Curr Pain Headache Rep (2015)9:37 DOI 10.1007/s11916-015-0512-1

SECONDARY HEADACHE (M ROBBINS, SECTION EDITOR)

Cancer and Referred Facial Pain Marcela Romero-Reyes 1,4 & Antonia Teruel 2 & Yi Ye 3

# Springer Science+Business Media New York 2015

Abstract Orofacial pain may be a symptom of diverse types of cancers as a result of local or distant tumor effects. The pain can be presented with the same characteristics as any other orofacial pain disorder, and this should be recognized by the clinician. Orofacial pain also can arise as a consequence of cancer therapy. In the present article, we review the mechanisms of cancer-associated facial pain, its clinical presentation, and cancer therapy associated with orofacial pain. Keywords Pain . Orofacial . Facial . Cancer

Introduction The fundamental purpose of the pain experience is protection, and this is underscored when pain is related to cancer. Orofacial This article is part of the Topical Collection on Secondary Headache * Marcela Romero-Reyes [email protected] Antonia Teruel [email protected] Yi Ye [email protected]

pain may be a presenting symptom of diverse types of cancers resulting from nociceptive/somatic, visceral, inflammatory, and neuropathic mechanisms [1, 2, 3•]. The characteristics of the pain can imitate the symptomatology of any orofacial pain disorder with descriptors of sharp, shooting, burning, pulling, dull, aching, and throbbing pain and refer pain to any craniofacial structure regionally or from a distant site. Therefore, cancer pain must be included in the differential diagnosis of patients with unexplained and intractable orofacial pain. In addition, pain also can be a devastating consequence for cancer patients since pain not only can arise as a result of the cancer itself, but also is the most common sequel of surgery, chemotherapy, and radiotherapy aimed to treat the cancer which results in greatly diminishing their quality of life [3•, 4, 5]. Orofacial pain may be caused by local and distant tumor effects. It can arise as a result of local or regional cancer such as the squamous cell carcinomas (SCC) of the oral mucosa [6] or mandible [7]; head and neck cancers such as nasopharyngeal and oropharyngeal carcinomas [8•] and as a result of intracranial tumors [9–11]; from systemic/hematopoietic malignancies such as leukemia, lymphoma, and multiple myeloma [12–14]; from metastatic malignancy in the case of lung, breast, prostate, and gastrointestinal tract cancers [15–18]; and rarely as a referred pain secondary to non-metastatic malignancy from lung and colon cancer [19–22]. Furthermore, orofacial pain as a consequence of cancer management is an unfortunate side effect. Painful inflammatory and ulcerative disorders, musculoskeletal pain, and neuropathic pain due to radiotherapy, chemotherapy, and surgical management are often reported [23, 24, 5].

1

Orofacial and Head Pain Service, Department of Oral and Maxillofacial Pathology Radiology and Medicine, New York University College of Dentistry, 345 East 24th Street, New York, NY 10010, USA

2

Herman Ostrow School of Dentistry, University of Southern California, 925 West 34th Street DEN, 4333, Los Angeles, CA 90089-0641, USA

3

Bluestone Center for Clinical Research, New York University College of Dentistry, 421 1st Ave, 1038, New York, NY 10010, USA

Mechanisms of Cancer-Associated Referred Facial Pain

4

Department of Oral & Maxillofacial, Pathology, Radiology & Medicine, New York University College of Dentistry, 345 East 24th Street, New York, NY 10010, USA

Cancer-related orofacial pain can be both regional and referred. Regional cancer pain is originated from the tumor site, while

