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Here we report that simultaneous inhibition of the three primary DNA damage recognition PI3 kinase-like kinases (PIKKs) -ATM, ATR, and DNA-PK- induces severe combinatorial synthetic lethality in mammalian cells. Utilizing Chinese hamster cell lines CHO and V79 and their respective PIKK mutants, we evaluated effects of inhibiting these three kinases on cell viability, DNA damage response, and chromosomal integrity. Our results demonstrate that while single or dual kinase inhibition increased cytotoxicity, inhibition of all three PIKKs results in significantly higher synergistic lethality, chromosomal aberrations, and DNA double-strand break (DSB) induction as calculated by their synergy scores. These findings suggest that the overlapping redundancy of ATM, ATR, and DNA-PK functions is critical for cell survival, and their combined inhibition greatly disrupts DNA damage signaling and repair processes, leading to cell death. This study provides insights into the potential of multi-targeted DDR kinase inhibition as an effective anticancer strategy, necessitating further research to elucidate underlying mechanisms and therapeutic applications.
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PURPOSE: Glioblastoma (GBM) is the most common type of primary malignant brain tumor and has a poor prognosis. Identifying novel targets and stratification strategies is urgently needed to improve patient survival. The present study aimed to identify clinically relevant genomic alterations in IDH-wildtype GBM using data from comprehensive genomic profiling (CGP) assays performed nationwide in Japan. METHODS: The CGP assay results of 392 IDH-wildtype GBM cases performed between October 2019 and February 2023 obtained from the Center for Cancer Genomics and Advanced Therapeutics were retrospectively analyzed. RESULTS: The median patient age was 52.5 years, and 207 patients (53%) were male. In the 286 patients for whom survival information was available, a protein-tyrosine phosphatase non-receptor type 11 (PTPN11) variant detected in 20 patients (6.8%) was extracted as the gene associated with significantly shorter overall survival (p = 0.002). Multivariate analysis demonstrated that the PTPN11 variant and poor performance status were independent prognostic indicators. In contrast, no prognostic impact was observed in the cohort in The Cancer Genome Atlas data. The discrepancy in the prognostic impact of the PTPN11 variant from these two pools might have resulted from differences in the biases affecting the survival of patients who underwent a CGP assay, including left-truncation and right-censored bias. However, survival simulation done to adjust for these biases showed that the prognostic impact of the PTPN11 variant was also significant. CONCLUSIONS: The PTPN11 variant was a negative prognostic indicator of IDH-wildtype GBM in the patient cohort with the CGP assay.
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Neoplasias Encefálicas , Glioblastoma , Humanos , Masculino , Pessoa de Meia-Idade , Feminino , Glioblastoma/patologia , Estudos Retrospectivos , Monoéster Fosfórico Hidrolases/genética , Neoplasias Encefálicas/patologia , Prognóstico , Isocitrato Desidrogenase/genética , Mutação , Proteína Tirosina Fosfatase não Receptora Tipo 11/genéticaRESUMO
PURPOSE: Leptomeningeal metastasis (LM) is a complication of surgery for brain metastasis and is a risk factor of poor prognosis. The risk of LM is particularly high after surgery for a breast cancer metastasis to the brain. If the risk of LM after surgical resection for a brain metastasis were predictable, appropriate adjuvant therapy could be administered to individual patients to improve their prognosis. The present study aimed to reveal the genetic characteristics of brain metastases as means of predicting LM in breast cancer patients. METHODS: Ten patients with brain metastases of breast cancer presented LM after surgical resection were analyzed by whole-exome sequencing. RESULTS: A chromodomain-helicase-DNA-binding protein 5 (CHD5) gene alteration was detected in nine cases (90%), including a nonsynonymous variant in four cases and copy number deletion in five cases. CHD5 protein expression was lost in nine cases and had decreased in one case. The frequency of CHD5 gene alteration in brain metastases with LM was significantly higher than in primary breast cancer (2.3%) or in brain metastases of breast cancer (0%) (p < 0.0001). CONCLUSIONS: These results suggested that the CHD5 gene alteration was associated with LM after surgical resection of breast cancer brain metastases. Searching for the gene alteration might predict the LM risk after surgical resection.
