62 research outputs found
Mutations in POLE and survival of colorectal cancer patients – link to disease stage and treatment
Recent molecular profiling studies reported a new class of ultramutated
colorectal cancers (CRCs), which are caused by exonuclease domain mutations
(EDMs) in DNA polymerase ϵ (POLE). Data on the clinical implications of these
findings as to whether these mutations define a unique CRC entity with
distinct clinical outcome are lacking. We performed Sanger sequencing of the
POLE exonuclease domain in 431 well-characterized patients with microsatellite
stable (MSS) CRCs of a population-based patient cohort. Mutation data were
analyzed for associations with major epidemiological, clinical, genetic, and
pathological parameters including overall survival (OS) and disease-specific
survival (DSS). In 373 of 431 MSS CRC, all exons of the exonuclease domain
were analyzable. Fifty-four mutations were identified in 46 of these samples
(12.3%). Besides already reported EDMs, we detected many new mutations in
exons 13 and 14 (corresponding to amino acids 410–491) as well as in exon 9
and exon 11 (corresponding to aa 268–303 and aa 341–369). However, we did not
see any significant associations of EDMs with clinicopathological parameters,
including sex, age, tumor location and tumor stage, CIMP, KRAS, and BRAF
mutations. While with a median follow-up time of 5.0 years, survival analysis
of the whole cohort revealed nonsignificantly different adjusted hazard ratios
(HRs) of 1.35 (95% CI: 0.82–2.25) and 1.44 (0.81–2.58) for OS and DSS
indicating slightly impaired survival of patients with EDMs, subgroup analysis
for patients with stage III/IV disease receiving chemotherapy revealed a
statistically significantly increased adjusted HR (1.87; 95%CI: 1.02–3.44). In
conclusion, POLE EDMs do not appear to define an entirely new clinically
distinct disease entity in CRC but may have prognostic or predictive
implications in CRC subgroups, whose significance remains to be investigated
in future studies
Structure and content of the EU-IVDR: current status and implications for pathology
Background
Regulation (EU) 2017/746 on in vitro diagnostic medical devices (IVDR) was passed by the European Parliament and the Council of the European Union on 5 April 2017 and came into force on 26 May 2017. A new amending regulation, which introduces a phased implementation of the IVDR with new transitional provisions for certain in vitro diagnostic medical devices (IVDs) and a later date of application of some requirements for in-house devices for healthcare facilities, was adopted on 15 December 2021.
The combined use of CE-certified IVDs (CE-IVDs), in-house IVDs (IH-IVDs), and research use only (RUO) devices are a cornerstone of diagnostics in pathology departments and crucial for optimal patient care. The IVDR not only regulates the manufacture and placement on the market of industrially manufactured IVDs, but also imposes conditions on the manufacture and use of IH-IVDs for internal use by healthcare facilities.
Objectives
Our work provides an overview of the background and structure of the IVDR and identifies core areas that need to be interpreted and fleshed out in the context of the legal framework as well as expert knowledge.
Conclusions
The gaps and ambiguities in the IVDR crucially require the expertise of professional societies, alliances, and individual stakeholders to successfully facilitate the implementation and use of the IVDR in pathology departments and to avoid aberrant developments
Next-generation sequencing facilitates detection of the classic E13-A20 EML4-ALK fusion in an ALK-FISH/IHC inconclusive biopsy of a stage IV lung cancer patient: a case report
Background: Inhibition of the oncogenic fusion-gene EML4-ALK is a current first-line approach for patients with stage IV non-small cell lung cancer. While FISH was established as the gold standard for identifying these patients, there is accumulating evidence that other methods of detection, i.e., immunohistochemistry and next-generation sequencing (NGS), exist that may be equally successful. However, the concordance of these methods is under investigation. Case presentation: Adding to the current literature, we here report a 56 year old female never-smoker with stage IV lung adenocarcinoma whose biopsy was IHC and FISH inconclusive but positive in NGS. Retroactive profiling of the resection specimen corroborated fusion reads obtained by NGS, FISH-positivity and showed weak ALK-positivity by IHC. Consequently, we diagnosed the case as ALK-positive rendering the patient eligible to crizotinib treatment. Conclusions: With IHC on biopsy material only, this case would have been overlooked withholding effective therapy
