ELK3 destabilization by speckle-type POZ protein suppresses prostate cancer progression and docetaxel resistance.

Accumulating evidence demonstrates that the activity regulation of ELK3, a member of the E26 transformation-specific oncogene family, is critical to regulating cell proliferation, migration, and survival in human cancers. However, the molecular mechanisms of how ELK3 induces chemoresistance in prostate cancer (PCa) have not been elucidated. In this study, we found that SPOP and ELK3 are an interacting partner. The interaction between SPOP and ELK3 resulted in increased ELK3 ubiquitination and destruction, assisted by checkpoint kinase-mediated ELK3 phosphorylation. Notably, the modulation of SPOP-mediated ELK3 protein stability affected the c-Fos-induced cell proliferation and invasion of PCa cells. The clinical involvement of the SPOP-ELK3 axis in PCa development was confirmed by an immunohistochemical assay on 123 PCa tissues, with an inverse correlation between increased ELK3 and decreased SPOP being present in ~80% of the specimens. This observation was supported by immunohistochemistry analysis using a SPOP-mutant PCa specimen. Finally, docetaxel treatment induced cell death by activating checkpoint kinase- and SPOP-mediated ELK3 degradation, while SPOP-depleted or SPOP-mutated PCa cells showed cell death resistance. Notably, this observation was correlated with the protein levels of ELK3. Taken together, our study reveals the precise mechanism of SPOP-mediated degradation of ELK3 and provides evidence that SPOP mutations contribute to docetaxel resistance in PCa.

Lazertinib versus Gefitinib as First-Line Treatment for EGFR-mutated Locally Advanced or Metastatic NSCLC: LASER301 Korean Subset.

PURPOSE: This subgroup analysis of the Korean subset of patients in the phase 3 LASER301 trial evaluated the efficacy and safety of lazertinib versus gefitinib as first-line therapy for epidermal growth factor receptor mutated (EGFRm) non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: Patients with locally advanced or metastatic EGFRm NSCLC were randomized 1:1 to lazertinib (240 mg/day) or gefitinib (250 mg/day). The primary endpoint was investigator-assessed progression-free survival (PFS). RESULTS: In total, 172 Korean patients were enrolled (lazertinib, n=87; gefitinib, n=85). Baseline characteristics were balanced between the treatment groups. One-third of patients had brain metastases (BM) at baseline. Median PFS was 20.8 months (95% confidence interval [CI], 16.7 to 26.1) for lazertinib and 9.6 months (95% CI, 8.2 to 12.3) for gefitinib (hazard ratio [HR], 0.41; 95% CI, 0.28 to 0.60). This was supported by PFS analysis based on blinded independent central review. Significant PFS benefit with lazertinib was consistently observed across predefined subgroups, including patients with BM (HR, 0.28; 95% CI, 0.15 to 0.53) and those with L858R mutations (HR, 0.36; 95% CI, 0.20 to 0.63). Lazertinib safety data were consistent with its previously reported safety profile. Common adverse events (AEs) in both groups included rash, pruritus, and diarrhoea. Numerically fewer severe AEs and severe treatment-related AEs occurred with lazertinib than gefitinib. CONCLUSION: Consistent with results for the overall LASER301 population, this analysis showed significant PFS benefit with lazertinib versus gefitinib with comparable safety in Korean patients with untreated EGFRm NSCLC, supporting lazertinib as a new potential treatment option for this patient population.

Clinical Practice Recommendations for the Use of Next-Generation Sequencing in Patients with Solid Cancer: A Joint Report from KSMO and KSP.

In recent years, next-generation sequencing (NGS)-based genetic testing has become crucial in cancer care. While its primary objective is to identify actionable genetic alterations to guide treatment decisions, its scope has broadened to encompass aiding in pathological diagnosis and exploring resistance mechanisms. With the ongoing expansion in NGS application and reliance, a compelling necessity arises for expert consensus on its application in solid cancers. To address this demand, the forthcoming recommendations not only provide pragmatic guidance for the clinical use of NGS but also systematically classify actionable genes based on specific cancer types. Additionally, these recommendations will incorporate expert perspectives on crucial biomarkers, ensuring informed decisions regarding circulating tumor DNA panel testing.

Genomic profiling of subcutaneous patient-derived xenografts reveals immune constraints on tumor evolution in childhood solid cancer.

