Butyrate inhibits the malignant biological behaviors of breast cancer cells by facilitating cuproptosis-associated gene expression.

BACKGROUND: Butyrate is a common short-chain fatty acids (SCFA), and it has been demonstrated to regulate the development of breast cancer (BC), while the underlying mechanism is still unreported. METHODS: Gas chromatography was used to measure the amounts of SCFA (acetate, propionate, and butyrate) in the feces. Cell viability was measured by the CCK-8 assay. The wound healing assay demonstrated cell migration, and the transwell assay demonstrated cell invasion. The levels of protein and gene were determined by western blot assay and RT-qPCR assay, respectively. RESULTS: The levels of SCFA were lower in the faecal samples from BC patients compared to control samples. In cellular experiments, butyrate significantly suppressed the cell viability, migration and invasion of T47D in a dose-dependent manner. In animal experiments, butyrate effectively impeded the growth of BC tumors. Toll like receptor 4 (TLR4) was highly expressed in the tumors from BC patients. Butyrate inhibited the expression of TLR4. In addition, butyrate promoted the expression of cuproptosis-related genes including PDXK (pyridoxal kinase) and SLC25A28 (solute carrier family 25 member 28), which was lowly expressed in BC tumors. Importantly, overexpression of TLR4 can reverses the promotion of butyrate to PDXK and SLC25A28 expression and the prevention of butyrate to the malignant biological behaviors of T47D cells. CONCLUSION: In summary, butyrate inhibits the development of BC by facilitating the expression of PDXK and SLC25A28 through inhibition of TLR4. Our investigation first identified a connection among butyrate, TLR4 and cuproptosis-related genes in BC progression. These findings may provide novel target for the treatment of BC.

Fruquintinib plus paclitaxel versus placebo plus paclitaxel for gastric or gastroesophageal junction adenocarcinoma: the randomized phase 3 FRUTIGA trial.

The vascular endothelial growth factor pathway plays a key role in the pathogenesis of gastric cancer. In the multicenter, double-blind phase 3 FRUTIGA trial, 703 patients with advanced gastric or gastroesophageal junction adenocarcinoma who progressed on fluorouracil- and platinum-containing chemotherapy were randomized (1:1) to receive fruquintinib (an inhibitor of vascular endothelial growth factor receptor-1/2/3; 4 mg orally, once daily) or placebo for 3 weeks, followed by 1 week off, plus paclitaxel (80 mg/m2 intravenously on days 1/8/15 per cycle). The study results were positive as one of the dual primary endpoints, progression-free survival (PFS), was met (median PFS, 5.6 months in the fruquintinib arm versus 2.7 months in the placebo arm; hazard ratio 0.57; 95% confidence interval 0.48-0.68; P < 0.0001). The other dual primary endpoint, overall survival (OS), was not met (median OS, 9.6 months versus 8.4 months; hazard ratio 0.96, 95% confidence interval 0.81-1.13; P = 0.6064). The most common grade ≥3 adverse events were neutropenia, leukopenia and anemia. Fruquintinib plus paclitaxel as a second-line treatment significantly improved PFS, but not OS, in Chinese patients with advanced gastric or gastroesophageal junction adenocarcinoma and could potentially be another treatment option for these patients. ClinicalTrials.gov registration: NCT03223376 .

Lumbar foraminal stenosis was associated with back pain and leg pain: epidemiological evidence from a population-based cohort.

