Xiangji Meng's research while affiliated with Shandong Cancer Hospital (Shandong Provincial Institute of Cancer Prevention and Treatment) and other places

e21009 Background: Despite immune checkpoint inhibitors (ICIs) have been proven effective in patients with advanced NSCLC, suboptimal therapeutic responses are seen in brain metastatic lesions. The heterogeneous cellular components in the tumor immune microenvironment (TIME) pose a challenge in understanding the low immune response. A comprehensive understanding of the heterogeneous TIME in primary and brain metastatic NSCLC is currently lacking, but crucial for improving ICI therapeutic responses in NSCLC patients with brain metastasis. Therefore, we use single cell RNA sequencing (scRNA-seq) to reveal distinct immune microenvironment in primary and brain metastatic lesion of NSCLC. Methods: Eight primary and nine brain metastatic NSCLC tumor samples were obtained through surgical resection. Immune cells (CD45+) were enriched through fluorescence-activated cell sorting (FACS) and subjected to scRNA-seq using the 10X Genomics platform. Sequencing reads were normalized and analyzed using R/Seurat package. Cellular components of each sample were determined based on known marker genes. Results: In our study, we observed a significant difference in the immune cell composition between primary and brain metastatic tumor samples. We found brain metastatic tumors are marked by an enrichment of TIMP1+ monocytes and PLTP+ tumor-associated macrophages (TAMs), both of which display heightened anti-inflammatory properties. In contrast, primary tumors exhibit an enrichment of FCN1+ monocytes and MARCO+ TAMs. Further analysis has revealed that the enrichment of TIMP1+ monocytes and PLTP+ TAMs is associated with a worse prognosis in patients receiving immunotherapy. Additionally, our examination of the transcriptome profile of CD8+ T cells showed an upregulation of inhibitory and exhausted signatures in brain metastatic tumor samples. Conclusions: Our study provided a comprehensive understanding of the TIME of primary and brain metastatic NSCLC and to gain deeper insights into the immunological mechanisms involved in the response to ICIs. The results of our study could prove valuable for the development of future immunotherapy strategies for NSCLC patients with brain metastasis.

Lung cancer patients with brain and leptomeningeal metastases usually have poor prognosis. For those patients with EGFR mutations, osimertinib, a third-generation tyrosine kinase inhibitor (TKI), is the first choice of treatment. However, drug resistance to osimertinib frequently occurs; and to date, the available follow-up treatment strategies have limited efficacy. In this case study, we report that treatments with olaparib, a Poly (ADP-ribose) polymerase (PARP) inhibitor, combined with dacomitinib, a second-generation EGFR TKI, benefited a lung cancer patient with osimertinib-resistant brain and leptomeningeal metastases. This 55-year-old male patient was found to have a pL858R mutation on EGFR exon 21 combined with TP53 and ERBB2 mutations after developing drug resistance to osimertinib treatment. Based on the genetic testing results, he was treated with olaparib and dacomitinib, and obtained 6 months of progression-free survival (PFS) and 13 months of overall survival (OS) after the diagnosis of leptomeningeal metastasis. This case report represents the first study applying PARP inhibitor in combination with dacomitinib in the treatment of leptomeningeal metastases after osimertinib resistance.

Inflammatory myofibroblastic tumor (IMT) is a rare mesenchymal tumor that can develop in numerous organs, most commonly in the lungs and rarely in the brain. Here, we reported a 55-year-old patient with nasopharyngeal IMT and the recurrence in the skull base, slope and pterygoid sinus who underwent cranial base and slope tumor resection. Postoperative magnetic resonance imaging (MRI) and multiplex immunohistochemistry (mIHC) showed tumor recurrence and metastasis to the intracalvarium. While genetic testing revealed no significant related gene mutations, tertiary mutations in NSD1 and SOX9 genes were identified in the tumor tissues. The patient achieved partial remission after receiving 7 cycles of immunotherapy (toripalimab 240 mg for 1 cycle followed by 6 cycles of sintilimab 200 mg), and MRI examination indicated an almost complete remission of intracranial IMT after 16 cycles of immunotherapy. In summary, the novel class of immune-targeted agents may be effective in clinical management of rare intracranial IMT.

