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Background and Purpose: To investigate the toxicity and survival outcomes of proton and carbon ion radiotherapy for patients with operable early-stage lung cancer who are eligible for lobectomy., Materials and Methods: This multicenter nationwide prospective cohort study included patients with operable early-stage lung cancer. Proton and carbon ion radiotherapy was performed according to the schedule stipulated in the unified treatment policy. Progression-free survival (PFS), overall survival (OS) and treatment-related toxicities were evaluated., Results: A total of 274 patients were enrolled and included in efficacy and safety analyses. The most common tumor type was adenocarcinoma (44 %), while 105 cases (38 %) were not histologically confirmed or diagnosed clinically. Overall, 250 (91 %) of the 274 patients had tumors that were peripherally situated, while 138 (50 %) and 136 (50 %) patients were treated by proton and carbon ion radiotherapy, respectively. The median follow-up time for all censored patients was 42.8 months (IQR 36.7-49.0). Grade 3 or severe treatment-related toxicity was observed in 4 cases (1.5 %). Three-year PFS was 80.5 % (95 % CI: 75.7 %-85.5 %) and OS was 92.5 % (95 % CI: 89.3 %-95.8 %). Pathological confirmation and clinical stage were factors significantly associated with PFS, while tumor location and particle-ion type were not. Meanwhile, clinical stage was significantly associated with OS, but pathological confirmation, tumor location, and particle-ion type were not., Conclusions: Particle therapy for operable early-stage lung cancer resulted in excellent 3-year OS and PFS in each subset. In this disease context, proton and carbon ion beam therapies are feasible alternatives to curative surgery., Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that would directly affect the research reported in this paper. Hideyuki Harada received Honoraria from Astrazeneca, Accuray, Chugai pharmaceutical, Takeda pharmaceutical, MSD, Eizai pharmaceutical, Phizer, Brainlab, Hitachi, Novartis, Guerbet Japan, GE Healthcare, Nihon Medi-Physics and Taiho pharmaceutical outside this work. Keita Mori received Honoraria from Chugai Pharmaceutical, Ono Pharmaceutical, Bristol Myers Squibb, Daiichi-Sankyo and Eli Lilly Japan outside this work. Hitoshi Ishikawa received Honoraria from Boston Scientific Corporation and MSD outside this work. Masaki Nakamura received Honoraria from Astrazeneca outside this work. Nobuteru Kubo received Honoraria from Astrazeneca outside this work. Miyako Satouchi received Honoraria from Chugai pharmaceutical, Astrazeneca,Eli Lilly Japan, Ono pharmaceutical, Bristol-Myers Squibb, MSD, Merck Janssen Pharmaceutical, Amgen, Taiho pharmaceutical, Pfizer, Daiichi-Sankyo, Eisai, Takeda pharmaceutical, Novartis, GlaxoSmithKline Consumer Healthcare Japan and Bayer pharmaceutical and research funding from GlaxoSmithKline, AstraZeneca, MSD, Janssen, Amgen, Taiho pharmaceutical, Ono pharmaceutical, Bristol Myers Squibb, Pfizer, Daiichi-Sankyo, and Eisai outside this work. Yoshiyuki Shioyama received Honoraria from Astrazeneca outside this work., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Chordoma, a rare malignant tumor arising from notochordal tissue, usually occurs along the spinal axis. Only a few published reports of primary lung chordomas exist. Herein, we present a case of primary lung chordoma and discuss important considerations for diagnosing rare chordomas., Case Presentation: We report a case of primary lung chordoma in a 39-year-old male with a history of testicular mixed germ-cell tumor of yolk sac and teratoma. Computed tomography revealed slow-growing solid lesions in the left lower lobe. We performed wedge resection for suspected germ-cell tumor lung metastasis. Histologically, large round or oval cells with eosinophilic cytoplasm were surrounded by large cells with granular, lightly eosinophilic cytoplasm. Tumor cells were physaliphorous. Immunohistochemistry was positive for brachyury, S-100 protein, epithelial membrane antigen, vimentin, and cytokeratin AE1/AE3, suggesting pulmonary chordoma. Re-examination of the testicular mixed germ-cell tumor revealed no notochordal elements. Although some areas were positive for brachyury staining, hematoxylin and eosin (HE) staining did not show morphological features typical of chordoma. Complementary fluorescence in situ hybridization (FISH) of the lung tumor confirmed the absence of isochromosome 12p and 12p amplification. Thus, a final diagnosis of primary lung chordoma was established., Conclusions: In patients with a history of testicular mixed germ cell tumors, comparison of histomorphology using HE and Brachyury staining of lung and testicular tumors, and analyzing isochromosome 12p and 12p amplification in lung tumors using FISH is pivotal for the diagnosis of rare lung chordomas., (© 2024. The Author(s).)

Objective . To investigate the effect of redistribution and reoxygenation on the 3-year tumor control probability (TCP) of patients with stage I non-small cell lung cancer (NSCLC) treated with carbon-ion radiotherapy. Approach . A meta-analysis of published clinical data of 233 NSCLC patients treated by carbon-ion radiotherapy under 18-, 9-, 4-, and single-fraction schedules was conducted. The linear-quadratic (LQ)-based cell-survival model incorporating the radiobiological 5Rs, radiosensitivity, repopulation, repair, redistribution, and reoxygenation, was developed to reproduce the clinical TCP data. Redistribution and reoxygenation were regarded together as a single phenomenon and termed 'resensitization' in the model. The optimum interval time between fractions was investigated for each fraction schedule using the determined model parameters. Main results. The clinical TCP data for 18-, 9-, and 4-fraction schedules were reasonably reproduced by the model without the resensitization effect, whereas its incorporation was essential to reproduce the TCP data for all fraction schedules including the single fraction. The curative dose for the single-fraction schedule was estimated to be 49.0 Gy (RBE), which corresponds to the clinically adopted dose prescription of 50.0 Gy (RBE). For 18-, 9-, and 4-fraction schedules, a 2-to-3-day interval is required to maximize the resensitization effect during the time interval. In contrast, the single-fraction schedule cannot benefit from the resensitization effect, and the shorter treatment time is preferable to reduce the effect of sub-lethal damage repair during the treatment. Significance. The LQ-based cell-survival model incorporating the radiobiological 5Rs was developed and used to evaluate the effect of the resensitization on clinical results of NSCLC patients treated with hypo-fractionated carbon-ion radiotherapy. The incorporation of the resensitization into the cell-survival model improves the reproducibility to the clinical TCP data. A shorter treatment time is preferable in the single-fraction schedule, while a 2-to-3-day interval between fractions is preferable in the multi-fraction schedules for effective treatments., (© 2024 Institute of Physics and Engineering in Medicine.)

