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Disturbed root development of permanent teeth after pediatric stem cell transplantation. Dental root development after SCT
Abstract
Deficient dental root development has been reported after conventional pediatric anticancer therapy, but less information is available on stem cell transplantation (SCT) recipients.
Root-crown (R/C) ratios of fully developed permanent teeth were assessed from panoramic radiographs of 52 SCT recipients, who were treated when they were age < 10 years. Using standard deviation scores (SDSs), the authors compared the R/C ratios to the corresponding tooth and gender-specific values in a healthy population. The percentage of affected R/C ratios per individual was examined in a subgroup of 39 (SG39) patients with advanced tooth development. The effects of total body irradiation (TBI) and SCT age on the R/C ratios were studied in TBI and high-dose chemotherapy (HDC = non-TBI) groups and in 3 age groups (< or = 3.0 years, 3.1-5.0 years, > or = 5.1 years).
Per individual, 77% of the fully developed permanent teeth were affected in SG39. At the tooth level, in 77% of the 945 teeth studied (52 patients), the R/C ratios were outside +/-2 SDSs. More teeth were affected in the TBI (85%) than in the non-TBI (55%) group (P < 0.001). The teeth of the patients who were ages 3.1-5.0 years old at SCT presented with the most severe aberrations of the R/C ratio (mean SDS = -4.4) whereas the teeth of the youngest (age < or = 3.0 years) and the oldest (age > or = 5.1 years) patients were equally affected (mean SDSs = -3.1 and -3.0, respectively).
Disturbances of dental root growth always followed pediatric SCT. HDC alone intensely harmed root growth but TBI further increased the adverse effects that were most extensive in the patients 3.1-5.0 years at SCT. These sequelae should be taken into account during the lifelong dental follow-up to minimize the clinical consequences of dental injuries.
... Developmental dental anomalies include tooth agenesis, microdontia (small-sized tooth), impaired and arrested root development, such as short V-shaped roots, and enamel hypoplasia [7][8][9][10]. These anomalies are characterized by defective hard tissue formation. ...
... The prevalence of dental anomalies among pediatric patients with cancer is relatively high at 55.5%, compared with the prevalence of 6.7% among healthy individuals [13,14]. Other studies have reported that the prevalence of dental anomalies ranged from 50-100% in patients who underwent SCT [15] and that disturbances in root development were present in all patients who underwent SCT [7]. ...
... A large amount of long-term data is required to evaluate late dental complications after SCT [16]. Most studies analyzed only specific factors in a limited numbers of samples [7,[17][18][19]. In addition, there are conflicting reports suggesting that dental disturbances can be attributed to chemotherapy regimens [20], the age of the patient and the use of cranial radiation therapy [11], or the effect of TBI [18]. ...
Objective:
This study aimed to investigate the prevalence and extent of dental developmental complications in patients who have undergone pediatric hematopoietic stem cell transplantation (SCT) and identify the risk factors.
Materials and methods:
We retrospectively investigated the clinical data warehouse of the Catholic Medical Center information system for identifying patients who: 1) visited the Department of Pediatrics between 2009 and 2019, 2) underwent SCT under the age of 10, and 3) had panoramic radiographs. Thus 153 patients were included in this study. The prevalence and extent of tooth agenesis, microdontia, and root malformation were assessed using panoramic radiographs obtained after SCT, and the risk factors were analyzed using regression analysis.
Results:
All 153 patients had at least one dental anomaly. When grouped according to the age at initial chemotherapy (≤ 2.5; 2.6-5.0; 5.1-7.5; > 7.5 years), the prevalence of agenesis showed statistically significant differences among the different age groups (P < 0.001). The prevalence of agenesis was highest in the youngest age group. As the initial age at chemotherapy increased, the number of affected teeth per patient decreased for all three anomalies. The location of the affected tooth was also influenced by the age at initial chemotherapy. Regression analysis demonstrated that young age at initial chemotherapy was a risk-increasing factor for tooth agenesis and microdontia.
Conclusions:
The age at initial chemotherapy may be a critical factor in determining the type, extent, and location of dental complications after SCT. These results suggest that careful dental follow-up and timely treatment are recommended for pediatric patients undergoing SCT.
... First signs of dental disturbances can be expected within one or two years of anticancer treatment 9 . Reported abnormalities include hypodontia (missing teeth), microdontia (the formation of small teeth), damage to root development (premature closure of the apex, tapering roots with apical constriction, root stunting and V-shaped degenerated root), hypoplasia and hypomineralization (including damage to the enamel structure, resulting in incomplete calcification), over-retention of primary teeth, impaction, premature eruption, malocclusion, decreased temporomandibular joint mobility, trismus and facial deformities [10][11][12][13][14][15][16][17][18][19][20] . ...
... Microdontia causes esthetic, functional and occlusal complications, which require professional dental treatment later in life. Alterations of tooth root were the most frequent malformation found in the current study; however, the rate of 21% was low compared to 86% and even 100% in other reports of cancer survivors 20 . In healthy populations, rates of 1.3%-5.6% ...
... In healthy populations, rates of 1.3%-5.6% have been reported 20 . As tooth development is a relatively slow process, DDA may become evident on radiographs only two years after a triggering event. ...
Survival following childhood cancer has increased considerably. In an observational cross-sectional study, we assessed the prevalence of dental developmental anomalies (DDA) among childhood cancer survivors according to types of anticancer treatment. Permanent teeth were examined clinically and radiographically in 121 adolescents with a history of childhood malignancies, to identify DDA, namely hypomineralization or hypoplasia, microdontia, root changes and hypodontia. DDA were observed in 56/121 individuals (46%), in 309/3388 teeth (9%). Hypomineralization or hypoplasia of enamel appeared in 21 (17%) patients. Altered root development appeared in 26 patients and hypodontia affected 13 (10%). Dental anomalies were observed in 36 (43%) individuals who received chemotherapy and not radiation, in 20 (52%) who received radiotherapy, and in 15 (60%) of those who received head and neck radiotherapy. Among patients who received only chemotherapy, young age (6 years or younger) was associated with a higher number of malformed teeth. In conclusion, antineoplastic treatment that combines chemotherapy and radiotherapy appears to increase the risk of DDA. Radiation to the head and neck area was shown to particularly increase the risk of DDA. No specific chemotherapy agent was found to be associated more than the others with DDA.
... The rst sign of dental disturbances can be expected within one or two years of anticancer treatment 9 . Reported abnormalities include: hypodontia / agenesis (missing teeth), microdontia (the formation of small teeth), damage to root development (premature closure of the apex, tapering roots with apical constriction, root stunting, and V-shaped degenerated root), hypoplasia and hypocalci cation (including damage to the enamel structure, resulting in incomplete calci cation), over-retention of primary teeth, impaction, premature eruption, malocclusion, decreased temporomandibular joint mobility, trismus and facial deformities [10][11][12][13][14][15][16][17][18][19][20] . ...
... Defects in enamel development and alterations in tooth size were equally distributed among the patients (17%). Future dental aberrations may be predicted to some extent by understanding them within the context of the developmental stage of tooth mineralization in which they occurred 20 . In the current study, 62 teeth of 21 patients (17%) displayed some form of hypocalci cation and hypoplasia. ...
... Microdontia causes esthetic, functional and occlusal complications, which require professional dental treatment later in life. Alterations of tooth root was the most frequent malformation found in the current study (21%) compared to 86.4% and even 100% in the literature 20 . This compares with a range of 1.3%-5.6% in healthy populations. ...
Objectives: Survival following childhood cancer has increased considerably. We examined associations of cancer therapy with the presence of Dental Developmental Anomalies (DDA)among childhood cancer survivors.
Procedure: 131 children who were diagnosed with malignancies during childhood were included. Permanent teeth were examined clinically and radiographically to identify DDA: hypocalcification or hypoplasia, microdontia, root changes and hypodontia.
Results: observed in 56 (46%) of 121 children, in 309 teeth (9%). Hypocalcification or hypoplasia of enamel appeared in 21 (17%) patients. Altered root development appeared in 26 patients and hypodontia affected 13(10%). Dental anomalies were observed in 36(43%) individuals who received chemotherapy and not radiation, in 20 (52.63%) who received radiotherapy, and in 15 (60%)of those who received head & neck radiotherapy. Young age (under 6 years) was associated with a higher number of malformed teeth among patients who received only chemotherapy. Various chemotherapy agents associated similarly with dental anomalies.
Conclusions: Antineoplastic treatment that combines chemotherapy and radiotherapy appears to increase the risk of developing DDA. Radiation to the head and neck area particularly increases the risk of DDA. No specific chemotherapy agent was found to be associated more than the others with dental side effects.
... Late side effects are defined as permanent changes caused by disease, treatment, or both [1,2,3,4,5]. It has been reported that at least one side effect and related health problems are observed in approximately 40% of children receiving cancer treatment [6,7,8,9,10,11]. Most of these late side effects are not very serious, but they can still cause functional and aesthetic problems later in life, which may cause a decrease in quality of life [7]. ...
... Pediatric patients who were diagnosed with cancer and treated in the Departments of Pediatric Hematology and Oncology and Radiation Oncology at Dokuz Eylül University and Ege University and in the Outpatient Clinic of Hematology and Oncology at Behçet Uz Children's Hospital between January 2000 and December 2010 were included in the study. The first signs of root development in permanent teeth are generally observed on panoramic radiographs beginning approximately at the age of 3 to 7.5 years [6,9]. For that reason, patients with an age over 8 years were included in the study and the dental examinations were made between 5 and 8 years after cancer therapy. ...
... Teeth with short roots or V-shaped roots were evaluated as root malformations (RMs). Hölttä's Defect Index was used for the assessment of root length as previously described [9,17]. Teeth for which the ratio between the root and crown length was below 1.6 were evaluated as short-rooted teeth. ...
Objective: The aim of this study is to determine the frequency of dental anomalies (DAs) (microdontia, hypodontia, hyperdontia, enamel defect, root malformation) in pediatric cancer patients at the ages
... The findings of this systematic review showed that chemo and radiation therapy affected both the crown and the root of the teeth, with the root defects being more prominent. This is in accordance with the results of most of the studies [14][15][16]19,21,24,26 that indicated a higher score for root defects. Impaired root growth was the most common root defect followed by agenesis, a finding that is in accordance with most of the studies reporting root defects. ...
... Impaired root growth was the most common root defect followed by agenesis, a finding that is in accordance with most of the studies reporting root defects. 15,16,[21][22][23][24]26 The most common crown defect in this review was microdontia, as found in most other relevant studies. 14,15,21,22,26,27 Direct comparison between results was not possible for all included studies due to the heterogeneity of the samples regarding cancer type, area of primary diagnosis, and chemotherapeutic protocols used for treatment that varied between different institutions. ...
... 15,16,[21][22][23][24]26 The most common crown defect in this review was microdontia, as found in most other relevant studies. 14,15,21,22,26,27 Direct comparison between results was not possible for all included studies due to the heterogeneity of the samples regarding cancer type, area of primary diagnosis, and chemotherapeutic protocols used for treatment that varied between different institutions. ...
Background:
This systematic review summarizes the prevalence of dental defects after chemo and radiation therapy and correlates the findings with specific characteristics of each treatment modality.
Methods:
Database search was performed for studies reporting dental late effects of chemo and radiation therapy. After data extraction and risk of bias assessment, prevalence of crown and root defects was assessed. Correlations between each defect and the characteristics of the antineoplastic treatment were performed.
Results:
Sixteen nonrandomized studies were included, yielding a total of 1300 patients with a mean age at diagnosis of 4.5 years. Results reported that root defects were more common than crown defects. The most common root defect was impaired root growth and microdontia the most common crown defect. Age, radiation dose and field were statistically associated with higher prevalence of dental defects.
Conclusion:
Defects were associated with combination of chemotherapy and radiotherapy, as used in current therapeutic antineoplastic modalities.
... Patients who undergo HSCT during childhood have a risk of at least 60% long-term morbidity of 1 or more organ systems [1][2][3][4][5]. Also, little is known about the impact of a HSCT on dental development [4][5][6][7][8][9]. ...
... However, disturbances of root development can be due to both genetic and extrinsic factors [14,15]. Because root development follows crown development, disturbances of the root development will more frequently be found in patients treated at an older age [5,8,13]. ...
... Our study patients were divided into 3 categories: <3 years old, 3 to 6 years old, and >6 years old. Comparable categories were used in previous research: <3 years old, 3 to 5 years old, and >5 years old [5][6][7][8]. This small difference in age was done to have proportional groups for statistical analysis. ...
... Late side effects are defined as permanent changes caused by disease, treatment, or both [1,2,3,4,5]. It has been reported that at least one side effect and related health problems are observed in approximately 40% of children receiving cancer treatment [6,7,8,9,10,11]. Most of these late side effects are not very serious, but they can still cause functional and aesthetic problems later in life, which may cause a decrease in quality of life [7]. ...
... Pediatric patients who were diagnosed with cancer and treated in the Departments of Pediatric Hematology and Oncology and Radiation Oncology at Dokuz Eylül University and Ege University and in the Outpatient Clinic of Hematology and Oncology at Behçet Uz Children's Hospital between January 2000 and December 2010 were included in the study. The first signs of root development in permanent teeth are generally observed on panoramic radiographs beginning approximately at the age of 3 to 7.5 years [6,9]. For that reason, patients with an age over 8 years were included in the study and the dental examinations were made between 5 and 8 years after cancer therapy. ...
... Teeth with short roots or V-shaped roots were evaluated as root malformations (RMs). Hölttä's Defect Index was used for the assessment of root length as previously described [9,17]. Teeth for which the ratio between the root and crown length was below 1.6 were evaluated as short-rooted teeth. ...
Objective:
The aim of this study is to determine the frequency of dental anomalies (DAs) (microdontia, hypodontia, hyperdontia, enamel defect, root malformation) in pediatric cancer patients at the ages <5 years and between 5 and 7 years, and understand their relationship with the received therapy.
Materials and methods:
Pediatric patients who were diagnosed with cancer and treated before the age of 7 years were investigated in a case- control design. The study included 93 pediatric patients whose ages at diagnosis were between 9 months and 7 years and whose treatments were completed before 5-8 years. Group A consisted of patients in the age range of 9 months to 4 years and Group B consisted of patients in the age range of 5-7 years. Seventy-two siblings with compatible dental age ranges were included in the control group. For both groups, intraoral examinations were performed and panoramic radiographs were taken.
Results:
Among the 93 pediatric patients, the mean age was 9.54±1.25 (range: 8-13 years) and 48 (51.6%) patients were male. The most common diagnosis was hematologic malignancy with a rate of 65.5%. At least one DA was detected in 7 (9.7%) individuals of the control group and in 78 (83.9%) of the patient group. While the patients in the study group had all kinds of DAs, those in the control group had only enamel defects. The rates of microdontia (p=0.077) and hypodontia (p=0.058) were detected to be significantly higher in Group A than in Group B. Root malformation was more common in patients receiving chemotherapy and radiotherapy than in those receiving only chemotherapy (p=0.006).
Conclusion:
In this study it was found that the pediatric patients who received cancer treatment before the age of 7 years constituted a high-risk group for DAs. The frequencies of microdontia and hypodontia were increased even more when the patient was treated for cancer before 5 years of age.
... Root formation of the central incisors and first permanent molars starts at approximately 3.5 years of age, with the second permanent molars starting at 7.5 years of age. 5 Disturbances can include: failure of root formation, short roots, V-shaped tapering and blunting of the apical area. 6 Root shortening in survivors, especially when moderate to severe, can have a significant impact on the long-term prognosis of the teeth. 6 However, if a patient has a reasonable occlusion with good oral hygiene and no periodontal disease, minor root shortening may not affect the tooth's lifespan. ...
