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Objective Optimal dose-fractionation regimen of stereotactic body radiotherapy for peripheral early-stage non-small cell lung cancer remains unclear. We retrospectively investigated outcomes of stereotactic body radiotherapy using CyberKnife at 54 Gy in three fractions in 26 patients (median age: 76 years) with pathologically confirmed T1b–T2aN0M0 non-small cell lung cancer. Methods A 54 Gy in three fractions was prescribed to cover the 99% of gross tumor volume. We estimated cumulative local control, progression-free survival and overall survival rates (Kaplan–Meier method), and toxicity (Common Toxicity Criteria for Adverse Events, version 5.0). Results All the tumors were located at peripheral area of lung. Mean distance from chest wall to tumor was 6.5 mm (range: 0–32 mm). The patients’ pathological diagnoses were: adenocarcinoma: n = 18, squamous cell carcinoma: n = 7 and non-small cell carcinoma: n = 1. Their stages were T1b: n = 9, T1c: n = 14 and T2a: n = 3. Median follow-up was 24 months (range: 6–54). Cumulative 2-year effect rates were local control: 100%, progression-free survival 70% and overall survival: 92%. Twenty patients developed grade one radiation pneumonitis, but grade 2 or greater radiation pneumonitis was not observed. Conclusions We found CyberKnife-stereotactic body radiotherapy for pathologically confirmed T1b–T2aN0M0 non-small cell lung cancer to be effective and safe. However, these results should be validated with a larger patient cohort and prospective follow-up monitoring.

The feasibility of intensity modulated radiotherapy (IMRT) with involved field radiotherapy (IFRT) for Japanese patients with locally advanced non-small cell lung cancer (LA-NSCLC) remains unclear. Here we reviewed our initial experience of IMRT with IFRT for Japanese patients with LA-NSCLC to evaluate the feasibility of the treatment. Twenty LA-NSCLC patients who were treated with IMRT with IFRT during November 2019 to October 2020 were retrospectively analyzed. All patients received 60 Gy in 30 fractions of IMRT and were administered concurrent platinum-based chemotherapy. The median patient age was 71 years old and the group included 15 men and 5 women. The patient group included 2 patients with stage IIB, 11 patients with stage IIIA, 5 patients with stage IIIB, and 2 patients with stage IIIC disease. Histological diagnosis was squamous cell carcinoma in 14 patients, adenocarcinoma in 5 patients, and non-small cell lung cancer in 1 patient. The median follow-up period was 8 months. The incidence of grade 3 or greater pneumonitis was 5%, and grade 3 or greater esophagitis was not observed. None of the patients developed regional lymph node, with only recurrence reported so far. These findings indicate that IMRT with IFRT for Japanese patients with LA-NSCLC is feasible in terms of acute toxicity. Further study with a larger number of patients and longer follow-up to clarify the effect of treatment on patient prognosis is required.

Background Palliative radiotherapy is one of the effective treatments for pelvic tumor with bleeding or pain. In this study, we evaluated the safety and efficacy of palliative radiotherapy (RT) for symptomatic pelvic tumors when delivered as 25 Gy in 5 fractions. Methods We retrospectively analyzed 34 patients (gynecological cancer: n = 14, rectal cancer: n = 5, metastatic pelvic bone tumor: n = 7, metastatic pelvic lymph node tumor: n = 5, synovial sarcoma of the pelvis: n = 1, prostate cancer: n = 1, and urothelial cancer: n = 1, who were treated between July 2016 and July 2021. Their symptoms were bleeding in 16 patients, pain in 17 patients, and both bleeding and pain in 1 patient. Hemostatic effect of RT was evaluated with pre and post treatment hemoglobin (Hb) values. If the Hb level reached a nadir and increased thereafter, we considered that there is a hemostatic response. Pain was evaluated with a numerical rating scale (NRS) and treatment response was defined as a decrease in NRS. Results Their median follow-up period was 4 months. Hemostatic response was observed in 82% of patients (14 of 17 patients). Pain relief response was observed in 78% of patients (14 of 18 patients). Acute adverse effects (AEs) included grade 1 diarrhea: n = 3, grade 1 dermatitis: n = 1, and grade 1 urinary frequency: n = 1; late AEs were not observed so far. Conclusions We think that 25 Gy of palliative RT in 5 fractions seems to be safe and effective for symptomatic pelvic tumors, similar to conventional palliative RT schedules.

Background/aim Positional uncertainty in spinal stereotactic body radiotherapy (SBRT) may cause fatal error, therefore, we investigated the intra-fractional spinal motion during SBRT and its time dependency. Patients and methods Thirty-one patients who received SBRT using CyberKnife were enrolled in the study. 2D kV X-ray spine images in two directions were taken before and during treatment. Image acquisition intervals during treatment were set at 35-60 sec. Automatic image matchings were performed between the reference digital reconstructed radiography (DRR) and live images, and the spinal position displacements were logged in six translational and rotational directions. If the displacements exceeded 2 mm or 1 degree, the treatment beam delivery was interrupted and the patient position was corrected by moving couch, and the couch adjustments were also logged. Based on the information, the time-dependent accumulated translational and rotational displacements without any couch adjustments were calculated. Results Spinal position displacements in all translational and rotational directions were correlated with elapsed treatment time. Especially, Right-Left displacements of >1 mm and >2 mm were observed at 4-6 and 8-10 min after treatment initiation, respectively. Rotational displacements in the Yaw direction >1° were observed at 10-15 min after treatment initiation. Conclusion The translational and rotational displacements systematically increased with elapsed treatment time. It is suggested that the spine position should be checked at least every 4-6 min or the treatment time should be limited within 4-6 minutes to ensure the irradiation accuracy within the millimeter or submillimeter range.