Introduction: The standard therapy for stage I NSCLC is surgery, but some operable patients refuse this option and instead undergo radiotherapy. Carbon-ion radiotherapy (CIRT) is a type of radiotherapy. The Japanese prospective nationwide registry study on CIRT began in 2016. Here, we analyzed real-world clinical outcomes of CIRT for operable patients with stage I NSCLC., Methods: All patients with operable stage I NSCLC treated with CIRT in Japan between 2016 and 2018 were enrolled. The dose fractionations for CIRT were selected from several options approved by the Japanese Society for Radiation Oncology. CIRT was delivered to the primary tumor, not to lymph nodes., Results: The median follow-up period was 56 months. Among 136 patients, 117 (86%) had clinical stage IA NSCLC and 19 (14%) had clinical stage IB NSCLC. There were 50 patients (37%) diagnosed clinically without having been diagnosed histologically. Most tumors (97%) were located in the periphery. The 5-year overall survival, cause-specific survival, progression-free survival, and local control rate were 81.8% (95% confidence interval [CI]: 75.1-89.2), 91.2% (95% CI: 86.0-96.8), 65.9% (95% CI: 58.2-74.6), and 95.8% (95% CI: 92.3-99.5), respectively. Multivariate analysis identified age as a significant factor for overall survival (p = 0.018), whereas age and consolidation/tumor ratio (p = 0.010 and p = 0.004) were significant factors for progression-free survival. There was no grade 4 or higher toxicity. Grade 3 radiation pneumonitis occurred in one patient., Conclusions: This study reports the long-term outcomes of CIRT for operable NSCLC in the real world. CIRT for operable patients has been found to have favorable outcomes, with tolerable toxicity., (Copyright © 2023 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Purpose: This study aimed to compare the outcomes of patients with ground-grass opacity (GGO)-dominant non-small cell lung cancer (NSCLC) who were treated with carbon ion radiotherapy (CIRT) versus segmentectomy., Methods: A retrospective review of medical records was conducted. The study included 123 cases of clinical stage 0/IA peripheral NSCLC treated with single-fraction CIRT from 2003 to 2012, 14 of which were determined to be GGO-dominant and were assigned to CIRT group. As a control, 48 consecutive patients who underwent segmentectomy for peripheral GGO-dominant clinical stage IA NSCLC were assigned to segmentectomy group., Results: The patients in CIRT group, compared with segmentectomy group, were significantly older (75 ± 7.2 vs. 65 ± 8.2 years, P = 0.000660), more likely to be male (13/14 vs. 22/48, P = 0.00179), and had a lower forced vital capacity (91 ± 19% vs. 110 ± 13%, P = 0.0173). There was a significant difference in the 5-years overall survival rate (86% vs. 96%, P = 0.000860), but not in the 5-years disease-specific survival rate (93% vs. 98%, P = 0.368)., Discussion: Compared with segmentectomy, CIRT may be an alternative option for patients with early GGO-dominant NSCLC who are poor candidates for, or who refuse, surgery., (© 2023. The Author(s).)

Anti-cancer treatments for lung cancer patients with interstitial lung disease (ILD) are challenging. The treatment options for ILD are often limited because of concerns that treatments can cause acute exacerbation (AE) of ILD. This study aimed to analyze the outcomes of carbon-ion radiotherapy (CIRT) for stage I non-small cell lung cancer (NSCLC) with ILD, using a multi-institutional registry. Patients with ILD who received CIRT for stage I NSCLC in CIRT institutions in Japan were enrolled. The indication for CIRT was determined by an institutional multidisciplinary tumor board, and CIRT was performed in accordance with institutional protocols. Thirty patients were eligible. The median follow-up duration was 30.3 months (range, 2.5-58 months), and the total dose ranged from 50 Gy (relative biological effectiveness [RBE]) to 69.6 Gy (RBE), and five different patterns of fractionation were used. The beam delivery method was passive beam in 19 patients and scanning beam in 11 patients. The 3-year overall survival (OS), cause-specific survival, disease-free survival (DFS) and local control (LC) rates were 48.2%, 62.2%, 41.2% and 88.1%, respectively. Grade > 2 radiation pneumonitis occurred in one patient (3.3%). In conclusion, CIRT is a safe treatment modality for stage I NSCLC with concomitant ILD. CIRT is a safe and feasible treatment option for early lung cancer in ILD patients., (© The Author(s) 2023. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background and Purpose: Radiotherapy is a standard treatment for inoperable stage I non-small cell lung cancer (NSCLC), and carbon-ion radiation therapy (CIRT) may be used for such treatment. Although CIRT for stage I NSCLC has demonstrated favorable outcomes in previous reports, the reports covered only single-institution studies. We conducted a prospective nationwide registry study including all CIRT institutions in Japan., Materials and Methods: Ninety-five patients with inoperable stage I NSCLC were treated by CIRT between May 2016 and June 2018. The dose fractionations for CIRT were selected from several options approved by the Japanese Society for Radiation Oncology., Results: The median patient age was 77 years. Comorbidity rates for chronic obstructive pulmonary disease and interstitial pneumonia were 43% and 26%, respectively. The most common schedule for CIRT was 60 Gy (relative biological effectiveness (RBE)) in four fractions, and the second most common was 50 Gy (RBE) in one fraction. The 3-year overall survival, cause-specific survival, and local control rates were 59.3%, 77.1%, and 87.3%, respectively. Female sex and ECOG performance status of 0-1 were favorable prognostic factors for overall survival in a multivariate analysis. No grade 4 or higher adverse event was observed. The 3-year cumulative incidence of grade 2 or higher radiation pneumonitis was 3.2%. The risk factors for grade 2 or higher radiation pneumonitis were a force expiratory volume in 1 second (FEV1) of <0.9 L and a total does of ≥ 67 Gy(RBE)., Conclusion: This study provides real-world treatment outcomes of CIRT for inoperable. stage I NSCLC in Japan., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier B.V. All rights reserved.)

Combined chemoradiotherapy (CRT) and programmed cell death-ligand 1 (PD-L1) blockade is a new care standard for unresectable stage III non-small-cell lung cancer (NSCLC). Although this consolidation therapy has improved the overall survival of patients with NSCLC, the synergistic action mechanisms of CRT and immunotherapy on T cells remain unclear. In addition, there is a paucity of reliable biomarkers to predict clinical responses to therapy. In this study, we analyzed T-cell receptor (TCR) sequences in the peripheral blood of five patients with NSCLC. T-cell receptor analysis was undertaken before treatment, after CRT, and after PD-L1 blockade. Notably, we observed the expansion and alteration of the dominant T-cell clonotypes in all cases with a complete response. In contrast, neither expansion nor alteration of the TCR repertoire was observed in cases with progressive disease. T cell expansion was initiated after CRT and was further enhanced after PD-L1 blockade. Our findings suggest the systemic effect of CRT on circulating T cells in addition to the curative effect on limited tumor sites. Dynamic changes in circulating T-cell clonotypes could have a prognostic significance for combined CRT and PD-L1 blockade., (© 2022 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Background: The prognosis of metastatic hepatoblastoma remains poor; to improve it, pulmonary metastasis must be controlled. Indocyanine green (ICG) fluorescent imaging has been used recently for lung metastasectomy. The objective of our study was to clarify the usefulness of ICG imaging for lung metastasectomy of hepatoblastoma using detailed clinicopathological analysis., Procedure: Patients with hepatoblastoma who underwent resection of pulmonary metastases with ICG fluorescent imaging were studied using a retrospective analysis of clinical information, a review of their surgical records, and a histological analysis of their metastatic nodules., Results: Sixteen patients were enrolled. In total, 61 ICG imaging-guided pulmonary metastasectomies were performed, and 350 ICG-positive and 23 ICG-negative specimens were identified. Tumors were confirmed in 250 of the ICG-positive specimens, including eight nonpalpable nodules, on microscopic examination. ICG-positive and tumor-negative specimens showed histological changes suggesting the regression of a tumor or bloodstream disturbance., Conclusions: Surgical resection is one of the few treatment strategies available to patients with hepatoblastoma with multiple relapses of pulmonary metastasis resistant to chemotherapy. This study demonstrates the high sensitivity of ICG imaging and that thorough metastasectomy can be achieved with ICG imaging. Because a number of false-positive specimens were detected, further optimization of the dose of ICG and the timing of its administration, and establishment of detection of ICG-positive, tumor-negative nodules during surgery are important issues. Several false-negative specimens were also detected, suggesting the presence of ICG-negative metastatic tumors. Palpation during surgery and imaging studies remain essential for detecting metastatic lesions, even in the era of ICG imaging., (© 2021 Wiley Periodicals LLC.)