Subcutaneous patient-derived xenografts (PDXs) are an important tool for childhood cancer research. Here, we describe a resource of 68 early passage PDXs established from 65 pediatric solid tumor patients. Through genomic profiling of paired PDXs and patient tumors (PTs), we observe low mutational similarity in about 30% of the PT/PDX pairs. Clonal analysis in these pairs show an aggressive PT minor subclone seeds the major clone in the PDX. We show evidence that this subclone is more immunogenic and is likely suppressed by immune responses in the PT. These results suggest interplay between intratumoral heterogeneity and antitumor immunity may underlie the genetic disparity between PTs and PDXs. We further show that PDXs generally recapitulate PTs in copy number and transcriptomic profiles. Finally, we report a gene fusion LRPAP1-PDGFRA. In summary, we report a childhood cancer PDX resource and our study highlights the role of immune constraints on tumor evolution.

Parentage influence on gene expression under acidification revealed through single-embryo sequencing.

The dissolution of anthropogenic carbon dioxide (CO2 ) in seawater has altered its carbonate chemistry in the process of ocean acidification (OA). OA affects the viability of marine species. In particular, calcifying organisms and their early planktonic larval stages are considered vulnerable. These organisms often utilize energy reserves for metabolism rather than growth and calcification as supported by bulk RNA-sequencing (RNA-seq) experiments. Yet, transcriptomic profiling of a bulk sample reflects the average gene expression of the population, neglecting the variations between individuals, which forms the basis for natural selection. Here, we used single-embryo RNA-seq on larval sea urchin Heliocidaris crassispina, which is a commercially and ecologically valuable species in East Asia, to document gene expression changes to OA at an individual and family level. Three paternal half-sibs groups were fertilized and exposed to 3 pH conditions (ambient pH 8.0, 7.7 and 7.4) for 12 h prior to sequencing and oxygen consumption assay. The resulting transcriptomic profile of all embryos can be distinguished into four clusters, with differences in gene expressions that govern biomineralization, cell differentiation and patterning, as well as metabolism. While these responses were influenced by pH conditions, the male identities also had an effect. Specifically, a regression model and goodness of fit tests indicated a significant interaction between sire and pH on the probability of embryo membership in different clusters of gene expression. The single-embryo RNA-seq approach is promising in climate stressor research because not only does it highlight potential impacts before phenotypic changes were observed, but it also highlights variations between individuals and lineages, thus enabling a better determination of evolutionary potential.

Acute Treatment with the M-Channel (Kv7, KCNQ) Opener Retigabine Reduces the Long-Term Effects of Repetitive Blast Traumatic Brain Injuries.

We investigated whether pharmacological increase of "M-type" (KCNQ, Kv7) K + channel currents by the M-channel opener, retigabine (RTG), acutely after repetitive traumatic brain injuries (rTBIs), prevents or reduces their long-term detrimental effects. rTBIs were studied using a blast shock air wave mouse model. Animals were monitored by video and electroencephalogram (EEG) records for nine months after the last injury to assess the occurrence of post-traumatic seizures (PTS), post-traumatic epilepsy (PTE), sleep-wake cycle architecture alterations, and the power of the EEG signals. We evaluated the development of long-term changes in the brain associated with various neurodegenerative diseases in mice by examining transactive response DNA-binding protein 43 (TDP-43) expression and nerve fiber damage ~ 2 years after the rTBIs. We observed acute RTG treatment to reduce the duration of PTS and impair the development of PTE. Acute RTG treatment also prevented post-injury hypersomnia, nerve fiber damage, and cortical TDP-43 accumulation and translocation from the nucleus to the cytoplasm. Mice that developed PTE displayed impaired rapid eye movement (REM) sleep, and there were significant correlations between seizure duration and time spent in the different stages of the sleep-wake cycle. We observed acute RTG treatment to impair injury-induced reduction of age-related increase in gamma frequency power of the EGG, which has been suggested to be necessary for a healthy aged brain. The data show that RTG, administered acutely post-TBI, is a promising, novel therapeutic option to blunt/prevent several long-term effects of rTBIs. Furthermore, our results show a direct relationship between sleep architecture and PTE.

Field application of cost-effective sensors for the monitoring of NH3, H2S, and TVOC in environmental treatment facilities and the estimation of odor intensity.

