Proton Beam Therapy for Intrahepatic Cholangiocarcinoma: A Multicenter Prospective Registry Study in Japan.

Introduction: Intrahepatic cholangiocarcinoma (ICC) can be treated with chemotherapy in unresectable cases, but outcomes are poor. Proton beam therapy (PBT) may provide an alternative treatment and has good dose concentration that may improve local control. Methods: Fifty-nine patients who received initial PBT for ICC from May 2016 to June 2018 at nine centers were included in the study. The treatment protocol was based on the policy of the Japanese Society for Radiation Oncology. Forty patients received 72.6-76 Gy (RBE) in 20-22 fr, 13 received 74.0-76.0 Gy (RBE) in 37-38 fr, and 6 received 60-70.2 Gy (RBE) in 20-30 fr. Overall survival (OS) and progression-free survival (PFS) were estimated by Kaplan-Meier analysis. Results: The 59 patients (35 men, 24 women; median age: 71 years; range: 41-91 years) had PS of 0 (n = 47), 1 (n = 10), and 2 (n = 2). Nine patients had hepatitis and all 59 cases were considered inoperable. The Child-Pugh class was A (n = 46), B (n = 7), and unknown (n = 6); the median maximum tumor diameter was 5.0 cm (range 2.0-15.2 cm); and the clinical stage was I (n = 12), II (n = 19), III (n = 10), and IV (n = 18). At the last follow-up, 17 patients were alive (median follow-up: 36.7 months; range: 24.1-49.9 months) and 42 had died. The median OS was 21.7 months (95% CI: 14.8-34.4 months). At the last follow-up, 37 cases had recurrence, including 10 with local recurrence. The median PFS was 7.5 months (95% CI: 6.1-11.3 months). In multivariable analyses, Child-Pugh class was significantly associated with OS and PFS, and Child-Pugh class and hepatitis were significantly associated with local recurrence. Four patients (6.8%) had late adverse events of grade 3 or higher. Conclusion: PBT gives favorable treatment outcomes for unresectable ICC without distant metastasis and may be particularly effective in cases with large tumors.

Proton beam reirradiation for locally recurrent rectal cancer patients with prior pelvic irradiation.

The aim of the present study was to report the feasibility of proton beam reirradiation for patients with locally recurrent rectal cancer (LRRC) with prior pelvic irradiation. The study population included patients who were treated with proton beam therapy (PBT) for LRRC between 2008 and December 2019 in our institution. Those who had a history of distant metastases of LRRC, with or without treatment, before reirradiation, were excluded. Overall survival (OS), progression-free survival (PFS) and local control (LC) were estimated using the Kaplan-Meier method. Ten patients were included in the present study. The median follow-up period was 28.7 months, and the median total dose of prior radiotherapy (RT) was 50 Gy (range, 30 Gy-74.8 Gy). The median time from prior RT to reirradiation was 31.5 months (range, 8.1-96.6 months), and the median reirradiation dose was 72 Gy (relative biological effectiveness) (range, 56-77 Gy). The 1-year/2-year OS, PFS and LC rates were 100%/60.0%, 20.0%/10.0% and 70.0%/58.3%, respectively, with a median survival time of 26.0 months. Seven patients developed a Grade 1 acute radiation dermatitis, and no Grade ≥ 2 acute toxicity was recorded. Grade ≥ 3 late toxicity was recorded in only one patient, who had developed a colostomy due to radiation-related intestinal bleeding. Reirradiation using PBT for LRRC patients who had previously undergone pelvic irradiation was feasible. However, the indications for PBT reirradiation for LRRC patients need to be considered carefully due to the risk of severe late GI toxicity.

Long-Term Control With Proton Beam Therapy for Recurrent Prostate Cancer in the Right Perineum Following Intensity-Modulated Radiation Therapy: A Case Report.

