NEAT1 Confers Radioresistance to Hepatocellular Carcinoma Cells by Inducing Autophagy through GABARAP.

A long noncoding RNA (lncRNA), nuclear enriched abundant transcript 1 (NEAT1) variant 1 (NEAT1v1), is involved in the maintenance of cancer stem cells (CSCs) in hepatocellular carcinoma (HCC). CSCs are suggested to play important roles in therapeutic resistance. Therefore, we investigated whether NEAT1v1 is involved in the sensitivity to radiation therapy in HCC. Gene knockdown was performed using short hairpin RNAs, and NEAT1v1-overexpressing HCC cell lines were generated by stable transfection with a NEAT1v1-expressing plasmid DNA. Cells were irradiated using an X-ray generator. We found that NEAT1 knockdown enhanced the radiosensitivity of HCC cell lines and concomitantly inhibited autophagy. NEAT1v1 overexpression enhanced autophagy in the irradiated cells and conferred radioresistance. Gamma-aminobutyric acid receptor-associated protein (GABARAP) expression was downregulated by NEAT1 knockdown, whereas it was upregulated in NEAT1v1-overexpressing cells. Moreover, GABARAP was required for NEAT1v1-induced autophagy and radioresistance as its knockdown significantly inhibited autophagy and sensitized the cells to radiation. Since GABARAP is a crucial protein for the autophagosome-lysosome fusion, our results suggest that NEAT1v1 confers radioresistance to HCC by promoting autophagy through GABARAP.

A phase II study of palliative radiotherapy combined with zoledronic acid hydrate for metastatic bone tumour from renal cell carcinoma.

PURPOSE: Palliative radiotherapy is the standard of care for bone metastases. However, skeletal-related events, defined as a pathologic fracture, paraplegia, surgery or radiotherapy for local recurrence, or severe pain in previously irradiated bone with radio-resistant histology type still present high incidence. The primary objective of this study was to determine whether zoledronic acid hydrate and palliative radiotherapy could prevent local skeletal-related events. METHODS: Eligible patients with bone metastases from renal cell carcinoma were treated with zoledronic acid hydrate every 3 or 4 weeks and concurrent palliative radiotherapy of 30 Gy in 3 Gy fractions. The criteria for radiotherapy were established by the treating physician, but patients with complicated bone metastases (impending pathological fracture or spinal cord compression) which needed immediate surgery were excluded. The primary endpoint was the local skeletal-related event-free survival rate at 1 year. RESULTS: Twenty-seven patients were included in the study. The median age was 65 (range, 50-84) years. Radiotherapy dose was 30 Gy for all patients except 1 whose radiotherapy was terminated due to brain metastasis progression at 18 Gy. Zoledronic acid hydrate was administered in a median of 12 (range, 0-34) times. The median follow-up period was 12 months and 19 months in patients who were still alive. Of 27 patients in the efficacy analysis, the 1-year local skeletal-related event-free rate was 77.6% (80% confidence interval, 66.2-89.0). Common grade 3 toxicities were hypocalcemia (1 [4%]), sGPT level increase (1 [4%]) and sGOT level increase (1 [4%]). There was no grade 4 or 5 toxicity. CONCLUSION: Zoledronic acid hydrate administration and palliative radiotherapy were a well-tolerated and promising treatment reducing skeletal-related events for bone metastases from renal cell carcinoma.

Palliative brachytherapy and external beam radiotherapy for dysphagia from esophageal cancer: a nationwide survey in Japan.

BACKGROUND: International guidelines recommend brachytherapy for patients with dysphagia from esophageal cancer, whereas brachytherapy is infrequently used to palliate dysphagia in some countries. To clarify the availability of palliative treatment for dysphagia from esophageal cancer and explain why brachytherapy is not routinely performed are unknown, this study investigated the use of brachytherapy and external beam radiotherapy for dysphagia from esophageal cancer. METHODS: Japanese Radiation Oncology Study Group members completed a survey and selected the treatment that they would recommend for hypothetical cases of dysphagia from esophageal cancer. RESULTS: Of the 136 invited facilities, 61 completed the survey (44.9%). Four (6.6%) facilities performed brachytherapy of the esophagus, whereas brachytherapy represented the first-line treatment at three (4.9%) facilities. Conversely, external beam radiotherapy alone and chemoradiotherapy were first-line treatments at 61 and 58 (95.1%) facilities, respectively. In facilities that performed brachytherapy, the main reason why brachytherapy of the esophagus was not performed was high invasiveness (30.2%). Definitive-dose chemoradiotherapy with (≥50 Gy) tended to be used in patients with expected long-term survival. CONCLUSIONS: Few facilities routinely considered brachytherapy for the treatment of dysphagia from esophageal cancer in Japan. Conversely, most facilities routinely considered external beam radiotherapy. In the future, it will be necessary to optimize external beam radiotherapy.

