Personalized therapy guided by longitudinal liquid biopsies for treatment of leptomeningeal disease from lung adenocarcinoma: A case report.

Molecular-based targeted therapies have significantly benefited certain patients with cancer; however, those with leptomeningeal disease (LMD) persistently exhibit a poor prognosis and are often excluded from clinical trials. Tumor-derived cell-free (cf)DNA, found in the cerebrospinal fluid (CSF) of patients with LMD, can assist in diagnosis and tracking of disease progression. However, the utilization of CSF to direct targeted cancer therapy has yet to be extensively explored. The present study reported the case of a patient with lung adenocarcinoma and LMD who was monitored by performing a series of liquid biopsies of CSF and blood. Targeted sequencing was performed on cfDNA from the CSF and plasma, and the variant allele frequencies (VAFs) of BRAF and NRAS mutations were assessed and analyzed in conjunction with the clinical presentation of the patient. The patient then underwent serial chemotherapy, radiation therapy, immunotherapy and targeted treatment based on the results of the liquid biopsies. Upon the LMD diagnosis, a BRAF p.V600E mutation was detected in plasma cfDNA. Consequently, the patient was treated with vemurafenib and responded favorably to this consolidation treatment for 13 months. After a relapse in July 2018, both BRAF p.V600E and NRAS p.Q61K mutations were detected in CSF supernatant and sediment cell samples, suggesting drug resistance. Therefore, the treatment strategy for the patient changed to cobimetnib plus vemurafenib. Notably, the changes of VAF in the CSF supernatant samples were associated with the clinical status of the patient. The patient survived for 33 months post-LMD diagnosis. The present case report highlights the potential use of liquid biopsy in personalized therapy, as it was instrumental in informing the combinational treatment plan of the patient, which ultimately proved beneficial.

The relationship between imaging features, therapeutic response, and overall survival in pediatric diffuse intrinsic pontine glioma.

We aimed to evaluate the relationship between imaging features, therapeutic responses (comparative cross-product and volumetric measurements), and overall survival (OS) in pediatric diffuse intrinsic pontine glioma (DIPG). A total of 134 patients (≤ 18 years) diagnosed with DIPG were included. Univariate and multivariate analyses were performed to evaluate correlations of clinical and imaging features and therapeutic responses with OS. The correlation between cross-product (CP) and volume thresholds in partial response (PR) was evaluated by linear regression. The log-rank test was used to compare OS patients with discordant therapeutic response classifications and those with concordant classifications. In univariate analysis, characteristics related to worse OS included lower Karnofsky, larger extrapontine extension, ring-enhancement, necrosis, non-PR, and increased ring enhancement post-radiotherapy. In the multivariate analysis, Karnofsky, necrosis, extrapontine extension, and therapeutic response can predict OS. A 25% CP reduction (PR) correlated with a 32% volume reduction (R2 = 0.888). Eight patients had discordant therapeutic response classifications according to CP (25%) and volume (32%). This eight patients' median survival time was 13.0 months, significantly higher than that in the non-PR group (8.9 months), in which responses were consistently classified as non-PR based on CP (25%) and volume (32%). We identified correlations between imaging features, therapeutic responses, and OS; this information is crucial for future clinical trials. Tumor volume may represent the DIPG growth pattern more accurately than CP measurement and can be used to evaluate therapeutic response.

Development and validation of a nomogram to predict leptomeningeal metastases in lung adenocarcinoma: Cervical lymph node metastasis is an important association factor.