The purpose of this study was to describe the results of definitive radiotherapy (RT) with concurrent chemotherapy for maxillary sinus carcinomas (MSCs) with neck lymph node metastasis to clarify its limitation. Local control (LC), progression-free survival (PFS) and overall survival (OS) rates were calculated using the Kaplan–Meier method and were compared between subgroups using the log rank test. Toxicity was classified using common terminology criteria of adverse events version 5.0. Eighteen patients with inoperable MSC with neck lymph node metastasis including 12 men and 6 women with a median age of 67 years were analyzed. The histologic diagnoses were as follows: 16 patients had squamous cell carcinomas and 2 had other histology. Four patients had stage T3 MSC, 6 had T4a and 8 had T4b. Among 18 patients, 7 received concurrent systemic chemotherapy and 11 received selective arterial chemo-infusion. The median follow-up period was 17 months. The 2-year LC, PFS and OS rates for the entire cohort were 34, 31 and 46%, respectively. No significant differences were observed for LC, PFS and OS rates between systemic chemotherapy and selective arterial chemo-infusion cohorts. Grade 3 or higher acute toxicity, including both non-hematological and hematological, was observed in nine patients (50%), while no grade 3 or higher late toxicity was observed. In conclusion, we described the results of definitive RT for MSCs with neck lymph node metastasis. Local recurrence of primary tumor was a frequent pattern of failure and it should be addressed in future study.

Background Durvalumab after concurrent chemoradiotherapy (CCRT) for locally advanced non‐small cell lung cancer (LA‐NSCLC) has been found to significantly improve overall survival (OS). However, the effect of durvalumab on local control remains unclear. Here, we evaluated the effect of the durvalumab on local control in comparison with the clinical result of patients treated with CCRT alone. Methods A total of 120 LA‐NSCLC patients including 76 patients with CCRT alone and 44 patients with CCRT followed by durvalumab were analyzed. Baseline patient characteristics of CCRT alone cohort and durvalumab cohort were compared with student's t test or Mann–Whitney U test for continuous variables and with chi‐squared test for categorical variables. Local control (LC), progression free survival (PFS) and OS rates were estimated using the Kaplan–Meier method and compared with the log‐rank test. Results There were 19 patients with stage II disease and 101 patients with stage III disease. Age, sex, histopathological type, T classification, N classification, clinical stage, tumor volume and dose fractionation schedule were not significantly different between the CCRT alone and durvalumab cohorts. The one‐year LC rate was significantly higher in the durvalumab cohort (86%) compared with the CCRT alone cohort (62%) (P = 0.005), whereas no significant difference was observed in either PFS (P = 0.864) or OS (P = 0.443) between the CCRT and durvalumab cohorts. Conclusions The one‐year LC rate was significantly higher in the durvalumab cohort compared with the CCRT alone cohort. Although the follow‐up period was too short to draw definitive conclusions, the study revealed that durvalumab might have a significant effect on LC. Key points Significant findings of the study Effect of durvalumab on local control after chemoradiotherapy for locally advanced non‐small cell lung cancer is unclear What this study adds The one‐year local control rate of chemoradiotherapy followed by durvalumab was significantly higher compared with chemoradiotherapy alone., The one‐year local control rate was 83% in the durvalumab cohort and 62% in the CCRT alone cohort, which was significantly different.

To evaluate treatment results and investigate predictors of local control.In this retrospective study of 236 patients with cervical cancer, we administered CT-based adaptive brachytherapy (BT) in combination with whole- pelvic (WP)- and central shielding (CS)- external beam radiotherapy (EBRT) with or without chemotherapy. The study cohort comprised patients with cervical cancer treated with definitive radiotherapy (RT) or concurrent chemoradiotherapy between June 2013 and March 2019. Local control (LC), overall survival (OS), and late toxicity were evaluated. Predictive factors for LC were analyzed by univariate and multivariate analyses.Median doses of WP- and CS-EBRT and BT were 30.6 GyThe combination of WP- and CS-EBRT and CT-based IGBT with or without concurrent chemotherapy produced favorable LC outcomes with low rates of late toxicities for patients with small or medium-sized tumors. However, LC was less favorable for patients who had large T3 disease, and the use of CS requires caution in these patients.

We retrospectively investigated the efficacy and safety of stereotactic body radiotherapy (SBRT) for T1N0M0 lung cancer using CyberKnife (CK) among 13 patients with severe pulmonary dysfunction which was defined as forced expiratory volume in 1 s (FEV1.0) of

Highlights • Incidence of grade ≥2 RP was 36% (including grade 3 RP: 5% and grade 5 RP: 3%). • Patient characteristics did not significantly differ between patient with grade ≥2 RP and grade ≤1 RP. • Dose-volume parameters were significantly higher among patients with grade ≥2 RP., Background and purpose We investigated the incidence and dose-volume relationships of radiation pneumonitis (RP) after concurrent chemoradiotherapy (CCRT) followed by durvalumab for locally advanced non-small-cell lung cancer (LA-NSCLC). Materials and methods We retrospectively analyzed records of 36 patients with LA-NSCLC who underwent CCRT followed by durvalumab. Incidence of RP was analyzed for correlations with clinical factors and dose-volume parameters of lung in radiotherapy. Results All patients received 60 Gy in 30 fractions of radiotherapy with concurrent chemotherapy. Over a median follow-up period of 7 months, incidence of grade ≥2 RP was 36% (including grade 3 RP: 5% and grade 5 RP: 3%). Age, sex, Brinkman index, and blood test results did not significantly differ between patients with grade ≥2 RP and grade ≤1 RP. Dose-volume parameters (lung volumes that received 5 Gy, 10 Gy, 20 Gy, 30 Gy, 40 Gy, 50 Gy, and mean lung dose) were significantly higher among patients with grade ≥2 RP compared with patients with grade ≤1 RP. Conclusion Incidence of grade ≥2 RP was 36% after CCRT followed by durvalumab for LA-NSCLC, but did not significantly differ from those of patients treated with CCRT alone. Lung dose-volume parameters were significantly correlated with RP.

