Untargeted metabolomics analysis of cerebrospinal fluid in patients with leptomeningeal metastases from non-small cell lung cancer.

OBJECTIVE: To explore and analyze the diagnostic value of metabolic markers in cerebrospinal fluid (CSF) in leptomeningeal metastases (LM) of non-small cell lung cancer (NSCLC). METHODS: Forty-six CSF samples from patients with NSCLC-LM were collected. Another 48 CSF samples from patients with nonmalignant neurological diseases were selected as control group. Metabolomic analysis of CSF was performed by high-performance liquid chromatography-mass spectrometry. Principal component analysis (PCA) and orthogonal partial least squares discriminant analysis (OPLS-DA) were applied for modeling. A multi-criteria evaluation system (variable importance value >1, multiple of change >2 and P < 0.05 for univariate analysis) was used to find differential metabolites between two groups. The subject working characteristic curves and pathway enrichment analysis were used to screen metabolites and pathways associated with NSCLC-LM. RESULTS: The PCA model and OPLS-DA model showed good overall data quality. Thirty endogenous differential metabolites were screened, and six potential biomarkers were further identified, including tyrosine (t = 3.37, P = 0.024, AUC = 0.967), phenylalanine (t = 3.98, P < 0.001, AUC = 0.992), pyruvate (t = 4.48, P < 0.001, AUC = 0.976), tryptophan (t = -2.5, P = 0.014, AUC = 0.935), adenosine monophosphate (t = -6.13, P < 0.001, AUC = 0.932) and glucose (t = -4.00, P < 0.001, AUC = 0.993). Thirty differential metabolites screened were subjected to metabolic pathway enrichment analysis and matched to 20 relevant metabolic pathways, of which the four most likely to cause metabolite changes were as follows: glycolysis and sugar metabolism synthesis, pyruvate metabolism, phenylalanine metabolism, and phenylalanine, tyrosine and tryptophan biosynthesis. CONCLUSIONS: Untargeted metabolomics can effectively screen for CSF metabolites specific to NSCLC-LM patients, and six potential metabolites and their metabolic pathways might be involved in the pathogenesis of NSCLC-LM.

Cerebrospinal fluid exosomal microRNAs as biomarkers for diagnosing or monitoring the progression of non-small cell lung cancer with leptomeningeal metastases.

Non-small-cell lung cancer (NSCLC) has a terrible consequence called leptomeningeal metastases (LM). It is crucial to look for novel biomarkers because none of the known biomarkers could effectively reflect the oncogenesis, progression and therapeutic responses of LM. Exosomal miRNAs from plasma have a critical function in lung cancer, according to growing data. However, unique biomarkers of cerebrospinal fluid (CSF) are more representative for patients with LM, which have not been reported. Here, we explore the possibility of using CSF-derived exosomal microRNAs as potential biomarkers for NSCLC-LM. Nine NSCLC-LM patients who received regular intrathecal chemotherapy with permetexed were divided into a partial response (PR) group and a progressive disease (PD) group. CSF samples were taken from all patients before and after intrathecal treatment and five non-cancerous controls. Using the size exclusion chromatography (SEC) method, the exosome microRNAs were isolated and profiled. Between LM patients and controls, 56 differentially expressed genes (DEGs) were found, of which three highly elevated diagnostic biomarkers (hsa-miR-183-5p, hsa-miR-96-5p and hsa-miR-182-5p) were ruled out. The two most significant DEGs between the untreated PR group and the PD group were determined to be upregulated hsa-miR-509-3p and downregulated hsa-miR-449a, and they may serve as potential indicators of intrathecal anti-pemetrexed treatment. Hsa-miR-1-3p increased gradually with the intrathecal chemotherapy in the PR group, which might offer a new approach to screen optimal patients and estimate the efficacy. This study revealed specific CSF exosomal miRNAs profile and dynamic changes of patients with NSCLC-LM for the first time and identified several potential exosomal miRNA biomarkers in diagnosis, drug resistance and prognosis.

Safety, Pharmacokinetic and Clinical Activity of Intrathecal Chemotherapy With Pemetrexed via the Ommaya Reservoir for Leptomeningeal Metastases From Lung Adenocarcinoma: A Prospective Phase I Study.

