The efficacy and safety of vincristine, irinotecan and anlotinib in Epithelioid Sarcoma.

BACKGROUND: Epithelioid sarcoma is a rare soft tissue sarcoma characterized by SMARCB1/INI1 deficiency. Much attention has been paid to the selective EZH2 inhibitor tazemetostat, where other systemic treatments are generally ignored. To explore alternative treatment options, we studied the effects of irinotecan-based chemotherapy in a series of epithelioid sarcoma patients. METHODS: We retrospectively reviewed data from patients with metastatic or unresectable epithelioid sarcoma at the Peking University People's Hospital treated with irinotecan (50 mg/m2/d d1-5 Q3W) in combination with Anlotinib (12 mg Qd, 2 weeks on and 1 week off) from July 2015 to November 2021. RESULTS: A total of 54 courses were administered. With a median follow up of 21.2 months (95% CI, 12.2, 68.1), the 5-year overall survival rate was 83.3%. Five of eight (62.5%) patients presented with unresectable localized lesions, including local tumor thrombosis and lymphatic metastasis. The other patients had unresectable pulmonary metastases. Six of eight (75%) patients had progressed following two lines of systemic therapy. The objective response rate reached 37.5% (three of eight patients) while stabilized disease was observed in 62.5% (five of eight) of patients. No patient had progressed at initial evaluation. At the last follow up, two patients were still using the combination and three patients had ceased the therapy due to toxicities such as diarrhea, nausea, and emesis. One patient changed to tazemetostat for maintenance and one patient stopped treatment due to coronavirus disease 2019 (COVID-19). Another patient stopped therapy as residual lesions had been radiated. CONCLUSIONS: The combination of irinotecan and Anlotinib as a salvage regimen may be considered another effective treatment option for refractory epithelioid sarcoma. TRIAL REGISTRATION: This study was approved in the Medical Ethics Committee of Peking University People's Hospital on October 28, 2022 (No.: 2022PHD015-002). The study was registered in Clinicaltrials.gov with identifier no. NCT05656222.

Two-step osteotomy/discectomy through cannulated screw (TOCS) technique for en bloc resection of spine tumor: surgical technique and preliminary results.

PURPOSE: We have developed a novel technique for osteotomy/discectomy during en bloc resection of spine tumors named two-step osteotomy/discectomy through cannulated screw (TOCS). This study aims at describing the procedure of TOCS technique and assessing its efficiency and safety. METHODS: We retrospectively reviewed fourteen patients who underwent en bloc resection for spine tumors using TOCS technique in our center between August 2018 and September 2022. The technique was based on a specially designed "slotted" cannulated screw which was a cannulated screw with a longitudinal slot to provide the accessibility of T-saw. During osteotomy/discectomy, the "slotted" cannulated screw was inserted obliquely along the plane between the dura and the posterior wall of spine in light of the planned osteotomy/discectomy plane under routine fluoroscopic imaging guidance. The T-saw was introduced through the screw, and the osteotomy/discectomy was performed sequentially in two steps under the guidance of the screw by turning the slot away and toward the dura. The intra-/perioperative complication, neurological function (determined by Frankel grading), surgical margin (determined by a pathologist using AJCC R system), follow-up details were documented. RESULTS: The mean duration of surgery was 599.3 (360-890) min with a mean volume of intra-operative hemorrhage of 2021.4 (800-5000) mL. The intra-/perioperative complications were found in four patients (28.6%). R0 and R1 resections were achieved in nine and five patients, respectively. There was no R2 resection. After a mean follow-up period of 30.6 (10-67) months, all patients were alive except one patient died ten months after surgery due to unrelated cause. No recurrence and implant failure were found. Thirteen patients (92.9%) exhibited completely normal neurological function same as their preoperative neurological status. CONCLUSION: Using TOCS technique can facilitate a precise, complete and safe osteotomy/discectomy procedure during en bloc resection for spine tumor without the aid of intra-operative navigation.

Exploratory study of an anti-PD-L1/TGF-ß antibody, TQB2858, in patients with refractory or recurrent osteosarcoma and alveolar soft part sarcoma: a report from Chinese sarcoma study group (TQB2858-Ib-02).

