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Objective: Lobectomy is the standard treatment for patients with early-stage non-small cell lung cancer (NSCLC). In recent years, an increasing number of patients with lung cancer have been treated using proton therapy (PT). We conducted a propensity score-matched analysis to compare the treatment outcomes of these 2 modalities., Methods: We retrospectively reviewed data from 275 patients with histologically confirmed clinical stage I NSCLC who underwent lobectomy (n = 206) or PT (n = 69) at our institution from July 2013 to December 2020. The end points were overall survival (OS), cause-specific survival, recurrence-free survival (RFS), local control, regional lymph node control, and distant control. Propensity score matching was performed to reduce selection bias in the 2 groups., Results: The matched cohort consisted of 59 patients who underwent lobectomy and 59 patients who underwent PT with a median follow-up period of 50 months. There were no significant differences in OS (P = .26), cause-specific survival (P = .33), RFS (P = .53), local control (P = .41), regional lymph node control (P = .98), and distant control (P = .31). In the lobectomy and PT groups, the 5-year OS rate was 85.8% and 79.1%, respectively, the RFS rate was 82.3% and 77.8%, and the local control rate was 92.1% and 96.6%., Conclusions: We found no difference in survival or disease control between lobectomy and PT in patients with histologically confirmed clinical stage I NSCLC. Despite these findings, the potential for unmeasured confounding factors remains, and randomized control trials are needed to better compare these treatment modalities., Competing Interests: Conflict of Interest Statement The authors reported no conflicts of interest. The Journal policy requires editors and reviewers to disclose conflicts of interest and to decline handling or reviewing manuscripts for which they may have a conflict of interest. The editors and reviewers of this article have no conflicts of interest., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Nineteen non-small cell lung cancer patients admitted for chemotherapy were investigated for cognitive dysfunction and factors affecting cognitive function. The results showed that the patients experienced some decline in cognitive function, and fatigue affected cognitive function and quality of life. Cognitive function in cancer patients affects their treatment choices, employment, and social life. We need to be aware of the cognitive dysfunction of cancer patients, and at the same time, we need to intervene with consideration for cognitive function, as fatigue can easily lead to a sense of cognitive decline.

We evaluated the tumor residual volumes considering six degrees-of-freedom (6DoF) patient setup errors in stereotactic radiotherapy (SRT) with multicomponent mathematical model using single-isocenter irradiation for brain metastases. Simulated spherical gross tumor volumes (GTVs) with 1.0 (GTV 1), 2.0 (GTV 2), and 3.0 (GTV 3)-cm diameters were used. The distance between the GTV center and isocenter (d) was set at 0-10 cm. The GTV was simultaneously translated within 0-1.0 mm (T) and rotated within 0°-1.0° (R) in the three axis directions using affine transformation. We optimized the tumor growth model parameters using measurements of non-small cell lung cancer cell lines' (A549 and NCI-H460) growth. We calculated the GTV residual volume at the irradiation's end using the physical dose to the GTV when the GTV size, d, and 6DoF setup error varied. The d-values that satisfy tolerance values (10%, 35%, and 50%) of the GTV residual volume rate based on the pre-irradiation GTV volume were determined. The larger the tolerance value set for both cell lines, the longer the distance to satisfy the tolerance value. In GTV residual volume evaluations based on the multicomponent mathematical model on SRT with single-isocenter irradiation, the smaller the GTV size and the larger the distance and 6DoF setup error, the shorter the distance that satisfies the tolerance value might need to be., (© 2023. Australasian College of Physical Scientists and Engineers in Medicine.)

Purpose: The effect of immuno-chemotherapy on patients with advanced non-small-cell lung cancer (NSCLC) harboring oncogenic mutations remains poorly understood. This study aimed to characterize the efficacy of immuno-chemotherapy and determine the optimal treatment strategy for such patients., Methods: We conducted this retrospective cohort study on patients with NSCLC harboring oncogenic driver alterations and treated with an immune checkpoint inhibitor combined with chemotherapy at five institutions. The clinical characteristics and outcomes of immuno-chemotherapy for NSCLC with oncogenic mutations in a real-world setting were analyzed., Results: Among 846 patients diagnosed with advanced or recurrent NSCLC between April 2017 and April 2021, 43 patients with oncogenic mutations were treated with immuno-chemotherapy. The median age of patients was 68 (range 44-78) years; 42% of patients never smoked, and adenocarcinoma was the most common histology (95%). In patients with KRAS mutations (n = 10) or PD-L1 expression of 50% or greater (n = 10), the disease control rate was 100%. The median progression-free survival (PFS) was 5.4, 6.3, and 8.9 months in patients harboring mutations in EGFR, KRAS, and other genes, respectively (P = 0.22). Patients with PD-L1 expression of 50% or greater had significantly longer median PFS than patients with PD-L1 expression of less than 50% (16.4 vs. 5.1 months; P = 0.001). Two patients experienced grade 3 immuno-related adverse events., Conclusion: Immuno-chemotherapy has a clinical benefit and is safe for patients with oncogenic mutations. Notably, patients with PD-L1 expression of 50% or more experience greater benefit from immuno-chemotherapy than those with PD-L1 expression of less than 50%., (© 2022. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Background: Patients with epidermal growth factor receptor (EGFR)-mutated, advanced non-small cell lung cancer have received immunochemotherapy as one of the treatment options after tyrosine kinase inhibitor (TKI) failure., Methods: We retrospectively examined EGFR-mutant patients treated with atezolizumab-bevacizumab-carboplatin-paclitaxel (ABCP) therapy or platinum-based chemotherapy (Chemo) after EGFR-TKI therapy at five institutions in Japan., Results: A total of 57 patients with EGFR mutation were analyzed. The median progression-free survival (PFS) and overall survival (OS) in the ABCP (n = 20) and Chemo (n = 37) were 5.6 and 20.9 months, 5.4 and 22.1 months, respectively (PFS, p = 0.39; OS, p = 0.61). In programmed death-ligand 1 (PD-L1)-positive patients, median PFS in the ABCP group was longer than in the Chemo group (6.9 vs. 4.7 months, p = 0.89). In PD-L1-negative patients, median PFS in the ABCP group was significantly shorter than in the Chemo group (4.6 vs. 8.7 months, p = 0.04). There was no difference in median PFS between the ABCP and Chemo groups in the subgroups of brain metastases, EGFR mutation status, or chemotherapy regimens, respectively., Conclusion: The effect of ABCP therapy and chemotherapy was comparable in EGFR-mutant patients in a real-world setting. The indication for immunochemotherapy should be carefully considered, especially in PD-L1-negative patients., (© 2023 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

Purpose: Patients with lung cancer and brain metastases represent a markedly heterogeneous population. Accurate prognosis is essential to optimally individualize care. In prior publications, we described the graded prognostic assessment (GPA), but a GPA for patients with small cell lung cancer (SCLC) has never been reported, and in non-small cell lung cancer (NSCLC), the effect of programmed death ligand 1 (PD-L1) was unknown. The 3-fold purpose of this work is to provide the initial report of an SCLC GPA, to evaluate the effect of PD-L1 on survival in patients with NSCLC, and to update the Lung GPA accordingly., Methods and Materials: A multivariable analysis of prognostic factors and treatments associated with survival was performed on 4183 patients with lung cancer (3002 adenocarcinoma, 611 nonadenocarcinoma, 570 SCLC) with newly diagnosed brain metastases between January 1, 2015, and December 31, 2020, using a multi-institutional retrospective database. Significant variables were used to update the Lung GPA., Results: Overall median survival for lung adenocarcinoma, SCLC, and nonadenocarcinoma was 17, 10, and 8 months, respectively, but varied widely by GPA from 2 to 52 months. In SCLC, the significant prognostic factors were age, performance status, extracranial metastases, and number of brain metastases. In NSCLC, the distribution of molecular markers among patients with lung adenocarcinoma and known primary tumor molecular status revealed alterations/expression in PD-L1 50% to 100%, PD-L1 1% to 49%, epidermal growth factor receptor, and anaplastic lymphoma kinase in 32%, 31%, 30%, and 7%, respectively. Median survival of patients with lung adenocarcinoma and brain metastases with 0, 1% to 49%, and ≥50% PD-L1 expression was 17, 19, and 24 months, respectively (P < .01), confirming PD-L1 is a prognostic factor. Previously identified prognostic factors for NSCLC (epidermal growth factor receptor and anaplastic lymphoma kinase status, performance status, age, number of brain metastases, and extracranial metastases) were reaffirmed. These factors were incorporated into the updated Lung GPA with robust separation between subgroups for all histologies., Conclusions: Survival for patients with lung cancer and brain metastases has improved but varies widely. The initial report of a GPA for SCLC is presented. For patients with NSCLC-adenocarcinoma and brain metastases, PD-L1 is a newly identified significant prognostic factor, and the previously identified factors were reaffirmed. The updated indices establish unique criteria for SCLC, NSCLC-nonadenocarcinoma, and NSCLC-adenocarcinoma (incorporating PD-L1). The updated Lung GPA, available for free at brainmetgpa.com, provides an accurate tool to estimate survival, individualize treatment, and stratify clinical trials., (Copyright © 2022 Elsevier Inc. All rights reserved.)

