Search

Abstract After menstruation the uterine spiral arteries are repaired through angiogenesis. This process is tightly regulated by the paracrine communication between endometrial stromal cells (EnSCs) and endothelial cells. Any molecular aberration in these processes can lead to complications in pregnancy including miscarriage or preeclampsia (PE). Placental growth factor (PlGF) is a known contributing factor for pathological angiogenesis but the mechanisms remain poorly understood. In this study, we investigated whether PlGF contributes to pathological uterine angiogenesis by disrupting EnSCs and endothelial paracrine communication. We observed that PlGF mediates a tonicity-independent activation of nuclear factor of activated T cells 5 (NFAT5) in EnSCs. NFAT5 activated downstream targets including SGK1, HIF-1α and VEGF-A. In depth characterization of PlGF - conditioned medium (CM) from EnSCs using mass spectrometry and ELISA methods revealed low VEGF-A and an abundance of extracellular matrix organization associated proteins. Secreted factors in PlGF-CM impeded normal angiogenic cues in endothelial cells (HUVECs) by downregulating Notch-VEGF signaling. Interestingly, PlGF-CM failed to support human placental (BeWo) cell invasion through HUVEC monolayer. Inhibition of SGK1 in EnSCs improved angiogenic effects in HUVECs and promoted BeWo invasion, revealing SGK1 as a key intermediate player modulating PlGF mediated anti-angiogenic signaling. Taken together, perturbed PlGF-NFAT5-SGK1 signaling in the endometrium can contribute to pathological uterine angiogenesis by negatively regulating EnSCs-endothelial crosstalk resulting in poor quality vessels in the uterine microenvironment. Taken together the signaling may impact on normal trophoblast invasion and thus placentation and, may be associated with an increased risk of complications such as PE.

Abstract Adenoid cystic carcinoma (ACC) of the trachea is a rare disease that is slow growing and has a risk of distant metastasis. The standard treatment for ACC of the trachea is surgery, but this tumor is often unresectable. In definitive radiotherapy using photons for unresectable ACC of the trachea, it is sometimes difficult to deliver a sufficient dose to the target without exceeding the tolerable dose to the surrounding normal tissues. Here, we report two cases of ACC of the trachea that received a high dose (74 Gy [relative biological effectiveness]) of proton beam therapy and achieved long‐term survival.

Abstract Background Proton beam therapy (PBT) has recently been included in Japan's social health insurance benefits package. This study aimed to determine the cost‐effectiveness of PBT for unresectable, locally advanced pancreatic cancer (LAPC) as a replacement for conventional photon radiotherapy (RT). Methods We estimated the incremental cost‐effectiveness ratio (ICER) of PBT as a replacement for three‐dimensional conformal RT (3DCRT), a conventional photon RT, using clinical evidence in the literature and expense complemented by expert opinions. We used a decision tree and an economic and Markov model to illustrate the disease courses followed by LAPC patients. Effectiveness was estimated as quality‐adjusted life years (QALY) using utility weights for the health state. Social insurance fees were calculated as the costs. The stability of the ICER against the assumptions made was appraised using sensitivity analyses. Results The effectiveness of PBT and 3DCRT was 1.67610615 and 0.97181271 QALY, respectively. The ICER was estimated to be ¥5,376,915 (US$46,756) per QALY. According to the suggested threshold for anti‐cancer therapy from the Japanese authority of ¥7,500,000 (US$65,217) per QALY gain, such a replacement would be considered cost‐effective. The one‐way and probabilistic sensitivity analyses demonstrated stability of the base‐case ICER. Conclusion PBT, as a replacement for conventional photon radiotherapy, is cost‐effective and justifiable as an efficient use of finite healthcare resources. Making it a standard treatment option and available to every patient in Japan is socially acceptable from the perspective of health economics.

Abstract Aim Hepatocellular carcinoma (HCC) with bile duct invasion (BDI) (BDIHCC) has a poor prognosis. Moreover, due to the paucity of reports, there is no consensus regarding optimal management of this clinical condition yet. The aim of this study was to clarify the efficacy and safety of proton beam therapy (PBT) for BDIHCC. Methods Between 2009 and 2018, 15 patients with BDIHCC underwent PBT at our institution. The overall survival (OS), local control (LC), and progression-free survival (PFS) curves were constructed using the Kaplan-Meier method. Toxicities were assessed using the Common Terminology Criteria of Adverse Events version 4.0. Results The median follow-up time was 23.4 months (range, 7.9–54.3). The median age was 71 years (range, 58–90 years). Many patients were Child A (n = 8, 53.3%) and most had solitary tumors (n = 11, 73.3%). Additionally, most patients had central type BDI (n = 11, 73%). The median tumor size was 4.0 cm (range, 1.5–8.0 cm). The 1-, 2-, and 3-year OS rates were 80.0%, 58.7% and 40.2%, respectively, and the corresponding LC and PFS rates were 93.3%, 93.3%, and 74.7% and 72.7%, 9.7%, and 0.0%, respectively. Acute grade 1/2 dermatitis (n = 7, 46.7%), and grades 2 (n = 1, 6.7%) and 3 (n = 1, 6.7%) cholangitis were observed. Late toxicities such as grade 3 gastric hemorrhage and pleural effusion were observed. No toxicities of grade 4 or higher were observed. Conclusions PBT was feasible with tolerable toxicities for the treatment of BDIHCC.

