SnapShot: Hypoxia-Inducible Factors.

Molecular oxygen (O2) is a key substrate for mitochondrial ATP production and numerous intracellular biochemical reactions. The maintenance of O2 homeostasis is therefore essential for the survival of most species. During O2 deprivation, mammalian cells rely on multiple adaptations mediated by the hypoxia-inducible factors (HIFs), mTOR, autophagy, and the ER stress response. This SnapShot will summarize recent reports expanding our current understanding of HIF-dependent adaptations to low O2 levels.

Hypoxia as a regulator of tumor stroma and metastasis.

Metastasis is the leading cause of mortality in most patients with cancer. Despite its clinical importance, mechanistic underpinnings of metastatic progression remain poorly understood. Hypoxia, a condition of insufficient oxygen availability, frequently occurs in solid tumors because of their high oxygen/nutrient demand and abnormal tumor vasculature. In this review, we describe the roles of hypoxia and hypoxia-inducible factor (HIF) signaling in the metastatic cascade, with an emphasis on recent biological insights from in vivo studies.

Evaluating a theory-based intervention for improving eHealth literacy in older adults: a single group, pretest-posttest design.

BACKGROUND: The Internet is considered an important channel for providing health information to older adults. We developed an intervention to improve eHealth literacy in older adults according to the information-motivation-behavioral skills (IMB) theory and Intervention Mapping. This study aimed to analyze the effect of a developed intervention on information, motivation, behavioral skills, and behaviors related to eHealth information in older adults. METHODS: Forty-six older adults over the age of 65 were recruited from two senior welfare centers in a city in South Korea. We divided the participants into four groups and conducted one intervention per group from March to December 2019. One intervention consisted of 5 sessions and was performed once a week (2 h/1 time) for 5 weeks, culminating in a total lecture time of 10 h. One lecture instructor and two assistant instructors supported the participants in the computer practices. RESULTS: Participants' computer/web knowledge, perceived ease of use, perceived enjoyment, and attitude toward eHealth information showed statistically significant increases. The eHealth literacy efficacy score, searching performance score, and understanding score were also significantly increased. However, there was no significant difference in perceived usefulness. CONCLUSION: The application of the current theory-based methodology can improve the quality of research in eHealth literacy. Additionally, various interventions should be developed and continuously applied to improve eHealth literacy among older adults.

The best-worse scaling approach: prioritizing burdensome menopause symptoms among Cambodian women.

The objective of this study was to prioritize the most burdensome menopause symptoms among Cambodian women utilizing the best-worst scale (BWS). In total, 180 women aged 40-60 who lived in a community setting were recruited from four regions of Cambodia via convenience sampling. Using the BWS, 12 choice sets were prepared by combining 11 symptoms from the menopause rating scale (MRS), and the BWS choice sets were generated with the orthogonal main effects design (OMED). Counting approach determined the women's health priorities and calculated the best-minus-worst (BW) score. The modeling approach measured each respondent's basic utility function. Of the 180 participants, 41.1% were between the ages of 40 and 49, and 25.0% were over 50. The counting and modeling approaches revealed that heart discomfort was the most burdensome symptom (coefficient 0.739, p < .001) followed by joint and muscular discomfort (coefficient 0.606, p < .001) and sleep problems (coefficient 0.507, p < .001), whereas vaginal dryness was the least burdensome symptoms (coefficient -0.164, p = .018). This study revealed that the most burdensome menopause symptom among Cambodian women was heart discomfort while vaginal dryness was the least burdensome. The BWS enabled to prioritize the burdensome menopausal symptoms which warrants future studies using the BWS.

Characterization and Health-Related Quality of Life in Older Adults With Disabilities According to Timing of Disability Onset.

The current study examined characteristics of early-onset and late-onset disability in older adults and identified predictors of health-related quality of life (HRQoL). This is a secondary data analysis of the 2017 national survey in South Korea. Participants were 4,014 older adults with disabilities, who were divided into an early-onset group (n = 2,229) and late-onset group (n = 1,785). Data were analyzed using complex sample analyses. Difficulties during outdoor activity and transportation use, self-rated health, and stress were common predictors in both groups. Comorbidity was a significant predictor only in the early-onset group. Use of information technology devices, household income, and perceived social discrimination were significant predictors in the late-onset group. Characteristics and predictors of HRQoL were different between groups, despite sharing common characteristics. It is necessary to improve support systems and health care services for older adults with disabilities. [Journal of Gerontological Nursing, 48(3), 37-47.].