OBJECTIVES: To determine the characteristics of lumbar foraminal stenosis (LFS) on magnetic resonance (MR) images and their association with back pain and radiating leg pain in a population-based sample of Chinese subjects. METHODS: This study was an extension of the Hangzhou Lumbar Spine Study, a cross-sectional study focusing on back pain and lumbar spine MR imaging findings. Questionnaire data, including demographics, lifestyle, occupational exposures, back pain and radiating leg pain were included. On lumbar spine MR images, disc degeneration was assessed using Pfirrmann grade and Modic changes were evaluated. Using Lee's scale, the L3-S1 intervertebral foramina were evaluated, with grade 2-3 representing substantial LFS and grade 0-1 no LFS. Characteristics of LFS were noted, and associations of LFS with back pain and radiating leg pain were examined. RESULTS: Among the 644 study subjects, 141 (21.9%) had at least one LFS, and its occurrence was associated with greater age (OR = 1.93 for each 10 years, p < 0.001). Substantial LFS was associated with the presence of back pain (OR = 1.92, p = 0.001) and the intensity of the worst back pain (Coef = 8.30, p < 0.001) over the past 12 months, and disabling back pain during their lifetime (OR = 2.25, p < 0.001). Substantial LFS was also associated with leg pain (OR = 14.27, p < 0.001), with a sensitivity of 75.7% for the presence of radiating leg pain and a specificity of 81.4%. CONCLUSION: Substantial LFS on MR images was a common age-related degenerative phenotype in adults, and appears to be an independent risk factor for back pain and leg pain.

Sub-pixel target fine spatial feature extraction method based on aperture coding and micro-scanning imaging mechanism.

The small imaging size of targets over long distances results in the loss of geometry and spatial features. Current methods are subject to sampling limitations and cannot accurately capture the spatial features of sub-pixel targets. This paper proposes a method to accurately locate and extract the fine spatial features of sub-pixel targets through aperture coding and micro-scanning imaging. First, the formation mechanism of imaging features for sub-pixel targets is analyzed. Second, the optical aperture is anisotropically coded in different directions to modulate the spreading spots of the target. The primary spreading direction and the center of the anisotropic spreading spots are extracted. The contour and the location of the target are determined from the spreading length and the intersections of the primary spreading directions. Then, the target is sampled by different detector units through various micro-scanning offsets. The pixel units containing different sub-pixel components of the target after offset are determined based on the location results. The fine spatial distribution of the sub-pixel target is reconstructed based on the intensity variations in the pixel units containing the target. Finally, the accuracy of the sub-pixel target fine spatial feature extraction method is validated. The results show a sub-pixel localization error of less than 0.02 and an effective improvement of the sub-pixel target spatial resolution. This paper provides significant potential for improving the ability to capture spatial features of targets over long distances.

The Role and Treatment Strategies of Ammonia-Related Metabolism in Tumor Microenvironment.

Tumor cells achieve their adaptability through various metabolic reprogramming processes. Among them, ammonia, as a traditional metabolic waste, plays an increasingly important role in the tumor microenvironment along with its associated metabolites. Other cells in the microenvironment can also reshape the immune status of the microenvironment by regulating ammonia-related metabolism, and targeting this metabolic aspect has emerged as a potential strategy for tumor treatment. In this study, we have systematically reviewed the source and destination of ammonia in tumor cells, as well as the links between ammonia and other biological processes. We have also analyzed the ammonia-related metabolic regulation of other cells (including T cells, macrophages, dendritic cells, natural killer cells, myeloid-derived suppressor cells, and stromal cells) in the tumor microenvironment, and summarized the tumor treatment methods that target this metabolism. Through ammonia-related metabolic reprogramming, tumor cells obtain the energy they need for rapid growth and proliferation. Multiple immune cells and stromal cells in the microenvironment also interact with each other through this metabolic regulation, ultimately leading to immune suppression. Despite the heterogeneity of tumors and the complexity of cellular functions, further research into therapeutic interventions targeting ammonia-related metabolism is warranted. This review has focused on the role and regulation of ammonia-related metabolism in tumor cells and other cells in the microenvironment, and highlighted the efficacy and prospects of targeted ammonia-related metabolism therapy.

Automatic segmentation of 15 critical anatomical labels and measurements of cardiac axis and cardiothoracic ratio in fetal four chambers using nnU-NetV2.