Abstract Introduction To confirm the feasibility of hypofractionated proton beam therapy (PBT), we compared the acute adverse event rates and International Prostate Symptom Score (IPSS) in prostate cancer patients treated with hypofractionated versus conventionally fractionated (2.0 Gy relative biological effectiveness (RBE)/fraction) PBT. Methods We reviewed 289 patients with prostate cancer, of whom 73, 100, and 116 patients were treated with 2.0, 2.5, and 3.0 Gy (RBE)/fraction, respectively. The endpoints were acute genitourinary and gastrointestinal toxicities and the IPSS, evaluated up to 6 months after PBT initiation. Results No significant differences were found in acute toxicity rates or the IPSS among the fractionation schedules. Diabetes mellitus, age, and androgen deprivation therapy were not identified as factors associated with the IPSS. Conclusion There were no significant differences in adverse events or quality of life among the three fractionation schedules early after PBT.

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

Objectives: To estimate appropriate dose-volume parameters for avoidance of pneumonitis in use of chemoradiotherapy and durvalumab for treatment of lung cancer. Materials and methods: Patients with non-small cell lung cancer treated with concurrent chemoradiotherapy followed by durvalumab at 9 centers were enrolled in the study. Three-dimensional radiotherapy, intensity modulated radiotherapy, and proton beam therapy were used. The frequency and severity of pneumonitis and the dose-volume relationship for normal lung were evaluated. Univariable and multivariable analyses were conducted to identify risk factors. A covariate adjusted hazard ratio was then estimated for the percentages of normal lung volume irradiated at ≥ X Gy (Vx) (X = 5–40) and lung volume non-irradiated at ≥ X Gy (X = 5–40), with the covariates selected in the variable selection. Cumulative incidence functions and covariate adjusted hazard ratios were also estimated for dichotomized variables, with estimated cut-off points. Results: A total of 91 patients were enrolled in the study. The median time from the start of radiotherapy to development of pneumonitis was 4.1 months. Pneumonitis was observed in 80 patients (88%), including grade 2 or severe pneumonitis in 31 (34%) and ≥ grade 3 pneumonitis in 11 (12%). Pneumonitis was inside the irradiation field in 73 of the 80 patients (91%). The selected factors for ≥ grade 2 pneumonitis were V20, and primary site (upper lobe) in multivariable analysis. The cut off value of V20 was 18.99%, and there was a significant difference between V20 of

Light flash and odor during radiation therapy are well-known phenomena, but the details are poorly understood, particularly in pediatric patients. Therefore, we conducted a prospective observational study of these events in pediatric patients (age ≤20 years old) who received radiotherapy at our center from January 2019 to November 2021. Light flash and odor were evaluated using a patient-reported checklist including the presence, strength, and duration of the phenomenon, and color of light or type of odor. 53 patients who received proton therapy (n=47) and photon radiotherapy (n=6) were enrolled in this study. The median age of the patients was 10, ranged from 5 to 20. The patients who was able to see the light flash was 4, and all of them received retina irradiation. This was equivalent to 57% of the patients who received radiotherapy to retina (n=7). The light was bright and colored mainly blue and purple, which seemed to be consistent with Cherenkov light. Odor was sensed by 9 (17%) patients, and seven patients of the 9 received nasal cavity irradiation. This was equivalent to 41% of the patients who received nasal cavity irradiation (n=17). Other 2 patients received proton therapy to brain tumor. The odors were mainly described as plastic, burnt and disinfectant, which may be caused by ozone generated during irradiation. These data suggest that pediatric patients with retinal and nasal cavity irradiation frequently sense light flashes or odor. So adequate care is necessary so that these patients are not worried about this phenomenon.

Abstract Background Screening and management of venous thromboembolism (VTE) after surgery is important in preventing sublethal VTE. However, the risk factors for VTE during interstitial brachytherapy (ISBT) remain unknown, and appropriate screening and management strategies are yet to be established. Therefore, this study aimed to evaluate the risk factors for VTE resulting from requisite bed rest during ISBT for gynecologic cancers. Methods We retrospectively analyzed 47 patients. For patients without definitive preceding radiotherapy, whole pelvic irradiation (30–50 Gy) followed by ISBT of 12–30 Gy/2–5 fx/1–3 days was administered to CTV D90. For patients with preceding radiotherapy, 36–42 Gy/6–7 fx/3–4 days was delivered by ISBT alone. The supine position was required during ISBT. D-dimer (DD) was measured at initial presentation, 1 week before ISBT, pre-ISBT, on the day of, and the day following needle removal. Patients were divided into three groups according to the risk of VTE and were managed accordingly; Group 1: DD was not detected (negative) before ISBT, Group 2: VTE was not detected on venous ultrasound imaging, although DD was positive before ISBT, and Group 3: VTE was detected (positive) before ISBT. An intermittent pneumatic compression device was used during ISBT; for the patients without VTE before ISBT. Heparin or oral anticoagulants were administered to patients with VTE before ISBT. Results Overall, the median values of DD pre-ISBT, on the day of, and on the day following needle removal were 1.0 (0.4–5.8), 1.1 (0.5–88.9), and 1.5 (0.7–40.6) μg/mL, respectively. After ISBT, no patients had deep vein thrombosis (DVT) in groups 1 and 2. In group 3, 7 of 14 patients experienced worsening of VTE but remained asymptomatic. In univariate analysis, DVT diagnosed before ISBT, Caprini score ≥ 7, and difference in DD values between pre-ISBT and the day of or the day following needle removal ≥ 1 were associated with the incidence or worsening of VTE. Conclusion DD should be measured before and after ISBT to detect the incidence or worsening of VTE in patients with DVT. The Caprini score may help in the prediction of VTE during or after ISBT.

