SummaryMolecular testing for the BCR-ABL1 fusion gene by real time quantitative polymerase chain reaction (RT-qPCR) is the most sensitive routine approach for monitoring the response to therapy of patients with chronic myeloid leukaemia. In the context of tyrosine kinase inhibitor (TKI) therapy, the technique is most appropriate for patients who have achieved complete cytogenetic remission and can be used to define specific therapeutic milestones. To achieve this effectively, standardization of the laboratory procedures and the interpretation of results are essential. We present here consensus best practice guidelines for RT-qPCR testing, data interpretation and reporting that have been drawn up and agreed by a consortium of 21 testing laboratories in the United Kingdom and Ireland in accordance with the procedures of the UK Clinical Molecular Genetics Society.
SummaryMolecular genetic assays for the detection of the JAK2 V617F (c.1849G>T) and other pathogenetic mutations within JAK2 exon 12 and MPL exon 10 are part of the routine diagnostic workup for patients presenting with erythrocytosis, thrombocytosis or otherwise suspected to have a myeloproliferative neoplasm. A wide choice of techniques are available for the detection of these mutations, leading to potential difficulties for clinical laboratories in deciding upon the most appropriate assay, which can lead to problems with inter-laboratory standardization. Here, we discuss the most important issues for a clinical diagnostic laboratory in choosing a technique, particularly for detection of the JAK2 V617F mutation at diagnosis. The JAK2 V617F detection assay should be both specific and sensitive enough to detect a mutant allele burden as low as 1-3%. Indeed, the use of sensitive assays increases the detection rate of the JAK2 V617F mutation within myeloproliferative neoplasms. Given their diagnostic relevance, it is also beneficial and relatively straightforward to screen JAK2 V617F negative patients for JAK2 exon 12 mutations (in the case of erythrocytosis) or MPL exon 10 mutations (thrombocytosis or myelofibrosis) using appropriate assays. Molecular results should be considered in the context of clinical findings and other haematological or laboratory results.
Assertion: Recommendations for following patients with Riata silicone-only leads for implantable cardioverter-defibrillators (ICDs) are not based on meaningful data, and SJM has not instituted clinical studies.Facts: We have conducted extensive bench and short-term studies, and on the basis of the scientific data and clinical experience, in which 85% of externalized conductors in returned leads functioned normally, we have worked with our independent medical advisory board to develop guidelines regarding care management. These guidelines have received support from both an expert panel of the Heart Rhythm Society and the Food and Drug Administration. No reports of a failure to pace or deliver a shock have been attributed to the presence of an externalized conductor.We recognize that externalized conductors still present complex care-management issues for physicians. To help inform future care-management recommendations, SJM initiated a 500-patient, multicenter study to evaluate the long-term performance of Riata silicone-only leads. SJM communicated all available information to physicians and regulatory bodies around the world, beginning in 2010. We updated physicians again in November 2011 and participated in a recent public physician forum on the topic, hosted by the Minneapolis Heart Institute Foundation.Assertion: There is no surveillance system in place to detect adverse events involving SJM's next-generation Durata leads.Facts: SJM created prospective, actively monitored registries to assess the performance of its Optim/Durata leads more than 5 years ago. 2,3 We feel that SJM has effective postmarketing surveillance to protect patient safety. We maintain three postmarketing-surveillance registries that include data on 10,836 leads that were implanted at 292 medical centers with more than 24,000 patient-years of experience representing the true clinical performance of Optim/Durata leads. To date, there have been no reports of externalization of conductors and a very low (0.09%) incidence of mechanical failure from any cause.Assertion: The Durata lead is similar in design to the Riata silicone-only lead.Facts: The Durata lead incorporates substantial design changes that considerably reduce the risk of externalization of conductors and improve overall reliability. These changes include increasing the insulation thickness by 50% with Optim (a material 50 times more abrasion-resistant than silicone) and repositioning the conductors in the lead to reduce cable tension. Furthermore, there have been no reports of externalization of conductors during the more than 5 years that the Durata lead has been on the market, with approximately 250,000 leads implanted worldwide.
Key Points• Germline JAK2V617I mutation as a sole genetic event does not suppress hematopoietic stem cells.• JAK2V617I induces weaker constitutive activation than JAK2V617F but considerable cytokine hyperresponsiveness.The association between somatic JAK2 mutation and myeloproliferative neoplasms (MPNs) is now well established. However, because JAK2 mutations are associated with heterogeneous clinical phenotypes and often occur as secondary genetic events, some aspects of JAK2 mutation biology remain to be understood. We recently described a germline JAK2V617I mutation in a family with hereditary thrombocytosis and herein characterize the hematopoietic and signaling impact of JAK2V617I. Through targeted sequencing of MPN-associated mutations, exome sequencing, and clonality analysis, we demonstrate that JAK2V617I is likely to be the sole driver mutation in JAK2V617I-positive individuals with thrombocytosis. Phenotypic hematopoietic stem cells (HSCs) were increased in the blood and bone marrow of JAK2V617I-positive individuals and were sustained at higher levels than controls after xenotransplantation. In signaling and transcriptional assays, JAK2V617I demonstrated more activity than wild-type JAK2 but substantially less than JAK2V617F. After cytokine stimulation, JAK2V617I resulted in markedly increased downstream signaling compared with wild-type JAK2 and comparable with JAK2V617F. These findings demonstrate that JAK2V617I induces sufficient cytokine hyperresponsiveness in the absence of other molecular events to induce a homogeneous MPN-like phenotype. We also provide evidence that the JAK2V617I mutation may expand the HSC pool, providing insights into both JAK2 mutation biology and MPN disease pathogenesis. (Blood. 2013;121(20):4156-4165)
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