Background/aim: This study investigated the effectiveness of pembrolizumab with or without chemotherapy on advanced-stage head and neck cancer (HNC), including nasopharyngeal, sinonasal cavity and external auditory canal cancer, in a real-world setting., Patients and Methods: We retrospectively collected data from 97 HNC patients who were treated with pembrolizumab alone (n=60) or with chemotherapy (n=37), and we investigated the association between clinicopathological findings and treatment response or prognosis., Results: Patients treated with pembrolizumab and chemotherapy had a 1-year overall survival (OS) of 72.8%, objective response rate (ORR) of 48.6%, and serious (≥G3) adverse events (AEs) of 29.7%. Patients treated with pembrolizumab alone had a 1-year OS of 51.9%, ORR of 21.7%, and ≥G3 AEs of 6.7%. Both the ORR and disease control rate (DCR) in the pembrolizumab with chemotherapy group were significantly better than those in the pembrolizumab group (p=0.074 and p=0.00101, respectively). Among patients with distant metastasis, patients on pembrolizumab with chemotherapy achieved significantly better OS than pembrolizumab alone (p=0.0039). Among patients in the pembrolizumab group, both AE-positive and better performance status were associated with longer OS (p=0.011 and p=0.0037, respectively)., Conclusion: Our real-world experience reinforces the durability and effectiveness of pembrolizumab for HNC patients. Additionally, our results suggest that pembrolizumab with chemotherapy might be recommended for patients with distant metastasis and no prior treatment. Further studies are needed to determine the optimal treatment strategy for HNC., (Copyright © 2022 International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Purpose: Dexamethasone (DEX)-sparing strategies (one-day DEX) with palonosetron as doublet antiemetic prophylaxis have previously been studied. However, DEX-sparing regimens with 5-hydroxytryptamine-3 receptor antagonist (5-HT 3 RA) and aprepitant (APR), as triplet antiemetic prophylaxis, have not been evaluated. This study aimed to evaluate the efficacy of a combination of 5-HT 3 RA, APR, and DEX on day 1 of carboplatin (CBDCA)-based chemotherapy in patients with lung cancer., Methods: Data were pooled from a nationwide, multicenter, prospective observational study using propensity score-matched analysis to compare the incidence of chemotherapy-induced nausea and vomiting (CINV) between one- and multiple-day DEX regimens in combination with 5-HT 3 RA plus APR., Results: Incidence of delayed nausea was significantly higher in the one-day than in the multiple-day DEX group. Incidence of nausea was also significantly higher in the one-day than in the multiple-day DEX group on days 3-5. Kaplan-Meier curves for nausea showed a significant difference between the two groups; however, there was no significant difference in the occurrence of vomiting or the Kaplan-Meier curves of time to vomiting., Conclusion: To the best of our knowledge, this study is the first to evaluate the efficacy of a DEX-sparing regimen by comparing one- and multiple-day DEX combined with 5-HT 3 RA and APR concerning CINV incidence in lung cancer patients receiving CBDCA-based chemotherapy. Antiemetic regimens of one-day DEX result in poor control of delayed nausea; therefore, we recommend the application of the DEX-sparing strategy only after careful patient selection while considering the development of nausea., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH, DE part of Springer Nature.)

Objectives: Selection criteria for palliative limited surgery in patients with non-small cell lung cancer (NSCLC) can vary by institution or surgeon. We retrospectively reviewed outcomes of poor-risk patients who underwent palliative segmentectomy (PS), using the National Clinical Database Risk Calculator (RC)., Methods: We retrospectively analyzed medical records of patients with NSCLC tumors ≥ 20 mm and consolidation/tumor ratios ≥ 0.5 on computed tomography, who underwent PS from January 2009 to March 2016. Median follow-up time was 47 months (range 2-102 months)., Results: We enrolled 67 patients (median age: 73.0 years), of whom 54 received thoracoscopic surgery and 28 received medial lymph-node dissection. The RC's mean predictive probability rate for perioperative mortality or severe complications was 7.1%. Of the 67 patients, 24 patients (43.0%) suffered post-surgical complications, including 2 (3%) who died in hospital; 17 eventually suffered NSCLC recurrences and/or metastases, 11 eventually died from NSCLC, and 17 died from other diseases. Five-year overall survival (OS) was 59.4%. When the patients were divided into high-risk (HR) and low-risk (LR) groups based on the RC, 5-year OS was significantly less in the HR group (43.9%) than in the LR group (82.2%; P < 0.05)., Conclusion: The RC, which was developed primarily to determine perioperative risk, can predict long-term prognosis for compromised patients who undergo PS.

Background: Adenoid cystic carcinoma (ACC) is a rare malignant tumor involving mostly the head and neck region, and frequently the salivary glands. The development of lung metastasis after treatment of the primary tumor is a common occurrence in ACC. Although lung metastases show a slow rate of growth, approximately 10% of patients die from distant metastases. The radioresistance of ACC limits the efficacy of conventional radiotherapy for lung metastases, and the optimal dose remains to be determined. Stereotactic body radiotherapy (SBRT) using CyberKnife can deliver a high dose to the lung tumor, while sparing the surrounding normal lung tissues, leading to favorable local control in non-squamous cell lung cancer and metastatic lung tumors. We report a case of lung metastases from ACC treated successfully with SBRT using CyberKnife., Case Presentation: A 76-year-old Japanese man with ACC who was treated with carbon ion radiotherapy for a primary oropharynx tumor presented with three metastatic lesions in the lung. The tumor masses were located in the right upper, right lower, and left lower lobes of the lungs. Surgical resection was not indicated because of the presence of multiple tumors. The patient underwent SBRT at 60 Gy in 10 sequential fractions for each tumor. The biologically effective dose based on an alpha/beta ratio of 2 Gy was 240 Gy per tumor. The percentage of the total lung volume irradiated with >20 Gy was 4.9%, 3.2%, and 2.6% for each tumor. The patient developed acute radiation pneumonitis during the initial therapy, which resolved at 6 months after the CyberKnife treatment. At 21 months after the first CyberKnife treatment, three tumors showed no signs of recurrence. No late toxicity was observed., Conclusions: SBRT using CyberKnife is an effective and feasible approach to the management of multiple lung metastases of ACC.

Background: Patients with lung cancer who are treated with carboplatin-based chemotherapy regimens often experience chemotherapy-induced nausea and vomiting (CINV). However, knowledge on the effect of regimen and cofactors on the risk of CINV is limited. This study aimed to analyze and compare the incidence of CINV between lung cancer patients undergoing carboplatin plus pemetrexed (CBDCA+PEM) and those undergoing carboplatin plus paclitaxel (CBDCA+PTX) chemotherapy., Methods: Pooled data of 240 patients from two prospective observational studies were compared using propensity score matching. Separate multivariate logistic regression analyses were used to identify risk factors for nausea and vomiting following chemotherapy., Results: Delayed nausea was significantly more common in patients treated with CBDCA+PEM than in those treated with CBDCA+PTX (51.1% vs. 36.2%, P = 0.04), but the incidence of vomiting did not significantly differ between the two groups (23.4% vs. 14.9%, P = 0.14). The occurrence of CINV peaked on day 4 in the CBDCA+PTX group and on day 5 in the CBDCA+PEM group. Multivariate analysis showed that female sex, younger age, and CBDCA+PEM regimen were independent risk factors for delayed nausea, while female sex was an independent risk factor for delayed vomiting., Conclusions: The CBDCA + PEM regimen has a higher risk of causing delayed nausea than the CBDCA + PTX regimen, and aggressive antiemetic prophylaxis should be offered to patients treated with CBDCA + PEM.