INTRODUCTION: Leptomeningeal metastasis (LM) is a highly fatal and debilitating complication of lung adenocarcinoma (LUAD) with limited therapeutic options. This study aimed to evaluate the efficacy and toxicities of intrathecal chemotherapy (IC) with pemetrexed via Ommaya reservoir in LUAD with refractory LM. METHODS: In this prospective, single-arm, phase I trial (ChiCTR2000028936), LUAD-LM patients who had progressed after at least two prior treatments were recruited. Pemetrexed from 30 mg to 50 mg was administered on Days 1 and 8 every 3 weeks via Ommaya reservoir. Serial samples of cerebrospinal fluid (CSF) and plasma were obtained for pharmacokinetic studies. The primary endpoint was progression-free survival (PFS), and the secondary endpoints included overall survival (OS), objective response rate (ORR), disease control rate (DCR), and therapeutic toxicities. RESULTS: Twenty-three patients were enrolled and analyzed, revealing an ORR of 43.5% (95% CI, 23.2%-63.8%) and DCR of 82.6% (95% CI, 61.2%-95.0%). The median PFS and OS were 6.3 and 9.5 months, respectively. Dose-limiting toxicity was only observed in 2 patients (2/23, 8.7%), and 30 mg pemetrexed was considered as the recommended dose for IC. Pharmacokinetic analysis showed that using Ommaya reservoirs, higher pemetrexed concentrations and prolonged half-lives were achieved in the CSF compared with lumbar puncture (LP). CONCLUSIONS: Intrathecal pemetrexed at a dose of 30 mg via Ommaya reservoirs on Days 1 and 8 every 21 days achieved promising disease control and satisfactory survival with moderate toxicities in resistant LUAD-LM, providing a feasible and effective option, especially for the patients who cannot tolerate LP.

Bedside ocular ultrasonography for diagnosing increased intracranial pressure in patients with leptomeningeal metastases from non-small-cell lung cancer.

OBJECTIVES: To explore the diagnostic accuracy of ultrasound measurement of optic nerve sheath diameter (ONSD) and optic disc height (ODH) in detecting intracranial hypertension in non-small-cell lung cancer (NSCLC) patients with leptomeningeal metastases (LM). METHODS: Seventy-two patients with NSCLC-LM and 65 patients with NSCLC were enrolled. The ONSD, ODH, eyeball transverse diameter (ETD), and eyeball vertical diameter (EVD) were measured by ultrasound. Subsequently, lumbar puncture was performed in NSCLC-LM patients to measure cerebrospinal fluid pressure (CSFP), and intrathecal chemotherapy was regularly implemented. Pearson's correlation analysis was used to analyze the relationship between CSFP and ultrasound findings. The diagnostic accuracy of ONSD, ODH, and combined ONSD and ODH was evaluated by receiver operating characteristic (ROC) curve analysis and the corresponding area under the ROC curve (AUC). RESULTS: The ONSD, ODH, ONSD/ETD, and ONSD/EVD values were higher in the NSCLC-LM group (all p < 0.05). The ONSD, ODH, ONSD/ETD, and ONSD/EVD values were all elevated in the abnormally elevated CSFP group (all p < 0.05). ONSD, ODH, ONSD/ETD, and ONSD/EVD were positively correlated with CSFP (r = 0.531, 0.383, 0.534, and 0.535, all p < 0.0001). The AUCs for ONSD, ODH, ONSD/ETD, and ONSD/EVD to detect CSFP >280 mmH2O were 0.787 (95% CI: 0.64-0.93, sensitivity 68.75%, specificity 91.07%), 0.885 (95% CI: 0.81-0.96, sensitivity 100%, specificity 69.64%), 0.765 (95% CI: 0.64-0.89, sensitivity 81.25%, specificity 64.29%), and 0.788 (95% CI: 0.64-0.93, sensitivity 56.25%, specificity 91.07%), respectively. When ONSD was combined with ODH, the AUC was 0.913 (95% CI: 0.83-0.99, sensitivity 87.85%, specificity 85.70%). Furthermore, intrathecal chemotherapy was associated with a downtrend in CSFP and ultrasound findings. CONCLUSION: There are important advantages of using bedside ultrasonography for detecting elevated CSFP in NSCLC-LM patients. Further research should be performed to evaluate the clinical significance of an enlarged ONSD and increased ODH in NSCLC-LM.