BACKGROUND: Accurate segmentation of critical anatomical structures in fetal four-chamber view images is essential for the early detection of congenital heart defects. Current prenatal screening methods rely on manual measurements, which are time-consuming and prone to inter-observer variability. This study develops an AI-based model using the state-of-the-art nnU-NetV2 architecture for automatic segmentation and measurement of key anatomical structures in fetal four-chamber view images. METHODS: A dataset, consisting of 1,083 high-quality fetal four-chamber view images, was annotated with 15 critical anatomical labels and divided into training/validation (867 images) and test (216 images) sets. An AI-based model using the nnU-NetV2 architecture was trained on the annotated images and evaluated using the mean Dice coefficient (mDice) and mean intersection over union (mIoU) metrics. The model's performance in automatically computing the cardiac axis (CAx) and cardiothoracic ratio (CTR) was compared with measurements from sonographers with varying levels of experience. RESULTS: The AI-based model achieved a mDice coefficient of 87.11% and an mIoU of 77.68% for the segmentation of critical anatomical structures. The model's automated CAx and CTR measurements showed strong agreement with those of experienced sonographers, with respective intraclass correlation coefficients (ICCs) of 0.83 and 0.81. Bland-Altman analysis further confirmed the high agreement between the model and experienced sonographers. CONCLUSION: We developed an AI-based model using the nnU-NetV2 architecture for accurate segmentation and automated measurement of critical anatomical structures in fetal four-chamber view images. Our model demonstrated high segmentation accuracy and strong agreement with experienced sonographers in computing clinically relevant parameters. This approach has the potential to improve the efficiency and reliability of prenatal cardiac screening, ultimately contributing to the early detection of congenital heart defects.

Insights into the Origin of Activity Enhancement via Tuning Electronic Structure of Cu2O towards Electrocatalytic Ammonia Synthesis.

The insight of the activity phase and reaction mechanism is vital for developing high-performance ammonia synthesis electrocatalysts. In this study, the origin of the electronic-dependent activity for the model Cu2O catalyst toward ammonia electrosynthesis with nitrate was probed. The modulation of the electronic state and oxygen vacancy content of Cu2O was realized by doping with halogen elements (Cl, Br, I). The electrocatalytic experiments showed that the activity of the ammonia production depends strongly on the electronic states in Cu2O. With increased electronic state defects in Cu2O, the ammonia synthesis performance increased first and then decreased. The Cu2O/Br with electronic defects in the middle showed the highest ammonia yield of 11.4 g h-1 g-1 at -1.0 V (vs. RHE), indicating that the pattern of change in optimal ammonia activity is consistent with the phenomenon of volcano curves in reaction chemistry. This work highlights a promising route for designing NO3-RR to NH3 catalysts.

Assessment of OCT-Based Macular Curvature and Its Relationship with Macular Microvasculature in Children with Anisomyopia.

INTRODUCTION: To evaluate the intraocular differences in optical coherence tomography (OCT)-based macular curvature index (MCI) among children with anisomyopia and to investigate the relationship between MCI and the macular microvasculature. METHODS: Fifty-two schoolchildren with anisometropia > 2.00 D were enrolled and underwent comprehensive examinations including cycloplegic refraction, axial length (AL), and swept source OCT/OCT angiography. OCT-based MCIs were determined from horizontal and vertical B-scans by a customized curve fitting model in MATLAB R2022 at 1-mm-, 3-mm-, and 6-mm-diameter circles at fovea. Characteristics and topographic variation of MCI was analyzed, and the relationships with microvascularity and its associated factors were investigated. RESULTS: MCI achieved high reliability and repeatability. There were overall larger MCIs in the more myopic eyes than the less myopic eyes in 1-mm-, 3-mm-, and 6-mm-diameter circles at fovea (all p < 0.001). For the topographic variation, horizontal MCI was significantly greater than vertical MCI (all p < 0.001), and was the largest in 6-mm circle, followed by 3-mm and 1-mm circles. Stronger correlation of horizontal MCI with myopic severity than vertical MCI was found. Partial Pearson's correlation found MCI was negatively associated with deep capillary plexus (DCP) vessel density (p = 0.016). Eyes with a higher MCI in a 6-mm circle were more likely to have longer AL (p < 0.001), lower DCP vessel density (p = 0.037), and thinner choroidal thickness (ChT) (p = 0.045). CONCLUSION: Larger MCI was found in the more myopic eyes of children with anisomyopia and was significantly associated with smaller DCP density, suggesting that MCI was an important indicator of myopia-related retinal microvascularity change, and it could be a valuable metric for myopia assessment in children.