... 6 Root shortening in survivors, especially when moderate to severe, can have a significant impact on the long-term prognosis of the teeth. 6 However, if a patient has a reasonable occlusion with good oral hygiene and no periodontal disease, minor root shortening may not affect the tooth's lifespan. 6 Therefore, optimal oral health is critical for these patients and often the treatment principle is to preserve what is present and avoid any harm to any teeth or mucosal tissues. ...
... 6 However, if a patient has a reasonable occlusion with good oral hygiene and no periodontal disease, minor root shortening may not affect the tooth's lifespan. 6 Therefore, optimal oral health is critical for these patients and often the treatment principle is to preserve what is present and avoid any harm to any teeth or mucosal tissues. Survivors undergoing orthodontic treatment may have risk factors which would need consideration, such as abnormal root morphology, root resorption, increased roots of the existing teeth were already shortened and there was a risk of ankylosis of UL13. ...
Overall, the survival rate of people affected by childhood cancer is increasing. It is important for dental professionals to understand the effects cancer treatment can have on growth and dental development. The aim of this case report is to describe the effects of both chemotherapy and radiotherapy on dental development, dental appearance and oral health in a 6-year-old female patient treated for synovial sarcoma. The numerous theories of tooth eruption described in the literature are summarized and this case report shows how, although root development was arrested, tooth eruption still occurred.
CPD/Clinical Relevance: The skeletal and dento-alveolar effects of chemotherapy and radiotherapy for treatment of childhood cancers are explored and exemplified by the case reported. The numerous tooth eruption theories that have been described are also discussed. Interestingly in this case report, tooth eruption still occurred despite incomplete root formation.
... Third molars were included in the analysis. In analysis of the prevalence of disturbances in root development, root shortage was confirmed if the root/crown length ratio was lower than 1.6 (according to a simplified Hölttä Defect Index) [13]. The ratio was estimated only in teeth with completed root development. ...
... Such dental anomalies were also found in 16.2% of patients treated for solid tumors and lymphomas and in 31% of patients who underwent stem cell transplantation at the ages of 1.0-9.4 years [13,14]. In a healthy population, hypodontia is found in 2 to 10% of people [15]. ...
... In contemporary studies, the estimated abnormality ranged from 1.3% to 5.6% in healthy populations, and from 0.3% to 1.5% if limited to taurodontic molars [16,23,24]. However, in cancer survivors, the prevalence of various disturbances in root development reported by other authors was much higher, reaching 86.4% or even 100% [13,14]. The discrepancy between the results of the current study and others might be explained in part by difference in the criteria used by different investigators. ...
Purpose:
The aim of this study was to compare the incidence of dental complications in childhood cancer survivors with that of healthy controls subjects, and to determine the possible influence of various factors associated with patient and treatment.
Materials and methods:
Sixty-one panoramic radiographs of the dentition of cancer survivors were compared with 521 radiographs of healthy patients at a similar age, between 5 and 18 years. The mean period from termination of therapy was 4.9 years (58.9 ± 34.3 months), and 51 (83.60%) children were under age 5 when therapy began.
Results:
Dental anomalies were found in 38 (62.29%) cancer survivors and 69 (13.24%) control subjects (p<0.0001). Agenesis of teeth was found in 19 (31.14%) cancer patients and in 48 (9.21%) control subjects. Microdontic teeth were found in 22 (36.06%) cancer survivors and 15 (2.87%) control subjects (p<0.001), whereas teeth with short roots were found in 7 (11.47%) cancer patients and 15 (2.87%) control subjects (p<0.01). Dental anomalies in cancer patients were more common in some tooth groups and were not observed in others. The frequency of dental anomalies did not show correlation with age at the beginning or termination or time of therapy.
Conclusion:
s Children under the age of 5 are in a high risk group for dental complications after anticancer treatment. Rudimentary chemotherapy has a considerable impact on the occurrence of dental anomalies.
... The syndrome eventually became known as DC and is classified as one of the inherited bone marrow failure syndromes (IBMFS) [7]. DC was defined by the association of three clinical features: dystrophic nails, oral leukoplakia (white spots on the tongue and oral mucosa), and abnormal skin pigmentation [8]. Although the principal clinical findings of these conditions are described as a triad, there is a high association of hematopoietic abnormalities with this syndrome [9][10][11][12]. ...
... Malignancies tend to occur earlier in life compared to the same malignancies in non-DC individuals and are often the cause of death of patients in the third, fourth, and fifth decade of life. Individuals with DC may develop independent tumors at more than one site [2,8,15]. Oral and dental abnormalities have been reported in a few cases and include hypodontia, short blunted roots, hypocalcification, thin enamel, gingival recession, gingival inflammation with oedema, gingival bleeding, alveolar bone loss, periodontitis, extensive caries, smooth atrophic tongue mucosa, leukoplakia, and lichen planus [4] (Table 2). ...
... Root development begins after the crown of the tooth is formed. The earliest root development of the permanent teeth occurs at about the age of 3 years, beginning with the central 4 Case Reports in Dentistry incisors [5,8,17,19]. The second permanent molar roots begin to form between 7 and 8. Insults to the developing teeth, such as radiation, chemotherapy, or hematopoietic stem cell transplant during that time, can disturb root development [8]. ...
Dyskeratosis congenital (DC) is a rare condition characterized by reticulate skin hyperpigmentation, mucosal leukoplakia, and nail dystrophy. More serious features are bone marrow involvement with pancytopenia and a predisposition to malignancy. The purpose of this case report is to describe the oral and dental findings in children with DC syndrome. A 10-year-old male diagnosed with DC was admitted because of extensive caries and toothache. Inadequate oral hygiene and extensive caries were observed in oral examination of the patient. Plaque accumulation was seen in gingival border of maxillary teeth. Papillary atrophy on the tongue was observed. Short and blunted roots of mandible incisors and upper and lower molars were determined on the radiographic examination. Dryness on the lips and commisuras, ectropion on his eyes, and epiphora were observed. Hematologic tests were performed and showed aplastic anemia at the age of 2. At the age of 4, the bone marrow transplantation was performed. Dermatological findings occurred after the bone marrow transplantation. The skin of the patient was thin, dry, and wrinkled in some areas. He had palmoplantar hyperkeratosis and syndactylia on his fingers. Endodontic treatment procedures were applied and other extensive caries are still being restored. The patient will be given full preventive care during regular follow-up. Oral hygiene was improved to the optimum level.
... On the basis of long-term follow-up studies, it has been reported that long-term survivors who received chemotherapy treatment in childhood have an increased risk of dental disturbances such as short-root tooth and microdontia [6][7][8][9][10][17][18][19]. The present study shows that CY inhibits the regular formation of HERS and can cause disturbances to the developing root of the molar. ...
... To evaluate the effects of CY on root development until occlusion completion, in this study we used CY alone. An additional reason for conducting the study was that in most clinical reports investigating the effects of cytostatic drugs on developing teeth in humans, several different drugs, sometimes in combination with irradiation, have been used [7,10,19]. This has made it difficult to distinguish the CY is an alkylating agent, accounting for its capacity to interfere with the division of cancer cells. ...
... Reduction in root size, and deviations from normal root morphology have also been reported in young humans treated with CY for different types of cancer [6,7,10,17,18]. Several studies have shown that such patients had significantly reduced root sizes in comparison to healthy children [8,9,19,30,31]. With regard to morphology, arrested root development resulting in short V-shaped roots and apical closure were relatively common in the CYtreated children [18,32]. It is reasonable to assume that these abnormalities are due to disturbances in cell activity similar to those seen in the mice given CY in the present study; however, there are numerous potential causes of disturbances in the tooth development of long-term survivors of malignant diseases that may alter growth. ...
Root development of permanent teeth is disturbed in survivors of childhood cancer. Cyclophosphamide (CY) is a cytostatic drug commonly used for chemotherapy in children with cancer. This study aimed to evaluate the effects of CY on the development of molar teeth until the completion of occlusion in young mice, focusing on Hertwig’s epithelial root sheath (HERS). We treated thirty-two 12-day-old ICR mice with CY (100 mg/kg; 100-CY group), and 36 control mice with saline. At 12, 14, 16, 20, 24, 27, 39, 60, and 76 days of age, the mandibular molars were removed. Soft X-ray radiographs were obtained in lateral projection. The root/crown length (R/C) ratio of the first molar was calculated. Serial sagittal sections were prepared and histomorphological hematoxylin and eosin (HE) staining and immunohistochemical (cytokeratin) studies were performed. The R/C ratio of the 100-CY group (0.78) was smaller than that of the control group (1.23) at 76 days (p < 0.05, t test). While all roots developed further after injection, microscopic examination showed that the roots of the first molars that developed in the 100-CY group were shorter than those in the control group. In addition, experimental mice showed apical closure of the roots. By 20 days after injection, the HERS had disappeared from the root surface in the 100-CY group. In conclusion, this study indicates that CY can induce a defect in HERS and cause early loss of HERS. Disruption of the epithelial sheath inhibits normal root formation, and it could cause irreversible short-root development.
... Dental anomalies include hypodontia, microdontia, enamel defects, root development disturbances, delayed eruption, and persistent deciduous teeth, which may lead to anatomical, functional, and esthetic disturbances and decreased quality of life [22,[24][25][26][27] The prevalence of hypodontia in CCS varies between 6% and 44% and is most commonly observed in second premolars and second molars [25,[28][29][30]. Studies showed a 22-78% prevalence of microdontia in CCS treated with HCT [29,[31][32][33][34]. Hypodontia and microdontia can cause spacing and movement of teeth resulting in poor dental alignment. ...
... Dental anomalies include hypodontia, microdontia, enamel defects, root development disturbances, delayed eruption, and persistent deciduous teeth, which may lead to anatomical, functional, and esthetic disturbances and decreased quality of life [22,[24][25][26][27] The prevalence of hypodontia in CCS varies between 6% and 44% and is most commonly observed in second premolars and second molars [25,[28][29][30]. Studies showed a 22-78% prevalence of microdontia in CCS treated with HCT [29,[31][32][33][34]. Hypodontia and microdontia can cause spacing and movement of teeth resulting in poor dental alignment. ...
With diagnostic and therapeutic advances, over 80% of children diagnosed with cancer become long-term survivors. As the number of childhood cancer survivors (CCS) continues to increase, dental practitioners become more likely to have CCS among their patients. CCS may develop late complications from damage caused by their cancer treatment to endocrine, cardiovascular, musculoskeletal, and other organ systems. These complications may surface decades after the completion of treatment. Adverse outcomes of childhood cancer treatment frequently involve oral and craniofacial structures including the dentition. Tooth development, salivary gland function, craniofacial growth, and temporomandibular joint function may be disturbed, increasing oral health risks in these individuals. Moreover, CCS are at risk of developing subsequent malignancies, which may manifest in or near the oral cavity. It is important that dental practitioners are aware of the childhood cancer history of their patients and have knowledge of potential late complications. Therefore, this narrative review aims to inform dental practitioners of late oral complications of cancer treatment modalities commonly used in pediatric oncology. Furthermore, selected common non-oral late sequelae of cancer therapy that could have an impact on oral health and on delivering dental care will be discussed.
... είναι ένας σημαντικός παράγοντας κινδύνου που προκαλεί ανωμαλίες διάπλασης δοντιών και ότι αυτές οι ανωμαλίες εμφανίζονται κυρίως στον 1 ο και 2 ο προγόμφιο και τον 2 ο γομφίο στα παιδιά 46,47,48,49 . Με αυτά τα ευρήματα συμφωνεί και το δικό μας περιστατικό, καθώς οι 1 οι και 2 οι προγόμφιοι και οι 2 οι μόνιμοι γομφίοι ήταν τα δόντια των οποίων η διάπλαση επηρεάστηκε εκτενώς. ...
... Λόγω της σύντομης ημίσειας ζωής των χημειοθεραπευτικών παραγόντων, οι οδοντικές ανωμαλίες είναι συνήθως εντοπισμένες και προκύπτουν από παροδικές μεταβολές στη λειτουργία οδοντοβλαστών και όχι από την πλήρη καταστροφή τους 55 . Ωστόσο, η εντατική, επαναλαμβανόμενη χημειοθεραπεία κατά τη στιγμή του αρχικού σχηματισμού των σκληρών ιστών μπορεί να προκαλέσει αγενεσία δοντιών 45,48 . ...
In recent years, there has been a significant increase in the survival rate of pediatric patients diagnosed with cancer, as a result of the therapeutic effect of regimens used for anticancer treatment. Despite the undisputed positive aspects of chemotherapy, undesirable effects have been reported in literature, since chemotherapy could lead to
long-term side effects in oral cavity. Those adverse effects include tooth development disturbances and disorders referring to the number, morphology and structure of teeth. In pediatric patients, that have been diagnosed with Ewing Sarcoma and hence went through chemotherapy, it has been reported that antineoplastic agents can lead to deficient dental root development, tooth development disturbances and even tooth agenesis. The absence of teeth brings about speaking and mastication difficulties, aesthetic problems and lack of self-confidence. It is extremely important that the pediatric dentist collaborates with other specialists (paediatrician, pediatric oncologist, orthodontist and prosthodontist) in order to eradicate patient’s problems in total. It is crucial for the clinical dentist to understand the mechanism of action of antineoplastic agents in depth and more specifically the way these factors are involved in the development of the stomatognathic system. The literature was reviewed using keywords pertinent to the subject and we ended up with 73 references. The aim of this study was to investigate the adverse effects of antineoplastic agents on the development of the stomatognathic system in pediatric patients. In addition to this, the present study includes a report of a clinical case of a 6.5-year-old girl, who was diagnosed with tooth development disturbances and had a history of Ewing Sarcoma treated with chemotherapy. Clinical and radiographic examination revealed development disturbances in 1st and 2nd premolars and 2nd permanent molars, resulting in hypodontia. Moreover, deciduous molars with arrested development of their roots, were also present in this case. In conclusion, it is
essential that the clinician should do a meticulous clinical and radiographic examination to patients who have undergone chemotherapy and have survived.
... Patient demographics and disease-and treatment-related characteristics were summarized using descriptive statistics and compared between the H&N RT and the non-H&N RT groups using the Mann-Whitney U test for continuous variables and Fisher's exact test for categorical variables. Age at diagnosis was divided into three categories, based on age ranges described in previous papers on dental late effects: 0-2.99 years, 3-4.99 years, and ≥5 years [19,26]. Frequencies of DDDs and oral health data were reported and compared according to treatment modality and age at diagnosis using Fisher's exact test. ...
... In our study, short-root anomaly was prevalent in survivors of any age at diagnosis, and was not significantly different between the age at diagnosis categories, which is consistent with another study of 69 CCSs [44]. In contrast, in a study of 52 stem cell transplantation recipients, root development was mostly affected in the age group between 3 and 5 years at diagnosis [26]. ...
Objectives:
The aim of this study was to identify the prevalence of and independent risk factors for long-term effects of childhood cancer treatment on the dentition and oral health in childhood cancer survivors (CCSs).
Methods:
This cross-sectional study is part of the Dutch Childhood Cancer Survivor Study (DCCSS) LATER 2. CCSs were diagnosed with cancer between 1963 and 2001. This study focuses on survey data of 154 CCSs on whom information about their oral health was received from their dentists (71.3%). Descriptive statistics and univariable and multivariable Poisson regression analyses were performed to determine the association between treatment characteristics and oral health data.
Results:
Of the study group, 36.3% had at least one DDD. The most prevalent DDDs were short-root anomaly (14.6%), agenesis (14.3%), and microdontia (13.6%). Risk factors for at least one DDD were younger age at diagnosis (<3 years) and dose-dependent alkylating agent therapy.
