A prospective study of dysgeusia and related symptoms in patients with multiple myeloma after autologous hematopoietic cell transplantation.

BACKGROUND: Dysgeusia is a common but understudied complication in patients undergoing autologous hematopoietic cell transplantation (auto-HCT). We assessed the feasibility of using chemical gustometry (CG) to measure dysgeusia and explored its associations with symptom burden, nutrition, chemotherapy pharmacokinetics (PK), and the oral microbiome. METHODS: We conducted a single-center, prospective feasibility study (NCT03276481) of patients with multiple myeloma undergoing auto-HCT. CG was performed longitudinally testing five flavors (sweet, sour, salty, bitter, umami) to calculate a total taste score (maximum score, 30). We measured caloric intake and patient-reported symptoms, assessing their correlation with oral microbiota composition and salivary and blood melphalan PK exposure. RESULTS: Among all 45 patients, 39 (87%) completed at least four (>60%) and 22 (49%) completed all six CG assessments. Median total CG scores remained stable over time but were lowest at day +7 (27, range 24-30) with recovery by day +100. Symptom burden was highest by day +10 (area under the curve, 2.9; range, 1.0-4.6) corresponding with the lowest median overall caloric intake (1624 kcal; range, 1345-2267). Higher serum/salivary melphalan levels correlated with higher patient-reported dysgeusia and lower caloric intake. Oral microbiota α-diversity was stable early and increased slightly by day +100. CONCLUSIONS: Assessment of dysgeusia by CG is feasible after auto-HCT. Most dysgeusia, symptom burden, and lowest caloric intake occurred during the blood count nadir. Higher melphalan concentrations correlated with more dysgeusia and poorer caloric intake. Future studies will aim to modulate melphalan exposure by PK-targeted dosing and characterize patient taste preferences to personalize diets for improved nutritional intake. LAY SUMMARY: Taste changes after cancer treatments are very common. We used chemical gustometry (taste testing) to study taste changes and to better understand why patients with multiple myeloma experience this symptom after autologous hematopoietic cell transplantation. We found that taste testing was feasible, taste changes peaked when blood counts were lowest, and most patients recovered their taste by 100 days after transplantation. Taste changes correlated with lower food intake and with higher levels of chemotherapy in the body. Future work will focus on using personalized chemotherapy doses to reduce taste changes and to match patients' individual taste preferences with their diets.

Photobiomodulation effects on head and neck squamous cell carcinoma (HNSCC) in an orthotopic animal model.

BACKGROUND: Photobiomodulation (PBM) has shown efficacy in preventing and treating cancer therapy-induced mucositis and dermatitis. However, there is contradictory information regarding the effect of PBM on (pre)malignant cells, which has led to questions regarding the safety of this technique. We address this issue using an orthotopic mouse model (Cal-33) with human squamous cell carcinoma of the oral cavity. METHODS: Mice with actively growing orthotopic Cal-33 head and neck carcinoma tumors were divided into 4 groups: control, PBM only, radiation therapy (RT) only, and PBM + RT. We performed three experiments: (1) PBM at 660 nm, 18.4 J/cm2, and 5 RT × 4 Gy doses delivered daily; (2) PBM at 660 nm, 18.4 J/cm2, and 1 × 15 Gy RT; and (3) PBM at 660 nm + 850 nm, 45 mW/cm2, 3.4 J/cm2, and 1 × 15 Gy RT. Mice were weighed daily and tumor volumes were evaluated by IVIS. Survival time was also evaluated. RESULTS: Animals treated with RT survived significantly longer and had significantly smaller tumor volume when compared with the control and PBM-only treatment groups. No significant differences were noted between the RT alone and PBM + RT groups in any of the experiments. CONCLUSION: Our results suggest that PBM at the utilized parameters does not provide protection to the tumor from the killing effects of RT.

Systematic review of natural and miscellaneous agents, for the management of oral mucositis in cancer patients and clinical practice guidelines - part 2: honey, herbal compounds, saliva stimulants, probiotics, and miscellaneous agents.

