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Proton beam therapy (PBT) is effective for pediatric tumors, but patients may require sedation and other preparations, which extend the treatment time. Pediatric patients were classified into sedation and non-sedation cases. Adult patients were classified into three groups based on irradiation from two directions without or with respiratory synchronization and patch irradiation. Treatment person-hours were calculated as follows: (time from entering to leaving the treatment room) × (number of required personnel). A detailed analysis showed that the person-hours required for the treatment of pediatric patients are about 1.4–3.5 times greater than those required for adult patients. With the inclusion of additional time for the preparation of pediatric patients, PBT for pediatric cases is two to four times more labor-intensive than for typical adult cases.

The first total synthesis of (–)-merrillianin (1), which is a natural sesquiterpene with a tri- fused structure having a cyclopentane ring and five- and seven-membered lactone parts, is demonstrated. This asymmetric total synthesis enabled the absolute stereo structure determination of naturally occurring (–)-1.

To assess the safety and efficacy of proton beam therapy (PBT) for muscle-invasive bladder cancer (MIBC), we examined the outcomes of 36 patients with MIBC (cT2-4aN0M0) who were enrolled in the Proton-Net prospective registry study and received PBT with concurrent chemotherapy from May 2016 to June 2018. PBT was also compared with X-ray chemoradiotherapy in a systematic review (X-ray (photon) radiotherapy). The radiotherapy consisted of 40–41.4 Gy (relative biological effectiveness (RBE) delivered in 20–23 fractions to the pelvic cavity or the entire bladder using X-rays or proton beams, followed by a boost of 19.8–36.3 Gy (RBE) delivered in 10–14 fractions to all tumor sites in the bladder. Concurrently, radiotherapy was given with intra-arterial or systemic chemotherapy of cisplatin alone or in combination with methotrexate or gemcitabine. Overall survival (OS), progression-free survival (PFS) and local control (LC) rates were 90.8, 71.4 and 84.6%, respectively, after 3 years. Only one case (2.8%) experienced a treatment-related late adverse event of Grade 3 urinary tract obstruction, and no severe gastrointestinal adverse events occurred. According to the findings of the systematic review, the 3-year outcomes of XRT were 57–84.8% in OS, 39–78% in PFS and 51–68% in LC. The weighted mean frequency of adverse events of Grade 3 or higher in the gastrointestinal and genitourinary systems was 6.2 and 2.2%, respectively. More data from long-term follow-up will provide us with the appropriate use of PBT and validate its efficacy for MIBC.

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.

Light flash and odor during radiotherapy have been suggested to be associated with younger age and retina and nasal cavity irradiation. Multivariate analyses including dose-volume histograms indicated that light flash was related to age, chiasmatic gland irradiation, and pituitary dose, and odor was related to age and nasal cavity irradiation.

Highlights • A total of 88 patients experienced light flashes among 416 who received photon radiotherapy and 205 who received proton beam therapy in our prospective study. • The frequency of light flashes during radiotherapy was associated with the retina dose and younger age, and were commonly blue or white light for brain or head and neck irradiation. • Light flashes were seen by only 35/524 patients (6.7%) without retinal irradiation, but by 13/33 (39.4%) and 41/64 (64.1%) with retinal maximum isodose lines of 10–50% and 60–100%, respectively. • Totals of 52, 15, 15, 9, 16 and 8 patients sensed light of blue, purple, yellow, red, white and other colors, respectively., Background Patients who receive radiation therapy sometimes complain of a light flash during irradiation. The details of the characteristics of this light have not been described. Purpose To evaluate light flashes during photon and proton radiotherapy. Methods and Materials A prospective observational study was performed in all adult patients (≥20 years old) who received photon and proton therapy at two centers between January 2019 and August 2020, except for patients who could not communicate and those with visual abnormality. Evaluations were obtained for the presence or absence of light flashes, light darkness (7 levels), light intensity (5 levels), frequency, light movement, light flashing, and time seeing the light, using a weekly checklist. Results A total of 650 courses were examined for 621 patients, of whom 416 received photon radiotherapy and 205 received proton beam therapy. The checklist indicated that 88 patients (16.1%) sensed light during photon or proton radiotherapy. In multivariate logistic regression analysis, the factors that were significantly associated with a light flash were a higher retina dose and younger age (p

