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Advancement in systemic therapy has increased the importance of local control (LC) of bone metastatic sites treated with radiotherapy in intermediate-term survivors (surviving ≥1 year). To establish individualized radiotherapy for bone metastases, factors affecting LC of bone metastases treated with traditional fractionated moderate dose palliative radiotherapy (FMRT) in intermediate-term survivors were evaluated. Between January 2010 and December 2019, 317 lesions in 240 patients treated with FMRT for bone metastases surviving for at least 1 year and followed-up with CT for at least 6 months were reviewed retrospectively. The median survival and radiographic follow-up times were 24 months (range, 12-123 months) and 20 months (range, 1-119 months), respectively. The median FMRT dose [biologically effective dose (BED)10] was 39.0 Gy (range, 28.0-71.7 Gy). Multivariate analysis revealed that age (≥70 years), non-vertebral bone metastasis, bone metastasis from moderate and unfavorable primary tumor sites (esophageal, colorectal, hepatobiliary/pancreatic, kidney/ureter and sarcoma/melanoma cancers), and no administration of post-FMRT bone-modifying agents (BMAs) were unfavorable factors for LC of bone metastasis. The 2-year LC rates for FMRT doses (BED10) ≤39.0 Gy and39.0 Gy were 90 and 87%, respectively. The 2-year LC rates of patients administered and not administered post-FMRT antineoplastic agents (ATs) were 91 and 78%, respectively. The sites of bone metastasis and primary tumors, and post-FMRT BMAs were factors associated with LC of bone metastasis in long-term survivors. However, a FMRT dose (BED10) ≥39.0 Gy and post-FMRT ATs were not significant factors.

Durvalumab (Durva) administration after chemoradiation therapy (CRT) in locally advanced non-small-cell lung cancer (NSCLC) is the standard of care, associated with relatively prolonged progression-free (PFS) and overall survival. However, pneumonitis occurs in 73.6% of Japanese patients. This retrospective study aimed to identify factors associated with Durva efficacy and safety, specifically, the risk of pneumonitis.This study included data from 26 consecutive patients with locally advanced NSCLC who underwent CRT followed by Durva. The rates of adverse events and PFS were examined.The median PFS time was 15.6 months (95% confidence interval [CI]: 8.7-not available). Patients developed pneumonitis of grade 1, 2, 3, and 4 at the rate of 62%, 27%, 12%, and 0%, respectively. The median PFS time was 6.4 months for patients with programmed death ligand 1 (PD-L1) expression level of 50% and not reached for patients with PD-L1 expression level of ≥50% (hazard ratio [HR], 0.19; 95% CI: 0.04-0.89), which was significantly prolonged. The cumulative incidence of pneumonitis grade 2 or above was significantly higher when the time between the last day of thoracic radiotherapy (TRT) and the start of Durva therapy was within 14 days compared to14 days (HR: 0.19; 95% CI: 0.06-0.59). This association was statistically significant in multivariate analysis.The initiation of Durva therapy within 14 days after TRT may increase the risk of pneumonitis grade 2 or above. Careful observation and suitable treatment are recommended.

Purpose Neutrophil-to-lymphocyte ratio (NLR) has been reported to be associated with treatment outcomes in various cancers; however, the optimal timing to measure NLR is unclear. In this study, “average-NLR” was newly devised, which reflects the NLR throughout the course of radiotherapy, and its usefulness was assessed for stage III non-small cell lung cancer (NSCLC) patients treated with chemoradiotherapy. Materials and methods A total of 111 patients who received definitive chemoradiotherapy for unresectable stage III NSCLC were reviewed. Patient/tumor-related factors, treatment-related, and NLR-related factors (average-NLR, pre- and post-radiotherapy NLR, NLR-nadir, NLR-maximum) were assessed using univariate and multivariate analyses. Results The median follow-up period was 43.8 months among the survivors. In the multivariate analysis, average-NLR and post-radiotherapy NLR were significant factors for the overall survival (OS) (p = 0.016 and 0.028) and distant failure (DF) (p = 0.008 and 0.040). For the patients with low, intermediate, and high average-NLR, the median OS was 41.2, 37.7, and 14.8 months, respectively, and the median DF free time was 52.5, 13.5, and 8.9 months, respectively. Conclusion Average-NLR and post-radiotherapy NLR were significant factors for the OS and DF. Average-NLR, which was available immediately after the completion of chemoradiotherapy, seemed to be helpful for treatment decisions.

