Table of Contents  
REVIEW ARTICLE
Year : 2016  |  Volume : 8  |  Issue : 1  |  Page : 3-11

Oral health of children with acute lymphoblastic leukemia: A review


1 Department of Pedodontics and Preventive Dentistry, The Oxford Dental College, Hospital and Research Centre, Bangalore, Karnataka, India
2 Department of Orthodontics, The Oxford Dental College, Hospital and Research Centre, Bangalore, Karnataka, India
3 Department of Prosthodontics, Krishnadevaraya Dental College, Bangalore, Karnataka, India
4 Department of Dentistry, Belgum Institute of Medical Sciences, Belgum, Karnataka, India

Date of Web Publication6-May-2016

Correspondence Address:
Dr. Kadalagere Lakshmana Girish Babu
Department of Pedodontics and Preventive Dentistry, The Oxford Dental College, Hospital and Research Centre, Bommanahalli, Hosur Road, Bangalore - 560 068, Karnataka
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0975-8844.181915

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  Abstract 

Leukemia is a malignancy of the bone marrow and blood. It is the most common childhood cancer in India. Advances in the treatment regimens have greatly increased the chances of survival. Both the disease and its treatment change the oral environment. In some cases, oral manifestations are the presenting feature of the disease and it will be the dentist's responsibility to identify the underlying disorder and guide the diagnosis of the patient. Hence, the aim of present article is to review the literature concerning the oral health of children with acute lymphoblastic leukemia (ALL).

Keywords: Dental caries, gingival, leukemia, oral health, periodontal, saliva, temporomandibular joint (TMJ), tooth morphology


How to cite this article:
Girish Babu KL, Mathew J, Doddamani GM, Narasimhaiah JK, Naik LR. Oral health of children with acute lymphoblastic leukemia: A review. J Orofac Sci 2016;8:3-11

How to cite this URL:
Girish Babu KL, Mathew J, Doddamani GM, Narasimhaiah JK, Naik LR. Oral health of children with acute lymphoblastic leukemia: A review. J Orofac Sci [serial online] 2016 [cited 2019 Mar 19];8:3-11. Available from: http://www.jofs.in/text.asp?2016/8/1/3/181915


  Introduction Top


Leukemia was first identified by researchers Virchow and Bennet in 1845. [1] It is a malignancy of the bone marrow and blood. It is associated with disseminated proliferation of immature or blast cells of the bone marrow that replace the normal marrow elements and tends to accumulate in various tissues of the body. [2] The main types of leukemia are lymphocytic leukemia (that involves an increase in lymphocytes) and myelogenous leukemia (that involves an increase in granulocytes).

Leukemia is the most common childhood cancer in India with the relative proportion varying between 25% and 40%. [3] Among various leukemias, acute lymphoblastic leukemia (ALL) accounts for 60-85% of all cases in children in India. [3] Children with ALL receive various forms of treatments including multiagent chemotherapy, radiation, surgery, and bone marrow and stem cell transplants. Advances in the treatment regimens have greatly increased chances of survival. However, leukemic children face an assault on oral health from both the disease and the treatment options.

Chemotherapy and radiotherapy are generally cytotoxic for rapidly multiplying malignant cells but also negatively impact the production of normal hemopoietic and secretary cells as these do not differentiate between normal and malignant cells. This side effect often results in immune-suppression, inducing a number of changes in oral tissues. These include mucositis, trismus, xerostomia, gingival bleeding, ulcerations, taste alteration, skin desquamation, and opportunistic infections, which further interrupts radiotherapy, inducing malnutrition or systemic infection. A combination of chemotherapy and radiotherapy may have an additive if not synergistic effect on the aforementioned complications. [4]

Both the disease and its treatment radically change the oral environment. In some cases, oral manifestations are the presenting feature of the disease and it is the dentist's responsibility to identify the underlying disorder and guide the diagnosis of the patient. Hence, the aim of the present article is to review the literature concerning the oral health of children with ALL.


  Classification of Oral Complications Seen in Leukemic Children Top


There have been several approaches to classify the oral complications in leukemic children; however, the most accepted and broad classification can be described as: [5],[6]

  1. Primary complications - These mainly occurr due to the disease itself, i.e., they result from leukemic infiltration in the oral structures such as the gingiva and bone, e.g., leukemic gingival enlargement.
  2. Secondary complications - These are usually associated with direct effect of radiation or chemotherapy, such as the ones associated with thrombocytopenia, anemia, and granulocytopenia. These include the tendency to bleed, susceptibility to infections, and ulcers.
  3. Tertiary complications - The tertiary complications are usually due to a complex interplay of the therapy itself, its side effect, and a systemic condition arising out of the therapy. They may be ulcerations, mucositis, taste alteration, skin desquamation, candidiasis, gingival bleeding, xerostomia, dysphasia, opportunistic infections, trismus, etc. Sometimes, latent and late effects such as some of the vascular lesions, tissue atrophy, permanent taste loss or change, fibrosis, edema, soft tissue necrosis, loss of teeth, salivary flow decrease, carious lesions, osteoradionecrosis, and chondronecrosis are also attributed to tertiary effects.



  Dental Caries Status Top


An increase in dental caries has been observed in patients with leukemia. However, dental caries does not occur due to the effect of either the disease process or radiotherapy or chemotherapy on the tooth structure. It is due to the alterations in the salivary gland, tendency to have a soft diet, change in oral microflora, and the inability to maintain oral hygiene. [6]

Dens et al. [7] conducted a study to examine caries prevalence, gingival health, and oral hygiene of 52 children receiving chemotherapy and found a significantly higher caries prevalence. Hegde et al. also observed higher caries prevalence in ALL children [8] than the healthy control group. Similarly, Nasim et al. observed a high decayed, missing, and filled teeth (DMFT) in leukemic children who were under treatment. [9] Azher et al. [10] observed that the number of decayed teeth in primary dentition was greater than that in permanent dentition, which was related to inadequacy in manual dexterity in the early stages and more prolonged time during which the primary teeth were exposed to the insult of bacterial plaque. However, Maciel et al. [11] found no significant differences in DMFT scores between leukemic children and the controls. This may have been due to the oral hygiene instructions that the multidisciplinary team gave these children and to the redoubled care of parents during treatment. Likewise, Cubukc and Günes [12] reported no significant difference in the caries experience before and after the initiation of chemotherapy in children with ALL.