BACKGROUND: Novel and effective immunotherapies are required for refractory or recurrent sarcomas. Transforming growth factor-beta (TGF-ß) is a diverse regulatory and fibrogenic protein expressed in multiple sarcoma tumors that promotes epithelial-mesenchymal transition and excessive deposition of extracellular matrix. This study evaluated the efficacy and safety of the anti-PD-L1/TGF-ß antibody TQB2858 in patients with refractory osteosarcoma and alveolar soft part sarcoma (ASPS). METHODS: This single-arm phase 1b exploratory study included patients with refractory osteosarcoma or ASPS who had previously undergone at least two lines of systemic therapy. Patients were administered 1200 mg of TQB2858 once every 3 weeks. The primary endpoint was objective response rate (ORR), with null and alternative hypotheses of ORR ≤5% and ≥20%, respectively. Exploratory biomarker analyses using immunohistochemistry (IHC) staining (for PD-L1 and TGF-ß) were performed on pre-treatment tumor samples. RESULTS: Eleven eligible patients were included in this study. TQB2858 did not demonstrate evidence of efficacy as 0/5 osteosarcomas had any objective response, while 2/6 ASPS showed a partial response. The median progression-free survivals were 1.51 (1.38, Not Evaluable) and 2.86 (1.38, Not Evaluable) months for the osteosarcoma and ASPS groups, respectively. None of the administered cycles met the criteria for unacceptable toxicity. Other Grade 3 toxicities included abnormal liver function and elevation of γ-glutamyl transferase. IHC analysis revealed that functional enrichment in the TGF-ß pathway or PD-L1 was not associated with treatment outcomes. CONCLUSIONS: The combination of PD-L1 and TQB2858 did not significantly improve the ORR in patients with recurrent osteosarcoma. However, it improved immunogenic responses in ASPS, even after progression upon anti-PD-1/PD-L1 therapy, with an acceptable safety profile. IHC profiling with pathway enrichment analysis may not have any predictive value for survival outcomes. TRIAL REGISTRATION: Prospectively registered in the Ethical Review Committee of Peking University People's Hospital. The trial registration number is 2021PHA105-001 and 2021PHA140-001 and the registration date was March 2, 2022. CLINICALTRIALS: gov Identifier CTR20213001 and CTR20220390.

Morphological, immunohistochemical, and genetic analyses of epithelioid gastrointestinal stromal tumors.

Epithelioid gastrointestinal stromal tumors (GISTs) are rare and may be confused with other tumors with epithelioid morphology. Therefore, herein, we collected 12 epithelioid GIST samples and summarized their morphological and immunohistochemical characteristics. Through genetic testing, we explored the correlation between morphology and gene mutations. The results showed that eight tumors showed focal or diffuse myxoid stromal changes with less cohesively arranged rhabdoid tumor cells; among these, five showed platelet-derived growth factor receptor alpha gene (PDGFRA) mutations. Signet ring cells with sclerosing stroma and receptor tyrosine kinase type III gene (KIT) mutations were present in two cases, which might be a KIT mutation-associated growth pattern in epithelioid GISTs. Succinate dehydrogenase gene (SDH) mutations were detected in three cases. Simultaneously, PDGFRA mutations were detected in two cases, and the Kirsten rat sarcoma viral oncogene homolog gene (KRAS) mutation was detected in another case. SDH-subunit B (SDHB) expression was partially weak and strongly diffuse in two cases with concurrent PDGFRA and SDHD mutations, respectively. The coexistence of PDGFRA and SDHD mutations may have affected SDHB expression. Altogether, we concluded that PDGFRA mutations may play an important role in co-mutant GIST pathogenesis.

Deep learning-enhanced radiomics for histologic classification and grade stratification of stage IA lung adenocarcinoma: a multicenter study.

Background: Preoperative prediction models for histologic subtype and grade of stage IA lung adenocarcinoma (LUAD) according to the update of the WHO Classification of Tumors of the Lung in 2021 and the 2020 new grade system are yet to be explored. We aim to develop the noninvasive pathology and grade evaluation approach for patients with stage IA LUAD via CT-based radiomics approach and evaluate their performance in clinical practice. Methods: Chest CT scans were retrospectively collected from patients who were diagnosed with stage IA LUAD and underwent complete resection at two hospitals. A deep learning segmentation algorithm was first applied to assist lesion delineation. Expansion strategies such as bounding-box annotations were further applied. Radiomics features were then extracted and selected followed by radiomics modeling based on four classic machine learning algorithms for histologic subtype classification and grade stratification. The area under the receiver operating characteristic curve (AUC) was used to evaluate model performance. Results: The study included 294 and 145 patients with stage IA LUAD from two hospitals for radiomics analysis, respectively. For classification of four histological subtypes, multilayer perceptron (MLP) algorithm presented no annotation strategy preference and achieved the average AUC of 0.855, 0.922, and 0.720 on internal, independent, and external test sets with 1-pixel expansion annotation. Bounding-box annotation strategy also enabled MLP an acceptable and stable accuracy among test sets. Meanwhile, logistic regression was selected for grade stratification and achieved the average AUC of 0.928, 0.837, and 0.748 on internal, independent, and external test sets with optimal annotation strategies. Conclusions: DL-enhanced radiomics models had great potential to predict the fine histological subtypes and grades of early-stage LUADs based on CT images, which might serve as a promising noninvasive approach for the diagnosis and management of early LUADs.