Internet health information education for older adults: A pilot study.

This study aimed to develop internet health information education program, and to explore the program's feasibility and preliminary effects. We made use of an intervention mapping approach and adopted as conceptual framework the information-motivation-behavioral skills model to develop the program. We evaluated the feasibility and the impact of the education program using a single-group pretest-posttest design using generalized equation estimation. Eleven older adults participated in the classes from January 25 to February 22, 2019. Each outcome of the behavioral theory-based components of the program-computer/Web knowledge (p < .001), attitude toward internet-based health information (p = .002), eHealth literacy score (p < .001), searching performance scores (p < .001), and level of understanding of internet-based health information (p = .002)-showed significant improvement immediately after the intervention. This pilot study reveals that a behavior theory-based education program for utilizing internet-based health information is an effective way to increase older adults' eHealth literacy.

Treatment strategy and outcomes in locally advanced head and neck squamous cell carcinoma: a nationwide retrospective cohort study (KCSG HN13-01).

BACKGROUND: By investigating treatment patterns and outcomes in locally advanced head and neck squamous cell carcinoma (LA-HNSCC), we aimed at providing valuable insights into the optimal therapeutic strategy for physicians in real-world practice. METHODS: This is a multi-institutional study enrolled the patients with stage III to IVB LA-HNSCC, except for nasopharyngeal carcinoma, from 2004 to 2015 in thirteen referral hospitals capable of multidisciplinary care. RESULTS: A total of 445 LA-HNSCC patients were analyzed. The median age was 61 years (range, 24-89). The primary tumor location was the oropharynx in 191 (43%), oral cavity in 106 (24%), hypopharynx in 64 (14%), larynx in 57 (13%) and other sites in 27 (6%). The most common stage was T2 in 172 (39%), and N2 in 245 (55%). Based on treatment intents, 229 (52%) of the patients received definitive concurrent chemoradiotherapy (CCRT) and 187 (42%) underwent surgery. Approximately 158 (36%) of the study population received induction chemotherapy (IC). Taken together, 385 (87%) of the patients underwent combined therapeutic modalities. The regimen for definitive CCRT was weekly cisplatin in 58%, 3-weekly cisplatin in 28% and cetuximab in 3%. The preferred regimen for IC was docetaxel with cisplatin in 49%, and docetaxel, cisplatin plus fluorouracil in 27%. With a median follow-up of 39 months, one-year and two-year survival rates were 89 and 80%, respectively. Overall survival was not significantly different between CCRT and surgery group (p = 0.620). CONCLUSIONS: In patients with LA-HNSCC, the majority of patients received combined therapeutic modalities. Definitive CCRT, IC then definitive CCRT, and surgery followed by adjuvant CCRT or radiotherapy are the preferred multidisciplinary strategies in real-world practice.

Diagnosis of Benign and Malignant Breast Lesions on DCE-MRI by Using Radiomics and Deep Learning With Consideration of Peritumor Tissue.