Pituitary stalk interruption syndrome (PSIS) is a rare disease associated with either isolated growth hormone deficiency (GHD) or combined pituitary hormone deficiency (CPHD). In older children and adults, most patients experience short stature or hypogonadism. Neonatal PSIS is extremely rare and is difficult to recognize due to absence of dwarfism. However, when this condition occurs in newborns, it is often life-threatening. Here, we collected patients with neonatal PSIS to clarify its characteristics to improve its early diagnosis. The patients included in this study were treated at the pediatric endocrine department of Shandong Provincial Hospital from January 2017 to July 2020. We obtained the clinical characteristics, endocrine hormone levels, pituitary magnetic resonance imaging (MRI) and further genetic data for all the patients. Hormone therapy was first given at the time of diagnosis, and the patients received regular follow-up. Three neonatal patients were identified in our clinic. The characteristics of these patients included hypoglycemia and jaundice, as well as CPHD, which included features such as micropenis and hypothyroidism. Genetic etiology was still hard to discover. All the patients responded well to alternative therapy, and the longest follow-up period was 3 years. Regular replacement ensures good prognosis. Sustained hypoglycemia and jaundice in newborns, indicate the presentation of PSIS. Early recognition is of great importance to avoid a life-threatening crisis.

Up to now, no proven effective medical therapy for surgery and radiation-refractory anaplastic meningioma (AM) exists. Patients with vascular endothelial growth factor receptor 2 (VEGFR-2) positive meningiomas showed significantly shorter progression-free survival. Apatinib is a small-molecule antiangiogenic agent that selectively inhibits VEGFR-2. We report three cases of recurrent AM (VEGFR-2 positive) treated with apatinib. After apatinib treatment, the best outcome for all three patients was the partial response. The Progression-free survival was 17.3 months, 10.3 months, and 14+ months, respectively. The third patient lost follow-up after the last review. The overall survival was 28.5 months and 18 months, respectively. The main adverse events were hypertension, hand-foot syndrome, and myelosuppression. Apatinib is active in recurrent AM patients and this is the first report in the world. It is promising to launch a Phase II clinical trial of apatinib to further evaluate its efficacy on AM. Background: Anaplastic meningioma (AM) are rare and aggressive tumors with high recurrence rates despite optimal surgical or medical management. Up to now, no proven effective medical therapy, surgery, or radiation-refractory for AM exist. The progression-free survival (PFS) of patients with vascular endothelial growth factor receptor 2 (VEGFR-2)-positive meningiomas was significantly low. Apatinib (YN968D1) is a small-molecule antiangiogenic agent that selectively inhibits VEGFR-2. Case presentation: Case #1: A 47-year-old Asian female patient with malignant meningioma underwent four operations and three radiotherapies. She was given a 500 mg apatinib daily oral treatment, and the dosage was halved to 250 mg 3 months into the treatment. According to the Response Assessment in Neuro-Oncology (RANO) evaluation criteria, the best outcome during treatment was the partial response (PR) 6 months after the treatment. The PFS was 17.3 months, whereas the overall survival (OS) was 28.5 months. The best change in the Karnofsky performance scale (KPS) was a 10-point increase. The main adverse events included anemia (grade II), thrombocytopenia (grade II), and proteinuria (grade I). Case #2: A 71-year-old Asian woman with AM underwent two operations and two gamma knife stereotactic radiotherapies. She was given a 500 mg apatinib daily oral treatment with a follow-up period of 18 months. apatinib was taken orally for 10 months. According to the RANO evaluation criteria, the best outcome during treatment was PR. The PFS was 10.3 months, whereas the OS was 18 months. The best change in KPS was a 20-point increase. The main adverse events included hypertension (grade II), hand–foot syndrome (grade II), and fecal ocular blood (grade II). Case #3: A 16-year-old Asian girl with AM underwent two operations and two radiotherapies. She was given a 250 mg apatinib daily oral treatment with a follow-up period of 16 months. Apatinib was taken orally for 8 months. The patient did not follow-up after the last review of the brain-enhanced magnetic resonance imaging. According to the RANO evaluation criteria, the best outcome during treatment was PR. The PFS was 14+ months, and the best change in KPS was a 10-point increase. The main adverse events included hypertension (grade I) and hand–foot syndrome (grade I). Conclusion: Apatinib is actively used in treating patients with recurrent AM. A randomized trial and phase II clinical trial of this inhibitor should be performed to further evaluate its efficacy in treating malignant meningioma.