Background: This study aimed to evaluate the clinical outcomes and dose-volume parameters of computed tomography CT-based brachytherapy for the vaginal recurrence of uterine cancer after hysterectomy. Methods: We evaluated 22 uterine cancer patients treated with CT-based brachytherapy for vaginal recurrence between December 2010 and August 2015. Interstitial brachytherapy (ISBT) was used when the vaginal tumor was thicker than 5 mm and/or located at extended extravaginal tissue, whereas intercavitary brachytherapy was performed if it was 5 mm or thinner. Results: Overall, 11 patients had cervical cancer, and 11 had endometrial cancer. The median pretreatment tumor size on magnetic resonance imaging was 17 mm (range, 0–45 mm). Four patients had vaginal recurrence recognized only in the gynecological examination. The primary location of recurrence was the vagina, with extravaginal extension observed in 9 patients. Seventeen patients (77%) received external beam radiotherapy and brachytherapy. ISBT was performed in 12 patients (55%). The median clinical target volume (CTV) D90 was 69.2 Gy (62.6–72.8 Gy). The median D2cc of the bladder, sigmoid, and rectum were 70.2 (63.8–77.6), 37.4 (30.0–43.6), and 52.8 Gy (38.6–63.5 Gy), respectively. Complete response was reached in all patients. The 5-year overall survival rate and local control rate (LC) were 84.8 and 95.5%, respectively. No patient experienced grade ≥3 complications. Conclusions: CT-based brachytherapy has the potential to become an essential treatment for vaginal recurrences of uterine cancer after hysterectomy as it can achieve good LC without increasing the rate of late complications for selected patients with less recurrences.

Abstract Background To evaluate the long‐term outcomes of high‐dose (74 GyE) proton beam therapy (PBT) with concurrent chemotherapy for stage III non‐small cell lung cancer (NSCLC). Methods Between July 2007 and March 2018, 45 patients with stage III NSCLC were treated with passive‐scattering PBT of 74 GyE and concurrent chemotherapy. Among the 45 patients, the median age was 62 years (range 39–79 years) and 32 patients were men. The clinical stages were stage IIIA in 14 patients and stage IIIB in 31 patients. Thirty‐six patients received chemotherapy consisting of cisplatin and vinorelbine. Results The median follow‐up time was 42.1 months (range 6.4–127.0 months) for all patients and 63.5 months (range 9.4–127.0 months) for the 12 survivors. The 3‐ and 5‐year overall survival rates were 63.7% and 38.8%, respectively, and the median overall survival was 49.1 months. Over the follow‐up period, disease recurrence was observed in 32 (71%) patients. The 3‐ and 5‐year progression‐free survival rates were 22.2% and 17.7%, respectively, with a median progression‐free survival of 13.1 months. In‐field control improved survival and the in‐field control rate was better in patients with T0–3 tumors (p = 0.023) and stage IIIA/IIIB‐N3 disease (p = 0.030). Dosimetric parameters of the heart and lung were not associated with survival. No grade 4 or 5 acute or late non‐hematologic toxicities were observed. Conclusions Passive‐scattering PBT of 74 GyE with chemotherapy showed favorable survival and a low incidence of severe adverse events in patients with stage III NSCLC.

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.

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.

Introduction: Proton beam therapy (PBT) is known to be an effective locoregional treatment for hepatocellular carcinoma (HCC). However, few comparative studies in treatment-naïve cases have been reported. The aim of this study was to compare the survival outcomes of PBT with those of radiofrequency ablation (RFA) in patients with treatment-naïve solitary HCC. Methods: Ninety-five consecutive patients with treatment-naïve HCC, a single nodule measuring ≤5 cm in diameter, and a Child-Pugh score of ≤8 who were treated with PBT at the University of Tsukuba Hospital between 2001 and 2013 were enrolled in the study. In addition, 836 patients with treatment-naïve HCC treated by RFA at the University of Tokyo Hospital during the same period were analyzed as controls. Recurrence-free survival (RFS) and overall survival (OS) were compared in 83 patient pairs after propensity score matching. Results: The 1-year, 3-year, and 5-year RFS rates were 86.6%, 49.5%, and 35.5%, respectively, in the PBT group and 59.5%, 34.0%, and 20.9% in the RFA group (p = 0.058); the respective OS rates were 97.6%, 77.8%, and 57.1% in the PBT group and 95.1%, 81.7%, and 67.7% in the RFA group (p = 0.16). Regarding adverse effects, no grade 3 or higher adverse events were noted in the PBT; however, two grade 3 adverse events occurred within 30 days of RFA in the RFA group, one hemoperitoneum and one hemothorax.. Discussion/Conclusion: After propensity score matching, PBT showed no significant difference in RFS and OS compared to RFA. PBT can be an alternative for patients with solitary treatment-naïve HCC.