Prolonged use of sugar-containing nystatin has been directly associated with the caries experience in children with ALL. [13] Kinirons et al. [13] showed that children with ALL using nystatin oral rinses for over 12 months were more susceptible to develop dental caries as compared to those who had received nystatin for shorter periods. A diminished salivary flow rate in children with ALL [8] may allow the sugar-containing nystatin and dental plaque to adhere to teeth surfaces and induce their fermentation. It is suggested that sugar-free antifungal oral rinses may contribute toward reducing the occurrence of dental caries in children with ALL; however, the role of regular oral hygiene maintenance regimes in this regard cannot be disregarded. But the oral mucosal inflammation induced by chemotherapy may prevent some patients from performing daily oral hygiene maintenance regimes. [14],[15]


  Tooth Morphology Top


It has been reported that ALL may negatively influence the dentoalveolar complex during its formation; [16] however, this association is dependent on various factors including age of the patient at diagnosis, type of drugs used for chemotherapy, and dosage of radiotherapy (if used as an adjunct to chemotherapy in severe cases). [17],[18],[19],[20],[21],[22]

An ideal chemotherapeutic agent should only destroy malignant cells. However, since chemotherapeutic agents do not have a selective toxicity for tumor cells, they may also influence healthy cells at proliferation stages. [17] They interfere with DNA synthesis and replication, RNA transcription, and cytoplasmic transport mechanisms. [18] Early anticancer treatment causes hypomineralization or hypomaturation of the enamel or formation of short, thin, tapered root. Clinically, the defective enamel and dentin will be seen as deformed and discolored crowns of the teeth. [22]

Studies [18],[19],[20] have demonstrated that chemotherapeutic agents (such as cyclophosphamide and vincristine) interfere with the cell cycle and with intracellular metabolism, thereby eliciting residual changes in dental development that may lead to microdontia, malformed teeth, and changes in the histomorphology of odontoblasts, with necrotic changes in preodontoblasts in the basal pulp region. In this regard, altered odontoblastic activity (a consequence of abnormal secretory function of microtubules and of complex changes in inter- and intracellular relationships) may negatively influence the morphology of a developing tooth. [18]

Maciel et al. [21] compared the incidence of dental anomalies in shape, size, number, and structure among 56 patients treated for ALL and a control group (n = 56). In this study, the mean age of children with and without ALL was 11.8 years and 11 years, respectively. The results showed several dental morphological anomalies in children with and without ALL including agenesis, enlarged pulp chambers hypoplasia, microdontia, short roots, supernumerary teeth, tapering roots and taurodontism; [21] however, agenesis, microdontia, short roots, and tapering roots were more prevalent in children with ALL as compared to their medically healthy counterparts. [20]

Head and neck radiation therapy is often given in combination with multiagent chemotherapy in the treatment of ALL. Direct radiation of the head and neck region can lead to bony hypoplasia of the jaws, orbits, and facial skeleton that may contribute to malocclusion. Radiotherapy has also been shown to arrest tooth development, which produces microdontia, enhances atrophy of the overlying soft tissue, causes enamel hypoplasia or incomplete calcification, and arrests root development. The younger the child, the greater is the risk for craniofacial and developmental abnormalities. [23]

Maguire and Welbury [24] reported that the effects of direct irradiation of the bone, soft tissues, and blood vessels are dose-related and have their most profound effects in rapidly growing patients. Irradiation to the central nervous system may reduce hypothalamic-pituitary function, resulting in diminished production of growth hormone and thyroid-stimulation hormone. This may, in turn, adversely affect craniofacial development and odontogenesis. It has been reported that a 10-Gy radiation dosage permanently damages the ameloblasts, whereas a 30-Gy radiation dose halts tooth development from the time the teeth are irradiated. [25] Sonis et al. [26] investigated the dentofacial development in 97 children diagnosed with ALL. These children were treated with either:

  1. Chemotherapy and 18-Gy cranial irradiation, or
  2. Chemotherapy with adjunct 24-Gy cranial irradiation.


The results showed that 94% of all patients and 100% of the children younger than 5 years of age at diagnosis had dental anomalies including arrested root development, enamel dysplasias, microdontia, and tooth agenesis. Mandibular growth was compromised in children receiving 24-Gy irradiation as compared to those receiving lesser dosages of radiotherapy for the treatment of ALL.

It is difficult to assess whether these defects are components of the therapy (multiagent chemotherapy or radiation therapy) or a result of the disease itself. The degree and severity of these effects appear to depend upon the child's age at diagnosis and the type and dose of cranial irradiation. Jaffe et al. [27] stated that other factors, which may cause these defects cannot be excluded such as antibiotic medications, systemic disturbances, fever, and poor nutritional habits. Local factors and/or normal variations must also be considered.

Rosenberg et al. [28] was first to study and identify altered dental root development associated with chemotherapy alone. The study consisted of 17 long-term survivors of childhood ALL treated with chemotherapy before the age of 10 years. They found that patients had an altered dental root development such as root tapering or narrowing, blunting of the root apex, and actual loss of root length, which was evident on periapical radiographs and most likely related to the chemotherapy treatment. Another report suggests that colchicine, vinblastine, and cyclophosphamide alter odontogenesis by the inhibition of dentin formation in rat incisors. [29]

Al-Ghani et al. [30] evaluated the dental abnormalities in 48 children with ALL with varying disease durations. The result showed that 37.5% of acute lymphoblastic leukemic patients had enamel hypoplasia. Enamel hypoplasia was more predominant in the anterior teeth than the posterior teeth. This high prevalence of enamel defects was related to the period of tooth development at the time of cytotoxic drug administration and radiation therapy, which is entirely consistent with severe disturbance to ameloblasts during the secretory or postsecretory phase activity. Thus, there was a significant correlation between the increment of disease duration and severity of enamel hypoplasia. Similar results were also seen by Pajari et al. [31]

