Emulsifiable oil-formulated Beauveria bassiana competes with imidacloprid for seasonal control of cereal aphids in Zhejiang, China.

BACKGROUND: Alternatives to neonicotinoids against cereal aphids are needed to mitigate aphid resistance and non-target effects. The emulsifiable oil formulations of two Beauveria bassiana strains, namely Bb registered as a mycoinsecticide and TBb overexpressing an endogenous virulence factor, were tested for seasonal control of cereal aphids at the elongating (April 7) to milk ripening (May 12) stages of winter wheat crop in Yuhang, Zhejiang. Each of three field trials consisted of blank control and the treatments (three randomized 100-m2 plots per capita) of each fungal strain sprayed biweekly at rates of 1.0 × 1013 and 1.5 × 1013 conidia ha-1 and 10% imidacloprid WP sprayed biweekly at a label rate. RESULTS: Tiller infestation percentage and aphid density in the 5-week field trials after the first spray were reduced to 18.7-22.4% and 9.1-12.4 aphids per tiller in the fungal treatments, and 12.8-25.3% and 2.8-20.9 aphids per tiller in the chemical treatment, contrasting with 49.2-60.3% and 37.1-108.5 aphids per tiller in the control. Percent control efficacies (±SD) computed with weekly aphid densities over the period averaged 84.0 ± 1.6 and 85.3 ± 1.8 versus 78.0 ± 4.0 and 79.9 ± 3.2 in the high-rate versus low-rate treatments of Bb and TBb, respectively, and 84.5 ± 7.8 in the chemical treatment. Imidacloprid showed faster kill action but more variable efficacy than the fungal treatments throughout the trials. CONCLUSION: Either Bb or TBb formulation competes with imidacloprid in reducing percent infestation and aphid density. The overall efficacy was significantly higher in the treatments of TBb than of Bb. © 2024 Society of Chemical Industry.

Iruplinalkib (WX-0593) Versus Crizotinib in ALK TKI-Naive Locally Advanced or Metastatic ALK-Positive NSCLC: Interim Analysis of a Randomized, Open-Label, Phase 3 Study (INSPIRE).

INTRODUCTION: Iruplinalkib (WX-0593) is a new-generation, potent ALK tyrosine kinase inhibitor (TKI) that has been found to have systemic and central nervous system (CNS) efficacy in ALK-positive NSCLC. We compared the efficacy and safety of iruplinalkib with crizotinib in patients with ALK TKI-naive, locally advanced or metastatic ALK-positive NSCLC. METHODS: In this open-label, randomized, multicenter, phase 3 study, patients with ALK-positive NSCLC were randomly assigned to receive iruplinalkib 180 mg once daily (7-d run-in at 60 mg once daily) or crizotinib 250 mg twice daily. The primary end point was progression-free survival (PFS) assessed by Independent Review Committee (IRC) per Response Evaluation Criteria in Solid Tumors version 1.1. Secondary end points included PFS by investigator, objective response rate (ORR), time to response, duration of response, intracranial ORR and time to CNS progression by IRC and investigator, overall survival, and safety. An interim analysis was planned after approximately 70% (134 events) of all 192 expected PFS events assessed by IRC were observed. Efficacy was analyzed in the intention-to-treat population. Safety was assessed in the safety population, which included all randomized patients who received at least one dose of the study drugs. This study is registered with Center for Drug Evaluation of China National Medical Products Administration (CTR20191231) and Clinicaltrials.gov (NCT04632758). RESULTS: From September 4, 2019, to December 2, 2020, a total of 292 patients were randomized and treated; 143 with iruplinalkib and 149 with crizotinib. At this interim analysis (145 events), the median follow-up time was 26.7 months (range: 3.7-37.7) in the iruplinalkib group and 25.9 months (range: 0.5-35.9) in the crizotinib group. The PFS assessed by IRC was significantly longer among patients in the iruplinalkib group (median PFS, 27.7 mo [95% confidence interval (CI): 26.3-not estimable] versus 14.6 mo [95% CI: 11.1-16.5] in the crizotinib group; hazard ratio, 0.34 [98.02% CI: 0.23-0.52], p < 0.0001). The ORR assessed by IRC was 93.0% (95% CI: 87.5-96.6) in the iruplinalkib group and 89.3% (95% CI: 83.1-93.7) in the crizotinib group. The intracranial ORR was 90.9% (10 of 11, 95% CI: 58.7-99.8) in the iruplinalkib group and 60.0% (nine of 15, 95% CI: 32.3-83.7) in the crizotinib group for patients with measurable baseline CNS metastases. Incidence of grade 3 or 4 treatment-related adverse events was 51.7% in the iruplinalkib group and 49.7% in the crizotinib group. CONCLUSIONS: Iruplinalkib was found to have significantly improved PFS and improved intracranial antitumor activity versus crizotinib. Iruplinalkib may be a new treatment option for patients with advanced ALK-positive and ALK TKI-naive NSCLC. FUNDING: This study was funded by Qilu Pharmaceutical Co., Ltd., Jinan, People's Republic of China, and partly supported by the National Science and Technology Major Project for Key New Drug Development (2017ZX09304015).

