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There are several reports of hepatic resection for postoperative hepatic metastatic recurrence of esophageal cancer. However, it is unclear whether surgery is the best local treatment for liver metastases. Thus, this study aimed to retrospectively analyze proton beam therapy (PBT) for postoperative liver metastatic recurrence of esophageal cancer without extrahepatic lesions and examine outcomes and adverse events. This single-center historical cohort study selected patients who underwent PBT at our proton therapy center between 2012 and 2018. The patients were selected based on the following criteria: primary esophagus carcinoma was resection and metachronous liver oligometastasis recurrence without extrahepatic tumors and no more than three liver metastases. This study included seven males with a median age of 66 (range, 58–78) years, and 15 lesions were included in the study. The median tumor size was 22.6 (7–55.3) mm. The most frequent dose was 72.6 Gy relative biological effect (RBE)/22 fractions (fr) for four lesions and 64 Gy (RBE)/8 fr for four lesions. The median survival time was 35.5 (13.2–119.4) months. The 1-, 2- and 3-year overall survival (OS) rates were 100%, 57.1% and 42.9%, respectively. The median progression-free survival (PFS) time was 8.7 (1.2–44.1) months. The 1-, 2- and 3-year PFS rates were 28.6%. The 1-, 2- and 3-year local control (LC) rates were 100%. No grade ≥4 radiation-induced adverse events (AEs) were observed. We conclude that PBT can be considered an alternative to hepatic resection for recurrent liver metastases postoperative esophageal cancer.

The purpose of this study was to outline the course and profile of adverse events specific to boron neutron capture therapy (BNCT) for head and neck cancer. This was a sub-analysis of the phase II JHN002 trial. Patients received 400 mg/kg borofalan(10B), followed by neutron irradiation. The course of adverse events after BNCT was documented in the JHN002 Look Up study. Patients were grouped into face/front (FF), face/lateral (FL) and neck (N) beam groups according to the point of skin incidence of the epithermal neutron beam axis, and the profile of adverse events dependent on beam incidence position was examined. The courses of adverse events in eight recurrent squamous cell carcinoma (R-SCC) and 13 recurrent or locally advanced non-SCC cases were analyzed. Median interval to complete recovery was 23 days (interquartile range (IQR), 14–48 days) for oral mucositis, 40 days (IQR, 24–56 days) for dermatitis, 58 days (IQR, 53–80 days) for dysgeusia and 156 days (IQR, 82–163 days) for alopecia. In the FF beam group, parotitis (P = 0.007) was less frequent, while oral mucositis (P = 0.032), fatigue (P = 0.002), conjunctivitis (P = 0.001), epistaxis (P = 0.001) and abdominal discomfort (P = 0.029) tended to be more frequent than in the FL and N beam groups. Courses and irradiation site-specific profiles of adverse events in BNCT for head and neck cancer were identified. This profile may be useful for considering interventions to prevent exacerbation of treatment-related adverse events on BNCT.

Background and purpose Boron neutron capture therapy (BNCT) can be performed without reactors due to development of cyclotron-based epithermal neutron source (C-BENS), which is optimized for treatment for deeper-seated tumors. The purpose of this study was to evaluate efficacy and safety of cyclotron-based BNCT with borofalan (10B) for recurrent or locally advanced head and neck cancer. Materials and methods In this open-label, phase II JHN002 trial of BNCT using C-BENS with borofalan (10B), patients with recurrent squamous cell carcinoma (R-SCC) or with recurrent/locally advanced non-squamous cell carcinoma (R/LA-nSCC) of the head and neck were intravenously administered 400 mg/kg borofalan (10B), followed by neutron irradiation. The tumor dose was determined passively as the mucosal maximum dose of 12 Gy-Eq. The primary endpoint was the objective response rate (ORR). Post-trial observational JHN002 Look Up study was planned for evaluating locoregional progression-free survival (LRPFS). Results Eight R-SCC and 13 R/LA-nSCC patients were enrolled. All R-SCC patients had prior radiotherapy with a median dose of 65.5 Gy (range, 59.4–76.0 Gy). The ORR for all patients was 71%, and complete response/partial response were 50%/25% in R-SCC and 8%/62% in R/LA-nSCC. The 2-year overall survival for R-SCC and R/LA-nSCC were 58% and 100%, respectively. The median LRPFS was 11.5 months for R-SCC. Frequently observed adverse events included alopecia (95%), hyperamylasemia (86%), and nausea (81%). Conclusion These data suggest that BNCT using C-BENS with borofalan (10B) is a promising treatment option for patients with R-SCC or R/LA-nSCC of the head and neck.

