Perioperative Toripalimab Plus Chemotherapy for Patients With Resectable Non-Small Cell Lung Cancer: The Neotorch Randomized Clinical Trial.

Importance: Adjuvant and neoadjuvant immunotherapy have improved clinical outcomes for patients with early-stage non-small cell lung cancer (NSCLC). However, the optimal combination of checkpoint inhibition with chemotherapy remains unknown. Objective: To determine whether toripalimab in combination with platinum-based chemotherapy will improve event-free survival and major pathological response in patients with stage II or III resectable NSCLC compared with chemotherapy alone. Design, Setting, and Participants: This randomized clinical trial enrolled patients with stage II or III resectable NSCLC (without EGFR or ALK alterations for nonsquamous NSCLC) from March 12, 2020, to June 19, 2023, at 50 participating hospitals in China. The data cutoff date for this interim analysis was November 30, 2022. Interventions: Patients were randomized in a 1:1 ratio to receive 240 mg of toripalimab or placebo once every 3 weeks combined with platinum-based chemotherapy for 3 cycles before surgery and 1 cycle after surgery, followed by toripalimab only (240 mg) or placebo once every 3 weeks for up to 13 cycles. Main Outcomes and Measures: The primary outcomes were event-free survival (assessed by the investigators) and the major pathological response rate (assessed by blinded, independent pathological review). The secondary outcomes included the pathological complete response rate (assessed by blinded, independent pathological review) and adverse events. Results: Of the 501 patients randomized, 404 had stage III NSCLC (202 in the toripalimab + chemotherapy group and 202 in the placebo + chemotherapy group) and 97 had stage II NSCLC and were excluded from this interim analysis. The median age was 62 years (IQR, 56-65 years), 92% of patients were male, and the median follow-up was 18.3 months (IQR, 12.7-22.5 months). For the primary outcome of event-free survival, the median length was not estimable (95% CI, 24.4 months-not estimable) in the toripalimab group compared with 15.1 months (95% CI, 10.6-21.9 months) in the placebo group (hazard ratio, 0.40 [95% CI, 0.28-0.57], P < .001). The major pathological response rate (another primary outcome) was 48.5% (95% CI, 41.4%-55.6%) in the toripalimab group compared with 8.4% (95% CI, 5.0%-13.1%) in the placebo group (between-group difference, 40.2% [95% CI, 32.2%-48.1%], P < .001). The pathological complete response rate (secondary outcome) was 24.8% (95% CI, 19.0%-31.3%) in the toripalimab group compared with 1.0% (95% CI, 0.1%-3.5%) in the placebo group (between-group difference, 23.7% [95% CI, 17.6%-29.8%]). The incidence of immune-related adverse events occurred more frequently in the toripalimab group. No unexpected treatment-related toxic effects were identified. The incidence of grade 3 or higher adverse events, fatal adverse events, and adverse events leading to discontinuation of treatment were comparable between the groups. Conclusions and Relevance: The addition of toripalimab to perioperative chemotherapy led to a significant improvement in event-free survival for patients with resectable stage III NSCLC and this treatment strategy had a manageable safety profile. Trial Registration: ClinicalTrials.gov Identifier: NCT04158440.

Deep learning-assisted identification and quantification of aneurysmal subarachnoid hemorrhage in non-contrast CT scans: Development and external validation of Hybrid 2D/3D UNet.

Accurate stroke assessment and consequent favorable clinical outcomes rely on the early identification and quantification of aneurysmal subarachnoid hemorrhage (aSAH) in non-contrast computed tomography (NCCT) images. However, hemorrhagic lesions can be complex and difficult to distinguish manually. To solve these problems, here we propose a novel Hybrid 2D/3D UNet deep-learning framework for automatic aSAH identification and quantification in NCCT images. We evaluated 1824 consecutive patients admitted with aSAH to four hospitals in China between June 2018 and May 2022. Accuracy and precision, Dice scores and intersection over union (IoU), and interclass correlation coefficients (ICC) were calculated to assess model performance, segmentation performance, and correlations between automatic and manual segmentation, respectively. A total of 1355 patients with aSAH were enrolled: 931, 101, 179, and 144 in four datasets, of whom 326 were scanned with Siemens, 640 with Philips, and 389 with GE Medical Systems scanners. Our proposed deep-learning method accurately identified (accuracies 0.993-0.999) and segmented (Dice scores 0.550-0.897) hemorrhage in both the internal and external datasets, even combinations of hemorrhage subtypes. We further developed a convenient AI-assisted platform based on our algorithm to assist clinical workflows, whose performance was comparable to manual measurements by experienced neurosurgeons (ICCs 0.815-0.957) but with greater efficiency and reduced cost. While this tool has not yet been prospectively tested in clinical practice, our innovative hybrid network algorithm and platform can accurately identify and quantify aSAH, paving the way for fast and cheap NCCT interpretation and a reliable AI-based approach to expedite clinical decision-making for aSAH patients.

