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BackgroundIntravenous administration of magnesium with a short hydration regimen is recommended for patients receiving high-dose cisplatin to protect against cisplatin-induced nephrotoxicity. However, the optimal dose of magnesium supplementation has not been clarified. The aim of this trial was to investigate the safety and efficacy of a short hydration regimen with 20 mEq of magnesium supplementation for lung cancer patients receiving cisplatin-based chemotherapy.MethodsThe key eligibility criteria included cytologically or histologically diagnosed lung cancer, candidacy for cisplatin-based (≥ 60 mg/m2) chemotherapy or chemoradiotherapy, no prior chemotherapy, aged 20–75 years, and adequate renal function. Cisplatin was administered with pre-hydration with 20 mEq of magnesium sulfate. Mannitol was administered just before cisplatin infusion to enforce diuresis. The primary endpoint was the proportion of patients who underwent cisplatin-based chemotherapy with a short hydration regimen with 20 mEq of magnesium supplementation without a grade 2 or higher elevation in creatinine.ResultsForty patients with a median age of 66 years (range 35–74) were prospectively enrolled. Median baseline creatinine was 0.71 mg/dL. Median dose of cisplatin in the first cycle was 80 mg/m2. In the first cycle, no patients developed grade 2 creatinine toxicity. During the treatment period, one patient developed grade 2 creatinine elevation; thus, the proportion of patients without a grade 2 or higher elevation in creatinine was 97.5% (95% confidence interval 86.8–99.9).ConclusionA short hydration regimen with 20 mEq of magnesium supplementation is safe and feasible for patients with lung cancer receiving cisplatin-based chemotherapy.

Various liquid biopsy methods have been developed for the non-invasive and early detection of diseases. In particular, the detection of circulating tumor cells (CTCs) and cancer-associated fibroblasts (CAFs) in blood has been receiving a great deal of attention. We have been developing systems and materials to facilitate such liquid biopsies. In this study, we further developed glass filters (with various patterns of holes, pitches, and non-adhesive coating) that can capture CTCs, but not white blood cells. We optimized the glass filters to capture CTCs, and demonstrated that they could be used to detect CTCs from lung cancer patients. We also used the optimized glass filters for detecting CAFs. Additionally, we further developed a system for visualizing the captured cells on the glass filters. Finally, we demonstrated that we could directly culture the captured cells on the glass filters. Based on these results, our high-performance glass filters appear to be useful for capturing and culturing CTCs and CAFs for further examinations.

Both pro‐ and anti‐oncogenic roles of miR‐221 and miR‐222 microRNAs are reported in several types of human cancers. A previous study suggested their oncogenic role in invasiveness in lung cancer, albeit only one cell line (H460) was used. To further evaluate involvement of miR‐221 and miR‐222 in lung cancer, we investigated the effects of miR‐221 and miR‐222 overexpression on six lung cancer cell lines, including H460, as well as one immortalized normal human bronchial epithelial cell line, HBEC4. miR‐221 and miR‐222 induced epithelial‐to‐mesenchymal transition (EMT)‐like changes in a minority of HBEC4 cells but, unexpectedly, both the microRNAs rather suppressed their invasiveness. Consistent with the prior report, miR‐221 and miR‐222 promoted growth in H460; however, miR‐221 suppressed growth in four other cell lines with no effects in one, and miR‐222 suppressed growth in three cell lines but promoted growth in two. These are the first results to show tumor‐suppressive effects of miR‐221 and miR‐222 in lung cancer cells, and we focused on clarifying the mechanisms. Cell cycle and apoptosis analyses revealed that growth suppression by miR‐221 and miR‐222 occurred through intra‐S‐phase arrest and/or apoptosis. Finally, lung cancer cell lines transfected with miR‐221 or miR‐222 became more sensitive to the S‐phase targeting drugs, possibly due to an increased S‐phase population. In conclusion, our data are the first to show tumor‐suppressive effects of miR‐221 and miR‐222 on lung cancer, warranting testing their potential as therapeutics for the disease. Previous studies suggested oncogenic roles of miR‐221 and miR‐222 microRNAs in lung cancer, and thus they are believed to function solely as oncogenes in lung cancer. However, by analyzing multiple lung cancer cell lines with diverse genetic alterations, we here show that miR‐221 and miR‐222 function also as tumor suppressors, as demonstrated by their growth suppressive and chemosensitizing effects, warranting testing their potential as novel therapeutics for lung cancer.