Correlation between ovarian follicular development and Hippo pathway in polycystic ovary syndrome.

BACKGROUND: For women of childbearing age, the biggest problem caused by polycystic ovary syndrome (PCOS) is infertility, which is mainly caused by anovulation, abnormal follicular development, proliferation of small antral follicles, and cystic follicles. The mechanism underlying its occurrence is not clear. The abnormal proliferation and development of follicles in PCOS patients is a complex process, which is affected by many factors. The objective of this study was to investigate the relationship between the Hippo pathway and follicular development in PCOS, and to further explore this relationship by using the YAP inhibitor verteporfin (VP). METHOD: 30 3-week-old BALB/C female rats were randomly divided into control group (n = 10), DHEA group (n = 10) and DHEA + VP group (n = 10). The morphology of ovary and the degree of follicular development were observed by HE staining, and the expression and location of AMH in ovarian follicles were observed by immunofluorescence. The ovarian reserve function index AMH, cell proliferation index PCNA and the ratio of Hippo pathway related proteins MST, LATS, YAP, P-YAP and P-YAP/YAP were detected by Western blot. RESULTS: After dividing 30 3-week-old female mice into control, dehydroepiandrosterone (DHEA; model of PCOS), and DHEA + VP groups, we found that the number of small follicles increased in the DHEA group compared to the control group. Additionally, in the DHEA group compared to the control group, anti-müllerian hormone (AMH; ovarian reserve index) increased, proliferating cell nuclear antigen (PCNA; cell proliferation index) decreased, and upstream (MST and LATS) and downstream (YAP and p-YAP) proteins in the Hippo pathway increased, though the p-YAP/YAP ratio decreased. VP ameliorated the increases in AMH, MST, LATS, YAP and p-YAP, but did not ameliorate the decrease in the p-YAP/YAP ratio. CONCLUSIONS: This study indicates that the increased small follicles in the ovaries and changes in ovarian reserve and cell proliferation may be closely related to Hippo pathway activation. This suggests that the Hippo pathway may be an important pathway affecting the proliferation and development of follicles and the occurrence of PCOS.

Machine learning-based prediction model for distant metastasis of breast cancer.

BACKGROUND: Breast cancer is the most prevalent malignancy in women. Advanced breast cancer can develop distant metastases, posing a severe threat to the life of patients. Because the clinical warning signs of distant metastasis are manifested in the late stage of the disease, there is a need for better methods of predicting metastasis. METHODS: First, we screened breast cancer distant metastasis target genes by performing difference analysis and weighted gene co-expression network analysis (WGCNA) on the selected datasets, and performed analyses such as GO enrichment analysis on these target genes. Secondly, we screened breast cancer distant metastasis target genes by LASSO regression analysis and performed correlation analysis and other analyses on these biomarkers. Finally, we constructed several breast cancer distant metastasis prediction models based on Logistic Regression (LR) model, Random Forest (RF) model, Support Vector Machine (SVM) model, Gradient Boosting Decision Tree (GBDT) model and eXtreme Gradient Boosting (XGBoost) model, and selected the optimal model from them. RESULTS: Several 21-gene breast cancer distant metastasis prediction models were constructed, with the best performance of the model constructed based on the random forest model. This model accurately predicted the emergence of distant metastases from breast cancer, with an accuracy of 93.6 %, an F1-score of 88.9 % and an AUC value of 91.3 % on the validation set. CONCLUSION: Our findings have the potential to be translated into a point-of-care prognostic analysis to reduce breast cancer mortality.

Impact of preoperative [18F]FDG PET/CT vs. contrast-enhanced CT in the staging and survival of patients with clinical stage I and II non-small cell lung cancer: a 10-year follow-up study.