Complete remission in leptomeningeal metastasis of NSCLC with rare EGFR-SEPT14 fusion treated with osimertinib combined with intrathecal chemotherapy with pemetrexed.

Leptomeningeal metastasis (LM) is one of the most serious complications of non-small cell lung cancer (NSCLC) without standard treatment guidelines and is always accompanied by poor prognosis. Identifying the types of gene mutations is essential to improve the outcome, and an increasing number of rare epidermal growth factor receptor (EGFR) mutations are revealed by next-generation sequencing (NGS). Here, we describe a case of a 56-year-old man who was diagnosed with lung adenocarcinoma and received thoracoscopic resection in May 2015. One year later, LM was confirmed by positive cerebrospinal fluid cytology. Given the existence of EGFR exon 19 deletions, erlotinib was implemented and achieved a short response for 10 months. Then the systemic therapy was changed to osimertinib and obtained clinical remission for 25 months. Owing to the resurgence of violent headache, retching and vomiting, NGS of cerebrospinal fluid was performed and two rare EGFR-SEPT14 fusions were found. Osimertinib combined bevacizumab, chemotherapy (carboplatin and abraxane) and dacomitinib were implemented in turn but ineffective. Thus, osimertinib combined intrathecal chemotherapy with pemetrexed were carried out and gained a complete remission of neurologic symptoms, stable lesions and long-term survival without notable side effects. This study presented the first case of NSCLC-LM harboring particular EGFR-SEPT14 fusions, who showed a durable response to osimertinib and intrathecal pemetrexed, providing a potential therapeutic option for NSCLC-LM patients with this particular mutation.

Treatment response to eribulin and anlotinib in lung metastases from rare perianal adenoid cystic carcinoma: a case report.

Adenoid cystic carcinoma (ACC) is a rare salivary glands tumor and often displays aggressive behavior with frequent relapse and metastasis. The terminal ACC lacks standard treatment guidelines and is always accompanied by poor prognosis. Here, we report a case of rare perianal ACC who received resection and palliative adjuvant radiation. Five years later, PET-computed tomography (CT) showed perianal recurrence and multiple pulmonary metastases. Combined chemotherapy with doxorubicin, carboplatin and cyclophosphamide was applied for two cycles but ineffective. Further next-generation sequencing analysis of perianal tissue demonstrated the v-myb avian myelobastosis viral oncogene homolog and nuclear factor I/B fusion gene and two novel BCL-6 corepressor (BCOR) mutations (p.F1106Tfs*5 and p.L1524Hfs*8). The therapy was switched to eribulin and anlotinib and has been performed for eight cycles. At recent follow-ups, MRI and CT examinations revealed the diminishing perianal and pulmonary lesions. This study presented the first case of perianal ACC with multiple pulmonary metastases and particular BCOR mutations, who presented a durable response to eribulin and anlotinib, providing a potential therapeutic option for advanced refractory ACC.

[Diagnostic Value of Locally Produced Tumor Markers and Blood Brain Barrier
Integrity in Lung Cancer Patients with Leptomeningeal Metastasis].