Retrospective analysis of definitive radiotherapy for neck node metastasis from unknown primary tumor: Japanese Radiation Oncology Study Group study.

OBJECTIVE: To investigate the optimal treatment method and risk factor of neck node metastasis from unknown primary tumors (NUP) treated by radiotherapy. METHODS: Retrospective case study based on a multi-institutional survey was conducted by the Japanese Radiation Oncology Study Group. Patients pathologically diagnosed as having NUP from 1998 to 2007 were identified. Univariate and multivariate analyses of overall survival (OS), progression free survival (PFS), neck progression free survival (NPFS) and mucosal progression free survival (MPFS) were evaluated. RESULTS: In total, 130 patients with median age of 65 years were included. Nodal stages N1, N2a, N2b and N2c were observed for 10, 26, 43, 12 and 39 patients, respectively. All the patients received radiotherapy (RT) with neck dissection in 60 and with chemotherapy in 67 cases. The median doses to the metastatic nodes, prophylactic neck and prophylactic mucosal sites were 60.0, 50.4 and 50.4 Gy, respectively. The median follow-up period for surviving patients was 42 months. Among 12 patients, occult primary tumors in the neck region developed after radiotherapy. The 5-year OS, PFS, NPFS and MPFS were 58.1%, 42.4%, 47.3% and 54.9%, respectively. Univariate analysis showed that lower N stage (N1-2b), non-bulky node (<6 cm) and negative extracapsular extension (ECE) status were the factors associated with favorable OS, PFS, NPFS and MPFS. Radical surgery proved to be a favorable factor of OS, NPFS and MPFS. On multivariate analysis, lower N stage and negative ECE status were correlated with improved survival. CONCLUSIONS: Lower nodal stage and negative ECE status showed a favorable impact on survival and disease control in patients with NUP treated by radiotherapy.

Usefulness of direct-conversion flat-panel detector system as a quality assurance tool for high-dose-rate 192Ir source.

The routine quality assurance (QA) procedure for a high-dose-rate (HDR) 192Ir radioactive source is an important task to provide appropriate brachytherapy. Traditionally, it has been difficult to obtain good quality images using the 192Ir source due to irradiation from the high-energy gamma rays. However, a direct-conversion flat-panel detector (d-FPD) has made it possible to confirm the localization and configuration of the 192Ir source. The purpose of the present study was to evaluate positional and temporal accuracy of the 192Ir source using a d-FPD system, and the usefulness of d-FPD as a QA tool. As a weekly verification of source positional accuracy test, we obtained 192Ir core imaging by single-shot radiography for three different positions (1300/1400/1500 mm) of a check ruler. To acquire images for measurement of the 192Ir source movement distance with varying interval steps (2.5/5.0/10.0 mm) and temporal accuracy, we used the high-speed image acquisition technique and digital subtraction. For accuracy of the 192Ir source dwell time, sequential images were obtained using various dwell times ranging from 0.5 to 30.0 sec, and the acquired number of image frames was assessed. Analysis of the data was performed using the measurement analysis function of the d-FPD system. Although there were slight weekly variations in source positional accuracy, the measured positional errors were less than 1.0 mm. For source temporal accuracy, the temporal errors were less than 1.0%, and the correlation between acquired frames and programmed time showed excellent linearity (R2 = 1). All 192Ir core images were acquired clearly without image halation, and the data were obtained quantitatively. All data were successfully stored in the picture archiving and communication system (PACS) for time-series analysis. The d-FPD is considered useful as the QA tool for the 192Ir source.

Quality of palliative radiotherapy assessed using quality indicators: a multicenter survey†.