Adenoid cystic carcinoma (ACC) is a very rare epithelial tumor of the salivary glands. Surgical resection is considered to be a standard therapy. However, the optimal treatment strategy for managing advanced cases has not yet been established. This study evaluated the efficacy and toxicity of proton beam therapy (PBT) combined with selective intra-arterial infusion chemotherapy (IAIC) using weekly cisplatin for locally advanced ACC of the base of the tongue. Between March 2009 and February 2018, 15 patients were treated. The median follow-up duration was 56 (range: 15–116) months. The 5-year local control and overall survival rates were 89% and 76%, respectively. With regard to late toxicities, grade 2 osteoradionecrosis was found in one patient and grade 5 pharyngeal necrosis was observed in one patient. Considering most cases were significantly advanced and inoperable, this therapy was effective in controlling the primary tumor, preserving function and maintaining the quality of life. Although improvements are needed to reduce adverse events, PBT in combination with IAIC can be a treatment option for locally advanced ACC of the base of the tongue.

ObjectiveThe purpose of this cross-sectional study was to evaluate the efficacy and safety of proton beam therapy for liver metastatic recurrence in gastric cancer patients.MethodsConsecutive patients who underwent proton beam therapy from 2010 to 2015 were isolated from our institutional database. Patients with extrahepatic metastatic lesions were excluded. Seven patients were enrolled. The median diameter of target lesions was 31 mm (13–68 mm). The most frequent dosage was 72.6 Gy equivalent in 22 fractions. The effectiveness was assessed based on the local control, overall survival and progression-free survival rates. The local control, overall survival and progression-free survival rates were calculated using the Kaplan–Meier method. Adverse events were described according to the patients’ medical records.ResultsThe median follow-up period was 41.7 months (20.7–66.3 months). The 3-year local control, overall survival and progression-free survival rates were 85.7, 68.6 and 43%, respectively. All patients completed proton beam therapy without interruption. No grade ≥3 adverse events were observed.ConclusionsProton beam therapy might be a treatment option for patients with liver metastasis of gastric cancer.

Background The purpose of the present study was to evaluate retrospectively the efficacy and safety of proton beam therapy for elderly patients (≥80 years of age) with non-small cell lung cancer. Methods Patients diagnosed with T1–4 N0 M0 non-small cell lung cancer and treated with proton beam therapy between January 2009 and 2015 were recruited from our database retrospectively. Toxicity was evaluated using The Common Terminology Criteria for Adverse Events version 4.0. Results Thirty-five patients, including 25 (71%) with clinically inoperable lung cancer, were administered proton beam therapy. The median age was 82 years (range: 80–87 years), and the median follow-up time was 34 months (range: 10–72 months). The median dose of proton beam therapy was 80.0 Gy relative biological effectiveness (RBE) (range: 60.0–80.0 Gy [RBE]), and all patients completed the treatments. All patients were followed for at least 23 months or until their death. The 3-year overall survival rate was 67.2% (90.0% in patients with operable lung cancer, and 58.2% in those with inoperable lung cancer). The 3-year local control rate was 86.5%. Two patients presented with grade 2 pneumonitis. The occurrence rate of grade 2 pneumonitis was significantly correlated with a high lung V20 (p = 0.030), and a high mean lung dose (p = 0.030), and a low ratio of lung volume spared from 0.05 Gy (RBE) dose (total lung volume minus lung volume irradiated at least 0.05 Gy [RBE]) (p = 0.030). However, there were no cases of grade 3 or higher radiation pneumonitis. Conclusions This study suggests that the proton beam therapy was feasible for elderly patients with non-small cell lung cancer and can be considered as one of the treatment choices for elderly patients with lung cancer.

Adenoid cystic carcinoma (ACC) is a very rare epithelial tumor of the salivary glands. Surgical resection is considered to be a standard therapy. However, the optimal treatment strategy for managing advanced cases has not yet been established. This study evaluated the efficacy and toxicity of proton beam therapy (PBT) combined with selective intra-arterial infusion chemotherapy (IAIC) using weekly cisplatin for locally advanced ACC of the base of the tongue. Between March 2009 and February 2018, 15 patients were treated. The median follow-up duration was 56 (range: 15–116) months. The 5-year local control and overall survival rates were 89% and 76%, respectively. With regard to late toxicities, grade 2 osteoradionecrosis was found in one patient and grade 5 pharyngeal necrosis was observed in one patient. Considering most cases were significantly advanced and inoperable, this therapy was effective in controlling the primary tumor, preserving function and maintaining the quality of life. Although improvements are needed to reduce adverse events, PBT in combination with IAIC can be a treatment option for locally advanced ACC of the base of the tongue.