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referred cancer pain is distant to the tumor site. The pathophysiology of cancer pain is complex and may involve inflammation, neuropathy, and tumorigenic mechanisms. Pain may result from the primary, systemic, or metastatic cancer and may reflect changes in both peripheral and central nervous systems. Mechanisms of Cancer Pain Peripheral Mechanisms Inflammation Inflammation has been considered as the Bseventh hallmark of cancer.^ Chronic inflammation predisposes individuals to certain types of cancers and often occurs throughout the process of cancer development [25]. Characteristics of inflammation include the presence of inflammatory cells, inflammatory mediators, tissue remodeling and repair, and angiogenesis in tumor microenvironment [25]. T lymphocytes, neutrophils, macrophages, mast cells, and dendritic cells are most commonly reported immune cells that participate in cancer-related inflammation [26, 25, 1]. Inflammation activates the cyclooxygenase pathway which releases pain generating prostanoids. Non-steroidal anti-inflammatory drug (NSAID) treatments are effective in mild to moderate cancer pain, especially at its early stages [25]. Besides inflammation at the primary tumor site, some patients also experience systemic inflammation with marked increase in white cell (neutrophil, lymphocyte, and platelet) count, acute phase proteins (C-reactive protein and albumin), neutrophil lymphocyte ratio (NLR), and platelet lymphocyte ratio (PLR) [27]. Systemic inflammatory responses are linked with the range of complex symptoms including pain, leading to decreased survival and prognosis [27]. Systemic inflammation was also found in animal models of oral squamous cell carcinoma (OSCC), where there was an increased plasma level of tumor necrosis factor alpha (TNF- ), interleukin-6 (IL-6), and nerve growth factor (NGF) [28]. OSCC mice not only exhibit nociception during oral functioning, but also have widespread nociception in the paw and tail. Whether the widespread nociception in OSCC mice is due to systemic inflammation is currently under investigation. Tumor-derived mechanisms There is a general consensus that cancer cells also produce nociceptive mediators that can directly excite and sensitize primary afferent neurons innervating the cancer microenvironment [29•]. Studies have revealed an expanding list of cancer-derived nociceptive mediators including ATP, protons, proteases, inflammatory cytokines such as TNF- and interleukins, neurotrophic factors, and endothelins [30, 28, 29•]. Many of these factors could also act on cancer itself, propelling cancer proliferation and metastasis [26, 31]. Once cancer metastasizes to other organs, it induces pain to the metastasized site which is usually more difficult to treat [26].

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Peripheral sprouting of primary afferent neurons In bone cancer models, it has been demonstrated that cancer pain may be generated by pathological sprouting and neuroma formation of sensory and sympathetic nerve fibers innervating the tumor [32]. The newly formed fibers exhibit unique morphology, organization, and high density. This sprouting can be blocked by sustained anti-NGF or Pan-Trk (TrkA, TrkB, TrkC) inhibitors [32]. Blocking nerve fiber sprouting and the formation of neuroma significantly inhibit cancer pain in preclinical models [32]. Perineural invasion Perineural invasion (PNI), a process whereby cancer cells spread along and invade nerves, is frequently observed in cancer patients and is significantly associated with tumor progression and local recurrence [33, 34]. Cancer cells invade nerves along the epineural, perineural, and endoneural spaces which leads to tissue infiltration and nerve damage [35•, 33] (Fig. 1). PNI is reported in up to 80 % of head and neck cancer patients. The dense nerve innervations in the head and neck facilitate access which worsens survival. The most affected nerves are the trigeminal and the facial nerve that have extensive network of fibers in the head and neck area [36]. PNI is most commonly found in SCC, followed by adenoid cystic carcinoma, lymphoma, and rhabdomyosarcoma [36, 37]. The possible role of PNI in cancer pain is best studied in patients with pancreatic cancer. Pancreatic cancer is painful and has highest rates of PNI among all cancers [33]. Patients with pancreatic cancer often complain of abdominal and back pain, and pain intensity is higher in patients with PNI [33]. The mechanism by which PNI enhances pain is unknown; however, the molecules that are involved in PNI such as neurotrophic factors are also important pain mediators [33, 36]. Additionally, molecular factors released by nerve fibers may accelerate growth and metastasis of cancer cells [36]. Cancer cells, on the other hand, can promote nerve sprouting and enlargement, resulting in pain [36]. Head and neck cancer has high incidence of PNI; therefore, it is conceivable that

Fig. 1 Histopathologic examination showing an adenoid cystic carcinoma of minor salivary gland origin showing perineural infiltration. Magnification high power ×400. Courtesy of Dr. Joan Phelan

