Prediction of mucositis risk secondary to cancer therapy: a systematic review of current evidence and call to action.

PURPOSE: Despite advances in personalizing the efficacy of cancer therapy, our ability to identify patients at risk of severe treatment side effects and provide individualized supportive care is limited. This is particularly the case for mucositis (oral and gastrointestinal), with no comprehensive risk evaluation strategies to identify high-risk patients. We, the Multinational Association for Supportive Care in Cancer/International Society for Oral Oncology (MASCC/ISOO) Mucositis Study Group, therefore aimed to systematically review current evidence on that factors that influence mucositis risk to provide a foundation upon which future risk prediction studies can be based. METHODS: We identified 11,018 papers from PubMed and Web of Science, with 197 records extracted for full review and 113 meeting final eligibility criteria. Data were then synthesized into tables to highlight the level of evidence for each risk predictor. RESULTS: The strongest level of evidence supported dosimetric parameters as key predictors of mucositis risk. Genetic variants in drug-metabolizing pathways, immune signaling, and cell injury/repair mechanisms were also identified to impact mucositis risk. Factors relating to the individual were variably linked to mucositis outcomes, although female sex and smoking status showed some association with mucositis risk. CONCLUSION: Mucositis risk reflects the complex interplay between the host, tumor microenvironment, and treatment specifications, yet the large majority of studies rely on hypothesis-driven, single-candidate approaches. For significant advances in the provision of personalized supportive care, coordinated research efforts with robust multiplexed approaches are strongly advised.

The pathogenesis of mucositis: updated perspectives and emerging targets.

Mucositis research and treatment are a rapidly evolving field providing constant new avenues of research and potential therapies. The MASCC/ISOO Mucositis Study Group regularly assesses available literature relating to pathogenesis, mechanisms, and novel therapeutic approaches and distils this to summary perspectives and recommendations. Reviewers assessed 164 articles published between January 2011 and June 2016 to identify progress made since the last review and highlight new targets for further investigation. Findings were organized into sections including established and emerging mediators of toxicity, potential insights from technological advances in mucositis research, and perspective. Research momentum is accelerating for mucositis pathogenesis, and with this has come utilization of new models and interventions that target specific mechanisms of injury. Technological advances have the potential to revolutionize the field of mucositis research, although focused effort is needed to move rationally targeted interventions to the clinical setting.

Novel anticoagulants: general overview and practical considerations for dental practitioners.

Currently, 4 novel Direct Oral Anticoagulants (DOACs) were approved by the FDA. This review focuses on these agents and proposes a matrix for the general dentists to assess bleeding risk in dental management of patient on DOACs. The outline covers the pharmacology of DOACs (rivaroxaban, apixaban, edoxaban and dabigatran), bleeding complications, risk associated with discontinuation, monitoring/reversal, and implications for the dental practitioners. A total of 18 randomized controlled trials were identified with mixed results in regards to the risk for bleeding. Considering the pharmacology of DOACs and challenges in monitoring and reversing their effect, the dentist should consider carefully the management of patients on DOACs as it may differ from patients on conventional anticoagulants. Based on the type of dental procedure and the medical risk assessment, several general treatment approaches can be considered: continue DOACs, time dental treatment as late as possible after the last DOACs dose, discontinue DOACs for 24hrs, or discontinue DOACs for 48hrs. Based on the current reported dental literature, limited dental surgery may benefit from the first 2 conservative options. However, this needs to be proven in comparative clinical trials.

Methodology for the MASCC/ISOO Mucositis Clinical Practice Guidelines Update.

Members of the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) recently completed the process of updating the MASCC/ISOO Clinical Practice Guidelines for the prevention and treatment of mucositis. These guidelines, originally published in 2004, and last updated in 2007, provide clinicians with objective, evidence-based recommendations for the management of mucositis secondary to cancer therapy. This brief paper describes the methodology used to conduct the most recent systematic review in 2011, and develop new guidelines, providing the basis for the update. The overriding aims of the process were to assess evidence of effectiveness of interventions for the prevention and treatment of mucositis and to produce clinical practice guidelines for the management of mucositis using best available evidence.

Heparanase expression in periapical granulomas and radicular cysts.

