Examining the impact of a leisure time intervention on participation in organized out-of-school activities among adolescents: a quasi-experimental study in Franklin County, KY, USA.

Guided by the Icelandic Prevention Model, a community-led coalition in Franklin County, KY, aimed to subsidize costs for participation in supervised organized leisure time programs among its youth via adaptation of the Reykjavik City Leisure Card program, locally known as the 'YES Card' voucher program. This study examined whether the proportion of students participating in supervised out-of-school activities and sports was higher in the YES Card intervention group compared to a similar group of youth who did not receive the voucher across two time points. Two waves of survey data were collected in one intervention middle school and two geographically and demographically similar comparison schools in 2020 (n for intervention = 112, n for comparison = 723) and 2021 (n for intervention = 134, n for comparison = 873). The expected age of students ranged between 12 and 15 years. Analyses were conducted using logistic regression. The YES Card receivers were two-and-a-half times more likely to participate in nonsport organized recreational activities [odds ratio, OR, 2.43 (95% confidence interval, CI, 1.07-5.52)] and almost twice as likely to participate in sports [OR: 1.91 (95%CI: 1.08-3.38)] over the 1-year study period, compared to non-YES Card youth. We conclude that Franklin County in KY in the USA has successfully adapted the Reykjavik City Leisure time voucher program.

Tibetan sound meditation for cognitive dysfunction: results of a randomized controlled pilot trial.

OBJECTIVE: Although chemotherapy-induced cognitive impairment is common among breast cancer patients, evidence for effective interventions addressing cognitive deficits is limited. This randomized controlled trial examined the feasibility and preliminary efficacy of a Tibetan Sound Meditation (TSM) program to improve cognitive function and quality of life in breast cancer patients. METHODS: Forty-seven breast cancer patients (mean age 56.3 years), who were staged I-III at diagnosis, 6-60 months post-chemotherapy, and reported cognitive impairment at study entry were recruited. Participants were randomized to either two weekly TSM sessions for 6 weeks or a wait list control group. Neuropsychological assessments were completed at baseline and 1 month post-treatment. Self-report measures of cognitive function (Functional Assessment of Cancer Therapy (FACT)-Cog), quality of life (SF-36), depressive symptoms (Center for Epidemiologic Studies Depression Scale), sleep disturbance (Pittsburgh Sleep Quality Index), fatigue (Brief Fatigue Inventory), and spirituality (FACT-Sp) were completed at baseline, the end of treatment, and 1 month later. RESULTS: Relative to the control group, women in the TSM group performed better on the verbal memory test (Rey Auditory Verbal Learning Test trial 1) (p = 0.06) and the short-term memory and processing speed task (Digit Symbol) (p = 0.09) and reported improved cognitive function (p = 0.06), cognitive abilities (p = 0.08), mental health (p = 0.04), and spirituality (p = 0.05) at the end of treatment but not 1 month later. CONCLUSIONS: This randomized controlled trial revealed that TSM program appears to be a feasible and acceptable intervention and may be associated with short-term improvements in objective and subjective cognitive function as well as mental health and spirituality in breast cancer patients.

Time for a new era in the evaluation of targeted therapies for patients with chronic myeloid leukemia: inclusion of quality of life and other patient-reported outcomes.

Health-related quality of life (HRQOL) and other patient-reported outcomes (PROs) might be crucial in comparing effectiveness of treatments as they could provide invaluable information to better inform clinical decision-making. This is particularly true in the era of targeted therapies (TT). A systematic review was undertaken on all studies with CML patients published from 1980 to 2010 and including a PRO evaluation. Out of 619 articles scrutinized, 15 met eligibility criteria and no study was published before 1995. Six dealt mainly with interferon-based therapies, 7 with bone marrow transplantation and only 2 evaluated PROs in the context of TT. No disease-specific, validated PRO instrument for these patients was found. The main evidence being that Imatinib provides clear advantage in terms of HRQOL over interferon-based treatments. There is lack of data concerning PROs in patients treated with current TT. Documenting HRQOL and side effects of CML treatments, from the patients' perspective is needed to evaluate overall treatment effectiveness and net clinical benefit of newer therapeutic strategies.