Many authors have observed that the severity of dental abnormalities (such as microdontia, hypoplasia, agenesis, V-shaped root, and shortened root) was greater in children who received treatment before 5 years of age and if amelogenesis was not complete. [32],[33],[34] Sonis [26] described developmental disturbances of the permanent dentition including arrested root development, resulting from therapy for childhood ALL. He suggested that immature teeth in children treated before the age of 5 years were at greater risk for developmental disturbances than mature teeth. The effects of combined chemotherapy and radiation on root development are an important consideration when a treatment plan including orthodontics is being considered for a patient with a history of ALL. Alternate plans may have to be chosen in cases with arrested root development. The risk of further root resorption as a result of orthodontic therapy must be weighed against the benefits of treatment. [35]


  Oral Mucositis Top


Oral mucositis is a frequent complication of ALL and represents the main cause of pain and discomfort. [36],[37],[38] Patient complains of burning and dryness of the mouth, difficulty in speaking and eating, and altered taste. The initial presentation of oral mucositis is erythema, followed by white desquamating plaques that are painful to touch. A more pronounced form of oral mucositis is characterized by epithelial crusting and ulceration. [39] Even a mild local irritant such as sharp teeth or restoration, presence of calculus, and plaque may aggravate the mucosal inflammation. Younger patients appear to have a greater risk of chemotherapy-induced mucositis, which may be attributed to a more rapid epithelial mitotic rate or the presence of more epidermal growth factor receptors. [6]

Mucositis is usually seen in 5-7 days following cancer medication but sometimes, it can be seen later too. It involves the soft palate, oropharynx, buccal and labial mucosa, floor of the mouth, and the ventral and lateral surfaces of the tongue. [5] The pain associated with mucositis may cause difficulty in eating, which leads to weight loss, anorexia, cachexia, and dehydration. [40]

Oral mucositis may occur as a result of both "direct" and "indirect" effects of chemotherapy on cells. [41] The direct effect occurs due to the nonspecific effect of antineoplastic drugs on cell proliferation, maturation, and replacement. Consequently, the renewal rate of the basal epithelium is reduced, and results in mucosal atrophy, mucositis, and ulceration. On the other hand, the indirect effect has been associated with the myelosuppressive action of drugs deregulating the immune system and repair process, thereby increasing the risk of infection associated with oral mucositis. [42] At present, the condition is often referred to as mucosal barrier injury (MBI). [43]

Many studies [44],[45],[46],[47] have reported an increased incidence of numerous oral mucosal anomalies including generalized ulcers, coated tongue, fetor oris, shallow papillae, tender oral mucosa, and oral mucosal infections (mucositis, candidiasis, herpes simplex, varicella/zoster, and cytomegalovirus) in patients with ALL. da Fonseca [48] and Alberth [49] have reported that the administration of certain drugs such as antifolates (methotrexate) and corticosteroids (prednisone) concurrent with the chemotherapy may influence the appearance of oral lesions.

Pels [43] found lesions of the mucositis type in the children with ALL, which were detected after 48 h to 6 months of chemotherapy; those were of varied intensity with periods without any pathological changes, which was related to the intensity of chemotherapy. Mucosal opacity followed by redness usually occurred within 2-4 days from the methotrexate infusion. Most intensive oral mucosal lesions developed over the first month of chemotherapy. Changes in the oral mucosa were of different severities. The following pathologies were observed: Localized erythema of the mucosa (Grade 1) in 35% of the children, pseudomembraneous mucosa (Grade 2) in 18% of the children, ulcers with extensive erythema (Grade 3) in 40% of the children, massive mucosal ulcers and tissue necrosis (Grade 4) in 4% of the patients. Wounds and difficult to heal ulcers were related to poor blood parameters. It was observed that healing was faster, especially with regard to oral mucosa ulceration, when blood morphological parameters improved. The lesions of mucositis type were neutropenia-dependent. Each child with neutropenia had fungal complications in the oral mucosa. Generally, no lesions were observed in the periods between subsequent protocols. After 6 months of chemotherapy, oral mucosa lesions were less intense and were observed in 3.17% of the children examined. Redness and erosions were the most frequent. No ulcers in the oral cavity were observed.

In a study conducted on Brazilian children with a mean age of 5 years, oral mucositis was reported in 71.4% of the children. [50] In a similar study conducted by Pels to assess oral mucosa in children with ALL during antineoplastic therapy, lesions of the mucositis type were observed in ALL children in the period from 48 h to 6 months, having various intensities and with periods without pathological lesions, which were related to the intensity of chemotherapy. [51] Borbasi et al. [52] reported oral mucositis to be the most distressing symptom experienced among patients who receive a high dose of chemotherapy for acute leukemia and bone marrow transplant. A South Indian study observed mucositis to be the most common manifestation seen in two (3.4%) children of the control group and in 12 (20.6%) children of the study group. [53]


  Oral Candidiasis Top


Although Candida species (predominantly Candida albicans) are part of the conventional oral flora; they may become opportunistic pathogens in children with ALL due to their immunocompromised condition. Simultaneously, a dry oral environment in these children also triggers Candida infections by stagnating Candida species on the oral soft tissues, particularly on the dorsum of the tongue. [54] It is one of the most common opportunistic infections seen.

Candida spp. adheres to the epithelial surface via extracellular polymeric materials and further penetrates by liberation of enzymes. The presentation may vary from soft white adherent patches on the oral mucosa seen in pseudomembraous candidiasis to erythematous painful eroded areas of erythematous form. Acute pseudomembranous candidiasis, which has been referred to as "thrush" traditionally shows a classical "curdled milk appearance" clinically. On scraping, the lesions show pinpoint hemorrhagic areas. [55]

Erythematous candidiasis, previously referred to as atrophic oral candidiasis, typically manifests as diffuse erythematous areas in the oral cavity. The appearance produced is not only due to atrophy of the oral mucosa but also due to an increased vascularization. It has been observed clinically that acute pseudomembranous candidiasis progresses to erythematous candidiasis. Often, it may also be manifested as angular cheilitis. Children with leukemia show immunosuppression and hence, they are at an increased risk of dissemination of Candida infection, which may be life-threatening. [56]

In the study by Ponce-Torres et al., [57] the prevalence of oral candidiasis among children with ALL was reported to be 6.12%, which was comparatively lower in contrast to the prevalence reported by previous studies. [53],[58] A possible explanation for this may be attributed to various factors including the degree of oral hygiene maintained by the subjects, severity of immunosuppression, and modifications in the drug regime patterns. Children with ALL undergoing chemotherapy developed mucositis and candidiasis within 1 week after antifolate and corticosteroid therapy. [57]