Background Expansion of preoperative edema (PE) is an independent poor prognostic factor in high-grade gliomas. Evaluation of PE provides important information that can be readily obtained from magnetic resonance imaging (MRI), but there are few reports on factors associated with PE. The goal of this study was to identify factors contributing to PE in Grade 3 (G3) and Grade 4 (G4) gliomas. Methodology PE was measured in 141 pathologically proven G3 and G4 gliomas, and factors with a potential relationship with PE were examined in univariate and multivariate analyses. The following eight explanatory variables were used: age, sex, Karnofsky performance status (KPS), location of the glioma, tumor diameter, pathological grade, isocitrate dehydrogenase (IDH)-1-R132H status, and Ki-67 index. Overall survival (OS) and progression-free survival (PFS) were calculated in groups divided by PE (1 vs. ≥1 cm) and by factors with a significant correlation with PE in multivariate analysis. Results In univariate analysis, age (p = 0.013), KPS (p = 0.012), pathology grade (p = 0.004), and IDH1-R132H status (p = 0.0003) were significantly correlated with PE. In multivariate analysis, only IDH1-R132H status showed a significant correlation (p = 0.036), with a regression coefficient of -0.42. The median follow-up period in survivors was 38.9 months (range: 1.2-131.7 months). The one-, two-, and three-year OS rates for PE1 vs. ≥1 cm were 77% vs. 68%, 67% vs. 44%, and 63% vs. 24% (p = 0.0001), respectively, and those for IDH1-R132H mutated vs. wild-type cases were 85% vs. 67%, 85% vs. 40%, and 81% vs. 21% (p0.0001), respectively. The one-, two-, and three-year PFS rates for PE1 vs. ≥1 cm were 77% vs. 49%, 64% vs. 24%, and 50% vs. 18% (p = 0.0002), respectively, and those for IDH1-R132H mutated vs. wild-type cases were 85% vs. 48%, 77% vs. 23%, and 73% vs. 14% (p0.0001), respectively. Conclusions IDH1-R132H status was found to be a significant contributor to PE. Cases with PE1 cm and those with the IDH1-R132H mutation clearly had a better prognosis.

Hepatocellular carcinoma (HCC) located in the caudate lobe (caudate HCC) is rare; however, patients with this type of tumour have poorer prognoses than those with HCC in other segments. Despite many published reports on the clinical usefulness of proton beam therapy (PBT) for HCC, data on the clinical outcomes of patients undergoing PBT for caudate HCC remain scarce. Therefore, the present study aimed to investigate the outcomes of this group of patients. Thirty patients with caudate HCC who underwent definitive PBT between February 2002 and February 2014 were retrospectively analysed. The total irradiation doses ranged from 55 to 77 (median 72.6) Gy relative biological dose. The median follow-up period was 37.5 (range, 3.0–152.0) months. The overall survival (OS) rates at one, three and five years were 86.6%, 62.8% and 46.1%, respectively. According to univariate and multivariate analyses, Child-Pugh A (P

Highlights • Proton beam therapy is likely to be safe for liver hemangiomas because, in our experience. • Proton beam therapy achieves good local control for liver hemangiomas without causing severe hepatic damage. • Proton beam therapy expected to minimize the risk of late adverse events., Background Hepatic hemangiomas are benign tumors with a favorable prognosis, but giant hepatic hemangiomas can cause abdominal symptoms and are indicated for treatment. Most cases are treated with surgery, but radiotherapy has also been used. However, to date, there have been no reports of proton beam therapy for a hepatic hemangioma. Case presentation A 46-year-old woman had a tumor of 80 × 80 mm in the left medial lobe of the liver, which was diagnosed as a giant hemangioma based on the contrast pattern. Therapy was required for a giant hepatic hemangioma with symptoms, but the patient refused blood transfusion due to religious reasons, which made surgical resection difficult. Therefore, she was referred to our hospital for proton beam therapy. At her first visit, liver function was Child-Pugh A (5 points) and there was no elevation of tumor markers. Proton beam therapy of 28.6 Gy (RBE) given in 13 fractions was performed without interruption. The only observed acute radiation toxicity was Grade 1 dermatitis. One year after proton beam therapy, the hemangioma had significantly decreased, and a complete response has been maintained for 15 years based on ultrasound and MRI. Conclusion This case is the first reported use of proton beam therapy for a hepatic hemangioma. The outcome suggests that this treatment may be effective for a giant liver hemangioma.