OBJECTIVE: To update the clinical practice guidelines for the management of oral mucositis (OM) that were developed by the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO). This part focuses on honey, herbal compounds, saliva stimulants, probiotics, and miscellaneous agents. METHODS: A systematic review was conducted by the Mucositis Study Group of MASCC/ISOO. The body of evidence for each intervention, in each clinical setting, was assigned an evidence level. The findings were added to the database used to develop the 2014 MASCC/ISOO clinical practice guidelines. Based on the evidence level, one of the following guidelines were determined: Recommendation, Suggestion, No Guideline Possible. RESULTS: A total of 78 papers were identified within the scope of this section, of which 49 were included in this review and merged with nine publications that were reported in the previous guidelines update. A new Suggestion was made for honey (combined topical and systemic delivery) for the prevention of OM in head and neck cancer patients receiving radiotherapy with or without chemotherapy. A new Suggestion clarified that chewing gum is not effective for the prevention of OM in pediatric patients with hematological or solid cancer treated with chemotherapy. No guideline was possible for other interventions. CONCLUSIONS: Numerous natural products and herbal remedies were studied for the management of OM. Of the agents reviewed in this systematic review, a guideline in favor was made for honey (combined topical and systemic), while a guideline against was made for chewing gum. Additional research is warranted to clarify the potential of other interventions.

Oral complications of cancer and cancer therapy: from cancer treatment to survivorship.

Answer questions and earn CME/CNE Oral complications resulting from cancer and cancer therapies cause acute and late toxicities that may be underreported, underrecognized, and undertreated. Recent advances in cancer treatment have led to changes in the incidence, nature, and severity of oral complications. As the number of survivors increases, it is becoming increasingly recognized that the aggressive management of oral toxicities is needed to ensure optimal long-term oral health and general well-being. Advances in care have had an impact on previously recognized oral complications and are leading to newly recognized adverse effects. Here, the authors briefly review advances in cancer therapy, including recent advances in surgery, oral care, radiation therapy, hematopoietic cell transplantation, and medical oncology; describe how these advances affect oral health; and discuss the frequent and/or severe oral health complications associated with cancer and cancer treatment and their effect upon long-term health. Although some of the acute oral toxicities of cancer therapies may be reduced, they remain essentially unavoidable. The significant impact of long-term complications requires increased awareness and recognition to promote prevention and appropriate intervention. It is therefore important for the primary oncologist to be aware of these complications so that appropriate measures can be implemented in a timely manner. Prevention and management is best provided via multidisciplinary health care teams, which must be integrated and communicate effectively in order to provide the best patient care in a coordinated manner at the appropriate time.

Taste disorders following cancer treatment: report of a case series.

PURPOSE: To present the findings of combined oral assessment and gustometry testing of a series of head and neck and hematologic malignancies in patients with self-reported taste change after cytotoxic therapies. METHODS: Patients with acute myeloid leukemia (AML), multiple myeloma (MM), and head and neck cancer (HNC) were evaluated for taste function. Chemical gustometry was conducted assessing chemosensory qualities that included sweet, sour, salty, bitter, umami, and spicy. NCI Common Terminology Criteria for Adverse Events (CTCAE) 4.0 and the Scale of Subjective Total Taste Acuity (STTA) were used to describe taste symptoms. Saliva flow rates were measured to determine the presence of hyposalivation. Patients were provided treatment trials for taste dysfunction, including zinc supplements, or medications that included clonazepam, megestrol acetate, and the cannabinoid dronabinol. RESULTS: According to STTA, hematology cases reported the incidence of grades 2 and 3 taste disturbances as 60% and 40%, respectively. For HNC patients, the incidence of grades 2 and 3 was 44% each. Gustometry tests confirmed dysgeusia in all patients evaluated. In the hematology group, 80% of patients exhibited a decrease in sweet taste perception, and no patients correctly identified umami taste. In the HNC group, most patients could not identify salt taste, 66% of patients reported "no sensation" with spicy taste, bitter taste was reduced in some, and increased or altered in others, while only one patient could identify umami taste. In the hematologic and HNC patient groups, 80% and 66% reported grade 2 dry mouth, respectively, according to CTCAE 4.0. After treatment for taste dysfunction, 71% of all patients in the present study reported improvements in taste function. CONCLUSIONS: Persisting dysgeusia in cancer survivors may be assessed by patient report and taste testing. The taste most affected in our patients was umami. Treatment trials with current interventions for dysgeusia appeared effective and should be considered in cancer survivors. Understanding taste and flavor function during and following cancer treatment is important in developing rational prospective preventive and interventional strategies.