Conclusions:
This study provides more insight into risk factors for oral health problems in Dutch CCSs. This information is essential in order to improve early detection, prevention, dental care, and quality of life. Further studies are needed in order to better define dose-related radiotherapy exposure of the developing teeth in correlation with oral health problems.
... vormde wortel, vertraagde eruptie van de blijvende en retentie van de tijdelijke gebitselementen, hyposialie en verstoringen in de craniofaciale groei (Duggal et al, 2003;Vaughan et al, 2005;Höltta et al, 2005;Avşar et al, 2007). Tevens kunnen er speekselveranderingen zijn en is de kans op het ontstaan van cariës groter (Dahllöf et al, 1997a;Dahllöf et al, 1997b;Wogelius et al, 2008). ...
... Dit onderzoek bevestigt eerdere rapportages die meldden dat de ontwikkeling van de blijvende dentitie wordt beïnvloed door kankertherapie (Duggal et al, 2003;Höltta et al, 2005;Vaughan et al, 2005;Avşar et al, 2007 ...
Veertig kinderen die vanwege een hematologische maligniteit een allogene stamceltransplantatie hadden ondergaan, namen minimaal 2 jaar na transplantatie deel aan een onderzoek. De onderzoekers verzamelden gegevens over subjectieve orale symptomen, bevindingen op een panoramische rontgenopname en gegevens van een mondonderzoek. Bijna alle kinderen hadden ontwikkelingsstoornissen, waaronder agenesieen, verkorte wortels en onvolledig gevormde wortels. De prevalenties van agenesieen van de eerste en de tweede premolaar in de maxilla en de mandibula en van de tweede molaar in de mandibula waren in de onderzoeksgroep significant groter dan de normatieve waarden. Kinderen die bij aanvang van de kankertherapie jonger waren dan 3 jaar hadden significant minder gebitselementen dan oudere kinderen. De verhouding tussen de lengte van de wortel en de kroon van de diverse gebitselementen was in de onderzoeksgroep ongunstiger dan in een gezonde Finse controlegroep. Door vervroegde wortelsluiting was de gemiddelde gebitsleeftijd hoger dan de gemiddelde chronologische leeftijd.
... Their occurrence depends on a number of factors, sometimes unknown. There is strong evidence that dental abnormalities are late adverse effects of antineoplastic therapy when it is introduced at a young age [4][5][6][7][8][9][10][11][12][13][14]. When the abnormalities concerning developing structures are discussed, age is frequently considered an important determining factor. ...
Simple Summary
Despite the multidrug nature of anticancer treatment, attempts are still being made to determine the relationship between the duration of chemotherapy, the dose of individual drugs, and the occurrence of dental developmental abnormalities. There are relatively few papers devoted to this issue, and all of them are based on the study groups composed of individuals receiving various treatment regimens. The current study includes a group of acute lymphoblastic leukemia survivors who underwent chemotherapy according to the ALL IC-BFM 2002 protocol. Contrary to the observations of some authors, the results of the current research suggest that the age at the start of chemotherapy is likely to be the strongest risk factor for toxic injury during tooth development. A small study cohort is a major limitation, but an evaluation of similar relationships at larger research centers would be helpful in better understanding the problem.
Abstract
The multidrug nature of anticancer treatment and different treatment protocols used in the studies are likely to be a major limitation in establishing real risk factors determining the occurrence of dental abnormalities. The authors aimed to establish a relationship between the duration and the dose of chemotherapy and the number of tooth adverse effects in the group receiving the same treatment. Of the 40 anticancer therapy recipients who attended the outpatient dental clinic, 7 leukemia survivors receiving the treatment according to the ALL IC-BFM 2002 protocol were selected. The study group consisted of four females and three males aged 92 to 207 months at the time of dental examination and 29 to 91 months at leukemia diagnosis. As a result of the clinical and radiological examination, dental abnormalities such as agenesis, tooth size reduction, root abnormalities, and taurodontia were identified, and the medical records of all survivors were reviewed in terms of drugs administered, their doses, and treatment schedules. No correlation was observed between the treatment duration of an intensive therapy, the entire therapy, and the number of tooth abnormalities. No relationship was also found between the number of dental abnormalities and the cumulative dose of vincristine, L-asparaginase, methotrexate, cyclophosphamide, cytarabine, and 6-mercaptopurine. The age at the onset of antineoplastic therapy is likely to be the strongest risk factor for toxic injury during tooth development.
... I Norge ble det i 2019 diagnosti sert 191 nye tilfeller i aldersgruppen 0-17 år, noe som gir en insi dens på 16-17 per 100 000 barn per år, omtrent på samme nivå som i resten av Europa (1). Insidensen har vaert stabil i Norge de siste 35 år, mens internasjonale undersøkelser viser en lett stigende ten dens (1,2). Leukemier og svulster i sentralnervesystemet utgjør ca. ...
Hovedbudskap
To av tre barn har senskader etter kreftbehandling
Lav alder og aggressiv behandling øker risikoen for orale senskader
Munnhulen må være sanert når kreftbehandling påbegynnes. Risiko for karies, infeksjoner og slimhinneproblem under kreftbehandling er stor
Orale senskader er en oversett årsak til redusert livskvalitet
Oppfølgingen av orale senskader etter barnekreft må systematiseres og forbedres
... Although the prevalence was relatively low in this study, we confirmed results reported previously. 11,12 In this long-term follow-up study, univariable analysis revealed that the prevalence of kidney, thyroid, and cardiovascular complications was significantly higher in survivors aged [?]18 years than in those aged <18 years. Künkele 13 reported that 17% acute leukemia survivors treated with HSCT showed renal toxicity. ...
We conducted a cross-sectional study using a questionnaire to explore the late effects in survivors of juvenile myelomonocytic leukemia (JMML). The attending pediatric hematologist oncologists completed the questionnaires. All survivors (N=30) had undergone allogeneic hematopoietic stem cell transplantation. Approximately 83% survivors showed more than one late effect. The identified late effects included endocrine, dental, skin, ophthalmologic, musculoskeletal, pulmonary, neurocognitive, and cardiovascular dysfunction. The prevalence of short stature and cardiovascular and kidney dysfunction was significantly elevated among survivors aged ≥18 years. Therefore, a multidisciplinary follow-up system for survivors of JMML is crucial.
... A retrospective evaluation of orthopantomograms of 70 childhood cancer survivors with a mean age of 4.17 years at diagnosis reported 62% of root defects, most commonly impaired root growth, and treated with radiotherapy [28]. Observing different root development disorders, the prevalence reaches an even higher rate, 77% [29]. Due to the young patient's age presented in this case, not all roots were developed so we cannot discuss and conclude that no arrested root development will happen in the future. ...
Chemotherapy used on pediatric patients especially those below 3 years of age causes disturbances in dental development. The aim of this case report was to present the late dental effects of chemotherapy in a patient treated for anaplastic ependymoma (WHO III) at an early age. Radiographic findings at the age of 9 years showed oligomicrodontia of six teeth, maxillary lateral incisors, and maxillary and mandibular first premolars. Pediatric cancer survivors after chemotherapy have an increased risk of one or more dental development disorders. To ensure proper dental care and to assess the long-term effects on oral health, tooth development, and occlusion, the involvement of a dentist is crucial. Adequate diagnosis and well-planned treatment of the dental defect can significantly improve patient oral health-related quality of life.
... Seventy five panoramic radiographs of teeth in cancer patients were analyzed by two examiners (A.H. and P.P.); in the case of discrepancies, they were discussed until the agreement was achieved. Among the anomalies recorded in the cancer patients, oligohypodontia (smaller number of teeth), microdontic teeth (at least half of size when compared to homonymous ones), and teeth with misshaped roots were observed (root shortage was confirmed if the root/crown length ratio was lower than 1.6, according to a simplified Hölttä Defect Index); [19]. The dental age of the cancer survivors was estimated with the Demirjian method, based on the stage of development of seven lower left permanent teeth [20]. ...
Background:
There is lack of data related to dental occlusion among children cured from cancer. The aim of our study was to compare the prevalence of malocclusion in cancer survivors and in healthy peers.
Methods:
A cross-sectional study was conducted on 225 children aged between 4 and 18 years, including 75 cancer survivors, and 150 sex and age-matched controls. All patients were orthodontically examined and malocclusion traits were recorded. In the cancer group, 75 panoramic radiographs were used to evaluate the prevalence of dental anomalies and dental age using the Demirjian scale. Data were analyzed by univariate statistical analysis with p-values p < 0.05 considered as statistically significant.
Results:
Malocclusion was found in 49 (65.33%) cancer survivors and 99 (65.56%) controls (p > 0.05). The cancer group demonstrated significantly higher likelihood of crossbite (p < 0.01) and malalignment of teeth (p = 0.031). The healthy controls were more likely to demonstrate open bite (p = 0.038). Cancer patients with posterior crossbite (p = 0.023) or dental malalignment had a more advanced dental age (p = 0.022). Survivors with crossbite had more teeth with short roots (p = 0.016). Those who were older when they started their cancer therapy were more likely to suffer from tooth disturbances (p = 0.019).
Conclusion:
Oncological treatment can alter the development of occlusion in cancer patients.
... Accordingly, more attention has been focused on the late effects of cancer treatment in long-term survivors and on their quality of life (2,3). For example, localized radiotherapy in the maxillofacial region to treat pediatric malignant tumors (4)(5)(6) and total-body irradiation (TBI) prior to hematopoietic stem cell transplantation in patients with childhood leukemia are well known to cause impaired or deficient tooth formation and failed or delayed tooth eruption (7)(8)(9). ...
To elucidate the mechanism underlying the failure of root formation after irradiation, we established a method of local irradiation of the molar tooth germ and demonstrated that radiation directly affected dental root development. In the current study, to locally irradiate the lower first molars of 5-day-old C57BL/6J mice, we used lead glass containing a hole as a collimator. We confirmed that our local irradiation method targeted only the tooth germ. The irradiated root was immature in terms of apical growth, and dentin formation was irregular along the outside of the root apices. Moreover, calcified tissue apically surrounded Hertwig's epithelial root sheath, which disappeared abnormally early. This method using a local irradiation experimental model will facilitate research into radiation-induced disorders of dental root formation.
... Developmentally, short-rooted teeth may be genetic and this condition is termed short root anomaly [20,21] or exogenous, which might be encountered during chemotherapy or radiotherapy. [22] Conclusion When a large collection of dentitions from one species is studied; it showed surprisingly large degree of variations in size and form. These variations might be affected by the environment where growth took place. ...
Background:
The presence of variations in crown and root measurements in deciduous teeth usually leads to complications during and after treatment. Hence, in order to improve the success rate in pediatric treatment, there must be proper knowledge of dental morphological and morphometric characteristics of deciduous teeth among different populations.
Objective:
The aim of the present study was to assess length of the crowns, length of the roots, roots to crown (R/C) ratio, and distance between the floor of pulp chamber to furcation using cone beam computed tomography (CBCT).
Materials and methods:
Extracted deciduous molar teeth were collected and divided into: group I: Deciduous mandibular first molars (lower D) (n = 16) and Group II: Deciduous mandibular second molars (lower E) (n = 21). The length of the crowns, length of the roots, R/C ratio and distance between the floor of pulp chamber and furcation were measured using CBCT. Data were statistically analyzed.
Results:
Lower D showed smaller crown length with a mean of 4.87 mm, longer mesial root length with a mean of 9.68 mm and greater R/C ratio with a mean of 2 mm when compared to lower E. As for the distal root length and the distance between the floor of the pulp chamber and the furcation area, both molars closely resembled each other. There was a statistical significant difference between both molars regarding mesial root length, crown length, and R/C ratio.
Conclusion:
The current study concluded that dental morphological characteristics are important in research as they provide valuable information about diversities within a population.
... In the group of cancer survivors, the presence of dental anomalies was estimated. Hypodontia was recognized when a tooth germ was missing, microdontia when a tooth was half or less of the size of a comparable homolog [8], and root shortage if the root/crown length ratio was lower than 1.6 (according to a simplified Hölttä Defect Index); [9]. ...
Purpose:
The study aimed to assess the differences in dental maturation between childhood cancer survivors and healthy children.
Materials and methods:
Fifty-nine cancer patients including 16 (27.1%) girls and 43 (72.8%) boys, aged between 4 and 16 years, underwent dental and radiographic examinations. The mean duration of anticancer therapy was 16.8 months (range, 1 to 47 months), and 4.6 years (range, 8 to 123 months) had passed since the termination of disease. The control group consisted of 177 panoramic radiographs of age- and sex-matched healthy individuals. Dental age (DA) was estimated with Demirjian's scale and delta age, i.e., DA-chronological age (CA), was used to compare groups.
Results:
The DA of cancer survivors was accelerated by almost 1 year compared to their CA (9.9±3.1 vs. 8.9±2.8; p=0.03). The greatest difference was observed among patients with brain tumor: delta (DA-CA) was 2.2±1.1 years. Among all cancer patients, only children with familial adenomatous polyposis (FAP)-associated hepatoblastoma (HP) demonstrated delayed DA, with regard to both other cancer survivors (p=0.01) and healthy patients (p=0.03). All four patients with HP suffered from FAP, and three of them had documented adenomatous polyposis coli (APC) genes mutation. The DA of cancer patients having teeth with short roots was significantly greater than that of the cancer survivors without this anomaly (12.8±3.2 vs. 9.0±2.4; p < 0.001).
Conclusion:
DA in children may be altered by cancer disease.
... All of the permanent teeth, except for the third molars, typically have erupted by age 13; thus, exposure to unfavorable factors during the critical period may disturb tooth development [18]. Tooth development depends on a series of inductive events involving genes coding for growth factors, such as those of the FGF, BMP, Wnt, and Hedgehog families, which regulate epithelial-mesenchymal interactions [19], and whose function can be regulated by environmental factors, such as anticancer drugs or antibiotics [20] or infections during pregnancy (such as rubella) [21], and maternal smoking during pregnancy [22]. ...
Tooth agenesis and disturbance of tooth eruption is the most prevalent oral defect, and is possibly caused by the interaction of genetic and environmental factors. We hypothesized that prenatal factors may affect tooth development. The objective of this study was to examine whether smoking during pregnancy was associated with missing teeth in the offspring during adolescence. The study population comprised pregnant women and their children registered (N = 1052) at Koshu city, Japan. When the expectant mothers visited the city office for pregnancy registration, a survey was conducted to ascertain their lifestyle habits. Data on missing teeth in the children were obtained from the compulsory dental health checkup during junior high school years. Multivariate logistic regression models were fitted to assess the association between missing teeth and lifestyle habits. A total of 772 children were studied. The prevalence of missing teeth in these children was 4.9%. Children whose mothers smoked six cigarettes or more per day were 4.59 (95% CI: 1.07–19.67) times more likely to present with missing teeth than those children whose mothers did not smoke, after adjustment for possible confounders. Our findings indicate that smoking during pregnancy can be a risk factor for missing teeth in the offspring.
... DRAs were those DAs that appeared more exclusively as a late effect of CHT and/or RT in CCSs compared with healthy individuals. 20,31 The most vulnerable proliferative cells are found in the epithelium of the Hertwig sheath, which is responsible for root formation and can be affected by CHT and/or RT. 32 The odontoblasts are responsible for maintaining the morphogenesis and structure of the Hertwig sheath, where the b-catenin odontoblastic molecule acts as an essential regulator of morphogenesis and root development. 33 A study in rats revealed that after the administration of a chemotherapeutic agent, dental root development was disrupted, causing cellular damage in odontoblasts and the Hertwig sheath. ...
Objective:
The aim of this study was to evaluate dental abnormalities and dental maturity (DM) in the permanent dentition of childhood cancer survivors (CCSs) in comparison with that of healthy individuals.
