The broadening scope of oral mucositis and oral ulcerative mucosal toxicities of anticancer therapies.

Oral mucositis (OM) is a common, highly symptomatic complication of cancer therapy that affects patients' function, quality of life, and ability to tolerate treatment. In certain patients with cancer, OM is associated with increased mortality. Research on the management of OM is ongoing. Oral mucosal toxicities are also reported in targeted and immune checkpoint inhibitor therapies. The objective of this article is to present current knowledge about the epidemiology, pathogenesis, assessment, risk prediction, and current and developing intervention strategies for OM and other ulcerative mucosal toxicities caused by both conventional and evolving forms of cancer therapy.

Recent advances in cancer therapy-associated oral mucositis.

Oral mucositis (OM) is a common and debilitating toxicity of cancer treatments - chemotherapy, radiotherapy, hematopoietic cell transplant, or combinations. OM is associated with severe oral pain and has negative impacts on patient function and quality of life. Additionally, OM has accompanying systemic complications that may have critical implications. These local and systemic consequences can alter cancer treatment, and add an economic burden. This review covers the clinical presentation and course of OM, differential diagnosis, clinical and economic impacts, pathogenesis, risk factors, assessment measures, biomarkers and prediction of OM, management, research advances in the development of new drugs and treatments, and big data.

Facial and trigeminal nerves neuropathy induced by atmospheric pressure changes: A meta-analysis.

BACKGROUND: Barometric pressure changes during flight or diving may cause facial barotrauma. Neuropathy of the fifth (CN5) or the seventh (CN7) cranial nerves is a rare manifestation of this condition. The aim of this study was to analyze risk factors for baroneuropathies of CN5 and CN7. METHODS: A search of PubMed and Cochrane Library databases was conducted to identify all published cases of CN5 and CN7 neuropathies. Only original case reports and series that documented events of neuropathies associated with the trigeminal nerve or facial nerve while flying, diving, or mountain climbing were included. Assessed variables included sex, medical history, age, setting (flight or diving), atmospheric pressure changes, number of episodes, symptoms, treatment, and recovery. RESULTS: We identified a total of 48 articles described >125 episodes in 67 patients. Mean age was 33.5 ± 12.1 years with a male predominance (76.1 %). Cases were equally distributed between flight and diving (50.7 %, 46.3 %, respectively). CN5 involvement was observed in 77.6 % of patients, with ear pain and facial numbness as the most common symptoms. The latter was correlated with positive otolaryngology medical history. CN7 was involved in 88.1 % of patients. Flying, as opposed to diving was correlated with spontaneous resolution of symptoms (86.7 % vs. 42.3 % of cases resolved spontaneously, respectively, p = 0.001). CONCLUSIONS: Flight is an equal risk factor to diving with respect to CN5 and CN7 barotrauma. Involvement of CN7 was observed in most cases, but possibly due to report-bias. Positive medical history is a risk factor for facial numbness.

Clinical use of photobiomodulation for the prevention and treatment of oral mucositis: the real-life experience of MASCC/ISOO members.

AIM: To assess clinical use and patient outcome of photobiomodulation (PBM) for oral mucositis (OM) prevention and treatment among specialized practitioners. METHODS: A poll was emailed to the members of the Mucositis Study Group of MASCC/ISOO. The PBM parameters used by the respondents were analyzed using exploratory statistical methods to identify combinations of PBM parameters (patterns) that characterize the variance in the protocols (principal component analysis). RESULTS: Responses were received from 101 MSG members, with 78 providing analyzable data. Most of the responders were dental practitioners or oral medicine specialists. PBM was used by 59% of the responders for OM or targeted therapy stomatitis. Technical parameters varied widely. Most responders used wavelengths ∼650 nm intra-orally. The spot-size and distance from the tissue were the main factors driving the variation. All PBM users noted that PBM relieved pain, either immediately or a delayed effect. High likelihood of pain relief (measured as responder's report of pain relief in 67-100% of patients) was reported by 22% and 19% of PBM users for immediate pain relief and delayed pain relief, respectively. The most common reported barriers to using PBM were financial considerations, time constraints, lack of training or experience and concern about the potential for malignant transformation or increased risk of cancer recurrence. CONCLUSIONS: The use of PBM for OM prevention or treatment is in early phases of adoption in practices, facing some obstacles to implement it. A wide variation in technical parameters was found. Nonetheless, responses indicate that PBM provided pain relief.