Comprehensive analysis of the prognostic implications and functional exploration of PAK gene family in human cancer.

BACKGROUND: The p21-activated kinase (PAK) family (PAKs) plays a key role in the formation and development of human tumors. However, a systematic analysis of PAKs in human cancers is lacking and the potential role of PAKs in cancer immunity has not been explored. METHODS: We used datasets from in The Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression database (GTEx). RESULTS: Based on TCGA datasets most PAKs show noteworthy differences in expression between tumors and corresponding normal tissues or across different tumor tissues. Patients with high expression of PAKs often show a worse prognosis. However, copy number variation, mutation, and DNA methylation of PAKs have limited impact on tumor development. Further analysis showed that the impact of PAKs on immunity varies with the type of tumor and the respective tumor microenvironment. PAK1 and PAK4 may be stronger predictors of immune characteristics, and are more suitable as drugs and molecular therapeutic targets. Furthermore, Cox regression analysis revealed that a PAK gene signature could be used as an independent prognostic factor for lower grade glioma (LGG) and glioblastoma (GBM). Gene set enrichment analysis (GSEA) analysis indicated that PAK genes may affect the occurrence and development of GBM through the PI3K signaling pathway. Further experiments verified that PAK1 and AKT1 have a significant interaction in GBM cells, and inhibiting the overactivation of PAK1 can significantly inhibit the proliferation of GBM cells. CONCLUSIONS: Our study provides a rationale for further research on the prognostic and therapeutic potential of PAKs in human tumors.

Circ_CLIP2 promotes glioma progression through targeting the miR-195-5p/HMGB3 axis.

BACKGROUND: Circular RNA (circRNA) has been demonstrated to play key roles in regulating glioma progression. Understanding the regulatory mechanism of circRNA in glioma is vital to reveal the pathogenesis of glioma and develop novel therapeutic strategies. Therefore, our study focuses on the role and underlying mechanism of Circ_CLIP2 in glioma. METHODS: The expression of Circ_CLIP2, miR-195-5p and HMGB3 in glioma cells and tissues were analyzed using qRT-PCR. Cell proliferation was determined with colony formation and MTT assays. Cell cycle and apoptosis were examined by flow cytometry. Western blot was conducted for analyzing HMGB3, PCNA, Bax, Bcl-2, cleaved-caspase 3, Wnt-1 and ß-catenin. Dual-luciferase reporter assay was measured to investigate the interaction among Circ_CLIP2, miR-195-5p and HMGB3. RESULTS: The expression of Circ_CLIP2 and HMGB3 were increased while miR-195-5p was down-regulated in glioma cells and patients. Silencing of Circ_CLIP2 inhibited cell proliferation, enhanced cell apoptosis and inhibited the Wnt/ß-catenin signaling pathway. Circ_CLIP2 suppressed miR-195-5p expression by directly sponging miR-195-5p. MiR-195-5p inhibited HMGB3 expression via directly targeting HMGB3. Knockdown of miR-195-5p facilitated cell proliferation, inhibited cell apoptosis and activated Wnt/ß-catenin signaling, which were reversed by silencing of HMGB3. CONCLUSION: Knockdown of Circ_CLIP2 suppresses glioma progression by targeting miR-195-5p/HMGB3 thus inhibiting Wnt/ß-catenin signaling. This study may provide potential therapeutic targets against glioma.

FLCN-regulated miRNAs suppressed reparative response in cells and pulmonary lesions of Birt-Hogg-Dubé syndrome.