The impact of immune checkpoint inhibitors (ICIs) on radiation-induced enterocolitis (RIE) after palliative radiotherapy (PRT) to the bowel has remained to be fully investigated. The aim of the present study was to investigate whether ICIs affect RIE after PRT. For this purpose, 32 lesions (vertebral bone, 13; pelvic bone, 12; adrenal gland, 3; lymph node, 3; liver, 1) in 28 patients with metastatic lung cancer who were treated with both PRT involving the bowel (8-48 Gy; typically 30 Gy in 10 fractions or 20 Gy in 5 fractions) and ICIs between December 2015 and June 2021 were retrospectively reviewed. A total of 12 lesions were treated with ICIs only prior to PRT, 16 received ICIs only after PRT and the remaining 4 received ICIs both prior to and after PRT. The 1-year overall survival rate was 53%. The median PRT dose was 30 Gy (range, 8-48 Gy) in 10 fractions (range, 1-24 fractions). The median interval between PRT and the closest administration of ICIs was 20.5 days (range, 1-212 days). Combination therapy with PRT and ICIs was well tolerated by the majority of patients. However, grade 2 or higher RIE occurred in 6.3% of the patients. In these patients, ICIs were administered within 7 days after completing PRT with 3.6 Gy or a higher-fraction dose (evaluated at the isocenter). There were significant differences in the incidence of RIE between administration of ICIs7 days after PRT completion and ≥7 days (P=0.05), between3.6 Gy per fraction and ≥3.6 Gy (P=0.04), and between maximum dose to 2 cc (D2cc) of large bowel3.3 Gy and D2cc of large bowel ≥3.3 Gy (P=0.02). There was no clear association between the incidence of RIE and any other factors. These results suggest that the administration of ICIs soon after PRT completion and a comparatively high fraction dose may potentially increase the risk of grade 2 or higher RIE.

Nitric oxide and reactive oxygen species regulate bone remodeling, which occurs via bone formation and resorption by osteoblasts and osteoclasts, respectively. Recently, we found that 8-nitro-cGMP, a second messenger of nitric oxide and reactive oxygen species, promotes osteoclastogenesis. Here, we investigated the formation and function of 8-nitro-cGMP in osteoblasts. Mouse calvarial osteoblasts were found to produce 8-nitro-cGMP, which was augmented by tumor necrosis factor-α (10 ng/ml) and interleukin-1β (1 ng/ml). These cytokines suppressed osteoblastic differentiation in a NO synthase activity-dependent manner. Exogenous 8-nitro-cGMP (30 μmol/L) suppressed expression of osteoblastic phenotypes, including mineralization, in clear contrast to the enhancement of mineralization by osteoblasts induced by 8-bromo-cGMP, a cell membrane-permeable analog of cGMP. It is known that reactive sulfur species denitrates and degrades 8-nitro-cGMP. Mitochondrial cysteinyl-tRNA synthetase plays a crucial role in the endogenous production of RSS. The expression of osteoblastic phenotypes was suppressed by not only exogenous 8-nitro-cGMP but also by silencing of the

Background Over the past decades, remarkable advancements in systemic drug therapy have improved the prognosis of patients with bone metastases. Individualization is required in external beam radiotherapy (EBRT) for bone metastases according to the patient’s prognosis. To establish individualized EBRT for bone metastases, we investigated factors that affect the local control (LC) of bone metastases. Methods Between January 2010 and December 2019, 536 patients received EBRT for 751 predominantly osteolytic bone metastases. LC at EBRT sites was evaluated with a follow-up computed tomography. The median EBRT dose was biologically effective dose (BED10) (39.0) (range of BED10: 14.4–71.7 Gy). Results The median follow-up time and median time of computed tomography follow-up were 11 (range 1–123) months and 6 (range 1–119) months, respectively. The 0.5- and 1-year overall survival rates were 73% and 54%, respectively. The 0.5- and 1-year LC rates were 83% and 79%, respectively. In multivariate analysis, higher age (≥ 70 years), non-vertebral bone metastases, unfavorable primary tumor sites (esophageal cancer, colorectal cancer, hepatobiliary/pancreatic cancer, renal/ureter cancer, sarcoma, melanoma, and mesothelioma), lower EBRT dose (BED10 10 = 39.0 and BED10 > 39.0 Gy. Conclusions Regarding tumor-related factors, primary tumor sites and the sites of bone metastases were significant for the LC. As for treatment-related factors, lower EBRT doses (BED10 10 = 39.0 Gy did not necessarily improve LC.

