The dilemma of radiation necrosis from diagnosis to treatment in the management of brain metastases.

Radiation therapy with stereotactic radiosurgery (SRS) or whole brain radiation therapy is a mainstay of treatment for patients with brain metastases. The use of SRS in the management of brain metastases is becoming increasingly common and provides excellent local control. Cerebral radiation necrosis (RN) is a late complication of radiation treatment that can be seen months to years following treatment and is often indistinguishable from tumor progression on conventional imaging. In this review article, we explore risk factors associated with the development of radiation necrosis, advanced imaging modalities used to aid in diagnosis, and potential treatment strategies to manage side effects.

microRNA blood signature for localized radiation injury.

A radiological accident, whether from industrial, medical, or malicious origin, may result in localized exposure to high doses of ionizing radiations, leading to the development of local radiation injury (LRI), that may evolve toward deep ulceration and necrosis of the skin and underlying tissues. Early diagnosis is therefore crucial to facilitate identification and management of LRI victims. Circulating microRNAs (miRNA) have been studied as potential diagnostic biomarkers of several diseases including hematological defects following whole-body irradiation (WBI). This study aims to identify a blood miRNA signature associated with LRI in a preclinical C57BL/6J mouse model of hindlimb irradiation using different 10-MV X-ray doses that lead to injuries of different severities. To this end, we first performed broad-spectrum plasma miRNA profiling, followed by a targeted validation step, on two independent animal cohorts. Using a multivariate sparse partial least square discriminant analysis, we identified a panel of eight circulating miRNAs able to segregate mice according to LRI severity. Interestingly, these miRNAs were previously associated with WBI (miR-150-5p, miR-342-3p, miR-146a-5p), inflammation (miR-18a-5p, miR-148b-3p, miR-532-5p) and skin diseases (miR-139-5p, miR-195-5p). Our results suggest the use of circulating miRNAs as suitable molecular biomarkers for LRI prognosis and diagnosis.

[Pathogenesis, diagnostic and therapeutic strategies for radiation-related caries].

Radiation-related caries is a common complication following head and neck tumor radiotherapy. It is a rapidly progressing and widespread destructive disease of tooth tissue after radiotherapy, which greatly affects the life quality of patients after radiotherapy. This article elucidates research progress in the pathogenic mechanisms, diagnosis and caries assessment, treatment, as well as prevention strategies for radiation-related caries, aiming to provide references for clinical prevention and treatment of radiation-related caries.

Predicting Radiation-Induced Lung Injury in Patients With Lung Cancer: Challenges and Opportunities.

Radiation-induced lung injury (RILI) is one of the main dose-limiting toxicities in radiation therapy (RT) for lung cancer. Approximately 10% to 20% of patients show signs of RILI of variable severity. The reason for the wide range of RILI severity and the mechanisms underlying its development are only partially understood. A number of clinical risk factors have been identified that can aid in clinical decision making. Technological advancements in RT and the use of strict organ-at-risk dose constraints have helped to reduce RILI. Predicting patients at risk for RILI may be further improved with a combination of cytokine assessments, γH2AX-assays in leukocytes, or epigenetic markers. A complicating factor is the lack of an objective definition of RILI. Tools such as computed tomography densitometry, fluorodeoxyglucose-positron emission tomography uptake, changes in lung function measurements, and exhaled breath analysis can be implemented to better define and quantify RILI. This can aid in the search for new biomarkers, which can be accelerated by omics techniques, single-cell RNA sequencing, mass cytometry, and advances in patient-specific in vitro cell culture models. An objective quantification of RILI combined with these novel techniques can aid in the development of biomarkers to better predict patients at risk and allow personalized treatment decisions.

Comprehensive geriatric assessment predicts radiation-induced acute toxicity in prostate cancer patients.