Purpose: To assess the predictive value of frailty and risk assessments for postoperative complications in lung cancer patients, we reviewed various risk indicators: including FEV1, ppoFEV1, the Zubrod performance status, the American Society of Anesthesiologist score, and risk models based on the Japan National Clinical Database (NCD) and the European Society of Thoracic Surgeons (ESTS) database., Methods: Patients who underwent elective surgery between April 2016 and May 2019 were enrolled. A statistical analysis was performed to compare any differences among the risk indicators., Results: The total number of patients enrolled was 193. Thirteen patients (6.7%) were classified as frail and 28 (14.5%) as pre-frail. Among the various risk indicators, the risk models based on the Japan NCD and the ESTS database revealed statistically significant differences in patients with and without postoperative complications (p value < 0.0001 and 0.0049, respectively), although there were no significant differences in frailty. The area under the receiver operating characteristic curve for risk models based on the Japan NCD registry and the ESTS registry was 0.70 and 0.64, respectively., Conclusions: Our analyses of a series of lung cancer patients showed that frailty was not a significant predictor of postoperative outcomes, while risk models based on academic society databases were found to have a significant predictive value.

Purpose: Prognostic significance of volumetric 18 F-fluorodeoxyglucose (FDG) positron emission tomography/computer tomography (PET/CT) parameters in carbon-ion radiotherapy (C-ion RT) treated stage I non-small cell lung cancer, and need of histology-wise separate cut-off values for risk stratification were assessed., Methods: Thirty-nine patients (29 men and 10 women, 71.9 ± 8.3 years) who underwent FDG PET/CT examinations before C-ion RT were retrospectively evaluated. FDG-PET parameters: standardized uptake values (SUVmax, SUVpeak, and SUVmean), metabolic tumor volume (MTV), and total lesion glycolysis (TLG), and clinicopathological variables were assessed for prognosis using Cox proportional hazards regression analysis. Mann-Whitney test compared medians of significant parameters between adenocarcinoma (AC) and squamous cell carcinoma (SCC), and Kaplan-Meier curves were plotted for median-based low- and high-risk groups., Results: Median follow-up period was 44.8 months. 1/2/3-year overall survival (OS), progression-free survival (PFS) and local control (LC) rates were 94.9/84.3/70.8, 82.1/69.2/58.4 and 97.3/85.7/82.3%. Multivariate analysis revealed age (hazard ratio, HR: 1.09; 95% confidence interval, CI: 1.0-1.19, p < 0.05) and MTV (HR 4.83, 95% CI 1.21-19.27, p < 0.03) predicted OS, and only MTV predicted PFS (HR 5.3, CI 1.32-21.35, p < 0.02) independently. Compared with AC, SCC had higher MTV (median, 6.625cm 3 vs 0.2 cm 3 , p < 0.01). Single MTV cut-off based on overall cohort was insignificant in SCC for PFS (p > 0.02); separate cut-offs of MTV, 0.2 cm 3 for AC (p < 0.03) and 6.625 cm 3 for SCC (p < 0.05) were relevant., Conclusion: Among all FDG PET/CT parameters, only MTV beared prognostic ability for stage I NSCLC treated with C-ion RT, and its histological variation may need consideration for risk-adapted therapeutic management.

Background and Purpose: This study aimed to assess dose distributions for stage I non-small cell lung cancer (NSCLC) with passive scattering carbon-ion radiotherapy (C-ion RT) using daily computed tomography (CT) images., Materials and Methods: We enrolled 10 patients with stage I NSCLC and acquired a total of 40 pre-fractional CT image series under the same settings as the planning CT images. These CT images were registered with planning CT images for dose evaluation using both bone matching (BM) and tumor matching (TM). Using deformable image registration, we generated accumulated doses. Moreover, the volumetric dose parameters were compared in terms of tumor coverage and lung exposure and statistical analyses were performed., Results: Overall, 25% of 40 fractional dose distributions were unacceptable with BM, compared with 2.5% with TM (P < 0.001). Using BM, three patients' accumulated dose distributions were unacceptable; however, all were satisfactory with TM (P < 0.001). No differences were observed in water-equivalent path length (WEL). The required margins in patients with poor dose distribution were 5.9 and 4.4 mm for BM and TM, respectively., Conclusions: This study establishes that CT image-based TM is robust compared with conventional BM for both daily and accumulated dose distributions. The effects of changes in WEL seem to be limited. Hence, daily CT alignment is recommended for patients with stage I NSCLC receiving C-ion RT., (Copyright © 2020 The Author(s). Published by Elsevier B.V. All rights reserved.)

Background/aim: GPR87 is a member of the cell surface molecular G protein-coupled receptors (GPCR) family and suggested to contribute to the viability of human tumor cells. Its tumor-specific expression and cell surface location make it a potential molecule for targeted therapy. In the present study, we aimed to examine the effect of silencing GPR87 expression and explore the possibility of establishing gene therapy against GPR87-overexpressing lung cancer., Materials and Methods: Twenty malignant cell lines were investigated and GPR87-overexpressing H358 and PC9 lung cancer cells were subjected to inhibiting experiments. A short hairpin siRNA targeting the GPR87 gene was transformed into an adenoviral vector (Ad-shGPR87). Real-time RT-PCR and western blot analyses were performed to evaluate gene and protein expression. Tumors derived from human H358 cells were subcutaneously implanted in nude mice for in vivo experiments., Results and Conclusion: About 50% (10/20) malignant cells showed GPR87-overexpression, especially for lung cancer cells (70%, 7/10). Ad-shGPR87 effectively down-regulated the GPR87 expression, and significantly inhibited the cell proliferation in GPR87-overexpressing H358 and PC9 cells. Treatment with Ad-shGPR87 exerted a significant antitumor effect against the GPR87-expressing H358 xenografts. In addition, the gene expression of H3.3, a recently proved activator for GPR87 transcription, was positively correlated with GPR87 gene expression. Furthermore, a significant decrease of KRAS and c-Myc expression was observed in both cell lines after Ad-shGPR87 infection. In conclusion, GPR87 may play a critical role in cancer cell proliferation, and indicate its potential as a novel target for lung cancer treatment., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: Myeloid cell leukemia-1 (MCL-1) is a member of the B-cell lymphoma-2 (Bcl-2) family of proteins, which regulate the intrinsic (mitochondrial) apoptotic cascade. MCL-1 inhibits apoptosis, which may be associated with resistance to cancer therapy. Therefore, in this study, the clinical role of MCL-1 in non-small cell lung cancer (NSCLC) was explored., Patients and Methods: This retrospective study included 80 patients with stage 1-3A NSCLC, who underwent surgery without preoperative treatment between 2010 and 2011. MCL-1 expression and Ki-67 index were determined via immunohistochemical staining. Apoptotic index (AI) was determined via terminal deoxynucleotidyl transferase dUTP nick end labeling., Results: The receiver operating characteristic curve analysis (area under curve=0.6785) revealed that MCL-1 expression in 30.0% of the NSCLC tumor cells was a significant cut-off for predicting prognosis. Tumors were considered MCL-1-positive if staining was observed in >30% of the cells. Thirty-six tumors (45.0%) were MCL-1-positive. However, there were no significant differences between MCL-1 expression and clinical variables. AI was lower in MCL-1-positive (2.2±3.6%) than in MCL-1-negative (5.2±7.9%) tumors, although the difference was not significant (p=0.1080). The Ki-67 index was significantly higher in MCL-1-positive than in MCL-1-negative tumors (18.0% vs. 3.0%; p<0.001). Five-year survival rate was significantly worse in patients with MCL-1-positive tumors (68.3%) than in those with MCL-1-negative tumors (93.1%, p=0.0057). Univariate [hazard ratio (HR)=5.041, p=0.0013], and multivariate analyses revealed that MCL-1 expression was a significant prognostic factor (HR=3.983, p=0.0411)., Conclusion: MCL-1 expression in NSCLC cells correlated inversely with AI and positively with Ki-67 index. MCL-1 may serve as a potential prognostic biomarker and a novel therapeutic target in NSCLC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background/aim: We performed multimodality therapy comprising preoperative chemotherapy, extrapleural pneumonectomy (EPP), and radiation therapy for patients with malignant pleural mesothelioma (MPM). Although multimodality therapy resulted in good prognosis, further improvement is required. Therefore, herein, we analysed the prognostic factors using surgical specimens and searched for suitable molecular targets to improve the prognosis after multidisciplinary treatment., Patients and Methods: Forty-six patients with MPM underwent multimodality therapy. Paraffin-embedded surgical samples were used for immunohistochemistry to evaluate the expression of phosphorylated (p-) AKT, extracellular signal-regulated kinase (ERK), mammalian target of rapamycin (mTOR), mitogen-activated protein kinase (MAPK), eukaryotic translation initiation factor 4E-binding protein 1 (4E-BP1), and S6 ribosomal protein (S6RP)., Results: On univariate and multivariate analyses, significant differences were observed according to the histological type, pathological stage, and p-mTOR expression rate., Conclusion: The prognosis of MPM is affected by p-mTOR expression, suggesting that molecular-targeted treatment might be used during multimodal therapy for MPM., (Copyright© 2019, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