High-power laser photobiomodulation therapy for immediate pain relief of refractory oral mucositis.

PURPOSE: We aimed to evaluate the efficacy of high-power (class IV) laser photobiomodulation (PBM) therapy for immediate pain relief due to oral mucositis (OM) refractory to recommended first-line therapy. METHODS: This retrospective study included 25 cancer patients with refractory chemotherapy- or radiotherapy-induced OM (16 and 9 patients, respectively) that were treated for pain relief with an intraoral InGaAsP diode laser (power density = 1.4 W/cm2 ). Pain was self-assessed immediately before and after laser treatment using a 0-to-10 numeric rating scale ([NRS], "0" = no pain, "10" = intolerable pain). RESULTS: Patients reported an immediate decrease in pain following 94% (74 of 79) of the PBM sessions, in 61% (48 sessions) the pain reduction was over 50%, and in 35% (28 sessions) the initial pain was completely eliminated. There were no reports of increased pain post-PBM. For chemotherapy and radiotherapy-treated patients, mean reduction in pain NRS post-PBM was 4.8 ± 2.5 (p < 0.001) and 4.5 ± 2.8 (p = 0.001), indicating a post-PBM reduction of 72% and 60% of the initial pain level, respectively. The analgesic benefit of PBM remained for a mean of 6.0 ± 5.1 days. One patient reported a transient burning sensation after one PBM session. CONCLUSIONS: High-power laser PBM may provide nonpharmacologic, patient-friendly, long-lasting, rapid pain relief for refractory OM.

Clinicians' experience with topical benzydamine and morphine for the management of oral mucositis: adverse effects and barriers.

INTRODUCTION: Among the evidence-based agents outlined in the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) mucositis guidelines, benzydamine and morphine are advised for the management of oral mucositis (OM) in certain cancer patients. This study is aimed to collect information from a group of highly experienced healthcare professionals in the field of oral mucositis about their clinical experience with these agents. METHODS: A survey questionnaire about the clinical experience with topical benzydamine and morphine to manage oral mucositis and their related adverse effects (AEs) was electronically distributed to the members of the Mucositis Study Group of MASCC/ISOO. RESULTS: Eighty-eight entries were recorded (response rate 25%), and 54 entries submitted complete questionnaires about the drug-related AE (completion rate 65%) and were used for the data analysis. Of the respondents, 44% and 27.7% prescribed benzydamine and morphine to manage their patients' oral mucositis, respectively. Lack of availability in the respondent's country was the common reason for not prescribing benzydamine and morphine (18.9% and 5.4%, respectively); however, a large portion of the respondents indicated that 'another reason' stopped them from prescribing these agents (51.3% and 73%, respectively). AEs to benzydamine or morphine were observed by 25.9% and 12.9% of respondents, respectively, with mild numbness and tingling as the most common drug-related AE for both agents. CONCLUSION: The use of topical benzydamine and morphine for the management of OM varies between countries. While relatively common, the AEs related to these agents are mild. Mitigating the barriers for prescribing them may increase their use.

Supportive care of cancer patients with a self-applied photobiomodulation device: a case series.

