Language：English   Publisher：(一社)日本癌治療学会  

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Language：Japanese   Publisher：日本分子腫瘍マーカー研究会  

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Language：English   Publisher：(一社)日本癌学会  

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Language：English   Publisher：(一社)日本癌学会  

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Language：Japanese   Publisher：日本結核・非結核性抗酸菌症学会関東支部学会・日本呼吸器学会関東地方会  

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Language：English   Publishing type：Research paper (scientific journal)  

Osimertinib induces a marked response in non-small-cell lung cancer (NSCLC) patients harboring epidermal growth factor receptor (EGFR) gene mutations. However, acquired resistance to osimertinib remains an inevitable problem. In this study, we aimed to investigate osimertinib-resistant mechanisms and evaluate the combination therapy of afatinib and chemotherapy. We established osimertinib-resistant cell lines (PC-9-OR and H1975-OR) from EGFR-mutant lung adenocarcinoma cell lines PC-9 and H1975 by high exposure and stepwise method. Combination therapy of afatinib plus carboplatin (CBDCA) and pemetrexed (PEM) was effective in both parental and osimertinib-resistant cells. We found that expression of thrombospondin-1 (TSP-1) was upregulated in resistant cells using cDNA microarray analysis. We demonstrated that TSP-1 increases the expression of matrix metalloproteinases through integrin signaling and promotes tumor invasion in both PC-9-OR and H1975-OR, and that epithelial-to-mesenchymal transition (EMT) was involved in H1975-OR. Afatinib plus CBDCA and PEM reversed TSP-1-induced invasion ability and EMT changes in resistant cells. In PC-9-OR xenograft mouse models (five female Balb/c-Nude mice in each group), combination therapy strongly inhibited tumor growth compared with afatinib monotherapy (5 mg/kg, orally, five times per week) or CBDCA (75 mg/kg, intraperitoneally, one time per week) + PEM (100 mg/kg, intraperitoneally, one time per week) over a 28-day period. These results suggest that the combination of afatinib plus CBDCA and PEM, which effectively suppresses TSP-1 expression, may be a promising option in EGFR-mutated NSCLC patients after the acquisition of osimertinib resistance.

DOI： 10.1111/cas.16199

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INTRODUCTION: A neurotrophic tropomyosin receptor kinase (NTRK)-tyrosine kinase inhibitor (TKI) has shown dramatic efficacy against malignant tumors harboring an NTRK fusion gene. However, almost all tumors eventually acquire resistance to NTRK-TKIs. METHOD: To investigate the mechanism of resistance to NTRK-TKIs, we established cells resistant to three types of NTRK-TKIs (larotrectinib, entrectinib, and selitrectinib) using KM12 colon cancer cells with a TPM3-NTRK1 rearrangement. RESULT: Overexpression of 3-hydroxy-3-methylglutaryl-CoA synthase 2 (HMGCS2) was observed in three resistant cells (KM12-LR, KM12-ER, and KM12-SR) by microarray analysis. Lower expression of sterol regulatory element-binding protein 2 (SREBP2) and peroxisome proliferator activated receptor α (PPARα) was found in two cells (KM12-ER and KM12-SR) in which HMGCS2 was overexpressed compared to the parental KM12 and KM12-LR cells. In resistant cells, knockdown of HMGCS2 using small interfering RNA improved the sensitivity to NTRK-TKI. Further treatment with mevalonolactone after HMGCS2 knockdown reintroduced the NTRK-TKI resistance. In addition, simvastatin and silibinin had a synergistic effect with NTRK-TKIs in resistant cells, and delayed tolerance was observed after sustained exposure to clinical concentrations of NTRK-TKI and simvastatin in KM12 cells. In xenograft mouse models, combination treatment with entrectinib and simvastatin reduced resistant tumor growth compared with entrectinib alone. CONCLUSION: These results suggest that HMGCS2 overexpression induces resistance to NTRK-TKIs via the mevalonate pathway in colon cancer cells. Statin inhibition of the mevalonate pathway may be useful for overcoming this mechanistic resistance.

DOI： 10.1002/cam4.7393

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Background: Immune checkpoint inhibitors (ICIs) can induce immune-related adverse events (irAEs). Liquid biomarkers to predict irAE occurrence are urgently needed. We previously developed an ELISA system to specifically detect soluble PD-L1 (sPD-L1) with PD-1-binding capacity (bsPD-L1). Here, we investigated the relationship between sPD-L1 and bsPD-L1 in gastric cancer (GC) and non-small cell lung cancer (NSCLC) treated with PD-1/PD-L1 blockade and their association with irAEs.

Methods: We examined sPD-L1, bsPD-L1, matrix metalloproteinases (MMPs), and proinflammatory cytokine levels by ELISA in plasma samples from 117 GC patients prior to surgery and 72 NSCLC patients prior to and at 2 months after ICI treatment (anti-PD-1, n = 48; anti-PD-L1, n = 24). In mice treated with anti-PD-1/PD-L1 antibodies (Abs), sPD-L1 levels and localization of Abs were examined by ELISA and immunohistochemistry, respectively.

Results:sPD-L1 was detected with higher frequency in GC patients than in NSCLC patients, whereas bsPD-L1 was detected with similar frequencies in GC and NSCLC patients. sPD-L1 levels were correlated with IL-1α, IL-1β, TNF-α, and IL-6 levels, while bsPD-L1 levels were correlated with MMP13, MMP3, and IFN-γ levels. In NSCLC patients, anti-PD-L1, but not anti-PD-1, treatment increased sPD-L1, which was associated with irAE development, but not with clinical outcomes. In mice, trafficking of anti-PD-L1 Abs to lysosomes in F4/80⁺ macrophages resulted in sPD-L1 production, which was suppressed by treatment with lysosomal degradation inhibitor chloroquine and macrophage depletion.

Conclusion: Anti-PD-L1-mediated lysosomal degradation induces sPD-L1 production, which can serve as an indicator to predict irAE development during anti-PD-L1 treatment.

DOI： 10.3389/fphar.2024.1384733

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Publishing type：Research paper (scientific journal)   Publisher：Frontiers Media SA  

Background

The tumor microenvironment (TME) impacts the therapeutic efficacy of immune checkpoint inhibitors (ICIs). No liquid biomarkers are available to evaluate TME heterogeneity. Here, we investigated the clinical significance of PD-1-binding soluble PD-L1 (bsPD-L1) in gastric cancer (GC) patients and non-small cell lung cancer (NSCLC) patients treated with PD-1/PD-L1 blockade.

Methods

We examined bsPD-L1, matrix metalloproteinases (MMPs), and IFN-γ levels in plasma samples from GC patients (n = 117) prior to surgery and NSCLC patients (n = 72) prior to and 2 months after ICI treatment. We also examined extracellular matrix (ECM) integrity, PD-L1 expression, and T cell infiltration in tumor tissues from 25 GC patients by Elastica Masson-Goldner staining and immunohistochemical staining for PD-L1 and CD3, respectively.

Results

bsPD-L1 was detected in 17/117 GC patients and 16/72 NSCLC patients. bsPD-L1 showed strong or moderate correlations with plasma MMP13 or MMP3 levels, respectively, in both GC and NSCLC patients. bsPD-L1 expression in GC was associated with IFN-γ levels and intra-tumoral T cell infiltration, whereas MMP13 levels were associated with loss of ECM integrity, allowing tumor cells to access blood vessels. Plasma MMP3 and MMP13 levels were altered during ICI treatment. Combined bsPD-L1 and MMP status had higher predictive accuracy to identify two patient groups with favorable and poor prognosis than tumor PD-L1 expression: bsPD-L1⁺MMP13^high in GC and bsPD-L1⁺(MMP3 and MMP13)^increased in NSCLC were associated with poor prognosis, whereas bsPD-L1⁺MMP13^low in GC and bsPD-L1⁺(MMP3 or MMP13)^decreased in NSCLC were associated with favorable prognosis.

Conclusion

Plasma bsPD-L1 and MMP13 levels indicate T cell response and loss of ECM integrity, respectively, in the TME. The combination of bsPD-L1 and MMPs may represent a non-invasive tool to predict recurrence in GC and the efficacy of ICIs in NSCLC.

DOI： 10.3389/fphar.2024.1384731

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Change within the intratumoral microbiome is a common feature in lung and other cancers and may influence inflammation and immunity in the tumor microenvironment, affecting growth and metastases. We previously characterized the lung cancer microbiome in patients and identified Acidovorax temperans as enriched in tumors. Here, we instilled A. temperans in an animal model driven by mutant K-ras and Tp53. This revealed A. temperans accelerates tumor development and burden through infiltration of proinflammatory cells. Neutrophils exposed to A. temperans displayed a mature, pro-tumorigenic phenotype with increased cytokine signaling, with a global shift away from IL-1β signaling. Neutrophil to monocyte and macrophage signaling upregulated MHC II to activate CD4+ T cells, polarizing them to an IL-17A+ phenotype detectable in CD4+ and γδ populations (T17). These T17 cells shared a common gene expression program predictive of poor survival in human LUAD. These data indicate bacterial exposure promotes tumor growth by modulating inflammation.

DOI： 10.1038/s41389-024-00513-6

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INTRODUCTION: Osimertinib is a standard treatment for patients with EGFR-mutant NSCLC. Although some osimertinib resistance mechanisms have been identified, nearly 50% of the mechanisms remain to be elucidated. This study was aimed at identifying non-genetic mechanisms underlying osimertinib resistance. METHODS: We established two osimertinib-resistant cell lines from EGFR mutation-positive PC-9 and HCC827 NSCLC cell lines (PC-9OR and HCC827OR, respectively) using a stepwise method. We compared the phosphoproteomic profiles of the osimertinib-resistant and parental cells using mass spectrometry. Upstream kinases were identified using the application Kinase Enrichment Analysis version 3. RESULTS: Phosphoproteomic analysis revealed 80 phosphorylation sites that were mutually up-regulated in PC-9OR and HCC827OR cells. The Kinase Enrichment Analysis version 3 analysis identified focal adhesion kinase (FAK) and proto-oncogene tyrosine-protein kinase Src (Src) as upstream kinases of these up-regulated phosphoproteins. The small-interfering RNA-mediated knockdown of FAK reduced Src phosphorylation and that of Src reduced FAK phosphorylation in both cell lines. Furthermore, FAK- or Src-specific small-interfering RNA treatments restored EGFR phosphorylation in PC-9OR and HCC827OR cells. The combination of FAK and Src inhibitors inhibited PC-9OR and HCC827OR cell proliferation in vitro and suppressed tumor growth in a xenograft mouse model. Immunohistochemistry of tumors from patients with EGFR-mutant NSCLC suggested that phosphorylated FAK and Src are involved in initial and acquired resistance to osimertinib. CONCLUSIONS: Phosphoproteomic analysis may help elucidate the mechanisms of resistance to molecular-targeted therapies in lung cancer. Mutual phosphorylation of FAK and Src is involved in osimertinib resistance. Thus, FAK and Src inhibition may be novel treatment strategies for osimertinib-resistant NSCLC.

DOI： 10.1016/j.jtocrr.2024.100668

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Small cell lung cancer (SCLC) is well known as a highly malignant neuroendocrine tumor. Immunotherapy combined with chemotherapy has become a standard treatment for extensive SCLC. However, since most patients quickly develop resistance and relapse, finding new therapeutic targets for SCLC is important. We obtained four microarray datasets from the Gene Expression Omnibus database and screened differentially expressed genes by two methods: batch correction and "RobustRankAggregation". After the establishment of a protein-protein interaction network through Cytoscape, seven hub genes (AURKB, BIRC5, TOP2A, TYMS, PCNA, UBE2C, and AURKA) with high expression in SCLC samples were obtained by eight CytoHubba algorithms. The Least Absolute Shrinkage and Selection Operator regression and the Wilcoxon test were used to analyze the differences in the immune cells' infiltration between normal and SCLC samples. The contents of seven kinds of immune cells were considered to differ significantly between SCLC samples and normal samples. A negative association was found between BIRC5 and monocytes in the correlation analysis between immune cells and the seven hub genes. The subsequent in vitro validation of experimental results showed that downregulating the expression of BIRC5 by siRNA can promote apoptotic activity of SCLC cells and inhibit their vitality, migration, and invasion. The use of BIRC5 inhibitor inhibited the vitality of SCLC cells and increased their apoptotic activity. BIRC5 may be a novel therapeutic target option for SCLC.

DOI： 10.1038/s41598-024-58454-4

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Ramucirumab plus docetaxel (RD) can cause febrile neutropenia (FN), which frequently requires the prophylactic administration of pegfilgrastim. However, the effects of prophylactic pegfilgrastim on FN prevention, therapeutic efficacy, and prognosis after RD have not been fully evaluated in patients with advanced non-small-cell lung cancer (NSCLC). Two hundred and eighty-eight patients with advanced NSCLC who received RD as second-line therapy after platinum-based chemotherapy plus PD-1 blockade were included. Patients were divided into groups with and without prophylactic pegfilgrastim, and adverse events, efficacy, and prognosis were compared between both groups. Of the 288 patients, 247 received prophylactic pegfilgrastim and 41 did not. The frequency of grade 3/4 neutropenia was 62 patients (25.1%) in the pegfilgrastim group and 28 (68.3%) in the control group (p < 0.001). The frequency of FN was 25 patients (10.1%) in the pegfilgrastim group and 10 (24.4%) in the control group (p = 0.018). The objective response rate was 31.2% and 14.6% in the pegfilgrastim and control groups (p = 0.039), respectively. The disease control rate was 72.9% in the pegfilgrastim group and 51.2% in the control group (p = 0.009). Median progression free survival was 4.3 months in the pegfilgrastim group and 2.5 months in the control group (p = 0.002). The median overall survival was 12.8 and 8.1 months in the pegfilgrastim and control groups (p = 0.004), respectively. Prophylactic pegfilgrastim for RD reduced the frequency of grade 3/4 neutropenia and febrile neutropenia and did not appear to be detrimental to patient outcome RD.Clinical Trial Registration Number: UMIN000042333.

