Positron Emission Tomography-Computed Tomography Compared with Invasive Mediastinal Staging in Non-small Cell Lung Cancer: Results of Mediastinal Staging in the Early Lung Positron Emission Tomography Trial

IntroductionPatients with non-small cell lung cancer (NSCLC) require careful preoperative staging to define resectability for potential cure. 18Fluorodeoxyglucose positron emission tomography combined with computed tomography (18FDG PET-CT) is widely used to stage NSCLC. If the mediastinum is positive on PET-CT examination, some practitioners conclude that the patient is inoperable and refer the patient for nonsurgical treatment.MethodsIn this analysis of a previously reported trial comparing PET-CT with conventional imaging in the diagnostic work-up of patients with clinical stage I, II, or IIIA NSCLC, we determined the accuracy of PET-CT in mediastinal staging compared with invasive mediastinal staging either by mediastinoscopy alone or by mediastinoscopy combined with thoracotomy.ResultsAll 149 patients had mediastinal nodal staging at mediastinoscopy alone (14), thoracotomy alone (64), or both (71). The sensitivity of PET-CT was 70% (95% confidence interval [CI], 48–85%), and specificity was 94% (95% CI, 88–97%). Of 22 patients with a PET-CT interpreted as positive for mediastinal nodes, 8 did not have tumor. The positive predictive value and negative predictive value were 64% (95% CI, 43–80%) and 95% (95% CI, 90–98%), respectively. Based on PET-CT alone, eight patients would have been denied potentially curative surgery if the mediastinal abnormalities detected by PET-CT had not been evaluated with an invasive mediastinal procedure.ConclusionsPET-CT assessment of the mediastinum is associated with a clinically relevant false-positive result. Our study confirms the need for pathologic confirmation of mediastinal lymph node abnormalities detected by PET-CT

Functional lung avoidance for individualized radiotherapy (FLAIR): Study protocol for a randomized, double-blind clinical trial.

BACKGROUND: Although radiotherapy is a key component of curative-intent treatment for locally advanced, unresectable non-small cell lung cancer (NSCLC), it can be associated with substantial pulmonary toxicity in some patients. Current radiotherapy planning techniques aim to minimize the radiation dose to the lungs, without accounting for regional variations in lung function. Many patients, particularly smokers, can have substantial regional differences in pulmonary ventilation patterns, and it has been hypothesized that preferential avoidance of functional lung during radiotherapy may reduce toxicity. Although several investigators have shown that functional lung can be identified using advanced imaging techniques and/or demonstrated the feasibility and theoretical advantages of avoiding functional lung during radiotherapy, to our knowledge this premise has never been tested via a prospective randomized clinical trial. METHODS/DESIGN: Eligible patients will have Stage III NSCLC with intent to receive concurrent chemoradiotherapy (CRT). Every patient will undergo a pre-treatment functional lung imaging study using hyperpolarized 3He MRI in order to identify the spatial distribution of normally-ventilated lung. Before randomization, two clinically-approved radiotherapy plans will be devised for all patients on trial, termed standard and avoidance. The standard plan will be designed without reference to the functional state of the lung, while the avoidance plan will be optimized such that dose to functional lung is as low as reasonably achievable. Patients will then be randomized in a 1:1 ratio to receive either the standard or the avoidance plan, with both the physician and the patient blinded to the randomization results. This study aims to accrue a total of 64 patients within two years. The primary endpoint will be a pulmonary quality of life (QOL) assessment at 3 months post-treatment, measured using the functional assessment of cancer therapy-lung cancer subscale. Secondary endpoints include: pulmonary QOL at other time-points, provider-reported toxicity, overall survival, progression-free survival, and quality-adjusted survival. DISCUSSION: This randomized, double-blind trial will comprehensively assess the impact of functional lung avoidance on pulmonary toxicity and quality of life in patients receiving concurrent CRT for locally advanced NSCLC. TRIAL REGISTRATION: Clinicaltrials.gov identifier: NCT02002052

Building the Field of Health Policy and Systems Research: An Agenda for Action

In the final article in a series addressing the current challenges and opportunities for the development of Health Policy and Systems Research (HPSR), Sara Bennett and colleagues lay out an agenda for action moving forward

A Canadian Study of Cisplatin Metabolomics and Nephrotoxicity (ACCENT): A Clinical Research Protocol