KEYNOTE-811: Potential to revise first-line therapy for metastatic human epidermal growth factor receptor 2-positive gastric cancer.

The first-line therapy pattern transition of metastatic HER2-positive gastric cancer is shifting. The KEYNOTE-811 study demonstrated that the addition of immunotherapy to the standard treatment of HER2-targeted therapy and chemotherapy showed good results in terms of PFS, especially in subgroup patients with PD-L1 CPS≥1. In the future, the first-line therapy pattern of metastatic HER2-positive gastric cancer will be radically changed based on ongoing randomized controlled clinical trials.

Design and sample size determination for multiple-dose randomized phase II trials for dose optimization.

The U.S. Food and Drug Administration (FDA) has launched Project Optimus to shift dose selection from the maximum tolerated dose (MTD) to the dose that produces the optimal risk-benefit tradeoff. One approach highlighted in the FDA's guidance involves conducting a randomized phase II trial following the completion of a phase I trial, where multiple doses (typically including the MTD and one or two doses lower than the MTD) are compared to identify the optimal dose that maximizes the benefit-risk tradeoff. This article focuses on the design of such a multiple-dose randomized trial, specifically the determination of the sample size. We generalized the standard definitions of type I error and power to accommodate the unique characteristics of dose optimization and derived a decision rule along with an algorithm to determine the optimal sample size. The resulting design is referred to as MERIT (Multiple-dosE RandomIzed Trial design for dose optimization based on toxicity and efficacy). Simulation studies demonstrate that MERIT has desirable operating characteristics, and a sample size between 20 and 40 per dosage arm often offers reasonable power and type I errors to ensure patient safety and benefit. To facilitate the implementation of the MERIT design, we provide software, available at https://www.trialdesign.org.

Phase 1b study of batiraxcept in combination with durvalumab in patients with platinum-resistant ovarian cancer.

Combining an immune checkpoint inhibitor with batiraxcept (AVB-S6-500), an AXL inhibitor that acts via selective binding to growth arrest-specific protein 6 (GAS6), may improve anti-tumor immunity in platinum-resistant ovarian cancer (PROC). This phase 1b trial of durvalumab in combination with escalating doses of batiraxcept enrolled patients with recurrent PROC (NCT04019288). The primary objective was to determine the toxicity profile of the combination. Eleven patients were enrolled on the trial. No dose-limiting toxicities were observed, and no objective responses were noted. Median progression free survival (PFS) was 1.81 months (95% confidence interval (CI) 1.71-2.40), and median overall survival (OS) was 4.53 months (95% CI 2.10-24.74). Batiraxcept effectively reduced serum GAS6 levels at 1-h post-treatment, resulting in trough levels below the limit of detection in all cases but one. In conclusion, the combination of batiraxcept and durvalumab was safe and tolerable but did not demonstrate anti-tumor activity in a heterogenous population of patients with recurrent PROC.

Development and validation of a nomogram for predicting mortality in patients with acute severe traumatic brain injury: A retrospective analysis.

