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Background and Purpose: This study aims to externally validate a predictive model for distant metastasis (DM) with computed tomography (CT)-based radiomics features in prospectively enrolled non-small-cell lung cancer patients undergoing dynamic tumor-tracking stereotactic body radiation therapy (DTT-SBRT)., Materials and Methods: The study collected retrospective data from 567 patients across 11 institutions as the training dataset and prospectively enrolled 42 patients from four institutions as the external test dataset. Four clinical features were collected, and 944 CT-based radiomic features were extracted from gross tumor volumes. After standardization and feature selection, DM predictive models were developed using fine and gray regression (FG) and random survival forest (RSF), incorporating clinical and radiomic features, and their combinations within the training dataset. Then, the model was applied to the test dataset, dividing patients into high- and low-risk groups based on medians of risk scores. Model performance was assessed using the concordance index (C-index), and the statistical significance between groups was evaluated using Gray's test., Results: In the training dataset, 122 of 567 patients (21.5%) developed DM, compared to 9 of 42 patients (21.4%) in the test dataset. In the test dataset, the C-indices of the clinical, radiomics, and hybrid models with FG were 0.559, 0.544, and 0.560, respectively, whereas those with RSF were 0.576, 0.604, and 0.627, respectively. The hybrid model with RSF, which exhibited the best predictive performance of all models, identified 7 of 23 patients (30.4%) as high risk and 2 of 19 patients (10.5%) as low risk for DM incidence in the test dataset (p = 0.116)., Conclusion: Although predictive models for DM lack significance when applied to prospectively enrolled cases undergoing DTT-lung SBRT, the model with RSF exhibits a consistent capacity to effectively classify patients at a high risk of developing DM., (© 2024 The Author(s). Journal of Applied Clinical Medical Physics is published by Wiley Periodicals, Inc. on behalf of The American Association of Physicists in Medicine.)

Background and Purpose: Symptomatic radiation pneumonitis (SRP) is a complication of thoracic stereotactic body radiotherapy (SBRT). As visual assessments pose limitations, artificial intelligence-based quantitative computed tomography image analysis software (AIQCT) may help predict SRP risk. We aimed to evaluate high-resolution computed tomography (HRCT) images with AIQCT to develop a predictive model for SRP., Materials and Methods: AIQCT automatically labelled HRCT images of patients treated with SBRT for stage I lung cancer according to lung parenchymal pattern. Quantitative data including the volume and mean dose (D mean ) were obtained for reticulation + honeycombing (Ret + HC), consolidation + ground-glass opacities, bronchi (Br), and normal lungs (NL). After associations between AIQCT's quantified metrics and SRP were investigated, we developed a predictive model using recursive partitioning analysis (RPA) for the training cohort and assessed its reproducibility with the testing cohort., Results: Overall, 26 of 207 patients developed SRP. There were significant between-group differences in the Ret + HC, Br-volume, and NL-D mean in patients with and without SRP. RPA identified the following risk groups: NL-D mean  ≥ 6.6 Gy (high-risk, n = 8), NL-D mean  < 6.6 Gy and Br-volume ≥ 2.5 % (intermediate-risk, n = 13), and NL-D mean  < 6.6 Gy and Br-volume < 2.5 % (low-risk, n = 133). The incidences of SRP in these groups within the training cohort were 62.5, 38.4, and 7.5 %; and in the testing cohort 50.0, 27.3, and 5.0 %, respectively., Conclusion: AIQCT identified CT features associated with SRP. A predictive model for SRP was proposed based on AI-detected Br-volume and the NL-D mean ., Competing Interests: Declaration of competing interest Tsuyoshi Oguma has received lecture fees from Kyowa Kirin, AstraZeneca, KYORIN Pharmaceutical, GlaxoSmithKline, Sanofi, and Boehringer Ingelheim. Kiminobu Tanizawa has received a research grant for the Department of Respiratory Medicine, Graduate School of Medicine, Kyoto University from FUJIFILM Corporation and Daiichi Sankyo Company, Limited. He has also received a research grant from the Japan Society for the Promotion of Science KAKENHI. Tomohiro Handa is in the employ of the collaborative research laboratory funded by Teijin Pharma Co., Ltd., and has also received research grants from FUJIFILM Corporation. Toyohiro Hirai has received a grant from FUJIFILM Corporation. Takashi Mizowaki has participated in a commissioned project and a collaborative research project with Varian Medical Systems, a collaborative research project with Hitachi Ltd. He has received scholarship donations from Hitachi Ltd, and speaker fees from Varian Medical Systems and Hitachi Ltd. The other authors have no competing interests to disclose., (Copyright © 2024 Elsevier B.V. All rights reserved.)

Background: Surgery is the standard care for patients with early-stage lung cancer, and stereotactic body radiation therapy is an option for those who are medically inoperable or refuse surgery. Medical developments in diagnostic and therapeutic strategies would prolong prognosis of patients with cancer. The number of patients with multiple cancers has also increased. Duplex primary malignant neoplasms are the most common, and triple or more primary malignant neoplasms were extremely rare. This is the first case of sextuple primary malignant neoplasms with lung cancer., Case Presentation: We report a case of two courses of stereotactic body radiation therapy for an 88-year-old Japanese male patient with six primary cancers in five organs. Cancers were detected in the thyroid, prostate, esophagus, bladder, and lungs. He also had a history of angina pectoris and had undergone percutaneous coronary intervention. Although he was capable of undergoing surgery for lung cancers, he refused it because he had experienced many invasive treatments, such as surgeries and percutaneous coronary intervention. In January 2020, the first stereotactic body radiation therapy was performed for the adenocarcinoma in the right lung. In March 2022, the second stereotactic body radiation therapy was performed for the nodule of the left lung. Although he complained of mild dyspnea after the first stereotactic body radiation therapy, we did not use steroids because his peripheral oxygen saturation was within the normal range. He had pleural effusion, cardiac dilatation, and pericardial effusion 2 months after the second stereotactic body radiation therapy, which improved with the use of compression stockings., Conclusion: A total of 43 and 17 months have passed since the first and second stereotactic body radiation therapy, respectively, there is no local recurrence and the patient can walk independently. We safely performed stereotactic body radiation therapy twice for our older patient with metachronous early-stage lung cancers. If another new tumor is detected, stereotactic body radiation therapy would be a good treatment option for the functional preservation of organs., (© 2024. The Author(s).)

Background: Centrally located lung tumours present a challenge because of their tendency to exhibit symptoms such as airway obstruction, atelectasis, and bleeding. Surgical resection of these tumours often requires sacrificing the lungs, making definitive radiotherapy the preferred alternative to avoid pneumonectomy. However, the proximity of these tumours to mediastinal organs at risk increases the potential for severe adverse events. To mitigate this risk, we propose a dual-method approach: deep inspiration breath-hold (DIBH) radiotherapy combined with adaptive radiotherapy. The aim of this single-centre, single-arm phase II study is to investigate the efficacy and safety of DIBH daily online adaptive radiotherapy., Methods: Patients diagnosed with centrally located lung tumours according to the International Association for the Study of Lung Cancer recommendations, are enrolled and subjected to DIBH daily online adaptive radiotherapy. The primary endpoint is the one-year cumulative incidence of grade 3 or more severe adverse events, as classified by the Common Terminology Criteria for Adverse Events (CTCAE v5.0)., Discussion: Delivering definitive radiotherapy for centrally located lung tumours presents a dilemma between ensuring optimal dose coverage for the planning target volume and the associated increased risk of adverse events. DIBH provides measurable dosimetric benefits by increasing the normal lung volume and distancing the tumour from critical mediastinal organs at risk, leading to reduced toxicity. DIBH adaptive radiotherapy has been proposed as an adjunct treatment option for abdominal and pelvic cancers. If the application of DIBH adaptive radiotherapy to centrally located lung tumours proves successful, this approach could shape future phase III trials and offer novel perspectives in lung tumour radiotherapy., Trial Registration: Registered at the Japan Registry of Clinical Trials (jRCT; https://jrct.niph.go.jp/ ); registration number: jRCT1052230085 ( https://jrct.niph.go.jp/en-latest-detail/jRCT1052230085 )., (© 2024. The Author(s).)

Background: Both geometric and dosimetric components are commonly considered when determining the margin for planning target volume (PTV). As dose distribution is shaped by controlling beam aperture in peripheral dose prescription and dose-escalated simultaneously integrated boost techniques, adjusting the margin by incorporating the variable dosimetric component into the PTV margin is inappropriate; therefore, geometric components should be accurately estimated for margin calculations., Purpose: We introduced an asymmetric margin-calculation theory using the guide to the expression of uncertainty in measurement (GUM) and intra-fractional motion. The margins in fiducial marker-based real-time tumor tracking (RTTT) for lung, liver, and pancreatic cancers were calculated and were then evaluated using Monte Carlo (MC) simulations., Methods: A total of 74 705, 73 235, and 164 968 sets of intra- and inter-fractional positional data were analyzed for 48 lung, 48 liver, and 25 pancreatic cancer patients, respectively, in RTTT clinical trials. The 2.5th and 97.5th percentiles of the positional error were considered representative values of each fraction of the disease site. The population-based statistics of the probability distributions of these representative positional errors (PD-RPEs) were calculated in six directions. A margin covering 95% of the population was calculated using the proposed formula. The content rate in which the clinical target volume (CTV) was included in the PTV was calculated through MC simulations using the PD-RPEs., Results: The margins required for RTTT were at most 6.2, 4.6, and 3.9 mm for lung, liver, and pancreatic cancer, respectively. MC simulations revealed that the median content rates using the proposed margins satisfied 95% for lung and liver cancers and 93% for pancreatic cancer, closer to the expected rates than the margins according to van Herk's formula., Conclusions: Our proposed formula based on the GUM and motion probability distributions (MPD) accurately calculated the practical margin size for fiducial marker-based RTTT. This was verified through MC simulations., (© 2023 American Association of Physicists in Medicine.)