Odor is usually a complex mixture of various compounds. In many countries, odor complaints have been addressed using the air dilution olfactory method (ADOM) to reduce their malodor complaint. In this study, continuous monitoring of ammonia, hydrogen sulfide, and total volatile organic compounds (TVOC) using sensors was conducted in facilities for municipal and livestock wastewater treatment (LWT), and for food waste composting (FWC). Odor intensity was modeled by multivariate linear regression using sensor monitoring data with air dilution measured by the ADOM. In testing the performance of sensors in the lab, all three sensors showed acceptable values for linearity, accuracy, repeatability, lowest detection limit, and response time, so the sensors were acceptable for application in the field. In on-site real-time monitoring, the three sensors functioned well in the three environmental facilities during the testing period. Average ammonia and hydrogen sulfide concentrations were high in the LWT facility, while TVOC showed the highest concentration in the FWC facility. A longer sampling time is necessary for ammonia monitoring. Odor intensity from individual sensor data correlated well to complex odor measured by the ADOM. Finally, we suggest a protocol for field application of sensor monitoring and odor data reproduction.Implications: We suggest a protocol for the field application of sensor monitoring and odor data estimation in this study. This study can be useful to a policy maker and field operator to reduce odor emission through the determination of a more effective treatment technology and removal pathway for individual odorants.

MicroRNA-769-3p Acts as a Prognostic Factor in Oral Squamous Cell Cancer by Modulating Stromal Genes.

miR-769-3p expression is suppressed in the stromal subtype of head and neck squamous cell carcinoma (HNSCC); however, its role in stromal HNSCC has not been fully elucidated. To investigate the biological relevance of miR-769-3p in the stromal phenotype, we established oral squamous cell cancer (OSCC) cell lines, namely CAL27, HSC3, and YD8, overexpressing miR-769-3p. miR-769-3p expression was positively and negatively correlated with interferon-gamma-related genes and MYC target gene sets, respectively. miR-769-3p decreased OSCC cell migration and invasion as well as mesenchymal marker expression and increased epithelial marker expression. Moreover, miR-769-3p enhanced OSCC cell sensitivity to 5-fluorouracil. High miR-769-3p expression was associated with good prognosis of HNSCC patients. Collectively, these results suggest that miR-769-3p suppression enhances stromal gene expression and promotes the epithelial-to-mesenchymal transition. Therefore, miR-769-3p may be a potential biomarker of the miRNA phenotype in OSCC patients.

Differential RNA expression of immune-related genes and tumor cell proximity from intratumoral M1 macrophages in acral lentiginous melanomas treated with PD-1 blockade.

Immune checkpoint inhibitors (ICIs) offer improved survival for patients with advanced malignant melanomas. However, only a subset of these patients exhibit an objective response rate of 10-40 % with ICIs. We aimed to ascertain the effects of RNA signatures and the spatial distribution of immune cells on the treatment outcomes of patients with malignant melanomas undergoing ICI therapy. Clinical data were retrospectively collected from ICI-treated patients with malignant melanoma; RNA expression profiles were examined via next-generation sequencing, whereas the composition, density, and spatial distribution of immune cells were determined via multiplex immunohistochemistry. Patients with poor and good responses to ICIs showed significant differences in mRNA expression profiles. Different spatial distributions of T-cells, macrophages, and NK cells as well as RNA signatures of immune-related genes were found to be closely related to therapeutic outcomes in ICI-treated patients with malignant melanomas. The spatial distributions of PD-1+ T-cells and activated M1 macrophages showed a significant correlation with favorable responses to ICIs. Our findings highlight the clinical relevance of the spatial proximity of immune cell subsets in the treatment outcomes of metastatic malignant melanoma.

Identification and Characterization of Cancer-Associated Fibroblast Subpopulations in Lung Adenocarcinoma.

Cancer-associated fibroblasts (CAFs) reside within the tumor microenvironment, facilitating cancer progression and metastasis via direct and indirect interactions with cancer cells and other stromal cell types. CAFs are composed of heterogeneous subpopulations of activated fibroblasts, including myofibroblastic, inflammatory, and immunosuppressive CAFs. In this study, we sought to identify subpopulations of CAFs isolated from human lung adenocarcinomas and describe their transcriptomic and functional characteristics through single-cell RNA sequencing (scRNA-seq) and subsequent bioinformatics analyses. Cell trajectory analysis of combined total and THY1 + CAFs revealed two branching points with five distinct branches. Based on Gene Ontology analysis, we denoted Branch 1 as "immunosuppressive", Branch 2 as "neoantigen presenting", Branch 4 as "myofibroblastic", and Branch 5 as "proliferative" CAFs. We selected representative branch-specific markers and measured their expression levels in total and THY1 + CAFs. We also investigated the effects of these markers on CAF activity under coculture with lung cancer cells. This study describes novel subpopulations of CAFs in lung adenocarcinoma, highlighting their potential value as therapeutic targets.