BACKGROUND: Computer-aided methods have been widely applied to diagnose lesions detected on breast MRI, but fully-automatic diagnosis using deep learning is rarely reported. PURPOSE: To evaluate the diagnostic accuracy of mass lesions using region of interest (ROI)-based, radiomics and deep-learning methods, by taking peritumor tissues into consideration. STUDY TYPE: Retrospective. POPULATION: In all, 133 patients with histologically confirmed 91 malignant and 62 benign mass lesions for training (74 patients with 48 malignant and 26 benign lesions for testing). FIELD STRENGTH/SEQUENCE: 3T, using the volume imaging for breast assessment (VIBRANT) dynamic contrast-enhanced (DCE) sequence. ASSESSMENT: 3D tumor segmentation was done automatically by using fuzzy-C-means algorithm with connected-component labeling. A total of 99 texture and histogram parameters were calculated for each case, and 15 were selected using random forest to build a radiomics model. Deep learning was implemented using ResNet50, evaluated with 10-fold crossvalidation. The tumor alone, smallest bounding box, and 1.2, 1.5, 2.0 times enlarged boxes were used as inputs. STATISTICAL TESTS: The malignancy probability was calculated using each model, and the threshold of 0.5 was used to make a diagnosis. RESULTS: In the training dataset, the diagnostic accuracy was 76% using three ROI-based parameters, 84% using the radiomics model, and 86% using ROI + radiomics model. In deep learning using the per-slice basis, the area under the receiver operating characteristic (ROC) was comparable for tumor alone, smallest and 1.2 times box (AUC = 0.97-0.99), which were significantly higher than 1.5 and 2.0 times box (AUC = 0.86 and 0.71, respectively). For per-lesion diagnosis, the highest accuracy of 91% was achieved when using the smallest bounding box, and that decreased to 84% for tumor alone and 1.2 times box, and further to 73% for 1.5 times box and 69% for 2.0 times box. In the independent testing dataset, the per-lesion diagnostic accuracy was also the highest when using the smallest bounding box, 89%. DATA CONCLUSION: Deep learning using ResNet50 achieved a high diagnostic accuracy. Using the smallest bounding box containing proximal peritumor tissue as input had higher accuracy compared to using tumor alone or larger boxes. LEVEL OF EVIDENCE: 3 Technical Efficacy: Stage 2.

Avalanche size distribution of an integrate-and-fire neural model on complex networks.

We considered the neural avalanche dynamics of a modified integrate-and-fire model on complex networks, as well as the neural dynamics in a fully connected network, random network, small-world network, and scale-free network. We observed the self-organized criticality of the neural model on complex networks. The probability distribution of the avalanche size and lifetime follow the power law at the critical synaptic strength. Neuronal dynamics on a complex network are not universal. The critical exponents of the avalanche dynamics depend on the structure of the complex network. We observed that the critical exponents deviate from the mean-field value.

EZH2 couples pancreatic regeneration to neoplastic progression.

Although the polycomb group protein Enhancer of Zeste Homolog 2 (EZH2) is well recognized for its role as a key regulator of cell differentiation, its involvement in tissue regeneration is largely unknown. Here we show that EZH2 is up-regulated following cerulein-induced pancreatic injury and is required for tissue repair by promoting the regenerative proliferation of progenitor cells. Loss of EZH2 results in impaired pancreatic regeneration and accelerates KRas(G12D)-driven neoplasia. Our findings implicate EZH2 in constraining neoplastic progression through homeostatic mechanisms that control pancreatic regeneration and provide insights into the documented link between chronic pancreatic injury and an increased risk for pancreatic cancer.

Palbociclib plus exemestane with gonadotropin-releasing hormone agonist versus capecitabine in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer (KCSG-BR15-10): a multicentre, open-label, randomised, phase 2 trial.