A randomized trial on the efficacy of methylphenidate and modafinil for improving cognitive functioning and symptoms in patients with a primary brain tumor.

Limited research is available regarding the efficacy of psychostimulants in treating cognitive function in primary brain tumor patients. An open-label, randomized, pilot trial examined both the general and differential efficacy of 4 weeks of methylphenidate (MPH) and modafinil (MOD) in 24 brain tumor patients. Participants completed cognitive tests and self-report measures of fatigue, sleep disturbance, mood and quality of life at baseline and after 4 weeks.Following stimulant treatment, there was evidence of a beneficial effect on test performance in speed of processing and executive function requiring divided attention. Patients with the greatest deficit in executive function at baseline appeared to derive the greatest benefit following stimulant therapy. Inconsistent, differential effects were found on a measure of attention in favor of MPH and on a measure of processing speed in favor of MOD. There was also evidence of a general beneficial effect on patient-reported measures of fatigue, mood, and quality of life, with no statistically significant differences between treatment arms in these measures over time. The results from this small pilot study should be interpreted with caution, but appear to warrant additional research, in larger study samples, targeting fatigue, processing speed and executive function, and exploring different doses of stimulants. Future studies may also wish to explore the specific patient factors that may be associated with responsiveness to psychostimulant treatment.

Neuropsychological dysfunction associated with cancer and cancer therapies: a conceptual review of an emerging target.

Neuropsychological dysfunction associated with cancer and cancer treatment is a growing concern. Methodological limitations permeate the corpus of research in this area and have limited our understanding of the multifactorial nature of this process. The following review provides a summary of the current state of knowledge and highlights future directions.

A prospective study of the incidence and open-label treatment of interferon-induced major depressive disorder in patients with hepatitis C.

Interferon (IFN) therapy has been associated with the development of Major Depressive Disorder (MDD) when given to patients with hepatitis C (HCV). The incidence, time course, risk factors, and treatment of IFN-induced MDD are poorly understood. The objectives of the present study were to determine the incidence of IFN-induced MDD, as well as to determine the efficacy of open-label antidepressant treatment, in particular selective serotonin reuptake inhibitors (SSRIs) for IFN-induced MDD. Thirty-nine HCV patients on IFN therapy were monitored weekly using the Beck Depression Inventory (BDI). Those who became depressed were treated with citalopram, a SSRI antidepressant. Main outcome measures included the incidence of IFN-induced MDD, as well as response rates to antidepressants in those patients who developed IFN-induced MDD. Our results showed that 13 of 39 patients (33%) developed IFN-induced MDD. There were no differences in age, gender, past history of MDD, or substance use between those who became depressed and those who did not. However, there were significantly fewer African American patients in the depressed group. Patients who developed IFN-induced MDD were on IFN therapy for an average of 12.1 weeks prior to the development of MDD. Eleven of 13 patients (85%) were responsive to antidepressant treatment. We conclude that IFN-induced MDD is common in HCV patients. Health care providers should follow IFN-treated HCV patients for the development of MDD, particularly between the 2nd and 5th months of IFN therapy. SSRIs, in particular citalopram, are an effective treatment for IFN-induced depression in HCV patients.

Phase II study of accelerated fractionation radiation therapy with carboplatin followed by PCV chemotherapy for the treatment of anaplastic gliomas.