BACKGROUND: Birt-Hogg-Dubé Syndrome (BHDS) characterised by skin fibrofolliculomas, kidney tumour and pulmonary cysts/pneumothorax is caused by folliculin (FLCN) germline mutations. The pathology of both neoplasia and focused tissue loss of BHDS strongly features tissue-specific behaviour of the gene. Isolated cysts/pneumothorax is the most frequent atypical presentation of BHDS and often misdiagnosed as primary spontaneous pneumothorax (PSP). Deferential diagnosis of BHDS with isolated pulmonary presentation (PSP-BHD) from PSP is essential in lifelong surveillance for developing renal cell carcinoma. METHODS: The expression profiles of microRNAs (miRNAs) in cystic lesions of PSP-BHD and PSP were determined via microarray. The selected upregulated miRNAs were further confirmed in the plasma of an expanded cohort of PSP-BHD patients by reverse transcription quantitative PCR (RT-qPCR). Their diagnostic accuracy was evaluated. Moreover, the cellular functions and targeted signalling pathways of FLCN-regulated miRNAs were assessed in various cell lines and in the lesion tissue contexts. RESULTS: Cystic lesions of PSP-BHD and PSP showed different miRNAs profiles with a significant upregulation of miR-424-5p and let-7d-5p in PSP-BHD. The combination of the two effectively predicted BHDS patients. In vitro studies revealed a suppressive effect of FLCN on miR-424-5p and let-7d-5p expressions specifically in lung epithelial cells. The ectopic miRNAs triggered epithelial apoptosis and epithelial transition of mesenchymal cells and suppressed the reparative responses in cells and tissues with FLCN deficiency. CONCLUSION: The upregulation of miR-424-5p and let-7d-5p by FLCN deficiency occurred in epithelial cells and marked the PSP-BHD condition, which contributed to a focused degenerative pathology in the lung of PSP-BHD patients.

Prognosis of primary tracheal tumor: A population-based analysis.

BACKGROUND: To elucidate the survival outcomes of tracheal tumors and to propose the potential stage of tracheal tumors. METHOD: All cases of primary tracheal malignant tumors were extracted from the Surveillance, Epidemiology, and End Results database (SEER) during 1973-2013. The overall survival was calculated using Kaplan-Meier method. Cox regression was utilized to identify the prognostic factors. RESULT: A total of 287 cases were finally included. The median age of the patients was 59 years. Male patients accounted for 56.1%. The median survival was 57 months. Patients were categorized as Extension1 to 4 (E1-4) and N0-N3. E1 group with size <4 cm had the best prognosis. While E1 >4 cm, E2 and E3 <3 cm groups had similar outcomes, which were superior to E3 >3 cm group. E4 was the worst. N0 patients had ideal prognosis, which were better than N1 and N2 patients. The 3-year survival rates of each T category were 74.7%, 57.3%, 28.1%, and 9.1%, respectively. In multivariate analysis, age, histology, tumor size, and extension were independent prognostic factors. CONCLUSION: Patients with old age, large tumor size, advanced extension or no surgery may have worse prognosis. The proposed T category of tracheal tumor incorporating tumor extension and size helped to predict survival outcomes.

A rapid NGS strategy for comprehensive molecular diagnosis of Birt-Hogg-Dubé syndrome in patients with primary spontaneous pneumothorax.

BACKGROUND: Primary spontaneous pneumothorax (PSP) or pulmonary cysts is one of the manifestations of Birt-Hogg-Dube syndrome (BHDS) that is caused by heterozygous mutations in FLCN gene. Most of the mutations are SNVs and small indels, and there are also approximately 10 % large intragenic deletions and duplications of the mutations. These molecular findings are generally obtained by disparate methods including Sanger sequencing and Multiple Ligation-dependent Probe Amplification in the clinical laboratory. In addition, as a genetically heterogeneous disorder, PSP may be caused by mutations in multiple genes include FBN1, COL3A1, CBS, SERPINA1 and TSC1/TSC2 genes. For differential diagnosis, these genes should also be screened which makes the diagnostic procedure more time-consuming and labor-intensive. METHODS: Forty PSP patients were divided into 2 groups. Nineteen patients with different pathogenic mutations of FLCN previously identified by conventional Sanger sequencing and MLPA were included in test group, 21 random PSP patients without any genetic screening were included in blinded sample group. 7 PSP genes including FLCN, FBN1, COL3A1, CBS, SERPINA1 and TSC1/TSC2 were designed and enriched by Haloplex system, sequenced on a Miseq platform and analyzed in the 40 patients to evaluate the performance of the targeted-NGS method. RESULTS: We demonstrated that the full spectrum of genes associated with pneumothorax including FLCN gene mutations can be identified simultaneously in multiplexed sequence data. Noteworthy, by our in-house copy number analysis of the sequence data, we could not only detect intragenic deletions, but also determine approximate deletion junctions simultaneously. CONCLUSIONS: NGS based Haloplex target enrichment technology is proved to be a rapid and cost-effective screening strategy for the comprehensive molecular diagnosis of BHDS in PSP patients, as it can replace Sanger sequencing and MLPA by simultaneously detecting exonic and intronic SNVs, small indels, large intragenic deletions and determining deletion junctions in PSP-related genes.