BACKGROUND: The goal of this study was to create a nomogram using routine parameters to predict leptomeningeal metastases (LMs) in advanced lung adenocarcinoma (LAC) patients to prevent needless exams or lumbar punctures and to assist in accurately diagnosing LMs. METHODS: Two hundred and seventy-three patients with LMs and brain metastases were retrospectively reviewed and divided into derivation (n = 191) and validation (n = 82) cohorts using a 3:7 random allocation. All LAC patients with LMs had positive cerebrospinal fluid cytology results and brain metastases confirmed by magnetic resonance imaging. Binary logistic regression with backward stepwise selection was used to identify significant characteristics. A predictive nomogram based on the logistic model was assessed through receiver operating characteristic curves. The validation cohort and Hosmer-Lemeshow test were used for internal validation of the nomogram. RESULTS: Five clinicopathological parameters, namely, gene mutations, surgery at the primary lung cancer site, clinical symptoms of the head, N stage, and therapeutic strategy, were used as predictors of LMs. The area under the curve was 0.946 (95% CI 0.912-0.979) for the training cohort and 0.861 (95% CI 0.761-0.961) for the internal validation cohort. There was no significant difference in performance between the two cohorts (p = 0.116). In the internal validation, calibration plots revealed that the nomogram predictions were well suited to the actual outcomes. CONCLUSIONS: We created a user-friendly nomogram to predict LMs in advanced lung cancer patients, which could help guide treatment decisions and reduce unnecessary lumbar punctures.

Furmonertinib and intrathecal pemetrexed chemotherapy rechallenges osimertinib-refractory leptomeningeal metastasis in a non-small cell lung cancer patient harboring EGFR20 R776S, C797S, and EGFR21 L858R compound EGFR mutations: a case report.

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are considered the first-line treatment for advanced or metastatic non-small cell lung cancer (NSCLC) patients harboring EGFR mutations. However, due to the rarity of cases, the response of EGFR-TKIs in patients harboring uncommon compound EGFR mutations still needs to be determined. Here, we demonstrated the case of a 47-year-old smoker diagnosed with leptomeningeal metastasis from NSCLC and had EGFR20 R776S, C797S, and EGFR21 L858R compound mutations. He was treated with furmonertinib combined with intrathecal pemetrexed chemotherapy following progression on osimertinib, which led to clinical improvement and successfully prolonged his survival by 3 months. Regrettably, the patient eventually died from heart disease. This report provides the first reported evidence for the use of furmonertinib and intrathecal pemetrexed chemotherapy in NSCLC patients harboring EGFR R776S/C797S/L858R mutations who progressed on previous EGFR-TKIs.

Stroke as initial manifestation of non-small cell lung cancer with Trousseau syndrome.

OBJECTIVE: Stroke is a rare but fatal complication of advanced cancer with Trousseau syndrome, especially as initial symptoms. Here, we report the clinical characteristics, treatment, and prognosis of patients with non-small cell lung cancer (NSCLC) who initially presenting with acute multiple cerebral infarction. METHODS: The clinical characteristics, imaging, treatment, and oncological outcomes of 10 patients diagnosed with Trousseau syndrome and NSCLC between 2015 and 2021 at Guangdong Sanjiu Brain Hospital were retrospectively collected and analyzed. The clinical course of two typical cases were presented. RESULTS: All 10 patients with pathologically confirmed lung adenocarcinoma initially presented with neurological symptoms, including hemiplegic paralysis (7 patients, 70%), dizziness (5 patients, 50%), and unclear speech (3 patients, 30%). The median age was 63.5 years. Eight and two cases were stage III and IV, respectively, at the initial diagnosis. Five patients underwent driver gene testing, revealing three patients with EGFR-sensitive mutations, one patient with ALK fusion, and one patient with wild-type EGFR. All 10 patients received antiplatelet therapy, and six patients subsequently received anti-cancer treatment. The median overall survival of the patients was 8.5 months (95% confidence interval) and 1-year survival rate was 57.1%. Patients who received antitumor treatment, especially those harboring driver gene mutations and received tyrosine kinase inhibitors, had better neurological symptom recovery and superior oncological prognosis (median overall survival, not reached versus 7.4 months, p = 0.038). CONCLUSION: Trousseau syndrome, presenting as multiple cerebral infarctions, is a rare complication of lung adenocarcinoma. Both antiplatelet and antitumor treatment are recommended to achieve better neurological recovery and oncological prognosis in these patients.

Efficacy and safety of osimertinib for leptomeningeal metastases from EGFR-mutant non-small cell lung cancer: a pooled analysis.