Heparanase is an endo-ß-D-glucuronidase enzyme which degrades heparan sulfate glycosaminoglycan side chains of proteoglycans in the extracellular matrix and in basement membranes. The aim of this study was to evaluate the expression of heparanase in periapical granulomas (PGs) and radicular cysts (RCs). Immunohistochemistry was used to assess heparanase expression in PGs and RCs. Parameters including stain intensity, location and cell type were used to characterize heparanase expression in the periapical lesions. Ordered categories (from weak to strong) were used to compare the level of heparanase staining in the PG and RC groups. Both epithelial cells and inflammatory cells were positive for heparanase. The relative staining of the epithelial cells was strong, whereas the relative staining of the inflammatory cells was weak. Significant differences in immunohistochemical staining of epithelial cells were observed between RCs and PGs (p = 0.002). The relative expression of heparanase in epithelial cells in RCs was strong. In PGs, lesions with few or no epithelial cells, heparanase was predominantly expressed weakly by inflammatory cells. PGs and RCs have the same infectious origin. Therefore, the different cellular sources of heparanase in these periapical lesions may imply that this enzyme has specific pathogenetic functions in RCs and PGs.

The importance of a thorough medical and pharmacological history before dental implant placement.

The risk of osteonecrosis in patients treated with bisphosphonates is well known and guidelines intended to prevent this complication have been established and accepted. Bisphosphonate related osteonecrosis of the jaws (BRONJ) is a unique condition in which even past administration of medication may be of current and future relevance. We present a case of BRONJ in the maxilla after dental implant placement. The patient suffered from osteoporosis and had been treated with oral alendronate sodium in the past. However, the medication was stopped two years before implant placement, and the treating dentist was unaware of the patient's past bisphosphonate use. Prevention of BRONJ is based on identifying at-risk patients, and then avoiding or modifying dentoalveolar surgical procedures in these individuals. Nevertheless, there seems to be some difficulties identifying patients at risk. We present some of the challenges that impede thorough assessment of a patient's medical background (review of systems) in the dental office, and suggest possible solutions.

[The use of antibiotic prophylaxis prior to dental procedures for the prevention of prosthetic joint infection].

Prosthetic joint infection (PJI) is a severe illness which may cause pain and discomfort, may damage the quality of life and may even be life-threatening. A variety of studies have demonstrated the presence of bacteria in a small but potentially dangerous number of prosthetic joint infections that may have originated in the oral cavity. Some dental treatments such as calculus removal, extractions, dental implants placements etc. and daily oral hygiene routines such as tooth brushing may cause bacteremia. Recently the American Academy of Orthopaedic Surgeons (AAOS) published updated guidelines for antibiotic prophylaxis to prevent prosthetic joint infections. These guidelines suggest a direct and established connection between dental treatments and prosthetic joint infections, and expand the criteria to prescribe antibiotic prophylaxis prior to dental procedures associated with bacteremia. The purpose of this review is to introduce these new guidelines, and to review the literature regarding the relationship between dental care and prosthetic joint infections.

Oral epithelial dysplasia and squamous cell carcinoma following allogeneic hematopoietic stem cell transplantation: clinical presentation and treatment outcomes.

Late complications of allogeneic hematopoietic stem cell transplantation (HSCT) include a risk of secondary malignancies. Optimization for early diagnosis and treatment of oral premalignant or malignant lesions requires an assessment of potential predisposing risk factors. The medical records of patients who developed oral epithelial dysplasia (OED) and oral squamous cell carcinoma (OSCC) following allogeneic-HSCT were reviewed. Data on HSCT course, chronic graft-versus-host disease (cGVHD), and clinical outcome were recorded; landmark survival was calculated. Twenty-six patients with OED (n=8) and OSCC (n=18) were identified with a median follow-up of 26.5 and 21.5 months, respectively. Premalignant and malignant oral lesions were diagnosed at a median time of 2.5 and 8 years after HSCT, respectively. Chronic GVHD was present in 96% of patients and of these, 96% had oral involvement. Multifocal oral cancer was found in 28% of cases, and localized recurrence was observed in 44% of cases. These results suggest that oral cGVHD may be considered a potential risk factor for the development of OSCC following allogeneic-HSCT. The observation that oral cancers were frequently multifocal and recurred locally suggests that these cancers may be more aggressive. Vigilant follow-up and coordination of care are critical.

[Chronic graft-versus-host-disease involving the oral mucosa: clinical presentation and treatment].