MicroRNAs let-7b/i suppress human glioma cell invasion and migration by targeting IKBKE directly.

We demonstrated that IKBKE is overexpressed in human gliomas and that the downregulation of IKBKE markedly inhibits the proliferative and invasive abilities of glioma cells, which is consistent with the results reported by several different research groups. Therefore, IKBKE represents a promising therapeutic target for the treatment of glioma. In the present study, we verified that the microRNAs let-7b and let-7i target IKBKE through luciferase assays and found that let-7b/i mimics can knock down IKBKE and upregulate E-cadherin through western blot analysis. Moreover, the expression levels of let-7b/i were significantly lower in glioma cell lines than that in normal brain tissues, as determined by quantitative real-time PCR. Furthermore, let-7b/i inhibit the invasion and migration of glioma cells, as determined through wound healing and Transwell assays. The above-mentioned data suggest that let-7b/i inhibit the invasive ability of glioma cells by directly downregulating IKBKE and indirectly upregulating E-cadherin.

High PHLPP expression is associated with better prognosis in patients with resected lung adenocarcinoma.

BACKGROUND: PH domain Leucine-rich-repeats protein phosphatase (PHLPP) is a novel family of Ser/Thr protein dephosphatases that play a critical role in maintaining the balance in cell signaling. PHLPP negatively regulates PI3K/Akt and RAF/RAS/' signaling activation, which is crucial in development, growth, and proliferation of lung cancer. The aim of this study was to investigate the association of PHLPP expression with biological behavior and prognosis of lung adenocarcinoma. METHODS: One hundred and fifty eight patients with pathologically documented stage I, II or IIIA lung adenocarcinoma were recruited in this study. Expression of PHLPP, p-AKT and p-ERK were evaluated by immunohistochemistry (IHC) in paraffin-embedded resected specimens. The correlation of their expression, which was dichotomized to low expression (a score of 0, 1) versus high expression (a score of 2, 3), with the clinicopathological parameters and prognosis of the patients also analyzed. RESULTS: High PHLPP expression rate in lung adenocarcinoma was 23.4 %. PHLPP expression level was significantly associated with tumor differentiation (p = 0.025) and tumor stage (p = 0.024). Patients with high expression of PHLPP showed significantly longer average survival time and higher 3 years survival rate than those with low expression of PHLPP (45 months versus 38 months, 85.8 % versus 73.5 % respectively) (Log rank test x(2) = 7.086, p =0.008). A significant inverse correlation was observed between PHLPP expression and p-AKT (r = -0.523, p = 0.000) or p-ERK (r = -0.530, p = 0.000). CONCLUSION: Our results suggest that high levels of PHLPP might reflect a less aggressive lung adenocarcinoma phenotype and predict better survival in patients with lung adenocarcinoma. PHLPP can be a potential prognostic marker to screen patients for favorable prognoses.

FLCN intragenic deletions in Chinese familial primary spontaneous pneumothorax.

Primary spontaneous pneumothorax (PSP) is a significant clinical problem, affecting tens of thousands patients annually. Germline mutations in the FLCN gene have been implicated in etiology of familial PSP (FPSP). Most of the currently identified FLCN mutations are small indels or point mutations that detected by Sanger sequencing. The aim of this study was to determine large FLCN deletions in PSP families that having no FLCN sequence-mutations. Multiplex ligation-dependent probe amplification (MLPA) assays and breakpoint analyses were used to detect and characterize the deletions. Three heterozygous FLCN intragenic deletions were identified in nine unrelated Chinese families including the exons 1-3 deletion in two families, the exons 9-14 deletion in five families and the exon 14 deletion in two families. All deletion breakpoints are located in Alu repeats. A 5.5 Mb disease haplotype shared in the five families with exons 9-14 deletion may date the appearance of this deletion back to approximately 16 generations ago. Evidences for founder effects of the other two deletions were also observed. This report documents the first identification of founder mutations in FLCN, as well as expands mutation spectrum of the gene. Our findings strengthen the view that MLPA analysis for intragenic deletions/duplications, as an important genetic testing complementary to DNA sequencing, should be used for clinical molecular diagnosis in FPSP.

Exosomal HMGB3 released by glioma cells confers the activation of NLRP3 inflammasome and pyroptosis in tumor-associated macrophages.

