Administration of docetaxel plus ramucirumab with primary prophylactic pegylated-granulocyte colony-stimulating factor for pretreated non-small cell lung cancer: a phase II study.

PURPOSE: Although docetaxel plus ramucirumab has shown superior treatment efficacy over docetaxel monotherapy for patients with non-small cell lung cancer (NSCLC), the high rate of febrile neutropenia (FN) presents a clinical problem. This study aimed to validate the primary prophylactic use of pegfilgrastim with docetaxel and ramucirumab treatment in Japanese patients with NSCLC. METHODS: Patients with NSCLC with progression after at least one round of chemotherapy were enrolled and administered docetaxel (60 mg/m2) plus ramucirumab (10 mg/kg) intravenously on day 1, followed by pegylated-granulocyte colony-stimulating factor (3.6 mg) on day 2 of a 21-day treatment cycle. The primary study endpoint was the percentage of patients who developed FN. Secondary endpoints included overall survival, progression-free survival, overall response rate, and safety. RESULTS: Overall, 20 patients (15 men and 5 women) were enrolled, of whom one developed FN, resulting in an overall FN rate of 5%. The response and disease control rates were 40% and 85%, respectively. The median progression-free survival was 6.6 (95% confidence interval [CI], 0.5-NR) months. The median overall survival was 18.4 (95% CI, 2.2-11.0) months. Six patients aged over 75 years were included in this study, and although most adverse events were durable, ramucirumab-associated adverse events occurred more frequently in these patients. CONCLUSIONS: We observed a 5% FN rate using primary prophylactic pegylated-granulocyte colony-stimulating factor with docetaxel plus ramucirumab in Japanese patients with NSCLC. While most adverse events were durable, elderly patients should be closely monitored.

Metabolic activity by 18F-FDG-PET/CT is predictive of early response after nivolumab in previously treated NSCLC.

BACKGROUND: Nivolumab, an anti-programmed death-1 (PD-1) antibody, is administered in patients with previously treated non-small cell lung cancer. However, little is known about the established biomarker predicting the efficacy of nivolumab. Here, we conducted a preliminary study to investigate whether 18F-FDG-PET/CT could predict the therapeutic response of nivolumab at the early phase. METHODS: Twenty-four patients were enrolled in this study. 18F-FDG-PET/CT was carried out before and 1 month after nivolumab therapy. SUVmax, metabolic tumour volume (MTV), and total lesion glycolysis (TLG) were calculated. Immunohistochemical analysis of PD-L1 expression and tumour-infiltrating lymphocytes was conducted. RESULTS: Among all patients, a partial metabolic response to nivolumab was observed in 29% on SUVmax, 25% on MTV, and 33% on TLG, whereas seven (29%) patients achieved a partial response (PR) based on RECIST v1.1. The predictive probability of PR (100% vs. 29%, p = 0.021) and progressive disease (100% vs. 22.2%, p = 0.002) at 1 month after nivolumab initiation was significantly higher in 18F-FDG on PET/CT than in CT scans. Multivariate analysis confirmed that 18F-FDG uptake after administration of nivolumab was an independent prognostic factor. PD-L1 expression and nivolumab plasma concentration could not precisely predict the early therapeutic efficacy of nivolumab. CONCLUSION: Metabolic response by 18F-FDG was effective in predicting efficacy and survival at 1 month after nivolumab treatment.

Dramatic Response of S-1 Administration to Chemorefractory Advanced Thymic Cancer.

Thymic cancer (TC) is a rare malignancy in thoracic tumors, and there has been no standard therapeutics for advanced or relapsed patients. The clinical significance of second-line or beyond chemotherapy for platinum refractory advanced TC remains unclear. Here, we present the experience of a patient with TC showing a complete response to S-1 as third-line chemotherapy. A 54-year-old female with TC was treated with carboplatin plus paclitaxel and thoracic radiotherapy as first-line chemoradiotherapy and amrubicin as second-line chemotherapy. After 3 cycles of amrubicin administration, the metastatic hepatic lesions revealed a markedly progressive disease. A single agent of S-1 was administered as sequencing chemotherapy. After 2 cycles of S-1, the patient achieved a complete remission of multiple metastatic sites. There was evidence of immunohistochemical staining of a low thymidylate synthase (TS) expression. The expression of TS may be closely associated with the efficacy of S-1 in patients with TC.

