Monitoring and optimising cognitive function in cancer patients: Present knowledge and future directions.

The potentially detrimental effects of cancer and related treatments on cognitive functioning are emerging as a key focus of cancer survivorship research. Many patients with central nervous system (CNS) or non-CNS tumours develop cognitive problems during the course of their disease that can result in diminished functional independence. We review the state of knowledge on the cognitive functioning of patients with primary and secondary brain tumours at diagnosis, during and after therapy, and discuss current initiatives to diminish cognitive decline in these patients. Similarly, attention is paid to the cognitive sequelae of cancer and cancer therapies in patients without CNS disease. Disease and treatment effects on cognition are discussed, as well as current insights into the neural substrates and the mechanisms underlying cognitive dysfunction in these patients. In addition, rehabilitation strategies for patients with non-CNS disease confronted with cognitive dysfunction are described. Special attention is given to knowledge gaps in the area of cancer and cognition, in CNS and non-CNS diseases. Finally, we point to the important role for cooperative groups to include cognitive endpoints in clinical trials in order to accelerate our understanding and treatment of cognitive dysfunction related to cancer and cancer therapies.

The effect of surface defects in early caries assessment using quantitative light-induced fluorescence (QLF) and micro-digital-photography (MDP).

OBJECTIVES: The purpose of this study was to consider the impact of surface defects on quantitative light-induced fluorescence (QLF) and micro-digital-photography (MDP) measures, in relationship to lesion depth. METHODS: Simulated enamel carious lesions were developed on 45 extracted human teeth. Images of each tooth were captured with both QLF and MDP. The teeth were sectioned and lesion depth was measured with polarized light microscopy (PLM). Pearson correlations were computed using data from the 27 lesions which did not have surface loss, and then separately based upon the 18 lesions which did display surface loss. MDP variables ΔR and ΔX measure reflected light, whereas QLF variables ΔF and ΔQ measure fluorescence. RESULTS: A strong correlation was identified between lesion depth and ΔF (r=-0.765, p<0.0001), and ΔQ (r=-0.827, p<0.0001) on intact lesions while a weak but suggestive, although non-significant, correlation was identified between average lesion depth and ΔR (r=0.369, p=0.059) and ΔX (r=0.595, p=0.0011). However, the corresponding correlation was not statistically significant, when lesions with surface loss were considered for QLF and MDP measures. CONCLUSIONS: QLF measures ΔF and ΔQ were strongly correlated with lesion depth in lab-simulated lesions with no surface loss, but not among lesions with surface defects. The two MDP-associated measures, ΔR and ΔX, could not be said to differ significantly when lesions with and without surface defects were compared with lesion depth. Because intact lesions can be remineralized, accurate assessment of their status is imperative for caries treatment. CLINICAL SIGNIFICANCE: Dental caries is still widely prevalent today. We now know that with early stage detection, remineralization can be accomplished. Being able to identify dental caries in its reversible stage (before physical surface loss) is paramount for the clinician to be able to treat the disease non-invasively.

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.

Effects of fluoridated milk on artificial enamel carious lesions: a pH cycling study.

OBJECTIVE: To investigate the relationship between concentration of fluoride in milk and its re-mineralizing efficacy, and to test whether increasing the volume of fluoridated milk has any effect on its re-mineralizing efficacy. METHODS: Third molars were painted leaving a 1 mm window on the buccal and/or lingual surfaces. Artificial carious lesions were induced using a de-mineralizing solution. The teeth were then sectioned longitudinally. Specimens were randomly assigned to 15 groups according to different concentrations and volume; i.e., 2.5 ppm, 5 ppm, 7.5 ppm, 10 ppm, 15 ppm, 20 ppm, and 250 ppm of fluoride with 25 ml/section and 50 ml/section. De-ionized water and plain milk were used as controls. Sections were subjected to pH cycling for 20 days. Polarized light microscopy and micro-radiography were utilized to record the lesion characteristics before and after pH cycling. RESULTS: Mean lesion depths decreased significantly in all the fluoride groups, and increased significantly in the control groups. There were no differences in percentage of lesion depth decrease when the volume was doubled for the same fluoride concentration. There were also no statistically significant differences between percentages of decrease in lesion depth when the concentration of fluoride in milk was increased. CONCLUSION: Fluoridated milk demonstrated a remineralization efficacy on early enamel carious lesions. A 2.5 ppm fluoride milk concentration provided similar remineralization potential to that of higher fluoride concentration in milk.