PURPOSE: The purpose of the present prospective study was to evaluate the significance of geriatric conditions measured by a comprehensive geriatric assessment (GA) for the prediction of the risk of high-grade acute radiation-induced toxicity. METHODS: A total of 314 prostate cancer patients (age ≥ 65 years) undergoing definitive radiotherapy at a tertiary academic center were included. Prior to treatment, patients underwent a GA. High-grade toxicity was defined as acute toxicity grade ≥ 2 according to standard RTOG/EORTC criteria. To analyze the predictive value of the GA, univariable and multivariable logistic regression models were applied. RESULTS: A total of 40 patients (12.7%) developed acute toxicity grade ≥ 2; high grade genitourinary was found in 37 patients (11.8%) and rectal toxicity in 8 patients (2.5%), respectively. Multivariable analysis revealed a significant association of comorbidities with overall toxicity grade ≥ 2 (odds ratio [OR] 2.633, 95% confidence interval [CI] 1.260-5.502; p = 0.010) as well as with high-grade genitourinary and rectal toxicity (OR 2.169, 95%CI1.017-4.625; p = 0.045 and OR 7.220, 95%CI 1.227-42.473; p = 0.029, respectively). Furthermore, the Activities of Daily Living score (OR 0.054, 95%CI 0.004-0.651; p = 0.022), social status (OR 0.159, 95%CI 0.028-0.891; p = 0.036), and polypharmacy (OR 4.618, 95%CI 1.045-20.405; p = 0.044) were identified as independent predictors of rectal toxicity grade ≥ 2. CONCLUSION: Geriatric conditions seem to be predictive of the development of high-grade radiation-induced toxicity in prostate cancer patients treated with definitive radiotherapy.

[Progressive radiation-induced rectal injury: is there an opportunity to get out of a vicious circle? A clinical case].

Radiation therapy is one of the main treatment option for prostate cancer used either independently or as a component of combined and complex treatment of the disease. Modern achievements make it possible to deliver doses of radiation that match the exact dimensions of the tumor for greater efficacy, with minimal exposure of the surrounding tissues, however, does not eliminate them. In most patients, clinical manifestations of chronic radiation proctitis occur during the first 2 years after radiation therapy. The article summarizes the current knowledge about pathophysiology, clinical manifestations, diagnostics and treatment options for this condition. In this paper, we present a case of complicated of chronic radiation proctitis.

Radiation-Induced Pericardial Disease: Mechanisms, Diagnosis, and Treatment.

PURPOSE OF REVIEW: We aim to give a concise overview of the different clinical manifestations of both acute and long-term radiotherapy-related pericardial diseases, the underlying pathophysiology as well as the diagnosis and treatment options. RECENT FINDINGS: Radiotherapy-related pericardial disease is common, but despite radiotherapy being a cornerstone of many cancer treatments, this disease entity is relatively underrepresented in clinical trials, resulting in a paucity of research data on pathophysiology and management. Since the development of innovative cancer treatments, survival has significantly improved. Therefore, the importance of long-term treatment-related side effects increases, most notably cancer treatment-related cardiovascular toxicity. In patients undergoing radiotherapy as a part of their cancer treatment, radiotherapy-related pericardial disease can manifest early (during or shortly after radiotherapy administration) or very late (several years to decades after treatment). This exceptionally long latency period confronts physicians with treatment-related side effects of radiotherapy regimens that may have been abandoned already.

Genitourinary Radiation Injury Following Prostate Cancer Treatment: Assessment of Cost and Health Care System Burden.

OBJECTIVE: To evaluate the healthcare resource impact of radiation injury following prostate cancer treatment. METHODS: Using IBM MarketScan, we performed a retrospective study of men with prostate cancer who were treated with radiotherapy and subsequently developed low-grade (LGRI) and high-grade radiation injury (HGRI). Radiation injury diagnoses included bladder neck stenosis, hematuria/cystitis, fistula, ureteral stricture, and incontinence. LGRI and HGRI included injury diagnosis without intervention and with intervention, respectively. Health care visits and costs were measured over 5 time periods including 2 years before radiation, 1 year before radiation, radiation to injury diagnosis, injury diagnosis to first intervention (LGRI), and following first intervention (HGRI). Negative binomial regression modeling was used to assess the effect of radiation injury on average cost adjusting for demographics and comorbidities. RESULTS: Between 2008 and 2017, we identified 121,027 men who received radiotherapy following prostate cancer diagnosis of which 10,057 (8.3%) experienced a HGRI. The frequency of urologic visits and average costs were similar in those without injury and LGRI. However, men with HGRI experienced higher visit frequency and monthly costs. Amongst high-grade injuries, urinary fistula had the highest frequency of visit utilization at 378 visits before first intervention and 245 visits after first intervention. Following radiation injury diagnosis, the average monthly cost was twice as high in those with HGRI ($85.78) compared to LGRI ($38.66). CONCLUSIONS: HGRI was associated with increased urologic health care use and average monthly cost when compared to those who experienced LGRI or no injury. Urinary fistula was associated with the largest resource burden.

