Fibroblast growth factor 13 is a microtubule-stabilizing protein regulating neuronal polarization and migration.

Secretory fibroblast growth factors (FGFs) and their receptors are known for their regulatory function in the early stages of neural development. FGF13, a nonsecretory protein of the FGF family, is expressed in cerebral cortical neurons during development and is a candidate gene for syndromal and nonspecific forms of X-chromosome-linked mental retardation (XLMR). However, its function during development remains unclear. We show that FGF13 acts intracellularly as a microtubule-stabilizing protein required for axon and leading process development and neuronal migration in the cerebral cortex. FGF13 is enriched in axonal growth cones and interacts directly with microtubules. Furthermore, FGF13 polymerizes tubulins and stabilizes microtubules. The loss of FGF13 impairs neuronal polarization and increases the branching of axons and leading processes. Genetic deletion of FGF13 in mice results in neuronal migration defects in both the neocortex and the hippocampus. FGF13-deficient mice also exhibit weakened learning and memory, which is correlated to XLMR patients' intellectual disability.

Duplex-Hierarchy Representation Learning for Remote Sensing Image Classification.

Remote sensing image classification (RSIC) is designed to assign specific semantic labels to aerial images, which is significant and fundamental in many applications. In recent years, substantial work has been conducted on RSIC with the help of deep learning models. Even though these models have greatly enhanced the performance of RSIC, the issues of diversity in the same class and similarity between different classes in remote sensing images remain huge challenges for RSIC. To solve these problems, a duplex-hierarchy representation learning (DHRL) method is proposed. The proposed DHRL method aims to explore duplex-hierarchy spaces, including a common space and a label space, to learn discriminative representations for RSIC. The proposed DHRL method consists of three main steps: First, paired images are fed to a pretrained ResNet network for extracting the corresponding features. Second, the extracted features are further explored and mapped into a common space for reducing the intra-class scatter and enlarging the inter-class separation. Third, the obtained representations are used to predict the categories of the input images, and the discrimination loss in the label space is minimized to further promote the learning of discriminative representations. Meanwhile, a confusion score is computed and added to the classification loss for guiding the discriminative representation learning via backpropagation. The comprehensive experimental results show that the proposed method is superior to the existing state-of-the-art methods on two challenging remote sensing image scene datasets, demonstrating that the proposed method is significantly effective.

Safety, efficacy and pharmacokinetics of BPI-9016M in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer: a phase Ib study.

BACKGROUND: As a potential target receptor tyrosine kinase, mesenchymal-epithelial transition factor (MET) exhibits high aberrant expression across various tumors. This study aimed to evaluated the safety, tolerability, efficacy and pharmacokinetics (PK) of BPI-9016M, a novel tyrosine kinase inhibitor (TKI) targeting c-MET, in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS/DESIGN: In this two-part multicenter phase Ib study, eligible patients with locally advanced or metastatic NSCLC harboring c-MET overexpression or MET exon 14 skipping mutation were enrolled into Part A (tested positive for c-MET overexpression [immunohistochemical staining score ≥ 2+]; 300 mg quaque die [QD], 450 mg QD and 600 mg QD cohorts) or Part B (tested positive for MET exon 14 skipping mutation; 400 mg bis in die [BID] cohort), respectively. The primary endpoints were safety, objective response rate (ORR) and disease control rate (DCR), the second endpoints were PK parameters, progression-free survival (PFS) and overall survival (OS). RESULTS: Between March 15, 2017 and September 18, 2021, 38 patients were enrolled (Part A, n = 34; Part B, n = 4). Of 38 patients, 32 (84.2%) patients completed the treatment protocol. As of the data cut-off date on January 27, 2022, all patients reported at least one treatment-emergent adverse event (TEAE). Ninety-two point one percent (35/38) of patients experienced treatment-related adverse events (TRAEs), and grade ≥ 3 TRAEs were observed in 11 (28.9%) patients. The most common TRAEs were elevated alanine aminotransferase (ALT, 14/38, 36.8%) and elevated aspartate aminotransferase (AST, 11/38, 28.9%). Only one (2.6%) patient had treatment-related serious adverse event (SAE) in 600 mg QD cohort due to thrombocytopenia. PK analysis showed BPI-9016M and its main metabolites (M1 and M2-2) reached steady state after seven days of continuous administration. At the dose of 300 mg QD and 450 mg QD, the exposure of BPI-9016M increased with increasing dose. Exposure of BPI-9016M was similar at 450 mg QD and 600 mg QD, which may exhibit a saturation trend. In all patients, ORR and DCR were 2.6% (1/38, 95% confidence interval [CI] 0.1-13.8%) and 42.1% (16/38, 95% CI 26.3-59.2%), respectively. Only one partial response (PR) patient was observed at a dose of 600 mg QD in Part A. In Part B, DCR was 75.0% (3/4, 95% CI 19.4-99.4%). The median PFS and OS in all 38 patients were 1.9 months (95% CI 1.9-3.7) and 10.3 months (95% CI 7.3-not evaluable [NE]), respectively. CONCLUSION: BPI-9016M showed manageable safety profile in c-MET overexpression or MET exon 14 skipping mutation patients with locally advanced or metastatic NSCLC, but showed limited efficacy. TRIAL REGISTRATION: Clinicaltrials.gov NCT02929290 (11/10/2016).