Radiation therapy (RT) is commonly used for the treatment of prostate cancer, with intensity-modulated radiation therapy (IMRT) and proton beam therapy (PBT) being the utilized modalities. This case report outlines the treatment course of a recurrent prostate cancer lesion in the right perineal musculature managed with proton therapy following IMRT. A 64-year-old Japanese man, diagnosed with prostate cancer and categorized as high risk according to the National Comprehensive Cancer Network guidelines, underwent six months of androgen deprivation therapy, which included bicalutamide and degarelix acetate. Six months after completing 78 Gy in 39 fractions of IMRT, the patient reported perineal to anal pain. Laboratory tests showed an elevated serum prostate-specific antigen (PSA) level, and pelvic MRI showed a mass lesion in the right perineal musculature. Consequently, the patient was diagnosed with recurrent prostate cancer. Thereafter, the patient underwent eight cycles of systemic chemotherapy with docetaxel; however, his pain progressively worsened. Subsequently, the treatment was switched to 12 cycles of cabazitaxel, which led to gradual pain relief. The patient received PBT at 60 Gy relative biological effectiveness in 30 fractions for the recurrent lesion. Five years after PBT, pelvic MRI showed no mass lesions in the prostate or surrounding tissues. The PSA levels remained low, less than 0.008 ng/ml, and there were no apparent late complications.

The Japanese nationwide cohort data of proton beam therapy for liver oligometastasis in breast cancer patients.

A nationwide multicenter cohort study on particle therapy was launched by the Japanese Society for Radiation Oncology in Japan in May 2016. We analyzed the outcome of proton beam therapy (PBT) for liver oligometastasis in breast cancers. Cases in which PBT was performed at all Japanese proton therapy facilities between May 2016 and February 2019 were enrolled. The patients were selected based on the following criteria: the primary cancer was controlled, liver recurrence without extrahepatic tumors and no more than three liver lesions. Fourteen females, with a median age of 57 years (range, 44-73) and 22 lesions, were included. The median lesion size, fraction (fr) size and biological effective dose were 44 (20-130) mm, 6.6 (2-8) gray (Gy) (relative biological effectiveness)/fr and 109.6 (52.7-115.2) Gy, respectively. The median follow-up period was 22.8 (4-54) months. The 1-, 2- and 3-year local control (LC) rates of liver metastasis from breast cancer were 100% for all. The 1-, 2- and 3-year overall survival rates were 85.7, 62.5 and 62.5%, respectively. The 1-, 2- and 3-year progression-free survival (PFS) rates were 50.0%, 33.3%, and 16.7%, respectively. The median PFS time was 16 months. Only one patient did not complete PBT due to current disease progression. One patient had Grade 3 radiation-induced dermatitis. None of the patients experienced radiation-induced liver failure during the acute or late phase. Owing to the low incidence of adverse events and the high LC rate, PBT appears to be a feasible option for liver oligometastasis in breast cancers.

Effects of the orexin receptor 2 agonist danavorexton on emergence from general anaesthesia and opioid-induced sedation, respiratory depression, and analgesia in rats and monkeys.

BACKGROUND: Delayed emergence from general anaesthesia, opioid-induced sedation, and opioid-induced respiratory depression is associated with perioperative complications. We characterised the preclinical effects of the orexin receptor 2 (OX2R)-selective agonist danavorexton (TAK-925) on emergence from anaesthesia and reversal of fentanyl-induced sedation, respiratory depression, and analgesia. METHODS: Emergence from isoflurane- or propofol-induced anaesthesia and fentanyl-induced sedation were investigated by righting reflex, rotarod, and electroencephalography in rats or monkeys. Fentanyl-induced respiratory depression was assessed by arterial blood gas analysis and whole-body plethysmography in rats and monkeys. Analgesia was evaluated using formalin- and skin incision-induced pain models in rats. RESULTS: Danavorexton shortened emergence from isoflurane- or propofol-induced anaesthesia and from fentanyl-induced sedation at 1 (P=0.005), 3 (P=0.006), and 3 mg kg-1 s.c. (P=0.022), respectively, by righting reflex in rats. Danavorexton (10 mg kg-1 s.c.) accelerated recovery from isoflurane-, propofol- and fentanyl-induced motor impairment in separate rotarod tests in rats (P=0.008, P=0.007, P=0.017, respectively), and reversed anaesthesia and fentanyl-induced delta-power increases. Danavorexton shortened emergence (return of righting reflex) from isoflurane- or propofol-induced anaesthesia at 1 (P=0.002) and 3 mg kg-1 (P=0.004), respectively, in cynomolgus monkeys. Danavorexton (10 mg kg-1 s.c.) reversed fentanyl-induced increase in Pco2 (P=0.006), and decrease in Po2 (P=0.015) and pH (P<0.001) in rats, and at 3 mg kg-1 s.c. reversed fentanyl-induced increase in Pco2 (P=0.007), and decrease in Po2 (P=0.013) and SO2 (P=0.036) in monkeys. Danavorexton increased minute volume and tidal volume in fentanyl-treated animals. Danavorexton at ≤10 mg kg-1 s.c. did not compromise fentanyl analgesia in rat formalin- and skin incision-induced pain models. CONCLUSIONS: Danavorexton promoted recovery from anaesthesia and fentanyl-induced sedation, and antagonised fentanyl-induced respiratory depression without compromising fentanyl analgesia.

