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Molecular Diagnostics of Chronic Myeloid Leukemia: Precision Medicine via Gold Nanoparticles
Published in Il-Jin Kim, Companion Diagnostics (CDx) in Precision Medicine, 2019
Raquel Vinhas, Alexandra R. Fernandes, Pedro V. Baptista
Precision oncology shows much potential through molecular advances.79,80 Indeed, research on CML molecular diagnostics now focuses on four key issues: (i) increase BCR–ABL1 detection sensitivity for MRD monitoring, and understand the real implication of therapy discontinuation in this subset of patients; (ii) increase the amount of information on transcript statuses, such as type of fusion transcript, occurrence of mutations and kinase activity, to support treatment choice; (iii) produce fast, cost-effective, and miniaturized methods for POC that assists conventional techniques; and (iv) finally, shift towards a more integrated strategy between diagnostics and therapeutics, i.e., theranostics using a single nanocarrier. As established by this chapter, nanotechnology offers multiple advantages to tackle the shortcomings of conventional procedures for the management of CML.
B-Lymphoblastic Leukemia/Lymphoma
Published in Wojciech Gorczyca, Atlas of Differential Diagnosis in Neoplastic Hematopathology, 2014
B-ALLs have been historically divided into pro-B-ALL (early-pre-B-ALL; TdT+/CD19+/CD10−), common ALL [CD10+ or common ALL antigen (CALLA+)], pre-B-ALL (CD10+/−; cytoplasmic IgM+), and mature B-ALL (surface IgM+). The majority of mature B-ALLs, which are characterized by L3 morphology (basophilic cells with prominent cytoplasmic vacuoles), expression of surface immunoglobulins, and higher incidence of CNS involvement, are now classified as Burkitt lymphoma (BL) in the leukemic phase. Common and pre-B-ALLs are often positive for t(9;22)/BCR–ABL (30%–50%). The pro-B-ALLs show t(4;11)(q34;q11)/ALL1–AF4. In a series by Cimino et al. [17], adult patients with pro-B-ALL had the ALL1–AF4 fusion transcript, originating from t(4;11) in 36.4% and t(9;22)/BCR–ABL in 9%. B-ALLs with t(9;22) often display an aberrant expression of pan-myeloid antigens (CD33 or less often CD13). Adult patients with early-pre-B-ALL and t(4;11) or t(9;22) have poor prognosis and the absence of both of these translocations correlates with a significantly better clinical outcome after intensive chemotherapy treatment [17]. CD10− pre-B-ALL has been identified as a high-risk subgroup of adult ALL associated with a high frequency of MLL aberrations and worse prognosis [18]. Pro-B-ALL and/or t(4;11)+ is associated with worse prognosis, but responds well to high-dose cytarabine therapy and stem cell transplantation.
MOLECULAR GENETICS OF HAEMATOLOGICAL DISEASES
Published in James Bishop, Cancer Facts, 1999
In 95% of patients with chronic myeloid leukaemia (CML), cytogenetic analysis reveais a reciprocal translocation, t(9;22), resulting in rearrangement of the BCR and c-ABL genes on the long arms of chromosomes 22 and 9 respectively. The BCR-ABL fusion (Stam et al., 1985) on the derivative chromosome 22 (the Philadelphia chromosome) encodes a p210 protein with markedly enhanced tyrosine kinase activity. Cytogenetic analysis is useful in monitoring the response to alpha-interferon, since an interferon-induced reduction in the proportion of Philadelphia positive metaphases below 35% is associated with a significant prolongation of the chronic phase of the disease, and henee of overall survival. Several non-random cytogenetic abnormalities occur frequendy in association with acute leukaemic transformation of the disease (e.g. second Philadelphia chromosome, trisomy 8, isochromosome 17, etc.). RT-PCR is used primarily to monitor MRD following allogeneic and autologous stem cell transplantation. The sensitivity of detection of the BCR-ABL fusion transcript by RT-PCR is around one leukaemic cell in 105-106 normal cells. Following transplantation, RT- PCR positivity may persist for up to 12 months. Patients who become and remain persistently
Neurotrophic tropomyosin receptor kinase (NTRK) fusion positive tumors: a historical cohort analysis
Published in Expert Review of Anticancer Therapy, 2023
Lauriane Lemelle, Delphine Guillemot, Anne-Laure Hermann, Arnaud Gauthier, Matthieu Carton, Nadège Corradini, Angélique Rome, Pablo Berlanga, Anne Jourdain, Aude Marie Cardine, Sarah Jannier, Hélène Boutroux, Anne Sophie Defachelles, Isabelle Aerts, Birgit Geoerger, Marie Karanian, François Doz, Hervé J Brisse, Gudrun Schleiermacher, Olivier Delattre, Gaëlle Pierron, Daniel Orbach