Systematic review of natural and miscellaneous agents for the management of oral mucositis in cancer patients and clinical practice guidelines-part 1: vitamins, minerals, and nutritional supplements.

PURPOSE: To update the clinical practice guidelines for the use of natural and miscellaneous agents 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 of Oral Oncology (MASCC/ISOO). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. The findings were added to the database used to develop the 2014 MASCC/ISOO clinical practice guidelines. Based on the evidence level, the following guidelines were determined: Recommendation, Suggestion, and No Guideline Possible. RESULTS: A total of 78 papers were identified within the scope of this section, out of which 29 were included in this part, and were analyzed with 27 previously reviewed studies. A new Suggestion was made for oral glutamine for the prevention of OM in head and neck (H&N) cancer patients receiving radiotherapy with concomitant chemotherapy. The previous Recommendation against the use of parenteral glutamine for the prevention of OM in hematopoietic stem cell transplantation (HSCT) patients was re-established. A previous Suggestion for zinc to prevent OM in H&N cancer patients treated with radiotherapy or chemo-radiotherapy was reversed to No Guideline Possible. No guideline was possible for other interventions. CONCLUSIONS: Of the vitamins, minerals, and nutritional supplements studied for the management of OM, the evidence supports a Recommendation against parenteral glutamine in HSCT patients and a Suggestion in favor of oral glutamine in H&N cancer patients for the management of OM.

Unlocking the Complex Flavors of Dysgeusia after Hematopoietic Cell Transplantation.

Dysgeusia is a frequently occurring symptom after hematopoietic cell transplantation (HCT) that has important long-term effects on physical, nutritional, and immunologic recovery, as well as on quality of life. Despite the relevance of this symptom, the study of dysgeusia in patients undergoing HCT has been limited, owing in part to its complexity. In this article, we review normal taste function and its clinical evaluation, discuss how dysgeusia uniquely affects patients undergoing HCT, and examine distinct, transplantation-related contributors to dysgeusia that may help elucidate strategies to ultimately reduce this symptom burden after transplantation.

Oral and Dental Health in Head and Neck Cancer Patients.

A diagnosis of head and neck cancer (HNC) is typically followed by therapy that is associated with immediate and long-lasting toxic consequences. HNC patients' oral health needs may be complex and are best addressed in multidisciplinary collaborative teams including surgical, medical, and radiation oncologists, dental providers, nutrition, speech/swallow specialists, and physical therapists. Oral health maintenance also requires patient compliance and caregiver support. The role of dental providers begins prior to cancer diagnosis and continues through survivorship. This includes oral screening and health maintenance, management of common oral complications such as mucositis, pain, infection, salivary dysfunction, altered taste, and dental decay, as well as complex issues that include soft tissue fibrosis, osteoradionecrosis of the jaw, dysphagia, and recurrent/new primary malignancies. As the number of potential therapeutic interventions for HNC increase, so do the spectrum of side effects affecting the oral cavity, oropharynx, and dentition. Specific approaches to oral care must be tailored to the idiosyncrasies of the patient and his/her therapy and condition. Oral and dental care is impacted by the patient's oral and dental status prior to cancer therapy, as well as the specific cancer type, location, stage, and its treatment and potential comorbid conditions. Communication between the dental professional and the oncology team is required for appropriate therapy and is best accomplished by integrated healthcare teams.

Photobiomodulation therapy in the management of oral mucositis: search for the optimal clinical treatment parameters.

This commentary attempts to clarify the setting of photobiomodulation (BPM) therapy in the management of oral mucositis. The suggested dose range balances efficacy data with our current understanding about PBM safety. The literature about the molecular basis of photobiomodulation and its controversial relationship to malignant transformation is briefly presented.

