Management ofDental Emergencies inChildren andAdolescents, First Edition. Editedby Klaus W.Neuhaus andAdrianLussi. © 2019 John Wiley & Sons Ltd. Published 2019 by John Wiley & Sons Ltd. Companion website: www.wiley.com/go/neuhaus/dental_emergencies245 IntroductionUniquely, disruptions in the formation and function of circulating blood cells trigger changes in the immune system, blood clotting and oxygen transportation. Whilst there is a quite frequent occurrence of anaemia, it plays a rather minor role in dentistry, since normally it is only mildly severe and quickly remedied.Haematological malignancies are rare, with an incidence of about 30/100 000 (Sant etal., 2010). The oral cavity is often affected in patients without functioning defence, and complications are common during dental intervention, especially when there is a lack of neutrophil granulocytes. In general, seriously ill haematological patients receive dental treatment at university centres.Infections within the oral cavity may also be initial manifestation of a haematological disorder. This should in particular be con-sidered when gingival bleeding occurs in otherwise healthy conditions and in the presence of petechiae.Wanted and unwanted medicinal effects on blood clotting and infection defence occur very often, due to the wide spread of corre-sponding diseases. This is related to treat-ments like the application of corticosteroids or anticoagulation in connection with atrial fibrillation. The effects of these medications are acutely relevant for the choice of dental treat-ment. However, in children and adolescents, medicinal anticoagulation is seldom applied. This is why it is not addressed in this chapter. High‐dose local irradiation is also rather seldom administered in the area of the mouth in children, and so it too is not discussed.We begin by explaining the basic concepts, before looking at specific problems associated with the oral mucosa that are often encoun-tered in connection with chemotherapy, total body irradiation and stem cell transplants. HaemostasisStopping the blood flow from injured blood vessels is a complex process, in which a number of factors interact. Successful haemostasis consists in three steps: (i) vaso-constriction to reduce the blood flow; (ii) formation of a platelet plug by thrombocyte adherence, activation and aggregation; and (iii) plasmatic coagulation by a cascade of proteins, which forms a stable clot. When thrombocytes come in contact with collagen in the exposed connective tissue, they attach there by mediation of the von Willebrand factor, a protein that adheres both to collagen 6.3Oral Problems inPatients Undergoing Haematology orOncology TreatmentAdrian M. Ramseier1, Jakob Passweg2 and Tuomas Waltimo11 Department of Oral Health & Medicine, University Center for Dental Medicine Basel, University of Basel, Basel, Switzerland2 Department of Hematology, University Hospital Basel, Basel, Switzerland 6.3 Haematology and Oncology246and to thrombocytes. Thus, the thrombo-cytes are activated. By releasing cytokines, more thrombocytes are attracted, and the plasmatic coagulation cascade is initiated. Through several intermediate stages, pro-thrombin is transformed, both intrinsically (activation factors) and extrinsically (tissue factor in the injured subendothelial tissue), to thrombin, which in turn polymerises fibrinogen to fibrin. This results in a net incorporating aggregated thrombocytes as well as erythrocytes, and thus forming a stable blood clot. Other factors are responsible for preventing exaggerated or spontaneous thrombus formation.Cellular Haemostasis Disorders (Thrombocytes)Depressed platelet count (thrombocytopaenia) and dysfunction of the platelet count (throm-bocytopahthies) can be either congenital or acquired. Table6.3.1 provides an overview of possible causes of thrombocytopaenia.The most commonly isolated thrombo-cytopaenia in children is the immune thrombocytopaenia (ITP) (Ishii, 2017). Thrombo cy to paenia may also occur following a replacement of normal bone marrow with leukaemic cells (e.g. in acute leukaemia) or bone marrow failure, or it may be inherited.Nonsteroidal anti‐inflammatory drugs (NSAIDs) inhibit platelet aggregation. With aspirin, such