Renal­rotation techniques in retroperitoneoscopic adrenalectomy for giant pheochromocytomas: a clinical intervention study with historical controls.

BACKGROUND: Dealing with the giant pheochromocytomas (maximum diameter ≥ 6 cm) has long been a tough challenge for urologists. We introduced a new retroperitoneoscopic adrenalectomy method modified with renal-rotation techniques to treat giant pheochromocytomas. METHODS: 28 diagnosed patients were prospectively recruited as the intervention group. Meanwhile, by referring to the historical records in our database, matched patients who had undergone routine retroperitoneoscopic adrenalectomy (RA), transperitoneal laparoscopic adrenalectomy (TA), or open adrenalectomy (OA) for giant pheochromocytomas were selected as controls. Perioperative and follow-up data were collected for comparative assessment. RESULTS: Among all the groups, the intervention group had the minimal bleeding volume (28.93 ± 25.94 ml, p < 0.05), the least intraoperative blood pressure variation (59.11 ± 25.68 mmHg, p < 0.05), the shortest operation time (115.32 ± 30.69 min, p < 0.05), the lowest postoperative ICU admission rates (7.14%, p < 0.05), and shortest drainage time length (2.57 ± 0.50 days, p < 0.05). Besides, compared with TA and OA groups, intervention group was also characterized by lower pain scores (3.21 ± 0.63, p < 0.05), less postoperative complications (p < 0.05), earlier diet initiation time (1.32 ± 0.48 postoperative days, p < 0.05) and ambulation time (2.68 ± 0.48 postoperative days, p < 0.05). Follow-up blood pressure and metanephrine and normetanephrine levels in all intervention group patients remained normal. CONCLUSION: Compared with RA, TA, and OA, retroperitoneoscopic adrenalectomy with renal-rotation techniques is a more feasible, efficient, and secure surgical treatment for giant pheochromocytomas. TRIAL REGISTRATION: This study has been prospectively registered on the Chinese Clinical Trial Registry website (ChiCTR2200059953, date of first registration: 14/05/2022).

Radical Decarboxylative Carbon-Nitrogen Bond Formation.

The carbon-nitrogen bond is one of the most prevalent chemical bonds in natural and artificial molecules, as many naturally existing organic molecules, pharmaceuticals, agrochemicals, and functional materials contain at least one nitrogen atom. Radical decarboxylative carbon-nitrogen bond formation from readily available carboxylic acids and their derivatives has emerged as an attractive and valuable tool in modern synthetic chemistry. The promising achievements in this research topic have been demonstrated via utilizing this strategy in the synthesis of complex natural products. In this review, we will cover carbon-nitrogen bond formation via radical decarboxylation of carboxylic acids, Barton esters, MPDOC esters, N-hydroxyphthalimide esters (NHP esters), oxime esters, aryliodine(III) dicarboxylates, and others, respectively. This review aims to bring readers a comprehensive survey of the development in this rapidly expanding field. We hope that this review will emphasize the knowledge, highlight the proposed mechanisms, and further disclose the fascinating features in modern synthetic applications.