Curr Pain Headache Rep (2015)9:37

PNI will also contribute to pain experienced in head and neck cancer patients. Central Mechanisms Repeated noxious input from the primary afferent neurons will lead to plastic changes in the dorsal horn neurons, by upregulating ion channels and receptors involved in nociception and/or by amplifying responses of the dorsal horn neurons to peripheral stimulations (central sensitization) [31, 32]. The hyperactivity of the dorsal horn neurons could lead to expansion of the receptive field. Increased sensitivity or expansion of receptive fields could occur in other supraspinal structures along the pain signaling pathway. Expansion of the receptive fields in spinal and supraspinal neurons is thought to play a role in pain perceptions involving areas that are not innervated by the injured peripheral nerve [1]. Mechanism for Cancer Referred Pain Peripheral Mechanisms Peripheral branching or sprouting of primary afferent neurons has been hypothesized as a mechanism of referred pain [38]. It has been hypothesized that individual sensory nerves send collaterals to innervate different body areas [38]. There is also some evidence suggesting that primary afferent neurons could project to the contralateral site of the dorsal horn, which contributes to the segmentally referred contralateral pain [38]. Central Mechanisms Segmentally referred pain may involve convergence of primary afferent neurons innervating different body regions onto a common population of the dorsal horn neurons [38]. Noxious stimulation of primary afferent neurons could change supraspinal pain pathways, strengthening the descending facilitation and/or weakening the descending inhibition on dorsal horn neurons in the spinal cord [38]. Such adaptive changes will then increase dorsal horn sensitization, or disinhibit dorsal horn neurons, and enlarge the receptive field of dorsal horn neurons in a non-topographical fashion [38]. Changes in spinal and supraspinal pain processing can also modify the activity of sensory fibers via an influence upon their central terminals, which in turn, result in the antidromic invasion of their peripheral branches [38]. Treatment-Related Immunotherapeutic strategies to re-stablish the survival and function of the immune effectors in addition to tumor-specific

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targets to eliminate cancer without causing damage to healthy tissue remain a challenge [39–41]. The common cancer treatments such as surgery, radiation, and chemotherapy often cause nerve damage. Surgery involves removing the tumor, including the nerve fibers that innervate the tumor. Depending on the chemotherapeutic agent used, the treatment could cause microtubule aggregation, neurocytotoxicity, or even neural death [5, 1]. As chemotherapy is not specific to the tumor site, nerves from multiple areas could be affected. Radiation can result in axonal injury, loss of nerve terminals, and suppression of Schwann cell proliferation and traumatize bone tissues and blood vessels, leading to tissue necrosis [1].

Orofacial Pain in Cancer Head and Neck Cancers Regional orofacial pain and other sensory disturbances occur in 80 % of patients with head and neck cancers [42]. An important predictor for the transition from oral precancer to cancer may be the onset of orofacial pain that is exacerbated during normal oral function [8]. Perineural spread of head and neck tumors can cause trigeminal neuropathy symptoms including paresthesia and numbness, in addition to motor denervation weakness and even headache [43, 37]. Around 90 % of the head and neck cancers are SCC [44], and the tongue is the most common site of oral cancer [45] in where the spontaneous complaint of facial pain has been reported as a primary symptom before oral cancer has been diagnosed in the tongue and floor of the mouth [46, 45, 44]. A retrospective study identified that in 19.2 % of 1412 oral cancer patients, pain was the initial complaint and was associated with advanced tumor, lymph nodes, and metastasis (TNM) stages [46]. The pain was localized in the teeth, neck, face, ear, palate, gingiva, and tongue, and it was described as burning mouth, sore throat, and pain at swallowing and chewing [46]. Primary intraosseous SCC of the jaws can present as pain in the region of a tooth or teeth and sometimes associated to an odontogenic cyst [47–49]. Osteosarcomas of the jaws present swelling of the area, pain, and paresthesia [50, 51]. Nasopharyngeal and oropharyngeal cancers may cause pain in the head and neck region due to nerve compression [52] and may present symptoms of trigeminal neuralgia, vague facial pain, and headache [53, 54]. Furthermore, the pain can be referred to the temporomandibular joint (TMJ) and described as dull aching pain, presenting limitation and deviation at mouth opening, trismus, clicking, and earache symptoms that can be misdiagnosed as temporomandibular disorders (TMD) [55, 56]. Intracranial tumors may present headache and orofacial pain symptoms; thus, neuroimaging must be considered to confirm the diagnosis [57]. Moreover, symptoms of trigeminal neuralgia, persistent idiopathic facial pain (atypical

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odontalgia), and TMD pain are the three most common pain presentations in patients with intracranial tumors that visit the dental professional [58]. Headache is a major symptom of brain tumors, and their presentation can be similar to primary headache disorders; therefore, cerebral neoplasias should be considered during the headache diagnosis [59, 60]. In regard to orofacial pain, middle and posterior cranial fossa tumors can cause trigeminal or glossopharyngeal neuralgia symptoms [61–65].