Tocilizumab (monoclonal anti-IL-6R antibody) reverses anlotinib resistance in osteosarcoma.

Purpose: Anlotinib, a tyrosine kinase inhibitor (TKI) has been in clinical application to inhibit malignant cell growth and lung metastasis in osteosarcoma (OS). However, a variety of drug resistance phenomena have been observed in the treatment. We aim to explore the new target to reverse anlotinib resistance in OS. Materials and Methods: In this study, we established four OS anlotinib-resistant cell lines, and RNA-sequence was performed to evaluate differentially expressed genes. We verified the results of RNA-sequence by PCR, western blot and ELISA assay. We further explored the effects of tocilizumab (anti- IL-6 receptor), either alone or in combined with anlotinib, on the inhibition of anlotinib-resistant OS cells malignant viability by CCK8, EDU, colony formation, apoptosis, transwell, wound healing, Cytoskeletal stain assays, and xenograft nude mouse model. The expression of IL-6 in 104 osteosarcoma samples was tested by IHC. Results: We found IL-6 and its downstream pathway STAT3 were activated in anlotinib-resistant osteosarcoma. Tocilizumab impaired the tumor progression of anlotinib-resistant OS cells, and combined treatment with anlotinib augmented these effects by inhibiting STAT3 expressions. IL-6 was highly expressed in patients with OS and correlated with poor prognosis. Conclusion: Tocilizumab could reverse anlotinib resistance in OS by IL-6/STAT3 pathway and the combination treatment with anlotinib rationalized further studies and clinical treatment of OS.

Integrated analysis of single-cell and bulk RNA sequencing data reveals an immunostimulatory microenvironment in tumor thrombus of osteosarcoma.

Tumor thrombus of bone sarcomas represents a unique reservoir for various types of cancer and immune cells, however, the investigation of tumor thrombus at a single-cell level is very limited. And it is still an open question to identify the thrombus-specific tumor microenvironment that is associated with the tumor-adaptive immune response. Here, by analyzing bulk tissue and single-cell level transcriptome from the paired thrombus and primary tumor samples of osteosarcoma (OS) patients, we define the immunostimulatory microenvironment in tumor thrombus of OS with a higher proportion of tumor-associated macrophages with M1-like states (TAM-M1) and TAM-M1 with high expression of CCL4. OS tumor thrombus is found to have upregulated IFN-γ and TGF-ß signalings that are related to immune surveillance of circulating tumor cells in blood circulation. Further multiplexed immunofluorescence staining of the CD3/CD4/CD8A/CD68/CCL4 markers validates the immune-activated state in the tumor thrombus samples. Our study first reports the transcriptome differences at a single-cell level between tumor thrombus and primary tumor in sarcoma.

Long-term follow-up of persistent pulmonary subsolid nodules: Natural course of pure, heterogeneous, and real part-solid ground-glass nodules.

BACKGROUND: Previous studies have suggested the applicability of three classifications of subsolid nodules (SSNs). However, few studies have unraveled the natural history of the three types of SSNs. METHODS: A retrospective study from two medical centers between November 2007 and November 2017 was conducted to explore the long-term follow-up results of three different types of SSNs, which were divided into pure ground-glass nodules (pGGNs), heterogeneous ground-glass nodules (hGGNs), and real part-solid nodules (rPSNs). RESULTS: A total of 306 consecutive patients, including 361 SSNs with long-term follow-up, were reviewed. The median growth times of pGGNs, hGGNs, and rPSNs were 7.7, 6.0, and 2.0 years, respectively. For pGGNs, the median period of development into rPSNs was 4.6 years, while that of hGGNs was 1.8 years, and the time from pGGNs to hGGNs was 3.1 years (p < 0.05). In SSNs with an initial lung window consolidation tumor ratio (LW-CTR) >0.5 and mediastinum window (MW)-CTR >0.2, all cases with growth were identified within 5 years. Meanwhile, in SSNs whose LW-CTR and MW-CTR were 0, it took over 5 years to detect nodular growth. Pathologically, 90.6% of initial SSNs with LW-CTR >0 were invasive carcinomas (invasive adenocarcinoma and micro-invasive adenocarcinoma). Among patients with rPSNs in the initial state, 100.0% of the final pathological results were invasive carcinoma. Cox regression showed that age (p = 0.038), initial maximal diameter (p < 0.001), and LW-CTR (p = 0.002) were independent risk factors for SSN growth. CONCLUSIONS: pGGNs, hGGNs, and rPSNs have significantly different natural histories. Age, initial nodule diameter, and LW-CTR are important risk factors for SSN growth.