Abstract Background The effectiveness of proton beam therapy (PBT) as initial treatment for patients with unresectable intrahepatic cholangiocarcinoma (ICC) is unclear, particularly as related to ICC histological subtypes. We performed this study to address this gap in knowledge. Methods Thirty-seven patients with unresectable ICC who underwent PBT as their initial treatment were evaluated. Twenty-seven patients had Child-Pugh class A liver function, 11 exhibited jaundice, and 10 had multiple tumors. Nineteen, 7, and 11 tumors were classified as mass forming (MF), periductal infiltrating (PI), and intraductal growth (IG) types, respectively, based on gross appearance in imaging studies. Patients were classified into the curative group (n = 25) and palliative group (n = 12) depending on whether the planning target volume covered all the macroscopic tumors. Results The 1- and 2-year overall survival rates were 60.3, and 41.4%, respectively; the median survival time (MST) was 15 months for all patients. The MSTs for curative and palliative groups were 25 and 7 months, respectively. Curative treatment and adjuvant chemotherapy significantly improved overall survival, while the presence of periductal infiltrating type tumors was a negative prognostic factor. In the curative group, the 1- and 2-year local control rates were 100 and 71.5%, respectively, while the 1-, and 2-year progression-free survival rates were 58.5, and 37.6%, respectively. No severe acute toxicities were observed. Three patients experienced grade 3 biliary tract infection, although it was unclear whether this was radiotherapy-related. Conclusion PBT may yield to improve survival and local tumor control among patients with unresectable ICC.

A limited window of receptivity is a prerequisite of reproductive success. Indispensable receptivity genes include cyclooxygenase 2 (COX2), an enzyme accomplishing formation of prostaglandin E2 (PGE2). A powerful regulator of PGE2 formation is Annexin A7 (ANXA7). The present study thus explored whether ANXA7 impacts on implantation and fertility. Here we show that ANXA7 is expressed in endometrial tissue and increases upon decidual transformation of human endometrial stromal cells (HESCs) in a time-dependent manner. Silencing ANXA7 significantly decreased the expression of PRL and IGFBP1, canonical decidual marker genes, but enhances COX2 and PGE2 levels. Genetic knockout of AnxA7 in mice significantly increases the number of implantation sites and litter sizes. Further, analysis of human endometrial biopsies showed that ANXA7 transcript and protein levels are decreased during the midluteal window of implantation in women suffering from recurrent pregnancy loss (RPL) when compared to subfertile patients. Taken together, the data indicate that ANXA7 has a conserved role in regulating endometrial receptivity and implantation.

LEFTY2 (endometrial bleeding associated factor; EBAF or LEFTYA), a cytokine released shortly before menstrual bleeding, is a negative regulator of cell proliferation and tumour growth. LEFTY2 down-regulates Na+/H+ exchanger activity with subsequent inhibition of glycolytic flux and lactate production in endometrial cancer cells. Glucose can be utilized not only for glycolysis but also for glycogen formation. Both glycolysis and glycogen formation require cellular glucose uptake which could be accomplished by the Na+ coupled glucose transporter-1 (SGLT1; SLC5A1). The present study therefore explored whether LEFTY2 modifies endometrial SGLT1 expression and activity as well as glycogen formation. Ishikawa and HEC1a cells were exposed to LEFTY2, SGLT1 and glycogen synthase (GYS1) transcript levels determined by qRT-PCR. SGLT1, GYS1 and phospho-GYS1 protein abundance was quantified by western blotting, cellular glucose uptake from 2-(N-(7-Nitrobenz-2-oxa-1,3-diazol-4-yl)Amino)-2-Deoxyglucose (2-NBDG) uptake, and cellular glycogen content utilizing an enzymatic assay and subsequent colorimetry. As a result, a 48-hour treatment with LEFTY2 significantly increased SGLT1 and GYS1 transcript levels as well as SGLT1 and GYS1 protein abundance in both Ishikawa and HEC1a cells. 2-NBDG uptake and cellular glycogen content were upregulated significantly in Ishikawa (type 1) but not in type 2 endometrial HEC1a cells, although there was a tendency of increased 2-NBDG uptake. Further, none of the effects were seen in human benign endometrial cells (HESCs). Interestingly, in both Ishikawa and HEC1a cells, a co-treatment with TGF-β reduced SGLT1, GYS and phospho-GYS protein levels, and thus reduced glycogen levels and again HEC1a cells had no significant change. In conclusion, LEFTY2 up-regulates expression and activity of the Na+ coupled glucose transporter SGLT1 and glycogen synthase GYS1 in a cell line specific manner. We further show the treatment with LEFTY2 fosters cellular glucose uptake and glycogen formation and TGF-β can negate this effect in endometrial cancer cells.

Abstract Background The mortality rate of ovarian cancer is the highest among all gynecological malignancies in Japan. Ovarian tumors are classified as benign, borderline malignant, or malignant. Anticipating the histological subtype with imaging only is often difficult because of several histological subtypes of epithelial ovarian tumors (such as serous, mucinous, endometrioid, clear cell, and Brenner tumors). In addition, the majority of mucinous tumors in the ovary are metastatic. Furthermore, mucinous tumors belong to one of the two different subclasses (i.e., intestinal and seromucinous types). Ovarian seromucinous cystic tumors of borderline malignancy are infrequent and only rarely coexist with other malignant tumors. Case presentation We have reported a 53-year-old Japanese woman with anaplastic carcinoma in an ovarian seromucinous cystic tumor of borderline malignancy. Her MRI and CT analysis revealed an ovarian tumor with a mural nodule, ascites, and peritoneal dissemination. Enhanced MRI revealed that the mural nodule was enhanced. Enhanced CT analysis revealed that the lymph nodes were not swollen. Intriguingly, the mural nodule crossed the cyst wall into the cavity and onto the surface. Her laboratory data revealed high serum CA 125 level. Cumulatively, these results suggested ovarian malignancy. The patient underwent hysterectomy with bilateral salpingo-oophorectomy, omentectomy, and resection of the disseminated lesions. Lymph node biopsy was omitted because of the suggestion of enhanced CT image findings and palpation during surgery. Her postoperative specimen examination determined FIGO at least stage IIIB, and accordingly, adjuvant chemotherapy was prescribed. After 3 years of the operation, the patient is presently alive without clinical tumor recurrences. Conclusion Imaging studies with pathognomonic findings contributed to ovarian cancer diagnosis in this case. To the best of our knowledge, this is the first study in English literature to report detailed classification of mucinous borderline malignancy, seromucinous cystic, and anaplastic carcinoma in an ovarian seromucinous cystic tumor of borderline malignancy.