OBJECTIVES: To elucidate the impact of [18F]FDG positron emission tomography/computed tomography (PET/CT) vs. CT workup on staging and prognostic evaluation of clinical stage (c) I-II NSCLC. METHODS: We retrospectively identified 659 cI-II NSCLC who underwent CT (267 patients) or preoperative CT followed by PET/CT (392 patients), followed by curative-intended complete resection in our hospital from January 2008 to December 2013. Differences were assessed between preoperative and postoperative stage. Five-year disease-free survival (DFS) and overall survival (OS) rates were calculated using the Kaplan-Meier approach and compared with log-rank test. Impact of preoperative PET/CT on survival was assessed by Cox regression analysis. RESULTS: The study included 659 patients [mean age, 59.5 years ± 10.8 (standard deviation); 379 men]. The PET/CT group was superior over CT group in DFS [12.6 vs. 6.9 years, HR 0.67 (95% CI 0.53-0.84), p < 0.001] and OS [13.9 vs. 10.5 years, HR 0.64 (95% CI 0.50-0.81), p < 0.001]. In CT group, more patients thought to have cN0 migrated to pN1/2 disease as compared with PET/CT group [26.4% (66/250) vs. 19.2% (67/349), p < 0.001], resulting in more stage cI cases being upstaged to pII-IV [24.7% (49/198) vs. 16.1% (47/292), p = 0.02], yet this was not found in cII NSCLC [27.5% (19/69) vs. 27.0% (27/100), p = 0.94]. Cox regression analysis identified preoperative PET/CT as an independent prognostic factor of OS and DFS (p = 0.002, HR = 0.69, 95% CI 0.54-0.88; p = 0.004, HR = 0.72, 95% CI 0.58-0.90). CONCLUSION: Addition of preoperative [18F]FDG PET/CT was associated with superior DFS and OS in resectable cI-II NSCLC, which may result from accurate staging and stage-appropriate therapy.

TPVB and general anesthesia affects postoperative functional recovery in elderly patients with thoracoscopic pulmonary resections based on ERAS pathway.

Objective: Thoracic surgery is easy to cause various perioperative complications, especially in elderly patients, due to their physical weakness and physiological function degeneration. Postoperative cognitive dysfunction is a common complication in elderly patients undergoing thoracic surgery. This study focuses on exploring the effects of thoracic paravertebral block (TPVB) combined with general anesthesia on postoperative functional recovery in elderly patients undergoing thoracoscopic radical resection for lung cancer based on enhanced recovery after surgery (ERAS) pathway. Methods: A total of 104 patients aged 60 years or older undergoing thoracoscopic radical resection of lung cancer were randomized into the combination group (n = 52) and the control group (n = 52). Patients in the control group were given general anesthesia alone, while patients in the combination group were given TPVB combined with general anesthesia. All patients applied the ERAS model for the perioperative intervention. Hemodynamic indices (heart rate [HR] and mean arterial pressure [MAP]) before anesthesia (T0), 5 min after thoracoscopic trocar placement (T1), at extubation (T2), 30 min after extubation (T3), and 6 h after the surgery (T4), postoperative analgesia, preoperative and postoperative serum pain stress factors (5-hydroxytryptamine [5-HT], prostaglandin E2 [PGE2], cortisol [Cor], substance P [SP], and norepinephrine [NE]), tumor markers (CYFRA21-1, CEA, and CA50), inflammatory factors (IL-6, TNF-α, and c-reactive protein (CRP)), lung function indicators (forced vital capacity [FVC] and forced expiratory volume in the first second [FEV1]), 6 min walking distance (6MWD), clinical recovery indicators, hospitalization status, and postoperative complications in patients between both groups were compared. Results: Compared with the control group, patients in the combination group had lower HR and MAP at T1-T4 time points, less intraoperative doses of remifentanil and propofol, less patient-controlled interscalene analgesia compression number 24 h after the surgery, lower visual analogue scale scores 24 h after the surgery, shorter hospitalization time, postoperative off-bed time, postoperative chest tube removal time, postoperative first feeding time and gastrointestinal function recovery time, reduced postoperative serum levels of 5-HT, PGE2, Cor, SP, NE, CYFRA21-1, CEA, CA50, IL-6, TNF-α, and CRP, decreased complications, and higher FVC, FEV1, and 6MWD. Conclusion: Based on the ERAS pathway, TPVB combined with general anesthesia in thoracoscopic surgery for lung cancer in elderly patients can effectively reduce the patients' hemodynamic fluctuations, alleviate postoperative pain, accelerate the recovery process, and reduce complications.