Graft versus host disease (GVHD) is an alloimmune inflammatory process, which results from a donor-origin cellular response against host tissues. The chronic syndrome of GVHD (cGVHD) occurs in approximately 50% of patients post hematopoietic stem cell transplantation (HSCT) and remains the leading cause of non-malignant mortality. Oral cavity is one of the most frequent sites involved in cGVHD, possibly only second to skin. The oral tissues targeted by cGVHD are the mucosae, the salivary glands, the musculoskeletal apparatus and the periodontal structures. The mucosal cGVHD is accompanied by pain and mucosal irritation. Patients with cGVHD present with mucosal erosion and atrophy, lichenoid-hyperkeratotic changes, pseudomembranous ulcerations and mucoceles. Dry mouth may exacerbate mucosal irritation and erosion. In addition to impaired oral functions, cGVHD may lead to secondary malignancies in the form of solid cancers, particularly squamous cell carcinomas of the oral cavity. Moreover, administration of systemic azathioprine, a commonly used immunosuppressive drug in cGVHD patients, may significantly increase the incidence of tumors of oral cavity. The increased risk of secondary malignancies indicates the need for lifelong surveillance, particularly in younger patients. Scoring of oral GVHD was first addressed by NIH only in 2005. The NIH consensus paper referred to standard criteria for diagnosis, classification, and response to treatment. These scales were introduced for clinical use, although they require prospective validation studies. In the past, other scales were suggested and may still be used for research purposes. Management of oral cGVHD is compromised of preventive protocols and when cGVHD is developed, systemic and topical treatment. Because the majority of patients with oral cGVHD will develop the extensive form of the disease, they will be treated systemically. Systemic treatment is based on steroids and immunosuppressants, and, thus, increases the frequency of opportunistic infections. Only a few well-designed controlled trials using systemic treatments for cGVHD assessed oral outcomes. When the oral mucosa is the only site resistant to high doses of systemic corticosteroids or when GVHD is manifested only in the oral mucosa, the treatment approach should be topical therapy. Topical steroid preparations are the mainstay of local treatment. Budesonide is a novel steroid preparation that is being developed in the recent years for cGVHD. Its high topical anti-inflammatory activity together with low systemic bioavailability may provide enhanced treatment effects for local oral disease while sparing the host immunity. Second line of topical therapy includes pharmacologic immunosuppressants and phototherapy, combined with palliative treatment. This article aims at presenting the novel information about the clinical presentation, scoring scales, long term complications and treatment for mucosal cGVHD.

Time to engraftment following allogeneic stem cell transplantation is significantly longer in patients with myelodysplastic syndrome than with acute myeloid leukemia.

Patients with myelodysplastic syndrome (MDS) commonly present with pancytopenia, suggesting that the marrow stroma fails to support the growth of both malignant and normal stem cells. We therefore retrospectively analyzed the duration to engraftment of neutrophils (> or =0.5 x 10(9)/l and > or =1.0 x 10(9)/l) and platelets (> or =20 and > or =50 x 10(9)/l) in 37 MDS patients and 42 patients suffering from primary AML, following allogeneic SCT. A significantly shorter time to engraftment was documented in AML as compared to MDS patients in all four parameters. These results held true even when we subgrouped the patients according to gender, age (50 years being the cutoff age between young and elderly patients), patient-donor relationship, donor match and intensity of conditioning. To the best of our knowledge, this is the first time that such a comparison has been made. We suggest that the longer duration of post transplant pancytopenia that is frequently observed in MDS patients may also influence post transplant outcome.

[Antibiotic prophylaxis for the prevention of infective endocarditis--new guidelines of the American Heart Association].

Within the last twelve month both the working party of the British Society for Antimicrobial Chemotherapy and the American Heart Association have changed their attitude towards antibiotic prophylaxis for the prevention of infective endocarditis dramatically. The major change is the exclusion of the groups of patients formerly known as the "low and medium" risk groups from the new treatment group. A brief summary of the American as well as the British recommendations for adults and children is reported.

Osteonecrosis of the jaw induced by orally administered bisphosphonates: incidence, clinical features, predisposing factors and treatment outcome.