BACKGROUND: Tumor markers (TM) in cerebrospinal fluid (CSF) are useful for diagnosing leptomeningeal metastasis (LM). It has not been fully exploited the diagnostic possibilities of the CSF levels since the basic fact that the TM concentration of CSF depends strongly upon the serum levels as well as upon the condition of the blood brain barrier (BBB). To analyze the intrathecal TM synthesis and evaluate the integrity of BBB can be helpful for the definitive diagnosis of LM. Therefore, the aim of this study was to further explore the clinical value of intrathecal TM synthesis and BBB in the diagnosis for the lung cancer patients with LM. METHODS: Twenty-five lung cancer patients with LM and 57 patients with nonmalignant neurological diseases (NMNDs) admitted to Nanjing Drum Tower Hospital from December 2016 to March 2020 were included. We compared the integrity of BBB and intrathecal TM synthesis between two groups, analyzed the correlation of CSF TM between the detection and intrathecal synthesis, and evaluated serial CSF cytology, the integrity of BBB and intrathecal TM synthesis when intrathecal chemotherapy for one patient. RESULTS: Ninety-four percent LM patients showed the dysfunction of BBB, and all LM patients showed at least one intrathecal synthesized TM in CSF. In one patient, the CSF cytology was negative for the first time, but LM was eventually diagnosed based on the the intrathecal TM synthesis and positive CSF cytology of repeated lumbar puncture. In LM group, no correlation was observed between the detection and intrathecal synthesized TM in CSF. In the control group, only 3.5% (2/57) NMNDs patients had the dysfunction of BBB and no patients had intrathecal TM synthesis, both the differences of which were statistically significant (P<0.05). Finally, evaluating the CSF cytology, integrity of BBB and intrathecal TM synthesis can be used to assess the intracranial treatment effect. Moreover, intrathecal TM synthesis changes earlier than cytology. CONCLUSIONS: The evaluation of intrathecal TM synthesis and integrity of BBB are novel clinical diagnostic tools. In addition, serial measurement of intrathecal synthesized TM may play an important role in monitoring efficacy of lung cancer patients with LM, which is worthy of further promotion and clinical application.

Three Novel EGFR Mutations (750_758del, I759S, T751_I759delinsS) in One Patient with Metastatic Non-Small Cell Lung Cancer Responding to Osimertinib: A Case Report.

Generations of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) can significantly improve the outcome of EGFR-positive NSCLC patients. However, acquired TKIs-resistant mutations are inevitable. Except the common EGFR alterations, more and more rare mutations are revealed by next-generation sequencing (NGS), the clinical significance of which are still unclear. Here, we report an advanced lung adenocarcinoma patient who harbored two novel EGFR exon 19 deletions (750_758del and I759S) at the beginning and exhibited a short response to icotinib for 7.0 months. Then, secondary resistance EGFR T751_I759delinsS occurred. Chemotherapy combined with bevacizumab and erlotinib was administered in turn but failed. Standard-dose osimertinib (80 mg daily) obtained durable clinical remission for 16 months, and high-dose osimertinib (160 mg daily) further prolonged the survival of 9 months after leptomeningeal metastases (LM) occurring. This study presented the first case of intractable terminal NSCLC in a patient with EGFR 750_758del, I759S and T751_I759delinsS mutations, who responded positively to osimertinib and achieved a prolonged OS of 52 months, providing a potential therapeutic option for the patients harboring these particular EGFR mutations.

[Different Gene Mutation Spectrum of the Paired CSF and Plasma Samples in Lung Adenocarcinoma with Leptomeningeal Metastases: the Liquid Biopsy Based on Circulating Tumor DNA].

BACKGROUND: Leptomeningeal metastasis (LM) are a severe complication of non-small cell lung cancer (NSCLC), and normally accompanied by poor prognosis. For the patients with targetable mutations, epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are the preferred treatment, but the acquired TKI resistance is inextricable. The aim of this study is to analyze the different gene mutation spectrum and mutation frequency of the cerebrospinal fluid (CSF) and plasma in NSCLC patients with LM, and screen out the drug-resistant mutations so as to guide the choice of treatment accurately. METHODS: The paired CSF and plasma samples were collected from the NSCLC-LM patients with acquired TKI resistance. Next generation sequencing (NGS) was used to detect the gene variations of circulating tumor DNA (ctDNA). RESULTS: A total of 18 NSCLC patients with LM were collected. Of the basic mutations, 11 cases (61.11%) were EGFR, 6 cases (33.33%) were anaplastic lymphoma kinase (ALK), and 1 case (5.56%) was ROS proto-oncogene 1, receptor tyrosine kinase (ROS1). Tumor protein p53 gene (TP53) and mesenchymal-epithelial transition factor (MET) were the two most frequently accompanying mutated genes in CSF ctDNA. The detected mutation rate of CSF samples was higher than that of plasma samples (100.00% vs 66.67%, P=0.006), and the maximum allelic fractions were all higher in CSF than in plasma (P<0.001). Abundant single-nucleotide variations (SNV) and copy number variants (CNV) were detected in CSF, the amount of both of which were more than in blood. In addition, the CSF and plasma samples of patients treated with several TKIs had more SNV mutations than patients who received only a single TKI treatment. CONCLUSIONS: For the patients of NSCLC, ctDNA in CSF could reveal genomic alterations of LM more exactly and overally than it in plasma, thus could be an optimal source of liquid biopsy for guiding therapy, monitoring therapeutic effect, and predicting prognosis.