Expression and Clinical Significance of Various Checkpoint Molecules in Advanced Osteosarcoma: Possibilities for Novel Immunotherapy.

OBJECTIVES: The fact that studies on anti-programmed cell death 1 (PD-1) or its relevant ligand 1 (PD-L1) have yielded such few responses greatly decreases the confidence in immunotherapy with checkpoint inhibitors for advanced osteosarcoma. We intended to characterize the expression of various checkpoint molecules with immunohistochemistry in osteosarcoma specimens and analyzed the relationship of the expression of these checkpoint molecules with patients' clinical courses. METHODS: This study was a retrospective non-intervention study from August 1st 2017 to March 1st 2020. Immunohistochemistry for B7-H3 (CD276, Cluster of Differentiation 276), CD47 (Cluster of Differentiation 47), PD-L1 (programmed cell death ligand 1), TIM3 (mucin-domain containing-3), TGF-ß (TransformingGrowth Factor ß), CXCR 4 (Chemokine Receptor 4), CD27 (Cluster of Differentiation 27), IDO1 (Indoleamine 2,3-dioxygenase 1), KIRs (Killer cell Immunoglobulin-like Receptors), and SDF-1 (Stromal cell-Derived Factor-1) was performed on 35 resected osteosarcoma specimens. Patients progressed upon first-line chemotherapy with evaluable lesions were qualified for this study, and their specimens previously stored in the pathological department repository would be retrieved for analysis. Associations between the immunohischemistry markers and clinicopathological variables and survival were evaluated by the χ2 displayed by cross-table, Cox proportional hazards regression model, and Kaplan-Meier plots. RESULTS: The positive rates of B7-H3, CD47, PD-L1, TIM3, and TGF-ß expression in this sample of 35 heavily treated osteosarcomas were 29% (10/35), 15% (5/35), 9% (3/35), 6% (2/35), and 6% (2/35), respectively, and diverse staining intensities were observed. Among these advanced patients, 15/35 (43%) had positive checkpoint expression, of which 33% (5/15) showed evidence of the co-expression of more than one checkpoint molecule. We did not find any obvious correlation with clinicopathological characteristics and the positive expression of these molecules. CONCLUSIONS: The present study highlights that only a small subset of progressive osteosarcomas, which had been heavily-treated, expressed tumor immune-associated checkpoint molecules, of which B7-H3 was the most positively expressed checkpoint and might be a promising target for further osteosarcoma investigation.

Deep Sylvian fissure meningiomas: A case report.

BACKGROUND: Deep Sylvian meningiomas are rare and difficult to diagnose when small tumours lead to various symptoms. The difficulty associated with surgery is underestimated. Our case involved a mass (11 mm × 12 mm × 12 mm in size) in the right Sylvian fissure. It is the smallest deep Sylvian meningioma known and might be more easily misdiagnosed than previous examples. CASE SUMMARY: A well-enhanced mass in the right Sylvian fissure of a 26-year-old male with a three-month history of seizure was identified via magnetic resonance imaging. The patient underwent operations twice for seizure control. During the first operation, the tumour was surrounded by the second segment of the middle cerebral artery and its numerous perforators. Partial resection had to be selected due to mild arterial damage. After the first operation, the patient presented with simple partial seizure. During reoperation, we isolated the anatomical structure near the tumour and the tumour over and removed it from its dorsal side by piecemeal resection. CONCLUSION: This case reported the smallest deep Sylvian meningioma according to a literature review. Preoperative diagnosis is a crucial step due to deep Sylvian meningioma firmly adhering to the middle cerebral artery and its perforators. Adequate preparation is crucial to ensure the success of surgery.

A Scoring System for Predicting Neoadjuvant Chemotherapy Response in Primary High-Grade Bone Sarcomas: A Multicenter Study.

