A network meta-analysis of efficacy and safety for first-line and second/further-line therapies in postmenopausal women with hormone receptor-positive, HER2-negative, advanced breast cancer.

BACKGROUND: Hormone receptor-positive/human epidermal growth factor receptor 2-negative (HR + /HER2 -) advanced breast cancer is a prevalent subtype among postmenopausal women. Despite the growing number of randomized clinical trials (RCTs) exploring this topic, the efficacy and safety of first-line and second/further-line treatments remain uncertain. Accordingly, our aim was to conduct a comprehensive evaluation of the efficacy and safety of these therapies through network meta-analysis. METHODS: RCTs were identified by searching Pubmed, Embase, and major cancer conferences. The efficacy of interventions was assessed using the hazard ratios (HRs) of progression-free survival (PFS) and overall survival (OS), while safety was indicated by the incidence of any grade adverse events (AEs), grade 3-5 AEs, AEs leading to treatment discontinuation, and AEs leading to death. Both time-variant HRs fractional polynomial models and time-invariant HRs Cox-proportional hazards models were considered for handling time-to-event data. Safety indicators were analyzed using Bayesian network meta-analysis. Additionally, subgroup analyses were conducted based on patient characteristics. RESULTS: A total of 41 RCTs (first-line 17, second/further-lines 27) were included in the analysis. For first-line treatment, the addition of Cyclin-dependent kinase 4 and 6 (CDK4/6) inhibitors to endocrine therapy significantly improved therapeutic efficacy in terms of both PFS and OS, demonstrating the best performance across all mechanisms. Specifically, the combination of Abemaciclib and Letrozole demonstrated the most favorable performance in terms of PFS, while Ribociclib plus Fulvestrant yielded the best outcomes in OS. Incorporating the immune checkpoint inhibitor Avelumab into the regimen with CDK4/6 inhibitors and selective estrogen receptor degraders significantly enhanced both PFS and OS in second-line or later treatments. Regarding safety, endocrine monotherapy performed well. Regarding safety, endocrine monotherapy performed well. There is mounting evidence suggesting that most CDK4/6 inhibitors may demonstrate poorer performance with respect to hematologic AEs. However, additional evidence is required to further substantiate these findings. CONCLUSIONS: CDK4/6 inhibitors, combined with endocrine therapy, are pivotal in first-line treatment due to their superior efficacy and manageable AEs. For second/further-line treatment, adding immune checkpoint inhibitors to CDK4/6 inhibitors plus endocrine therapy may produce promising results. However, to reduce the results' uncertainty, further trials comparing these novel treatments are warranted. TRIAL REGISTRATION: Registration number: PROSPERO (CRD42022377431).

Mechanistic research: Selenium regulates virulence factors, reducing adhesion ability and inflammatory damage of Helicobacter pylori.

BACKGROUND: The pathogenicity of Helicobacter pylori is dependent on factors including the environment and the host. Although selenium is closely related to pathogenicity as an environmental factor, the specific correlation between them remains unclear. AIM: To investigate how selenium acts on virulence factors and reduces their toxicity. METHODS: H. pylori strains were induced by sodium selenite. The expression of cytotoxin-associated protein A (CagA) and vacuolating cytotoxin gene A (VacA) was determined by quantitative PCR and Western blotting. Transcriptomics was used to analyze CagA, CagM, CagE, Cag1, Cag3, and CagT. C57BL/6A mice were infected with the attenuated strains subjected to sodium selenite induction, and H. pylori colonization, inflammatory reactions, and the cell adhesion ability of H. pylori were assessed. RESULTS: CagA and VacA expression was upregulated at first and then downregulated in the H. pylori strains after sodium selenite treatment. Their expression was significantly and steadily downregulated after the 5th cycle (10 d). Transcriptome analysis revealed that sodium selenite altered the levels affect H. pylori virulence factors such as CagA, CagM, CagE, Cag1, Cag3, and CagT. Of these factors, CagM and CagE expression was continuously downregulated and further downregulated after 2 h of induction with sodium selenite. Moreover, CagT expression was upregulated before the 3rd cycle (6 d) and significantly downregulated after the 5th cycle. Cag1 and Cag3 expression was upregulated and downregulated, respectively, but no significant change was observed by the 5th cycle. C57BL/6A mice were infected with the attenuated strains subjected to sodium selenite induction. The extent of H. pylori colonization in the stomach increased; however, sodium selenite also induced a mild inflammatory reaction in the gastric mucosa of H. pylori-infected mice, and the cell adhesion ability of H. pylori was significantly weakened. CONCLUSION: These results demonstrate that H. pylori displayed virulence attenuation after the 10th d of sodium selenite treatment. Sodium selenite is a low toxicity compound with strong stability that can reduce the cell adhesion ability of H. pylori, thus mitigating the inflammatory damage to the gastric mucosa.

