004-1.065], p=0.026) and PT (INR) (odds ratio: 29.660 [3.363-261.598], p=0.002) in laboratory tests. PVST thickness at C2 (odds ratio: 1.953 [1.609-2.370], p<0.001) and C6 level (odds ratio: 1.179 [1.054-1.319], p=0.004) was also shown as an independent variable for prediction. CONCLUSION: Among patients with sore throat or neck pain, patients with dysphagia, foreign body sensation, severe pain, and submandibular pain are more likely to have DN. DNI can cause serious complications; therefore, patients with the above symptoms should be closely observed due to the potential for significant complications.

Validity of the Korean triage and acuity scale in older patients compared to the adult group.

INTRODUCTION: While many patients visit the emergency department (ED) for various reasons, medical resources are limited. Therefore, various triage scale systems have been used to predict patient urgency and severity. South Korea has developed and used the Korean Triage and Accuracy Scale (KTAS) based on the Canadian classification tool. As the elderly population increases, the number of elderly patients visiting the ED also increases. However, in KTAS, there is no consideration for the elderly, and the same classification system as adults. The aim of this study is to verify the ability of KTAS to predict severity levels in the elderly group, compared to the adult group. METHODS: This is a retrospective study for patients who visited the ED at two centers between February 1, 2018 and January 31, 2021. The initial KTAS level, changed level at ED discharge, general patient character, ED treatment results, in-hospital mortality, and lengths of hospital and ED stays were acquired. Area under the receiver operating characteristics (AUROC) was used to verify the severity prediction ability of the elderly group to KTAS, and logistic regression analysis was used for the prediction up-triage of KTAS. RESULTS: The enrolled patients in the study were 87,220 in the adult group and 37,627 in the elderly group. The proportion of KTAS up-triage was higher in the elderly group (1.9 % vs. 1.2 %, p < 0.001). The AUROC for the overall admission rate was 0.686, 0.667 in the adult and elderly group, the AUROC for ICU admission was 0.842, 0.767, and the AUROC for in-hospital mortality prediction was 0.809, 0.711, indicating a decrease in the AUROC value in the elderly group. The independent factors of the up-triage predictors were old age, male gender, pulse, and ED length of stay, and old age was the most influential variable. CONCLUSION: KTAS was poorly associated with severity in the elderly than in adults, and it was found that up-triaging was more likely to occur in the elderly. The severity and urgency of patients over 65 years of age should not be underestimated when initially determining the triage scale.

Structural insights into the multifunctionality of rabies virus P3 protein.

Viruses form extensive interfaces with host proteins to modulate the biology of the infected cell, frequently via multifunctional viral proteins. These proteins are conventionally considered as assemblies of independent functional modules, where the presence or absence of modules determines the overall composite phenotype. However, this model cannot account for functions observed in specific viral proteins. For example, rabies virus (RABV) P3 protein is a truncated form of the pathogenicity factor P protein, but displays a unique phenotype with functions not seen in longer isoforms, indicating that changes beyond the simple complement of functional modules define the functions of P3. Here, we report structural and cellular analyses of P3 derived from the pathogenic RABV strain Nishigahara (Nish) and an attenuated derivative strain (Ni-CE). We identify a network of intraprotomer interactions involving the globular C-terminal domain and intrinsically disordered regions (IDRs) of the N-terminal region that characterize the fully functional Nish P3 to fluctuate between open and closed states, whereas the defective Ni-CE P3 is predominantly open. This conformational difference appears to be due to the single mutation N226H in Ni-CE P3. We find that Nish P3, but not Ni-CE or N226H P3, undergoes liquid-liquid phase separation and this property correlates with the capacity of P3 to interact with different cellular membrane-less organelles, including those associated with immune evasion and pathogenesis. Our analyses propose that discrete functions of a critical multifunctional viral protein depend on the conformational arrangements of distant individual domains and IDRs, in addition to their independent functions.

Effects of an Initial Single Dose of Intravenous Antibiotics on Emergency Department Revisits Among Elderly Patients with Urinary Tract Infections.

PURPOSE: Urinary tract infection (UTI) is the second most common infectious disease among older adults. It is important that the treatment strategy used for older patients with UTIs in the emergency department (ED) be adequate. The effectiveness of an initial single dose of intravenous antibiotics in the ED for treating UTIs has not been extensively studied. Therefore, we investigated the clinical outcomes of single-dose intravenous antibiotic administration before discharge from the ED in elderly patients with UTIs. MATERIALS AND METHODS: This retrospective study was conducted among patients who visited two academic tertiary hospitals in Seoul, South Korea. We included all patients older than 65 years of age with UTI who visited the ED and were directly discharged between 1 January and 31 December 2019 (n = 429). The patients were divided into two groups according to whether they received a single dose of intravenous antibiotics before ED discharge. RESULTS: Patients who received intravenous antibiotics had a higher 72-hour revisit rate (43 [15.4%] vs 10 [6.7%], p = .009) and a longer mean duration of therapy (total days of antibiotics use) (11 [4.00 - 15.00] vs 5 [3.00 - 11.00], p < .001) than patients who received only oral antibiotics. However, the rate of admission after revisits did not differ significantly between the groups (27 [62.8%] vs 5 [50.0%], p = .492). CONCLUSION: Older patients with severe UTIs were prescribed intravenous antibiotics in the ED. Decisions on admission or discharge should be made carefully for older patients with UTIs who are prescribed intravenous antibiotics in the ED.