Highlights • A cervical desmoid tumor could be successfully controlled with proton therapy. • Desmoid tumors commonly occur in the limbs and trunk, rarely in the neck. • Proton beam therapy was selected to reduce radiation related adverse events., Desmoid tumors are benign, but may have a locally invasive tendency that commonly results in local recurrence. Most occur on the body trunk or extremities, whereas a head and neck desmoid tumor is relatively rare. The efficacy of radiotherapy has been suggested and 50–60 Gy is used for unresectable or recurrent desmoid tumors, but there are few reports of use of particle beam therapy. However, since this tumor occurs more often in younger patients compared to malignant tumors and the prognosis is favorable, there may be an advantage of this therapy. We treated a male patient with a head and neck recurrent desmoid tumor with proton beam therapy (PBT) at a dose of 60 Gy (RBE). This patient underwent surgical resection as initial treatment, but the tumor recurred only six months after surgery, and resection was performed again. After PBT, the tumor gradually shrank and complete remission has been achieved for 10 years without any severe late toxicity. Here, we report the details of this case, with a review of the literature. We suggest that PBT may reduce the incidence of second malignant tumors by reducing the dose exposure around the planning target volume.

Unirradiated liver volume (ULV) preservation rate is an important factor associated with radiation-induced liver disease (RILD) in patients with hepatocellular carcinoma (HCC) undergoing proton beam therapy (PBT). The purpose of this study is to identify the predictors for ULV preservation and quantify the capacity of proton beams in normal liver sparing during PBT. We reviewed planning data of 92 patients with single intrahepatic HCC tumors undergoing PBT. The potential clinical and planning factors that may affect ULV preservation were involved in multiple linear regression for ULV preservation rate. The significant factors were determined to be predictors and their influences were quantified. The median ULV preservation rate was 62.08%. All the assessed clinical factors showed significant effects on ULV preservation rate: clinical target volume (CTV), P

Light flash and odor during radiotherapy are well-known phenomena. Two prospective observational studies have indicated that 55% of patients observed a light flash during irradiation of the retina and 27% of patients sensed an odor during radiotherapy for the nasal cavity. A prospective observational study was performed in all patients at our hospital who received total body irradiation (TBI) between January 2019 to October 2021. Light flash and odor during TBI were examined using the same method as that used in previous studies. A total of 32 patients received TBI during the study period. The patients had a median age of 41 (18–60) years, and included 20 males and 12 females. A survey checklist showed that 14 patients (44%) sensed light and 14 patients (44%) sensed odor during TBI,. The color of the light during irradiation was yellow in six cases, white in four cases, and blue in four cases. The intensity of the light was 2–5 (median 3, 1 is very weak, 5 is very strong) and the time over which the light flash was felt was 4–60 s (median 10 s). Two patients each sensed smells of plastic, ozone and bleach, and others sensed one smell each. The intensity of the odor was 1–4 (median 3, 1 is very weak, 5 is very strong) and the time over which the odor was sensed was 1–25 s (median 3 s). We conclude that light flashes and odors are each sensed by 44% of patients during TBI. Various types of light flashes and odors were reported in this study.