Background/aim The treatment outcome of locally advanced non-small cell lung cancer (LA-NSCLC) has been improved over the past years but local failure is still common for these patients. The purpose of this study is to analyze the pattern of local failure and its risk factor of concurrent chemo-radiotherapy (CCRT) for locally advanced LA-NSCLC. Patients and methods We evaluated 77 patients treated with CCRT for LA-NSCLC from July 2007 to December 2017 at our institution. Most of the patients were treated with 60 Gy in 30 fractions of radiotherapy and concurrent chemotherapy. The median follow-up time was 26 months. Results Among the 77 patients, 50 developed progressive disease during follow-up, including 14 with only local recurrence (LR), 10 with only distant metastasis and 26 with both. Of the 14 patients with only LR, 12 had primary tumor recurrence and 2 had recurrence in lymph nodes. A primary tumor volume of 50 cm3 was identified as the optimal cut-off value that was significantly correlated with primary tumor recurrence and overall survival. Conclusion Primary tumor recurrence without lymph node and distant metastasis was observed in 12 patients (16%). Primary tumor volume of 50 cm3 was the optimal cut-off value for the prediction of primary tumor recurrence.

Background Chemoradiotherapy followed by durvalumab is the standard treatment for the patients with local advanced non-small cell lung cancer (NSCLC). There is a real-world data about the management of adverse events, such as pneumonitis, according to the different institutions. Here, we present the experience regarding the management of adverse events after the initiation of durvalumab as daily practice. Methods From July 2018 to August 2019, 41 patients with locally advanced NSCLC, who underwent chemoradiotherapy followed by durvalumab, were retrospectively analyzed in the study using our medical records. Results The median age of patients was 72 years (range: 51-80 years). A total of 33 patients were male and eight were female, and 40 patients (98%) received a total radiation dose of 60 Gy as concomitant chemoradiotherapy. The median V20 for the entire cohort was 18.9% (range: 3.5-29.9). Any adverse events during chemoradiotherapy and durvalumab were observed in 32 patients (78.0%), while three patients (7.3%) experienced grade 3 toxicities. In total, 25 (61.0%) patients experienced pneumonitis, four (9.8%) thyroid dysfunction, three (7.3%) myopathy, two (4.9%) rash or eruption, one (2.4%) bowel disease and one (2.4%) malaise. Grade 3 pneumonitis, thyroid dysfunction and myopathy were observed in one (2.4%), one (2.4%) and one (2.4%), respectively. A total of 22 (53.7%) patients were unable to continue durvalumab due to pneumonitis. However, durvalumab was finally readministered to six patients. Conclusions The adherence to lung dose constraints such as V20 as well as close treatment monitoring are a prerequisite for the management of pneumonitis during maintenance therapy with durvalumab.

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

Despite their outstanding antitumour activity in mice, the limited supply from the natural sources has prevented drug discovery/development based on intact halichondrins. We achieved a total synthesis of C52-halichondrin-B amine (E7130) on a >10 g scale with >99.8% purity under GMP conditions. Interestingly, E7130 not only is a novel microtubule dynamics inhibitor but can also increase intratumoural CD31-positive endothelial cells and reduce α-SMA-positive cancer-associated fibroblasts at pharmacologically relevant compound concentrations. According to these unique effects, E7130 significantly augment the effect of antitumour treatments in mouse models and is currently in a clinical trial. Overall, our work demonstrates that a total synthesis can address the issue of limited material supply in drug discovery/development even for the cases of complex natural products.

Definitive radiotherapy for cervical cancer consists of external-beam radiotherapy (EBRT) and brachytherapy. In EBRT, a central shield (CS) reduces the dose to the rectum and bladder. The combination of whole-pelvic (WP)- and CS-EBRT and brachytherapy is the standard radiotherapy protocol in Japan. Despite clinical studies, including multi-institutional clinical trials, showing that the Japanese treatment protocol yields favorable treatment outcomes with low rates of late radiation toxicities, dose–volume parameters for the Japanese treatment protocol remain to be established. We conducted a retrospective dose–volume analysis of 103 patients with uterine cervical cancer treated with the Japanese protocol using computed tomography–based adaptive brachytherapy. The 2-year overall survival and 2-year local control rates according to FIGO stage were 100% and 100% for Stage I, 92% and 94% for Stage II, and 85% and 87% for Stage III–IV, respectively. Late adverse effects in the rectum and bladder were acceptable. Receiver operating characteristic analysis discriminated recurrence within the high-risk clinical target volume (HR-CTV) (n = 5) from no local recurrence (n = 96), with the optimal response obtained at a dose of 36.0 GyEQD2 for HR-CTV D90 and 28.0 GyEQD2 for HR-CTV D98. These values were used as cut-offs in Fisher exact tests to show that high HR-CTV D90 and HR-CTV D98 doses for brachytherapy sessions were significantly associated with tumor control within the HR-CTV. These data suggest a contribution of brachytherapy to local tumor control in WP- and CS-EBRT and brachytherapy combination treatment, warranting validation in multi-institutional prospective studies.