Purpose: To develop a prediction model (PM) for target positioning using diaphragm waveforms extracted from CBCT projection images., Methods: Nineteen patients with lung cancer underwent orthogonal rotational kV x-ray imaging lasting 70 s. IR markers placed on their abdominal surfaces and an implanted gold marker located nearest to the tumor were considered as external surrogates and the target, respectively. Four different types of regression-based PM were trained using surrogate motions and target positions for the first 60 s, as follows: Scenario A: Based on the clinical scenario, 3D target positions extracted from projection images were used as they were (PM CL ). Scenario B: The short-arc 4D-CBCT waveform exhibiting eight target positions was obtained by averaging the target positions in Scenario A. The waveform was repeated for 60 s (W 4D-CBCT ) by adapting to the respiratory phase of the external surrogate. W 4D-CBCT was used as the target positions (PM 4D-CBCT ). Scenario C: The Amsterdam Shroud (AS) signal, which depicted the diaphragm motion in the superior-inferior direction was extracted from the orthogonal projection images. The amplitude and phase of W 4D-CBCT were corrected based on the AS signal. The AS-corrected W 4D-CBCT was used as the target positions (PM AS-4D-CBCT ). Scenario D: The AS signal was extracted from single projection images. Other processes were the same as in Scenario C. The prediction errors were calculated for the remaining 10 s., Results: The 3D prediction error within 3 mm was 77.3% for PM 4D-CBCT , which was 12.8% lower than that for PM CL . Using the diaphragm waveforms, the percentage of errors within 3 mm improved by approximately 7% to 84.0%-85.3% for PM AS-4D-CBCT in Scenarios C and D, respectively. Statistically significant differences were observed between the prediction errors of PM 4D-CBCT and PM AS-4D-CBCT ., Conclusion: PM AS-4D-CBCT outperformed PM 4D-CBCT , proving the efficacy of the AS signal-based correction. PM AS-4D-CBCT would make it possible to predict target positions from 4D-CBCT images without gold markers., (© 2023 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Purpose: The feasibility of a deep learning-based markerless real-time tumor tracking (RTTT) method was retrospectively studied with orthogonal kV X-ray images and clinical tracking records acquired during lung cancer treatment., Methods: Ten patients with lung cancer treated with marker-implanted RTTT were included. The prescription dose was 50 Gy in four fractions, using seven- to nine-port non-coplanar static beams. This corresponds to 14-18 X-ray tube angles for an orthogonal X-ray imaging system rotating with the gantry. All patients underwent 10 respiratory phases four-dimensional computed tomography. After a data augmentation approach, for each X-ray tube angle of a patient, 2250 digitally reconstructed radiograph (DRR) images with gross tumor volume (GTV) contour labeled were obtained. These images were adopted to train the patient and X-ray tube angle-specific GTV contour prediction model. During the testing, the model trained with DRR images predicted GTV contour on X-ray projection images acquired during treatment. The predicted three-dimensional (3D) positions of the GTV were calculated based on the centroids of the contours in the orthogonal images. The 3D positions of GTV determined by the marker-implanted RTTT during the treatment were considered as the ground truth. The 3D deviations between the prediction and the ground truth were calculated to evaluate the performance of the model., Results: The median GTV volume and motion range were 7.42 (range, 1.18-25.74) cm 3 and 22 (range, 11-28) mm, respectively. In total, 8993 3D position comparisons were included. The mean calculation time was 85 ms per image. The overall median value of the 3D deviation was 2.27 (interquartile range: 1.66-2.95) mm. The probability of the 3D deviation smaller than 5 mm was 93.6%., Conclusions: The evaluation results and calculation efficiency show the proposed deep learning-based markerless RTTT method may be feasible for patients with lung cancer., (© 2022 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, LLC on behalf of The American Association of Physicists in Medicine.)

Chemoradiotherapy followed by consolidation durvalumab (CCRT+D) improves survival in patients with stage III non-small-cell lung cancer (NSCLC). We compared recurrence patterns and survival in the CCRT+D and CCRT cohorts. We conducted a multicenter, retrospective study in Japan. Patients who received CCRT for stage III NSCLC were included in this study. Of 178 eligible patients, 136 were in the CCRT+D and 42 were in the CCRT cohorts. Locoregional recurrence (LR), LR plus distant metastases (DM), and DM were observed in 20.6%, 8.8%, 27.9% of the CCRT+D, and 26.2%, 16.7% and 33.3% of the CCRT cohorts, respectively. In-field recurrence was the most common LR pattern in both cohorts. Squamous cell carcinoma and PD-L1 expression < 1%, and female sex and EGFR mutations were significantly associated with an increased risk of LR and DM. In patients with any risk factors for LR, the incidence of LR was similar in the CCRT+D and CCRT (39.5% vs 45.5%). The 24 month progression-free survival (PFS) and overall survival (OS) were 40.3% and 69.4% in the CCRT+D and 24.7% and 61.0% in the CCRT cohorts, respectively. Poor performance status and no consolidation durvalumab were significantly associated with shorter PFS. There was a significant difference in PFS between the CCRT+D and CCRT in the propensity score-matched cohort (HR = 0.51, P = 0.005). In conclusion, consolidation durvalumab decreased both LR and DM, and significantly improved PFS. However, in-field recurrence was still a major problem, as well as DM., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

We applied two propensity score-based analyses to simultaneously compare three treatment modalities-stereotactic body radiotherapy (SBRT), lobectomy, or sublobar resection (SLR)-for stage I non-small cell lung cancer (NSCLC), with the aim of clarifying the average treatment effect (ATE) and formulating a risk-adapted approach to treatment selection. A retrospective review of 823 patients aged ≥65 years who underwent SBRT, lobectomy, or SLR for stage I NSCLC was conducted. The following two analyses using machine learning-based propensity scores were performed: (i) propensity score weighting (PSW) to assess the ATE in the entire cohort, and (ii) propensity score subclassification (PSS) to evaluate treatment effects of subgroups. PSW showed no significant difference in the 5-year overall survival (OS) between SBRT and SLR (60.0% vs 61.2%; P = 0.70) and significant difference between SBRT and lobectomy (60.0% vs 77.6%; P = 0.026). Local (LR) and distant recurrence (DR) rates were significantly lower in lobectomy than in SBRT, whereas there was no significant difference between SBRT and SLR. PSS identified four subgroups with different patient characteristics: lobectomy-oriented (5-year cumulative incidences of non-lung cancer death, 7.5%), SLR-oriented (14.2%), SBRT-oriented (23.8%) and treatment-neutral subgroups (16.1%). Each subgroup showed different survival trends regarding the three treatments. The ATE of SBRT was not significantly different from that of SLR, but it was inferior to lobectomy. Four subgroups with different risks of non-lung cancer death and different survival trends for each treatment were identified. These would help decision-making for patients with stage I NSCLC., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Prophylactic cranial irradiation (PCI) is recommended for patients with limited-stage small-cell lung cancer (LS-SCLC) who respond well to initial treatment. However, PCI is often omitted because of its potential neurotoxicity in the era of modern diagnostic imaging devices. In the present study, we aimed to investigate the risk factors for brain metastasis (BM) in patients eligible for PCI and who may benefit more from it. Patients with LS-SCLC who responded well to definitive thoracic chemoradiotherapy were included in the present study. Competing risk regression was used to identify factors associated with BM, and the Kaplan-Meier method was used to assess overall survival (OS). Between 2004 and 2017, 62 patients were eligible for PCI and were analyzed. Of these, 38 (61.3%) underwent PCI. Overall, 17 patients (27.4%) developed BM, with a 2-year cumulative incidence of 22.8%. Multivariate analysis (MVA) revealed that pretreatment elevated pro-gastrin-releasing peptide (ProGRP) levels were associated with an increased risk for BM (HR, 7.96, P = 0.0091). PCI tended to reduce the risk of BM (HR, 0.33; P = 0.051). The use of PCI was associated with improved OS in patients with ProGRP levels > 410 pg/mL (P = 0.008), but not in those with ProGRP ≤ 410 pg/mL (P = 0.9). Pretreatment ProGRP levels may be useful in predicting the development of BM in patients with LS-SCLC who achieved a good response to initial therapy and to determine which patients should undergo PCI., (© The Author(s) 2022. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Background and Purpose: This study aimed to evaluate the safety and efficacy of dynamic tumor tracking-stereotactic body radiotherapy (DTT-SBRT) for lung tumors., Materials and Methods: Patients with cStage I primary lung cancer or metastatic lung cancer with an expected range of respiratory motion of ≥10 mm were eligible for the study. The prescribed dose was 50 Gy in four fractions. A gimbal-mounted linac was used for DTT-SBRT delivery. The primary endpoint was local control at 2 years., Results: Forty-eight patients from four institutions were enrolled in this study. Forty-two patients had primary non-small-cell lung cancer, and six had metastatic lung tumors. DTT-SBRT was delivered for 47 lesions in 47 patients with a median treatment time of 28 min per fraction. The median respiratory motion during the treatment was 13.7 mm (range: 4.5-28.1 mm). The motion-encompassing method was applied for the one remaining patient due to the poor correlation between the abdominal wall and tumor movement. The median follow-up period was 32.3 months, and the local control at 2 years was 95.2% (lower limit of the one-sided 85% confidence interval [CI]: 90.3%). The overall survival and progression-free survival at 2 years were 79.2% (95% CI: 64.7%-88.2%) and 75.0% (95% CI: 60.2%-85.0%), respectively. Grade 3 toxicity was observed in one patient (2.1%) with radiation pneumonitis. Grade 4 or 5 toxicity was not observed., Conclusion: DTT-SBRT achieved excellent local control with low incidences of severe toxicities in lung tumors with respiratory motion., (Copyright © 2022 The Author(s). Published by Elsevier B.V. All rights reserved.)