PURPOSE: To conduct a Phase II one-arm study to evaluate the long-term efficacy and safety of accelerated fractionated radiotherapy combined with i.v. carboplatin for patients with previously untreated anaplastic gliomas. METHODS AND MATERIALS: Between 1988 and 1992, 90 patients received 1.9-2.0-Gy radiation 3 times a day with 2-h infusions of 33 g/m(2) carboplatin for two 5-day cycles separated by 2 weeks. After radiotherapy, patients received procarbazine, lomustine (CCNU), and vincristine (PCV) for 1 year or until the tumor progressed. RESULTS: Ninety patients were evaluable for analysis. Histologically, 69 had anaplastic astrocytoma; 14, anaplastic oligoastrocytoma; and 7, anaplastic oligodendroglioma. Gross total resection was performed in 20 (22%), subtotal resection in 45 (50%), and biopsy in 25 (28%); reoperation (total or subtotal resection) was performed in 50 (56%) patients. A multivariate analysis showed that a younger age (p = 0.026), Karnofsky performance score (KPS; p = 0.009), and brain necrosis (p = 0.0002) were predictive of a better survival. Results from analysis of extent of surgery (biopsy, subtotal resection, gross total resection) approached significance (p = 0.058). Radiation dose, irradiated tumor volume, and techniques used (boost and fields) were not significant variables. The median survival (MS) of all anaplastic glioma patients was 28.1 months; for anaplastic astrocytoma patients, MS was 28.7 months and 40.8 months for the combined anaplastic oligodendroglioma/oligoastrocytoma patients. Long-term survival occurred in 25% of anaplastic glioma patients who were alive 8.6 years after treatment was initiated. Treatment-induced necrosis was documented by surgery or autopsy in 19 (21%) patients; 21 (23%) had a mixed pattern of necrosis and tumor; and an additional 13 (14%) patients who did not have surgical or autopsy demonstration of predominant radiation necrosis had magnetic resonance imaging (MRI) evidence of radiation necrosis. Serious clinical neurologic deterioration and/or dementia requiring full-time caregiver attention were observed in 9 (10%) patients. CONCLUSION: When comparable selection criteria are applied, the rate of MS in this study is inferior to results attainable with current radiation and chemotherapy approaches, although the rates of long-term survival are comparable. Theoretically, patients failing therapy and dying earlier than anticipated may be because of excessive central nervous system (CNS) toxicity resulting from the combination of accelerated fractionated irradiation, intensive carboplatin chemotherapy before each radiation fraction, and postirradiation PCV chemotherapy. On the other hand, patients with treatment-induced necrosis survived significantly longer than patients who did not demonstrate MRI or histologic evidence of necrosis (MS, 106 months vs. 18-33 months).

Cognitive and mood disturbance as causes and symptoms of fatigue in cancer patients.

Fatigue, cognitive dysfunction, and depression are very common in cancer patients. A relationship among the three entities is recognized but poorly understood. Factors that contribute to this poor understanding are the subjective nature of the symptoms, multiple potential causes, and a lack of reliable assessment tools. An understanding of fatigue in cancer patients may benefit from studies of chronic fatigue syndrome (CFS) and other nonmalignant diseases indicating that cognitive impairment varies with physical and mental fatigue, and that symptoms of depression experienced by patients with physical illnesses and primary mood disorders are qualitatively different. The multidimensional nature of fatigue suggests that interventions should be patient-specific. They could be related to lifestyle or involve the use of specific behavioral or pharmacologic therapies. As is the case with depression and cognitive disorders, targeted interventions against cancer-related fatigue will benefit from a better understanding of its potential biologic causes. Consideration of cognitive dysfunction and depression complicates the understanding of cancer-related fatigue; however, it provides opportunities to assist patients who must deal with this serious problem.

Phase II trial and pharmacokinetic evaluation of cytosine arabinoside for leptomeningeal metastases from breast cancer.

