Long-Term Analysis of Resilience of the Oral Microbiome in Allogeneic Stem Cell Transplant Recipients.

Stem cell transplantation (SCT) is associated with oral microbial dysbiosis. However, long-term longitudinal data are lacking. Therefore, this study aimed to longitudinally assess the oral microbiome in SCT patients and to determine if changes are associated with oral mucositis and oral chronic graft-versus-host disease. Fifty allogeneic SCT recipients treated in two Dutch university hospitals were prospectively followed, starting at pre-SCT, weekly during hospitalization, and at 3, 6, 12, and 18 months after SCT. Oral rinsing samples were taken, and oral mucositis (WHO score) and oral chronic graft-versus-host disease (NIH score) were assessed. The oral microbiome diversity (Shannon index) and composition significantly changed after SCT and returned to pre-treatment levels from 3 months after SCT. Oral mucositis was associated with a more pronounced decrease in microbial diversity and with several disease-associated genera, such as Mycobacterium, Staphylococcus, and Enterococcus. On the other hand, microbiome diversity and composition were not associated with oral chronic graft-versus-host disease. To conclude, dysbiosis of the oral microbiome occurred directly after SCT but recovered after 3 months. Diversity and composition were related to oral mucositis but not to oral chronic graft-versus-host disease.

A randomized controlled trial of manual versus powered tooth brushing during haematopoietic stem cell transplantation.

AIM: To compare manual and powered tooth brushing (MT and PT) with respect to patient compliance to brushing frequency advice, plaque removal and severity of oral mucositis (OM) in patients undergoing hematopoietic stem cell transplantation (HSCT) after high-dose chemotherapy. MATERIALS & METHODS: A randomized controlled trial was conducted. Forty-six patients scheduled to receive myeloablative conditioning regimen before autologous HSCT were included and randomly assigned to control (MT, n = 23) or test (PT, n = 23) groups. Starting at day 1 (day of hospital admission for HSCT), brushing frequency (patient recorded diary), plaque scores (Plaque Control Index) and oral mucositis (Oral Mucositis Nursing Index) were recorded daily. Data for days 1 to 17 were analysed using regression analysis and general linear models. RESULTS: Few patients maintained 4 times per day brushing, but most brushed at least 2 times per day throughout the study. In PT, overall plaque scores were lower by 6.98% (p = .006) as compared to MT. No differences were seen in OM scores between the groups (p = .968). A small but significant positive correlation was found between plaque scores and OM severity: R2 =0.15 (p < .01). CONCLUSIONS: Powered tooth brushing resulted in lower plaque scores, but was not associated with reduced OM severity. Individual plaque scores were positively related to OM severity.

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

PURPOSE: To update the 2013 Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) clinical practice guidelines on oral cryotherapy for the management of oral mucositis (OM) caused by cancer therapies. METHODS: A systematic review was conducted by the Mucositis Study Group of MASCC/ISOO. The evidence for each intervention for specific cancer treatment modalities was assigned a level of evidence (LoE). The findings were added to the database used to develop the 2013 MASCC/ISOO clinical practice guidelines. Based on the LoE, the guidelines were set as: recommendation, suggestion, or no guideline possible. RESULTS: A total of 114 papers were identified: 44 from PubMed and 70 from Web of Science. After abstract triage and merging with the 2013 database, 36 papers were reviewed. The LoE for prevention of OM with oral cryotherapy in patients undergoing autologous hematopoietic stem cell transplant using high-dose melphalan conditioning protocols was upgraded, and the guideline changed to recommendation. Additionally, the recommendation for prevention of OM with oral cryotherapy in patients receiving bolus 5-fluorouracil for the treatment of solid tumors was confirmed. No guidelines were possible for other clinical settings. CONCLUSIONS: The evidence supports recommendations for the use of oral cryotherapy for the prevention of OM for either (i) patients undergoing autologous hematopoietic stem cell transplant with high-dose melphalan conditioning protocols or (ii) patients receiving bolus 5-fluorouracil chemotherapy.

Microbial changes in relation to oral mucositis in autologous hematopoietic stem cell transplantation recipients.

