Mette Pedersen

MYC translocation partner gene determines survival of patients with large B-cell lymphoma with MYC- or double-hit MYC/BCL2 translocations

In large B‐cell lymphoma (LBCL) MYC‐ and MYC/BCL2 double‐hit (DH) translocations have been associated with inferior survival. We hypothesised that the negative prognostic impact of MYC translocation was determined by an immunoglobulin MYC translocation partner gene (IG‐MYC), as opposed to a non‐immunoglobulin partner gene (nonIG‐MYC). In a prospective, unselected cohort of 237 LBCL patients MYC and BCL2 translocations were identified by Flourescent in situ hybridisation (FISH) with split probes. MYC translocation partner gene was identified by IGH/MYC fusion probes and/or kappa/lambda split probes. Clinical data were collected from patient files. MYC translocation was identified in 28/225 patients. IG‐MYC translocation partner gene was identified in 12/24 patients. DH translocation was identified in 23/228 patients. IG‐MYC translocation partner gene was identified in 9/19 DH patients. Neither MYC‐nor DH translocation showed correlation with survival. However, MYC translocation with IG‐MYC translocation partner gene was associated with worse OS compared with both MYC translocation with nonIG‐MYC translocation partner gene (P = 0.02) as well as absence of MYC translocation (P = 0.03). In patients with DH a similar, however, stronger correlation was seen (P = 0.003 and P = 0.0004 respectively). MYC – or DH translocation with nonIG‐MYC translocation partner gene was not associated with worse overall survival (P = 0.2 and P = 0.3 respectively). Most patients received Rituximab (86%) and CHOP/CHOP‐like chemotherapy regimes (81%). We suggest that prognostic stratification of LBCL patients by MYC and/or DH translocations should include identification of MYC translocation partner gene because approximately half of the cases harbour nonIG‐MYC translocation partner genes with no or minor influence on survival.

Genetic and Functional Drivers of Diffuse Large B Cell Lymphoma

Diffuse large B cell lymphoma (DLBCL) is the most common form of blood cancer and is characterized by a striking degree of genetic and clinical heterogeneity. This heterogeneity poses a major barrier to understanding the genetic basis of the disease and its response to therapy. Here, we performed an integrative analysis of whole-exome sequencing and transcriptome sequencing in a cohort of 1,001 DLBCL patients to comprehensively define the landscape of 150 genetic drivers of the disease. We characterized the functional impact of these genes using an unbiased CRISPR screen of DLBCL cell lines to define oncogenes that promote cell growth. A prognostic model comprising these genetic alterations outperformed current established methods: cell of origin, the International Prognostic Index comprising clinical variables, and dual MYC and BCL2 expression. These results comprehensively define the genetic drivers and their functional roles in DLBCL to identify new therapeutic opportunities in the disease.

Mutation of TP53, translocation analysis and immunohistochemical expression of MYC, BCL-2 and BCL-6 in patients with DLBCL treated with R-CHOP

Diffuse large B-cell lymphoma (DLBCL) is an aggressive lymphoma with diverse outcomes. Concurrent translocation of MYC and BCL-2 and/or BCL-6, and concurrent immunohistochemical (IHC) high expression of MYC and BCL-2, have been linked to unfavorable treatment responses. TP53-mutated DLBCL has also been linked to worse outcome. Our aim was to evaluate the aforementioned issues in a cohort of 155 patients uniformly treated with R-CHOP-like therapies. We performed direct sequencing of TP53 exons 5, 6, 7 and 8 as well as fluorescence in-situ hybridization (FISH) of MYC, BCL-2 and BCL-6, and IHC of MYC, BCL-2 and BCL-6. In multivariate analysis, TP53 mutations in L3 and loop-sheet helix (LSH) associated with a risk ratio (RR) of disease-specific survival (DSS) of 8.779 (pu2009=u20090.022) and a RR of disease-free survival (DFS) of 10.498 (pu2009=u20090.011). In IHC analysis BCL-2 overexpression was associated with inferior DFS (pu2009=u20090.002) and DSS (pu2009=u20090.002). DLBCL with BCL-2 and MYC overexpression conferred inferior survival in all patients (DSS, pu2009=u20090.038 and DFS, pu2009=u20090.011) and in patients with non-GC phenotype (DSS (pu2009=u20090.013) and DFS (pu2009=u20090.010). Our results imply that in DLBCL, the location of TP53 mutations and IHC analysis of BCL-2 and MYC might have a role in the assessment of prognosis.

Future aspects of cellular and molecular research in clinical voice treatment aspects of optical coherence tomography

Focus is upon our clinical experience in a prospective cohort study on cure of dystonia where the mode of treatment was fexofenadine tablets and local budesonide inhaler in the larynx, and in a randomized controlled trial of lifestyle change related to acid provocation of food and habits in laryngopharyngeal reflux (LPR). The advanced high-speed films is one new tool, another being optical coherence tomography (OCT), which should be used in the future in randomized controlled trials. We are focusing on OCT of the swallowing process in the oesophagaus and larynx as well as the vocal fold function. It can be shown on OCT how the layer of the vocal folds develop, possibly corresponding to hormonal and paediatric development. The arytenoid area in the larynx should also be focused upon with OCT in pathology. The thyroid function is related to voice and the swallowing function, both hormonally and pathoanatomically. We know too little about voice and thyroid hormones in an updated way as well as the outer anatomic supporting muscular structure of the larynx, related to thyroid immune degeneration and cysts. Also, here OCT analyses might be of value.

What we can learn about hereditary dystonia from HSDI of the glottis

This study examined efficacy of the innate immune defence via the mannose binding lectin (MBL) in a cohort of 55 dystonic patients prospectively referred to the clinic with laryngeal mucosal complaints, who were placed on local steroids (budesonid inhaler, 400 μg 2 times daily) and antihistamines (fexofenadin 180 mg mostly 3 times daily) with adjuvant lifestyle corrections. Treatment efficacy of the larynx was assessed based on mucosal findings of the vocal folds examined with High speed mucosa studies comprising simultaneous high speed digital imagines (HSDI), kymography, electroglottography (EGG) and voice acoustics combined with a visual score of arytenoids oedema, as these measures are indicative of the magnitude of laryngitis. Lactose and gluten intolerance and immunological analyses of the innate system were made systematically. Results showed that the genetic aspects of immunology did not reveal a role for the innate immune system, represented by the mannose binding lectin (MBL). An unexpected positive effect of the larynx treatment on dystonia symptoms was found evidenced by reduction of dystonic complaints and more normative results of High speed mucosa, and a reduction of oedema of the inter arytenoids region. Symptoms relieve and better quality of life was observed on follow up for the dystonia complaints.

Advanced micro scanning in laryngology: implications of new advanced scanning in relation to HSDI acquired signals

The objective was to provide a comprehensive overview of the advanced microscopes (light and electron) and to implicate how laryngeal science can benefit. The Core Facility for Integrated Microscopy (CFIM) has a wide range of state-of the art light and electron microscopes for users of all levels of experience and from any discipline. To explore the increasing findings with the high-speed film, researchers need to know more about the underlying pathology (tissue changes at cellular level). The scientists need to have access to state-of-the-art light and electron microscopes ready for use in their research, as well as the necessary technical assistance and support.