This phase II study's aim was to confirm the efficacy and safety of hypofractionated carbon-ion radiotherapy in patients with stage I peripheral nonsmall cell lung cancer (NSCLC). The study encompassed 37 patients with histologically proven peripheral stage I NSCLC in the period June 2010-March 2015. All underwent the planned full dose of carbon-ion radiotherapy, administered with relative biological effectiveness of 52.8 Gy and 60 Gy (divided into four fractions over 1 week) for T1 and T2a tumors, respectively. The 2-year local control rate was set as the primary endpoint, while overall survival, progression-free survival, and the incidence rates of acute and late adverse events were secondary endpoints. The patients were followed up for 56.3 months overall and 62.2 months in the surviving patients, respectively. The actuarial local control rates were 91.2% after 2 years, and 88.1% after 5 years. No differences were found between the T1 and T2a tumors in the 5-year local control rate (90.9% vs 86.7%, P = .75). The actuarial overall survival rates achieved 91.9% for 2-year and 74.9% for 5-year period. T1 tumors showed actuarial 5-year overall survival rates of 80%, compared to 66.7% in T2a tumors. Two patients with T2a tumors and either severe emphysema or bronchiectasis experienced lung toxicity ≥ grade 2, in contrast to T1 patients who only experienced mild toxicities (lower than grade 2). The findings suggest that carbon-ion radiotherapy is effective and safe for peripheral stage I NSCLC; however, further clinical evaluations are needed to confirm its therapeutic efficacy. Trial registration: UMIN000003797. Registered 21 June 2010, prospectively registered., (© 2019 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Objective: After securing a sufficient surgical margin at wedge resection and finding no pathologic evidence of residual tumor at the surgical margin, a considerable number of patients develop local recurrence. We investigated the correlation between sub-pleural lymphatic flow and local recurrence., Methods: We retrospectively reviewed the medical records of 144 non-small cell lung cancer patients who underwent wedge resection between January 2006 and December 2014 at our institution., Results: Postoperative recurrence was observed in 36 patients (25%). Of these, local recurrence was observed in 29 patients (80.5%). The proportion of all recurrence and local recurrence were significantly higher among patients with lymphatic vessel invasion (LVI) (p < 0.0001). Recurrence-free survival rate was significantly lower in patients with LVI (24.8%) than in patients without LVI (80.2%, p < 0.0001). Multivariate logistic regression analysis demonstrated LVI (odds ratio = 6.420, p = 0.0009) as a significant predictor of local recurrence., Conclusions: Intratumoral lymphatic invasion represents a major cause of local recurrence. Although we should aim for radical surgery whenever possible, when limited surgery is the only option, postoperative adjuvant treatment may need to be considered for patients showing lymphatic invasion even at an early stage.

Decreased cell adhesion has been reported as a significant negative prognostic factor of lung cancer. However, the molecular mechanisms responsible for the cell incohesiveness in lung cancer have not yet been elucidated in detail. We herein describe a rare histological variant of lung adenocarcinoma consisting almost entirely of individual cancer cells spreading in alveolar spaces in an incohesive pattern. A whole exome analysis of this case showed no genomic abnormalities in CDH1 or other genes encoding cell adhesion molecules. However, whole mRNA sequencing revealed that this case had an extremely high expression level of mucin 21 (MUC21), a mucin molecule that was previously shown to inhibit cell-cell and cell-matrix adhesion. The strong membranous expression of MUC21 was found on cancer cells using mAbs recognizing different O-glycosylated forms of MUC21. An immunohistochemical analysis of an unselected series of lung adenocarcinoma confirmed that the strong membranous expression of MUC21 correlated with incohesiveness. Thus, MUC21 could be a promising biomarker with potential diagnostic and therapeutic applications for lung adenocarcinoma showing cell incohesiveness., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Cancer-specific antigens expressed in the cell membrane have been used as targets for several molecular targeted strategies in the last 20 years with remarkable success. To develop more effective cancer treatments, novel targets and strategies for targeted therapies are needed. Here, we examined the cancer cell membrane-resident "cis-bimolecular complex" as a possible cancer target (cis-bimolecular cancer target: BiCAT) using proximity proteomics, a technique that has attracted attention in the last 10 years. BiCAT were detected using a previously developed method termed the enzyme-mediated activation of radical source (EMARS), to label the components proximal to a given cell membrane molecule. EMARS analysis identified some BiCAT, such as close homolog of L1 (CHL1), fibroblast growth factor 3 (FGFR3) and α2 integrin, which are commonly expressed in mouse primary lung cancer cells and human lung squamous cell carcinoma cells. Analysis of cancer specimens from 55 lung cancer patients revealed that CHL1 and α2 integrin were highly co-expressed in almost all cancer tissues compared with normal lung tissues. As an example of BiCAT application, in vitro simulation of effective drug combinations used for multiple drug treatment strategies was performed using reagents targeted to BiCAT molecules. The combination treatment based on BiCAT information moderately suppressed cancer cell proliferation compared with single administration, suggesting that the information about BiCAT in cancer cells is useful for the appropriate selection of the combination among molecular targeted reagents. Thus, BiCAT has the potential to contribute to several molecular targeted strategies in future., (© 2019 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: Nintedanib targets VEGF receptors 1-3, PDGF receptors α and β, FGF receptors 1-3, and Src and Abl kinases, which are all implicated in malignant pleural mesothelioma pathogenesis. Here, we report the final results of the phase 3 part of the LUME-Meso trial, which aimed to investigate the efficacy and safety of pemetrexed plus cisplatin combined with nintedanib or placebo in unresectable malignant pleural mesothelioma., Methods: This double-blind, randomised, placebo-controlled phase 3 trial was done at 120 academic medical centres and community clinics in 27 countries across the world. Chemotherapy-naive adults (aged ≥18 years) with unresectable epithelioid malignant pleural mesothelioma and ECOG performance status 0-1 were randomly assigned 1:1 via an independently verified random number-generating system to receive up to six 21-day cycles of pemetrexed (500 mg/m 2 ) plus cisplatin (75 mg/m 2 ) on day 1, then nintedanib (200 mg twice daily) or matched placebo on days 2-21. Patients without disease progression after six cycles received nintedanib or placebo maintenance on days 1-21 of each cycle. The primary endpoint was progression-free survival (investigator-assessed according to mRECIST) in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of their assigned study drug. This study is registered with ClinicalTrials.gov, number NCT01907100., Findings: Between April 14, 2016, and Jan 5, 2018, 541 patients were screened and 458 were randomly assigned to either the nintedanib group (n=229) or the placebo group (n=229). Median treatment duration was 5·3 months (IQR 2·8-7·3) in the nintedanib group and 5·1 months (2·7-7·8) in the placebo group. After 250 events, progression-free survival was not different between the nintedanib group (median 6·8 months [95% CI 6·1-7·0]) and the placebo group (7·0 months [6·7-7·2]; HR 1·01 [95% CI 0·79-1·30], p=0·91). The most frequently reported grade 3 or worse adverse event in both treatment groups was neutropenia (73 [32%] in the nintedanib group vs 54 [24%] in the placebo group). Serious adverse events were reported in 99 (44%) patients in the nintedanib group and 89 (39%) patients in the placebo group. The only serious adverse event occurring in at least 5% of patients in either group was pulmonary embolism (13 [6%] vs seven [3%])., Interpretation: The primary progression-free survival endpoint of the phase 3 part of LUME-Meso was not met and phase 2 findings were not confirmed. No unexpected safety findings were reported., Funding: Boehringer Ingelheim., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Objectives: Recently, the use of video-assisted thoracoscopic surgery (VATS) segmentectomy for pulmonary malignancies has increased. For non-palpable lesions, securing a sufficient surgical margin is more likely to be uncertain. The purpose of this study was to evaluate the usefulness of our intraoperative navigation system in combination with the infrared thoracoscopy (IRT)-indocyanine green (ICG) method and intraoperative computed tomography (CT) during VATS segmentectomy for non-palpable pulmonary malignancies., Methods: This study involved 12 consecutive patients who underwent both IRT-ICG and intraoperative CT-assisted thoracoscopic segmentectomy. Identification of the intersegmental line on the visceral pleura was visualized using IRT-ICG. The intersegmental line was marked by clipping, and intraoperative CT scan was performed under bilateral lung ventilation. The intraoperative CT images were used by the surgeons to confirm the correct anatomic segmental border and to secure a sufficient resection margin., Results: A well-defined intersegmental line was observed in 83.3% of the patients. The rate of concordance between 3-dimensional (3D)-CT images reconstructed from intraoperative CT and preoperative simulation 3D-CT imaging was 91.7%. The mean surgical margin assessed on gross examination by the pathologist was 22.3 ± 4.5 mm. Complete resection was achieved in all patients using this approach., Conclusions: Imaging support including preoperative simulation, IRT-ICG and intraoperative CT enables surgeons to perform definitive VATS segmentectomy for non-palpable lesions.