The aim of this prospective, two center study was to investigate the dynamics of the microbial changes in relation to the development of ulcerative oral mucositis in autologous SCT (autoSCT) recipients. Fifty-one patients were diagnosed with multiple myeloma and treated with high-dose melphalan followed by autoSCT. They were evaluated before, three times weekly during hospitalization, and three months after autoSCT. At each time point an oral rinse was collected and the presence or absence of ulcerative oral mucositis (UOM) was scored (WHO scale). Oral microbiome was determined by using 16S rRNA amplicon sequencing and fungal load by qPCR. Twenty patients (39%) developed UOM. The oral microbiome changed significantly after autoSCT and returned to pre-autoSCT composition after three months. However, changes in microbial diversity and similarity were more pronounced and rapid in patients who developed UOM compared to patients who did not. Already before autoSCT, different taxa discriminated between the 2 groups, suggesting microbially-driven risk factors. Samples with high fungal load (>0.1%) had a significantly different microbial profile from samples without fungi. In conclusion, autoSCT induced significant and reversible changes in the oral microbiome, while patients who did not develop ulcerative oral mucositis had a more resilient microbial ecosystem.

Salivary Changes before and after Hematopoietic Stem Cell Transplantation: A Systematic Review.

Severe oral problems, including oral mucositis (OM) and xerostomia, often occur after conditioning therapy for hematopoietic stem cell transplantation (HSCT). Saliva plays a major role in protecting the oral mucosa and teeth. Alterations in salivary flow rate or salivary components resulting in decreased salivary defence mechanisms may affect oral/mucosal health and may influence the severity of OM. A systematic review was conducted to assess the current scientific knowledge on changes in salivary function and composition before and after HSCT. All English or Dutch articles examining salivary flow rate or salivary components before and after HSCT were included after title/abstract selection by 2 independent reviewers (weighted κ = .91). After quality assessment and exclusion of all research groups with both children age <14 years and adults, 33 articles were included for data analysis. Overall, the salivary flow rate was decreased at several days and months after HSCT. Although several salivary components were studied, most components were examined in only 1 or 2 studies with different patient populations or at different time points after HSCT. At 7 days after HSCT, albumin and proinflammatory cytokines were increased, whereas secretory IgA and components of the salivary antioxidant system were decreased. Secretory IgA levels were still reduced at 1 month after HSCT but returned to pre-HSCT values at 6 months after HSCT. Lactoferrin, secretory leukocyte protease inhibitor, and ß2-microglobulin levels were increased at 6 months after HSCT. Our findings show that changes in saliva reflect an inflammatory response occurring immediately after HSCT, followed by evidence of increased salivary antimicrobial defense mechanisms by 6 months after HSCT.

Physical exercise prior to hematopoietic stem cell transplantation: A feasibility study.

PURPOSE: This study explores the feasibility and preliminary effectiveness of an exercise program in people scheduled for hematopoietic stem cell transplantation (HSCT). METHODS: In this controlled clinical trial, we compare pre-transplantation exercise to no exercise in the waiting period for an allogeneic of autologous HSCT. The supervised individually tailored exercise program (4-6 weeks) consisted of aerobic endurance, muscle strength, and relaxation exercises, administered twice a week in the period prior to HSCT. Feasibility was determined based on inclusion rate, attrition rate, adherence to intervention, safety, and satisfaction (0-10). Preliminary effectiveness was determined primarily by self-perceived physical functioning, quality of life (QOL), and fatigue. Secondary outcomes were global perceived effect (GPE), blood counts, hospital stay, and physical fitness. RESULTS: Forty-six patients were eligible, of whom 29 (69%) participated: 14 in the intervention group and 15 in the control group. The adherence rate to training was 69%. No adverse events or injuries occurred. Satisfaction of training conditions was high (mean 9.2 ± 1.3). Positive (follow-up) trends in favor of the intervention group were found for self-perceived physical functioning, QOL, fatigue, GPE, blood counts, and hospital stay. CONCLUSION: Exercise prior to HSCT is safe and feasible, and positive trends suggest favorable preliminary effectiveness. Adherence to the exercise program needs to be optimized in a future trial.