BACKGROUND: Recent evidence links the prognosis of traumatic brain injury (TBI) to various factors, including baseline clinical characteristics, TBI specifics, and neuroimaging outcomes. This study focuses on identifying risk factors for short-term survival in severe traumatic brain injury (sTBI) cases and developing a prognostic model. METHODS: Analyzing 430 acute sTBI patients from January 2018 to December 2023 at the 904th Hospital's Neurosurgery Department, this retrospective case-control study separated patients into survival outcomes: 288 deceased and 142 survivors. It evaluated baseline, clinical, hematological, and radiological data to identify risk and protective factors through univariate and Lasso regression. A multivariate model was then formulated to pinpoint independent prognostic factors, assessing their relationships via Spearman's correlation. The model's accuracy was gauged using the Receiver Operating Characteristic (ROC) curve, with additional statistical analyses for quantitative factors and model effectiveness. Internal validation employed ROC, calibration curves, Decision Curve Analysis (DCA), and Clinical Impact Curves (CIC) to assess model discrimination, utility, and accuracy. The International Mission for Prognosis and Analysis of Clinical Trials in TBI (IMPACT) and Corticosteroid Randomization After Significant Head injury (CRASH) models were also compared through multivariate regression. RESULTS: Factors like unilateral and bilateral pupillary non-reactivity at admission, the derived neutrophil to lymphocyte ratio (dNLR), platelet to lymphocyte ratio (PLR), D-dimer to fibrinogen ratio (DFR), infratentorial hematoma, and Helsinki CT score were identified as independent risk factors (OR > 1), whereas serum albumin emerged as a protective factor (OR < 1). The model showed superior predictive performance with an AUC of 0.955 and surpassed both IMPACT and CRASH models in predictive accuracy. Internal validation confirmed the model's high discriminative capability, clinical relevance, and effectiveness. CONCLUSIONS: Short-term survival in sTBI is significantly influenced by factors such as pupillary response, dNLR, PLR, DFR, serum albumin levels, infratentorial hematoma occurrence, and Helsinki CT scores at admission. The developed nomogram accurately predicts sTBI outcomes, offering significant clinical utility.

Cetuximab plus FOLFOXIRI versus cetuximab plus FOLFOX as conversion regimen in RAS/BRAF wild-type patients with initially unresectable colorectal liver metastases (TRICE trial): A randomized controlled trial.

BACKGROUND: It remains unclear whether intensification of the chemotherapy backbone in tandem with an anti-EGFR can confer superior clinical outcomes in a cohort of RAS/BRAF wild-type colorectal cancer (CRC) patients with initially unresectable colorectal liver metastases (CRLM). To that end, we sought to comparatively evaluate the efficacy and safety of cetuximab plus FOLFOXIRI (triplet arm) versus cetuximab plus FOLFOX (doublet arm) as a conversion regimen (i.e., unresectable to resectable) in CRC patients with unresectable CRLM. METHODS AND FINDINGS: This open-label, randomized clinical trial was conducted from April 2018 to December 2022 in 7 medical centers across China, enrolling 146 RAS/BRAF wild-type CRC patients with initially unresectable CRLM. A stratified blocked randomization method was utilized to assign patients (1:1) to either the cetuximab plus FOLFOXIRI (n = 72) or cetuximab plus FOLFOX (n = 74) treatment arms. Stratification factors were tumor location (left versus right) and resectability (technically unresectable versus ≥5 metastases). The primary outcome was the objective response rate (ORR). Secondary outcomes included the median depth of tumor response (DpR), early tumor shrinkage (ETS), R0 resection rate, progression-free survival (PFS), overall survival (not mature at the time of analysis), and safety profile. Radiological tumor evaluations were conducted by radiologists blinded to the group allocation. Primary efficacy analyses were conducted based on the intention-to-treat population, while safety analyses were performed on patients who received at least 1 line of chemotherapy. A total of 14 patients (9.6%) were lost to follow-up (9 in the doublet arm and 5 in the triplet arm). The ORR was comparable following adjustment for stratification factors, with 84.7% versus 79.7% in the triplet and doublet arms, respectively (odds ratio [OR] 0.70; 95% confidence intervals [CI] [0.30, 1.67], Chi-square p = 0.42). Moreover, the ETS rate showed no significant difference between the triplet and doublet arms (80.6% (58/72) versus 77.0% (57/74), OR 0.82, 95% CI [0.37, 1.83], Chi-square p = 0.63). Although median DpR was higher in the triplet therapy group (59.6%, interquartile range [IQR], [50.0, 69.7] versus 55.0%, IQR [42.8, 63.8], Mann-Whitney p = 0.039), the R0/R1 resection rate with or without radiofrequency ablation/stereotactic body radiation therapy was comparable with 54.2% (39/72) of patients in the triplet arm versus 52.7% (39/74) in the doublet arm. At a median follow-up of 26.2 months (IQR [12.8, 40.5]), the median PFS was 11.8 months in the triplet arm versus 13.4 months in the doublet arm (hazard ratio [HR] 0.74, 95% CI [0.50, 1.11], Log-rank p = 0.14). Grade ≥ 3 events were reported in 47.2% (35/74) of patients in the doublet arm and 55.9% (38/68) of patients in the triplet arm. The triplet arm was associated with a higher incidence of grade ≥ 3 neutropenia (44.1% versus 27.0%, p = 0.03) and diarrhea (5.9% versus 0%, p = 0.03). The primary limitations of the study encompass the inherent bias in subjective surgical decisions regarding resection feasibility, as well as the lack of a centralized assessment for ORR and resection. CONCLUSIONS: The combination of cetuximab with FOLFOXIRI did not significantly improve ORR compared to cetuximab plus FOLFOX. Despite achieving an enhanced DpR, this improvement did not translate into improved R0 resection rates or PFS. Moreover, the triplet arm was associated with an increase in treatment-related toxicity. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03493048.