Background Brain metastases from differentiated thyroid cancer are uncommon, and the prognosis of patients with them is poor. To explore the optimal treatment for this entity, we retrospectively investigated incidence and features of brain metastases from differentiated thyroid cancer that appeared during and after radioactive iodine therapy. Methods Between 2002 and 2012, 89 patients of differentiated thyroid cancer were included (median age, 63-years; male/female = 29/60). The median follow-up time from first ablation was 63 months (range: 1–175 months). The median cumulative radioactive iodine dose was 8.51 GBq (range: 1.11–42.55 GBq). Results During the follow-up, brain metastases occurred in four (4.5 %) patients. The median follow-up time after first ablation of four patients was 69 months (22, 63, 76 and 105 months). They had already had extracranial metastases at first ablation (lung metastases: 3, lung and bone metastases: 1), and had one or more lesions resistant to radioactive iodine therapy at diagnosis of brain metastasis. Three of them had experienced major hemorrhage from brain metastasis. Survival time intervals from the diagnosis to brain metastasis were 2.5, 3.6, 13 and 13.1 months. Conclusion Brain metastases of differentiated thyroid cancer were relatively uncommon. Prognosis of patients with brain metastasis was unfavorable because of frequent major brain hemorrhage and frequent existence of concomitant extracranial lesions resistant to radioactive iodine therapy. To prevent intracranial hemorrhage, early treatment seemed to be necessary for brain metastases from differentiated thyroid cancer.

Pericardial effusion is an important late toxicity after concurrent chemoradiotherapy (CCRT) for locally advanced esophageal cancer. We investigated the clinical and dosimetric factors that were related to pericardial effusion among patients with thoracic esophageal cancer who were treated with definitive CCRT using the two opposed fields technique (TFT) or the four-field technique (FFT), as well as the effectiveness of FFT. During 2007–2015, 169 patients with middle and/or lower thoracic esophageal cancer received definitive CCRT, and 94 patients were evaluable (51 FFT cases and 43 TFT cases). Pericardial effusion was observed in 74 patients (79%) and appeared at 1–18.5 months (median: 5.25 months) after CCRT. The 1-year incidences of pericardial effusions were 73.2% and 76.7% in the FFT and TFT groups, respectively (P = 0.6395). The mean doses to the pericardium were 28.6 Gy and 31.8 Gy in the FFT and TFT groups, respectively (P = 0.0259), and the V40 Gy proportions were 33.5% and 48.2% in the FFT and TFT groups, respectively (P < 0.0001). Grade 3 pericardial effusion was not observed in patients with a pericardial V40 Gy of

PURPOSE/OBJECTIVE(S) With the advance of systemic therapy, long-term survivors have increased and importance of long-term local control of bone metastases has increased in recent years. The purpose of this study was to search for factors affecting local control of bone metastatic lesions in external-beam radiotherapy (EBRT) for cases with long-term survival of ≥1-year. MATERIALS/METHODS Between December 2010 and April 2019, 349 lesions (vertebral body, 214; pelvic, 73; rib/ sternal, 22; extremity, 35; skull, 6) in 259 patients received EBRT, and survived for ≥1-years after EBRT. Local control was evaluated by follow-up CT. Doses of EBRT were 8-50 Gy (median 30 Gy). RESULTS One and three-year control rates at EBRT sites were 95% and 86%, respectively. Local recurrence was observed in 9.7% (34 lesions in 31 patients). Sex, age of > 70, bone metastases other than vertebrae, bone metastases from unfavorable primary tumor sites (hepatobiliary/pancreatic/colorectal/thyroid/renal cell carcinoma), and without bone modified agents (BMAs) and/or systemic therapy (ST) after EBRT were statistically significant poor local control factors (P = 0.036, 0.038, 0.001, 30 Gy), bone cortex destruction and without ST before EBRT (P = 0.623, 0.887, and 0.568, respectively). In multivariate analysis, bone metastases other than vertebrae, bone metastases from unfavorable primary tumor sites and without BMAs were significant unfavorable factors for local control (P = 0.011, 0.0004, and 0.028, respectively). CONCLUSION EBRT dose escalation of > 30 Gy did not seem to be useful. Although further studies are needed, primary tumor and bone metastatic sites were associated with local control. In addition, the use of BMAs is useful in terms of local control.