Patients often report a sense of smell during radiation therapy (RT), but the details of these events are not well understood. The purpose of the study was to evaluate events of smell during photon RT and proton beam therapy (PBT).The subjects were all adult patients (≥20 years old) treated with photon RT or PBT at two centers from January 2019 to August 2020, with the exclusion of those with communication difficulties or olfactory abnormality. The presence of smell, odor type, intensity (five levels), and time period was examined prospectively using a weekly checklist.A total of 649 courses were examined in 620 patients who received photon RT (n=415) or PBT (n=205). A smell during the procedure was sensed by 51 patients (8.2%). In multivariate logistic regression analysis, nasal cavity dose (p=0.002), age (p0.001), and photon RT (p=0.018) were identified as significant factors associated with a sense of smell. Smell occurred in only 23/515 patients (4.5%) in whom the nasal cavity was not irradiated, but in 4/19 (21.1%) and 24/86 (27.9%) with nasal cavity maximum isodose lines of 10%-50% and 60%-100%, respectively. Patients who received photon RT sensed a smell (43/415; 10.4%) more frequently than those treated with PBT (8/205; 3.9%). Of the 51 patients who sensed a smell, 32 (63%) reported a burnt smell, eight (16%) a chemical smell, two (4%) a sour smell, and nine another smell (copier machine, sweet, garbage, etc.).The sense of a smell appears to be common during RT and this sensation is significantly associated with the nasal cavity dose, younger age, and photon RT.

Background and objective Postoperative radiotherapy is usually indicated for both grade 3 glioma and grade 4 glioblastoma. However, the treatment results and tumor features of grade 3 glioma clearly differ from those of glioblastoma. There is limited information on outcomes and tumor progression for grade 3 glioma. In this study, we evaluate the result of postoperative radiotherapy for grade 3 glioma and focus on the correlation of MRI findings with prognosis. Methods In this study, 99 of 110 patients with grade 3 glioma who received postoperative radiotherapy and were followed up for more than one year were retrospectively analyzed. The total irradiation dose was 60.0 Gy in 30 fractions, and daily temozolomide or two cycles of nimustine (ACNU) was concurrently administered during radiotherapy. The median follow-up period was 46 months (range: 2-151 months). Results In multivariate analysis, pathology [anaplastic oligodendroglioma (AO) vs. anaplastic astrocytoma (AA)], the status of surgical resection (biopsy vs. partial resection or more), and contrast enhancement (enhanced by MRI image or not) were significant factors for overall survival (OS). The five-year OS for AO vs. AA cases were 76.8% vs. 46.1%, total to partial resection vs. biopsy cases were 72.7% vs. 21.0%, and non-enhanced vs. enhanced cases were 82.5% vs. 45.6%, respectively. In multivariate analysis, the status of surgical resection and longer extension of preoperative edema (PE) were significant factors for progression-free survival (PFS). The five-year PFS for the total to partial resection vs. biopsy cases were 52.9% vs. 10.7%, and non-extensive PE vs. extensive PE (EPE) cases were 62.2% vs. 19.1%, respectively. Conclusion Our results suggest that a contrast-enhanced tumor on MRI and a longer PE may also be significantly associated with OS and PFS among grade 3 glioma patients.

Background This study was conducted to evaluate late toxicities in adolescent and young adult (AYA) patients who received photon or proton therapy. Methodology A total of 106 AYA patients who received proton and photon therapy and were followed-up for more than two years were retrospectively evaluated. The median age of patients was 22 years (range, 15-29 years). A total of 47 patients were male and 59 were female. A total of 35 and 71 patients received photon and proton therapy, respectively. All but one patient received radiotherapy with curative intent. The target disease was benign and malignant in 28 and 78 patients, respectively. Results The median follow-up period in all patients was 62 months (range: 24-293 months). Grade 3 or higher toxicity was observed in 20 patients. There was one case of grade 5 toxicity (myelodysplastic syndrome), which was probably due to chemotherapy. No other secondary cancers were observed. Regarding life events, 15 and 88 patients were married and unmarried at the start of radiotherapy, respectively. Of the 88 unmarried patients, five were married after radiotherapy. Occupation and education were evaluated in 71 patients. Of the 71 patients, 33 were students, 21 were employed, and 16 were unemployed. Of the 33 students, eight were employed and 11 were at a higher educational grade after radiotherapy. Of the 21 employed patients, 17 had the same jobs and four had lost their jobs after radiotherapy. For the 16 unemployed patients, all remained unemployed. Conclusions This study is one of the largest studies to focus on life after radiation therapy among AYAs and suggests that cancer treatment has an influence on life events.