Comprehensive aesthetic corrections of gynecomastia using the reproducible safe and minimally invasive surgical strategy.

BACKGROUND: Minimally invasive access and fast recovery are trends of gynecomastia surgery. We placed great importance on liposuction and modified original pull-through technique. The purpose of this study was to present a refined surgical strategy for gynecomastia in grade I and II. METHODS: The refined strategy embraced enhanced liposuction to remove the intraglandular fat sufficiently, followed by open resection of gland using the pull-through and bottom-up technique with adjuvant liposuction in the end. Surgical data were recorded and satisfactory questionnaires with 5-point scales were administered during follow-up. RESULTS: Between January 2017 and May 2022, 165 patients underwent enhanced liposuction combined with the pull-through and bottom-up technique for gland excision. Age ranged from 12 to 56 years. The median length of surgery was 100 min. A median of 300 ml of fat was aspirated and a median of 20.8 g of gland was excised. Seventy-seven patients (46.7%) responded the questionnaires at least 6 months postoperatively, and the average overall satisfaction was 4.68 ± 0.52 points. Thirteen sides of breasts developed complications with a rate of 4.0%. CONCLUSION: Enhanced liposuction combined with pull-through and bottom-up technique proved effective to treat grade I and II gynecomastia with minimal scarring and high satisfaction. The refined strategy was simple and safe, and would obtain optimal outcomes even for inexperienced surgeons.

Thermally-induced atropisomerism promotes metal-organic cage construction.

Molecular folding regulation with environmental stimuli is critical in living and artificial molecular machine systems. Herein, we described a macrocycle, cyclo[4] (1,3-(4,6-dimethyl)benzene)[4](1,3-(4,6-dimethyl)benzene)(4-pyridine). Under 298 K, it has three stable stiff atropisomers with names as 1 (Cs symmetry), 2 (Cs symmetry), and 3 (C4v symmetry). At 393 K, 1 can reversibly transform into 2, but at 473 K, it can irrevocably transform into 3. At 338 K, 3 and (PhCN)2PdCl2 complex to produce the metal-organic cage 4. Only at 338 K does the combination of 1 or 2 and (PhCN)2PdCl2 create a gel-like structure. Heating both gels to 473 K transforms them into 4. In addition to offering a thermally accelerated method for modifying self-assembled systems using macrocyclic building blocks, this study also has the potential to develop the nanoscale transformation material with a thermal response.

Interaction between intratumoral microbiota and tumor mediates the response of neoadjuvant therapy for rectal cancer.

Background: Previous observations have demonstrated that the response to neoadjuvant chemoradiotherapy (nCRT) is highly variable in patients with locally advanced rectal cancer (LARC). Recent studies focusing on the intratumoral microbiota of colorectal cancer have revealed its role in oncogenesis and tumor progression. However, limited research has focused on the influence of intratumoral microbiota on the nCRT of LARC. Methods: We explored the microbial profiles in the tumor microenvironment of LARC using RNA-seq data from a published European cohort. Microbial signatures were characterized in pathological complete response (pCR) and non-pCR groups. Multi-omics analysis was performed between intratumor microbiomes and transcriptomes. Results: Microbial α and ß diversity were significantly different in pCR and non-pCR groups. Twelve differential microbes were discovered between the pCR and non-pCR groups, six of which were related to subclusters of cancer-associated fibroblasts (CAFs) associated with extracellular matrix formation. A microbial risk score based on the relative abundance of seven differential microbes had predictive value for the nCRT response (AUC = 0.820, p < 0.001). Conclusion: Our study presents intratumoral microbes as potential independent predictive markers for the response of nCRT to LARC and demonstrates the underlying mechanism by which the interaction between intratumoral microbes and CAFs mediates the response to nCRT.

Cyclometalated Half-Sandwich Ruthenium Complexes: Preparation, Structure, and Catalytic Synthesis of Phenolic Esters from Aryl Halides without Using External CO under Air.