The aim of this study was to evaluate the efficacy and safety of proton beam therapy for patients with locally recurrent parotid cancer. Between 2009 and 2012, ten patients with locally recurrent parotid gland cancer were treated with proton beam therapy (70.2 Gy equivalents in 32 fractions) with or without intra-arterial infusion chemotherapy of cisplatin (50 mg/body/week, for a total of 5–8 weeks). The median follow-up was 24 months (range 10–49 months). The 1-year overall survival and local control rates were 80 %, and the 3-year overall survival and local control rates were 60 %. None of the patients experienced grade 3–5 toxicities in the treatment or the follow-up periods. These findings suggest that proton beam therapy could be applied effectively and safely for patients with locally recurrent parotid gland cancer.

The effect of proton beam therapy (PBT) on various cancers is controversial. We aimed to evaluate the efficacy and safety of PBT with alternating chemoradiotherapy (ACRT) for patients with stage I–III esophageal cancer. Two cycles of systemic chemotherapy with a continuous infusion of 5‐fluorouracil (5‐FU) on days 1–5 and a 5h infusion of nedaplatin (NDP) on day 6 were accompanied by thoracic irradiation using X‐ray therapy and PBT. During the first half of the treatment, X‐rays were delivered to the prophylactic area. During the second half of the treatment, proton beams were used to irradiate the involved field. To reduce the dose of cardiac irradiation, proton beams were delivered with posterior and posterior oblique angles. Between January 2009 and December 2012, 47 patients were enrolled in this study. The median follow‐up duration was 29 months for all patients and 40 months for survivors. The 3 year overall survival rate, progression‐free survival rate, and local control rate were 59.2%, 56.3%, and 69.8%, respectively. With respect to grade 3–4 late toxicities, there were no pleural or pericardial effusions, but two patients (4.3%) had esophageal stenosis, one patient (2.1%) had fistula, and two patients (4.3%) developed radiation pneumonitis. PBT with ACRT might have the potential to reduce the risk of cardiac damage and might become one of the primary methods of esophageal cancer treatment.

This study aimed to evaluate the therapeutic effect and toxicity of proton beam therapy in combination with intra-arterial infusion chemotherapy in patients with squamous cell carcinoma of the maxillary gingiva. Between December 2010 and March 2016, 30 patients with T4 squamous cell carcinoma of the maxillary gingiva were treated with radiotherapy and retrograde intra-arterial infusion chemotherapy using cisplatin (20&ndash, 40 mg/m2, 4&ndash, 6 times). Radiotherapy was basically administered using boost proton beam therapy for primary tumor and neck lymph node tumors, following 36&ndash, 40 Gy photon radiation therapy delivered to the prophylactic area, to a total dose of 70.4&ndash, 74.8 Gy. The median follow-up was 33 months. The 3-year local control and overall survival rates were 69% and 59%, respectively. Major grade 3 or higher acute toxicities included mucositis, neutropenia, and dermatitis in 12 (40%), 5 (17%), and 3 (10%) patients, respectively. No grade 3 or higher late toxicities were observed. These results suggested that proton beam therapy in combination with intra-arterial infusion chemotherapy was not inferior to other treatment protocols and should be considered as a safe and effective option in patients with T4 squamous cell carcinoma of the maxillary gingiva.

Background. Evidence has suggested that radiation therapy with a lower dose per fraction may be a reasonable option for the treatment of centrally located non-small cell lung cancer (NSCLC). The aim of this study was to evaluate the safety and efficacy of two proton beam therapy (PBT) protocols for stage I NSCLC and to determine prognostic factors.Material and methods. This study included patients clinically diagnosed with stage I NSCLC. Based on the location of the tumor, one of the two PBT protocols was administered. Patients with peripherally located tumors were given 66 Gy relative biological dose effectiveness (RBE) over 10 fractions (Protocol A) while patients with centrally located tumors were given 80 Gy (RBE) over 25 fractions (Protocol B).Results. Between January 2009 and May 2012, 56 eligible patients were enrolled (protocol A: 32 patients; protocol B: 24 patients). The three-year overall survival (OS), progression-free survival (PFS), and local control (LC) rates were 81.3% [95% confidence interval (CI) 75.9–86.7%], 73.4% (95% CI 67.2–79.6%), and 96.0% (95% CI 93.2–98.8%), respectively. There were no significant differences in outcomes between the two protocols. Late grade 2 and 3 pulmonary toxicities were observed in nine patients (13.4%) and one patient (1.5%), respectively; no grade 4 or 5 toxicities were observed. Sex, age, performance status, T-stage, operability, and tumor pathology were not associated with OS and PFS. Only maximum standardized uptake value (SUVmax; < 5 vs. ≥ 5) was identified as a significant prognostic factor for OS and PFS.Conclusion. Both high-dose PBT protocols achieved high LC rates with tolerable toxicities in stage I NSCLC patients, and SUVmax was a significant prognostic factor.