Alcohol, microbiome, life style influence alcohol and non-alcoholic organ damage.

This paper is based upon the "8th Charles Lieber's Satellite Symposium" organized by Manuela G. Neuman at the Research Society on Alcoholism Annual Meeting, on June 25, 2016 at New Orleans, Louisiana, USA. The integrative symposium investigated different aspects of alcohol-induced liver disease (ALD) as well as non-alcohol-induced liver disease (NAFLD) and possible repair. We revealed the basic aspects of alcohol metabolism that may be responsible for the development of liver disease as well as the factors that determine the amount, frequency and which type of alcohol misuse leads to liver and gastrointestinal diseases. We aimed to (1) describe the immuno-pathology of ALD, (2) examine the role of genetics in the development of alcoholic hepatitis (ASH) and NAFLD, (3) propose diagnostic markers of ASH and non-alcoholic steatohepatitis (NASH), (4) examine age and ethnic differences as well as analyze the validity of some models, (5) develop common research tools and biomarkers to study alcohol-induced effects, 6) examine the role of alcohol in oral health and colon and gastrointestinal cancer and (7) focus on factors that aggravate the severity of organ-damage. The present review includes pre-clinical, translational and clinical research that characterizes ALD and NAFLD. Strong clinical and experimental evidence lead to recognition of the key toxic role of alcohol in the pathogenesis of ALD with simple fatty infiltrations and chronic alcoholic hepatitis with hepatic fibrosis or cirrhosis. These latter stages may also be associated with a number of cellular and histological changes, including the presence of Mallory's hyaline, megamitochondria, or perivenular and perisinusoidal fibrosis. Genetic polymorphisms of ethanol metabolizing enzymes and cytochrome p450 (CYP) 2E1 activation may change the severity of ASH and NASH. Other risk factors such as its co-morbidities with chronic viral hepatitis in the presence or absence of human deficiency virus were discussed. Dysregulation of metabolism, as a result of ethanol exposure, in the intestine leads to colon carcinogenesis. The hepatotoxic effects of ethanol undermine the contribution of malnutrition to the liver injury. Dietary interventions such as micro and macronutrients, as well as changes to the microbiota have been suggested. The clinical aspects of NASH, as part of the metabolic syndrome in the aging population, have been presented. The symposium addressed mechanisms and biomarkers of alcohol induced damage to different organs, as well as the role of the microbiome in this dialog. The microbiota regulates and acts as a key element in harmonizing immune responses at intestinal mucosal surfaces. It is known that microbiota is an inducer of proinflammatory T helper 17 cells and regulatory T cells in the intestine. The signals at the sites of inflammation mediate recruitment and differentiation in order to remove inflammatory inducers and promote tissue homeostasis restoration. The change in the intestinal microbiota also influences the change in obesity and regresses the liver steatosis. Evidence on the positive role of moderate alcohol consumption on heart and metabolic diseases as well on reducing steatosis have been looked up. Moreover nutrition as a therapeutic intervention in alcoholic liver disease has been discussed. In addition to the original data, we searched the literature (2008-2016) for the latest publication on the described subjects. In order to obtain the updated data we used the usual engines (Pub Med and Google Scholar). The intention of the eighth symposia was to advance the international profile of the biological research on alcoholism. We also wish to further our mission of leading the forum to progress the science and practice of translational research in alcoholism.

Photobiomodulation therapy in the management of chronic oral graft-versus-host disease.

AIM: Patients treated with allogeneic hematopoietic stem cell transplantation (HSCT) may experience oral complications associated with chronic graft-versus-host disease (cGVHD). These complications may significantly affect quality of life, even many years post-HSCT. Current treatment options for oral cGVHD are limited and often include steroid or other immunomodulatory medications, which may not adequately control the oral condition. A non-immunosuppressive intervention for symptomatic relief in oral cGVHD would thus be a welcome addition to the treatment paradigm. MATERIALS AND METHODS: We report seven cases of oral cGVHD that were treated with photobiomodulation therapy (PBM), previously known as low-level laser therapy (LLLT). Patients underwent at least two PBM treatments per week in addition to local treatment with steroids, and if on systemic therapies, these were either unchanged or dosage was reduced during the period of PBM therapy. Follow-up data is presented for 4 weeks of treatment. RESULTS: Oral pain, sensitivity, and dry mouth improved in most patients. These findings suggest PBM therapy may represent an additional approach for management of oral cGVHD, and suggest that controlled studies should be conducted to confirm the efficacy and safety of PBM therapy in oral cGVHD and to determine optimal PBM therapy protocols.