Efficacy of Icotinib, an EGFR Tyrosine Kinase Inhibitor in Non-Small Cell Lung Cancer Patients with Exon 19 Deletion and Exon 21 L858R: A Retrospective Analysis in China.

INTRODUCTION: The effect of icotinib on non-small cell lung cancer (NSCLC) patients with EGFR exon 19 deletions (19-Del) or L858R point mutation in exon 21 (21-L858R) remains inconsistent. This study aimed to evaluate the efficacy and safety of icotinib in patients with advanced NSCLC harboring these 2 EGFR mutations. METHODS: We retrospectively assessed the clinical effects of first-line icotinib on advanced NSCLC patients with 2 classic EGFR mutations. Kinase activity assays were used to reaffirm the preclinical efficacy. RESULTS: Among 2,757 patients, 2,365 (86%) harbored 19-Del (1,346/2,757, 49%) or 21-L858R (1,019/2,757, 37%) mutation. Patients with 19-Del had a higher response rate (ORR; 67.8 vs. 62.1%; p = 0.0039) and disease control rate (98.5 vs. 97.2%; p = 0.0223) than those with 21-L858R mutation. The median progression-free survival (PFS) in the 19-Del group (22.3 months, 95% confidence interval [CI]: 21.3-23.4) was significantly longer than that in the 21-L858R group (20.4 months, 95% CI: 19.5-21.7) (p = 0.004). In multivariate analysis, mutation types, clinical stage, and smoking history were significant factors for PFS. Additionally, an in vitro study indicated the 50% inhibitory concentrations (IC50) of icotinib was lower for EGFR 19-Del than 21-L858R. CONCLUSION: These results suggest that EGFR 19-Del confers superior PFS and response to the icotinib treatment compared to 21-L858R.

Intratumoral heterogeneity and genetic characteristics of prostate cancer.

Prostate cancer is a heterogeneous disease and optimum gene targeting treatment is often impermissible. We aim to determine the intratumoral genomic heterogeneity of prostate cancer and explore candidate genes for targeted therapy. Exome sequencing was performed on 37 samples from 16 patients with prostate cancer. Somatic variant analysis, copy number variant (CNV) analysis, clonal evolution analysis and variant spectrum analysis were used to study the intratumoral genomic heterogeneity and genetic characteristics of metastatic prostate cancer. Our study confirmed the high intratumoral genetic heterogeneity of prostate cancer in many aspects, including number of shared variants, tumor mutation burden (TMB), variant genes, CNV burden, weighted genome instability index (wGII), CNV profiles, clonal evolutionary process, variant spectrum and mutational signatures. Moreover, we identified several common genetic characteristics of prostate cancer. Alterations of DNA damage repair genes, RTK/RAS pathway associated gene RASGRF1 and autophagy gene EPG5 may be involved in tumorigenesis in prostate cancer. CNV burden and DNA damage repair (DDR) genes may be associated with metastasis of prostate cancer.

Rapid exacerbation featuring acute leukemoid reaction after retrolaparoscopic nephrectomy: a rare case report of renal cell carcinoma with postoperative comprehensive genomic profiling.

BACKGROUND: Rapid lethal exacerbation and recurrence featuring acute leukemoid reaction (ALR) after retrolaparoscopic radical nephrectomy (RN) is a relatively rare clinical incident. Performing the reoperation for the patient and analyzing the tissue-based genetic mutation information postoperatively are a skill-demanding and meaningful task, which have been even more rarely reported. CASE PRESENTATION: We present a case with a large right renal mass (13.0 × 10.0 × 8.0 cm). This 71-year-old male patient underwent the retrolaparoscopic RN in our department. The operation was technically precise and successful with final pathological diagnosis of hybrid (clear cell and papillary type) renal cell carcinoma (RCC). However, 10 days after the patient was discharged, he was readmitted with the chief complaint of high fever with severe right flank pain. CT scanning revealed that right retroperitoneal hematoma and the blood routine showed the dramatic elevation of white blood cell count (WBC). Even though the immediate broad-spectrum antibiotics were administered without delay and subsequent percutaneous puncturing and drainage was performed, the patient's condition still exacerbated rapidly. In spite of the reoperation of hematoma evacuation, the patient died of multiple organ failure 10 days after the reoperation. The pathological result of reoperation showed the necrotic and hematoma tissue blended with RCC tumor cells (nuclear grading III), and both of the postoperative tissue-originated comprehensive genomic profiling by using the specimens from the RN and reoperation respectively indicated significant mutations of some oncogenes which might have potential relevance with ALR. Besides, both of the immunohistochemical (IHC) staining results from primary surgical renal mass and reoperative resected tissue revealed the positive expressions of granulocyte colony-stimulating factor (G-CSF). CONCLUSIONS: ALR may be a predictor of poor prognosis in patients with RCC, and comprehensive genomic profiling as well as the alterative expression of G-CSF can help to provide potential valuable genetic etiological information and evidence for guiding the potential effective molecular-targeting therapy.