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Neoplasias Encefálicas , Neoplasias da Mama , Carcinomatose Meníngea , Humanos , Feminino , Neoplasias da Mama/genética , Neoplasias da Mama/cirurgia , Neoplasias da Mama/patologia , Neoplasias Encefálicas/genética , Neoplasias Encefálicas/cirurgia , Neoplasias Encefálicas/secundário , Carcinomatose Meníngea/secundário , Prognóstico , DNA Helicases/metabolismo , Proteínas do Tecido Nervoso/genéticaRESUMO
Recently, intensity-modulated radiation therapy (IMRT) is used worldwide, highly accurate verification of the location using image-guided radiation therapy (IGRT) has become critical. However, the use of cone-beam computed tomography (CBCT) to ascertain the location each time raises concerns about its influence on radiotherapy dosage and increased radiation exposure. The purpose of this study was to measure the absorbed dose using nine kilovoltage (kV) devices and two megavoltage (MV) devices (total 11 devices) at eight facilities, compare the absorbed dose among the devices, and assess the characteristics of the respective devices to ensure optimal clinical operation. For the measurement of the absorbed dose, a farmer-type ionization chamber dosimeter, calibrated using a 60Co and an IMRT dose verification phantom manufactured from water-equivalent material RW3, was used to measure the absorbed dose at nine points in the phantom for two regions, the pelvic and cephalic region. The average absorbed dose of the pelvic region was 3.09±0.21 cGy in kV-CBCT (OBI), 1.16±0.16 cGy in kV-CBCT (XVI), 5.64±1.48 cGy in MV-CBCT (4 MV), and 6.33±1.54 cGy in MV-CBCT (6 MV). The average absorbed dose of the cephalic region was 0.38±0.03 cGy in kV-CBCT (OBI), 0.23±0.06 cGy in kV-CBCT (XVI), 4.02±0.72 cGy in MV-CBCT (4 MV), and 4.46±0.77 cGy in MV-CBCT (6 MV). There was a difference in the absorbed dose at the measured points as well as in the dose distribution in the phantom cross section. No major difference was observed in the absorbed dose among identical devices, but a difference was identified among the devices installed at multiple facilities. Therefore, the angle of rotation should be paid attention to when CBCT is taken, and the image-taking conditions should be determined. In addition, it is important to handle the devices only after ascertaining the absorbed dose of each device.
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Tomografia Computadorizada de Feixe Cônico/métodos , Radioterapia Guiada por Imagem/métodos , Calibragem , Tomografia Computadorizada de Feixe Cônico/instrumentação , Imagens de Fantasmas , Dosagem Radioterapêutica , Planejamento da Radioterapia Assistida por ComputadorRESUMO
A combined system comprising the TrueBeam linear accelerator and a new real-time, tumor-tracking radiotherapy system, SyncTraX, was installed in our institution. The goals of this study were to assess the capability of SyncTraX in measuring the position of a fiducial marker using color fluoroscopic images, and to evaluate the dosimetric and geometric accuracy of respiratory-gated radiotherapy using this combined system for the simple geometry. For the fundamental evaluation of respiratory-gated radiotherapy using SyncTraX, the following were performed:1) determination of dosimetric and positional characteristics of sinusoidal patterns using a motor-driven base for several gating windows; 2) measurement of time delay using an oscilloscope; 3) positional verification of sinusoidal patterns and the pattern in the case of a lung cancer patient; 4) measurement of the half-value layer (HVL in mm AL), effective kVp, and air kerma, using a solid-state detector for each fluoroscopic condition, to determine the patient dose. The dose profile in a moving phantom with gated radiotherapy having a gating window ≤ 4 mm was in good agreement with that under static conditions for each photon beam. The total time delay between TrueBeam and SyncTraX was < 227 ms for each photon beam. The mean of the positional tracking error was < 0.4 mm for sinusoidal patterns and for the pattern in the case of a lung cancer patient. The air-kerma rates from one fluoroscopy direction were 1.93 ± 0.01, 2.86 ± 0.01, 3.92 ± 0.04, 5.28 ± 0.03, and 6.60 ± 0.05 mGy/min for 70, 80, 90, 100, and 110 kV X-ray beams at 80 mA, respectively. The combined system comprising TrueBeam and SyncTraX could track the motion of the fiducial marker and control radiation delivery with reasonable accuracy; therefore, this system provides significant dosimetric improvement. However, patient exposure dose from fluoroscopy was not clinically negligible.