Out-of-hospital cardiac arrest due to cervical spine injury by uncertain trauma: A study of two cases.

Cervical spinal cord injury is a well-known cause of cardiac arrest in trauma victims. Unless trauma is definitively suspected, emergency medical services teams perform resuscitation in the pre-hospital stage without cervical spine immobilization. During advanced cardiovascular life support (ACLS), intubation with cervical spinal immobilization causes difficulty in accessing the airway, thus, immobilization tends to not be performed, unless the patient is a clear case of trauma. We report two patients with out-of-hospital cardiac arrests (OHCA) due to cervical fractures that have occurred without clear trauma. In these cases, pre-existing cervical spine lesions was additional informed and identification of the cervical spine fractures was delayed. Emergency medical physicians tend to neglect cervical spine injury when the likelihood of trauma is unclear in a patient presenting with OHCA. These cases urge physicians to consider the possibility of cervical spinal injuries, even in cases of minor trauma. If there is a possibility of cervical spinal injury, imaging should not be delayed and should be followed by appropriate treatment.

The impact of COVID-19 pandemic on revisits to emergency department.

AIM: This study presents the impact of COVID-19 on revisits to the emergency department comparing revisit rates and characteristics between the pre-COVID-19 and COVID-19 periods. METHODS: This multi-center retrospective study included patients over 18 years of age who visited emergency departments during the pre-COVID-19 period and the COVID-19 pandemic. The revisit rates were analyzed according to five age groups; 18-34, 35-49, 50-64, 65-79, and ≥ 80 years, and three revisit time intervals; 3, 9, and 30 days. Also, we compared the diagnosis and disposition at revisit between the study periods. RESULTS: The revisit rates increased with age in both study periods and the revisit rates among all age groups were higher in the COVID-19 period. The proportion of infectious and respiratory diseases decreased during the COVID-19 period. The ICU admission rate and mortality at the revisit among patients aged ≥ 80 years were lower in the COVID-19 period than in the pre-COVID-19 period. CONCLUSION: The revisit rates increased with age in both study periods and there were several changes in the diagnosis and disposition at the revisit in the COVID-19 period.

Early lactate clearance for predicting outcomes in patients with gastrointestinal bleeding.

BACKGROUND: Acute gastrointestinal bleeding (GI bleeding) can range from mild symptoms to life-threatening conditions that require emergency intervention. Therefore, it is important to first identify the high-risk and low-risk patients in the emergency department (ED). AIMS: This study aimed to investigate the usefulness of a three-hourly interval for determining the lactate clearance, which is shorter than the time interval in previous studies, in order to predict the prognosis early in patients with GI bleeding. METHODS: This retrospective study involved patients who visited for complaining of GI bleeding symptoms. Initial lactate levels were measured upon arrival at the ED and measured again 3 h later after performing initial resuscitation. And 3-h lactate clearance was calculated. Lactate and 3-h lactate clearance for predicting outcomes were evaluated by the area under the receiver operating characteristic (AUROC) curve. RESULTS: A total of 104 patients were enrolled and 21 patients (20.2%) died in the hospital. Multivariate logistic regression showed that 3-h lactate clearance was a significant predictor of in-hospital mortality. The AUROC of 3-h lactate clearance for predicting in-hospital mortality was 0.756. The sensitivity and specificity were 66.67% and 75.90%. On combining lactate clearance, total bilirubin, and PTT, the AUROC was 0.899 for predicting in-hospital mortality. CONCLUSIONS: This study validated that lactate clearance at three-hourly intervals is useful for early prediction of mortality and prognosis in patients with GI bleeding. It is important to perform not only an initial lactate measurement, but also a follow-up lactate measurement after initial resuscitation to check the lactate clearance.

A Phase 2 Study of Palbociclib for Recurrent or Refractory Advanced Thymic Epithelial Tumors (KCSG LU17-21).