Background: The most important step in lung segmentectomy is to determine an appropriate intersegmental plane to obtain sufficient pre- and intraoperative margins. Inappropriate dissection of the lung parenchyma leads to loss of oncological validity and additionally causes various complications such as pneumonia, prolonged air leakage, lung congestion, and atelectasis., Objectives: In this study, we evaluated the validity of segmentectomy for non-small cell lung cancer (NSCLC) based on evaluation of survival outcomes and recurrence patterns., Operative Technique: In principle, we usually perform video-assisted thoracic surgery segmentectomy. Hilar dissection is performed along the intersegmental vein under ultrasonographic guidance, and the peripheral lung parenchyma is subsequently stapled. We usually create inflation-deflation lines from before to determine the intersegmental lines. Recently, near-infrared fluorescence imaging with indocyanine green is also used., Methods: We retrospectively reviewed data of 101 patients who underwent segmentectomy for lung cancer between 2007 and 2014., Results: The 5- and 10-year overall survival rates were 84% and 62%, respectively. The 5- and 10-year recurrence-free survival rates were 83% and 63%, respectively. Recurrence at the surgical margin occurred in 5 patients( pulmonary stump:4 patients, bronchial stump:1 patient)., Conclusion: Segmentectomy may be acceptable for patients with Stage I NSCLC. Accurate determination of the intersegmental plane is essential to avoid stump recurrence.

We compared less invasive surgery with conventional surgery for malignant pleural mesothelioma (MPM). We retrospectively reviewed consecutive patients with MPM who received surgery at Hyogo College of Medicine between July 2004 and April 2016. Patients underwent multimodal treatment comprising chemotherapy (neoadjuvant and/or adjuvant) and surgery with or without 54 Gy hemithoracic radiotherapy. Patients were grouped into 3 groups according to the surgery intended: Conventional extrapleural pneumonectomy was intended in Group 1 (until August 2009); less invasive extrapleural pneumonectomy was intended in Group 2 (after September 2009); pleurectomy/decortication was intended in Group 3 (after September 2012). We included 152 patients (median age 64 [37-71] years; 131 men, 21 women), mostly with epithelioid subtypes (91.4%). Of them, 149 (98.0%) underwent neoadjuvant chemotherapy and 117 (77.0%) underwent surgery (60 had extrapleural pneumonectomy and 57 had pleurectomy/decortication). Macroscopic complete resection was achieved in 94.9% (111/117), and the mortality rates at 30 and 90 days were 1.7% (2/117) and 3.4% (4/117), respectively. The overall median survival time and progression-free survival for all 152 patients were 34.9 and 17.4 months. The overall median survival time for Groups 1, 2, and 3 were 18.5, 41.9, and 43.4 months, respectively. The progression-free survival for Groups 1, 2, and 3 were 12.0, 24.5, and 21.8 months, respectively. Compared with conventional surgical techniques, less invasive surgery for MPM yielded lower surgical risks and comparable or improved survival., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Malignant pleural mesothelioma (MPM) is a global health issue, the principal cause of which is exposure to asbestos. The prevalence is anticipated to rise over the next 2 decades, particularly in developing countries, due to the 30-50-year latency period between exposure to asbestos and carcinogenic development. Unresectable MPM has a poor prognosis and limited treatment options and, as such, there is a broad range of therapeutic targets of interest, including angiogenesis, immune checkpoints, mesothelin, as well as chemotherapeutic agents. Recently, the results of several randomized trials in the first-line setting combining antiangiogenic agents with chemotherapy have been reported. This review examines the scientific rationale for targeting angiogenesis in the treatment of unresectable MPM and analyzes recent clinical results with antiangiogenic agents in development (bevacizumab, nintedanib, and cediranib) for the management of MPM., (Copyright © 2019. Published by Elsevier Inc.)

Purpose: Inhibition of focal adhesion kinase has been shown to selectively kill mesothelioma cells that express low levels of moesin-ezrin-radixin-like protein (merlin). On this basis, we designed a randomized, phase II trial to investigate whether defactinib as maintenance therapy after standard first-line chemotherapy could improve progression-free survival (PFS) in patients with malignant pleural mesothelioma (MPM)., Methods: This global, double-blind, randomized, placebo-controlled trial was conducted in patients with advanced MPM and disease control after at least four cycles of first-line chemotherapy. Patients were stratified for merlin and then randomly assigned (in a 1:1 fashion) to receive either oral defactinib or placebo until disease progression, unacceptable toxicity, or withdrawal occurred. The coprimary end points were PFS and overall survival (OS). Quality of life (QoL) was assessed using the Lung Cancer Symptom Scale for Mesothelioma tool., Results: Three hundred forty-four patients were randomly assigned to receive either defactinib (n = 173) or placebo (n = 171). The median PFS was 4.1 months (95% CI, 2.9 to 5.6 months) for defactinib versus 4.0 months (95% CI, 2.9 to 4.2 months) for placebo. The median OS was 12.7 months (95% CI, 9.1 to 21 months) for defactinib versus 13.6 months (95% CI, 9.6 to 21.2 months) for placebo (hazard ratio, 1.0; 95% CI, 0.7 to 1.4). Although shorter survival for both defactinib- and placebo-treated patients was observed, in the patients who had merlin-low MPM compared with the patients who had merlin-high MPM, there were no statistical differences in response rate, PFS, OS, or QoL between the treatment groups. The most common grade 3 or worse adverse events were nausea, diarrhea, fatigue, dyspnea, and decreased appetite., Conclusion: Neither PFS nor OS was improved by defactinib after first-line chemotherapy in patients with merlin-low MPM. Defactinib cannot be recommended as maintenance therapy for advanced MPM.

Competing Interests: Competing interests: None declared.

A 63-year-old man was pointed out with a mediastinal tumor on chest computed tomography (CT). On positron emission tomography-CT, fluorodeoxyglucose accumulation with a maximum standardized uptake value of 12.70 was seen in this tumor. Scar-like nodule was found in the apex of the right lung, but no abnormal accumulation was observed in this nodule. The level of carcinoembryonic antigen was abnormally elevated. We performed mediastinal tumorectomy under thoracoscopic surgery. Since arterial oxygen saturation fell during intraoperative one-lung ventilation, we finished the surgery without resection of right apex nodule. Histologically, mediastinal tumor was diagnosed as metastatic adenocarcinoma in lymph node. Because immunohistochemical staining suggested lung adenocarcinoma as the primary site, the right apex nodule was resected. Pathological diagnosis of this nodule was scar fibrosis. No other malignant lesions were detected, and therefore we finally diagnosed this tumor as mediastinal lymph node carcinoma of unknown primary site. The patient was given adjuvant chemotherapy, and at present, 37 months after surgery, the patient remains free of the disease.