  Other Infections Top


Milins et al. [59] and Sixou et al. [60] have shown an increased proliferation and colonization of Gram-negative bacteria including  Escherichia More Details coli, Pseudomonas aeruginosa, Klebsiella, and Enterobacter species in the oral cavity of patients with ALL as compared to their healthy counterparts. Similarly, Gram-positive bacteria including Staphylococcus and Enterococcus have also been isolated from the oral mucosa of immunocompromised patients. [61] The viral infections seen in children with leukemia are herpes simplex, varicella zoster, cytomegalovirus, adenovirus, and Epstein barr virus. Herpes simplex is clinically manifested as multiple ulcers at the corners of the mouth, lips, palate, and gingiva. An erythema may also be seen around the ulcerative lesions. Varicella zoster is seen as multiple blisters, which show a protracted course. It may involve the lungs, central nervous system (CNS), and liver and is associated with high morbidity. Other infections seen in these patients include tuberculosis and pneumonia. [6]


  Hemorrhage Top


The patients on chemotherapy and radiation often show signs of bleeding or hemorrhage from the oral cavity. It may range from a minor bleed from the inflamed gingiva to ecchymosis, hematoma, or hemorrhage depending upon the severity of thrombocytopenia, oral hygiene, and contributing factors such as sharp tooth. Gingiva, buccal mucosa, tongue, floor of the mouth, and hard and soft palates are the most common sites of petechiae. Ecchymosis is commonly found on the tongue and floor of the mouth. Trauma associated with an oral function can also induce hemorrhage. Spontaneous mucosal petechiae and gingival bleeding can occur when the platelet level drops below 20,000 cells per mm 3 . Intraoral bleeding can be alarming to patients and caregivers for future complications. [6]


  Gingival and Periodontal Health Top


Gingival hyperplasia, which is one of the most common findings of the disease, is usually generalized and varies in severity. It is characterized by progressive enlargement of the interdental papillae as well as the marginal and attached gingiva. In the most pronounced form, the crowns of the teeth may be covered. The gingiva appears as swollen, devoid of stippling, and pale red to deep purple in color. [62] Gingival infiltration by leukemic cells also predispose the leukemic children to bleeding. [63] Gingival hyperplasia is more common in acute than in chronic leukemia; [62],[63] nonetheless, the development of gingival infiltration is unpredictable in any individual patient. Spontaneous bleeding or bleeding from traumatic brushing may be commonly seen from the gingiva in patients receiving chemotherapy. It occurs mainly due to poor oral hygiene but can be exacerbated by reduced platelet counts.

Generally, gingival hyperplasia resolves completely or at least partly with effective leukemia chemotherapy. [63] Azher et al. [10] reported mild to moderate gingival inflammation, which was a contrast to the results obtained by Nasim et al. [9] where a significant deterioration of the gingival condition was observed in patients undergoing chemoradiation therapy (52%). Hegde et al. [8] investigated the periodontal health status in children with and without ALL. In this study,120 children aged between 4 years and 10 years (90 children with ALL and 30 medically healthy controls) were included. The gingival health in children with and without ALL was assessed by a modified gingival index. They observed gingival inflammation to be more often in children with ALL as compared to healthy controls. Gingival inflammation was also directly associated with the duration of chemotherapy.

In a cross-sectional study, the prevalence of periodontal inflammatory conditions was investigated in 49 children (mean age in years: 7.34 ± 3.3) with ALL. [57] In this study, the prevalence of gingivitis and periodontitis in children with ALL were reported to be 91.84% and 16.32%, respectively. Sonis et al. [64] investigated the periodontal inflammatory conditions in 69 children undergoing treatment for ALL. The results showed that the patients who received 24 grays (Gy) of cranial radiotherapy (RT) had significantly higher plaque and periodontal index as compared to patients who received 18 Gy of cranial RT. It is known that a reduced salivary flow rate (due to chemotherapy-induced salivary gland hypoplasia) favors dental plaque accumulation, which if left uncontrolled, may trigger periodontal inflammation in immunocompromised patients. [8],[65],[66]


  Dysguesia/Taste Alteration Top


Direct radiation to the oral cavity may result in damage to the gustatory buds. Due to highly viscous and minimal saliva, the eatables do not reach the taste buds situated in the posterior part of the tongue and may also cause taste alteration. It causes 50% reduction in the perception of bitter and sour tastes. Chemotherapy drugs also causes bad taste, termed as "venous taste phenomenon" that results from the diffusion of the drug into the oral cavity. Taste loss is often transitional as the affected buds usually regenerate. Partial or total recovery may occur between 2 months and 12 months after myelosuppresive therapy. [67]


  Saliva Top


Xerostomia or reduced salivation is one of the most frequent effects of radiotherapy in the head and neck region. [6] Salivary glands are expected to be relatively radio-resistant due to slow turnover rates of their cells. Yet, changes in the saliva may be seen quantitatively and qualitatively shortly after antineoplastic therapy. Since there is an increase in viscosity and proportion of organic material, the color of the saliva may change from transparent to opaque white or yellow. The pH and buffering capacity of saliva decreases, and there is alteration in electrolyte levels. The radiation therapy causes fibrosis, degeneration of salivary acinar cells, and necrosis of salivary glands that lead to these changes. Due to low pH, the oral flora shows a shift from Gram-positive to Gram-negative bacteria. [5]

Decreased flow and increased viscosity can also cause difficulty with chewing, swallowing, speech, etc. There is a significant increase in the prevalence of infections such as candidiasis, periodontal disease, and caries due to alteration in pH and oral flora. Lack of adequate saliva also hampers the function of taste buds resulting in taste alteration, dislike for food, and subsequent appetite loss. This is further complicated by episodes of nausea, vomiting, pain, and discomfort, resulting in a fall in the general health of the patient. [6] Pels observed decreased levels of phosphorous and calcium ions in the saliva of ALL children. [43]


  Temporomandibular Joint Problems Top


The association between ALL and disorders of the temporomandibular joint (TMJ) has been inadequately addressed. Limited mouth opening or trismus is often seen as an oral complication induced by antineoplastic therapy. It is mainly a consequence of edema, cellular destruction, and muscular fibrosis caused by chemotherapeutic agents. Sometimes the muscles coming in the direct path of radiation can also develop fibrosis or degeneration. Limited mouth opening may also lead to an inadequate oral hygiene, further hampering the health of the oral cavity. Also, it may be hypothesized that tooth morphological disorders may result in poor dental occlusion (poor alignment of teeth) and if it remains neglected, may lead to TMJ disorders. [6]

In the study by Welbury et al., [68] mouth opening was investigated in 37 children with leukemia. The results showed no variation in mouth opening; however, it is notable that these leukemic children were not exposed to any form of radiation therapy. [69] Nasim et al. [9] observed tenderness of TMJ in leukemic children. This suggests that children with ALL undergoing cranial irradiation as an adjunct to chemotherapy are more susceptible to TMJ dysfunction as compared to children undergoing only chemotherapy for the treatment of ALL.


