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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) [ABSTRACT FROM AUTHOR]

The article presents a case study of a 65-year-old woman was referred to our hospital with stage IV squamous non-small cell lung cancer (NSCLC) of the left upper lobe. It notes Nivolumab therapy allowed new subcutaneous mass on the left upper abdomen. The article discusses she was treated with radiotherapy to the left upper abdomen, which was effective and nivolumab therapy was paused.

Objectives Surgery with curative intent is the standard treatment for stage I lung adenocarcinoma. However, disease recurrence occurs in a third of patients. Prognostic biomarkers are needed to improve postoperative management. Here, we evaluate the utility of Homeobox A9 (HOXA9) promoter methylation, alone or in combination with Blood Vessel Invasion (BVI) assessment, for prognostic stratification of stage I lung adenocarcinoma patients. Materials and methods We developed a Droplet Digital PCR (ddPCR) assay to measure HOXA9 promoter methylation in formalin-fixed paraffin-embedded (FFPE) biospecimens generated during routine pathology. The prognostic value of HOXA9 promoter methylation and BVI, alone and in combination, was evaluated by Kaplan-Meier survival and Cox regression analyses in a cohort of 177 stage I lung adenocarcinoma patients from the NCI-MD study. Results The ddPCR assay showed linearity, sensitivity and specificity for measuring HOXA9 promoter methylation down to 0.1% methylated DNA input. The HOXA9 promoter was methylated de novo in FFPE tumors ( P <  0.0001). High methylation was independently associated with worse cancer-specific survival (Hazard Ratio [HR], 3.37; P  = 0.0002) and identified high-risk stage IA and IB patients. Addition of this molecular marker improved a risk model comprised of clinical and pathologic parameters (age, gender, race, stage, and smoking history; nested likelihood ratio test; P  = 0.0004) and increased the C-index from 0.60 (95% CI 0.51–0.69) to 0.68 (0.60–0.76). High methylation tumors displayed high frequency of TP53 mutations and other molecular characteristics associated with aggressiveness. BVI was independently associated with poor outcome (HR, 2.62; P  = 0.054). A score that combined BVI with HOXA9 promoter methylation further stratified high-risk patients (trend P  = 0.0001 comparing 0, 1 or 2 positive markers). Conclusions ddPCR can be used to quantify HOXA9 promoter methylation in FFPE samples. Alone or combined with BVI in a prognostic classifier, HOXA9 promoter methylation could potentially inform the clinical management of patients with early-stage lung adenocarcinoma. [ABSTRACT FROM AUTHOR]

The occurrence of ocular metastasis from lung cancer is uncommon. In our current case, we report on a 64-year-old male patient found to have metastatic lesions in both choroids after being diagnosed with lung adenocarcinoma. As the patient was found to have a mutation in the epidermal growth factor receptor (EGFR), he was treated with the EGFR tyrosine kinase inhibitor (EGFR TKI), afatinib. However, the treatment response suggested the presence of a progressive disease. Thus, due to cancerous meningitis, the patient’s treatment was changed from afatinib to erlotinib, in addition to adding bevacizumab. Although the general condition of the patient did not change, improvement was noted for the choroidal metastasis. Moreover, the drug change also resulted in an improvement of the visual power of both eyes. Therefore, the results for this patient suggest that systemic administration of erlotinib and bevacizumab may be an effective treatment that leads to morphological and functional improvement in choroidal metastasis cases. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Objectives: Only a few prospective studies have been conducted to examine the efficacy and safety of systemic chemotherapy for patients with pulmonary sarcomatoid carcinomas (PSCs). There is, thus, a crucial need to develop novel treatment strategies for this rare tumor. Patients and methods: Chemotherapy-naïve patients with histologically confirmed PSCs were assigned to receive either carboplatin/paclitaxel alone (CP) or with bevacizumab (CPB) followed by bevacizumab maintenance. The primary endpoint was overall response rate (ORR). Secondary endpoints included overall survival (OS), progression-free survival (PFS), and safety. Results: This study was closed before accumulating the expected number of cases due to slow patient accrual. Eventually, 16 patients were enrolled. The ORR was 25.0% and disease control rate was 56.3%. CPB was administered in all four patients with an objective response [partial response (PR)]; among the four PR cases, two patients had pleomorphic carcinoma, and two had carcinosarcoma. Median PFS and median survival time (MST) in all the enrolled patients were 2.6 months and 8.8 months, respectively. Median PFS was 1.2 months in the CP group and 4.2 months in the CPB group. In addition, MST was 7.9 months in the CP group and 11.2 months in the CPB group. Hematological and non-hematological adverse events were common and reversible, although ileus (grade 4) and nasal bleeding (grade 3) occurred in one case each in the CPB group. Conclusions: CPB might be effective as first-line treatment for PSCs. Further study is warranted to clarify the role of cytotoxic chemotherapy for this rare and aggressive tumor. Clinical trials registration: University Hospital Medical Information Network (UMIN) Clinical Trial Registry (UMIN000008707). [ABSTRACT FROM AUTHOR]

