Exploring Memory Systems After Pediatric Posterior Fossa Tumor: From Memory Profile Comparisons in Nonirradiated Versus Irradiated Patients to Episodic Memory Tests Capable of Detecting Radiation-induced Hippocampal Damage.

AIMS: Pediatric posterior fossa tumor (PFT) survivors experience long-term cognitive sequelae, including memory disorders, for which irradiation is one of the main risk factors. The aims of the present study were to (1) explore the profile of impairment in episodic, semantic, working and procedural memory systems in irradiated versus nonirradiated PFT survivors, and (2) test whether an autobiographical questionnaire and a two-phase ecological test (Epireal) assessing episodic memory are more sensitive to radiation-induced hippocampal damage than commonly used tests. MATERIALS AND METHODS: A total of 60 participants (22 irradiated PFT survivors, 17 nonirradiated PFT survivors, and 21 controls) were included in the prospective IMPALA study. They all underwent a broad battery of tests assessing the different memory systems in two 2-day sessions 3 weeks apart. We performed between-groups comparisons and analyzed impairment profiles, using -1.65 SDs as a cut-off. For irradiated patients, correlations were calculated between mean radiation doses to key brain structures involved in memory (hippocampus, cerebellum, and striatum) and corresponding memory scores. RESULTS: PBT survivors performed significantly more poorly than controls (p < 0.001) on conventional tests of episodic, semantic and working memory: 64% of irradiated patients and 35% of nonirradiated patients had a deficit in at least two memory systems, with episodic memory impairment being more specific to the irradiated group. Epireal had a larger effect size than the other episodic memory tests, allowing us to detect deficits in a further 18% of irradiated patients. These deficits were correlated with the mean radiation dose to the left hippocampus. CONCLUSION: Memory impairment is a frequent long-term cognitive sequela in PFT survivors, especially after radiation therapy. New ecological tests of episodic memory that are more sensitive to radiation-induced deficits than conventional tests could yield specific markers of the toxicity of medial temporal lobe irradiation.

Radiotherapy management of paediatric cancers with synchronous metastasis.

Cancer in childhood represent 1% of all the new diagnosed cancers. About 30% of children with cancer receive radiation therapy, representing about 600 to 700 patients per year in France. As a consequence, paediatric cancers with synchronous metastasis is a very rare situation in oncology, with usually poor standard of care. However, considerable efforts are made by paediatric oncology scientific societies to offer trials or treatment consensus despite these rare situations. The article proposes to synthesize the radiotherapy management of both primary tumour and synchronous metastasis in the most "common" childhood or adolescent cancers.

A Prospective Study of Arterial Spin Labelling in Paediatric Posterior Fossa Tumour Survivors: A Correlation with Neurocognitive Impairment.

AIMS: Posterior fossa tumours (PFTs), which account for two-thirds of paediatric brain tumours, are successfully treated in about 70% of patients, but most survivors experience long-term cognitive impairment. We evaluated arterial spin labelling (ASL), a common, non-invasive magnetic resonance imaging (MRI) technique, as a biomarker of cognitive impairment in a paediatric PFT survivor population. MATERIALS AND METHODS: Sixty participants were prospectively analysed. PFT survivors were at least 5 years post-treatment and had been treated as appropriate for their age and type of tumour. Group 1 had received radiotherapy and Group 2 had not. Group 3 were healthy controls matched to Group 1 for age, sex and handedness. All participants underwent cognitive assessment and multimodal MRI, including an ASL perfusion sequence. We used semi-quantitative ASL methods to assess differences in mean perfusion in the thalamus, caudate, putamen and hippocampus. RESULTS: Statistically, no significant associations between cognitive data and radiation doses were identified. Compared with healthy controls, Group 1 patients had significantly lower overall mean perfusion values (20-30% lower, depending on the cerebral structure) and Group 2 had slightly lower mean perfusion values (5-10% lower). Perfusion values did not correlate with total prescribed irradiation doses nor with doses received by different cerebral structures. Episodic and semantic memory test scores were significantly lower in Group 1 and correlated with lower mean absolute perfusion values in the hippocampus (P < 0.04). CONCLUSIONS: These preliminary results indicate that radiotherapy affects the perfusion of specific cerebral structures and identify perfusion as a potential biomarker of hippocampus-dependent memory deficit.