Introduction and objectives: E7130 is a novel anti-cancer agent created from a total synthetic study of the natural compound norhalichondrin B, and is evaluated in a clinical study currently (NCT03444701). Previous pre-clinical study reported that E7130 had both cancer cell proliferation inhibitory activity and tumor microenvironment ameliorating activities featuring vascular remodeling effect and anti-CAF (cancer-associated fibroblasts) effect. Intratumoral hypoxia induces tumor malignancy and causes resistance against anti-cancer drugs including anti-estrogen agents (eg fulvestrant). It is hypothesized that vascular remodeling effect of E7130 mitigates hypoxia-induced resistant mechanism of ER (estrogen receptor) + breast cancer against anti-estrogen agents, resulting in improving anti-tumor activity of fulvestrant in combination with E7130. Experimental procedure: ERα expression levels in human ER+ breast cancer cell lines under hypoxic or normoxic culture condition were examined by FCM (flow cytometry) analysis. The histological changes after treatment with E7130 were examined by immunohistochemical analyses in the MCF-7 subcutaneous xenograft model. Anti-tumor activity of E7130 in combination with fulvestrant were examined in concurrent and in sequential treatment in the MCF-7 model. Summary: In vitro hypoxic culture condition down-regulated ERα expression in MCF-7 and T-47D compared with normoxic condition. E7130 had no effect on the ERα expression level in the cancer cells in vitro. On the contrary, E7130 increased ERα expression level in the cancer cells concomitantly with an increase of CD31-positive endothelial cell number (ie vascular remodeling effect) in MCF-7 xenograft tumor. These results suggested that E7130 up-regulated ERα expression in cancer cells not by cell-autonomous manner but by mitigating intratumoral hypoxia via its vascular remodeling effect. Concurrent combination therapy of E7130 at 90 μg/kg with fulvestrant at 250 mg/kg significantly inhibited the tumor growth compared with each monotherapy. In sequential combination therapy, pretreatment of E7130 followed by fulvestrant showed superior anti-tumor activity to posttreatment of E7130 following fulvestrant. Severe body weight loss was not observed in any treatment groups. Conclusions: The vascular remodeling effect of E7130 increased ERα expression in cancer cells in vivo, and sensitized ER+ breast cancer against fulvestrant to achieve promising combinational anti-tumor activity. Our data provides compelling evidence that E7130 attenuates tumor malignancy by its tumor microenvironment ameliorating effects and improves current anti-cancer therapy in combination with other drugs. Citation Format: Takanori Abe, Satoshi Kawano, Ken Ito, Taro Semba, Kimiyo Tabata, Hiroki Jozawa, Osamu Asano, Yoshito Kishi. Tumor microenvironment ameliorating effect of E7130 sensitized ER+ breast cancer against fulvestrant [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1865.

Background This multi‐institutional retrospective study focused on the clinical outcome of carbon‐ion radiotherapy (C‐ion RT) for non‐squamous cell malignant tumors of the nasopharynx. Methods The Japan Carbon‐ion Radiation Oncology Study Group collected and analyzed data for 43 patients with non‐squamous cell malignant tumors of the nasopharynx treated with C‐ion RT at four institutions in Japan. Results Twenty‐nine patients had adenoid cystic carcinomas, seven had malignant melanomas, three had adenocarcinomas, two had mucoepidermoid carcinomas, and two had other pathologies. Twenty‐six of the 43 patients (61%) had T4 tumors. The most common dose‐fractionation schedule was 64 Gy (relative biological effectiveness) in 16 fractions. The median follow‐up period was 30 months. The 2‐year local control (LC) and overall survival (OS) rates were 88% and 84%, respectively. For late toxicity, one patient developed grade 4 optic nerve disorder and two developed grade 5 pharyngeal hemorrhage. Actual incidence of grade 3 or higher late adverse events was 19%, and included cranial nerve dysfunction, jaw bone necrosis, central nervous system necrosis, and ear inflammation. Conclusions C‐ion RT provided good LC and OS rates with acceptable toxicity for treatment of non‐squamous cell malignant tumors of the nasopharynx.

The aim of this study is to analyze the incidence and risk factors for pneumonitis when immune checkpoint inhibitors (ICIs) are combined with palliative thoracic radiotherapy (RT) for lung cancer. We retrospectively evaluated 29 patients with lung cancer who received ICIs after palliative thoracic RT (30 Gy in 10 fractions). Their ICIs were pembrolizumab (n = 17), nivolumab (n = 8) and atezolizumab (n = 4). Median follow-up period was 10 months. The median interval between starting RT and starting ICI was 25 days. Pneumonitis events were grade 1 (n = 10; 34%), grade 2 (n = 4; 14%) and grade 3 (n = 3; 10%). Obstructive pneumonia was significantly associated with grade ≥ 2 pneumonitis (P = 0.036). Age, sex, ICI agent, interval between RT and ICI and history of ICI before RT were not associated with grade ≥ 2 pneumonitis. Tumor volume; Brinkman index; dosimetric factors, such as lung V5, V10, V20, V30 and mean lung dose (MLD); lactate dehydrogenase; and C-reactive protein did not significantly differ between the grade ≤ 1 and grade ≥ 2 pneumonitis groups. Levels of sialylated carbohydrate antigen KL-6 were evaluated in 27 patients before RT; they significantly differed between patients with grade ≤ 2 pneumonitis (mean: 431 U/ml) and those with grade ≥ 3 pneumonitis (mean: 958 U/ml; P