R2R3-MYB transcription factor CsMYB60 controls mature fruit skin color by regulating flavonoid accumulation in cucumber.

Skin color is an important trait that determines the cosmetic appearance and quality of fruits. In cucumber, the skin color ranges from white to brown in mature fruits. However, the genetic basis for this important trait remains unclear. We conducted a genome-wide association study of natural cucumber populations, along with map-based cloning techniques, on an F2 population resulting from a cross between Pepino (with yellow-brown fruit skin) and Zaoer-N (with creamy fruit skin). We identified CsMYB60 as a candidate gene responsible for skin coloration in mature cucumber fruits. In cucumber accessions with white to pale yellow skin color, a premature stop mutation (C to T) was found in the second exon region of CsMYB60, whereas light yellow cucumber accessions exhibited splicing premature termination caused by an intronic mutator-like element insertion in CsMYB60. Transgenic CsMYB60c cucumber plants displayed a yellow-brown skin color by promoting accumulation of flavonoids, especially hyperoside, a yellow-colored flavonol. CsMYB60c encodes a nuclear protein that primarily acts as a transcriptional activator through its C-terminal activation motif. RNA sequencing and DNA affinity purification sequencing assays revealed that CsMYB60c promotes skin coloration by directly binding to the YYTACCTAMYT motif in the promoter regions of flavonoid biosynthetic genes, including CsF3'H, which encodes flavonoid 3'-hydroxylase. The findings of our study not only offer insight into the function of CsMYB60 as dominantly controlling fruit coloration, but also highlight that intronic DNA mutations can have a similar phenotypic impact as exonic mutations, which may be valuable in future cucumber breeding programs.

Transformation of dissolved organic matter during groundwater arsenite removal using air cathode iron electrocoagulation.

Dissolve organic matters (DOM) usually showed negative effect on the removal of inorganic arsenic (As) in groundwater by electrochemical approaches, yet which parts of sub-component within DOM played the role was lack of evidence. Herein, we investigated the effects of land-source humic-like acid (HA) on groundwater As(III) removal using air cathode iron electrocoagulation, based on the parallel factor analysis of three-dimensional excitation-emission matrix and statistical methods. Our results showed that the land-source HA contained five kinds of components and all components presented significantly negative correlations with the removal of both As(III) and As(V). However, the high aromatic fulvic-like acid and low aromatic humic-like acid components of land-source HA presented the opposite correlations with the concentration of As(III) during the reaction. The high aromaticity fulvic-like components of land-source HA (Sigma-Aldrich HA, SAHA) produced during the reaction facilitated the oxidation of As(III) due to its high electron transfer capacities and good solubility in wide pH range, but the low aromaticity humic-like ones worked against the oxidation of As(III). Our findings offered the novel insights for the flexible activities of DOM in electron Fenton system.