RadioTransNet, Radiotherapy Translational and Preclinical Research Network: Results from the dedicated French cancer institute (INCa) call for projects.

PURPOSE: The RadioTransNet project is a French initiative structuring preclinical and translational research in radiation therapy for cancer at national level. The network's activities are organized around four chosen priorities, which are: target definition, normal tissue, combined treatments and dose modelling. The subtargets linked to these four major priorities are unlimited. They include all aspects associated with fundamental radiobiology, preclinical studies, imaging, medical physics research and transversal components clearly related to these scientific areas, such as medical oncology, radio-diagnostics, nuclear medicine and cost-effectiveness considerations. METHOD: During its first phase of activity, four workshops following the consensus conference model and based on scientific and medical state of the art in radiotherapy and radiobiology were organized on the four above-mentioned objectives to identify key points. Then a road map has been defined and served as the basis for the opening in 2022 of a dedicated call, SEQ-RTH22, proposed by the French cancer national institute (INCa). RESULTS: Four research projects submitted by RadioTransNet partners have been selected to be supported by INCa: the first by Professor Anne Laprie from Oncopole Claudius-Regaud and Inserm ToNic in Toulouse on neurocognition and health after pediatric irradiation, the second submitted by Fabien Milliat from IRSN aims to study decryption and targeting of endothelial cell-immune cells interactions to limit radiation-induced intestinal toxicity, the third project, submitted by Yolanda Prezado from institut Curie-CNRS on proton minibeam radiotherapy as a new approach to reduce toxicity, and the latest project proposed by R. de Crevoisier from centre Eugène-Marquis in Rennes on predictive multiscale models of head and neck radiotoxicity induced for optimized personalized radiation therapy. Topics of each of these projects are presented here. CONCLUSION: RadioTransNet project has been launched in 2018, supported by INCa, in order to structure and promote preclinical research in oncology radiotherapy and to favor collaboration between the actors of this research. INCa relied on RadioTransNet initiatives and activities, resulting in the opening of dedicated call for projects. Beyond its first main goals, RadioTransNet network is able to help to fund the human and technical resources necessary to conduct optimal translational and preclinical research in radiation oncology.

[Characteristics of radiotherapy for adolescents and young adults]. / Caractéristiques de la radiothérapie chez les adolescents et les jeunes adultes.

Radiotherapy for adolescents and young adults is complex in several aspects. The population is very heterogeneous and has characteristics derived from both paediatric and adult populations both in terms of pathology (anatomical pathology, response to treatment) and the patient's physical, biological and psychological characteristics. This article reviews the characteristics to be taken into account in adolescent and young adult patients radiotherapy and more particularly in some of the most common diseases.

[Radiation dose intensification for glioblastoma]. / Majoration de dose d'irradiation pour les glioblastomes.

Glioblastoma is the most common brain tumor in adults; its treatment includes surgical excision or biopsy followed by radio-chemotherapy. Even if radiotherapy increases the survival of all patients regardless of their age or their general condition, there are always sources of radioresistance, where relapses occur and therefore treatment fails. Indeed, these foci result in a local relapse, which is observed in 95% of cases in the irradiation fields. We will describe here the current approaches to overcome this radioresistance by dose escalation, without or with guidance by metabolic and functional imaging (dose-painting). We will detail several prospective trials including the French phase III trial, SPECTRO-GLIO, randomizing the use of an integrated boost guided by spectrometric magnetic resonance imaging and similar trials developed across the Atlantic. We will also discuss approaches using different PET markers as well as diffusion or perfusion magnetic resonance imaging.

[Practice changing clinical trials in radiation oncology in 2022]. / Les essais qui changent les pratiques : le point en 2022.

This section highlights selected specific new recommendations and/or updates that have been published during the very last years in the fields of stereotactic radiotherapy, pediatrics, lung cancer, gynecologic and breast cancer, as well as in the area of radiation oncology of urogenital cancer.

[Paediatric radiation oncology in France: state of the art]. / Radiothérapie pédiatrique en France : mise au point.