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

Lung cancer is a leading cause of cancer-related deaths worldwide. Radiotherapy is an essential treatment modality for inoperable non-small cell lung cancer (NSCLC). Stereotactic body radiotherapy (SBRT) is the standard treatment for early-stage NSCLC because of its favorable local control (LC) compared to conventional radiotherapy. Carbon ion radiotherapy (CIRT) is a kind of external beam radiotherapy characterized by a steeper dose distribution and higher biological effectiveness. Several prospective studies have shown favorable outcomes. However, there is no direct comparison study between CIRT and SBRT to determine their benefits in the management of early-stage NSCLC. Thus, we conducted a retrospective, single-institutional, and contemporaneous comparison study, including propensity score-adjusted analyses, to clarify the differences in oncologic outcomes. The 3-year overall survival (OS) was 80.1% in CIRT and 71.6% in SBRT (p = 0.0077). The 3-year LC was 87.7% in the CIRT group and 79.1% in the SBRT group (p = 0.037). Multivariable analyses showed favorable OS and LC in the CIRT group (hazard risk [HR] = 0.41, p = 0.047, HR = 0.30, p = 0.040, respectively). Log-rank tests after propensity score matching and Cox regression analyses using propensity score confirmed these results. These data provided a positive efficacy profile of CIRT for early-stage NSCLC.

Background/aim A retrospective study was conducted to evaluate the safety and efficacy of stereotactic body radiotherapy (SBRT) for pulmonary oligometastasis from colorectal cancer (CRC). Patients and methods Patients with pulmonary oligometastasis from CRC who were treated with SBRT between April 2010 and October 2018 were enrolled in this study. All patients underwent SBRT using Cyberknife® with a dose of 54-60 Gy in 3 fractions to 99% of the clinical target volume. The treatment efficacy was evaluated by the local control (LC) and overall survival (OS) rates. The toxicity was evaluated using the National Cancer Institute's Common Terminology Criteria for Adverse Events version 4.0. Results Twenty-six lesions in 20 patients were treated with SBRT. The median follow-up duration was 19 months (range=6-98 months). Local recurrence occurred in 6 of 26 lesions with a median follow-up of 12 months. The 2-year LC and OS rates were 65.8% and 88.6%, respectively. No patient developed ≥ grade 2 toxicity in the lung and other sites. Conclusion Although very high doses were delivered to the tumors with SBRT, the LC of pulmonary metastasis from CRC was not satisfactory when compared to that for stage I primary non-small cell lung cancer reported in the literature.

Background/aim The relationship between sarcopenia and prognosis in carbon ion radiotherapy (C-ion RT) for hepatocellular carcinoma (HCC) has not yet been reported, therefore we analyzed the presence or absence of sarcopenia before C-ion RT as a prognostic factor for patients with HCC. Patients and methods Data were retrospectively collected for patients who had undergone C-ion RT for HCC between September 2010 and December 2016. For defining the presence or absence of sarcopenia, skeletal muscles in the third lumbar vertebrae level were measured. Clinical outcomes were compared in the sarcopenia and non-sarcopenia groups. Results Of the 68 patients who were analyzed, 22 were classified into the sarcopenia and 46 into the non-sarcopenia groups. Median follow-up of patients was 33.5 months. The three-year overall survival (OS) rates in the sarcopenia and non-sarcopenia groups were 66% and 77%, respectively (p=0.51). Conclusion Sarcopenia was not a prognostic factor for patients with HCC treated with C-ion RT, which was effective in HCC patients with sarcopenia without worsening the OS.

Background and purpose We aimed to evaluate the relationship between brainstem necrosis and dose–volume histograms in patients with head and neck tumors after carbon-ion radiotherapy. Material and methods We evaluated 85 patients with head and neck tumors who underwent carbon-ion radiotherapy and were followed-up for ≥12 months. Brainstem necrosis was evaluated using the Common Terminology Criteria for Adverse Events (version 4.0). Results The median follow-up was 24 months, and four patients developed grade 1 brainstem necrosis, with 2-year and 3-year cumulative rates of 2.8% and 6.5%, respectively. Receiver operating characteristic curve analysis revealed the following significant cut-off values: a maximum brainstem dose of 48 Gy (relative biological effectiveness [RBE]), D1 cm 3 of 27 Gy (RBE), V40 Gy (RBE) of 0.1 cm 3 , V30 Gy (RBE) of 0.7 cm 3 , and V20 Gy (RBE) of 1.4 cm 3 . Multivariate analysis revealed that V30 Gy (RBE) was most significantly associated with brainstem necrosis. The 2-year cumulative rates were 33% and 0% for V30 Gy (RBE) of ≥0.7 cm 3 and 3 , respectively ( p Conclusions The present study indicated that the dose constraints might help minimize brainstem necrosis after carbon-ion radiotherapy.

We previously reported that eribulin mesylate (eribulin), a tubulin‐binding drug (TBD), could remodel tumor vasculature (i.e. increase tumor vessels and perfusion) in human breast cancer xenograft models. However, the role of this vascular remodeling in antitumor effects is not fully understood. Here, we investigated the effects of eribulin‐induced vascular remodeling on antitumor activities in multiple human cancer xenograft models. Microvessel densities (MVD) were evaluated by immunohistochemistry (CD31 staining), and antitumor effects were examined in 10 human cancer xenograft models. Eribulin significantly increased MVD compared to the controls in six out of 10 models with a correlation between enhanced MVD levels and antitumor effects (R 2 = 0.54). Because of increased MVD, we next used radiolabeled liposomes to examine whether eribulin treatment would result in increased tumoral accumulation levels of these macromolecules and, indeed, we found that eribulin, unlike vinorelbine (another TBD) enhanced them. As eribulin increased accumulation of radiolabeled liposomes, we postulated that this treatment might enhance the antitumor effect of Doxil (a liposomal anticancer agent) and facilitate recruitment of immune cells into the tumor. As expected, eribulin enhanced antitumor activity of Doxil in a post‐erlotinib treatment H1650 (PE‐H1650) xenograft model. Furthermore, infiltrating CD11b‐positive immune cells were significantly increased in multiple eribulin‐treated xenografted tumors, and natural killer (NK) cell depletion reduced the antitumor effects of eribulin. These findings suggest a contribution of the immune cells for antitumor activities of eribulin. Taken together, our results suggest that vascular remodeling induced by eribulin acts as a microenvironment modulator and, consequently, this alteration enhanced the antitumor effects of eribulin.