Pyrolysis and steam gasification properties of mangroves.

The rising atmospheric CO2 emissions from the burning of fossil fuels remains a global concern. Mangrove forests, which are important for global biodiversity, are known for their high carbon fixation capacity. However, the characteristics of the pyrolysis and gasification of mangroves remain unclear. Thus, this study focused on mangroves' basic pyrolysis and steam gasification properties for use as a gasification fuel. Three mangrove species: Rhizophora mucronata, Bruguiera cylindrica, and Avicennia marina, were used as experimental samples. In addition, three species of land wood were used for comparison: Eucalyptus, Japanese cedar, and Japanese cypress. In addition to the raw sample, a demineralized sample was used for each sample to account for the influence of the alkali and alkaline earth metals (AAEMs) on pyrolysis and steam gasification. Thermogravimetric analysis was performed to obtain thermogravimetric curves of mangroves and land wood. A laboratory-scale instrument for pyrolysis and gasification using a batch-type horizontal electric furnace was also used at 800 °C in an inert and steam atmosphere. The char yield of raw mangroves was high and independent of the Klason lignin content, suggesting that AAEMs influence char formation during the initial pyrolysis of the mangroves. The results of pyrolysis and gasification under steam atmosphere showed that the H2 production ratio (Steam/Inert) from mangroves was 2.52-5.33, compared to 1.76-2.35 for land woods, the addition of steam significantly enhanced the steam gasification of mangroves. Mangroves contain relatively large amounts of AAEMs, which indicates their potential as a gasification feedstock.

Defossilization and decarbonization of hydrogen production using plastic waste: Temperature and feedstock effects during thermolysis stage.

The replacement of natural gas with plastic-derived pyrolysis gas can defossilize H2 production, while subsequent capture, utilization and storage of carbon in a solid form can decarbonize the process. The objective of this study was to investigate H2 production from three types of plastics using a process comprising pyrolysis (600 °C) and thermolysis stages (1200-1500 °C). Depending on the plastic feedstock and thermolysis temperature, the laboratory-scale setup generated 1000-1350 mL/min product gas with H2 purity of 74.3-94.2 vol%. The recovery of 5-9 wt% molecular H2 per mass of plastics was achieved. Other products included solid residue (0.1-12 wt%) and oil (8-52 wt%) from the pyrolysis reactor, solid carbon (36-53 wt%) and gas impurities (2-16 wt%) from the thermolysis reactor. The purity of H2 gas was detrimentally influenced by polyethylene terephthalate in the feedstock due to the dilution of gas by CO. The decomposition of methane containing in the pyrolysis gas was the limiting reaction step during H2 production and improved at higher thermolysis temperature. Three solid carbon structures were formed during the thermolysis stage regardless of the plastic type: carbon black aggregates, carbon black aggregates coated with a layer of pyrolytic carbon and a carbon film on the inner reactor wall. Among the three types of carbon, the highest valorization potential was identified for carbon black aggregates. Plastic feedstock composition had little if any effect on carbon black properties, while high thermolysis temperature (1500 °C) reduced the particle sizes and increased the surface area of aggregates.

Comparative analysis of different response criteria at early phase after PD-1 blockade in non-small lung cancer.