Retrolaparoscopic adrenalectomy assisted by three-dimensional reconstructed digital model in a patient with situs inversus totalis.

BACKGROUND: Situs inversus totalis is a relatively rare congenital anomaly. Performing the retrolaparoscopic adrenalectomy for the patient with situs inversus totalis is a skill-demanding and challenging surgical task, which has been even more rarely reported. CASE PRESENTATION: We present a case with a large right adrenal mass (10.2 × 9.4 × 7.9 cm) complicated by situs inversus totalis. This 59-year-old female patient underwent the retrolaparoscopic adrenalectomy in our department. In order to facilitate the surgical orientation and improve the manipulating accuracy, the data from computed tomography images was extracted and the three-dimensional digital model was reconstructed. Under the assistance of preoperative planning and intraoperative navigation by the three-dimensional digital model, the retrolaparoscopic adrenalectomy was technically precise and successful. The targeted adrenal tumor was excised completely with final pathological diagnosis of adrenocortical adenoma. CONCLUSIONS: Retrolaparoscopic adrenalectomy can be performed safely in patients with situs inversus totalis. The assistance of preoperative planning and intraoperative navigation by the reconstructed three-dimensional digital model can facilitate the operation and lead to more precise vessel manipulation and accurate excision of tumor that is both effective and safe.

Endoplasmic reticulum stress is involved in apoptosis of detrusor muscle in streptozocin-induced diabetic rats.

AIMS: Endoplasmic reticulum stress (ERS) has been proven to be associated with apoptosis and plays a critical role in the development of many diabetic complications. In the pathogenesis of diabetic cystopathy (DCP), the role of ERS is still unclear. Our study is aimed at the investigation of the involvement of ERS-associated detrusor muscle apoptosis in streptozocin (STZ)-induced diabetic rats. METHODS: At different timepoints (4, 8, 12, and 16 weeks after induction of type 1 diabetic rat models), hematoxylin & eosin (H&E) staining was performed to assess the histological changes of the diabetic detrusor; the sub-cellular ultrastructure, especially the zone of endoplasmic reticulum (ER), was observed by transmission electron microscopy (TEM), and the terminal deoxynucleotidyl transferase-mediated DNA nick-end labeling (TUNEL) staining was used to identify the enhanced apoptosis. Moreover, the expression of three hallmarks of ERS-associated apoptosis, including glucose-regulated protein 78 (GRP78), CCAAT/enhancer-binding protein homologous protein (CHOP), and caspase12, was detected by quantitative real-time polymerase chain reaction (qRT-PCR) and Western blot. RESULTS: Light microscopic impairments of histology, including progressive loosely packed muscle bundles and increased fibrous tissue, can be seen; the ultrastructural changes featuring the swollen and fused cisternaes in ER zone and deformed nucleus were also observed in the detrusor smooth muscle (DSM). Increased apoptosis and elevated expression of GRP78, CHOP, and caspase12 at both protein and mRNA levels in a time-dependent fashion were detected. CONCLUSIONS: The occurrence of ERS-associated apoptosis may be involved in the development of DCP and may contribute to the diabetic detrusor impairment. Neurourol. Urodynam. 36:65-72, 2017. © 2015 Wiley Periodicals, Inc.

Icotinib, a selective EGF receptor tyrosine kinase inhibitor, for the treatment of non-small-cell lung cancer.

