Exploiting evolutionary principles to prolong tumor control in preclinical models of breast cancer.

Conventional cancer treatment strategies assume that maximum patient benefit is achieved through maximum killing of tumor cells. However, by eliminating the therapy-sensitive population, this strategy accelerates emergence of resistant clones that proliferate unopposed by competitors-an evolutionary phenomenon termed "competitive release." We present an evolution-guided treatment strategy designed to maintain a stable population of chemosensitive cells that limit proliferation of resistant clones by exploiting the fitness cost of the resistant phenotype. We treated MDA-MB-231/luc triple-negative and MCF7 estrogen receptor-positive (ER(+)) breast cancers growing orthotopically in a mouse mammary fat pad with paclitaxel, using algorithms linked to tumor response monitored by magnetic resonance imaging. We found that initial control required more intensive therapy with regular application of drug to deflect the exponential tumor growth curve onto a plateau. Dose-skipping algorithms during this phase were less successful than variable dosing algorithms. However, once initial tumor control was achieved, it was maintained with progressively smaller drug doses. In 60 to 80% of animals, continued decline in tumor size permitted intervals as long as several weeks in which no treatment was necessary. Magnetic resonance images and histological analysis of tumors controlled by adaptive therapy demonstrated increased vascular density and less necrosis, suggesting that vascular normalization resulting from enforced stabilization of tumor volume may contribute to ongoing tumor control with lower drug doses. Our study demonstrates that an evolution-based therapeutic strategy using an available chemotherapeutic drug and conventional clinical imaging can prolong the progression-free survival in different preclinical models of breast cancer.

Perfectionistic self-presentation and suicide in a young woman with major depression and psychotic features.

A woman in her midtwenties with a history of major depressive disorder and a recent major depressive episode with mood-congruent psychotic features died by suicide. Two weeks before her death, she demonstrated exceptional elevations on the nondisplay of imperfection factor of Hewitt and Flett's Perfectionistic Self-Presentation Scale. Perfectionism and especially perfectionistic self-presentation have been strongly associated with suicide across several populations, accounting for unique variance in suicidality beyond depression and hopelessness. Yet interpersonal facets of perfectionism are not recognized as clinical risk factors for suicide. There is also a paucity of research on perfectionism in relation to psychotic symptoms. This case account illustrates the role of perfectionistic self-presentation in suicides that occur seemingly without warning and, to our knowledge, this is the first examination of perfectionistic self-presentation and suicide in a case where psychotic features occurred. This study, though single case-based, draws attention to perfectionism and perfectionistic self-presentation and their potential roles in suicide, especially when accompanied by other risk factors. Future research in this area may elucidate the role of perfectionism in suicide, singularly and in the context of a comprehensive clinical risk assessment, demonstrating whether perfectionism confers information about suicide risk beyond known clinical risk factors.

Testing a modification of cognitive adaptation training: streamlining the model for broader implementation.

Cognitive adaptation training (CAT) is a home-based, manualized treatment that utilizes environmental supports to improve target behaviors and functional outcomes in persons with schizophrenia. Although clinical trials have shown CAT to be effective across functional, clinical, and treatment adherence domains, when the intervention is withdrawn clients experience significant declines. The aim of the current study was to test a modified version of CAT, which decreases the duration of intensive CAT intervention while utilizing ongoing case management-supported CAT to maintain the fundamental components of the treatment. Twenty-three people participated in an outcome study of the modified version of CAT, evaluating improvements after 4months of CAT specialist intervention and after an additional 5months of case manager support. Analysis revealed significant improvements in adaptive functioning, psychiatric symptomatology, and goal attainment, which were maintained throughout case management follow-up. This suggests that an intervention that has previously demonstrated good functional outcomes in randomized trials might sustain its impacts in an abbreviated format with support from existing case managers.

The VAGUS insight into psychosis scale--self-report and clinician-rated versions.

The aim of this study was to develop self-report and clinician-rated versions of an insight scale that would be easy to administer, sensitive to small changes, and inclusive of the core dimensions of clinical insight into psychosis. Ten-item self-report (VAGUS-SR) and five-item clinician-rated (VAGUS-CR) scales were designed to measure the dimensions of insight into psychosis and evaluated in 215 and 140 participants, respectively (www.vagusonline.com). Tests of reliability and validity were performed. Both the VAGUS-SR and VAGUS-CR showed good internal consistency and reliability. They demonstrated good convergent and discriminant validity. Both versions were strongly correlated with one another and with the Schedule for the Assessment of Insight and Birchwood Insight Scale. Exploratory factor analyses identified three possible latent components of insight. The VAGUS-CR and VAGUS-SR are valid, reliable and easy to administer. They are build on previous insight scales with separate clinician-rated and self-report versions. The VAGUS-SR exhibited a multidimensional factor structure. Using a 10-point Likert scale for each item, the VAGUS has the capacity to detect small, temporally sensitive changes in insight, which is essential for intervention studies with neurostimulation or rapidly acting medications.

Elevated brain monoamine oxidase A binding in the early postpartum period.

CONTEXT: The early postpartum period is a time of high risk for a major depressive episode (or postpartum depression), with a prevalence of 13%. During this time, there is a heightened vulnerability for low mood because postpartum blues is common. Severe postpartum blues can herald the onset of postpartum depression. The neurobiological mechanisms to explain postpartum blues and the high risk for the onset of postpartum depression in the first few weeks after delivery are unclear. Estrogen levels drop 100- to 1000-fold during the first 3 to 4 days postpartum, and changes in estrogen levels have an inverse relationship with monoamine oxidase A (MAO-A) density. However, MAO-A levels have never been measured in the early postpartum period. OBJECTIVE: To determine whether brain MAO-A binding is elevated in the early postpartum period. DESIGN: Case-control study. SETTING: Tertiary care academic psychiatric hospital in Toronto, Ontario, Canada. PARTICIPANTS: Fifteen healthy women who were 4 to 6 days postpartum and 15 healthy women who had not recently been postpartum underwent carbon 11-labeled harmine positron emission tomography scanning. All women were nonsmoking and medication free. MAIN OUTCOME MEASURE: MAO-A total distribution volume, an index of MAO-A density, was measured in prefrontal cortex, anterior cingulate cortex, anterior temporal cortex, thalamus, dorsal putamen, hippocampus, and midbrain. RESULTS: MAO-A total distribution volume was significantly elevated (mean, 43%) throughout all analyzed brain regions during the early postpartum period. CONCLUSIONS: Elevated MAO-A levels in the early postpartum period can be interpreted as a marker of a monoamine-lowering process that contributes to the mood change of postpartum blues. Rather than a purely psychosocial model, we propose a neurobiological model of estrogen decline, followed by elevated MAO-A binding, low mood, and subsequently a period of high risk for major depressive episodes. Our model has important implications for preventing postpartum depression and for developing therapeutic strategies that target or compensate for elevated MAO-A levels during postpartum blues.