DOI： 10.1038/s41598-024-54166-x

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A 73-year-old man with lung squamous cell carcinoma was administered carboplatin + nab-paclitaxel + pembrolizumab for four cycles. Subsequently, he presented with multiple purpuras on his extremities, joint swelling on his fingers, abdominal pain, and diarrhea, accompanied by acute kidney injury (AKI), increased proteinuria, hematuria, and elevated C-reactive protein levels. Skin biopsy showed leukocytoclastic vasculitis as well as IgA and C3 deposition in the vessel walls. Based on these findings, the patient was diagnosed with IgA vasculitis as an immune-related adverse event (irAE) induced by carboplatin + nab-paclitaxel + pembrolizumab. After discontinuation of pembrolizumab and glucocorticoids, the symptoms immediately resolved. Regular monitoring of skin, blood tests, and urinalysis are necessary, and the possibility of irAE IgA vasculitis should be considered in cases of purpura and AKI during treatment with immune checkpoint inhibitors.

DOI： 10.3389/fimmu.2024.1370972

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INTRODUCTION: Necitumumab plus gemcitabine and cisplatin (GCN) is a standard therapy for patients with advanced lung squamous cell carcinoma (LSqCC). However, the efficacy and tolerability of GCN in second-line or later treatment for patients previously treated with immune checkpoint inhibitors (ICIs) remain unknown. METHODS: This multicenter, retrospective, cohort study assessed the efficacy and tolerability of GCN initiated between November 1, 2019 and March 31, 2022 as second-line to fourth-line treatment in patients with advanced LSqCC who had been pretreated with ICIs. The primary end point was progression-free survival (PFS). RESULTS: A total of 93 patients from 35 institutions in Japan were enrolled. The median PFS, median overall survival (OS), and objective response rate were 4.4 months (95% confidence interval [CI]: 3.8-5.3), 13.3 months (95% CI: 9.6-16.5), and 27.3% (95% CI: 18.3-37.8), respectively. The median PFS, median OS, and objective response rate for second-line, third-line, and fourth-line treatment groups were 4.8 months, 3.8 months, and 4.3 months (p = 0.24); 15.7 months, 11.6 months, and 10.1 months (p = 0.06); and 31.0%, 13.6%, and 37.5% (p = 0.22), respectively. The severity of GCN-related skin disorders was associated with longer PFS (p < 0.05) and OS (p < 0.05). The frequencies of grade ≥3 skin disorders, hypomagnesemia, pneumonitis, and febrile neutropenia were 16.1%, 7.5%, 1.1%, and 4.3%, respectively. There were no treatment-related deaths. CONCLUSIONS: GCN for ICI-pretreated patients with LSqCC seems tolerable and offers promising efficacy regardless of treatment line, and ICI pretreatment might enhance GCN efficacy.

DOI： 10.1016/j.jtocrr.2023.100593

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BACKGROUND: Baseline tumor size (BTS) is one of the prognostic factors of advanced non-small cell lung cancer (NSCLC) treated with immunotherapy. However, its prognostic value in patients with locally advanced NSCLC receiving durvalumab maintenance therapy remains unclear. METHODS: The present study retrospectively reviewed 136 patients with unresectable stage III NSCLC who underwent CRT and durvalumab at two institutions in Japan. The maximum diameter of the target lesion (max BTS) before CRT was measured, the best response to CRT before durvalumab was evaluated, and the impact of the response on durvalumab was explored. Progression-free survival (PFS) and overall survival (OS) were defined as the time from the day of starting durvalumab. RESULTS: Of the total cohort, 133 (97.8%) patients had at least one measurable lesion. The best response to CRT resulting in CR, PR, and SD was seen in 0 (0%), 69 (51.9%), and 64 (48.1%) patients, respectively. PFS was significantly longer in the patients with PR than in those with SD after CRT (median not reached vs. 20.0 months; HR: 0.51; P = 0.023). Moreover, the absence of a massive lesion (max BTS < 50 mm) was associated with a superior CRT response (P < 0.001). CONCLUSION: The best response to induction CRT was associated with better PFS in patients with stage III NSCLC receiving durvalumab following chemoradiotherapy. Although the absence of a massive lesion was associated with a better response to induction CRT in this cohort, this was not translated into PFS and OS benefit.

DOI： 10.1007/s10147-023-02436-5

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INTRODUCTION: Pervious studies reported the association of TTF-1 expression with the efficacy of platinum-doublet chemotherapy in combination with immune checkpoint inhibitors in advanced nonsquamous NSCLC. Nevertheless, the predictive value of extent of TTF-1 expression (diffuse or focal TTF-1 positivity) remains unclear. METHODS: The present study retrospectively reviewed 74 patients with TTF-1-positive recurrent or advanced nonsquamous NSCLC receiving first-line chemoimmunotherapy in a single institution in Japan. TTF-1 expression score in pretreatment tumor specimens was evaluated using immunohistochemistry, and the impact of chemoimmunotherapy response was analyzed. RESULTS: In the total cohort, ≥50% of the tumor cells were TTF-1 positive (i.e., diffusely TTF-1 positive) in specimens of 61 patients (82.4%), whereas 10% to 49% of the tumor cells were TTF-1 positive (i.e., focally TTF-1 positive) in specimens of the remaining 13 patients (17.6%). In multivariate analysis, the median progression-free survival and overall survival (OS) were significantly longer in patients with diffusely TTF-1-positive tumors than in those with focally TTF-1-positive tumors (14.2 versus 9.2 mo, p = 0.01 and 30.2 versus 17.3 mo, p = 0.01, respectively). Moreover, the median OS was significantly longer in patients receiving chemoimmunotherapy including pemetrexed than in those receiving chemoimmunotherapy not including pemetrexed among the patients with diffusely TTF-1-positive tumors (not attained versus 23.2 mo, p < 0.01). CONCLUSIONS: The positive extent of diffuse TTF-1 expression associated with patient outcome was an independent predictive factor for better progression-free survival and OS in patients with advanced nonsquamous NSCLC receiving chemoimmunotherapy.

DOI： 10.1016/j.jtocrr.2023.100578

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Language：Japanese   Publisher：(有)科学評論社  

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BACKGROUND: The epidermal growth factor receptor (EGFR) mutation is a risk factor associated with brain metastases (BMs) in patients with non-small cell lung cancer (NSCLC). This study aimed to evaluate the impact of osimertinib early dose reduction on BM worsening. METHODS: We retrospectively analyzed EGFR-mutant NSCLC patients treated with osimertinib as first-line treatment between August 2018 and October 2021. To evaluate the impact of osimertinib early dose reduction, we performed a landmark analysis of patients who achieved disease control at 4 months. Patients were divided into two groups according to whether the osimertinib dose was reduced or not, within 4 months after the start of treatment. We evaluated the time to BMs onset or progression, progression-free survival, and overall survival. RESULTS: In total, 62 NSCLC patients with EGFR mutations were analyzed. Thirteen patients experienced early dose reduction of osimertinib treatment. Seven patients received osimertinib 40 mg daily, and six received 80 mg every other day. The most common reason for dose reduction was gastrointestinal toxicity (n = 4), followed by skin rashes (n = 3). The time to BMs onset or progression was significantly shorter in patients who experienced early dose reduction than in those who continued regular treatment (Hazard ratio 4.47, 95% confidence interval, 1.52-13.11). The 1-year cumulative incidence of BM onset or progression was 23.1% in the reduced-dose group and 5.0% in the standard dose group. The risk of worsening BMs with early dose reduction of osimertinib treatment was higher in patients who had BMs before treatment and in younger patients. CONCLUSION: Early dose reduction of osimertinib was a risk factor for the worsening of BMs. A higher risk was associated with younger patients and those presenting BMs before treatment.

DOI： 10.1002/cam4.6393

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Most multigene mutation tests require tissue specimens. However, cytological specimens are easily obtained in the clinical practice and provide high-quality DNA and RNA. We aimed to establish a test that utilizes cytological specimens and performed a multi-institutional study to investigate the performance of MINtS, a test based on next-generation sequencing. A standard procedure for specimen isolation was defined. The specimens were considered suitable for the test if >100 ng DNA and >50 ng RNA could be extracted from them. In total, 500 specimens from 19 institutions were investigated. MINtS detected druggable mutations in 63% (136 of 222) of adenocarcinomas. Discordant results between MINtS and the companion diagnostics were observed in 14 of 310 specimens for the EGFR gene, and 6 of 339 specimens for the ALK fusion genes. Confirmation by other companion diagnostics for the EGFR mutations or the clinical response to an ALK inhibitor all supported the results obtained by MINtS. MINtS along with the isolation procedure presented in the current study will be a platform to establish multigene mutation tests that utilize cytological specimens. UMIN000040415.

DOI： 10.1111/cas.15831

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PURPOSE: Vascular endothelial growth factor (VEGF) inhibitors are widely used in chemotherapy for non-small lung cancer (NSCLC). The purpose of the current study was to examine the impact of background cardiovascular risk factors on VEGF inhibitor-related adverse vascular events (VEGF-related AVEs) in patients with NSCLC who also had comorbidities. METHODS: We conducted a retrospective study of 118 NSCLC patients treated with bevacizumab or ramucirumab from April 2010 to December 2022. We compared baseline cardiovascular risk factors with VEGF-related AVEs. RESULTS: VEGF-related AVEs and discontinuation due to VEGF-related AVEs were reported in 54 patients and 21 patients, respectively. VEGF-related AVEs were significantly more common with male sex, smoking history, history of hypertension, dyslipidemia, diabetes mellitus, or cardiovascular disease. Discontinuation due to VEGF-related AVEs was significantly more common in patients with history of hypertension or chronic kidney disease. VEGF-related AVEs were significantly more common in patients with ≥ 3 cardiovascular risk factors than patients with < 3. Discontinuation due to VEGF-related AVEs was significantly more common in patients with ≥ 4 cardiovascular risk factors than patients with < 4. Multivariate analysis demonstrated that male sex, hypertension, and ≥ 6 cycles of VEGF inhibitors were each associated with VEGF-related AVEs and hypertension was associated with discontinuation due to VEGF-related AVEs. CONCLUSION: Our study demonstrated that history of hypertension was independently associated with increased risk of both VEGF-related AVEs and discontinuation due to VEGF-related AVEs. In conclusion, we need to be aware of VEGF-related AVEs when using VEGF inhibitors for patients with ≥ 3 cardiovascular risk factors.

DOI： 10.1007/s00432-023-05092-4

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BACKGROUND: Ferroptosis is an iron-dependent programmed cell death mode induced by the toxic buildup of phospholipid peroxidation. Although it is known to affect the initiation and growth of tumors, the association between ferroptosis-related genes (FRGs) and small cell lung cancer (SCLC) has yet to be established. METHODS: We used the gene expression omnibus (GEO) and ferroptosis database (FerrDb) to acquire information on SCLC and its associated FRGs. Marker genes were subsequently identified using Least Absolute Shrinkage and Selection Operator (LASSO) and support vector machine recursive feature eilmination (SVM-RFE) algorithms and analyzed for single-gene function and pathway enrichment. Using the drug-gene interaction database (DGIdb), we identified forty drugs targeting six marker genes. The competing endogenous RNA (ceRNA) network revealed the regulation pattern for long non-coding RNA (LncRNA)-microRNA (miRNA)-messenger RNA (mRNA) based on marker genes. RESULTS: Six differentially expressed FRGs (ATG3, MUC1, RRM2, IDH2, PARP1, and EZH2) were identified as marker genes with accurate diagnostic capabilities. According to single-gene function and pathway enrichment analyses, these marker genes may be involved in immunomodulation and the cell cycle, as well as numerous pathways connected to tumorigenesis, including the JAK-STAT and PPAR signal pathways. In addition, CIBERSORT analysis showed that MUC1 and PARP1 expression may affect the immune microenvironment in SCLC. CONCLUSIONS: We confirmed the accuracy of marker genes for the diagnosis of SCLC using a logistic regression model, thus providing further opportunities to study SCLC-related mechanisms. The accuracy of these results for the diagnosis of SCLC must now be confirmed by further research prior to clinical application.