To evaluate the efficacy and safety of carbon-ion radiotherapy for non-squamous cell carcinoma of the head and neck, 35 patients were enrolled in this prospective study. The primary end-point was the 3-year local control rate, and the secondary end-points included the 3-year overall survival rate and adverse events. Acute and late adverse events were evaluated according to the Common Terminology Criteria for Adverse Events, version 4.0. The median follow-up time for all patients was 39 months. Thirty-two and three patients received 64.0 Gy (relative biological effectiveness) and 57.6 Gy (relative biological effectiveness) in 16 fractions, respectively. Adenoid cystic carcinoma was dominant (60%). Four patients had local recurrence and five patients died. The 3-year local control and overall survival rates were 93% and 88%, respectively. Acute grade 2-3 radiation mucositis (65%) and dermatitis (31%) was common, which improved immediately with conservative therapy. Late mucositis of grade 2, grade 3, and grade 4 were observed in 11, one, and no patients, respectively. There were no adverse events of grade 5. Carbon-ion radiotherapy achieved excellent local control and overall survival rates for non-squamous cell carcinoma. However, the late mucosal adverse events were not rare, and meticulous treatment planning is required. Trial registration no. UMIN000007886.

Mouthpieces are used to fix the positions of the lower jaw and teeth during carbon-ion radiotherapy for head and neck tumors. We used a customized mouthpiece to reduce radiation mucositis by displacing the tongue. Acute radiation mucositis gradually increased for the palate and tongue after approximately six irradiation fractions (maximal mean grade: palate, 2.5 during radiation fractions 15; tongue, 0.8 during radiation fractions 12 and 13). The mean grade of mucositis was significantly lower for the tongue than for the palate from irradiation fraction six until two weeks after irradiation. Keywords: Carbon-ion radiotherapy, Head and neck tumor, Customized mouthpiece

The present study (University Hospital Medical Information Network study no. UMIN000003797) aimed to evaluate whether the maximum standardized uptake value (SUVmax) of pretreatment 18F-fluorodeoxyglucose-positron emission tomography (FDG-PET) is prognostic factor for stage I non-small cell lung cancer (NSCLC) treated with carbon ion radiotherapy (C-ion RT). Patients treated between June 2010 and June 2013 at Gunma University Heavy Ion Medical Center (Maebashi, Japan) on a prospective protocol were included in the present study. Patients with T1a-b and T2a NSCLC were treated with C-ion RT at a dose of 52.8 Gy [relative biological effectiveness (RBE)] and 60.0 Gy (RBE), respectively, in four fractions. Prior to treatment, all patients underwent FDG-PET, in which the SUVmax of primary tumors was evaluated. Local control, progression-free survival (PFS), and overall survival (OS) were calculated. A total of 45 patients were analyzed and the median follow-up period was 28.9 months. The 2-year local control, PFS and OS rates for all patients were 93, 78 and 89%, respectively. The mean SUVmax of primary tumors was 5.5, and patients were divided into higher (≥5.5) and lower (

The umbilical vessels have two arteries and one vein, and thrombosis rarely occursin the umbilical vein and arteries. Umbilical artery thrombosis (UAT) has a low incidence ratecompared with umbilical venous thrombosis. Discordant umbilical arteries (DUAs), wherein thesize of the arteries is different, has rarely been reported, and the smaller umbilical artery has alsobeen described as the hypoplastic umbilical artery (HUA). UAT and HUA/DUAs can be relatedto poor perinatal outcomes or fetus malformation. We herein present a case of a nulliparous andprimigravid 37-year-old Japanese pregnant woman, with sonographic diagnosis of single umbilicalartery at 24 weeks of gestation by the loss of left-sided umbilical artery. Subsequently, serologicaltest showed elevated serum immunoglobulin M (IgM) and IgG antibodies for cytomegalovirus(CMV). Neither morphological nor growth abnormality of the fetus was sonographically found,and no CMV DNA was detected in the vaginal discharge. Clinical follow-up was performed, andthe fetus was small for gestational age during the course of the observation. At 40 and 5/7 weeksof gestation, vaginal delivery was attempted, but cesarean delivery was performed because fetaldistress was suspected by cardiotocography. An appropriate-for-age female neonate withoutanomaly was born, and the Apgar score was 8 and 9 after 1 and 5 min, respectively. Neitherelevated serum anti-CMV IgM antibodies nor presence of CMV DNA in the urine was found inthe neonate. Six days after cesarean section, the mother and neonate were discharged withoutany problems. A thin and hypercoiled umbilical cord was found macroscopically, and pathologyconfirmed that the umbilical cord had one vein and two arteries, which included an HUA showingocclusive thrombosis. The placenta showed no apparent abnormalities except for a small infarctionat the marginal zone. CMV infection was not found in the umbilical cord and placenta. Thepathogenesis of UAT was speculated to be related to the hypercoiled umbilical cord. This is thefirst case of a healthy, appropriate-for-age, full-term neonate born with UAT.