Background: Idiopathic interstitial pneumonias (IIPs) are associated with increased risk of lung cancer. In Japan, acute exaberation of IIPs induced by anticancer treatment is a critical issue. For this reason, there is limited available evidence regarding the optimal treatment approach for lung cancer patients complicated with IIPs. Our previous prospective pilot study demonstrated the safety and efficacy of weekly paclitaxel in combination with carboplatin for advanced non-small-cell lung cancer (NSCLC) with IIPs. The current study was conducted to confirm the results of the same combination therapy used in a larger patient population. Methods: Chemotherapy-naïve patients with advanced stage or post-operative recurrent NSCLC patients complicated by IIPs were enrolled. Patients received paclitaxel (100 mg/m2) on days 1, 8, and 15, and carboplatin (AUC 5.0) once every 4 weeks. Results: Thirty-three of 35 enrolled patients were evaluable for analysis and received a median of four treatment cycles (range 1–6). Four patients (12.1%; 95% confidence interval 3.4–28.2%) had acute exacerbation (AEx)-related IIPs to the study treatment. However, no fatalities due to AEx were observed. The overall response was 69.7%. The median progression-free survival, median survival time, and 1-year survival were 6.3 months, 19.8 months, and 55.4%, respectively. Conclusions: The efficacy of carboplatin plus weekly paclitaxel treatment for advanced NSCLC patients with IIPs was comparable to that of conventional chemotherapy in advanced NSCLC patients without IIPs. Moreover, the primary endpoint was set to the frequency of treatment-related acute exacerbation, and the primary endpoint was met. These results suggest that patients with advanced NSCLC complicated by IIPs may benefit from this combination chemotherapy. [ABSTRACT FROM AUTHOR]

The primary aim of this in vitro simulation study was to evaluate the utility of gene expression profile analysis in predicting the effect of varying drug combinations for the treatment of lung cancer. Using 10 human cancer cell lines, we focused our gene expression analysis on a cohort of candidate sensitivity-prediction factors, previously reported using cDNA filter arrays, with a view to predicting the ability of a set of anti-cancer drugs commonly used to treat lung cancer, namely cisplatin, 5-fluorouracil (5FU), SN38, docetaxel, gemcitabine, and vinorelbine. Altered expression of genes for glutathione-S-transferase-pi, uridine phosphorylase, O-6-methylguanine-DNA methyltransferase, and multidrug resistance 1 was identified in lung cancer cell lines. Drug sensitivity testing, in the form of methylthiotetrazol analysis, was performed using these six anti-cancer drugs against the panel of 10 lung cancer cell lines. We compared the predicted chemosensitivity based on the gene expression pattern of 19 well-known sensitivity-related genes with the cytotoxic activity of each of these anti-cancer drugs. Molecular profiling data predicted resistance to CDDP in LK-2 cells, 5FU in LK-2, PC7, A549, NCI-N231, Lu135 cells, irinitecan in PC9 cells, and VNR in PC7 cells. However, the prediction efficacy (number of predicted inactive drugs by gene expression analysis/number of inactive drugs by methylthiotetrazol assay) was 21.6% (8 of 37). No false-positive findings in relation to sensitivity-related genes were obtained on the basis of this molecular analysis. Thus, prediction of sensitivity to lung cancer by molecular analysis appears possible. With elucidation of additional drug sensitivity factors, selection of appropriate anticancer drugs by gene expression profiling may make it possible to increase the response rate in lung cancer chemotherapy. [ABSTRACT FROM AUTHOR]

