Combination treatment with bevacizumab plus erlotinib for meningeal carcinomatosis of afatinib-resistant EGFR mutated lung cancer without T790M mutation: a case report.

Meningeal carcinomatosis in lung cancer is known to have a very poor prognosis. Here we report a case in which bevacizumab plus erlotinib (BE) was effective against meningeal carcinomatosis from afatinib-resistant EGFR mutation-positive lung cancer. A 61-year-old man started afatinib, a 2nd generation molecular targeting drug, as first-line treatment for lung adenocarcinoma cT1bN0M1a stage IVA harboring EGFR exon19 deletion mutation. This treatment shrank the tumor and allowed sustained control of tumor growth. After 19 months from the start of treatment, head MRI revealed brain metastasis in the cerebellum and meningeal carcinomatosis with loss of appetite and slurred speech, in response to which whole-brain irradiation was performed. Head MRI 1 month after whole-brain irradiation showed no change in the disseminated lesions of the cerebellum. In Japan, osimertinib treatment after failure of EGFR-TKI treatments requires the T790M mutation in the tumor, blood or body fluid, so BE treatment was started as second-line treatment. Brain MRI showed improvement in cerebellar disseminated lesions 1 month after the start of BE treatment. BE treatment controlled intrapulmonary metastases, pleural disseminated lesions and meningeal carcinomatosis for 6 months. BE treatment as second-line treatment should be considered as an option for meningeal carcinomatosis of EGFR tyrosine kinase inhibitor (TKI) -resistant EGFR mutated lung cancer.

Treatment with immune checkpoint inhibitors after EGFR-TKIs in EGFR-mutated lung cancer.

BACKGROUND: Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) have become the gold standard for EGFR-mutated non-small cell lung cancer (NSCLC) treatment. Immune checkpoint inhibitors (ICIs) have been developed for the treatment of several malignancies, including lung cancer. However, it is known that ICIs have poorer efficacy in EGFR-mutated NSCLC. METHODS: We collected data for patients with EGFR-mutated NSCLC receiving monotherapy with ICIs after EGFR-TKIs between December 2015 and March 2020 in three institutions, and retrospectively analyzed the association between patient characteristics and efficacy of ICIs. RESULTS: A total of 25 patients were included in this study. We defined responders as patients undergoing 90 days or longer of ICI treatment. Comparing characteristics between responders and non-responders, more tumors with L858R EGFR mutation were observed in responders than in non-responders (L858R: 66.7% and 25.0%, respectively, p < 0.05). There was no difference in incidence of T790M resistance mutation before ICI treatment. The PD-L1 positive rate was slightly higher in responders but not statistically significant (22.2% and 12.5%, respectively). Median duration of EGFR-TKI pretreatment was shorter in ICI responders compared with nonresponders (13.3 and 19.9 months, respectively). The survival of patients with L858R tumors was significantly longer than that of patients with exon 19 deletion (HR: 0.35, 95% CI: 0.13-0.93, p = 0.026). CONCLUSIONS: ICI treatment tends to have better efficacy in patients with L858R-mutated tumors. This study suggests that patients with L858R-mutated NSCLC are candidates for ICI treatment after EGFR-TKI treatment.

Analysis of bevacizumab treatments and metastatic sites of lung cancer.

INTRODUCTION: Liver metastasis has not been sufficiently evaluated in lung cancer so far. We retrospectively analyzed the distant metastasis of Non-squamous non-small cell lung cancer (NSQ-NSCLC), including liver metastasis, and association between prognosis and therapeutic effect of bevacizumab treatment. PATIENTS AND METHODS: Clinical data were collected from 1954 patients with lung cancer admitted in our hospital between 1st April 2011 and 31 March 2019. Information is extracted from the electronic medical record. Main collection data was the age, gender, smoking history, performance status, histology and driver mutation, distant metastasis site. Efficacy data of treatment including treatment duration and survival time were obtained from medical record, image data and local registry. RESULTS: Total 366 patients receiving any chemotherapy with NSQ-NSCLC were eligible for this study. Most frequent extrathoracic metastasis is bone (N = 59) followed by brain (37), liver (18), adrenal gland (23), and OS analysis showed liver metastasis was worse prognosis compared to brain and bone metastasis (median OS: 11.6, 18.9, 15.0, respectively). Bevacizumab treatment was tend to have favorable efficacy in patients with each metastatic sites, especially, induced significant longer OS for patients with liver metastasis. CONCLUSION;: Though this study was retrospective study for small sized metastatic patients, the study suggested that liver metastasis was refractory, and that bevacizumab treatment might improve the worse prognosis.