The spread through air spaces (STAS) is recognized as a negative prognostic factor in patients with early-stage lung adenocarcinoma. The present study aimed to develop a machine learning model for the prediction of STAS using peritumoral radiomics features extracted from preoperative CT imaging. A total of 339 patients who underwent lobectomy or limited resection for lung adenocarcinoma were included. The patients were randomly divided (3:2) into training and test cohorts. Two prediction models were created using the training cohort: a conventional model based on the tumor consolidation/tumor (C/T) ratio and a machine learning model based on peritumoral radiomics features. The areas under the curve for the two models in the testing cohort were 0.70 and 0.76, respectively (P = 0.045). The cumulative incidence of recurrence (CIR) was significantly higher in the STAS high-risk group when using the radiomics model than that in the low-risk group (44% vs. 4% at 5 years; P = 0.002) in patients who underwent limited resection in the testing cohort. In contrast, the 5-year CIR was not significantly different among patients who underwent lobectomy (17% vs. 11%; P = 0.469). In conclusion, the machine learning model for STAS prediction based on peritumoral radiomics features performed better than the C/T ratio model., (© 2022. The Author(s).)

Cancer recurrence due to tumor cell quiescence after therapy and long-term remission is associated with cancer-related death. Previous studies have used cell models that are unable to return to a proliferative state; thus, the transition between quiescent and proliferative states is not well understood. Here, we report monolayer cancer cell models wherein the human non-small cell lung carcinoma cell line H2228 and pancreatic cancer cell line AsPC-1 can be reversibly induced to a quiescent state under hypoxic and serum-starved (HSS) conditions. Transcriptome and metabolome dual-omics profiles of these cells were compared with those of the human lung adenocarcinoma cell line A549, which was unable to enter a quiescent state under HSS conditions. The quiescence-inducible cells had substantially lower intracellular pyruvate and ATP levels in the quiescent state than in the proliferative state, and their response to sudden demand for energy was dramatically reduced. Furthermore, in quiescence-inducible cells, the transition between quiescent and proliferative states of these cells was regulated by the balance between the proliferation-promoting Ras and Rap1 signaling and the suppressive AGE/RAGE signaling. These cell models elucidate the transition between quiescent and proliferative states, allowing the development of drug-screening systems for quiescent tumor cells., (© 2022. The Author(s).)

Marital status has been proposed as a promising prognostic factor in many malignancies, including non-small-cell lung cancer (NSCLC). However, its prognostic value is still unclear for individual non-surgical treatments for stage I NSCLC. This study investigated the prognostic value of marital status in patients with early-stage NSCLC treated with stereotactic body radiotherapy (SBRT). Patients with early-stage NSCLC treated with SBRT between January 2003 and March 2014 at our institute were enrolled, and marital status at the time of SBRT was investigated. Propensity score matching (PSM) was applied to reduce potential selection bias between the married and unmarried groups. Two hundred and forty patients (median age 77 years; 152 married, 87 unmarried) were analyzed. The unmarried included higher proportions of the elderly, women, never smokers, and those with decreased pulmonary function compared to the married. PSM identified 53 matched pairs of married and unmarried patients, with no significant difference in patient background parameters. The 5-year overall survival (OS) was 52.8% and 46.9% in the married and unmarried groups, respectively (P = 0.26). There was no significant difference in NSCLC death or non-NSCLC death between the two groups (P = 0.88 and 0.30, respectively). There was no significant difference in OS between married and unmarried male patients (n = 85, 5-year OS, 52.6% vs. 46.0%; P = 0.42) and between married and unmarried female patients (n = 21, 54.5% vs. 50.0%; P = 0.44). In conclusion, marital status was not associated with OS in patients receiving SBRT for early-stage NSCLC., Competing Interests: The authors have declared that no competing interests exist.

Purpose: Clear evidence indicating whether surgery or stereotactic body radiation therapy (SBRT) is best for non-small-cell lung cancer (NSCLC) is lacking. SBRT has many advantages. We used artificial neural networks (NNs) to predict treatment outcomes for patients with NSCLC receiving SBRT, aiming to aid in decision making., Patients and Methods: Among consecutive patients receiving SBRT between 2005 and 2019 in our institution, we retrospectively identified those with Tis-T4N0M0 NSCLC. We constructed two NNs for prediction of overall survival (OS) and cancer progression in the first 5 years after SBRT, which were tested using an internal and an external test data set. We performed risk group stratification, wherein 5-year OS and cancer progression were stratified into three groups., Results: In total, 692 patients in our institution and 100 patients randomly chosen in the external institution were enrolled. The NNs resulted in concordance indexes for OS of 0.76 (95% CI, 0.73 to 0.79), 0.68 (95% CI, 0.60 to 0.75), and 0.69 (95% CI, 0.61 to 0.76) and area under the curve for cancer progression of 0.80 (95% CI, 0.75 to 0.84), 0.72 (95% CI, 0.60 to 0.83), and 0.70 (95% CI, 0.57 to 0.81) in the training, internal test, and external test data sets, respectively. The survival and cumulative incidence curves were significantly stratified. NNs selected low-risk cancer progression groups of 5.6%, 6.9%, and 7.0% in the training, internal test, and external test data sets, respectively, suggesting that 48% of patients with peripheral Tis-4N0M0 NSCLC can be at low-risk for cancer progression., Conclusion: Predictions of SBRT outcomes using NNs were useful for Tis-4N0M0 NSCLC. Our results are anticipated to open new avenues for NN predictions and provide decision-making guidance for patients and physicians., Competing Interests: Atsuya TakedaConsulting or Advisory Role: Accuray Japan K.K.Research Funding: Varian Medical Systems Yukinori MatsuoResearch Funding: Varian Medical SystemsNo other potential conflicts of interest were reported.

Background: Although the prognosis of patients experiencing recurrences after surgery for pancreatic cancer is extremely poor, patients who develop recurrence in the lung have a better prognosis compared to other types of recurrence. We performed a histo-immunological analysis of the metastatic specimens to identify specific features of this patient subgroup., Methods: We performed immunohistochemistry for CD4+, CD8+, CD45RO+, Foxp3, and PD-L1 in the lung (n = 22), peritoneal (n = 18), and liver (n = 6) metastases of pancreatic cancer. As microenvironmental and immunonutritional investigations, the tumor-stroma ratio and prognostic nutritional index (PNI) were utilized in the integrative analysis of immunological features., Results: We identified significantly increased tumor-infiltrating CD4+, CD8+, and CD45RO+ cells in lung metastasis, compared with peritoneal and liver metastases (lung vs. peritoneum/liver, CD4: P < 0.001/P = 0.015, CD8: P < 0.001/P = 0.038, CD45RO: P = 0.022/P = 0.012). The CD8/Foxp3 ratio was higher in the lung than in the liver (P = 0.024). PD-L1 expression was significantly higher in lung metastasis than in peritoneal metastasis (P = 0.010). Furthermore, we found that lung metastasis had fewer cancer stroma than peritoneal metastasis (P < 0.001). A higher PNI was observed in patients with lung metastasis, and PNI was positively correlated with tumor-infiltrating lymphocytes in metastatic sites., Conclusion: We identified that lung metastasis revealed an immunologically "hot" tumor with increased TILs and PD-L1 expression. This specific feature suggests that patients with lung metastasis can be candidates for immunotherapy, such as immune checkpoint inhibitors; therefore, our study provides a framework for developing individualized treatment strategies for this patient subgroup., (© 2022. The Author(s) under exclusive licence to Japan Society of Clinical Oncology.)

Purpose: The purpose of this study was to assess the impact of local recurrence (LR) on cause-specific death (CSD) in patients with non-small cell lung cancer (NSCLC) treated with stereotactic body radiotherapy (SBRT). A dynamic prediction model that incorporated LR as a time-dependent covariate was used., Methods and Materials: This study included 535 stage I (cT1-T2aN0M0) NSCLC patients treated with SBRT from two institutions. We developed a landmark dynamic prediction model to estimate the probability of a CSD. This model determined the probability of surviving for an additional 3 years at different prediction time points during follow-up, given the history of recurrence status. The baseline covariates included in the model were age, sex, T stage, and histology, while the time-dependent covariates were LR and regional and/or distant recurrence (RDR) status., Results: Overall, 137 patients (25.6%) died of lung cancer within a median follow-up of 4.1 years. Of the 195 patients who developed recurrence, 28, 125, and 42 patients had LR only, RDR only, and both, respectively. The landmark model showed that older age, advanced T stage, LR, and RDR were significantly associated with an increased risk of subsequent CSD. Among these covariates, LR (odds ratio [OR], 8.5; 95% confidence interval [CI], 6.0-12.0; P < .001) and RDR (OR, 11.6; 95% CI, 9.1-14.9; P < .001) demonstrated strong effects on CSD within 3 years after the prediction time points. The dynamic prediction provided information on the probability of future CSD according to individual recurrence status during follow-up., Conclusions: Dynamic prediction using the landmark model showed that LR had a substantial impact on subsequent CSD, which was comparable to that of RDR. This result supports the notion that strategies to improve local control are reasonable., (Copyright © 2021 Elsevier Inc. All rights reserved.)

To evaluate the reproducibility of dose-based radiomic (dosiomic) features between dose-calculation algorithms for lung stereotactic body radiation therapy (SBRT). We analyzed 105 patients with early-stage non-small cell lung cancer who underwent lung SBRT between March 2011 and December 2017. Radiation doses of 48, 60, and 70 Gy were prescribed to the isocenter in 4-8 fractions. Dose calculations were performed using X-ray voxel Monte Carlo (XVMC) on the iPlan radiation treatment planning system (RTPS). Thereafter, the radiation doses were recalculated using the Acuros XB (AXB) and analytical anisotropic algorithm (AAA) on the Eclipse RTPS while maintaining the XVMC-calculated monitor units and beam arrangements. A total of 6808 dosiomic features were extracted without preprocessing (112 shape, 144 first-order, and 600 texture features) or with wavelet filters to eight decompositions (1152 first-order and 4800 texture features). Features with absolute pairwise concordance correlation coefficients-|CC con |-values exceeding or equaling 0.85 were considered highly reproducible. Subgroup analyses were performed considering the wavelet filters and prescribed doses. The numbers of highly reproducible first-order and texture features were 34.8%, 26.9%, and 31.0% for the XVMC-AXB, XVMC-AAA, and AXB-AAA pairs, respectively. The maximum difference between the mean |CC con | values was 0.70 and 0.11 for the subgroup analyses of wavelet filters and prescribed dose, respectively. The application of wavelet filter-based dosiomic analyses may be limited when using different types of dose-calculation algorithms for lung SBRT., (© 2022. Japanese Society of Radiological Technology and Japan Society of Medical Physics.)