Advanced non-small-cell lung cancer (NSCLC) is the main cause for cancer-related mortality. Treatments for advanced NSCLC are largely palliative and a benefit plateau appears to have reached with the platinum-based chemotherapy regimens. EGF receptor (EGFR) tyrosine kinase inhibitors gefitinib, erlotinib and afatinib came up with prolonged progression-free survival and improved quality of life, especially in EGFR-mutated patients. Icotinib is an oral selective EGFR tyrosine kinase, which was approved by China Food and Drug administration in June 2011 for treating advanced NSCLC. Its approval was based on the registered Phase III trial (ICOGEN), which showed icotinib is noninferior to gefitinib. This review will discuss the role of icotinib in NSCLC, and its potential application and ongoing investigations.

Application of the ESMO Magnitude of Clinical Benefit Scale to assess the clinical benefit of antibody drug conjugates in solid cancer: a systematic descriptive analysis of phase III and pivotal phase II trials.

OBJECTIVE: The aim of this study was to assess the clinical benefit value of approved antibody drug conjugates (ADCs) for solid tumours using the European Society for Medical Oncology Magnitude of Clinical Benefit Scale (ESMO-MCBS) V.1.1. DESIGN: Systematic descriptive analysis. DATA SOURCES: PubMed was searched for publications from 1 January 2000 to 18 October 2023. ELIGIBILITY CRITERIA: We included the phase III randomised controlled trials or phase II pivotal trials leading to approval of ADCs in solid tumours. DATA EXTRACTION AND SYNTHESIS: Two independent reviewers extracted data and discrepancies were resolved by consensus in the presence of a third investigator. RESULTS: ESMO-MCBS Scores were calculated for 16 positive clinical trials of eight ADCs, which were first approved by the US Food and Drug Administration (FDA), the European Medicines Agency (EMA), the China National Medical Products Administration and the Japanese Pharmaceuticals and Medical Devices Agency for solid cancers. Among 16 trials, 4 (25%) met the ESMO-MCBS benefit threshold grade, while 12 (75%) of the regimens did not meet the ESMO-MCBS benefit threshold grade. 5 (31%) of the 16 trials had no published scorecard on the ESMO website due to the approval by other jurisdictions but not by the FDA or EMA. Discrepancies between our results and the ESMO scorecard were observed in 4 (36%) of 11 trials, mostly owing to integration of more recent data. CONCLUSIONS: ESMO-MCBS is an important tool for assessing the clinical benefit of cancer drugs, but not all drugs met the meaningful benefit threshold.

Ensartinib in the treatment of anaplastic lymphoma kinase-positive locally advanced or metastatic patients with lung squamous or adenosquamous carcinoma: A real-world, retrospective study.

AIM: To report the efficacy and safety of ensartinib, an anaplastic lymphoma kinase (ALK) inhibitor, in treating patients with ALK-positive advanced lung squamous cell carcinoma (LUSC) or lung adenosquamous carcinoma (LASC) in China. METHODS: This retrospective study analyzed data for 36 advanced-stage patients with ALK-positive LUSC (cohort A) and 13 patients with ALK-positive LASC (cohort B) between December 16, 2020 and December 16, 2021. All patients received once-daily ensartinib 225 mg. Outcome analysis included the demographic characteristics, tumor response, progression-free survival (PFS), and treatment-related adverse events (TRAE). RESULTS: Among the 49 patients, the majority were under 65 years old (73.5%), non-smokers (85.7%), had an Eastern Cooperative Oncology Group Performance Status of 0-1 (77.6%), and were at stage IV (71.4%). All patients were included in the efficacy and safety analysis. Seven PFS events were reported in cohort A while no patients experienced PFS events in cohort B. The median PFS was not estimable for both cohorts. In cohort A, the objective response rate (ORR) was 63.9%, and the disease control rate (DCR) was 83.3%. In the cohort B, the ORR was 76.9% and the DCR was 100.0%. Rash was the only TRAE reported in the cohort A (8.3%) and cohort B (23.1%). No patients had grade 3 or higher TRAE. CONCLUSION: Ensartinib has been tentatively proven favorable efficacy and tolerability in the treatment of patients with ALK-positive advanced LUSC or LASC in the real-world. However, confirmatory studies are still needed in larger sample sizes.

Network meta-analysis of treatments for perineal extramammary paget's disease: Focusing on performance of recurrence prevention.