We sought to identify potential evidence-practice gaps in palliative radiotherapy using quality indicators (QIs), previously developed using a modified Delphi method. Seven QIs were used to assess the quality of radiotherapy for bone metastases (BoM) and brain metastases (BrM). Compliance rate was calculated as the percentage of patients for whom recommended medical care was conducted. Random effects models were used to estimate the pooled compliance rates. Of the 39 invited radiation oncologists, 29 (74%) from 29 centers participated in the survey; 13 (45%) were academic and 16 (55%) were non-academic hospitals. For the QIs, except for BoM-4, the pooled compliance rates were higher than 80%; however, for at least some of the centers, the compliance rate was lower than these pooled rates. For BoM-4 regarding steroid use concurrent with radiotherapy for malignant spinal cord compression, the pooled compliance rate was as low as 32%. For BoM-1 regarding the choice of radiation schedule, the compliance rate was higher in academic hospitals than in non-academic hospitals (P = 0.021). For BrM-3 regarding the initiation of radiotherapy without delay, the compliance rate was lower in academic hospitals than in non-academic hospitals (P = 0.016). In conclusion, overall, compliance rates were high; however, for many QIs, practice remains to be improved in at least some centers. Steroids are infrequently used concurrently with radiotherapy for malignant spinal cord compression.

Incidence of and risk factors for non-hematologic toxicity with combined radiotherapy and CDK4/6 inhibitors in metastatic breast cancer using dose-volume parameters analysis: a multicenter cohort study.

BACKGROUND: There is a lack of data on combined radiotherapy (RT) and cyclin-dependent kinase 4 and 6 inhibitor (CDK4/6i) risk factors and toxicity. This study aimed to assess the incidence of and risk factors for non-hematologic toxicities in patients treated with combined RT and CDK4/6i using dose-volume parameter analysis. METHODS: We conducted a retrospective multicenter cohort study of patients with metastatic breast cancer receiving RT within 14 days of CDK4/6i use. The endpoint was non-hematologic toxicities. Patient characteristics and RT treatment planning data were compared between the moderate or higher toxicities (≥ grade 2) group and the non-moderate toxicities group. RESULTS: Sixty patients were included in the study. CDK4/6i was provided at a median daily dose of 125 mg and 200 mg for palbociclib and abemaciclib, respectively. In patients who received concurrent RT and CDK4/6i (N = 29), the median concurrent prescribed duration of CDK4/6i was 14 days. The median delivered RT dose was 30 Gy and 10 fractions. The rate of grade 2 and 3 non-hematologic toxicities was 30% and 2%, respectively. There was no difference in toxicity between concurrent and sequential use of CDK4/6i. The moderate pneumonitis group had a larger lung V20 equivalent dose of 2 Gy per fraction and planning target volume than the non-moderate pneumonitis group. CONCLUSIONS: Moderate toxicities are frequent with combined RT and CDK4/6i. Caution is necessary concerning the combined RT and CDK4/6i. Particularly, reducing the dose to normal organs is necessary for combined RT and CDK4/6i.

Income and Employment of Patients at the Start of and During Follow-up After Palliative Radiation Therapy for Bone Metastasis.

Purpose: The aim of this study was to understand the income and employment status of patients at the start of and during follow-up after palliative radiation therapy for bone metastasis. Methods and Materials: From December 2020 to March 2021, a prospective multi-institutional observational study was conducted to investigate income and employment of patients at the start of administration of radiation therapy for bone metastasis and at 2 and 6 months after treatment. Of 333 patients referred to radiation therapy for bone metastasis, 101 were not registered, mainly because of their poor general condition, and another 8 were excluded from the follow-up analysis owing to ineligibility. Results: In 224 patients analyzed, 108 had retired for reasons unrelated to cancer, 43 had retired for reasons related to cancer, 31 were taking leave, and 2 had lost their jobs at the time of registration. The number of patients who were in the working group was 40 (30 with no change in income and 10 with decreased income) at registration, 35 at 2 months, and 24 at 6 months. Younger patients (P = 0), patients with better performance status (P = 0), patients who were ambulatory (P = .008), and patients with lower scores on a numerical rating scale of pain (P = 0) were significantly more likely to be in the working group at registration. There were 9 patients who experienced improvements in their working status or income at least once in the follow-up after radiation therapy. Conclusions: The majority of patients with bone metastasis were not working at the start of or after radiation therapy, but the number of patients who were working was not negligible. Radiation oncologists should be aware of the working status of patients and provide appropriate support for each patient. The benefit of radiation therapy to support patients continuing their work and returning to work should be investigated further in prospective studies.

