Reframing cancer: challenging the discourse on cancer and cancer drugs-a Norwegian perspective : Reframing Cancer.

BACKGROUND: As the range of therapeutic options in the field of oncology increases, so too does the strain on health care budgets. The imbalance between what is medically possible and financially feasible is frequently rendered as an issue of tragic choices, giving rise to public controversies around health care rationing. MAIN BODY: We analyse the Norwegian media discourse on expensive cancer drugs and identify four underlying premises: (1) Cancer drugs are de facto expensive, and one does not and should not question why. (2) Cancer drugs have an indubitable efficacy. (3) Any lifetime gained for a cancer patient is an absolute good, and (4) cancer patients and doctors own the truth about cancer. Applying a principle-based approach, we argue that these premises should be challenged on moral grounds. Within the Norwegian public discourse, however, the premises largely remain unchallenged due to what we find to be unjustified claims of moral superiority. We therefore explore alternative framings of the issue of expensive cancer drugs and discuss their potential to escape the predicament of tragic choices. CONCLUSIONS: In a media discourse that has seemingly stagnated, awareness of the framings within it is necessary in order to challenge the current tragic choices predicament the discourse finds itself in. In order to allow for a discourse not solely concerned with the issue of tragic choices, the premises that underlie it must be subjected to critical examination. As the field of oncology advances rapidly, we depend on a discussion of its opportunities and challenges that is meaningful, and that soberly addresses the future of cancer care-both its potential and its limits.

Titrating Complex Mass Cytometry Panels.

We describe here a simple and efficient antibody titration approach for cell-surface markers and intracellular cell signaling targets for mass cytometry. The iterative approach builds upon a well-characterized backbone panel of antibodies and analysis using bioinformatic tools such as SPADE. Healthy peripheral blood and bone marrow cells are stained with a pre-optimized "backbone" antibody panel in addition to the progressively diluted (titrated) antibodies. Clustering based on the backbone panel enables the titration of each antibody against a rich hematopoietic background and assures that nonspecific binding and signal spillover can be quantified accurately. Using a slightly expanded backbone panel, antibodies quantifying changes in transcription factors and phosphorylated antigens are titrated on ex vivo stimulated cells to optimize sensitivity and evaluate baseline expression. Based on this information, complex panels of antibodies can be thoroughly optimized for use on healthy whole blood and bone marrow and are easily adaptable to the investigation of samples from for example clinical studies. © 2019 The Authors. Cytometry Part A published by Wiley Periodicals, Inc. on behalf of International Society for Advancement of Cytometry.

Enhanced cognitive behaviour therapy (CBT-E) for severe and extreme anorexia nervosa in an outpatient eating disorder unit at a public hospital: a quality-assessment study.

BACKGROUND: The aim of this quality-assessment study was to determine the outcome of patients with severe and extreme anorexia nervosa (AN) in a real-world outpatient setting. METHODS: Twenty-one adults with AN and a body mass index (BMI) of < 16 were recruited from consecutive referrals to an outpatient clinic at a public hospital in Western Norway. All enrolled patients were provided with enhanced cognitive behaviour therapy (CBT-E) to treat their AN, commencing between January 2013 and December 2016. Their BMI was recorded at baseline, at the end of CBT-E and 1 year after the end of treatment. RESULTS: Ten patients completed the CBT-E treatment and achieved a large weight gain with the change remaining stable at follow-up. Eleven patients did not complete the treatment but had a significant increase in BMI at the premature end of treatment. One year after end of therapy 14/21 (66.7%) of the patients had BMI above 18.5 kg/m2. No severe complications were observed during therapy. CONCLUSIONS: Although 52.4% of the patients did not complete outpatient CBT-E, the findings of this quality-assessment study support previous findings indicating that CBT-E may represent a valid alternative to inpatient treatment in patients with severe and extreme AN.

Sex disparity in acute myeloid leukaemia with FLT3 internal tandem duplication mutations: implications for prognosis.

Incidence, molecular presentation and outcome of acute myeloid leukaemia (AML) are influenced by sex, but little attention has been directed at untangling sex-related molecular and phenotypic differences between female and male patients. While increased incidence and poor risk are generally associated with a male phenotype, the poor prognostic FLT3 internal tandem duplication (FLT3-ITD) mutation and co-mutations with NPM1 and DNMT3A are overrepresented in female AML. Here, we have investigated the relationship between sex and FLT3-ITD mutation status by comparing clinical data, mutational profiles, gene expression and ex vivo drug sensitivity in four cohorts: Beat AML, LAML-TCGA and two independent HOVON/SAKK cohorts, comprising 1755 AML patients in total. We found prevalent sex-associated molecular differences. Co-occurrence of FLT3-ITD, NPM1 and DNMT3A mutations was overrepresented in females, while males with FLT3-ITDs were characterized by additional mutations in RNA splicing and epigenetic modifier genes. We observed diverging expression of multiple leukaemia-associated genes as well as discrepant ex vivo drug responses, suggestive of discrete functional properties. Importantly, significant prognostication was observed only in female FLT3-ITD-mutated AML. Thus, we suggest optimization of FLT3-ITD mutation status as a clinical tool in a sex-adjusted manner and hypothesize that prognostication, prediction and development of therapeutic strategies in AML could be improved by including sex-specific considerations.