Hyperthermia induced by heat stress (HS) is known to inhibit proliferation and induce cell death in cancer. We previously demonstrated that checkpoint kinase 1 (Chk1) contributes to G2/M arrest and cell survival under HS; however, the role of Chk2, a functional analog of Chk1, in regulation of the cell cycle and cell death under HS is still unknown. Here, we addressed the role of Chk2 using Molt-4 cells with p53-targeted shRNA (Molt-4/shp53) and parental control cells (Molt-4/V). Chk2 inhibition suppressed C-terminal acetylation of p53 and delayed the induction of p53-target genes in Molt-4/V cells under HS; however, Chk2 inhibition failed to inhibit apoptosis induced by HS, indicating that Chk2 was dispensable for p53-dependent apoptosis under HS. In contrast, Chk2 inhibition abrogated G2/M arrest and promoted cell death induced by HS in HeLa cells and Molt-4/shp53 cells. Thus, we demonstrated for the first time that Chk2 was required for cell cycle arrest and cell survival, particularly in cells with p53 defects under HS. These findings indicated that Chk2 may be a selective target for p53-mutated or -deficient cancer treated with hyperthermia.

Hepatocellular carcinoma (HCC) with inferior vena cava tumor thrombus (IVCTT) is rare and regarded as an advanced disease stage with poor prognosis. Treatment effect data regarding HCC with IVCTT is scarce and clear evidence has not been established. This study, therefore, aims to examine the safety and effectiveness of proton beam therapy (PBT) for HCC patients with IVCTT. From January 2005 to December 2014, a total of 21 HCC patients with IVCTT were analyzed. The total irradiation doses ranged from 50 to 74 (median 72.6) gray relative biological effectiveness. The follow-up period was 4–120 (median 21) months. Regarding acute toxicities, dermatitis of grade 1–2 was observed in all patients, while no grade 3 or higher late toxicity events were encountered. The overall survival (OS) rates for all patients were 62%, 33%, and 19% at 1, 2, and 3 years, respectively. No local recurrences for the treated lesions, including IVCTT, were observed. According to univariate analysis, IVCTT extension type was not associated with prognosis, but only tumor number significantly affected the OS rate (p = 0.003). For 10 single lesion patients, the longest survival time was 120 months with OS rates of 82%, 64%, and 36% at 1, 2, and 3 years, respectively. PBT is safe and effective for HCC patients with IVCTT, especially those with single lesion status. PBT is an important treatment option for HCC patients with IVCTT.

Simple Summary Radiotherapy has a key role in treatment of pediatric cancer and has greatly improved survival in recent years. However, vertebrae are often included in the irradiated area, and this may affect growth after treatment. In this study, we examined the relationship of the dose of proton beam therapy with subsequent growth of 353 vertebral bodies in 23 children (10 boys, 13 girls) with a median age at treatment of 4 years old and a median observation period of 13.9 months. Most importantly, we found that the growth rate of vertebral bodies decreased even at a low proton beam therapy dose, which indicates the need for careful planning of the irradiation area in this patient population. Growth inhibition was clearly dose-dependent, and proton beam therapy had the same growth inhibitory effect as photon radiotherapy, at least within the irradiated field. Abstract Impairment of bone growth after radiotherapy for pediatric bone cancer is a well-known adverse event. However, there is limited understanding of the relationship between bone growth and irradiation dose. In this study, we retrospectively analyzed bone growth impairment after proton beam therapy for pediatric cancer. A total of 353 vertebral bodies in 23 patients under 12 years old who received proton beam therapy were evaluated. Compared to the non-irradiated vertebral body growth rate, the irradiated vertebral body rate (%/year) was significantly lower: 77.2%, 57.6%, 40.8%, 26.4%, and 14.1% at 10, 20, 30, 40, and 50 Gy (RBE) irradiation, respectively. In multivariate analysis, radiation dose was the only factor correlated with vertebral body growth. Age, gender, and vertebral body site were not significant factors. These results suggest that the growth rate of the vertebral body is dose-dependent and decreases even at a low irradiated dose. This is the first report to show that proton beam therapy has the same growth inhibitory effect as photon radiotherapy within the irradiated field.

