A biological staging model for operable non-small cell lung cancer

Background Currently the best prognostic index for operable non-small cell lung cancer (NSCLC) is the TNM staging system. Molecular biology holds the promise of predicting outcome for the individual patient and identifying novel therapeutic targets. Angiogenesis, matrix metalloproteinases (MMP)-2 and -9, and the erb/HER type I tyrosine kinase receptors are all implicated in the pathogenesis of NSCLC. Methods A retrospective analysis of 167 patients with resected stage I-IIIa NSCLC and >60 days postoperative survival with a minimum follow up of 2 years was undertaken. Immunohistochemical analysis was performed on paraffin embedded sections for the microvessel marker CD34, MMP-2 and MMP-9, EGFR, and c-erbB-2 to evaluate the relationships between and impact on survival of these molecular markers. Results Tumour cell MMP-9 (HR 1.91 (1.23-2.97)), a high microvessel count (HR 1.97 (1.28-3.03)), and stage (stage II HR 1.44 (0.87-2.40), stage IIIa HR 2.21 (1.31-3.74)) were independent prognostic factors. Patients with a high microvessel count and tumour cell MMP-9 expression had a worse outcome than cases with only one (HR 1.68 (1.04-2.73)) or neither (HR 4.43 (2.29-8.57)) of these markers. EGFR expression correlated with tumour cell MMP-9 expression (p<0.001). Immunoreactivity for both of these factors within the same tumour was associated with a poor prognosis (HR 2.22 (1.45-3.41)). Conclusion Angiogenesis, EGFR, and MMP-9 expression provide prognostic information independent of TNM stage, allowing a more accurate outcome prediction for the individual patient. The development of novel anti-angiogenic agents, EGFR targeted therapies, and MMP inhibitors suggests that target specific adjuvant treatments may become a therapeutic option in patients with resected NSCLC.

Does stage of illness impact treatment response in bipolar disorder? Empirical treatment data and their implication for the staging model and early intervention

Objective: The staging model suggests that early stages of bipolar disorder respond better to treatments and have a more favourable prognosis. This study aims to provide empirical support for the model, and the allied construct of early intervention.

Methods: Pooled data from mania, depression, and maintenance studies of olanzapine were analyzed. Individuals were categorized as having had 0, 1–5, 6–10, or >10 prior episodes of illness, and data were analyzed across these groups.

Results: Response rates for the mania and maintenance studies ranged from 52–69% and 10–50%, respectively, for individuals with 1–5 previous episodes, and from 29–59% and 11–40% for individuals with >5 previous episodes. These rates were significantly higher for the 1–5 group on most measures of response with up to a twofold increase in the chance of responding for those with fewer previous episodes. For the depression studies, response rates were significantly higher for the 1–5 group for two measures only. In the maintenance studies, the chance of relapse to either mania or depression was reduced by 40–60% for those who had experienced 1–5 episodes or 6–10 episodes compared to the >10 episode group, respectively. This trend was statistically significant only for relapse into mania for the 1–5 episode group (p = 0.005).

Conclusion: Those individuals at the earliest stages of illness consistently had a more favourable response to treatment. This is consistent with the staging model and

Treatment response for acute depression is not associated with number of previous episodes: lack of evidence for a clinical staging model for major depressive disorder

Mental illness has been observed to follow a neuroprogressive course, commencing with prodrome, then onset, recurrence and finally chronic illness. In bipolar disorder and schizophrenia responsiveness to treatment mirrors these stages of illness progression, with greater response to treatment in the earlier stages of illness and greater treatment resistance in chronic late stage illness.

Using data from 5627 participants in 15 controlled trials of duloxetine, comparator arm (paroxetine, venlafaxine, escitalopram) or placebo for the treatment of an acute depressive episode, the relationship between treatment response and number of previous depressive episodes was determined. Data was dichotomised for comparisons between participants who had >3 previous episodes (n=1697) or ≤3 previous episodes (n=3930), and additionally for no previous episodes (n=1381) or at least one previous episode (n=4246). Analyses were conducted by study arm for each clinical trial, and results were then pooled.

There was no significant difference between treatment response and number of previous depressive episodes. This unexpected finding suggests that treatments to reduce symptoms of depression during acute illness do not lose efficacy for patients with a longer history of illness.

