Monique Stokman

Rescue of Salivary Gland Function after Stem Cell Transplantation in Irradiated Glands

Head and neck cancer is the fifth most common malignancy and accounts for 3% of all new cancer cases each year. Despite relatively high survival rates, the quality of life of these patients is severely compromised because of radiation-induced impairment of salivary gland function and consequential xerostomia (dry mouth syndrome). In this study, a clinically applicable method for the restoration of radiation-impaired salivary gland function using salivary gland stem cell transplantation was developed. Salivary gland cells were isolated from murine submandibular glands and cultured in vitro as salispheres, which contained cells expressing the stem cell markers Sca-1, c-Kit and Musashi-1. In vitro, the cells differentiated into salivary gland duct cells and mucin and amylase producing acinar cells. Stem cell enrichment was performed by flow cytrometric selection using c-Kit as a marker. In vitro, the cells differentiated into amylase producing acinar cells. In vivo, intra-glandular transplantation of a small number of c-Kit+ cells resulted in long-term restoration of salivary gland morphology and function. Moreover, donor-derived stem cells could be isolated from primary recipients, cultured as secondary spheres and after re-transplantation ameliorate radiation damage. Our approach is the first proof for the potential use of stem cell transplantation to functionally rescue salivary gland deficiency.

Preventive Intervention Possibilities in Radiotherapy- and Chemotherapy-induced Oral Mucositis: Results of Meta-analyses

The aim of these meta-analyses was to evaluate the effectiveness of interventions for the prevention of oral mucositis in cancer patients treated with head and neck radiotherapy and/or chemotherapy, with a focus on randomized clinical trials. A literature search was performed for reports of randomized controlled clinical studies, published between 1966 and 2004, the aim of which was the prevention of mucositis in cancer patients undergoing head and neck radiation, chemotherapy, or chemoradiation. The control group consisted of a placebo, no intervention, or another intervention group. Mucositis was scored by either the WHO, the National Cancer Institute-Common Toxicity Criteria (NCI-CTC) score, or the absence or presence of ulcerations, or the presence or absence of grades 3 and 4 mucositis. The meta-analyses included 45 studies fulfilling the inclusion criteria, in which 8 different interventions were evaluated: i.e., local application of chlorhexidine; iseganan; PTA (polymyxin E, tobramycine, and amphotericin B); granulocyte macrophage-colony-stimulating factor/granulocyte colony-stimulating factor (GM-CSF/G-CSF); oral cooling; sucralfate and glutamine; and systemic administration of amifostine and GM-CSF/G-CSF. Four interventions showed a significant preventive effect on the development or severity of oral mucositis: PTA with an odds ratio (OR) = 0.61 (95% confidence interval [CI], 0.39–0.96); GM-CSF, OR = 0.53 (CI: 0.33–0.87); oral cooling, OR = 0.3 (CI: 0.16–0.56); and amifostine, OR = 0.37 (CI: 0.15–0.89). To date, no single intervention completely prevents oral mucositis, so combined preventive therapy strategies seem to be required to ensure more successful outcomes.

Parotid and submandibular/sublingual salivary flow during high dose radiotherapy

It was studied whether differences in acute radiosensitivity exist between parotid and submandibular/sublingual glands. The results revealed that salivary flow rates decreased dramatically during the first 2 weeks of radiotherapy. Neither recovery nor significant differences were observed between the production of saliva from the parotid and submandibular/sublingual glands during the 13 weeks observation period.