Clinical and genomic landscape of RAS mutations in gynecologic cancers.

BACKGROUND: We aimed to describe RAS mutations in gynecologic cancers as they relate to clinicopathologic and genomic features, survival, and therapeutic implications. METHODS: Gynecologic cancers with available somatic molecular profiling data at our institution between February 2010 and August 2022 were included and grouped by RAS mutation status. Overall survival was estimated by Kaplan-Meier method, and multivariable analysis was performed using Cox proportional-hazards model. RESULTS: Of 3328 gynecologic cancers, 523 (15.7%) showed any RAS mutation. Patients with RAS-mutated tumors were younger (57 vs 60 years non-mutated), had higher prevalence of endometriosis (27.3% vs 16.9%), and lower grades (grade 1/2, 43.2% vs 8.1%, all p<0.0001). Highest prevalence of KRAS mutation was in mesonephric-like endometrial (100%, n=9/9), mesonephric-like ovarian (83.3%, n=5/6), mucinous ovarian (60.4%), and low-grade serous ovarian (44.4%) cancers. After adjustment for age, cancer type, and grade, RAS mutation was associated with worse overall survival (HR=1.3, p=0.001). Specific mutations were in KRAS (13.5%), NRAS (2.0%), and HRAS (0.51%), most commonly KRAS G12D (28.4%) and G12V (26.1%). Common co-mutations were PIK3CA (30.9%), PTEN(28.8%), ARID1A (28.0%), and TP53 (27.9%), of which 64.7% were actionable. RAS+MAPK pathway-targeted therapies were administered to 62 patients with RAS-mutated cancers. While overall survival was significantly higher with therapy (8.4 years [95%CI 5.5-12.0] vs 5.5 years [95%CI 4.6-6.6], HR=0.67, p=0.031), this effect did not persist in multivariable analysis. CONCLUSION: RAS mutations in gynecologic cancers have a distinct histopathologic distribution and may impact overall survival. PIK3CA, PTEN, and ARID1A are potentially actionable co-alterations. RAS pathway-targeted therapy should be considered.

A Bayesian quasi-likelihood design for identifying the minimum effective dose and maximum utility dose in dose-ranging studies.

Most existing dose-ranging study designs focus on assessing the dose-efficacy relationship and identifying the minimum effective dose. There is an increasing interest in optimizing the dose based on the benefit-risk tradeoff. We propose a Bayesian quasi-likelihood dose-ranging design that jointly considers safety and efficacy to simultaneously identify the minimum effective dose and the maximum utility dose to optimize the benefit-risk tradeoff. The binary toxicity endpoint is modeled using a beta-binomial model. The efficacy endpoint is modeled using the quasi-likelihood approach to accommodate various types of data (e.g. binary, ordinal or continuous) without imposing any parametric assumptions on the dose-response curve. Our design utilizes a utility function as a measure of benefit-risk tradeoff and adaptively assign patients to doses based on the doses' likelihood of being the minimum effective dose and maximum utility dose. The design takes a group-sequential approach. At each interim, the doses that are deemed overly toxic or futile are dropped. At the end of the trial, we use posterior probability criteria to assess the strength of the dose-response relationship for establishing the proof-of-concept. If the proof-of-concept is established, we identify the minimum effective dose and maximum utility dose. Our simulation study shows that compared with some existing designs, the Bayesian quasi-likelihood dose-ranging design is robust and yields competitive performance in establishing proof-of-concept and selecting the minimum effective dose. Moreover, it includes an additional feature for further maximum utility dose selection.