aggregation is irreversible, except by the production of new thrombocytes.Small petechial haemorrhages on skin and on the mucosa are the typical sign of marred thrombocytes; often, they occur on the lower extremities (gravity) or in the oral cavity. In case of severe thrombocytopaenia, they can become confluent (ecchymoses). Spontaneous bleeding starts only with a platelet count of 20–30 × 109/l (Scully, 2014). Depending on the severity of the disorder, it can result from minor traumata, gingival bleeding or suffusions on the skin.The normal platelet count is 150–450 × 109/l; a value of >100 × 109/l is thought to be ideal for surgical intervention. With values >50 × 109/l and good functioning of the existing platelets, dentoalveolar surgery can normally be performed without bleeding complications (Henderson et al., 2001). Measures like compression, wound suture and local haemostatics are usually sufficient. With values of <30 × 109/l, spontaneous bleeding can occur. In this situation, the indication of surgical treatment should be carefully considered, and surgery should be conducted in collaboration with haematology. Haemostasis can be improved by transfusion of thrombocyte concentrates. This is recom-mended during dentoalveolar intervention with a platelet count of <50 × 109/l, as well as Table6.3.1 Causes ofthrombocytopaenia (Hoffbrand andMoss, 2016).Failure of platelet productionSelective megakaryocyte depressionRare congenital defectsDrugs, chemicals, viral infectionsPart of general bone marrow failureCytotoxic drugsRadiotherapyAplastic anaemiaLeukaemiaMyelodysplastic syndromesMyelofibrosisMarrow infiltration (e.g. carcinoma, lymphoma, Gaucher’s disease)Multiple myelomaMegaloblastic anaemiaHIV infectionIncreased consumption of plateletsImmuneAutoimmuneIdiopathicAssociated with systemic lupus erythematosus, chronic lymphocytic leukaemia or lymphomaInfections: Helicobacter pylori, human immuno-deficiency virus (HIV), other viruses, malariaDrug‐induced, e.g. heparinPost‐transfusional purpuraFoeto‐maternal alloimmune thrombocytopaeniaDisseminated intravascular coagulationThrombotic thrombocytopaenic purpuraAbnormal distribution of plateletsSplenomegaly, e.g. liver diseaseDilutional lossMassive transfusion of stored blood to bleeding patients Disorders oftheImmune System/Granulocytes247during maxillofacial intervention with a platelet count of <100 × 109/l (Scully, 2014).The success of thrombocyte transfusions needs to be checked: it is essential to measure the platelet count prior to and after trans-fusion. Patients who do not adequately react to thrombocyte transfusions constitute a special problem. In such cases, therapeutic interventions can be performed whilst trans-fusion continues.Plasmatic Coagulation DisordersCongenital coagulation disorders include haemophilia A (factor VIII deficiency) and the much rarer haemophilia B (factor IX deficiency). Only the male gender is affected by haemophilia B. Spontaneous haemor-rhaging and strong life‐threatening postop-erative bleeding may occur. Missing factors can be added; however, there is insufficient evidence from randomised controlled trials to assess the most effective and safe haemo-static treatment to prevent bleeding in peo-ple with haemophilia or other congenital bleeding disorders undergoing surgical pro-cedures (Coppola etal., 2015; Spivakovsky etal., 2015).In von Willebrand disease, the von Willebrand factor is missing or malfunc-tioning. Because of this, platelet function is impaired. Von Willebrand disease is classified into a number of subcategories, and is asso-ciated with slight to considerable bleeding disorders. Disorders oftheImmune System/GranulocytesDefence comprises cellular elements, all of which belong to the leucocytes. The various cells evolved from one multipotent stem cell of haematopoiesis, which is capable of differ-entiating into different cell lines with various functions: ● Neutrophilic granulocytes are implicated in nonspecific immunity against bacteria and fungi. Basophilic granulocytes are involved in hypersensitivity reactions (asthma, urticaria, allergic rhinitis and anaphylaxis). Eosinophilic granulocytes play a role in the defence against parasites. ● Lymphocytes are subdivided