BACKGROUND: Previous evidences has highlighted the pivotal role of NOD-like receptor family pyrin domain-containing 3 (NLRP3)-mediated inflammasomes and pyroptosis activation in driving tumor malignancy and shaping the tumor microenvironment. Herein, we aimed to elucidate the impact of high-mobility group box 3 (HMGB3) released in glioma-derived exosomes on macrophage infiltration in gliomas, NLRP3 inflammasome activation and polarization. METHODS: Transcripts and protein levels of HMGB3, and cytokines associated with macrophage phenotypes and pyroptosis were assessed in glioma tissues and cell lines (U251, LN229, T98G, A172) using qRT-PCR and/or Western blot analysis. Exosomes secreted from LN229 and NHA cells were isolated via differential ultracentrifugation and characterized by transmission electron microscopy (TEM), nanoparticle tracking analysis (NTA), and analysis of exosome-related markers. PKH67 staining was employed to examine exosomes uptake by THP-1 differentiated macrophages. Flow cytometry was utilized to assess macrophage pyroptotic rates and polarization-related markers. RESULTS: HMGB3 expression was elevated in glioma tissues, serum samples and tumor cell lines. Kaplan-Meier curves revealed a positive correlation between higher HMGB3 expression and poor overall survival and recurrence-free survival. Moreover, glioma tissues with increased HMGB3 expression exhibited significant upregulation of M2 macrophages markers (CD68, CD206, Arg1) and NLRP3 inflammasome components (NLRP3, IL-1ß, ASC), suggesting that HMGB3 was closely associated with macrophage infiltration and NLRP3 inflammasome activation. Notably, HMGB3 was found to be enriched in glioma cell- secreted exosomes and could be internalized by macrophages. Knockdown of HMGB3 in glioma cell exosomes could restrain M2 macrophage polarization, NLRP3 inflammasome activation and pyroptosis. CONCLUSION: These findings suggested that glioma cells secreted exosomal HMGB3 could facilitate macrophage M2 polarization, pyroptosis and inflammatory infiltration, indicating HMGB3 might be a poor prognosis factor for glioma.

ZNF384 transcriptionally activated MGST1 to confer TMZ resistance of glioma cells by negatively regulating ferroptosis.

BACKGROUND: Drug resistance is one of the major reasons of the poor prognosis and recurs frequently in glioma. Ferroptosis is considered to be a new therapeutic strategy for glioma. METHODS: Microsomal glutathione S-transferase 1 (MGST1) expression in glioma samples was ensured through GAPIA database, qRT-PCR, western blotting assay and immunohistochemistry. The interaction between zinc finger protein 384 (ZNF384) and MGST1 promoter was analyzed through UCSC and JASPAR databases and further verified by ChIP and luciferase reporter assay. Cell viability and IC50 value of temozolomide (TMZ) was measured by CCK-8 assay. The production of MDA, GSH and ROS and the level of Fe2+ were determined using the corresponding kit. RESULTS: MGST1 expression was increased in clinical glioma tissues and glioma cells. MGST1 expression was increased but ferroptosis was suppressed in TMZ-resistant cells when contrasted to parent cells. MGST1 silencing downregulated IC50 value of TMZ and cell viability but facilitated ferroptosis in TMZ-resistant cells and parent glioma cells. Moreover, our data indicated that ZNF384 interacted with MGST1 promoter and facilitated MGST1 expression. ZNF384 was also increased expression in TMZ-resistant cells, and showed a positive correlation with MGST1 expression in clinical level. ZNF384 decreasing enhanced the sensitivity of resistant cells to TMZ, while the effect of ZNF384 could be reversed by overexpression of MGST1. CONCLUSION: MGST1 transcription is regulated by transcription factor ZNF384 in TMZ-resistant cells. ZNF384 confers the resistance of glioma cells to TMZ through inhibition of ferroptosis by positively regulating MGST1 expression. The current study may provide some new understand to the mechanism of TMZ resistance in glioma.

Deep learning-assisted detection and segmentation of intracranial hemorrhage in noncontrast computed tomography scans of acute stroke patients: a systematic review and meta-analysis.