It has been suggested that this referred pain is mediated by the vagus nerve [76]. Compression of the vagus nerve by lung or mediastinal disease may cause a convergence of visceral and somatic afferent nerve inputs to the trigeminal tract and trigeminal nucleus caudalis giving pain symptomatology in these territories [76], and this may also explain the orofacial pain referral from pancreatic cancer.

Metastatic Tumors

Sensory disturbances in the orofacial region due to systemic cancer have been reported. Lymphomas are the second most common neoplasm of the craniofacial region, after SCCs [77]. Lymphoma, leukemia, and myeloma can be painful when they infiltrate bone and gingiva and when in close proximity to teeth [77–80]. These systemic cancers can present not only pain but also numbness or both, such as described as numb chin syndrome (NCS). NCS is a neuropathy characterized by numbness and hypoesthesia in the distribution of the mental nerve [81••]. In addition to NCS, pain and paresthesia can be present due to neuroleukemiosis, which is a known infiltration of the mental nerve by leukemic cells such as in the case of B acute lymphoblastic leukemia [82, 83••]. Multiple myeloma can cause osteolytic lesions inducing root resorption, odontogenic and bone pain, tooth mobility, and swelling which can present a diagnostic challenge to rule out an odontogenic cause or systemic disease [80].

Primary malignancies originated from the lung, kidney, esophagus, thyroid, liver, prostate, breast, female genital organs, colon, and rectum can metastasize to the orofacial region [66, 17, 67•]. The orofacial region is an uncommon area for metastasis, but it is important to note that in a retrospective study of 114 cases of metastatic tumors in the jaws, 60 % of these cases reported that the lesion in the jaw was the single indication of a primary malignancy elsewhere [16]. Bone metastases (e.g., mandible) present persistent pain, paresthesia, and swelling which are more common than soft tissue metastases (e.g., gingiva) in a proportion of 2:1 [66, 68]. Even though uncommon, in addition to the mandible, choroidal and orbital metastases from thyroid carcinomas have been reported in where orofacial pain is accompanied with blurred vision [69]. Furthermore, in a review of the literature regarding metastasis to the TMJ, from a total of 28 cases that presented with an history of malignant neoplasm, 34 % of the primary tumors were localized in the breast and 21 % in the lung. Moreover, the authors presented three cases in which TMJ pain was the first symptom of metastasis [70••]. Trigeminal neuralgia has been reported as a symptom of breast cancer when the metastatic lesion involved the pterygopalatine fossa [71] and in prostate cancer involving the mandible [72]. Therefore, it is crucial for the clinician to include cancer/ metastasis in the differential diagnosis. Non-Metastatic Tumors Orofacial pain referred from non-metastatic cancer from another site is very rare, however, may be under-reported and under-recognized. In the literature, ipsilateral orofacial pain has been reported as the only symptom of non-metastatic lung cancer and the pain has been described as severe, debilitating, aching, and with paroxysmal exacerbations with poor response to therapy [73, 19, 74]. Mediastinal malignant disease secondary to lung cancer has been also present in patients with intractable, unexplained, ipsilateral facial pain [21]. Symptoms of debilitating facial pain presented as cluster headache also have been reported in patients with non-metastatic lung cancer [19]. Moreover, trigeminal neuralgia has been reported as a sole symptom of pancreatic cancer [75•].