PURPOSE: To compare different response criteria using computed tomography (CT) and positron emission tomography (PET) in measuring response and survival in the early phase after programmed death-1 (PD-1) blockade monotherapy in patients with advanced non-small cell lung cancer (NSCLC). METHODS: A total of 54 patients with advanced NSCLC who had 2-deoxy-2-[fluorine-18]-fluoro-D-glucose PET or CT at baseline, and 4 and 9 weeks after PD-1 blockade, were registered. Therapeutic response was assessed according to the Response Evaluation Criteria in Solid Tumors (RECIST), the immune-modified RECIST (irRECIST), the PET Response Criteria in Solid Tumors (PERCIST), the immune-modified PERCIST (iPERCIST), and the European Organization for Research and Treatment of Cancer (EORTC) criteria for dichotomous groups, such as responders vs. non-responders and controlled vs. uncontrolled diseases. Cohen's κ was used to evaluate the concordance among the different criteria. RESULTS: The concordance between CT and PET response criteria was fair or slight for responders vs. non-responders, but the agreement between iPERCIST and irRECIST was moderate for controlled vs. uncontrolled diseases. The agreement between EORTC and PERCIST or iPERCIST in detecting responders was higher in the application of metabolic tumor volume (MTV) and total lesion glycolysis (TLG) than in the standardized uptake value corrected for lean body mass (SUL)peak. To distinguish controlled from uncontrolled disease, RECIST, irRECIST, and PET criteria (PERCIST, iPERCIST, and EORTC) defined by MTV or TLG were found to be significant predictors of progression-free survival. To distinguish responders from non-responders, iPERCIST by SULpeak or EORTC by TLG were identified as significant indicators. The EORTC criteria using TLG for the detection of responders or uncontrolled diseases had a significantly higher predictive value for response assessment. CONCLUSIONS: The EORTC criteria based on TLG for the early detection of responders and uncontrolled disease were effective as a response assessment at 4 weeks after the PD-1 blockade. When SULpeak was not used but MTV or TLG was, the agreement between EORTC and PERCIST or iPERCIST was almost perfect.

Predictive significance of circulating tumor DNA against patients with T790M-positive EGFR-mutant NSCLC receiving osimertinib.

Circulating tumor DNA (ctDNA) provides molecular information on tumor heterogeneity. The prognostic usefulness of ctDNA after first-line epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) are limited. Therefore, the present study evaluated ctDNA during osimertinib administration as a second-line or more setting to identify the relationship between EGFR mutation levels and outcomes in patients with advanced non-small cell lung cancer (NSCLC). Forty patients with EGFR T790M-positive NSCLC receiving osimertinib after prior EGFR-TKI treatment were registered. Plasma samples were collected at osimertinib pretreatment, after 1 month of treatment, and at the time of progressive disease (PD). ctDNA analysis was performed by digital polymerase chain reaction. The detection rate of copy numbers of exon 19 deletion, L858R, and T790M in plasma samples was significantly lower 1 month after osimertinib than at pretreatment, and significantly higher at PD than at 1 month, whereas that of C797S was significantly higher at PD than at 1 month. No statistically significant difference was observed in the copy numbers of exon 19 deletion, L858R, T790M, and C797S between complete response or partial response and stable disease or PD. The detection of T790M at PD after osimertinib initiation was a significant independent prognostic factor for predicting shorter prognosis, and the presence of major EGFR mutations at pretreatment and PD was closely linked to worse survival after osimertinib initiation. Molecular testing based on ctDNA is helpful for predicting outcomes of osimertinib treatment in T790M-positive NSCLC after previous EGFR-TKI treatment.

Prospective assessment using 18F-FDG PET/CT as a novel predictor for early response to PD-1 blockade in non-small-cell lung cancer.