PURPOSE: Oral mucositis (OM) and prolonged wound healing are common side-effects of cancer treatments. Photobiomodulation (PBM), previously called low-level laser, is currently part of the official guideline for OM prevention. However, all the PBM protocols relate to office-based devices, operated by professional health caregivers, requiring frequent applications. In the following case series, we present our experience with a self-applied consumer home-use PBM device for supportive care. METHODS: Five patients receiving cancer treatment presented at the clinic (female:male 3:2, 55-76 years old) with OM grade 3/4 (n=2), post-surgical non-healing wounds (n=3), and dermatitis (n=1). The PBM treatment (808 nm, 250 mW peak power, 15KHz, 5 J/min, ray size 4.5×1.0cm2) was self-applied by the patients. The protocol included extra/intra-oral applications, over the wound bed/margins and adjacent lymph nodes. RESULTS: The treatment was found effective for resolving OM with rapid pain relief and accelerated healing in post-operative wounds and dermatitis, without reported adverse events. Patients found routine easy to follow and painless, and the protocol was easily integrated as an adjuvant treatment to standard care at the clinic or home while not requiring additional time from the staff. CONCLUSIONS: Side-effects induced by cancer therapy have a detrimental effect on the patient's well-being and may delay or even prevent the patients from completing treatment regimens. PBM is already an established tool for supportive treatment in cancer patients. The advent of a self-applied personal PBM treatment with easy-to-apply protocols for a variety of side-effects makes this technology an important accessible and safe supportive care option.

Pain characteristics in medication-related osteonecrosis of the jaws.

PURPOSE: To characterise pain from medication-related osteonecrosis of the jaws (MRONJ) and the effects of antimicrobial treatment on it. METHODS: Data from files of patients diagnosed with MRONJ according to the position paper of the American Association of Oral and Maxillofacial Surgeons (2014) and Multinational Association of Supportive Care in Cancer and American Society of Clinical Oncology (2019) were collected retrospectively, including gender, age, primary disease, bone-modifying agents (BMAs)/anti-angiogenics, administration route, involved jaw, location, and exposure size. The patients were treated according to the abovementioned position papers' recommendations, i.e. all patients who suffered from pain were staged as 2 or 3 and treated with systemic amoxicillin, or doxycycline or clindamycin in case of sensitivity, and local antiseptic and hygiene instructions. RESULTS: Data from 77 MRONJ patients (aged 65.09 ± 11.9 years old) were analysed. Most (90.1%) received bisphosphonates for cancer (79%) and osteoporosis (17%). A total of 67.5% experienced pain; 36.5% had moderate-to-severe pain. Female gender was significantly associated with the presence of pain (p = 0.002). Osteonecrosis lesions after dento-alveolar surgery had a higher risk of pain development than spontaneous lesions (p = 0.045). Medical and oncologic background, type of pharmacotherapy, lesion size, and location were not associated with pain levels. Worse initial pain was significantly associated with better relief following MRONJ treatment (p = 0.045). Meaningful pain reduction (≥ 50%) was significantly correlated with initial pain severity (p = 0.0128, OR = 4.75). CONCLUSIONS: Pain from infection and inflammation often accompanies MRONJ. The presence of pain is correlated with longer BMAs pre-therapy and if surgery preceded the MRONJ. Persistency of the mild pain together with a resistance to common antimicrobial treatment, although not complete, is a feature that MRONJ pain shares with neuropathic-"like" pain, and requires further study and consideration during treatment.

Photobiomodulation (low-level laser) therapy for immediate pain relief of persistent oral ulcers in chronic graft-versus-host disease.

PURPOSE: To determine the immediate pain-relieving effect of photobiomodulation therapy (PBMt) in patients with oral ulcers of chronic graft-versus-host disease (cGVHD) refractory to first line therapy with topical corticosteroids. METHODS: This retrospective study included all patients who underwent PBMt for pain relief of refractory oral cGVHD lesions. PBMt was applied using an intraoral approach to all sites with mucosal lesions, using a 940 nm InGaAsP diode laser device, with the following parameters: pulsed modulation (duty cycle of 50%), power 0.7 W, illuminated spot size 7.1 cm2, irradiance 98.6 mW/cm2, and irradiation time 90 s per point. Pain was self-assessed using a 0-to-10 scale immediately before and after PBMt. RESULTS: Data from eleven patients with a total of 56 PBMt sessions were analyzed. In 48 (85.7%) sessions, the patients reported less pain immediately after treatment, with a reduction of ≥ 50% of the initial pain level in 43 (76.8%) sessions. Mean pre- and post-treatment pain levels were 5.20 ±2.7 and 1.38 ±2.1, respectively (p < 0.001), i.e., a post-treatment reduction of 73.4% of the initial pain level. The benefits of the treatment remained for a mean of 6.50 ±5.4 days (range of 2 to 14 days). No adverse effects were reported. CONCLUSIONS: PBMt seems to be a promising treatment modality for refractory oral cGVHD lesions as a rapid pain reliever with relatively long-lasting effects.