PURPOSE: To determine the efficacy and pharmacokinetics of intraventricular cytosine arabinoside (Ara-C) as front-line treatment for leptomeningeal metastases from breast cancer. METHODS: Ten patients newly diagnosed with leptomeningeal metastases (LMM) from breast cancer were treated with 100 mg intraventricular cytosine arabinoside (IVT Ara-C) via an Ommaya reservoir. Treatment was administered three times a week for 2 weeks, then once a week for 4 weeks, and then once every 6 weeks for four cycles to responding patients. Nine patients were evaluable clinically, and seven patients underwent testing to determine the pharmacokinetic profile of Ara-C in the cerebrospinal fluid (CSF). RESULTS: Two patients had partial responses lasting 9 and 40 weeks, respectively. Two other patients had stable disease. The median survival duration was 30 weeks (range: 5-58 weeks). Seven patients died from LMM. Acute toxic effects associated with IVT Ara-C included meningismus, nausea, vomiting, and myelosuppression. The median peak Ara-C level in CSF was 16.69+/-6.30 mM (SD). The half life for elimination was 1.45+/-0.61 h (SD) There was no drug accumulation between courses. Neuropsychological evaluations were completed in eight patients, six (75%) of whom had preexisting cognitive deficits. Their condition generally improved over the course of treatment until the LMM progressed. No neurotoxic side effects of IVT Ara-C were observed in the two patients who had normal baseline cognitive assessments. CONCLUSIONS: IVT Ara-C at this dose and schedule has minimal activity as initial treatment for LMM from breast cancer despite achievement of high peak levels of the drug in the cerebrospinal fluid. A liposomal Ara-C formulation is currently under investigation.

NGF gene transfer to intrinsic basal forebrain neurons increases cholinergic cell size and protects from age-related, spatial memory deficits in middle-aged rats.

Administration of nerve growth factor (NGF) by intracerebroventricular infusion or transplantation of NGF-secreting cells to the basal forebrain improves spatial memory in aged animals. Using the adeno-associated virus (AAV) vector system, basal forebrain neurons were transduced to produce NGF ectopically for long intervals (at least 9 months). Rats received intraseptal injections of either the control vector, pTR-UF4, or the pTR-NGFmyc at 3 months of age, prior to testing their performance in the Morris water task. An age-related decrease in the acquisition of the hidden platform location was found at 12 months of age in the pTR-UF4 control group, but not in the pTR-NGFmyc group. Further, when compared to 3 month old untreated animals, the control group, but not the pTR-NGFmyc group, was impaired at 12 months of age. Concomitant to preventing age-related memory deficits, the NGF gene transfer increased cholinergic neuron size by 34% in the medial septum. This approach may therefore represent a viable therapy for age-related dementia involving dysfunction in cholinergic activity and memory, such as Alzheimer's disease.

Cognitive function as a predictor of survival in patients with recurrent malignant glioma.

PURPOSE: To determine the contribution of cognitive function in predicting the survival of patients with recurrent malignant brain tumors. PATIENTS AND METHODS: A total of 80 patients with recurrent glioblastoma multiforme or anaplastic astrocytoma were seen for baseline evaluations before beginning a phase I or phase II clinical trial. Each patient received a battery of nine brief tests measuring cognitive function, ability to perform activities of daily living (ADLs), and quality of life (QOL). Tests were given monthly after treatment was begun. RESULTS: Performance on a test of verbal memory was independently and strongly related to survival after accounting for age, Karnofsky performance status score, histology, and time since diagnosis. Models incorporating three of nine and all nine tests in the battery accounted for significantly more variance in survival than did the clinical variables alone. Measures of QOL and ADLs (bathing, feeding, and so on) were not independently related to survival, although they provide clinical information that is important for patient care. CONCLUSION: These results indicate that a multifaceted assessment of cognition, QOL, and patient function is practical for brain tumor patients in clinical trials and can provide information regarding the relative risks versus benefits of new treatment regimens that supplements the information from the usual clinical variables.

Neurocognitive dysfunction in cancer patients.

Many cancer patients experience impairments of neurocognitive function, including memory loss, distractibility, difficulty in performing multiple tasks (multitasking), and a myriad of other symptoms. Patients may also concurrently suffer from mood disturbance and symptoms that compromise their ability to function adequately, including fatigue and pain. The etiologies of these problems are diverse and include the direct effects of cancer within the central nervous system (CNS), indirect effects of certain cancers (e.g., paraneoplastic brain disorders), and both diffuse and highly specific effects of cancer treatments on the brain. In addition to these cancer-related causes, patients may have coexisting neurologic or psychiatric disorders that affect their cognition and mood. Careful assessment of patients complaining of neurocognitive or behavioral problems is essential to providing appropriate interventions and maximizing their ability to carry out usual activities.

