Clinical Article CROSS-SECTIONAL

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Effect of Anticancer Therapy on Ectopic Eruption of Permanent First MolarsYoonsik Ko, DDS1 Kitae Park, DDS, PhD2 Ji-Yeon Kim, DDS, PhD3

In recent years, advances in the treatment of childhood cancer have led to long-term cures and a high survival rate.1,2 As the number of pediatric cancer survivors increases, however, so does the incidence of delayed adverse effects of anticancer treatment. These adverse effects include damage to the gonadal, pulmonary, cardiac, and nervous systems.3 Given that developing odontogenic cells are susceptible to chemotherapeutic agents, dental defects can potentially occur, such as arrested root development, inhibition of dentine formation, and enamel defects.4 An increase in the prevalence of dental caries and deterioration of jaw development have also been described.5-8 Developmental disturbances may also result in complicated tooth eruption disorders, such as ectopic eruption (defined as a tooth erupting in an abnormal position), which is most frequently observed in the permanent first molars (PFMs); (Figure 1).9

The prevalence of ectopic eruption of PFMs is between two percent and six percent.10 Two thirds of ectopically erupting PFMs, however, correct spontaneously from a locked position and erupt into occlusion. Otherwise, PFMs can cause exfoliation of primary second molars, which may result in mesial migration of the PFMs. This provokes a decrease in arch length and delays the eruption of the permanent second premolar.11 Therefore, early diagnosis and treatment precludes more complicated ortho- dontic problems later in life.

The causes of ectopic eruption of the PFMs are not well known.11,12 The disturbance of bone growth and delayed calcifi- cation, however, may affect their eruption.11 In patients receiving anticancer therapy, developmental disturbance of the teeth and jaw may influence ectopic eruption of PFMs. Yet, there currently is no method of quantitative analysis of the relationship between anticancer therapy and ectopic eruption of PFMs.

The purpose of this study was to investigate the association between anticancer therapy and ectopic eruption of permanent first molars.

MethodsThis study was reviewed and approved by the Institutional Review Board of Samsung Medical Center, Seoul, South Korea. This study evaluated patients who had visited the Department of Pediatric Dentistry at Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, between October 1, 2009 and Sep- tember 30, 2010. A total of 601 five- to seven-year-olds who had radiographs taken during this period were initially enrolled.

One investigator analyzed electronic medical records (EMRs) and radiographs, including bitewing, periapical, and panoramic radiographs. Through EMRs, cases of ectopic eruption were diag- nosed, and the history of ectopic correction was investigated. From radiographs, the root resorption of the primary second molar and the position of the PFMs were investigated.

Patients who received anticancer drugssuch as cortico- steroids for nonmalignant diseases, including hemangioma and idiopathic thrombocytopenic purpurawere excluded from the study. Patients whose radiographs clearly did not include or show permanent first molars were also excluded. Among the 601 pa- tients, 37 children were excluded based on these exclusion criteria (six from the anticancer therapy group, mean age=five years, 10 months old; 31 from the control group, mean age=six years, one month old). Finally, 76 children who had been treated for ped- iatric cancer were selected as the anticancer therapy group and 488 healthy children served as the control group (Table 1). All 76 children who had anticancer therapy received chemotherapy. Among these, 49 also received hematopoietic stem cell transplant- ation (HSCT) and 20 had both HSCT and radiation therapy.

Diagnostic criteria of ectopic eruption were cases in which the PFMs were impacted in the primary second molar with or without root resorption of the primary second molar. The prev- alence of ectopic eruption was compared between the anticancer therapy group and control group. In the former, the relationship between ectopic eruption and HSCT, radiation therapy, and age

1Dr. Ko is a Captain, Korean Army Medical Corps, 5th Infantry Division, Gyeonggido; 2Dr. Park is a professor and chair, Department of Pediatric Dentistry, The Institute of Oral Health Science, Samsung Medical Center, at Sungkyunkwan University School of Medicine at Seoul; and 3Dr. Kim is an associate professor, Department of Pediatric Dentistry School of Dentistry, Pusan National University, Dental Research Institute, at Busan, all in South Korea.Correspond with Dr. Kim at jychaee@gmail.com or jychaee@pusan.ac.kr