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Marcadores Fiduciais , Fluoroscopia/instrumentação , Neoplasias Pulmonares/radioterapia , Aceleradores de Partículas/instrumentação , Imagens de Fantasmas , Planejamento da Radioterapia Assistida por Computador/métodos , Sistemas Computacionais , Humanos , Movimento , Fótons , Radioterapia Assistida por Computador/métodos , RespiraçãoRESUMO
PURPOSE: The aim of this study was to reduce the exposed dose of radiotherapy treatment planning computed tomography (CT) by using low tube voltage technique. MATERIALS AND METHODS: We used tube voltages of 80 kV, 100 kV, and 120 kV, respectively. First, we evaluated exposure dose with CT dose index (CTDI) for each voltage. Second, we compared image quality indexes such as modulation transfer function (MTF), noise power spectrum (NPS), and contrast to noise ratio (CNR) of phantom images with each voltage. Third, CT to electron density tables were measured in three voltages and monitor unit value was calculated along with clinical cases. Finally, CT surface exposed dose of chest skin was measured by thermoluminescent dosimeter (TLD). RESULTS: In image evaluation MTF and NPS were approximately equal; CNR slightly decreased, 2.0% for 100 kV. We performed check radiation dose accuracy for each tube voltage with each model phantom. As a result, the difference of MU value was not accepted. Finally, compared with 120 kV, CTDIvol and TLD value showed markedly decreased radiation dose, 60% for 80 kV and 30% for 100 kV. CONCLUSION: Using a technique with low tube voltages, especially 100 kV, is useful in radiotherapy treatment planning to obtain 20% dose reduction without compromising 120 kV image quality.
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Tomografia Computadorizada por Raios X/métodos , Elétrons , Humanos , Doses de Radiação , Pele/efeitos da radiação , Dosimetria TermoluminescenteRESUMO
The artery of Davidoff and Schechter (ADS) is mostly identified in pathological conditions such as dural arteriovenous fistulas and brain tumors. Herein, we report a rare case of a ruptured aneurysm of the ADS, which was one of the feeders of a falcotentorial dural arteriovenous fistula. We performed endovascular embolization of the aneurysm and parent artery using n-butyl-2-cyanoacrylate. Complete occlusion of the fistula was achieved by another feeder after the acute phase. To our best knowledge, only a few reports on embolization of ruptured ADS aneurysms exist. Furthermore, this is the first report on the embolization of a ruptured ADS aneurysm using n-butyl-2-cyanoacrylate. This case highlights that endovascular n-butyl-2-cyanoacrylate embolization could be a useful treatment for a ruptured ADS aneurysm.