BACKGROUND: Endocrine treatment is recommended by clinical guidelines as the preferred treatment option for premenopausal as well as postmenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. In real-world clinical practice, however, a substantial number of patients are treated with chemotherapy. We aimed to compare the clinical antitumour activity and safety of palbociclib plus endocrine therapy with that of capecitabine chemotherapy in premenopausal women with hormone receptor-positive, HER2-negative metastatic breast cancer. METHODS: This multicentre, open-label, randomised, phase 2 study was done in 14 academic institutions in South Korea. Premenopausal women aged 19 years or older with hormone receptor-positive, HER2-negative breast cancer that had relapsed or progressed during previous tamoxifen therapy and with an Eastern Cooperative Oncology Group performance status of 0-2 were included. One line of previous chemotherapy for metastatic breast cancer was allowed. Patients were randomly assigned, using a random permuted block design (with a block size of two), to receive palbociclib plus combination endocrine therapy (oral exemestane 25 mg per day for 28 days and oral palbociclib 125 mg per day for 21 days every 4 weeks plus leuprolide 3·75 mg subcutaneously every 4 weeks) or chemotherapy (oral capecitabine 1250 mg/m2 twice daily for 2 weeks every 3 weeks). Randomisation was stratified by previous chemotherapy for metastatic breast cancer and visceral metastasis. The primary endpoint was progression-free survival. All analyses were done in a modified intention-to-treat population that excluded patients who did not receive study medication. This study is registered with ClinicalTrials.gov, NCT02592746, and is ongoing for follow-up of overall survival. FINDINGS: Between June 15, 2016, and Dec 10, 2018, 189 patients were enrolled, of whom 184 were randomly assigned to the palbociclib plus endocrine therapy group (n=92) or the capecitabine group (n=92). Six patients in the capecitabine group withdrew from the study before drug administration; therefore, 92 patients in the palbociclib plus endocrine therapy group and 86 patients in the capecitabine group were included in the modified intention-to-treat analyses. 46 (50%) of 92 patients in the palbociclib plus endocrine therapy group and 45 (51%) of 92 in the capecitabine group were treatment naive for metastatic breast cancer. During a median follow-up of 17 months (IQR 9-22), median progression-free survival was 20·1 months (95% CI 14·2-21·8) in the palbociclib plus endocrine therapy group versus 14·4 months (12·1-17·0) in the capecitabine group (hazard ratio 0·659 [95% CI 0·437-0·994], one-sided log-rank p=0·0235). Treatment-related grade 3 or worse neutropenia was more common in the palbociclib plus endocrine therapy group than in the capecitabine group (69 [75%] of 92 vs 14 [16%] of 86 patients). 2 (2%) patients in the palbociclib plus endocrine therapy group and 15 (17%) patients in the capecitabine group had treatment-related serious adverse events. No treatment-related deaths occurred. INTERPRETATION: Exemestane plus palbociclib with ovarian function suppression showed clinical benefit compared with capecitabine in terms of improved progression-free survival in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer. Palbociclib plus exemestane with ovarian suppression is an active treatment option in premenopausal patients with hormone receptor-positive, HER2-negative metastatic breast cancer who have been pretreated with tamoxifen. FUNDING: Pfizer, Shinpoong, and Daewoong Korea and Takeda.

Efficacy and tolerability of ramucirumab monotherapy or in combination with paclitaxel in gastric cancer patients from the Expanded Access Program Cohort by the Korean Cancer Study Group (KCSG).

BACKGROUND: Ramucirumab improves survival in gastric cancer patients. The efficacy and safety of ramucirumab outside of a clinical trial were evaluated using an expanded access program (EAP). METHODS: Advanced gastric cancer patients treated with ramucirumab in combination with paclitaxel or with ramucirumab monotherapy in a Korean EAP were evaluated. Baseline characteristics were assessed for progression-free survival (PFS) and overall survival (OS), and adverse events were evaluated according to the treatment regimen. RESULTS: Of 265 patients, 228 received ramucirumab plus paclitaxel, and 37 received ramucirumab monotherapy. Grade 3 or 4 neutropenia was more common with ramucirumab plus paclitaxel than with ramucirumab monotherapy (46.7 vs. 8.1%). Gastrointestinal (GI) perforation developed in seven patients (3.1%) in the ramucirumab plus paclitaxel group. The overall response and disease control rates were 16.6 and 66.3% in the ramucirumab plus paclitaxel group, and 5.4 and 37.8% in the ramucirumab monotherapy group, respectively. PFS and OS were 3.8 and 8.6 months in the ramucirumab plus paclitaxel group, and 1.8 and 6.4 months in the ramucirumab monotherapy group, respectively. In multivariate analysis, alkaline phosphatase, albumin, and neutrophil-to-lymphocyte ratio (NLR) were the independent prognostic factors for PFS, while albumin, NLR, number of metastatic sites, and large amount of ascites were independent prognostic factors for OS. CONCLUSION: In the Korean EAP cohort, ramucirumab showed similar efficacy to the results of the previous trials for gastric cancer. However, the level of GI perforation was slightly increased in the ramucirumab plus paclitaxel group.

Clinical trial of nintedanib in patients with recurrent or metastatic salivary gland cancer of the head and neck: A multicenter phase 2 study (Korean Cancer Study Group HN14-01).