Oral white lesion in patients post-hematopoietic stem cell transplantation: a case series demonstrating the diagnostic dilemma.

The current National Institutes of Health (NIH) consensus paper excluded "white hyperkeratotic plaque" from the diagnostic criteria for oral chronic graft-versus-host disease (cGVHD) in order to ensure malignant transformation is not overlooked. Therefore, an isolated oral white plaque is recommended to be subjected to biopsy and pathologic examination. The cases described in this paper shed a new light on the clinical approach to oral white plaque post-hematopoietic stem cell transplantation. The objectives of this article are to demonstrate that a white plaque does not contradict a diagnosis of oral cGVHD, and to highlight the clinical considerations for taking a biopsy.

Oral verruciform xanthoma in chronic graft-versus-host disease patients.

BACKGROUND: Verruciform xanthoma (VX) is an uncommon benign epithelial lesion which mainly appears in inflamed oral epithelium. In this study, our aim was to present new cases of oral VX (OVX) in chronic graft-versus-host disease (cGVHD) and review the literature. METHODS: We conducted a retrospective chart review of cGVHD patients (2012-2019) to reveal cases of OVX. The demographics, medical background, clinical presentation, treatment provided, and follow-up were obtained. Additionally, Medline was searched using the terms "graft-versus-host disease," "verruciform xanthoma," and "oral." Of the articles, the above-mentioned demographic and clinical features were retrieved. RESULTS: The patient pool included 133 oral cGVHD patients. Three cGVHD patients (males, aged 15-49 years, post-hematologic malignancy) were diagnosed with OVX. All patients had oral mucosal lichenoid lesions, but not in close proximity to the VX lesion. Medline searches revealed 9 cases of OVX in cGVHD patients reported in the literature. Eleven of the 12 patients had oral mucosal lichenoid lesions. Four patients had multiple OVX lesions. All lesions were asymptomatic. Six patients had lesions in the masticatory mucosa (hard palate and gingiva) and 4 patients had lesions in the buccal mucosa. CONCLUSIONS: To the best of our knowledge, this is the largest published OVX in cGVHD series, including 12 patients. It appears that despite the higher prevalence in cGVHD patients relative to the general population, OVXs do not necessarily develop in sites with lichenoid lesions. It is advised that clinicians be familiar with the clinical and histological features in order to consider OVX in the differential diagnosis of oral lesions in cGVHD patients.

MASCC/ISOO clinical practice guidelines for the management of mucositis: sub-analysis of current interventions for the management of oral mucositis in pediatric cancer patients.

OBJECTIVE: The aim of this sub-analysis was to highlight the MASCC/ISOO clinical practice guidelines for the management of oral mucositis (OM) in pediatric patients and to present unique considerations in this patient population. METHODS: This sub-analysis of the pediatric patient population is based on the systematic review conducted by the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISSO) published in 2019/2020. Studies were scored and assigned a level of evidence based on previously published criteria. Data regarding adverse effects and compliance was collected from the original publications. RESULTS: A total of 45 papers were included and assessed in this sub-analysis, including 21 randomized controlled trials (RCTs). Chewing gum was demonstrated to be not effective in preventing OM in pediatric cancer patients in 2 RCTs. The efficacy of all other interventions could not be determined based on the available literature. CONCLUSION: There is limited or conflicting evidence about interventions for the management of OM in pediatric cancer patients, except for chewing gum which was ineffective for prevention. Therefore, currently, data from adult studies may need to be extrapolated for the management of pediatric patients. Honey and photobiomodulation therapy in this patient population had encouraging potential. Implementation of a basic oral care protocol is advised amid lack of high level of evidence studies.