Anti-programmed death-1 (PD-1) blockade is a standard treatment for advanced non-small-cell lung cancer (NSCLC). However, no appropriate modality exists for monitoring its therapeutic response immediately after initiation. Therefore, we aimed to elucidate the clinical relevance of 18F-FDG PET/CT versus CT in predicting the response to PD-1 blockade in the early phase. This prospective study included a total of 54 NSCLC patients. 18F-FDG PET/CT was performed at 4 weeks and 9 weeks after PD-1 blockade monotherapy. Maximum standardized uptake values (SULmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) were evaluated. Among all patients, partial metabolic response and progressive metabolic disease after PD-1 blockade were observed in 35.2% and 11.1% on SULmax, 22.2% and 51.8% on MTV, and 27.8% and 46.3% on TLG, respectively, whereas a partial response (PR) and progressive disease (PD), respectively, based on RECIST v1.1 were recognized in 35.2% and 35.2%, respectively. The predictive probability of PR (MTV: 57.9% vs. 21.1%, p = 0.044; TLG: 63.2% vs. 21.1%, p = 0.020) and PD (MTV: 78.9% vs. 47.3%, p = 0.002; TLG: 73.7% vs. 21.1%, p = 0.007) detected based on RECIST at 4 weeks after PD-1 blockade initiation was significantly higher using MTV or TLG on 18F-FDG uptake than on CT. Multivariate analysis revealed that metabolic response by MTV or TLG at 4 weeks was an independent factor for response to PD-1 blockade treatment. Metabolic assessment by MTV or TLG was superior to morphological changes on CT for predicting the therapeutic response and survival at 4 weeks after PD-1 blockade.

Plasma plastin-3: A tumor marker in patients with non-small-cell lung cancer treated with nivolumab.

Plastin-3 (PLS3) is a circulating tumor cell marker associated with aggressive cancer phenotypes. The present study aimed to investigate the usability of plasma PLS3 concentration in assessing the diagnosis, prognosis and sensitivity to treatment in patients with non-small-cell lung cancer (NSCLC) treated with nivolumab. A total of 33 patients with recurrent or advanced NSCLC were treated with nivolumab, and 10 healthy volunteers were retrospectively enrolled. Plasma concentrations of PLS3 were determined by ELISA. Plasma PLS3 concentration in patients with NSCLC was significantly higher compared with that in healthy volunteers (median 7.64 ng/ml vs. 3.13 ng/ml, P<0.001). Univariate analysis indicated that PLS3 ≤5.43 ng/ml was a predictor of partial response. Patients with PLS3 >8.55 ng/ml exhibited a poorer prognosis compared with those in the PLS3 ≤8.55 ng/ml group. A high plasma PLS3 concentration was a predictor of poor overall survival. In conclusion, plasma PLS3 concentration was identified as a marker for the diagnosis, treatment sensitivity and prognosis in patients with NSCLC treated with nivolumab. Plasma PLS3 may be a clinically useful tumor marker in patients with NSCLC; future prospective studies may confirm these results and explore its use in other cancers.

Interstitial lung disease secondary to alectinib after interstitial injury induced by crizotinib.

An 84-year-old male had a recurrence after surgical resection against Stage IIIA pulmonary adenocarcinoma and was treated with crizotinib due to harboring the anaplastic lymphoma kinase fusion gene. The patient exhibited crizotinib-induced interstitial lung disease (ILD), and alectinib was administered because of progressive disease. However, ILD appeared in both lungs again after alectinib treatment. This is the first case of ILD, resulting from alectinib administration after crizotinib-induced ILD. We should pay careful attention to patients who are treated with alectinib after crizotinib-induced ILD.

Occurrence of Hematological Malignancy in Long-term Survivors With Advanced Thymic Cancer.

BACKGROUND: Limited information is available on the occurrence of synchronous malignancy in patients with advanced thymic cancer (TC) who have achieved long-term survival due to sequential chemotherapy. Here, we present two cases of hematological malignancies in long-term survivors with advanced TC. CASE REPORTS: A 56-year-old man underwent surgical resection following the diagnosis of TC with a histological indication of squamous cell carcinoma. He received sequential chemotherapy, including carboplatin plus paclitaxel, amrubicin, and S-1, due to multiple pulmonary metastases. After >4 years of first-line chemotherapy, he developed consistent myelosuppression and a definite diagnosis of acute promyelocytic leukemia was made following bone marrow analysis. A 49-year-old man with advanced TC received carboplatin plus paclitaxel with amrubicin as second-line therapy due to recurrence. Amrubicin was administered for 54 cycles but T-cell lymphoblastic lymphoma without recurrence of TC was confirmed following transbronchial nodal biopsy due to marked lymphadenopathy. CONCLUSION: Physicians should be alert to the occurrence of hematological malignancy in patients with thymic cancer.