Study design:
A retrospective, case-control study, with convenience sampling, evaluated 111 panoramic radiographs (PRs) of CCSs compared with 111 PRs of healthy individuals matched for age and gender. Dental anomalies (DAs) were associated with age of cancer diagnosis and type of antineoplastic treatment. DM was assessed by using the Demirjian method.
Results:
A higher prevalence of microdontia, hypodontia, and dental root anomalies were present in CCSs compared with healthy individuals (P < .05). CCSs were the only individuals with 10 or greater DAs compared with healthy individuals. Microdontia was the only DA associated with age of cancer diagnosis less than 71 months (P < .05). Impacted teeth were associated with multimodal cancer treatment (P < .001). DM did not present a significant statistical difference between CCSs and healthy individuals (P > .05).
Conclusions:
CCSs had a higher prevalence of DAs without DM alteration compared with healthy individuals. Age of cancer diagnosis and type of treatment can influence the prevalence of some dental abnormalities.
... The consequence of both treatment types can be salivary changes [2][3][4], oral infections, and orodental development alterations [2,5,6]. Treatment with these modalities during the early stages of tooth development can lead to dental agenesis or microdontia, and during later stages can disturb root development [7]. The varying ability of cytotoxic agents and radiotherapy to cause sub-lethal or lethal damage to tooth-forming cells contribute to the clinical outcome. ...
Purpose
More attention has been focused on the long-term side effects of treatment protocols since impressive advances in childhood cancer treatment have resulted in a growing population of patients. The purpose of this study was to investigate the disturbances of dento-facial development in children who were long-term survivors of childhood malignancies.
Methods
Fifty-three children (mean age, 10 years + 4 months) in long-term remission underwent oral/dental and radiographic examinations after completion of therapy. Crown and root malformations, gingival/periodontal status, enamel defects, discolorations, decayed and unerupted teeth, premature apexifications, agenesis, maximal interincisal opening and lateral movement of jaws, and soft tissue abnormalities were noted. Caries were evaluated by the decayed-missing-filled teeth (DMFT) index. Forty healthy children (mean age, 12 years + 4 months) belonging to the same age group and socioeconomic community were served as controls. All participants in the study were evaluated in terms of craniofacial development.
Results
The data of the study showed that higher prevalence of root malformation, unerupted teeth, and enamel hypoplasia were detected as a consequence of childhood cancer and/or antineoplastic therapy. Although no differences of craniofacial growth and development were observed between groups (P > 0.05), plaque and gingival index scores were statistically higher in the study group (P < 0.05).
Conclusion
A range of variations in dental structures is recognized as a side effect of childhood cancer therapy in long-term survivors of pediatric malignancies that may affect their quality of life.
... Defective enamel is created, because osteodentin interferes with the normal interaction of dentin and enamel. Enamel and dentin defects lead to tooth dwarfism, blunted and tapered root, incomplete calcification, premature apical closure, and lack of eruption [77,78,[82][83][84][85][86][87]. ...
... The main reasons for short roots are disturbances during dental root development and resorption of originally well-developed roots. 13 Underexplored topics regarding palatally impacted canines include apical dilacerations and crown/root ratios. Therefore, the aims of this study were to investigate the relationships between the presence of a severe apical curvature or a hook, other lesser root curvatures and the crown/root ratio in subjects with and without palatally impacted maxillary canines. ...
Introduction:
The aim of this study was to investigate the relationships between an apical curvature or a hook and the crown/root ratio in subjects with and without palatally impacted maxillary canines.
Methods:
An experimental group of 44 patients (17 boys, 27 girls; mean age, 13.6 years) with 59 palatally impacted maxillary canines was selected from the records of patients referred to a radiology practice for cone-beam imaging. If a patient had bilateral palatally impacted canines, 1 canine was randomly selected for analysis. The palatally impacted canine group was matched for age and sex with 49 normal subjects (25 boys, 24 girls; mean age, 13.2 years) with 98 canines. Cone-beam DICOM files were imported into In Vivo imaging software (version 5.3; Anatomage, San Jose, Calif) for analysis. The angulations and linear variables of the maxillary canines were measured by using the software measurement tools. Chi-square and independent t tests were used to test for differences between the groups.
Results:
The presence of a hook at the apical third and other root curvature were significantly different between the 2 groups (P <0.001 and P <0.05, respectively). Of the 44 palatally impacted canines, 16 (36.4%) had an apical hook and only 1 canine in the control group had an apical hook (1.0%). The mean root length of the palatally impacted canines was 2.66 mm shorter (P <0.001), and the mean crown/root ratio was significantly greater for the palatally impacted canines compared with the nonimpacted group (P <0.001).
Conclusions:
Palatally impacted canines have a greater tendency to develop apical hooks and are less likely to develop other root curvatures than are nonimpacted canines. Also, they have shorter roots resulting in larger crown/root ratios compared with the control group.
... The severity of defects and number of teeth involved in this environmental insult are influenced by the age of the child when he/she received the treatment. [52] The effect of dioxin on tooth development has been reported as an increase in prevalence of hypomineralisation of teeth in Kotka and Anjalankoski in Finland and as an increase in prevalence of tooth agenesis and hypomineralised enamel among people exposed to it in Seveso, Italy . [53]This has been verified in the laboratory in experimental animals . ...
... The severity of defects and number of teeth involved in this environmental insult are influenced by the age of the child when he/she received the treatment. [52] The effect of dioxin on tooth development has been reported as an increase in prevalence of hypomineralisation of teeth in Kotka and Anjalankoski in Finland and as an increase in prevalence of tooth agenesis and hypomineralised enamel among people exposed to it in Seveso, Italy . [53]This has been verified in the laboratory in experimental animals . ...
Tooth agenesis is the most prevalent craniofacial congenital anomaly in humans. The term refers to an isolated disorder in the absence of non-dental phenotypes but is also used to describe the manifestation of missing teeth in syndromes. The affected individuals suffer from compromised masticatory functions and have decreased quality of life. Discerning the genetic etiology of tooth agenesis not only improves our understanding of normal tooth development but also provides a fundamental basis for developing potential therapeutic strategies for this anomaly. To date, MSX1, Pax9, Axin2, Eda, And Wnt10a have been established as candidate genes associated with non-syndromic tooth agenesis.This article reviews the recently discovered genes involved in dental agenesis , and provides an update on the aetiological factors underlying this common malformation.
... Alternative sources of hematopoietic cells are required for those without an HLA-matched sibling. International URD and cord blood registries have been established to find donors for those patients [6][7][8][9][10][11][12][13][14][15][16]. As of May 2014, there were over 23 million URDs and greater than 600,000 cord blood units from 52 countries in international registries [17]. ...
Hematopoietic cell transplantation is a potentially curative therapeutic modality for a wide range of pediatric malignant and nonmalignant diseases. Hematopoietic cell transplantation has evolved over time to include more indications for transplantation and broad-spectrum treatment and supportive care strategies. This review will address the process of transplantation, donor and stem cell sources, complications, and transplantable diseases.
... Both amelogenins and soluble dentin proteins showed bone induction activity like bone morphogenetic protein and induce differentiation of mesenchymal cell into chondrocyte and osteocyte [40]. For dental root development conventional pediatric anticancer therapy is also used by using stem cell transplantation [41]. skin wound healing through transplantation medicine. ...
Present review article emphasizes use of various stem cell types, biological scaffold materials, genes and factors essentially required in wound healing, transplantation and regeneration of tooth implants. All recent developments in tooth engineering used for successful regeneration of tooth, induction of enamel and formation of dentin complexes are highlighted. In addition, genes, factors and minerals required in vascularization and maintenance of microenvironment for responsiveness to cells are also elucidated as most attractive candidates for regeneration therapy. Present review also elucidates use of stable and durable biodegradable polymer scaffolds materials and cementum/periodontal-ligament complex formation. There is a need to widen the horizon of bio-root engineering technology for successful repairing of tooth injuries and replacement of fractured or traumatized tooth. For this purpose, use of implantation of cultured stem cells, adhesion factors and biomaterials can provide stable attachment of dental implants. This review also sketch upon need of newer technologies and more adhesive biocompatible biomaterials for successful dental implants and enamel regenerative therapies.
... The primary longterm oral effects reported after cancer treatment during the developmental stage of the teeth are enamel hypomineralization (discolored areas), enamel hypoplasia (thin or lack of enamel in areas), delayed or arrested tooth development, microdontia (small teeth), and hypodontia (developmentally missing teeth) [4][5][6][7][8][9]. Dental aberrations are most frequently observed after local radiotherapy, hematopoietic stem cell transplantation (HSCT), and treatment at a young age (≤5 years) [7][8][9][10][11][12][13][14]. An association between dental disturbances and exposure to alkylating agents (e.g., cyclophosphamide) and plant alkaloids (e.g., vincristine) has been reported [15][16][17], and anthracyclines (e.g., doxorubicin) have been shown to cause such disturbances in animal models [18,19]. ...
Purpose:
Factors associated with the long-term dental effects after chemotherapy for childhood malignancies have not been well described. The primary aims of this study were as follows: (1) to assess whether age at diagnosis and treatment-related factors are associated with dental defects in survivors of childhood acute lymphoblastic leukemia (ALL) and (2) to assess the survivors' annual expenses for dental treatment compared to reference data.
Methods:
This cross-sectional study enrolled 111 Norwegian survivors of ALL diagnosed before the age of 16. All of the subjects completed a questionnaire and underwent medical and oral examinations. Dental defects were registered according to the individual defect index, with 0 = no defects and 140 = anodontia, and the caries experience was registered according to the decayed-missing-filled teeth index (DMFT). Age-matched reference data were drawn from a national general population survey (n = 555).
Results:
The mean age at examination was 29.1 years (SD 7.2), and mean follow-up period was 22.9 years (SD 7.3). In a regression model, diagnoses occurring at ≤5 years of age (B = -9.6, p < 0.001) and a cumulative dose of anthracyclines >120 mg/m(2) (B = 11.5, p < 0.001) were strongly associated with more severe dental defects. Survivors treated after the age of 5 had experienced more caries than those treated at a younger age [DMFT 9.6 (SD 6.1) vs. 6.0 (SD 4.6), respectively; p = 0.001]. High annual expenses for dental treatment were reported by a larger percentage of the reference population compared to the survivor group (18 vs. 9 %, respectively; p = 0.02).
Conclusions:
The age at diagnosis and the dose of anthracyclines appear to be strongly associated with the severity of dental defects, although few survivors reported high annual expenses for dental treatment. The increased risk of dental defects during adulthood should be communicated to ALL survivors.
... Disturbed root growth in permanent teeth occurred when HSCT was performed before 10 years of age. [69] Among the late dental effects, hypoplasia of enamel and/or roots occurred among patients under 18 years of age. [70] Proper dental care and rehabilitation can improve the quality of life. ...
Organ transplantation is a widely undertaken procedure and has become an important alternative for the treatment of different end-stage organ diseases that previously had a poor prognosis. The field of organ transplant and hematopoietic stem cell transplant is developing rapidly. The increase in the number of transplant recipients also has an impact on oral and dental services. Most of the oral problems develop as a direct consequence of drug-induced immunosuppression or the procedure itself. These patients may present with oral complaints due to infections or mucosal lesions. Such lesions should be identified, diagnosed, and treated. New treatment strategies permit continuous adaptation of oral care regimens to the changing scope of oral complications. The aim of this review is to analyze those oral manifestations and to discuss the related literature.
... Zahŕňujúc tretie moláre, počty pa cientov s agenézou a/ alebo mikrodonciou trvalých zubov predstavovali 100 % u pa cientov transplantovaných vo veku < 3 roky, 78 % pa cientov liečených vo veku 3,1-5,0 rokov a 50 % pa cientov vo veku > 5 rokov. Tieto abnormality bývajú spojené s problémami oklúzie [30]. ...
Childhood cancer therapy often increases the risk of dental complications, such as tooth and roots agenesis, microdontia, abnormal development of tooth enamel, increased risk of cavity and other abnormalities. In a comparison with other late adverse effects of chemotherapy, radiotherapy and hematopoietic stem cell transplantion, a relative small number of clinical stud-ies observing patients for more than two years after completion of anticancer treatment was published. In this article, we review the incidence of dental abnormalities caused by commonly used anticancer treatment modalities as well as discuss their risk factors. Early identification of high-risk patients, early detection and management of dental abnormalities and better education of patients or their guardians, may have an impact on quality of life of cancer survivors.Key words: chemotherapy - radiotherapy - late effects - tooth abnormalities - childhood cancer The authors declare they have no potential conflicts of interest concerning drugs, products, or services used in the study. The Editorial Board declares that the manuscript met the ICMJE "uniform requirements" for biomedical papers.Submitted: 3. 3. 2014Accepted: 4. 12. 2014.
... The R/C ratio is reduced following a decrease in the root length in the instances such as bone marrow transplant, chemotherapy, cleft palate, and trauma cases. [2,[5][6] Trauma with crown fracture, attrition, and dental caries results in an increase in the ratio. Al-Jamal et al. reported that the effect of cleft palate on adjacent teeth, particularly incisors and canines, and incomplete root development may cause an increase in the R/C ratio. ...
Statement of the Problem: Determining the crown-root ratio is crucial in many dental clinical decisions. There are no reliable data presented for Iranian population.
Purpose: The aim of this study was to assess the root-crown ratio of permanent teeth with regards to the relationship of gender and jaw type using panoramic radiographs. The reliability of method was also assessed.
Materials and Method: The crown and root lengths of teeth were measured by a digital caliper on panoramic radiographs of 185 individuals except for the third molars. A total of 1994 teeth was studied and 50.8% of the teeth belonged to males and 49.2% belonged to females. The modified Lind method was applied.
Results: The highest mean root-crown ratios in both arches of both genders were obtained in the second premolars, followed by the first premolars and canines. In both genders, the lowest root-crown ratios were found in the maxillary central incisors. In male patients, the mean root-crown ratio was higher (p= 0.003) than that of females. Using Bland-Altman analysis, a non-significant difference of 0.006 (95% CI: -0.012-0.024) and 0.0002 (95% CI: -0.011-0.011) were found for intra-observer and inter-observer agreement, respectively.
Conclusion: Assessment of the root-crown ratio in permanent dentition could be performed on panoramic radiographs with acceptable reproducibility in an Iranian Population. Considering observed differences, our findings suggest that for the accurate assessment, this ratio must be calculated for male and female patients and also for the upper and lower jaws, separately.
Multiple adult female CB6F1 mice presented with supernumerary incisors after preconditioning with chemotherapy and totalbody irradiation for bone marrow transplantation (BMT). Mice received nonmyeloablative total body irradiation (3 Gy) andeither cyclophosphamide or bendamustine, followed by BMT and posttransplantation cyclophosphamide or bendamustine.Here we describe the clinical presentation, μCT findings, and histopathologic evaluation of the affected mice. These analysesconfirmed the gross diagnosis and revealed details of the abnormal tooth morphology. We surmise that the combination oftotal body irradiation and chemotherapy resulted in the abnormal formation of supernumerary incisors. Supernumerary teethshould be considered as a potential confounding factor in tracking weight loss after BMT. These conditions can be managedto allow animals to reach their intended scientific endpoint.
Background:
Structural anomalies of teeth are observed at high rates in childhood cancer survivors (CCS). Several therapeutic exposures have been shown to be associated with dental developmental disturbances. This study was conducted to analyze the risk factors for dental developmental abnormality (DDA) and investigate the association between age at the time of cancer treatment and DDA in CCS.