Malignant tumors harboring a NTRK gene fusion (Neurotrophic receptor tyrosine kinase) were first identified several decades ago [1]. Initially, this fusion was highly associated with ETV6 (NTRK3 –ETV6) and mainly reported in infantile fibrosarcoma (IFS). However, other NTRK fusion positive tumors (NTRK-FPT) have been identified more recently involving NTRK1, NTRK2, and NTRK3 in a broad range of pediatric and adult malignancies [2]. Today, the prevalence of the NTRK fusion transcript could be estimated to be present in approximately 2–3% of some more common tumors [3]. In addition, NTRK receptors are also often expressed in human tumors, such as melanoma, esophageal, cervical and lung squamous cell carcinomas, and also in thyroid carcinoma [4–8]. In routine diagnostic procedures, these tumors can be screened based on the positivity for pan-TRK marker by immuno-histochemistry (IHC) [9]. In addition, different techniques can confirm the presence of a somatic NTRK fusion: FISH (fluorescence in situ hybridization), RT-PCR (reverse transcription polymerase-chain reaction) and RNA/DNA-based next-generation sequencing (NGS). The recent clinical development of a new class of compounds blocking the NTRK molecular pathway gives an important hope to find a specific way to treat patients with these tumors [10,11]. Therefore, the promising results of these new drugs (larotrectinib, entrectinib, and repotrectinib) lead to the reconsideration of their role in the overall treatment strategy of these tumors [12–14].
Validation of PRKCB Immunohistochemistry as a Biomarker for the Diagnosis of Ewing Sarcoma
Published in Fetal and Pediatric Pathology, 2023
Victor Zota, Gene P. Siegal, David Kelly, Julia A. Bridge, Anders Berglund, Katherine Bui, Farah Khalil, Damon R. Reed, Soner Altiok, Anthony Magliocco, Marilyn M. Bui
An accurate diagnosis of classic ES is mainly facilitated by the detection of a fusion gene event involving the EWSR1 gene (less commonly, FUS substitutes for EWSR1) with one of the ETS family members. The most frequent fusion partner of EWSR1 is FLI1 (90% to 95%), followed by ERG (5% to 10%), with other occasionally identified targets, such as ETV1, ETV4, and FEV (each <1%). The most frequently employed method for detecting an EWSR1 gene rearrangement is FISH, using commercially available break-apart probes. Due to EWSR1 gene promiscuity to fuse with various genes, it is important to correlate the molecular cytogenetic results if only using the EWSR1 break apart probe (and not a fusion FISH probe set, such as EWSR1-FLI1 or EWSR1-ERG) with other pathologic and clinical data to rule out other entities that involve this locus. RT-PCR can be used to directly demonstrate the EWSR1-FLI1 fusion transcript, but detection of the other less common ES EWSR1 fusion gene partners require additional RT-PCR testing with fusion gene–partner specific primers and/or possibly consensus primers. Both FISH and RT-PCR require specialized equipment and technical expertise, which are not as accessible as the equipment needed for IHC. RNA of inadequate quality to perform RT-PCR is also a limitation.
Extracellular vesicles from plasma have higher tumour RNA fraction than platelets
Published in Journal of Extracellular Vesicles, 2020
Kay Brinkman, Lisa Meyer, Anne Bickel, Daniel Enderle, Carola Berking, Johan Skog, Mikkel Noerholm
Secondly, biomarker detection must be sufficiently specific to distinguish the biomarker from the complex background of a biofluid sample. The specificity of detection is governed by the uniqueness of the biomarker and the ability to develop an assay that detects the biomarker without interference from the background. The decision of which fraction of a biofluid sample to use is determined by where the biomarker signal to background noise is most favourable. When a biomarker is very unique, e.g. an RNA fusion transcript or translocation (e.g. EML4-ALK), it is possible to create a very specific assay and it may not be necessary to fractionate the biofluid sample as exemplified by Bettegowda et al. who analysed gene rearrangements in the cell fraction rather than enriching for the circulating tumour cells [8], since any fractionation of the sample may lead to loss of copies of the biomarker. However, in case of expression profiling of RNA of tumour origin or detection of mutations that do not involve large translocations, it is beneficial to enrich the sample. Especially in expression analysis, the tumour- and background-RNAs are identical and it is impossible to distinguish the transcripts of tumour and non-tumour origin. Thus, any background copies of non-tumour origin are simply diluting the tumour signal and it is pivotal to use the biofluid compartment with the optimal biomarker-to-background ratio to ensure the least degree of dilution of tumour biomarker signal.