Factors associated with quality of life in patients receiving palliative radiotherapy for bone metastases: a secondary cross-sectional analysis of data from a prospective multicenter observational study.

OBJECTIVE: To identify factors significantly associated with quality of life (QOL) and determine if these associations are strong enough to predict certain aspects of QOL without measuring them. METHODS: We conducted an exploratory secondary analysis of baseline data of 224 patients (enrolled between December 2020 and March 2021) from a previously published prospective observational study on radiotherapy for bone metastases at 26 centres. Using univariable linear regression, we assessed the association between patient/treatment factors and QOL scale scores as measured by the European Organization for Research and Treatment of Cancer (EORTC) QOL Questionnaire Core 15-Palliative (QLQ-C15-PAL) and the EORTC QOL Questionnaire Bone Metastases module (QLQ-BM22). RESULTS: Age and sex were not significantly associated with QOL. Worse performance status, higher pain scores, and opioid and single-fraction use were significantly associated with most QOL scales; these four factors were associated with worse global QOL, worse functioning status, and more severe symptoms. The coefficients of determination for most QOL scales were less than 0.2, indicating that most of the variability in QOL scores was not explained by any of the explanatory variables. CONCLUSION: Performance status, pain intensity, and opioid and single-fraction use were significantly associated with most QOL scales. However, the associations were not strong enough to estimate QOL. ADVANCES IN KNOWLEDGE: To date, the association between treatment factors and QOL in patients with bone metastases has not been fully studied. We identified the factors that were significantly associated with QOL and found that these associations were not strong enough to predict QOL.

Design of hemispherical radio frequency (RF) capacitive-type electrode free of edge effects for treatment of intracavitary tumors.

A new hemispherical electrode to heat oral cavity cancer is proposed. The electrode does not produce a hot spot around its edge, a feature that usually arises when using radio frequency (RF) capacitive-type heating. The hemispherical electrode was designed by computer simulation using a 3-D finite element method. To assess its practicality and effectiveness, we built a prototype hemispherical electrode and evaluated its heating characteristics by phantom experiments. The heating effects on the phantom were measured by thermography. The concave phantom surface in contact with the hemispherical electrode showed a uniform increase in temperature, with no obvious edge effect. The proposed electrode allows non-invasive RF capacitive-type heating for intracavity tumors that was not previously considered possible, and should contribute to the multidisciplinary treatment of intracavity tumors.

Practice patterns for postoperative radiation therapy in patients with metastases to the long bones: a survey of the Japanese Radiation Oncology Study Group.

Evidence regarding postoperative radiation therapy (PORT) for metastases to the long bones is lacking. Characterizing the current practice patterns and identifying factors that influence dose-fractionation schedules are essential for future clinical trials. An internet-based survey of the palliative RT subgroup of the Japanese Radiation Oncology Study Group was performed in 2017 to collect data regarding PORT prescription practices and dose-fractionation schedules. Responders were also asked to recommend dose-fractionation schedules for four hypothetical cases that involved a patient with impending pathological fractures and one of four clinical features (poor prognosis, solitary metastasis, radio-resistant primary tumor or expected long-term survival). Responders were asked to indicate their preferred irradiation fields and the reasons for the dose fractionation schedule they chose. Responses were obtained from 89 radiation oncologists (67 institutions and 151 RT plans) who used 22 dose-fractionation schedules, with the most commonly used and recommended schedule being 30 Gy in 10 fractions. Local control was the most common reason for preferring longer-course RT. High-dose fractionated schedules were preferred for oligometastasis, and low-dose regimens were preferred for patients with a poor prognosis; however, single-fraction RT was not preferred. Most respondents recommended targeting the entire orthopedic prosthesis. These results indicated that PORT using 30 Gy in 10 fractions to the entire orthopedic prosthesis is preferred in current Japanese practice and that single-fraction RT was not preferred. Oligometastasis and poor prognosis influenced the selection of high- or low-dose regimens.