Basic oral care for hematology-oncology patients and hematopoietic stem cell transplantation recipients: a position paper from the joint task force of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and the European Society for Blood and Marrow Transplantation (EBMT).

PURPOSE: Hematology-oncology patients undergoing chemotherapy and hematopoietic stem cell transplantation (HSCT) recipients are at risk for oral complications which may cause significant morbidity and a potential risk of mortality. This emphasizes the importance of basic oral care prior to, during and following chemotherapy/HSCT. While scientific evidence is available to support some of the clinical practices used to manage the oral complications, expert opinion is needed to shape the current optimal protocols. METHODS: This position paper was developed by members of the Oral Care Study Group, Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology (MASCC/ISOO) and the European Society for Blood and Marrow Transplantation (EBMT) in attempt to provide guidance to the health care providers managing these patient populations. RESULTS: The protocol on basic oral care outlined in this position paper is presented based on the following principles: prevention of infections, pain control, maintaining oral function, the interplay with managing oral complications of cancer treatment and improving quality of life. CONCLUSION: Using these fundamental elements, we developed a protocol to assist the health care provider and present a practical approach for basic oral care. Research is warranted to provide robust scientific evidence and to enhance this clinical protocol.

Oral complaints and dental care of haematopoietic stem cell transplant patients: a qualitative survey of patients and their dentists.

PURPOSE: Little is known about the understanding of the oral and dental needs of haematopoietic stem cell transplant (HSCT) patients or about dentists' views and experiences regarding this patient group. This information is essential if we want to improve the standard of peri-HSCT dental care. The primary objective of this qualitative survey was to explore the following: (1) The understanding of dental care pre- and post-HSCT (2) The subjective oral complaints of HSCT patients both short- and long-term (3) The relationship of these oral complaints to the severity of oral mucositis during hospitalization The secondary objective was to explore the opinions of dentists regarding dental care before and after HSCT. PATIENTS AND METHODS: All adult patients who survived HSCT at the Radboud University Medical Centre between 2010 and 2011 (n = 101) received a questionnaire. During hospitalization, mucositis scores were recorded daily in the patient's chart. The patients' dentist (n = 88) was also sent a questionnaire after permission of the patient. RESULTS: Ninety-six out of 101 patients (95%) responded. The average period since HSCT was 19 months (range 8-31 months). The overall mean maximum mucositis score was 6.6 (sd = 3.3). Only eight patients reported not having visited a dentist pre-HSCT. The majority of the patients (59%) reported short-term oral complaints, and 28% reported long-term oral complaints. Fifty-two dentists responded (59%). Nine had not performed pre-HSCT screening and eight dentists reported screening their patients but could not complete the necessary treatments. Only 44 dentists succeeded in completing the required treatments. The most important advice of the dentist was to reinforce the importance of regular dental care. CONCLUSION: Most patients report short-term and/or long-term oral complaints after HSCT. Most dentists stress the importance of regular dental care before and after HSCT but report not being familiar with the particular dental care needs of this patient group. The high response rate and the high rate of HSCT-related oral complaints emphasize the need of further research in this area.

Systematic review of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the management of oral mucositis in cancer patients.

PURPOSE: The aim of this project was to develop clinical practice guidelines on the use of antimicrobials, mucosal coating agents, anesthetics, and analgesics for the prevention and management of oral mucositis (OM) in cancer patients. METHODS: A systematic review of the available literature was conducted. The body of evidence for the use of each agent, in each setting, was assigned a level of evidence. Based on the evidence level, one of the following three guideline determinations was possible: recommendation, suggestion, or no guideline possible. RESULTS: A recommendation was developed in favor of patient-controlled analgesia with morphine in hematopoietic stem cell transplant (HSCT) patients. Suggestions were developed in favor of transdermal fentanyl in standard dose chemotherapy and HSCT patients and morphine mouth rinse and doxepin rinse in head and neck radiation therapy (H&N RT) patients. Recommendations were developed against the use of topical antimicrobial agents for the prevention of mucositis. These included recommendations against the use of iseganan for mucositis prevention in HSCT and H&N RT and against the use of antimicrobial lozenges (polymyxin-tobramycin-amphotericin B lozenges/paste and bacitracin-clotrimazole-gentamicin lozenges) for mucositis prevention in H&N RT. Recommendations were developed against the use of the mucosal coating agent sucralfate for the prevention or treatment of chemotherapy-induced or radiation-induced OM. No guidelines were possible for any other agent due to insufficient and/or conflicting evidence. CONCLUSION: Additional well-designed research is needed on prevention and management approaches for OM.