Water-soluble diruthenium complexes bearing acetate and carbonate bridges: highly efficient catalysts for aerobic oxidation of alcohols in water.

The aerobic oxidation of alcohols in water can be performed efficiently in the presence of a catalytic amount of the water-soluble diruthenium complex Ru2(micro-OAc)3(micro-CO3) under an atmospheric pressure (1 atm) of O2.

Selective blockade of astrocytic glutamate transporter GLT-1 with dihydrokainate prevents neuronal death during ouabain treatment of astrocyte/neuron cocultures.

Glutamate (Glu) is a major excitatory neurotransmitter of the mammalian central nervous system and under normal conditions plays an important role in information processing in the brain. Therefore, extracellular Glu is subject to strong homeostasis. Astrocytes in the brain have been considered to be mainly responsible for the clearance of extracellular Glu. In this study, using mixed neuron/astrocyte cultures, we investigated whether astrocytic Glu transporter GLT-1 is crucial to the survival of neurons under various conditions. Treatment of the mixed cultures with a low concentration of Glu did not produce significant death of neurons. However, cotreatment with dihydrokainate (DHK), a specific blocker of GLT-1, resulted in significant neuronal death that was suppressed by an antagonist of N-methyl-D-aspartate (NMDA) receptors. These results suggested that astrocytic GLT-1 participated in the clearance of extracellular Glu and protected neurons from NMDA receptor-mediated toxicity. When the cultures were treated with ouabain, an inhibitor of Na(+)/K(+)-ATPase, a low concentration of Glu resulted in massive neuronal death that was also suppressed by cotreatment with an antagonist of NMDA receptors. In this case, however, cotreatment with DHK significantly protected neurons from death, suggesting that GLT-1 was responsible for the death of neurons. The present study provides evidence suggesting that astrocytes use their Glu transporter GLT-1 to protect neurons from Glu toxicity, but, ironically, also use GLT-1 to kill neurons through Glu toxicity depending on their status.

Photolytic flash-induced intercellular calcium waves using caged calcium ionophore in cultured astrocytes from newborn rats.

Waves of elevated intracellular free calcium that propagate between neighboring astrocytes are important for the intercellular communication between astrocytes as well as between neurons and astrocytes. However, the mechanisms responsible for the initiation and propagation of astrocytic calcium waves remain unclear. In this study, intercellular calcium waves were evoked by focal photolysis of a caged calcium ionophore (DMNPE-caged Br A23187) in cultured astrocytes from newborn rats. The focal photolysis of the caged compound resulted in the increase in intracellular calcium in a single astrocyte, and this increase then propagated to neighboring astrocytes. We also analyzed the spatiotemporal characteristics of the intercellular calcium waves, and estimated the propagation pathways for them. The method using a caged calcium ionophore described in this study provides a new in vitro model for the analysis of intercellular calcium waves.

Increased resistance to nitric oxide cytotoxicity associated with differentiation of neuroblastoma-glioma hybrid (NG108-15) cells.

Nitric oxide (NO), synthesized by the enzyme nitric oxide synthase (NOS), acts as an intercellular messenger associated with various physiological and pathological events. In this study, we investigated whether there exits a difference in the vulnerability to NO-induced cytotoxicity between undifferentiated and differentiated NG108-15 cells, and if so, the mechanisms responsible for the difference. Following a 7- to 8-day exposure to dibutyryl cAMP (dbcAMP), NG108-15 cells exhibited a neuron-like morphology associated with the expression of the neuronal protein, synaptophysin, and with increased NADPH-d activity. Neuron-like differentiated NG108-15 cells acquired resistance to exogenously applied NO. This increased resistance to NO toxicity in differentiated cells was almost completely cancelled out by inhibiting the activity of superoxide dismutase (SOD), but not by inhibiting the activity of NOS. The present study suggested that the activity of SOD increased in parallel with the activity of NOS associated with differentiation and was crucial for the acquired resistance to NO toxicity in differentiated cells.