Value of mammographic microcalcifications and MRI-enhanced lesions in the evaluation of residual disease after neoadjuvant therapy for breast cancer.

Background: Microcalcifications persist even if a patient with breast cancer achieves pathologic complete response (pCR) as confirmed by surgery after neoadjuvant treatment (NAT). In practice, surgeons tend to remove all the microcalcifications. This study aimed to explore the correlation between changes in the extent of microcalcification after NAT and pathological tumor response and compare the accuracy of mammography (MG) and magnetic resonance imaging (MRI) in predicting the size of residual tumors. Methods: This was a retrospective study which included a consecutive series of patients in Guangdong Provincial People's Hospital. Between January 2010 and January 2020, 127 patients with breast cancer and Breast Imaging Reporting and Data System (BI-RADS) 4-5 microcalcifications were included in this study. The maximum diameter of the microcalcifications on MG and lesion enhancement on MRI pre- and post-NAT were measured. The correlations between the changes in residual microcalcifications on MG and pCR were analyzed. Intraclass correlation coefficients (ICCs) were computed between the extent of the residual microcalcifications, residual enhancement, and residual tumor size. Results: There were no statistically significant differences in the changes in microcalcifications after NAT according to the RECIST criteria on MRI (P=0.09) and Miller-Payne grade (P=0.14). MRI showed a higher agreement than did residual microcalcifications on MG in predicting residual tumor size (ICC: 0.771 vs. 0.097). Conclusions: MRI is more accurate for evaluating residual tumor size in breast cancer. In our study, the extent of microcalcifications on MG after NAT had nearly no correlation with the pathological size of the residual tumor. Therefore, residual tumors with microcalcifications may not necessarily be a contraindication to breast-conserving surgery.

MRI-based Quantification of Intratumoral Heterogeneity for Predicting Treatment Response to Neoadjuvant Chemotherapy in Breast Cancer.

Background Breast cancer is highly heterogeneous, resulting in different treatment responses to neoadjuvant chemotherapy (NAC) among patients. A noninvasive quantitative measure of intratumoral heterogeneity (ITH) may be valuable for predicting treatment response. Purpose To develop a quantitative measure of ITH on pretreatment MRI scans and test its performance for predicting pathologic complete response (pCR) after NAC in patients with breast cancer. Materials and Methods Pretreatment MRI scans were retrospectively acquired in patients with breast cancer who received NAC followed by surgery at multiple centers from January 2000 to September 2020. Conventional radiomics (hereafter, C-radiomics) and intratumoral ecological diversity features were extracted from the MRI scans, and output probabilities of imaging-based decision tree models were used to generate a C-radiomics score and ITH index. Multivariable logistic regression analysis was used to identify variables associated with pCR, and significant variables, including clinicopathologic variables, C-radiomics score, and ITH index, were combined into a predictive model for which performance was assessed using the area under the receiver operating characteristic curve (AUC). Results The training data set was comprised of 335 patients (median age, 48 years [IQR, 42-54 years]) from centers A and B, and 590, 280, and 384 patients (median age, 48 years [IQR, 41-55 years]) were included in the three external test data sets. Molecular subtype (odds ratio [OR] range, 4.76-8.39 [95% CI: 1.79, 24.21]; all P < .01), ITH index (OR, 30.05 [95% CI: 8.43, 122.64]; P < .001), and C-radiomics score (OR, 29.90 [95% CI: 12.04, 81.70]; P < .001) were independently associated with the odds of achieving pCR. The combined model showed good performance for predicting pCR to NAC in the training data set (AUC, 0.90) and external test data sets (AUC range, 0.83-0.87). Conclusion A model that combined an index created from pretreatment MRI-based imaging features quantitating ITH, C-radiomics score, and clinicopathologic variables showed good performance for predicting pCR to NAC in patients with breast cancer. © RSNA, 2023 Supplemental material is available for this article. See also the editorial by Rauch in this issue.

Screening biomarkers for predicting the efficacy of immunotherapy in patients with PD-L1 overexpression.