A series of cyclometalated C,N-chelate half-sandwich ruthenium complexes based on N-heterocyclic ligands were prepared through a simple route with good yields. These air- and moisture-stable cyclometalated ruthenium complexes showed excellent catalytic efficiency in phenoxy carbonylation of aryl halides with phenyl formate derivatives as a CO source and phenol as a coupling partner under air. Ester products were obtained with high yields at room temperature and without the need for an inert atmosphere. The excellent catalytic activity, broad substrate range, and mild reaction conditions made this catalytic system potential for industrial production. In addition, DFT study has been carried out to elaborate the possible mechanism of this Ru-catalyzed reaction.

Intratumoural microbiome can predict the prognosis of hepatocellular carcinoma after surgery.

BACKGROUND: The dismal prognosis of hepatocellular carcinoma (HCC) is closely associated with characteristics of the tumour microenvironment (TME). Recent studies have confirmed the presence and potential influence of the microbiome in TME on cancer progression. Elucidating the relationship between microbes in the TME and cancer could provide valuable insights into novel diagnostic markers and therapeutic strategies for HCC and thus warrants a closer investigation of the role of intratumoural microbiome in the HCC TME. METHODS: We determined the presence of intratumoural microbiome using fluorescence in situ hybridisation, and explored the microbial community profiles in the HCC TME in paired tumour and adjacent normal tissues using 16S rDNA sequencing. Microbial signatures were characterised in the paired group, and their correlation with clinical characteristics was further investigated. We clustered the microbial signatures of tumour tissues by hepatotypes, and further analysis was performed to elucidate the independent prognostic value of the hepatotypes. RESULTS: This study revealed that microbial profiles and community networks differed notably between tumours and adjacent normal tissues. Proteobacteria and Actinobacteria were the most abundant phyla in the HCC TME. The TME microbial profiles also revealed heterogeneities between individuals and between multiple tumour lesions. Clustering of the microbial profiles into two hepatotypes revealed different microbial network patterns. Additionally, the hepatotypes were revealed to be independent prognostic factors in patients with resected HCC. CONCLUSIONS: Our study illuminates the microbial profiles in the TME of HCC and presents the hepatotype as a potential independent biomarker for the prognostic prediction of HCC after surgery.

Is Breast Magnetic Resonance Imaging Superior to Sonography in Gynecomastia Evaluation and Surgery Planning.

BACKGROUND: Data on the value of magnetic resonance imaging (MRI) in the preoperative evaluation and surgery planning of gynecomastia are limited. The purpose of this study is to reveal MRI features and categories of gynecomastia and compare surgical outcomes following MRI and sonography as well as their diagnostic accuracy. METHODS: The area of the gland and the whole breast on the transverse plane via nipple of MRI were measured to calculate the ratio between them. Areola, mass and branch patterns were categorized to represent three different gynecomastia type on MRI. 183 patients were included, with 38 in MRI group and 145 in sonography group. Diagnostic accuracy was assessed by the level of agreement between preoperative imaging findings and intraoperative observations. Surgical data, patients' satisfaction and complications were compared between the two groups. RESULTS: MRI in 75 gynecomastic breasts demonstrated the average ratio of the gland to the whole breast was 10.6%±13.3%. The most common MRI categories were branch patterns (45.3%). The diagnostic concordance rate of MRI was higher than sonography (100% vs. 86.8%, p = 0.001). Among those junior surgeons, the length of surgery was reduced in MRI group (100 min vs. 115 min, p = 0.048). There was no difference in terms of patient's satisfaction and complication rate between MRI and sonography. CONCLUSION: MRI was superior to sonography in diagnostic accuracy to assess the tissue components of gynecomastia and provided informative guidance especially for junior surgeons. Surgical outcomes were comparable regardless of the use of MRI or sonography for evaluation. LEVEL OF EVIDENCE IV: IThis journal requires that authors assign a level of evidence to each article. For a full description of these Evidence-Based Medicine ratings, please refer to the Table of Contents or the online Instructions to Authors www.springer.com/00266 .

Footprints: Stamping hallmarks of lung cancer with patient-derived models, from molecular mechanisms to clinical translation.