Response assessment in neuro-oncology (a report of the RANO group): assessment of outcome in trials of diffuse low-grade gliomas.

Although low-grade gliomas (LGG) have a less aggressive course than do high-grade gliomas, the outcome of these tumours is ultimately fatal in most patients. Both the tumour and its treatment can cause disabling morbidity, particularly of cognitive functions. Because many patients present with seizures only, with no other signs and symptoms, maintenance of quality of life and function constitutes a particular challenge in LGG. The slow growth pattern of most LGG, and the rare radiological true responses despite a favourable clinical response to treatment, interferes with the use of progression-free survival as the primary endpoint in trials. Overall survival as an endpoint brings logistical challenges, and is sensitive to other non-investigational salvage therapies. Clinical trials for LGG need to consider other measures of patient benefit such as cognition, symptom burden, and seizure activity, to establish whether improved survival is reflected in prolonged wellbeing. This Review investigates clinical and imaging endpoints in trials of LGG, and provides response assessment in neuro-oncology (RANO) criteria for non-enhancing tumours. Additionally, other measures for patients with brain tumours that assess outcome are described. Similar considerations are relevant for trials of high-grade gliomas, although for these tumours survival is shorter and survival endpoints generally have more value than they do for LGG.

Development of gold standard ion-selective electrode-based methods for fluoride analysis.

BACKGROUND/AIMS: Currently available techniques for fluoride analysis are not standardized. Therefore, this study was designed to develop standardized methods for analyzing fluoride in biological and nonbiological samples used for dental research. METHODS: A group of nine laboratories analyzed a set of standardized samples for fluoride concentration using their own methods. The group then reviewed existing analytical techniques for fluoride analysis, identified inconsistencies in the use of these techniques and conducted testing to resolve differences. Based on the results of the testing undertaken to define the best approaches for the analysis, the group developed recommendations for direct and microdiffusion methods using the fluoride ion-selective electrode. RESULTS: Initial results demonstrated that there was no consensus regarding the choice of analytical techniques for different types of samples. Although for several types of samples, the results of the fluoride analyses were similar among some laboratories, greater differences were observed for saliva, food and beverage samples. In spite of these initial differences, precise and true values of fluoride concentration, as well as smaller differences between laboratories, were obtained once the standardized methodologies were used. Intraclass correlation coefficients ranged from 0.90 to 0.93, for the analysis of a certified reference material, using the standardized methodologies. CONCLUSION: The results of this study demonstrate that the development and use of standardized protocols for F analysis significantly decreased differences among laboratories and resulted in more precise and true values.

Cancer and cancer-therapy related cognitive dysfunction: an international perspective from the Venice cognitive workshop.

A subset of survivors has cognitive impairment after cancer treatment. This is generally subtle, but may be sustained. In October 2006, the second international cognitive workshop was held in Venice. The workshop included neuropsychologists, clinical and experimental psychologists, medical oncologists, imaging experts, and patient advocates. The main developments since the first Cognitive Workshop in 2003 have been the following. (i) studies evaluating cognitive function in patients receiving chemotherapy for cancers other than breast cancer, and in patients receiving hormonal therapy for cancer. (ii) The publication of longitudinal prospective studies which have shown that some patients already exhibit cognitive impairment on neuropsychological testing before receiving chemotherapy, and some patients have deterioration in cognitive functioning from pre- to postchemotherapy. (iii) Studies of the underlying mechanisms of cognitive impairment both in patients and in animal models. (iv) Use of structural and functional imaging techniques to study changes in brain morphology and activation patterns associated with chemotherapy. (v) At present cognitive research in cancer is limited by methodological challenges and the lack of standardization in neuropsychological studies. The current workshop addressed many of these issues and established an international task force to provide guidelines for future research and information on how best to manage these symptoms.