Abstract To evaluate preliminary results of proton radiotherapy (PRT) for pediatric patients with rhabdomyosarcoma (RMS). From 1987 to 2014, PRT was conducted as initial radiotherapy in 55 patients (35 males, 20 females, median age 5 years, range 0–19) with RMS at four institutes in Japan. Thirty‐one, 18, and six patients had embryonal, alveolar, and other RMS, respectively. One, 11, 37, and six patients were in IRSG groups I, II, III, and IV, respectively, and the COG risk group was low, intermediate, and high for nine, 39, and seven patients, respectively. The irradiation dose was 36–60 GyE (median: 50.4 GyE). The median follow‐up period was 24.5 months (range: 1.5–320.3). The 1‐ and 2‐year overall survival rates were 91.9% (95% CI: 84.3–99.5%) and 84.8% (95% CI 75.2–94.3%), respectively, and these rates were 100% and 100%, 97.1% and 90.1%, and 57.1% and 42.9% for COG low‐, intermediate‐, and high‐risk groups, respectively. There were 153 adverse events of Grade ≥3, including 141 hematologic toxicities in 48 patients (87%) and 12 radiation‐induced toxicities in nine patients (16%). Proton‐specific toxicity was not observed. PRT has the same treatment effect as photon radiotherapy with tolerable acute radiation‐induced toxicity.

Abstract Background Understanding the irradiated area and dose correctly is important for the reirradiation of organs that deform after irradiation, such as the liver. We investigated the spatial registration error using the deformable image registration (DIR) software products MIM Maestro (MIM) and Velocity AI (Velocity). Methods Image registration of pretreatment computed tomography (CT) and posttreatment CT was performed in 24 patients with liver tumors. All the patients received proton beam therapy, and the follow-up period was 4–14 (median: 10) months. We performed DIR of the pretreatment CT and compared it with that of the posttreatment CT by calculating the dislocation of metallic markers (implanted close to the tumors). Results The fiducial registration error was comparable in both products: 0.4–32.9 (9.3 ± 9.9) mm for MIM and 0.5–38.6 (11.0 ± 10.0) mm for Velocity, and correlated with the tumor diameter for MIM (r = 0.69, P = 0.002) and for Velocity (r = 0.68, P = 0.0003). Regarding the enhancement effect, the fiducial registration error was 1.0–24.9 (7.4 ± 7.7) mm for MIM and 0.3–29.6 (8.9 ± 7.2) mm for Velocity, which is shorter than that of plain CT (P = 0.04, for both). Conclusions The DIR performance of both MIM and Velocity is comparable with regard to the liver. The fiducial registration error of DIR depends on the tumor diameter. Furthermore, contrast-enhanced CT improves the accuracy of both MIM and Velocity. Institutional review board approval H28-102; July 14, 2016 approved.

An international group of 22 liver cancer experts from 18 institutions met in Miami, Florida to discuss the optimal utilization of proton beam therapy (PBT) for primary and metastatic liver cancer. There was consensus that PBT may be preferred for liver cancer patients expected to have a suboptimal therapeutic ratio from XRT, but that PBT should not be preferred for all patients. Various clinical scenarios demonstrating appropriateness of PBT vs. XRT were reviewed.

Surgical resection is the first choice for treatment of a thymic carcinoid tumor and radiotherapy is often performed as adjuvant therapy. Here, we report a case of an unresectable and chemoresistant thymic carcinoid tumor that was treated successfully using standalone proton beam therapy (PBT). The patient was a 66-year-old woman in whom surgical resection of the tumor was impossible because of cardiac invasion. Therefore, chemotherapy was administered. However, the tumor grew to 15 cm in diameter and she developed severe superior vena cava (SVC) syndrome. She was referred to our hospital and received PBT at a dose of 74 GyE in 37 fractions. PBT was conducted without severe early toxicities. After PBT, the tumor mildly shrunk to 13 cm in diameter and SVC syndrome almost disappeared. Subsequently, the tumor has continued to decrease in size slowly over the last 2 years and late toxicities have not been observed. Our experience with this case suggests that PBT may be effective for an unresectable thymic carcinoid tumor.