Glasgow prognostic score predicts efficacy and prognosis in patients with advanced non-small cell lung cancer receiving EGFR-TKI treatment.

BACKGROUND: Lung cancer is the leading cause of cancer-related deaths. Although epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) are effective for advanced non-small cell lung cancer (NSCLC) harboring EGFR mutations, some patients experience little or no response. The Glasgow prognostic score (GPS) is an inflammation-related score based on C-reactive protein (CRP) and albumin concentrations, and has prognostic value in various cancer settings. This study aimed to evaluate whether GPS could predict response of NSCLC to EGFR-TKIs. METHODS: This retrospective multicenter study evaluated patients with NSCLC harboring EGFR mutations who received EGFR-TKI monotherapy from October 2006 to December 2016. GPS values were determined using CRP and albumin concentrations from before initiation of EGFR-TKIs. The Kaplan-Meier method and Cox proportional hazard models were used to evaluate progression-free survival (PFS) and overall survival (OS). RESULTS: In 214 patients, 141, 43, and two patients had GPS values of 0, 1, and 2, respectively. The GPS independently predicted the efficacy of EGFR-TKIs; good GPS (0-1) conferred significantly better PFS (hazard ratio [HR]: 0.59, 95% confidence interval [CI]: 0.38-0.96, P = 0.03) and OS (HR: 0.56, 95% CI: 0.33-0.96, P = 0.03). Multivariate analysis confirmed that a good GPS (0-1) independently predicted good PFS and OS among patients who had PS of 0-1. Good GPS (0-1) independently predicted good OS among patients receiving treatment in first-line settings. CONCLUSIONS: The GPS independently predicted the efficacy of EGFR-TKIs for EGFR-mutated NSCLC; however, further studies are needed to validate our findings. KEY POINTS: SIGNIFICANT FINDINGS OF THE STUDY: Glasgow prognostic score (GPS) independently predicted the efficacy of epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) treatment for EGFR-mutated NSCLC. WHAT THIS STUDY ADDS: The findings presented in this paper will help to identify patients who will be expected to experience limited or no response to EGFR-TKI treatment by using GPS.

Prospective Feasibility Study of Amrubicin and Bevacizumab Therapy for Patients With Previously Treated Advanced NSCLC.

BACKGROUND/AIM: The efficacy of the combination of amrubicin and bevacizumab against advanced non small-cell lung cancer (NSCLC), as a second or third-line treatment, was evaluated. PATIENTS AND METHODS: Amrubicin was administered for 3 days to patients with previously treated advanced NSCLC, whereas bevacizumab was administered on day 1 of each cycle; this regimen was repeated every 3 weeks. RESULTS: Among the 16 patients, an overall response rate of 12.5% (for two patients) was achieved, and the overall disease control rate was 93.7%. Progression free survival and overall survival were 8.5 and 16.6 months, respectively. Grade 3 or 4 haematological toxicities were leukopenia, neutropenia, and febrile neutropenia. Grade 3 proteinuria and infection were the non haematological adverse events. CONCLUSION: The combination of amrubicin and bevacizumab is a promising regimen in the second or third-line treatment for advanced non-squamous NSCLC; however, physicians must recognise the risk of proteinuria related with this regimen.

Efficacy and safety of S-1 monotherapy in previously treated elderly patients (aged ≥75 years) with non-small cell lung cancer: A retrospective analysis.