Effects of pre-radiation exposure to LLLT of normal and malignant cells.

PURPOSE: Low-level laser therapy (LLLT) efficacy for the prevention of cancer treatment-induced oral mucositis (OM) has been amply described. However, potential protection of malignant cells remains a legitimate concern for clinicians. We tested LLLT-induced protection from ionizing radiation killing in both malignant and normal cells. METHODS: We treated six groups each of normal human lymphoblasts (TK6) and human leukemia cells (HL60) with He-Ne LLLT (632.8 nm, 35 mW, CW, 1 cm(2), 35 mW/cm(2) for 3-343 s, 0.1-12 J/cm(2)) prior to exposure to ionizing radiation (IR). Cells were then incubated and counted daily to determine their survival. Optimization of IR dose and incubation time was established prior to testing the effect of LLLT. RESULTS: Growth curves for both cell lines showed significant declines after exposure to 50-200 cGy IR when compared to controls. Pre-radiation exposure to LLLT (4.0 J/cm(2)) followed by 1-h incubation blocked this decline in TK6 but not in HL60 cells. The latter cells were sensitized to the killing effects of IR in a dose-dependent manner. CONCLUSION: This study shows that pre-IR LLLT treatment results in a differential response of normal vs. malignant cells, suggesting that LLLT does not confer protection and may even sensitize cancer cells to IR killing.

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.

PURPOSE: There is a large body of evidence supporting the efficacy of low level laser therapy (LLLT), more recently termed photobiomodulation (PBM), for the management of oral mucositis (OM) in patients undergoing radiotherapy for head and neck cancer (HNC). Recent advances in PBM technology, together with a better understanding of mechanisms involved, may expand the applications for PBM in the management of other complications associated with HNC treatment. This article (part 1) describes PBM mechanisms of action, dosimetry, and safety aspects and, in doing so, provides a basis for a companion paper (part 2) which describes the potential breadth of potential applications of PBM in the management of side-effects of (chemo)radiation therapy in patients being treated for HNC and proposes PBM parameters. METHODS: This study is a narrative non-systematic review. RESULTS: We review PBM mechanisms of action and dosimetric considerations. Virtually, all conditions modulated by PBM (e.g., ulceration, inflammation, lymphedema, pain, fibrosis, neurological and muscular injury) are thought to be involved in the pathogenesis of (chemo)radiation therapy-induced complications in patients treated for HNC. The impact of PBM on tumor behavior and tumor response to treatment has been insufficiently studied. In vitro studies assessing the effect of PBM on tumor cells report conflicting results, perhaps attributable to inconsistencies of PBM power and dose. Nonetheless, the biological bases for the broad clinical activities ascribed to PBM have also been noted to be similar to those activities and pathways associated with negative tumor behaviors and impeded response to treatment. While there are no anecdotal descriptions of poor tumor outcomes in patients treated with PBM, confirming its neutrality with respect to cancer responsiveness is a critical priority. CONCLUSION: Based on its therapeutic effects, PBM may have utility in a broad range of oral, oropharyngeal, facial, and neck complications of HNC treatment. Although evidence suggests that PBM using LLLT is safe in HNC patients, more research is imperative and vigilance remains warranted to detect any potential adverse effects of PBM on cancer treatment outcomes and survival.

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.