Systemic Cancer

Paraneoplastic Syndrome Rare causes of sensory neuropathies may be considered such as paraneoplastic neuropathy, in where a timely diagnosis is essential and may lead to discover an occult tumor. Paraneoplastic syndrome refers to sign and symptoms that result of the presence of cancer but not as a result of the local mass. It is presented similarly as an autoimmune response where immune mechanisms attack the nervous system when trying to fight cancer cells. Associated malignancies include small cell lung cancer, breast cancer, hematologic malignancies, and gynecologic tumors [84]. The occurrence of paraneoplastic neuropathies in the orofacial region is unclear [85], but it has been reported as trigeminal pain in a case of small cell lung carcinoma in where the first symptom was intermittent burning pain in the left side of her face in the region of V2, in addition to some numbness with a month history of asthenia and diarrhea [86].

Orofacial Pain in Cancer Therapy A very significant and unfortunate problem is the presence of pain as a consequence of cancer therapy. Orofacial pain, especially the neuropathic type, can arise as a result of

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Orofacial pain as a symptom of cancer

Location of the Cancer

Commonly affected anatomical structures

Signs and Symptoms in the orofacial region

Example of type of cancer

Regional

Extracranial Salivary glands, jaw bones, paranasal sinuses, soft tissues of oral cavity Intracranial Middle and posterior cranial fossa

Pain, oral discomfort, trigeminal sensory Nasopharyngeal cancer—pain often referred to disturbances, headache, earache. Pain often temporomandibular joint region, resembling described as aching, dull, or pressing TMD.

Facial pain, trigeminal neuralgia-like pain associated with subtle neurological deficits, and headache Metastatic Bone metastases: posterior mandible, Presence of pain, a mass lesion, and Metastatic breast cancer of the jaw—pain and cancer angle of the jaw and ramus neurological changes, namely paresthesia abnormal sensations such as tingling, burning (common source: breast, colon, lung, prostate, and lung cancer) Soft tissue of the oral cavity ( most Pain may be present, however it is a rare common source is lung cancer) occurrence Systemic Hematologic cancers such leukemia Pain is reported, but it seems to be secondary Multiple myeloma in the mandible— cancer to increased risk of infections common to radiographs show B punched out^ lesions that these patients may be associated with dental pain and Lymphomas Mass lesion in the oral cavity that is associated paresthesia with discomfort. NonLung cancer causing compression of Dull, continuous pain, that can also be Lung cancer—unilateral aching around the ear, metastatic the vagus nerve and other episodic and progressive associated with jaws, and temporal regions that is on the same cancer at a nociceptive pathways mediastinal weight loss, hemoptysis, persistent cough, side of the tumor. distant site or other head and neck structures and chest wall pain Paraneoplastic Most frequently associated with Neuropathies Lung cancer patient may have numbness, syndromes small cell lung cancer paresthesia, and burning pain, with predilection for the upper limbs (not clear for the orofacial pain region) Adapted from [85]

chemotherapy, radiotherapy, and surgery (tumor resection) or combination of these therapies [23, 1]. Chemotherapeutic agents can induce severe peripheral neurotoxicity at the level of dorsal root ganglia and spinal cord affecting neurons and glia [87]. The management of these patients involves anticonvulsants, antidepressants, topical agents, local anesthetics, opioids, cannabinoids, and NMDA antagonists [88]. In addition to neuropathic pain, head and neck surgery and radiation can induce musculoskeletal complaints. Myofascial pain and trismus are present as contracture, fibrosis, and scarring of the muscles of mastication and TMJ ligaments [89•, 90, 91, 52] resulting in severe limitations of mouth opening; therefore, it is recommended that patients start an exercise protocol before and after the procedure to maintain a maximum mouth opening [91]. Oral mucositis is present in approximately 90 % of the patients undergoing chemotherapy and radiotherapy for head and neck cancers [92], and it also can be seen in patients undergoing hematopoietic stem cell transplantation [93]. This condition is extremely painful, and it is characterized by ulcerative lesions in the alimentary mucosa affecting significantly the quality of life of the sufferer [92, 94]. The mucosa changes are induced by inflammation, loss of epithelial junctional integrity, cytotoxicity from chemotherapeutic drugs, and myelosuppression due to treatment [95]. Because of the