BACKGROUND: S-1 monotherapy is effective and feasible for previously treated patients with advanced non-small cell lung cancer (NSCLC). However, it is not clear whether its effectiveness and tolerability in elderly patients are equivalent to those in younger patients. Hence, this study aimed to evaluate the efficacy and feasibility of S-1 monotherapy in elderly patients with NSCLC who had previously received other treatments. METHODS: We included 96 elderly patients (aged ≥75 years) with advanced NSCLC treated with S-1 alone as a subsequent-line treatment at 12 medical facilities between January 2005 and March 2018 in this study. The baseline characteristics of the patients, response to S-1 monotherapy, and adverse events (AEs) were investigated, retrospectively. RESULTS: A total of 68 male and 28 female patients (median age, 78 [range: 75-86] years) were analyzed. In elderly patients who were treated with S-1 monotherapy as a subsequent-line treatment, the objective response rate, disease control rate, median progression-free survival (PFS), and overall survival (OS) were 8.3%, 43.8%, 3.4 months, and 9.6 months, respectively. Observed AEs included anorexia, anemia, nausea, fatigue, reduced platelet count, and skin hyperpigmentation. Treatment-related death was observed in one patient because of pneumonitis. In patients who experienced no progressive disease, subsequent-line S-1 alone was associated with longer PFS and OS. CONCLUSIONS: S-1 monotherapy is effective and feasible as a subsequent-line treatment in elderly patients who were previously treated for NSCLC, and it produces results. S-1 monotherapy could be one of the treatment choices for elderly patients with previously treated NSCLC.

Efficacy and safety of immune checkpoint inhibitor monotherapy in pretreated elderly patients with non-small cell lung cancer.

PURPOSE: Immune checkpoint inhibitors (ICIs) are an effective subsequent-line treatment for patients with advanced non-small cell lung cancer (NSCLC). However, it remains unclear whether the efficacy and safety of subsequent-line ICI monotherapy in elderly patients (aged ≥ 75 years) are similar to that in non-elderly patients. Therefore, we aimed to investigate the efficacy and safety of ICI monotherapy in pretreated elderly patients with NSCLC. METHODS: Between January 2016 and February 2018, 131 elderly patients with advanced NSCLC who received subsequent-line ICI monotherapy at 13 Japanese institutions were enrolled in this study. Baseline characteristics, the efficacy of ICI treatment, and adverse events were evaluated. RESULTS: Ninety-eight men and 33 women (median age 77 [range 75-87] years) were enrolled. Among those who received subsequent-line ICI monotherapy, the overall response, disease control rates, median progression-free survival (PFS), and overall survival (OS) were 27.4%, 61.8%, 4.5 months, and 16.0 months, respectively. Adverse events such as anorexia, fatigue, pneumonitis, and hypothyroidism were observed. There were two treatment-related deaths due to pneumonitis and thrombocytopenia. Subsequent-line ICI monotherapy in patients with good performance status (PS), receiving steroids for immune-related adverse events (irAEs), and exhibiting partial response (PR) was associated with improved PFS, as well as OS in patients with good PS and PR. CONCLUSIONS: Subsequent-line ICI monotherapy in elderly patients, with previously treated NSCLC, was effective, safe and showed outcomes equivalent to those in non-elderly patients. Immunotherapy provides a survival benefit for elderly patients, who exhibit its efficacy and a favorable general condition.

Direct analysis of saturated hydrocarbons using glow discharge plasma ionization source for mass spectrometry.