Background and Purpose: Patient positioning was compared by tumor matching (TM) and conventional bony structure matching (BM) in carbon ion radiotherapy for stage I non-small cell lung cancer to evaluate the robustness of TM and BM in determining interfractional error., Material and Methods: Sixty irradiation fields were analyzed. Computed tomography (CT) images acquired before treatment initiation for confirmation (Conf-CT) were obtained under the same settings as the treatment planning CT images and used to evaluate both positioning methods. The dose distributions were recalculated for Conf-CT using both BM and TM, and the dose-volume histogram parameters [V 95% of clinical target volume, V 5Gy(RBE) of normal lung, and acceptance ratio (ratio of cases with V 95%  > 95%)] were evaluated. The required margin, which in 90% of cases achieved the acceptable condition, was also examined., Results: Using BM and TM, the median V 95% was 98.93% and 100% (p < 0.001) and the mean V 5Gy(RBE) was 135.9 and 125.8 (p = 0.694), respectively. The estimated required margins were 7.9 and 3.3 mm and increased by 53.9% and 2.5% of V 5Gy(RBE) , respectively, compared with planning., Conclusions: TM ensured a better dose distribution than did BM. To enable TM, volumetric imaging is crucial and should replace 2D radiographs for carbon therapy of stage I lung cancer., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Close homolog of L1 (CHL1) and its truncated form mainly play crucial roles in mouse brain development and neural functions. Herein, we newly identified that truncated form of CHL1 is produced and released from lung tumor tissue in a mouse model expressing human EML4-ALK fusion gene. Both western blot and direct ELISA analysis revealed that mouse CHL1 level in serum (including serum extracellular vesicles) was significantly elevated in EML4-ALK transgenic mice. The correlation between the tumor size and the amount of CHL1 secretion could be examined in this study, and showed a significant positive correlation in a tumor size-dependent manner. Considering these results, the measurement of circulating CHL1 level may contribute to assess a tumor progression in human lung tumor patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Purpose: We designed and evaluated a simple method for predicting the effects of intra-fractional and/or inter-fractional motion on dose distribution during carbon ion radiotherapy (CIRT) for solitary-lesion stage I lung cancer., Methods: The proposed method uses computed tomography (CT) images from treatment planning and intra-tumoral and/or inter-tumoral displacement. The predicted dose distribution (PDD) was calculated by replacing the current tumor region with the stopping power ratio (SPR) of the lung and replacing the moved tumor region with the SPR of the tumor. The actual dose distribution (ADD) was calculated without the replacement. Ten patients with solitary-lesion stage I lung cancer were retrospectively studied to evaluate the prediction method's accuracy. Four PDDs for intra-fractional motion (gate-in, exhalation, gate-out, inhalation phases during four-dimensional CT) and two PDDs for inter-fractional motion (CT images acquired 1-2 days before treatment) with bone- and tumor-matching methods were compared with each of six ADDs on each CT scan. Percentages of the planning/clinical target volumes (PTV/CTV) receiving >95% of the prescribed dose (V 95 ) and of minimum doses covering 95% of the PTV/CTV (D 95 ) were compared with dose volume histogram parameters., Results: The maximum tumor displacements occurred in the superior-inferior direction, with intra-fractional motion values of 3.75 and 8.97 mm for the superior and inferior directions, respectively, and inter-fractional values of 9.61 and 4.10 mm. The maximum average error for PTV V 95 regarding intra-fractional motion was -0.43% for the gate-out phase and -0.63% for the inhalation phase. There were no significant differences for these parameters (P = 0.541, P = 0.571). Average errors for PTV and CTV V 95 with inter-fractional motion with bone matching were 2.2% and 2.9%, respectively, with no significant differences (P = 0.387, P = 0.155)., Conclusions: The accuracy of the proposed method was good. Hence, it is feasible to use the proposed method during CIRT to predict dose distribution with respect to intra-fractional motion and/or inter-fractional motion of the tumor in patients with solitary-lesion stage I lung cancer., (© 2018 American Association of Physicists in Medicine.)

Performance of thoracoscopic pulmonary segmentectomy for primary lung cancer or pulmonary metastases has recently increased. In patients with emphysema, identification of the intersegmental line is often difficult. For nonpalpable lesions, securing a sufficient surgical margin is more likely to be uncertain. The purpose of this study was to evaluate the efficacy of intraoperative computed tomography (CT) scan during video-assisted thoracoscopic surgery (VATS) pulmonary segmentectomy. This study included 12 patients who underwent intraoperative CT-assisted VATS segmentectomy between January 2015 and August 2016. After dividing the corresponding vessels and bronchi, the intersegmental line was marked by clipping, and intraoperative CT scan was performed under bilateral lung ventilation. The intraoperative CT or 3-dimensional CT reconstruction images were used by the surgeons to confirm the correct anatomical segmental border and to secure a sufficient resection margin. In all patients, the location of the lesions to be resected, the intersegmental border, and the surgical margins could be confirmed while performing VATS segmentectomy. Complete resection was achieved in all patients. Although the pathologic margins tended to be shorter than the surgical margins on intraoperative CT images, there was a strong correlation between these 2 variables (r = 0.963, P < 0.0001). Intraoperative CT scan during VATS segmentectomy was useful for identifying the location of nonpalpable lesions, confirming anatomical intersegmental borders and securing the resection margins. Intraoperative CT navigation could enable a more definitive VATS segmentectomy for nonpalpable lesions., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Purpose: We developed a system for calculating patient positional displacement between digital radiography images (DRs) and digitally reconstructed radiography images (DRRs) to reduce patient radiation exposure, minimize individual differences between radiological technologists in patient positioning, and decrease positioning time. The accuracy of this system at five sites was evaluated with clinical data from cancer patients. The dependence of calculation accuracy on the size of the region of interest (ROI) and initial position was evaluated for clinical use., Methods: For a preliminary verification, treatment planning and positioning data from eight setup patterns using a head and neck phantom were evaluated. Following this, data from 50 patients with prostate, lung, head and neck, liver, or pancreatic cancer (n = 10 each) were evaluated. Root mean square errors (RMSEs) between the results calculated by our system and the reference positions were assessed. The reference positions were manually determined by two radiological technologists to best-matching positions with orthogonal DRs and DRRs in six axial directions. The ROI size dependence was evaluated by comparing RMSEs for three different ROI sizes. Additionally, dependence on initial position parameters was evaluated by comparing RMSEs for four position patterns., Results: For the phantom study, the average (± standard deviation) translation error was 0.17 ± 0.05, rotation error was 0.17 ± 0.07, and ΔD was 0.14 ± 0.05. Using the optimal ROI size for each patient site, all cases of prostate, lung, and head and neck cancer with initial position parameters of 10 mm or under were acceptable in our tolerance. However, only four liver cancer cases and three pancreatic cancer cases were acceptable, because of low-reproducibility regions in the ROIs., Conclusion: Our system has clinical practicality for prostate, lung, and head and neck cancer cases. Additionally, our findings suggest ROI size dependence in some cases., (© 2018 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Background/aim: The aim of this study was to assess the feasibility and safety of hypofractionated carbon-ion radiotherapy (C-ion RT) in patients with stage III non-small cell lung cancer (NSCLC)., Patients and Methods: Patients with untreated, histologically proven, unresectable stage III NSCLC and not candidates for chemotherapy were included in this study. C-ion RT was planned and administered with 4 Gy (relative biological effectiveness (RBE)) in daily fractions for a total dose of 64 Gy (RBE) without combined chemotherapy. Dose-limiting toxicity (DLT) was defined as suspension of C-ion RT treatment for 2 weeks due to ≥ grade 2 pneumonitis, or any other ≥ grade 3 adverse event, or as any ≥ grade 4 adverse event within 3 months from the start of treatment., Results: Six patients were treated between June 2013 and December 2014. The planned full dose of C-ion RT (64 Gy (RBE)) was completed in all patients. No patient developed DLT, and no patient experienced toxicities of ≥grade 3 severity. The overall response rate was 100%, and local tumor control was achieved in all patients during the survival period., Conclusion: Hypofractionated C-ion RT of patients with stage III NSCLC was feasible and well tolerated. Although the number of patients in this study was small, the results support further investigations to confirm the long-term therapeutic efficacy of this treatment., (Copyright© 2018, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

A 63-year-old man was admitted to our department following a secondary medical examination. Blood tests showed high levels of liver enzymes, IgG, IgG4, and antinuclear antibody. Computed tomography showed tumors in the bilateral lower lobes of the lungs and pleural thickening. After pleural and liver biopsy procedures, he was conclusively diagnosed with IgG4-related lung pseudotumor and pleural inflammation with autoimmune hepatitis. We started treatment with prednisolone 40 mg/day, and chest radiograph and blood tests showed signs of improvement. This was a rare case that suggested an association between IgG4-related disease and autoimmune hepatitis.

Malignant pleural mesothelioma(MPM)is a highly aggressive tumor with a poor prognosis and an increasing incidence worldwide. The only standard first-line chemotherapy for patients with unresectable MPM is cisplatin(CDDP)plus peme- trexed(PEM)(CDDP/PEM), with a median overall survival of about 12months and a median progression-free survival(PFS) of less than 6 months. There are no treatments with proven benefit on survival for relapsed MPM patients. Therefore, novel therapeutic strategies are urgently required. Several molecular pathways involved in MPM have been identified; these include growth factor signaling pathways, cell cycle regulation, apoptosis, and angiogenesis. Fortunately, several agents targeting these processes have yielded promising results in preliminary trials. The addition of vascular endothelial growth factor(VEGF) inhibitor bevacizumab to the standard CDDP/PEM provides a 2.7-month survival benefit. Triple angiokinase inhibitor nintedanib, inhibiting the VEGFR, PDGFR, and FGFR, plus standard chemotherapy demonstrated a significant improvement in median PFS of 3.7 months in the overall study population, and a greater median PFS benefit of 4.0 months in epithelioid MPM. Mesothelin is an attractive target protein expressed on mesothelioma cells. Amatuximab, a chimeric anti-mesothelin antibody, in combination with CDDP/PEM, is currently being tested in randomized, double-blind, placebo-controlled phase II study. Anetumab ravtansine, mesothelin-directed antibody drug conjugate, was evaluated in a randomized trial to compare to vinorelbine in patients with MPM who have high mesothelin expression and have progressed on CDDP/PEM-based first-line chemotherapy. However, anetumab ravtansine was not superior to vinorelbine in primary endpoint of PFS(4.3 months vs 4.5 months). Immune checkpoint blockades have demonstrated promising preclinical and clinical results in several cancer types, and are currently being investigated in clinical trials for MPM patients. PD-L1 expression in tumor tissue of MPM was reported, ranging between 20% and 70%. PD-L1 expression was significantly associated with a worse survival and overexpression was more common in sarcomatoid histology. This review summarizes clinical results for the latest systemic treatments in MPM.