Androgen receptor is a primary transcription factor involved in the proliferation of prostate cancer cells. Thus, hormone therapy using antiandrogens, such as bicalutamide, is a first-line treatment for the disease. Although hormone therapy initially reduces the tumor burden, many patients eventually relapse, developing tumors with acquired endocrine resistance. Elucidation of the molecular mechanisms underlying endocrine resistance is therefore a fundamental issue for the understanding and development of alternative therapeutics for advanced prostate cancer. In the present study, we performed short hairpin RNA (shRNA)-mediated functional screening to identify genes involved in bicalutamide-mediated effects on LNCaP prostate cancer cells. Among such candidate genes selected by screening using volcano plot analysis, ribosomal protein L31 (RPL31) was found to be essential for cell proliferation and cell-cycle progression in bicalutamide-resistant LNCaP (BicR) cells, based on small interfering RNA (siRNA)-mediated knockdown experiments. Of note, RPL31 mRNA is more abundantly expressed in BicR cells than in parental LNCaP cells, and clinical data from ONCOMINE and The Cancer Genome Altas showed that RPL31 is overexpressed in prostate carcinomas compared with benign prostate tissues. Intriguingly, protein levels of the tumor suppressor p53 and its targets, p21 and MDM2, were increased in LNCaP and BicR cells treated with RPL31 siRNA. We observed decreased degradation of p53 protein after RPL31 knockdown. Moreover, the suppression of growth and cell cycle upon RPL31 knockdown was partially recovered with p53 siRNA treatment. These results suggest that RPL31 is involved in bicalutamide-resistant growth of prostate cancer cells. The shRNA-mediated functional screen in this study provides new insight into the molecular mechanisms and therapeutic targets of advanced prostate cancer.

Background/Aim: Radiotherapy is a salvage therapy type for postoperative recurrence of esophageal cancer. Compared to conventional photon-based radiotherapy, proton beam therapy can reduce the irradiated dose to the surrounding organs, facilitating the management of patients who are unfit for radiotherapy. In this study, the outcomes and toxicity of proton beam therapy for postoperative lymph node oligorecurrence of esophageal cancer were investigated. Patients and Methods: We retrospectively evaluated the clinical outcomes and toxicity of 13 sites in 11 patients treated with proton beam therapy for postoperative lymph node oligorecurrence of esophageal cancer. In total, eight men and three women with a median age of 68 years (range=46-83 years) were included. Results: The median follow-up period was 20.2 months. During the follow-up period, four patients died of esophageal cancer. Eight of the 11 patients developed recurrence; of these, seven patients had recurrence outside the irradiated field, and one had recurrence inside and outside the irradiated field. The 2-year overall survival, progression-free survival, and local control rates were 48.0%, 27.3%, and 84.6%, respectively. The median survival time was 22.4 months. There were no severe acute or late adverse events. Conclusion: Proton beam therapy could be a safe and effective treatment method for postoperative lymph node oligorecurrence of esophageal cancer. It may be beneficial even in cases where conventional photon-based radiotherapy is difficult to administer in combination with increased doses or with chemotherapy. [ABSTRACT FROM AUTHOR]

Objective: Rare disease. Background: Vaginal wall hemangiomas are extremely rare, benign, vascular tumors of the female genitalia. Most cases occur in childhood, but a few cases can be acquired; however, the mechanism of hemangioma formation remains unknown. Most hemangiomas involving female genital organs are small and asymptomatic. However, huge hemangiomas can cause irregular genital bleeding, infertility, and miscarriage. Surgical excision and embolization are the most common treatment options. We reveal that sclerotherapy achieved good outcomes in a patient with an intractable huge vaginal wall hemangioma. Case Report: A 71-year-old woman visited a local doctor with concerns of frequent urination. A ring pessary was inserted after a diagnosis of pelvic organ prolapse. However, symptoms did not improve, and the patient consulted another hospital. The previous physician diagnosed vaginal wall tumors and prolapse and performed a colporrhaphy. However, she was referred to our hospital with heavy intraoperative bleeding. Imaging examination revealed a huge hemangioma on the vaginal wall, which was histologically diagnosed as a cavernous hemangioma. Angiography revealed hemorrhage in the right peripheral vaginal artery. Owing to concerns regarding extensive vaginal wall necrosis caused by arterial embolization, sclerotherapy using monoethanolamine oleate was selected. Hemostasis was achieved 1 month after sclerotherapy, and postoperative imaging showed the lesion had shrunk in size. No recurrence of hemangioma was observed 19 months after surgery. Conclusions: We report a case of a large vaginal wall intractable bleeding hemangioma. Sclerotherapy can be a suitable treatment option for large vaginal hemangiomas that are too extensive to be treated using surgery or arterial embolization. [ABSTRACT FROM AUTHOR]

Background/Aim: To evaluate the outcome of definitive salvage radiotherapy (RT) in non-small cell lung cancer (NSCLC) patients with oligo-recurrence in regional lymph nodes after surgery. Patients and Methods: Between January 2003 and December 2016, 33 patients with NSCLC were reviewed from radiotherapy database at our hospital. All patients received photon or proton salvage RT for metastases in the regional lymph nodes. Results: The median follow-up from salvage RT was 35.2 (range=5.9-89.6) months. Recurrences occurred in 18 (55%) patients, and the 3-year overall and progression-free survival rates were 63.8% and 45.1%, respectively. Regional and local control improved patients’ survival and these control rates were increased by use of concurrent chemotherapy (p=0.039) and proton RT (p=0.084). No grade 4 acute or late nonhematologic toxicities were observed. Conclusion: Salvage RT is an effective treatment for NSCLC patients with oligorecurrence at regional lymph nodes. [ABSTRACT FROM AUTHOR]