PURPOSE: Immunotherapy plays an important role in non-small cell lung cancer (NSCLC); in particular, immune checkpoint inhibitors (ICIs) therapy has good therapeutic effects in PD-L1-positive patients. This study aims to screen NSCLC patients with PD-L1-positive expression and select effective biomarkers for ICI immunotherapy. METHODS: Collected tumor samples from the Affiliated Cancer Hospital of Xinjiang Medical University and 117 patients with stage III-IV NSCLC were included in the study. All patients were on first- or second-line therapy and not on targeted therapy. Based on the molecular profiles and clinical features, we screened biomarkers for predicting the efficacy of immunotherapy in patients with PD-L1 overexpression. RESULTS: 117 NSCLC patients receiving ICIs immunotherapy were enrolled. First, we found that immunotherapy was more effective in patients with positive PD-L1 expression. Second, we found that ROS1 gene mutations, KRAS gene mutations, tumor stage, and the endocrine system diseases history are independent prognostic factors for PD-L1 positive patients. Then we combined independent risk factors and constructed a new Nomogram to predict the therapeutic efficacy of ICIs immunotherapy in PD-L1 positive patients. The Nomogram integrates these factors into a prediction model, and the predicted C-statistic of 3 months, 6 months and 12 months are 0.85, 0.84 and 0.85, which represents the high predictive accuracy of the model. CONCLUSIONS: We have established a model that can predict the efficacy of ICIs immunotherapy in PD-L1 positive patients. The model consists of ROS1 gene mutations, KRAS gene mutations, tumor staging, and endocrine system disease history, and has good predictive ability.

Safety and efficacy of atezolizumab in Chinese patients with previously treated locally advanced or metastatic non-small cell lung cancer: An open-label, single-arm, multicenter study.

OBJECTIVES: To evaluate the long-term safety and efficacy of atezolizumab monotherapy in Chinese patients with previously treated, locally advanced or metastatic non-small cell lung cancer (NSCLC). MATERIALS AND METHODS: In this open-label, single-arm, multicenter study, patients received atezolizumab 1200 mg intravenously on Day 1 of each 21-day cycle. The primary endpoint was incidence of atezolizumab-related serious adverse events (SAEs). Secondary endpoints included other safety and efficacy measures. Patients with available tumor tissue and blood samples underwent biomarker analyses. Patients with available tumor biopsies underwent exome sequencing. RESULTS: The safety and evaluable populations included 101 and 97 patients, respectively. Exome sequencing data were available for 31 patients. Median follow-up time was 27.43 months. Atezolizumab-related SAEs and immune-related adverse events occurred in 25.7% and 47.5% of the safety population, respectively, and in the following subgroups: central nervous system metastases (n = 14), 35.7% and 35.7%; squamous NSCLC (n = 39), 33.3% and 53.8%. The 24-month overall survival rate was 37.4%. Median overall survival and progression-free survival by RECIST v1.1 were 15.31 and 2.86 months, respectively; objective response rate was 16.5% in the evaluable population. PRRC2C (odds ratio: 12.780, P = 0.014) and ZMYND8 (odds ratio: 19.963, P = 0.016) gene mutations were significantly enriched in atezolizumab responders vs non-responders. Patients with CD8+ TILs > 10% vs ≤ 10% were significantly more likely to be atezolizumab responders. CONCLUSION: No new safety concerns were raised, and clinically meaningful benefits of atezolizumab monotherapy were shown. The results of the biomarker analyses may guide future therapeutic strategies.

Interim survival analysis of the randomized phase III GEMSTONE-302 trial: sugemalimab or placebo plus chemotherapy as first-line treatment for metastatic NSCLC.

The randomized, double-blinded, multi-center, phase III GEMSTONE-302 ( NCT03789604 ) study evaluated the efficacy and safety of sugemalimab versus placebo in combination with chemotherapy as first-line treatment for metastatic non-small-cell lung cancer (NSCLC). In this study, 479 treatment-naive patients with stage IV squamous or non-squamous NSCLC without known EGFR sensitizing mutations, ALK, ROS1 or RET fusions were randomized (2:1) to receive 1,200 mg of sugemalimab (n = 320) or placebo (n = 159) every 3 weeks in combination with platinum-based chemotherapy for up to four cycles, followed by maintenance therapy with sugemalimab or placebo for squamous NSCLC and sugemalimab or placebo plus pemetrexed for non-squamous NSCLC. Placebo-treated patients could cross over to receive sugemalimab monotherapy on disease progression. The primary endpoint was investigator-assessed progression-free survival (PFS) and the secondary endpoints included overall survival (OS) and objective response rate. Sugemalimab plus chemotherapy has demonstrated significant PFS prolongation in the primary analysis as reported previously. As of 22 November 2021, the prespecified interim OS analysis showed significant improvement with the addition of sugemalimab to chemotherapy (median OS = 25.4 versus 16.9 months; hazard ratio = 0.65; 95% confidence interval = 0.50-0.84; P = 0.0008). Sugemalimab plus chemotherapy provided superior PFS and OS compared to placebo plus chemotherapy, supporting the use of sugemalimab as a first-line treatment option for metastatic NSCLC.