Background/aim: Chemoresistance to paclitaxel (PTX) significantly ameliorates therapeutic efficacy in patients with non-small cell lung cancer (NSCLC), especially in advanced stages, deteriorating the progression free and overall survival rates. One of the critical mechanisms contributing to drug resistance is the excretion of PTX from target cells via efflux pumps. Ivermectin was developed as a bactericidal agent against parasites; however, it has recently been shown to inhibit the proliferation of human cancer cells. Hence, we aimed to evaluate the therapeutic potential of ivermectin in combination with PTX and investigate the molecular mechanisms by which ivermectin overcomes PTX resistance., Materials and Methods: We assessed the antitumor effects of ivermectin in A549 cells treated with or without PTX. We also established PTX-resistant cells using this cell line and explored the underlying mechanisms. Additionally, we evaluated whether ivermectin attenuates PTX-resistance with the retrieval of drug sensitivity., Results: Combined treatment of A549 cells with PTX and ivermectin inhibited cell growth. These cells acquired chemoresistance upon long-term exposure to gradually increasing PTX concentrations, which was accompanied by ABCB1 mRNA up-regulation, and subsequent overproduction of P-glycoprotein (P-gp). Consistent with this, P-gp over-expression resulted in a PTX-resistant phenotype. Notably, the simultaneous ivermectin treatment during the gradual exposure completely abolished P-gp expression, leading to an increased intracellular PTX concentration and sustained PTX sensitivity. Ivermectin was found to regulate P-gp expression via the EGFR/ERK/Akt/NF-[Formula: see text]B pathway., Conclusion: Combined treatment of PTX-resistant A549 cells with ivermectin and PTX may circumvent PTX resistance caused by P-gp induction, highlighting a novel therapeutic avenue for drug repurposing., (Copyright © 2024 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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., (© 2024 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

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., (© 2024 The Author(s). Cancer Medicine published by John Wiley & Sons Ltd.)

Background: Everolimus, a mammalian target of rapamycin inhibitor used as an antineoplastic drug, is associated with a remarkably high incidence of interstitial lung disease (ILD). The clinical and pathological characteristics of ILD caused by everolimus have not been thoroughly investigated; therefore, we aimed to elucidate the features of everolimus-associated ILD., Methods: We retrospectively reviewed the medical records of patients who received everolimus for cancer treatment at our hospital. Patient backgrounds were compared between the ILD and non-ILD groups. Chest computed tomography (CT), changes in biomarkers, and lung histopathological features were analyzed for ILD cases., Results: Sixty-six patients were reviewed, and ILD developed in 19. There were no differences in patient demographics between the ILD and non-ILD groups. The severity of ILD was grade 1 (G1) in 9 and grade 2 (G2) in 10 cases. Chest CT showed organizing pneumonia (OP) or a hypersensitive pneumonia pattern. The levels of lactate dehydrogenase, C-reactive protein, Krebs von den lungen-6, and surfactant protein-D (SP-D) at the onset of ILD were significantly higher than those at baseline. Analysis of G1 and G2 ILD subgroups showed a higher SP-D levels in the G2 subgroup. Five patients underwent lung biopsies; all specimens demonstrated alveolitis with lymphocytic infiltration and granulomatous lesions, and some had OP findings., Conclusions: Everolimus-associated ILD is mild and has a favorable prognosis. Patients with symptomatic ILD were more likely to have higher SP-D levels than those with asymptomatic ILD. Granulomatous lesions are an important pathological feature of everolimus-associated ILD.

