Lori J. Bernstein

Cytokines and their relationship to the symptoms and outcome of cancer

Tumours contain immune cells and a network of pro- and anti-inflammatory cytokines, which collaborate in the development and progression of cancer. Cytokine profiles might prove to be prognostic. The systemic effects of pro-inflammatory cytokines are associated with fatigue, depression and cognitive impairment, and can affect quality of life before, during and after treatment. In people with advanced cancer, pro-inflammatory cytokines are additionally associated with anorexia and cachexia, pain, toxicity of treatment and resistance to treatment. However, physical activity might modify cytokine levels and decrease fatigue in patients with cancer, and might also improve their prognosis.

The effects of encoding task on age-related differences in the functional neuroanatomy of face memory.

Age-related differences in brain activity mediating face recognition were examined using positron emission tomography. Participants encoded faces using a pleasant-unpleasant judgment, a right-left orientation task, and intentional learning. Scans also were obtained during recognition. Both young and old groups showed signficant effects of encoding task on recognition accuracy, but older adults showed reduced accuracy overall. Increased brain activity in older adults was similar to that seen in young adults during conditions associated with deeper processing, but was reduced during the shallow encoding and recognition conditions. Left prefrontal activity was less in older adults during encoding, but greater during recognition. Differential correlations of brain activity and behavior were found that suggest older adults use unique neural systems to facilitate face memory.

Long-term neurocognitive outcomes in young adult survivors of childhood acute lymphoblastic leukemia.

Five-year survival rates of childhood acute lymphoblastic leukemia (ALL) exceed 80% due to central nervous system-directed treatment including cranial radiation (CRT) and chemotherapy. However, these treatments are associated with neurocognitive compromise, the extent of which is correlated with higher dose and younger age at treatment. The aims of this study were to explore long-term neurocognitive outcomes in adult survivors of childhood ALL, and to identify measures sensitive to neurotoxicity in long-term survivors. We examined 24 adults who received 18 Gy CRT and chemotherapy for treatment of ALL between ages 2 and 15 years (median, 5.5). Time since diagnosis ranged from 6 to 26 years (median, 16.6). Younger age at diagnosis and longer time since diagnosis were associated with lower scores on a computerized battery that requires speed and accuracy across a number of domains (MicroCog), and other standardized neurocognitive tests. When compared with population norms, MicroCog indices were below average in survivors diagnosed with ALL before age 5, but only the reasoning/calculation index was below average in survivors diagnosed with ALL after age 5. In contrast, intelligence quotient (IQ) scores were average. In addition to confirming earlier studies showing that younger children are more vulnerable to treatment-related neurotoxicity, here we show that deficits exist many years post treatment even with a relatively lower dose of CRT, and that these deficits are especially evident on tasks involving rapid processing of information.

Auditory feature conjunction in patients with schizophrenia

The neural mechanisms supporting performance during single feature and feature conjunction tasks were investigated in patients with schizophrenia and age-matched controls using event-related brain potentials. In different blocks of trials, participants responded to auditory targets defined by one of two pitches, one of two locations, or both pitch and location. All participants were faster and more accurate in detecting targets defined by a single feature than for targets defined by a conjunction of features. Compared with the single feature conditions, conjunction targets were associated with enhanced negativity between 200 and 250ms (N2) post-stimulus and showed a delayed P3b latency. Compared with controls, patients with schizophrenia showed reduced N1 and N2 amplitude elicited by single and conjunctive targets. The results are consistent with defective perceptual mechanisms in schizophrenia. The fact that both performance and P3b amplitude were similar in patients and controls suggests that controlled processes compensate for processes normally carried out by early perceptual mechanisms.