MASCC/ISOO clinical practice guidelines for the management of mucositis secondary to cancer therapy.

BACKGROUND: Mucositis is a significant toxicity of cancer therapy with numerous systemic sequelae. The goal of this systematic review was to update the Multinational Association of Supportive Care in Cancer and International Society of Oral Oncology (MASCC/ISOO) Clinical Practice Guidelines for the management of mucositis. METHODS: The literature was reviewed systematically to identify interventions for mucositis. Studies were rated according to the presence of major and minor flaws according to previously published criteria. The body of evidence for each intervention and in each treatment setting was assigned a level of evidence based on previously published criteria. Guidelines were developed based on the level of evidence, with 3 possible guideline determinations: recommendation, suggestion, or no guideline possible. RESULTS: The guideline covers evidence from 1197 publications related to oral or gastrointestinal mucositis. Thirteen new guidelines were developed for or against the use of various interventions in specific treatment settings, and 11 previous guidelines were confirmed after aa review of new evidence. Thirteen previously established guidelines were carried over because there was no new evidence for these interventions. CONCLUSIONS: The updated MASCC/ISOO Clinical Practice Guidelines for mucositis provide professional health caregivers with a clinical setting-specific, evidence-based tool to help with the management of mucositis in patients who have cancer.

Oral mucosal changes associated with primary diseases in other body systems.

Systemic diseases may manifest in the oral cavity. This chapter reviews the oral mucosal pathology in blood diseases, gastrohepatic diseases, kidney diseases, immunologic and connective tissue diseases, endocrine diseases, pulmonary diseases, nutritional deficiencies, dermatologic diseases, as well as cancer-associated oral mucosal conditions. The oral mucosa is one of the most commonly affected tissues and may present with unique clinical appearances. Oral mucosal involvement may be the first presentation of the systemic disease or reflect activity or progression of the primary condition. Therefore, it is of importance to be familiar with oral mucosal manifestations of these systemic diseases.

Systematic review of photobiomodulation for the management of oral mucositis in cancer patients and clinical practice guidelines.

PURPOSE: To systematically review the literature and update the evidence-based clinical practice guidelines for the use of photobiomodulation (PBM), such as laser and other light therapies, for the prevention and/or treatment of oral mucositis (OM). METHODS: A systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO) using PubMed and Web of Science. We followed the MASCC methods for systematic review and guidelines development. The rigorously evaluated evidence for each intervention, in each cancer treatment setting, was assigned a level-of-evidence (LoE). Based on the LoE, one of the following guidelines was determined: Recommendation, Suggestion, or No Guideline Possible. RESULTS: Recommendations are made for the prevention of OM and related pain with PBM therapy in cancer patients treated with one of the following modalities: hematopoietic stem cell transplantation, head and neck (H&N) radiotherapy (without chemotherapy), and H&N radiotherapy with chemotherapy. For each of these modalities, we recommend 1-2 clinically effective protocols; the clinician should adhere to all parameters of the protocol selected. Due to inadequate evidence, currently, No Guideline Possible for treatment of established OM or for management of chemotherapy-related OM. The reported clinical settings were extremely variable, limiting data integration. CONCLUSIONS: The evidence supports the use of specific settings of PBM therapy for the prevention of OM in specific patient populations. Under these circumstances, PBM is recommended for the prevention of OM. The guidelines are subject to continuous update based on new published data.

Improvement of dry mouth following intraductal irrigation of salivary glands.