Elevated expression of c-kit in small venous malformations of blue rubber bleb nevus syndrome
The blue rubber bleb nevus syndrome (BRBNS, syn. bean syndrome) is a rare disease
characterized by multiple cutaneous and gastrointestinal venous malformations
associated with severe bleeding. However, the underlying molecular mechanisms
are unknown and no targeted therapeutic approach exists to date. Here we report
the case of a 19-year-old male patient with severe BRBNS in whom we analyzed the
expression of tyrosine kinases frequently involved in tumor development by
immunohistochemistry (vascular endothelial growth factor receptor-2, stem cell
growth factor receptor (c-kit), platelet-derived growth factor
receptor-β, and stem cell tyrosine kinase-1). A prominent expression of
c-kit was detectable in smaller blood vessels, which also showed a moderate
expression of the proliferation marker MIB1. Surprisingly, other growth factor
receptors stained negatively. We therefore conclude that pharmacological
inhibition of the c-kit signaling pathway in cavernous hemangiomas by selective
kinase inhibitors may offer options in the treatment of BRBNS patients
Pitfalls in mutational testing and reporting of common KIT and PDGFRA mutations in gastrointestinal stromal tumors
<p>Abstract</p> <p>Background</p> <p>Mutation analysis of <it>KIT </it>and <it>PDGFRA </it>genes in gastrointestinal stromal tumors is gaining increasing importance for prognosis of GISTs and for prediction of treatment response. Several groups have identified specific mutational subtypes in <it>KIT </it>exon 11 associated with an increased risk of metastatic disease whereas GISTs with <it>PDGFRA </it>mutations often behave less aggressive. Furthermore, in advanced GIST disease with proven <it>KIT </it>exon 9 mutation the doubled daily dose of 800 mg imatinib increases the progression free survival and is now recommended both in the European and the American Guidelines. In Germany, there are still no general rules how to perform mutational analysis.</p> <p>Methods</p> <p>When comparing results from six different molecular laboratories we recognized the need of standardisation. Six German university laboratories with experience in mutation analysis in GISTs joined together to develop recommendations for the mutation analysis of the most common and clinically relevant hot spots, i. e. <it>KIT </it>exons 9 and 11 and <it>PDGFRA </it>exon 18. We performed a three-phased interlaboratory trial to identify pitfalls in performing molecular analysis in GISTs.</p> <p>Results</p> <p>We developed a design for a continuous external laboratory trial. In 2009 this external trial was conducted by 19 laboratories via the initiative for quality assurance in pathology (QuiP) of the German Society of Pathology and the Professional Association of German Pathologists.</p> <p>Conclusions</p> <p>By performing a three-phased internal interlaboratory trial and conducting an external trial in Germany we were able to identify potential pitfalls when performing KIT and PDGFRA mutational analysis in gastrointestinal stromal tumors. We developed standard operation procedures which are provided with the manuscript to allow other laboratories to prevent these pitfalls.</p
KRAS, EGFR, PDGFR-α, KIT and COX-2 status in carcinoma showing thymus-like elements (CASTLE)
Модернизация автоматизированной системы блока стабилизации давления магистрального насосного агрегата на нефтеперекачивающей станции
Объектом исследования является блок стабилизации давления магистрального насосного агрегата. Цель работы – модернизация автоматизированной системы блока стабилизации давления магистрального трубопровода нефтеперекачивающей станции с использованием ПЛК, на основе выбранной SCADA-системы. В данном проекте была разработана система контроля и управления технологическим процессом на базе промышленных контроллеров Modicon M340 BMXP34 2020, с применением SCADA-системы.The object of investigation is the pressure stabilization unit of the main pump unit. The purpose of the work is the modernization of the automated system for stabilizing the pressure of the main pipeline of the oil pumping station using PLCs, based on the SCADA system chosen. In this project, a system for monitoring and controlling the process was developed on the basis of industrial controllers Modicon M340 BMXP34 2020, using a SCADA system
Multicenter Immunohistochemical ALK-Testing of Non-Small-Cell Lung Cancer Shows High Concordance after Harmonization of Techniques and Interpretation Criteria
Correction: Automated Universal BRAF State Detection within the Activation Segment in Skin Metastases by Pyrosequencing-Based Assay U-BRAFV600
Semiconductor‐Based Sequencing of Formalin‐Fixed, Paraffin‐Embedded Colorectal Cancer Samples
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