Objectives: Osimertinib is a standard treatment for patients with EGFR-mutant non-small cell lung cancer (NSCLC) and is highly effective for brain metastases (BMs). However, it is unclear whether local treatment (LT) for BMs prior to osimertinib administration improves survival in EGFR-mutant NSCLC. We aimed to reveal the survival benefit of upfront local treatment (LT) for BMs in patients treated with osimertinib., Materials and Methods: This multicenter retrospective study included consecutive patients with EGFR mutation (19del or L858R)-positive NSCLC who had BMs before osimertinib initiation between August 2018 and October 2021. We compared overall survival (OS) and central nervous system progression-free survival (CNS-PFS) between patients who received upfront LT for BMs (the upfront LT group), and patients who received osimertinib only (the osimertinib-alone group). Inverse-probability treatment weighting (IPTW) analysis was performed to adjust for potential confounding factors., Results: Of the 121 patients analyzed, 57 and 64 patients had 19del and L858R, respectively. Forty-five and 76 patients were included in the upfront LT group and the osimertinib-alone groups, respectively. IPTW-adjusted Kaplan-Meier curves showed that the OS of the upfront LT group was significantly longer than that of the osimertinib-alone group (median, 95 % confidence intervals [95 %CI]: Not reached [NR], NR-NR vs. 31.2, 21.7-33.2; p = 0.021). The hazard ratio (HR) for OS and CNS-PFS was 0.37 (95 %CI, 0.16-0.87) and 0.36 (95 %CI, 0.15-0.87), respectively., Conclusions: The OS and CNS-PFS of patients who received upfront LT for BMs followed by osimertinib were significantly longer than those of patients who received osimertinib alone. Upfront LT for BMs may be beneficial in patients with EGFR-mutant NSCLC treated with osimertinib., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Takehiro Tozuka has received honoraria from CHUGAI PHARMACEUTICAL and AstraZeneca. Rintaro Noro has received honoraria from CHUGAI PHARMACEUTICAL, AstraZeneca, Merck Pharmaceutical, Pfizer Pharmaceutical, Meijiseika Pharmaceutical, GlaxoSmithKline Pharmaceutical, Daiichi Sankyo Pharmaceutical, and has received Fund for the Promotion of Joint International Research (Fostering Joint International Research), and Grant-in-Aid for Scientific Research (C). Taiki Hakozaki has received honoraria from Chugai Pharmaceutical, Ono Pharmaceutical, and Eisai. Tomoyuki Naito has received honoraria from AstraZeneca. Yukio Hosomi has received honoraria from AstraZeneca, Eli Lilly Japan, Taiho Pharmaceutical, Chugai Pharmaceutical, Ono Pharmaceutical, Bristol-Myers Squibb, Kyowa Kirin, Nippon Kayaku, Takeda, Eisai, Novartis, and Pfizer. Takashi Hirose has received honoraria from AstraZeneca. Tetsuya Okano has received honoraria from Taiho Pharmaceutical Co., Ltd., Chugai Pharmaceutical Co., Ltd., Nippon Boehringer Ingelheim Co., Ltd., AstraZeneca K.K., Bristol-Myers Squibb K.K., Eli Lilly Japan K.K., Takeda Pharmaceutical Co., Ltd, and has received from Payment for expert testimony from Pharmaceuticals and Medical Devices Agency. Masahiro Seike has received honoraria from AstraZeneca, MSD K.K, Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Pfizer Novartis, Takeda Pharmaceutical, Kyowa Hakko Kirin, Nippon Kayaku, Daiichi-Sankyo Company, Merck Biopharma, Amgen inc, and has received grants or contracts from any entity from Taiho Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Nippon Boehringer Ingelheim, Nippon Kayaku, and Kyowa Hakko Kirin]., (Copyright © 2024 Elsevier B.V. All rights reserved.)

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., Competing Interests: Dr. Tozuka has received honoraria from Chugai Pharmaceutical and AstraZeneca. Dr. Noro has received honoraria from Chugai Pharmaceutical Co., Ltd., AstraZeneca K.K., and Glaxo Smith Klein, and has received 17KK0177 Fund for the Promotion of Joint International Research (Fostering Joint International Research). Dr. Nakamichi has received honoraria from AstraZeneca, Chugai Pharmaceutical, Bristol-Myers Squibb/Ono Pharmaceutical, Taiho Pharmaceutical, Takeda, Merck Sharp & Dohme, and Kyowa Kirin. Dr. Miyanaga has received honoraria from AstraZeneca, Nippon Kayaku, Merck Pharmaceutical, Kyowa Kirin, and Pfizer, Inc. Dr. Seike has received honoraria from AstraZeneca, MSD K.K., Chugai Pharmaceutical, Taiho Pharmaceutical, Eli Lilly, Ono Pharmaceutical, Bristol-Myers Squibb, Nippon Boehringer Ingelheim, Pfizer, Novartis, Takeda Pharmaceutical, Kyowa Hakko Kirin, Nippon Kayaku, Daiichi Sankyo Company, Merck Biopharma, and Amgen Inc., and has received research funding from 10.13039/100009954Taiho Pharmaceutical, 10.13039/100010795Chugai Pharmaceutical, Eli Lilly, 10.13039/100017346Nippon Boehringer Ingelheim, 10.13039/100018046Nippon Kayaku, and 10.13039/501100004095Kyowa Hakko Kirin. All remaining authors report no conflict of interest., (© 2024 by the International Association for the Study of Lung Cancer.)