into T‐cells, which have the important function of differentiating between foreign and self, B‐cells, which are amongst other things responsible for the production of antibodies (plasma cells, memory cells), and NK‐cells, which play an essential role in protecting against virus cells and tumour cells. ● Monocytes migrate into tissue, where they become macrophages. They can recognise exogenous material, ingest it (phagocyto-sis), dissolve it and present it at their cell surface. This causes the activation of other defence cells (antigen presentation) (Kasper etal., 2015).CausesHaematological DisordersAbnormalities in the immune response may have many different causes. There might be disturbances in the differentiation of individual or all cell lines. This can result in functional reduction of the cell line(s) affected, in a deficiency of these cells (lym-phopaenia: T‐cells and B‐cells, neutropaenia) or in an overproduction, which can replace the production of other cell lines in the bone marrow. Table6.3.2 provides a list of haema-tological disorders.Disorders oftheImmune System through MedicationDisorders of the immune system can occur as a wanted or unwanted effect of many chemotherapeutics and immunosuppres-sives. Particular emphasis must be given to glucocorticoids like dexamethasone and prednisone, but other immunosuppressives like cyclosporin A (Sandimmun), tacrolimus (Prograf) and the folic acid antagonist meth-otrexate (Methotrexat) can also have this effect. 6.3 Haematology and Oncology248Physical DamageBlood formation can be impaired by irradia-tion, either therapeutic or accidental. Stem cells and lymphocytes are especially vulner-able. Thus, a reduction in lymphocytes can be observed at a very early stage after irra-diation, whilst the number of granolocytes, thrombocytes and erythrocytes decreases only as damage to the stem cells progresses.Clinical Oral AppearanceSometimes, haematological disorders can be discovered by the dentist. Manifestations of haematological disorders in the oral cavity can cause suspicion and suggest additional investigations: ● Bleeding of the oral mucosa that does not result from gingivitis may be an indication of coagulation abnormalities due to a vari-ety of causes. Petechial haemorrhages, and haemorrhages at other places in the oral mucosa, are typical for thrombocytopae-nia (Hoffbrand and Moss, 2016). ● In case of acute myeloid leukaemia, gingi-val swelling can be determined (Figure6.3.1) (Kasper etal., 2015). Occasionally, this can also be seen after treatment with cyclo-sporine A and tacrolimus.Table6.3.2 World Health Organization (WHO) Classification ofHematologic Malignancies (Abridged Version) (Aster andBunn, 2017).Subtype Putative cell of originMyeloid neoplasmsAcute myeloid leukemia (AML)AML with recurrent genetic aberrationsAML without recurrent genetic aberrationsAML following cytotoxic therapyEarly myeloid progenitorMyeloproliferative neoplasmsChronic myeloid leukemiaPolycythemia veraEssential thrombocythemiaChronic eosinophilic leukemiaPrimary myelofibrosisHematopoietic stem cell or early myeloid progenitorMyelodysplastic syndromes Early myeloid progenitorLymphoid neoplasmsImmature B‐cell and T‐cell tumorsB‐cell acute lymphoblastic leukemia/lymphomaT‐cell acute lymphoblastic leukemia/lymphomaEarly B‐cell progenitorEarly T‐cell progenitorMature B‐cell tumorsChronic lymphocytic leukemia/small lymphocytic lymphomaMantle cell lymphomaFollicular lymphomaBurkitt lymphomaDiffuse large B‐cell lymphomaPost‐germinal center B cellNaïve B cellGerminal center B cellGerminal center B cellGerminal center or post‐germinal center B cellPlasma cell tumors and related entitiesMultiple myelomaLymphoplasmacytic lymphomaPost‐germinal center B cellMature B‐cellMature T‐cell and natural killer cell tumors Mature T‐cell or natural killer cellHodgkin lymphoma Germinal center or post‐germinal center B cell Disorders oftheImmune System/Granulocytes249 ● Unusual infections in terms of frequency, manifestation or the occurrence of rare microbes are signs of possible immuno-suppression. Candida infections are encountered quite often (Figure 6.3.2), and non‐Candida albicans species (e.g. tropicalis, krusei and parapsilosis) are increasingly being