Development and validation of a nomogram for predicting lymph node metastasis in ductal carcinoma in situ with microinvasion: A SEER population-based study.

BACKGROUND: Ductal carcinoma in situ with microinvasion (DCIS-MI) is a special type of breast cancer. It is an invasive lesion less than 1.0 mm in size related to simple ductal carcinoma in situ (DCIS). Lymph node metastasis (LNM) in DCIS-MI often indicates a poor prognosis. Therefore, the management of lymph nodes plays a vital role in the treatment strategy of DCIS-MI. Since DCIS-MI is often diagnosed by postoperative paraffin section and immunohistochemical detection, to obtain the best clinical benefits for such patients, we aim to establish and verify a nomogram to predict the possibility of lymph node metastasis in DCIS-MI patients and help preoperative or intraoperative clinical decision-making. METHODS: A retrospective analysis of patients with DCIS-MI in the Surveillance, Epidemiology, and End Results (SEER) database from 2010 to 2019 was performed. The study cohort was randomly divided into a training cohort and a validation cohort at a ratio of 7:3. The risk factors were determined by univariate and multivariate logistic regression analyses in the training cohort, and a nomogram was constructed. The receiver operating characteristic (ROC) curve, calibration curve, and decision curve analysis (DCA) were used to evaluate the nomogram in the training set and validation set. An independent data cohort was obtained from the Shanghai Jiao Tong University Breast Cancer Database (SJTU-BCDB) for external validation. RESULTS: This study included 3951 female patients from SEER with DCIS-MI, including 244 patients with regional lymph node metastasis, accounting for 6.18% of the total. An independent test set of 323 patients from SJTU-BCDB was used for external validation. According to the multifactorial logistic regression analysis results, age at diagnosis, ethnicity, grade, and surgical modality were included in the prediction model. The areas under the ROC curves (AUCs) were 0.739 (95% CI: 0.702~0.775), 0.732 (95% CI: 0.675~0.788), and 0.707 (95%CI: 0.607-0.807) in the training, validation and external test groups, suggesting that the column line graphs had excellent differentiation. The calibration curves slope was close to 1, and the model's predicted values were in good agreement with the actual values. The DCA curves showed good clinical utility. CONCLUSION: In this study, we constructed accurate and practical columnar maps with some clinical benefit to predict the likelihood of lymph node metastasis in patients with postoperatively diagnosed DCIS-MI and provide a reference value for specifying treatment strategies.

Near-infrared imaging of head and neck squamous cell carcinoma using indocyanine green that targets the αvß6 peptide.

Significance: Head and neck squamous cell carcinoma (HNSCC) has a particularly poor prognosis. Improving the surgical resection boundary, reducing local recurrence, and ultimately ameliorating the overall survival rate are the treatment goals. Aim: To obtain a complete surgical resection (R0 resection), we investigated the use of a fluorescent imaging probe that targets the integrin subtype αvß6, which is upregulated in many kinds of epithelial cancer, using animal models. Approach: αvß6 expression was detected using polymerase chain reaction (PCR) and immunoprotein blotting of human tissues for malignancy. Protein expression localization was observed. αvß6 and epidermal growth factor receptor (EGFR) were quantified by PCR and immunoprotein blotting, and the biosafety of targeting the αvß6 probe material was examined using Cell Counting Kit-8 assays. Indocyanine green (ICG) was used as a control to determine the localization of the probe at the cellular level. In vivo animal experiments were conducted through tail vein injections to evaluate the probe's imaging effect and to confirm its targeting in tissue sections. Results: αvß6 expression was higher than EGFR expression in HNSCC, and the probe showed good targeting in in vivo and in vitro experiments with a good safety profile. Conclusions: The ICG-αvß6 peptide probe is an exceptional and sensitive imaging tool for HNSCC that can distinguish among tumor, normal, and inflammatory tissues.