BACKGROUND: Deep learning (DL)-assisted detection and segmentation of intracranial hemorrhage stroke in noncontrast computed tomography (NCCT) scans are well-established, but evidence on this topic is lacking. MATERIALS AND METHODS: PubMed and Embase databases were searched from their inception to November 2023 to identify related studies. The primary outcomes included sensitivity, specificity, and the Dice Similarity Coefficient (DSC); while the secondary outcomes were positive predictive value (PPV), negative predictive value (NPV), precision, area under the receiver operating characteristic curve (AUROC), processing time, and volume of bleeding. Random-effect model and bivariate model were used to pooled independent effect size and diagnostic meta-analysis data, respectively. RESULTS: A total of 36 original studies were included in this meta-analysis. Pooled results indicated that DL technologies have a comparable performance in intracranial hemorrhage detection and segmentation with high values of sensitivity (0.89, 95% CI: 0.88-0.90), specificity (0.91, 95% CI: 0.89-0.93), AUROC (0.94, 95% CI: 0.93-0.95), PPV (0.92, 95% CI: 0.91-0.93), NPV (0.94, 95% CI: 0.91-0.96), precision (0.83, 95% CI: 0.77-0.90), DSC (0.84, 95% CI: 0.82-0.87). There is no significant difference between manual labeling and DL technologies in hemorrhage quantification (MD 0.08, 95% CI: -5.45-5.60, P =0.98), but the latter takes less process time than manual labeling (WMD 2.26, 95% CI: 1.96-2.56, P =0.001). CONCLUSION: This systematic review has identified a range of DL algorithms that the performance was comparable to experienced clinicians in hemorrhage lesions identification, segmentation, and quantification but with greater efficiency and reduced cost. It is highly emphasized that multicenter randomized controlled clinical trials will be needed to validate the performance of these tools in the future, paving the way for fast and efficient decision-making during clinical procedure in patients with acute hemorrhagic stroke.

Deep learning-based quantification of total bleeding volume and its association with complications, disability, and death in patients with aneurysmal subarachnoid hemorrhage.

OBJECTIVE: The relationships between immediate bleeding severity, postoperative complications, and long-term functional outcomes in patients with aneurysmal subarachnoid hemorrhage (aSAH) remain uncertain. Here, the authors apply their recently developed automated deep learning technique to quantify total bleeding volume (TBV) in patients with aSAH and investigate associations between quantitative TBV and secondary complications, adverse long-term functional outcomes, and death. METHODS: Electronic health record data were extracted for adult patients admitted to a single institution within 72 hours of aSAH onset between 2018 and 2021. An automatic deep learning model was used to fully segment and quantify TBV on admission noncontrast head CT images. Patients were subgrouped by TBV quartile, and multivariable logistic regression, restricted cubic splines, and subgroup analysis were used to explore the relationships between TBV and each clinical outcome. RESULTS: A total of 819 patients were included in the study. Sixty-six (8.1%) patients developed hydrocephalus, while 43 (5.3%) experienced rebleeding, 141 (17.2%) had delayed cerebral ischemia, 88 (10.7%) died in the 12 months after discharge, and 208 (25.7%) had a modified Rankin Scale score ≥ 3 12 months after discharge. On multivariable analysis, patients in the highest TBV quartile (> 37.94 ml) had an increased risk of hydrocephalus (adjusted OR [aOR] 4.38, 95% CI 1.61-11.87; p = 0.004), rebleeding (aOR 3.26, 95% CI 1.03-10.33; p = 0.045), death (aOR 6.92, 95% CI 1.89-25.37; p = 0.004), and 12-month disability (aOR 3.30, 95% CI 1.62-6.72; p = 0.001) compared with the lowest TBV quantile (< 8.34 ml). The risks of hydrocephalus (nonlinear, p = 0.025), rebleeding, death, and disability (linear, p > 0.05) were positively associated with TBV by restricted cubic splines. In subgroup analysis, TBV had a stronger effect on 12-month outcome in female than male patients (p for interaction = 0.0499) and on rebleeding prevalence in patients with endovascular coiling than those with surgical clipping (p for interaction = 0.008). CONCLUSIONS: Elevated TBV is associated with a greater risk of hydrocephalus, rebleeding, death, and poor prognosis.

EGFR co-mutation is associated with the risk of recurrence in invasive lung adenocarcinoma with the micropapillary component.