DOI： 10.31083/j.fbl2806125

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BACKGROUND: Amrubicin (AMR) is one of the most active agents for small-cell lung cancer (SCLC). However, hematologic toxicity and infection at a commonly used dose (40 mg/m2) is problematic; the optimal dose remains undetermined. PATIENTS AND METHODS: To evaluate the optimal dose of AMR in terms of efficacy and safety, we reviewed consecutive data on patients with relapsed SCLC who received AMR at doses of 40, 35, and 30 mg/m2 (on days 1-3) at Nippon Medical School Hospital between October 2010 and November 2021. RESULTS: We reviewed the data of 86 patients (20, 45, 27 who received AMR doses of 40, 35, 30 mg/m2, respectively) according to our study criteria. For patients  ≥ 75 years, the proportion who received second-line treatment tended to be higher in the 30-35 mg/m2 group. Objective response rates were 37/46/35%, median progression-free survival (PFS) were 3.0/4.7/3.2 months, and median overall survival (OS) were 7.8/16.3/8.0 months, respectively. Grade 4 neutropenia occurred in 58/39/31% of patients, which was higher for the 40 mg/m2 group. The incidence of febrile neutropenia did not differ between groups. Multivariate analysis identified the AMR dose was not associated with longer PFS and OS. CONCLUSION: Treatment with AMR between 30 and 35 mg/m2 showed relatively mild hematologic toxicity compared with AMR at 40 mg/m2, without any significant difference in efficacy. Lower dose of AMR for relapsed SCLC could be a promising treatment option.

DOI： 10.1007/s10147-023-02343-9

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BACKGROUND: Ramucirumab plus docetaxel (RD) is a promising treatment for previously treated advanced non-small cell lung cancer (NSCLC). However, its clinical significance after platinum-based chemotherapy plus programmed death-1 (PD-1) blockade remains unclear. RESEARCH QUESTION: What is the clinical significance of RD as a second-line treatment after the failure of chemo-immunotherapy in NSCLC? STUDY DESIGN AND METHODS: In this multicentre retrospective study, 288 patients with advanced NSCLC who received RDas second-line therapy after platinum-based chemotherapy plus PD-1 blockade, at 62 Japanese institutions from January 2017 to August 2020, were included. Prognostic analyses were performed using the log-rank test. Prognostic factor analyses were performed using a Cox regression analysis. RESULTS: A total of 288 patients were enrolled: 222 were men (77.1%), 262 were aged <75 years (91.0%), 237 (82.3%) had smoking history and 269 (93.4%) had a performance status (PS) of 0-1. One hundred ninety-nine patients (69.1%) were classified as adenocarcinoma (AC) and 89 (30.9%) as non-AC. The types of PD-1 blockade used in the first-line treatment were anti-PD-1 antibody and anti-programmed death-ligand 1 antibody in 236 (81.9%) and 52 (18.1%) patients, respectively. The objective response rate for RD was 28.8% (95% confidence interval [CI], 23.7-34.4). The disease control rate was 69.8% (95% CI, 64.1-75.0).The median progression free survival and overall survival were 4.1 months (95% CI, 3.5-4.6) and 11.6 months (95% CI, 9.9-13.9), respectively. In a multivariate analysis, non-AC and PS 2-3 were independent prognostic factors for worse progression free survival , while bone metastasis on diagnosis, PS 2-3 and non-AC were identified as independent prognostic factors for poor overall survival. INTERPRETATION: RD is a feasible second-line treatment in patients with advanced NSCLC who had received combined chemo-immunotherapy with PD-1 blockade. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000042333.

DOI： 10.1016/j.ejca.2023.01.025

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BACKGROUND: Platinum-based combination therapy plus a programmed cell death 1/programmed cell death ligand 1 (PD-1/PD-L1) inhibitor is a standard treatment for patients with stage IV non-small cell lung cancer. However, necitumumab is used with gemcitabine and cisplatin as a first-line treatment option for squamous cell lung cancer (SqCLC). Furthermore, the combination of necitumumab with immune checkpoint inhibitors has the potential to enhance tumor immunity and improve the therapeutic effect. Thus, we planned and initiated this phase I/II study to evaluate the safety and efficacy of necitumumab plus pembrolizumab, nanoparticle albumin-bound (nab)-paclitaxel), and carboplatin therapy for patients with previously untreated SqCLC. PATIENTS AND METHODS: In phase I, the primary endpoint is the tolerability and recommended dose of necitumumab combined with pembrolizumab plus nab-paclitaxel and carboplatin. In phase II, the primary endpoint is the overall response rate. Secondary endpoints are disease control rate, progression-free survival, overall survival, and safety. Forty-two patients will be enrolled in phase II. CONCLUSION: This is the first study to investigate the efficacy and safety of necitumumab plus pembrolizumab combined with platinum-based chemotherapy in patients with previously untreated SqCLC.

DOI： 10.1016/j.cllc.2023.01.008

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BACKGROUND: Versatile biomarkers for immune checkpoint inhibitors (ICI) efficacy in patients with cancer remain to be identified. Liquid biopsy using serum-derived exosomal microRNAs (miRNAs) are widely investigated as diagnostic and therapeutic outcome predictors in patients with cancer. However, exosomal miRNAs linked to the response to ICI in patients with non-small cell lung cancer (NSCLC) remain elusive thus far. METHODS: The value of serum-derived exosomal miRNAs in predicting the effect of anti-programmed cell death-1 (PD-1)/anti-programmed cell death-ligand 1 (PD-L1) monotherapy in 41 patients with advanced NSCLC was assessed. We performed functional analysis of candidate miRNAs using NSCLC cell lines. RESULTS: Exosomal miR-125a-3p was associated with response to treatment with ICI. Exosomal miR-125a-3p was more useful in predicting response to ICI versus tumoral PD-L1 in patients with low PD-L1 expression (≤50%). Moreover, high expression of miR-125a-3p was associated with worse progression-free and overall survival. In H1975 and H441 cells, induction of miR-125a-3p regulated PD-L1 expression via suppression of neuregulin 1 (NRG1). CONCLUSIONS: Exosomal miR-125a-3p is a potential predictor of response to anti-PD-1/PD-L1 therapy in advanced NSCLC patients with low PD-L1 expression.

DOI： 10.1016/j.gene.2023.147177

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Alectinib is a selective anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitor as standard therapy for ALK-rearranged non-small cell lung cancer (NSCLC). Hemolytic anemia is considered as a rare but significant adverse event with alectinib. Here, we report a case of a 73-year-old female with lung adenocarcinoma, harbouring an ALK fusion gene, who received alectinib as second-line therapy and developed gradually progressive grade 4 (6.4 g/dL) drug-induced hemolytic anemia (DIHA) after complete response. We discontinued alectinib and performed a blood transfusion for the severe anemia. The anemia improved with no recurrence of lung adenocarcinoma over 10 months. Regular hematologic monitoring and the possibility of DIHA should be considered in case of progressive hemolytic anemia during alectinib treatment.

DOI： 10.2147/OTT.S398375

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Anaplastic lymphoma kinase-positive (ALK-positive) lung adenocarcinoma with multiple liver metastases accounts for a relatively small number of cases of non-small cell lung cancer. Several ALK-tyrosine kinase inhibitors (ALK-TKIs) are available for the treatment of lung cancer. However, there is limited evidence on the treatment of multiple liver metastases in patients with lung cancer that are refractory to ALK-TKIs. We report the case of a 42-year-old male patient with ALK-positive lung adenocarcinoma who experienced rapid progression to multiple liver metastases while receiving treatment with alectinib. Biopsy of the liver metastases revealed echinoderm microtubule-associated protein-like 4-ALK (EML4-ALK) fusion and tumor protein p53 (TP53) mutation; notably, ALK secondary mutations were not detected. Despite the sequential administration of third-generation ALK-TKIs, the liver metastases did not respond, the serum levels of total bilirubin and biliary enzymes continued to increase, and the patient's general appearance worsened. Finally, the patient exhibited a remarkable clinical response to treatment with a combination of atezolizumab, bevacizumab, carboplatin, and paclitaxel (ABCP). ABCP is one of the optimal options for ALK-positive lung cancer with liver metastasis that is refractory to ALK-TKIs therapy.

DOI： 10.2147/OTT.S404035

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：TAYLOR & FRANCIS LTD  

Some of the most common causes of chronic cough include cough variant asthma (CVA), bronchial asthma (BA), and asthma-COPD overlap (ACO). Although there is some overlap in the etiology of these diseases, it is clinically important to attempt an early differential diagnosis due to treatment strategies and prognoses. Spirometry and impulse oscillometry (IOS) before and after bronchodilator inhalation were analyzed for clinically diagnosed CVA (cCVA, n = 203), BA (cBA, n = 222), and ACO (cACO, n = 61).A significant difference in ΔFEV1 was observed between cBA and cCVA (ΔFEV1 improvement of 122.5 mL/5.4% and 65.7mL/2.2%, respectively), but no difference was observed in ΔPEF, ΔV50, or ΔV25. Except for R20 (resistance at 20 Hz), significant differences between the three groups were observed in IOS. In IOS, cCVA and cBA showed comparable peripheral airway response to bronchodilator which was thought to be commensurate with changes in V50 and V25. cACO improved ΔFEV1 improvement of 81.0 mL/6.2% and was distinguished by a downward Xrs (respiratory system reactance) waveform with a limited bronchodilator response. FEV1/FVC, %FEV1, and %V25 had relatively strong correlations with the three IOS parameters, X5 (reactance at 5 Hz), Fres (resonant frequency), and ALX (low-frequency reactance area), in the correlation between IOS and spirometers.Changes in IOS parameters were more sensitive in this study than changes in FEV1 or the flow-volume curve. Considering the benefits and relevance of the two different tests, simultaneous IOS and spirometry testing were useful in the diagnosis of asthmatic cough.

DOI： 10.1080/02770903.2022.2094803

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BACKGROUND: Small cell lung cancer (SCLC) is a highly aggressive disease with a poor prognosis. Although most patients initially respond to topoisomerase inhibitors, resistance rapidly emerges. The aim, therefore, is to overcome resistance to topoisomerase I (irinotecan) or II (etoposide) inhibitors in SCLCs. METHODS: To identify key factors in the chemoresistance of SCLCs, we established four cell lines resistant to etoposide or an active metabolite of irinotecan, SN-38, from SCLC cell lines and evaluated RNA profiles using parental and newly established cell lines. RESULTS: We found that the drug efflux protein, ATP-binding cassette sub-family B member 1 (ABCB1), was associated with resistance to etoposide, and ATP-binding cassette sub-family G member 2 (ABCG2) was associated with resistance to SN-38 by RNA sequencing. The inhibition of ABCB1 or ABCG2 in each resistant cell line induced synergistic apoptotic activity and promoted drug sensitivity in resistant SCLC cells. The ABC transporter inhibitors, elacridar and tariquidar, restored sensitivity to etoposide or SN-38 in in vitro and in vivo studies, and promoted apoptotic activity and G2-M arrest in resistant SCLC cells. CONCLUSIONS: ABC transporter inhibitors may be a promising therapeutic strategy for the purpose of overcoming resistance to topoisomerase inhibitors in patients with SCLC.

DOI： 10.1111/1759-7714.14527

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BACKGROUND: Research has shown that some microbiomes are linked to cancer. Hence, we hypothesize that alterations in the respiratory microbiome might be associated with lung cancer. METHODS: Through droplet digital polymerase chain reaction analysis, we investigated the abundance of Acidovorax in surgically resected primary tumors and corresponding nontumor lung tissues obtained from 50 Japanese patients with non-small cell lung cancer. RESULTS: The rate of positivity for Acidovorax in tumor and nontumor tissues was 44 and 26%, respectively. The abundance of Acidovorax in tumor tissues was significantly higher in patients with nonsquamous cell carcinoma complicated by chronic obstructive pulmonary disease (COPD) and those who relapsed after surgical resection (p < 0.05). In tumor tissues, the results of the univariate and multivariate analyses revealed that only COPD exerted a direct effect on the abundance of Acidovorax (p < 0.05). Furthermore, the presence of Acidovorax was high in lung cancer patients with COPD comorbidity (65%) and TP53 gene mutation; only one of the nontumor tissues was positive for Acidovorax. In patients with lung cancer complicated by COPD, Acidovorax tended to be present in both the tumor and nontumor areas. CONCLUSIONS: This study identified novel microbiota involved in lung cancer with COPD comorbidity. The results suggested that Acidovorax may be a useful biomarker in the screening for lung cancer. Further studies are warranted to validate the clinical significance of the microbiome in a larger independent patient cohort.

DOI： 10.1111/1759-7714.14463

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BACKGROUND: Although corticosteroids are expected to be a candidate therapy for coronavirus disease 2019 (COVID-19) through the suppression of cytokine production, the efficacy in non-severe patients who do not require supplemental oxygen remains controversial. The aim of this study was to investigate the efficacy of corticosteroid therapy for non-severe patients. METHODS: We performed a retrospective observational study for 10 patients with non-severe COVID-19 who received corticosteroid therapy at our institute between July 1, 2020, and January 31, 2021. RESULTS: The median age of the 10 patients was 60 years, and nine patients were male. Nine of the 10 patients had multiple comorbid conditions (e.g., hypertension, diabetes and obesity). Although blood oxygen saturation was maintained above 95%, all patients showed persistent fever and deterioration of their chest imaging findings. Thus, we decided to initiate corticosteroid treatment. The median duration from the onset of symptoms to the initiation of corticosteroid therapy was eight days. All patients used dexamethasone (6 mg/day) as corticosteroid therapy, and the median period was 7.5 days. After the start of corticosteroid therapy, all patients showed a rapid clinical improvement, and no patients showed severe progression. CONCLUSION: The latest World Health Organization guidance recommends against corticosteroid treatment for non-severe patients. In this report, we showed that the early administration of corticosteroids during the non-critical phase, when oxygen supplementation is not required, was useful for the early improvement and prevention of severe disease in patients with risk factors for severe COVID-19 and worsening clinical symptoms.