Routine CT examinations are crucial in colorectal cancer patients (CCPs); however, the high frequency of radiation exposure is a significant concern. This study investigated the radiation dose, image quality, and diagnostic performance of tin filter-based spectral shaping chest−abdominal−pelvic (CAP) CT for CCPs. We reviewed 44 CCPs who underwent single-phase enhanced tin-filtered 100 kV (TF100kV) and standard 120 kV (ST120kV) CAP CT on separate days. Radiation metrics including the volume CT dose index (CTDIvol), dose-length product (DLP), and effective dose (ED) were calculated for both protocols. Two radiologists assessed the presence of the following lesions: lung metastasis, liver metastasis, lymph node metastasis, peritoneal dissemination, and bone metastasis. The area under the receiver operating characteristic curve (AUC) was calculated for the diagnostic performance of each protocol. Radiation metrics of the TF100kV protocol were significantly lower than those of the ST120kV protocol (CDTIvol 1.60 ± 0.31 mGy vs. 14.4 ± 2.50, p < 0.0001; DLP 107.1 (95.9−125.5) mGy·cm vs. 996.7 (886.2−1144.3), p < 0.0001; ED 1.93 (1.73−2.26) mSv vs. 17.9 (16.0−20.6), p < 0.0001, respectively). TF100kV protocol achieved comparable diagnostic performance to that of the ST120kV protocol (AUC for lung metastasis: 1.00 vs. 0.94; liver metastasis: 0.88 vs. 0.83, respectively). TF100kV protocol could substantially reduce the radiation dose by 89% compared to that with the ST120kV protocol while maintaining good diagnostic performance in CCPs.

Natural killer (NK) cells are key effectors of the innate immune system, but major differences between human and murine NK cells have impeded translation. Outbred dogs offer an important link for studies of NK biology and immunotherapy. We analyzed gene expression of putative NK populations from healthy dogs and dogs with naturally-occurring cancers examining differential gene expression across multiple conditions, including steady-state, in vitro activation with cytokines and co-culture, and in vivo activation with inhaled IL-15 in dogs receiving IL-15 immunotherapy. We also compared dog, mouse and human CD3-NKp46+ NK cells using a novel orthologous transcriptome. Distinct transcriptional profiles between NK populations exist between conditions and in vitro versus in vivo treatments. In cross-species analysis, canine NK cells were globally more similar to human NK cells than mice. These data define canine NK cell gene expression under multiple conditions and across species, filling an important gap in translational NK studies., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Gingrich, Reiter, Judge, York, Yanagisawa, Razmara, Sturgill, Basmaci, Brady, Stoffel, Murphy, Rebhun, Brown and Canter.)

Purpose: The clinical significance of carbon-ion radiotherapy (CIRT) for octogenarians with locally advanced non-small-cell lung cancer (LA-NSCLC) remains unclear. We aimed to evaluate the clinical outcomes of CIRT alone for octogenarians with LA-NSCLC., Materials and Methods: We evaluated 32 patients who underwent CIRT alone between 1997 and 2015. The median age was 82.0 years (range, 80-88 years). In terms of clinical stage (UICC 7th edition), 7 (21.9%), 10 (31.3%), 11 (34.4%), and 4 (12.5%) patients had stage IIA, IIB, IIIA, and ΙΙΙB disease, respectively. The median CIRT dose was 72.0 Gy (relative biological effectiveness), and the median follow-up period was 33.1 months., Results: All patients successfully completed CIRT. Regarding grade ≥ 2 toxicities, 1 (3.1%), 3 (9.4%), and 4 (0.7%) patients developed grade 3 radiation pneumonitis, grade 2 radiation pneumonitis, and grade 2 dermatitis, respectively. No grade ≥ 4 toxicities were observed. The 2 year LC, PFS, and OS rates were 83.5%, 46.7%, and 68.0%, respectively., Conclusion: CIRT alone is safe and effective for octogenarians with LA-NSCLC.

Since it is difficult to obtain tumor tissue via airway observation for lung cancer patients with a poor respiratory condition, endoscopic ultrasound with bronchoscope-guided fine-needle-aspiration (EUS-B-FNA), a transesophageal procedure, is effective for such patients. We herein report three patients with driver oncogenes taken to the emergency department because of lung cancer-related symptoms. EUS-B-FNA was performed because of the patients' poor respiratory conditions to detect driver oncogenes. The general conditions improved, and the patients achieved a long-term survival with tyrosine kinase inhibitors. Our findings suggest that EUS-B-FNA should be considered to detect driver oncogenes in lung cancer patients despite poor respiratory conditions in emergency departments.

The patient was a 73-year-old man who was referred to our hospital for increasing bilateral lung nodules. Video-assisted left S9-10 segmentectomy and right S1, S3 partial resection were performed separately for suspect of synchronous double lung cancer. Colonoscopy was performed because left lung tumor was difficult to distinguish between primary lung cancer and metastatic lung cancer. Colonoscopy did not find advanced cancer lesion. We diagnosed the left lung tumor as pT1b, cN0, cM0, Stage ⅠA2 intestinal adenocarcinoma. The right lung tumor was diagnosed as pT1c, cN0, cM0, Stage ⅠA3 papillary adenocarcinoma. Intestinal adenocarcinoma is a rare tissue subtype of lung adenocarcinoma and colonoscopy is useful modality for ruling out metastatic colorectal cancer.

A 64-year-old female presented to our hospital with a chronic cough. She was diagnosed with cStage ⅢA small cell lung cancer(cT2aN2M0, limited disease). On admission for chemoradiation therapy, laboratory data incidentally revealed liver dysfunction. Further examination resulted in the patient being diagnosed with autoimmune hepatitis. Oral prednisolone therapy was started, and after the improvement of liver function tests, consecutive chemoradiation therapy with cisplatin and etoposide was administered. To the best of our knowledge, this is the first report of a patient with autoimmune hepatitis and small cell lung cancer. Autoimmune hepatitis might arise as a paraneoplastic syndrome.

We herein report a 66-year-old woman with advanced lung adenocarcinoma [programmed cell death and its ligand 1 (PD-L1) tumor proportion score 60%] lacking driver oncogenes in whom meningeal carcinomatosis, along with sudden onset dizziness, deafness, and consciousness disturbance, appeared after second-line chemotherapy. Whole-brain radiation therapy (WBRT) and Pembrolizumab were subsequently administered, and third-line chemotherapy with Pembrolizumab is now ongoing. At the time of writing, the patient has achieved a 23-month survival without disease progression. Our findings suggest that the combination of WBRT and an immune checkpoint inhibitor is effective for non-small-cell lung cancer patients lacking driver oncogenes who develop meningeal carcinomatosis.

Noninvasive diagnostics using circulating tumor cells (CTCs) are expected to be useful for decision making in precision cancer therapy. AXL, a receptor tyrosine kinase is associated with tumor progression, epithelial-to-mesenchymal transition (EMT), and drug resistance, and is a potential therapeutic target. However, the epithelial markers generally used for CTC detection may be not enough to detect AXL-expressing CTCs due to EMT. Here, we evaluated the detection of AXL-expressing CTCs using the mesenchymal marker vimentin with a microcavity array system. To evaluate the recovery of cancer cells, spike-in experiments were performed using cell lines with varying cytokeratin (CK) or vimentin (VM) expression levels. With high CK and low VM-expressing cell lines, PC-9 and HCC827, the recovery rate of AXL-expressing cancer cells was 1%-17% using either CK or VM as markers. Whereas, with low CK and high VM-expressing cell lines, MDA-MB231 and H1299, it was 52%-75% using CK and 72%-88% using VM as a marker. For clinical evaluation, peripheral blood was collected from 20 non-small cell lung cancer patients and CTCs were detected using CK or VM as markers in parallel. Significantly more AXL-expressing single CTCs were detected in VM-positive than CK-positive CTCs (P < .001). Furthermore, CTC clusters were identified only among VM-positive CTCs in 20% of patients. Patients with one or more prior treatments harbored significantly more VM-positive AXL-expressing CTCs, suggesting the involvement of these CTCs in drug resistance. These results indicate the necessity of integrating mesenchymal markers with CTC detection and this should be further evaluated clinically., (© 2020 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)