Stopping by looking: A driver-pedestrian interaction study in a coupled simulator using head-mounted displays with eye-tracking.

Automated vehicles (AVs) can perform low-level control tasks but are not always capable of proper decision-making. This paper presents a concept of eye-based maneuver control for AV-pedestrian interaction. Previously, it was unknown whether the AV should conduct a stopping maneuver when the driver looks at the pedestrian or looks away from the pedestrian. A two-agent experiment was conducted using two head-mounted displays with integrated eye-tracking. Seventeen pairs of participants (pedestrian and driver) each interacted in a road crossing scenario. The pedestrians' task was to hold a button when they felt safe to cross the road, and the drivers' task was to direct their gaze according to instructions. Participants completed three 16-trial blocks: (1) Baseline, in which the AV was pre-programmed to yield or not yield, (2) Look to Yield (LTY), in which the AV yielded when the driver looked at the pedestrian, and (3) Look Away to Yield (LATY), in which the AV yielded when the driver did not look at the pedestrian. The driver's eye movements in the LTY and LATY conditions were visualized using a virtual light beam. Crossing performance was assessed based on whether the pedestrian held the button when the AV yielded and released the button when the AV did not yield. Furthermore, the pedestrians' and drivers' acceptance of the mappings was measured through a questionnaire. The results showed that the LTY and LATY mappings yielded better crossing performance than Baseline. Furthermore, the LTY condition was best accepted by drivers and pedestrians. Eye-tracking analyses indicated that the LTY and LATY mappings attracted the pedestrian's attention, while pedestrians still distributed their attention between the AV and a second vehicle approaching from the other direction. In conclusion, LTY control may be a promising means of AV control at intersections before full automation is technologically feasible.

Discussing POLST-facilitated hospice care enrollment in patients with terminal cancer.

PURPOSE: A multicenter prospective study to evaluate the feasibility of Physician Orders for Life-Sustaining Treatment (POLST) in oncology practice was conducted between June and December 2017. Factors associated with POLST completion and follow-up outcomes were analyzed. METHODS: Patients with terminal cancer, aged ≥ 20 years and capable of communicating, were enrolled from seven hospitals. Demographic data were collected and updated in February 2021. Descriptive statistics and logistic regression analyses were conducted. RESULTS: Among 336 patients, 105 (31.3%) completed POLST, which was more common in male (p = 0.029), patients with better performance (p < 0.001), longer duration of follow-up (p = 0.037), and those living with children (p = 0.023). Male (odds ratio [OR], 2.30; 95% confidence interval [CI], 1.17-3.51; p = 0.012), having good performance status (OR, 2.38; 95% CI, (1.35-4.19); p = 0.003), transferred from other departments (OR, 0.50; 95% CI, (0.26-0.98); p = 0.045), and living with children (OR, 1.94; 95% CI, (1.11-3.47); p = 0.020) were significant predictors of POLST completion. Patients who completed POLST were more likely to enroll in hospice care (p = 0.012) or experience out-of-hospital death (p = 0.016) at end-of-life (EOL). POLST completion showed a strong association with hospice enrollment at EOL (OR, 2.61; 95% CI, (1.08-6.32); p = 0.033). CONCLUSION: Gender, patient performance, timing of POLST discussion, and type of household were associated with POLST completion. Earlier discussions on POLST could reinforce hospice enrollment or non-aggressive EOL care.

Prognostic value of Dickkopf-1 and ß-catenin expression according to the antitumor immunity of CD8-positive tumor-infiltrating lymphocytes in biliary tract cancer.