Patients and methods:
Fifty-six CCS were enrolled. Orthopantomography and dental examination were performed in all the patients. We evaluated the prevalence of DDA and analyzed the risk factors for each type of DDA.
Results:
DDAs were observed in 46.4% of CCS, including hypodontia in 9 (16.1%), abnormal roots in nine (16.1%), enamel defects/hypoplasia in 6 (10.7%), and microdontia in 12 (21.4%) patients. The number of patients with abnormal roots was significantly higher in the group treated with stem cell transplantation or at an age older than 4 years. We observed that the formation period of abnormal teeth coincided with the treatment period in the majority of CCS with DDA.
Conclusions:
Particularly regarding the root abnormality, treatment at elder age may be a risk factor for root developmental disturbances. Risk evaluation, appropriate follow-up, and early detection of dental issues are required for all CCS.
Better cancer treatment has led to an increasing number of cancer survivors in Norway, but cancer is still the second most common cause of death. New treatment regimens and increased survival often imply longer treatment time and more cycles of chemotherapy. In many cases, this leads to increased risk of both short and long-term adverse effects.
The primary aim of this thesis was to investigate oral adverse effects in Norwegian cancer patients treated with chemotherapy for cancers outside the head and neck region at different phases of the disease trajectory. It also aimed to investigate if patients had received any information about oral complications or care, and if long-term survivors of childhood cancer experienced higher annual expenses for dental treatment compared to references.
Three study populations with current or previous cancer diagnoses were investigated: outpatients receiving chemotherapy, inpatients receiving palliative care, and adult survivors of childhood acute lymphoblastic leukemia. All three studies had a cross-sectional design and included an oral examination with registration of clinical findings such as caries, gingival health, mucosal disease/alterations, and dental developmental disturbances as well as oral symptoms. In the studies of the outpatients and palliative care patients, a self-report registration form including items regarding information received, a symptom assessment tool, and an evaluation tool for the patient’s general condition was used. The survivors filled out a mailed questionnaire that included various questions relating to oral health and oral health expenses, which enabled a comparison of self-reported oral health and oral health expenses to a matched reference population.
Oral discomfort was highly prevalent in the outpatients receiving chemotherapy and the palliative care patients. Xerostomia, mucositis and a high number of systemic drugs were associated with oral discomfort in patients receiving chemotherapy. Xerostomia and taste alterations were associated with oral discomfort in the palliative care patients. Few patients in both groups remembered receiving information about oral complications or care. In the survivors, dental developmental defects such as microdontia, arrested root development, and enamel hypoplasia were prevalent. Receiving a cancer diagnosis at the age of five years or less and high cumulative doses of anthracyclines were associated with increased severity of dental developmental defects. Diagnosis at a higher age was associated with higher caries experience. No significant difference was found when comparing survivors to a reference population regarding annual expenses for dental treatment.
The results from this thesis indicate that there is a need for a continuous focus on how to inform about, prevent, diagnose, and manage oral cancer-related adverse effects at all stages of the disease trajectory. A systematic collaboration with dental professionals may increase the detection of oral adverse effects at an early stage; facilitate prevention and/or early treatment of oral adverse effects, thereby improving symptom management.
Pediatric cancer therapy has advanced to become curative for many types of cancer. The overall survival of patients treated for childhood cancer is now in the range of 90%. The May 2009 issue of the Journal of Clinical Oncology reported improved survival from about 30% in 1960 to 80% in 2004. An epidemiologic study (Mariotto et al. 2009) estimated that in the United States alone, there are more than 300,000 survivors of childhood cancer. However, this success has not come without a price. Pediatric cancer therapy is given during a time of growth, and late effects in the oral cavity can alter the growth and development of teeth and bones and affect overall health for the duration of a patient’s life. The severity of these clinical and anatomical complications depends on tumor diagnosis, therapy exposure (chemotherapy, radiation, hematopoietic stem cell transplantation or a combination of several therapies), patient age and developmental status at the time of therapy and the resulting toxicity. In this chapter we will discuss some of the most important oral complications in pediatric oncology, with a focus on late effects of cancer and its treatment. Early complications will also be briefly described. Although the emphasis of this book is neurologic malignancy, oral complications occur in association with such malignancies because of the type of cancer therapy used. The prevention and management of these complications will be discussed, as well as the need for collaboration between dental providers and the oncology team for the improvement of outcomes.
A reduction in the mortality secondary to relapse, infections, graft versus host disease, and other acute transplant related complications is leading to improved survival rates and thus an ever-increasing population of hematopoietic cell transplant (HCT) survivors. For survivors of HCT during childhood, late effects can have a significant adverse impact on their overall functional outcomes and quality of life. This chapter will highlight what we are learning about long-term risks that may either be preventable with appropriate monitoring and screening or manageable with appropriate interventions. It is increasingly important that our long-term survivors be educated regarding their potential long-term risks and that they continue to receive periodic evaluations by providers who are knowledgeable regarding the unique issues that HCT survivors may face.
It is estimated that over 50,000 autologous or allogeneic hematopoietic cell transplants (HCT) are performed worldwide every year and that number continues to grow. Total body irradiation (TBI) began as and remains an integral part of the transplantation conditioning process in addition to high-dose chemotherapy (HD-CTX). In addition to its role as a tumor cytotoxic agent, the eradication of host hematopoietic and immunological cells is equally important particularly for allogeneic transplants. As the number of HCT increases worldwide and the survival continues to improve, the late deleterious consequences of HCT will increasingly become paramount. The late effects of HCT and in particular, TBI are manifest in practically every organ system and may have significant impact on the quality of life of surviving patients years after transplantation. Patients must be followed meticulously and appropriate interventions executed to minimize the impact of late treatment effects. This chapter examines the acute and long-term consequences of TBI in combination with various preparative regimens by specific organ sites.
Because cure rates for children with acute lymphoblastic leukemia (ALL) have improved since the 1970s, concern regarding late treatment sequelae plays a prominent role in contemporary therapy planning. Earlier reports described long-term complications after relatively homogeneous, less-intensive chemotherapy given with cranial or craniospinal irradiation for central nervous system (CNS) preventive therapy. Recognition of new prognostic clinical and biologic features has permitted risk-directed treatment that now cures 80% or more of children with ALL. In particular, recent trials have focused on intensifying systemic chemotherapeutic agents that control ALL in the CNS in an effort to eliminate cranial radiation and its associated late effects. Continued surveillance of the survivor population is important to define long-term health outcomes after these modern, intensive therapies. Similarly, the long-term survival of children with acute myeloid leukemia (AML) has improved substantially in the last decade with the use of more intensive chemotherapy regimens and allogeneic hematopoietic cell transplantation and advances in supportive care. Today, 50–60% of children with AML are cured of their disease. The increasing numbers of long-term survivors of AML likewise mandate the evaluation of late treatment sequelae and their effect on morbidity and mortality.
Children treated with hematopoietic stem cell transplantation (HSCT), particularly allogeneic HSCT, are at particular risk for late effects of therapy. Chronic graft-versus-host disease (cGVHD) is a major cause of morbidity in these survivors. In addition, the source of stem cells and the transplant conditioning regimen (which may include both chemotherapy and total body irradiation) impact survivors’ long-term risks. These risks are frequently compounded by the types of cancer therapy received prior to the transplant. Survivors of allogeneic transplant require lifelong follow-up by a medical team with expertise in this population. This care is directed by guidelines such as those published by the Children’s Oncology Group. Since most body systems can be impacted by HSCT and its therapy, long-term care frequently involves input from multiple medical sub-specialists. Co-ordination of this care through a cancer survivor or HSCT clinic can optimize long-term medical and psychosocial outcomes in HSCT survivors.
Neuroblastoma is a common malignant tumor of the sympathetic nervous system in childhood, arises from embryonic neural crest cells. The period of tooth development is matched with peak times of diagnosis and treatment of neuroblastoma. The intensive multimodality treatment including radiotherapy and chemotherapy is used in patients with neuroblastoma has been shown to have late adverse effects and disturbances in dental development like tooth agenesis, microdontia, enamel hypoplasia and short roots. A 8-year old girl had been on medication and radiotherapy for neuroblastoma since she was 15 months old at Department Pediatrics, Chonnam National University Hospital. Oligodontia, microdontia, and short root formation was notable in clinical and radiological examination. Mobility of lower permanent incisor was detected and measured at about degree 2. Resin wire splint using mini-screw implantation on buccal alveolar bone was conducted for maintenance of mandibular incisors and alveolar bone. Excessive mobility has been eliminated and maintained well so far. Further treatment is planned for re-evaluation of mobility, preventing dental caries and regular oral hygiene management. Although we need further evaluation, this treatment could be one of alternative therapy for those who have similar dental anomalies.
Childhood cancer, such as that manifested by neuroblastoma and hepatoblastoma tumors, is one of the leading causes of death for young children. Chemotherapy is one of the most important approaches available, though it is considered to cause tooth developmental disturbances when patients receive treatment during that period of development. Microdontia, disturbed root development, hypodontia and enamel hypoplasia are reported to be possible late adverse effects of chemotherapy. We analyzed 3 children, for whom chemotherapy had been given for treatment of cancer from the ages of 1 to 2.5 years old. Intraoral examinations revealed microdont of the bilateral maxillary lateral incisors and canines in 1 case, whereas that of the bilateral mandibular first premolars was shown in another. Orthopantomograph examinations revealed congenital absence of the first and second premolars in all 3 cases. The developmental period of the affected teeth in these cases appeared to correspond to the chronological age when chemotherapy was administered.
Introduction. Recent years have seen an increasing number of patients, who underwent treatment for cancer or are in the active treatment. Children, as well as adults, with an oncological medical history, should have the same access to orthodontic treatment as those who are healthy. However, comprehensive treatment of cancer patients results in a number of complications. Some of them represent a risk of adverse effects during orthodontic treatment. Aim of the study. To discuss the impact of cancer treatment on the craniofacial structures and the possibility of orthodontic treatment of patients with history of cancer. Material and methods. Three electronic databases "MEDLINE", "SCOPUS", "SCIENCE DIRECT" were analyzed, and articles in Polish corresponding to the subject of the article were hand-searched. Keywords used in this paper are: "cancer", "orthodontics", "treatment" and "leukemia". Only English- and Polish-language literature were included. Publications, which were consistent with the theme of this review, have been read and their citations were verified. If among the cited articles there was one relating to the theme of the review, it was included. Results. Based on the literature certain points have been discussed: the influence of chemotherapy and radiation therapy on the development of bone structure, oncological treatment and the development of the facial skeleton, occlusion and dentition anomaly resulting from the therapy and orthodontic treatment for oncological patient. Conclusions. Anti-cancer therapy triggers facial skeleton and dentition anomalies in growing patients. Orthodontic treatment should be postponed until the end of the full cycle of anti-cancer therapy. During the therapy less aggravating treatment plan, as well as appliances that do not irritate mucous membrane should be taken into consideration.
Objective: The aim of this study was to evaluate 1. the differences among the cleft sides of unilateral cleft lip and palate (UCLP) patients, non-cleft sides of the same UCLP patients and well matched control patients in the root development and position of permanent upper central incisors and 2. possible gender differences.
Materials and methods: The study sample consisted of 40 patient (20 males and 20 females; mean age: 14.84±3.2 years) with non-syndromic UCLP patients, and 40 control patients (20 males and 20 females; mean age: 13.38±1.6 years). Cone-beam computed tomography (CBCT) images were taken off from all patients. All tomographs were obtained in supine position by using CBCT (NewTom 5G, QR, Verona, Italy).
Results: Significant smaller root volume of central incisor was observed on the cleft side than on the non-cleft side of UCLP patients (P < 0.05). No significant difference in the root development and position of the central incisors was found between the non-cleft side of the UCLP and the control group (P > 0.05). There were no statistically significant gender differences in any linear, angular, or volumetric measurements (P > 0.05). Only the root volume of the cleft side was smaller in females than in males (P < 0.05).
Conclusions: In general, root volumes of central incisors on the cleft side were 12.15 per cent smaller than non-cleft side. Root development of the central incisor was much more influenced by the cleft in females than in males.
The intensive treatment of hematological malignancy can cause dental abnormalities when applied during the period of dental and craniofacial development. Here, we report a case of absence of numerous teeth after treatment of neonatal leukemia.
An 11-year-old boy was referred to our hospital complaining of delayed (no) eruption of many teeth. The patient had a history of neonatal acute monocytic leukemia. He had undergone systemic chemotherapy and allogeneic peripheral blood stem cell transplantation (PBSCT) during the period between 7 days and 9 months after his birth. Intraoral examination and a panoramic radiograph revealed absence of 25 of the permanent teeth (12, 13, 14, 15, 17, 18, 22, 23, 24, 25, 27, 28, 31, 32, 33, 34, 35, 37, 38, 41, 42, 44, 45, 47, and 48). Microdontia of the bilateral maxillary central incisors and right mandibular canine and taurodontism of the bilateral maxillary first molars were also observed. The developmental period of these affected teeth agreed with the period of chemotherapy and PBSCT.
An unfavourable root-crown (R/C) ratio caused by short dental roots may result from a developmental deficiency, root resorption after orthodontic treatment, or dental trauma. In the assessment of root shortening, subjective grading has often been used. For objective tooth measurements, varying materials and methods may make the results impossible to compare. This study used a simple, objective method to assess the R/C ratio (relative root length) of mature permanent teeth from panoramic radiographs (PRGs), tested its reproducibility and calculated the mean values of R/C ratios and their variations in a healthy Caucasian (Finnish) population. Two thousand seven hundred and seventy-nine teeth were measured on 108 PRGs. The intra- and inter-examiner reproducibility of the assessment method was good (Pearson correlation coefficients 0.87 and 0.83, respectively; P < 0.001) and the mean R/C ratios did not differ between the repeated measurements (P > 0.05). The biological variance in all cases exceeded the error variance for each tooth. These facts suggest that the method reported in this study can be used in the assessment of the relative root length of 'normal' teeth and its alterations in teeth with developmental or acquired aberrations of dental roots. Males, overall, tended to have higher R/C ratios than females; P-values varied from non-significant to less than 0.01. With the exception of the permanent lateral incisors in males and the permanent second molars in both genders, the ratios of the antagonist teeth were significantly greater in the mandible than in the maxilla (P < 0.05 for the lateral incisors of females; P < 0.001 for all other teeth). Consequently, in quantifying root shortening in developmentally short-rooted teeth, tooth- and gender-specific reference values should be employed. The Finnish R/C data reported here for all teeth except third molars could be used for comparison with other populations, patient groups or individuals where crown-root aberrations are suspected.
A histological study of 21 teeth from 9 patients who had received cytotoxic chemotherapy for malignant disease showed increased prominence of incremental lines in the dentine. The number and distribution of these lines corresponded to periods of intravenous therapy and vincristine appeared to be the most likely cause. This effect was probably due to temporary disturbance of microtubular function in the odontoblasts resulting in decreased secretion of collagenous dentine matrix. Calcification appeared to be unaffected.
Oral health and disturbances in dental development were studied in long-term survivors after antineoplastic therapy. Fifty-seven children treated with combination chemotherapy and 19 children treated with total body irradiation (TBI) prior to bone marrow transplantation (BMT) were examined. The variables studied were dental caries, salivary flow, salivary microbial counts, enamel disturbances, and disturbances in dental development. The results showed no increased caries experience in children treated with BMT or chemotherapy compared with controls. Children treated with BMT had a significantly lower salivary secretion rate of 0.7 +/- 0.4 ml/min, compared with 1.1 +/- 0.5 in the chemotherapy group, and 1.3 +/- 0.6 in the control group (P < 0.05). The clinical examination showed equal numbers of teeth affected by disturbances in enamel mineralization in the BMT and chemotherapy groups. A mean 15.9 +/- 8.2 teeth were affected by disturbances in root development in the BMT group compared with 1.2 +/- 1.6 in the chemotherapy group (P < 0.001). The results show that children who are long-term survivors of pediatric malignant diseases exhibit a wide range of disturbances in the oral cavity. In this study the most severe disturbances are found in children treated with total body irradiation prior to BMT.