Background/aim: We evaluated the efficacy and safety of carbon-ion radiotherapy (CIRT) alone for Stage III non-small-cell lung cancer (NSCLC)., Patients and Methods: Data of 65 patients (median age=73 years) with Stage III NSCLC who underwent CIRT alone in the QST Hospital, Chiba, Japan, between 1997 and 2015 were retrospectively analysed. The median dose was 72.0 Gy (relative biological effectiveness)., Results: The median follow-up was 27.6 months (range=1.6-207.7 months). Two-year local control, progression-free survival (PFS), and overall survival (OS) rates were 73.9%, 38.6%, and 54.9%, respectively. Overall, 1 (2%), 4 (6%), and 1 (2%) patient developed Grade 4 (mediastinal haemorrhage), Grade 3 (radiation pneumonitis), and Grade 3 (bronchial fistula) toxicities, respectively. On univariate analysis, clinical T and N stage and CIRT timing were significant predictors of PFS and OS; clinical target volume was a significant predictor of PFS., Conclusion: CIRT alone is effective with acceptable toxicity for Stage III NSCLC., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: The study was conducted to evaluate the clinical and computed tomography (CT) findings of non-small cell lung cancer (NSCLC) patients to distinguish between ALK gene rearrangement, EGFR mutation, and non-ALK/EGFR (no genetic abnormalities)., Methods: We enrolled 201 patients with primary NSCLC who had undergone molecular testing for both ALK gene rearrangement and EGFR mutation. The clinical features and CT findings of the main lesion and associated pulmonary abnormalities were investigated., Results: Female gender (P = 0.0043 vs. non-ALK/EGFR), young age (P = 0.0156 vs. EGFR), and a light or never smoking history (P = 0.0039 vs. non-ALK/EGFR) were significant clinical characteristics of NSCLC with ALK gene rearrangement. The significant CT characteristics compared to NSCLC with EGFR mutation were a large mass (P = 0.0155), solid mass (P = 0.0048), and no air bronchogram (P = 0.0148). A central location (P = 0.0322) and lymphadenopathy (P = 0.0353) were also more frequently observed. Coexisting emphysema was significantly less frequent in NSCLC patients with ALK gene rearrangement (P = 0.0135) than non-ALK/EGFR., Conclusions: NSCLC with ALK gene rearrangement was more likely to develop in younger women with a light or never smoking history. The characteristic CT findings of NSCLC with ALK gene rearrangement were a large solid mass, less air bronchogram, a central location, and lymphadenopathy., (© 2019 The Authors. Thoracic Cancer published by China Lung Oncology Group and John Wiley & Sons Australia, Ltd.)

The efficacy and safety of carbon-ion radiotherapy (CIRT) for locally advanced non-small-cell lung cancer (LA-NSCLC) remain unclear. We reported the clinical outcomes of CIRT for LA-NSCLC. Data for 141 eligible patients who received CIRT between 1995 and 2015 were retrospectively analyzed. Local control (LC), locoregional control (LRC), progression-free survival (PFS) and overall survival (OS) were calculated using the Kaplan-Meier method. The median age was 75.0 years. Overall, 21 (14.9%), 57 (40.4%), 43 (30.5%) and 20 (14.2%) patients had T1, T2, T3 and T4 disease, respectively. Moreover, 51 (36.2%), 45 (31.9%), 40 (28.4%) and 5 (3.5%) patients had N0, N1, N2 and N3 disease, respectively. Furthermore, 34 (24.1%), 42 (29.8%), 45 (31.9%) and 20 (14.2%) patients had stages IIA, IIB, IIIA and ΙΙΙB disease, respectively. Overall, 62 (44.0%), 60 (42.6%), 8 (5.7%) and 11 (7.8%) patients had adenocarcinoma, squamous cell carcinoma, large cell carcinoma, and others, respectively. The median dose was 72.0 Gy (relative biological effectiveness). No patient received concurrent chemotherapy. Median follow-up periods were 29.3 (1.6-207.7) and 40.0 (10.7-207.7) months for all patients and survivors, respectively. Two-year LC, PFS and OS rates were 80.3%, 40.2% and 58.7%, respectively. Overall, 1 (0.7%), 5 (3.5%) and 1 (0.7%) patient developed Grades 4 (mediastinal hemorrhage), 3 (radiation pneumonitis) and 3 (bronchial fistula) toxicities, respectively. Multivariate analysis showed adenocarcinoma and N2/3 classification as significant poor prognosticators of PFS. CIRT is an effective treatment with acceptable toxicity for LA-NSCLC, especially for elderly patients or patients with severe comorbidities who cannot be treated with surgery or chemoradiotherapy., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Intrathoracic recurrence after carbon-ion radiotherapy for primary or metastatic lung tumors remains a major cause of cancer-related deaths. However, treatment options are limited. Herein, we report on the toxicity and efficacy of re-irradiation with carbon-ion radiotherapy for locoregionally recurrent, metastatic, or secondary lung tumors. Data of 95 patients with prior intrathoracic carbon-ion radiotherapy who were treated with re-irradiation with carbon-ion radiotherapy at our institution between 2006 and 2016 were retrospectively analyzed. Seventy-three patients (76.8%) had primary lung tumors and 22 patients (23.2%) had metastatic lung tumors. The median dose of initial carbon-ion radiotherapy was 52.8 Gy (relative biological effectiveness) and the median dose of re-irradiation was 66.0 Gy (relative biological effectiveness). None of the patients received concurrent chemotherapy. The median follow-up period after re-irradiation was 18 months. In terms of grade ≥3 toxicities, one patient experienced each of the following: grade 5 bronchopleural fistula, grade 4 radiation pneumonitis, grade 3 chest pain, and grade 3 radiation pneumonitis. The 2-year local control and overall survival rates were 54.0% and 61.9%, respectively. In conclusion, re-irradiation with carbon-ion radiotherapy was associated with relatively low toxicity and moderate efficacy. Re-irradiation with carbon-ion radiotherapy might be an effective treatment option for patients with locoregionally recurrent, metastatic, or secondary lung tumors., (© 2018 The Authors. Cancer Science published by John Wiley & Sons Australia, Ltd on behalf of Japanese Cancer Association.)

Lung metastasis constitutes the leading cause of the death in patients with osteosarcoma. We have previously reported that plasminogen activator inhibitor-1 (PAI-1) regulates the invasion and lung metastasis of osteosarcoma cells in a mouse model and as well as in clinical samples. In the present study, we examined the anti-metastatic effect of SK-216, a small compound PAI-1 inhibitor, in human 143B osteosarcoma cells. An in vitro study showed that SK-216 treatment suppressed invasion activity by inhibiting PAI-1 expression in 143B cells, but had no influence on their proliferation or migration. 143B cells treated with SK-216 exhibited reduced matrix metalloproteinase-13 (MMP-13) secretion in a dose-dependent manner. Moreover, intraperitoneal injection of SK-216 into mouse models resulted in downregulation of PAI-1 expression levels in the primary tumors and showed suppression of lung metastases without influencing the proliferative activity of the tumor cells in the primary lesions. These results indicate that SK-216, a PAI-1 inhibitor, may serve as a novel drug to prevent lung metastasis in human osteosarcoma., Competing Interests: The authors declare no conflict of interest.