Purpose The aim of this study was to compare the dose-volume parameters of fiducial marker matching (MM) with vertebral body matching (VM) in patient positioning for carbon ion radiotherapy for primary hepatic cancer. Materials and methods Twenty patients with primary hepatic cancer were retrospectively studied to assess changes in reproducibility of tumor position and dose distribution on two CT scans. One was for treatment planning and another was for dose confirmation, acquired the day before the first treatment day. The coverage of the clinical target volume (CTV) (D98) and normal liver volume excluding the CTV which received 20 Gy relative biological effectiveness (RBE) (V20) were used as evaluation parameters. Additionally, the correlation of tumor movement and D98 was calculated in VM and MM. The prescription dose was 60.0 Gy (RBE) delivered in four fractions (15 Gy/fx). Results The median (range) D98 for VM and MM was 57.9 (20.8–59.9) and 59.9 (57.2–60.3) Gy (RBE), respectively. The median (range) V20 for VM and MM was 17.9 (4.8–44.4) and 16.2 (4.7–44.9) Gy (RBE), respectively. The D98 for MM was significantly larger than that for VM (p = 0.001), although V20 showed no significant difference (p > 0.05). Twelve patients were clinically acceptable (D98 > 57 Gy (RBE)) with VM, while all patients were clinically acceptable with MM. Marker movement correlated with a decrease of D98 for VM (R = −0.814). Conclusion Compared with VM, MM was clinically acceptable in all patients. This suggests that MM is more robust than VM.

Background: Hypopharyngeal cancer is relatively rare disease and continues to have a poor prognosis. This study analyzed the efficacy and safety of radiotherapy for stage I-IVB hypopharyngeal cancer. Patients and Methods: Between 2000 and 2015, 72 patients were treated with definitive radiotherapy and 29 patients with stage IVA were treated with postoperative radiotherapy. Results: With definitive radiotherapy, the 3-year locoregional control rates for stage I-II, III, IVA, and IVB disease were 89%, 74%, 51% and 0%, respectively. The 3-year overall survival rates for patients with stage I-II, III, IVA and IVB disease were 84%, 89%, 55% and 15%, respectively. In patients with stage IVA disease treated with postoperative radiotherapy, 3-year locoregional control and overall survival rates were 83% and 75%, respectively, which were significantly better than those treated with definitive radiotherapy. Conclusion: Definitive radiotherapy was effective for stage I-III disease. Surgery and postoperative radiotherapy improved the survival rate of patients with stage IVA hypopharyngeal cancer.

Background and objectives: Natural products have been a rich source of inspiration for drug discovery as demonstrated by the fact that over one-third of current therapeutic agents are natural products or compounds derived from them. Particularly, when the supply of a natural product from the natural source is limited, organic synthesis can offer a solution. However, with increasing structural complexity, this approach becomes exponentially more challenging, as a synthesis must meet various requirements, including high overall efficiency, scalability, cost-effectiveness, and product purity as well as conforming to good manufacturing practice (GMP) regulations. Despite the outstanding in vivo antitumor activity in mice, the limited supply from the natural sources has prevented drug development based on intact halichondrins. Methods: We successfully synthesized 19.5 g of C52-halichondrin-B alcohol with 99.84% purity via a total synthesis. From 15.0 g of this material, we obtained 11.5 g of C52-halichondrin-B amine (E7130) with 99.81% purity under GMP conditions. With totally synthetic E7130, a novel microtubule dynamics inhibitor, we studied the activities in both of in vitro and in vivo. The inhibitory activity of E7130 towards tubulin polymerization was analyzed in the cell-free system in which tubulin polymerization could be monitored by fluorescence enhancement due to the incorporation of a fluorescence reporter into the microtubules during polymerization. We analyzed in vivo antitumor activities using both a human cancer cell line orthotopic transplantation mouse model and subcutaneous xenograft models. The immunohistochemical analyses were performed with tumor tissues collected from mouse models to analyze histological changes after treatment with E7130. Results: E7130 is a novel microtubule dynamics inhibitor with exceedingly potent in vitro and in vivo anticancer activities. Significantly, E7130 not only is cytotoxic, but can also increase CD31-positive endothelial cells in tumors and reduce α-SMA-positive cancer-associated fibroblasts at pharmacologically relevant compound concentrations. Notably, this dual activity has been recognized for the first time through this study. According to these unique tumor microenvironment ameliorative effects, E7130 can augment the effect of other antitumor treatments in mouse models. In particular, a dose of 90 µg/kg, one-half of the maximum tolerated dose in mice, showed a prominent combinational effect with cetuximab, which suggests that E7130 has a different mechanism than other microtubule-targeted drugs. Conclusions: E7130 ameliorates the tumor microenvironment to improve cancer treatment when used in combination with other compounds. The data provide compelling evidence that E7130 is a promising molecular-targeting anticancer agent. Citation Format: Satoshi Kawano, Takanori Abe, Ken Ito, Kenzo Yahata, Kazunobu Kira, Tsuyoshi Akagi, Makoto Asano, Kentaro Iso, Yuki Sato, Fumiyoshi Matsuura, Isao Ohashi, Yasunobu Matsumoto, Minetaka Isomura, Takeo Sasaki, Takashi Fukuyama, Yusuke Miyashita, Yosuke Kaburagi, Akira Yokoi, Osamu Asano, Takashi Owa, Yoshito Kishi. E7130 derived from total synthesis of halichondrin as a novel tumor-microenvironment ameliorator [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4179.