A radiographic dental examination was performed in 16 children conditioned with total body irradiation (TBI) and cyclophosphamide (CY) prior to bone marrow transplantation (BMT), and in 52 children treated with multiagent chemotherapy. For each child, three age- and sex-matched healthy controls were selected. Evaluation of disturbances in dental development and tooth size was based on planimetric measurements of mandibular teeth on panoramic radiographs. Short V-shaped roots were diagnosed in 94 per cent of the children treated with TBI/CY compared with 19 per cent in the chemotherapy group (P < 0.001). Children receiving TBI/CY also exhibited a pronounced reduction in tooth size compared with the controls. Reductions varied from 19 per cent in incisors to 39 per cent in the second molars. In the chemotherapy group the corresponding values were 7 and 15 per cent respectively. When comparing crown/root ratios, the indices for incisors, canines (P < 0.05) and molars (P < 0.01) in the BMT group were significantly higher than the corresponding values in the control group. This indicates that the reduction in root size was more pronounced than the reduction in crown size. The premolars in the BMT group exhibited a similar reduction in crown and root size. All developing teeth were affected by multiagent chemotherapy and radiation therapy. The most severe disturbances were found in children treated with TBI/CY at a young age.
Minimal data about oral and dental health in long-term survivors after BMT are available. We studied the dental status of 27 children (19 males, eight females) with leukaemia, followed up with a routine oral examination, panoramic tomogram and, when necessary, an endoral radiograph at a median of 2 years (range 1-10) after BMT. Community periodontal index treatment necessity (CPITN), dental caries, missing or filled permanent teeth (DMFT) and dento-facial alterations according to WHO criteria were registered and evaluated. Median age of the patients at BMT was 9 years (range 1.1-17.9). The mean DMFT score ranged from 1.6 to 12.4 according to age at examination and was slightly higher than that which we previously reported in children who received chemotherapy alone. CPITN showed the presence of soft deposits in 77.7%, serious gingivitis in 59.2% and parodontal involvement in 3.7% of cases. Dento-facial abnormalities were found in 55.5% of patients, while 62.9% of the patients had tooth abnormalities or agenesis. Nine out of 27 patients (33%) had root hypoplasia. A negative impact on DMFT index due to multiple post-BMT factors was found. Age is the crucial factor in determining a developmental defect of enamel and root. The follow-up of long-term survivors after BMT should include regular dental examination.
Impaired growth after TBI prior to BMT has been a constant finding in children with leukemia. The growth of poor-risk neuroblastoma (NBL) survivors treated with myeloablative preparative regimens and ABMT at the Hospital for Children and Adolescents, University of Helsinki, since 1982 is reported. Two separate groups were analyzed: (1) The TBI- patients (n = 15) were conditioned with high-dose chemotherapy only. They had been treated at the age of 1.0-6.3 (mean 3.0) years and the post-ABMT follow-up time was 1.5-14.5 (mean 7.7) years. (2) The TBI+ patients (n = 16) had received TBI in addition to high-dose chemotherapy. They had been treated at the age of 1.3-4. 8 (mean 3.0) years, and the post-ABMT follow-up time was 1.5-8.0 (mean 4.7) years. The height standard deviation score (SDS) was similar for the two groups at the time of diagnosis, -0.3 +/- 1.2 (mean +/- s.d.), and at the time of ABMT, -0.7 +/- 1.1. After transplantation, the height SDS continued to decrease in the TBI+ group, the mean being -2.0 SDS at 5 years after ABMT. In the TBI-group, the mean height SDS remained within -0.7 to -0.9 to the 10 years of follow-up. Five patients received growth hormone (GH) therapy starting 2-6 years after ABMT. They all had low GH secretion in provocative tests. All showed some response to GH therapy. The mean height SDS increased 0.4 SDS during the 3 years following the start of GH therapy, while in the untreated patients a decrease of 0. 8 SDS during the corresponding time (P = 0.009) was observed. We conclude that NBL patients grow poorly following ABMT when TBI is included in the conditioning regimen, but close to normally when treated without TBI. The need for GH therapy should be evaluated early to avoid an unnecessary decrease in final height.
Purpose
To determine the frequency and types of dental abnormalities among children treated at a young age for cancer, as represented by neuroblastoma.
Patients and Methods
We retrospectively reviewed the dental records and panoramic radiographs of 542 children who were treated for neuroblastoma at our institution over a 31‐year period. Patients in our study had to meet the following criteria: they were treated on an institutional protocol, they had undergone panoramic radiography, and their dental follow‐up continued for at least 2 years after diagnosis. We evaluated the frequency of clinically or radiographically apparent microdontia, excessive caries, root stunting, hypodontia, and enamel hypoplasia in our study population.
Results
Of the 52 patients who met the study criteria, 71% developed dental abnormalities, comprising microdontia in 38%, excessive caries in 29%, root stunting in 17%, hypodontia in 17%, and enamel hypoplasia in 17%. In nearly half (23) of our patients, neuroblastoma was diagnosed on or before their first birthday.
Conclusion
Children treated for neuroblastoma are at high risk for abnormal dental development. The abnormalities in these patients may require extensive dental care and can compromise their quality of life. Frequent dental examinations and an intense oral hygiene program before, during, and after treatment may improve overall dental health. Med. Pediatr. Oncol. 30:22–27, 1998. © 1998 Wiley‐Liss, Inc.
Survival from childhood cancer has markedly improved over recent decades following major advances in available treatments and supportive care, such that now around 75%–80% of children with cancer will be alive 5 years from diagnosis. The number of long-term survivors is therefore increasing, and it has been estimated that, by the year 2010, about one in 715 of the adult population will have been treated for cancer in childhood. Because of this, the emphasis in the management of childhood cancer has changed, from “cure at any cost” to one in which quality of life after treatment has become increasingly important. Thus, whilst continuing to strive for improved survival, attention must be directed towards minimizing the late effects of treatment. Adverse late effects of childhood cancer treatment are diverse and include growth impairment, disorders of the endocrine system, infertility, abnormalities of cardiac and pulmonary function, renal and hepatic impairment, second malignancies, and cognitive and psychosocial difficulties. This chapter focuses on these consequences of childhood cancer treatment. Long-term follow-up of these patients is essential, in order that adverse effects are diagnosed early and appropriate counselling and therapeutic intervention instituted. Awareness of the etiology and prevalence of late complications will allow modifications of treatment that will improve the quality of life for long-term survivors of childhood cancer. Endocrine disorders and growth impairment Collectively, disorders of the endocrine system represent the commonest long-term complication of cancer treatment, with one study demonstrating endocrine abnormalities in up to 40% of such patients at follow-up.
Cytostatic antibiotics of the anthracycline class are the best known of the chemotherapeutic agents that cause cardiotoxicity. Alkylating agents such as cyclophosphamide, ifosfamide, cisplatin, carmustine, busulfan, chlormethine and mitomycin have also been associated with cardiotoxicity. Other agents that may induce a cardiac event include paclitaxel, etoposide, teniposide, the vinca alkaloids, fluorouracil, cytarabine, amsacrine, cladribine, asparaginase, tretinoin and pentostatin. Cardiotoxicity is rare with some agents, but may occur in >20% of patients treated with doxorubicin, daunorubicin or fluorouracil.
Cardiac events may include mild blood pressure changes, thrombosis, electrocardiographic changes, arrhythmias, myocarditis, pericarditis, myocardial infarction, cardiomyopathy, cardiac failure (left ventricular failure) and congestive heart failure. These may occur during or shortly after treatment, within days or weeks after treatment, or may not be apparent until months, and sometimes years, after completion of chemotherapy.
Anumber of risk factors may predispose a patient to cardiotoxicity. These are: cumulative dose (anthracyclines, mitomycin); total dose administered during a day or a course (cyclophosphamide, ifosfamide, carmustine, fluorouracil, cytarabine); rate of administration (anthracyclines, fluorouracil); schedule of administration (anthracyclines); mediastinal radiation; age; female gender; concurrent administration of cardiotoxic agents; prior anthracycline chemotherapy; history of or pre-existing cardiovascular disorders; and electrolyte imbalances such as hypokalaemia and hypomagnesaemia. The potential for cardiotoxicity should be recognised before therapy is initiated. Patients should be screened for risk factors, and an attempt to modify them should be made.
Monitoring for cardiac events and their treatment will usually depend on the signs and symptoms anticipated and exhibited. Patients may be asymptomatic, with the only manifestation being electrocardiographic changes. Continuous cardiac monitoring, baseline and regular electrocardiographic and echocardiographic studies, radionuclide angiography and measurement of serum electrolytes and cardiac enzymes may be considered in patients with risk factors or those with a history of cardiotoxicity.
Treatment of most cardiac events induced by chemotherapy is symptomatic. Agents that can be used prophylactically are few, although dexrazoxane, a cardioprotective agent specific for anthracycline chemotherapy, has been approved by the US Food and Drug Administration. Cardiotoxicity can be prevented by screening and modifying risk factors, aggressively monitoring for signs and symptoms as chemotherapy is administered, and continuing follow-up after completion of a course or the entire treatment. Prompt measures such as discontinuation or modification of chemotherapy or use of appropriate drug therapy should be initiated on the basis of changes in monitoring parameters before the patient exhibits signs and symptoms of cardiotoxicity.
In this population-based material from the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden), 2860 children below 15 years of age were diagnosed with acute lymphoblastic leukemia (ALL) from July 1981 to June 1998. The annual incidence was 3.9/100 000 children and was stable throughout the study period. The development from regional or national protocols to common Nordic treatment protocols for all risk groups was completed in 1992 through a successive intensification with multidrug chemotherapy, including pulses of methotrexate in high doses and avoidance of cranial irradiation in most children. The overall event-free survival (EFS) at 5 years has increased from 56.5 ± 1.7% in the early 1980s to 77.6 ± 1.4% during the 1990s. The main improvements were seen in children with non-high risk leukemia. In high-risk patients, progress has been moderate, especially in children with high WBC (⩾100 × 109/l) at diagnosis. During the last time period (January 1992–June 1998), only 10% of the patients have received cranial irradiation in first remission, while 90% of the patients have received pulses of high dose methotrexate (5–8 g/m2) isolated or combined with high-dose cytosine arabinoside (total dose 12 g/m2) plus multiple intrathecal injections of methotrexate as CNS-targeted treatment, not translating into increased cumulative incidence of CNS relapse.
Conditioning before bone marrow transplantation (BMT) with total body irradiation (TBI) and cyclophosphamide carries the risk of severe long-term complications. The aim of the present study was to determine absorbed doses in the craniofacial area during TBI, using thermoluminescent dosimeters for both in vivo techniques and phantom measurements. The results from the phantom study showed that the mean deviation from the reference dose varied between -5.1 and +11.1%. The superficial part of left parotid gland received 11.1 +/- 1.5% more radiation compared with the reference. In patients, deviations from the reference dose varied in individual patients between -22.4 and +20.1% in various intra-oral sites. Since a small increase in dose can result in a significantly increased risk of pathology, the observed dose inhomogeneities for structures receiving tangentially directed radiation therapy, such as the parotid glands, may contribute to salivary dysfunction after TBI.
BACKGROUND
The objective of the current study was to examine the occurrence of tooth agenesis and microdontia in pediatric stem cell transplantation (SCT) recipients.METHODS
The impact of total body irradiation (TBI) and age at SCT on agenesis and microdontia of permanent teeth was examined in 55 patients from panoramic radiographs. Assessment A1 (for tooth agenesis and microdontia) excluded the third molars, and assessment A2 (for tooth agenesis) included the third molars. Patients were grouped according to TBI status (the TBI group vs. the non-TBI group) and age at SCT (patients age ≤ 3.0 years [Group Y], patients ages 3.1–5.0 years [Group M], and patients age ≥ 5.1 years [Group O]).RESULTSFrom 1 to 12 teeth were missing in 77%, 40%, and 0% of patients (assessment A1) in Groups Y, M, and O, respectively (Group Y vs. Group M, P = 0.055; Group Y vs. Group O, P < 0.001; and Group M vs. Group O, P = 0.002), increasing to 83%, 78%, and 43%, respectively, when the third molars were included (assessment A2; P values were not significant). Correspondingly, 75%, 60%, and 13%, respectively, of patients had 1–12 microdontic teeth (assessment A1: Group Y vs. Group M, P = 0.306; Group Y vs. Group O, P < 0.001; and Group M vs. Group O, P = 0.003). Recipient age at the time of SCT was found to have a negative correlation with the number of missing teeth (P = 0.001) and microdontic teeth (P = 0.005). TBI appeared to have little effect on the prevalence of tooth agenesis (assessment A1: TBI group, 32%; non-TBI group, 29%; assessment A2: TBI group, 72%; non-TBI group, 46%; P values were not significant) or on the prevalence of microdontia (assessment A1: TBI, 41%; non-TBI, 50%; P value was not significant). A tendency toward an increased number of affected teeth was noticed in the group of patients who received TBI.CONCLUSIONS
Depending on their age at SCT, 50–100% of pediatric SCT recipients will later present with agenesis and/or microdontia of permanent teeth that may jeopardize occlusal development. Young age (≤ 5.0 years) at SCT was found to be a stronger risk factor than TBI, although TBI caused additive impairment. Cancer, 2005. © 2004 American Cancer Society.
PurposeTo determine the frequency and types of dental abnormalities among children treated at a young age for cancer, as represented by neuroblastoma.Patients and Methods
We retrospectively reviewed the dental records and panoramic radiographs of 542 children who were treated for neuroblastoma at our institution over a 31-year period. Patients in our study had to meet the following criteria: they were treated on an institutional protocol, they had undergone panoramic radiography, and their dental follow-up continued for at least 2 years after diagnosis. We evaluated the frequency of clinically or radiographically apparent microdontia, excessive caries, root stunting, hypodontia, and enamel hypoplasia in our study population.ResultsOf the 52 patients who met the study criteria, 71% developed dental abnormalities, comprising microdontia in 38%, excessive caries in 29%, root stunting in 17%, hypodontia in 17%, and enamel hypoplasia in 17%. In nearly half (23) of our patients, neuroblastoma was diagnosed on or before their first birthday.Conclusion
Children treated for neuroblastoma are at high risk for abnormal dental development. The abnormalities in these patients may require extensive dental care and can compromise their quality of life. Frequent dental examinations and an intense oral hygiene program before, during, and after treatment may improve overall dental health. Med. Pediatr. Oncol. 30:22–27, 1998. © 1998 Wiley-Liss, Inc.
abstract— Cyclophosphamide in doses of 25, 50, 75. 100, 125, and 150 mg/kg was administered to 60 rats in 6 groups. Histomorphologic investigations of maxillary and mandibular incisors two weeks later revealed the following dose-dependent reactions: (1) interruped odontogenesis, (2) circular and mesio-distal dental constrictions, (3) niche-like dentinal defects, (4) differentiation of a postexperimental tooth, and (5) cyst formation and circulatory disturbances. Differences were observed in the frequencies of lesions in maxillary and mandibular incisors, and between labial and lingual aspects of the teeth. The results were related to roentgen irradiation effects, with which they largely concur
abstract – An investigation of roentgen-ray induced enamel and dentin changes in the maxillary incisor in the rat was undertaken to assess the relative radiosensitivity of amelogenesis and dentinogenesis. Seventy Sprague-Dawley rats received whole body irradiation with exposures between 500 and 950 rad. Five animals served as controls. During the experimental period all the animals were given an injection of oxytetracycline. The animals were killed 5–21 d after irradiation. Ground sagittal sections of the incisors were examined microradiographically and with fluorescence microscopy. The irradiation produced elongated external hypoplastic lesions in the enamel and niches in the dentin. The extent of the lesions varied with the radiation dose. The variation in the extent and appearance of the lesions was much greater in the dentin than in the enamel. Even the smallest dose regularly produced changes in the enamel but seldom in the dentin. Amelogenesis thus proved to be more radiosensitive than dentinogenesis.