BACKGROUND: The aim of this study was to evaluate the efficacy and safety of osimertinib for the treatment of leptomeningeal metastases (LM) from epidermal growth factor receptor (EGFR)-mutant non-small cell lung cancer (NSCLC). METHODS: We conducted a systematic review and meta-analysis to aggregate the clinical outcomes of patients with LM from EGFR-mutant NSCLC treated with osimertinib. A comprehensive literature search for published and unpublished studies was implemented in April 2021 of PubMed, EMBASE, the Cochrane Library, and several international conference databases, in accordance with the PRISMA guidelines. Meta-analysis of proportions was conducted to calculate the pooled rate of overall response rate (ORR), disease control rate (DCR), one-year overall survival (OS), and adverse events (AEs). RESULTS: A total of eleven studies (five prospective and six retrospective) including 353 patients were included. The majority of patients (346/353, 98.0%) received osimertinib as ≥ 2nd-line treatment for LM, either at a dosage of 80 mg (161/353, 45.6%) or 160 mg (191/353, 54.1%). The pooled rates of ORR and DCR were 42% (95% CI 24% to 59%) and 93% (95% CI 88% to 97%), respectively. The pooled one-year OS rate was 59% (95% CI 53% to 65%) in 233 patients from five studies. The highest incidence of AEs of all grades was rash (53%), followed by diarrhea (45%), paronychia (35%), decreased appetite (35%), and dry skin (27%), based on data from four studies. CONCLUSIONS: Our study highlighted and confirmed the meaningful efficacy and a manageable safety profile of osimertinib for the treatment of LM from EGFR-mutant advanced NSCLC.

Gene Signatures for Latent Radiation-Induced Lung Injury Post X-ray Exposure in Mouse.

Objective: To investigate the X-ray-specific sensitive genes and potential signaling pathways involved in the latent period of radiation-induced lung injury (RILI) in mouse models. Method: Mice were randomized into groups for whole thoracic irradiation with a single fraction of 20 Gy X-ray or 12.5 Gy carbon heavy ion. Lungs were harvested 3 weeks after the irradiation, whole RNA was extracted and detected with the genome-wide transcriptional microarrays. Differentially expressed genes (DEGs) were calculated for each group and the X-ray-specific sensitive genes were determined, followed by the gene enrichment analysis of those DEGs exploring the potentially relevant signaling pathways and biological processes in latent RILI. Results: Three weeks after irradiation, gene expression levels varied between groups. 76 up-regulated DEGs were determined with mice in the X-ray group and gene ontology enrichment analysis for biological process (GO-BP) obtained several processes which were associated with radiation reaction, mitotic, immune cell chemotaxis or metastasis, immune factors, p53 apoptosis, and tissue remodeling. KEGG signaling pathway enrichment analysis showed that those 76 up-regulated DEGs were enriched in p53, IL-17, FoXO, melanoma, and non-small-cell lung cancer signaling pathways. By comparing the DEGs in X-ray and heavy ion groups, X-ray-specific sensitive genes were determined, the top 10 genes were Adamts9, Aacs, Col6a2, Fdps, Mdk, Mcam, Stbd1, Lbh, Ak3, and Emid1. The expression level of the top 10 genes was found to be significantly higher in the X-ray group than in the control and heavy ion groups. Conclusion: Our research determined the X-ray-specific sensitive gene set in mice lungs after exposure to radiation. The gene set could be used as a genetic marker to suggest the latency of RILI. The enrichment analysis results suggested that the relevant signaling pathways were potentially involved in the development of RILI. Further validation of those genes and signaling pathways is needed to confirm these findings.

Atypical primary central nervous system lymphoma and glioblastoma: multiparametric differentiation based on non-enhancing volume, apparent diffusion coefficient, and arterial spin labeling.