Objective This study aimed to determine the efficacy and tolerability of apatinib plus dose-dense temozolomide (TMZ) as first-line treatment for recurrent glioblastoma (rGBM). Methods Patients with rGBM were enrolled in this study. Patients were subjected to concurrent treatment of apatinib (500 mg qd) and dose-dense TMZ (100 mg/m², 7 days on with 7 days off) until disease progression or intolerable toxicity. Efficacy was evaluated using Response Assessment in Neuro-Oncology criteria for high-grade glioma. Safety was assessed using NCI-CTCAE 4.0. Survival was estimated with Kaplan–Meier curve and log rank test. Results From March 2016 to January 2018, 20 eligible patients who had relapsed from the standard chemoradiotherapy regimen (TMZ and radiotherapy) were enrolled in this study. The median follow-up time was 12 months. All patients were eligible for efficacy analysis. The objective response rate (ORR) was 45%. The disease control rate (DCR) was 90%. The median progress-free survival time was 6 months (95% CI, 5.3 to 7.8 months). The 6-month progression-free survival rate was 50%. The median overall survival was 9 months (95% CI, 8.2 to 12.2 months). The most common treatment-related adverse events were hypertension (21%), hand–foot syndrome (16%), leukopenia (14%), and thrombocytopenia (12%). Conclusion Apatinib combined with dose-dense TMZ was effective in terms of PFS, ORR, and DCR and was well tolerated after appropriate dose reduction in the Chinese population tested. Further randomized controlled clinical studies are needed to confirm the efficacy of apatinib combined with TMZ for treatment of rGBM.

Background Invasive pituitary adenomas often recurred after postoperative radiotherapy and are difficult to treat. Temozolomide is an alkylating cytostaticum and has been reported to reduce pituitary tumor size and hormone hypersecretion. However, this is far from enough. Pituitary adenomas have relatively high expression of vascular endothelial growth factor. Therefore an antiangiogenic agent has been used in a small number of aggressive or malignant pituitary tumors after recurrence. Apatinib (YN968D1) is a small-molecule antiangiogenic agent that selectively inhibits VEGFR-2 and also mildly inhibits c-Kit and c-Src tyrosine kinases, abundant in invasive pituitary adenomas. Case Description We present a 41-year-old female with a growth hormone (GH)-secreting invasive pituitary adenoma causing menstrual disorder and headache symptoms. Over 3 years, she underwent 4 surgeries and a stereotactic radiosurgery, but the results were poor. Two months after the fourth operation, she started treatment with temozolomide (200 mg/m², days 1−5, 28 days, orally) and apatinib (0.425 g, daily, orally). Her GH level dropped to normal with a >90% decrease in tumor size, after 1-year treatment. There was no evidence of recurrence by imaging or by serum GH levels over 31.5 months of follow-up. Conclusions We successfully treated this patient with recurrent invasive pituitary adenoma with temozolomide and apatinib for 31.5 months without recurrence. Angiogenesis is an active process in the cases of invasive pituitary adenomas that cannot be controlled by conventional therapy.