Neurocognitive effects of therapeutic irradiation for base of skull tumors.

PURPOSE: To determine whether radiation therapy delivered to the paranasal sinuses causes any long-term impairment in neurocognitive function as a result of incidental brain irradiation. METHODS AND MATERIALS: Nineteen patients who received paranasal sinus irradiation at least 20 months and up to 20 years before assessment were given a battery of neuropsychologic tests of cognitive function. Radiation was delivered by a three-field (one anteroposterior and two lateral) technique. The median radiation dose was 60 Gy (range 50-68 Gy) in fractions of 1.8 to 2 Gy. The volume of irradiated brain was calculated from planning computed tomography slices or simulation films. The results of the neuropsychologic tests were compared to normative control values. RESULTS: Memory impairment was found in 80% of the patients, and one-third manifested difficulty with visual-motor speed, frontal lobe executive functions, and fine motor coordination. Two of the patients had frank brain necrosis with resultant dementia and blindness, and three had evidence of brain atrophy. Three of the fourteen patients without documented cerebral atrophy or necrosis were disabled from their normal activities. Three patients also developed pituitary dysfunction. Neurocognitive symptoms were related to the total dose of radiation delivered but not to the volume of brain irradiated, side of radiation boost, or chemotherapy treatment. The pattern of test findings was consistent with radiation injury to subcortical white matter. CONCLUSIONS: Radiation therapy for paranasal sinus cancer may cause delayed neurocognitive side effects. Currently, however, the development of severe adverse effects appears to be decreasing because of improvements in the techniques used to deliver radiation. Lowering the total dose and improving dose distributions should further decrease the incidence of delayed brain injury due to radiation.

Peptides corresponding to the N and C termini of IkappaB-alpha, -beta, and -epsilon as probes of the two catalytic subunits of IkappaB kinase, IKK-1 and IKK-2.

The signal-inducible phosphorylation of serines 32 and 36 of IkappaB-alpha is the key step in regulating the subsequent ubiquitination and proteolysis of IkappaB-alpha, which then releases NF-kappaB to promote gene transcription. The multisubunit IkappaB kinase (msIKK) responsible for this phosphorylation contains two catalytic subunits, termed IKK-1 and IKK-2. Using recombinant IKK-2, a kinetic pattern consistent with a random, sequential binding mechanism was observed with the use of a peptide corresponding to amino acids 26-42 of IkappaB-alpha. Values of 313 microM, 15.5 microM, and 1.7 min(-1) were obtained for K(peptide), K(ATP), and k(cat), respectively. The value of alpha, a factor by which binding of one substrate changes the dissociation constant for the other substrate, was determined to be 0.2. Interestingly, the recombinant IKK-1 subunit gave similar values for alpha and K(ATP), but values of 1950 microM and 0.016 min(-1) were calculated for K(peptide) and k(cat), respectively. This suggests that the IKK-2 catalytic subunit provides nearly all of the catalytic activity of the msIKK complex with the IKK-1 subunit providing little contribution to catalysis. Using peptides corresponding to different regions of IkappaB-alpha within amino acids 21-47, it was shown that amino acids 31-37 provide most binding interactions (-4.7 kcal/mol of binding free energy) of the full-length IkappaB-alpha (-7.9 kcal/mol) with the IKK-2. This is consistent with the observation that IKK-2 is able to phosphorylate the IkappaB-beta and IkappaB-epsilon proteins, which have consensus phosphorylation sites nearly identical to that of amino acids 31-37 of IkappaB-alpha. A peptide corresponding to amino acids 279-303 in the C-terminal domain of IkappaB-alpha was unable to activate IKK-2 to phosphorylate an N-terminal peptide, which is in contrast to the results observed with the msIKK. Moreover, the IKK-2 catalyzes the phosphorylation of the full-length IkappaB-alpha and the amino acid 26-42 peptide with nearly equal efficiency, while the msIKK catalyzes the phosphorylation of the full-length IkappaB-alpha 25,000 times more efficiently than the 26-42 peptide. Therefore, the C terminus of IkappaB-alpha is important in activating the msIKK through interactions with subunits other than the IKK-2.