Clinical implications of a staging model for bipolar disorders

A model of staging in the field of bipolar disorder (BD) should offer a means for clinicians to predict response to treatment and more general outcome measures, such as the level of functioning and autonomy. The present staging model emphasizes the assessment of patients in the interepisodic period and includes: latent phase: individuals who present mood and anxiety symptoms and increased risk for developing threshold BD; Stage I – patients with BD who present well established periods of euthymia and absence of overt psychiatric morbidity between episodes; Stage II – patients who present rapid cycling or current axis I or II comorbidities; Stage III – patients who present a clinically relevant pattern of cognitive and functioning deterioration, as well as altered biomarkers; and Stage IV – patients who are unable to live autonomously and present altered brain scans and biomarkers. Such a model implies a longitudinal appraisal of clinical variables, as well as assessment of neurocognition and biomarkers in the interepisodic period. Staging facilitates understanding of the mechanisms underlying progression of the disorder, assists in treatment planning and prognosis and, finally, underscores the imperative for early intervention.

The potential utility of a staging model as a course specifier: a bipolar disorder perspective.

Staging models are widely used in clinical medicine, and offer an insight into the progressive nature of many disorders. In general, the earlier stages of illness may be associated with a better prognosis and a higher treatment response. Once chronicity is reached, more complex and invasive treatments may be required, and the utility of treatments may decline. There is evidence that treatment response is greatest in the early phases of the disorder. There is also a progressive social and psychological burden of ongoing illness. This is paralleled by the twin notions of neuroprotection, which is supported by increasing evidence that structural changes in the disorder may be progressive and reversible with algorithm appropriate treatment, and that of early intervention, which posits that the optimal window for intervention is early in the illness course. A staging model compliments existing and proposed classifications of bipolar disorder, adding a temporal dimension to a cross sectional view. It may inform treatment choice and prognosis, and could have utility as a course specifier.

Biomarkers and clinical staging in psychiatry

Personalized medicine is rapidly becoming a reality in today's physical medicine. However, as yet this is largely an aspirational goal in psychiatry, despite significant advances in our understanding of the biochemical, genetic and neurobiological processes underlying major mental disorders. Preventive medicine relies on the availability of predictive tools; in psychiatry we still largely lack these. Furthermore, our current diagnostic systems, with their focus on well-established, largely chronic illness, do not support a pre-emptive, let alone a preventive, approach, since it is during the early stages of a disorder that interventions have the potential to offer the greatest benefit. Here, we present a clinical staging model for severe mental disorders and discuss examples of biological markers that have already undergone some systematic evaluation and that could be integrated into such a framework. The advantage of this model is that it explicitly considers the evolution of psychopathology during the development of a mental illness and emphasizes that progression of illness is by no means inevitable, but can be altered by providing appropriate interventions that target individual modifiable risk and protective factors. The specific goals of therapeutic intervention are therefore broadened to include the prevention of illness onset or progression, and to minimize the risk of harm associated with more complex treatment regimens. The staging model also facilitates the integration of new data on the biological, social and environmental factors that influence mental illness into our clinical and diagnostic infrastructure, which will provide a major step forward in the development of a truly pre-emptive psychiatry.

Setting the stage : from prodrome to treatment resistance in bipolar disorder

Bipolar disorder is common, and both difficult to detect and diagnose. Treatment is contingent on clinical needs, which differ according to phase and stage of the illness. A staging model could allow examination of the longitudinal course of the illness and the temporal impact of interventions and events. It could allow for a structured examination of the illness, which could set the stage for algorithms that are tailored to the individuals needs. A staging model could further provide as structure for assessment, gauging treatment and outcomes. The model incorporates prodromal stages and emphasizes early detection and algorithm appropriate intervention where possible. At the other end of the spectrum, the model attempts to operationalize treatment resistance. The utility of the model will need to be validated by empirical research.

Staging childhoods : experiments in authentic theatre making practice with children

This practice-led PhD project investigates the ways in which society positions children through a broad set of social, cultural and historical considerations and examines these within the frame of theatre making. The study proposes a model of practice that moves beyond participant empowerment toward a more dynamic understanding of the creative process that sees adults and children working together to create mainstream artistic product. It contends that this model creates conditions conducive to authentic theatre making practice with children as evidenced in the researcher’s original performance work Joy Fear and Poetry.

Barrett's Esophagus and Associated Adenocarcinoma : studies on pathogenesis, clinical staging and cost-utility of cancer treatment