OBJECTIVE: Currently, there is a lack of good clinical tools for evaluating the effect of chemotherapy preoperatively on primary high-grade bone sarcomas. Our goal was to investigate the predictive value of the clinical findings and establish a scoring system to predict chemotherapy response. METHODS: We conducted a retrospective multicenter cohort study and reviewed 322 patients with primary high-grade bone sarcomas. Patients who routinely received neoadjuvant chemotherapy and underwent primary tumor resection with an assessment of tumor necrosis rate (TNR) were enrolled in this study. The medical records of patients were collected from November 1, 2011, to March 1, 2018, at Peking University People's Hospital (PKUPH) and Peking University Shougang Hospital (PKUSH). The mean age of the patients was 16.2 years (range 3-52 years), of whom 65.5% were male. The clinical data collected before and after neoadjuvant chemotherapy included the degree of pain, laboratory inspection, X-ray, CT, contrast-enhanced magnetic resonance (MR), and positron emission tomography-computed tomography (PET-CT). Several machine learning models, including logistic regression, decision trees, support vector machines, and neural networks, were used to classify the chemotherapy responses. Area under the curve (AUC) of the scoring system to predict chemotherapy response is the primary outcome measure. RESULTS: For patients without events, a minimum follow-up of 24 months was achieved. The median follow-up time was 43.3 months, and it ranged from 24 to 84 months. The 5 years progression-free survival (PFS) of the included patients was 54.1%. The 5 years PFS rate was 39.7% for poor responders and 74.9% for good responders. Features such as longest diameter reduction ratio (up to three points), clear bone boundary formation (up to two points), tumor necrosis measured by magnetic resonance (up to two points), maximum standard uptake value (SUVmax ) decrease (up to three points), and significant alkaline phosphatase decrease (up to 1 point) were identified as significant predictors of good histological response and constituted the scoring system. A score ≥4 predicts a good response to chemotherapy. The scoring system based on the above factors performed well, achieving an AUC of 0.893. For nonmeasurable lesions (classified by the revised Response Evaluation Criteria in Solid Tumors [RECIST 1.1]), the AUC was 0.901. CONCLUSION: We first devised a well-performing comprehensive scoring system to predict the response to neoadjuvant chemotherapy in primary high-grade bone sarcomas.

Clinical Manifestations of Pulmonary Mucormycosis in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation: A 21-Case Series Report and Literature Review.

Introduction: Mucormycosis is a rare, invasive disease caused by opportunistic pathogens related to the Mucorales order with high fatality rates in immunocompromised hosts, especially in recipients of allogeneic hematopoietic stem cell transplantation (allo-HSCT). Diagnosis and treatment of pulmonary mucormycosis in recipients of allo-HSCT remains challenging. Purpose: The aim of this study is to summarize and analyze the clinical features of pulmonary mucormycosis in recipients of allo-HSCT to explore further clinical research directions for this rare fungal infection in the particular populations. Methods: We retrospectively reviewed pulmonary mucormycosis in patients who received allo-HSCT in our hospital from January 2010 to December 2020. A total of 21 patients fulfilled the diagnostic criteria for pulmonary mucormycosis according to the European Organization for Research and Treatment of Cancer and Mycoses Study Group (EORTC/MSG) criteria. Demographic and clinical data, mycological and histopathological records, and treatment and prognosis data were collected. Clinical variables were compared between survivors and nonsurvivors. The survival days of patients with and without graft-versus-host disease (GVHD) and hemoptysis were compared separately. Results: Most of the recipients of allo-HSCT were male patients with a mean age of 43 years. Acute myeloid leukemia (AML) was the most common primary hematologic malignancy. Extrapulmonary involvement accounted for 28.6%, of the cases, including central nervous system (n = 5) and skin and soft tissue (n = 1). The median time to infection was 96 days after allo-HSCT. Clinical presentations were nonspecific, including fever (76.2%) and cough (85.7%), as well as dyspnea (19.0%), chest pain (38.1%), and hemoptysis (61.9%). Ground-glass infiltrates (95.0%) and nodules/masses (80%) were the most common radiographic patterns on chest CT. The most common pathogen was Rhizopus (63.2%), and breakthrough infection accounted for 90.5%. Fifteen of the patients died within one year, and the median time from diagnosis to death was 47 days. Conclusion: Mucormycosis is a fatal infection disease. Opportunistic infections in recipients of allo-HSCT are mainly breakthrough infections and may have a seasonal distribution (summer and autumn) and more cases of death in autumn. The marked reversed halo sign can be seen both in the initial stage of infection and after antifungal treatment. In our case series, patients with pulmonary mucormycosis with extrapulmonary involvement 100% died within one year. There are more patients with GVHD before infection and hemoptysis in nonsurvivors than survivors within 100 days. Patients with GVHD before infection and hemoptysis have a shorter survival time than those without.