A systematic review of dental disease in patients undergoing cancer therapy

IntroductionThis purpose of this systematic review was to evaluate the literature and update our current understanding of the impact of present cancer therapies on the dental apparatus (teeth and periodontium) since the 1989 NIH Development Consensus Conference on the Oral Complications of Cancer Therapies.Review methodA systematic literature search was conducted with assistance from a research librarian in the databases MEDLINE/PubMed and EMBASE for articles published between 1 January 1990 and 31 December 2008. Each study was independently assessed by two reviewers. Taking into account predetermined quality measures, a weighted prevalence was calculated for the prevalence of dental caries, severe gingival disease, and dental infection. Data on DMFT/dmft, DMFS/dmfs, plaque, and gingival indexes were also gathered. The level of evidence, recommendation, and guideline (if possible) were given for published preventive and management strategies.ResultsSixty-four published papers between 1990 and 2008 were reviewed. The weighted overall prevalence of dental caries was 28.1%. The overall DMFT for patients who were post-antineoplastic therapy was 9.19 (SD, 7.98; n = 457). The overall plaque index for patients who were post-antineoplastic therapy was 1.38 (SD, 0.25; n = 189). The GI for patients who were post-chemotherapy was 1.02 (SD, 0.15; n = 162). The weighted prevalence of dental infections/abscess during chemotherapy was reported in three studies and was 5.8%.ConclusionsPatients who were post-radiotherapy had the highest DMFT. The use of fluoride products and chlorhexidine rinses are beneficial in patients who are post-radiotherapy. There continues to be lack of clinical studies on the extent and severity of dental disease that are associated with infectious complications during cancer therapy.

Stem cells and the repair of radiation-induced salivary gland damage.

Hyposalivation underlying xerostomia after radiotherapy is still a major problem in the treatment of head and neck cancer. Stem cell therapy may provide a means to reduce radiation-induced hyposalivation and improve the quality of life of patients. This review discusses the current status in salivary gland stem cell research with respect to their potential to attenuate salivary gland dysfunction. Knowledge on the embryonic development, homeostasis and regeneration after atrophy of the salivary glands has provided important knowledge on the location of the salivary gland as well as on the factors that influence proliferation and differentiation. This knowledge has helped to locate, isolate and characterize cell populations that contain the salivary gland stem cell, although the exact tissue stem cell is still unidentified. The role that stem/progenitor cells play in the response to radiation and the factors that can influence stem/progenitor induced proliferation and differentiation are discussed. Finally, the mobilization and transplantation of stem cells and supportive cells and their potential to attenuate radiation-induced salivary gland damage are discussed. Based on the major advances made in the field of stem cell research, stem cell-based therapy has great potential to allow prevention or treatment of radiation-induced hyposalivation.

Oral mucositis and selective elimination of oral flora in head and neck cancer patients receiving radiotherapy: a double-blind randomised clinical trial

Mucositis is an acute inflammation of the oral mucosa because of radiotherapy and/or chemotherapy. All patients receiving radiotherapy in the head and neck region develop oral mucositis. The aim of this study was to analyse the effects of selective oral flora elimination on radiotherapy-induced oral mucositis, in a double-blind, randomised, placebo-controlled trial. Sixty-five patients with a malignant tumour in the head and neck regions to be treated with primary curative or postoperative radiotherapy participated in this study. The patients received either the active lozenges of 1 g containing polymyxin E 2 mg, tobramycin 1.8 mg and amphotericin B 10 mg (PTA) (33 patients) or the placebo lozenges (32 patients), four times daily during the full course of radiotherapy. Mucositis, changes in the oral flora, quality of feeding and changes of total body weight were assessed. Mucositis score did not differ between the groups during the first 5 weeks of radiotherapy. Nasogastric tube feeding was needed in six patients (19%) of the placebo group and two patients (6%) of the PTA group (P=0.08). Mean weight loss after 5 weeks of radiation was less in the PTA group (1.3 kg) (s.d.: 3.0) than in the placebo group (2.8 kg) (s.d.: 2.9) (P=0.05). Colonisation index of Candida species and Gram-negative bacilli was reduced in the PTA group and not in the placebo group (P<0.05). No effect on other microorganisms was detected. In conclusion, selective oral flora elimination in head and neck irradiation patients does not prevent the development of severe mucositis.

Systematic review of amifostine for the management of oral mucositis in cancer patients

PurposeThe aim of this study was to review the available literature from 1966 until December 31, 2010 and define clinical practice guidelines for the use of amifostine for the prevention and treatment of oral mucositis in cancer patients.MethodsA systematic review was conducted by the Mucositis Study Group of the Multinational Association of Supportive Care in Cancer/International Society of Oral Oncology. The body of evidence for the use of amifostine, 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, or no guideline possible.ResultsThirty papers were reviewed for evidence on amifostine as an intervention for oral mucositis. No guideline was possible for amifostine in any cancer treatment setting due to inadequate and conflicting evidence.ConclusionReview of the amifostine studies for the prevention and treatment of oral mucositis has found insufficient evidence to support its use in any cancer treatment setting for this purpose. Additional well-designed research is needed to clarify the role of amifostine as an intervention for oral mucositis.