Objective: This prospective study used the EQ-5D utility and Visual Analogue Scale (VAS) scores to analyse the potential usefulness of proxy responses in quality of life assessments of Japanese patients with terminal lung cancer sufficiently healthy to communicate and reply by themselves. We did not investigate the potential usefulness of using proxy responses for patients who could not respond by themselves., Design: A prospective observational study., Setting: Single centre., Participants: The EQ-5D and VAS responses were gathered from 30 in-hospital patients with lung cancer for a total of three observation points. At nearly the same time, two nurses responded by providing proxy responses., Primary and Secondary Outcome Measures: EQ-5D and VAS responses., Results: There were no significant differences between the patients' and nurses' responses for EQ-5D utility and VAS scores. For the five dimensions of the EQ-5D, significant differences were found between the patients' and nurses' responses for usual activities (patients' response 1.64±0.07, nurses' response 1.41±0.05, p=0.03) and anxiety/depression (patients' response: 1.40±0.05, nurses' response: 1.19±0.03, p=0.02). There was a significant weak positive correlation between patients' and nurses' responses regarding changes in responses from the first to the third observation point (Spearman's rank correlation coefficient ρ=0.228; p<0.01)., Conclusion: The results suggest that proxy responses are useful because there were no significant differences between the patients' and nurses' responses for EQ-5D utility and VAS scores at the three observation points. These findings should, however, be verified in future large-scale trials., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: In infrared reflective (IR) marker-based hybrid real-time tumor tracking (RTTT), the internal target position is predicted with the positions of IR markers attached on the patient's body surface using a prediction model. In this work, we developed two artificial intelligence (AI)-driven prediction models to improve RTTT radiotherapy, namely, a convolutional neural network (CNN) and an adaptive neuro-fuzzy inference system (ANFIS) model. The models aim to improve the accuracy in predicting three-dimensional tumor motion., Methods: From patients whose respiration-induced motion of the tumor, indicated by the fiducial markers, exceeded 8 mm, 1079 logfiles of IR marker-based hybrid RTTT (IR Tracking) with the gimbal-head radiotherapy system were acquired and randomly divided into two datasets. All the included patients were breathing freely with more than four external IR markers. The historical dataset for the CNN model contained 1003 logfiles, while the remaining 76 logfiles complemented the evaluation dataset. The logfiles recorded the external IR marker positions at a frequency of 60 Hz and fiducial markers as surrogates for the detected target positions every 80-640 ms for 20-40 s. For each logfile in the evaluation dataset, the prediction models were trained based on the data in the first three quarters of the recording period. In the last quarter, the performance of the patient-specific prediction models was tested and evaluated. The overall performance of the AI-driven prediction models was ranked by the percentage of predicted target position within 2 mm of the detected target position. Moreover, the performance of the AI-driven models was compared to a regression prediction model currently implemented in gimbal-head radiotherapy systems., Results: The percentage of the predicted target position within 2 mm of the detected target position was 95.1%, 92.6% and 85.6% for the CNN, ANFIS, and regression model, respectively. In the evaluation dataset, the CNN, ANFIS, and regression model performed best in 43, 28 and 5 logfiles, respectively., Conclusions: The proposed AI-driven prediction models outperformed the regression prediction model, and the overall performance of the CNN model was slightly better than that of the ANFIS model on the evaluation dataset., (© 2022. The Author(s).)

Background: SWI/SNF-related, matrix-associated, actin-dependent regulator of chromatin, subfamily A, member 4-deficient thoracic sarcoma (SMARCA4-DTS) is a rare disease that has recently been described as an entity. It is characterized by an aggressive clinical course and specific genetic alterations. As an immunohistological feature, the tumors are deficient in SMARCA4 and SMARCA2 and express sex-determining region Y (SRY)-box 2 (SOX2). Occasionally, there are cases that are less frequent and difficult to distinguish from SMARCA4-deficient non-small cell lung carcinoma (SMARCA4-dNSCLC). Therefore, the 5th edition of the World Health Organization (WHO) classification describes thoracic SMARCA 4-deficient undifferentiated tumors (SMARCA4-UT). In contrast, Carney's triad is a syndrome that combines three rare soft tissue tumors: gastric leiomyosarcoma, pulmonary chondroma, and extra-adrenal paraganglioma. Protein kinase cAMP-dependent type I regulatory subunit alpha (PRKAR1A) has been proposed as the causative gene. Both diseases are valuable cases; moreover, there have been no previous reports of their coexistence., Case Presentation: A 43-year-old man visited our hospital because of respiratory distress. Computed tomography revealed a large mass measuring 55 mm in the upper lobe of the right lung and front mediastinum, with metastases in the surrounding lymph nodes. Needle biopsy was performed for diagnosis, and histological examination of the samples revealed monotonous epithelioid-like cells with loose binding and sheet-form proliferation. The tumor cells had distinct nuclei with some rhabdoid-like cells. Immunohistochemical analysis revealed that the tumor cells were positive for AE1AE3, SOX2, CD34, and p53 and negative for SMARCA4 and SMARCA2. The patient died 6 months after admission, without any treatment. Autopsy revealed ganglioneuroma and enchondroma suggestive of an incomplete Carney complex., Conclusion: SMARCA4-UT is a rare and recently established disease. While it is difficult to diagnose, it is necessary to distinguish undifferentiated carcinoma, large cell carcinoma, Ewing sarcoma, and epithelioid sarcoma when diagnosing tumors involving the mediastinum. Moreover, cases of SMARCA4-UT with ganglioneuroma and enchondroma are very rare. We discuss and report a case of SMARCA4-UT in which we also examined ARID1A and SLC7A11expression., (© 2022. The Author(s).)

Micropapillary adenocarcinoma of the lung is a type of cancer associated with a poor prognosis and is characterized by the presence of tumor cells with a ring‑like glandular structure floating within alveolar spaces. In the present study, the association between its morphological, biochemical and immunohistochemical characteristics, and malignancy was investigated using the KU‑Lu‑MPPt3 cell line established from a patient with MIP adenocarcinoma. Two subpopulations of KU‑Lu‑MPPt3 cells, namely adhesive (AD) and clumpy and suspended (CS) cells, were prepared and subjected to DNA microarray, reverse transcription‑quantitative PCR, western blot and immunostaining analyses. Protein expression patterns were compared between the cell types and their derived tissues using immunostaining. The results revealed similar protein expression patterns between the tumor cells found in the alveolar spaces and CS cells, which exhibited morphological characteristic of MIP adenocarcinoma. Based on the results of DNA microarray analysis, the present study then focused on Akt and focal adhesion kinase (FAK), which were markedly activated in the KU‑Lu‑MPPt3 CS and AD cells, respectively. Following KU‑Lu‑MPPt3 CS cell plating onto collagen‑coated culture dishes, some cells exhibited a transformation of their morphology into KU‑Lu‑MPPt3 AD‑like cells within a few days, and their Akt and FAK activities were similar to those of the AD cells. Additionally, the inhibition of Akt and FAK activities with Akt and FAK inhibitors reduced KU‑Lu‑MPPt3 CS cell adhesion and proliferation. Thus, the aforementioned results indicated that the phosphorylation of FAK and Akt may play a crucial role in the regulation of KU‑Lu‑MPPt3 CS cell adhesion and proliferation, respectively. Furthermore, the malignant potential of MIP adenocarcinoma may be attributed to these morphological and biochemical alterations in the KU‑Lu‑MPPt3 cells.

Background: Restrictive pulmonary dysfunction (RPD) is a risk factor for perioperative complications during gastrointestinal surgery. We hypothesized that high airway pressure due to RPD results in increased intraoperative blood loss during liver surgery. Thus, we investigated the effects of RPD on perioperative outcomes for liver resection., Methods: This study included 496 patients who underwent curative liver resection at our hospital between April 2009 and April 2020. Perioperative outcomes for the RPD and control groups were compared. Restrictive pulmonary dysfunction was defined as % vital capacity <80%., Results: Forty-one patients (8.3%) had RPD. No significant differences were observed in intraoperative blood losses (440 mL vs 320 mL, P = .340), overall complication rates (29.3% vs 31.2%, P = .797), or pulmonary complication rates (4.9% vs 9.0%, P = .286) between the RPD and control groups. In the 256 patients who underwent anatomical liver resection, 18 patients (7.0%) had RPD. The intraoperative blood loss was significantly higher in the RPD group (925 mL vs 456 mL, P = .013), but no differences in the overall complication rates (44.4% vs 37.3%, P = .528) or pulmonary complication rates (11.1% vs 10.5%, P = .589) between the two groups were detected. A multivariate analysis showed that RPD was an independent risk factor for intraoperative blood loss ≥500 mL during anatomical liver resection (odds ratio 4.132; 95% confidence interval 1.135-15.045; P = .031)., Discussion: Restrictive pulmonary dysfunction may be a risk factor for intraoperative blood loss during anatomical liver resection, which requires exposure of the main hepatic vein.

This study aimed to evaluate the impact of pretreatment C-reactive protein (CRP) and skeletal muscle mass (SMM) on outcomes after stereotactic body radiotherapy (SBRT) for T1N0M0 non-small cell lung cancer (NSCLC) as a supplementary analysis of JCOG0403. Patients were divided into high and low CRP groups with a threshold value of 0.3 mg/dL. The paraspinous musculature area at the level of the 12th thoracic vertebra was measured on simulation computed tomography (CT). When the area was lower than the sex-specific median, the patient was classified into the low SMM group. Toxicities, overall survival (OS) and cumulative incidence of cause-specific death were compared between the groups. Sixty operable and 92 inoperable patients were included. In the operable cohort, OS significantly differed between the CRP groups (log-rank test p = 0.009; 58.8% and 83.6% at three years for high and low CRP, respectively). This difference in OS was mainly attributed to the difference in lung cancer deaths (Gray's test p = 0.070; 29.4% and 7.1% at three years, respectively). No impact of SMM on OS was observed. The incidence of Grade 3-4 toxicities tended to be higher in the low SMM group (16.7% vs 0%, Fisher's exact test p = 0.052). In the inoperable cohort, no significant impact on OS was observed for either CRP or SMM. The toxicity incidence was also not different between the CRP and SMM groups. The present study suggests that pretreatment CRP level may provide prognostic information in operable patients receiving SBRT for early-stage NSCLC., (© The Author(s) 2021. Published by Oxford University Press on behalf of The Japanese Radiation Research Society and Japanese Society for Radiation Oncology.)