Background: Cisplatin, a chemotherapy used to treat solid tumors, causes acute kidney injury (AKI), a known risk factor for chronic kidney disease and mortality. AKI diagnosis relies on biomarkers which are only measurable after kidney damage has occurred and functional impairment is apparent; this prevents timely AKI diagnosis and treatment. Metabolomics seeks to identify metabolite patterns involved in cell tissue metabolism related to disease or patient factors. The A Canadian study of Cisplatin mEtabolomics and NephroToxicity (ACCENT) team was established to harness the power of metabolomics to identify novel biomarkers that predict risk and discriminate for presence of cisplatin nephrotoxicity, so that early intervention strategies to mitigate onset and severity of AKI can be implemented. Objective: Describe the design and methods of the ACCENT study which aims to identify and validate metabolomic profiles in urine and serum associated with risk for cisplatin-mediated nephrotoxicity in children and adults. Design: Observational prospective cohort study. Setting: Six Canadian oncology centers (3 pediatric, 1 adult and 2 both). Patients: Three hundred adults and 300 children planned to receive cisplatin therapy. Measurements: During two cisplatin infusion cycles, serum and urine will be measured for creatinine and electrolytes to ascertain AKI. Many patient and disease variables will be collected prospectively at baseline and throughout therapy. Metabolomic analyses of serum and urine will be done using mass spectrometry. An untargeted metabolomics approach will be used to analyze serum and urine samples before and after cisplatin infusions to identify candidate biomarkers of cisplatin AKI. Candidate metabolites will be validated using an independent cohort. Methods: Patients will be recruited before their first cycle of cisplatin. Blood and urine will be collected at specified time points before and after cisplatin during the first infusion and an infusion later during cancer treatment. The primary outcome is AKI, defined using a traditional serum creatinine-based definition and an electrolyte abnormality-based definition. Chart review 3 months after cisplatin therapy end will be conducted to document kidney health and survival. Limitations: It may not be possible to adjust for all measured and unmeasured confounders when evaluating prediction of AKI using metabolite profiles. Collection of data across multiple sites will be a challenge. Conclusions: ACCENT is the largest study of children and adults treated with cisplatin and aims to reimagine the current model for AKI diagnoses using metabolomics. The identification of biomarkers predicting and detecting AKI in children and adults treated with cisplatin can greatly inform future clinical investigations and practices

Discovering ligands for a microRNA precursor with peptoid microarrays

We have screened peptoid microarrays to identify specific ligands for the RNA hairpin precursor of miR-21, a microRNA involved in cancer and heart disease. Microarrays were printed by spotting a library of 7680 N-substituted oligoglycines (peptoids) onto glass slides. Two compounds on the array specifically bind RNA having the sequence and predicted secondary structure of the miR-21 precursor hairpin and have specific affinity for the target in solution. Their binding induces a conformational change around the hairpin loop, and the most specific compound recognizes the loop sequence and a bulged uridine in the proximal duplex. Functional groups contributing affinity and specificity were identified, and by varying a critical methylpyridine group, a compound with a dissociation constant of 1.9 μM for the miR-21 precursor hairpin and a 20-fold discrimination against a closely-related hairpin was created. This work describes a systematic approach to discovery of ligands for specific pre-defined novel RNA structures. It demonstrates discovery of new ligands for an RNA for which no specific lead compounds were previously known by screening a microarray of small molecules

Scientific overview: CSCI-CITAC annual general meeting and young investigator’s forum 2010

In 2010, the annual general meeting of the Clinical Investigator Trainee Association of Canada – Association des cliniciens-chercheurs en formation du Canada (CITAC-ACCFC) and the Canadian Society for Clinician Investigators (CSCI) was held between September 20 and 22 in Ottawa. Several globally-renowned scientists, including this year’s CSCI/Royal College Henry Friesen Award recipient, Dr. Paul Kubes, Distinguished Scientist Award recipient, Dr. Gideon Koren and Joe Doupe Young Investigator Award recipient, Dr. Torsten Neil, discussed a variety of topics relating to the role of technology in medicine. The meeting was well attended by clinician scientists and trainees from across Canada and offered trainees mentorship and networking opportunities in addition to showcasing their research at the young investigator forum. The aim of this scientific overview is to highlight the research presented by trainees at both the oral plenary session as well as the poster presentation sessions of this meeting. Similar to last year’s meeting [1], research questions being investigated by trainees covered the spectrum of medical disciplines, encompassing both basic science as well as clinical areas, and are summarized below. [1] Ong Tone, S., Dugani, S., Marshall, H., Shamji, M.F., Murray, J-C., and Bossé, D. 2010 Scientific overview of the CSCI-CITAC 2009 conference. Clin Invest Med 33: E69-72, E73-6