The occurrence of MYC-negative Burkitt lymphoma (BL) has been discussed for many years. The real frequency of the MYC insertion in MYC-negative BL is still unknown. Fine-needle aspiration biopsies of 108 consecutive patients with clinicopathologically suspected BL (suspBL) were evaluated by flow cytometry, classical cytogenetics, and fluorescence in situ hybridization (FISH). We found 12 cases (11%) without the MYC rearrangement by FISH with a MYC breakapart probe: two patients (1.9%) with cryptic MYC/IGH fusion (finally diagnosed as BL) and 10 patients (9.3%) with 11q gain/loss (finally diagnosed as Burkitt-like lymphoma with 11q aberration). The exact breakpoints of the cryptic MYC/IGH were investigated by next-generation sequencing. The MYC insertions’ breakpoints were identified in PVT1 in the first case, and 42 kb upstream of 5′MYC in the second case. To date, a molecular characterization of the MYC insertion in BL has only been reported in one case. Detailed descriptions of our MYC insertions in a routinely and consecutively diagnosed suspBL cohort will contribute to resolving the issue of MYC negativity in BL. In our opinion, the presence of the MYC insertions in BL and other lymphomas might be underestimated, because routine genetic diagnostics are usually based on FISH only, without karyotyping.
Considering the vast biological diversity and high mortality rate in high-grade ovarian cancers, identification of novel biomarkers, enabling precise diagnosis and effective, less aggravating treatment, is of paramount importance. Based on scientific literature data, we selected 80 cancer-related genes and evaluated their mRNA expression in 70 high-grade serous ovarian cancer (HGSOC) samples by Real-Time qPCR. The results were validated in an independent Northern American cohort of 85 HGSOC patients with publicly available NGS RNA-seq data. Detailed statistical analyses of our cohort with multivariate Cox and logistic regression models considering clinico-pathological data and different TP53 mutation statuses, revealed an altered expression of 49 genes to affect the prognosis and/or treatment response. Next, these genes were investigated in the validation cohort, to confirm the clinical significance of their expression alterations, and to identify genetic variants with an expected high or moderate impact on their products. The expression changes of five genes, PROM1, CXCL8, RUNX1, NAV1, TP73, were found to predict prognosis or response to treatment in both cohorts, depending on the TP53 mutation status. In addition, we revealed novel and confirmed known SNPs in these genes, and showed that SNPs in the PROM1 gene correlated with its elevated expression.
EMSY, a BRCA2–associated protein, is amplified and overexpressed in various sporadic cancers. This is the first study assessing the clinical impact of its expression and polymorphisms on ovarian cancer (OvCa) outcome in the context of the chemotherapy regimen used. In 134 frozen OvCa samples, we assessed EMSY mRNA expression with Reverse Transcription-quantitative PCR, and also investigated the EMSY gene sequence using SSCP and/or PCR-sequencing. Clinical relevance of changes in EMSY mRNA expression and DNA sequence was evaluated in two subgroups treated with either taxane/platinum (TP, n=102) or platinum/cyclophosphamide (PC, n=32). High EMSY expression negatively affected overall survival (OS), disease-free survival (DFS) and sensitivity to treatment (PS) in the TP-treated subgroup (p-values: 0.001, 0.002 and 0.010, respectively). Accordingly, our OvCa cell line studies showed that the EMSY gene knockdown sensitized A2780 and IGROV1 cells to paclitaxel. Interestingly, EMSY mRNA expression in surviving cells was similar as in the control cells. Additionally, we identified 24 sequence alterations in the EMSY gene, including the previously undescribed: c.720G>C, p.(Lys240Asn); c.1860G>A, p.(Lys620Lys); c.246-76A>G; c.421+68A>C. In the PC-treated subgroup, a heterozygous genotype comprising five SNPs (rs4300410, rs3814711, rs4245443, rs2508740, rs2513523) negatively correlated with OS (p-value=0.009). The same SNPs exhibited adverse borderline associations with PS in the TP-treated subgroup. This is the first study providing evidence that high EMSY mRNA expression is a negative prognostic and predictive factor in OvCa patients treated with TP, and that the clinical outcome may hinge on certain SNPs in the EMSY gene as well.
BackgroundDolutegravir (DTG), a second-generation integrase strand transfer inhibitor (INSTI), is currently among the most commonly used antiretroviral agents. Recent reports have raised concerns about their safety, especially with regard to neuropsychiatric adverse effects (neuropsychiatric AEs).PurposeTo assess the neurotoxicity associated with DTG in the treatment of human immunodeficiency virus infected patients (HIV +).To compare our results with those published in recent reports.Material and methodsWe performed a descriptive, retrospective and observational study in which all HIV +patients treated with DTG were enrolled between January 2015 and September 2017. Demographic, analytical and clinical data were collected in EXCEL® 2013: age, sex, adverse effects (AEs), antiretroviral therapy (ART) and reasons for discontinuation, from the Digital Clinical History (Diraya) and FarmaTools® software.ResultsDuring the study period, 292 patients initiated ART containing DTG. Treatment was discontinued in 16.78% (median age 59 years (26–87), 65.3% males). Of these, 79.5% were in concomitant ART with abacavir/lamivudine (ABC/3TC), 10.2% with tenofovir/emtricitabine (TDF/FTC), 4% with etravirine (ETR) and the remaining ones with potentiated protease inhibitors.Most of the patients (85.7%) discontinued treatment during the first year. In 18 patients (36.7%) the reason for DTG discontinuation was neuropsychiatric AEs: insomnia (55.5%), anxiety, asthaenia and nervousness (22.2% respectively), dizziness (11.1%) and, less frequently, paranoid ideas and nightmares (5.6%).Neuropsychiatric AEs were more frequent in females (53%) than in males (28.1%), with a median age of 51 years (34–87). Neurotoxicity was reversible in 100% of patients when DTG was discontinued and more frequentl in those receiving concomitant treatment with ABC/3TC (83.3%).ConclusionEarly discontinuation of dolutegravir from neurotoxicity was frequent, mainly in females and in patients who initiated abacavir/lamivudine at the same time, but not in elderly patients. Therefore, our results agree with those already published in recent reports. As dolutegravir is one of the most commonly used antiretroviral options both in naive and pretreated patients, further research on their safety and neurotoxicity mechanisms are needed.Reference and/or Acknowledgements1. Hoffmann C, Welz T, Sabranski M, Kolb M, Wolf E, StellbrinkHJ, Wyen C. Higher rates of neuropsychiatric adverse events leading to dolutegravir discontinuation in women and older patients. HIV Med2017;18:56–63.No conflict of interest
prior to the patient leaving the PICU, and paediatric CCPs perform discharge medication reviews. By involving the PICU team in the medication discharge process, we aim to improve the quality and safety of step-down prescribing.
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