The ionization source based on glow discharge plasma using ambient air is driven by a pulsed direct-current voltage for soft plasma ionization (SPI). The novelty of this work is that molecular ions [M+13]+ related to the analyte species (M), which may be formed by numerous oxidation, can be dominantly detected as a base peak with little or no fragmentation of them in an air plasma at a pressure of several kPa. The unique ion [M+13]+ was assigned to the oxidation product, [M+O-3H]+, which was confirmed as a deuterated ion [M+O-3D]+ ([M+10]+) by using a deuterated solvent. The ionization reactions were suggested that the product ion [M+O-3H]+ may arise from hydride abstraction reaction of M with O2+•, dehydrogenation reaction of [M-H]+• and subsequently oxidation reaction of [M-3H]+ with O3. n-Alkane mixtures was also measured to evaluate the intermolecular interaction in this system. The limits of detection (LOD) were in the range of 0.126-1.68 ppmv and the relative standard deviation (RSD) for repeatability was approximately 10.0% at the lowest concentration. To our knowledge, this is the first report demonstrating that the spectrum pattern of saturated hydrocarbons could be directly determined without any complicated fragmentation.

Removal of gaseous elemental mercury by hydrogen chloride non-thermal plasma modified biochar.

Hydrogen chloride (HCl) non-thermal plasma was applied to introduce Cl active sites on biochar prepared from sorghum straw in this study. Surface modified biochar was then placed in flue gas with typical components to investigate its elemental mercury (Hg0) capture ability. To elucidate the adsorption mechanism & binding properties, samples were characterized by N2 adsorption, scanning electron microscopy with energy dispersive spectrometer (SEM-EDS) and X-ray absorption near edge structure (XANES) analysis of Hg LIII-edge, Cl K-edge and S K-edge. Experimental results showed that HCl plasma modification successfully increased Cl active sites on biochar and greatly increased its mercury removal efficiency. Both HCl treatments (w/without plasma involvement) altered biochar's surface structure and layered structure generated. XANES spectra revealed that adsorbed-Hg on HCl-treated biochars mainly in the form of Hg+. Gaseous Hg0 was believed to heterogeneously react with chlorinated sites through electron-transfer and formed Hg2Cl2 compounds. With the presence of NO or SO2 in the system, adsorbed mercury existed on biochar mainly as Hg+. SO2 competed and inhibited the adsorption of Hg0; while NO promoted Hg0 removal capacity by increasing the active sites and enhancing the adsorption kinetics of adjacent Cl-containing sites.

An Exploratory Randomized Phase II Trial Comparing CDDP Plus S-1 With Bevacizumab and CDDP Plus Pemetrexed With Bevacizumab Against Patients With Advanced Non-squamous Non-small Cell Lung Cancer.

BACKGROUND/AIM: It remains unclear which chemotherapeutic regimens are better for the addition of bevacizumab. We conducted an exploratory randomized phase II trial comparing first-line S-1 plus cisplatin with bevacizumab and pemetrexed plus cisplatin with bevacizumab in patients with advanced non-squamous non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Chemotherapy-naïve patients received S-1 (80 mg/m2) from day 1 to day 14 plus cisplatin (80 mg/m2) on day 1 with bevacizumab (15 mg/kg) on day 1, followed by maintenance with bevacizumab plus S-1 (SCB) on day 1 every 3 weeks and pemetrexed (500 mg/m2) on day 1 plus cisplatin (75 mg/m2) on day 1 with bevacizumab (15 mg/kg) on day 1 followed by maintenance bevacizumab plus pemetrexed (PCB) on day 1 every 3 weeks. The expression of thymidylate synthase (TS) was analyzed using immunohistochemistry. RESULTS: Forty-eight patients were enrolled in this study, and eligible patients were randomly assigned at 1:1 ratio to receive SCB (n=24) or PCB (n=24). The median number of chemotherapy and maintenance therapy for SCB and PCB was 4 (range, 1-6 cycles) and 4 (range, 2-6 cycles), and 5 (range, 0-39 cycles) and 5 (range, 0-28 cycles), respectively. The overall response rate (ORR) for PCB and SCB were 54.2% and 83.3%, respectively (p=0.06). The median progression-free survival (PFS) and overall survival (OS) for PCB and SCB were 406 and 351 days, (p=0.96), and 678 and 1190 days, respectively (p=0.23). The mild adverse events were observed in both regimens. TS expression was more predictive of the chemotherapeutic response in SCB compared to PCB, but not for PFS. CONCLUSION: The combination regimen of SCB was identified as having a similar activity and tolerability to that of PCB in patients with advanced non-squamous NSCLC.