BACKGROUND: Salivary gland cancers (SGCs) are uncommon and account for less than 5% of all head and neck cancers, but they are histologically heterogeneous. No specific therapy, including targeted agents, has consistently improved clinical outcomes in recurrent/metastatic SGC. Recent studies suggest that vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor (PDGFR) play important roles in SGC. Nintedanib is a potent small-molecule, triple-receptor tyrosine kinase inhibitor (VEGFR1, VEGFR2, and VEGFR3; fibroblast growth factor receptor 1 [FGFR1], FGFR2, and FGFR3; and PDGFRα and PDGFRß). This study sought to determine the antitumor activity of nintedanib in patients with recurrent or metastatic SGC. METHODS: This open-label, multicenter, phase 2, single-arm study was conducted at 11 hospitals in South Korea. Patients with pathologically confirmed recurrent and/or metastatic SGC for whom at least 1 line of systemic chemotherapy had failed were enrolled. Nintedanib was given orally at 200 mg twice a day until disease progression or unacceptable toxicity. The primary endpoint was the response rate. The secondary endpoints were progression-free survival, overall survival, toxicity, and the disease-control rate. The Simon 2-stage minimax design was used. RESULTS: The median age of the patients was 54 years, 60% were female, and 95% had an Eastern Cooperative Oncology Group performance status of 0 or 1. The majority of the patients had adenoid cystic carcinoma (65%), and 40% received at least 2 prior rounds of chemotherapy. After 20 patients were enrolled, the study was stopped because no responders were observed at stage I. There were no partial responses, but the disease-control rate was 75% (15 of 20). The median duration of stable disease was 8.2 months (range, 1.76-12.36 months). At the time of the data cutoff, with a median follow-up of 9.5 months, the median overall survival had not been reached, and the progression-free survival rate at 6 months was 60% (95% confidence interval, 0.34-0.79). Grade 3 adverse events included liver enzyme elevation (25%) and nausea/vomiting (5%). Four patients who required a dose reduction because of a grade 3 liver enzyme elevation showed no further grade 3 events. CONCLUSIONS: Single-agent nintedanib did not yield a partial response but did achieve a 75% disease-control rate with long-term stabilization in SGC patients. Because of the high rate and long duration of disease control with a good safety profile, further investigation is warranted. Cancer 2017;123:1958-1964. © 2017 American Cancer Society.

Germ Cell Tumor Targeting Chemotherapy in Gastric Adenocarcinoma with an Endodermal Sinus Tumor Component: A Case Report.

The most common sites for extragonadal germ cell tumors are the midline mediastinum, retroperitoneum and, much less frequently, the stomach. The stomach-originated primary germ cell tumor carries a poor prognosis, especially when metastasis occurs to the liver, with a mean survival time of 1 month. We describe the case of a 77-year-old male who presented with usual symptoms of gastric malignancy. Gastrectomy was performed. Histopathology of surgically resected tissue revealed a mixture of adenocarcinoma and endodermal sinus tumor components with α-fetoprotein production. After liver metastasis was identified, oxaliplatin and capecitabine were administered as palliative chemotherapy. The response was poor. For the second-line therapy, bleomycin, etoposide, and cisplatin (BEP) therapy was initiated. The overall response to these drugs was a partial response and the residual liver lesion was considered to be resectable. The patient died of pneumonia 11 months following the BEP session, representing an overall survival time of 22 months. Gastric adenocarcinoma with a germ cell tumor component is uncommon and an effective combination of chemotherapeutic agents is not yet clear. In this case, the patient received germ cell tumor-targeting chemotherapy and showed a durable response. Hence, germ cell-targeting cytotoxic agents have potential as the 'front-line regimen'.

A Tailored Intervention for Improving Diabetes Self-care Among Adults With Visual Impairment: A Pilot Study.

OBJECTIVES: Our aim in this study was to develop and evaluate a tailored intervention for improving diabetes self-care among people with visual impairment (TID-VI) in South Korea. METHODS: The TID-VI program was designed around the barriers, resources, and perceptual factors to promote diabetes self-care in those with visual impairment (VI). A single-arm pilot study was conducted to evaluate the feasibility and preliminary effects of the intervention. Diabetes self-efficacy, self-care behaviours, depression, health-related quality of life, and clinical outcomes (fasting blood glucose, glycated hemoglobin [A1C], lipids, and blood pressure) were measured before, and up to 2 months after the 12-week intervention. RESULTS: All 14 participants completed TID-VI. Diabetes self-efficacy, diabetes self-care behaviours, depression, and health-related quality of life showed improvement from baseline that was sustained at 2 months. Although high- and low-density lipoprotein also improved, there were no differences in blood glucose, A1C, total cholesterol, or blood pressure at 2 months. CONCLUSIONS: A theory-driven, tailored intervention specific to the needs of adults with VI can produce substantial improvements in patient-reported quality of life and health status outcomes, although the benefits are yet to be confirmed in a controlled study.