INTRODUCTION: Thymic epithelial tumors (TETs) are rare but are the most common tumors of the anterior mediastinum. Platinum-based combination chemotherapy is the standard of care for such tumors and is associated with a 50% to 90% objective response rate (ORR) in metastatic disease. Nevertheless, there is no standard chemotherapeutic option after failure of platinum-based combination chemotherapy. Genetic alterations associated with the cell cycle, including pRB, p16INK4A, and cyclin D1, are most often observed in TETs. On the basis of these results, we conducted a phase 2 trial to evaluate the efficacy and safety of palbociclib in patients with recurrent or refractory advanced TETs. METHODS: This is a phase 2, multicenter, open-label, single-arm study of palbociclib monotherapy in patients with recurrent or metastatic advanced TETs who failed one or more cytotoxic chemotherapies. The patients received 125 mg of oral palbociclib daily for 21 days, followed by a 7-day break. The primary end point was progression-free survival (PFS). The secondary end points were ORR, duration of response, overall survival, and safety. RESULTS: Between August 2017 and October 2019, a total of 48 patients were enrolled. The median number of previous chemotherapies was one (range: one to four), and 21 (43.7%) of 48 patients received thymectomy. By the WHO classification, the patients were type A (n = 1), type B1 (n = 2), type B2 (n = 8), type B3 (n = 13), thymic carcinoma (n = 23), and unknown (n = 1). With a median follow-up of 14.5 months (range: 0.8-38.2), the median number of cycles of palbociclib monotherapy was 10 (range: 1-40). The ORR was 12.5% (four partial responses in thymoma and two partial responses in thymic carcinoma). The PFS at 6 months was 60.2%, and the median PFS was 11.0 months (95% confidence interval: 4.6-17.4). The median overall survival was 26.4 months (95% confidence interval: 17.4-35.4). The most common treatment-related adverse events of any grade were neutropenia (62.5%), anemia (37.5%), and thrombocytopenia (29.1%), and the most common grade 3/4 treatment-related hematologic adverse event was neutropenia (41.7%). Neutropenia above grade 3 was reversible, and there were no cases with neutropenic fever. CONCLUSIONS: Palbociclib monotherapy was well tolerated and had encouraging efficacy in patients with TETs who failed platinum-based combination chemotherapy.

Totality outcome of afatinib sequential treatment in patients with EGFR mutation-positive non-small cell lung cancer in South Korea (TOAST): Korean Cancer Study Group (KCSG) LU-19-22.

Background: Irrespective of the first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor chosen, acquired resistance to therapy is inevitable. Therefore, a key consideration when assessing therapeutic choices is the availability of subsequent treatment options following disease progression. We assessed clinical outcomes in patients who received first-line afatinib treatment with various second-line treatments including osimertinib for patients acquiring the T790M mutation. Methods: A total of 737 EGFR mutation-positive (EGFR M+) non-small cell lung cancer (NSCLC) patients receiving first-line afatinib treatment were categorized by second-line treatment: T790M+ sequentially treated with osimertinib (cohort A, n=116); T790M- given chemotherapy or others (cohort B, n=143); patients with unknown T790M status (cohort C, n=111); and patients who were undergoing afatinib treatment at the time of data collection, were dead, had discontinued afatinib treatment due to serious adverse events or were lost to follow-up (cohort D, n=367). The primary outcomes were total time on treatment (TOT) and TOT for first-line (TOT-1) and second-line treatments (TOT-2). Secondary outcomes were objective response rates (ORR), overall survival (OS), and central nervous system (CNS) efficacy. Results: Median total TOT in cohorts A, B, C, and D were 35.10 months [95% confidence interval (CI): 30.09-43.53 months], 18.80 months (95% CI: 16.92-20.20 months), 12.00 months (95% CI: 10.22-14.98 months), and 42.60 months (95% CI: 30.95-59.23 months), respectively. The ORR of patients given afatinib was 75.7%. In patients with initial brain metastasis without local treatment, the CNS response rate was 67.0% and CNS progression-free survival was 24.70 months (95% CI: 19.84-33.15 months). Conclusions: This study showed that sequential approach of afatinib followed by second line treatment is an effective therapeutic strategy for EGFR M+ NSCLC patients.

Sequence grammar underlying the unfolding and phase separation of globular proteins.

Aberrant phase separation of globular proteins is associated with many diseases. Here, we use a model protein system to understand how the unfolded states of globular proteins drive phase separation and the formation of unfolded protein deposits (UPODs). We find that for UPODs to form, the concentrations of unfolded molecules must be above a threshold value. Additionally, unfolded molecules must possess appropriate sequence grammars to drive phase separation. While UPODs recruit molecular chaperones, their compositional profiles are also influenced by synergistic physicochemical interactions governed by the sequence grammars of unfolded proteins and cellular proteins. Overall, the driving forces for phase separation and the compositional profiles of UPODs are governed by the sequence grammars of unfolded proteins. Our studies highlight the need for uncovering the sequence grammars of unfolded proteins that drive UPOD formation and cause gain-of-function interactions whereby proteins are aberrantly recruited into UPODs.