Proton beam therapy (PBT) is a curative treatment for hepatocellular carcinoma (HCC), because it can preserve liver function due to dose targeting via the Bragg peak. However, the degree of direct liver damage by PBT is unclear. In this study, we retrospectively analyzed liver/biliary enzymes and total bilirubin (T-Bil) as markers of direct liver damage during and early after PBT in 300 patients. The levels of these enzymes and bilirubin were almost stable throughout the treatment period. In patients with normal pretreatment levels, aminotransferase (AST), alanine aminotransferase (ALT), alkaline phosphatase (ALP), gamma-glutamyl transpeptidase (GGT), and T-Bil were abnormally elevated in only 2 (1.2%), 1 (0.4%), 0, 2 (1.2%), and 8 (3.5%) patients, respectively, and in 8 of these 13 patients (61.5%) the elevations were temporary. In patients with abnormal pretreatment levels, the levels tended to decrease during PBT. GGT and T-Bil were elevated by 1.62 and 1.57 times in patients who received 66 Gy (RBE) in 10 fractions and 74 Gy (RBE) in 37 fractions, respectively, but again these changes were temporary. These results suggest that direct damage to normal liver caused by PBT is minimal, even if a patient has abnormal pretreatment enzyme levels.

Background and Purpose: Worsening lower urinary tract symptoms (LUTS) are a frequent adverse event following proton beam therapy (PBT) for localized prostate cancer. We investigated the differences in worsening LUTS among patients who received PBT at different times of day. Participants and Methods: Among 173 patients who underwent PBT for prostate cancer, 168 patients (median age 68.5 years) completed international prostate symptom score (IPSS) questionnaires and were included. Changes in the IPSS from baseline to the end of PBT were assessed by multiple linear regression analysis for age, National Comprehensive Cancer Network risk classification, androgen deprivation therapy, fractional PBT dose, clinical target volume, severity of IPSS, diabetes, LUTS medication use before PBT, anti-coagulant therapy and radiation time of day (morning (08:30&ndash, 10:30), around noon (10:31&ndash, 14:30), and late afternoon (14:31&ndash, 16:30)). Results: IPSS total score and IPSS-Quality of Life (QoL) score (12 patients were excluded due to missing IPSS-QoL score) increased from eight to 14.9 (p &lt, 0.0001) and from two to four (p &lt, 0.0001), respectively. Time of day (morning) was the only determinant for worsening LUTS (&beta, = &minus, 0.24, p &lt, 0.01), voiding subscore (&beta, 0.22, p &lt, 0.05) and IPSS-QoL (&beta, 0.27, p &lt, 0.005), and was a determinant in item four (urgency) (&beta, 0.28, p &lt, 0.005) with age (&beta, = 0.19, p &lt, 0.05). Conclusions: Morning PBT for localized prostate cancer significantly ameliorated worsening LUTS and improved QoL compared with treatment around noon or late afternoon. Chronoradiation therapy for localized prostate cancer may be effective and further research to elucidate the underlying mechanism is warranted.

Purpose: Malignant fibrous histiocytoma (MFH) is one of the most common soft tissue sarcomas. The standard treatment is adequate surgical resection; in addition, radiation therapy plays a major role in perioperative treatment in most cases. Herein, we report the case of a patient with a large MFH who was successfully treated with combined proton beam therapy (PBT) and local hyperthermia (LH). Case Presentation: A 60-year-old man presented with a 6×4-cm mass on his left thigh. Histopathology and immunohistochemistry indicated MFH, and he refused limb amputation. He received treatment with PBT at a dose at 72 GyE in 18 fractions. To cover the entire large target lesion, we used a patch-field protocol. He also concurrently received 7 courses of LH. The combination therapy achieved long-term local control without severe acute or late toxicity during the 7-year follow-up period. Conclusions: This case suggests that the combination of PBT and LH may be an option as a limb-preserving treatment for large inoperable MFH in the extremities.