Tapia Syndrome and Severe Pain Induced by Occipital Bone Metastasis of Prostate Cancer.

Tapia syndrome is characterized by unilateral tongue paralysis, hoarseness, and dysphagia. It is often associated with issues in the lower cranial nerves and is rarely caused by malignant tumors. A 71-year-old Japanese male with prostate cancer and bone metastases experienced severe headaches, oral discomfort, dysphagia, and hoarseness for a month. Neurological examination revealed left-sided tongue atrophy and left vocal cord paralysis, suggesting problems with cranial nerves IX and XII. CT scans showed bone metastasis in the left occipital bone. Brain MRI showed no brain or meningeal metastasis, but neck MRI revealed a mass near the left hypoglossal canal. His prostate-specific antigen (PSA) level was 53.2 ng/mL. Based on these findings, we diagnosed him with occipital bone metastasis of prostate cancer with Tapia syndrome. We treated him with palliative radiation therapy (RT), delivering 30 Gy in 10 fractions over two weeks. We did not use drug treatment or chemotherapy due to side effects and the patient's preferences. After just one day of RT, his severe headache and oral discomfort significantly improved. By the end of the two-week treatment, his hoarseness had also improved, and he was able to eat. However, tongue atrophy had not improved three months after RT. We presented a unique case of palliative RT for occipital bone metastasis of prostate cancer with Tapia syndrome. Within two weeks, the patient's headache and dysphagia had greatly improved, although tongue atrophy remained partially unresolved after palliative RT.

The Japanese nationwide cohort data of proton beam therapy for liver oligometastasis in esophagogastric cancer patients.

A nationwide multicenter cohort study on particle therapy was launched by the Japanese Society for Radiation Oncology in Japan in May 2016. We analyzed the outcome of proton beam therapy (PBT) for liver oligometastasis of esophagogastric cancers. Cases in which PBT was performed at all PBT facilities in Japan between May 2016 and February 2019 were enrolled. The patients were selected based on the following criteria: controlled primary cancer, liver recurrence without extrahepatic tumors and no more than three liver lesions. Twenty-two males and two females with a median age of 69 (range, 52-80) years and 35 lesions were included. This study included 6 patients with esophageal and 18 patients with gastric cancer. The median lesion size, fraction size and biological effective dose (BED)10 were 32 (7-104) mm, 3.8 gray (relative biological effect)/fractions (Gy (RBE)/fr) (2-8 Gy (RBE)/fr) and 96.9 (88.8-115.2) Gy, respectively. The median follow-up period was 18 (4-47) months. The 1-, 2- and 3-year overall survival (OS) rates were 75, 51.8 and 45.3%, respectively, and the median OS was 25.3 months. The 1-, 2- and 3-year cumulative local recurrence (LR) rates were 3, 6 and 6%, respectively. Patients' age (P < 0.01), performance status (P = 0.017) and tumor size (P = 0.024) were significant OS-related factors. No Grade 3 or higher adverse events (AEs) were observed. Owing to the low incidence of AEs and the low LR cumulative incidence, PBT is a feasible option for liver oligometastasis of esophagogastric cancers.

Proton beam therapy for extrahepatic biliary tract cancer: Analysis with prospective multi-institutional patients' registration database, Proton-Net.

