How Should One be an Outsider?: Virginia Woolf's Common Reader as a Theory of Subjectivity in Interwar England

This project examines Virginia Woolf’s conceptualization of the outsider as a political position with recourse to the figure of the common reader she theorizes early in her writing career. Woolf’s common reader, I argue, is first and foremost a response to the interwar “battle of the brows.” Unique in their belief in the common reader, Woolf’s early essays on form and aesthetics ask readers to consider their position as consumers in relation to the writers who insisted upon the discourse of the great divide between high and middlebrow art. This project suggests the common reader is more than Woolf’s contribution to the “battle of the brows,” however, and it presents the common reader as the precursory figure in a theory of intersectional subjectivity that is the foundation for Woolf’s politics of everyday life, which reached maturity late in her career with the “Society of Outsiders.” Viewing the common reader this way helps connect Woolf’s later works, which are generally viewed as her more political writings, with her early, formally experimental works by way of a theory of subjectivity that makes one’s discursive subject position central to an outsider politics based on performative subversion. Woolf’s focus on subject positions and performative subversion marks hers as a politics of the body, and this work explores the role various social institutions, including the university, the military, the family, and the asylum, play in disciplining subjects and their bodies in Woolf’s fiction and essays. In texts including Jacob’s Room, Mrs Dalloway, A Room of One’s Own, Three Guineas, Between the Acts, as well as a number of Woolf’s shorter essays, I examine Woolf’s depictions of subjects, their bodies, and the institutions that shape and mould them, and through her theorization of the common reader and society of outsiders explore Woolf’s theory of subjectivity designed to confound and subvert these institutions using the very same bodies they sought to discipline and optimize to serve their ideological purposes

Near miss or standard of care? DPYD screening for cancer patients receiving fluorouracil

5-fluorouracil (5-FU) and its pro-drug capecitabine are widely used anticancer agents. Most 5-FU catabolism is dependent on dihydropyrimidine dehydrogenase (DPD) encoded by the DPYD gene, and DPYD variants that reduce DPD function increase 5-FU toxicity. Most DPD deficient patients are heterozygous and can be treated with reduced 5-FU dosing. We describe a patient with a genotype associated with near complete absence of DPD function, and severe and likely fatal toxicity with 5-FU treatment. The patient was treated effectively with alternative systemic therapy. Routine pretreatment DPYD genotyping is recommended by the European Medicines Agency, and guidelines for use of 5-FU in DPD deficient patients are available. However, outside the province of Quebec, routine pretreatment screening for DPD deficiency remains unavailable in Canada. It is likely our patient would have died from 5-FU toxicity under the current standard of care, but instead provides an example of the potential benefit of DPYD screening on patient outcomes

Grass silage for biorefinery – Separation efficiency and aerobic stability of silage and solid fraction

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Application of a policy framework for the public funding of drugs for rare diseases

BACKGROUND: In many countries, decisions about the public funding of drugs are preferentially based on the results of randomized trials. For truly rare diseases, such trials are not typically available, and approaches by public payers are highly variable. In view of this, a policy framework intended to fairly evaluate these drugs was developed by the Drugs for Rare Diseases Working Group (DRDWG) at the request of the Ontario Public Drug Programs. OBJECTIVE: To report the initial experience of applying a novel evaluation framework to funding applications for drugs for rare diseases. METHODS: Retrospective observational cohort study. MEASURES: Clinical effectiveness, costs, funding recommendations, funding approval. KEY RESULTS: Between March 2008 and February 2013, eight drugs were evaluated using the DRDWG framework. The estimated average annual drug cost per patient ranged from 28,000 to 1,200,000 Canadian dollars (CAD). For five drugs, full evaluations were completed, specific funding recommendations were made by the DRDWG, and funding was approved after risk-sharing agreements with the manufacturers were negotiated. For two drugs, the disease indications were determined to be ineligible for consideration. For one drug, there was insufficient natural history data for the disease to provide a basis for recommendation. For the five drugs fully evaluated, 32 patients met the predefined eligibility criteria for funding, and five were denied based on predefined exclusion criteria. CONCLUSIONS: The framework improved transparency and consistency for evaluation and public funding of drugs for rare diseases in Ontario. The evaluation process will continue to be iteratively refined as feedback on actual versus expected clinical and economic outcomes is incorporated. © 2014 Society of General Internal Medicine

OATP1B1 and tumour OATP1B3 modulate exposure, toxicity, and survival after irinotecan-based chemotherapy