seen. What should be noted is that these are often resistant to common therapeutics. Typical for leukae-mias are virus reactivations of, for instance, herpes zoster and herpes sim-plex virus (HSV) (Ramseier etal., 2015). Intraoral ulcers and large aphtae are com-mon manifestations of HSV. All of these infections can cause severe pain. ● Swelling of the lymph nodes and anaemia (recognisable by paleness of the mucosa) may point towards a haematological dis-order. So might fever and night sweats recorded in the medical history.Clinical SignificanceWhen an immune deficiency exists, a possible haematogeneous spreading of microorgan-isms may be expected after intervention. Together with the haematologist or family doctor, it needs to be determined whether prophylactic antibiotics should be imple-mented or whether treatment should just be postponed.A focus search should be conducted prior to haematological treatment by chemother-apy or haematopoietic stem cell transplan-tation (HSCT). Ideally, located infection foci are treated first; however, this is not always possible because of the already limited immune response and wound healing, or because of the urgency of treating the malig-nant tumours.In patients who have received allogeneic stem cell transplantation, the current situa-tion concerning immune response should always be clarified with the attending haema-tologist: when appropriate, prophylactic antibiotics should be given prior to tooth cleaning, deep scaling, caries treatment and extractions, or else the treatment must simply be postponed.In chemotherapeutic treatment, which is sometimes accompanied by total body irradiation, hyposalivation occurs on a regular basis. The result may be increased susceptibility to caries, gingivitis, periodon-titis, mucocutaneous diseases and fungal infections (Bagattoni etal., 2014; Buglione etal., 2016).After allogeneic stem cell transplantation, acute and chronic rejection reactions may occur (graft‐versus‐host disease, GvHD). The oral mucosa shows typical lichenoid changes with or without erythematous lesions, ulcers or mucoceles. Often, hyposalivation takes place at the same time, combined with a correspondingly increased risk of caries, periodontitis and infections of the mucosa. Long‐term effects include secondary malig-nant tumours of the oral mucosa. Because of this, the oral mucosa needs to be inspected regularly and thoroughly. The indication for Figure6.3.1 Gingival swelling and acute myeloid leukaemia.Figure6.3.2 Thrush (Candida). 6.3 Haematology and Oncology250biopsy sampling should be wide and generous for the exclusion and detection of malig-nancy, respectively (Elad etal., 2015). AnaemiaAnaemia is defined by a reduction of the haemoglobin concentration in the blood. Common causes are vitamin B12, folic acid and iron deficiencies caused by chronic bleeding, for instance due to excessive men-strual flow or chronic diseases like tumours. Other causes include innate haemoglobin synthesis disorders such as sickle‐cell anaemia and thalassaemia.Clinical SignificanceAnaemias hardly have an effect on dental treatment. The following manifestations could indicate anaemia and necessitate further clarification with the family doctor: com-plaints about reduced performance, weak-ness, heart palpitations and dyspnoea under stress, as well as the occurrence of pale skin or mucosa. Angular cheilitis, burning tongue or dysphagia (Plummer–Vinson syndrome) may appear in case of iron deficiency. Vitamin B12 and folic acid deficiencies cause burning tongue with impaired sense of taste and trophic glossitis with disappearing papillae. MucositisMucositis is an inflammation of the mucous membranes of the gastrointestinal tract as a consequence of chemotherapy and radiation therapy. Patients who are receiving HSCT or irradiation in the area of the mouth are affected particularly often.Oral mucositis is associated with ery-thema, and at times with ulcerations and violent pain. It is one of the most frequent side effects of cancer treatment, and is often the reason for reducing the treatment dose or for having to postpone treatment. It also may necessitate tube feeding or parenteral nutrition.Pathogenesis has not yet been fully clarified, although