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The last decade has seen rapid progress in the use of genomic tests, including gene panels, whole‐exome sequencing, and whole‐genome sequencing, in research and clinical cancer care. These advances have created expansive opportunities to characterize the molecular attributes of cancer, revealing a subset of cancer‐associated aberrations called driver mutations. The identification of these driver mutations can unearth vulnerabilities of cancer cells to targeted therapeutics, which has led to the development and approval of novel diagnostics and personalized interventions in various malignancies. The applications of this modern approach, often referred to as precision oncology or precision cancer medicine, are already becoming a staple in cancer care and will expand exponentially over the coming years. Although genomic tests can lead to better outcomes by informing cancer risk, prognosis, and therapeutic selection, they remain underutilized in routine cancer care. A contributing factor is a lack of understanding of their clinical utility and the difficulty of results interpretation by the broad oncology community. Practical guidelines on how to interpret and integrate genomic information in the clinical setting, addressed to clinicians without expertise in cancer genomics, are currently limited. Building upon the genomic foundations of cancer and the concept of precision oncology, the authors have developed practical guidance to aid the interpretation of genomic test results that help inform clinical decision making for patients with cancer. They also discuss the challenges that prevent the wider implementation of precision oncology. [ABSTRACT FROM AUTHOR]

We recently published results of targeted sequencing applied to 928 unselected cases of diffuse large B-cell lymphoma (DLBCL) listed in the Haematological Malignancy Research Network (HMRN) registry.1 Clustering allowed us to resolve five genomic subtypes. (D) IPI-adjusted hazard ratios for classified patients treated with R-CHOP (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine, prednisolone) are shown relative to the unclassified "Other" patients. Hazard ratios (HR) were calculated using a Cox model based on either overall survival or progression free survival, as indicated. gl In summary, we conclude that mutation-only data from targeted sequencing allows a confident LymphGen classification in just over 50% of patients. Unadjusted and IPI-adjusted hazard ratios for R-CHOP-treated patients classified by either Modified HMRN or the LymphGen classifier relative to the unclassified "Other" patients. [Extracted from the article]

The article presents a guideline for healthcare professionals on the investigation and management of eosinophilia, an elevation of the eosinophil count above levels observed in healthy subjects. Topics discussed include the causes of eosinophilia, how patients presenting with eosinophilia are diagnosed, and key recommendations for the treatment of eosinophilia.

The guideline group regarding the diagnosis and management of myelofibrosis was selected to be representative of UK-based medical experts, together with a contribution from a single expert from the USA. MEDLINE and EMBASE were searched systematically for publications in English from 1966 until August 2011 using a variety of key words. The writing group produced the draft guideline, which was subsequently revised by consensus of the members of the General Haematology and Haemato-oncology Task Forces of the British Committee for Standards in Haematology ( BCSH). The guideline was then reviewed by a sounding board of UK haematologists, the BCSH and the British Society for Haematology Committee and comments incorporated where appropriate. The criteria used to state levels and grades of evidence are as outlined in the Procedure for Guidelines commissioned by the BCSH; the ' GRADE' system was used to score strength and quality of evidence. The objective of this guideline is to provide healthcare professionals with clear guidance on the investigation and management of primary myelofibrosis, as well as post-polycythaemic myelofibrosis (post- PV MF) and post-thrombocythemic myelofibrosis (post- ET MF) in both adult and paediatric patients. [ABSTRACT FROM AUTHOR]

The hypoxia-inducible factors (HIFs; isoforms HIF-1, HIF-2, HIF-3) mediate many responses to hypoxia. Their regulation is principally by oxygen-dependent degradation, which is initiated by hydroxylation of specific proline residues followed by binding of von Hippel-Lindau (VHL) protein. Chuvash polycythemia is a disorder with elevated HIF. It arises through germline homozygosity for hypomorphic VHL alleles and has a phenotype of hematological, cardiopulmonary, and metabolic abnormalities. This study explores the phenotype of two other HIF pathway diseases: classic VHL disease and HIF-2 gain-of-function mutation. No cardiopulmonary abnormalities were detected in classic VHL disease. HIF-2 gain-of-function mutations were associated with pulmonary hypertension, increased cardiac output, increased heart rate, and increased pulmonary ventilation relative to metabolism. Comparison of the HIF-2 gain-of-function responses with data from studies of Chuvash polycythemia suggested that other aspects of the Chuvash phenotype were diminished or absent. In classic VHL disease, patients are germline heterozygous for mutations in VHL, and the present results suggest that a single wild-type allele for VHL is sufficient to maintain normal cardiopulmonary function. The HIF-2 gain-of-function phenotype may be more limited than the Chuvash phenotype either because HIF-1 is not elevated in the former condition, or because other HIF-independent functions of VHL are perturbed in Chuvash polycythemia. [ABSTRACT FROM AUTHOR]

Constitutive activation of Janus kinase (Jak) 2 is the most prevalent pathogenic event observed in the myeloproliferative disorders (MPD), suggesting that inhibitors of Jak2 may prove valuable in their management. Inhibition of the Aurora kinases has also proven to be an effective therapeutic strategy in a number of haematological malignancies. AT9283 is a multi-targeted kinase inhibitor with potent activity against Jak2 and Aurora kinases A and B, and is currently being evaluated in clinical trials. To investigate the therapeutic potential of AT9283 in the MPD we studied its activity in a number of Jak2-dependent systems. AT9283 potently inhibited proliferation and Jak2-related signalling in Jak2-dependent cell lines as well as inhibiting the formation of erythroid colonies from haematopoietic progenitors isolated from MPD patients with Jak2 mutations. The compound also demonstrated significant therapeutic potential in vivo in an ETV6-JAK2 ( TEL-JAK2) murine leukaemia model. Inhibition of both Jak2 and Aurora B was observed in the model systems used, indicating a dual mechanism of action. Our results suggest that AT9283 may be a valuable therapy in patients with MPD and that the dual inhibition of Jak2 and the Aurora kinases may potentially offer combinatorial efficacy in the treatment of these diseases. [ABSTRACT FROM AUTHOR]

This study looked for clonal diversity in patients with a myeloproliferative neoplasm associated with more than one acquired genetic lesion. A tyrosine kinase mutation and a cytogenetic lesion were present in the same clone in six of seven patients. By contrast, the genetic lesions were present in separate clones in all six patients with two tyrosine kinase pathway mutations. Moreover, in two patients the clones were genetically unrelated by X-chromosome inactivation studies. These data demonstrated clonal diversity in a subset of patients with early stage haematopoietic malignancy and showed, for the first time, that such clones may arise independently. [ABSTRACT FROM AUTHOR]

The article suggests to revise the British Committee for Standards in Haematology (BCSH) guidelines for myelofibrosis. It mentions the use of Janus kinase 1(JAK1) or Janus kinase 2(JAK2) inhibitor Ruxolitinib approved for use in the European Union and mutations in the Calreticulin gene (CALR) as the reason for revision in the guidelines. It adds that the previous guidelines recommends consideration of JAK inhibitor therapy for patients who fails hydroxycarbamide therapy.

A letter to the editor is presented in response to the article concerning the prevalence of JAK2 V617F and exon 12 mutations in polycythaemia vera.