Objective: There are several prognostic indices (PIs) to predict overall survival (OS) in malignant pleural mesothelioma (MPM) patients. Before using a clinical prediction model in the actual clinical setting, empiric evaluation of its performance based on datasets that were not used to develop the model (i.e., external validation) is essential. The purpose of this study was to conduct an external validation of the PIs for MPM., Materials and Methods: A retrospective cohort study was performed on MPM patients treated at 2 tertiary hospitals in Japan between 2007 and 2015. The primary outcome was OS. Harrell's c-index, and was calculated to examine the discrimination of three models. The bootstrapping technique was used to evaluate optimism., Results: The participants comprised 183 patients who underwent surgical treatment (n=61), chemotherapy (n=101), and best supportive care (BSC, n=21). The median OS rates were 1014days for surgery, 690days for chemotherapy, and 545days for best supportive care (BSC). The respective discriminations (95% confidence interval) of the Eastern Cooperative Oncology Group Performance Status, the European Organisation for Research and Treatment of Cancer index, regimen, PS, histology or stage (rPHS) index, and Tagawa index for the OS of MPM patients were 0.532 (0.444-0.620), 0.560 (0.472-0.648), 0.584 (0.452-0.716), and 0.525 (0.453-0.596) for surgery; 0.632 (0.539-0.724), 0.622 (0.548-0.696), 0.677 (0.587-0.766), and 0.545 (0.436-0.653) for chemotherapy; and 0.504 (0.365-0.644), 0.583 (0.456--0.710), 0.704 (0.508-0.899), and 0.583 (0.436-0.730) for BSC., Conclusions: Each PI showed poor discrimination for MPM patients who underwent surgical treatment. The rPHS index showed moderate discrimination for patients given chemotherapy and BSC., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background/aim: To analyze the accuracy of patient positioning and dose distribution quality using a fiducial marker-matching technique in carbon-ion radiotherapy (C-ion RT) for stage I lung cancer., Patients and Methods: Thirteen patients with 26 fiducial markers and 104 radiation fields were examined. Change in the fiducial marker position coordinates from the gross tumor volume center (Δm), and change in the water-equivalent path length of the chest wall (ΔWEL) were measured in each radiation field. Criterion for an acceptable change in dose distribution was defined as the percentage of D95 (%D95) at gross tumor volume greater than 90% of the prescribed dose., Results: Thirteen radiation fields (12.5%) were classified as unacceptable. Δm and ΔWEL had significant negative correlations with %D95 and thus were significant factors related to unacceptable irradiation fields., Conclusion: Patient positioning using a fiducial marker-matching technique resulted in 12.5% of radiation fields demonstrating unacceptable degradation due to Δm and ΔWEL., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Additional chemotherapy is often not feasible in patients with recurrent malignant pleural mesothelioma (MPM) undergoing extrapleural pneumonectomy (EPP), due to deteriorated cardiopulmonary reserve. We thus examined the feasibility and efficacy of additional chemotherapy in patients with recurrent MPM after EPP., Methods: A retrospective review was conducted of 59 consecutive patients who underwent bi-/tri-modal treatment with induction chemotherapy, EPP, and radiation therapy from July 2004 to August 2013 at Hyogo College of Medicine (Nishinomiya, Japan)., Results: Of 59 patients, 39 (male/female = 31/8, right/left = 15/24, pathological stage I/II/III/IV = 1/7/23/3, bi-/tri-modality = 27/12) relapsed at a median age of 62 (range 37-71) years. The median time to recurrence after EPP was 11.6 months. Of the 39 relapsed patients, 12 received best supportive care alone, six started but discontinued chemotherapy, and the remaining 21 (53%) completed more than three cycles of intravenous chemotherapy. The median survival time after EPP was significantly longer in 21 patients who received additional chemotherapy than in 18 patients who did not (39.2 vs. 12.2 months, P = 0.009)., Conclusions: Additional systemic chemotherapy was successfully administered in more than 50% of relapsed patients after bi-/tri-modal treatment, which included EPP, and resulted in a longer survival in comparison with best supportive care alone.

Carbon-ion radiation therapy (CIRT) for advanced non-small-cell lung cancer (NSCLC) has not been well studied to date. This paper aimed to analyze a retrospective multicenter survey for detecting problems with the use of CIRT for Stage II and III NSCLC (7th UICC TNM Staging System). Inclusion was restricted to patients with Stage II and III NSCLC who received CIRT from November 2003 to December 2014. We gathered the data from three CIRT operating centers on July 2015. Patients with radiotherapy history, patients with cancers other than lung cancer, and those receiving palliative therapies were excluded. The patient characteristics, prescribed dose/fraction, survival rates, and adverse effects were analyzed. The total number of patients was 64 (male: 49, female: 15). Of these, 53 patients were medically inoperable. The median age was 76 years (range 46-91), and the median follow-up period was 18.5 months (range 3.2-121.5). The clinical staging consisted of 10 Stage IIA, 30 Stage IIB, 23 Stage IIIA and 1 Stage IIIB. The median prescribed dose was 72.0 Gy (RBE) (range 52.8-72.0) in 16 fractions (range 4-16). The 2-year overall survival, progression-free survival, and local control rates were 62.2% [confidence interval (CI): 47.5-76.9], 42.3% (CI: 28.8-55.8) and 81.8% (CI: 69.9-94.0), respectively. There were no higher than Grade 2 adverse effects observed. CIRT for inoperable Stage II and III NSCLC could be implemented without severe adverse effects, but the clinical staging (including lymph node status) was inhomogeneous. In addition, the prescribed dose and fractionation were not standardized. Further data accumulation and a multiple centers prospective trial for evaluating clinical stage-based results are required., (© The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: Mesothelioma of peritoneal origin has wider variation in treatment outcomes than mesothelioma of pleural origin, likely because peritoneal mesothelioma comprises borderline malignant variants and aggressive malignant peritoneal mesothelioma (MPeM). This study retrospectively evaluates the efficacy of first-line systemic pemetrexed and cisplatin chemotherapy in MPeM., Research Design and Methods: Twenty-four patients with histologically proven MPeM were treated with pemetrexed plus cisplatin as a first-line systemic chemotherapy. The response was evaluated radiologically according to standard Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Twenty-two patients underwent 18 F-fluorodeoxyglucose positron emission tomography/(FDG-PET)/computed tomography(CT) at baseline, and 13 were eligible for metabolic assessment., Results: Two complete responses and 9 partial responses were achieved. Overall response rate and disease control rate were 45.8% and 91.7%, respectively. Median progression-free survival and median overall survival were 11.0 months and 15.8 months, respectively. Wet- type MPeM had significantly longer survival (40.9 months median) than other clinical types (15.5 months) (P = 0.045). The baseline maximum standardized uptake value in 22 patients was 8.93 (range, 2.5-16.77)., Conclusions: Systemic pemetrexed plus cisplatin is active for MPeM. Disparity with the outcome of cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (CRS/HIPEC) needs to receive more emphasis, since peritoneal mesothelioma has a 5-year survival rate of 50%.