FLT3-ITD mutations in acute myeloid leukaemia - molecular characteristics, distribution and numerical variation.

Recurrent somatic internal tandem duplications (ITD) in the FMS-like tyrosine kinase 3 (FLT3) gene characterise approximately one third of patients with acute myeloid leukaemia (AML), and FLT3-ITD mutation status guides risk-adapted treatment strategies. The aim of this work was to characterise FLT3-ITD variant distribution in relation to molecular and clinical features, and overall survival in adult AML patients. We performed two parallel retrospective cohort studies investigating FLT3-ITD length and expression by cDNA fragment analysis, followed by Sanger sequencing in a subset of samples. In the two cohorts, a total of 139 and 172 mutant alleles were identified in 111 and 123 patients, respectively, with 22% and 28% of patients presenting with more than one mutated allele. Further, 15% and 32% of samples had a FLT3-ITD total variant allele frequency (VAF) < 0.3, while 24% and 16% had a total VAF ≥ 0.7. Most of the assessed clinical features did not significantly correlate to FLT3-ITD numerical variation nor VAF. Low VAF was, however, associated with lower white blood cell count, while increasing VAF correlated with inferior overall survival in one of the cohorts. In the other cohort, ITD length above 50 bp was identified to correlate with inferior overall survival. Our report corroborates the poor prognostic association with high FLT3-ITD disease burden, as well as extensive inter- and intrapatient heterogeneity in the molecular features of FLT3-ITD. We suggest that future use of FLT3-targeted therapy could be accompanied with thorough molecular diagnostics and follow-up to better predict optimal therapy responders.

Development of Personalized Molecular Therapy for Acute Myeloid Leukemia.

Acute myeloid leukemia (AML) is characterized by extensive clinical and biological heterogeneity. Despite vast advances in understanding the molecular pathology in AML during the last two decades few new AML therapeutics have been approved by the European Medicines Agency. Since 2005 only the epigenetic modulators decitabine and azacytidine, as well as histamine (plus interleukin- 2) have been approved against AML. None of these have outstanding efficiency, and decitabine and azacytdine have only been incorporated in frontline therapy of AML with limited enthusiasm. The majority of AML patients are frail and elderly, and lack of mild but effective agents for this patient cohort constitutes a major unmet need as overall survival remains poor. Along with the recent advancements in the molecular characterization of AML, numerous targeted therapies have been tested in clinical trials. In this review, we discuss the biological rationale for a selection of these novel therapeutic approaches, including epigenetic modifiers, agents targeting signalling pathways and inhibitors of nuclear-cytoplasmic shuttling. Further we discuss some of the possible shortcomings in current trial design that could explain the apparent incoherence between our improved biological knowledge and the lack of progress in therapy development of AML.

Targeted Therapy of FLT3 in Treatment of AML-Current Status and Future Directions.

Internal tandem duplications (ITDs) of the gene encoding the Fms-Like Tyrosine kinase-3 (FLT3) receptor are present in approximately 25% of patients with acute myeloid leukemia (AML). The mutation is associated with poor prognosis, and the aberrant protein product has been hypothesized as an attractive therapeutic target. Various tyrosine kinase inhibitors (TKIs) have been developed targeting FLT3, but in spite of initial optimism the first generation TKIs tested in clinical studies generally induce only partial and transient hematological responses. The limited treatment efficacy generally observed may be explained by numerous factors; extensively pretreated and high risk cohorts, suboptimal pharmacodynamic and pharmacokinetic properties of the compounds, acquired TKI resistance, or the possible fact that inhibition of mutated FLT3 alone is not sufficient to avoid disease progression. The second-generation agent quizartinb is showing promising outcomes and seems better tolerated and with less toxic effects than traditional chemotherapeutic agents. Therefore, new generations of TKIs might be feasible for use in combination therapy or in a salvage setting in selected patients. Here, we sum up experiences so far, and we discuss the future outlook of targeting dysregulated FLT3 signaling in the treatment of AML.