Vincristine in doses of 0.1, 0.3, 0.5 and 0.7 mg/kg was administered to 60 rats in four groups. Histomorphologic investigation of the odontoblast population in the maxillary incisors revealed dose-dependent reactions consisting of (1) swelling of the odontoblasts and an accumulation of abnormal mitotic cells in the germinative parts of the pulp after 5 h, (2) a supervening necrosis and destruction of some odontoblasts and of the mitotic cells after 24 h, and (3) after 3 d, a reversal to normal structure in some parts of the odontoblast population, but a further development of the vincristine-induced changes, with severe cellular derangement and irregular predentin production, in others.
Fifty‐two children in remission from childhood cancer and 41 siblings underwent a full clinical and radiographic dental examination. All the children had received chemotherapy. The leukaemic patients had received radiotherapy also, but not involving the jaws. There was no significant difference in dental caries experience between the treated children and the siblings, but significantly more dental anomalies were detected radiographically in the treated group.
Résumé. Nous avons examine 52 enfants en remission de cancer infantile, et 41 de leurs freres et soeurs, par examen dentaire clinique et radiologique complets. Tous ces enfants avaient étè sous Chimiotherapie les lencemiques sous radiotherapie mais non aux machoises, Nous n'avons trouve aucune difference significative de caries dentaires entre les enfants traites et non traites (freres et soeurs), mais plus d'anomalies dentaires radiographiques dans le groupe traite (statistiquement) significatif).
Zusammefassung. 52 Krebskranke Kinder in der Remissionsphase und 41 weitere Kinder wurden klinisch und röntgologisch zahnärztlich untersucht. Alle Kinder erhielten Chemotherapie. Die Leukemie Patienten wurden auch bestrahlt aber nicht die Kiefer. In Bezug der Kariesanfälligkeit wurde kein Unterschied festgestellt zwischen der behandelten und der nicht behandelten Gruppe, aber eine signifikante grössere Anzahl von Zahna‐nomalien wurden röntgologisch bei der behandelten Gruppen gefunden.
Resumen. Un total de 52 niños en remisión de cancer y 41 hermanos(as) recibieron un examen clínico y radiográfico completo. Todos los niños habían recibido quimioterapia. Los pacientes leucémicos tambien recibieron radioterapia, pero no en los maxilares. No hubo diferencia significativa en la experiencia de caries dental entre los niños tratados y los hermanos(as), pero significativamente, más anomalías dentales feuron radigráficamente detectadas en el grupo tratado.
Ninety-seven children who were diagnosed with acute lymphoblastic leukemia before 10 years of age and treated with chemotherapy alone, chemotherapy plus 1800-cGy cranial irradiation (RT), or chemotherapy plus 2400-cGy RT were evaluated for effects of therapy on dentofacial development. All patients were seen at least 5 years postdiagnosis. Dental abnormalities were determined from panoramic radiographs, and craniofacial evaluations were made from lateral cephalometric radiographs. Ninety-one (94%) of all patients and 41 (100%) of patients younger than 5 years of age at diagnosis had abnormal dental development. The severity of these abnormalities was greater in children who received treatment before 5 years of age and in those who received RT. Observed dental abnormalities included tooth agenesis, arrested root development, microdontia, and enamel dysplasias. Craniofacial abnormalities occurred in 18 of 20 (90%) of those patients who received chemotherapy plus 2400-cGy RT before 5 years of age. Mean cephalometric values of this group showed significant deficient mandibular development. The results of this study suggest that the severity of dentofacial-developmental abnormalities secondary to antileukemia therapy are related to the age of the patient at the initiation of treatment and the use of cranial RT.
The effect of adriamycin (1 mg/liter) on the development of the golden hamster 3-day-old second maxillary molars (M2) was investigated in vitro. Exposure of the molars to 1 mg/liter adriamycin during the first 2 hours of culture produced smaller teeth 3-7 days later, as determined by measurements of dry weights and by histological observations. Higher doses caused severe necrosis. The more differentiated pulp fibroblasts showed osteodentin formation 3 days after treatment with adriamycin (1 mg/liter), while the more immature ones underwent necrosis. The phenotypic changes brought on by the drug were permanent, and osteodentin continued to be formed throughout the course of this study. In addition the cervical loop region was inhibited from growing, while the production of the matrices of enamel and dentin appeared to be increased at 3 and 5 days after treatment. Electron microscopy of the forming osteodentin matrix revealed a random arrangement of banded collagen fibers during the early stage of osteodentin formation. As more matrix was formed, the collagen became quite compact and appeared quite similar to dentin. Finally, matrix vesicles were found among the collagenous matrix that was not yet mineralized. With the exception of the increased production of enamel and dentin, these in vitro results confirmed those earlier in vivo studies on the effect of adriamycin on rat incisor tooth.
The dental status of 16 children who had been treated with bone marrow transplantation (BMT) for serious bone marrow diseases was followed for up to 6 years. Several types of disturbances in dental development were observed in children who had been conditioned with total body irradiation (TBI) at 10 Gy before BMT. Thus, impaired root development that caused short V-shaped roots was found in all patients, a complete failure of root development and premature apical closure were found in five patients, enamel hypoplasia was observed in four patients, and microdontia was observed in three patients conditioned with TBI. Patients younger than 6 years of age at BMT exhibited the most severe and extensive dental aberrations. The TBI at 10 Gy appeared to be the major cause of the disturbances found.
Seventeen patients treated for acute lymphoblastic leukemia by combination chemotherapy before their reaching 10 years of age were studied for altered dental root development of their premolar teeth. Five of the 17 patients showed subjective radiographic evidence of marked shortening of the premolar dental roots; 13 had thinning of the roots. A quantitative analysis was developed and verified, which disclosed a 63.33% to 84.38% reduction of premolar root length when compared with the mean of the historical controls. With recent significant increases in long-term survival rates of children with malignancies, altered dental development becomes an important factor to follow years after chemotherapy is discontinued. The findings of these chemotherapy-associated dental development changes impacts on the patient's quality of life and also can serve as a research tool to assess permanent effects of chemotherapy on normal tissue growth and development.
Fifty-two long-term survivors of childhood leukemia or solid tumors had a clinical dental examination along with 49 of their sibling. The 52, with an additional 30 examined in a previous study, were studied radiologically with a panoramic tomogram. All children with leukemia had received chemotherapy for 2 or 3 years and irradiation on standard protocols and the solid tumor group had received chemotherapy for 6 to 24 months. There was no difference between siblings and patients for dental caries, gingivitis, and oral hygiene, mouth opening, overjet, and overbite. More solid-tumor patients had abnormal occlusion (P less than 0.02) and those with abnormalities tended to have been treated at an earlier age. Enamel opacities and hypoplasia were more common in patients than siblings and in the leukemia than in the solid tumor group. Sixty-five percent of the children had abnormalities on radiologic examination including failure of the tooth to develop, small crown, hypoplasia of the crown, and abnormal root development. In most cases the radiologic abnormality could be correlated in time with the patient's treatment and a knowledge of the normal time of tooth development. Three teeth extracted during the course of the study were examined histologically and these showed prominent incremental lines which could be correlated in time with vincristine treatment.
Effects of multiple injections of the cytotoxic drug doxorubicin hydrochloride (Adriamycin) on incisor mesenchymal cells were studied by light microscopy. Rats were killed 1 day after two and three injections, and 1 day and 5 days after four injections. Doses of 5 and 10 mg/kg were used and given on consecutive days. Necrotic alterations expanded in preodontoblast and basal pulp regions when the total dose was increased and finally embraced the entire progenitive part of the incisor. The necrotic area became encapsulated by cellular predentin produced by differentiated pulp cells to prevent further tissue damage, and commencing regeneration was observed after 5 days. When the total dose was split up, the cytotoxicity of doxorubicin increased.
The effects of actinomycin D on the development of odontogenic tissues were studied in the mandibular incisor teeth of rats. Morphologically, there was no evidence that actinomycin D interfered with the differentiation of ameloblasts nor with the functions of the enamel organ. In the pulpal tissues, the principal changes observed were necrosis of germinal cells, oedema throughout the apical areas, formation of dentine niches and production of osteodentine within the niches. Cytotoxic effects occurred only in cells which were beginning to differentiate towards odontoblasts, The anterior and posterior limits of these effects were sharply defined.
Sixty-eight long-term survivors of childhood cancer were evaluated for dental and maxillofacial abnormalities. Forty-five patients had received maxillofacial radiation for lymphoma, leukemia, rhabdomyosarcoma, and miscellaneous tumors. Forty-three of the 45 patients and the remaining 23 who had not received maxillofacial radiation also received chemotherapy. Dental and maxillofacial abnormalities were detected in 37 of the 45 (82%) radiated patients. Dental abnormalities comprised foreshortening and blunting of roots, incomplete calcification, premature closure of apices, delayed or arrested tooth development, and caries. Maxillofacial abnormalities comprised trismus, abnormal occlusal relationships, and facial deformities. The abnormalities were more severe in those patients who received radiation at an earlier age and at higher dosages. Possible chemotherapeutic effects in five of 23 patients who received treatment for tumors located outside the head and neck region comprised acquired amelogenesis imperfecta, microdontia of bicuspid teeth, and a tendency toward thinning of roots with an enlarged pulp chamber. Dental and maxillofacial abnormalities should be recognized as a major consequence of maxillofacial radiation in long-term survivors of childhood cancer, and attempts to minimize or eliminate such sequelae should involve an effective interaction between radiation therapists, and medical and dental oncologists.
Vincristine is one of the cytostatic drugs present in cocktails commonly used for the treatment of cancer in children. The aim of this study was to evaluate biochemically and histologically the toxic effects of this drug on the developing tooth in vitro using the organ culture model in order to be able to predict what damage the drug can induce in the developing teeth from children undergoing anti-neoplastic chemotherapy. The most profound effect of the drug (10(-8)M-10(-4)M vincristine) on the developing tooth germ was the induction of mitotic arrests at the cervical loop and in the inter-cuspal regions. The 10(-4)M-10(-6)M vincristine doses were cytotoxic to most cells in the developing tooth germ. The 10(-7)M vincristine dose apart from induction of mitotic arrests, did not appear to be cytotoxic to the mature differentiated secretory cells. However, this dose induced incomplete nuclear polarization of the differentiating ameloblasts and odontoblasts. At 10(-8)M vincristine, the only effect observed were mitotic arrests; the secretory cells did not appear to have been affected at all. On the other hand, mineralization (TCA-soluble 45Ca and 32P uptake) was dose-dependently decreased from 10(-7)M vincristine upwards. 10(-9)M vincristine, the lowest dose tested, did not induce any changes in the developing tooth germ. The organ culture data indicate that 10(-9)M vincristine is the highest (safe) dose which does not induce any toxic effects in the developing hamster tooth germ.(ABSTRACT TRUNCATED AT 250 WORDS)
This paper provides an overview of recent studies that have enhanced our understanding of the biological mechanisms that operate during root development. For the most part, these studies have been performed on rodents. As significant species differences have been shown to exist, this data cannot necessarily be extrapolated to the human model. The events associated with root odontoblast differentiation are reviewed in comparison to similar events in coronal odontoblast differentiation. Morphological as well as phenotypic differences are outlined and the inductive role of the epithelial root sheath is discussed. Both acellular and cellular cementum formation are reviewed highlighting morphological and phenotypic differences. The potential influence of the epithelial root sheath in the formation of both tissues is compared and contrasted. Finally, a discussion of the fate of the epithelial root sheath is presented with emphasis placed upon the possible roles of apoptosis and epithelium-mesenchymal transition.
Disturbances in dental development were studied with the use of radiography and histology in a patient with acute lymphoblastic leukemia who was treated with induction chemotherapy at 2.3 years of age and bone marrow transplantation at 4.3 years of age. The follow-up 9.5 years after bone marrow transplantation showed evidence of short tapered roots, enamel hypoplasia, microdontia, and aplasia. A histologic examination of two extracted permanent teeth showed that the crown of the maxillary lateral incisor exhibited numerous incremental lines that corresponded closely to the treatment periods with cytotoxic drugs. The maxillary second premolar exhibited regularly spaced incremental lines in the enamel and dentine. A gross hypoplasia was seen in the cervical part of the crown corresponding to the time of administration of 10 Gy total body irradiation. The results indicate that chemotherapy mainly induces qualitative disturbances in dentine and enamel, whereas total body irradiation induces both qualitative and quantitative changes.
Cardiotoxicity is a potential adverse effect of anthracycline (A) therapy. Radiotherapy (XRT) may also cause a variety of cardiac complications. The purpose of the present study was to evaluate these cardiac side-effects in children and adolescents treated for cancer. We assessed the cardiac status of 91 patients, divided into three groups: Group A (n = 53) had anthracyclines at a mean cumulative dose of 410 mg/m2, group A+XRT (n = 26) had both chest irradiation (XRT) and A (mean 360 mg/m2), and group XRT (n = 12) had XRT alone. The patients differed from the controls in both systolic and diastolic indices of myocardial function. In echocardiography, the left ventricular (LV) contractility was abnormal in 32% in group A, in 50% in group A+XRT, and in 8% in group XRT. In radionuclide cineangiography, the LV ejection fraction was subnormal in 19% in group A, in 24% in group A+XRT, and in 1 patient in group XRT. A higher cumulative dose of A predicted decreased contractility. Treatment with A and/or XRT often leads to cardiotoxicity. Although in most cases this cardiotoxicity seems to be mild and subclinical, the long-term clinical sequelae merit further evaluation.
To evaluate the following prospectively in poor-risk neuroblastoma (NBL) patients: (1) the feasibility and efficacy of in vivo purging of bone marrow; and (2) the outcome after autologous bone marrow transplantation (ABMT) when immunologically tumor-free, unpurged autografts were used.
Twenty-three children with poor-risk NBL were evaluated during induction chemotherapy by repeat bone marrow examinations, including aspirate, biopsy, and an immunofluorescence method using the anti-GD2 monoclonal antibody 3A7. Nineteen patients completed the program with surgery with or without local irradiation followed by ABMT.
Autologous bone marrow grafts, both immunologically and cytologically clean, were obtained and used in 19 of 23 children. The overall 4-year disease-free survival of the 19 grafted children was 53%, with a toxic death rate of 16% and a posttransplant relapse rate of 37%. According to the in vivo purging efficacy of the 18 children with initial marrow disease, the following three groups were formed: patients with (1) perfect in vivo purging (n = 5); (2) eventually successful in vivo purging (n = 8); and (3) unsuccesful in vivo purging (n = 5). The 4-year DFS was 100%, 67%, and 0%, respectively (P < 0.001). The five patients with unsuccessful in vivo purging failed because of resistant/progressive bulky disease.
In patients with poor-risk NBL, in vivo purging of bone marrow by conventional chemotherapy is feasible, can be monitored, and the purging efficacy during the first 3 months after diagnosis is a strong prognostic factor reflecting tumor responsiveness to therapy. Autografting with immunologically clean, unpurged marrows gives a DFS well comparable to previous studies using ex vivo purging.