The role of ß-catenin and Dickkopf-1 (DKK1) is dependent on the specific immunobiology of T cell inflammation in biliary tract cancer (BTC). We aimed to analyze the role of DKK1 or ß-catenin as a prognostic factor in BTC, and determine the clinical associations of ß-catenin and DKK1 with CD8+ tumor-infiltrating lymphocytes (TIL). We used data from The Cancer Genome Atlas Research Network and the clinicopathological data of 145 patients with BTC who had undergone primary radical resection between 2006 and 2016. CD8+ TIL expression was a significant predictor of favorable overall survival (OS) and relapse-free survival (RFS) (median OS, 34.9 months in high-TIL, 16.7 months in low-TIL, P < 0.0001 respectively; median RFS, 27.1 months in high-TIL, 10.0 months in low-TIL, P < 0.0001 respectively). In the high-CD8+ TIL BTC group, the tumor expression of ß-catenin and DKK1 had a significant negative impact on either OS or RFS. In the low-TIL BTC group, there were no differences according to ß-catenin and DKK1 expression. Cox regression multivariate analysis demonstrated that CD8+ TIL and ß-catenin retained significant association with OS. Among patients with resected BTC, the ß-catenin and DKK1 protein and high CD8+ TIL levels were associated with poor and good clinical outcomes, respectively.

A Phase 1/2 Study of Lazertinib 240 mg in Patients With Advanced EGFR T790M-Positive NSCLC After Previous EGFR Tyrosine Kinase Inhibitors.

INTRODUCTION: This integrated analysis of a phase 1/2 study (NCT03046992) evaluated the efficacy and safety of lazertinib, a third-generation EGFR tyrosine kinase inhibitor (TKI), in patients with advanced EGFR T790M-positive NSCLC after previous EGFR TKI therapy. METHODS: Adults with EGFR mutation-positive NSCLC that progressed after prior EGFR-directed TKIs received once daily oral lazertinib 240 mg continuously until disease progression. Prior TKIs to treat T790M-positive NSCLC were prohibited. Primary endpoints were safety and objective response rate (ORR). Secondary endpoints included progression-free survival, overall survival, and intracranial ORR. RESULTS: A total of 78 patients received lazertinib 240 mg at 17 centers in South Korea. Among patients with T790M-positive tumors at baseline (N = 76), one (1.3%) had a complete response and 41 (53.9%) had partial responses, giving an ORR of 55.3% (95% confidence interval [CI]: 44.1-66.4). Median progression-free survival was 11.1 months (95% CI: 5.5-16.4). Median overall survival was not reached (median follow-up = 22.0 mo). In patients with measurable intracranial lesions (n = 7), one (14.3%) had a complete intracranial response and five (71.4%) had partial responses, giving an intracranial ORR of 85.7% (95% CI: 59.8%-100.0%). The most common treatment-emergent adverse events were rash (37.2%), pruritus (34.6%), and paresthesia (33.3%); most were mild to moderate in severity. Serious drug-related adverse events occurred in three patients (gastritis, pneumonia, pneumonitis). The major mechanism of resistance was EGFR T790M loss. CONCLUSIONS: Lazertinib 240 mg/d has a manageable safety profile with durable antitumor efficacy, including brain metastases, in patients with advanced T790M-positive NSCLC after previous EGFR TKI therapy.

Hyperosmolar hyperglycemic state as the first manifestation of type 1 diabetes mellitus in an adolescent male: a case report.

A hyperosmolar hyperglycemic state (HHS) is a life-threatening complication rarely seen in children and adolescents with type 1 diabetes mellitus (T1DM). However, early diagnosis and proper treatment are vital to reduce the high morbidity and mortality rates associated with HHS. We describe a male patient who presented with polydipsia, polyuria, and a drowsy mental status. His initial biochemistry results demonstrated severe hyperglycemia (1,456 mg/dL), hyperosmolarity of 359 mOsm/kg (effective osmolarity, 323 mOsm/kg), and mild acidosis (venous pH, 7.327). The patient was diagnosed with HHS and T1DM based on the presence of hyperosmolarity, hyperglycemia, and positivity for antiglutamic acid antibodies. Intensive intravenous fluid and regular insulin (0.025 units/kg/hr) were administered. After hydration and insulin treatment, the patient's mental status and serum glucose and sodium levels improved, and no neurological complications were observed. In summary, most cases of HHS are observed in adult patients with type 2 diabetes. However, occurrences in children and adolescents with T1DM have also been reported. Therefore, HHS should be considered in the differential diagnosis of hyperglycemic emergencies.

Neuroprotective Roles of the Adenosine A3 Receptor Agonist AST-004 in Mouse Model of Traumatic Brain Injury.