Central nervous system efficacy of rezivertinib (BPI-7711) in advanced NSCLC patients with EGFR T790M mutation: A pooled analysis of two clinical studies.

BACKGROUND: Rezivertinib (BPI-7711) is a novel third-generation epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) which revealed the systematic and central nervous system (CNS) antitumor activities for EGFR T790M-mutated advanced NSCLC in previous clinical studies and is further analyzed here. METHODS: Eligible patients from the previous phase I and phase IIb studies of rezivertinib were included for pooled analysis. Post-progressive patients who received a prescribed dosage (≥180 mg) of rezivertinib orally once daily were included in full analysis set (FAS), while those with stable, asymptomatic CNS lesions, including measurable and non-measurable ones at baseline were included in CNS full analysis set (cFAS). Patients with measurable CNS lesions were included in CNS evaluable for response set (cEFR). BICR-assessed CNS objective response rate (CNS-ORR), CNS disease control rate (CNS-DCR), CNS duration of response (CNS-DoR), CNS progression-free survival (CNS-PFS), and CNS depth of response (CNS-DepOR) were evaluated. RESULTS: 355 patients were included in FAS, among whom 150 and 45 patients were included in cFAS and cEFR. This pooled analysis showed the CNS-ORR was 32.0% (48/150; 95% CI: 24.6-40.1%) and the CNS-DCR was 42.0% (63/150; 95% CI: 34.0-50.3%) in cFAS, while that in cEFR were 68.9% (31/45; 95% CI: 53.4-81.8%) and 100% (45/45; 95% CI: 92.1-100.0%). In cEFR, the median CNS-DepOR and the mean of CNS-DepOR were -52.0% (range: -100.0 to 16.1%) and -46.8% (95% CI: -55.5 to -38.1%). In cFAS, the median CNS-DoR and CNS-PFS were 13.8 (95% CI: 9.6-not calculable [NC]) and 16.5 (95% CI: 13.7-NC) months. CONCLUSIONS: Rezivertinib demonstrated encouraging clinical CNS efficacy among advanced NSCLC patients with EGFR T790M mutation and CNS metastases.

Use of Pretreatment Multiparametric MRI to Predict Tumor Regression Pattern to Neoadjuvant Chemotherapy in Breast Cancer.

RATIONALE AND OBJECTIVES: To develop an easy-to-use model by combining pretreatment MRI and clinicopathologic features for early prediction of tumor regression pattern to neoadjuvant chemotherapy (NAC) in breast cancer. MATERIALS AND METHODS: We retrospectively analyzed 420 patients who received NAC and underwent definitive surgery in our hospital from February 2012 to August 2020. Pathologic findings of surgical specimens were used as the gold standard to classify tumor regression patterns into concentric and non-concentric shrinkage. Morphologic and kinetic MRI features were both analyzed. Univariable and multivariable analyses were performed to select the key clinicopathologic and MRI features for pretreatment prediction of regression pattern. Logistic regression and six machine learning methods were used to construct prediction models, and their performance were evaluated with receiver operating characteristic curve. RESULTS: Two clinicopathologic variables and three MRI features were selected as independent predictors to construct prediction models. The apparent area under the curve (AUC) of seven prediction models were in the range of 0.669-0.740. The logistic regression model yielded an AUC of 0.708 (95% confidence interval [CI]: 0.658-0.759), and the decision tree model achieved the highest AUC of 0.740 (95% CI: 0.691-0.787). For internal validation, the optimism-corrected AUCs of seven models were in the range of 0.592-0.684. There was no significant difference between the AUCs of the logistic regression model and that of each machine learning model. CONCLUSION: Prediction models combining pretreatment MRI and clinicopathologic features are useful for predicting tumor regression pattern in breast cancer, which can assist to select patients who can benefit from NAC for de-escalation of breast surgery and modify treatment strategy.

Central nervous system efficacy of furmonertinib (AST2818) in patients with EGFR T790M mutated non-small cell lung cancer: a pooled analysis from two phase 2 studies.