Table 2 Important clinical considerations for cancer pain localized in the orofacial region For proper diagnosis of any pain arising in the orofacial region, clinicians should take a thorough medical history and should include the following: onset of symptoms, location, quality and pain patterns, intensity, referral patterns of the pain, and modifying factors. This information may provide a possible etiology for the pain. Upon physical examination, the painful area should be examined; nonetheless, clinicians should always keep in mind that the source of pain could be located in a distant site. While pain itself cannot and should not be used as a sole diagnostic criterion for cancer, clinicians should keep in mind that cancer pain diagnosis is a diagnosis made by exclusion and can only be reached after all obvious and common etiologies have been thoroughly investigated and ruled out. Cancer pain descriptors are the same as other non-cancer conditions in the orofacial region and can range from mild discomfort to severe sharp shooting pain. Other descriptors include the following: dull, aching, burning, tingling, numbness, stabbing, or throbbing. In some cancers, pain has been shown to be an initial symptom, but in others, it could be a late finding appearing only in advanced stages, thus leading to delayed diagnosis which is associated with poor prognosis When in doubt, seek the referral to an orofacial pain specialist for further evaluation.

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pain, the proper nutrition of the patient is being compromised since some patients are unable to be eating by mouth; patients may experience difficulty in performing their oral hygiene routine, and due to the decrease in salivary flow (xerostomia) commonly seen in these patients, they have an increased susceptibility for rampant caries. Moreover, the lesions can be colonized not only by the normal microflora but also by fungal infections such as candidiasis and herpes simplex virus [91, 95, 92]. Oral mucositis treatment options include a wide array of mouthwashes with analgesic, anesthetic, anti-inflammatory, and antimicrobial properties and systemic pharmacological agents and oral mucosal protectants to form a barrier to protect the affected mucosa against irritation [92, 91]. It is important to note that in addition to the pain or because of the pain, patients with head and neck cancers have challenges in eating, talking swallowing, and breathing, factors that decrease greatly their quality of life [96•, 97••]. Sometimes, because of the pain, it is needed a reduction in dose of cancer therapy affecting the cancer prognosis [92, 95, 23].

analgesic ladder has been shown to be successful in achieving adequate pain control in 80–90 % of patients [3•], pain management continues to be a challenge for many patients mainly due to development of side effects, tolerance to medications, and patient’s fears of the medications. Nonetheless, management should pursue adequate pain control and enhancement of quality of life. And finally, when orofacial pain is a consequence of cancer therapy, preventive modalities to decrease pain and enhance oral function should be implemented. Acknowledgments We would like to thank Dr. Joan Phelan, professor and chair of the Oral and Maxillofacial Pathology, Radiology and Medicine at NYU College of Dentistry for the picture of the adenoid cystic carcinoma of minor salivary gland origin. Compliance with Ethics Guidelines Conflict of Interest Marcela Romero Reyes, Antonia Teruel, and Yi Ye each declare no potential conflicts of interest. Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

Conclusion Cancer-related pain in the orofacial region can be a symptom not only of regional tumors but also of distant cancer (Table 1); therefore, it is imperative for the clinician to recognize that the site of pain can be different of the actual source of the pain (Table 2). There is a lack of new findings in recent years with regard to the mechanisms of how cancer refers pain from a distant site to the orofacial region, but some new clinical case reports support the fact that cancer metastasis does not necessarily need to happen to have pain referral. What remains the same is that cancer-related pain is complex and often the result of the combination of several mechanisms such as inflammation and neuropathic processes, such as central sensitization and neuroplastic changes. Its prevalence and its intensity have been correlated with more advanced tumors; however, in certain cases it may be the first presenting symptom. As a matter of fact, one of the earliest signs of cancer recurrence has been reported to be orofacial pain. While pain itself cannot and should not be used as a sole diagnostic criterion for cancer, clinicians should keep in mind that cancer pain diagnosis is a diagnosis made by exclusion and can only be reached after all obvious and common etiologies have been thoroughly investigated and ruled out. Therefore, knowledge of the diverse orofacial pain disorders and a careful clinical evaluation and investigation are essential. Since cancer-associated pain has been correlated with increased morbidity and decreased quality of life, a proper diagnosis and a sound understanding of the pain-generating mechanisms are necessary to help the patient with pain control. Even though the World Health Organization (WHO)

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