Recognition and Management of the Long-term Effects of Cranial Radiation.

OPINION STATEMENT: Cranial radiation is ubiquitous in the treatment of primary malignant and benign brain tumors as well as brain metastases. Improvement in radiotherapy targeting and delivery has led to prolongation of survival outcomes. As long-term survivorship improves, we also focus on prevention of permanent side effects of radiation and mitigating the impact when they do occur. Such chronic treatment-related morbidity is a major concern with significant negative impact on patient's and caregiver's respective quality of life. The actual mechanisms responsible for radiation-induced brain injury remain incompletely understood. Multiple interventions have been introduced to potentially prevent, minimize, or reverse the cognitive deterioration. Hippocampal-sparing intensity modulated radiotherapy and memantine represent effective interventions to avoid damage to regions of adult neurogenesis. Radiation necrosis frequently develops in the high radiation dose region encompassing the tumor and surrounding normal tissue. The radiographic findings in addition to the clinical course of the patients' symptoms are taken into consideration to differentiate between tissue necrosis and tumor recurrence. Radiation-induced neuroendocrine dysfunction becomes more pronounced when the hypothalamo-pituitary (HP) axis is included in the radiation treatment field. Baseline and post-treatment evaluation of hormonal profile is warranted. Radiation-induced injury of the cataract and optic system can develop when these structures receive an amount of radiation that exceeds their tolerance. Special attention should always be paid to avoid irradiation of these sensitive structures, if possible, or minimize their dose to the lowest limit.

Outcomes of haemorrhagic radiation proctitis at a South African tertiary hospital.

BACKGROUND: Haemorrhagic radiation proctitis occurs in 5-10% of patients undergoing radiotherapy. In our resourceconstrained South African setting, this study aimed to describe the clinicopathological spectrum and management of radiation proctitis referred to a tertiary centre, to address the deficit in our setting-specific understanding of the condition. METHODS: This was a sub-analysis of data from an existing colorectal cancer registry at the Inkosi Albert Luthuli Central Hospital in Durban. We reviewed the registry for all patients between 2008 and 2019 with haemorrhagic radiation proctitis and describe the various patient characteristics, treatments and outcomes for these patients. RESULTS: Fifty-eight patients with haemorrhagic radiation proctitis were identified. Colonoscopy findings included bleeding (58 patients), endoscopic proctitis (30 patients) and rectal stricture (7 patients). The median time elapsed between radiotherapy and development of symptoms was 16.5 months (IQR 12-25). Median number of argon plasma coagulation (APC) sessions for endoscopic healing or symptom resolution was three sessions (IQR 2-4). At follow-up, 35 patients had complete healing and 19 patients had symptom improvement. Complications occurring during or after APC therapy included rectal ulceration (2 patients) and rectovaginal fistula (1 patient). CONCLUSION: APC is a safe and effective treatment modality with complete resolution or significant improvement in symptomatology in the vast majority of patients with three or four treatments. Morbidity is likely to be related to ongoing radiation effects.

Establishment of a prediction model for severe acute radiation enteritis associated with cervical cancer radiotherapy.