BACKGROUND: Furmonertinib (AST2818) is a brain penetrant pan-epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) targeting both EGFR sensitizing mutations and T790M mutation. We report the pooled central nervous system (CNS) efficacy data of furmonertinib in patients with EGFR T790M mutated non-small cell lung cancer (NSCLC) from two phase 2 studies. METHODS: This was a pooled, post-hoc analysis of two phase 2 studies (NCT03127449 [phase 2a study of furmonertinib], NCT03452592 [phase 2b study of furmonertinib]). In the phase 2a study, patients received furmonertinib 40 mg, 80 mg, 160 mg, or 240 mg orally once daily. In the phase 2b study, all patients received furmonertinib 80 mg orally once daily. CNS efficacy of furmonertinib was analyzed in patients with baseline CNS lesions by an independent review center per Response Evaluation Criteria in Solid Tumors version 1.1. RESULTS: A total of 132 patients with baseline CNS metastases were included in this analysis. In 52 patients with measurable CNS lesions, CNS objective response rates were zero (0/1), 65% (22/34), 85% (11/13), and 25% (1/4), and CNS disease control rates were zero (0/1), 97% (33/34), 100% (13/13), and 100% (4/4) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively. In patients with measurable or non-measurable CNS lesions, median CNS progression-free survival was 2.8 months (95% confidence interval [CI] 1.4-8.3), 11.6 months (95% CI 8.3-13.8), 19.3 months (95% CI 5.5-not available [NA]), and not reached (95% CI 2.8 months-NA) in the 40 mg, 80 mg, 160 mg, and 240 mg orally once daily group, respectively. CONCLUSIONS: Furmonertinib showed promising CNS efficacy in doses of 80 mg orally once daily or higher in patients with EGFR T790M mutated NSCLC. TRIAL REGISTRATION: Both studies were registered on ClinicalTrial.gov. The phase 2a study was registered with NCT03127449 on April 25, 2017; The phase 2b study was registered with NCT03452592 on March 2, 2018.

Efficacy and safety of iruplinalkib (WX-0593) in ALK-positive crizotinib-resistant advanced non-small cell lung cancer patients: a single-arm, multicenter phase II study (INTELLECT).

BACKGROUND: Iruplinalkib (WX-0593) is an anaplastic lymphoma kinase (ALK)/c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor. Here we reported the single-arm, phase II study (INTELLECT) results of the efficacy and safety of iruplinalkib for ALK-positive crizotinib-resistant advanced non-small cell lung cancer (NSCLC) patients. METHODS: ALK-positive crizotinib-resistant advanced NSCLC patients aged ≥18 years, with Eastern Cooperative Oncology Group performance status of 0-2 were eligible. Patients received iruplinalkib 180 mg orally once daily for a 21-day cycle with a 7-day lead-in phase at 60 mg orally once daily. The primary endpoint was the independent review committee (IRC)-assessed objective response rate (ORR). RESULTS: From August 7, 2019, to October 30, 2020, 146 patients were included. As of the data cut-off date on November 30, 2021, the median follow-up time was 18.2 months (95% confidence interval [CI] 16.8-18.8). IRC-assessed ORR and disease control rate (DCR) were 69.9% (95% CI 61.7-77.2%) and 96.6% (95% CI 92.2-98.9%), respectively. Investigator-assessed ORR and DCR were 63.0% (95% CI 54.6-70.8%) and 94.5% (95% CI 89.5-97.6%), respectively. Investigator-assessed median duration of response and progression-free survival (the same as median time to progression) were 13.2 months (95% CI 10.4-17.7) and 14.5 months (95% CI 11.7-20.0), respectively. Corresponding IRC-assessed results were 14.4 months (95% CI 13.1-not evaluable [NE]), 19.8 months (95% CI 14.5-NE), and NE (95% CI 14.5-NE), respectively. Investigator-assessed intracranial ORRs were 46% (41/90, 95% CI 35-56%) in patients with central nervous system metastases and 64% (27/42, 95% CI 48-78%) in patients with measurable intracranial lesions. Overall survival data were immature. Treatment-related adverse events (TRAEs) occurred in 136/146 (93.2%) patients. The most common TRAEs were aspartate aminotransferase increased (63 [43.2%]), alanine aminotransferase increased (54 [37.0%]), and blood creatine phosphokinase increased (51 [34.9%]). Dose interruption, reduction, and discontinuation due to TRAEs occurred in 21 (14.4%), 16 (11.0%), and four (2.7%) patients, respectively. CONCLUSIONS: In this study, iruplinalkib (WX-0593) demonstrated favorable efficacy and manageable safety profiles in patients with ALK-positive crizotinib-resistant advanced NSCLC. Iruplinalkib could be a new treatment option for this patient population. TRIAL REGISTRATION: Center for Drug Evaluation of National Medical Products Administration of China: CTR20190789, registered on April 28, 2019; ClinicalTrials.gov: NCT04641754, registered on November 24, 2020.