OBJECTIVES: To evaluate the multiparametric diagnostic performance with non-enhancing tumor volume, apparent diffusion coefficient (ADC), and arterial spin labeling (ASL) to differentiate between atypical primary central nervous system lymphoma (PCNSL) and glioblastoma (GBM). METHODS: One hundred and fifty-eight patients with pathologically confirmed typical PCNSL (n = 59), atypical PCNSL (hemorrhage, necrosis, or heterogeneous contrast enhancement, n = 29), and GBM (n = 70) were selected. Relative minimum ADC (rADCmin), mean (rADCmean), maximum (rADCmax), and rADCmax-min (rADCdif) were obtained by standardization of the contralateral white matter. Maximum cerebral blood flow (CBFmax) was obtained according to the ASL-CBF map. The regions of interests (ROIs) were manually delineated on the inner side of the tumor to further generate a 3D-ROI and obtain the non-enhancing tumor (nET) volume. The area under the curve (AUC) was used to evaluate the diagnostic performance. RESULTS: Atypical PCNSLs showed significantly lower rADCmax, rADCmean, and rADCdif than that of GBMs. GBMs showed significantly higher CBFmax and nET volume ratios than that of atypical PCNSLs. Combined three-variable models with rADCmean, CBFmax, and nET volume ratio were superior to one- and two-variable models. The AUC of the three-variable model was 0.96, and the sensitivity and specificity were 90% and 96.55%, respectively. CONCLUSION: The combined evaluation of rADCmean, CBFmax, and nET volume allowed for reliable differentiation between atypical PCNSL and GBM. KEY POINTS: • Atypical PCNSL is easily misdiagnosed as glioblastoma, which leads to unnecessary surgical resection. • The nET volume, ADC, and ASL-derived parameter (CBF) were lower for atypical PCNSL than that for glioblastoma. • The combination of multiple parameters performed well (AUC = 0.96) in the discrimination between atypical PCNSL and glioblastoma.

Knockdown of circ_CLIP2 regulates the proliferation, metastasis and apoptosis of glioma cells through miR-641/EPHA3/STAT3 axis.

A great amount of reaches have confirmed that circular RNAs (circRNAs) are novel regulators in glioma progression. Here, our work aimed to probe the specific role of circ_CLIP2 in glioma. The mRNA and protein expressions were analyzed by qRT-PCR and western blot, respectively. Cell viability, migration, invasion and apoptosis were examined by MTT assay, tranwell and flow cytometry assays, respectively. Moreover, the binding relationships between circ_CLIP2, microRNA (miR)-641 and erythropoietin-producing human hepatocellular (Eph)A3 were verified by dual luciferase reporter gene assay and/or RIP assay. The following data showed that circ_CLIP2 and EPHA3 were markedly increased in glioma tissues and cells, while miR-647 was downregulated. Gain- and loss-of-function experiments discovered that circ_CLIP2 knockdown remarkably inhibited cell proliferation, migration and invasion and promoted cell apoptosis of glioma cells, while these effects of circ_CLIP2 knockdown were abolished by miR-641 inhibition. Circ_CLIP2 was proved as a sponge of miR-641 to competitively upregulate EPHA3 expression. In addition, EPHA3 overexpression could abolish the inhibitory effects of miR-641 overexpression on the malignant behaviors of glioma cells by activating the signal transducer and activator of transcription 3 (STAT3). These findings elucidated that circ_CLIP2 knockdown suppressed glioma development by regulation of the miR-641/EP HA3/STAT3 axis, which provided a novel mechanism for understanding the pathogenesis of glioma.

Efficacy and safety of combined immunotherapy and stereotactic radiosurgery in NSCLCBM patients and a novel prognostic nomogram: A real-world study.