Visual feature conjunction in patients with schizophrenia: an event-related brain potential study

The neural mechanisms supporting performance during single feature and feature conjunction detection were investigated in patients with schizophrenia and age-matched controls using event-related brain potentials. In different blocks of trials, participants responded to visual targets defined by one of two colors, one of two orientations, or both color and orientation. All participants were faster and more accurate in detecting targets defined by a single feature than for targets defined by a conjunction of features. Relative to controls, patients made more errors and were slower in detecting targets defined by a combination of features. Patients also generated a smaller N2 wave to single and conjunctive targets, and showed greater P3b reduction over the right hemisphere for conjunctive targets than for targets defined by color only. In addition, target stimuli generated an increased negativity at the occipital sites that varied in scalp distribution with the attended features in controls but not in patients. Both behavioral and electrophysiological data provide converging evidence for deficits in integrating visual features in schizophrenia and suggest that processing features of visual objects in schizophrenia are partly supported by distinct functional networks.

Binding visual features during high-rate serial presentation.

The neural mechanism supporting performance during single and feature conjunction detection was investigated using event-related brain potentials. In different blocks of trials, participants responded to visual targets defined by one of two colors, one of two orientations, or both color and orientation. Participants were faster and more accurate in detecting targets defined by a single feature than for targets defined by a conjunction of features. Compared with the single feature conditions, conjunction targets were associated with enhanced negativity between 230 and 270 ms post-stimulus and showed a delayed P3 latency. The relative timing of feature specific attention effects isolated in difference potential shows that feature conjunction occurs concurrently with the analysis of single features.

Cognitive Dysfunction after Chemotherapy For Breast Cancer

Approximately 13 million adult cancer survivors live in the United States; about 2 million of them were diagnosed over 20 years ago (National Cancer Institute, 2012). Current 5-year survival rates are close to 70% and rising, so the number of people living with the physical and mental health consequences of cancer and cancer treatment will increase. One of these consequences is cognitive decline, popularly known as chemo-brain. The papers in this symposium reflect some of the approaches used to understand the nature and course of cognitive decline in women with breast cancer. Oncology research has long recognized that cognition may be affected by cancer. This was attributed to distress until 1978, when cognitive symptoms in breast cancer patients were attributed to ‘‘organic brain syndrome’’ (Levine, Silverfarb, & Lipowski, 1978). The first reports documenting greater cognitive deficits in cancer patients treated with chemotherapy than in patients who did not receive chemotherapy were published in the early 1980s (Greer and Silberfarb, 1982; Oxman and Silberfarb, 1980; Silberfarb, 1983). Following a lull, Wieneke and Dienst (1995) showed that breast cancer survivors treated with chemotherapy performed more than two standard deviations below test norms on tests of memory, mental flexibility, processing speed, attention, visuospatial ability, and/or motor function. Performance was correlated with length of treatment but not depression or time since treatment. Since then, studies examining cancer, chemotherapy, and cognition have increased exponentially. However, the field is relatively new and there is a great deal we do not understand. Although many studies using self-reported concerns distinguish people who received chemotherapy from those who have not (Pullens, De Vries, & Roukema, 2010), cohort studies using standardized neuropsychological measures often reveal ‘‘average’’ abilities relative to population norms (Anderson-Hanley, Sherman, Riggs, Agocha, Compas, 2003; Correa & Ahles, 2008; Stewart, Bielajew, Collins, Parkinson, & Tomiak, 2006; Wefel & Schagen, 2012). Discrepancies between patients’ complaints and objective test performance (Bender et al., 2008; Castellon et al., 2004; Cimprich, So, Ronis, & Trask, 2005; Hermelink et al., 2007) are frustrating for cancer survivors who express concerns about concentration, memory, processing speed, word-finding, decision making, and problem solving (Pullens et al., 2010). These changes hinder people from returning to work, school, or household obligations (Oberst, Bradley, Gardiner, Schenk, & Given, 2010), and affect psychological well-being (Boykoff, Moieni, & Subramanian, 2009) as well as relationships with the medical team, family and friends (Munir, Burrows, Yarker, Kalawsky, & Bains, 2010). In young adults with cancer, 27% fail to return to school or work 15–35 months after diagnosis and 30% report memory, attention and processing speed problems (Parsons et al., 2012). Although cognitive decline may be one factor contributing to these outcomes, other reasons may underlie the discrepancy between subjective concerns and performance. Wefel and Schagen (this issue) provide compelling evidence that quiets suspicions about motivation or secondary gain (e.g., perhaps due to return to work, disability support, or other issues). Their analysis of large samples of breast cancer patients showed no evidence of noncredible performance on performance validity testing. Another challenge is making sense of variable results across studies. The divergence between subjective and objective deficits indicates that they are not identical constructs; direct measurement of performance is important to characterize abilities rather than only relying on patient report. Yet across crosssectional and longitudinal studies that use neuropsychological tools, either no impairment is found, or there is variability in which cognitive domains are impaired and the magnitude of impairment (see Vardy & Tannock, 2007 for review). These discrepancies may result from methodological differences, including but not limited to:

Outcomes toolbox for head and neck cancer research.

Clinical research in head and neck cancer traditionally focused on tumor control. As survival improves, it is increasingly recognized that the side‐effects of multimodality treatment can be profound and enduring. Thus, clinical trials require patient‐reported and functional outcomes.

Pretreatment Differences in Intraindividual Variability in Reaction Time between Women Diagnosed with Breast Cancer and Healthy Controls.

OBJECTIVES Chemotherapy has adverse effects on cognitive performance in women treated for breast cancer, but less is known about the period before chemotherapy. Studies have focused on mean level of performance, yet there is increasing recognition that variability in performance within an individual is also an important behavioral indicator of cognitive functioning and underlying neural integrity. METHODS We examined intraindividual variability (IIV) before chemotherapy and surgery in women diagnosed with breast cancer (n=31), and a healthy control group matched on age and education (n=25). IIV was calculated across trials of a computerized Stroop task, including an examination of the slowest and fastest trials of reaction time (RT) responses. RESULTS The groups were equivalent on overall accuracy and speed, and participants in both groups were less accurate and slower on incongruent trials compared with congruent trials. However, women with breast cancer became more variable with increased task difficulty relative to healthy controls. Among the slowest RT responses, women with breast cancer were significantly more variable than healthy controls on incongruent trials. This suggests that a specific variability-producing process (e.g., attentional lapses) occurs in task conditions that require executive control (e.g., incongruent trials). CONCLUSIONS Results are consistent with other evidence of executive dysfunction among women treated for breast cancer. These findings highlight the importance of pretreatment assessment and show that variability in performance provides information about cognition that measures of central tendency do not.

Executive functioning impairment in women treated with chemotherapy for breast cancer: a systematic review

PurposeWomen with breast cancer have reported adverse cognitive effects following chemotherapy. Evidence is mixed on whether executive functioning is particularly impaired in women treated with chemotherapy, in part due to the wide range of tasks used to measure executive processes. We performed a systematic review of the published literature to evaluate whether some subcomponents of executive functioning are more vulnerable to impairment than others among breast cancer survivors who had been treated with chemotherapy.MethodsStudies published as of April 2017 were identified using three electronic databases (MEDLINE, PsycINFO, and Web of Science) and a manual search of relevant reference lists. The methodological quality of included studies was assessed using a checklist of predefined criteria.ResultsOf 1280 identified articles, a total of 41 were included for review. Study findings were categorized into three primary subdomains of executive functioning: inhibition, shifting, and updating. Although there was heterogeneity in the neuropsychological measures used to assess executive functioning, tests could be grouped into the subcomponents they assessed. Inhibition appears relatively spared from the effects of chemotherapy, whereas impairments in shifting and updating are more commonly found following chemotherapy.ConclusionsExamination of subcomponents of executive functioning is recommended to better characterize the nature of executive dysfunction in women treated with chemotherapy. Future studies should include executive functioning tasks of varying complexity, use of multiple tasks to increase reliability, and alternative indices to capture performance, such as within-person variability.