considerable progress has been made in recent years. The procedure can be broken down into five stages: initiation, pri-mary damage response, signal amplification, ulceration and healing (Sonis, 2004). It is a complex interaction of cells from the mucosa and submucosa that is regulated by cytokines such as tumour necrosis factor alpha (TNF‐α), interleukins 6 (IL‐6) and 1b (IL‐1b) and cyclooxygenase 2 (COX‐2). The oral microbiome also plays a role (Sonis, 2011; Al‐Dasooqi etal., 2013; Villa and Sonis, 2015; Cinausero etal., 2017).There are a variety of approaches to the treatment and prophylaxis of oral mucositis. Cryotherapy and low‐level light therapy (LLLT) are recommended for children receiving chemotherapy or HSCT condition-ing with regimens associated with a high rate of mucositis, whilst keratinocyte growth fac-tor (KGF) is recommended for cooperative children receiving HSCT conditioning with regimens associated with a high rate of severe mucositis (Lalla etal., 2014; Villa and Sonis, 2016; Sung etal., 2017): ● Cryotherapy involves cooling the oral mucosa with ice whilst the patient receives chemotherapy by short infusion. Because of the vasoconstriction in the cooled mucosa, fewer cytotoxic substances are supposed to arrive there. Thus, the method is only suitable for chemotherapeutic agents which are administered in short infusion and have a short half‐life. However, it is inexpensive and readily accessible (Sung etal., 2017). ● LLLT (also called photobiomodulation, PBM) is the therapeutic use of light (e.g. visible, near‐infrared or infrared light), which is absorbed by endogenous chromophores and triggers nonthermal, noncytotoxic biochemical reactions by photochemical and photophysical effects, leading to physiological alterations (Bensadoun and Nair, 2012, 2015; Zecha GraftversusHost Disease251et al., 2016a,b). However, the method is laborious and is not available everywhere. ● KGF (e.g. Palifermin) is an epithelium growth factor. Since there are no studies on its use, and since there is the possibility of thickening the oral mucosa and causing long‐term damage, it should only be applied in selected cases where there is a high risk of severe mucositis (Sung etal., 2017).As with all children, good oral hygiene should be ensured. Professional tooth cleaning can reduce pain in case of mucositis (Kubota etal., 2015). Graft‐versus‐Host DiseaseDespite immunosuppressive treatment, GvHD occurs in almost 25% of cases following allogeneic HSCT, with the mouth being one of the most frequently affected organs (Flowers etal., 2002; Meier, 2011). It can significantly impair quality of life. Oral GvHD impresses by hyposalivation, lichenoid hyperkeratotic striae or plaque with or without erythematous changes (Figure6.3.3). Addi-tionally, ulcerations and superficial mucoce-les may occur. The ulcerations can be very painful. In certain circumstances, severe (a) (b)(c)Figure6.3.3 (a–c) Graft‐versus‐host disease. 6.3 Haematology and Oncology252sclerosis develops as a late effect, restricting mouth or jaw opening and reducing mobility of the tongue. Persistant chronic GvHD is associated with increased risk of squamous cell carcinomas. Viral factors like human papillomavirus (HPV) seem to be of signifi-cance in the aetiology and pathogenesis of this type of carcinoma. ManagementIn case of existing abnormalities of the oral mucosa like aphthae and GvHD, products containing sodium lauryl sulphate or men-thol frequently cannot be tolerated because they cause pain. Affected patients mostly avoid them, along with spicy food. They may have to use toothpaste that is free of sodium lauryl sulphate. Products with antimicrobial and protective effects on the oral mucosa are recommended for oral rinsing. Alleviating dry mouth with moisturising agents and cov-ering open aphthae can help relieve the pain.After allogeneic HSCT, regular examina-tions of the mucous membranes are essen-tial, in order to discover secondary carcinoma early (Majhail etal., 2012). Secondary infec-tions occur frequently in cases of poor oral hygiene, which may also increase the inten-sity of GvHD. Thus, maintaining good oral hygiene is very important. However, such lesions may hamper attempts in this direc-tion, because of