PURPOSE: There is a large body of evidence supporting the efficacy of low-level laser therapy (LLLT), more recently termed photobiomodulation (PBM) for the management of oral mucositis (OM) in patients undergoing radiotherapy for head and neck cancer (HNC). Recent advances in PBM technology, together with a better understanding of mechanisms involved and dosimetric parameters may lead to the management of a broader range of complications associated with HNC treatment. This could enhance patient adherence to cancer therapy, and improve quality of life and treatment outcomes. The mechanisms of action, dosimetric, and safety considerations for PBM have been reviewed in part 1. Part 2 discusses the head and neck treatment side effects for which PBM may prove to be effective. In addition, PBM parameters for each of these complications are suggested and future research directions are discussed. METHODS: Narrative review and presentation of PBM parameters are based on current evidence and expert opinion. RESULTS: PBM may have potential applications in the management of a broad range of side effects of (chemo)radiation therapy (CRT) in patients being treated for HNC. For OM management, optimal PBM parameters identified were as follows: wavelength, typically between 633 and 685 nm or 780-830 nm; energy density, laser or light-emitting diode (LED) output between 10 and 150 mW; dose, 2-3 J (J/cm(2)), and no more than 6 J/cm(2) on the tissue surface treated; treatment schedule, two to three times a week up to daily; emission type, pulsed (<100 Hz); and route of delivery, intraorally and/or transcutaneously. To facilitate further studies, we propose potentially effective PBM parameters for prophylactic and therapeutic use in supportive care for dermatitis, dysphagia, dry mouth, dysgeusia, trismus, necrosis, lymphedema, and voice/speech alterations. CONCLUSION: PBM may have a role in supportive care for a broad range of complications associated with the treatment of HNC with CRT. The suggested PBM irradiation and dosimetric parameters, which are potentially effective for these complications, are intended to provide guidance for well-designed future studies. It is imperative that such studies include elucidating the effects of PBM on oncology treatment outcomes.

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

BACKGROUND: Mucositis is a highly significant, and sometimes dose-limiting, toxicity of cancer therapy. 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 mucositis. METHODS: A literature search was conducted to identify eligible published articles, based on predefined inclusion/exclusion criteria. Each article was independently reviewed by 2 reviewers. Studies were rated according to the presence of major and minor flaws as per previously published criteria. The body of evidence for each intervention, 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 literature search identified 8279 papers, 1032 of which were retrieved for detailed evaluation based on titles and abstracts. Of these, 570 qualified for final inclusion in the systematic reviews. Sixteen new guidelines were developed for or against the use of various interventions in specific treatment settings. In total, the MASCC/ISOO Mucositis Guidelines now include 32 guidelines: 22 for oral mucositis and 10 for gastrointestinal mucositis. This article describes these updated guidelines. CONCLUSIONS: The updated MASCC/ISOO Clinical Practice Guidelines for mucositis will help clinicians provide evidence-based management of mucositis secondary to cancer therapy.

Appropriate and necessary oral care for people with cancer: guidance to obtain the right oral and dental care at the right time.

PURPOSE: The identification of experienced and knowledgeable dental specialists to provide appropriate oral care for cancer patients, as well as the integration of this care within general oncology management, may be a challenge. This paper discusses the general and additional requirements for dental care providers to support the cancer patient and provide prevention and/or treatment for oral complications of cancer therapy. METHODS: We performed a literature review of specific issues regarding the oral cavity and adjacent structures in the cancer patient, including detection and early diagnosis of oral malignancy. We incorporated the systemic effects of cancer and its therapy that affect oral disease and treatment. We present a summary of how to seek expert dental care for cancer patients and for referral from the dental and medical community. RESULTS: Due to the complexity conferred by the disease and its treatment, cancer patients require educated, experienced dentists for treatment and/or prevention of oral-related morbidity. Correct diagnosis and evidence-based prophylactic and therapeutic oral care can significantly improve patient quality of life and reduce morbidity and healthcare costs. CONCLUSIONS: The knowledge and expertise of dental professionals regarding prevention/treatment of complications and secondary malignant lesions in cancer patients are critical. Integration of oral care with the oncology care and in survivors requires effective communication between dental and medical providers beginning ideally at diagnosis. These clinicians may be identified at the cancer center, nearby hospital dental programs, and, less commonly, in the community.