Paediatric radiotherapy differs greatly from its practice in adults mainly because of the age (median age 6 years), which poses the problem of irradiation of healthy tissues in a growing organism, causing sequelae, difficult compliance and management of parents. These particularities require a dedicated education and specific organisation that was set progressively concerning indications, quality control, exhaustive collection of native dosimetry, long-term follow-up and clinical and translational research, as well as accreditations to practice paediatric radiotherapy, in close collaboration with the French society of child and adolescent cancer and leukaemia (SFCE), under the aegis of the French group of paediatric radiotherapy (GFRP). This organization is a pioneer in the development of pediatric radiotherapy quality controls, which are becoming the European standard and in the collection of native dosimetry integrated with the follow-up of possible late-effects, constituting the most important international database.

Guide for paediatric radiotherapy procedures.

A third of children with cancer receive radiotherapy as part of their initial treatment, which represents 800 paediatric irradiations per year in France carried out in 15 specialized centres approved on the recommendations of the French national cancer institute in decreasing order of frequency, the types of cancer that require irradiation are: brain tumours, neuroblastomas, Ewing's sarcomas, Hodgkin's lymphomas, soft tissue sarcomas including rhabdomyosarcomas, and nephroblastomas. The treatment guidelines follow the recommendations of the French society for childhood cancers (SFCE) or the French and European prospective protocols. The therapeutic indications, the technical and/and ballistic choices of complex cases are frequently discussed during bimonthly paediatric radiotherapy technical web-conferences. All cancers combined, overall survival being 80%, long-term toxicity logically becomes an important concern, making the preparation of treatments complex. The irradiation methods include all the techniques currently available: 3D conformational irradiation, intensity modulation radiation therapy, irradiation under normal or hypofractionated stereotaxic conditions, brachytherapy and proton therapy. We present the update of the recommendations of the French society for radiation oncology on the indications, the technical methods of realization and the organisation and the specificities of paediatric radiation oncology.

[Interest of image-guided radiotherapy for brain tumors and positioning control]. / Apport du guidage par l'image pour le repositionnement au cours de la radiothérapie des tumeurs encéphaliques.

A narrow therapeutic index and more and more patients with long survival characterize primary and second brain tumors. Image-guided radiotherapy can increase accuracy of the patient's position during a course of intracranial irradiation thanks to a direct or indirect visualization of targets volumes. Treatment reproducibility and organ at risk-sparing are the primary issues, particularly with the development of stereotactic radiotherapy and protontherapy. Regarding intracranial treatments, image-guided radiotherapy seems to be a repetitive task based on skeletal structures registration. And yet, this innovation makes possible to assess the dosimetric impact of daily positioning variations avoiding invasive immobilizations. Image-guided radiotherapy offers automated tools to limit time consumption and furthers adaptive radiotherapy opportunities. Nevertheless, medical evaluation is still necessary and image processing should be strictly defined (frequency, use, performance). The purpose of this article is to describe image-guidance in brain irradiation, as repositioning tool and to focus on its recent prospects.

[Green tongue phenomenon, or diagnosis via Google]. / Le phénomène de la langue verte, ou le diagnostic par Google.

BACKGROUND: Regular cannabis use may be associated with several oral changes not usually identified by dermatologists: xerostomia, increased risk of caries, periodontitis, leukoedema, gingival hyperplasia, and higher prevalence and density of Candida albicans, leukoplakia or gingivitis. PATIENTS AND METHODS: We report herein the appearance of a characteristic green tongue in a patient following intensive marijuana inhalation. DISCUSSION: This complication has rarely been reported in the medical literature. Paradoxically, it is clearly described in different Internet search engines, particularly Google.

Clinical and diagnosis characteristics of breast cancers in women with a history of radiotherapy in the first 30years of life: A French multicentre cohort study.

PURPOSE: Irradiation (>3Gy) to the breast or axillae before 30years of age increases the risk of secondary breast cancer (SBC). The purpose of this article is to describe the clinical characteristics of SBC and the way of diagnosis in young women (before the age of national screening) in France who had received previous radiotherapy for a childhood or a young adulthood cancer. PATIENTS AND METHODS: This retrospective, multicentre study reviewed the medical records of women with SBC before the age of the national screening who had received irradiation (≥3Gy) on part or all of the breast before 30years of age, for any type of tumour except BC. RESULTS: A total of 121 SBC were detected in 104 women with previous radiotherapy. Twenty percent of SBC were detected during regular breast screening and 16% of the women had a regular radiological follow-up. CONCLUSION: Our results points out that the main proportion of childhood cancer survivors did not benefit from the recommended breast cancer screening. This result is comparable to other previously published studies in other countries. A national screening programme is necessary and should take into account the patient's age, family history, personal medical history and previous radiotherapy to reduce the number of SBC diagnosed at an advanced stage.