BACKGROUND: Cervical cancer is one of the most common gynecological malignant tumors. Radiation enteritis (RE) leads to radiotherapy intolerance or termination of radiotherapy, which negatively impacts the therapeutic effect and seriously affects the quality of life of patients. If the incidence of RE in patients can be predicted in advance, and targeted clinical preventive treatment can be carried out, the side effects of radiotherapy in cervical cancer patients can be significantly reduced. Furthermore, accurate prediction of RE is essential for the selection of individualized radiation dose and the optimization of the radiotherapy plan. AIM: To analyze the relationships between severe acute RE (SARE) of cervical cancer radiotherapy and clinical factors and dose-volume parameters retrospectively. METHODS: We included 50 cervical cancer patients who received volumetric modulated arc therapy (VMAT) from September 2017 to June 2018 in the Department of Radiotherapy at The First Affiliated Hospital Soochow University. Clinical and dose-volume histogram factors of patients were collected. Logistic regression analysis was used to evaluate the predictive value of each factor for SARE. A nomogram to predict SARE was developed (SARE scoring system ≥ 3 points) based on the multiple regression coefficients; validity was verified by an internal verification method. RESULTS: Gastrointestinal and hematological toxicity of cervical cancer VMAT gradually increased with radiotherapy and reached the peak at the end of radiotherapy. The main adverse reactions were diarrhea, abdominal pain, colitis, anal swelling, and blood in the stool. There was no significant difference in the incidence of gastrointestinal toxicity between the radical and postoperative adjuvant radiotherapy groups (P > 0.05). There were significant differences in the small intestine V20, V30, V40, and rectal V40 between adjuvant radiotherapy and radical radiotherapy after surgery (P < 0.05). Univariate and multivariate analyses revealed anal bulge rating (OR: 14.779, 95%CI: 1.281-170.547, P = 0.031) and disease activity index (DAI) score (OR: 53.928, 95%CI: 3.822-760.948, P = 0.003) as independent predictors of SARE. CONCLUSION: Anal bulge rating (> 0.500 grade) and DAI score (> 2.165 points) can predict SARE. The nomogram shows potential value in clinical practice.

Quality evaluation of guidelines for the diagnosis and treatment of radiation enteritis.

OBJECTIVE: To systematically evaluate the guidelines for the diagnosis and treatment of radioactive enteritis, compare their differences and reasons and provide some reference for updating them. METHODS: This study used guidelines related to radiation enteritis by searching a database. Four independent reviewers used the AGREE II evaluation tool to evaluate the quality of the included guidelines, collate their main recommendations, and analyze the highest evidence supporting the main recommendations. RESULTS: Six diagnostic and therapeutic guidelines for radiation enteritis were included in this study, one of which, the American Society for Gastrointestinal Endoscopy guidelines, had an overall score of over 60%, which is worthy of clinical recommendation. In the diagnosis and treatment of radioactive rectal injury, the recommendations for hemorrhagic endoscopic treatment are mature and mainly include (I) argon plasma coagulation; (II) formalin treatment; (III) bipolar electrocoagulation; (IV) heater probe; (V) radiofrequency ablation; and (VI) cryoablation. CONCLUSION: The methodological quality of radioactive enteritis guidelines is unequal; even in the same guidelines, different domains have a large difference. For radioactive rectal damage diagnosis, a type of endoscopic treatment recommendation is more mature, but the overall diagnosis and treatment of radioactive enteritis still lacks high-quality research evidence.

New Insights into the Understanding of Mechanisms of Radiation-Induced Heart Disease.

OPINION STATEMENT: Cancer patients who receive high-dose thoracic radiotherapy may develop radiation-induced heart disease (RIHD). The clinical presentation of RIHD comprises coronary artery atherosclerosis, valvular disease, pericarditis, cardiomyopathy, and conduction defects. These complications have significantly reduced due to the improved radiotherapy techniques. However, such methods still could not avoid heart radiation exposure. Furthermore, people who received relatively low-dose radiation exposures have exhibited significantly elevated RIHD risks in cohort studies of atomic bomb survivors and occupational exposures. The increased potential in exposure to natural and artificial ionizing radiation sources has emphasized the necessity to understand the development of RIHD. The pathological processes of RIHD include endothelial dysfunction, inflammation, fibrosis, and hypertrophy. The underlying mechanisms may involve the changes in oxidative stress, DNA damage response, telomere erosion, mitochondrial dysfunction, epigenetic regulation, circulation factors, protein post-translational modification, and metabolites. This review will discuss the recent advances in the mechanisms of RIHD at cellular and molecular levels.

[Radiation induced brachial plexopathy: Diagnosis, risk factors, principles of care]. / La plexite radique : épidémiologie, diagnostic, facteurs de risque et prise en charge.

Radiation plexitis, also known as radiation-induced brachial neuropathy is a rare toxicity following axillary, breast, cervical or thoracic radiotherapy, first described in 1966 by Stoll and Andrew. Although improvements in radiotherapy techniques have greatly reduced its risk over the past seventy years, its severe form remains a dreaded complication that is difficult to manage in patients with increased life expectancy. This article summarizes the epidemiological elements, risk factors, diagnostic methods, doses and constraints to be respected in radiotherapy and the treatment strategies of radiation plexitis.