Traumatic brain injury (TBI) remains one of the greatest public health concerns with increasing morbidity and mortality rates worldwide. Our group reported that stimulation of astrocyte mitochondrial metabolism by P2Y1 receptor agonists significantly reduced cerebral edema and reactive gliosis in a TBI model. Subsequent data on the pharmacokinetics (PK) and rapid metabolism of these compounds suggested that neuroprotection was likely mediated by a metabolite, AST-004, which binding data indicated was an adenosine A3 receptor (A3R) agonist. The neuroprotective efficacy of AST-004 was tested in a control closed cortical injury (CCCI) model of TBI in mice. Twenty-four (24) hours post-injury, mice subjected to CCCI and treated with AST-004 (0.22 mg/kg, injected 30 min post-trauma) exhibited significantly less secondary brain injury. These effects were quantified with less cell death (PSVue794 fluorescence) and loss of blood brain barrier breakdown (Evans blue extravasation assay), compared to vehicle-treated TBI mice. TBI-treated mice also exhibited significantly reduced neuroinflammatory markers, glial-fibrillary acidic protein (GFAP, astrogliosis) and ionized Ca2+-binding adaptor molecule 1 (Iba1, microgliosis), both at the mRNA (qRT-PCR) and protein (Western blot and immunofluorescence) levels, respectively. Four (4) weeks post-injury, both male and female TBI mice presented a significant reduction in freezing behavior during contextual fear conditioning (after foot shock). AST-004 treatment prevented this TBI-induced impairment in male mice, but did not significantly affect impairment in female mice. Impairment of spatial memory, assessed 24 and 48 h after the initial fear conditioning, was also reduced in AST-004-treated TBI-male mice. Female TBI mice did not exhibit memory impairment 24 and 48 h after contextual fear conditioning and similarly, AST-004-treated female TBI mice were comparable to sham mice. Finally, AST-004 treatments were found to increase in vivo ATP production in astrocytes (GFAP-targeted luciferase activity), consistent with the proposed mechanism of action. These data reveal AST-004 as a novel A3R agonist that increases astrocyte energy production and enhances their neuroprotective efficacy after brain injury.

Inhibition of STAT3 enhances sensitivity to tamoxifen in tamoxifen-resistant breast cancer cells.

BACKGROUND: The mechanisms of endocrine resistance are complex, and deregulation of several oncogenic signalling pathways has been proposed. We aimed to investigate the role of the EGFR and Src-mediated STAT3 signalling pathway in tamoxifen-resistant breast cancer cells. METHODS: The ER-positive luminal breast cancer cell lines, MCF-7 and T47D, were used. We have established an MCF-7-derived tamoxifen-resistant cell line (TamR) by long-term culture of MCF-7 cells with 4-hydroxytamoxifen. Cell viability was determined using an MTT assay, and protein expression levels were determined using western blot. Cell cycle and annexin V staining were analysed using flow cytometry. RESULTS: TamR cells showed decreased expression of estrogen receptor and increased expression of EGFR. TamR cells showed an acceleration of the G1 to S phase transition. The protein expression levels of phosphorylated Src, EGFR (Y845), and STAT3 was increased in TamR cells, while phosphorylated Akt was decreased. The expression of p-STAT3 was enhanced according to exposure time of tamoxifen in T47D cells, suggesting that activation of STAT3 can cause tamoxifen resistance in ER-positive breast cancer cells. Both dasatinib (Src inhibitor) and stattic (STAT3 inhibitor) inhibited cell proliferation and induced apoptosis in TamR cells. However, stattic showed a much stronger effect than dasatinib. Knockdown of STAT3 expression by siRNA had no effect on sensitivity to tamoxifen in MCF-7 cells, while that enhanced sensitivity to tamoxifen in TamR cells. There was not a significant synergistic effect of dasatinib and stattic on cell survival. TamR cells have low nuclear p21(Cip1) expression compared to MCF-7 cells and inhibition of STAT3 increased the expression of nuclear p21(Cip1) in TamR cells. CONCLUSIONS: The EGFR and Src-mediated STAT3 signalling pathway is activated in TamR cells, and inhibition of STAT3 may be a potential target in tamoxifen-resistant breast cancer. An increase in nuclear p21(Cip1) may be a key step in STAT3 inhibitor-induced cell death in TamR cells.

DeepRePath: Identifying the Prognostic Features of Early-Stage Lung Adenocarcinoma Using Multi-Scale Pathology Images and Deep Convolutional Neural Networks.