the pain. Depending on the condition, several dental hygiene treatments a year–including oral hygiene instructions– are recommended.For oral GvHD, topical steroids (e.g. bude-sonide or dexamethasone) are recommended as first‐line therapy. Extracorporeal photo-pheresis is considered a second‐line systemic therapy for steroid‐refractory GvHD. Local anaesthetics may be helpful in pain control (Dignan etal., 2012).All carious lesions should be restored. It is advisable to encourage patients to practise good oral hygiene and additional fluoridation (either by direct application or via fluoridation splints at home or in a dental practice).Existing odontogenic infections should receive therapy, preferably prior to immuno-suppression. In this way, systemic infections connected with blood stem cell transplants can be reduced by one‐third, and the deaths of an additional 18/10 000 treated patients can be avoided (Elad etal., 2008). However, the extraction of teeth necessitates a long healing period (2 weeks), and there is often an urgent need for therapy, especially in leu-kaemia patients, so dental treatment must frequently be postponed until after blood stem cell transplantation. Due to the danger of haematogenic spread, dental treatments should be conducted by giving antibiotic prophylaxis.Generally, in immunosuppressed patients, contact should be made with the attending physician as soon as is possible. At times, referral to university dental clinics is recom-mended, as they deal with immunosup-pressed patients every day–including during inpatient treatment–and can meet all diag-nostic needs. The objectives in giving dental treatment to immunosuppressed patients are prevention of infection, pain relief, mainte-nance of function, treatment of complica-tions and improvement of quality of life. ReferencesAl‐Dasooqi, N., Sonis, S. T., Bowen, J. M., Bateman, E., Blijlevens, N., Gibson, R. J., etal. 2013. Emerging evidence on the pathobiology of mucositis. Supportive Care in Cancer, 21(11), 3233–41.Aster, J. C., Bunn, H. F. 2017. Pathophysiology of Blood Disorders, 2nd edn. New York: McGraw‐Hill.Bagattoni, S., D’Alessandro, G., Prete, A., Piana, G., Pession, A. 2014. Oral health and References253dental late adverse effects in children in remission from malignant disease. A pilot case‐control study in Italian children. European Journal of Paediatric Dentistry, 15(1), 45–50.Bensadoun, R. J., Nair, R. G. 2012. Low‐level laser therapy in the prevention and treatment of cancer therapy‐induced mucositis: 2012 state of the art based on literature review and meta‐analysis. Current Opinions in Oncology, 24(4), 363–70.Bensadoun, R. J., Nair, R. G. 2015. Low‐level laser therapy in the management of mucositis and dermatitis induced by cancer therapy. Photomedicine and Laser Surgery, 33(10), 487–91.Buglione, M., Cavagnini, R., Di Rosario, F., Sottocornola, L., Maddalo, M., Vassalli, L., etal. 2016. Oral toxicity management in head and neck cancer patients treated with chemotherapy and radiation: dental pathologies and osteoradionecrosis (part 1) literature review and consensus statement. Critical Reviews in Oncology/Hematology, 97, 131–42.Cinausero, M., Aprile, G., Ermacora, P., Basile, D., Vitale, M. G., Fanotto, V., etal. 2017. New frontiers in the pathobiology and treatment of cancer regimen‐related mucosal injury. Frontiers in Pharmacology, 8(8), 354.Coppola, A., Windyga, J., Tufano, A., Yeung, C., Di Minno, M. N. 2015. Treatment for preventing bleeding in people with haemophilia or other congenital bleeding disorders undergoing surgery. Cochrane Database of Systematic Reviews, 9(2), CD009961.Dignan, F. L., Scarisbrick, J. J., Cornish, J., Clark, A., Amrolia, P., Jackson, G., etal. 2012. Organ‐specific management and supportive care in chronic graft‐versus‐host disease. British Journal of Haematology, 158(1), 62–78.Elad, S., Thierer, T., Bitan, M., Shapira, M. Y., Meyerowitz, C. 2008. A decision analysis: the dental management of patients prior to hematology cytotoxic therapy or hematopoietic stem cell transplantation. Oral Oncology, 44(1), 37–42.Elad, S., Raber‐Durlacher, J. E., Brennan, M. T., Saunders, D. P., Mank, A. P., Zadik, Y., etal. 2015. Basic oral care for hematology‐oncology