BACKGROUND: Invasive lung adenocarcinoma (LUAD) patients with the micropapillary (MPP) component tend to have extremely poor prognosis. To optimize clinical outcomes, a better understanding of specific concurrent gene alterations and their impact on the prognosis of patients with the MPP component is necessary. METHOD: A total of 621 Chinese patients with surgically resected invasive LUAD who underwent genetic testing for lung cancer were enrolled in this retrospective study. The genomic profiling of major lung cancer-related genes based on next-generation sequencing (NGS) was carried out on formalin-fixed paraffin-embedded tumor samples. RESULT: Among 621 patients with invasive LUAD, 154 (24.8%, 154/621) had the MPP component. We found that PIK3CA (4.5% vs 1.3%), KRAS (9.1% vs 4.7%), and ROS1 (2.6% vs 0.4%) were more frequent in patients with the MPP component than those without the MPP component (P < 0.05). The co-mutation occurred in 66 patients (10.6%, 66/621), of which 19 patients with the MPP component. Most of them were EGFR co-mutations (89.5%, 17/19), including EGFR and PIK3CA, EGFR and ERBB2, and other types. Patients with the MPP component who harbored EGFR co-mutations showed significantly worse recurrence-free survival (RFS) than single EGFR mutation (median RFS 20.1 vs 30.5 months; hazard ratio [HR]: 8.008; 95% confidence interval [CI]: 1.322-48.508). CONCLUSIONS: Patients with the MPP component harbored the co-mutation of driver genes had a higher risk of recurrence after surgery, especially in patients with EGFR co-mutation. EGFR co-mutation was a significant prognostic factor for RFS in patients with the MPP component.

Explainable machine learning in outcome prediction of high-grade aneurysmal subarachnoid hemorrhage.

OBJECTIVE: Accurate prognostic prediction in patients with high-grade aneruysmal subarachnoid hemorrhage (aSAH) is essential for personalized treatment. In this study, we developed an interpretable prognostic machine learning model for high-grade aSAH patients using SHapley Additive exPlanations (SHAP). METHODS: A prospective registry cohort of high-grade aSAH patients was collected in one single-center hospital. The endpoint in our study is a 12-month follow-up outcome. The dataset was divided into training and validation sets in a 7:3 ratio. Machine learning algorithms, including Logistic regression model (LR), support vector machine (SVM), random forest (RF), and extreme gradient boosting (XGBoost), were employed to develop a prognostic prediction model for high-grade aSAH. The optimal model was selected for SHAP analysis. RESULTS: Among the 421 patients, 204 (48.5%) exhibited poor prognosis. The RF model demonstrated superior performance compared to LR (AUC = 0.850, 95% CI: 0.783-0.918), SVM (AUC = 0.862, 95% CI: 0.799-0.926), and XGBoost (AUC = 0.850, 95% CI: 0.783-0.917) with an AUC of 0.867 (95% CI: 0.806-0 .929). Primary prognostic features identified through SHAP analysis included higher World Federation of Neurosurgical Societies (WFNS) grade, higher modified Fisher score (mFS) and advanced age, were found to be associated with 12-month unfavorable outcome, while the treatment of coiling embolization for aSAH drove the prediction towards favorable prognosis. Additionally, the SHAP force plot visualized individual prognosis predictions. CONCLUSIONS: This study demonstrated the potential of machine learning techniques in prognostic prediction for high-grade aSAH patients. The features identified through SHAP analysis enhance model interpretability and provide guidance for clinical decision-making.

Comprehensive analyses of m1A regulator-mediated modification patterns determining prognosis in lower-grade glioma (running title: m1A in LGG).

N1-methyladenosine (m1A) modification is a crucial post-transcriptional regulatory mechanism of messenger RNA (mRNA) in living organisms. Few studies have focused on analysis of m1A regulators in lower-grade gliomas (LGG). We employed the Nonnegative Matrix Factorization (NMF) technique on The Cancer Genome Atlas (TCGA) dataset to categorize LGG patients into 2 groups. These groups exhibited substantial disparities in terms of both overall survival (OS) and levels of infiltrating immune cells. We collected the significantly differentially expressed immune-related genes between the 2 clusters, and performed LASSO regression analysis to obtain m1AScores, and established an m1A-related immune-related gene signature (m1A-RIGS). Next, we categorized all patients with LGG into high- and low-risk subgroups, predictive significance of m1AScore was confirmed by conducting univariate/multivariate Cox regression analyses. Additionally, we confirmed variations in immune-related cells and ssGSEA and among the high-/low-risk subcategories in the TCGA dataset. Finally, our study characterized the effects of MSR1 and BIRC5 on LGG cells utilizing Edu assay and flow cytometry to explore the effects of modulation of these genes on glioma. The results of this study suggested that m1A-RIGS may be an excellent prognostic indicator for patients with LGG, and could also promote development of novel immune-based treatment strategies for LGG. Additionally, BIRC5 and MSR1 may be potential therapeutic targets for LGG.

The novel EGFR mutations (p.E746_S752delinsI, p.T751_I759delinsG, p.L747_S752delinsAA) in patients with non-small cell lung cancer and the clinical treatment strategy: three case reports.