Clinical and economic benefits of image-guided system in functional endoscopicsinus surgery: a retrospective chart review study in China.

BACKGROUND: Image-guided system (IGS) has been gradually applied in the field of rhinology, making functional endoscopic sinus surgery (FESS) a truly minimally invasive and precise surgery. This study was based on real-world data from China hospitals and aimed to evaluate the clinical and economic benefits of the IGS navigation system in FESS. METHODS: This was a two-center retrospective chart review of patients with chronic rhinosinusitis who underwent FESS, including open frontal sinus between July 1, 2018 and December 31, 2019 in China. The intervention group consisted of 100 patients who underwent FESS with the IGS navigation system (IGS group), and the control group consisted of 100 patients who underwent conventional FESS (Non-IGS group). Data were collected from surgical notes and hospital medical records. The primary endpoints for clinical effectiveness and safety were avoid rehospitalization due to bleeding, avoid reoperation due to bleeding, and avoid reoperation due to recurrence. RESULTS: There were no cases of rehospitalization due to bleeding, reoperation due to bleeding, and reoperation due to recurrence in the IGS group, with an avoidance rate of 100%. In the non-IGS group, there were four cases of rehospitalization and reoperation due to bleeding, with an avoidance rate 96.00% (P = 0.121). No cases of reoperation due to recurrence were in the non-IGS group. The total hospitalization cost was 17,391.51 CNY in the IGS group and 17,742.41 CNY in the non-IGS group per patient, with no statistical difference between the two groups (P = 0.715). Compared with the non-IGS group, the IGS group had an overall cost saving of 350.90 CNY per patient. Although the procedure-related medical costs of IGS group were increased by 1,286.12 CNY compared with the non-IGS group, this was more than offset by other costs. CONCLUSION: The results of the study indicated that the IGS may avoid occurrence of rehospitalization and reoperation due to postoperative bleeding. Although the use of navigation technology increased the cost of surgery, its clinical effectiveness brought other medical cost savings, resulting in no significant difference in the overall cost of navigation surgery compared to conventional surgery. The IGS should be considered cost-effectiveness in the treatment of FESS.

Magnesium alleviates aluminum-induced growth inhibition by enhancing antioxidant enzyme activity and carbon-nitrogen metabolism in apple seedlings.

Previous studies have determined that magnesium (Mg) in appropriate concentrations prevents plants from suffering from abiotic stress. To better understand the mechanism of Mg alleviation of aluminum (Al) stress in apple, we investigated the effect of Mg on plant growth, photosynthetic fluorescence, antioxidant system, and carbon (C) and nitrogen (N) metabolism of apple seedlings under Al toxicity (1.5 mmol/L) via a hydroponic experiment. Al stress induced the production of reactive oxygen in the leaves and roots and reduced the total dry weight (DW) by 52.37 % after 20 days of treatment relative to plants grown without Al, due to hindered photosynthesis and alterations in C and N metabolism. By contrast, total DW decreased by only 11.07 % in the Mg-treated plants under Al stress. Supplementation with 3.0 mmol/L Mg in the Al treatment decreased Al accumulation in the apple plants and reduced Al-induced oxidative damage by enhancing the activity of antioxidant enzymes (superoxide dismutase, catalase, and peroxidase) and reducing the production of H2O2 and malondialdehyde (MDA). Under Al stress, the Mg-treated plants showed a 46.17 % higher photosynthetic rate than the non-treated plants. Supplementation with Mg significantly increased the sucrose content by increasing sucrose synthase (SS) and sucrose-phosphate synthase (SPS) activities. Moreover, Mg facilitated the transport of 13C-carbohydrates from the leaves to roots. Regarding N metabolism, the nitrate reductase (NR), glutamine synthase (GS), and glutamate synthase (GOGAT) activities in the roots and leaves of the Mg-treated plants were significantly higher than those of the non-treated plants under Al stress. Compared with the non-treated plants under Al stress, the Mg-treated plants exhibited a significantly high level of NO3- and soluble protein content in the leaves, roots, and stems, but a low level of free amino acids. Furthermore, Mg significantly improved nitrogen accumulation and enhanced the transport of 15N from the roots to leaves. Overall, our results revealed that Mg alleviates Al-induced growth inhibition by enhancing antioxidant capacity and C-N metabolism in apple seedlings.