DOI： 10.1272/jnms.JNMS.2022_89-409

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Thymic carcinoma is a relatively rare type of malignant tumor. The present retrospective study evaluated the efficacy and safety of carboplatin plus nanoparticle albumin-bound paclitaxel for the treatment of advanced thymic carcinoma. The study included data from 12 patients with advanced thymic carcinoma treated in the Nippon Medical School Hospital (Tokyo, Japan). Response to treatment, patient survival and treatment safety were assessed. The objective response rate was 66.7% (8/12 patients). Disease control was achieved in 11 patients (91.7%). At the median follow-up time of 27.6 months (range, 6.2-75.1 months), the median progression-free survival and median first-line overall survival times were 16.7 months [95% confidence interval (CI), 13.2-37.7] and 14.3 months (95% CI, 4.7-54.6), respectively. There was no occurrence of febrile neutropenia or treatment-related death. The results of the present study showed that carboplatin plus nanoparticle albumin-bound paclitaxel was effective and safe. Therefore, it is a promising chemotherapy regimen for the treatment of advanced thymic carcinoma.

DOI： 10.3892/mco.2022.2520

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Pembrolizumab is an immune checkpoint inhibitor (ICI) that targets programmed death-1. Although ICIs have shown efficacy in the treatment of lung cancer, they have also been reported to cause a variety of immune-related adverse events (irAEs). Hepatotoxicity is a known irAEs, but currently, there is not enough information on its pathological characteristics and treatment. We report the case of a 70-year-old man with advanced squamous-cell lung cancer who developed severe grade 4 hepatitis on day 8 after receiving carboplatin, nab-paclitaxel, and pembrolizumab as fourth-line therapy. We treated him with steroid therapy the day after a liver biopsy was performed to investigate his pathological features, which led to a rapid and remarkable improvement. Confirmation of immune-related hepatotoxicity by pathological findings allowed the early tapering and discontinuation of steroid therapy. Performing a liver biopsy and verifying histological characteristics are needed for successful treatment with short-term steroids when drug-induced hepatitis caused by anti-cancer therapy including pembrolizumab is considered.

DOI： 10.2147/OTT.S361467

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Background: Chromosomal inversions involving anaplastic lymphoma kinase (ALK) and echinoderm microtubule associated protein like 4 (EML4) generate a fusion protein EML4-ALK in non-small cell lung cancer (NSCLC). The understanding of EML4-ALK function can be improved by a functional study using normal human cells. Methods: Here we for the first time conduct such study to examine the effects of EML4-ALK on cell proliferation, cellular senescence, DNA damage, gene expression profiles and transformed phenotypes. Results: The lentiviral expression of EML4-ALK in mortal, normal human fibroblasts caused, through its constitutive ALK kinase activity, an early induction of cellular senescence with accumulated DNA damage, upregulation of p16INK4A and p21WAF1, and senescence-associated β-galactosidase (SA-β-gal) activity. In contrast, when EML4-ALK was expressed in normal human fibroblasts transduced with telomerase reverse transcriptase (hTERT), which is activated in the vast majority of NSCLC, the cells showed accelerated proliferation and acquired anchorage-independent growth ability in soft-agar medium, without accumulated DNA damage, chromosome aberration, nor p53 mutation. EML4-ALK induced the phosphorylation of STAT3 in both mortal and hTERT-transduced cells, but RNA sequencing analysis suggested that the different signaling pathways contributed to the different phenotypic outcomes in these cells. While EML4-ALK also induced anchorage-independent growth in hTERT-immortalized human bronchial epithelial cells in vitro, the expression of EML4-ALK alone did not cause detectable in vivo tumorigenicity in immunodeficient mice. Conclusions: Our data indicate that the expression of hTERT is critical for EML4-ALK to manifest its in vitro transforming activity in human cells. This study provides the isogenic pairs of human cells with and without EML4-ALK expression.

DOI： 10.1186/s12885-021-07905-6

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Language：Japanese   Publisher：(NPO)日本肺癌学会  

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Background/Aim: Pulmonary pleomorphic carcinoma (PPC) is a rare and aggressive tumor that is resistant to treatment. The expression and prognostic value of programmed cell death-ligand 1 (PD-L1) and its association with epithelial mesenchymal transition (EMT) in PPC remains unclear. Patients and Methods: The expression of PD-L1 and EMT markers, such as E-cadherin, vimentin, zinc finger E-boxbinding homeobox 1 (ZEB-1), and cellular mesenchymal epithelial transition (c-Met) was evaluated by immuno-histochemistry in 16 patients with PPC who underwent surgical resection. Results: The expression of PD-L1 varied between carcinomatous and sarcomatous areas. Positive correlations between PD-L1 and vimentin expression in carcinomatous areas (r=0.668, p=0.005) and PD-L1 and ZEB-1 expression in sarcomatous areas (r=0.562, p=0.023) were found. High PD-L1 and ZEB-1 expression in sarcomatous areas predicted poor survival (p=0.045 and p=0.012, respectively). Conclusion: PD-L1 expression associated with ZEB1 expression in the sarcomatoid component of patients with PPC may be useful for predicting patient prognosis.

DOI： 10.21873/ANTICANRES.15028

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Language：Japanese   Publisher：(一社)日本呼吸器学会  

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Osimertinib is the standard treatment for epidermal growth factor receptor (EGFR)-mutant non-small-cell lung cancer. However, drug-induced interstitial lung disease (ILD) is recognized as a serious adverse event associated with EGFR-tyrosine kinase inhibitors (TKIs). We herein report a 78-year-old woman with stage IV lung adenocarcinoma harboring an EGFR L858R mutation on exon 21 who received rechallenge treatment with afatinib after osimertinib-induced ILD with an organizing pneumonia pattern. This is the first report of successful rechallenge with afatinib after osimertinib-induced ILD. Treatment with other EGFR-TKIs after osimertinib-induced ILD may be an option for subsequent therapy.

DOI： 10.2169/internalmedicine.5435-20

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Antibody-drug conjugate (ADC) was novel type of anticancer drugs. Trastuzumab deruxtecan (T-DXd), a human epidermal growth factor receptor 2 (HER2) targeting ADC, can be a novel treatment option for HER2 alternation (mutation, expression, amplification) advanced-stage non-small-cell lung cancer (NSCLC) from DESTINY-Lung01 result. Herein, we report a successful treatment with T-DXd for NSCLC harboring HER2 exon 20 insertion mutation in a patient with poor performance status (PS). We presented a case of a 52-year-old heavily pretreated female patient diagnosed with lung adenocarcinoma (cT1bN3M0, stage IIIB). After fifth-line pretreatment of systemic chemotherapy, primary tumor recurrence, pleural effusion, and miliary lung metastases were observed. The patient presented with hypoxia requiring oxygen therapy via nasal cannula at a flow rate of 4 L per minute, cancer pain, and cachexia requiring opioid treatment. Her Eastern Cooperative Oncology Group PS score was assessed 3. Comprehensive genomic profiling revealed HER2 exon 20 insertion mutation. After treatment with T-DXd was approved by the ethical review committee of Nippon Medical School Hospital, treatment was started. The tumor size decreased significantly, and her PS score decreased from 3 to 1, with improvement of hypoxia, cancer pain, and cachexia. The patient is still receiving treatment, without disease progression 6 months after starting treatment with T-DXd. Despite cases of poor PS, NGS should be performed and target therapy including ADCs should be considered.

DOI： 10.2147/OTT.S341290

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Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2020-3068

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DOI： 10.1158/1538-7445.AM2020-5892

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Background: Pleurodesis is the standard of care for non-small cell lung cancer (NSCLC) patients with symptomatic malignant pleural effusion (MPE). However, there is no standard management for MPE uncontrolled by pleurodesis. Most patients with unsuccessful MPE control are unable to receive effective chemotherapy. Vascular endothelial growth factor (VEGF) plays an important role in the pathogenesis of MPE. This multicenter, phase II study investigated the effects of bevacizumab plus chemotherapy in nonsquamous NSCLC patients with unsuccessful management of MPE. Methods: Nonsquamous NSCLC patients with MPE following unsuccessful tube drainage or pleurodesis received bevacizumab (15 mg/kg) plus chemotherapy every three weeks. The primary endpoint was pleural effusion control rate (PECR), defined as the percentage of patients without reaccumulation of MPE at eight weeks. Secondary endpoints included pleural progression-free survival (PPFS), safety, and quality of life (QoL). Results: A total of 20 patients (median age: 69 years; 14 males; 20 adenocarcinomas; six epidermal growth factor receptor mutations) were enrolled in nine centers. The PECR was 80% and the primary end point was met. The PPFS and the overall survival (OS) were 16.6 months and 19.6 months, respectively. Patients with high levels of VEGF in the MPE had shorter PPFS (P = 0.010) and OS (P = 0.002). Toxicities of grade ≥ 3 included neutropenia (50%), thrombocytopenia (10%), proteinuria (10%), and hypertension (2%). The cognitive QoL score improved after treatment. Conclusions: Bevacizumab plus chemotherapy is highly effective with acceptable toxicities in nonsquamous NSCLC patients with uncontrolled MPE, and should be considered as a standard therapy in this setting. Key points: Significant findings of the study: Bevacizumab plus chemotherapy is highly effective with acceptable toxicities in nonsquamous NSCLC patients with uncontrolled MPE. What this study adds: Bevacizumab plus chemotherapy should be considered as a standard treatment option for patients with uncontrolled MPE. Clinical trial registration: UMIN000006868 was a phase II study of efficacy of bevacizumab plus chemotherapy for the management of malignant pleural effusion (MPE) in nonsquamous non-small cell lung cancer patients with MPE unsuccessfully controlled by tube drainage or pleurodesis (North East Japan Study Group Trial NEJ-013B) (http://umin.sc.jp/ctr/).

DOI： 10.1111/1759-7714.13472

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：ELSEVIER IRELAND LTD  

Introduction: The majority of pulmonary carcinoid (PC) tumors can be cured by surgical resection alone, but a significant proportion of patients experience recurrence. As PC is insensitive to conventional chemotherapy, further clarification of the molecular mechanisms of metastasis is needed in order to develop targeted therapeutics. Methods: We performed comprehensive whole-exome sequencing (WES) of primary tumors and corresponding normal lung tissues from 14 PC patients (including 4 patients who developed postsurgical distant metastasis) and RNA sequencing of primary tumors from 6 PC patients (including 4 patients who developed postsurgical distant metastasis). Exon array-based gene expression analysis was performed in 25 cases of PC. Results: We identified a total of 139 alterations in 136 genes. MUC6 and SPTA1 were recurrently mutated at a frequency of 21% (3/14) and 14% (2/14), respectively. Mucin protein family genes including MUC2, MUC4 and MUC6 were mutated in a mutually exclusive manner in 36% (5/14). Pathway analysis of the mutated genes revealed enrichment of genes involved in mitogen-activated protein kinase (MAPK) signaling, regulation of the actin cytoskeleton and focal adhesion, and transforming growth factor (TGF)-β signaling. RNA sequencing revealed a total of 8 novel fusion transcripts including one derived from a chromosomal translocation between the TRIB2 and PRKCE genes. All of the 8 fusion genes were detected in primary PCs that had developed metastasis after surgical resection. We identified 14 genes (DENND1B, GRID1, CLMN, DENND1B, NRP1, SEL1L3, C5orf13, TNFRSF21, TES, STK39, MTHFD2, OPN3, MET, and HIST1H3C) up-regulated in 5 PCs that had relapsed after surgical resection. Conclusions: In this study we identified novel somatic mutations and chromosomal rearrangements in PC by examining clinically aggressive cases that had developed postsurgical metastasis. It will be essential to validate the clinical significance of these genetic changes in a larger independent patient cohort.

DOI： 10.1016/j.lungcan.2020.03.027

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BACKGROUND: The participation of patients in the decision-making process related to their treatment is strongly recommended. This study was conducted to develop and evaluate a support tool that can help patients make decisions related to their own treatment. METHODS: Twenty cancer patients who were hospitalized for first line treatment were enrolled on the study. Before hospitalization, a 'Check sheet on treatment selection', which contained 14 questions, was distributed to patients and/or their families. After hospitalization, the attending physician explained the treatment while referring to the written check sheet. Also, at the time of discharge, the patients's responses to the 'Questionnaire on check sheet and treatment selection' were collected in order to evaluate the utility of the check sheet. Finally, the 'Questionnaire of the check sheet' was handed to the attending physician to evaluate. RESULTS: Of the fourteen patients who responded to the questionnaire, all indicated that the check sheets were helpful for decision-making, and that using the sheets empowered them to ask their doctors questions. Only one person felt uncomfortable with compiling the check sheet.Physicians stated that the check sheet facilitated patient decision-making and improved communication with patients. However, there was an opinion that this activity increased the administrative burden of medical professionals. CONCLUSION: Almost all patients stated that the check sheet used in this study was useful as a decision support tool, and also facilitated the communication between doctors and patients. Before incorporation into general clinical practice, this increased benefit should be weighed against the potential extra administrative workload imposed on clinicians.