The conventional two-dimensional (2D) tumor cell lines in Petri dishes have played an important role in revealing the molecular biological mechanism of lung cancer. However, they cannot adequately recapitulate the complex biological systems and clinical outcomes of lung cancer. The three-dimensional (3D) cell culture enables the possible 3D cell interactions and the complex 3D systems with co-culture of different cells mimicking the tumor microenvironments (TME). In this regard, patient-derived models, mainly patient-derived tumor xenograft (PDX) and patient-derived organoids discussed hereby, are with higher biological fidelity of lung cancer, and regarded as more faithful preclinical models. The significant Hallmarks of Cancer is believed to be the most comprehensive coverage of current research on tumor biological characteristics. Therefore, this review aims to present and discuss the application of different patient-derived lung cancer models from molecular mechanisms to clinical translation with regards to the dimensions of different hallmarks, and to look to the prospects of these patient-derived lung cancer models.

The multivariate cox regression model for complete enteral nutrition after primary anastomosis in neonates with intestinal atresia.

Objective: Enteral feeding after intestinal atresia has always been a concern for clinicians. But the present studies mainly focused on single factors. This research aimed to comprehensively analyze the multiple factors on complete enteral nutrition after primary anastomosis, and establish the convenient prediction model. Methods: We retrospectively collected reliable information in neonates with intestinal atresia form January 2010 to June 2022. The cox regression analysis was performed to select independent risk factors and develop nomogram. Subsequently, ROC curve, calibration curve and decision curve were drawn to thoroughly evaluate the accuracy and applicability of the model. Results: The predictors finally included in the model were gestational age, meconium peritonitis, distance from the anastomosis to the ileocecal region, diameter ratio of proximal to distal bowels, and time of initial feeding. The nomogram of predicting the probability of week 2, week 3 and week 4 was drawn and their area under the curve were 0.765, 0.785 and 0.747, respectively. Similarly, calibration and decision curve indicated that the prediction model had a great prediction performance. Conclusion: The clinical value of predictive models can be recognized. The hope is that the predictive model can help pediatricians reduce hospital costs and parental anxiety.

Prediction nomogram for evaluating the probability of postoperative fever in children with acute appendicitis.

Objective: The purpose of this study was to establish a predictive model of postoperative fever in children with acute appendicitis through retrospective analysis, and the prediction ability of the model is demonstrated by model evaluation and external validation. Methods: Medical records information on children undergoing surgery for acute appendicitis within 2 years were retrospectively collected, prospective collection was performed for external validation in the next 3 months. The patients were divided into two groups according to whether the postoperative body temperature exceeded 38.5°C. Multivariate logistic regression analysis was used to determine independent risk factors and develop regression equations and nomogram. ROC curve, calibration curve and decision curve were made for model evaluation. Finally, the clinical implication of the prediction model was clarified by associating postoperative fever with prognosis. Results: High risk factors of postoperative fever included in the prediction model were onset time (X1), preoperative temperature (X2), leukocyte count (X3), C-reactive protein (X4) and operation time (X5). The regression equation is logit (P) = 0.005X1+0.166X2+0.056X3+0.004X4+0.005X5-9.042. ROC curve showed that the area under the curve (AUC) of the training set was 0.660 (0.621, 0.699), and the AUC of the verification set was 0.712 (0.639, 0.784). The calibration curve suggested that the prediction probability was close to the actual probability. Decision curve analysis (DCA) showed that patients could benefit from clinician's judgment. Furthermore, prognostic analysis showed children presenting with postoperative fever had the more duration of postoperative fever, hospitalization stays and cost, except for rehospitalization. Conclusion: All the results revealed that the model had good predictive ability. Pediatricians can calculate the probability of postoperative fever and make timely interventions to reduce pain for children and parents.

Fused Lateral Clitoral Hood and Labia Minora: New Classification Based on Anatomic Variation of the Clitoral Hood-Labia Minora Complex and Simple Surgical Management.

BACKGROUND: Existing classifications of the clitoral hood-labia minora complex (CLC) have neglected its integrity and anatomic variation, resulting in failure to optimize approaches tailored to individuals. OBJECTIVES: The aim of this study was to present a new classification system for comprehensive evaluation of variations of the CLC and to introduce a simple surgical approach for the fused type. METHODS: Anatomic variations of the CLC were classified into 3 types: isolated labia minora or lateral clitoral hood hypertrophy (Type 1); conventional combined hypertrophy (Type 2); and fused lateral clitoral hood and labia minora (Type 3). A modified procedure for the fused type was performed in 4 steps: the anterior border of labia minora was defined first, then the hypertrophic lateral clitoral hood and labia minora were each removed separately, and finally the junction region was trimmed. Satisfaction questionnaires were administered during follow-ups. RESULTS: Among all 301 patients (602 sides), Type 2 was the most common variation (285 sides, 47.3%). Type 3 variations in 67 patients (105 sides, 17.5%) were identified, and 77.6% of these patients answered the questionnaires 3 months after surgery. For patients with type 3 variations, the satisfaction rate in the 4-step excision group was 91.7%, which was significantly higher than that in the wedge excision group (56.3%) (P = 0.01). The complication rate of the 4-step excision was 2.5%. CONCLUSIONS: Preoperative evaluation based on the new classification facilitated recognition of variations of the CLC, especially of the fused type. The 4-step excision is a simple, effective, and safe approach to treat the fused variation with high satisfaction.