Treatment response to intrathecal chemotherapy with pemetrexed via an Ommaya reservoir in EGFR-mutated leptomeningeal metastases from non-small cell lung cancer: a case report.

Leptomeningeal metastasis (LM) is one of the most severe complications of non-small cell lung cancer (NSCLC), and it lacks standard treatment guidelines and is always accompanied by poor prognosis. We report a patient who was definitively diagnosed as LM from NSCLC with a targeted mutation of epidermal growth factor receptor (EGFR) via magnetic resonance imaging (MRI) and positive cerebrospinal fluid (CSF) cytology. Tyrosine kinase inhibitors (TKIs) were implemented but ineffective. Then the patient received the installation of an intraventricular Ommaya reservoir. Thirty mg of pemetrexed and other adjuvant treatments were implemented on days 1 and 8 every 3 weeks via the Ommaya reservoir. This treatment regimen resulted in the alleviation of the neurological symptoms, the clearing of CSF cytology and a reduced lesion of LM without notable side effects. At recent follow-ups, MRI examinations revealed the sustained stable LM lesion. We report the first successful example of administering intrathecal chemotherapy with pemetrexed via an Ommaya reservoir, providing a new therapeutic approach against LM from NSCLC.

[Auxiliary Diagnostic Value of Tumor Markers in the Cerebrospinal Fluid and Blood for Leptomeningeal Metastasis from Non-small Cell Lung Cancer].

BACKGROUND: Leptomeningeal metastasis (LM) is one of the most common causes of death in patients with advanced non-small cell lung cancer (NSCLC), which is defined as malignant cells spreading to meninges and cerebrospinal fluid (CSF). Therefore, early diagnosis and timely treatment are essential. CSF cytology is the gold standard for LM diagnosis, however, it has a low sensitivity for diagnosis and can't be used to evaluate the treatment effect. The aim of this study was to assess the clinical value of serum and CSF tumor markers (TM) in the diagnosis and treatment of NSCLC patients with LM. METHODS: Nineteen patients with NSCLC-LM and 27 patients with nonmalignant neurological diseases (NMNDs) were included. We tested the levels and positive rates of carbohydrate antigen (CEA), carbohydrate antigen-125 (CA125), cytokeratin 19 fragments (CYFRA21-1) and neurone specific enolase (NSE) in CSF and serum, compared the sensitivity and specificity in the diagnosis of LM between different groups, and analyzed the correlation of detection between serum and CSF. Finally, we measured serum and CSF TM dynamically in 2 patients with NSCLC developing LM in an attempt to correlate these with the treatment response of extracranial and intracranial, respectively. RESULTS: The levels and positive rates of TM in CSF and serum in LM group were higher than those in NMNDs (P<0.05). In LM group, the levels of CEA, CYFRA21-1 and CEA were significantly higher in CSF than that in the serum (P<0.05), whereas, there was no statistical significance in positive rates of TM between CSF and serum (P>0.05). In CSF, CYFRA21-1 has the highest sensitivity (88.2%) and CEA has the best specificity (92.3%) to distinguish patients between LM and NMNDs. For combined detection of CEA, CA125, CYFRA 21-1 and NSE in CSF, when at least CEA or NSE was positive in patients with LM, the sensitivity and negative predictive value were 100.0%, and the specificity was 74.1%. When both CYFRA21-1 and NSE were positive, the specificity and positive predictive value were 100.0%, and the sensitivity was 78.9%. Furthermore, subgroup analysis showed that the detection rates of TM in CSF cytology positive population was higher than that in typical abnormalities magnetic resonance imaging population, but there was no statistical difference (P>0.05). The detection of TM between serum and CSF in LM patients had no significant correlation. Moreover, biochemical properties of CSF from ventricle and lumbar puncture are similar, therefore evaluating the levels of TM in serum and CSF dynamically can be used to assess the extracranial and intracranial treatment effect, respectively. CONCLUSIONS: Our study demonstrates that Serum and CSF TM can work as an auxiliary clinical diagnostic tool, which has a potential value in early diagnosis of NSCLC patients with LM. Serial measurement of TM may play an important role in the clinical management of NSCLC patients with LM, which is worthy of further promotion and clinical application.