The prognosis of patients with lung adenocarcinoma (LUAD), especially early-stage LUAD, is dependent on clinicopathological features. However, its predictive utility is limited. In this study, we developed and trained a DeepRePath model based on a deep convolutional neural network (CNN) using multi-scale pathology images to predict the prognosis of patients with early-stage LUAD. DeepRePath was pre-trained with 1067 hematoxylin and eosin-stained whole-slide images of LUAD from the Cancer Genome Atlas. DeepRePath was further trained and validated using two separate CNNs and multi-scale pathology images of 393 resected lung cancer specimens from patients with stage I and II LUAD. Of the 393 patients, 95 patients developed recurrence after surgical resection. The DeepRePath model showed average area under the curve (AUC) scores of 0.77 and 0.76 in cohort I and cohort II (external validation set), respectively. Owing to low performance, DeepRePath cannot be used as an automated tool in a clinical setting. When gradient-weighted class activation mapping was used, DeepRePath indicated the association between atypical nuclei, discohesive tumor cells, and tumor necrosis in pathology images showing recurrence. Despite the limitations associated with a relatively small number of patients, the DeepRePath model based on CNNs with transfer learning could predict recurrence after the curative resection of early-stage LUAD using multi-scale pathology images.

DeepCUBIT: Predicting Lymphovascular Invasion or Pathological Lymph Node Involvement of Clinical T1 Stage Non-Small Cell Lung Cancer on Chest CT Scan Using Deep Cubical Nodule Transfer Learning Algorithm.

The prediction of lymphovascular invasion (LVI) or pathological nodal involvement of tumor cells is critical for successful treatment in early stage non-small cell lung cancer (NSCLC). We developed and validated a Deep Cubical Nodule Transfer Learning Algorithm (DeepCUBIT) using transfer learning and 3D Convolutional Neural Network (CNN) to predict LVI or pathological nodal involvement on chest CT images. A total of 695 preoperative CT images of resected NSCLC with tumor size of less than or equal to 3 cm from 2008 to 2015 were used to train and validate the DeepCUBIT model using five-fold cross-validation method. We also used tumor size and consolidation to tumor ratio (C/T ratio) to build a support vector machine (SVM) classifier. Two-hundred and fifty-four out of 695 samples (36.5%) had LVI or nodal involvement. An integrated model (3D CNN + Tumor size + C/T ratio) showed sensitivity of 31.8%, specificity of 89.8%, accuracy of 76.4%, and AUC of 0.759 on external validation cohort. Three single SVM models, using 3D CNN (DeepCUBIT), tumor size or C/T ratio, showed AUCs of 0.717, 0.630 and 0.683, respectively on external validation cohort. DeepCUBIT showed the best single model compared to the models using only C/T ratio or tumor size. In addition, the DeepCUBIT model could significantly identify the prognosis of resected NSCLC patients even in stage I. DeepCUBIT using transfer learning and 3D CNN can accurately predict LVI or nodal involvement in cT1 size NSCLC on CT images. Thus, it can provide a more accurate selection of candidates who will benefit from limited surgery without increasing the risk of recurrence.

Changes in the palliative performance scale may be as important as the initial palliative performance scale for predicting survival in terminal cancer patients.

OBJECTIVE: The accurate estimation of expected survival in terminal cancer patients is important. The palliative performance scale (PPS) is an important factor in predicting survival of hospice patients. The purpose of this study was to examine how initial status of PPS and changes in PPS affect the survival of hospice patients in Korea. METHOD: We retrospectively examined 315 patients who were admitted to our hospice unit between January 2017 and December 2018. The patients were divided based on the PPS of ≥50% (group A) and ≤40% (group B). We performed survival analysis for factors associated with the length of survival (LOS) in group A. Based on the hospice team's weekly evaluation of PPS, we examined the effect of initial levels and changes in group A on the prognosis of patients who survived for 2 weeks or more. RESULTS: At the time of admission to hospice, 265 (84.1%) patients were PPS ≥50%, and 50 (15.9%) were PPS ≤40%. The median LOS of PPS ≥50% and PPS ≤40% were 15 (2-158 days) and 9 (2-43 days), respectively. Male, gastrointestinal cancer, and lower initial PPS all predicted poor prognosis in group A. Male, gastrointestinal cancer, and a PPS change of 10% or greater, compared with initial status 1 week and 2 weeks of hospitalization, were all predictors of poor prognosis in group A patients who survived for 2 weeks or longer. SIGNIFICANCE OF RESULTS: Our research demonstrates the significance of PPS change at 1 week and 2 weeks, suggesting the importance of evaluating not only initial PPS but also change in PPS.