Epidermal growth factor receptor (EGFR) is an established driver gene in non-small cell lung cancer (NSCLC) and the common Exon 19 del mutation (p.E746_A750 del) has exhibited remarkable responses for EGFR tyrosine kinase inhibitors (TKIs). However, there is even less comprehension of the treatment strategy in NSCLC patients harboring uncommon Exon 19 delins mutation. Here, we identified three novel EGFR Exon 19 mutations (p.E746_S752delinsI, p.T751_I759delinsG, p.L747_S752delinsAA), and described the clinical treatment process. To our knowledge, the EGFR p.E746_S752delinsI mutation of the patient with advanced NSCLC could benefit from the treatment with Icotinib. Otherwise, for the NSCLC patients with early-stage, one harboring p.T751_I759delinsG mutation had an excellent recovery and the other harboring p.L747_S752delinsAA experienced a relapse after receiving horacoscopic radical resection, which means the patients with different Exon 19 delins mutation might have different prognosis. Our study also demonstrated that next-generation sequencing (NGS) is a crucial tool in guiding clinical treatment decisions in NSCLC. Furthermore, the real incidence of these mutation is not known, the routinely use of NGS surely will increase the detection of EGFR del-ins respect to the old tools used to screen for EGFR mutations.

Empirical assessment of carbon emissions in Guangdong Province within the framework of carbon peaking and carbon neutrality: a lasso-TPE-BP neural network approach.

The escalating global greenhouse gas emission crisis necessitates a robust scientific carbon accounting framework and innovative development approaches. Achieving emission peaks remains the primary goal for emission reduction. Guangdong Province, a pivotal region in China, faces pressure to reduce carbon emissions. In this study, data was leveraged from the China Carbon Accounting Database (CEADS) and panel data from the "Guangdong Statistical Yearbook" spanning 1997 to 2022. Factors impacting carbon emissions were selected based on Guangdong Province's carbon reduction goals, macroeconomic development strategies, and economic-population dynamics. To address multicollinearity, lasso regression identified key factors, including population size, economic development level, energy intensity, and technology factors. A novel STIRPAT extended model, combined with the BP neural network optimized using the TPE algorithm, enhanced carbon emission predictions for Guangdong Province. Employing scenario analysis, five scenarios were generated in alignment with the planning policies of Guangdong Province, to forecast carbon emissions from 2020 to 2050. The results suggest that to achieve a win-win situation for both economic development and environmental protection, Guangdong Province should prioritize the energy-saving scenario (S2), which aligns with the "13th Five-Year Plan's" ecological and green development directives, to reach a projected carbon peak of 637.05Mt by 2030. In conclusion, recommendations for carbon reduction are proposed in the areas of low-carbon transformation for the population, sustainable economic development, and the development of low-carbon technologies.

Effect of Surgical Clipping versus Endovascular Coiling on the Incidence of Delayed Cerebral Ischemia in Patients with Aneurysmal Subarachnoid Hemorrhage: A Multicenter Observational Cohort Study with Propensity Score Matching.

OBJECTIVE: The effect of surgical clipping (SC) and endovascular coiling (EC) on the incidence of delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH) has always been a controversial topic. Hence, it is necessary to reanalyze the effects of the 2 surgical methods on DCI, which determines the choice of the most favorable method for patients who are suitable for both surgical modalities. METHODS: A multicenter retrospective observational cohort study was performed to evaluate all consecutive patients with aSAH admitted to 5 medical centers in China between April 2019 and June 2021. Univariable and multivariable analyses were used to confirm risk factors of DCI after aSAH. A 1:1 propensity score matching model was generated in the EC and SC groups to reduce the influence of all confounding factors on DCI. RESULTS: A total of 412 patients were included, and 115 patients (27.9%) developed DCI. After propensity score matching for controlling demographic information, past medical history, admission clinical status, aneurysm characteristics, and inflammatory factors associated with DCI, 133 patients with SC and 133 patients with EC treatment were matched. The results of the matched cohorts indicate a significantly lower incidence of DCI when patients received EC than SC (31.9% vs. 20%; adjusted odds ratio, 1.87; 95% confidence interval, 1.08-3.29; P = 0.027). CONCLUSIONS: The study found that the patients who received SC treatment had a higher incidence of DCI than did those who received EC and suggested that ruptured intracerebral aneurysm is preferentially coiled rather than clipped if the aneurysm is suitable for both surgical modalities.