An evaluation of the response to neoadjuvant chemotherapy for osteosarcoma of extremities: PERCIST versus RECIST 1.1 criteria after long-term follow-up.

OBJECTIVE: The aim of this study was to compare the recent Positron emission tomography (PET) Response Criteria in Solid Tumors (PERCIST) and Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria for evaluating the response of osteosarcoma to neoadjuvant chemotherapy of the extremities. METHODS: We retrospectively reviewed patients with osteosarcoma of the extremities who received neoadjuvant chemotherapy and then surgical resection at Peking University People's Hospital. Fluorine-18 fluorodeoxyglucose positron emission tomography/computed tomography (18F-FDG PET/CT) and magnetic resonance imaging (MRI) were performed prior to chemotherapy and before surgical resection. Therapeutic response was assessed separately by the PERCIST and RECIST 1.1 criteria. The association between the data acquired by the PERCIST and RECIST 1.1 criteria was then analyzed by Wilcoxon's signed-rank test. The association between the PERCIST criteria and the pathological necrosis rate was analyzed by Fisher's exact test. Finally, the impact of a range of clinicopathological factors on overall survival (OS) and event-free survival (EFS) was analyzed by Cox proportional hazards regression. RESULTS: We recruited 68 patients with a median follow-up of 74 months (range 45-102 months). The evaluations resulting from the RECIST 1.1 and PERCIST criteria were significantly different (p = 0.000). Only two responders were identified according to the RECIST 1.1 criteria. However, 34 responders were identified by the PERCIST criteria. Data arising from the PERCIST criteria were in accordance with the pathological necrosis rate. Survival analysis showed that metastasis at diagnosis, poor pathological response, and disease progression (according to the RECIST 1.1 or PERCIST criteria) were all associated with a poor prognosis (p < 0.05). CONCLUSION: Our data indicate that the PERCIST criteria are significantly more sensitive than RECIST 1.1 criteria to identify more responders when evaluating the response of osteosarcoma to neoadjuvant chemotherapy.

EGFR mutation is not a prognostic factor for CNS metastasis in curatively resected lung adenocarcinoma patients.

INTRODUCTION: For NSCLC patients with complete resection, the prognostic role of EGFR mutation for recurrence, especially for CNS metastasis, is still controversial. In this study, we aimed to identify the characteristics of the recurrence pattern of lung adenocarcinoma based on EGFR mutation status. METHODS: Overall, 888 patients with completely surgically resected LUAD who underwent EGFR mutation status analysis from two Chinese institutions were included. Sites and data of initial recurrence were recorded. The recurrence patterns according to EGFR mutation status were estimated by Kaplan-Meier analysis, and hazard rate curves were generated. RESULTS: 245 (27.6%) of 888 patients suffered from recurrence. Before and after PSM, there were no statistically significant differences between the EGFR mutation and EGFR WT groups for all types of recurrence, including CNS metastasis. Multivariable Cox analysis revealed that EGFR status was not a risk factor for all types of recurrence, including CNS metastasis (HR 0.88, 95% CI 0.54-1.46, p = 0.632). The CNS metastasis hazard curve in the EGFR mutation group showed that the first peak occurred at approximately 24-26 months after surgery, which was 10 months later than that in the EGFR WT group. In addition, the second peak time in the EGFR mutation group was approximately 2 years later than that in the EGFR WT group. CONCLUSIONS: EGFR mutation was not an independent prognostic factor for postoperative recurrence. EGFR-mutated LUADs did not have a clinical course with a higher incidence of CNS metastasis. However, the peak hazards for recurrence of CNS metastasis occur at a later time point in the EGFR mutant group compared with the EGFR wild type group.

Chemical diversity, biological activities and Traditional uses of and important Chinese herb Sophora.