UNLABELLED: Osteonecrosis of the jaw (ONJ) is a well-known devastating side effect of bisphosphonate therapy for cancer. Several ONJ cases of patients using oral bisphosphonates have been reported in the literature. The present study analyzed the clinical features, predisposing factors, and treatment outcome of 11 patients with oral bisphosphonates-related ONJ. INTRODUCTION AND HYPOTHESIS: Osteonecrosis of the jaw (ONJ) is a well-known side effect of parenteral bisphosphonates therapy. Although ONJ has been reported in patients using oral bisphosphonates, documentation of this entity is sparse. It was hypothesized that the clinical features, predisposing factors, and treatment outcome of this population are different from those of oncologic patients. METHODS: This retrospective bi-central study involved 98 ONJ patients, 13 of whom were treated with oral bisphosphonates. Two patients were excluded because of previous use of intravenous bisphosphonates. The profiles of 11 patients were analyzed. RESULTS: The mean duration of alendronate use before developing ONJ was 4.1 years. ONJ was triggered by dental surgery in 9 patients and by ill-fitted dentures in 2. Heavy smokers were the most recalcitrant subjects. Among the nine patients with at least 6 months of follow-up, ONJ healed completely in three, partially in four, and not at all in two. CONCLUSIONS: ONJ is a rare devastating side effect of oral bisphosphonates associated with patient morbidity and high financial burden. Clinicians must be aware of this entity and inform patients of the risks of dental surgery. The synergistic effect of smoking in the pathogenesis of ONJ should be further investigated.

Orofacial pain in cancer: part I--mechanisms.

The mechanisms involved, and possible treatment targets, in orofacial pain due to cancer are poorly understood. The aim of the first of this two-part series is to review the involved pathophysiological mechanisms and explore their possible roles in the orofacial region. However, there is a lack of relevant research in the trigeminal region, and we have therefore applied data accumulated from experiments on cancer pain mechanisms in rodent spinal models. In the second part, we review the clinical presentation of cancer-associated orofacial pain at various stages: initial diagnosis, during therapy (chemo-, radiotherapy, surgery), and in the post-therapy period. In the present article, we provide a brief outline of trigeminal functional neuro-anatomy and pain-modulatory pathways. Tissue destruction by invasive tumors (or metastases) induces inflammation and nerve damage, with attendant acute pain. In some cases, chronic pain, involving inflammatory and neuropathic mechanisms, may ensue. Distant, painful effects of tumors include paraneoplastic neuropathic syndromes and effects secondary to the release of factors by the tumor (growth factors, cytokines, and enzymes). Additionally, pain is frequent in cancer management protocols (surgery, chemotherapy, and radiotherapy). Understanding the mechanisms involved in cancer-related orofacial pain will enhance patient management.

Orofacial pain in cancer: part II--clinical perspectives and management.

Cancer-associated pain is extremely common and is associated with significant physical and psychological suffering. Unfortunately, pain associated with cancer or its treatment is frequently under-treated, probably due to several factors, including phobia of opioids, under-reporting by patients, and under-diagnosis by healthcare workers. The most common etiology of cancer pain is local tumor invasion (primary or metastatic), involving inflammatory and neuropathic mechanisms; these have been reviewed in Part I. As malignant disease advances, pain usually becomes more frequent and more intense. Additional expressions of orofacial cancer pain include distant tumor effects, involving paraneoplastic mechanisms. Pain secondary to cancer therapy varies with the treatment modalities used: Chemo-radiotherapy protocols are typically associated with painful mucositis and neurotoxicity. Surgical therapies often result in nerve and tissue damage, leading, in the long term, to myofascial and neuropathic pain syndromes. In the present article, we review the clinical presentation of cancer-associated orofacial pain at various stages: initial diagnosis, during therapy (chemo-, radiotherapy, surgery), and in the post-therapy period. As a presenting symptom of orofacial cancer, pain is often of low intensity and diagnostically unreliable. Diagnosis, treatment, and prevention of pain in cancer require knowledge of the presenting characteristics, factors, and mechanisms involved.

Osteomylelitis and necrosis of the jaw in patients treated with bisphosphonates: a comparative study focused on multiple myeloma.

It was reported that multiple myeloma (MM)-patients suffer from a higher incidence of osteomyelitis and necrosis of the jaws than patients treated with bisphosphonates for other reasons. The aim of this study is to report about 57 cases of bisphosphonate-related osteomyelitis and necrosis of the jaws (BON) and to investigate the differences between BON in MM and non-MM patients. Clinical and laboratory data of 57 cases were assessed. The features of BON and clinical-outcome were compared between the two groups. Treatment approach was assessed as a contributing-factor to treatment-outcome. Clinical presentation included exposed bone, pain, swelling and suppuration with little variation between the two groups. Past dento-alveolar surgery was common in both study-groups. Treatment outcome was poor (33% and 25% responded to treatment in MM group and non-MM group, respectively). Treatment modality did not affect the treatment outcome. The clinical presentation described in this case series should alert the physician to the possibility of BON. Although the literature shows a higher incidence of BON in MM patients compared to non-MM patients, our study suggests that the severity of the clinical presentation and the response to treatment are not worse in MM patients compared with non-MM patients. The predisposition of MM patients to BON should be further investigated.