We retrospectively investigated the impact on survival of early tumor reduction during definitive radiotherapy for inoperable stage III non-small cell lung cancer (NSCLC) patients, according to their histological subtypes. Between November 2006 and December 2012, 152 consecutive patients with inoperable stage III NSCLC who underwent definitive radiotherapy were reviewed retrospectively. Forty-one patients were excluded for not satisfying the inclusion criteria. Forty-five (40.5 %) and 48 (43.2 %) patients were diagnosed with squamous cell carcinoma (SQC) and adenocarcinoma (ADC), respectively. The tumor reduction rate (TRR) was defined as follows: TRR = 1−[gross tumor volume (GTV) on computed tomography at shrinking irradiation field planning]/(GTV on computed tomography at the initial treatment planning). The Cox proportional hazard model was used to identify significant prognostic factors for overall survival (OS) and progression-free survival (PFS). We evaluated 111 patients, with a median follow-up time of 52.2 months in surviving patients. The median TRR was 45.9 %. In all patients, there were significant associations between TRR and PFS (P = 0.036) on multivariate analysis, although TRR had no correlation with OS (P = 0.141). With respect to histological subtype, multivariate analyses revealed that a higher TRR showed significant associations with better OS and PFS in the SQC group (P = 0.013 and 0.040, respectively). In contrast, a higher TRR was associated with poorer OS in the ADC group (P = 0.030); there was no association between TRR and PFS. We found that a higher TRR is a promising prognostic factor for better survival and disease control in SQC patients.

Objective: To determine the helpful factorsto distinguish prostate-specific antigen failure from prostate-specific antigen bounce with large magnitude. Methods: From October 2004 to December 2009, 242 patients with prostate cancer treated with 125 I brachytherapy were analyzed, 88 patients were excluded because the follow-up durations were shorter than 5 years. Their median follow-up was 80.4 months (60.0–123.9). Prostate-specific antigen failurewasdetermined usingthe Phoenix definition. Prostate-specific antigenbouncewas definedas an increase ≥0.2 ng/ml above the nadir, followed by a spontaneous return to the nadir. Prostatespecific antigen bounce +2 was defined as a prostate-specific antigen rise by 2.0 ng/ml or more above the nadir. Results: The 5-year biochemical relapse-free survival rate was 90.2%. Prostate-specific antigen failure and prostate-specific antigen bounce +2 were seen in 23 patients (14.9%) and 12 patients (7.8%), respectively. On univariate analysis, age at implant (P= 0.028), T stage (P= 0.020), time to prostatespecific antigen failure or prostate-specific antigen bounce (time to onset) (P = 0.0008), prostatespecific antigen velocity (P = 0.0003) and prostate-specific antigen doubling time (P = 0.0004) were significant for the distinction between prostate-specific antigen failure and prostate-specific antigen bounce +2. On multivariate analysis, no factor was the statistically significant factor. On receiver operating characteristic curve analysis, time to onset with a cutoff value of 29.8 months, prostate-specific antigen velocity of 0.18 ng/ml/month and prostate-specific antigen doubling time of 6.3 months had the highest accuracy of 82.9, 82.9 and 82.9% for prostate-specific antigen failure, respectively. Conclusions: Time to onset, prostate-specific antigen velocity and prostate-specific antigen doubling time would be helpful for distinction between prostate-specific antigen failure and prostatespecific antigen bounce +2.