Objective: To explore the effectiveness of combined immunotherapy (IT) and stereotactic radiosurgery (SRS) and address the gap between evidence-based clinical practice and academic knowledge of optimal timing of IT relative to SRS. In addition, to meet the unmet need for an up-to-date prognostic assessment model in the era of IT. Methods: The data of 86 non-small cell lung cancer brain metastasis (NSCLCBM) patients treated with SRS to 268 brain metastases (BMs) were retrospectively extracted from our hospital database. The Kaplan-Meier analysis was employed for overall survival (OS) and a log-rank test for comparison between groups. Cox proportional hazards regression models were used to identify the significant prognostic factors. The prognostic nomogram was established utilizing the rms package of R software. Results: IT was found to be associated with improved OS (from BM diagnosis: HR 0.363, 95% CI 0.199 - 0.661, P < 0.001; from SRS: HR 0.472, 95% CI 0.260 - 0.857, P = 0.014). Individuals who received IT in combination with SRS had better OS than those who didn't (from the day of BM diagnosis: 16.8 vs. 8.4 months, P = 0.006; from the day of SRS: 12 vs. 7 months, P = 0.037). Peri-SRS timing of IT administration was a significant prognostic factor for OS (from BM diagnosis: HR 0.132, 95% CI 0.034 - 0.517, P = 0.004; from SRS: HR 0.14, 95% CI 0.044 - 0.450, P = 0.001). Initiating IT after SRS led to superior OS than concurrent or before (from BM diagnosis: 26.5 vs. 14.1 vs. 7.1 months; from SRS: 21.4 vs. 9.9 vs. 4.1 months, respectively). Additionally, we build a nomogram incorporating IT, cumulative intracranial tumor volume (CITV), and recursive partitioning analysis (RPA), demonstrating a remarkable prognosis prediction performance for SRS-treated NSCLCBM patients. Conclusion: Peri-SRS IT is a promising approach in treating NSCLCBM, as improved OS was observed without significantly increasing adverse events. Receipt of IT post-SRS was associated with superior OS than those who received IT concurrently or before. Incorporating IT and CITV into the RPA index could augment its prognosis assessment value for SRS-treated NSCLCBM patients, predominantly in the wild-type.

Noninvasive Prediction of Histological Grading in Pediatric Low-Grade Gliomas Using Preoperative T2-FLAIR Radiomics Features.

OBJECTIVE: To investigate the clinical application value of radiomics based on magnetic resonance T2-fluid attenuated inversion recovery (FLAIR) sequence images to distinguish pediatric low-grade gliomas of histological grades 1 and 2. METHODS: A retrospective study of pediatric low-grade gliomas treated in our institution from April 2017 to July 2021. The histological grading follows the 2021 WHO (World Health Organization) classification of tumors of the central nervous system and contains the necessary molecular phenotype information. The 3D slicer (https://slicer.org/) is used to outline volume of interest based on T2-FLAIR sequence and extract three-dimensional imaging features. All enrolled cases are randomly assigned to training set and test set according to 7:3; SMOTE (Synthetic Minority Oversampling Technique) method was used to balance the data of the training set, and then min-max normalization was used to normalize the data of the radiomics features. Dimension reduction and screening were carried out through Pearson correlation coefficients, analysis of variance (ANOVA), and least absolute shrinkage and selection operator (LASSO) algorithms for the radiomics features. The best binary logistic regression model is established by using the best subset regression, and the receiver operating characteristic curve, calibration curve and decision curve are used to analyze and evaluate the model. RESULTS: A total of 113 patients were enrolled, 79 in the training set and 34 in the test set. There was no significant difference in sex and age between WHO grade 1 and 2 pediatric low-grade gliomas. A total of 1643 radiomics features were extracted from T2-FLAIR images, and finally 9 features were selected to construct a binary logistic regression model. The areas under the curve were 0.902 (95% confidence interval, 0.814-0.967) and 0.831 (95% confidence interval, 0.613-0.975) for the training and test sets, with sensitivities of 86.70% and 85.7% and specificities of 81.3% and 59.3%, respectively. For model calibration, the mean absolute errors were 0.054 and 0.058 for the training and test sets, respectively. The decision curve analysis showed clinical gains for using the model in both the training and testing sets. CONCLUSIONS: The T2-FLAIR radiomics model can be used for preoperative identification of grade 1 and grade 2 pediatric low-grade gliomas.

Lorlatinib for ALK-fused, infant-type hemispheric glioma with lung metastasis: a case report.

Infant-type hemispheric glioma, a new subtype of pediatric high-grade glioma, arises in the cerebral hemispheres. Despite better survival outcomes, the treatment of infant-type hemispheric glioma is still facing challenges. Here, we reported a case of QKI-ALK fusion, infant-type hemispheric glioma with lung metastasis who achieved a complete clinical response after lorlatinib treatment. This typical case demonstrated the importance of appropriate molecularly targeted treatments in ALK-fused tumors, and lorlatinib may serve as an effective complement to conventional chemotherapy and radiotherapy in primary glioma harboring ALK fusions and its metastasis.

The PTEN-associated immune prognostic signature reveals the landscape of the tumor microenvironment in glioblastoma.