Detecting molecular targets in specimens from patients with lung cancer is essential for targeted therapy. Recently, we developed a highly sensitive, rapid-detection device (an immuno-wall device) that utilizes photoreactive polyvinyl alcohol immobilized with antibodies against a target protein via a streptavidin–biotin interaction. To evaluate its performance, we assayed epidermal growth factor receptor ( EGFR ) mutations, such as E746_A750 deletion in exon 19 or L858R substitution in exon 21, both of which are common in non-small cell lung cancer and important predictors of the treatment efficacy of EGFR tyrosine kinase inhibitors. The results showed that in 20-min assays, the devices detected as few as 1% (E746_A750 deletion) and 0.1% (L858R substitution) of mutant cells. Subsequent evaluation of detection of the mutations in surgically resected lung cancer specimens from patients with or without EGFR mutations and previously diagnosed using commercially available, clinically approved genotyping assays revealed diagnostic sensitivities of the immuno-wall device for E746_A750 deletion and L858R substitution of 85.7% and 87.5%, respectively, with specificities of 100% for both mutations. These results suggest that the immuno-wall device represents a good candidate next-generation diagnostic tool, especially for screening of EGFR mutations.

Background The Cockcroft–Gault formula is commonly used as a substitute for glomerular filtration rate (GFR) in Calvert's formula for carboplatin dosing, where adjusting serum creatinine measured using the enzymatic method with 0.2 mg/dL has been suggested in Japan. However, the effects of these adjustments on efficacy in patients with non‐small‐cell lung cancer remain unknown. Methods We conducted a post hoc analysis of the PREDICT1 study (CJLSG1201), a multicenter prospective observational trial of carboplatin–pemetrexed. Glomerular filtration rate values in Calvert's formula were back‐calculated from the administered dosages of carboplatin and the reported value of the target area under the curve. We estimated the serum creatinine adjustments and divided the patients into crude and adjusted groups. Results Patients in the crude group (N = 169) demonstrated similar efficacy to those in the adjusted group (N = 104) in progression‐free survival (PFS) and overall survival (OS) (hazard ratio [HR], 1.02; 95% confidence interval [CI], 0.76–1.35; p = 0.916 vs. HR, 0.87; 95% CI, 0.65–1.17; p = 0.363), with higher grade 3–4 hematologic toxicity. Among patients aged ≥75 years, the crude group (N = 47) showed superior efficacy compared with the adjusted group (N = 17) in PFS and OS (HR, 0.37; 95% CI, 0.20–0.69; p = 0.002 vs. HR, 0.43; 95% CI, 0.23–0.82; p = 0.010). Conclusions Serum creatinine adjustment may be associated with similar efficacy compared to the crude serum creatinine value. In older patients, the adjustment should be cautiously applied owing to the potential for reduced efficacy. Adjustment of serum creatinine measured using the enzymatic method with 0.2 mg/dL in creatinine clearance calculation using the Cockcroft–Gault formula is associated with similar clinical efficacy and a low incidence of toxicity compared with those of non‐adjusted values in patients with preserved renal function eligible for carboplatin–pemetrexed treatment. However, adjustments should be used with special caution in older patients owing to the potential for reduced efficacy.

To identify potential therapeutic targets for lung cancer, we performed semi‐genome‐wide shRNA screening combined with the utilization of genome‐wide expression and copy number data. shRNA screening targeting 5043 genes in NCI‐H460 identified 51 genes as candidates. Pathway analysis revealed that the 51 genes were enriched for the five pathways, including ribosome, proteasome, RNA polymerase, pyrimidine metabolism and spliceosome pathways. We focused on the proteasome pathway that involved six candidate genes because its activation has been demonstrated in diverse human malignancies, including lung cancer. Microarray expression and array CGH data showed that PSMA6, a proteasomal subunit of a 20S catalytic core complex, was highly expressed in lung cancer cell lines, with recurrent gene amplifications in some cases. Therefore, we further examined the roles of PSMA6 in lung cancer. Silencing of PSMA6 induced apoptosis or G2/M cell cycle arrest in cancer cell lines but not in an immortalized normal lung cell line. These results suggested that PSMA6 serves as an attractive target with a high therapeutic index for lung cancer. By doing an integrative analysis we have identified PSMA6, a subunit of the proteasome complex, as one of the most promising targets for lung cancer. We showed that PSMA6 knockdown suppressed the viability of cancer cells through the induction of apoptosis or cell cycle arrest at G2/M, with only a minimal effect on normal lung epithelial cells. Our data suggested that targeting PSMA6 for lung cancer may be an attractive novel therapeutic strategy.