DOI： 10.1272/jnms.JNMS.2021_88-401

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Background: Interstitial lung disease (ILD) induced by immune checkpoint inhibitors (ICIs) is a potentially life-threatening adverse event. The purpose of this study was to evaluate whether the development of immune-related adverse events (irAEs), especially ILD, was associated with treatment efficacy and to research the features and risk factors of ILD in advanced non-small cell lung cancer (NSCLC). Methods: Between December 2015 and November 2018, 130 advanced NSCLC patients were treated with nivolumab, pembrolizumab or atezolizumab. The patients were categorized into two groups (irAEs group or non-irAEs group). Subsequently, we divided the irAEs group into two groups based on the incidence of ILD (ILD group and irAEs-non-ILD group). Treatment efficacy and the characteristics of ILD were evaluated. Results: A total of 39 (30%) patients developed irAEs. ILD was observed in 16 (12%) patients. Patients with ILD had a higher objective response rate (ORR) compared with irAEs-non-ILD patients and non-irAEs patients (63%, 43% and 22%, respectively). Median progression-free survival (mPFS) was 15.9 months in ILD patients, 5.4 months in irAEs-non-ILD patients and 3.3 months in non-irAEs patients (log-rank test, P = 0.033). Pre-existing interstitial pneumonia (IP) was an independent risk factor for ILD-induced ICIs (odds ratio [OR] 14.7; 95% confidence interval [CI]: 2.16–99.6, P = 0.006). Conclusions: ORR and PFS were significantly better in ILD patients than in irAEs-non-ILD and non-irAEs patients. Pre-existing history of IP was an independent risk factor for ILD-induced ICIs.

DOI： 10.1111/1759-7714.13364

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

The total RSK immunoblot in HUH-6 cells in Fig. 3A as well as the total S6K1 immunoblot in JHH1 cells and p-S6K1 immunoblot in JHH-2 cells in Fig. 3C were inadvertently duplicated. These errors have now been corrected and do not affect the results or conclusions of this work. The authors wish to express their sincere apology to the editors and readers of Molecular & Cellular Proteomics for any confusion or inconvenience.

DOI： 10.1074/mcp.AAC119.001903

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Background: S-1 plus cisplatin is a standard chemotherapy regimen for advanced non-small cell lung cancer (NSCLC). The addition of bevacizumab has been shown to significantly improve overall survival (OS) in patients with advanced non-squamous (NSq) NSCLC who received carboplatin plus paclitaxel, however, failed to show an OS advantage in patients who received cisplatin plus gemcitabine. Methods: Chemotherapy-naive patients with Stage IIIB, IV or recurrent non-SQ NSCLC were treated with a 3-week cycle of S-1 80 mg/m2 on days 1–14, cisplatin 60 mg/m2 on day 8 and bevacizumab 15 mg/kg on day 8 for 4–6 cycles. Patients without progressive disease (PD) received maintenance bevacizumab 15 mg/kg on day 1 with a 3-week cycle and S-1 80 mg/m2 every other day. The primary endpoint was progression-free survival (PFS). Secondary endpoints were objective response rate (ORR), OS, toxicity profile and Quality of life (QOL). Results: From June 2013 to January 2015, 39 eligible patients were enrolled from eight institutions. Thirty-one patients (79%) completed four cycles of induction chemotherapy, and maintenance chemotherapy was initiated in 23 patients (59%). Median PFS, OS and ORR were 7.3 months (95% CI: 5.9–8.7), 21.4 months (95% CI: 14.7—not reached) and 64%, respectively. The most common grade 3/4 toxicities were leukopenia (12.8%), neutropenia (23.0%) and hypertension (28.2%). QOL analyses showed detrimental effects after initiation of the regimen. Conclusions: S-1 plus cisplatin in combination with bevacizumab met the primary endpoint in patients with advanced NSq-NSCLC. RR was anticipated to be high with acceptable toxicities.

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DOI： 10.1158/1538-7445.AM2019-1602

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DOI： 10.1158/1538-7445.AM2019-4648

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DOI： 10.1158/1538-7445.SABCS18-3806

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Background Nanoparticle albumin-bound paclitaxel is indicated for the treatment of patients with lung cancer. It can induce interstitial lung disease, but the incidence of nanoparticle albumin-bound paclitaxel-associated interstitial lung disease in clinical practice has not been determined. We investigated the incidence of interstitial lung disease in patients with lung cancer who had received nanoparticle albumin-bound paclitaxel therapy at our institution. Methods We reviewed clinical data for patients with advanced lung cancer who received nanoparticle albumin-bound paclitaxel with or without carboplatin or bevacizumab therapy at the Nippon Medical School Main Hospital between April 2013 and September 2017. Interstitial lung disease was diagnosed based on clinical symptoms, radiographic findings and exclusion of other diseases. Results A total of 110 advanced lung cancer patients received nanoparticle albumin-bound paclitaxel, and nine of them (8.2%) developed interstitial lung disease. Of those who developed interstitial lung disease, eight were treated with corticosteroids and three received cyclophosphamide pulse therapy. High-resolution computed tomography images demonstrated diffuse alveolar damage pattern pneumonitis in seven patients and organized pneumonia pattern pneumonitis in two patients. Six of the patients with diffuse alveolar damage pattern pneumonitis died from respiratory failure. The two patients with organized pneumonia pattern pneumonitis recovered. The incidence of interstitial lung disease was 19.0% (8/42) among patients with preexisting interstitial pneumonia and 1.5% (1/68) among those without preexisting interstitial pneumonia. Six patients with preexisting interstitial pneumonia met the criteria for acute exacerbation of interstitial pneumonia (14.3%). Conclusion Nanoparticle albumin-bound paclitaxel-associated interstitial lung disease was a severe and potentially fatal adverse event. We found it demonstrated diffuse alveolar damage or organized pneumonia pattern pneumonitis, and preexisting interstitial pneumonia was associated with higher rate of nanoparticle albumin-bound paclitaxel-associated interstitial lung disease.

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DOI： 10.1007/978-981-13-7295-7_10

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DOI： 10.1158/1557-3265.AACRIASLC18-PR07

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Anaplastic lymphoma kinase tyrosine kinase inhibitors (ALK-TKIs) induce a dramatic response in non-small cell lung cancer (NSCLC) patients with the ALK fusion gene. However, acquired resistance to ALK-TKIs remains an inevitable problem. In this study, we aimed to discover novel therapeutic targets to conquer ALK-positive lung cancer. We established three types of ALK-TKI (crizotinib, alectinib and ceritinib)-resistant H2228 NSCLC cell lines by high exposure and stepwise methods. We found these cells showed a loss of ALK signaling, overexpressed AXL with epithelial-mesenchymal transition (EMT), and had cancer stem cell-like (CSC) properties, suggesting drug-tolerant cancer cell subpopulations. Similarly, we demonstrated that TGF-β1 treated H2228 cells also showed AXL overexpression with EMT features and ALK-TKI resistance. The AXL inhibitor, R428, or HSP90 inhibitor, ganetespib, were effective in reversing ALK-TKI resistance and EMT changes in both ALK-TKI-resistant and TGF-β1-exposed H2228 cells. Tumor volumes of xenograft mice implanted with established H2228-ceritinib-resistant (H2228-CER) cells were significantly reduced after treatment with ganetespib, or ganetespib in combination with ceritinib. Some ALK-positive NSCLC patients with AXL overexpression showed a poorer response to crizotinib therapy than patients with a low expression of AXL. ALK signaling-independent AXL overexpressed in drug-tolerant cancer cell subpopulations with EMT and CSC features may be commonly involved commonly involved in intrinsic and acquired resistance to ALK-TKIs. This suggests AXL and HSP90 inhibitors may be promising therapeutic drugs to overcome drug-tolerant cancer cell subpopulations in ALK-positive NSCLC patients for the reason that ALK-positive NSCLC cells do not live through ALK-TKI therapy.

DOI： 10.18632/oncotarget.25531

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Background The aim of this trial was to evaluate the safety and efficacy of oral hydration as a substitute for intravenous hydration after cisplatin (CDDP) administration. Methods The major eligibility criteria included patients with lung cancer, indications for a CDDP-based regimen at a dose of 60 mg/m 2 or higher, an age of between 20 and 74 years and adequate renal function. Antiemetic prophylaxis consisted of an appropriate dose of palonosetron, aprepitant, dexamethasone and magnesium sulfate (8 mEq). Five hundred millilitres of commercially available oral hydration solution (OS-1: Otsuka Pharmaceutical Factory, Tokushima, Japan) was used as a substitute for intravenous posthydration. The planned sample size was 46 to reject a proportion of 70% under an expectation of 88% with a power of 90% and an alpha error of 5%. Results Between May and November 2013, 31 men and 15 women with a median (range) age of 65 (33-74) years were enrolled from three institutions. Of these, five received adjuvant chemotherapy, 17 received definitive chemoradiotherapy and 24 received chemotherapy for advanced diseases. The median (range) number of chemotherapy cycles was 4 (1-5). After the first cycle of CDDP administration, none of the patients experienced a creatinine elevation of grade 2 or higher, thereby meeting the primary endpoint. Of the 46 patients, 45 (97.8%, 95% CI 88.2 to 99.9) completed the CDDP-based chemotherapy without grade 2 or higher renal dysfunction. Conclusion Oral hydration can be used as a safe and convenient substitute for intravenous posthydration for CDDP administration at the standard dose. Trial registration number UMIN000010201.

DOI： 10.1136/esmoopen-2017-000288

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DOI： 10.1158/1538-7445.AM2017-3209

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Background/Aim: We evaluated the usefulness of reverse transcription-polymerase chain reaction (RT-PCR) for detecting anaplastic lymphoma kinase (ALK) translocations using cytology samples from lung cancer patients. Materials and Methods: We analyzed ALK translocations by RT-PCR in cytology samples from lung cancer patients diagnosed at the Nippon Medical School Hospital between 2013 and 2015. Immunochemistry (IHC) and break-apart fluorescence in situ hybridization (FISH) were also performed on available tissue samples. Results: A total of 155 cytology samples were analyzed in our study. We obtained 115 (68%) samples from bronchial lavage. We were able to determine 153 (99%) results by RT-PCR with 4 (3%) positive samples. The four samples positive by RT-PCR were also positive by IHC and FISH performed on the tissue samples collected simultaneously. Conclusion: RT-PCR is a suitable method for detecting ALK translocations using cytology samples from patients with primary lung cancer, especially when tissue samples are not available.

DOI： 10.21873/anticanres.11696

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DOI： 10.1200/JCO.2017.35.15_suppl.e21660

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DOI： 10.1016/j.jtho.2016.11.1810

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Objective: Amrubicin, which is used as a chemotherapeutic agent for lung cancer, can induce interstitial lung disease. There is insufficient evidence on the incidence of amrubicin-associated interstitial lung disease under practical use settings. We therefore investigated the occurrence of interstitial lung disease in the patients with lung cancer who received amrubicin in our institution. Methods: We reviewed the data of all patients with lung cancer who received amrubicin at the Nippon Medical School Hospital from March 2002 to April 2015. Interstitial lung disease was diagnosed based on clinical symptoms, radiographic findings and the exclusion of other diseases. Results: We reviewed 92 consecutive patients with lung cancer. Amrubicin-associated interstitial lung disease occurred in 3 of the 92 patients (3.3%): 2 were definite interstitial lung disease and 1 was possible interstitial lung disease. The severity of interstitial lung disease was mild to moderate, and interstitial lung disease improved with or without corticosteroid therapy in all cases. The findings in a computed tomography image analysis showed preexisting pulmonary fibrosis (n = 13), including interstitial pneumonitis (n = 10) and radiation fibrosis (n = 3). No patients showed the presence of honeycomb lung. Among the 13 patients, 1 (7.7%) developed interstitial lung disease after amrubicin chemotherapy. Conclusion: Interstitial lung disease occurred in 3.3% of the patients in our study; this appeared to be less frequent than the rates in previous reports. Preexisting pulmonary fibrosis may be a risk factor for interstitial lung disease; however, no fatal cases were found among the patients with asymptomatic pulmonary fibrosis without honeycomb lung. It is thus considered to be necessary to carefully assess the possibility of preexisting pulmonary fibrosis and clarify the presence or absence of honeycomb lung before starting amrubicin chemotherapy.