Combined Detection of Exosome Concentration and Tumor Markers in Gastric Cancer.

It has been an established fact that exosomes act as a mediator in tumor microenvironment as well as participate actively in intercellular communication between cancer cells. Exosomes carry a variety of molecular cargoes that prevent cyclic degradation and represent the cells of their origin. In this study, the difference in expression levels of exosomes was measured for diagnosis of gastric cancer. We isolated exosomes from plasma by size-selective method. The morphology of the exosomes was characterized by transmission electron microscopy, and the particle size and concentration of the exosomes were detected by NanoSight's Nanoparticle Tracking Analysis. Results indicated that the expression level of exosomes in gastric cancer patients was higher than that in healthy individuals. The specificity and sensitivity were 65.2% and 73.1%, respectively. Currently, clinical tumor markers for gastric cancer detection mainly included Carbohydrate antigen 72-4 (CA72-4), Alpha-fetoprotein, Carbohydrate antigen 125, Carbohydrate antigen 19-9 (CA19-9), Carcinoembryonic Antigen, Carbohydrate antigen 242. When we combined positive rate for combined gastric cancer biomarkers, results showed that exosomes concentration +CA19-9 and exosomes concentration +CA72-4 in the two-combined test can provide enough positive rate. Therefore, it can be concluded that for gastric cancer, the concentration of exosomes may be regarded as a diagnostic indicator, eventually.

Durable response to pulsatile icotinib for central nervous system metastases from EGFR-mutated non-small cell lung cancer: A case report.

BACKGROUND: Central nervous system (CNS) metastases are a catastrophic complication of non-small cell lung cancer (NSCLC), including brain and leptomeningeal carcinomatosis, and are always accompanied by a poor prognosis. Despite the continuous development of existing treatments, the therapy of CNS metastases remains challenging. CASE SUMMARY: We report a patient who was definitively diagnosed with brain and leptomeningeal metastases from NSCLC with a targeted mutation in epidermal growth factor receptor (EGFR). A standard dosage of icotinib (125 mg three times daily) was implemented but ineffective. CNS lesions developed despite stable systemic control, so pulsatile icotinib (1125 mg every 3 d) was administered. This new strategy for administration has lasted 25 mo so far, and resulted in complete remission of neurological symptoms, almost vanished lesions, and longer survival with no notable side effects. CONCLUSION: This is the first successful example of pulsatile icotinib for treating isolated CNS progression from EGFR mutation-positive NSCLC, providing a new alternative for the local treatment of CNS metastases.

[Use of Ommaya Reservoirs to Deliver Pemetrexed in Leptomeningeal Metastasis from Non-small Cell Lung Cancer: A Case Report and Review of the Literature].

Leptomeningeal metastasis (LM) is one of the most severe complications of non-small-cell lung cancer (NSCLC), and its incidence is increasing gradually with the progress of targeted therapies. There are currently no standard guidelines for the therapy of LM. Intrathecal chemotherapy is the mainstay of treatment for NSCLC patients with LM, but the optimal drug, administration route and mode, and dosage remain unclear. We report a case of LM from NSCLC, who received the intrathecal chemotherapy with pemetrexed by Ommaya reservoir after prior targeted therapies. This local treatment improved the quality of life, and obtained the clearing of CSF cytology and stable lesions of LM without any notable side effects. After confirmation of LM, the patient has survived 17 months until now. Here we report the first case to demonstrate the potential effectiveness of intrathecal pemetrexed by Ommaya reservoir for the treatment of LM of NSCLC, summarize the safety and effectiveness of intrathecal chemotherapy in combination with related literatures, and provide a new strategy for local treatment of LM in clinical.
.