Esophageal and gastroesophageal junction (GEJ) adenocarcinoma is rapidly increasing disease with a pathophysiology connected to oxidative stress. Exact pre-treatment clinical staging is essential for optimal care of this lethal malignancy. The cost-effectiviness of treatment is increasingly important. We measured oxidative metabolism in the distal and proximal esophagus by myeloperoxidase activity (MPA), glutathione content (GSH), and superoxide dismutase (SOD) in 20 patients operated on with Nissen fundoplication and 9 controls during a 4-year follow-up. Further, we assessed the oxidative damage of DNA by 8-hydroxydeoxyguanosine (8-OHdG) in esophageal samples of subjects (13 Barrett s metaplasia, 6 Barrett s esophagus with high-grade dysplasia, 18 adenocarcinoma of the distal esophagus/GEJ, and 14 normal controls). We estimated the accuracy (42 patients) and preoperative prognostic value (55 patients) of PET compared with computed tomography (CT) and endoscopic ultrasound (EUS) in patients with adenocarcinoma of the esophagus/GEJ. Finally, we clarified the specialty-related costs and the utility of either radical (30 patients) or palliative (23 patients) treatment of esophageal/GEJ carcinoma by the 15 D health-related quality-of-life (HRQoL) questionnaire and the survival rate. The cost-utility of radical treatment of esophageal/GEJ carcinoma was investigated using a decision tree analysis model comparing radical, palliative, and hypothetical new treatment. We found elevated oxidative stress ( measured by MPA) and decreased antioxidant defense (measured by GSH) after antireflux surgery. This indicates that antireflux surgery is not a perfect solution for oxidative stress of the esophageal mucosa. Elevated oxidative stress in turn may partly explain why adenocarcinoma of the distal esophagus is found even after successful fundoplication. In GERD patients, proximal esophageal mucosal anti-oxidative defense seems to be defective before and even years after successful antireflux surgery. In addition, antireflux surgery apparently does not change the level of oxidative stress in the proximal esophagus, suggesting that defective mucosal anti-oxidative capacity plays a role in development of oxidative damage to the esophageal mucosa in GERD. In the malignant transformation of Barrett s esophagus an important component appears to be oxidative stress. DNA damage may be mediated by 8-OHdG, which we found to be increased in Barrett s epithelium and in high-grade dysplasia as well as in adenocarcinoma of the esophagus/GEJ compared with controls. The entire esophagus of Barrett s patients suffers from increased oxidative stress ( measured by 8-OhdG). PET is a useful tool in the staging and prognostication of adenocarcinoma of the esophagus/GEJ detecting organ metastases better than CT, although its accuracy in staging of paratumoral and distant lymph nodes is limited. Radical surgery for esophageal/GEJ carcinoma provides the greatest benefit in terms of survival, and its cost-utility appears to be the best of currently available treatments.

Model Unveiling

Dr. Gibson and others look at a model of the Brock Campus that includes the proposed Academic Staging Building (Mackenzie Chown Complex).

What decision rules might pink-footed geese use to depart on migration? An individual-based model

Decisions taken during migration can have a large effect on the fitness of birds. Migration must be accurately timed with food availability to allow efficient fueling but is also constrained by the optimal arrival date at the breeding site. The decision of when to leave a site can be driven by energetics (sufficient body stores to fuel flight), time-related cues (internal clock under photoperiodic control), or external cues (temperature, food resources). An individual based model (IBM) that allows a mechanistic description of a range of departure decision rules was applied to the spring migration of pink-footed geese (Anser brachyrhynchus) from wintering grounds in Denmark to breeding grounds on Svalbard via 2 Norwegian staging sites. By comparing predicted with observed departure dates, we tested 7 decision rules. The most accurate predictions were obtained from a decision rule based on a combination of cues including the amount of body stores, date, and plant phenology. Decision rules changed over the course of migration with the external cue decreasing in importance and the time-related cue increasing in importance for sites closer to breeding grounds. These results are in accordance with descriptions of goose migration, following the “green-wave”: Geese track the onset of plant growth as it moves northward in spring, with an uncoupling toward the end of the migration if time is running out. We demonstrate the potential of IBMs to study the possible mechanisms underlying stopover ecology in migratory birds and to serve as tools to predict consequences of environmental change.

Stochastic atmospheric assistance and the use of emergency staging sites by migrants

Numerous animals move vast distances through media with stochastic dynamic properties. Avian migrants must cope with variable wind speeds and directions en route, which potentially jeopardize fine-tuned migration routes and itineraries. We show how unpredictable winds affect flight times and the use of an intermediate staging site by red knots (Calidris canutus canutus) migrating from west Africa to the central north Siberian breeding areas via the German Wadden Sea. A dynamic migration model incorporating wind conditions during flight shows that flight durations between Mauritania and the Wadden Sea vary between 2 and 8 days. The number of birds counted at the only known intermediate staging site on the French Atlantic coast was strongly positively correlated with simulated flight times. In addition, particularly light-weight birds occurred at this location. These independent results support the idea that stochastic wind conditions are the main driver of the use of this intermediate stopover site as an emergency staging area. Because of the ubiquity of stochastically varying media, we expect such emergency habitats to exist in many other migratory systems, both airborne and oceanic. Our model provides a tool to quantify the effect of winds and currents en route.