OBJECTIVES: To assess the effect of major salivary gland intraductal irrigations (IGs) to relieve mouth dryness. METHODS: We retrospectively analyzed the records of patients with mouth dryness who underwent major salivary gland IG during 2013-2015. Records included demographics, medical background, dry mouth etiologies and symptomatology, and results of sialometry and sialo-cone-beam computerized tomography. Subjective improvement following the IG procedure (yes/no) and sustained subjective improvement (mouth dryness relief for ≥1 month) were recorded. Objective improvement was assessed by comparing the mean unstimulated (USF) and stimulated (SSF) whole salivary flow (WSF) rate before and after the IG. RESULTS: Seventy-four patients were included [mean age: 59.08 ± 12.46 years]. Improvement was detected in the USF (p = .027), but not in the SSF (p = .878). Fifty-five (84.6%) noted subjective improvement, while 10 (15.4%) did not. Subjective improvement was positively associated with the USF following IG (p = .037), with salivary gland swelling episodes (p = .033), and with difficulties in swallowing dry foods (p = .014). Of those with subjective improvement, 45 (81.8%) reported sustained improvement, which was positively associated with lack of a gritty eye sensation (p = .042) and abnormal sialo-CBCT findings (p = .001). CONCLUSIONS: Major salivary gland IG is a simple and safe procedure that may relieve dry mouth for a relatively extended duration. Further studies are needed to confirm these preliminary findings and assess their underlying mechanisms.

Long-term scopolamine treatment and dental caries.

OBJECTIVES: To investigate whether scopolamine, an anticholinergic agent which induces hyposalivation, represents a risk factor for the occurrence of dental caries. MATERIALS AND METHODS: A retrospective cohort study was carried out among sailors treated with scopolamine for seasickness. The study population included 370 young healthy male adults (18-30 years old) who served in the Israel Navy between 2012 and 2016. Of these, 66 subjects who were chronically treated with intermittent administration of scopolamine, either by the oral or transdermal route, were assigned to the study group. Documented subject characteristics included age, socioeconomic status, level of education, body mass index, smoking history, and dental hygiene. Follow-up lasted 1 to 3.5 years. RESULTS: Two- to 3.5-year follow-up revealed a higher risk of dental caries in 15 of 16 subjects (93.8%) treated with an average of 50.9 mg scopolamine, in contrast to only 71 of 108 control subjects (65.7%) (RR = 1.43, p = 0.02 [95% CI = 1.18-1.72]). Follow-up for 1-1.5 years revealed a lower occurrence of dental caries in both the study group (11/22, 50.0%) and the control group (46/104, 44.2%). Follow-up of 1.5-2 years also revealed less dental caries, in 16/28 subjects (57.1%) in the study group and 51/92 subjects (55.4%) in the control group. The differences were not statistically significant. CONCLUSIONS: In healthy young adults, prolonged intermittent use of scopolamine was found to be a risk factor for the development of dental caries. CLINICAL SIGNIFICANCE: Dental care and hygiene should be intensified when administering hyposalivatory anticholinergic agents.

Trigeminal Neuropathy After Mandibular Fractures: Epidemiology and Neurophysiologic Diagnosis.

OBJECTIVES: To study the trigeminal nerve neuropathy prevalence after mandibular fractures and follow nerve recovery and to examine associations with clinical features. SUBJECTS: The files of 304 patients treated for 424 mandibular fractures in Hadassah Medical Center between 2001 and 2008 were analyzed. Twenty-five patients with paresthesia were examined by electro-diagnostic conduction test (quantitative sensory testing). RESULTS: The most common fracture sites were the symphysis (28.5%) and condyle (21.4%). A strong correlation between fracture severity and treatment modality was found. Nerve damage occurred in 13.4% of nondisplaced fractures and in 65.3% of >5 mm displaced fractures. Patients who were treated by open reduction internal fixation demonstrated the biggest difference in quantitative sensory testing values between the affected and nonaffected sides. C nerve fibers were the most damaged and least regenerated. There was correlation between damage perception and objective test results. CONCLUSIONS: There is a correlation between fracture type and displacement severity on neurologic deficit and prognosis. The objective neurosensory damage was manifested by higher nerve excitation threshold on the injured side. Patients should be informed on the prognosis of neurologic deficit according to fracture type.