[Radiotherapy for paediatric cancers]. / Radiothérapie des cancers de l'enfant.

The purpose of this article is to describe the specificities of paediatric radiation oncology: cancer types, radiotherapy indications, techniques, organisation and reglementary framework.

[French organization of paediatric radiation treatment: Results of a survey conducted by the radiotherapy Committee of the French Society of Paediatric Cancers (SFCE)]. / Organisation française de la radiothérapie pédiatrique : résultats d'une enquête du comité radiothérapie de la Société française des cancers de l'enfant (SFCE).

PURPOSE: Radiotherapy is a rare indication in paediatric oncology, with 800 to 900 children in treatment per year in France. Child cancers represent approximately 1% of cancers in France and half occur before the age of 5 years. Paediatric radiation requires appropriate tools, local, time and specific training. In France, in 2015, 18 centres are accredited by the French National Cancer Institute (INCa) for this activity. MATERIAL AND METHODS: Survey conducted in February 2015 on the care of children (0 to 18 years) in radiotherapy departments in France. The survey was sent to the radiation oncologists involved in the 18 centres. The questions concerned the qualitative and quantitative aspect, medical and organizational aspects, and the involvement of assistant practitioners in the management of this activity. RESULTS: Seventeen centres responded. In 2014, 889 children under 18 were treated in radiotherapy departments. These departments are working together with one to four paediatric oncology departments. Regarding access to general anaesthesia: three centres perform one to seven treatment(s) under anaesthesia per year, three centres eight to ten treatments under anaesthesia per year, three centres ten to 24 treatments under anaesthesia per year and nine centres out of 17 use hypnosis techniques. In terms of human resources, in 2015, 29 radiation therapists have a paediatric radiotherapy activity. Involvement of assistant practitioners is growing and specific training are desired. Regarding treatment preparation and delivery, 13 centres have specific paediatric contentions, 14 of 16 centres employ radiation intensity modulated if dosimetry is more satisfying with 11 regularly to the craniospinal irradiation. Radiotherapy on moving areas with respiratory gating or hypofractionation is under developed. CONCLUSION: Paediatric radiation therapy is a specific activity requiring a dedicated management, both in human, organizational, medical and scientific aspects.

[Postoperative external beam radiotherapy for medullary thyroid carcinoma with high risk of locoregional relapse]. / Radiothérapie postopératoire des carcinomes médullaires de la thyroïde à haut risque de rechute locorégionale.

PURPOSE: To assess the outcome of locally advanced medullary thyroid carcinoma treated with surgery and adjuvant external beam radiotherapy. PATIENTS AND METHODS: Twenty-nine consecutive patients with non-metastatic medullary thyroid carcinoma treated in our institution between January 1995 and December 2012 were retrospectively evaluated. All underwent curative-intended optimal surgery, followed by external beam radiotherapy because of high risk of locoregional relapse. Twelve patients were stage III, 16 IVa and 1 IVb. Positive surgical margins were present in 11 cases (10 R1 and 1 R2). Median and average preradiotherapy serum calcitonin were 141pg/mL and 699pg/mL, respectively. Fourteen patients received 3D-conformal radiotherapy and 15 received intensity-modulated radiotherapy. Median prescribed dose was 63Gy to the high-risk volumes and 54Gy to the low-risk volumes. Treatment was delivered in 30 fractions. The median gap between surgery and radiotherapy was 1.9months. Median follow-up was 76.4months. RESULTS: Kaplan-Meier estimates of 5-year locoregional relapse-free survival and overall survival were 79 and 96 %, respectively. Among the five locoregional relapses, two were related to a macroscopic metastatic cervical lymph node that was unfortunately not removed during the lymphadenectomy. Eight of ten patients with microscopic positive margins (R1) were controlled regarding the thyroidectomy bed. Eight patients had normal serum calcitonin after external beam radiotherapy, of whom only one developed a locoregional relapse during follow-up. Regarding the 21 patients with persistent positive serum calcitonin after treatment, only ten developed a macroscopic locoregional or distant relapse. One grade III and no grade IV acute morbidity were reported. Fifteen patients reported grade II chronic morbidity and no grade III/IV. CONCLUSION: Maximal surgery followed by adjuvant external beam radiotherapy as a treatment for locally advanced medullary thyroid carcinoma provides a high rate of long-term locoregional control and overall survival with limited toxicity. Postoperative external beam radiotherapy should be considered when patients present features indicating a high risk of locoregional relapse.