  Osteoradionecrosis Top


Osteoradionecrosis is considered as one of the most severe and serious oral complications of radiotherapy for the head and neck region. The etiological factor responsible is radiation, which damages the endothelial linings of the vessels of the bones resulting in hypocellularity and vasculitis followed by obliterate endarteritis, ischemia, fistula, and sometimes pathological fracture of the bone. The mucosa also becomes thinner with telangiectasia formation in the irradiated area. This makes it more susceptible to mechanical injury. There is a decrease in collagen formation and the capacity for wound-healing. There is decreased blood flow due to alterations in the vessels, thus reducing nutrients and defense cells. This causes bone ischemia, especially if the bone is subjected to trauma, e.g., tooth extraction. The most common site for osteoradionecrosis is the mandible due to its relatively poor vascularization and the presence of teeth. [6]


  Oral Hygiene Top


Poor oral hygiene poses significant problems in patients undergoing chemotherapy as oral lesions are painful, cause ulcerations, and eventually result in poor nutrition, underhydration, and may create a life threat eventually. Complications that develop within the oral cavity are likely to prolong the treatment time and increase its costs too. [70],[71],[72],[73],[74],[75] Oral hygiene status and lowered concentrations of calcium, phosphate, and magnesium ions in the saliva in leukemic children during chemotherapy may affect the intensity of the pathological changes in the oral mucosa.

Al-Mashhadane conducted a study to evaluate the oral health status among children receiving chemotherapy. It was found that the chemotherapeutic agents modify the oral health and there was a significant increase in plaque and gingival indices. [76] In a study by Azher et al., [10] more than half of the patients examined had a poor oral hygiene and needed oral care regimen for the maintenance of infection-free oral cavity to minimize the negative effects of chemotherapy. However, in a study conducted by Pels and Mielnik-Blaszczak to evaluate the oral hygiene status in children with ALL during the anticancer treatment protocol, it was found that oral hygiene was significantly better in children with ALL than in healthy children. The result was attributed to the oral hygiene regimen that the ALL children were following during the cancer treatment protocol. [77] In an another study by Pels et al., oral hygiene status was notably better and there was a decreased incidence of dental plaque in children with ALL, compared to children from the control group. [78] Authors from the center in Wroclaw observed a good oral hygiene in children with ALL and acute nonlymphoblastic leukemia, which made gingivitis less advanced and more localized. Some authors showed that in 48.3% of the patients' dental plaque was present on less than 40% of the tooth surfaces examined. These authors also observed poor oral hygiene in only 25.8% of ALL children and generalized gingivitis in only 9.6% of ill children. They also noted that the oral hygiene index had a significant positive correlation with the gingival index. [79] Dens et al. observed a negative correlation between age and the plaque index between children undergoing chemotherapy. [80]

Fleming and Kinirons demonstrated that the incidence of dental plaque was the same in children with ALL and in children with good general health. [13] High values of oral hygiene status and gum condition indices were presented by Sonis et al. although they noted statistically significant differences only in the group of children with ALL undergoing radiotherapy. The mean simplified oral hygiene index (OHI-S) in their studies of children with ALL who received only chemotherapy was 4.9 ± 3.3. They explained the high values of these indices by the greater number of teeth with abnormalities and irregular surface of the enamel in the patients. [64] Avsar et al. examined children with total remission and found significantly higher indicators of the plaque index and gingival index as compared to their healthy peers. [81] Uderzo et al. examined the state of the periodontium of leukemic children after transplants (allogenic or autogenic). They observed the presence of soft deposits in 77.7%, gingivitis in 59.2%, and pathological changes in the periodontium in 3.7% of the examined children. [69] Brazilian authors, after having examined children with ALL for 7 months, demonstrated that the systematic use of 0.12 chlorhexidine indeed decreased the inflammatory conditions and ulceration of gums. [50] In a study of children with hematological diseases, Mielnik-Błaszczak noted that oral hygiene in ill children was better than in healthy children. The mean value of the OHI in their study was 1.04, which was noted in 39% of ill children. [82] Pels et al. observed that children with ALL from the rural environment have a worse state of oral hygiene than children from towns. But a significantly better oral hygiene was observed in children with ALL, compared with children in the control group. The better condition of oral hygiene in children with ALL than children in the control group was the result of the oral hygiene regime that the children were following during cancer treatment protocols. [77]

Establishment of good oral hygiene in these patients becomes difficult due to their young age and debilitating nature of the disease, which prevents the performance of good oral hygiene. It is necessary to make an assessment of oral hygiene in this group of children during chemotherapy. [78]


  Conclusion Top


The dentist plays a fundamental role in the early diagnosis of leukemia. Frequently the first signs of the disease occur in the mouth, and patients usually seek dental care believing that the diseases are of local origin. Initial laboratory tests may be quite normal or show subtle changes that do not target for cancer. It is essential for the professional to be able to clearly recognize oral physiological characteristics and when identifying a change of normalcy, to fully investigate it by requesting for additional tests or referring the patient to specialized professionals.