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BACKGROUND AND PURPOSE: Quality indicators (QIs) for radiotherapy have been proposed by several groups, but no study has been conducted to correlate the implementation of indicators specific to patient safety over the course of the clinical process with an institution's background. An initial large-scale survey was conducted to understand the implementation status of QIs established for quality assurance and patient safety in radiotherapy and the relationship between implementation status and an institutions' background. MATERIALS AND METHOD: Overall, 68 QIs that were established by this research team after a pilot survey were used to assess structures and processes for quality assurance and patient safety. Data on the implementation of QIs and the institutions' backgrounds were obtained from designated cancer care hospitals in Japan. RESULTS: Overall, 284 institutions (72 %) responded and had a median QI achievement rate of 60.8 %. QIs with low implementation rates, such as the implementation of an error reporting system and establishment of a quality assurance department, were identified. The QI achievement rate and scale of the institution were positively correlated, and the achievement rate of all QIs was significantly higher (p < 0.001) in institutions capable of advanced treatments, such as intensity-modulated radiotherapy, and those with a quality assurance department. CONCLUSION: A large-scale survey on QIs revealed their implementation and relationship with a facility's background. QIs that require improvement were identified, and that these QIs might be effective in providing advanced medical care to many patients.
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Indicadores de Qualidade em Assistência à Saúde , Radioterapia de Intensidade Modulada , Humanos , Segurança do Paciente , Hospitais , JapãoRESUMO
In conducting dosimetric assays of seed sources containing iodine-125 (125I), several major guidelines require the medical physicist to verify the source strength before patient treatment. Japanese guidelines do not mandate dosimetric assays at medical facilities, but since 2017, three incidents have occurred in Japan wherein seeds with incorrect strengths were delivered to medical facilities. Therefore, this study aimed to survey the current situation and any barriers to conducting the dosimetric assay of iodine-125 seeds at medical facilities in Japan. We conducted a questionnaire-based survey from December 2020 to April 2021, to examine whether seed assay and verification of the number of seeds delivered were being performed. We found that only 9 facilities (16%) performed seed assay and 28 (52%) verified the number of seeds. None of the facilities used an assay method that ensured traceability. The reasons for not performing an assay were divided into two categories: lack of resources and legal issues. Lack of resources included lack of instruments, lack of knowledge of assay methods, shorthand, or all of the above, whereas legal issues included the inability to resterilize iodine-125 seeds distributed in Japan and/or purchase seeds dedicated to the assay. Dosimetric assays, including simple methods, are effective in detecting calibration date errors and non-radioactive seeds. The study findings suggest that familiarization of medical personnel with these assay methods and investigation of the associated costs of labor and equipment should be recommended, as these measures will lead to medical reimbursement for quality assurance.
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Braquiterapia , Radioisótopos do Iodo , Humanos , Braquiterapia/métodos , Japão , Inquéritos e Questionários , Dosagem RadioterapêuticaRESUMO
This technical report provides useful information on the current status and issues of quality control in 125I seed source strength measurement for Permanent Prostate Brachytherapy in Japan.With the spread of 125I seed brachytherapy, the traceability of source strength measurements with the single-seed assay was established in Japan. This allows medical facilities to measure reference air kerma rate of 125I seeds with their own well-type of ionization chamber. However, it is difficult to maintain the traceability chain because the 125I reference air kerma rate standards have been hardly utilized by medical facilities so far. Meanwhile, some serious incidents of contamination of the different source strengths and dead seeds were reported in Japan.To address the specific issues in Japan, JASTRO Brachytherapy Subcommittee established a working group (WG) in 2021. The goal of this WG is to investigate the management methods of source strength measurement used in medical facilities, and to discuss the ideal and practicable methods of source management such as verifying the number of seeds and source strength. Initially, a questionnaire survey was conducted to facilities offering 125I seed brachytherapy in Japan. Sixty-seven out of 95 facilities responded (response rate 70.5%). This survey revealed that 41% of facilities did not perform either confirmation of the number of seeds or measurement of source strength. There are several reasons why the source strength was not measured in those facilities. For example, 125I seeds are provided under the sterilized conditions; quality assurance by source suppliers is reliable; and there is not sufficient staff.The single-seed assay is regarded as an internationally standardized and the most reliable measurement method. Therefore, it is an essential measurement technique to ensure traceability of source strength measurements. However, our survey found that most Japanese facilities do not perform single-seed assays. Meanwhile, some facilities have performed batch assay as an alternative method, in which all of the multiple sources in a batch are measured while loaded into sterilized cartridges. Although the measurement by the batch assay is less accurate than the one by the single-seeded assay, the batch assay does not require re-sterilization of the source and can be performed quickly. It might be useful to detect unexpected errors such as differences in the number of sources and abnormalities in source strength.In this report, we will introduce several methods of source strength measurement that have been implemented in medical facilities. The quality assurance of 125I seed sources in prostate interstitial brachytherapy should be provided not only by the source suppliers but also by the medical facilities that use sources to treat patients. We hope that medical facilities will refer to this technical report and use it as an aid to quality assurance in their own facilities.