Background and objectives: Despite the outstanding antitumor activity of halichondrins in mice, the limited supply from the natural sources has prevented drug development using intact halichondrins. We achieved a total synthesis of C52-halichondrin-B amine (E7130) under good manufacturing practice (GMP) conditions. E7130 is not only a novel microtubule dynamics inhibitor, but also a novel tumor-microenvironment ameliorator. E7130 can increase intratumoral CD31-positive endothelial cells and reduce α-SMA-positive cancer-associated fibroblasts (CAFs) at pharmacologically relevant compound concentrations. Here, we analyzed the molecular mechanisms of the α-SMA-positive CAF reduction with E7130. Methods: The expression levels of α-SMA, ECM proteins, ER-TR7 (pan-fibroblast marker), and Ki67 were examined using E7130-treated tumors. In vitro co-culture experiments, normal human fibroblasts were co-cultured with human cancer cells. To examine the effects of E7130 on the TGF-β-induced CAF activation, normal human fibroblasts were treated with TGF-β (final concentration of 1 ng/mL) and E7130 at the several concentrations, and gene expression analysis and immunocytochemical analysis were conducted. Results: E7130 reduced α-SMA-positive CAF and malignant ECM proteins without changing total fibroblast number in tumors. The in vitro co-culture system revealed that TGF-β from cancer cells activate normal human fibroblast and increased α-SMA expression. In addition, treatment with E7130 interfered with α-SMA induction by TGF-β in fibroblasts without growth inhibitory activity. We further found that E7130 inhibited TGF-β-induced PI3K/AKT/mTOR pathway, which resulted in the reduction of α-SMA expression in fibroblasts. Moreover, TGF-β treatment enhanced β-tubulin expression and focal adhesions formation, which were diminished by co-treatment with E7130 in fibroblasts. Many signaling complexes are assembled in focal adhesion sites, and those complexes dispatch several downstream signals, including those involved in the PI3K/AKT/mTOR pathway. Conclusions: Drug discovery using halichondrins was based on their outstanding in vivo antitumor (inhibitory) activity in mice and bone metastasis in mouse melanoma model first reported in 1996. From these results, we hypothesized that halichondrins are not simple microtubule-targeted compounds in tumor cell, and have developed E7130, which harbors unique tumor microenvironment ameliorating effects. Here we proved that E7130 impedes the TGF-β-induced myofibroblast transdifferentiation process without killing the fibroblast by disrupting microtubule network formation, which is important for focal adhesion assembly and thereby the downstream activation of the PI3K/AKT/mTOR pathway. Citation Format: Takanori Abe, Satoshi Kawano, Ken Ito, Kenzo Yahata, Kazunobu Kira, Tsuyoshi Akagi, Makoto Asano, Kentaro Iso, Yuki Sato, Fumiyoshi Matsuura, Isao Ohashi, Yasunobu Matsumoto, Minetaka Isomura, Takeo Sasaki, Takashi Fukuyama, Yusuke Miyashita, Yosuke Kaburagi, Akira Yokoi, Osamu Asano, Takashi Owa, Yoshito Kishi. Mechanism of action analysis of anti-CAF activity of E7130, a novel tumor-microenvironment ameliorator [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 4183.

Notch4 is selectively expressed on tumor endothelial cells and hypothesized to contribute to cancer malignancy through mechanisms including tumor angiogenesis regulation and promoting drug resistance. We developed E7011, a humanized IgG2κ antibody targeting Notch4 receptor signaling. To obtain anti-human Notch4 monoclonal antibody, human Notch4 3EGFR (epidermal growth factor repeat) domain - NRR (negative regulatory region) - SEAP (secreted alkaline phosphatase) - His protein was immunized to mice and 6698 hybridomas were obtained. By screening these clones with the Notch4 binding assay and Notch4-specific gal4-fusion luciferase reporter assay, mouse anti-human Notch4 mAb clone (6-3-A6) was selected. The CDRs (complementarity determining regions) of 6-3-A6 were grafted into the variable regions of human IgG2κ, and E7011, novel humanized anti-human Notch4 monoclonal antibody, was developed by screening in assays above. The biomolecular interaction analysis showed that E7011 is able to bind to human and mouse Notch4-NRR domain-SEAP-His, and inhibit human Notch4 receptor signaling in an antibody-dose dependent manner as well as 6-3-A6. IHC analysis showed that Notch4 was expressed on CD31 positive endothelial cells in Calu6 human non-small cell lung carcinoma xenograft tumor. Intravenous administration of E7011 at 1, 3, 10 mg/kg in twice a week significantly decreased tumor growth compared with control IgG treatment without severe body weight loss. We also investigated the functional tumor angiogenesis by hoechest dye-perfusion and staining with anti-CD31 antibody in the Calu6 xenograft model. E7011 treatment significantly decreased hoechst-positive perfusion area compared with vehicle treatment. In conclusion, E7011 is a novel antitumor agent that is a specific signal inhibitor targeting the Notch4 receptor and suppresses tumor growth through decreasing tumor vessel function in based on preclinical studies. Citation Format: Yusuke Adachi, Yoshimasa Sakamoto, Youya Nakazawa, Sho Tachino, Ken Ito, Takanori Abe, Yukinori Minoshima, Kana Hoshino-Negishi, Hideaki Ogasawara, Tomomi Kawakatsu, Miyuki Nishimura, Masashi Shimizu, Kazuhiro Tahara, Toshitaka Sato, Katsuhisa Suzuki, Kishan Agarwala, Masao Iwata, Yasuhiro Funahashi, Kenichi Nomoto, Yoichi Ozawa, Junji Matsui, Toshio Imai, Yu Kato. E7011, a novel anti-angiogenesis inhibitor targeting Notch4 receptor signal pathway [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 1485.