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., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Pulmonary involvement associated with inflammatory bowel disease (IBD) are a rare extraintestinal manifestation (EIM) of inflammatory bowel disease (IBD), we herein presented two cases. Case 1: 53-year-old man with Crohn's disease treated with mesalazine and azathioprine. Pulmonary nodular shadows were incidentally detected on chest imaging, and revealed granulomas through transbronchial lung biopsy. Case 2: 68-year-old man with ulcerative colitis treated with mesalazine. He presented with fever and respiratory symptoms, and chest imaging showed multiple nodular infiltrates. He was diagnosed with organizing pneumonia by lung biopsy. Both cases were diagnosed to have pulmonary involvement associated with inflammatory bowel disease (IBD) according to multidisciplinary examination including positron emission tomography-computed tomography (FDG-PET) and pathological test. Pulmonary manifestations with IBD may not always require discontinuation of drugs or additional use of steroids or immunosuppressants., Competing Interests: None., (© 2023 The Authors.)

Superior mesenteric artery (SMA) syndrome is a rare disease, characterized by the narrowing of the third portion of the duodenum between the aorta and SMA. The cause of the stenosis is a decrease in retroperitoneal fat between the aorta and SMA. In this report, we present two cases of SMA syndrome that occurred during chemotherapy for lung cancer. The first case was a 61-year-old male treated with nanoparticle albumin-bound-paclitaxel (nab-PTX) for lung adenocarcinoma. On day 23 of the first course of nab-PTX, he was admitted to our hospital due to vomiting and weight loss of 15.6 kg in 10 months. He was diagnosed with SMA syndrome through computed tomography, and drainage was performed using a nasogastric tube. Conservative treatment was successful, and the patient was able to continue therapy with nab-PTX. The second case was a 70-year-old male with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer. He was admitted to our hospital due to vomiting and dizziness while receiving treatment with pembrolizumab, as well as weight loss of 14.6 kg in 6 months. He was diagnosed with SMA syndrome using computed tomography. Conservative treatment using a nasogastric tube led to improvement, and the patient was able to continue treatment with pembrolizumab after discharge. This is the first report of SMA syndrome in patients with lung cancer undergoing chemotherapy with nab-PTX or pembrolizumab. Late diagnosis and treatment render SMA syndrome a potentially fatal disease. Vomiting and weight loss during chemotherapy are known treatment-related side effects; in patients developing these adverse effects, the presence of SMA syndrome should be suspected and managed appropriately., Competing Interests: Conflict of interestThe authors report no conflicts of interest in this work., (© The Author(s) under exclusive licence to The Japan Society of Clinical Oncology 2022.)

Objectives: Afatinib is an effective treatment for patients with epidermal growth factor receptor (EGFR) mutation-positive non-small cell lung cancer (NSCLC). However, the toxicity associated with this agent often leads to dose modifications. The aim of this study was to assess the efficacy, safety and plasma concentrations of low dose afatinib monotherapy in patients with EGFR mutation-positive NSCLC., Patients and Methods: This was a multicenter, single-arm, open-label, phase II trial involving treatment-naïve patients with advanced EGFR mutation-positive NSCLC. From March 2017 to September 2018, 53 patients were enrolled from 21 institutions in Japan. Patients initially received afatinib 20 mg/day orally. For patients in whom the tumor progressed within stable disease, the investigators were able to increase the afatinib dose (10 mg increments). The primary endpoint was progression-free survival (PFS). The threshold and expected median PFS was 9.2 and 13.8 months, respectively. Additionally, the correlation of the plasma concentration of low-dose afatinib with clinical outcome and adverse events were evaluated., Results: The median age of patients was 70 years (range: 37-85 years); 28 patients (52.8%) were females. The median duration of the follow-up was 20.8 months. The median PFS, and overall survival were 12.6 months (90% confidence interval [CI]: 9.7-14.3 months), and not reached, respectively. The primary endpoint was met. The objective response rate and disease control rate were 66.0% (95% CI: 51.7-78.5) and 92.5% (95% CI: 81.8-97.9), respectively. Grade ≥ 3 adverse events occurred in 12 patients (22.6%), including diarrhea in four patients (7.5%). The rate of adverse events was lower than that observed in previous phase III studies of 40 mg afatinib., Conclusion: Based on its promising clinical efficacy and tolerability profile, monotherapy with low-dose afatinib should become one of the standard therapies for EGFR mutation-positive NSCLC., (Copyright © 2021. Published by Elsevier B.V.)