Physical exercise for patients undergoing hematopoietic stem cell transplantation: systematic review and meta-analyses of randomized controlled trials.

BACKGROUND: The treatment-related burden for patients undergoing hematopoietic stem cell transplantation (HSCT) may be relieved by physical exercises. PURPOSE: The purpose of this study was to summarize and analyze the evidence provided by randomized controlled trials (RCTs) on physical exercise interventions among patients with cancer undergoing HSCT. DATA SOURCES: PubMed, CINAHL, EMBASE, the Cochrane Library, and PEDro were searched for relevant RCTs up to October 1, 2011. STUDY SELECTION: Two reviewers screened articles on inclusion criteria and indentified relevant RCTs. DATA EXTRACTION: Two authors assessed the selected articles for risk of bias. Data extraction was performed by 1 reviewer. Meta-analyses were undertaken to estimate the outcomes quality of life (QOL), psychological well-being and distress, and fatigue. DATA SYNTHESIS: Eleven studies were included, with study populations consisting of recipients undergoing either an allogeneic or autologous HSCT (n=734). Four studies had low risk of bias. The exercise interventions were performed before, during, and after hospitalization for the HSCT. Different exercise programs on endurance, resistance and/or activities of daily living training, progressive relaxation, and stretching were used. Meta-analyses showed that exercise during hospitalization led to a higher QOL (weighted mean difference=8.72, 95% confidence interval=3.13, 14.31) and less fatigue (standardized mean difference=0.53, 95% confidence interval=0.16, 0.91) in patients with an allogeneic HSCT at the moment of discharge from the hospital. No marked effects were found for psychological well-being and distress. Individual study results suggested significant positive effects on QOL, fatigue, psychological well-being and distress, and physical functioning. LIMITATIONS: Prevalent shortcomings in the included studies were the heterogeneity among studies and the lack of blinding of participants, personnel, and outcome assessment. CONCLUSIONS: The results suggest that recipients of HSCT may benefit from physical exercise.

Continuous non-invasive monitoring of the skin temperature of HSCT recipients.

GOALS OF WORK: Empirical antibiotic therapy usually started in patients who are neutropenic following treatment with cytostatic chemotherapy for a haematological malignancy as soon as fever develops to forestall fulminant sepsis. Hence, accurate and timely detection of fever is crucial to the successful management of infectious complications in these patients. We report an investigation of the feasibility and validity of continuous non-invasive body temperature measurement. PATIENTS AND METHODS: The feasibility of non-invasive continuous measurement of the skin temperature was investigated using the Propaq(R) device in a cohort of 33 patients receiving an allogeneic HSCT who were all at risk of developing a febrile episode. Non-invasive continuous measurement of the skin temperature (CST) was compared with a standard episodic axillary temperature measurement (EAT) five times daily using a Terumo(R) device. The study period entailed monitoring during the 10 or 12 days that profound neutropenia was expected to be present. MAIN RESULTS: Measuring the skin temperature continuously and accurately by using the Propaq(R) was feasible. The CST correlated well with the EAT measurements (Pearson r = 0.782). Compared to EAT, the start of empirical therapy could be started 2.5 h earlier when relying on continuous measurements than was possible with EAT. CONCLUSION: Continuous skin temperature measurements are feasible and valid compared to the conventional temperature measurement and may improve the management of infections by earlier detection of fever in neutropenic patients.

A review of quality assessment of the methodology used in guidelines and systematic reviews on oral mucositis.