Automatic quantification of multi-modal rigid registration accuracy using feature detectors.

In radiotherapy, the use of multi-modal images can improve tumor and target volume delineation. Images acquired at different times by different modalities need to be aligned into a single coordinate system by 3D/3D registration. State of the art methods for validation of registration are visual inspection by experts and fiducial-based evaluation. Visual inspection is a qualitative, subjective measure, while fiducial markers sometimes suffer from limited clinical acceptance. In this paper we present an automatic, non-invasive method for assessing the quality of intensity-based multi-modal rigid registration using feature detectors. After registration, interest points are identified on both image data sets using either speeded-up robust features or Harris feature detectors. The quality of the registration is defined by the mean Euclidean distance between matching interest point pairs. The method was evaluated on three multi-modal datasets: an ex vivo porcine skull (CT, CBCT, MR), seven in vivo brain cases (CT, MR) and 25 in vivo lung cases (CT, CBCT). Both a qualitative (visual inspection by radiation oncologist) and a quantitative (mean target registration error-mTRE-based on selected markers) method were employed. In the porcine skull dataset, the manual and Harris detectors give comparable results but both overestimated the gold standard mTRE based on fiducial markers. For instance, for CT-MR-T1 registration, the mTREman (based on manually annotated landmarks) was 2.2 mm whereas mTREHarris (based on landmarks found by the Harris detector) was 4.1 mm, and mTRESURF (based on landmarks found by the SURF detector) was 8 mm. In lung cases, the difference between mTREman and mTREHarris was less than 1 mm, while the difference between mTREman and mTRESURF was up to 3 mm. The Harris detector performed better than the SURF detector with a resulting estimated registration error close to the gold standard. Therefore the Harris detector was shown to be the more suitable method to automatically quantify the geometric accuracy of multimodal rigid registration.

Identification of a candidate biomarker from perfusion MRI to anticipate glioblastoma progression after chemoradiation.

OBJECTIVE: To identify relevant relative cerebral blood volume biomarkers from T2* dynamic-susceptibility contrast magnetic resonance imaging to anticipate glioblastoma progression after chemoradiation. METHODS: Twenty-five patients from a prospective study with glioblastoma, primarily treated by chemoradiation, were included. According to the last follow-up MRI confirmed status, patients were divided into: relapse group (n = 13) and control group (n = 12). The time of last MR acquisition was tend; MR acquisitions performed at tend-2M, tend-4M and tend-6M (respectively 2, 4 and 6 months before tend) were analyzed to extract relevant variations among eleven perfusion biomarkers (B). These variations were assessed through R(B), as the absolute value of the ratio between ∆B from tend-4M to tend-2M and ∆B from tend-6M to tend-4M. The optimal cut-off for R(B) was determined using receiver-operating-characteristic curve analysis. RESULTS: The fraction of hypoperfused tumor volume (F_hPg) was a relevant biomarker. A ratio R(F_hPg) ≥ 0.61 would have been able to anticipate relapse at the next follow-up with a sensitivity/specificity/accuracy of 92.3 %/63.6 %/79.2 %. High R(F_hPg) (≥0.61) was associated with more relapse at tend compared to low R(F_hPg) (75 % vs 12.5 %, p = 0.008). CONCLUSION: Iterative analysis of F_hPg from consecutive examinations could provide surrogate markers to predict progression at the next follow-up. KEY POINTS: • Related rCBV biomarkers from DSC were assessed to anticipate GBM progression. • Biomarkers were assessed through their patterns of variation during the follow-up. • The fraction of hypoperfused tumour volume (F_hP g ) seemed to be a relevant biomarker. • An innovative ratio R(F_hP g ) could be an early surrogate marker of relapse. • A significant time gain could be achieved in the management of GBM patients.

[Value of neck dissection before definitive radiation therapy for locoregionally advanced squamous cell carcinoma of the head and neck]. / Place du curage ganglionnaire avant radiothérapie exclusive dans la prise en charge des carcinomes épidermoïdes localement évolués des voies aérodigestives supérieures.