BACKGROUND: Sophora flavescens Aiton (SF), also known as Kushen (Chinese:), has been an important species in Chinese medicine since the Qin and Han dynasties. It is also recognized as a plant resource suitable for the globalization of Chinese medicine. Traditionally, it has been used in various ethnic medical systems in East Asia, especially in China, to kill insects and dispel dampness. Sophora flavescens is commonly used for clearing heat-clearing, killing worms, and diuretic. Nowdays, accumulating studies demonstrated its anticancer and cardioprotection. OBJECTIVE OF THE REVIEW: This paper aims to systematically review information on the genus, pharmacological and toxicological significance, chemical composition and biological activity of Sophora flavescens. To promoting its development and application. To summarize recent findings regarding to the metabolism, pharmacological/toxicological effects of Sophora flavescens. MATERIAL AND METHODS: Online academic databases (including PubMed, Google Scholar, Web of Science and CNKI) were searched using search terms of "Sophora flavescens Aiton", "Ku shen", "Pharmacology", "Active ingredient", "Toxicology" and combinations to include published studies of Sophora flavescens Aiton primarily from 1970-2021. Several critical previous studies beyond this period were also included and other related terms. CONCLUSION: Sophora flavescens has a broad spectrum of biological activities associated with Sophora flavescens has been considered a valuable resource in both traditional and modern medicine. However, there is a lack of in-depth studies on the medicinal uses of Sophora flavescens. Moreover, further studies on single chemical components should be conducted based on the diversity of chemical structures, significant biological activities and clinical applications. The discovery of its bioactive molecules and multi-component interactions would be of great importance for the clinical application of Sophora flavescens spp. Detailed pharmacological and toxicological studies on the classic prescriptions of Sophora flavescens are also needed. It is more beneficial to the wide application of SF plant and facilitates the worldwide promotion of modern Chinese medicine. However, an increasing number of reports indicate that the administration of Sophora flavescens has serious adverse effects. Its main toxic effects are neurotoxicity and acute toxicity, which have caused widespread concern worldwide. In addition, the alkaloids of Sophora flavescens are distributed in the heart, liver, stomach and large intestine. They are excreted from the body through gluconeogenesis, which is the mode of action of certain therapeutic mechanisms of action such as anticancer. The detailed metabolic study of alkaloids and other components of Sophora flavescens in vivo needs to be further investigated. It is important to improve the pharmacological effects and reduce the toxicity of Sophora flavescens. For this purpose, structural modification of active components of Sophora flavescens or combination with other drugs is very essential.

Onodi cell mucocele with cholesterol granuloma is more likely to cause serious optic neuropathy, compared with simple Onodi cell mucocele.

OBJECTIVE: The objective is to describe the clinical features, treatments, and outcomes of a case series of patients with Onodi cell mucocele, with or without cholesterol granuloma (CG). MATERIAL AND METHODS: We retrospectively reviewed the medical records of eight patients diagnosed with Onodi cell mucocele at a single tertiary care university hospital in Beijing, China, between January 2017 and September 2020. Data regarding nasal symptoms, ocular symptoms, sinus computed tomography findings, treatments, histopathological results, and clinical outcomes were extracted. RESULTS: We identified eight patients (six men and two women) of an average age of 48.1 (range, 26-70) years. Four patients presented nasal symptoms. Three patients presented ocular symptoms. Among them, one patient experienced concurrent nasal and ocular symptoms. Two patients were diagnosed based on a physical examination in the absence of nasal or ocular symptoms. All patients underwent endoscopic sinus surgery. The pathological specimens showed mucocele in four cases and mucocele with CG in the other four cases. Among the four cases with CG, three cases presented with decreased vision. After endoscopic sinus surgery, one patient recovered completely, and two patients showed significant improvement. CONCLUSION: If Onodi cell opacity is observed, especially with optic neuropathy, mucocele and CG are important differential diagnoses. The combination of mucocele and CG is more likely to promote bone destruction and cause serious optic neuropathy than simple mucocele. Endoscopic sinus surgery is appropriate. Diagnoses, treatments, and follow-up should be performed by a multidisciplinary team.

Single-cell RNA sequencing reveals the multi-cellular ecosystem in different radiological components of pulmonary part-solid nodules.