Purpose: To investigate carbon-ion radiotherapy (CIRT) for in-field recurrence of stage I non-small cell lung cancer (NSCLC) initially treated with CIRT., Materials and Methods: From January 2007 to March 2014, patients initially treated for stage I NSCLC with CIRT and relapsed in-field were candidates. Overall survival (OS) rate, local control (LC) rate, progressive free survival (PFS) rate, dose to the lungs and skin, and adverse effects were analyzed., Results: Twenty-nine patients were eligible. Median age at re-irradiation was 74years (range 53-90). Median observation period from the first day of re-irradiation was 29months (4-88months). Median prescribed dose was 46.0Gy (RBE) as initial treatment and 66.0Gy (RBE) in 12 fractions as re-irradiation. Two-year OS, LC, and PFS rates after re-irradiation were 69.0% (95% CI: 50.3-83.0), 66.9% (95% CI: 47.5-81.9), and 51.7% (95% CI: 34.1-68.9). Median skin maximum dose was 53.8Gy (RBE) (range 4.4-103.1) and median of mean lung dose was 7.3Gy (RBE) (range 2.6-14.0). There were no severer than grade 2 adverse effects except one (3.4%) grade 3 bacterial pneumonia, which was not considered radiation-induced., Conclusion: CIRT for stage I NSCLC local recurrence is an acceptable definitive re-treatment., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Background: Lung cancer is frequently complicated by interstitial lung disease (ILD). Treatment protocols for lung cancer patients with ILD have not been established; surgery, chemotherapy, and radiotherapy can all cause acute exacerbation of ILD. This study evaluated the toxicity and efficacy of carbon ion radiotherapy (CIRT) in patients with non-small cell lung cancer (NSCLC) and ILD., Methods: Between June 2004 and November 2014, 29 patients diagnosed with NSCLC and ILD were treated with CIRT. No patient was eligible for curative surgery or conventional radiotherapy secondary to ILD. Owing to prior symptomology, radiation pneumonitis (RP) and symptom progression pre- and post-treatment were evaluated. The relationships between RP and clinical factors were investigated., Results: Twenty-eight men and one woman, aged 62 to 90 years old, were followed for 2.7-77.1 months (median: 22.8 months). Single-grade symptomatic progression (grade 2-3) was observed in 4 patients, while 1 patient experiencedtwo-grade progression. Two patients experienced radiation-induced acute exacerbation. Local control at 3 years was 63.3% (72.2% for stage I disease); survival at 3 years was 46.3% (57.2% for stage I disease). Eighteen patients had died by the time of this writing, 10 of lung cancer progression. Radiation pneumonitis post-treatment progression correlated with dosimetric factors of the lungs (V5, V10) and a low pre-treatment serum surfactant protein-D., Conclusions: We found that CIRT may be useful as a low-risk, curative option for NSCLC patients with ILD, a population that is typically ineligible for conventional therapy. The DVH analysis showed that minimizing the low-dose region is important for reducing the risk of severe RP., Trial Registration: NIRS-9404 . Registered 1 March 1994.

We report 2 infantile cases of pulmonary tumor carrying a chimeric A2M-ALK gene. A2M-ALK is a newly identified anaplastic lymphoma kinase (ALK)-related chimeric gene from a tumor diagnosed as fetal lung interstitial tumor (FLIT). FLIT is a recently recognized infantile pulmonary lesion defined as a mass-like lesion that morphologically resembles the fetal lung. Grossly, FLIT characteristically appears as a well-circumscribed spongy mass, whereas the tumors in these patients were solid and firm. Histologically, the tumors showed intrapulmonary lesions composed of densely proliferating polygonal or spindle-shaped mesenchymal cells with diffuse and dense infiltrations of inflammatory cells forming microcystic or micropapillary structures lined by thyroid transcription factor 1-positive pneumocytes, favoring inflammatory myofibroblastic tumor rather than FLIT. The proliferating cells were immunoreactive for ALK, and A2M-ALK was identified in both tumors with reverse-transcription polymerase chain reaction. The dense infiltration of inflammatory cells, immunoreactivity for ALK, and identification of an ALK-related chimeric gene suggested a diagnosis of inflammatory myofibroblastic tumor. Histologically, most reported FLITs show sparse inflammatory infiltrates and a relatively low density of interstitial cells in the septa, although prominent infiltration of inflammatory cells and high cellularity of interstitial cells are seen in some FLITs. The present cases suggest that ALK rearrangements, including the chimeric A2M-ALK gene, may be present in these infantile pulmonary lesions, especially those with inflammatory cell infiltration. We propose that these infantile pulmonary lesions containing a chimeric A2M-ALK gene be categorized as a specific type of inflammatory myofibroblastic tumor that develops exclusively in neonates and infants., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Carbon-ion radiotherapy (CIRT) is a promising treatment for locally advanced non-small-cell lung cancer, especially for patients with inoperable lung cancer. Although the incidence of CIRT-induced radiation pneumonitis (RP) ≥ grade 2 ranges from 2.5 to 9.9%, the association between CIRT-induced RP and dosimetric parameters is not clear. Herein, we identified prognostic factors associated with symptomatic RP after CIRT for patients with non-small-cell lung cancer., Methods: Clinical results of 65 patients treated with CIRT between 2000 and 2015 at the National Institute of Radiological Sciences were retrospectively analyzed. Clinical stage II B disease (TNM classification) was the most common stage among the patients (45%). The median radiation dose was 72 Gy (68-76) relative biological effectiveness (RBE) in 16 fractions. In cases involving metastatic lymph nodes, prophylactic irradiation of mediastinal lymph nodes was performed at a median dose of 49.5 Gy (RBE). The median follow-up was 22 months., Results: Grade 2 and grade 3 RP occurred in 6 and 3 patients (9 and 5%), respectively. No patients developed grade 4 or 5 RP. Using univariate analysis, vital capacity as a percentage of predicted (%VC), forced expiratory volume in 1 s (FEV1), mean lung dose (MLD), volume of lung receiving ≥5 Gy (RBE) (V 5 ), V 10 , V 20 and V 30 were determined to be the significant predictive factors for ≥ grade 2 RP. The receiver operating characteristic (ROC) analysis revealed the cutoff values for %VC, FEV1, MLD, V 5 , V 10 , V 20 and V 30 for ≥ grade 2 RP, which were 86.9%, 1.16 L, 12.5 Gy (RBE), 28.8, 29.9, 20.1 and 15.0%, respectively. In addition, the multivariate analysis revealed that %VC <86.9% (odds ratio = 13.7; p = 0.0041) and V 30  ≥ 15% (odds ratio = 6.1; p = 0.0221) were significant risk factors., Conclusions: Our study demonstrated the risk factors for ≥ grade 2 RP after carbon-ion radiotherapy for patients with locally advanced lung cancer.

Objectives: Our objective was to report initial results of a dose escalation trial of single-fraction carbon ion radiotherapy for peripheral stage I NSCLC., Methods: Between April 2003 and February 2012, a total of 218 patients were treated. The total dose was raised from 28 to 50 Gy (relative biological effectiveness [RBE]). There were 157 male and 61 female patients, with a median age of 75 years. Of the tumors, 123 were stage T1 and 95 were stage T2. A total of 134 patients (61.5%) were medically inoperable. By histological type, there were 146 adenocarcinomas, 68 squamous cell carcinomas, three large cell carcinomas, and one mucoepidermoid carcinoma., Results: The median follow-up was 57.8 months (range 1.6-160.7). The overall survival rate at 5 years was 49.4%. The local control (LC) rate was 72.7%. A statistically significant difference in LC rate (p = 0.0001, log-rank test) was seen between patients receiving 36 Gy (RBE) or more and those receiving less than 36 Gy (RBE). In 20 patients irradiated with 48 to 50 Gy (RBE), the LC rate at 5 years was 95.0%, the overall survival rate was 69.2%, and the progression-free survival rate was 60.0% (median follow-up was 58.6 months). With dose escalation, LC tended to improve. As for adverse lung and skin reactions, there were no patients with grade 3 or higher reactions, and less than 2% had a grade 2 reaction. Regarding chest wall pain, only one patient had grade 3 late toxicity., Conclusions: We have reported the outcome of a dose escalation study of single-fraction carbon ion radiotherapy for stage I NSCLC, showing the feasibility of obtaining excellent results comparable to those with previous fractionated regimens., (Copyright © 2016 International Association for the Study of Lung Cancer. Published by Elsevier Inc. All rights reserved.)