To identify novel therapeutic targets for non‐small cell lung cancer (NSCLC), we conducted an integrative study in the following 3 stages: (i) identification of potential target gene(s) through shRNA functional screens in 2 independent NSCLC cell lines; (ii) validation of the clinical relevance of identified gene(s) using public databases; and (iii) investigation of therapeutic potential of targeting the identified gene(s) in vitro. A semi‐genome‐wide shRNA screen was performed in NCI‐H358 cells, and was integrated with data from our previous screen in NCI‐H460 cells. Among genes identified in shRNA screens, 24 were present in both NCI‐H358 and NCI‐H460 cells and were considered potential targets. Among the genes, we focused on eIF2β, which is a subunit of heterotrimeric G protein EIF2 and functions as a transcription initiation factor. The eIF2β protein is highly expressed in lung cancer cell lines compared with normal bronchial epithelial cells, and gene copy number analyses revealed that eIF2β is amplified in a subset of NSCLC cell lines. Gene expression analysis using The Cancer Genome Atlas (TCGA) dataset revealed that eIF2β expression is significantly upregulated in lung cancer tissues compared with corresponding normal lung tissues. Furthermore, high eIF2β expression was correlated with poor survival in patients with lung adenocarcinoma, as shown in other cohorts using publicly available online tools. RNAi‐mediated depletion of eIF2β suppresses growth of lung cancer cells independently of p53 mutation status, in part through G1 cell cycle arrest. Our data suggest that eIF2β is a therapeutic target for lung cancer. Through semi‐genome wide shRNA screens using two lung cancer cell lines, we have identified the subunit eIF2β of translation‐initiation factor EIF2 as a potential therapeutic target for lung cancer. We show that eIF2β is highly expressed in lung cancer, in correlation with poor patient prognosis and that its knockdown induces G1 cell cycle arrest in lung cancer cell lines. These suggest therapeutic potential of targeting eIF2β for lung cancer.

To identify novel therapeutic targets for non‐small cell lung cancer ( NSCLC ), we conducted an integrative study in the following 3 stages: (i) identification of potential target gene(s) through sh RNA functional screens in 2 independent NSCLC cell lines; (ii) validation of the clinical relevance of identified gene(s) using public databases; and (iii) investigation of therapeutic potential of targeting the identified gene(s) in vitro. A semi‐genome‐wide sh RNA screen was performed in NCI ‐H358 cells, and was integrated with data from our previous screen in NCI ‐H460 cells. Among genes identified in sh RNA screens, 24 were present in both NCI ‐H358 and NCI ‐H460 cells and were considered potential targets. Among the genes, we focused on eIF 2β, which is a subunit of heterotrimeric G protein EIF 2 and functions as a transcription initiation factor. The eIF 2β protein is highly expressed in lung cancer cell lines compared with normal bronchial epithelial cells, and gene copy number analyses revealed that eIF 2 β is amplified in a subset of NSCLC cell lines. Gene expression analysis using The Cancer Genome Atlas ( TCGA ) dataset revealed that eIF 2 β expression is significantly upregulated in lung cancer tissues compared with corresponding normal lung tissues. Furthermore, high eIF 2 β expression was correlated with poor survival in patients with lung adenocarcinoma, as shown in other cohorts using publicly available online tools. RNA i‐mediated depletion of eIF 2 β suppresses growth of lung cancer cells independently of p53 mutation status, in part through G1 cell cycle arrest. Our data suggest that eIF 2 β is a therapeutic target for lung cancer.

To identify potential therapeutic targets for lung cancer, we performed semi‐genome‐wide sh RNA screening combined with the utilization of genome‐wide expression and copy number data. sh RNA screening targeting 5043 genes in NCI ‐H460 identified 51 genes as candidates. Pathway analysis revealed that the 51 genes were enriched for the five pathways, including ribosome, proteasome, RNA polymerase, pyrimidine metabolism and spliceosome pathways. We focused on the proteasome pathway that involved six candidate genes because its activation has been demonstrated in diverse human malignancies, including lung cancer. Microarray expression and array CGH data showed that PSMA 6 , a proteasomal subunit of a 20S catalytic core complex, was highly expressed in lung cancer cell lines, with recurrent gene amplifications in some cases. Therefore, we further examined the roles of PSMA 6 in lung cancer. Silencing of PSMA 6 induced apoptosis or G2/M cell cycle arrest in cancer cell lines but not in an immortalized normal lung cell line. These results suggested that PSMA 6 serves as an attractive target with a high therapeutic index for lung cancer.