Altered signaling pathway in the dysmorphogenesis of telencephalon in the Gli3 depressed mouse embryo, Pdn/Pdn.

The responsible gene of genetic polydactyly/arhinencephaly mouse (Pdn/Pdn) is Gli3. Pdn/Pdn exhibits absence of the olfactory bulb, suggesting telencephalic dysmorphogenesis. It has been cleared that a transposon was inserted into intron 3 of the Gli3 gene in the Pdn mouse. Adequate PCR primers in the intron 3 and transposon allowed us to discriminate +/+, Pdn/+ and Pdn/Pdn embryos. After genotyping of the Pdn embryos using genomic DNA from the yolk sac membrane, gene expressions in the embryo proper were analyzed by DNA microarray, real-time PCR and whole-mount in situ hybridization (WISH) methods. DNA microarray detected 368 depressed and 425 over-expressed genes in the Pdn/Pdn mouse embryos on day 9 of gestation. In these genes, six signaling pathway and 20 transcription factor genes were included. From these genes, we further investigated Gli3, Emx2, Wnt8b and Wnt7b gene expressions using real-time PCR and WISH, and depression of these gene expression amounts and altered expression patterns were confirmed. Although alterations of Shh and Fgf8 gene expressions were not detected in the DNA microarray, as these genes have been closed up in the telencephalic morphogenesis, we investigated these gene expressions by real-time PCR and WISH. Shh gene expression amount and pattern were not changed. Alteration of Fgf8 gene expression amount was not detected also in the real-time PCR, but altered expression pattern was detected in the Pdn/Pdn embryos by WISH. From the present data, we suggested that Emx2, Wnt8b, Wnt7b and Fgf8 are the important Gli3 signaling pathway in the morphogenesis of telencephalon.

A phase II study of afatinib treatment for elderly patients with previously untreated advanced non-small-cell lung cancer harboring EGFR mutations.

OBJECTIVE: The efficacy and safety of afatinib in elderly patients with EGFR-mutated non-small-cell lung cancer (NSCLC) have not been evaluated. This study aimed to assess the efficacy and safety of afatinib in elderly chemotherapy-naive patients with NSCLC harboring sensitive EGFR mutations. MATERIALS AND METHODS: We prospectively assessed the clinical effects of afatinib as a first-line treatment for elderly (age ≥70 years) NSCLC patients with EGFR mutations (exon 19 deletion or exon 21 L858R mutation). All patients were initially administered afatinib (30 mg/day). RESULTS: Between May 2014 and August 2017, 40 patients (13 men, 27 women) with adenocarcinoma were included in our analysis. The median age was 77 years (range, 70-85 years). The dose was reduced in 19 patients. The objective overall response and disease control rates were 72.5% and 100%, respectively, and the median progression-free survival and overall survival were 12.9 months and not reached, respectively. Common adverse events (AEs) included diarrhea, rash/acne, and anemia. Major grade 3 or higher toxicities included diarrhea (12.5%), mucositis (7.5%), and pneumonitis (7.5%). Afatinib treatment was discontinued in 8 patients owing to AEs of elevated amylase (n = 1), liver dysfunction (n = 1), rash/acne (n = 1), nail change (n = 1), anorexia (n = 2), pneumonitis (n = 2), and diarrhea (n = 2). Two patients died due to treatment-related pneumonitis. CONCLUSIONS: This is the first study that verified the efficacy and feasibility of first-line chemotherapy with afatinib at 30 mg/day in elderly patients with advanced NSCLC harboring sensitive EGFR mutations. First-line afatinib of 30 mg/day could be a treatment option in this patient population.