Standard treatment for localized renal pelvis and ureter cancer is surgery. Previously, the primary role of radiation therapy (RT) in cancer treatment was to control pain and hemostasis as palliative or as adjuvant therapy following surgery. In this report, we describe 5 patients with the disease treated with proton beam therapy (PBT) as curative treatment. Between September 2009 and July 2013, 5 males with renal pelvis (n=3) or ureter (n=2) cancer were treated by PBT with hypofractionated [72.6 Gy relative biological effectiveness (RBE)/22 fractions] or conventional [64-66 Gy (RBE)/32-33 fractions] fractionation. The median patient age was 72 years (range, 59-85 years). Three patients were deemed unfit for surgery. Local hypofractionated PBT was performed in 2 patients with T1-2N0M0 diseases, while prophylactic lymph node irradiation using a patch irradiation technique was performed for the remaining 3 patients, who had T3-4 disease. Two patients with T3-4 disease received chemotherapy prior to definitive PBT. No serious acute or late toxicities were observed in any patient. Local tumor control was achieved in 3 patients (60%); however, distant metastases were observed in 2 patients. Four of the five patients (80%) evaluated in the present study survived for >3 years. The data is limited; however, PBT appears to be a potential option for patients with renal pelvis or ureter cancer, especially for those who are unsuitable for radical surgery.

Hyperthermia induced by heat stress (HS) is known to inhibit proliferation and induce cell death in cancer. We previously demonstrated that checkpoint kinase 1 (Chk1) contributes to G

Objectives:We aimed to identify dynamic CT features that can be used for prediction of local recurrence of hepatocellular carcinoma (HCC) after proton beam therapy (PBT).Methods:We retrospectively retrieved CT scans of patients with PBT-treated HCC, taken between January 2004 and December 2016. 17 recurrent lesions and 34 non-recurrent lesions were retrieved. The attenuation difference between irradiated tumor and irradiated parenchyma (ADHCC-IP) was compared in the two groups by using the Mann–Whitney U test. Cut-off value of ADHCC-IPwas estimated by using the Youden index.Results:The follow-up time after PBT initiation ranged from 374 to 2402 days (median, 1069 days) in recurrent lesions, and 418 to 2923 days (median, 1091.5 days) in non-recurrent lesions (p = 0.892). The time until appearance of local recurrence after PBT initiation ranged from 189 to 2270 days (median, 497 days). ADHCC-IPof recurrent lesions [mean, −21.8 Hounsfield units (HU); from −95 to −31 HU] was significantly greater than that of non-recurrent lesions (mean, −51.7 HU; from −117 to −12 HU) at 1–2 years in portal venous phase (p = 0.039). 5-year local tumor control rates were 0.93 and 0.56 in lesions with ADHCC-IPat 1–2 years in PVP < −55 and ≥ −55 HU, respectively.Conclusion:The attenuation difference between irradiated HCC and irradiated liver parenchyma in portal venous phase at 1-2 years after PBT can predict long-term local recurrence of HCC after treatment.Advances in knowledge:We identified a cut-off value for contrast enhancement of HCC after PBT that could predict future local recurrence.