Investigating the attenuating effect of telmisartan against radiation-induced intestinal injury using 18F-FDG micro-PET imaging.

BACKGROUND AND OBJECTIVE: This study was aimed to investigate the ability of 18F-Fluro-deoxy-glucose (18F-FDG)-based micro-positron emission tomography (microPET) imaging to evaluate the efficacy of telmisartan, a highly selective angiotensin II receptor antagonist (ARA), in intestinal tissue recovery process after in vivo irradiation. METHODS: Male Balb/c mice were randomly divided into four groups of control, telmisartan, irradiation, and telmisartan + irradiation. A solution of telmisartan in phosphate-buffered saline (PBS) was administered orally at 12 mg/kg body weight for seven consecutive days prior to whole body exposing to a single sub-lethal dose of 5 Gy X-rays. The mice were imaged using 18F-FDG microPET at 9 and 30 days post-irradiation. The 18F-FDG uptake in jejunum was determined according to the mean standardized uptake value (SUVmean) index. Tissues were also processed in similar time points for histological analysis. RESULTS: The 18F-FDG microPET imaging confirmed the efficacy of telmisartan as a potent attenuating agent for ionizing radiation-induced injury of intestine in mice model. The results were also in line with the histological analysis indicating that pretreatment with telmisartan reduced damage to the villi, crypts, and intestinal mucosa compared with irradiated and non-treated group from day 9 to 30 after irradiation. CONCLUSION: The results revealed that 18F-FDG microPET imaging could be a good candidate to replace time-consuming and invasive biological techniques for screening of radioprotective agents. These findings were also confirmed by histological examinations which indicated that telmisartan can effectively attenuates radiation injury caused by ionizing-irradiation.

Value of DWI Combined with Magnetic Resonance Spectroscopy in the Differential Diagnosis between Recurrent Glioma and Radiation Injury: A Meta-Analysis.

To analyse the value of the apparent diffusion coefficient (ADC) in diffusion-weighted imaging (DWI) and the choline (Cho)/creatine (Cr) ratio and Cho/N-acetyl-aspartate (NAA) ratio in magnetic resonance spectroscopy (MRS) in the differential diagnosis between recurrent glioma and radiation injury. Chinese and English studies related to the diagnosis of recurrent glioma and radiation injury using DWI and MRS and published before 15 October 2022 were retrieved from PubMed, Embase, the Cochrane Library, China National Knowledge Infrastructure, China Biomedical Literature Database, VIP Journal Database, and Wanfang Database for a meta-analysis. A total of 11 articles were included in this study. ADC was lower in the recurrent glioma group than in the radiation injury group (standardized mean difference = -1.29, 95% confidence interval (CI) (-1.87, -0.71), P < 0.001). The Cho/Cr ratio was higher in the recurrent glioma group than in the radiation injury group (weighted mean difference = 0.65, 95% CI (0.40, 0.90), and P < 0.001). The Cho/NAA ratio was higher in the recurrent glioma group than in the radiation injury group, as evidenced by the sensitivity analysis. The sensitivity and specificity of the Cho/Cr ratio were 0.85 (0.73-0.92) and 0.82 (0.67-0.91), respectively, and the area under the curve was 0.86. The sensitivity and specificity of the Cho/NAA ratio were 0.82 (0.66-0.91) and 0.94 (0.69-0.99), respectively, and the area under the curve was 0.93. This meta-analysis showed that ADC, Cho/Cr, and Cho/NAA ratios all had high sensitivity and specificity. Therefore, DWI combined with MRS can effectively improve the diagnosis of recurrent glioma and radiation injury.

Smoking and Radiation-induced Skin Injury: Analysis of a Multiracial, Multiethnic Prospective Clinical Trial.