Endocrine therapy using antiestrogens and aromatase inhibitors is usually efficient to treat patients with hormone-sensitive breast cancer. Many patients with endocrine therapy, however, often acquire resistance. In the present study, we performed functional screening using short hairpin RNA library to dissect genes involved in antiestrogen tamoxifen resistance in MCF-7 breast cancer cells. We identified seven candidate genes that are associated with poor prognosis of breast cancer patients based on clinical dataset. The expression levels of six out of seven genes were higher in 4-hydroxytamoxifen (OHT) resistant MCF-7 (OHTR) cells compared with parental MCF-7 cells. Among the six selected genes, siRNA-mediated knockdown of PSMD1 and TSPAN12 markedly reduced the proliferation of OHTR cells. Notably, the knockdown of proteasome 26S subunit PSMD1 exhibited cell cycle arrest and the accumulation of p53 protein through inhibiting p53 protein degradation. In accordance with p53 accumulation, its target genes p21 and SFN were also upregulated by PSMD1 silencing. Taken together, PSMD1 was identified as a potential gene that plays a role in the development of tamoxifen resistance in breast cancer cells. These findings will provide a new insight for the mechanism underlying endocrine therapy resistance and a prognostic and therapeutic molecular target for advanced breast cancer. [ABSTRACT FROM AUTHOR]

The efficacy and safety of proton beam therapy (PBT) were retrospectively evaluated in 111 consecutive patients with prostate cancer who underwent definitive PBT between 2008 and 2012. Following exclusion of 18 patients due to treatment suspension, loss to follow-up, and histology, the analysis included 93 patients with a median age of 68 years (range, 49-81 years). A total of 7, 32 and 54 prostate cancer patients were classified as low-, intermediate- and high-risk, respectively, as follows: High-risk, T≥3a or prostate-specific antigen (PSA) ≥20 ng/ml or Gleason Score ≥8; low-risk, T =2b and PSA≤10 ng/ml and Gleason Score=6; intermediate-risk, all other combinations. The median initial prostate-specific antigen (PSA) level was 9.75 ng/ml (range, 1.4-100 ng/ml) and the median Gleason score was 7 (range, 6-10). Patients with low-risk disease received 74 GyE (relative biological effectiveness= 1.1) in 37 fractions, and those at intermediate or higher risk received 78 GyE in 39 fractions. Complete androgen blockade (CAB) therapy was performed from 6 months prior to PBT for patients with intermediate- or high-risk disease. CAB was continued during PBT and then terminated at the end of PBT for intermediate-risk patients. Patients at high risk continued CAB for 3 years. No combination therapy was used for low-risk patients. All the patients were followed up for >2 years after PBT, and all but one were PSA failure-free. The Common Terminology Criteria for Adverse Events v.4.0 was used to evaluate late adverse events. One patient developed grade 3 non-infectious cystitis and hematuria. Grade 2 urinary frequency was observed in 1 patient, and grade 2 rectal bleeding occurred in 4 patients. Of the 4 patients with grade 2 rectal bleeding, 2 received anticoagulant therapy, but none had diabetes mellitus or another high-risk comorbidity. The median time to occurrence of an adverse event of grade ≥2 was 14 months (range, 3-41 months). Therefore, the present retrospective study revealed that PBT at 78 GyE/39 Fr was well-tolerated and achieved good tumor control in patients with prostate cancer. [ABSTRACT FROM AUTHOR]

Liver metastasis from breast cancer (LMBC) is an incurable, fatal disease with a very poor prognosis. Although various local treatments have been applied, their clinical utility has not been established. The purpose of this study was to investigate the safety and effectiveness of proton beam therapy (PBT) for the treatment of patients with LMGC. A total of 8 female patients (aged 38-63 years) with LMBC who received PBT between 2002 and 2012 were retrospectively reviewed. Patients who had tumors confined to the liver were investigated, whereas patients with extrahepatic tumors were excluded. A total of 5 patients had solitary tumors and 3 had multiple tumors. The total irradiation dose was 66-72.6 Gray equivalent [Gy relative biological effectiveness (RBE)] and 2 patients received concurrent chemotherapy or hormone therapy. The overall and progression-free survival (OS and PFS) rates, local control (LC) rate and adverse effects were investigated. All the patients completed treatment without interruption and late adverse effects of grade >3 were not observed. The OS rate was 88/73/58%, the PFS rate was 50/25/0% and the LC rate was 86/86/86% at 1/3/5 years, respectively. Thus, PBT is a safe treatment and the OS and PFS rates are comparable to those with other local treatments. PBT may be considered as an effective local treatment option for the treatment of LMBC patients. [ABSTRACT FROM AUTHOR]