Objectives: Carbon ion radiotherapy (CIRT) has been expected to be an alternative for surgery for early-stage non-small-cell lung cancer (NSCLC) and adopted as the second-best choice even in operable patients although local recurrence after CIRT is sometimes experienced. The purpose of this study was to investigate the demographic data, perioperative courses and therapeutic outcomes of patients who underwent salvage resection for local recurrence after CIRT., Methods: From November 1994 to February 2012, CIRT was applied for 602 c-T1/T2/T3N0M0 NSCLC lesions of 599 patients at the National Institute of Radiological Science. A total of 95 (16%) patients were diagnosed as having local recurrence, of whom 12 underwent salvage surgeries. The medical records were retrospectively reviewed., Results: There were 7 men and 5 women (mean age, 63 ± 7.4 years). The clinical stages upon initial presentation with NSCLC were as follows: 4 IA, 7 IB and 1 IIB. All the patients were operable, but refused surgery and underwent CIRT. The median progression-free survival time after CIRT was 20 months (range, 7.1-77 months), and salvage surgery was performed at a median of 24 months (range, 9-78 months) after CIRT. All surgeries were successfully performed without any significant CIRT-related adhesions during the surgery, resulting in no mortality or Clavien-Dindo grade 3-4 postoperative complications. However, the distribution of pathological stages was as follows: 4 IA, 3 IB, 2 IIB, 2 IIIA and 1 IV, which included 6 upstages from the clinical stages before CIRT. The Kaplan-Meier estimate of overall survival after the salvage surgery showed that the 3-year survival rate was 82%., Conclusions: The dose intensity of CIRT spared the hilum of the lungs and parietal pleura, none of the patients developed adhesions outside of the radiation field, such that the salvage surgeries for local recurrence after CIRT were safe and feasible., (© The Author 2015. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Purpose: In an aging society, many senior citizens want less invasive treatment because of potential medical complications. The National Institute of Radiological Sciences has started to treat stage I lung cancer with single-fraction carbon-ion radiation therapy (CIRT) as a dose escalation prospective phase 1/2 trial. We evaluated the efficacy and safety of CIRT for patients 80 years of age and older, undergoing single-fraction CIRT., Methods and Materials: Peripheral non-small cell lung cancer patients who were treated with single-fraction CIRT were prospectively followed. We analyzed the data from among these patients 80 years of age and older., Results: There were 70 patients. Median age was 83 years (range: 80-89) and median follow-up period was 42.7 months (range: 12-128 months). Three-year local control, cause-specific survival, and overall survival rates were 88.0%, 81.6%, and 72.4%, respectively. Five-year local control, cause-specific survival, and overall survival rates were 85.8%, 64.9%, and 39.7%, respectively. There were no adverse effects higher than grade 2 either in the acute or late phase in terms of skin and lung. Analgesic agents were necessary for only 5 patients (7.1%), to relieve muscular or rib fracture pain caused by irradiation., Conclusions: Single-fraction CIRT was low-risk and effective, even for the elderly., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Background: The purpose of this study was to test the hypothesis that the genetic backgrounds of lung cancers could affect the spatial distribution of brain metastases., Methods: CT or MR images of 200 patients with a total of 1033 treatment-naive brain metastases from lung cancer were retrospectively reviewed (23 by CT and 177 by MRI). All images were standardized to the human brain MRI atlas provided by the Montreal Neurological Institute 152 database. Locations, depths from the brain surface, and sizes of the lesions after image standardization were analyzed., Results: The posterior fossa, the anatomic "watershed areas," and the gray-white matter junction were confirmed to be more commonly affected by lung cancer brain metastases, and brain metastases with epidermal growth factor receptor (EGFR) L858R mutation occurred more often in the caudate, cerebellum, and temporal lobe than those with exon 19 deletion of EGFR. Median depths of the lesions from the brain surface were 13.7 mm (range, 8.6-21.9) for exon 19 deleted EGFR, 11.5 mm (6.6-16.8) for L858R mutated, and 15.0 mm (10.0-20.7) for wild-type EGFR. Lesions with L858R mutated EGFR were located significantly closer to the brain surface than lesions with exon 19 deleted or wild-type EGFR (P = .0032 and P < .0001, respectively). Furthermore, brain metastases of adenocarcinoma lung cancer patients with a history of chemotherapy but not molecular targeted therapy were located significantly deeper from the brain surface (P = .0002)., Conclusion: This analysis is the first to reveal the relationship between EGFR mutation status and the spatial distribution of brain metastases of lung cancer., (© The Author(s) 2015. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

We encountered a case of uterine leiomyosarcoma with multiple lung metastases. The patient was a 52-year-old woman who underwent total abdominal hysterectomy and bilateral salpingo-oophorectomy followed by chemotherapy with gemcitabine and docetaxel. After 1 cycle of chemotherapy, the lung metastasis was reduced, but at the same time, she developed bilateral pneumothorax. Chemical pleurodesis using talc was performed. The lungs were expanded and stabilized in 7 days. After 5 cycles of chemotherapy were administered, no recurrence of pneumothorax and adverse effects were observed.

Background: Although concurrent chemoradiotherapy (CCRT) has become the standard approach for unresectable locally advanced non-small cell lung cancer (LA-NSCLC), most patients are not candidates for this treatment because of comorbidities. We evaluated the safety and efficacy of carbon ion radiotherapy (CIRT) in LA-NSCLC patients., Methods: Patients with stage IIA to IIIA (UICC 7th edition) LA-NSCLC were enrolled in a sequential phase I/II trial. For a phase I dose escalation study, the total prescribed dose was increased by 4 Gray equivalents (GyE) in 2 steps, from 68 to 72 GyE and then to 76 GyE, using 16 fractions over 4 weeks. After determining the recommended dose, the phase II trial was started in an expanded cohort., Results: Of the 36 patients treated in phase I, 2 grade 3 adverse events (radiation pneumonitis and tracheoesophageal fistula) were observed in the 76 GyE group. Accordingly, for phase II, the next consecutive 26 patients were treated with 72 GyE, with no grade 3 to 5 toxicities resulting. A total of 62 eligible patients were recruited. The majority of patients (49 of 62) were N0 or N1 patients, and the rest (13 of 62) were single-station N2 patients. The median follow-up period was 25.2 months. The 2-year local control rate (LCR) and overall survival (OS) for the entire cohort were 93.1% and 51.9%, respectively. In particular, patients with cT3-4N0 had an excellent prognosis; the 2-year OS and LCR were 69.3% and 100%, respectively., Conclusions: Short-course CIRT monotherapy shows promise as an effective nonsurgical treatment for inoperable LA-NSCLC., (© 2014 American Cancer Society.)

To achieve precise and sensitive detection of chemotherapy-resistant hepatoblastoma pulmonary metastases, we performed surgery using indocyanine green (ICG) fluorescence imaging navigation. Lung metastasectomies were performed in 10 patients aged from 1 to 11 years. ICG (0.5 mg/kg) was injected intravenously 24 h before the operation. After a thoracotomy had been performed, a 760-nm infrared ray was applied to the lung using a generator and the 830-nm evoked fluorescence was collected and visualized on a real-time display. In total, 250 fluorescence-positive lesions were extirpated in 37 operations. All of the pathologically positive lesions were clearly fluorescence positive. The diameter of the smallest detectable lesion was 0.062 mm. In two patients, there were 29 extirpated lesions that were pathologically proven not to be hepatoblastoma metastases. Although a problem of false positive remains, this method is very useful for the detection of small pulmonary metastases.

Background: To moving lung tumors, we applied a respiratory-gated strategy to carbon-ion pencil beam scanning with multiple phase-controlled rescanning (PCR). In this simulation study, we quantitatively evaluated dose distributions based on 4-dimensional CT (4DCT) treatment planning., Methods: Volumetric 4DCTs were acquired for 14 patients with lung tumors. Gross tumor volume, clinical target volume (CTV) and organs at risk (OARs) were delineated. Field-specific target volumes (FTVs) were calculated, and 48Gy(RBE) in a single fraction was prescribed to the FTVs delivered from four beam angles. The dose assessment metrics were quantified by changing the number of PCR and the results for the ungated and gated scenarios were then compared., Results: For the ungated strategy, the mean dose delivered to 95% of the volume of the CTV (CTV-D95) was in average 45.3 ± 0.9 Gy(RBE) even with a single rescanning (1 × PCR). Using 4 × PCR or more achieved adequate target coverage (CTV-D95 = 46.6 ± 0.3 Gy(RBE) for ungated 4 × PCR) and excellent dose homogeneity (homogeneity index =1.0 ± 0.2% for ungated 4 × PCR). Applying respiratory gating, percentage of lung receiving at least 20 Gy(RBE) (lung-V20) and heart maximal dose, averaged over all patients, significantly decreased by 12% (p < 0.05) and 13% (p < 0.05), respectively., Conclusions: Four or more PCR during PBS-CIRT improved dose conformation to moving lung tumors without gating. The use of a respiratory-gated strategy in combination with PCR reduced excessive doses to OARs.