INTRODUCTION: Perineal extramammary paget's disease (EMPD) is characterized with high recurrence rate. Although numerous therapeutic measures for this disease have been reported so far, it is unknown whether there is significant difference in their recurrence-preventing efficiency. This study aims to compare the recurrence outcomes of reported perineal EMPD treatments. METHODS: We searched public databases of for published studies concerning perineal EMPD treatments. After screening by inclusion and exclusion criteria, we extracted the data relevant to recurrence rate, and conducted network meta-analysis (NMA) by using Bayesian random-effects approach. RESULTS: Our analysis included 29 previous studies (involving both male and female patients) and 11 treatment designs which are wide local excision (WLE), local excision (LE), Mohs micrographic surgery (MMS), radiotherapy (RT), radical vulvectomy (RV), photodynamic therapy (PDT), lasers (LS), imiquimod, and WLE+RT, WLE+PDT, WLE+LS. Comparing with WLE, the MMS showed significant advantage in reducing recurrence [OR: 0.18 (0.03-0.87)], while none of the rest treatments has statistically significant results. After removing outlier studies, MMS still has the significant advantages [OR: 0.35 (0.11-0.82)], and LE turned to be the treatment with worst performance [OR: 13 (2.50-110)]. Covariance analysis of follow-up length, gender differences, and lesion locations indicated only short follow-up time could affect the recurrence statistics, which tend to conceal the real differences. Funnel plot demonstrated there is no significant small study effect. CONCLUSION: MMS has the best performance on reducing perineal EMPD recurrence, while LE exhibits the worst capability in such regard. Recurrence-preventing abilities of other treatments have no significant difference between each other.

A retrospective study of ensartinib-treated ALK-positive locally advanced or metastatic NSCLC patients in China.

Aim: This retrospective study aimed to assess the efficacy and safety of ensartinib in Chinese patients with ALK-positive advanced NSCLC in real-world clinical practice. Methods: Clinical data from ALK-positive NSCLC patients treated with ensartinib in China were collected and analyzed. Efficacy end points included objective response rate and progression-free survival. Safety profiles were also evaluated. Results: A total of 682 patients were included in this study. The study demonstrated promising efficacy with an objective response rate of 54.0%, and the median progression-free survival was not estimable. Ensartinib exhibited a manageable safety profile with treatment-related adverse events (TRAEs) consistent with prior clinical trials. The most common TRAE was rash (21.1%) and no TRAE led to death. Conclusion: Ensartinib is active and well tolerated for ALK-positive NSCLC patients in real-world clinical settings.

Targeted therapies have significantly improved outcomes for patients with ALK-positive NSCLC. Ensartinib, a drug which blocks an enzyme in the body called ALK tyrosine kinase, has shown to be efficient and well tolerated in clinical trials. However, real-world evidence is crucial to confirm its effectiveness and safety in diverse patient populations. We analyzed the real-world outcomes of ensartinib treatment in 682 ALK-positive NSCLC patients in China, by looking at past records. The results showed that ensartinib demonstrated positive effects in most patients, meaning it helped in controlling their cancer progression. Side effects affected approximately one quarter of patients and most reported side effects were mild. Rash was the most reported side effect, accounting for about 21%. This study provides valuable insights into the real-world clinical performance of ensartinib, confirming its effectiveness and safety as a treatment option for ALK-positive NSCLC patients.

Efficacy and safety of vorolanib plus everolimus in metastatic renal cell carcinoma: A three-arm, randomised, double-blind, multicentre phase III study (CONCEPT).