An early intervention reduces the frequency of problems, minimizing the risk for oral and associated systemic complications. The knowledge of oral health status in these patients is important for the treating oncologists and hematologists. Since the occurrence of oral complications is related to several factors, the multidisciplinary team including the oncologist, hematologist, pediatric dental surgeon, and intensive care expert is required for management of these conditions as it is essential to improve the quality of life of leukemic children.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

 
  References Top

1.
Genc A, Atalay T, Gedikoglu G, Zulfikar B, Kullu S. Leukemic children: Clinical and histopathological gingival lesions. J Clin Pediatr Dent 1998;22:253-6.  Back to cited text no. 1
    
2.
Ferretti GA, Ash RC, Brown AT, Largent BM, Kaplan A, Lillich TT. Chlorhexidine for prophylaxis against oral infections and associated complications in patients receiving bone marrow transplants. J Am Dent Assoc 1987;14:461-7.  Back to cited text no. 2
    
3.
Ribera JM, Oriol A. Acute lymphoblastic leukemia in adolescents and young adults. Hematol Oncol Clin North Am 2009;23:1033-42, vi.  Back to cited text no. 3
    
4.
Ilgenli T, Oren H, Uysal K. The acute effects of chemotherapy on the oral cavity. Prevention and management. Turkish J Cancer 2001;31:93-105.  Back to cited text no. 4
    
5.
Emidio TC, Maeda YC, Caldo-Teixeira AS, Puppin-Rontani RM. Oral manifestations of leukemia and antineoplastic treatment - A literature review (part II). Braz J Health 2010;1:136-49.  Back to cited text no. 5
    
6.
Mathur VP, Dhillon JK, Kalra G. Oral health in children with leukemia. Indian J Palliat Care 2012;18:12-8.  Back to cited text no. 6
[PUBMED]  Medknow Journal  
7.
Dens F, Boute P, Otten J, Vinckier F, Declerck D. Dental caries, gingival health, and oral hygiene of long term survivors of paediatric malignant diseases. Arch Dis Child 1995;72:129-32.  Back to cited text no. 7
    
8.
Hegde AM, Joshi S, Rai K, Shetty S. Evaluation of oral hygiene status, salivary characteristics and dental caries experience in acute lymphoblastic leukemic (ALL) children. J Clin Pediatr Dent 2011;35:319-23.  Back to cited text no. 8
    
9.
Nasim VS, Shetty YR, Hegde AM. Dental health status in children with acute lymphoblastic leukemia. J Clin Pediatr Dent 2007;31:210-3.  Back to cited text no. 9
    
10.
Azher U, Shiggaon N. Oral health status of children with acute lymphoblastic leukemia undergoing chemotherapy. Indian J Dent Res 2013;24:523.  Back to cited text no. 10
[PUBMED]  Medknow Journal  
11.
Maciel JC, de Castro CG Jr, Brunetto AL, Di Leone LP, da Silveira HE. Oral health and dental anomalies in patients treated for leukemia in childhood and adolescence. Pediatr Blood Cancer 2009;53:361-5.  Back to cited text no. 11
    
12.
Cubukc CE, Günes AM. Caries experience of leukemic children during intensive course of chemotherapy. J Clin Pediatr Dent 2008;32:155-8.  Back to cited text no. 12
    
13.
Kinirons MJ, Fleming P, Boyd D. Dental caries experience of children in remission from acute lymphoblastic leukaemia in relation to the duration of treatment and the period of time in remission. Int J Paediatr Dent 1995;5:169-72.  Back to cited text no. 13
    
14.
Epstein JB, Vickars L, Spinelli J, Reece D. Efficacy of chlorhexidine and nystatin rinses in prevention of oral complications in leukemia and bone marrow transplantation. Oral Surg Oral Med Oral Pathol 1992;73:682-9.   Back to cited text no. 14
    
15.
Kusumakumary P, Sankaranarayanan R, Padmakumary G, Varghese C, Kumar SR, Nair MK. Childhood cancer in Kerala, India. Lancet 1991;338:455-6.  Back to cited text no. 15
[PUBMED]    
16.
Pui CH, Campana D, Evans WE. Childhood acute lymphoblastic leukemia - Current status and future perspectives. Lancet Oncol 2001;2:597-607.   Back to cited text no. 16
    
17.
Maguire A, Welbury RR. Long-term effects of antineoplastic chemotherapy and radiotherapy on dental development. Dent Update 1996;23:188-94.  Back to cited text no. 17
    
18.
Goho C. Chemoradiation therapy: Effect on dental development. Pediatr Dent 1993;15:6-12.  Back to cited text no. 18
    
19.
Vahlsing HL, Kim SK, Feringa ER. Cyclophosphamide-induced abnormalities in the incisors of the rat. J Dent Res 1977;56:809-16.  Back to cited text no. 19
    
20.
Stene T. Effect of vincristine on odontoblasts in rat incisor. Scand J Dent Res 1978;86:346-56.  Back to cited text no. 20
[PUBMED]    
21.
Goodman ED, Fuks AB. The effects of anti-leukemic therapy on the developing dentition:case report. Pediatr Dent 1985;7:318-21.  Back to cited text no. 21
[PUBMED]    
22.
Dahllöf G, Rozell B, Forsberg CM, Borgström B. Histologic changes in dental morphology induced by high dose chemotherapy and total body irradiation. Oral Surg Oral Med Oral Pathol 1994;77:56-60.  Back to cited text no. 22
    
23.
Xavier AM, Hegde AM. Preventive protocols and oral management in childhood leukemia - the pediatric specialist's role. Asian Pac J Cancer Prev 2010;11:39-43.   Back to cited text no. 23
    
24.
Mladosievicova B, Jurkovic R, IzakovicovaHolla L. Dental abnormalities after treatment for childhood cancer. Klin Onkol 2015;28:20-3.  Back to cited text no. 24
    
25.
Javed F, Utreja A, Bello Correa FO, Al-Askar M, Hudieb M, Qayyum F, et al. Oral health status in children with acute lymphoblastic leukemia. Crit Rev Oncol Hematol 2012;83:303-9.  Back to cited text no. 25
    
26.
Kaste SC, Hopkins KP, Jenkins JJ 3 rd . Abnormal odontogenesis in children treated with radiation and chemotherapy: Imaging findings. AJR Am J Roentgenol 1994;162:1407-11.  Back to cited text no. 26
    
27.
Sonis AL, Tarbell N, Valachovic RW, Gelber R, Schwenn M, Sallan S. Dentofacial development in long-term survivors of acute lymphoblastic leukemia. A comparison of three treatment modalities. Cancer 1990;66:2645-52.  Back to cited text no. 27
    