Introduction: It was reported that proton beam therapy (PBT) reduced the normal brain dose compared with X-ray therapy for pediatric brain tumors. We considered whether there was not the condition that PBT was more disadvantageous than intensity modulated photon radiotherapy (IMRT) and 3D conventional radiotherapy (3D-CRT) for treatment of pediatric brain tumors about the dose reduction for the normal brain when the tumor location or tumor size were different.Methods: The subjects were 12 patients treated with PBT at our institute, including 6 cases of ependymoma treated by local irradiation and 6 cases of germinoma treated by irradiation of all four cerebral ventricles. IMRT and 3D-CRT treatment plans were made for these 12 cases, with optimization using the same planning conditions as those for PBT. Model cases were also compared using sphere targets with different diameters or locations in the brain, and the normal brain doses with PBT, IMRT and 3D-CRT were compared using the same planning conditions.Results: PBT significantly reduced the average dose to normal brain tissue compared to 3D-CRT and IMRT in all cases. There was no difference between 3D-CRT and IMRT. The average normal brain doses for PBT, 3D-CRT, and IMRT were 5.1-34.8% (median 14.9%), 11.0-48.5% (23.8%), and 11.5-53.1% (23.5%), respectively, in ependymoma cases; and 42.3-61.2% (48.9%), 54.5-74.0% (62.8%), and 56.3-72.1% (61.2%), respectively, in germinoma cases. In the model cases, PBT significantly reduced the average normal brain dose for larger tumors and for tumors located at the periphery of the brain.Conclusion: PBT reduces the average dose to normal brain tissue, compared with 3D-CRT and IMRT. The effect is higher for a tumor that is larger or located laterally. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the hyperfractionated high-dose proton beam therapy (PBT) for patients with clival chordomas. Methods: Records for 19 patients with pathologically verified clival chordomas treated with surgery followed by hyperfractionated PBT were retrospectively reviewed. The first 9 consecutive patients were treated with 77.44 cobalt gray equivalents (CGEs) in 64 fractions, and the latter 10 patients were treated with 78.4 CGE in 56 fractions. Results: The median follow-up period of all 19 cases was 61.7 months with a range from 31.5 to 115.4 months. At 5 years, the local control, cause-specific and overall survival rates for all 19 cases were 75%, 94% and 83.2%, respectively. Whereas the 5-year local control, cause-specific and over all survival rates of the latter 10 cases were 100%, 100% and 88.9%, respectively, with a median follow-up period of 59.5 months. One of the first nine patients demonstrated bilateral temporal lobe radiation necrosis, who were successfully treated conservatively. In the latter cohort, two cases showed transient neurological symptoms probably due to brain stem ischaemia, but both cases recovered completely with conservative treatment. Conclusion: The hyperfractionated high-dose scheme combined with maximum surgical removal was shown to be efficient for patients with clival chordomas. Advances in knowledge: High-dose proton beam radiotherapy using a hyperfractionation scheme yielded a more favourable outcome than previous reports. [ABSTRACT FROM AUTHOR]

The present study reports treatment outcomes of locally advanced and unresectable squamous cell carcinoma of the ethmoid sinus (SCC-ES) following proton beam therapy (PBT). Between January 1997 and December 2012, 7 patients (median age, 63 years) with SCC-ES underwent definitive PBT. All tumors were categorized as T4bN0M0 (2009 UICC tumor-node-metastasis classification) and were treated using conventional fractionation at a median total dose of 72 Gy equivalents (GyE; range, 70.4-76 GyE). Imaging diagnosis for the initial treatment effect within 3 months of PBT revealed that a complete response (CR) was achieved in 2 patients and a partial response (PR) in 5 patients. The overall median survival time of the patients was 43 months (range, 12-62 months), and 4 patients survived for ≥3 years. No recurrence was observed in the 2 patients who exhibited an initial CR treatment effect; however, locoregional recurrences occurred in 4/5 patients who exhibited a PR. No grade 3 or severe acute toxicities were observed, but the late toxicities of grade 3 contralateral optic nerve damage and cataracts developed in 1 and 2 patients, respectively. Based on the findings of the present study, intensification of the local treatment effect may be important for yielding favorable treatment outcomes, since no distant metastasis was observed. PBT is therefore a potentially useful treatment tool for unresectable SCC-ES. [ABSTRACT FROM AUTHOR]

Background: Proton-beam radiotherapy (PBT) has been shown to be effective to hepatocellular carcinoma (HCC) as a nonsurgical local treatment option. However, HCC still remains as one of the most difficult cancers to be cured because of frequent recurrences. Thus, methods to inhibit the recurrence need to be explored. To prevent the HCC recurrence, we here report on a prospective phase I study of 'in situ' tumor vaccination using CalTUMP, a newly developed immunoadjuvant consisting of BCG extract bound to hydroxyapatite and microparticulated tuberculin, following local PBT for HCC.Methods: Patients with locally advanced recurrent HCC, which had been heavily pretreated with various treatments, were enrolled. PBT was performed with the conventional method to the target HCC. Subsequently, CalTUMP was injected into the same irradiated-tumor three times at one-week intervals. Three dose-levels of CalTUMP (1/10, 1/3, and 1/1) were administered to 3 patients each. Vital signs, blood samples, ultrasound, and computed tomographic scans were monitored to evaluate the safety.Results: Three intratumoral injections of CalTUMP following PBT (median dose: 72.6 GyE) were accomplished in 9 patients. Transient low-grade fever and minor laboratory changes were observed in 7 patients after CalTUMP injections. No other treatment-related adverse events were observed. Median progression-free survival was 6.0 months (range: 2.1-14.2) and 4 patients were progression-free for more than 1 year.Conclusions: Intratumoral injection of CalTUMP following PBT was feasible and safe in patients with heavily pre-treated HCC. Further clinical studies to evaluate the efficacy of this in situ tumor vaccination are warranted. [ABSTRACT FROM AUTHOR]

Purpose: To evaluate the effectiveness and feasibility of proton therapy for head and neck cancers. Patients and Methods: From 1983 to 2000, 33 patients with head and neck malignancies but no history of surgical resection were treated with 250-MeV protons with or without X-ray irradiation. This study retrospectively evaluated local control, survival, and treatment sequelae of these patients. The median total target dose using protons with or without X-rays was 76 Gy (range: 42?99 Gy) and the median proton dose per fraction 2.8 Gy (range: 1.5?6.0 Gy). Results: Overall 5-year survival and local control rates were 44% and 74%, respectively. One (3%) and six patients (18%) suffered from treatment-related acute and late toxicity > grade 3 (RTOG/EORTC acute and late radiation morbidity scoring criteria). One patient with a history of radiotherapy suffered from acute toxicity > grade 3. Conclusion: Proton therapy appeared to offer high local control rates with few toxicities relative to conventional radiotherapy. However, late toxicity was seen in areas where large radiation doses had been given. [ABSTRACT FROM AUTHOR]