patients and hematopoietic stem cell transplantation recipients: a position paper from the joint task force of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and the European Society for Blood and Marrow Transplantation (EBMT). Supportive Care in Cancer, 23(1), 223–36.Flowers, M. E., Parker, P. M., Johnston, L. J., Matos, A. V., Storer, B., Bensinger, W. I., etal. 2002. Comparison of chronic graft‐versus‐host disease after transplantation of peripheral blood stem cells versus bone marrow in allogeneic recipients: long‐term follow‐up of a randomized trial. Blood, 100(2), 415–19.Henderson, J. M., Bergman, S., Salama, A., Koterwas, G. 2001. Management of the oral and maxillofacial surgery patient with thrombocytopenia. Journal of Oral and Maxillofacial Surgery, 59(4), 421–7.Hoffbrand, A. V., Moss, P. A. H. 2016. Hoffbrand’s Essential Haematology, 7th edn. Chichester, UK: Wiley‐Blackwell.Ishii, E. (ed.). 2017. Hematological Disorders in Children, Pathogenesis and Treatment. Singapore: Springer Nature.Kasper, D. L., Fauci, A. S., Hauser, S. L., Longo, D. L., Jameson, J. L., Loscalzo, J. (eds). 2015. Harrison’s Principles of Internal Medicine, 19th edn. New York: McGraw‐Hill.Kubota, K., Kobayashi, W., Sakaki, H., Nakagawa, H., Kon, T., Mimura, M., etal. 2015. Professional oral health care reduces oral mucositis pain in patients treated by superselective intra‐arterial chemotherapy concurrent with radiotherapy for oral cancer. Supportive Care in Cancer, 23(11), 3323–9.Lalla, R. V., Bowen, J., Barasch, A., Elting, L., Epstein, J., Keefe, D. M., etal. 2014. MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy. Cancer, 120(10), 1453–61. Erratum in: Cancer, 121(8), 1339. 6.3 Haematology and Oncology254Majhail, N. S., Rizzo, J. D., Lee, S. J., Aljurf, M., Atsuta, Y., Bonfim, C., etal. 2012. Recommended screening and preventive practices for long‐term survivors after hematopoietic cell transplantation. Biology of Blood and Marrow Transplantation, 18(3) 348–71.Meier, J. K., Wolff, D., Pavletic, S., Greinix, H., Gosau, M., Bertz, H., etal. 2011. Oral chronic graft‐versus‐host disease: report from the International Consensus Conference on clinical practice in cGVHD. Clinical Oral Investigations, 15(2), 127–39.Ramseier, A. M., Filippi, A., Halter, J., Waltimo, T. 2015. Orale Manifestationen bei Immunsuppression. Quintessenz, 66(1), 1–9.Sant, M., Allemani, C., Tereanu, C., De Angelis, R., Capocaccia, R., Visser, O., etal. 2010. Incidence of hematologic malignancies in Europe by morphologic subtype: results of the HAEMACARE project. Blood, 116(19), 3724–34.Scully, C. 2014. Scully’s Medical Problems in Dentistry, 7th edn. London: Churchill Livingstone Elsevier.Sonis, S. T. 2004. The pathobiology of mucositis. Nature Reviews Cancer, 4(4), 277–84.Sonis, S. T. 2011. Oral mucositis. Anti‐Cancer Drugs, 22(7), 607–12.Spivakovsky, S., Keenan, A. V., Congiusta, M., Spivakovsky, Y. 2015. Congenital bleeding disorders and dental surgery. Evidence Based Dentistry, 16(3), 90–1.Sung, L., Robinson, P., Treister, N., Baggott, T., Gibson, P., Tissing, W., etal. 2017. Guideline for the prevention of oral and oropharyngeal mucositis in children receiving treatment for cancer or undergoing haematopoietic stem cell transplantation. BMJ Supportive & Palliative Care, 7(1), 7–16.Villa, A., Sonis, S. T. 2015. Mucositis: pathobiology and management. Current Opinion in Oncology, 27(3), 159–64.Villa, A., Sonis, S. T. 2016. Pharmacotherapy for the management of cancer regimen‐related oral mucositis. Expert Opinion on Pharmacotherapy, 17(13), 1801–7.Zecha, J. A., Raber‐Durlacher, J. E., Nair, R. G., Epstein, J. B., Sonis, S. T., Elad, S., etal. 2016a. Low level laser therapy/photobiomodulation in the management of side effects of chemoradiation therapy in head and neck cancer: part 1: mechanisms of action, dosimetric, and safety considerations. Supportive Care in Cancer, 24(6), 2781–92.Zecha, J. A., Raber‐Durlacher, J. E., Nair, R. G., Epstein, J. B., Elad, S., Hamblin, M. R., etal. 2016b. Low‐level laser therapy/photobiomodulation in the management of side effects of chemoradiation therapy in head and neck cancer: part 2: proposed applications and treatment protocols. Supportive Care in Cancer, 24(6), 2793–805.