Purpose: To predict radiation pneumonitis (RP) grade 2 or worse after lung stereotactic body radiation therapy (SBRT) using dose-based radiomic (dosiomic) features., Methods: This multi-institutional study included 247 early-stage nonsmall cell lung cancer patients who underwent SBRT with a prescribed dose of 48-70 Gy at an isocenter between June 2009 and March 2016. Ten dose-volume indices (DVIs) were used, including the mean lung dose, internal target volume size, and percentage of entire lung excluding the internal target volume receiving greater than x Gy (x = 5, 10, 15, 20, 25, 30, 35, and 40). A total of 6,808 dose-segmented dosiomic features, such as shape, first order, and texture features, were extracted from the dose distribution. Patients were randomly partitioned into two groups: model training (70%) and test datasets (30%) over 100 times. Dosiomic features were converted to z-scores (standardized values) with a mean of zero and a standard deviation (SD) of one to put different variables on the same scale. The feature dimension was reduced using the following methods: interfeature correlation based on Spearman's correlation coefficients and feature importance based on a light gradient boosting machine (LightGBM) feature selection function. Three different models were developed using LightGBM as follows: (a) a model with ten DVIs (DVI model), (b) a model with the selected dosiomic features (dosiomic model), and (c) a model with ten DVIs and selected dosiomic features (hybrid model). Suitable hyperparameters were determined by searching the largest average area under the curve (AUC) value in the receiver operating characteristic curve (ROC-AUC) via stratified fivefold cross-validation. Each of the final three models with the closest the ROC-AUC value to the average ROC-AUC value was applied to the test datasets. The classification performance was evaluated by calculating the ROC-AUC, AUC in the precision-recall curve (PR-AUC), accuracy, precision, recall, and f1-score. The entire process was repeated 100 times with randomization, and 100 individual models were developed for each of the three models. Then the mean value and SD for the 100 random iterations were calculated for each performance metric., Results: Thirty-seven (15.0%) patients developed RP after SBRT. The ROC-AUC and PR-AUC values in the DVI, dosiomic, and hybrid models were 0.660 ± 0.054 and 0.272 ± 0.052, 0.837 ± 0.054 and 0.510 ± 0.115, and 0.846 ± 0.049 and 0.531 ± 0.116, respectively. For each performance metric, the dosiomic and hybrid models outperformed the DVI models (P < 0.05). Texture-based dosiomic feature was confirmed as an effective indicator for predicting RP., Conclusions: Our dose-segmented dosiomic approach improved the prediction of the incidence of RP after SBRT., (© 2021 American Association of Physicists in Medicine.)

Liquid-based cytology (LBC) specimens of lung adenocarcinoma have the potential to be widely used for genetic analysis. However, formaldehyde contained in some LBC preservation solutions can cause DNA fragmentation during specimen storage, rendering the samples unsuitable for molecular analysis. To investigate a novel preservation technique for improved DNA stability, which was evaluated by mutation analysis of epidermal growth factor receptor (EGFR) gene in human lung adenocarcinoma cell lines. Cells were fixed in CytoRich Red preservation solution. After 30 min of fixation, cells were either stored using the conventional method (suspended in preservation solution) or washed in phosphate-buffered saline and stored as a cell pellet (newly proposed method). The effect of storage was evaluated after 5, 7, and 9 days of storage at ambient temperature. The cell pellet group was also tested after 14 and 28 days. Specifically, we evaluated the DNA stability, DNA yield, and sample suitability for polymerase chain reaction (PCR), and EGFR mutation detection. The DNA yields and degree of stability from the cell pellet group were higher than those from the suspension group at every time point examined. PCR amplification from the cell pellet group was successful up to day 28. Mutation detection using the Cycleave PCR method indicated that the Ct values of the cell pellet group were significantly lower than those of the suspension group. Storing LBC specimens as a cell pellet post-fixation can maintain the DNA quality for a longer period than the conventional method, making it a promising strategy for molecular analysis.

BACKGROUND Hyponatremia is an electrolyte disorder frequently encountered by clinicians. Secondary adrenal insufficiency due to pituitary metastatic tumors should be considered as an alternative diagnosis when clinicians encounter patients with lung cancer who demonstrate hyponatremia. However, masked central diabetes insipidus should also be considered to prevent critical dehydration when glucocorticoid replacement therapy will be initiated. CASE REPORT A 70-year-old man with advanced lung adenocarcinoma demonstrated high-grade hyponatremia of 122 mmol/L. Magnetic resonance imaging disclosed a metastatic pituitary tumor and endocrinological examinations confirmed panhypopituitarism, including secondary adrenal insufficiency. Hydrocortisone replacement revealed masked diabetes insipidus with elevation of serum sodium levels that reached 151 mmol/L. Desmopressin administration was required to prevent water depletion and to immediately ameliorate the hypernatremia. CONCLUSIONS This is the first case report of masked diabetes insipidus that demonstrated high-grade hyponatremia. Secondary adrenal insufficiency can mask the hypernatremia that is a typical manifestation of diabetes insipidus. Physicians should consider adrenal insufficiency and diabetes insipidus due to pituitary metastasis of advanced malignancies, even when they encounter patients with hyponatremia.

There is dearth of data regarding the long-term survival outcomes of salvage surgery after stereotactic body radiotherapy for early-stage non-small-cell lung cancer, as previous studies have included a short follow-up period. There is also scarce information on the management of re-relapse in previous studies. This study examined the long-term survival outcomes of patients who underwent salvage surgery for isolated local relapse (LR). We reviewed consecutive patients who underwent salvage surgery for isolated LR after stereotactic body radiotherapy for early-stage non-small-cell lung cancer between 1999 and 2015. All patients were followed up until death or at least 5 years from salvage surgery. Twelve patients were included for analysis. The median follow-up from isolated LR was 62.4 (range: 14.3-152.1) months. The 5-year overall survival rate was 58.3%, updated from 79.5% in our previous report. During the interim, new re-relapses did not occur, whereas there were 5 additional deaths. The median survival after re-relapse was 32.6 months. Our follow-up report confirmed that our patient selection for salvage surgery appeared to be appropriate and that long-term follow-up is required to assess the outcomes of patients undergoing salvage surgery. Long-term follow-up would provide detailed information on late re-relapses, treatment and outcomes of re-relapses and mortality from any causes., (© The Author(s) 2020. Published by Oxford University Press on behalf of the European Association for Cardio-Thoracic Surgery. All rights reserved.)

Purpose: To predict local recurrence (LR) and distant metastasis (DM) in early stage non-small cell lung cancer (NSCLC) patients after stereotactic body radiotherapy (SBRT) in multiple institutions using breath-hold computed tomography (CT)-based radiomic features with random survival forest., Methods: A total of 573 primary early stage NSCLC patients who underwent SBRT between January 2006 and March 2016 and met the eligibility criteria were included in this study. Patients were divided into two datasets: training (464 patients in 10 institutions) and test (109 patients in one institution) datasets. A total of 944 radiomic features were extracted from manually segmented gross tumor volumes (GTVs). Feature selection was performed by analyzing inter-segmentation reproducibility, GTV correlation, and inter-feature redundancy. Nine clinical factors, including histology and GTV size, were also used. Three prognostic models (clinical, radiomic, and combined) for LR and DM were constructed using random survival forest (RSF) to deal with total death as a competing risk in the training dataset. Robust models with optimal hyper-parameters were determined using fivefold cross-validation. The patients were dichotomized into two groups based on the median value of the patient-specific risk scores (high- and low-risk score groups). Gray's test was used to evaluate the statistical significance between the two risk score groups. The prognostic power was evaluated by the concordance index with the 95% confidence intervals (CI) via bootstrapping (2000 iterations)., Results: The concordance indices at 3 yr of clinical, radiomic, and combined models for LR were 0.57 [CI: 0.39-0.75], 0.55 [CI: 0.38-0.73], and 0.61 [CI: 0.43-0.78], respectively, whereas those for DM were 0.59 [CI: 0.54-0.79], 0.67 [CI: 0.54-0.79], and 0.68 [CI: 0.55-0.81], respectively, in the test dataset. The combined DM model significantly discriminated its cumulative incidence between high- and low-risk score groups (P < 0.05). The variable importance of RSF in the combined model for DM indicated that two radiomic features were more important than other clinical factors. The feature maps generated on the basis of the most important radiomic feature had visual difference between high- and low-risk score groups., Conclusions: The radiomics approach with RSF for competing risks using breath-hold CT-based radiomic features might predict DM in early stage NSCLC patients who underwent SBRT although that may not have potential to predict LR., (© 2020 American Association of Physicists in Medicine.)