Background and purpose: To examine the role of proton beam therapy (PBT) in the treatment of extrahepatic biliary tract cancer (EBC). Methods and materials: We analyzed the data accumulated in the Proton-Net database, which prospectively registered all individual patient data treated with PBT in all Japanese proton institutions from May 2016 to June 2019. The primary endpoint was overall survival (OS), and the secondary endpoints were local control (LC), progression-free survival (PFS), and toxicity. Results: Ninety-three patients with unresectable and/or recurrent EBC were treated with PBT using a median prescribed dose of 67.5 Gy (RBE) (range, 50-72.6 Gy) in 25 (22-30 fractions). With a median follow-up of 16.3 months, the median survival time was 20.1 months and the 2-year OS was 37.8%. Two-year PFS and LC rates were 20.6% and 66.5%, respectively. Poor liver function (Child-Pugh B, C), a narrower distance between the tumor and digestive tract (2 cm >), and a larger tumor diameter (2 cm <) were identified as poor prognostic factors for OS. PBT-related grade 3 ≤ acute and late adverse events occurred in 5.4% and 4.3% of patients, respectively, including one gastrointestinal late toxicity (duodenal ulcer). Conclusions: This is the largest prospectively accumulated series of PBT for EBC, and PBT showed favorable outcomes with acceptable toxicity profiles.

Particle beam therapy versus photon radiotherapy for extrahepatic biliary cancer-systemic review and meta-analysis.

Particle beam therapy (PT) is a potentially promising approach to the treatment of extrahepatic biliary cancer (EBC) because of its unique dose distribution using the Bragg peak. However, the superiority of PT to photon radiotherapy (XT) remains unclear. Therefore, we conducted a systematic review and meta-analysis to compare PT and XT for the treatment of EBC. The primary endpoint was overall survival (OS), which was pooled using a random-effects model. Nine articles comprising a total of 1558 patients (seven XT articles, n = 1488 patients; two PT articles, n = 70 patients) were screened. In addition, we compared the outcomes of XT and PT with the outcomes available from a prospective data registry (proton-net). The 1-year OS probability rates were 55, 65 and 72% for the XT group, PT group and PT registry, respectively. The 2-year OS probability rates were 26, 38 and 38% for the XT group, PT group and PT registry, respectively. The 3-year OS probability rates were 12, 35 and 18% for the XT group, PT group and PT registry, respectively. Although the difference between the 1-year OS rates of the XT group and PT registry was statistically significant, no other significant superiority was observed among these groups. In conclusion, the efficacy of PT was not superior to that of XT during this meta-analysis.

Orexin 2 receptor-selective agonist danavorexton (TAK-925) promotes wakefulness in non-human primates and healthy individuals.

The orexin 2 receptor-selective agonist danavorexton (TAK-925) has been shown to produce wake-promoting effects in wild-type mice, narcolepsy-model mice, and individuals with narcolepsy type 1 and type 2. Here, we report wake-promoting effects of danavorexton in non-human primates and healthy men during their sleep phase. Electroencephalogram analyses revealed that subcutaneous administration of danavorexton significantly increased wakefulness in common marmosets (p < 0.05 at 0.1 mg kg-1 , and p < 0.001 at 1 mg kg-1 and 10 mg kg-1 ) and cynomolgus monkeys (p ≤ 0.05 at 1 mg kg-1 and 3 mg kg-1 ). In a phase 1b crossover, randomized, double-blind, placebo-controlled and active-controlled study in sleep-deprived healthy participants (ClinicalTrials.gov identifier: NCT03522506), modafinil 300 mg (used to demonstrate assay sensitivity) and continuous infusion of danavorexton 44 mg and danavorexton 112 mg showed statistically superior wake-promoting effects to placebo (n = 18). Measured using the Maintenance of Wakefulness Test, mean (standard deviation) sleep latencies during infusion of danavorexton 44 mg, danavorexton 112 mg and placebo were 21.4 (8.9), 31.8 (3.2) and 9.2 (6.4) min, respectively. Least-squares mean difference from placebo in average sleep latency was 16.8 min with danavorexton 44 mg and 30.2 min with danavorexton 112 mg (both p < 0.001). Karolinska Sleepiness Scale scores were statistically significantly lower (indicating decreased sleepiness) for participants receiving danavorexton than for those receiving placebo during infusion (danavorexton 44 mg, p = 0.010; danavorexton 112 mg, p < 0.001). Together, these results indicate that an orexin 2 receptor agonist increases wakefulness in non-human primates and healthy individuals during their sleep phase.

Outcomes and Prognostic Factors for Locally Recurrent Rectal Cancer Treated With Proton Beam Therapy.