Polymorphous low-grade adenocarcinoma is a rare malignant tumor that mainly occurs in salivary glands, particularly in the hard palate. To date, surgery has been the most commonly used treatment method with the aim of achieving negative margins of resection. Here, we report a case of a 51-year-old woman who presented with a painless growing mass in her oral cavity with Rouviere’s lymph node metastasis. Laboratory data showed severe anemia because of bleeding from the tumor. We inserted two catheters into the bilateral external carotid arteries via the superficial temporal arteries, and began continuous intra-arterial infusion with cisplatin and a cisplatin-neutralizing agent. The bleeding stopped after the first infusion, and we continued with weekly arterial cisplatin infusion and proton beam therapy (70.4 GyE in 32 fractions). A decrease in tumor volume has been maintained for 2 years, with no evidence of new metastasis.

OBJECTIVE This study aimed to evaluate the efficacy and toxicity of proton beam therapy combined with cisplatin intra-arterial infusion via a superficial temporal artery as treatment for maxillary sinus carcinoma. METHODS Twenty-six patients with confirmed maxillary sinus carcinoma were enrolled in this study from May 2009 to April 2011. Patients underwent proton beam therapy and intra-arterial infusion chemotherapy with cisplatin. RESULTS The median total dose was 70.4 GyE per 32 fractions, and the median dose of cisplatin was 300 mg/body for six cycles of intra-arterial infusion. The 3-year overall survival rate was 58% for all patients (n = 26), 58% for patients with stage T4 disease (n = 12), 57% for patients with

The single nucleotide polymorphism (SNP) rs13438494 in intron 24 of PCLO was significantly associated with bipolar disorder in a meta-analysis of genome-wide association studies. In this study, we performed functional minigene analysis and bioinformatics prediction of splicing regulatory sequences to characterize the deep intronic SNP rs13438494. We constructed minigenes with A and C alleles containing exon 24, intron 24, and exon 25 of PCLO to assess the genetic effect of rs13438494 on splicing. We found that the C allele of rs13438494 reduces the splicing efficiency of the PCLO minigene. In addition, prediction analysis of enhancer/silencer motifs using the Human Splice Finder web tool indicated that rs13438494 induces the abrogation or creation of such binding sites. Our results indicate that rs13438494 alters splicing efficiency by creating or disrupting a splicing motif, which functions by binding of splicing regulatory proteins, and may ultimately result in bipolar disorder in affected people.

Background We examined the efficacy and toxicity of proton beam therapy (PBT) for treating advanced cholangiocarcinoma. Methods The clinical data and outcomes of 28 cholangiocarcinoma patients treated with PBT between January 2009 and August 2011 were retrospectively examined. The Kaplan–Meier method was used to estimate overall survival (OS), progression-free survival (PFS), and local control (LC) rates, and the log-rank test to analyze the effects of different clinical and treatment variables on survival. Acute and late toxicities were assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. Results The median age of the 17 male and 11 female patients was 71 years (range, 41 to 84 years; intrahepatic/peripheral cholangiocarcinoma, n = 6; hilar cholangiocarcinoma/Klatskin tumor, n = 6; distal extrahepatic cholangiocarcinoma, n = 3; gallbladder cancer, n = 3; local or lymph node recurrence, n = 10; size, 20–175 mm; median 52 mm). The median radiation dose was 68.2 Gy (relative biological effectiveness [RBE]) (range, 50.6 to 80 Gy (RBE)), with delivery of fractions of 2.0 to 3.2 Gy (RBE) daily. The median follow-up duration was 12 months (range, 3 to 29 months). Fifteen patients underwent chemotherapy and 8 patients, palliative biliary stent placement prior to PBT. OS, PFS, and LC rates at 1 year were 49.0%, 29.5%, and 67.7%, respectively. LC was achieved in 6 patients, and was better in patients administered a biologically equivalent dose of 10 (BED10) > 70 Gy compared to those administered 70 Gy. Gastrointestinal toxicities, especially those of the duodenum, are dose-limiting toxicities associated with PBT, and early metastatic progression remains a treatment obstacle.