BACKGROUND: Early-stage lung adenocarcinoma that radiologically manifests as part-solid nodules, consisting of both ground-glass and solid components, has distinctive growth patterns and prognosis. The characteristics of the tumour microenvironment and transcriptional features of the malignant cells of different radiological phenotypes remain poorly understood. METHODS: Twelve treatment-naive patients with radiological part-solid nodules were enrolled. After frozen pathology was confirmed as lung adenocarcinoma, two regions (ground-glass and solid) from each of the 12 part-solid nodules and 5 normal lung tissues from 5 of the12 patients were subjected to single-cell sequencing by 10x Genomics. We used Seurat v3.1.5 for data integration and analysis. RESULTS: We comprehensively dissected the multicellular ecosystem of the ground-glass and solid components of part-solid nodules at the single-cell resolution. In tumours, these components had comparable proportions of malignant cells. However, the angiogenesis, epithelial-to-mesenchymal transition, KRAS, p53, and cell-cycle signalling pathways were significantly up-regulated in malignant cells within solid components compared to those within ground-glass components. For the tumour microenvironment, the relative abundance of myeloid and NK cells tended to be higher in solid components than in ground-glass components. Slight subtype composition differences existed between the ground-glass and solid components. The T/NK cell subsets' cytotoxic function and the macrophages' pro-inflammation function were suppressed in solid components. Moreover, pericytes in solid components had a stronger communication related to angiogenesis promotion with endothelial cells and tumour cells. CONCLUSION: The cellular landscape of ground-glass components is significantly different from that of normal tissue and similar to that of solid components. However, transcriptional differences exist in the vital signalling pathways of malignant and immune cells within these components.

Quality of life and Q-TWiST were not adversely affected in Ewing sarcoma patients treated with combined anlotinib, irinotecan, and vincristine: (Peking University People's Hospital Ewing sarcoma trial-02, PKUPH-EWS-02).

BACKGROUND: Combined treatment with anlotinib, irinotecan, as well as vincristine for advanced Ewing sarcoma (EWS) has been verified been effective in the prospective trial of Peking University People's Hospital EWS trial-02. We aimed to assess the dynamic changes in health-related quality of life (QoL) and the benefit-risk in quality-adjusted survival in current study. METHODS: Twelve "pediatric" patients and 23 "adult" patients were enrolled. QoL was assessed with the EORTC QLQ-C30 for adults and PedsQL 3.0 Cancer Module for children and adolescents. The quality-adjusted time without symptoms of disease progression or toxicity of treatment (Q-TWiST) analysis was used to describe treatment results. RESULTS: Progression-free survival was not accompanied by diminished QoL. Differences in scores on the QoL global health status and specific functioning before, during, and after treatment were not significantly different with time (P = .14 for adults and .91 for children). During treatment, there was a statistically insignificant trend towards improved QoL with reduced tumor burden (P = .14 for adults and .10 for children), but QoL significantly declined with progression of disease (P = .05 for adults and .04 for children). The most common adverse events were neutropenia (12.1%), leukopenia (16.6%), anemia (12.7%), and diarrhea (4.93%). Results across the trial analyses showed that the median time of Q-TWiST was 0.73 (interquartile range, 0-1.57) months, whereas the median time with toxicity before disease progression was 3.9 (interquartile range, 2.3, 6.1). CONCLUSION: QoL exhibited a trend towards improvement in accordance with high objective response in this trial with the receipt of combination therapy of anlotinib, vinsristine, and irinotecan for advanced EWS. The toxicity profile did not translate into significantly worse overall scores during treatment.

Apatinib plus ifosfamide and etoposide for relapsed or refractory osteosarcoma: A retrospective study in two centres.

For osteosarcoma that progresses following first-line chemotherapy, prognosis remains poor although anti-angiogenesis tyrosine kinase inhibitors (TKIs) have been verified to prolong progression-free survival. Apatinib has led to positive responses in the treatment of refractory osteosarcoma. However, it demonstrates only short-lived activity, and the disease control rate of musculoskeletal lesions is worse compared with that of pulmonary lesions. This treatment failure has been partly overcome by the addition of ifosfamide and etoposide (IE). The present study retrospectively compared the activity of apatinib + IE in relapsed or refractory osteosarcoma in two sarcoma centres in China. The included patients had received a combination of apatinib 500 mg (orally) daily and the IE regimen (n=33) between June 3 2017 and July 17 2020. The tumour burden was considerable in these patients: 16/33 (48.5%) Patients had lung and musculoskeletal lesions, and 31/33 (93.9%) patients had progressed to two lines of therapies at baseline. With a median follow-up duration of 28.4 [interquartile range (IQR), 16.1-38.3] months, 21/33 (63.6%) patients had objective responses, and the median event-free survival was 11.4 (IQR, 6.7-18.4) months. The median overall survival time was 19.8 (IQR, 13.1-30.6) months. At the last follow-up, 16/33 patients had tumour downstaging, and all lesions had been completely resected. For osteosarcoma with multiple sites of metastasis, apatinib + IE demonstrated clinically meaningful antitumor activity and delayed disease progression in patients with recurrent or refractory osteosarcoma after failure of chemotherapy. This combination with manageable toxicity deserves further investigation in prospective trials.