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.

[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.

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.

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.

[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.
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Treatment Response To Osimertinib In EGFR-Mutated Leptomeningeal Metastases From Non-Small Cell Lung Cancer: A Case Series.

Therapy for leptomeningeal metastases (LM) from non-small cell lung cancer (NSCLC) is challenging, and conventional treatments have little impact on the disease course. We report three cases that were definitively diagnosed as LM from NSCLC with a mutation of epidermal growth factor receptor (EGFR) L858R. The systemic therapies of chemotherapy, local radiotherapy, and early generation tyrosine kinase inhibitors (TKIs) were implemented but ineffective. Three patients were treated with the third-generation TKI osimertinib at 80 mg daily, despite their different detection levels of T790M in the cerebrospinal fluid (CSF) and plasma, and achieved symptomatic remission, a decline of carcinoembryonic antigen (CEA) levels, and stable lesions. After the progression of LM, osimertinib at 160 mg daily further lengthened the quality of life and survival time of patients without any notable side effects during treatment. Recent related studies and our cases indicate that osimertinib has a positive effect on LM from EGFR-mutant NSCLC, regardless of T790M status.

miR-126 suppresses epithelial-to-mesenchymal transition and metastasis by targeting PI3K/AKT/Snail signaling of lung cancer cells.

Although previous studies have demonstrated that dysregulation of microRNA (miR)-126 is associated with the progression of several types of cancer, including lung cancer, the relationship between miR-126 and lung cancer metastasis remains unclear. SPC-A1 lung cancer cells were transfected with miR-126 mimic and negative control using Lipofectamine® 3000. Following 2 h, TGF-ß1 was used to induce epithelial-to-mesenchymal transition (EMT). The protein expression levels of EMT markers: E-cadherin, fibronectin, N-cadherin and vimentin were detected by western blot analysis or immunofluorescence staining. The results demonstrated that ectopic expression of miR-126 significantly suppresses the epithelial-to-mesenchymal transition process, which is considered to be the initial step of tumor metastasis, in SPC-A1 lung cancer cells. In addition, lentivirus-delivered miR-126 was demonstrated to endow Lewis lung carcinoma (LLC) cells with the ability to suppress lung metastasis in vivo. Previous studies have demonstrated that the molecular signals for this phenomenon involve the inhibition of the phosphoinositide 3-kinase/protein kinase B/Snail pathway by miR-126. The protein levels of p-PDK1 (S241) and p-AKT (S473) decreased in miR-126 mimic transfected SPC-A1 and LLC cells, compared with the control group, which were detected by western blot analysis. Reverse transcription-quantitative polymerase chain reaction and western blot analysis results indicated that the expression of Snail decreased in miR-126 mimic transfected SPC-A1 and LLC cells. In conclusion, these results revealed an important role for miR-126 in the regulation of the invasive and metastatic potential of lung cancer, and suggested a potential application for miR-126 in lung cancer treatment.

HRD1 sensitizes breast cancer cells to Tamoxifen by promoting S100A8 degradation.

Estrogen receptor alpha positive (ER+) of breast cancer could develop resistance to antiestrogens including Tamoxifen. Our previous study showed that the E3 ubiquitin ligase HRD1 played an important role in anti-breast cancer. However, its role in chemotherapy resistance hasn't been reported. In this study, we found that HRD1 expression was downregulated in Tamoxifen-resistant breast cancer cell line MCF7/Tam compared to the Tamoxifen sensitive cell line MCF7. Moreover, S100A8 is the direct target of HRD1 by proteome analysis. Our data showed that HRD1 decreased the protein level of S100A8 through ubiquitination while HRD1 was regulated by acetylation of histone. More importantly, HRD1 knockdown significantly increased the cell survival of MCF7 cells to the Tamoxifen treatment. HRD1 overexpression sensitized MCF7/Tam cells to the Tamoxifen treatment in vitro and in vivo. In conclusion, the decrease of HRD1 expression contributed to Tamoxifen resistance in breast cancer.

APOE genotype and age modifies the correlation between cognitive status and metabolites from hippocampus by a 2D (1)H-MRS in non-demented elders.

Purpose. To examine the associations among age, Apolipoprotein E (APOE) genotype, metabolic changes in the hippocampus detected by 2D (1)H magnetic resonance spectroscopy (MRS), and neuropsychological measures of cognition in non-demented elders. Materials and Methods. We studied a cohort of 16 cognitively normal controls (CN) and 11 amnestic mild cognitive impairment (aMCI) patients between 66 and 88 years old who were genotyped for APOE genetic polymorphism. Measurements of 2D(1)H-MRS metabolites were obtained in the hippocampus region. Adjusting by age among all subjects, the association between metabolic changes and cognitive function was measured by Spearman partial rank-order correlation. The effect of APOE status was measured by separating the subjects into APOE genotype subgroups, including the APOEε4 carriers and APOEε4 non-carriers. Results. In contrast to the CN group matched with age, gender, and education, aMCI patients showed increased myo-inositol (mI)/Creatine (Cr) ratio only in the right hippocampus. No differences were noted on N-acetylaspartate (NAA)/Cr and mI/NAA from bilateral hippocampus, and so was mI/Cr ratio in left hippocampus between aMCI and CN. The mI/Cr ratio from the right hippocampus in non-demented elders was negatively correlated with Montreal Cognitive Assessment (MoCA) scores. Whether ε4 genotype or age was added as a covariate, none of the correlation effects remained significant. Additionally, adjusting for age and APOE genotype together, there was no significant correlation between them. Conclusion. Since the higher mI/Cr from the right hippocampus of the patients with aMCI than those from CN, the mI/Cr could be a more specific predictor of general cognitive function in aMCI patients. There is an association between higher mI/Cr in right hippocampus and worse cognitive function for the non-demented older adults, and the correlation could be modified by APOE status and age. That provided a window on objectively understanding the mechanism between the brain metabolites and the influence factors in non-demented elders.

Angiotensin II promotes the progression of human gastric cancer.

The renin-angiotensin system (RAS) plays an important role in cardiovascular homeostasis, carcinogenesis­related angiogenesis and cell proliferation. The present study was undertaken to determine the expression of angiotensin (Ang) II, Ang II type 1 and 2 receptors (AT1R and AT2R), and the activity of the angiotensin­converting enzyme (ACE) in gastric cancer tissue. The study further examined the roles of Ang II in the growth of gastric cancer cells in nude mice and in the migration and proliferation of MKN45 human gastric cancer cells. Gastric cancer tissue samples were obtained from gastric cancer patients. The levels of Ang II, AT1R and AT2R, as well as ACE activity were increased in tissues from gastric cancer patients compared to healthy tissues. A gastric cancer model was established by intraperitoneally injecting MKN45 human gastric cancer cells in nude mice, intraperitoneally injecting Ang II and measuring the tumor size every two days. Ang II treatment caused an increase in the size and weight of the tumor mass in nude mice, whereas the AT1R antagonist losartan significantly inhibited the size and weight of the tumor. While Ang II enhanced the migratory and proliferative rate of MKN45 human gastric cancer cells, these were significantly reduced following treatment with losartan. These results indicate that RAS is activated in gastric cancer patients and Ang II promotes the progression of gastric cancer in nude mice, as well as the migration and proliferation of MKN45 human gastric cancer cells.