BACKGROUND: Vorolanib is a highly potent tyrosine kinase inhibitor (TKI) targeting vascular endothelial growth factor receptor (VEGFR) and platelet-derived growth factor receptor. This three-arm, randomised, registered study aimed to assess the combination of vorolanib and everolimus or vorolanib alone versus a control arm of everolimus as second-line treatment in patients with metastatic renal cell carcinoma (RCC). PATIENTS AND METHODS: Patients with advanced or metastatic RCC who had received one prior VEGFR-TKI were randomised (1:1:1) to receive the combination of vorolanib and everolimus or either monotherapy. Patients with brain metastases were excluded. The primary end-point was progression-free survival (PFS) assessed by the independent review committee per Response Evaluation Criteria in Solid Tumours v1.1. RESULTS: Between 10th March 2017 and 30th May 2019, 399 patients (133 in each group) were enrolled. By the cutoff date (30th April 2020), a significant improvement in PFS was detected in the combination group compared with the everolimus group (10.0 versus 6.4 months; hazard ratio, 0.70; P = 0.0171). PFS was similar between the vorolanib group and the everolimus group (median: 6.4 versus 6.4 months; hazard ratio, 0.94; P = 0.6856). A significantly higher objective response rate was observed in the combination group than in the everolimus group (24.8% versus 8.3%; P = 0.0003), whereas there was no significant difference between the vorolanib group and the everolimus group (10.5% versus 8.3%; P = 0.5278). The overall survival data were immature. A total of 96 (72.2%), 52 (39.1%) and 71 (53.4%) grade 3 or higher treatment-related adverse events occurred in the combination group, vorolanib group and everolimus group, respectively. CONCLUSIONS: The addition of vorolanib to everolimus as 2nd-line treatment for patients with advanced or metastatic RCC who have experienced cancer progression after VEGFR-TKI therapy provided a better objective response rate and PFS than everolimus alone with a manageable safety profile. TRIAL REGISTRATION: ClinicalTrials.gov, NCT03095040; Chinadrugtrials, CTR20160987.

Befotertinib (D-0316) versus icotinib as first-line therapy for patients with EGFR-mutated locally advanced or metastatic non-small-cell lung cancer: a multicentre, open-label, randomised phase 3 study.

BACKGROUND: Befotertinib (D-0316) is a novel, selective oral third-generation epidermal growth factor receptor (EGFR) tyrosine-kinase inhibitor. This phase 3 trial compared the efficacy and safety of befotertinib with icotinib as a first-line treatment for patients with EGFR mutation-positive locally advanced or metastatic non-small-cell lung cancer (NSCLC). METHODS: This study was a multicentre, open-label, randomised, controlled phase 3 study at 39 hospitals in China. Eligible patients were 18 years of age or older, had histologically confirmed locally advanced or metastatic stage IIIB, IIIC, or IV unresectable NSCLC, and had confirmed exon 19 deletions or exon 21 Leu858Arg mutation. Patients were randomly assigned (1:1) via an interactive web response system to receive either oral befotertinib (75-100 mg once daily) or oral icotinib (125 mg three times per day) in 21-day cycles until disease progression or withdrawal criteria were met. Randomisation was stratified by type of EGFR mutation, CNS metastasis status, and gender, and participants, investigators, and data analysts were not masked to treatment allocation. The primary endpoint was independent review committee (IRC)-assessed progression-free survival in the full analysis set, which comprised all randomly assigned patients. All patients who received at least one dose of the study drug were included in safety analyses. This study was registered with ClinicalTrials.gov, NCT04206072, and the overall survival follow-up is still in progress. FINDINGS: Between Dec 24, 2019, and Dec 18, 2020, 568 patients were screened, of whom 362 were randomly assigned to the befotertinib (n=182) or icotinib (n=180) group; all 362 patients were included in the full analysis set. Median follow-up was 20·7 months (IQR 10·2-23·5) in the befotertinib group and 19·4 months (10·3-23·5) in the icotinib group. Median IRC-assessed progression-free survival was 22·1 months (95% CI 17·9-not estimable) in the befotertinib group and 13·8 months (12·4-15·2) in the icotinib group (hazard ratio 0·49 [95% CI 0·36-0·68], p<0·0001). Grade 3 or higher treatment-related adverse events occurred in 55 (30%) of 182 patients in the befotertinib group and in 14 (8%) of 180 patients in the icotinib group. Treatment-related serious adverse events were reported in 37 (20%) patients in the befotertinib group and in five (3%) patients in the icotinib group. Two (1%) patients in the befotertinib group and one (1%) patient in the icotinib group died due to treatment-related adverse events. INTERPRETATION: Befotertinib demonstrated superior efficacy compared with icotinib in first-line treatment for patients with EGFR mutation-positive NSCLC. Although serious adverse events were more common in the befotertinib than the icotinib arm, the safety profile of befotertinib was manageable overall. FUNDING: Betta Pharmaceuticals (China). TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section.

The application of full-size three-dimensional individual printed model combined with three-dimensional digital demonstration can facilitate patient's preoperative comprehension to robotic-assisted laparoscopic partial nephrectomy.