This study aimed to investigate the feasibility of independent calculation-based verification of volumetric-modulated arc therapy (VMAT)-stereotactic body radiotherapy (SBRT) for patients with lung cancer using a secondary treatment planning system (sTPS). In all, 50 patients with lung cancer who underwent VMAT-SBRT between April 2018 and May 2019 were included in this study. VMAT-SBRT plans were devised using the Collapsed-Cone Convolution in RayStation (primary TPS: pTPS). DICOM files were transferred to Eclipse software (sTPS), which utilized the Eclipse software, and the dose distribution was then recalculated using Acuros XB. For the verification of dose distribution in homogeneous phantoms, the differences among pTPS, sTPS, and measurements were evaluated using passing rates of a dose difference of 5% (DD5%) and gamma index of 3%/2 mm (γ3%/2 mm). The ArcCHECK cylindrical diode array was used for measurements. For independent verification of dose-volume parameters per the patient's geometry, dose-volume indices for the planning target volume (PTV) including D 95% and the isocenter dose were evaluated. The mean differences (± standard deviations) between the pTPS and sTPS were then calculated. The gamma passing rates of DD5% and γ3%/2 mm criteria were 99.2 ± 2.4% and 98.6 ± 3.2% for pTPS vs. sTPS, 92.9 ± 4.0% and 94.1 ± 3.3% for pTPS vs. measurement, and 93.0 ± 4.4% and 94.3 ± 4.1% for sTPS vs. measurement, respectively. The differences between pTPS and sTPS for the PTVs of D 95% and the isocenter dose were -3.1 ± 2.0% and -2.3 ± 1.8%, respectively. Our investigation of VMAT-SBRT plans for lung cancer revealed that independent calculation-based verification is a time-efficient method for patient-specific quality assurance., (© 2020 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Personalised medicine for primary lung cancers (PLCs) requires molecular analysis of cancer tissue or cells. The primary objective of the present prospective study was to assess the concordance between epidermal growth factor receptor (EGFR) gene mutation detection and echinoderm microtubule-associated protein-like (EML) 4-anaplastic lymphoma kinase protein (ALK) expression using liquid-based cytology (LBC) samples and matched histology samples of PLC patients. A total of 117 patients who underwent surgical resection of non-small cell PLC were enrolled. Cytological specimens scratched from the resected PLC lesion were fixed in CytoRich Red. DNA extracted from LBC samples was examined for EGFR gene mutations. Anaplastic lymphoma kinase arrangement was analysed by immunostaining and fluorescence in situ hybridisation. Our patient cohort comprised 93 cases of adenocarcinoma, 16 squamous cell carcinoma, three adenosquamous carcinoma, two large cell neuroendocrine carcinoma, one pleomorphic carcinoma and two other cases. Sixty-six (58.4%) LBC samples harboured EGFR gene mutations. The overall concordance rate in EGFR gene mutation status, including minor mutations, between histologic and paired LBC specimens (N = 105) was 100%. The overall concordance rate of EGFR gene mutation status, including minor mutations and ALK status according to immunostains between histologic and paired LBC specimens, was 100% (105/105) and 100% (48/48), respectively. Genotyping and protein expression studies can be reliably performed using LBC samples prepared with CytoRich Red. Analysis of such samples may guide individual therapy in PLC patients.

Background: Concurrent chemoradiotherapy (CCRT) is the gold standard for limited-stage small-cell lung cancer (LS-SCLC); however, most patients inevitably experience relapse. We hypothesized consolidation amrubicin following CCRT to be a potential treatment for LS-SCLC., Patients and Methods: All enrolled patients were treated using induction CCRT consisting of four cycles of etoposide and cisplatin plus concurrent thoracic radiotherapy. Eligible patients then received three cycles of amrubicin as consolidation therapy (consolidation population). The primary endpoint was the 2-year progression-free survival rate in the consolidation population., Results: Of the 36 intention-to-treat patients, 28 (78%) received amrubicin and 24 (67%) completed all planned treatments. The 2-year progression-free survival rate and overall response rate were 35.7% and 86%, respectively. The median progression-free and overall survival were 14.3 and 60.9 months, respectively. There were no treatment-related deaths in the intention-to-treat population., Conclusion: This study was terminated due to slow patient accrual; however, this treatment strategy was feasible and demonstrated promising efficacy., (Copyright© 2020, International Institute of Anticancer Research (Dr. George J. Delinasios), All rights reserved.)

Background: Chemoradiotherapy is the standard treatment for locally advanced non-small cell lung cancer. Unlike metastatic disease, histological differences are usually not considered while planning chemoradiotherapy. This study aimed to compare clinical outcomes and relapse patterns between squamous cell carcinomas and adenocarcinomas, and investigated possible histology-specific approaches for chemoradiotherapy in locally advanced non-small cell lung cancer., Methods: We retrospectively analyzed the outcomes and relapse patterns in patients who received definitive chemoradiotherapy for locally advanced non-small cell lung cancer in Katsura hospital between 2003 and 2012., Results: A total of 68 and 33 patients with squamous cell carcinomas and adenocarcinomas, respectively, were enrolled. Patients with adenocarcinoma had less advanced T stages, and a larger proportion of female patients. Other factors were not different between the two groups. The median follow-up duration in all patients and survivors was 21.3 months and 91.4 months, respectively. Median survival and relapse-free survival were not significantly different between the two groups. In contrast, the failure patterns and incidences of distant failure were significantly different. Patients with squamous cell carcinomas had predominantly locoregional disease features and a shorter duration from relapse to death compared to patients with adenocarcinoma., Conclusion: Failure pattern was significantly different between the two histologies. Among relapsed patients, the prognosis was poorer in those with squamous cell carcinomas than those with adenocarcinomas. Further studies, to evaluate histology-specific approaches in chemoradiotherapy, are warranted.

We developed a synchrotron-based real-time-image gated-spot-scanning proton-beam therapy (RGPT) system and utilized it to clinically operate on moving tumors in the liver, pancreas, lung, and prostate. When the spot-scanning technique is linked to gating, the beam delivery time with gating can increase, compared to that without gating. We aim to clarify whether the total treatment process can be performed within approximately 30 min (the general time per session in several proton therapy facilities), even for gated-spot-scanning proton-beam delivery with implanted fiducial markers. Data from 152 patients, corresponding to 201 treatment plans and 3577 sessions executed from October 2016 to June 2018, were included in this study. To estimate the treatment process time, we utilized data from proton beam delivery logs during the treatment for each patient. We retrieved data, such as the disease site, total target volume, field size at the isocenter, and the number of layers and spots for each field, from the treatment plans. We quantitatively analyzed the treatment process, which includes the patient load (or setup), bone matching, marker matching, beam delivery, patient unload, and equipment setup, using the data obtained from the log data. Among all the cases, 90 patients used the RGPT system (liver: n = 34; pancreas: n = 5; lung: n = 4; and prostate: n = 47). The mean and standard deviation (SD) of the total treatment process time for the RGPT system was 30.3 ± 7.4 min, while it was 25.9 ± 7.5 min for those without gating treatment, excluding craniospinal irradiation (CSI; head and neck: n = 16, pediatric: n = 31, others: n = 15); for CSI (n = 11) with two or three isocenters, the process time was 59.9 ± 13.9 min. Our results demonstrate that spot-scanning proton therapy with a gating function can be achieved in approximately 30-min time slots., (© 2019 The Authors. Journal of Applied Clinical Medical Physics published by Wiley Periodicals, Inc. on behalf of American Association of Physicists in Medicine.)

Purpose: To compare radiomic features extracted from diagnostic computed tomography (CT) images with and without contrast enhancement in delayed phase for non-small cell lung cancer (NSCLC) patients., Methods: Diagnostic CT images from 269 tumors [non-contrast CT, 188 (dataset NE); contrast-enhanced CT, 81 (dataset CE)] were enrolled in this study. Eighteen first-order and seventy-five texture features were extracted by setting five bin width levels for CT values. Reproducible features were selected by the intraclass correlation coefficient (ICC). Radiomic features were compared between datasets NE and CE. Subgroup analyses were performed based on the CT acquisition period, exposure value, and patient characteristics., Results: Eighty features were considered reproducible (0.5 ≤ ICC). Twelve of the sixteen first-order features, independent of the bin width levels, were statistically different between datasets NE and CE (p < 0.05), and the p-values of two first-order features depending on the bin width levels were reduced with narrower bin widths. Sixteen out of sixty-two features showed a significant difference, regardless of the bin width (p < 0.05). There were significant differences between datasets NE and CE with older age, lighter body weight, better performance status, being a smoker, larger gross tumor volume, and tumor location at central region., Conclusions: Contrast enhancement in the delayed phase of CT images for NSCLC patients affected some of the radiomic features and the variability of radiomic features due to contrast uptake may depend largely on the patient characteristics., (Copyright © 2019 Associazione Italiana di Fisica Medica. Published by Elsevier Ltd. All rights reserved.)

Background: Malignant pleural mesothelioma (MPM) is a debilitating disease of the pleural cavity. It is primarily associated with previous inhalation of asbestos fibers. These fibers initiate an oxidant coupled inflammatory response. Repeated exposure to asbestos fibers results in a prolonged inflammatory response and cycles of tissue damage and repair. The inflammation-associated cycles of tissue damage and repair are intimately involved in the development of asbestos-associated cancers. Macrophages are a key component of asbestos-associated inflammation and play essential roles in the etiology of a variety of cancers. Macrophages are also a source of C-C motif chemokine ligand 2 (CCL2), and a variety of tumor-types express CCL2. High levels of CCL2 are present in the pleural effusions of mesothelioma patients, however, CCL2 has not been examined in the serum of mesothelioma patients., Methods: The present study was carried out with 50 MPM patients and 356 subjects who were possibly exposed to asbestos but did not have disease symptoms and 41 healthy volunteers without a history of exposure to asbestos. The levels of CCL2 in the serum of the study participants was determined using ELISA., Results: Levels of CCL2 were significantly elevated in the serum of patients with advanced MPM., Conclusions: Our findings are consistent with the premise that the CCL2/CCR2 axis and myeloid-derived cells play an important role in MPM and disease progression. Therapies are being developed that target CCL2/CCR2 and tumor resident myeloid cells, and clinical trials are being pursued that use these therapies as part of the treatment regimen. The results of trials with patients with a similar serum CCL2 pattern as MPM patients will have important implications for the treatment of MPM.