Amplitude-based gating aids treatment planning in scanned particle therapy because it gives better control of uncertainty with the gate window. We have installed an X-ray fluoroscopic imaging system in our treatment room for clinical use with an amplitude-based gating strategy. We evaluated the effects of this gating under realistic organ motion conditions using 4 DCT data of lung and liver tumors. 4 DCT imaging was done for 24 lung and liver patients using the area-detector CT. We calculated the field-specific target volume (FTV) for the gating window, which was defined for a single respiratory cycle. Prescribed doses of 48 Gy relative biological effectiveness (RBE)/fraction/four fields and 45 Gy RBE/two fractions/two fields were delivered to the FTVs for lung and liver treatments, respectively. Dose distributions were calculated for the repeated first respiratory cycle (= planning dose) and the whole respiratory data (= treatment dose). We applied eight phase-controlled rescannings with the amplitude-based gating. For the lung cases, D95 of the treatment dose (= 96.0 ± 1.0%) was almost the same as that of the planning dose (= 96.6 ± 0.9%). D(max)/D(min) of the treatment dose (= 104.5 ± 2.2%/89.4 ± 2.6%) was slightly increased over that of the planning dose (= 102.1 ± 1.0%/89.8 ± 2.5%) due to hot spots. For the liver cases, D95 of the treatment dose (= 97.6 ± 0.5%) was decreased by ∼ 1% when compared with the planning dose (= 98.5 ± 0.4%). D(max)/D(min) of the treatment dose was degraded by 3.0%/0.4% compared with the planning dose. Average treatment times were extended by 46.5 s and 65.9 s from those of the planning dose for lung and liver cases, respectively. As with regular respiratory patterns, amplitude-based gated multiple phase-controlled rescanning preserves target coverage to a moving target under irregular respiratory patterns., (© The Author 2014. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Background: The purpose of this study was to evaluate the efficacy and feasibility of carbon ion radiotherapy (CIRT) for oligo-recurrent lung tumors from colorectal cancer (CRC)., Methods: From May 1997 to October 2012, 34 consecutive patients with oligo-recurrent pulmonary metastases from CRC were treated with CIRT. The patients were not surgical candidates for medical reasons or patient refusal. Using a respiratory-gated technique, carbon ion therapy was delivered with curative intent using 4 coplanar beam angles. A median dose of 60 GyE (range, 44-64.8 GyE) was delivered to the planning target volume (PTV), with a median daily dose of 15 GyE (range, 3.6-44 GyE). Treatment outcome was analyzed in terms of local control rate (LCR), survival rate, and treatment-related complications., Results: In total, 34 patients with 44 oligo-recurrent pulmonary lesions were treated with CIRT. Median follow-up period was 23.7 months. The 2- and 3-year actuarial LCRs of the treated patients were 85.4% ± 6.2% and 85.4% ± 6.2%, respectively. Overall survival was 65.1% ± 9.5% at 2 years, and 50.1% ± 10.5% at 3 years. Although survival rates were relatively worse in the subsets of patients aged<63 years or with early metastasis (< 36 months after resection of primary site), these factors were not significantly correlated with overall survival (P=0.13 and 0.19, respectively). All treatment-related complications were self-limited, without any grade 3-5 toxicity., Conclusions: CIRT is one of the most effective nonsurgical treatments for colorectal lung metastases, which are relatively resistant to stereotactic body radiotherapy. CIRT is considered to be the least invasive approach even in patients who have undergone repeated prior thoracic metastasectomies.

Patients with skin metastasis always had disseminated metastases in many organs. We herein report an unusual case with skin metastasis from small cell lung cancer (SCLC). The patient was treated with platinum-containing chemotherapy, and the response to the therapy was evaluated as partial response. The patient had slowly progressive disease and died of SCLC 16 months after the diagnosis of the diseases. If skin lesions, whether it may be typical or not, are found in SCLC patients, biopsy from the lesion would be considered to perform. Although trunk may be the most common sites, it is important to suspect such metastasis occurs in patients with SCLC.

Case 1: Case 1 involved a 42-year-old woman who had been diagnosed as having advanced breast cancer (Stage III B). She had previously received 6 courses of cyclophosphamide, epirubicin, and 5-fluorouracil CEF, 14 courses of weekly paclitaxel, and 2 courses of vinorelbine( VNR). After the courses of chemotherapy, she underwent modified radical mastectomy with axillary lymph node dissection. Two years after surgery, lung metastases were found, and the patient received 6 courses of weekly paclitaxel and 13 courses of nab-paclitaxel. However, the lung metastases progressed after the courses of chemotherapy, and therefore, we decided to administer eribulin as third-line chemotherapy. Eribulin was effective against the lung metastases for more than 1 year. Case 2: Case 2 involved a 52-year-old woman who had been diagnosed as having Stage IIB breast cancer. She had received 4 courses of CEF and 4 courses of docetaxel as neo-adjuvant chemotherapy. After chemotherapy, she underwent breast-conserving surgery with axillary lymph node dissection. Five years postoperatively, multiple liver metastases were found, and the patient received 3 courses. However, the liver metastases progressed after this chemotherapy. Subsequently, we administered nab-paclitaxel; however, it produced severe side effects. We then decided to administer eribulin as second-line chemotherapy. Eribulin was effective against the liver metastases for more than 1 year.

Fetal lung interstitial tumor, a newly recognized lung lesion in infants, was first reported in 2010. Here, we report the first Japanese case of fetal lung interstitial tumor which was originally diagnosed as atypical congenital cystic adenomatoid malformation/congenital pulmonary airway malformation type 3. A 7-day-old girl was referred to our hospital with respiratory distress and a left lung mass and she subsequently underwent left lower lobectomy. The specimen showed a 5 cm solid mass with a fibrous capsule. Histological examination revealed immature airspaces and interstitium, containing bronchioles and cartilage. The epithelial and interstitial cells contained abundant glycogen granules. Immunohistochemistry showed nuclear/cytoplasmic expression of β-catenin in the epithelial and interstitial cells. β-catenin gene mutations and trisomy 8 were not detected, so a neoplastic origin could not be confirmed. The histological findings were partly consistent with normal fetal lung at the canalicular stage, pulmonary interstitial glycogenosis, and congenital cystic adenomatoid malformation/congenital pulmonary airway malformation type 3. In this report, we compare the above conditions and discuss the pathogenesis of fetal lung interstitial tumor., (© 2013 The Authors. Pathology International © 2013 Japanese Society of Pathology and Wiley Publishing Asia Pty Ltd.)

A 30-year-old man underwent a left lobectomy and S5/6 partial hepatectomy in August 2001 for hepatocellular carcinoma (HCC). A lung tumor was detected by positron emission tomography (PET-CT) 8 years after the surgery. In May 2010, he received pulmonary tumor resection and the histopathological findings revealed metastasis of HCC. However a metastatic brain tumor was detected by computed tomography (CT) in September 2010, therefore surgery and radiation therapy were subsequently performed. Thereafter, metastatic hilar lymph node appeared in December 2010, therefore we performed systemic chemotherapy using S-1/cisplatin combined with radiation therapy for the metastatic tumor. The tumor was markedly decreased and no shadow was detected by PET-CT. He has been followed up in the outpatient clinic with no recurrence.

A 70-year-old female patient underwent pylorus-preserving pancreaticoduodenectomy for carcinoma of the ampulla of Vater in March 2007. In April 2009, multiple lung metastases were detected by CT scanning. The patient was treated with S-1 (80mg/day, day 1-28, followed by 2-weeks withdrawal)from April 2009. The shrinkage of lung metastases was diagnosed as a complete response based on the Response Evaluation Criteria in Solid Tumors(RECIST). No severe toxicities were observed. S-1 is an effective and safe anti-cancer agent available for lung metastases of carcinoma of the ampulla of Vater.