Glioblastoma (GBM) is a common brain tumor with a complex and diverse tumor microenvironment (TME). As PTEN mutation is the most common mutation in GBM, we aimed to investigate how PTEN mutation regulates the immune response in GBM TME and thus affects the prognosis of GBM patients. In this study, we conducted a comprehensive analysis of multiple levels of data, including whole-exome sequencing (WES), transcriptome RNA sequencing, patient survival and immune signatures, to study the relationship between PTEN mutation and TME in GBM. We developed an immune-related prognostic signature (IPS) based on the PTEN-associated immune-related genes (IRGs), and the IPS exhibited a powerful prognosis prediction capacity in different GBM cohorts. A scoring nomogram based on the IPS was also established for clinical application. In addition, the correlations of the IPS with tumor immune cell infiltration and immune checkpoints were systematically analyzed. This study illustrates the influence of PTEN mutation on the immune microenvironment of GBM. Our IPS, which is sensitive to PTEN mutation status, can enhance the prognosis prediction ability for GBM patients and provides potential targets for immunotherapy.

Radiomics features based on MRI predict BRAF V600E mutation in pediatric low-grade gliomas: A non-invasive method for molecular diagnosis.

OBJECTIVE: To investigate the clinical application value of radiomics features based on preoperative magnetic resonance imaging for predicting B-Raf proto-oncogene serine/threonine-protein (BRAF) V600E mutation in pediatric low-grade gliomas. MATERIALS AND METHODS: The clinical, imaging, and pathological data from 113 pediatric patients with low-grade gliomas patients were retrospectively analyzed. Using open-source software, three-dimensional imaging features were extracted on the basis of FLAIR sequences, and the radiomics process was analyzed to dichotomize BRAFV600E mutant and wild type. All cases were randomly divided into the training and test sets according to a 7:3 training and test group ratio, and a 5-fold cross-validation was performed on the training set. The optimal hyperparameters were selected to build the prediction model, and the test set was used for external validation to assess the diagnostic value of the model using the receiver operating characteristic curve. RESULTS: The training set comprised 79 patients (47 males, 32 females, mean age 9.86 ± 5.20) and the test set comprised 34 patients (20 males, 14 females, mean age 10.97 ± 5.14). Sex, age, and brain side were not significant predictors of BRAF, and tumor location on the supratentorial region was a BRAF predictor (p < 0.05). The radiomics model constructed by principal component analysis for dimensionality reduction, Kruskal-Wallis for filtering of features, and random forest as a classifier performed best. In the training set, the mean area under the curve (AUC) with a five-fold cross-validation was 0.72 ( ± 0.057; 95 % confidence interval (CI), 0.602-0.831) and AUC of the test set was 0.875 ( ± 0.062; 95 % CI, 0.731-0.983). CONCLUSION: The use of a radiomics model based on FLAIR sequences can help predict BRAF V600E mutations in pediatric low-grade gliomas.

Case Report: Clinicopathological and Genetic Features of IDH-Mutant Brainstem Glioma in Adults: Report of Five Cases.

Adult brainstem gliomas are rare central nervous system tumors that represent a heterogeneous group of tumors. Somatic IDH mutations are uncommon in adult brainstem gliomas and there are few relevant clinical studies. Here, we reported five patients with IDH1 mutations associated with brainstem gliomas, including four cases of IDH1 R132H mutations and one case of R132G mutation. All patients were treated with focal intensity-modulated radiation therapy (IMRT) with concurrent temozolomide (TMZ). One patient died, one relapsed, and three survived to date. All these cases carried a pathogenic variant of TP53, among whom 1 harbored ATRX mutation and 1 had H3K27M mutation. Moreover, we also found some genes related to a worse prognosis, such as CDK4/6 amplification. These findings demonstrate that the specific characteristics of IDH-mutant brainstem gliomas should be considered in diagnostic workflows to make therapeutic regimens and improve the prognosis.

Survival outcomes, hematologic complications and growth impairment after sequential chemoradiotherapy in intracranial NGGCTs: a retrospective study.