PURPOSE: Optimal timing of neck dissection remains debated in the conservative management of patients with locoregionally advanced squamous cell carcinoma of the head and neck. PATIENTS AND METHODS: The files of 63 patients with radiographic evidence of bulky or necrotic nodal metastases treated by up-front neck dissection and definitive radiotherapy between 2000 and 2012 at two institutions were retrospectively reviewed. RESULTS: The primary site was oropharyngeal, hypopharyngeal or laryngeal in 63%, 21% and 13% cases, respectively. Overall, 83% of the tumours were staged pN2b or more. Extracapsular spread was found in 48 cases (77%). After a 48-month median follow-up, the 3-year locoregional control and overall survival were 88% and 68%, respectively. Only one isolated failure occurred in the dissected neck. CONCLUSION: This combination therapy provides a good locoregional tumour control. It should be considered as an option in laryngeal, hypopharyngeal or oropharyngeal squamous cell carcinomas with bulky or necrotic nodal metastases at presentation.

Paediatric brain tumours: A review of radiotherapy, state of the art and challenges for the future regarding protontherapy and carbontherapy.

BACKGROUND AND PURPOSE: Brain tumours are the most frequent solid tumours in children and the most frequent radiotherapy indications in paediatrics, with frequent late effects: cognitive, osseous, visual, auditory and hormonal. A better protection of healthy tissues by improved beam ballistics, with particle therapy, is expected to decrease significantly late effects without decreasing local control and survival. This article reviews the scientific literature to advocate indications of protontherapy and carbon ion therapy for childhood central nervous system cancer, and estimate the expected therapeutic benefits. MATERIALS AND METHODS: A systematic review was performed on paediatric brain tumour treatments using Medline (from 1966 to March of 2014). To be included, clinical trials had to meet the following criteria: age of patients 18 years or younger, treated with radiation, and report of survival. Studies were also selected according to the evidence level. A secondary search of cited references found other studies about cognitive functions, quality of life, the comparison of photon and proton dosimetry showing potential dose escalation and/or sparing of organs at risk with protontherapy; and studies on dosimetric and technical issues related to protontherapy. RESULTS: A total of 7051 primary references published were retrieved, among which 40 clinical studies and 60 papers about quality of life, dose distribution and dosimetry were analysed, as well as the ongoing clinical trials. These papers have been summarized and reported in a specific document made available to the participants of a final 1-day workshop. Tumours of the meningeal envelop and bony cranial structures were excluded from the analysis. Protontherapy allows outstanding ballistics to target the tumour area, while substantially decreasing radiation dose to the normal tissues. There are many indications of protontherapy for paediatric brain tumours in curative intent, either for localized treatment of ependymomas, germ-cell tumours, craniopharyngiomas, low-grade gliomas; or panventricular irradiation of pure non-secreting germinoma; or craniospinal irradiation of medulloblastomas and metastatic pure germinomas. Carbon ion therapy is just emerging and may be studied for highly aggressive and radioresistant tumours, as an initial treatment for diffuse brainstem gliomas, and for relapse of high-grade gliomas. CONCLUSION: Both protontherapy and carbon ion therapy are promising for paediatric brain tumours. The benefit of decreasing late effects without altering survival has been described for most paediatric brain tumours with protontherapy and is currently assessed in ongoing clinical trials with up-to-date proton devices. Unfortunately, in 2015, only a minority of paediatric patients in France can receive protontherapy due to the lack of equipment.

[Which dose constraints on which critical organs in paediatric radiation therapy?]. / Quelles contraintes pour quels organes à risque en radiothérapie chez l'enfant ?

Cancers in childhood are rare, representing 1% of all the cancers in developing countries. On the whole, the overall survival approaches 75% at 5 years. The radiation dose decrease in lots of indications as well as better optimized planning treatments lead to decrease the long-term toxicities in some indications. However, the radiation toxicity remains frequent, often specific of pediatric situations. Long-term toxicities are mainly neurologic, sensitive, endocrine, or linked to growth impairment (bones or muscular). Radio-induced second-cancers are also frequent after a long follow-up after cancer in childhood but will not be discussed here. Doses to critical organs as well as the most frequent radio-induced late-effects will be discussed in this paper.