28.
Jaffe N, Toth BB, Hoar RE, Ried HL, Sullivan MP, McNeese MD. Dental and maxillofacial abnormalities in long-term survivors of childhood cancer: Effects of treatment with chemotherapy and radiation to the head and neck. Pediatrics 1984;73:816-23.  Back to cited text no. 28
[PUBMED]    
29.
Rosenberg SW, Kolodney H, Wong GY, Murphy ML. Altered dental root development in long-term survivors of pediatric acute lymphoblastic leukemia. A review of 17 cases. Cancer 1987;59:1640-8.  Back to cited text no. 29
[PUBMED]    
30.
Mataki S. Comparison of the effect of colchincine and vinblastine on the inhibition of dentinogenesis in rat incisors. Arch Oral Biol 1981;26:955-61.  Back to cited text no. 30
[PUBMED]    
31.
Al-Ghani AB, Hasan MN, Hassan MJ. Enamel hypoplasia in patients with acute lymphoblastic leukemia. J Bagh College Dentistry 2005;17:53-6.  Back to cited text no. 31
    
32.
Pajari U, Lanning M, Larmas M. Prevalence and location of enamel opacities in children after anti-neoplastic therapy. Community Dent Oral Epidemiol 1988;16:222-6.  Back to cited text no. 32
    
33.
Dahllof G, Barr M, Bolme P, Modeer T, Lonnqvist B, Ringden O, Heimdahl A. Disturbances in dental development after total body irradiation in bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol 1988;65:41-4.  Back to cited text no. 33
    
34.
Pajari U, Lanning M. Developmental defects of teeth in survivors of childhood ALL are related to the therapy and age at diagnosis. Med Pediatr Oncol 1995;24:310-4.  Back to cited text no. 34
    
35.
Nunn JH, Welbury RR, Gordon PH, Kernahan J, Craft AW. Dental caries and dental anomalies in children treated by chemotherapy for malignant disease: A study in the north of England. Int J Pediatr Dent 1991;1:131-5.  Back to cited text no. 35
    
36.
Runge ME, Edwards DL. Orthodontic treatment for an adolescent with a history of acute lymphoblastic leukemia. Pediatr Dent 2000;22:494-8.  Back to cited text no. 36
    
37.
Lino MD, Carvalho FB, Oliveira LR, Magalhães EB, Pinheiro AL, Ramalho LM. Laser phototherapy as a treatment for radiotherapy-induced oral mucositis. Braz Dent J 2011;22:162-5.   Back to cited text no. 37
    
38.
Lima AG, Antequera R, Peres MP, Snitcosky IM, Federico MH, Villar RC. Efficacy of low-level laser therapy and aluminum hydroxide in patients with chemotherapy and radiotherapy-induced oral mucositis. Braz Dent J 2010;21:186-92.   Back to cited text no. 38
    
39.
Sonis ST. Mucositis: The impact, biology and therapeutic opportunities of oral mucositis. Oral Oncol 2009;45:1015-20.   Back to cited text no. 39
    
40.
Parulekar W, Mackenzie R, Bjarnason G, Jordan RC. Scoring oral mucositis. Oral Oncol 1998;34:63-71.   Back to cited text no. 40
    
41.
Ps SK, Balan A, Sankar A, Bose T. Radiation induced oral mucositis. Indian J Palliat Care 2009;15:95-102.  Back to cited text no. 41
    
42.
Sonis ST. New thoughts on the initiation of mucositis. Oral Dis 2010;16:597-600.   Back to cited text no. 42
    
43.
Peterson DE. Research advances in oral mucositis. Curr Opin Oncol 1999;11:261-6.   Back to cited text no. 43
    
44.
Pels E. Oral hygiene status and selected saliva biomarkers in children with acute lymphoblastic leukemia during anticancer therapy. J Leuk 2013;1:115.  Back to cited text no. 44
    
45.
Williams MC, Lee GT. Childhood leukemia and dental considerations. J Clin Pediatr Dent 1991;15:160-4.  Back to cited text no. 45
    
46.
Levy-Polack MP, Sebelli P, Polack NL. Incidence of oral complications and application of a preventive protocol in children with acute leukemia. Spec Care Dentist 1998;18:189-93.   Back to cited text no. 46
    
47.
Sepúlveda E, Brethauer U, Rojas J, Fernández E, Le Fort P. Oral ulcers in children under chemotherapy: Clinical characteristic and their relation with Herpes Simplex Virus type 1 and Candida albicans. Med Oral Patol Oral Cir Bucal 2005;10(Suppl 1):E1-8.  Back to cited text no. 47
    
48.
Anirudhan D, Bakhshi S, Xess I, Broor SH, Arya LS. Etiology and outcome of oral mucosal lesions in children on chemotherapy for acute lymphoblastic leukemia. Indian Pediatr 2008;45:47-51.  Back to cited text no. 48
    
49.
da Fonseca MA. Dental care of the pediatric cancer patient. Pediatr Dent 2004;26:53-7.   Back to cited text no. 49
    
50.
Alberth M, Majoros L, Kovalecz G, Borbás E, Szegedi I, J Márton I, et al. Significance of oral Candida infections in children with cancer. Pathol Oncol Res 2006;12:237-41.  Back to cited text no. 50
    
51.
Costa EM, Fernandes MZ, Quindere LB, de Souza LB, Pinto LP. Evaluation of an oral preventive protocol in children with acute lymphoblastic leukemia. Pesqui Odontol Bras 2003;17:147-50.  Back to cited text no. 51
    
52.
Pels E. Oral mucositis in children suffering from acute lymphoblastic leukemia. Contemp Oncol (Pozn) 2012;16:12-5.  Back to cited text no. 52
    
53.
Borbasi S, Cameron K, Quested B, Olver I, To B, Evans D. More than a sore mouth: Patients' experience of oral mucositis. Oncol Nurs Forum 2002;29:1051-7.  Back to cited text no. 53
    
54.
Subramaniam P, Babu KL, Nagarathna J. Oral manifestations in acute lymphoblastic leukemic children under chemotherapy. J Clin Pediatr Dent 2008;32:319-24.  Back to cited text no. 54
    
55.
Javed F, Klingspor L, Sundin U, Altamash M, Klinge B, Engström PE. Periodontal conditions, oral Candida albicans and salivary proteins in type 2 diabetic subjects with emphasis on gender. BMC Oral Health 2009;9:12.  Back to cited text no. 55
    