Bisphosphonates and hip and nontraumatic subtrochanteric femoral fractures in the Veterans Health Administration.

PURPOSE: Subtrochanteric femoral shaft fractures after little or no trauma have been reported in long-term users of bisphosphonates, but risks relative to hip fracture protective effects and among men are not clear. We examined associations between bisphosphonate use and nontraumatic subtrochanteric (NTST) femoral fractures and hip fractures in the Veterans Health Administration. METHODS: This retrospective cohort study was conducted using 1998-2007 Veterans Health Administration electronic medical records data on 78,155 individuals who had a fragility fracture at age 45 years or older. Time-to-event analysis examined associations of bisphosphonates with risk of NTST femoral fracture and, separately, hip fracture, controlling for sociodemographics, medications, and comorbid medical conditions. RESULTS: The cohort had a mean age 66.5 years (32.5% were ≥75 years old) at the time of their first fracture, and 69.3% were observed for 6 or more years; only 11.8% were prescribed bisphosphonates during observation. During follow-up, 408 had an NTST femoral second fracture, and 1584 had a hip second fracture. Compared with those never on bisphosphonates, the adjusted hazard ratio for NTST femoral second fracture among patients on 4 years of therapy or longer was 0.40 (95% confidence interval, 0.16-0.97) and for hip second fracture was 0.38 (95% confidence interval, 0.24-0.61). CONCLUSIONS: Bisphosphonate treatment in this high-risk cohort was infrequent with few long-term users, limiting power to assess long-term effects. Nontraumatic subtrochanteric femoral fractures were uncommon, and longer bisphosphonate use was associated with lower (not higher) risk. In men, risks of NTST femoral fractures associated with bisphosphonate treatment may be low in contrast to substantial protective benefits for hip fracture.

Systematic review of natural agents for the management of oral mucositis in cancer patients.

PURPOSE: The aim of this study was to review the available literature and define clinical practice guidelines for the use of natural agents for the prevention and treatment of oral mucositis. 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. The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, and no guideline possible. RESULTS: A total of 49 papers across 15 interventions were examined. A new suggestion was developed in favor of systemic zinc supplements administered orally in the prevention of oral mucositis in oral cancer patients receiving radiation therapy or chemoradiation (Level III evidence). A recommendation was made against the use of intravenous glutamine for the prevention of oral mucositis in patients receiving high-dose chemotherapy prior to hematopoietic stem cell transplant (Level II evidence). No guideline was possible for any other agent, due to inadequate and/or conflicting evidence. CONCLUSIONS: Of the various natural agents reviewed here, the available evidence supported a guideline only for two agents: a suggestion in favor of zinc and a recommendation against glutamine, in the treatment settings listed above. Well-designed studies of other natural agents are warranted.

Systematic review of miscellaneous agents for the management of oral mucositis in cancer patients.

PURPOSE: The aim of this systematic review was to analyze the available literature and define clinical practice guidelines for the use of the following agents for the prevention and treatment of oral mucositis (OM): allopurinol, midline mucosa-sparing radiation blocks, payayor, pentoxifylline, timing of radiation therapy (RT) (morning versus late afternoon), pilocarpine, bethanechol, chewing gum, propantheline, and tetrachlorodecaoxide. 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). The body of evidence for each intervention, in each cancer treatment setting, was assigned an evidence level. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, no guideline possible. RESULTS: A total of 32 papers across 10 interventions were examined. New suggestions were developed against the use of systemic pilocarpine administered orally for prevention of OM during RT in head and neck cancer patients and in patients receiving high-dose chemotherapy, with or without total body irradiation, prior to hematopoietic stem cell transplantation. A suggestion was also made against the use of systemic pentoxifylline administered orally for the prevention of OM in patients undergoing bone marrow transplantation. No guideline was possible for any other agent reviewed due to inadequate and/or conflicting evidence. CONCLUSIONS: None of the agents reviewed was determined to be effective for the prevention or treatment of OM. Two agents, pilocarpine and pentoxifylline, were determined to be ineffective, in the populations listed above. Additional well-designed research is needed on other interventions.