AIMS AND OBJECTIVES: The objective of this study was to identify and to assess the quality of evidence-based guidelines and systematic reviews we used in the case of oral mucositis, to apply general quality criteria for the prevention and treatment of oral mucositis in patients receiving chemotherapy, radiotherapy or both. DESIGN: Systematic review. METHODS: Literature searches were carried out in several electronic databases and websites. Publications were included if they concerned oral mucositis involving adults treated for cancer and had been published after 1 January 2000. As far as systematic reviews were concerned, the article had to report a search strategy, if the search was minimally conducted in the database PubMed or Medline and the articles included in the review were subjected to some kind of methodological assessment. The Appraisal of Guidelines for Research and Education (AGREE) instrument was used to assess the quality of the guidelines and the Overview Quality Assessment Questionnaire (OQAQ) was used for the quality of systematic reviews. RESULTS: Thirty-one articles met the inclusion criteria of which 11 were guidelines and 20 were systematic reviews. Nine of the 11 guidelines did not explicitly describe how they identified, selected and summarised the available evidence. Reviews suffered from lack of clarity, for instance, in performing a thorough literature search. The quality varied among the different guidelines and reviews. CONCLUSION: Most guidelines and systematic reviews had serious methodological flaws. RELEVANCE TO CLINICAL PRACTICE: There is a need to improve the methodological quality of guidelines and systematic reviews for the prevention and treatment of oral mucositis if they are to be used in clinical practice.

Providing oral care in haematological oncology patients: nurses' knowledge and skills.

In the international literature, the most commonly recommended intervention for managing oral mucositis is good oral care, assuming that nurses have sufficient knowledge and skills to perform oral care correctly. The aim of the present study was to investigate if knowledge and skills about oral care improve when education in oral care is provided to nurses in charge of patients who are at risk of oral mucositis. This intervention study consists of a baseline test on the knowledge and skills of nurses of the haematology wards of two different hospitals. Oral care education sessions were given in one hospital and follow-up tests were performed in both hospitals. Nursing records were examined and observations of nurses performing oral care were made at baseline as well as at follow-up. The results show significant differences in the scores for knowledge and skills before and after the education, whereas there was no difference in scores at the two points in time for the comparison hospital, where no education had taken place. The records test showed no differences at baseline or follow-up for the two groups. Observations showed that nurses who followed the education session implemented the oral care protocol considerably better than those who did not attended. Education in oral care has a positive influence on the knowledge and skills of nurses who care for patient at risk of oral mucositis, but not on the quality of oral care documentation.

Guidelines for the assessment of oral mucositis in adult chemotherapy, radiotherapy and haematopoietic stem cell transplant patients.

Oral mucositis (OM) is a serious consequence of some chemotherapy and radiotherapy regimens. A number of reliable instruments are available to assess OM, but none are universally accepted. A unique collaboration of multi-disciplinary experts from Europe was formed to make recommendations on OM assessment, based on a systematic literature review and the experts' experience. The main recommendations are listed. There should be a comprehensive baseline assessment. OM should be frequently assessed using a standardised instrument, or a combination of instruments. Physical, functional and subjective changes should be measured. Subjective measures should be assessed prior to any physical examination. The use of pain scoring, in particular patient self-reporting, should form part of any OM assessment. Any assessment instrument should be validated, easy to use and comfortable for the patient. Training of, and monitoring in, the use of the instrument is vital to successful monitoring of OM.

Management of oral mucositis at European transplantation centres.

Oral mucositis (OM), which occurs in many patients with hematologic malignancies treated with high-dose therapy and stem cell transplantation, is associated with substantial clinical, economic, and quality-of-life (QOL) consequences. It has been associated with an increased need for total parenteral nutrition and opioid analgesics, prolonged hospital stays, and increased risk of infection. The research subgroup of the European Group for Blood and Marrow Transplantation Nurses Group surveyed nurses at transplantation centres for their thoughts about the clinical, QOL, and economic consequences of OM; tools for assessing OM; strategies for preventing and treating OM; and the need for the development and implementation of treatment guidelines. The responses from 46 centres, in 16 countries, indicated that most nurses (91%) believe OM has a large effect on patients' QOL. Nurses are not highly satisfied with current treatments for OM, but they believe the discomfort is reduced with oral care protocols and mouthwashes. Oral mucositis is routinely and frequently assessed, however there are inconsistencies in how it is managed. Most centres used unpublished, centre-specific guidelines, and the survey found that most nurses agreed that published national guidelines would be valuable for standardising the assessment and management of OM.