Fludarabine-based reduced intensity conditioning for stem cell transplantation of Fanconi anemia patients from fully matched related and unrelated donors.

Reduced intensity conditioning has been suggested as a desirable therapeutic modality for the treatment of patients with malignant and nonmalignant indications, but it seems particularly attractive for patients with Fanconi anemia due to their increased sensitivity to chemoradiotherapy. Between November 1996 and September 2003, 7 patients (1 male and 6 female; age range, 3-31 years; median age, 9.5) were conditioned with a fludarabine-based protocol for stem cell transplantation without radiation. In vivo T-cell depletion was accomplished with anti-thymocytic globulin or Campath-1H (alemtuzumab). Graft-versus-host disease prophylaxis consisted of low-dose cyclosporine alone. Eight transplantations were carried out for 7 patients using bone marrow, peripheral blood, and/or cord blood as sources of stem cells. All patients received transplants from HLA-A, -B, -C, and -DR matched donors, 5 from family members and 2 from matched unrelated donors. One patient did not engraft her first matched unrelated donor and underwent a second transplantation from another matched unrelated donor, after which she engrafted well. All 7 patients are alive and well, fully reconstituted with donor cells, and with 100% performance status. In conclusion, fludarabine-based preparative protocols are well tolerated, facilitate rapid engraftment with minimal toxicity, and should be considered an essential component of choice for patients with Fanconi anemia.

A prospective, double-blind phase II study evaluating the safety and efficacy of a topical histamine gel for the prophylaxis of oral mucositis in patients post hematopoietic stem cell transplantation.

The aim of this study was to evaluate the safety, tolerability and efficacy of a topical gel containing histamine dihydrochloride (HDC) versus a placebo gel in preventing oral mucositis in hematopoietic stem cell transplantation (HSCT) patients. A total of 45 patients post-HSCT were enrolled in a prospective longitudinal, placebo-controlled, double-blind study. Patients were evaluated twice weekly for oral mucositis (OMAS, NCI score), oral pain (VAS), oral function and salivary flow rate. Compliance was assessed using a patient diary. Oral mucositis developed in 85% of the HDC group and 63% of the placebo group. The mean maximal intensity for NCI score was 1.45+/-1 in the HDC group and 1.21+/-1.27 in the placebo group (P=0.37). The mean duration of oral mucositis was 4.7+/-3.6 and 2.33+/-2.23 days in the HDC and placebo groups, respectively (P=0.06). The same trends were measured with OMAS. Visual analogue scale for oral pain and oral function was not significantly different between the two groups. Histamine dihydrochloride was found to be safe. In the search for topical agents for the prevention of mucositis, we found that HDC neither improves nor worsens oral mucositis in HSCT patients. The balance between the pro- and anti-inflammatory effects of HDC should be investigated further in order to acquire a clinically effective topical medication based on its anti-inflammatory properties.

Low transplant-related mortality with allogeneic stem cell transplantation in elderly patients.

Historically, age >60 years was considered a contraindication for allogeneic stem cell transplantation (allo-SCT). In recent years, elderly (>60 years) patients have become eligible for allo-SCT due to the application of reduced intensity conditioning (RIC). The present report summarizes our cumulative experience in a cohort of 17 elderly patients (age 60-67, median 62.5 years) with hematological malignancies treated with 18 allo-SCT procedures, mostly nonmyeloablative. In all, 14 patients received fludarabine and busulfan/busulfex regimen, three patients were conditioned with the fludarabine and low-dose TBI and one patient received busulfan alone. All patients displayed tri-lineage engraftment. The time to recovery of absolute neutrophil count >/=0.5 x 10(9)/l was 9-27 days (median 14 days). The time interval to platelet recovery >/=20 x 10(9)/l was 3-96 days (median 11 days). Veno-occlusive disease occurred only in 3/18 procedures and subsided with conventional treatment. Nonfatal transplant-related complications occurred in 6/18 (33.3%) procedures including: renal failure, arrhythmia, CNS bleeding, cystitis, typhlitis and gastrointestinal bleeding. Transplant-related mortality occurred in 6/18 (33.3%) episodes. Of the 17 patients, 12 (12/18 episodes) were discharged. Five of 17 (29%) patients survived (median follow-up 11 m, range 8-53 m). Our data suggest that RIC-allo-SCT may be safely applied in the elderly, suggesting that allogeneic immunotherapy may become an important tool for treatment of hematological malignancies without an age limit.