Purpose: Our objective was to report the outcome and prognostic factors for patients with locally recurrent rectal cancer (LRRC) treated with proton beam therapy (PBT) at our institution. Methods and Materials: The study included PBT-treated patients with LRRC between December 2008 and December 2019. Treatment response was stratified using an initial imaging test after PBT. Overall survival (OS), progression-free survival (PFS), and local control (LC) were estimated using the Kaplan-Meier method. Each outcome's prognostic factors were verified using the Cox proportional hazards model. Results: Twenty-three patients were enrolled (median follow-up, 37.4 months). There were 11 patients with complete response (CR) or complete metabolic response (CMR), 8 with partial response or partial metabolic response, 2 with stable disease or stable metabolic response, and 2 with progressive disease or progressive metabolic disease. Three- and 5-year OS, PFS, and LC were 72.1% and 44.6%, 37.9% and 37.9%, and 55.0% and 47.2%, respectively, with 54.4 months' median survival time. The maximum standardized uptake value of fluorine-18-fluorodeoxyglucose-positron emission tomography-computed tomography (18F-FDG-PET/CT) before PBT (cutoff value, 10) showed significant differences in OS (P = .03), PFS (P = .027), and LC (P = .012). The patients who achieved CR or CMR after PBT had significantly better LC than those with non-CR or non-CMR (hazard ratio, 4.49; 95% confidence interval, 1.14-17.63; P = .021). Older patients (aged ≥65 years) had significantly higher LC and PFS rates. Patients with pain before PBT and larger tumors (≥30 mm) also had significantly lower PFS. Of 23 patients, 12 (52%) experienced further local recurrence after PBT. One patient developed grade 2 acute radiation dermatitis. Regarding late toxicity, grade 4 late gastrointestinal toxic effects were recorded in 3 patients, in 2 of whom reirradiation was associated with further local recurrence after PBT. Conclusions: The results showed that PBT may have potential to be a good treatment option for LRRC. 18F-FDG-PET/CT before and after PBT may be useful for assessing tumor response and predicting outcomes.

Effectiveness of proton beam therapy for liver oligometastatic recurrence in patients with postoperative esophagus cancer.

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.

Safety of hydrogel spacers for rectal wall protection in patients with prostate cancer: A retrospective analysis of 200 consecutive cases.

OBJECTIVE: To evaluate the safety and complications of hydrogel spacer implantation. METHODS: This single-center historical cohort study retrospectively analyzed cases of hydrogel spacer implantation between October 2018 and March 2022. The survey items were the rates of possible hydrogel injection implementation, the success rate of hydrogel implantation including asymmetry, higher position, rectal wall infiltration, subcapsular injection, and other adverse events, and width created by the spacer. To investigate the learning curve, 1, 2, and 3 points were assigned to adverse event grades G1, G2, and G3, respectively. Spacer effectiveness obstruction, such as asymmetry was assigned 3 points. A Mann-Whitney U test was performed to assess statistically significant differences. RESULTS: The study included a total of 200 patients with a median (range) age of 70 (44-85) years. In 10 (5%) patients, hydrogel injection implementation was not possible. Of 190 patients who underwent hydrogel spacer placement, 168 (88%) received a satisfactory placement. The median (range) width of hydrogel spacers was 13.1 (4.4-18.7) mm. Spacer asymmetry, higher position, rectal wall infiltration, and prostate subcapsular infiltration occurred in 7 (3.7%), 5 (2.6%), 12 (6.3%), and 1 (0.5%) patients, respectively. G1 and G3 adverse events occurred in 13 (7%) and 4 (2%) patients, respectively. Practitioner #1 who performed the highest number of procedures had significantly (p = 0.04) lower total scores in group B. CONCLUSION: Spacer implantation yielded favorable outcomes with a high percentage of appropriate spacer implantation, and few major complications.

Clinical outcomes and factors involved in the local control of proton beam therapy for oligometastatic liver tumors in patients with colorectal cancer.