DOI： 10.1093/jjco/hyw043

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Amrubicin, which is used as a chemotherapeutic agent for lung cancer, can induce interstitial lung disease. There is insufficient evidence on the incidence of amrubicin-associated interstitial lung disease under practical use settings. We therefore investigated the occurrence of interstitial lung disease in the patients with lung cancer who received amrubicin in our institution.We reviewed the data of all patients with lung cancer who received amrubicin at the Nippon Medical School Hospital from March 2002 to April 2015. Interstitial lung disease was diagnosed based on clinical symptoms, radiographic findings and the exclusion of other diseases.We reviewed 92 consecutive patients with lung cancer. Amrubicin-associated interstitial lung disease occurred in 3 of the 92 patients (3.3%): 2 were definite interstitial lung disease and 1 was possible interstitial lung disease. The severity of interstitial lung disease was mild to moderate, and interstitial lung disease improved with or without corticosteroid therapy in all cases. The findings in a computed tomography image analysis showed preexisting pulmonary fibrosis (n = 13), including interstitial pneumonitis (n = 10) and radiat

DOI： 10.1093/jjco/hyw043

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Nintedanib (BIBF1120) is a multi-targeted angiokinase inhibitor and has been evaluated in idiopathic pulmonary fibrosis and advanced non-small cell lung cancer (NSCLC) patients in clinical studies. In the present study, we evaluated the antitumor effects of nintedanib in 16 NSCLC cell lines and tried to identify microRNA (miRNA) associated with sensitivity to nintedanib. No correlations between FGFR, PDGFR and VEGFR family activation and sensitivity to nintedanib were found. The difference in miRNA expression profiles between 5 nintedanib-sensitive and 5 nintedanib-resistant cell lines was evaluated by miRNA array and quantitative RT-PCR analysis (qRT-PCR). Expression of miR-200b, miR-200a and miR-141 belonging to the miR-200 family which contributes to epithelial-mesenchymal transition (EMT), was significantly lower in 5 nintedanib-resistant than in 5 nintedanib-sensitive cell lines. We examined the protein expression of EMT markers in these 10 NSCLC cell lines. E-cadherin expression was lower, and vimentin and ZEB1 expression were higher in 5 nintedanib-resistant cell lines. PC-1 was the most sensitive of the NSCLC cell lines to nintedanib. We established nintedanib-resistant PC-1 cells (PC-1R) by the stepwise method. PC-1R cells also showed decreased expression of miR-200b, miR-141 and miR-429 and increased expression of ZEB1 and ZEB2. We confirmed that induction of miR-200b or miR-141 enhanced sensitivity to nintedanib in nintedanib-resistant A549 and PC1-R cells. In addition, we evaluated the response to gefitinib in combination with nintedanib after TGF-β1 exposure of A549 cells. Nintedanib was able to reverse TGF-β1-induced EMT and resistance to gefitinib caused by miR-200b and miR-141 upregulation and ZEB1 downregulation. These results suggested that the miR-200/ZEB axis might be predictive biomarkers for sensitivity to nintedanib in NSCLC cells. Furthermore, nintedanib combined with gefitinib might be a novel therapeutic strategy for NSCLC cells with EMT phenotype and resistance to gefitinib.

DOI： 10.3892/ijo.2016.3331

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Background: Mammalian target of rapamycin (mTOR) inhibitors have anti-tumor effects against renal cell carcinoma, pancreatic neuroendocrine cancer and breast cancer. In this study, we analyzed the antitumor effects of mTOR inhibitors in small cell lung cancer (SCLC) cells and sought to clarify the mechanism of resistance to mTOR inhibitors. Methods: We analyzed the antitumor effects of three mTOR inhibitors including everolimus in 7 SCLC cell lines by MTS assay. Gene-chip analysis, receptor tyrosine kinases (RTK) array and Western blotting analysis were performed to identify molecules associated with resistance to everolimus. Results: Only SBC5 cells showed sensitivity to everolimus by MTS assay. We established two everolimus resistant-SBC5 cell lines (SBC5 R1 and SBC5 R10) by continuous exposure to increasing concentrations of everolimus stepwise. SPP1 and MYC were overexpressed in both SBC5 R1 and SBC5 R10 by gene-chip analysis. High expression levels of eukaryotic translation initiation factor 4E (eIF4E) were observed in 5 everolimus-resistant SCLC cells and SBC5 R10 cells by Western blotting. MYC siRNA reduced eIF4E phosphorylation in SBC5 cells, suggesting that MYC directly activates eIF4E by an mTOR-independent bypass pathway. Importantly, after reduction of MYC or eIF4E by siRNAs, the SBC5 parent and two SBC5-resistant cells displayed increased sensitivity to everolimus relative to the siRNA controls. Conclusion: These findings suggest that eIF4E has been shown to be an important factor in the resistance to everolimus in SCLC cells. Furthermore, a link between MYC and mTOR-independent eIF4E contribute to the resistance to everolimus in SCLC cells. Control of the MYC-eIF4E axis may be a novel therapeutic strategy for everolimus action in SCLC.

DOI： 10.1186/s12885-015-1202-4

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Abstract Background: Non-small-cell lung cancers (NSCLCs) harboring translocations in anaplastic lymphoma kinase (ALK) are highly sensitive to small-molecule ALK kinase inhibitors, such as crizotinib. Case presentation: We describe a case of post-operative local recurrence of lung adenocarcinoma in an 81 year-old male. He underwent radiation and received chemotherapy with docetaxel, but neither treatment regimen was effective. Following identification of ALK rearrangements, crizotinib treatment was initiated. After treatment with crizotinib for 5 days, adverse events including acute renal failure (grade 2/CTCAE ver4.0) and congestive heart failure (grade 3) occurred. Crizotinib modified treatment was required. Half dose of crizotinib treatment could not control tumor progression. Ultimately, crizotinib was administrated at a dose of 250 mg twice daily every 3 day dosing for 13 months with maintenance of the anti-tumor effect. Conclusion: This is the first case report that skip schedule was more effective than dose reduction daily in crizotinib administration for ALK rearranged NSCLC patient with severe adverse events.

DOI： 10.1186/s13104-015-1126-8

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Patients with non-small cell lung cancer (NSCLC) EGFR mutations have shown a dramatic response to EGFR inhibitors (EGFRTKI). EGFR T790M mutation and MET amplification have been recognized as major mechanisms of acquired resistance to EGFRTKI. Therefore, MET inhibitors have recently been used in NSCLC patients in clinical trials. In this study, we tried to identify the mechanism of acquired resistance to MET inhibitors. We analyzed the antitumor effects of two MET inhibitors, PHA-665752 and crizotinib, in 10 NSCLC cell lines. EBC-1 cells with MET amplification were the only cells that were sensitive to both MET inhibitors. We established PHA- 665752-resistant EBC-1 cells, namely EBC-1R cells. Activation of KRAS, EGFR, and FGFR2 signaling was observed in EBC-1R cells by FISH and receptor tyrosine kinase phosphorylation antibody arrays. EBC-1R cells also showed overexpression of ATP-binding cassette subfamily B member 1 (ABCB1) as well as phosphorylation of MET. EBC-1R cells grew as cell spheres that exhibited cancer stem cell-like (CSC) properties and epithelial-mesenchymal transition (EMT). The level of miR- 138 that targeted ABCB1 was decreased in EBC-1R cells. ABCB1 siRNA and the ABCB1 inhibitor elacridar could reduce sphere numbers and suppress EMT. Elacridar could also reverse resistance to PHA-665752 in EBC-1R cells. Our study demonstrated that ABCB1 overexpression, which was associated with CSC properties and EMT, was involved in the acquired resistance to MET inhibitors. Inhibition of ABCB1 might be a novel therapeutic strategy for NSCLC patients with acquired resistance to MET inhibitors.

DOI： 10.1158/1535-7163.MCT-15-0050

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Tumor angiogenesis contributes to the development of tumor progression. Several vascular endothelial growth factor(VEGF)-targeted agents, administered either as single agents or in combination with chemotherapy, have been shown to benefit patients with advanced-stage malignancies. In particular, bevacizumab is a humanized monoclonal antibody that specifically targets VEGF, inhibiting angiogenesis, thereby impeding tumor growth and survival. It is also possible that combined VEGF and the epidermal growth factor (EGFR) pathway blockade could further enhance antitumor efficacy and help prevent resistance to therapy. Preclinical and clinical studies have shown new various molecular targets and the functional characteristics of tumor angiogenesis, which may provide strategies for improving the therapeutic benefit.

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Other Link： http://search.jamas.or.jp/link/ui/2015306275

Language：English   Publisher：AMER ASSOC CANCER RESEARCH  

DOI： 10.1158/1538-7445.AM2015-184

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DOI： 10.1158/1538-7445.AM2015-756

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Introduction: Malignant mesothelioma (MM) is an aggressive neoplasm causatively associated with exposure to asbestos. MM is rarely responsive to conventional cytotoxic drugs, and the outcome remains dismal. It is, therefore, necessary to identify the signaling pathways that drive MM and to develop new therapeutics specifically targeting the molecules involved. Methods: We performed comprehensive RNA sequencing of 12 MM cell lines and four clinical samples using so-called next-generation sequencers. Results: We found 15 novel fusion transcripts including one derived from chromosomal translocation between the large tumor suppressor 1 (LATS1) and presenilin-1 (PSEN1) genes. LATS1 is one of the central players of the emerging Hippo signaling pathway. The LATS1-PSEN1 fusion gene product lacked the ability to phosphorylate yes-associated protein and to suppress the growth of a MM cell line. The wild-type LATS1 allele was undetectable in this cell line, indicating two-hit genetic inactivation of its tumor suppressor function. Using pathway-targeted exon sequencing, we further identified a total of 11 somatic mutations in four Hippo pathway genes (neurofibromatosis type 2 [NF2], LATS2, RASSF1, and SAV1) in 35% (8 of 23) of clinical samples. Nuclear staining of yes-associated protein was detected in 55% (24 of 44) of the clinical samples. Expression and/or phosphorylation of the Hippo signaling proteins, RASSF1, Merlin (NF2), LATS1, and LATS2, was frequently absent. Conclusions: The frequent alterations of Hippo pathway molecules found in this study indicate the therapeutic feasibility of targeting this pathway in patients with MM.

DOI： 10.1097/JTO.0000000000000493

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Malignant pleural mesothelioma (MPM) is a rapidly fatal malignancy that is increasing in incidence in Japan. In this study, we performed gene and microRNA (miRNA) expression profiling to identify novel therapeutic targets in MPM cells. Based on relative sensitivities to pemetrexed (PEM) and the histone deacetylase (HDAC) inhibitor, vorinostat (SAHA), 211H cells were determined to be the only sensitive MPM cell line out of the 6 tested. On the same series of cell lines, we performed whole genome transcriptomic profiling via DNA microarrays and pathway analysis of the derived data. Of particular note, IL-18 gene expression levels were significantly higher in the cell lines that were either drug resistant or displayed intermediate sensitivity, compared to the sensitive 211H cell line. Pathway analysis revealed IL-18 as an important gene associated with drug sensitivity of MPM cells. A relationship between IL-18 overexpression and drug resistance was also observed following targeted assessment of 10 cytokine genes using quantitative RT-PCR. miRNA expression profiles were evaluated in the MPM cell line panel in order to discern the mechanism of IL-18 induction in the drug-resistant lines. We found that miR-379 and miR-411 belonged to the same cluster of miRNAs located on chromosome 14q32 that commonly target the IL-18 gene. Luciferase reporter assays revealed that miR-379 and miR-411 directly target the IL-18 gene. Introduction of miR-379 plus miR-411, as well as IL-18 silencing, significantly suppressed the invasive capacity of MESO1 cells in vitro. Furthermore, the use of either PEM or SAHA together with miR-379 plus miR-411 mimics mediated increased sensitivity to these drugs in MESO1 cells. These results suggest that the miR-379/411 cluster may provide new therapeutic opportunities for advanced MPM patients, depending on the nature of IL-18 gene expression.

DOI： 10.3892/or.2014.3481

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DOI： 10.1158/1538-7445.AM2014-784

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DOI： 10.1158/1538-7445.AM2014-5206

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Background: Combined pulmonary fibrosis and emphysema (CPFE) patients may be at significantly increased risk of lung cancer compared with either isolated emphysema or pulmonary fibrosis patients. Acute exacerbation (AE) of interstitial lung disease caused by anticancer treatment is the most common lethal complication in Japanese lung cancer patients. Nevertheless, the clinical significance of CPFE compared with isolated idiopathic interstitial pneumonias (IIPs) in patients with lung cancer is not well understood. Methods: A total of 1536 patients with lung cancer at Nippon Medical School Hospital between March 1998 and October 2011 were retrospectively reviewed. Patients with IIPs were categorized into two groups: (i) CPFE; IIP patients with definite emphysema and (ii) non-CPFE; isolated IIP patients without definite emphysema. The clinical features, anti-cancer treatments and outcomes of the CPFE group were compared with those of the non-CPFE group. Results: CPFE and isolated IIPs were identified in 88 (5.7%) and 63 (4.1%) patients respectively, with lung cancer. AE associated with initial treatment occurred in 22 (25.0%) patients in the CPFE group and in 8 (12.7%) patients in the non-CPFE group, irrespective of treatment modality. Median overall survival (OS) of the CPFE group was 23.7 months and that of the non-CPFE group was 20.3 months (P= 0.627). Chemotherapy was performed in a total of 83 patients. AE associated with chemotherapy for advanced lung cancer occurred in 6 (13.6%) patients in the CPFE group and 5 (12.8%) patients in the non-CPFE group. Median OS of the CPFE group was 14.9 months and that of the non-CPFE group was 21.6 months (P= 0.679). Conclusion: CPFE was not an independent risk factor for AE and was not an independent prognosis factor in lung cancer patients with IIPs. Therefore, great care must be exercised with CPFE as well as IIP patients when performing anticancer treatment for patients with lung cancer. © 2014 Elsevier Ireland Ltd.