PURPOSE: This study aimed to evaluate the clinical features, prognostic factors, and survival outcomes for patients with intracranial nongerminomatous germ cell tumors (NGGCTs), with a particular focus on treatment toxicity for long-term survivors. METHODS: Intracranial NGGCTs treated with platinum-based chemotherapy and craniospinal irradiation (CSI) in our institution were retrospectively analyzed. Hematological complications following sequential chemoradiotherapy as well as height and weight in childhood survivors were evaluated. Plasma growth hormone (GH) concentrations prior to and after radiotherapy were obtained for the comparisons. RESULTS: A total of 111 intracranial NGGCTs were included. The 3­year overall survival (OS) and event-free survival (EFS) rates were 83.5% ± 3.9% and 71.0% ± 4.8%, respectively. A combined treatment modality consisting of ≥ 4 cycles of platinum-based chemotherapy and CSI was associated with an improved OS (P = 0.003) and EFS (P < 0.001). Thrombocytopenia of any grade occurred in 35.4% (34/96) of patients, and the threshold age for an increased risk of thrombocytopenia was 14 years (area under the curve AUC = 0.752, P < 0.0001) as derived from receiver operating characteristic (ROC) analysis. Growth impediment was found in 8 of 56 (14%) patients. The age for receiving radiotherapy was found to inversely correlate with height development, revealing a cut-off age of 11.5 years for risking growth impairment (AUC = 0.806, P = 0.004). Consistently, a significant decline in plasma growth hormone after radiotherapy was observed in patients ≤ 11.5 years (P < 0.01) but not patients > 11.5 years. (P > 0.05). CONCLUSION: Our study suggested that a combined treatment modality with at least four cycles of chemotherapy and CSI was safe and effective for patients with intracranial NGGCTs. Radiotherapy should be used with caution for patients < 11.5 years due to growth impairment.

A preparation method for the organoid model of patient-derived glioblastoma / 中国肿瘤生物治疗杂志

@#[摘 要] 目的：探讨胶质母细胞瘤（GBM）患者肿瘤组织来源的GBM类器官（GBO）模型的制备方法。方法：选取2021年广东三九脑科医院新诊断经病理确诊的8例GBM患者的新鲜肿瘤组织标本，将其剪成0.5~1 mm大小的组织碎片并用特制的培养基进行培养，待其成球且直径达到1 mm时剪小传代，同时选取培养2周以上的GBO进行石蜡包埋、切片，后进行H-E染色和免疫组化染色检测，并与亲本GBM组织进行组织学与细胞学的比较。结果：成功培养2例可传代冻存的GBO，并建立GBO生物库。H-E染色结果显示，GBO保留了与亲本GBM组织相似的组织结构和细胞形态；免疫组化实验结果显示，GBO与GBM组织中GFAP、OLIG2、Ki67和ATRX分子的表达情况一致。结论：将患者来源的GBM组织在体外剪小并用特制培养基培养，可构建与GBM患者肿瘤组织在组织和细胞层面一致的GBO。

A Novel Six Autophagy-Related Genes Signature Associated With Outcomes and Immune Microenvironment in Lower-Grade Glioma.

Since autophagy and the immune microenvironment are deeply involved in the tumor development and progression of Lower-grade gliomas (LGG), our study aimed to construct an autophagy-related risk model for prognosis prediction and investigate the relationship between the immune microenvironment and risk signature in LGG. Therefore, we identified six autophagy-related genes (BAG1, PTK6, EEF2, PEA15, ITGA6, and MAP1LC3C) to build in the training cohort (n = 305 patients) and verify the prognostic model in the validation cohort (n = 128) and the whole cohort (n = 433), based on the data from The Cancer Genome Atlas (TCGA). The six-gene risk signature could divide LGG patients into high- and low-risk groups with distinct overall survival in multiple cohorts (all p < 0.001). The prognostic effect was assessed by area under the time-dependent ROC (t-ROC) analysis in the training, validation, and whole cohorts, in which the AUC value at the survival time of 5 years was 0.837, 0.755, and 0.803, respectively. Cox regression analysis demonstrated that the risk model was an independent risk predictor of OS (HR > 1, p < 0.05). A nomogram including the traditional clinical parameters and risk signature was constructed, and t-ROC, C-index, and calibration curves confirmed its robust predictive capacity. KM analysis revealed a significant difference in the subgroup analyses' survival. Functional enrichment analysis revealed that these autophagy-related signatures were mainly involved in the phagosome and immune-related pathways. Besides, we also found significant differences in immune cell infiltration and immunotherapy targets between risk groups. In conclusion, we built a powerful predictive signature and explored immune components (including immune cells and emerging immunotherapy targets) in LGG.