Half-Sandwich Iridium Complexes Based on ß-Ketoamino Ligands: Preparation, Structure, and Catalytic Activity in Amide Synthesis.

A series of ß-ketoamino-based N,O-chelate half-sandwich iridium complexes with the general formula [Cp*IrClL] have been prepared in good yields. These air-insensitive iridium complexes showed desirable catalytic activity in an amide preparation under mild conditions. A number of amides with diverse substituted groups were furnished in a one-pot reaction with good-to-excellent yields through an amidation reaction of NH2OH·HCl with aldehydes in the presence of these iridium(III) precursors. The excellent catalytic activity, mild reaction conditions, and broad substrate scope gave this type of iridium catalyst potential for use in industry. All of the obtained iridium complexes were well characterized by different spectroscopy techniques. The exact molecular structure of complex 3 has been confirmed by single-crystal X-ray analysis.

Comparison of Prognostic Value of Red Cell-Related Parameters of Biliary Tract Cancer After Surgical Resection and Integration of a Prognostic Nomogram: A Retrospective Study.

INTRODUCTION: Biliary tract cancer (BTC) comprises infrequently occurring neoplasms with poor prognoses. Red blood cell-related parameters are commonly reported prognostic factors. We aimed to compare and evaluate the clinical value of red blood cell-related parameters and develop a prognostic nomogram. METHODS: The analysis involved 418 patients with BTC who underwent surgery from December 2003 to April 2017. Patients were divided into training and validation cohorts. Red blood cell-related parameters were compared using Kaplan-Meier analysis, the area under receiver-operating characteristic curve (AUC), and C-index. Predictive abilities were evaluated using Cox regression. We developed a nomogram incorporating superior parameters verified using calibration curves, internal validation, and subgroup analysis. The nomogram was compared with the tumour-node-metastasis staging system through ROC, C-index, and Kaplan-Meier analysis. RESULTS: A combined parameter comprising haemoglobin, albumin, lymphocytes, and platelets (HALP), which was superior to other red blood cell-related parameters, indicated a high risk of worse overall survival when low. Univariate analysis revealed that HALP together with other clinical characteristics was associated with overall survival. Multivariate analysis revealed that HALP, tumour-node-metastasis staging, and operative outcome were independent predictors of poor overall survival. Internal validation proved the predictive value of the nomogram. Additional statistical analyses established the advantages of the nomogram vs. tumour-node-metastasis staging. CONCLUSION: HALP was a superior red blood cell-related parameter and an independent predictor of prognosis. Our nomogram based on HALP, tumour-node-metastasis staging, and operative outcome is a promising model for predicting overall survival.

Unique TP53 neoantigen and the immune microenvironment in long-term survivors of Hepatocellular carcinoma.

Neoantigens are T-cell antigens derived from protein-coding mutations in tumor cells. Although neoantigens have recently been linked to anti-tumor immunity in long-term survivors of cancers such as melanoma, their prognostic and immune-modulatory role in many cancer types remain unexplored. We investigate neoantigens in hepatocellular carcinoma (HCC) through a combination of whole exome sequencing (WES), RNA sequencing (RNA-seq), computational bioinformation, and immunohistochemistry. Our analysis reveals that patients carried with TP53 neoantigen have a longer overall survival than others (p = 0.0371) and they showed higher Immune score (p = 0.0441), higher cytotoxic lymphocytes infiltration (p = 0.0428), and higher CYT score (p = 0.0388). In contrast, the prognosis is not associated with TMB and neoantigen load. Our study draws a preliminary conclusion that it is not TMB or neoantigen load but the TP53 specific neoantigen is related to overall survival of HCC patients. We suggest that the TP53 neoantigen may affect prognosis by regulating anti-tumor immunity and that the TP53 neoantigen may be harnessed as potential targets for immunotherapies of HCC.