Given the growing interest in using proton beam therapy (PBT) for hepatocellular carcinoma (HCC), it is possible that transarterial chemoembolization (TACE) could be used for selected patients who have previously undergone PBT. However, these cases can be technically challenging to treat and require appropriate preparation. Thus, we aimed to identify angiographic findings in this setting. We retrospectively identified 31 patients (28 men and 3 women, mean age: 69 years, range: 43–84 years) who underwent hepatic angiography plus TACE or transarterial infusion chemotherapy (TAI) for HCC that recurred after PBT (July 2007 to June 2018). We discovered four angiographic findings, which we speculate were related to the previous PBT. 18 patients experienced recurrence in the irradiated field, and 13 patients experienced recurrence outside the irradiated field. 29 patients underwent TACE and only 2 patients underwent TAI. The mean number of previous PBT treatments was 1.3 ± 0.6 (range: 1–4). The median interval from the earliest PBT treatment to hepatic angiography was 559 days (range: 34–5,383 days), and the median interval from the latest PBT treatment to hepatic angiography was 464 days (range: 34–5,383 days). Abnormal staining of the irradiated liver parenchyma was observed in 22 patients, which obscured the angiographic tumor staining in 4 patients. Development of a tortuous tumor feeder vessel was observed in 13 patients. Development of an extrahepatic collateral pathway was observed in 7 patients. Development of an arterioportal or arteriovenous shunt was observed in 4 patients. Based on these findings, we conclude that PBT was associated with various angiographic findings during subsequent transarterial chemotherapy for recurrent HCC, and familiarity with these findings will be important in developing appropriate treatment plans.

Hyperthermia induced by heat stress (HS) inhibits the proliferation of cancer cells and induces their apoptosis. However, the mechanism underlying HS-induced apoptosis remains elusive. Here, we demonstrated a novel evidence that checkpoint kinase 1 (Chk1) plays crucial roles in the apoptosis and regulation of cell cycle progression in cells under HS. In human leukemia Jurkat cells, interestingly, the ataxia telangiectasia and Rad-3 related (ATR)-Chk1 pathway was preferentially activated rather than the ataxia telangiectasia mutated (ATM)-checkpoint kinase 2 (Chk2) pathway under HS. The selective inhibitors of ATR or Chk1 abrogated HS-induced apoptosis in human leukemia Jurkat cells whereas the inhibition of ATM or Chk2 caused only marginal effects. Inhibition of ATR and Chk1 also abrogated G2/M checkpoint activation by HS in Jurkat cells. The effects of small interfering RNA targeting Chk1 were similar to those of the selective inhibitor of Chk1. In addition, the efficiencies of Chk1 inhibition on G2/M checkpoint abrogation and apoptosis induction were confirmed in the adherent cancer cell lines HeLa, HSC3, and PC3, suggesting that the targeting of Chk1 can be effective in solid tumors cells. In conclusion, these findings indicate a novel molecular basis of G2/M checkpoint activation and apoptosis in cells exposed to HS.

The asymmetric aldol reaction of heteroatom-substituted ketene silyl acetals with achiral aldehydes has been developed by the promotion of tin(II) triflate coordinated with a chiral diamine to afford the corresponding aldols having chiral tertiary alcohols at the α-positions. This reaction has been successfully applied to the construction of the basic skeletons of buergerinins F and G starting from achiral materials. (+)-Buergerinin G, a potentially antiphlogistic and febrifuge agent having a unique trioxatricyclo[5.3.1.0 1,5 ]undecane skeleton, is stereoselectively prepared by means of the enantioselective aldol reactions via ten linear steps from crotonaldehyde in 18% overall yield including an effective intramolecular Wacker-type ketalization of the dihydroxy-γ-lactone as a key step. In addition to the former establishment for the synthesis of (+)-buergerinin F, effective divergent methods for the preparation of buergerinins F and G were developed through a unified optically active aldol-type intermediate, which was generated from the tetrasubstituted ketene silyl acetal with crotonaldehyde by the asymmetric Mukaiyama aldol reaction.

To establish a method of measuring interconnect line-edge roughness (LER), low-k line patterns were observed and electric field concentration was simulated on the basis of observation results. Wedge-shaped LERs were observed at the edges of low-k lines, and the bottom and the top widths of the average wedge feature were 60 and 7 nm (or smaller), respectively. Simulation showed that LER causes serious electric field concentration, which may cause the degradation of time-dependent dielectric breakdown (TDDB) lifetime at 100-nm-pitch Cu/low-k interconnects. The maximum electric field strength depends on the conventional LER metric 3Rq, but depends more strongly on the wedge angle, the curvature of the tip. That is, other metrics such as wedge angle can predict fatal electric field concentration caused by LER than the conventional metric 3Rq.