BACKGROUND AND PURPOSE: There are no existing reports on proton beam therapy (PBT) for local control (LC) of liver metastasis of colorectal cancer (LMCRC). We calculated the LC rate of PBT for LMCRC and explored the influence of each factor on the LC rate. MATERIALS AND METHODS: Cases in which PBT was performed at our center between 2009 and 2018 were retrospectively selected from the database. Patients with LMCRC without extrahepatic lesions and no more than three liver metastases were included. Effectiveness was assessed based on LC, overall survival (OS), and progression-free survival (PFS) rates. Adverse events (AEs) are described. Factors that may be related to LC were also investigated. RESULTS: This study included 23 men and 18 women, with a median age of 66 (range 24-87) years. A total of 63 lesions were included in the study. The most frequent dose was 72.6 Gy (relative biological effectiveness)/22 fractions. The median follow-up period was 27.6 months. The 3­year LC, OS, and PFS rates were 54.9%, 61.6%, and 16.7%, respectively. Our multivariate analysis identified the distance between the tumor and the gastrointestinal (GI) tract as a factor associated with LC (P = 0.02). No grade ≥ 3 AEs were observed. None of the patients experienced liver failure during the acute or late phase. CONCLUSION: Care must be taken with tumors that have reduced planning target volume coverage owing to organs at risk restrictions, especially in tumors near the GI tract.

Proton Beam Therapy for Lung Oligometastatic Recurrence in Patients With Esophageal Cancer.

Local treatment of oligometastatic esophagogastric cancer has been reported to improve overall survival (OS) compared to systemic therapy alone. This study evaluated the feasibility and safety of proton beam therapy (PBT) for the treatment of lung oligometastatic recurrence in esophageal cancer patients. This single-center historical cohort study enrolled 11 patients who underwent PBT for lung oligometastasis from esophageal cancer between 2010 and 2019. The selection criteria were that the primary esophageal cancer was controlled and no more than three lung metastases without outside lung tumors were present. OS, progression-free survival (PFS), and local control (LC) rates and adverse events (AEs) were assessed. Factors that may be related to OS were also investigated. The median follow-up period was 27.8 months (8.8-141.3 months). The one-, two-, and three-year OS rates were 81.8%, 72.7%, and 51.9%, respectively (median OS time: 43.7 months); PFS rates were 45.5%, 27.3%, and 27.3%, respectively (median PFS time: 8.8 months); and LC rates were 92.3%, 72.7%, and 72.7%, respectively. The eighth edition of tumor-node-metastasis (TNM) classification for esophageal cancer was the only significant OS-related factor (p = 0.0309). No grade ≥ 3 AEs were observed. Based on the low incidence of AEs and acceptable LC rate, PBT is a feasible option for the treatment of lung oligometastasis in esophageal cancer patients.

Particle Beam Therapy for Intrahepatic and Extrahepatic Biliary Duct Carcinoma: A Multi-Institutional Retrospective Data Analysis.

To examine the efficacy and toxicity of particle beam therapy (PT) for biliary duct carcinoma (BDC) and compare the outcomes between extrahepatic BDC (eBDC) and intrahepatic BDC (iBDC). We analyzed multi-institutional data from May 2009 to December 2019. The primary endpoint was overall survival (OS), and the secondary endpoints were local control (LC), progression-free survival (PFS) and toxicity. We included 150 patients with unresectable BDC treated with PT using a median prescribed dose of 70.2 GyRBE (range, 44-77 GyRBE) in 25 fractions (range, 10-38 fractions). With a median follow-up of 13.0 months, median survival time (MST) was 21 months, and 2-year OS was 44.8%. For eBDC and iBDC, the MSTs were 20 and 23 months, respectively. Two-year PFS and LC rates were 20.6% and 66.5%, respectively. Vascular invasion, prescribed dose and serum tumor marker level (carcinoembryonic antigen: CEA) were identified as poor prognostic factors for OS. A higher radiation dose EQD2 ≥ 67 Gy showed superior OS, with a hazard ratio of 0.341. The radiation dose of PT is an important predisposing factor for overall survival. The MST for patients with eBDC given a higher radiation dose was 25 months, compared to 15 months for those given the lower dose and 23 months for patients with iBDC (all iBDC given higher doses). iBDC and eBDC duct carcinomas showed equivalent outcomes with PT, especially when treated with a high radiation dose. In detailed analysis, baseline CEA level in iBDC, and radiation dose and GTV in eBDC were statistically significant predicators for OS. Acute and late toxicity grade ≥3 occurred in 2.2% and 2.7% of patients, respectively, including two late grade-5 toxicities. In conclusion, PT showed good efficacy for BDC, both eBDC and iBDC, with a low incidence of severe toxicity.