Abstract: Purpose: The purpose of this study was to investigate the association between anticancer therapy and ectopic eruption of permanent first molars (PFMs). Methods: This study evaluated 564 five- to seven-year-old patients (anticancer therapy group=76; control group=488) who had radiographs taken between October 1, 2009 and September 30, 2010. The prevalence of ectopic eruption of PFMs was compared between the anticancer therapy group and control group. In the anticancer therapy group, the association between ectopic eruption and radiation therapy, hematopoietic stem cell transplantation (HSCT), and age at the start of treatment was also evaluated. Results: The overall prevalence of ectopic eruption was approximately six percent, with a significantly higher rate in the anticancer therapy group (~16 percent) than in the control group (~five percent; P

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at the start of treatment was also evaluated. Regarding radiation therapy, local radiation therapy was excluded from the investiga- tion because it did not focus on the maxillofacial region in any patients in this study. Therefore, only patients who received sys- temic radiation therapy were included.

Since anticancer therapy was started immediately after diag- nosis, the date when the patients were diagnosed with cancer was assumed to be the same as the start of treatment. Patients were divided into four groups according to age at the start of treatment:

(1) less than one year; (2) greater than or equal to one and less than two years; (3) greater than or equal to two and less than three years; and(4) greater than or equal to three years.

Statistical methods. Statistical analyses were performed using SAS 9.1.3 software (SAS Institute, Inc, Cary, N.C., USA). Fishers exact test was used to investigate the relationship between two specific variables, and Bonferronis correction was used to de- termine the influence of age at the start of treatment on ectopic eruption. Statistical significance was defined as P.05.

ResultsEctopic eruption was found in 35 out of 564 patients (~6 percent), with a significantly higher prevalence in the anticancer therapy group (~16 percent) than the control group (~5 percent; P

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The total number of teeth that ectopically erupted was 59. Among them, 47 were on the maxilla and 12 were on the man- dible. In the control group, approximately 89 percent (31/35) of ectopic eruption cases occurred in the maxilla, and the remaining approximately 11 percent (4/35) occurred in the mandible. In the anticancer therapy group, approximately 67 percent (16/24) of eruptions were in the maxilla, and approximately 33 percent (8/24) occurred in the mandible (Table 4). Although there was a higher prevalence of ectopic eruption on the mandible in the anticancer therapy group than in the control group, the difference was not significant (P=.05).

DiscussionThe causes of ectopic eruption of the PFMs are not well known, and it is thought that multifactorial etiologies are involved.11,12 In 1968, Pulver suggested six factors that influence the first molar eruption13 but could not find one specific factor that contrib-utes to ectopic eruption, suggesting that a combination of factors is involved. One such factor is alteration in the chronology of bone growth in relation to calcification and eruption of the molar. Previous studies have demonstrated that radiation therapy with chemotherapy impairs odontogenesis and chemotherapy alone can result in dental anomalies and developmental disturbances.6,14-16 Growth retardation has a particularly profound impact on rapidly growing tissues.17 For this reason, the most severe interference in skeletal development due to anticancer therapy occurs during the periods of maximum bone growth from birth to six years old.5 In this study, all patients in the anticancer therapy group received anticancer therapy before seven years old. Therefore, the increased prevalence of ectopic eruption among patients with anticancer therapy may arise from disturbance of tooth calcification and underdevelopment of skeletal growth.

Analysis of cephalometric radiographs may be distinct evi- dence for the assessment of skeletal growth retardation. Cephalo- metric radiographs, however, were not taken routinely in this age group unless for specific purposes such as orthodontic necessity. Taking cephalometry strictly for research purposes may cause ethical problems. For these reasons, the current study is limited in its analysis regarding the degree of growth retardation. Further studies with quantitative and definite analyses may be necessary in the near future.

Since this studys findings apply only to dental patients and not to the general population, our results may have some limita- tions. Nevertheless, our results correspond well to those of previous studies. In the control group of this study, the preva-lence of ectopic eruption of the PFMs was approximately five per- cent, similar to the prevalence reported by Bjerklin and Kurol in healthy children.18 Also, other studies have reported prevalence ranging between two percent and six percent.10

Several previous studies demonstrated that the severity of dental malformation depends on the stage of tooth development and type and dosage of anticancer agents employed.5,19 In this study, patients who started anticancer therapy after three years old had a lower prevalence of ectopic eruption. This is probably be- cause the roots of the primary second molar are fully developed at approximately three years old, and the enamel of the PFMs is completely formed at nearly the same age.20,21 If anticancer therapy is given before three years old, it can disturb the growth of the teeth and disrupt the eruption pattern.