The effect of cyclophosphamide (Cy) on tooth development was studied in molars of 18 young Sprague-Dawley rats. Doses of 30 mg/kg body weight of Cy dissolved in 1 ml 0.9% NaCl were administered to 18 experimental rats and 1 ml 0.9% NaCl to 18 control rats at 10 and 13 days of age. The most obvious changes in the experimental teeth could be seen in the developing pulp of the third molar and developing roots of the first and second molars. Wide cell-free areas appeared in the third molar 2 days after the last injection; later these areas turned into mineralized osteodentin. Similar areas could be observed also in the roots of the first and second molars. These changes were related to the developmental stage of the area.
The major challenge for this generation of children's cancer specialists is to sustain the significant improvement in survival rates, while at the same time minimising treatment-induced late adverse effects. The available evidence suggests that, following first line treatment of acute lymphoblastic leukaemia (ALL), current treatment regimens used in the UK are unlikely to cause sterilisation in either gender. For men who are treated for Hodgkin's disease with 6 or more courses of antineoplastic therapy, azoospermia is the rule. Childhood studies have clearly indicated that the prepubertal testis is not protected from antineoplastic therapy that is potentially sterilising. The interpretation of tests of ovarian function in women treated for cancer in childhood is difficult, but there is increasing evidence of ovarian dysfunction in children treated for Hodgkin's disease. Reassuringly there is no evidence of an increased risk of miscarriage following antineoplastic therapy or an increased number of abnormalities in the offspring. The growth patterns and requirement for growth hormone replacement therapy in children treated for ALL are still unclear. There is good evidence that the intensity and duration of combination cytotoxic antineoplastic therapy received by children with ALL influences the pattern of growth, and that adjuvant antineoplastic therapy for children treated for a brain tumour is an important factor in final height achieved. A child who has been treated for cancer should not be discharged from follow-up. Late effects may have significant implications in later life, and an understanding of these effects is essential to enable balanced decisions to be made regarding the benefits and risks of currently available agents.
Advances in treatment protocols over the past 20 years have resulted in much improved survival rates for children with cancer. As more children survive, the emphasis has moved from "saving children at all costs' to saving children "at least cost to the child' and protocols are continually reviewed with this in mind. As more dental practitioners are likely to encounter children who have survived malignant disease, this paper looks at the long-term effects of treatment modalities on the dentoalveolar complex.
The roles of epithelium in the development, structure and function of the tissues of tooth support are reviewed. Epithelium is involved in initiating odontogenesis which includes the tissues of tooth support and this role is discussed. Particular attention is paid to Hertwig's epithelial root sheath and its participation in the formation of the hyaline layer on the root surface as well as its possible role in initiating the differentiation of cementoblasts. The possible functions of the epithelial cell rests are reviewed and it is concluded that as yet no function can be ascribed to them. Evidence for an increasing role for dental epithelium in tooth eruption is presented and the role of dental epithelium in establishing the dentogingival junction is discussed, with the conclusion drawn that this role temporary.
The aim of this study was to evaluate the toxic effects of actinomycin D on the developing hamster tooth germ in organ culture. Hamster tooth germs during early secretory amelogenesis were exposed in vitro for 24 h to 10(-9) M-5 x 10(-5) M actinomycin D. Actinomycin D dose-dependently (> or = 10(-7) M) decreased the tooth germ dry weight but mineralization was affected only by doses > or = 10(-5) M. However, the uptakes of TCA-insoluble 32P and [3H]thymidine were significantly reduced dose-dependently from > or = 10(-8) M actinomycin D, indicating that the drug inhibits the synthesis of phosphate-containing macromolecules as well as DNA synthesis. Histologically, 10(-8) M actinomycin D was the lowest dose which was not toxic to any cell type in the developing tooth germ. At 10(-7) M actinomycin D, the most sensitive cells were the proliferating pre-odontoblasts followed by pre-ameloblasts; the mature secretory ameloblasts and odontoblasts appeared unaffected. Higher doses resulted in increased cytotoxicity to the secretory cells and, eventually, total degeneration of most cells. The data suggest that children treated for cancer during tooth development using anti-chemotherapy cocktails containing actinomycin D (serum levels > 10(-7) M) may develop defects later on in the mature dentition as a direct consequence of the toxicity of the drug to the tooth organ.
The purpose of this study was to define the therapy-associated dental abnormalities in survivors of acute lymphoblastic leukemia (ALL). We reviewed the clinical records and panoramic radiographs of 423 survivors of ALL who were treated on one of four consecutive protocols (1975-1991). Dental abnormalities included root stunting, microdontia, hypodontia, taurodontia (enlarged pulp chambers), and over-retention of primary teeth. The frequency of these factors was determined in relation to age at initiation of treatment (< or = 8 years vs > 8 years), addition of cranial irradiation, and chemotherapeutic protocol. A total of 423 patients met the study criteria. The abnormalities comprised root stunting in 24.4% (n = 103), microdontia in 18.9% (n = 80), hypodontia in 8.5% (n = 36), taurodontia in 5.9% (n = 25), and over-retention of primary dentition in 4.0% (n = 17). Patients who were < or = 8 years old at diagnosis or who received cranial irradiation therapy developed more dental abnormalities than did those > 8 years and those who did not receive cranial irradiation (42 vs 32%). Survivors of childhood ALL often have dental abnormalities that may affect their quality of life. Dental evaluation at diagnosis and frequent follow-up may help to ensure appropriate preventive measures and minimize dental and periodontal disease.
Scanning electron microscopy was used to study the effect of cyclophosphamide (Cy) on molar development in 18 Sprague-Dawley rats from 15 to 48 days of age after birth. Doses of 30 mg/kg body weight of Cy dissolved in 1 ml 0.9% NaCl were given to the rats at 10 and 13 days of age. Eighteen control rats had injections of 1 ml 0.9% NaCl at the same ages. The most obvious changes in the experimental teeth were found in the developing roots of the first and second molars and in both the crown and roots of the third molar. The roots of the first and second molars were short and showed apical closure in the experimental rats. In addition to the disturbances in crown and root formation, the third molars were also significantly reduced in total size as compared with the third molars in the control rats.
This review discusses the effects of treatment of pediatric malignancies on the musculoskeletal system with an emphasis on plain radiographic and MR imaging findings following radiation therapy, chemotherapy, bone marrow transplantation and hematopoietic growth factor administration.
Osteoporosis and pathologic fractures are occasionally found in patients with childhood acute lymphoblastic leukemia (ALL). This study was performed to determine the degree of possible osteopenia in long-term survivors of childhood ALL.
Lumbar spine (L2-L4) and femoral neck bone mineral densities (BMDs) (g/cm2) were measured in 29 survivors (aged 12 to 30 years, median 17) of childhood ALL 2 to 20 (median 8) years after discontinuation of chemotherapy. These results were compared with those from 273 healthy controls and expressed as a percentage of the age- and sex-matched control values (mean +/- standard deviation).
Lumbar and femoral BMDs were significantly reduced in survivors of childhood ALL. Particularly, male gender (lumbar: 91.7 +/- 10.4%, p = 0.008; femoral: 91.9 +/- 11.3%, p = 0.005) and a history of cranial irradiation (lumbar: 93.0 +/- 8.9%, p = 0.005; femoral: 94.4 +/- 13.3%, p = 0.03) were associated with low lumbar and femoral BMDs.
The detected deficit in bone density in survivors of childhood ALL may predispose these patients to osteoporotic fractures later in adulthood. A follow-up of BMD in survivors of childhood ALL should facilitate the identification of patients who would require specific therapeutic interventions to prevent further decrease of their skeletal mass and preserve their BMD.
Conditioning before bone marrow transplantation (BMT) with total body irradiation (TBI) and cyclophosphamide carries the risk of severe long-term complications. The aim of the present study was to determine absorbed doses in the craniofacial area during TBI, using thermoluminescent dosimeters for both in vivo techniques and phantom measurements. The results from the phantom study showed that the mean deviation from the reference dose varied between -5.1 and +11.1%. The superficial part of left parotid gland received 11.1 +/- 1.5% more radiation compared with the reference. In patients, deviations from the reference dose varied in individual patients between -22.4 and +20.1% in various intra-oral sites. Since a small increase in dose can result in a significantly increased risk of pathology, the observed dose inhomogeneities for structures receiving tangentially directed radiation therapy, such as the parotid glands, may contribute to salivary dysfunction after TBI.
The aim of this study was to evaluate, under organ culture conditions, the cytotoxic effects of daunorubicin on tooth development. Three-day-old maxillary hamster second molars were exposed for 24 h in vitro to 108-10-4 M daunorubicin and then evaluated biochemically and histologically. At 10-6 M daunorubicin dose-dependently decreased tooth germ dry weight, cell proliferation ([3H]thymidine uptake), and insoluble [32P] phosphate uptake (phosphorylation of macromolecules). [45Ca]calcium uptake, a marker for mineralization, was significantly affected only at the highest concentration (10-4 M) tested. Histologically, 10-6 M daunorubicin induced necrosis of the proliferating but not the differentiated protein-secreting cells. At 10-4 M, however, all cells were dead. These results indicate that daunorubicin is particularly toxic to the proliferating cells of the tooth germ. Thus, it can be postulated that children treated with daunorubicin may develop defects in the erupted teeth mainly associated with those regions that were in the proliferating stage at the onset of anticancer chemotherapy.
Mammalian dentition consists of teeth that develop as discrete organs. From anterior to posterior, the dentition is divided into regions of incisor, canine, premolar and molar tooth types. Particularly teeth in the molar region are very diverse in shape. The development of individual teeth involves epithelial-mesenchymal interactions that are mediated by signals shared with other organs. Parts of the molecular details of signaling networks have been established, particularly in the signal families BMP, FGF, Hh and Wnt, mostly by the analysis of gene expression and signaling responses in knockout mice with arrested tooth development. Recent evidence suggests that largely the same signaling cascade is used reiteratively throughout tooth development. The successional determination of tooth region, tooth type, tooth crown base and individual cusps involves signals that regulate tissue growth and differentiation. Tooth type appears to be determined by epithelial signals and to involve differential activation of homeobox genes in the mesenchyme. This differential signaling could have allowed the evolutionary divergence of tooth shapes among the four tooth types. The advancing tooth morphogenesis is punctuated by transient signaling centers in the epithelium corresponding to the initiation of tooth buds, tooth crowns and individual cusps. The latter two signaling centers, the primary enamel knot and the secondary enamel knot, have been well characterized and are thought to direct the differential growth and subsequent folding of the dental epithelium. Several members of the FGF signal family have been implicated in the control of cell proliferation around the non-dividing enamel knots. Spatiotemporal induction of the secondary enamel knots determines the cusp patterns of individual teeth and is likely to involve repeated activation and inhibition of signaling as suggested for patterning of other epithelial organs.
Cytostatic antibiotics of the anthracycline class are the best known of the chemotherapeutic agents that cause cardiotoxicity. Alkylating agents such as cyclophosphamide, ifosfamide, cisplatin, carmustine, busulfan, chlormethine and mitomycin have also been associated with cardiotoxicity. Other agents that may induce a cardiac event include paclitaxel, etoposide, teniposide, the vinca alkaloids, fluorouracil, cytarabine, amsacrine, cladribine, asparaginase, tretinoin and pentostatin. Cardiotoxicity is rare with some agents, but may occur in >20% of patients treated with doxorubicin, daunorubicin or fluorouracil. Cardiac events may include mild blood pressure changes, thrombosis, electrocardiographic changes, arrhythmias, myocarditis, pericarditis, myocardial infarction, cardiomyopathy, cardiac failure (left ventricular failure) and congestive heart failure. These may occur during or shortly after treatment, within days or weeks after treatment, or may not be apparent until months, and sometimes years, after completion of chemotherapy. A number of risk factors may predispose a patient to cardiotoxicity. These are: cumulative dose (anthracyclines, mitomycin); total dose administered during a day or a course (cyclophosphamide, ifosfamide, carmustine, fluorouracil, cytarabine); rate of administration (anthracyclines, fluorouracil); schedule of administration (anthracyclines); mediastinal radiation; age; female gender; concurrent administration of cardiotoxic agents; prior anthracycline chemotherapy; history of or pre-existing cardiovascular disorders; and electrolyte imbalances such as hypokalaemia and hypomagnesaemia. The potential for cardiotoxicity should be recognised before therapy is initiated. Patients should be screened for risk factors, and an attempt to modify them should be made. Monitoring for cardiac events and their treatment will usually depend on the signs and symptoms anticipated and exhibited. Patients may be asymptomatic, with the only manifestation being electrocardiographic changes. Continuous cardiac monitoring, baseline and regular electrocardiographic and echocardiographic studies, radionuclide angiography and measurement of serum electrolytes and cardiac enzymes may be considered in patients with risk factors or those with a history of cardiotoxicity. Treatment of most cardiac events induced by chemotherapy is symptomatic. Agents that can be used prophylactically are few, although dexrazoxane, a cardioprotective agent specific for anthracycline chemotherapy, has been approved by the US Food and Drug Administration. Cardiotoxicity can be prevented by screening and modifying risk factors, aggressively monitoring for signs and symptoms as chemotherapy is administered, and continuing follow-up after completion of a course or the entire treatment. Prompt measures such as discontinuation or modification of chemotherapy or use of appropriate drug therapy should be initiated on the basis of changes in monitoring parameters before the patient exhibits signs and symptoms of cardiotoxicity.
This follow-up study aimed to assess the frequency of late effects on glucose and lipid metabolism after bone-marrow transplantation in childhood.
23 long-term survivors (median age 20 years) were studied 3-18 years after bone-marrow transplantation and compared with 23 healthy controls matched for age and sex and with 13 patients in remission from leukaemia.
12 (52%) of the 23 bone-marrow transplantation patients had insulin resistance, including impaired glucose tolerance in six and type 2 diabetes in four. The core signs of the metabolic syndrome (hyperinsulinaemia and hypertriglyceridaemia combined), were found in nine (39%) of the bone-marrow transplantation patients compared with one (8%) of the 13 leukaemia patients and none of the healthy controls (p=0.0015). The frequency of insulin resistance increased with the time since bone-marrow transplantation. Abdominal obesity, but not overweight, was common among the patients with insulin resistance.
Long-term survivors of bone-marrow transplantation are at substantial risk of insulin resistance, impaired glucose tolerance, and type 2 diabetes even at normal weight and young age. They also develop typical signs of the metabolic syndrome. We advocate measurement of serum lipids, fasting blood glucose, and serum insulin for the follow-up of all patients who undergo transplants in childhood, to be continued regularly and possibly life-long.
In this population-based material from the five Nordic countries (Denmark, Finland, Iceland, Norway and Sweden), 2860 children below 15 years of age were diagnosed with acute lymphoblastic leukemia (ALL) from July 1981 to June 1998. The annual incidence was 3.9/100,000 children and was stable throughout the study period. The development from regional or national protocols to common Nordic treatment protocols for all risk groups was completed in 1992 through a successive intensification with multidrug chemotherapy, including pulses of methotrexate in high doses and avoidance of cranial irradiation in most children. The overall event-free survival (EFS) at 5 years has increased from 56.5 +/- 1.7% in the early 1980s to 77.6 +/- 1.4% during the 1990s. The main improvements were seen in children with non-high risk leukemia. In high-risk patients, progress has been moderate, especially in children with high WBC (> or =100 x 10(9)/l) at diagnosis. During the last time period (January 1992-June 1998), only 10% of the patients have received cranial irradiation in first remission, while 90% of the patients have received pulses of high dose methotrexate (5-8 g/m2) isolated or combined with high-dose cytosine arabinoside (total dose 12 g/m2) plus multiple intrathecal injections of methotrexate as CNS-targeted treatment, not translating into increased cumulative incidence of CNS relapse.