DOI： 10.1016/j.lungcan.2014.05.016

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Language：English   Publishing type：Research paper (scientific journal)   Publisher：AMER SOC BIOCHEMISTRY MOLECULAR BIOLOGY INC  

Sorafenib is a multi-kinase inhibitor that has been proven effective for the treatment of unresectable hepatocellular carcinoma (HCC). However, its precise mechanisms of action and resistance have not been well established. We have developed high-density fluorescence reverse-phase protein arrays and used them to determine the status of 180 phosphorylation sites of signaling molecules in the 120 pathways registered in the NCI-Nature curated database in 23 HCC cell lines. Among the 180 signaling nodes, we found that the level of ribosomal protein S6 phosphorylated at serine residue 235/236 (p-RPS6 S235/236) was most significantly correlated with the resistance of HCC cells to sorafenib. The high expression of p-RPS6 S235/236 was confirmed immunohistochemically in biopsy samples obtained from HCC patients who responded poorly to sorafenib. Sorafenib-resistant HCC cells showed constitutive activation of the mammalian target of rapamycin (mTOR) pathway, but whole-exon sequencing of kinase genes revealed no evident alteration in the pathway. p-RPS6 S235/236 is a potential biomarker that predicts unresponsiveness of HCC to sorafenib. The use of mTOR inhibitors may be considered for the treatment of such tumors. © 2014 by The American Society for Biochemistry and Molecular Biology, Inc.

DOI： 10.1074/mcp.M113.033845

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Epithelial-mesenchymal transition (EMT) has recently been recognized as a key element of cell invasion, migration, metastasis, and drug resistance in several types of cancer, including non-small cell lung cancer (NSCLC). Our aim was to clarify microRNA (miRNA)-related mechanisms underlying EMT followed by acquired resistance to epidermal growth factor receptor tyrosine kinase inhibitor (EGFR-TKI) in NSCLC. miRNA expression profiles were examined before and after transforming growth factor b1 (TGF-b1) exposure in four human adenocarcinoma cell lines with or without EMT. Correlation between expressions of EMT-related miRNAs and resistance to EGFR-TKI gefitinib was evaluated. miRNA array and real-time quantitative reverse transcription PCR (qRT-PCR) revealed that TGF-b1 significantly induced overexpression of miR-134, miR-487b, and miR-655, which belong to the same cluster located on chromosome 14q32, in lung adenocarcinoma cells with EMT. MAGI2 (membrane-associated guanylate kinase, WW, and PDZ domain-containing protein 2), a predicted target of these miRNAs and a scaffold protein required for PTEN, was diminished in A549 cells with EMT after the TGF-b1 stimulation. Overexpression of miR-134 and miR-487b promoted the EMT phenomenon and affected the drug resistance to gefitinib, whereas knockdown of these miRNAs inhibited the EMT process and reversed TGF-b1-induced resistance to gefitinib. Our study demonstrated that the miR-134/487b/655 cluster contributed to the TGF-b1-induced EMT phenomenon and affected the resistance to gefitinib by directly targeting MAGI2, in which suppression subsequently caused loss of PTEN stability in lung cancer cells. The miR-134/miR-487b/miR-655 cluster may be a new therapeutic target in patients with advanced lung adenocarcinoma, depending on the EMT phenomenon. Mol Cancer Ther; 13(2); 444-53. © 2013 American Association for Cancer Research.

DOI： 10.1158/1535-7163.MCT-13-0448

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Background: The EML4-ALK (echinoderm microtubule-associated protein-like 4 gene and the anaplastic lymphoma kinase gene) fusion oncogene represents a novel molecular target in a small subset of non-small-cell lung cancers (NSCLCs). The EML4-ALK fusion gene occurs generally in NSCLC without mutations in epidermal growth factor receptor (EGFR) and KRAS.Case presentation: We report that a case of EML4-ALK-positive NSCLC with EGFR mutation had a response of stable disease to both an EGFR tyrosine kinase inhibitor (EGFR-TKI) and ALK inhibitor.Conclusions: We described the first clinical report of a patient with EML4-ALK-positive NSCLC with EGFR mutation that had a response of stable disease to both single-agent EGFR-TKI and ALK inhibitor. EML4-ALK translocation may be associated with resistance to EGFR-TKI, and EGFR signaling may contribute to resistance to ALK inhibitor in EML4-ALK-positive NSCLC. © 2013 Miyanaga et al.; licensee BioMed Central Ltd.

DOI： 10.1186/1471-2407-13-262

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Background: A phase II study was conducted in order to determine the tumor efficacy and tolerance of alternating chemotherapy for extensive-stage small cell lung cancer (ED-SCLC). Patients and Methods: Twenty patients with previously-untreated ED-SCLC were enrolled in the study. At least four courses of chemotherapy consisting of alternation of two drug combinations were given: alternating cycles of amrubicin and cisplatin with weekly administration of irinotecan and cisplatin at 3- or 4-week intervals. Results: The overall response rate was 85.0% (17/20). The median duration of overall survival and progression-free survival were 359 days and 227 days, respectively. Hematological toxicity was the main adverse event. Grade 3 or 4 neutropenia, thrombocytopenia and anemia were observed in 20 (100%), 4 (20%) and 6 (30%) patients, respectively. With regard to non-hematological adverse events, grade 3 or 4 anorexia, diarrhea, febrile neutropenia and infection were observed in 5 (25%), 2 (10%), 2 (10%) and 2 (10%) patients, respectively. No treatment-related death occurred during either regimen. Conclusion: The novel alternating non-cross-resistant chemotherapy was probably active against ED-SCLC and had acceptable toxicities. Further evaluation of this treatment for ED-SCLC in randomized phase III trials is warranted.

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Background: High-grade neuroendocrine tumours (HGNTs) of the lung manifest a wide spectrum of clinical behaviour, butno method for predicting their outcome has been established. Materials and methods: We newly established a monoclonal antibody specifically recognizing the product of the alternatively spliced ACTN4 transcript (namely, variant actinin-4), and used it to examine the expression of variant actinin-4 immunohistochemically in a total of 609 surgical specimens of various histological subtypes of lung cancer. Results: Variant actinin-4 was expressed in 55% (96/176) of HGNTs, but in only 0.8% (3/378) of non-neuroendocrine(NE) lung cancers. The expression of variant actinin-4 was significantly associated with poorer overall survival in HGNT patients (P = 0.00021, log-rank test). Multivariate analysis using the Cox proportional hazards model showed that the expression of variant actinin-4 was the most significant independent negative predictor of survival in HGNT patients(hazard ratio (HR), 2.15; P = 0.00113) after the presence of lymph node metastasis (HR, 2.25; P = 0.00023). Conclusions: The expression of variant actinin-4 is an independent prognostic factor for patients with HGNTs. This protein has a high affinity for filamentous actin polymers and likely promotes aggressive behaviour of cancer cells. The present clinical findings clearly support this notion. © The Author 2012. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved.

DOI： 10.1093/annonc/mds215

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Background: A phase II study was conducted to determine the tumor efficacy and tolerance of alternating chemotherapy in extensive-stage small-cell lung cancer (ED-SCLC). Patients and Methods: Thirty-six patients with previously untreated ED-SCLC were enrolled in the study. At least four courses of chemotherapy consisting of alternation of two drug combinations were given: alternating cycles of etoposide and carboplatin (EC) with weekly administration of irinotecan and cisplatin (IP) at 3- or 4-week intervals. Results: The overall response rate was 81.8%. The median duration of survival and progression-free survival were 314 days and 144 days, respectively. Hematological toxicity was the main adverse event. Grade 3 or 4 neutropenia, thrombocytopenia and anemia were observed in 69.2, 25.6 and 23.1% of the patients, respectively. Severe diarrhea (10.8%) was remarkable during the IP regimen. Conclusion: This novel alternating chemotherapy for patients with ED-SCLC showed moderate tumor efficacy and an acceptable safety profile.

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DOI： 10.2142/biophys.52.S124_3

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Language：Japanese   Publishing type：Research paper (scientific journal)   Publisher：Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

The most used standard therapy for malignant pleural effusion(MPE)is tube thoracostomy drainage, except in cases where there are few pleural effusions or no symptoms. It has been reported that instilling an intrapleural agent is necessary for producing pleurodesis after tube thoracostomy drainage. To date, numerous chemical agents for the treatment of MPE have been studied. These include antibiotics, antineoplastic agents, biological response modifiers and others, that showed various degrees of chemical sclerosis. It was entered on a randomized comparison of tetracycline and bleomycin for treatment of MPE. The rate and time to recurrence were both significantly greater with bleomycin. In comparison, Talc was superior to bleomycin for control of MPE. Therefore, thoracoscopic pleurodesis with talc is now considered to be the gold standard treatment for MPE. However, talc has not been commercially available in Japan. We sought to evaluate the efficacy and toxicity of three intrapleural therapy regimens consisting of bleomycin, OK-432 or cisplatin plus etoposide(PE), for the management of malignant pleural effusion in previously untreated non-small cell lung cancer. The primary endpoint, pleural progression-free survival did not differ significantly between groups. Intrapleural treatment using OK-432 in the management of MPE was selected because it had the highest 4-week pleural progression-free survival rate and toxicity was tolerable. At present, OK- 432 is the standard agent used in Japan.

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It is desirable to find more appropriate therapeutic opportunities in non-small-cell lung cancer (NSCLC) due to the current poor prognosis of affected patients. Recently, several histone deacetylase (HDAC) inhibitors, including suberoylanilide hydroxamic acid (SAHA), have been reported to exhibit antitumor activities against NSCLC. S-1, a novel oral fluorouracil anticancer drug, has been developed for clinical use in the treatment of NSCLC in Japan. Using an MTT assay, we analyzed the growth-inhibitory effect of 5-fluorouracil (5-FU), S-1, and SAHA against three NSCLC cell lines, as well as the breast cancer cell line MCF7 which is known to be highly sensitive to 5-FU. Combined treatment with low-dose SAHA enhanced 5-FU- and S-1-mediated cytotoxicity and resulted in synergistic effects, especially in 5-FU-resistant cells. Both the mRNA and protein expression levels of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and orotate phosphoribosyltransferase (OPRT), which are associated with 5-FU sensitivity/response, were analyzed in the cells undergoing treatment. 5-Fluorouracil-resistant lung cancer cells displayed high expression of TS mRNA and protein. Suberoylanilide hydroxamic acid down-regulated TS mRNA and protein expression, as well as repressed the rapid induction of this factor during 5-FU treatment, in all examined cell types. We also examined the status of the Rb-E2F1 pathway, with SAHA up-regulating p21waf1/cip1 expression via promoter histone acetylation; this, in turn, blocked the Rb-E2F1 pathway. We conclude that combination therapy with SAHA and S-1 in lung cancer may be promising due to its potential to overcome S-1 resistance via modulation of 5-FU/S-1 sensitivity-associated biomarker (TS) by HDAC inhibitor. (Cancer Sci 2010). © 2010 Japanese Cancer Association.

DOI： 10.1111/j.1349-7006.2010.01559.x

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Previously, we performed a molecular pharma-cological study that applied a combination of DNADNADNA microarray-based gene expression profiling and drug sensitivity tests in vitro with a view to designing an improved chemotherapeutic strategy for advanced lung cancer. Utilizing recent key technological advances in proteomics, particularly antibody array-based methodologies, the current study aimed to examine the benefit of protein expression profiling in an analogous molecular pharmacological context. We performed protein expression analysis in a panel of lung cancer cell lines via an antibody array approach. Using a modified NCI program, we related cell line-specific proteomic profiles to the previously determined cytotoxic activity of a selection of commonly used anticancer agents, namely docetaxel, paclitaxel, gemcitabine, vinorelbine, 5-fluorouracil (5-FU), SN38, cisplatin (CDDP) and carboplatin (CBDCA). In addition, we compared these results with those obtained from our prior DNADNADNA microarray-based transcriptomic study. In our expression-drug correlation analysis using antibody array, gemcitabine consistently belonged to an isolated cluster. Docetaxel, paclitaxel, 5-FU, SN38, CBDCA and CDDP were gathered together into one large cluster. These results coincided with those generated by the prior transcriptomic study. Various genes were commonly listed that differentiated gemcitabine from the others. The identified factors associated with drug sensitivities were different between both analyses. Our proteomic profiling data provided confirmation of the previous transcript expression-drug sensitivity correlation analysis. These results suggest that chemotherapy regimens that include gemcitabine should be evaluated in second-line chemotherapy in cases where the first-line chemotherapy did not include this drug. Protein expression-drug sensitivity correlations in lung cancer cells in vitro may provide useful information in determining the most appropriate therapeutic options for lung cancer patients.

DOI： 10.3892/etm_00000007

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Purpose: Bi-weekly administrations of nimustine hydrochloride (ACNU) plus paclitaxel were evaluated in this phase II study in patients with refractory small cell lung cancer (SCLC). Methods: Patients who had disease progression within 3 months after treatment with irinotecan (CPT-11)-containing regimens were entered. They were treated with every other week administrations of ACNU 50 mg/m2 plus paclitaxel 110 mg/m2 on day 1 over 2 weeks. Results: Twenty-four patients (20 males and 4 females, median age of 64 years, 17 patients with Eastern Cooperative Oncology Group [ECOG] performance status [PS] 0-1 and 7 patients with PS 2) participated in the trial. Of the 24 refractory patients after CPT-11 containing regimens, 17 patients had been given etoposide plus platinum. There were six partial responses, and an overall response rate of 25% (95% confidence interval, 10-46%) was obtained. The median time to progression and the median survival time after enrollment into this study were 2.8 and 5.8 months, respectively. The median overall survival from the first-line treatment was 19.5 months. The major toxicity was myelosuppression. Grade 4 neutropenia occurred in 13% of patients, and Grade 4 thrombocytopenia was observed in 13% of patients. There was one treatment-related death, attributed to pneumonitis. Conclusion: Bi-weekly administrations of ACNU plus paclitaxel provided a practical and well-tolerated regimen that was active for CPT-11-refractory SCLC. © 2009 Elsevier Ireland Ltd. All rights reserved.