Background: Treatment of advanced and metastatic colorectal cancer with irinotecan is hampered by severe toxicities. The active metabolite of irinotecan, SN-38, is a known substrate of drug-metabolising enzymes, including UGT1A1, as well as OATP and ABC drug transporters.Methods:Blood samples (n=127) and tumour tissue (n=30) were obtained from advanced cancer patients treated with irinotecan-based regimens for pharmacogenetic and drug level analysis and transporter expression. Clinical variables, toxicity, and outcomes data were collected.Results:SLCO1B1 521C was significantly associated with increased SN-38 exposure (P\u3c0.001), which was additive with UGT1A1∗28. ABCC5 (rs562) carriers had significantly reduced SN-38 glucuronide and APC metabolite levels. Reduced risk of neutropenia and diarrhoea was associated with ABCC2-24C/T (odds ratio (OR)=0.22, 0.06-0.85) and CES1 (rs2244613; OR=0.29, 0.09-0.89), respectively. Progression-free survival (PFS) was significantly longer in SLCO1B1 388G/G patients and reduced in ABCC2-24T/T and UGT1A1∗28 carriers. Notably, higher OATP1B3 tumour expression was associated with reduced PFS.Conclusions:Clarifying the association of host genetic variation in OATP and ABC transporters to SN-38 exposure, toxicity and PFS provides rationale for personalising irinotecan-based chemotherapy. Our findings suggest that OATP polymorphisms and expression in tumour tissue may serve as important new biomarkers

Cost-effectiveness of using a gene expression profiling test to aid in identifying the primary tumour in patients with cancer of unknown primary.

We aimed to investigate the cost-effectiveness of a 2000-gene-expression profiling (GEP) test to help identify the primary tumor site when clinicopathological diagnostic evaluation was inconclusive in patients with cancer of unknown primary (CUP). We built a decision-analytic-model to project the lifetime clinical and economic consequences of different clinical management strategies for CUP. The model was parameterized using follow-up data from the Manitoba Cancer Registry, cost data from Manitoba Health administrative databases and secondary sources. The 2000-GEP-based strategy compared to current clinical practice resulted in an incremental cost-effectiveness ratio (ICER) of $44,151 per quality-adjusted life years (QALY) gained. The total annual-budget impact was$36.2 million per year. A value-of-information analysis revealed that the expected value of perfect information about the test\u27s clinical impact was $4.2 million per year. The 2000-GEP test should be considered for adoption in CUP. Field evaluations of the test are associated with a large societal benefit.The Pharmacogenomics Journal advance online publication, 29 March 2016; doi:10.1038/tpj.2015.94

Second-line hormonal therapy for men with chemotherapy-naive, castration-resistant prostate cancer: American society of clinical oncology provisional clinical opinion

ASCO provisional clinical opinions (PCOs) offer direction to the ASCO membership after publication or presentation of potential practice-changing data. This PCO addresses second-line hormonal therapy for chemotherapy-näive men with castration-resistant prostate cancer (CRPC) who range from being asymptomatic with only biochemical evidence of CRPC to having documented metastases but minimal symptoms. Clinical Context The treatment goal for CRPC is palliation. Despite resistance to initial androgen deprivation therapy, most men respond to second-line hormonal therapies. However, guidelines have neither addressed second-line hormonal therapy for nonmetastatic CRPC nor provided specific guidance with regard to the chemotherapy-näive population. Recent Data Six phase III randomized controlled trials and expert consensus opinion inform this PCO. Provisional Clinical Opinion For men with CRPC, a castrate state should be maintained indefinitely. Second-line hormonal therapy (eg, antiandrogens, CYP17 inhibitors) may be considered in patients with nonmetastatic CRPC at high risk for metastatic disease (rapid prostate-specific antigen doubling time or velocity) but otherwise is not suggested. In patients with radiographic evidence of metastases and minimal symptoms, enzalutamide or abiraterone plus prednisone should be offered after discussion with patients about potential harms, benefits, costs, and patient preferences. Radium-223 and sipuleucel-T also are options. No evidence provides guidance about the optimal order of hormonal therapies for CRPC beyond second-line treatment. Prostate-specific antigen testing every 4 to 6 months is reasonable for men without metastases. Routine radiographic restaging generally is not suggested but can be considered for patients at risk for metastases or who exhibit symptoms or other evidence of progression. Additional information is available at www.asco.org/genitourinary-cancer-guidelines and www.asco.org/guidelineswiki