INTRODUCTION: Smoking during breast radiotherapy (RT) may be associated with radiation-induced skin injury (RISI). We aimed to determine if a urinary biomarker of tobacco smoke exposure is associated with increased rates of RISI during and after breast RT. PATIENTS AND METHODS: Women with Stage 0-IIIA breast cancer treated with breast-conserving surgery or mastectomy followed by RT to the breast or chest wall with or without regional nodal irradiation were prospectively enrolled on a multicenter study assessing acute/late RISI. 980 patients with urinary cotinine (UCot) measurements (baseline and end-RT) were categorized into three groups. Acute and late RISI was assessed using the ONS Acute Skin Reaction scale and the LENT-SOMA Criteria. RESULTS: Late Grade 2+ and Grade 3+ RISI occurred in 18.2% and 1.9% of patients, respectively-primarily fibrosis, pain, edema, and hyperpigmentation. Grade 2+ late RISI was associated with UCot group (P= 006). Multivariable analysis identified UCot-based light smoker/secondhand smoke exposure (HR 1.79, P= .10) and smoking (HR 1.60, p = .06) as non-significantly associated with an increased risk of late RISI. Hypofractionated breast RT was associated with decreased risk of late RISI (HR 0.51, P=.03). UCot was not associated with acute RISI, multivariable analysis identified race, obesity, RT site/fractionation, and bra size to be associated with acute RISI. CONCLUSIONS: Tobacco exposure during breast RT may be associated with an increased risk of late RISI without an effect on acute toxicity. Smoking cessation should be encouraged prior to radiotherapy to minimize these and other ill effects of smoking.

TNF-α Indicates Radiation-induced Liver Injury After Interstitial High Dose-rate Brachytherapy.

BACKGROUND/AIM: The aim of the present study was to determine whether the early systemic markers of inflammation, interleukin-6 (IL-6) and tumor necrosis factor-α (TNF-α), respond to high dose-rate (HDR) brachytherapy, and their possible correlation with radiation-induced liver injury of patients with liver metastases. PATIENTS AND METHODS: This prospective study included 20 tumor patients (TP) undergoing irradiation-based interstitial HDR brachytherapy (iBT) of liver metastases, who received total radiation ablative doses to the planning target volume ranging from 15 to 25 Gy, depending on the tumor entity. Hepatobiliary magnetic resonance imaging (MRI) was performed 6 weeks after iBT to assess the maximum extent of focal radiation-induced liver injury (fRILI). Furthermore, blood samples for the pro-inflammatory cytokine response were taken one day prior to and 6 weeks after irradiation. IL-6 and TNF-α were measured by flow cytometry. Ten healthy volunteers (HV) were used as control group. RESULTS: Compared to HV, TNF-α was significantly enhanced in TP before and after therapy (p<0.05 for both comparisons), while IL-6 increase at baseline was not statistically significant. HDR brachytherapy significantly reduced IL-6 levels after 6 weeks in TP (p<0.05). IL-6 levels after 6 weeks have shown a significant negative correlation with the tumor volume (r=-0.5606; p=0.0261), while no significant correlation was observed between baseline IL-6 or follow-up IL-6 levels with the fRILI. Baseline TNF-α levels positively correlated with the tumor volume (r=0.4342; p=0.0492), and post treatment TNF-α levels showed a significant correlation with the fRILI (r=0.7404; p=0.0022). CONCLUSION: TNF-α was correlated with both tumor volume and radiation-induced liver injury; thus, representing a promising biomarker for focal radiation-induced liver injury.

Radiation-Induced Cardiovascular Toxicities.

OPINION STATEMENT: Several seminal papers over the last decade have furthered our recognition of radiation-induced heart disease (RIHD) as an important potential toxicity following radiation therapy (RT) to the chest. Investigators continue to evaluate the subacute and long-term effects of RT. In addition, studies are determining whether certain cardiac substructures are more sensitive to radiation, working to identify risk factors for the development of RIHD, and testing screening and mitigation strategies for RIHD. Multiple groups and expert consensus guidelines have published whole-heart and cardiac substructure dose constraints based on available data and cancer type. The authors recommend readers to familiarize themselves with the guidelines for screening and mitigating RIHD in adults and children, which advocate for cardiovascular risk assessment and reduction before and following RT, as well as cardiovascular imaging at appropriate follow-up intervals for early recognition of subclinical cardiovascular disease. Referrals to cardiology or cardio-oncology can also be helpful in prevention, screening, and mitigation strategies.

SMART syndrome: two cases highlighting a complex and rare complication of brain irradiation.

Stroke-like migraine attacks after radiation therapy (SMART) syndrome is a rare complication of radiotherapy with complex neurological impairment. Patients present with neurological symptoms and signs such as migraine, hemianopsia, hemiplegia, aphasia and/or seizures-without recurrence of neoplastic disease. In this report, we describe SMART syndrome in two adult patients 4 and 14 years following brain irradiation, respectively.