Geographical and ecological analyses of multiple myeloma in Denmark: Identification of potential hotspot areas and impact of urbanisation.

BACKGROUND: The aetiology of multiple myeloma (MM) is unknown but various environmental exposures are suspected as risk factors. We present the first paper analysing the geographical distribution of MM in Denmark at the municipal level to investigate variations that could be explained by environmental exposures. METHODS: Patients diagnosed with MM in Denmark during 2005-2020 were identified from nationwide registries and grouped into the 98 Danish municipalities based on residence. The age- and sex-standardised incidence rate (SIR) of each municipality was compared to the national incidence in a funnel plot with 95% control limits. Differences in SIRs of rural, suburban, and urban areas were evaluated with incidence rate ratios. RESULTS: In total, 5243 MM patients were included. Overall, we found a heterogeneous geographical distribution of MM and a potential hotspot in southern Denmark. This hotspot contains three municipalities with SIRs above the 95% control limit assuming considerably higher rate of MM compared to the national incidence rate. A significant higher SIR was found in rural areas compared to urban areas. CONCLUSION: The geographical distribution of MM in Denmark indicates that the risk of developing MM depends on place of residence probably due to environmental factors.

Evaluation of semi-automatic 3D reconstruction for studying geometry of dendritic spines.

BACKGROUND: Spine geometry is considered to reflect synapse function. An accurate and fast method for 3D reconstruction of spines is considered a valuable tool for the purpose of studying spine geometry. Currently, most studies employ manual or automatic reconstruction methods, which still suffer from either poor accuracy or extreme time-consumption. The semi-automatic reconstruction method has previously been described as a time-economic and accurate tool for spine number counting. The purpose of this study is to further validate the semi-automatic method with regards to spine geometry investigation, by comparing it with the manual method as well as with the automatic method. METHODS: In this study, dendritic trees of six pyramidal neurons that belong to layers II/III of mouse frontal cortex are stained using the Golgi method. Thereafter, spines from 42 dendritic branches are 3D reconstructed by manual, semi-automatic and automatic methods using Imaris software. Spine features, including spine volume, spine area, spine length and spine neck length, and the relative distribution of classified stubby, mushroom and thin spines are compared between the semi-automatic method and the two other methods. RESULTS: Results from the semi-automatic and the manual reconstruction methods are in line with respect to all measured spine geometric features as well as spine classes. However, significant difference has been detected between the two methods and the automatic method in spine length, spine neck length and spine volume. Compared to the manual method, both the semi-automatic and the automatic methods have significantly reduced the spine reconstruction time. CONCLUSION: These findings suggest that the semi-automatic method may represent both a time-economic and reliable option for the purpose of studying spine geometry.

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.