Proton Beam Therapy With Space-Making Surgery (Omental Plombage) for Oligorecurrent Liver Metastasis of Esophageal Adenocarcinoma.

Proton beam therapy (PBT) with space-making surgery has been used recently; however, its effectiveness for recurrent esophageal cancer (EC) is unclear. We herein report an unusual case of successful PBT with space-making surgery (omental plombage) for recurrent liver metastasis after EC surgery. A 58-year-old Japanese man underwent proximal gastrectomy for esophagogastric (EG) junction cancer seven months before presentation to our hospital. Microscopic findings after the surgery showed that the tumor was adenocarcinoma of the EG junction (pT1N0M0, stage I). Seven months after the proximal gastrectomy, liver metastases in S6 and S8 were revealed by positron emission tomography-computed tomography. Initial PBT was performed for those two liver metastases, and complete response (CR) was obtained for both liver metastases. Recurrence of liver metastasis in S2 was found eight months after the first PBT, and CR was achieved by chemotherapy. However, new liver metastasis recurred in S2. Considering the effects of radiation exposure on the surrounding gastrointestinal organs, we performed space-making surgery to place the omentum around the liver metastasis. We were able to complete the second PBT for the liver metastasis with 72.6 Gy relative biological effectiveness in 22 fractions. After the second PBT, the patient survived for seven years without recurrence. PBT with space-making surgery (omental plombage) for recurrent liver metastasis after EC surgery is considered to be a therapeutic option.

Orexin 2 receptor-selective agonist danavorexton improves narcolepsy phenotype in a mouse model and in human patients.

Narcolepsy type 1 (NT1) is a sleep disorder caused by a loss of orexinergic neurons. Narcolepsy type 2 (NT2) is heterogeneous; affected individuals typically have normal orexin levels. Following evaluation in mice, the effects of the orexin 2 receptor (OX2R)-selective agonist danavorexton were evaluated in single- and multiple-rising-dose studies in healthy adults, and in individuals with NT1 and NT2. In orexin/ataxin-3 narcolepsy mice, danavorexton reduced sleep/wakefulness fragmentation and cataplexy-like episodes during the active phase. In humans, danavorexton administered intravenously was well tolerated and was associated with marked improvements in sleep latency in both NT1 and NT2. In individuals with NT1, danavorexton dose-dependently increased sleep latency in the Maintenance of Wakefulness Test, up to the ceiling effect of 40 min, in both the single- and multiple-rising-dose studies. These findings indicate that OX2Rs remain functional despite long-term orexin loss in NT1. OX2R-selective agonists are a promising treatment for both NT1 and NT2.

Profile analysis of adverse events after boron neutron capture therapy for head and neck cancer: a sub-analysis of the JHN002 study.

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.

Successful treatment with proton beam therapy for a solitary sternal metastasis of breast cancer: a case report.

BACKGROUND: Breast cancer infrequently metastasizes to the sternum as solitary metastasis. We experienced successful treatment with proton beam therapy for a case of sternal metastasis of breast cancer. This case demonstrates for the first time the role of proton therapy in the treatment of oligometastatic sternal metastasis with limited tolerance of normal tissue due to previous photon irradiation. CASE PRESENTATION: A 40-year-old Japanese female presented with lumpiness in her left breast. The patient was diagnosed with breast cancer (cT1N0M0, cStage IA) and underwent partial mastectomy with axillary lymph node dissection. After the mastectomy, the patient received radiation therapy with 50 Gy in 25 fractions for initial irradiation of the left breast. After the initial irradiation of 50 Gy, the patient received 10 Gy in five fractions of a sequential boost for the tumor bed to a total dose of 60 Gy. Although the patient was administered tamoxifen after radiation therapy, solitary sternal metastasis occurred 6 months after radiation therapy. She refused chemotherapy and requested proton beam therapy for her sternal metastasis. The daily proton beam therapy fractions were 2.5 relative biological effectiveness, receiving a total dose of 70 Gy relative biological effectiveness. An acute side effect of grade 2 dermatitis according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0. occurred during proton beam therapy, but there was no acute or late complication of more than grade 3. At 3 years after proton beam therapy, the patient remains in complete remission without surgery or chemotherapy. DISCUSSION AND CONCLUSION: Proton beam therapy for solitary sternal metastasis of breast cancer is considered to be a therapeutic option.