Regarding radiation therapy in this study, the same dose of systemic radiation therapy was used (9.9 Gy over three days). Patients receiving local radiation therapy were excluded from the investigation because the radiation did not focus on the maxillo- facial region. As for chemotherapy, different dosages, durations of treatment, and types of anticancer agents were used according to each patients stage and type of cancer (eg, solid tumor vs. blood cancer). Dosage of chemotherapy, however, was not classified quantitatively in this study. Likewise, patients can be classified according to transplantation type (allogenic vs autologous trans- plantation) and/or the number of transplantations. Since these are limitations of this study, further study regarding dosage and/or classification of anticancer treatment is necessary in the near future.

In previous reports, chemotherapy with radiation therapy resulted in severe dental disturbances, whereas chemotherapy alone has not been reported to produce severe problems.5,14,22 Since most children receive more than one type of therapy, however, it is difficult to completely distinguish the sequelae of chemotherapy from radiation effects. Moreover, in this study, supplementary radiation therapy and HSCT did not significantly influence the prevalence of ectopic eruption. Such results might be possible for the following reasons. First, the supplementary radiation therapy and HSCT were performed for a short period compared to chemo-therapy. Second, none of this studys patients had local radiation therapy focused on the maxillofacial region.

Though it was not statistically significant, the anticancer therapy group showed a higher prevalence of ectopic eruption on the mandible than the control group. In 1989, Berkowitz et al. reported that growth retardation of the mandible is affected more by anticancer therapy than the nasomaxillary complex.7 It is not clear, however, why growth of the mandible is more sensitive to anticancer therapy, and Berkowitz et al. did not propose specific mechanisms to explain this observation. Further study into the underlying mechanism is, therefore, necessary.

ConclusionBased on this studys results, the following conclusions can be made:

1. The prevalence of ectopic eruption of permanent first molars increased in patients with anticancer therapy, especially in children who started anticancer therapy be-fore they were three years old.

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* Fishers exact test was used to investigate the relationship between two specific variables.

Table 4. DISTRIBUTION OF ECTOPIC ERUPTION ACCORDING TO MAXILLA AND MANDIBLE*

Control groupn (%)

Anticancer therapy

group n (%)

P-value

Maxilla (n=47) 31 (89) 16 (67) .05Mandible (n=12) 4 (11) 8 (33)

Total (n=59) 35 (100) 24 (100)

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Abstract of Electronic Publication in this IssueScientific Article IN VITRO

Microbial Microleakage Assessment of a New Hydrophilic Fissure Sealant: A Laboratory StudyAli Bagherian, DDS, MS1 Mahsa Ahmadkhani, DDS2 Mahmood Sheikhfathollahi, PhD3 Reza Bahramabadinejad, MSc4

Abstract: Purpose: The purpose of this study was to compare microbial leakage of a new hydrophilic sealant with that of a conventional hydro- phobic resin-based sealant. Methods: One hundred extracted, caries-free, human maxillary premolars were randomly divided into five groups. Those in Groups 1, 2, and 3 had dry, wet, and artificial saliva-contaminated occlusal surfaces, respectively, and were sealed with a hydrophilic sealant, while those in Groups 4 and 5 had dry and wet occlusal surfaces, respectively, and were sealed with a hydrophobic sealant. A newly designed microbial penetration method utilizing Streptococcus mutans as an indicator was tested for leakage assessment. Data were analyzed using SPSS 15.0 software, and the significance level was set at =0.05. Results: The log rank test indicated a statistically significant difference in leakage rates among the five groups. Mantel-Cox log-rank test findings showed that Group 3 had the highest leakage rate, with Groups 2 and 4 having the lowest. There was no statistically significant difference in leakage rate between Groups 2 and 4. Conclusions: With respect to the limitations of an in vitro study, our findings suggest that hydrophilic sealants are an acceptable alternative to hydrophobic sealants. (Pediatr Dent 2013;35:E194-E198) Received September 22, 2012 | Last Revision March 5, 2013 | Accepted March 11, 2013

KEYWORDS: PIT AND FISSURE SEALANTS, DENTAL LEAKAGE, HYDROPHILICITY