Mood and cognitive disorders in cancer patients receiving cytokine therapy.

Chronic treatment with cytokines is associated with the development of mood and cognitive changes that suggests frontal-subcortical cerebral dysfunction. There is large individual variability in the type and severity of specific symptoms that are reported. The CNS effects of cytokines can be disassociated from the effects of chronic disease, other treatments and medications, and psychological responses to illness. The length of treatment and dose are both important factors in the development of mood disturbance. The finding that treatment chronicity is important makes long-term follow-up of patients on cytokine therapy all the more vital. Most adverse effects of cytokines improve with appropriate treatment of symptoms, although dose reduction or cessation of therapy may be necessary in individual cases. Future studies will be needed to better identify at-risk individuals, to compare the efficacy of various interventions, including antidepressants, stimulants, and opiate antagonists, and to assess the feasibility of treating at-risk individuals prophylactically.

The hippocampus: normal anatomy and pathology.

The hippocampus is a complex and fascinating region of the brain that has enormous clinical significance. Specifically, small imaging abnormalities may cause major symptoms. We believe that the detection of these lesions will be improved if imaging clinicians have an organized reference that facilitates identification of the cellular zones that comprise the hippocampus.

Klüver-Bucy syndrome after bilateral selective damage of amygdala and its cortical connections.

Isolated symmetric damage to the amygdala and their cortical connections occurred in an individual following cancer treatment. The lesions were imaged after reversal of hyponatremia. The patient displayed marked behavioral changes including visual agnosia, hypersexuality, hyperorality, a tendency to react to every visual stimulus, and memory deficits. The cluster of neurobehavioral symptoms is similar to previously reported accounts of Klüver-Bucy syndrome and suggests the importance of bilateral amygdala involvement in these behavioral changes.

Neurobehavioral functioning of adults with pituitary disease.

Neurobehavioral disorders are not infrequent in adults with pituitary disease. The disorders can be due to compression of brain structures important for cognitive and emotional function, effects of hormonal imbalance on sensitive structures, post-surgical disruption of connecting pathways, adverse reactions to medical therapy, and adverse delayed effects of radiation therapy. A multidisciplinary team approach to the treatment of pituitary tumors will allow for the early diagnosis of neurobehavioral disorders and the institution of pharmacologic and behavioral interventions.

Methylphenidate therapy improves cognition, mood, and function of brain tumor patients.

PURPOSE: Patients with malignant glioma develop progressive neurobehavioral deficits over the course of their illness. These are caused both by the effects of the disease and the effects of radiation and chemotherapy. We sought to determine whether methylphenidate treatment would improve these patients' neurobehavioral functioning despite their expected neurologic deterioration. PATIENTS AND METHODS: Thirty patients with primary brain tumors underwent neuropsychologic assessment before and during treatment with methylphenidate. Ability to function in activities of daily living and magnetic resonance imaging (MRI) findings were also documented. Patients were assessed on 10, 20, and 30 mg of methylphenidate twice daily. RESULTS: Significant improvements in cognitive function were observed on the 10-mg twice-daily dose. Functional improvements included improved gait, increased stamina and motivation to perform activities, and in one case, increased bladder control. Adverse effects were minimal and immediately resolved when treatment was discontinued. There was no increase in seizure frequency and the majority of patients on glucocorticoid therapy were able to decrease their dose. Gains in cognitive function and ability to perform activities were observed in the setting of progressive neurologic injury documented by MRI in half of the subjects. CONCLUSION: This study demonstrated improved patient function in the setting of a progressive neurologic illness. Methylphenidate should be more widely considered as adjuvant brain tumor therapy.