56.
Scully C. Oral and Maxillofacial Medicine: The Basis of Diagnosis and Treatment. 4 th ed. London: Elsevier Science Limited; 2004. p. 252-68.  Back to cited text no. 56
    
57.
Greenberg MS, Glick M, Skip JA. Burket's Oral Medicine. 11 th ed. Hamilton: BC Decker Inc; 2008. p. 79-84.  Back to cited text no. 57
    
58.
Ponce-Torres E, Ruíz-Rodríguez Mdel S, Alejo-González F, Hernández-Sierra JF, Pozos-Guillén Ade J. Oral manifestations in pediatric patients receiving chemotherapy for acute lymphoblastic leukemia. J Clin Pediatr Dent 2010;34:275-9.  Back to cited text no. 58
    
59.
Costa EM, Fernandes MZ, Quinder LB, de Souza LB, Pinto LP. Evaluation of an oral preventive protocol in children with acute lymphoblastic leukemia. Pesqui Odontol Bras 2003;17:147-50.  Back to cited text no. 59
    
60.
Milins B, Martin MV, Williams MC. Raised salivary endotoxin concentration as a predictor of infection in pediatric leukemia patients. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1999; 88:50-5.  Back to cited text no. 60
    
61.
Sixou JL, de Medeiros-Batista O, Bonnaure-Mallet M. Modifications of the microflora of the oral cavity arising during immunosuppressive chemotherapy. Eur J Cancer B Oral Oncol 1996;32B:306-10.  Back to cited text no. 61
    
62.
Sheehy EC, Beighton D, Roberts GJ. The oral microbiota of children undergoing liver transplantation. Oral Microbiol Immunol 2000; 15:203-10.  Back to cited text no. 62
    
63.
McKenna SJ. Leukemia. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2000;89:137-9.  Back to cited text no. 63
    
64.
Cooper CL, Loewen R, Shore T. Gingival hyperplasia complicating acute myelomonocytic leukemia. J Can Dent Assoc 2000;66:78-9.  Back to cited text no. 64
    
65.
Sonis AL, Waber DP, Sallan S, Tarbell NJ. The oral health of long-term survivors of acute lymphoblastic leukaemia: A comparison of three treatment modalities. Eur J Cancer B Oral Oncol 1995; 31B:250-2.  Back to cited text no. 65
    
66.
Javed F, Sundin U, Altamash M, Klinge B, Engström PE. Self-perceived oral health and salivary proteins in children with type1 diabetes. J Oral Rehabil 2009;36:39-44.   Back to cited text no. 66
    
67.
Javed F, Romanos GE. Impact of diabetes mellitus and glycemic control on the osseointegration of dental implants: A systematic literature review. J Periodontol 2009;80:1719-30.  Back to cited text no. 67
    
68.
Pavlatos J, Gilliam KK. Oral care protocols for patients undergoing cancer therapy. Gen Dent 2008;56:464-80; 495-6.   Back to cited text no. 68
[PUBMED]    
69.
Welbury RR, Craft AW, Murray JJ, Kernahan J. Dental health of survivors of malignant disease. Arch Dis Child 1984;59:1186-7.  Back to cited text no. 69
[PUBMED]    
70.
Uderzo C, Fraschini D, Balduzzi A, Galimberti S, Arrigo C, Biagi E, et al. Long-term effects of bone marrow transplantation on dental status in children with leukaemia. Bone Marrow Transplant 1997;20:865-9.  Back to cited text no. 70
    
71.
Epstein JB, Schubert MM. Managing pain in mucositis. Semin Oncol Nurs 2004;20:30-7.  Back to cited text no. 71
    
72.
Sonis ST, Elting LS, Keefe D, Peterson DE, Schubert M, et al.; Mucositis Study Section of the Multinational Association for Supportive Care in Cancer; International Society for Oral Oncology. Perspectives on cancer therapy-induced mucosal injury: Pathogenesis, measurement, epidemiology, and consequences for patients. Cancer 2004;100(Suppl):1995-2025.  Back to cited text no. 72
    
73.
Herrstedt J. Prevention and management of mucositis in patients with cancer. Int J Antimicrob Agents 2000;16:161-3.  Back to cited text no. 73
    
74.
Karolewska E, Konopka T, Pupek M, Chaber R. Mucositis in children with Leukemia and salivary defense factors. Dent Med Probl 2007;44:30-6.   Back to cited text no. 74
    
75.
Karolewska E, Konopka T. Preventive-therapeutic dental care protocol in children with leukemia. Czas Stomatol 2006;59:245-52.   Back to cited text no. 75
    
76.
Peterson DE. New strategies for management of oral mucositis in cancer patients. J Support Oncol 2006;4(Suppl 1):9-13.  Back to cited text no. 76
    
77.
Al-Mashhadane FA. Oral Health Status among children receiving chemotherapy. Al-Rafidain Dent J 2007;7:96-100.   Back to cited text no. 77
    
78.
Pels E, Mielnik-Blaszczak M. Oral hygiene in children suffering from acute lymphoblastic leukemia living in rural and urban regions. Ann Agric Environ Med 2012;19:529-33.  Back to cited text no. 78
    
79.
Pels E, Mielnik-Błaszczak M. State of oral hygiene and levels of selected salivary parameters in children with acute lymphoblastic Leukemia. Pol J Environ Stud 2007;16:114-7.   Back to cited text no. 79
    
80.
Konopka T, Mendrela E, Norowska M, Kozłowski Z, Chaber R, Toporski J. The symptoms of leukemia in the mouth. Czas Stomatol 2001;54:217-25.  Back to cited text no. 80
    
81.
Fleming P, Kinirons MJ. Study of the dental health of children in remission from acute lymphoblastic leukemia in Northern Ireland. Community Dent Oral Epidemiol 1993;21:309-12.   Back to cited text no. 81
    
82.
Avşar A, Elli M, Darka O, Pinarli G. Long-term effects of chemotherapy on caries formation, dental development, and salivary factors in childhood cancer survivors. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 2007;104:781-9.  Back to cited text no. 82
    




 

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  In this article
Abstract
Introduction
Dental Caries Status
Tooth Morphology
Oral Mucositis
Oral Candidiasis
Other Infections
Hemorrhage
Gingival and Per...
Dysguesia/Taste ...
Saliva
Temporomandibula...
Osteoradionecrosis
Oral Hygiene
Conclusion
Classification o...
References

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