BACKGROUND: In this study, it was aimed to evaluate the feasibility and effectiveness of full-size three-dimensional individual printed model (3D-IPM) based on computerized tomography (CT) reconstruction combined with 3D individual digital models (3D-IDMs) for improving the patient's and their families' comprehension levels of robotic-assisted laparoscopic partial nephrectomy (RALPN) preoperatively. METHODS: Between January 2020 and January 2021, 37 patients underwent RALPN in our institution. 3D individual digital models (3D-IDMs) were reconstructed based on the data of computerized tomography (CT) scanning and full-size 3D-IPMs were fabricated correspondingly. For each patient and his/her closest accompanying immediate family member (CAIFM) (spouse or son/daughter), two semi-structured conversations were held by using CT films (1st conversation) and 3D-IPM combined with 3D-IDM demonstration (2nd one) respectively. The preoperative levels of comprehension were evaluated quantitatively by using a self-made preoperative comprehending score (PCS) in the patients and CAIFMs. RESULTS: All the fabrications of full-size 3D-IPMs and all the operations were technically successful. The total PCS elevated significantly by presenting 3D-IPM combined with 3D-IDM demonstration compared with CT films (42.5 vs 35.5 in patients, P < 0.001; 42.9 vs 35.8 in CAIFMs, P < 0.001). Sub-PCSs in the evaluating aspects of renal anatomy, mass characteristics, the upcoming RALPN procedure, potential complication risks, and prognosis also showed a uniformed climbing pattern with the assistance of 3D-IPM+3D-IDM. CONCLUSION: The application of 3D-IPM presentation combined with 3D-IDM demonstration can improve the preoperative comprehension of patient and CAIFM to RALPN with more direct-viewing and verisimilar presentation, and can be used in RALPN patient education for increasing patients' and their families' cognitive empowerment.

Epidermoid cyst in ureter: A case report.

RATIONALE: Uro-originated epidermoid cysts, especially located in the upper urinary tract are rare and only 4 cases of epidermoid cyst occurring in the upper urinary tract have been reported worldwide so far. In the previous cases, the cysts were diagnosed as tumors and organs were removed. PATIENT CONCERNS AND DIAGNOSIS: We report a case of epidermoid cyst in ureter in a 48-year-old female patient admitted to the local hospital suffering from paroxysmal pain in the right hypochondriac for 8 years. INTERVENTIONS AND OUTCOMES: She underwent right ureteroscopy in order to rule out the possibility of urinary epithelial carcinoma. The tumor was pathological diagnosed as a benign ureterocyst epidermoid. Postoperatively, the patient showed good recovery. During the 24-month follow-up period, the patient remained well and free of complications. CONCLUSION: This case illustrates that benign epidermoid cysts can appear in the ureter, although it is extremely rare. It also indicates that perioperative examinations must be exhaustive to avoid the further injury to the patients.

Vorolanib, a novel tyrosine receptor kinase receptor inhibitor with potent preclinical anti-angiogenic and anti-tumor activity.

Vorolanib (CM082) is a multi-targeted tyrosine kinase receptor inhibitor with a short half-life and limited tissue accumulation that has been shown to reduce choroidal neovascularization in rats. In this preclinical study, vorolanib demonstrated competitive binding and inhibitory activities with KDR, PDGFRß, FLT3, and C-Kit, and inhibited RET and AMPKα1 more weakly than sunitinib, indicating more stringent kinase selectivity. Vorolanib inhibited vascular endothelial growth factor (VEGF)-induced proliferation of human umbilical vein endothelial cells (HUVECs) and HUVEC tube formation in vitro. In mouse xenograft models, vorolanib inhibited tumor growth of MV-4-11, A549, 786-O, HT-29, BxPC-3, and A375 cells in a dose-dependent fashion. Complete tumor regression was achieved in the MV-4-11 xenograft model. No significant toxicities were observed in vorolanib groups, whereas a significant negative impact on body weights was observed in the sunitinib group at a dose of 40 mg/kg qd. Overall, vorolanib is a novel multi-kinase receptor inhibitor with potent preclinical anti-angiogenic and anti-tumor activity that is potentially less toxic than other similar kinase inhibitors.