Purpose: We compared image quality and volume of a moving simulated tumour and of lung tumours in patients who were treated with stereotactic body radiotherapy (SBRT) in a 16-row multi-detector CT (MDCT) versus a 320-row area-detector CT (ADCT). Tumour volumes in each respiratory phase were also evaluated., Materials and Methods: We acquired static and four-dimensional CT (4DCT) images of a moving phantom with 10- and 30-mm amplitudes with three periods of patterns (2, 4, and 6 s). Breath-hold and 4DCT images were acquired for 12 lung tumour patients who underwent SBRT. Image data were acquired via MDCT and ADCT. The tumours were delineated in each respiratory phase and their volumes in end-expiratory/end-inspiratory phase and mid-respiratory phase were compared., Results: In the phantom study, tumour volumes were smaller and closer to the static image when evaluated by ADCT than by MDCT. In the clinical study, average tumour volumes ± standard deviations were 9.58 ± 1.07 cm 3 with MDCT (2.5-mm slice), and 7.12 ± 0.23 cm 3 with ADCT (p < 0.01). Tumour volumes were closer to that of the breath hold CT in all patients evaluated by ADCT than by MDCT. Unlike MDCT, tumour volumes acquired by ADCT were smaller in end-expiratory or end-inspiratory phase than in the mid-respiratory phase., Conclusions: Tumour volumes in each of the respiratory phases in ADCT were significantly smaller and closer to the static image than the corresponding volumes in MDCT. This suggests that treated volume can be reduced if ADCT is used in treatment planning., (Copyright © 2019 Elsevier B.V. All rights reserved.)

Background: Liquid-based cytology (LBC) is a useful cytopathological method, and LBC lung adenocarcinoma specimens may be used for genetic analysis in the near future. In the current study, the authors determined whether LBC specimens can be used for epidermal growth factor receptor (EGFR) mutation analysis in human lung adenocarcinoma cell lines., Methods: Genomic DNA was extracted from 3 lung adenocarcinoma cell lines that were fixed in LBC preservation solution using 2 protocols (one for cultured cells and one for tissues) of a DNA extraction kit. Different fixation times were tested for each protocol: 30 minutes, 1 hour, and 1 to 9 days. As controls, cells also were fixed in 10% formalin or 95% ethanol. The authors investigated the effect of fixation time on DNA fragmentation, polymerase chain reaction (PCR) amplification, and EGFR mutation detection., Results: The DNA yield of LBC specimens tended to decrease depending on fixation time. When using the DNA extraction protocol for tissues, PCR amplification was successful after 9 days of fixation, although extracted genomic DNA that was fixed for >1 hour demonstrated fragmentation. Mutation analyses using the Cycleave PCR method were successful after 7 days of fixation. The DNA extraction protocol for tissues was appropriate for lung adenocarcinoma cell lines that were stored for >1 day in a preservative solution. The results of the current study demonstrated that EGFR mutations can be detected on day 7 using lung adenocarcinoma cell lines fixed in CytoRich Red preservative., Conclusions: When LBC specimens are used for targeted molecular genetic testing, the appropriate preservative solution and extraction protocol first should be determined., (© 2018 American Cancer Society.)

Purpose: A dose escalation study to determine the recommended dose with stereotactic body radiation therapy (SBRT) for peripheral T2N0M0 non-small cell carcinomas (JCOG0702) was conducted. The purpose of this paper is to report the survival and the late toxicities of JCOG0702., Materials and Methods: The continual reassessment method was used to determine the dose level that patients should be assigned to and to estimate the maximum tolerated dose. The starting dose was 40 Gy in four fractions at D95 of PTV., Results: Twenty-eight patients were enrolled. Ten patients were treated with 40 Gy at D95 of PTV, four patients with 45 Gy, eight patients with 50 Gy, one patient with 55 Gy and five patients with 60 Gy. Ten patients were alive at the last follow-up. Overall survival (OS) for all patients was 67.9% (95% CI 47.3-81.8%) at 3 years and 40.8% (95% CI 22.4-58.5%) at 5 years. No Grade 3 or higher toxicity was observed after 181 days from the beginning of the SBRT. Compared to the toxicities up to 180 days, chest wall related toxicities were more frequent after 181 days., Conclusions: The 5-year OS of 40.8% indicates the possibility that SBRT for peripheral T2N0M0 non-small cell lung cancer is superior to conventional radiotherapy. The effect of the SBRT dose escalation on OS is unclear and further studies are warranted.

Purpose: The purpose of the present study was to retrospectively evaluate impact of pre-treatment skeletal muscle mass (SMM) on overall survival and non-lung cancer mortality after stereotactic body radiotherapy (SBRT) for patients with stage I non-small cell lung cancer (NSCLC)., Methods and Materials: One-hundred and eighty-six patients whose abdominal CT before the treatment was available were enrolled into this study. The patients were divided into two groups of SMM according to gender-specific thresholds for unilateral psoas area. Operability was judged by the treating physician or thoracic surgeon after discussion in a multi-disciplinary tumor board., Results: Patients with low SMM tended to be elderly and underweight in body mass index compared with the high SMM. Overall survival in patients with the low SMM tended to be worse than that in the high SMM (41.1% and 55.9% at 5 years, P = 0.115). Cumulative incidence of non-lung cancer death was significantly worse in the low SMM (31.3% at 5 years compared with 9.7% in the high SMM, P = 0.006). Multivariate analysis identified SMM and operability as significant factors for non-lung cancer mortality. Impact of SMM on lung cancer death was not significant. No difference in rate of severe treatment-related toxicity was observed between the SMM groups., Conclusion: Low SMM is a significant risk factor for non-lung cancer death, which might lead to worse overall survival, after SBRT for stage I NSCLC. However, the low SMM does not increase lung cancer death or severe treatment-related toxicity., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: This pilot study aimed to evaluate the safety and efficacy of a dose escalation method for the treatment of peripheral lung tumors by administrating steep dose gradients in the target volumes via stereotactic body radiotherapy (SBRT)., Patients and Methods: Patients with peripheral lung tumors were enrolled onto this study and treated with SBRT using a total dose of 70 Gy in 4 fractions at target isocenter, covering the planning target volume surface with 70% of the isodose. The primary end point was the rate of grade 2 or higher radiation pneumonitis (RP) within 1 year., Results: A total of 35 patients were enrolled onto this study between September 2014 and January 2016. Thirty-two patients with primary lung cancers and 3 patients with lung metastases were treated with SBRT. Grade 2 RP was observed in 4 patients within 1 year. No severe RP (grade 3 or higher) was observed within the follow-up period. The median follow-up period was 21.2 months (range, 4.2-31.7 months). Local recurrence was observed in a single patient with lung metastasis. No local recurrence was observed within the follow-up period in the 32 patients with primary lung cancer. The local control and overall survival rates at 2 years were 95.7% (95% confidence interval, 72.9-99.4) and 85.2% (95% confidence interval, 67.8-93.6), respectively., Conclusion: This dose escalation method with steep dose gradients using SBRT for peripheral lung tumors was safe in the subacute phases. These results also suggest that this method can obtain excellent local control rates., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Background: Oligo-recurrence has been considered to confer improved prognosis than other oligometastatic conditions, and stereotactic body radiation therapy (SBRT) is considered as an option of local therapy for lung or liver metastases. The purpose of this study was to investigate the efficacy and safety of SBRT for lung and liver oligo-recurrent lesions and evaluate predictive factors for local control and prognosis., Methods: This retrospective study included patients who presented with 1-3 matachronous lung or liver metastases, and treated with SBRT between May 2013 and March 2016 at a single institution. All patients harbored a controlled primary lesion. Patients with < 6 months of follow-up were excluded. Local control, progression free survival, and overall survival rates were analyzed according to the Kaplan-Meier product limit method. Univariable log-rank and multivariable Cox regression analyses were performed to clarify predictive factors for local control and prognosis. Toxicity was graded according to the Common Terminology Criteria for Adverse Events, version 4.0., Results: Seventy-six patients with a total of 70 and 44 lung and liver lesions were included. The median follow-up period was 21 (range, 7-43) months. The 1-year local control, progression-free survival and overall survival rates were 89, 38 and 96%, respectively. Smaller gross tumor volume and additional chemotherapy after SBRT were significant predictive factors for better local control (p = 0.005 and p = 0.047), and the presence of a single metastatic lesion was a significant factor of good progression free survival (p = 0.008). Additional chemotherapy after SBRT was not a significant predictive factor but conferred to better overall survival (p = 0.078). Among colorectal cancer patients, post SBRT chemotherapy was significantly associated with better OS (p = 0.025). Over grade 3 adverse event was seen in only one patient., Conclusion: SBRT is a safe and effective treatment for patients with lung and liver oligo-recurrence. Additional chemotherapy after SBRT improved local control, and single metastatic lesion was a significant predictive factor of better PFS in this study. Among colorectal cancer patients, additional chemotherapy after SBRT significantly associated better OS.

Background: During therapeutic beam irradiation, an unvisualized three-dimensional (3D) target position should be estimated using an external surrogate with an estimation model. Training periods for the developed model with no additional imaging during beam irradiation were optimized using clinical data., Methods: Dual-source 4D-CBCT projection data for 20 lung cancer patients were used for validation. Each patient underwent one to three scans. The actual target positions of each scan were equally divided into two equal parts: one for the modeling and the other for the validating session. A quadratic target position estimation equation was constructed during the modeling session. Various training periods for the session-i.e., modeling periods (T M )-were employed: T M  ∈ {5,10,15,25,35} [s]. First, the equation was used to estimate target positions in the validating session of the same scan (intra-scan estimations). Second, the equation was then used to estimate target positions in the validating session of another temporally different scan (inter-scan estimations). The baseline drift of the surrogate and target between scans was corrected. Various training periods for the baseline drift correction-i.e., correction periods (T C s)-were employed: T C  ∈ {5,10,15; T C  ≤ T M } [s]. Evaluations were conducted with and without the correction. The difference between the actual and estimated target positions was evaluated by the root-mean-square error (RMSE)., Results: The range of mean respiratory period and 3D motion amplitude of the target was 2.4-13.0 s and 2.8-34.2 mm, respectively. On intra-scan estimation, the median 3D RMSE was within 1.5-2.1 mm, supported by previous studies. On inter-scan estimation, median elapsed time between scans was 10.1 min. All T M s exhibited 75th percentile 3D RMSEs of 5.0-6.4 mm due to baseline drift of the surrogate and the target. After the correction, those for each T M s fell by 1.4-2.3 mm. The median 3D RMSE for both the 10-s T M and the T C period was 2.4 mm, which plateaued when the two training periods exceeded 10 s., Conclusions: A widely-applicable estimation model for the 3D target positions during beam irradiation was developed. The optimal T M and T C for the model were both 10 s, to allow for more than one respiratory cycle., Trial Registration: UMIN000014825 . Registered: 11 August 2014.