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Braquiterapia , Neoplasias da Próstata , Masculino , Humanos , Braquiterapia/métodos , Próstata , Dosagem Radioterapêutica , Radioisótopos do Iodo/uso terapêutico , Neoplasias da Próstata/radioterapiaRESUMO
OBJECTIVE: Left ventricular assist devices (LVADs) are an epoch-making treatment option for patients with severe heart failure; however, the patients occasionally experience severe acute ischemic strokes (AISs). Although mechanical thrombectomy is considered as an effective treatment for severe AIS in patients with LVADs, there remains a paucity of data on the long-term outcomes. This study aimed to investigate the acute-phase efficacy and long-term outcomes of mechanical thrombectomy for AIS patients with LVADs. METHODS: We retrospectively reviewed 9 cases in 8 patients with LVADs who developed AIS and underwent mechanical thrombectomy from July 2014 to November 2021 at our hospital. Clinical information, including the National Institutes of Health Stroke Scale score and modified Rankin Scale score before and after thrombectomy, the details of procedures, and the long-term outcomes after thrombectomy, was retrospectively reviewed and statistically analyzed. RESULTS: Effective recanalization was achieved in 89% of the 9 cases. The median National Institutes of Health Stroke Scale score improved from 12 (range, 8-29) to 5 (range, 0-29) after mechanical thrombectomy. The median total follow-up duration was 1327 (range, 78-2659) days. Of the 8 patients, 3 patients underwent heart transplantation, and the LVAD was removed after recovery of the patient's heart function. One patient awaited heart transplantation. CONCLUSIONS: This study revealed the long-term benefit of mechanical thrombectomy for AIS in patients with LVADs, eventually achieving 50% of independence from LVADs.
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Isquemia Encefálica , Coração Auxiliar , AVC Isquêmico , Acidente Vascular Cerebral , Isquemia Encefálica/etiologia , Coração Auxiliar/efeitos adversos , Humanos , Estudos Retrospectivos , Acidente Vascular Cerebral/etiologia , Trombectomia/métodos , Resultado do TratamentoRESUMO
PURPOSE: To quantify dose delivery errors for high-dose-rate image-guided brachytherapy (HDR-IGBT) using an independent end-to-end dose delivery quality assurance test at multiple institutions. The novelty of our study is that this is the first multi-institutional end-to-end dose delivery study in the world. MATERIALS AND METHODS: The postal audit used a polymer gel dosimeter in a cylindrical acrylic container for the afterloading system. Image acquisition using computed tomography, treatment planning, and irradiation were performed at each institution. Dose distribution comparison between the plan and gel measurement was performed. The percentage of pixels satisfying the absolute-dose gamma criterion was reviewed. RESULTS: Thirty-five institutions participated in this study. The dose uncertainty was 3.6% ± 2.3% (mean ± 1.96σ). The geometric uncertainty with a coverage factor of kâ¯=â¯2 was 3.5 mm. The tolerance level was set to the gamma passing rate of 95% with the agreement criterion of 5% (global)/3 mm, which was determined from the uncertainty estimation. The percentage of pixels satisfying the gamma criterion was 90.4% ± 32.2% (mean ± 1.96σ). Sixty-six percent (23/35) of the institutions passed the verification. Of the institutions that failed the verification, 75% (9/12) had incorrect inputs of the offset between the catheter tip and indexer length in treatment planning and 17% (2/12) had incorrect catheter reconstruction in treatment planning. CONCLUSIONS: The methodology should be useful for comprehensively checking the accuracy of HDR-IGBT dose delivery and credentialing clinical studies. The results of our study highlight the high risk of large source positional errors while delivering dose for HDR-IGBT in clinical practices.