The association between CYP2C19 genotype and of in-stent restenosis among patients with vertebral artery stent treatment.

AIMS: Preventing stroke through endovascular treatment with vertebral artery stent remains a great challenge due to the occurrence of an in-stent restenosis. MATERIALS & METHODS: In this study, a retrospective analysis was conducted in 90 patients who had been treated with VAS between 2004 and 2011 in Nanjing Drum Tower Hospital. Patients were followed up at 3 months, 6 months,and 1 year after VAS treatment and annually thereafter. For each time point, neurological function tests, vessel ultrasound and computer tomography angiography were performed to preliminarily screen the vessel stenosis. Digital subtraction angiography was used to verify the narrow sign on CTA or ultrasound. Clinical features of each patient including clopidogrel metabolization genes (CYP2C19, CYP3A4, and P2Y12) were recorded with purpose to investigate the possible risk factors for the development of ISR. RESULTS: Single factor analysis dem-onstrated that hyperlipidemia (P < 0.05) and CYP2C19 (P < 0.01) loss-of-function geno-type increased the likelihood of ISR. A multiple logistic cox regression analysis also showed that stroke patients with hyperlipidemia (HR 3.719, 95% CI: 1.094-12.637, P = 0.035), and CYP2C19 loss-of-function genotype (HR 2.959, 95% CI: 1.325-6.610, P = 0.008) were more likely to suffer from ISR. Furthermore, CYP2C19 alleles were mainly divided into three groups: wt/wt (CYP2C19 *1/*1), wt/m (CYP2C19 *1/*2 and *1/*3), and m/m (CYP2C19 *2/*2,*2/*3 and*3/*3). Recurrent rate of ischemic stroke in m/m and wt/m groups was higher than the wt/wt group (OR: 0.141, 95% CI: 0.016-1.221, P = 0.042). CONCLUSION: The study leads to the conclusion that hyperlipidemia and CYP2C19 impotency are possible risk factors for the development of ISR in VAS-treated patients with ischemic. Moreover, VAS-treated patients with CYP2C19 impotency were susceptible to recurrent stroke during our 54-month follow-up.

Cervicocranial arterial dissection: an analysis of the clinical features, prognosis, and treatment efficacy.

Clinical features and therapeutic strategies of cervicocranial arterial dissection (CCAD) are still unclear. A retrospective review was conducted on 71 CCAD patients. Diagnosed by DSA and outcome evaluation was through mRS scores follow-up 12 months. All patients were allocated into three groups according to clinical situation: 1) subarachnoid hemorrhage (SAH), 2) ischemic symptoms and 3) mass effect. CCAD with anterior circulation arterial dissection (ACAD) had higher ischemia than that with posterior circulation arterial dissection (PCAD) (p=0.023). The non-aneurysmal dissection (NAD) patients were susceptible to ischemia (p=0.00) and patients with aneurismal dissection (AD) were more susceptible to SAH (p=0.001); The outcome of patients with SAH was significantly worse than patients with other manifestations (p=0.012). Following up one year, the outcome of CCAD involving posterior inferior cerebellar artery (PICA) was significantly worse than the other area (p=0.035). There was no statistically significant difference in mRS scores between endovascular treatment and conservative treatment (p=0.052) at one year follow-up. Patients suffering from SAH that received endovascular treatment experienced improved outcomes than patients with conservative treatment (p=0.033). The patients in the ACAD, NAD and extracranial CCAD groups were more likely to suffer from ischemia, while patients in the AD group were susceptible to SAH. CCAD with SAH or involving PICA had poor prognoses. The therapeutic efficacy of conservative treatment is nearly equal to endovascular treatment in CCAD patients follow up 12 months; however, endovascular treatment may decrease the risk of mortality for the patient with SAH.