Purpose: To assess the local recurrence (LR) rate and timing after stereotactic body radiation therapy (SBRT) for non-small cell lung cancer using long-term follow-up data from a single institution., Methods and Materials: Patients with primary or recurrent non-small cell lung cancer with or without pathologic verification, with tumors <3 cm, treated with SBRT (isocenter prescription of 48 Gy in 4 fractions) between April 1998 and August 2014, and with >6 months' follow-up were eligible. The LR rate was calculated by the cumulative incidence function, accounting for death as a competing risk. Univariate and multivariate analyses were performed to identify prognostic factors for LR., Results: A total of 216 patients and 230 tumors were analyzed. The median follow-up time of tumors without LR was 3.9 years, and the crude number of LR cases was 49 (21%). The actuarial rate of LR was 19% (95% confidence interval, 14%-25%) at 5 years. The number of LR cases in each period was 10 in year 1, 17 in year 2, 9 in year 3, 3 in year 4, 3 in year 5, and 7 after 5 years. Among 73 tumors with >5 years' follow-up, we observed 7 late LRs. The tumor histology of these late LRs was adenocarcinoma in 3, squamous cell carcinoma in 2, and unknown in 2 (1 of the unknown cases was confirmed as adenocarcinoma following salvage surgery). The median time to LR was 2.1 years (interquartile range, 1.5-4.2 years) for adenocarcinoma compared with 1.3 years (interquartile range, 1.0-2.3 years) for squamous cell carcinoma. Multivariate analysis revealed that larger tumor size, squamous cell histology compared with adenocarcinoma, and use of abdominal compression for respiratory motion management were independent negative prognostic factors for LR., Conclusions: Long-term follow-up data demonstrated that late LR was not uncommon and that careful follow-up after SBRT is needed, especially in patients with adenocarcinoma., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Although several studies have evaluated the local control and survival outcomes in patients undergoing stereotactic body radiotherapy (SBRT) for pulmonary oligometastases, little data are available on the management of local relapse. Here, we present 3 patients who underwent lobectomy and mediastinal lymph node dissection as salvage pulmonary metastasectomy for local relapse after SBRT. The postoperative course has been uneventful for all 3 patients, with no evidence of disease at 40, 51, and 6 months from the salvage metastasectomy. Our experience suggests that salvage pulmonary metastasectomy may be associated with local control and long-term survival in carefully selected patients., (Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.)

Knowledge of the imaging doses delivered to patients and accurate dosimetry of the radiation to organs from various imaging procedures is becoming increasingly important for clinicians. The purposes of this study were to calculate imaging doses delivered to the organs of lung cancer patients during real-time tumor tracking (RTTT) with three-dimensional (3D), and four-dimensional (4D) cone-beam computed tomography (CBCT), using Monte Carlo techniques to simulate kV X-ray dose distributions delivered using the Vero4DRT. Imaging doses from RTTT, 3D-CBCT and 4D-CBCT were calculated with the planning CT images for nine lung cancer patients who underwent stereotactic body radiotherapy (SBRT) with RTTT. With RTTT, imaging doses from correlation modeling and from monitoring of imaging during beam delivery were calculated. With CBCT, doses from 3D-CBCT and 4D-CBCT were also simulated. The doses covering 2-cc volumes (D2cc) in correlation modeling were up to 9.3 cGy for soft tissues and 48.4 cGy for bone. The values from correlation modeling and monitoring were up to 11.0 cGy for soft tissues and 59.8 cGy for bone. Imaging doses in correlation modeling were larger with RTTT. On a single 4D-CBCT, the skin and bone D2cc values were in the ranges of 7.4-10.5 cGy and 33.5-58.1 cGy, respectively. The D2cc from 4D-CBCT was approximately double that from 3D-CBCT. Clinicians should Figure that the imaging dose increases the cumulative doses to organs.

Purpose: The purpose of this review article was to summarize available data on the efficacy and safety of salvage radiotherapy for isolated local or regional recurrence after prior stereotactic body radiotherapy for lung cancer., Methods: Studies were systematically searched on PubMed, following which suitable papers were selected. Reported outcomes and toxicities were qualitatively reviewed., Results: Nineteen papers, which were retrospective studies based on single institution experiences, were selected. Sixteen papers were on salvage radiotherapy for local tumor recurrence, and the remaining 3 papers evaluated radiotherapy for regional failures after stereotactic body radiotherapy for lung cancer. Patient cohorts in the selected papers seemed very frail with 2-year survival of 30% to 40% after the salvage. Local control was reported to be approximately 60% to 70%, which is worse than that after primary stereotactic body radiotherapy. Reported rates of toxicity grade 3 or worse were considered acceptable. Larger target volume and central tumor localization were suggested as risk factors for severe toxicities. Dosimetric data on patients having toxicities were found to help with considering dose constraints for organs at risk., Conclusion: Based on data from a limited number of articles, salvage radiotherapy is a reasonable treatment option for select patients with local or regional tumor recurrence after prior stereotactic body radiotherapy for lung cancer. Optimal patient selection and dose prescription can be clarified with a larger study that include more data on experiences with salvage radiotherapy.

Stereotactic body radiotherapy (SBRT) is widely used as a curative treatment option for stage I non-small-cell lung cancer, but for patients with stage I small-cell lung cancer, the role of stereotactic body radiotherapy is unclear. In this study, we retrospectively analyzed the outcomes of a subset of patients with stage I small-cell lung cancer treated with stereotactic body radiotherapy in the database of the Japanese Radiological Society-Multi-Institutional stereotactic body radiotherapy Study Group. The 43 patients treated with stereotactic body radiotherapy for stage I small-cell lung cancer between 2004 and 2012 at 11 Japanese institutions were studied: median age = 77 years; 32 (74%) males and 11 females; and 80% were medically inoperable. The clinical stage was IA in 31 and IB in 12. In all patients, the lung tumors were pathologically proven as small-cell lung cancer. A total dose of 48 to 60 Gy was administered in 4 to 8 fractions. The median biologically effective dose (α/β = 10 Gy) was 105.6 Gy. Chemotherapy and prophylactic cranial irradiation were administered in only 8 patients, respectively. The median follow-up time was 23.2 months. The 2-year overall survival, progression-free survival, and distant metastasis-free survival rates were 72.3%, 44.6%, and 47.2%, respectively. The 2-year local control was 80.2%. Regarding the patterns of failure, distant metastasis, lymph node metastasis, and local recurrence were observed in 47%, 28%, and 16% of patients, respectively. No ≥grade 3 stereotactic body radiotherapy-related toxicities were observed. Although stereotactic body radiotherapy was thus revealed to be effective for the local control of stage I small-cell lung cancer, the incidence of distant metastases was high. Further investigations of larger cohorts are needed, including analyses of the effects of combined chemotherapy.

Systemic inflammation and poor nutritional status have a negative effect on the outcomes of cancer. Here, we analyzed the effects of the pretreatment inflammatory and nutritional status on clinical outcomes of locally advanced non-small-cell lung cancer (NSCLC) patients treated with chemoradiotherapy. We retrospectively reviewed 89 patients with locally advanced NSCLC treated with chemoradiotherapy between July 2006 and June 2013. Serum C-reactive protein (CRP) was assessed as an inflammatory marker, and serum albumin, body mass index (BMI) and skeletal mass index were assessed as nutritional status markers. The relationships between these markers and overall survival (OS) were assessed. The median OS was 24.6 months [95% confidence interval (CI): 19.4-39.3 months]. During follow-up, 58 patients (65%) had disease recurrence and 52 patients (58%) died. In multivariate Cox hazard analysis, CRP levels and BMI approached but did not achieve a significant association with OS (P = 0.062 and 0.094, respectively). Recursive partitioning analysis identified three prognostic groups based on hazard similarity (CRP-BMI scores): 0 = CRP < 0.3 mg/dl, 1 = CRP ≥ 0.3 mg/dl and BMI ≥ 18.5 kg/m2, and 2 = CRP ≥ 0.3 mg/dl and BMI < 18.5 kg/m2. The CRP-BMI score was significantly associated with OS (P = 0.023). Patients with scores of 0, 1 and 2 had median OS of 39.3, 24.5 and 14.5 months, respectively, and the scores also predicted the probability of receiving salvage treatment after recurrence. The CRP-BMI score is thus a simple and useful prognostic marker of clinical outcome for patients with locally advanced NSCLC treated with chemoradiotherapy., (© The Author 2017. Published by Oxford University Press on behalf of The Japan Radiation Research Society and Japanese Society for Radiation Oncology.)

Purpose: Lung adenocarcinomas with a micropapillary pattern (MPP) are characterized by more frequent and pronounced vascular invasion, higher incidence and more advanced lymph node involvement and poorer prognosis than papillary adenocarcinomas without an MPP. Here we established a new lung cancer cell line featuring micropapillary structure., Methods: A 73-year-old never-smoker Japanese female, presenting with an abnormal chest shadow, was diagnosed with a clinical T2aN0M0 Stage IB lung adenocarcinoma and underwent left upper lobectomy with mediastinal lymph node dissection. Pathological study demonstrated a T2aN2M0 Stage IIIA micropapillary adenocarcinoma. Tumor cells were obtained from freshly resected lung material and used to establish the KU-Lu-MPPt3 cell line., Results: The KU-Lu-MPPt3 cells featured adherent monolayers, adherent tufts, and suspended tufts without adhesion under the same culture conditions. The cells were positive for cytokeratin, epithelial cell-adhesion molecules, E-cadherin, mucin-1, thyroid transcription factor-1, vimentin, and anti-programmed death ligand 1. Xenograft tumors clearly demonstrated micropapillary structures. Sequencing and fragment analysis of the epidermal growth factor receptor in the primary tumor tissue and KU-Lu-MPPt3 cells revealed an in-frame deletion E746-A750 in exon 19., Conclusions: This cell line represents a new model system for molecular studies of lung adenocarcinoma which may be suitable for investigation of cancer spread and also for development of molecular-targeting and immunotherapies, both in vitro and in vivo.