Individualized Nomogram for Predicting Survival in Patients with Brain Metastases After Stereotactic Radiosurgery Utilizing Driver Gene Mutations and Volumetric Surrogates.

It is well-known that genomic mutational analysis plays a significant role in patients with NSCLC for personalized treatment. Given the increasing use of stereotactic radiosurgery (SRS) for brain metastases (BM), there is an emerging need for more precise assessment of survival outcomes after SRS. Patients with BM and treated by SRS were eligible in this study. The primary endpoint was overall survival (OS). Cox regression models were used to identify independent prognostic factors. A survival predictive nomogram was developed and evaluated by Concordance-index (C-index), area under the curve (AUC), and calibration curve. From January 2016 to December 2019, a total of 356 BM patients were eligible. The median OS was 17.7 months [95% confidence interval (CI) 15.5-19.9] and the actual OS at 1- and 2-years measured 63.2 and 37.6%, respectively. A nomogram for OS was developed by incorporating four independent prognostic factors: Karnofsky Performance Score, cumulative tumor volume, gene mutation status, and serum lactate dehydrogenase. The nomogram was validated in a separate cohort and demonstrated good calibration and good discriminative ability (C-index = 0.780, AUC = 0.784). The prognostic accuracy of the nomogram (0.792) was considerably enhanced when compared with classical prognostic indices, including the Graded Prognostic Assessment (0.708), recursive partitioning analysis (0.587), and the SRS (0.536). Kaplan-Meier curves showed significant differences in OS among the stratified low-, median- and high-risk groups (P < 0.001). In conclusion, we developed and validated an individualized prognostic nomogram by integrating physiological, volumetric, clinical chemistry, and molecular biological surrogates. Although this nomogram should be validated by independent external study, it has a potential to facilitate more precise risk-stratifications to guide personalized treatment for BM.

A non-small cell lung cancer (NSCLC) patient with leptomeningeal metastasis harboring rare epidermal growth factor receptor (EGFR) mutations G719S and L861Q benefited from doubling dosage of osimertinib: a case report.

Leptomeningeal metastasis (LM) is a rare but lethal complication of advanced non-small cell lung cancer (NSCLC) that has a devastating impact on patient survival and quality of life. Osimertinib, an irreversible tyrosine kinase inhibitor, is approved as a therapy for advanced NSCLC with epidermal growth factor receptor (EGFR) mutation. However, the efficacy and optimal dosage of osimertinib in the treatment of NSCLC patients with LM who harbor uncommon EGFR mutations have yet to be fully investigated. Herein, we report a case of an advanced NSCLC patient with LM carrying EGFR G719S and L861Q, who was successfully treated by osimertinib at 160 mg. The patient initially presented with clear cell renal carcinoma and renal metastatic adenocarcinoma, and underwent right nephrectomy. At 2 months after nephrectomy, he developed a disturbance of consciousness and was subsequently diagnosed with NSCLC with LM by meningeal biopsy pathology and cerebrospinal fluid (CSF) cytology. Next-generation sequencing detected the rare EGFR mutations G719S and L861R in the meningeal biopsy tissues. The patient was then administered osimertinib at 80 mg quaque die (QD); after 1 month of treatment, his symptoms were alleviated. However, two months later, he experienced epileptic episode. Subsequently, the osimertinib dosage was doubled to 160 mg QD. After 1 month of treatment, the patient achieved central nervous system (CNS) response, and at the time of this manuscript's submission, he had maintained stable disease (SD) for more than 1 year. To our knowledge, this study provides the first clinical evidence that the administration of osimertinib at 160 mg once daily can achieve an encouraging, durable response in an NSCLC patient with LM carrying EGFR G719S and L861Q.