DOI： 10.1016/j.lungcan.2009.03.003

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DOI： 10.1272/jnms.76.44

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It is known that an epidermal growth factor receptor (EGFR) gene mutation(s) is present in a percentage of non-small cell lung cancers (NSCLCs). Gefitinib, an inhibitor of the tyrosine kinase activity of EGFR, is effective on most of them. The EGFR mutation status alone cannot fully predict the response to gefitinib and the prognosis for the patients. We hypothesized that information on the expression levels of phosphorylated-EGFR and -Akt, and E-cadherin, alone or in combination with information on the EGFR mutation, may refine our ability of prediction. We investigated 24 NSCLCs that had recurred after surgery and were treated with gefitinib. Specimens resected by surgery were subjected to the peptide nucleic acid-locked nucleic acid polymerase chain reaction clamp reaction to determine the EGFR mutation status, and to immunohistochemical staining of phosphorylated-EGFR and -Akt, and E-cadherin to determine their expression levels. The EGFR mutation status was predictive of responsive disease (complete response: CR + partial response: PR) and controlled disease (CR + PR + stable disease: SD). Positive E-cadherin staining was predictive of longer time to progression (12.4 vs. 5.9 months, p<0.05) and overall survival (OS) (18.4 vs. 13.0 months, p<0.05). Together the patients with an EGFR mutation and the patients with positive E-cadherin staining defined a patient group with a median OS of 18.4 months and excluded the patient group with the median OS of 3.7 months. Neither p-Akt nor p-EGFR staining was associated with the response and survival. In patients with surgically resected NSCLC tumors, the EGFR mutation status and E-cadherin staining can select patients who will benefit from gefitinib therapy.

DOI： 10.3892/or.19.2.377

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To ascertain the potential for histone deacetylase (HDAC) inhibitor-based treatment in non-small cell lung cancer (NSCLC), we analyzed the antitumor effects of trichostatin A (TSA) and suberoylanilide hydroxamic acid (vorinostat) in a panel of 16 NSCLC cell lines via 3-(4,5-dimethylthiazol-2-yl)-2,5- diphenyltetrazolium bromide assay. TSA and vorinostat both displayed strong antitumor activities in 50% of NSCLC cell lines, suggesting the need for the use of predictive markers to select patients receiving this treatment. There was a strong correlation between the responsiveness to TSA and vorinostat (P < 0.0001). To identify a molecular model of sensitivity to HDAC inhibitor treatment in NSCLC, we conducted a gene expression profiling study using cDNA arrays on the same set of cell lines and related the cytotoxic activity of TSA to corresponding gene expression pattern using a modified National Cancer Institute program. In addition, pathway analysis was done with Pathway Architect software. We used nine genes, which were identified by gene-drug sensitivity correlation and pathway analysis, to build a support vector machine algorithm model by which sensitive cell lines were distinguished from resistant cell lines. The prediction performance of the support vector machine model was validated by an additional nine cell lines, resulting in a prediction value of 100% with respect to determining response to TSA and vorinostat. Our results suggested that (a) HDAC inhibitors may be promising anticancer drugs to NSCLC and (b) the nine-gene classifier is useful in predicting drug sensitivity to HDAC inhibitors and may contribute to achieving individualized therapy for NSCLC patients. Copyright © 2008 American Association for Cancer Research.

DOI： 10.1158/1535-7163.MCT-07-2140

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To understand the mechanisms of PTEN inactivation, which is reported to be involved in tumor progression and drug resistance in lung cancer, we analyzed the expression levels of PTEN at mRNA and protein levels, along with the genetic and epigenetic status of the PTEN gene, in a panel of lung cancer cell lines. Western blot analysis showed that six out of 25 (24%) cell lines displayed low expression of PTEN protein. The level of PTEN mRNA correlated well with corresponding protein expression in each of these six cell lines. In two of the six cell lines genomic analysis revealed homozygous deletions of the PTEN gene. Another two of the six cell lines displayed hypermethylation of the PTEN gene promoter assessed by methylation-specific PCR. The levels of PTEN mRNA and protein expression in PC9/f9 and PC9/f14 cells, which are gefitinib-resistant derivatives of the gefitinib-sensitive cell line, PC9, were reduced compared to the parental line. After treatment with the demethylating agent 5-aza-2′deoxycytidine (5-AZA) and the histone deacetyltransferase (HDAC) inhibitor Trichostatin A (TSA), the expression levels of PTEN mRNA and protein in these four cell lines (PC9/f9, PC9/f14, PC10 and PC14) were actually restored. In summary, reduction in PTEN protein expression was regulated by histone deacetylation and hypermethylation of the gene promoter, as well as homozygous deletion. In addition, we demonstrated that the combination treatment of gefitinib and TSA induced significant growth inhibition in gefitinib-resistant PC9/f9 and PC9/f14 cells. These findings suggest that the combination of the epidermal growth factor receptor tyrosine kinase inhibitor gefitinib with the demethylating agent 5-AZA and the HDAC inhibitor TSA may be a useful strategy for the treatment of some lung cancers.

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DOI： 10.1272/manms.14.201

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Representative driver oncogenes such as epidermal growth factor receptor (EGFR), anaplastic lymphoma kinase (ALK), KRAS, and B-rapidly accelerated fibrosarcoma (BRAF) have recently been identified as new genetic aberrations in patients with non-small cell lung cancer (NSCLC). Additionally, rearranged during transfection (RET) and c-ros oncogene 1 (ROS1) fusion genes, which are minor-driver oncogenes, are each found in 1–2 % of NSCLC and represent distinct molecular subsets. Studies based on preclinical and clinical studies of several fusion-positive patients indicate that inhibiting the kinase activity of the RET and ROS1 fusion proteins is a promising therapeutic strategy. Therefore, there are several ongoing clinical trials aimed at examining the efficacy of tyrosine kinase inhibitors (TKIs) against fusion proteins in patients with fusion-positive NSCLC. Other minor gene mutations (HER2/ERBB2, NTRK1, NRG1, FGFR1/FGFR3, DDR2, and PIK3CA) that are targetable by existing TKIs have also been identified in patients with NSCLCs. It is necessary to establish systematic genomic testing algorithms to identify defined subsets of patients with NSCLC for whom effective drug therapies are available either commercially or through clinical trials.

DOI： 10.1007/978-981-10-2002-5_12

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DOI： 10.2482/haigan.55.119

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DOI： 10.11241/jsmtmr.29.3

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DOI： 10.1272/jnms.81.292

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DOI： 10.1272/manms.10.207

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Language：Japanese   Publisher：Japanese Society of Oral Oncology  

In cancer clinical practice, metastasis is an important prognostic factor, and so elucidation of the mechanism of metastasis at the molecular level is desirable. Cell motility is intricately related to metastasis, and dynamic change in the actin cytoskeleton is one of the most important factors regulating motility. Actinin-4 (gene name: ACTN4), which is a novel actin bundling protein, has been identified by our laboratory. Expression of actinin-4 protein leads to the formation of cell processes and increases motility. Clinicopathologically, increased expression of actinin-4 protein not only affects the prognosis in invasive ductal carcinoma of the breast, but also correlates with lymph node metastasis in colon cancer. In small cell lung cancer, a splice variant has been isolated as a cancer/testis antigen, and may also serve as a diagnostic marker. Recently, increases in actinin-4 protein were found to be attributable to ACTN4 gene copy number amplification. ACTN4 gene amplification has been identified in ovarian and pancreatic cancer. This review discusses the biological role of actinin-4 in cancer metastasis and invasion.

DOI： 10.5843/jsot.24.95

CiNii Books

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Language：English   Publishing type：Research paper, summary (international conference)   Publisher：OXFORD UNIV PRESS  

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Language：English   Publisher：日本癌学会  

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Language：English   Publisher：日本癌学会  

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Language：English   Publisher：NATURE PUBLISHING GROUP  

Background: Enzastaurin, an oral serine-threonine kinase inhibitor, was initially developed as an ATP-competitive selective inhibitor against protein kinase CΒ. However, the mechanism by which enzastaurin contributes to tumourigenesis remains unclear. Methods: We analysed the anti-tumour effects of enzastaurin in 22 lung cancer cell lines to ascertain the potential for enzastaurin-based treatment of lung cancer. To identify molecules or signalling pathways associated with this sensitivity, we conducted a gene, receptor tyrosine kinases phosphorylation and microRNA expression profiling study on the same set of cell lines.Results:We identified eight genes by pathway analysis of molecules having gene-drug sensitivity correlation, and used them to build a support vector machine algorithm model by which sensitive cell lines were distinguished from resistant cell lines. Pathway analysis revealed that the JAK/STAT signalling pathway was one of the main ones involved in sensitivity to enzastaurin. Overexpression of JAK1 was observed in the sensitive cells by western blotting. Simultaneous administration of enzastaurin and JAK inhibitor inhibited enzastaurin-induced cell growth-inhibitory effect. Furthermore, lentiviral-mediated JAK1-overexpressing cells were more sensitive to enzastaurin than control cells. Conclusion: Our results suggested that the JAK1 pathway may be used as a single predictive biomarker for enzastaurin treatment. The anti-tumour effect of enzastaurin should be evaluated in lung cancer with overexpressed JAK pathway molecules. © 2012 Cancer Research UK All rights reserved.

DOI： 10.1038/bjc.2012.7

Web of Science

Scopus

PubMed

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Language：Japanese   Publisher：Japanese Society for Molecular Tumor Marker Research  

DOI： 10.11241/jsmtmr.27.33

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Language：Japanese   Publisher：日本臨床プロテオーム研究会  

DOI： 10.14905/jscp.2012.0_20

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Language：Japanese  

DOI： 10.1272/manms.8.304

J-GLOBAL

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2012&ichushi_jid=J04260&link_issn=&doc_id=20121220260022&doc_link_id=10.1272%2Fmanms.8.304&url=https%3A%2F%2Fdoi.org%2F10.1272%2Fmanms.8.304&type=J-STAGE&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00007_3.gif

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The most used standard therapy for malignant pleural effusion (MPE) is tube thoracostomy drainage, except in cases where there are few pleural effusions or no symptoms. It has been reported that instilling an intrapleural agent is necessary for producing pleurodesis after tube thoracostomy drainage. To date, numerous chemical agents for the treatment of MPE have been studied. These include antibiotics, antineoplastic agents, biological response modifiers and others, that showed various degrees of chemical sclerosis. It was entered on a randomized comparison of tetracycline and bleomycin for treatment of MPE. The rate and time to recurrence were both significantly greater with bleomycin. In comparison, Talc was superior to bleomycin for control of MPE. Therefore, thoracoscopic pleurodesis with talc is now considered to be the gold standard treatment for MPE. However, talc has not been commercially available in Japan. We sought to evaluate the efficacy and toxicity of three intrapleural therapy regimens consisting of bleomycin, OK-432 or cisplatin plus etoposide (PE), for the management of malignant pleural effusion in previously untreated non-small cell lung cancer. The primary endpoint, pleural progression-free survival did not differ significantly between groups. Intrapleural treatment using OK-432 in the management of MPE was selected because it had the highest 4-week pleural progression-free survival rate and toxicity was tolerable. At present, OK-432 is the standard agent used in Japan.

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2011&ichushi_jid=J00296&link_issn=&doc_id=20110422470005&doc_link_id=%2Fab8gtkrc%2F2011%2F003804%2F005%2F0524-0527%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2011%2F003804%2F005%2F0524-0527%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

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Language：Japanese   Publisher：(株)メディカルレビュー社  

経口補水液を併用したshort hydration法による高用量シスプラチン(CDDP)投与時の安全性および忍容性を検討した。CDDP 60mg/m2以上を含む2剤併用化学療法を初回導入した胸部悪性疾患患者59例を対象とした。59例中20例がアプレピタントを用いた制吐薬レジメンを使用した。1コース目における悪心・嘔吐等のG1(軽度)、G2(中等度)、G3(重度)それぞれの発現状況は、悪心が16例、6例、2例、嘔吐が3例、2例、なし、食欲不振が24例、11例、3例でいずれも遅発性を示し、これらにより追加輸液およびステロイド投与を必要とした症例は11例であった。治療関連死はなく、副作用にてレジメンを変更した症例は9例で、変更理由として遅発性の悪心・食欲不振が4例、アレルギー、心不全+G2 Cr上昇、糖尿病コントロール不良、不整脈、PS低下が各1例報告された。

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J-GLOBAL

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Language：Japanese   Publisher：特定非営利活動法人 日本呼吸器内視鏡学会  

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DOI： 10.18907/jjsre.32.Special_S212_3

J-GLOBAL

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