Efficacy of routine pre-radiation dental screening and dental follow-up in head and neck oncology patients on intermediate and late radiation effects. A retrospective evaluation

BACKGROUND AND PURPOSE Head-neck radiotherapy is accompanied by a life-long risk of developing severe oral problems. This study retrospectively assessed oral foci detected during pre-radiation dental screening and follow-up in order to assess risk factors for developing oral problems after radiotherapy. MATERIALS AND METHODS Charts of 185 consecutive head-neck cancer patients, subjected to a pre-radiation dental screening in the University Medical Center Groningen, the Netherlands, between January 2004 and December 2008 were reviewed. Eighty (partially) dentulous patients scheduled for curative head-neck radiotherapy met the inclusion criteria. RESULTS Oral foci were found in 76% of patients, predominantly periodontal disease. Osteoradionecrosis had developed in 9 out of 80 patients (11%). Overall, patients presenting with periodontal pockets ≥ 6mm at dental screening had an increased risk (19%) of developing osteoradionecrosis compared to the total group of patients. Patients in whom periodontal disease treatment was composed of initial periodontal in stead of removal of the affected teeth, the risk of developing osteoradionecrosis was even higher, viz. 33%. CONCLUSIONS A worse periodontal condition at dental screening and initial periodontal therapy to safeguard these patients to develop severe oral sequelae after radiotherapy were shown to be major risk factors of developing osteoradionecrosis.

Human Salivary Gland Stem Cells Functionally Restore Radiation Damaged Salivary Glands

Adult stem cells are often touted as therapeutic agents in the regenerative medicine field, however data detailing both the engraftment and functional capabilities of solid tissue derived human adult epithelial stem cells is scarce. Here we show the isolation of adult human salivary gland (SG) stem/progenitor cells and demonstrate at the single cell level in vitro self‐renewal and differentiation into multilineage organoids. We also show in vivo functionality, long‐term engraftment, and functional restoration in a xenotransplantation model. Indeed, transplanted human salisphere‐derived cells restored saliva production and greatly improved the regenerative potential of irradiated SGs. Further selection for c‐Kit expression enriched for cells with enhanced regenerative potencies. Interestingly, interaction of transplanted cells with the recipient SG may also be involved in functional recovery. Thus, we show for the first time that salispheres cultured from human SGs contain stem/progenitor cells capable of self‐renewal and differentiation and rescue of saliva production. Our study underpins the therapeutic promise of salisphere cell therapy for the treatment of xerostomia. Stem Cells 2016;34:640–652

The effect of a calcium phosphate mouth rinse on (chemo) radiation induced oral mucositis in head and neck cancer patients: a prospective study.

OBJECTIVES Promising results of a calcium phosphate (CP) mouth rinse on reduced severity of oral mucositis have been reported. The aim of this study was to determine the effect of a CP mouth rinse on the frequency, duration and severity of (chemo) radiation induced oral mucositis in patients with head-neck cancer. MATERIAL AND METHOD patients with oral malignancies, treated with (chemo) radiotherapy, were included. Patients rinsed four times a day with a CP mouth rinse. Patients not willing to rinse with the CP mouth rinse served as control. Mucositis was scored according to the WHO score at baseline and twice a week during the full course of (chemo) radiotherapy. Patients self-reported mouth-throat soreness (MTS) was evaluated at the same time interval using a diary in the CP mouth rinse group. The outcomes on MTS were compared with a historical control group. RESULTS Fifty-two patients were analysed: 25 CP mouth rinse group, 11 control group and 16 historical group. There was no significant difference between the CP group and control group on development and severity of oral mucositis. No significant difference was found for subjective outcomes on MTS between the CP group and the historical group. CONCLUSIONS The CP mouth rinse seems to have no influence on the frequency, duration and severity of oral mucositis during (chemo) radiation in patients with head and neck cancer. A trend to develop less MTS for drinking and eating was found when applying the CP mouth rinse.