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Braquiterapia , Humanos , Braquiterapia/métodos , Dosagem Radioterapêutica , Dosímetros de Radiação , Catéteres , Tomografia Computadorizada por Raios X , Radiometria/métodos , Imagens de FantasmasRESUMO
This study investigates the quality indicators (QIs) of medical care that are expected to be introduced to radiotherapy departments in Japan and evaluates whether the QIs reflect the characteristics of the treatment facilities. For this purpose, a questionnaire survey was administered to radiotherapy treatment facilities in Japan. A consensus of early QI candidates was obtained from the panel members. The characteristics identified in the candidate QIs were subdivided into 140 items covering 27 domains of medical-care contents in radiotherapy departments. These 140 items were compiled into a questionnaire, which was administered to 15 treatment facilities in Japan. The primary results indicated that 36 items in five domains are useful QI contents. The secondary findings indicated that the provision of advanced radiotherapy to several patients, the waiting time, and the radiotherapy initiated depend on the manpower of the departmental staff.
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Indicadores de Qualidade em Assistência à Saúde , Radioterapia/normas , Humanos , Japão , Inquéritos e QuestionáriosRESUMO
In 2016, the American Association of Physicists in Medicine (AAPM) has published a report of task group (TG) 100 with a completely new concept, entitled "application of risk analysis methods to radiation therapy quality management." TG-100 proposed implementation of risk analysis in radiotherapy to prevent harmful radiotherapy accidents. In addition, it enables us to conduct efficient and effective quality management in not only advanced radiotherapy such as intensity-modulated radiotherapy and image-guided radiotherapy but also new technology in radiotherapy. It should be noted that treatment process in modern radiotherapy is absolutely more complex and it needs skillful staff and adequate resources. TG-100 methodology could identify weakness in radiotherapy procedure through assessment of failure modes that could occur in overall treatment processes. All staff in radiotherapy have to explore quality management in radiotherapy safety.
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Radioterapia Guiada por Imagem , Radioterapia de Intensidade Modulada , Humanos , Risco , Estados UnidosRESUMO
We investigated respiratory reproducibility from position errors of gold internal fiducial markers for breath-hold (BH) and real-time tumor tracking (RTT) techniques for stereotactic body radiotherapy in lung tumors. The relationship between position errors and dose indexes was checked for both techniques. The stereotactic body radiotherapy plan in lung tumors was planned for 29 patients. The tumor positioning was arranged using 1.5 mm diameter gold internal fiducial markers. First, CT images were acquired to analyze position errors of gold markers for BH and RTT techniques. The offset plans for both techniques were calculated by displacing the mean position errors. The dose indexes (D98, D95, D2, mean dose) in a planning target volume were evaluated from dose volume histograms for the original plan, BH, and RTT offset plans. The relationship between position errors and dose indexes was analyzed using the root mean square (RMS) for both techniques. For the BH, the RMS was 3.29 mm at the lower lobe. Similarly, it was 1.34 mm for the RTT. The difference for D98 by position error for BH was -7.0 ± 10.8% at the lower lobe and the difference of all dose indexes for the RTT was less than 1%. The D2 and mean dose for both techniques were nearly the same as those of the original plan. In conclusion, the adaptation of the BH technique should be ≤2 mm RMS. If the position error is >2 mm RMS, the RTT technique should be used instead of the BH technique.