Silent struggles to self-manage high blood pressure among deaf sign language users: a qualitative study.

AIMS: Tailored self-management support of hypertension, considering language and communication, is important for minorities, specifically in the deaf community. However, little is known about the experiences of hypertension self-management in deaf individuals who use sign language. This study aimed to explore the factors and processes of self-management in deaf sign language users with hypertension. METHODS AND RESULTS: Ten men and women who used sign language participated in this study. Data were collected using in-depth personal interviews conducted in the presence of a sign language interpreter between November 2022 and February 2023. All interviews were recorded and transcribed for conventional content analysis. Qualitative analyses identified four categories related to the self-management of hypertension among participants: personal factors (chronic hand pain, unique language and communication, and efforts to turn crisis into opportunities), family and socioeconomic factors (family support and financial burden of living), challenges (limited health literacy and alienation from health education), and desire for health education considering the deaf community. CONCLUSION: The results of this study suggest that family support, socioeconomic status, hand pain, and health literacy should be considered for the planning and development of health education on self-management of hypertension in deaf individuals. In addition, this health education requires cooperation with qualified sign language interpreters in healthcare settings.

Comparison Study of a Thermal-Driven Microstructure in a High-Ni Cathode for Lithium-Ion Batteries: Critical Calcination Temperature for Polycrystalline and Single-Crystalline Design.

High-Ni layered oxide cathodes are promising candidates for lithium-ion batteries due to their high energy density. However, their cycle stability is compromised by the poor mechanical durability of the particle microstructure. In this study, we investigate the impact of the calcination temperature on microstructural changes, including primary particle growth and pore evolution, using LiNi0.88Mn0.08Co0.04O2 (N884), with an emphasis on the critical calcination temperature for polycrystalline and single-crystal designs in high-Ni cathodes. As the calcination temperature increases, the primary particles undergo a rectangular growth pattern while the pore population decreases. Beyond a certain critical temperature (in this case, 850 °C), a sudden increase in primary particle size and a simultaneous rapid reduction in the pore population are observed. This sudden microstructure evolution leads to poor cycle retention in N884. In contrast, single-crystal particles, free of grain boundaries, synthesized at this critical temperature exhibit superior cycle retention, underscoring the significance of microstructural design over crystalline quality for achieving long-term cyclability. Our study sheds light on the interplay between calcination temperature and microstructural evolution, proposing the critical temperature as a key criterion for single-crystal synthesis.

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.

A Histone Methylation-MAPK Signaling Axis Drives Durable Epithelial-Mesenchymal Transition in Hypoxic Pancreatic Cancer.

The tumor microenvironment in pancreatic ductal adenocarcinoma (PDAC) plays a key role in tumor progression and response to therapy. The dense PDAC stroma causes hypovascularity, which leads to hypoxia. Here, we showed that hypoxia drives long-lasting epithelial-mesenchymal transition (EMT) in PDAC primarily through a positive-feedback histone methylation-MAPK signaling axis. Transformed cells preferentially underwent EMT in hypoxic tumor regions in multiple model systems. Hypoxia drove a cell autonomous EMT in PDAC cells, which, unlike EMT in response to growth factors, could last for weeks. Furthermore, hypoxia reduced histone demethylase KDM2A activity, suppressed PP2 family phosphatase expression, and activated MAPKs to post-translationally stabilize histone methyltransferase NSD2, leading to an H3K36me2-dependent EMT in which hypoxia-inducible factors played only a supporting role. Hypoxia-driven EMT could be antagonized in vivo by combinations of MAPK inhibitors. Collectively, these results suggest that hypoxia promotes durable EMT in PDAC by inducing a histone methylation-MAPK axis that can be effectively targeted with multidrug therapies, providing a potential strategy for overcoming chemoresistance. SIGNIFICANCE: Integrated regulation of histone methylation and MAPK signaling by the low-oxygen environment of pancreatic cancer drives long-lasting EMT that promotes chemoresistance and shortens patient survival and that can be pharmacologically inhibited. See related commentary by Wirth and Schneider, p. 1739.

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

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