Enlargement of the hippocampal angle: a new index of Alzheimer disease.

BACKGROUND: Imaging diagnosis of Alzheimer disease (AD), the leading cause of dementia, requires evaluation of the extent of hippocampal atrophy. Coronal magnetic resonance (MR) images of patients with AD often demonstrate outward rotation of the hippocampus that is altered from a long horizontal elliptical to a long vertical elliptical shape. Such rotation may be related to the disease process of AD. PURPOSE AND METHODS: To determine whether hippocampal rotation is associated with AD, we investigated MR images from 11 patients with AD and 11 normal controls, measuring the hippocampal angle (HA) and the volume of the left hippocampus on coronal T(1)-weighted MR images. The HA is the angle between a horizontal line orthogonal to the falx cerebri and the uncal sulcus line between the deepest point of the uncal sulcus and the point nearest to the side of the ambient cistern in the uncal gyrus facing the uncal sulcus. The HA is measured on the most rostral slice in which the uncal sulcus can be identified and increases with hippocampal rotation. RESULTS: We found correlation between the HA and standardized hippocampal volume in the AD group, but not in controls. CONCLUSION: Hippocampal rotation is a new marker associated with the pathology of AD.

Brain activation during the spot the differences game.

Spot the Differences is a simple and popular game in which an observer compares a pair of similar pictures to detect the differences between them. Functional activation of the brain while playing this game has not been investigated. We used functional magnetic resonance imaging to investigate the main cortical regions involved in playing this game and compared the sites of cortical activation between a session of playing the game and a session of viewing 2 identical pictures. The right posterior parietal cortex showed more activation during game playing, and cortical activation volume correlated with game-playing accuracy. This cortical region may play an important role in awareness of differences between 2 similar pictures.

Results of radiation therapy for superficial esophageal cancer using the standard radiotherapy method recommended by the Japanese Society of Therapeutic Radiology and Oncology (JASTRO) Study Group.

BACKGROUND: Superficial esophageal cancer (SEC) is defined as esophageal cancer limited to the submucosal layers, including mucosal cancer and submucosal cancer, and is squamous cell carcinoma in most patients. In 2000, the Japanese Society of Therapeutic Radiology and Oncology (JASTRO) Study Group for SEC published a consensus guideline of standard radiotherapy methods. In this study, the interim treatment outcomes of SEC patients, who had received radiation therapy following the standard radiotherapy methods, were investigated. PATIENTS AND METHODS: From 2000 to 2003, a total of 141 SEC patients were treated in 24 institutions in Japan. RESULTS: The 1-, 2- and 3-year survival rates were 95%, 90% and 90%, respectively, for patients with mucosal cancer and 90%, 81% and 70%, respectively, for patients with submucosal cancer. The overall survival was better in patients who had undergone chemotherapy than in patients who had received radiation therapy alone, though the difference was not statistically significant. The clinical target volume (CTV) did not influence overall survival and intracavitary irradiation did not influence the local control rate in either patients with mucosal or submucosal cancer. Radiation-induced esophageal ulcer was not observed in this series. CONCLUSION: The standard radiotherapy methods are safe and effective for treating SEC. However, the usefulness of chemotherapy and intracavitary irradiation and the optimal setting of the CTV should be clarified by future randomized trials.

Mesoblastic nephroma: a case report of prenatal detection by MR imaging.

We report a case of mesoblastic nephroma detected prenatally by magnetic resonance (MR) imaging. MR imaging could provide valuable information about the origin and nature of a fetal abdominal mass and help define the relationship of the mass to adjacent structures.

Fluorodeoxyglucose Uptake on Positron Emission Tomography Is a Useful Predictor of Long-Term Pain Control After Palliative Radiation Therapy in Patients With Painful Bone Metastases: Results of a Single-Institute Prospective Study.

