Mette Marcussen

Molecular Characteristics of High-Dose Melphalan Associated Oral Mucositis in Patients with Multiple Myeloma: A Gene Expression Study on Human Mucosa.

Background Toxicity of the oral and gastrointestinal mucosa induced by high-dose melphalan is a clinical challenge with no documented prophylactic interventions or predictive tests. The aim of this study was to describe molecular changes in human oral mucosa and to identify biomarkers correlated with the grade of clinical mucositis. Methods and Findings Ten patients with multiple myeloma (MM) were included. For each patient, we acquired three buccal biopsies, one before, one at 2 days, and one at 20 days after high-dose melphalan administration. We also acquired buccal biopsies from 10 healthy individuals that served as controls. We analyzed the biopsies for global gene expression and performed an immunohistochemical analysis to determine HLA-DRB5 expression. We evaluated associations between clinical mucositis and gene expression profiles. Compared to gene expression levels before and 20 days after therapy, at two days after melphalan treatment, we found gene regulation in the p53 and TNF pathways (MDM2, INPPD5, TIGAR), which favored anti-apoptotic defense, and upregulation of immunoregulatory genes (TREM2, LAMP3) in mucosal dendritic cells. This upregulation was independent of clinical mucositis. HLA-DRB1 and HLA-DRB5 (surface receptors on dendritic cells) were expressed at low levels in all patients with MM, in the subgroup of patients with ulcerative mucositis (UM), and in controls; in contrast, the subgroup with low-grade mucositis (NM) displayed 5–6 fold increases in HLA-DRB1 and HLA-DRB5 expression in the first two biopsies, independent of melphalan treatment. Moreover, different splice variants of HLA-DRB1 were expressed in the UM and NM subgroups. Conclusions Our results revealed that, among patients with MM, immunoregulatory genes and genes involved in defense against apoptosis were affected immediately after melphalan administration, independent of the presence of clinical mucositis. Furthermore, our results suggested that the expression levels of HLA-DRB1 and HLA-DRB5 may serve as potential predictive biomarkers for mucositis severity.

Spontaneous fractures of the mandible concept & treatment strategy.

Background Spontaneous fractures of the mandible dispose a surgical challenge in comparisons to fractures caused by trauma due to several complicating factors. Additionally: controversies exist concerning the terminology of the field. Material and Methods We conducted a retrospective study of all patients with mandibular fractures, with exclusion of fractures of the coronoid process and the alveolar process, treated at the Department of Oral and Maxillofacial Surgery, Aalborg University Hospital, Denmark between February 2003 and February 2013. Data collected from the medical records included sex, age, cause of fracture, site of fracture, and treatment. Results We identified 517 patients with 684 mandible fractures. Twenty-five of these were spontaneous fractures and 659 fractures were of traumatic origin. Condylar fractures rarely occur spontaneously, but constitute the majority of the traumatic fractures. Excluding these fractures from the analysis, we found a non-surgical approach in 14 of 24 (58%) of the spontaneous fractures and 110 of 376 (29%) of the traumatic fractures. This was statistically significant. Conclusions We found a statistical significant difference in favor of non-surgical approach in spontaneous fractures and we discussed the treatment challenges of these fractures. We addressed the terminological controversies regarding pathological fractures, and suggested the term spontaneous fractures denoting a fracture occurring during normal jaw function being either pathological or non-pathological. Key words:Mandibular fractures, spontaneous fractures, pathological fractures, traumatic fractures, treatment.

Oral mucosa tissue gene expression profiling before, during, and after radiation therapy for tonsil squamous cell carcinoma

Background Radiation-therapy (RT) induces mucositis, a clinically challenging condition with limited prophylactic interventions and no predictive tests. In this pilot study, we applied global gene-expression analysis on serial human oral mucosa tissue and blood cells from patients with tonsil squamous cell cancer (TSCC) to identify genes involved in mucositis pathogenesis. Methods and findings Eight patients with TSCC each provided consecutive buccal biopsies and blood cells before, after 7 days of RT treatment, and 20 days following RT. We monitored clinical mucositis and performed gene-expression analysis on tissue samples. We obtained control tissue from nine healthy individuals. After RT, expression was upregulated in apoptosis inducer and inhibitor genes, EDA2R and MDM2, and in POLH, a DNA-repair polymerase. Expression was downregulated in six members of the histone cluster family, e.g., HIST1H3B. Gene expression related to proliferation and differentiation was altered, including MKI67 (downregulated), which encodes the Ki-67-proliferation marker, and KRT16 (upregulated), which encodes keratin16. These alterations were not associated with the clinical mucositis grade. However, the expression of LY6G6C, which encodes a surface immunoregulatory protein, was upregulated before treatment in three cases of clinical none/mild mucositis, but not in four cases of ulcerative mucositis. Conclusion RT caused molecular changes related to apoptosis, DNA-damage, DNA-repair, and proliferation without a correlation to the severity of clinical mucositis. LY6G6C may be a potential protective biomarker for ulcerative mucositis. Based on these results, our study model of consecutive human biopsies will be useful in designing a prospective clinical validation trial to characterize molecular mucositis and identify predictive biomarkers.

A systematic review of molecular responses to cancer therapy in normal human mucosa

OBJECTIVE Cancer therapy-induced inflammation of oral and gastrointestinal mucosae affects patients nonuniformly. Preventive strategies are limited; no biomarker exists for pretreatment identification of patients likely to be severely affected. Animal models are preferred for studying molecular responses in mucosae during chemotherapy, but translation into clinical practice is difficult. We performed a systematic review to retrieve articles that described molecular changes in human mucosae during cancer therapy. STUDY DESIGN We searched MEDLINE and Ovid Embase searches for studies reported in the English language literature from January 1990 to November 2016 and studies referenced in selected articles, which analyzed mucosae from patients at risk of developing mucositis during cancer therapy. Two authors extracted data according to predefined data fields, including study quality indicators. RESULTS We identified 17 human studies on chemotherapy (n = 9) and radiotherapy (n = 8), but no studies on targeted therapy. Studies were heterogeneous with regard to patient cohorts, analysis methods, cancer treatments, biopsy timings, and correlations to clinical mucositis. Consequently, a meta-analysis was not feasible. CONCLUSIONS Few human studies described the molecular responses of the normal mucosa to cancer therapy. Studies were heterogeneous and had sparse correlations to clinical mucositis. We proposed a model for acquiring data on treatment- and disease-specific phenotypes and transcriptomes for predictive or preventive initiatives.