In this study, we report 2 pediatric cases of nuclear protein of the testis (NUT) midline carcinoma (NMC) suggestive of pulmonary origin: case 1 was a 14-year-old Japanese boy and case 2 was a 7-year-old Japanese girl. Initial symptoms of both cases were prolonged cough and chest pain, and the case 2 patient also complained of lumbago and lumbar mass due to bone metastases. Imaging studies revealed that pulmonary tumors from both patients were located at the hilar region of the lower lobe. Biopsies of the tumors showed undifferentiated carcinoma in case 1 and combined undifferentiated and squamous cell carcinoma in case 2. Despite intensive treatment with chemotherapy and radiation, progression of neither tumor was controlled, and both patients died of the tumors at 1 year (case 1) and 4 months (case 2) after onset of disease. Both tumors were diffusely positive for p63 and NUT expression and were partially positive for various cytokeratins. Reverse transcription polymerase chain reaction analysis and subsequent direct sequencing revealed that the bromodomain-containing protein 4-NUT chimeric gene was present in tumor tissue of both patients, leading to a diagnosis of NMC. The tumor cells of case 1 were also positive for thyroid transcription factor-1 expression, but those of case 2 were negative. Histologic examination of the surgically removed lung tumor of case 1 indicated that the origin of the tumor was basal cells of the bronchiolar epithelia.

Purpose: The aim of this study was to investigate the change of 3'-[¹⁸F]fluoro-3'-deoxy-L: -thymidine (¹⁸FLT) uptake in normal bone marrow (BM) after inevitable radiation., Procedures: Twenty-one non-small cell lung cancer patients who received carbon ion radiotherapy (CIRT) were studied with ¹⁸FLT-positron emission tomography/computed tomography (PET/CT) at pre- and post-CIRT. Radiation dose was calculated by radiation planning. Irradiated BM was divided into three groups (<10% of maximum dose, 10-30%, and >30%)., Results: ¹⁸FLT uptake clearly decreased at >10% irradiated areas and mildly decreased at <10% areas. ¹⁸FLT uptake was lowest just after CIRT, somewhat increased at 3 months, and remained unchanged for more than 1 year. There was no significant difference between 10-30% and >30% areas., Conclusion: ¹⁸FLT revealed that BM function decreased by small dose such as <4.2-4.4 GyE/1 fraction of CIRT and is eradicated by >4.2-4.4 GyE/1 fraction.

Purpose: We compared four-dimensional (4D) layer-stacking and conventional carbon ion beam distribution in the treatment of lung cancer between ungated and gated respiratory strategies using 4DCT data sets., Methods and Materials: Twenty lung patients underwent 4DCT imaging under free-breathing conditions. Using planning target volumes (PTVs) at respective respiratory phases, two types of compensating bolus were designed, a full single respiratory cycle for the ungated strategy and an approximately 30% duty cycle for the exhalation-gated strategy. Beams were delivered to the PTVs for the ungated and gated strategies, PTV(ungated) and PTV(gated), respectively, which were calculated by combining the respective PTV(Tn)s by layer-stacking and conventional irradiation. Carbon ion beam dose distribution was calculated as a function of respiratory phase by applying a compensating bolus to 4DCT. Accumulated dose distributions were calculated by applying deformable registration., Results: With the ungated strategy, accumulated dose distributions were satisfactorily provided to the PTV, with D95 values for layer-stacking and conventional irradiation of 94.0% and 96.2%, respectively. V20 for the lung and Dmax for the spinal cord were lower with layer-stacking than with conventional irradiation, whereas Dmax for the skin (14.1 GyE) was significantly lower (21.9 GyE). In addition, dose conformation to the GTV/PTV with layer-stacking irradiation was better with the gated than with the ungated strategy., Conclusions: Gated layer-stacking irradiation allows the delivery of a carbon ion beam to a moving target without significant degradation of dose conformity or the development of hot spots., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Objective: The aim of this study was to investigate the clinical value of 3'-deoxy-3'-[F]fluorothymidine-positron emission tomography/computed tomography (FLT-PET/CT) for lung cancer patients receiving carbon-ion radiotherapy., Methods: Twenty consecutive patients with lung cancer underwent FLT-PET/CT before and after carbon-ion radiotherapy. Fifty minutes after intravenous injection of approximately 300 MBq of FLT, PET/CT data were acquired. Maximal standardized uptake value of the tumor was measured, from which the reduction rate of tumor FLT uptake was calculated. After treatment, the patients were followed (17-42 months for survivors) for the development of recurrence and survival., Results: Primary responses to carbon-ion radiotherapy were partial in 13 patients, stable disease in six patients, and nonevaluable in one patient. Although tumor FLT uptake significantly decreased after treatment (P < 0.001), the presence of radiation pneumonitis hampered its precise evaluation. During the follow-up period, nine patients developed recurrence, and seven patients died including two deaths from other causes. Pretreatment FLT uptake of patients who developed recurrence and who died of lung cancer were significantly higher than that of patients who did not (P = 0.008 and 0.007, respectively). Kaplan-Meier analysis using a cut-off value also supported the prognostic value of pre-carbon-ion radiotherapy FLT-PET/CT., Conclusion: This investigation suggests that FLT-PET/CT is feasible in evaluating lung cancer patients undergoing carbon-ion radiotherapy. The presence of radiation pneumonitis can influence tumor FLT uptake and needs special attention. Pre-carbon-ion radiotherapy FLT-PET/CT seems to have a prognostic value and may contribute to decision-making on the treatment strategy.

Introduction: Sixteen percent of patients with gastric cancer will develop pulmonary metastases. Standard of care for these patients is systemic chemotherapy with a median survival of 6 months and a 5-year survival of only 2%. Our aim was to critically evaluate the published data on pulmonary resection for metastatic gastric cancer (MGC) and to analyze the potential rationale for surgical management to determine which patients may benefit from this approach., Methods: The Pubmed and SCOPUS databases were queried for all studies reporting on pulmonary resections for MGC. All available clinicopathologic data were analyzed., Results: Twenty-one studies from 1975 to 2008 reported 48 pulmonary resections in 43 patients including five repeat resections and four extrapulmonary metastasectomies. Eighty-two percent (34/43) of patients had solitary lesions with a median size of 24 mm (4-90 mm). Median time from gastrectomy to pulmonary resection was 35 months (0-120 months). At a median follow-up of 23 months, 15 of 43 (35%) patients were alive without disease, and two patients died without disease. Median survival was 29 months (3-84 months) after pulmonary metastasectomy and 65 months (5-180 months) after gastrectomy. Fifty-six percent (24/43) of patients had another recurrence at a median of 12 months (range: 6-48 months) after resection including 30% (13/43) of patients with pulmonary recurrences. Overall 5-year survival was 33%., Conclusions: Pulmonary metastasectomy for MGC can potentially result in long-term survival in a highly selected group of patients and should be considered for those who present with small, isolated lesions after a prolonged disease-free interval.

Purpose: To determine pretreatment serum CYFRA21-1 levels as indicators of poor prognosis in patients with non-small cell lung cancer (NSCLC)., Methods: 1,202 consecutive patients, diagnosed pathologically with NSCLC from January 1999 to December 2009, were entered in this study. To obtain optimal cutoff points of CYFRA21-1 for these endpoints, a running log-rank statistical method was applied., Results: The cutoff level for the maximum log-rank statistical value of one-year survival in patients with NSCLC was 18.0 ng/ml. These results could be applied to patients with squamous cell carcinoma. In multivariate analysis, elevated (>18.0 ng/ml) levels of CYFRA21-1 was confirmed as being an unfavourable prognostic factor., Conclusion: CYFRA21-1 assay has a clinical significance for identifying patients with poor prognosis among those with early and advanced NSCLC. Elevated serum CYFRA21-1 levels at the time of diagnosis may be a useful noninvasive marker for identifying the risk of early death from NSCLC.