Introduction: To investigate the genomic profiles of patients with lung cancer with idiopathic pulmonary fibrosis (IPF-LC), mechanism of carcinogenesis, and potential therapeutic targets., Methods: We analyzed 29 matched, surgically resected, cancerous and noncancerous lung tissues (19 IPF-LC and 10 non-IPF-LC) by whole-exome sequencing and bioinformatics analysis and established a medical-engineering collaboration with the Department of Engineering of the Tokyo University of Science., Results: In IPF-LC, CADM1 and SPC25 were mutated at a frequency of 47% (9 of 19) and 53% (10 of 19), respectively. Approximately one-third of the IPF-LC cases (7 of 19; 36%) had both mutations. Pathway analysis revealed that these two genes are involved in transforming growth factor-β1 signaling. CADM1 and SPC25 gene mutations decreased the expression of CADM1 and increased that of SPC25 revealing transforming growth factor-β1-induced epithelial-to-mesenchymal transition and cell proliferation in lung cancer cells. Furthermore, treatment with paclitaxel and DNMT1 inhibitor suppressed SPC25 expression., Conclusions: CADM1 and SPC25 gene mutations may be novel diagnostic markers and therapeutic targets for IPF-LC., (© 2021 by the International Association for the Study of Lung Cancer.)

Background/aim: Malignant mesothelioma (MM) is an aggressive tumor with poor prognosis. The establishment of a new diagnostic and therapeutic approach for MM is expected. This study investigated the diagnostic significance of tenascin XB (TNXB) for MM., Materials and Methods: TNXB gene expression was found to be significantly higher in MM tumor tissues compared to paired normal tissues, as assessed by the Gene Expression Omnibus database. The inhibition of TNXB using small interfering RNAs suppressed the proliferation and colony formation of MM cells. Expression of TNXB and calretinin, a current diagnostic marker of MM, was evaluated by immunohistochemistry., Results: The sensitivity and specificity of TNXB for MM were 80.0% and 69.5%, respectively. When the detection of TNXB was combined with that of calretinin, 83.3% of MM cases were detected., Conclusion: These findings suggest that TNXB is a novel diagnostic biomarker for MM. A combination of detecting TNXB and calretinin may be useful for the differential diagnosis of MM from lung adenocarcinoma., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Recent clinical trials have shown that immune checkpoint blockades that target either PD-1 or PD-L1 yield remarkable responses in a subgroup of patients with non-small cell lung cancer (NSCLC)., Materials and Methods: We retrospectively examined, by immunohistochemical analysis, 211 NSCLC samples. Using 32 independent samples, we also evaluated PD-L1 expression in NSCLC patients with EGFR gene mutations treated by EGFR-TKIs., Results: Overall survival of PD-L1-positive stages I-III NSCLC and stage I NSCLC and stages I-III squamous cell carcinoma (SQ) were significantly shorter than those of PD-L1-negative NSCLC (p<0.01 and p=0.02 and p=0.01, respectively). In stage I NSCLC and stages I-III SQ, PD-L1 expression was found to be independent predictor of death after multivariate analysis. Response to EGFR-TKIs was not significantly different between PD-L1-positive and PD-L1-negative NSCLC patients with EGFR mutations., Conclusion: PD-L1 expression was a significant independent predictor of poor outcome in NSCLC patients., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

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.

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.