PURPOSE: To determine whether fluorodeoxyglucose positron emission tomography (FDG-PET) before and after palliative radiation therapy (RT) can predict long-term pain control in patients with painful bone metastases. METHODS AND MATERIALS: Thirty-one patients with bone metastases who received RT were prospectively included. Forty painful metastatic treatment fields were evaluated. All patients had undergone pre-RT and post-RT PET/CT scanning. We evaluated the relationships between the pre-RT, post-RT, and changes in maximum standardized uptake value (SUVmax) and the pain response, and between SUVmax and pain relapse of the bone metastases in the treatment field. In addition, we compared the SUVmax according to the length of time from the completion of RT to pain relapse of the bone metastases. RESULTS: Regarding the pain response at 4 weeks after the completion of RT, there were 36 lesions of 27 patients in the responder group and 4 lesions of 4 patients in the nonresponder group. Changes in the SUVmax differed significantly between the responder and nonresponder groups in both the early and delayed phases (P=.0292 and P=.0139, respectively), but no relationship was observed between the pre-RT and post-RT SUVmax relative to the pain response. The responder group was evaluated for the rate of relapse. Thirty-five lesions of 26 patients in the responder group were evaluated, because 1 patient died of acute renal failure at 2 months after RT. Twelve lesions (34%) showed pain relapse, and 23 lesions (66%) did not. There were significant differences between the relapse and nonrelapse patients in terms of the pre-RT (early/delayed phases: P<.0001/P<.0001), post-RT (P=.0199/P=.0261), and changes in SUVmax (P=.0004/P=.004). CONCLUSIONS: FDG-PET may help predict the outcome of pain control in the treatment field after palliative RT for painful bone metastases.

A Nationwide Survey in Japan of Palliative Radiotherapy for Bleeding in Gastrointestinal and Genitourinary Tumor Patients.

BACKGROUND: In end-stage cancer, bleeding may markedly influence the patient's quality of life, and radiotherapy plays an important role in the control of the bleeding. In particular, there is no clear evidence of the benefit of palliative radiotherapy for cancers including gastric, rectal, and bladder cancers. A clarification of the current status of palliative radiotherapy for bleeding is needed. METHODS: A survey was conducted by the palliative radiotherapy working group of the Japanese Radiation Oncology Study Group (JROSG), focusing on annual cases of radiotherapy for tumors of the upper and lower gastrointestinal tracts and genitourinary organs (excluding the uterus) and applicable fractionated doses for three hypothetical patients. RESULTS: A total of 54 radiation oncologists at 43 facilities answered. Most of the facilities reported that they conducted hemostatic irradiation for less than one patient per year, though the median annual number of patients treated with radiotherapy in these facilities was 594. The most frequently observed doses per fraction for two of the hypothetical cases were 3.0 and 2.0 Gy. On the other hand, in each case, the numbers of fractions reported varied markedly among the respondents, ranging from 20 Gy in five fractions to over 30 fractions. CONCLUSIONS: Especially in gastric cancer, hemostatic irradiation is rarely performed in most facilities in Japan. An optimal dose fractionation has not been established. Thirty Gy in 10 fractions is one of the most frequently used regimens, but re-bleeding was observed in approximately one-third of the patients.

Acute encephalopathy associated with intravenous immunoglobulin therapy.

Intravenous immunoglobulin therapy is useful against various immune system disorders and viral infections. It is generally safe, and serious adverse reactions are uncommon. We report a rare case of acute encephalopathy following intravenous immunoglobulin therapy for human herpes virus 6 infection in a child. MR imaging findings suggest that the dominant causative mechanism of acute encephalopathy is cytotoxic edema, and the findings indicate 2 primary mechanisms. Reversibility of the restriction of water diffusion (low apparent diffusion coefficient value) on diffusion-weighted MR imaging suggests intramyelinic edema in the myelin sheath, and an increase of glutamate and glutamine complex peak on MR spectroscopy suggests excitotoxic injury to the neurons and astrocytes.

Brain stem glioblastoma with multiple large cyst formation and leptomeningeal dissemination in a 4-year-old girl.

The authors report a 4-year-old girl who developed brain stem glioblastoma. Meningeal irritation was present at onset. Magnetic resonance imaging revealed intracranial and intraspinal leptomeningeal dissemination, which progressed faster than the original tumor. Multiple large cysts developed at the interhemispheric and prepontine cisterns, resulting in progressive obstructive hydrocephalus. The patient survived only 5 months after presentation. Histology was verified by autopsy.