Decreased cell-substratum adhesion is crucially involved in metastasis. Previous studies demonstrated that lung cancer with floating cell clusters in histology is more likely to develop metastasis. In the present study, we investigated whether cancer cells in long-term, three-dimensional low attachment cultures acquire high metastatic potential; these cells were then used to examine the mechanisms underlying metastasis. Two KRAS-mutated adenocarcinoma cell lines (A549 and H441) were cultured and selected on ultra-low attachment culture dishes, and the resulting cells were defined as FL (for floating) sublines. Cancer cells were inoculated into NOD/SCID mice via an intracardiac injection, and metastasis was evaluated using luciferase-based imaging and histopathology. In vitro cell growth (in attachment or suspension cultures), migration, and invasion were assayed. A whole genomic analysis was performed to identify key molecular alterations in FL sublines. Upon detachment on low-binding dishes, parental cells initially formed rounded spheroids with limited growth activity. However, over time in cultures, cells gradually formed smaller spheroids that grew slowly, and, after 3-4 months, we obtained FL sublines that regained prominent growth potential in suspension cultures. On ordinary dishes, FL cells reattached and exhibited a more spindle-shaped morphology than parental cells. No marked differences were observed in cell growth with attachment, migration, or invasion between FL sublines and parental cell lines; however, FL cells exhibited markedly increased growth potential under suspended conditions in vitro and stronger metastatic abilities in vivo. A genomic analysis identified epithelial-mesenchymal transition (EMT) and c-Myc amplification in A549-FL and H441-FL cells, respectively, as candidate mechanisms for metastasis. The growth potential of FL cells was markedly inhibited by lentiviral ZEB1 knockdown in A549-FL cells and by the inhibition of c-Myc through lentiviral knockdown or the pharmacological inhibitor JQ1 in H441-FL cells. Long-term three-dimensional low attachment cultures may become a useful method for investigating the mechanisms underlying metastasis mediated by decreased cell-substratum adhesion.

Mps One Binder Kinase Activator (MOB)1A/1B are core components of the Hippo pathway. These proteins, which coactivate LArge Tumour Suppressor homologue kinases, are also tumour suppressors. To investigate MOB1A/B's roles in normal physiology and lung cancer, we generated doxycycline (Dox)-inducible, bronchioalveolar epithelium-specific, null mutations of MOB1A/B in mice (SPC-rtTA/(tetO) 7 -Cre/Mob1a flox/flox /Mob1b -/- ; termed luMob1DKO mice). Most mutants (70%) receiving Dox in utero (luMob1DKO (E6.5-18.5) mice) died of hypoxia within 1 h post-birth. Their alveolar epithelial cells showed increased proliferation, impaired YAP1/TAZ-dependent differentiation and decreased surfactant protein production, all features characteristic of human respiratory distress syndrome. Intriguingly, mutant mice that received Dox postnatally (luMob1DKO (P21-41) mice) did not develop spontaneous lung adenocarcinomas, and urethane treatment-induced lung tumour formation was decreased (rather than increased). Lungs of luMob1DKO (P21-41) mice exhibited increased detachment of bronchiolar epithelial cells and decreased numbers of the bronchioalveolar stem cells thought to initiate lung adenocarcinomas. YAP1/TAZ-NKX2.1-dependent expression of collagen XVII, a key hemidesmosome component, was also reduced. Thus, a MOB1-YAP1/TAZ-NKX2.1 axis is essential for normal lung homeostasis and expression of the collagen XVII protein necessary for alveolar stem cell maintenance in the lung niche.

Carbon-ion radiotherapy (CIRT) is an advanced radiotherapy and has achieved good local control, even in tumors that are resistant to conventional photon beam radiotherapy (PBRT). However, distant metastasis control is an important issue. Recently, the combination of radiotherapy and immunotherapy has attracted the attention. In immunotherapy, dendritic cells (DCs) play a pivotal role in the anti-tumor immune system. However, the mechanisms underlying the combination therapy of DCs and radiotherapy have been unclear. In the present study, we evaluated anti-metastatic effects of this combination therapy, focused on the irradiation type and the route of DC administration, using a mouse model. C3H/He mice bearing NR-S1 cells were treated with CIRT or PBRT, using biologically equivalent doses. Subsequently, DCs were administered intratumorally (IT) or intravenously (IV). IV and IT DC administrations combined with CIRT to the local tumor, but not alone, significantly suppressed pulmonary metastasis, whereas the combination of DCs with PBRT suppressed metastasis at a relatively higher dose. Additionally, the anti-metastatic effect was greater in IV DC administration compared with in IT DC administration in both CIRT and PBRT. The expression levels of CD40 and IL-12 in DCs were significantly increased after co-culturing with CIRT-treated NR-S1 cells. In addition, IV administration of those co-cultured DCs significantly suppressed pulmonary metastasis. Furthermore, ecto-calreticulin levels from CIRT-treated NR-S1 cells significantly increased compared with those of a PBRT-treated tumor. Taken together, these results suggest that local CIRT combined with IV DCs augments an immunogenicity of the tumor cells by ecto-calreticulin expression and the maturation of DCs to stimulate anti-tumor immunity to decrease lung metastases., (© The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Aim: Adjuvant platinum-based chemotherapy is recommended for patients with completely resected stage II (N1) or III (N2) non-small cell lung cancer (NSCLC). However, the optimal chemotherapy regimen is difficult to predict for individual patients. Our previous prospective study on individualized treatment according to biomarker status, such as excision repair cross-complementing 1 (ERCC1), class III β-tubulin (tubulin), thymidylate synthase (TYMS) and ribonucleotide reductase M1 (RRM1), achieved encouraging results in patients with advanced NSCLC. The present study further examined the effect of biomarker-based adjuvant chemotherapy in patients with completely resected NSCLC., Patients and Methods: Between January 2006 and December 2014, 66 patients with localized (stage I-IIIA) NSCLC who underwent R0 operation received 2-4 cycles of platinum doublet adjuvant chemotherapy: Platinum plus docetaxel, platinum plus pemetrexed for adenocarcinoma, and platinum plus tegafur/gimeracil/oteracil combination (TS-1) for squamous cell carcinoma (SCC) were selected according to the registered protocol at each period. Immunohistochemistry was used to evaluate the biomarkers: ERCC1 status for platinum, tubulin for docetaxel, and TYMS for pemetrexed and TS-1. A matched chemotherapy regimen meant that platinum plus docetaxel was administered in patients negative for ERCC1 and negative for tubulin, platinum plus pemetrexed in patients with adenocarcinoma positive for tubulin, negative for ERCC1 and negative for TYMS, and platinum plus TS-1 in those with SCC positive for tubulin, negative for ERCC1 and negative for TYMS., Results: The 5-year survival rate was 77.5% considering all 66 patients, and 85.7%, 71.8%, and 78.8% for those with p-stage I, II, and III, respectively. Patients who received a matched chemotherapy regimen (n=13; platinum plus docetaxel in eight, platinum plus pemetrexed in five) had significantly better 5-year survival than patients with unmatched biomarker status (n=53) (100% vs. 71.0%, p=0.0011)., Conclusion: Customized adjuvant chemotherapy based on biomarker examination significantly improved the survival of patients with NSCLC, regardless of p-stage., (Copyright© 2017, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

The safety and efficacy of carbon-ion radiotherapy for advanced non-small cell lung cancer have not been established. We evaluated the clinical outcomes and dose-volume histogram parameters of carbon-ion radiotherapy compared with photon therapy in T2b-4N0M0 non-small cell lung cancer. Twenty-three patients were treated with carbon-ion radiotherapy between May 2011 and December 2015. Seven, 14, and 2 patients had T2b, T3, and T4, respectively. The median age was 78 (range, 53-91) years, with 22 male patients. There were 12 adenocarcinomas, 8 squamous cell carcinomas, 1 non-small cell lung carcinoma, and 2 clinically diagnosed lung cancers. Eleven patients were operable, and 12 patients were inoperable. Most patients (91%) were treated with carbon-ion radiotherapy of 60.0 Gy relative biological effectiveness (RBE) in 4 fractions or 64.0 Gy (RBE) in 16 fractions. Local control and overall survival rates were calculated. Dose-volume histogram parameters of normal lung and tumor coverages were compared between carbon-ion radiotherapy and photon therapies, including three-dimensional conformal radiotherapy (3DCRT) and intensity-modulated radiotherapy (IMRT). The median follow-up of surviving patients was 25 months. Three patients experienced local recurrence, and the 2-year local control rate was 81%. During follow-up, 5 patients died of lung cancer, and 1 died of intercurrent disease. The 2-year overall survival rate was 70%. Operable patients had a better overall survival rate compared with inoperable patients (100% vs. 43%; P = 0.04). There was no grade ≥2 radiation pneumonitis. In dose-volume histogram analysis, carbon-ion radiotherapy had a significantly lower dose to normal lung and greater tumor coverage compared with photon therapies. Carbon-ion radiotherapy was effectively and safely performed for T2b-4N0M0 non-small cell lung cancer, and the dose distribution was superior compared with those for photon therapies. A Japanese multi-institutional study is ongoing to prospectively evaluate these patients and establish the use of carbon-ion radiotherapy.