Effect of an alcohol-free, 1% chlorhexidine gel as an adjunct to a fluoridated dentifrice using an intraoral crown model.

BACKGROUND/AIMS: The use of chlorhexidine as a topically applied oral antiseptic is well documented; however, clinical studies examining the effects of chlorhexidine gel on in situ dental caries are limited. This study utilized an in situ caries model and a modified crossover design to examine whether the addition of a biweekly topical, alcohol-free, 1% chlorhexidine digluconate gel to a daily fluoridated dentifrice inhibited artificial caries in dental tissues better than the fluoridated dentifrice alone when compared to a nonfluoridated placebo dentifrice. METHODS: Thirty patients were recruited based on their need for a mandibular, full crown. Artificial caries lesions were created in extracted human teeth and enamel and root tissue sections 100 mum in thickness were characterized using polarized light microscopy. The sections were fixed in the crown and placed on the prepared tooth. The participants were assigned a placebo toothpaste, a toothpaste with 1,100 ppm F or a 1,100 ppm F toothpaste followed by 1 ml of 1% chlorhexidine gel at day 1 and day 14 (chlorhexidine+). Patients were instructed to brush twice daily for 4 weeks. Following each round, the sections in the crown were replaced with new sections. The sections were recharacterized and the mean changes were compared using ANOVA at alpha = 0.05. RESULTS: The chlorhexidine + Fdentifrice and the F dentifrice alone significantly reduced lesion area in enamel tissue when compared to the placebo dentifrice. Both treatments also inhibited lesion progression and initiation in root tissue better than control in this model system. Although the chlorhexidine+ group enhanced remineralization and inhibited lesion progression better than the F(-) dentifrice alone for all outcomes measured, the differences were not significant. CONCLUSIONS: The chlorhexidine, in conjunction with a fluoride dentifrice, was no more effective than the fluoride dentifrice alone. Further study is needed before this 1% alcohol-free chlorhexidine gel should be recommended as an adjunct to a fluoride dentifrice in the treatment of dental caries.

Effects of different amounts of a low fluoride toothpaste on primary enamel lesion progression: a preliminary study using in vitro pH-cycling system.

AIMS: To evaluate and compare the efficacy of pea and half-pea portions of child formula fluoride (500 ppm) toothpaste on artificially created enamel lesions in primary teeth. METHODS: Sound primary incisors were painted with nail varnish, leaving a 1 mm wide window and then placed in a demineralising solution for 96 h to produce artificial carious lesions 60-100 microm deep. The teeth were longitudinally sectioned (100 microm thick) and divided into 3 groups. Group A: treated with a pea-sized portion of a non-fluoride containing toothpaste (1:3, toothpaste: deionized water), while Groups B and C were treated with half-pea-sized and pea-sized portions of a 500 ppm fluoride containing toothpaste, respectively. The pH-cycling model was utilized for 7 days. RESULTS: Groups A and B lesions increased in depth by 60% while those in Group C increased by 19%. The mineral content of the surface zone decreased significantly in Groups A and B but not in Group C. CONCLUSION: Reduction of the amount of fluoride toothpaste to less than a pea-size in order to minimize the risk of fluorosis should be undertaken with caution because it may compromise the cariostatic effects of the toothpaste.

The effects of child formula toothpastes on enamel caries using two in vitro pH-cycling models.

AIMS/OBJECTIVES: To compare, using two pH-cycling models, the de/remineralisation effects of children's toothpastes on primary teeth. DESIGN: In vitro single-section and pH-cycling models. METHODS: Primary teeth were placed in demineralising solution for 96 hours to produce artificial carious lesions 60-100 microm deep. They were cut into 100 microm thick sections and assigned to 6 groups. Sections in Groups A and D were exposed to a non-fluoridated toothpaste, those in Groups B and E to half-pea-sized (0.16g) and those in Groups C and F to pea-sized portions (0.32g) of a 500ppm F toothpaste. pH-cycling Model I (Groups A, B, C), without added fluoride, ran for 7 days, while Model II (Groups D, E, F), with 0.25ppm F, ran for 10 days. OUTCOME MEASUREMENTS: Lesions were evaluated using polarised light microscopy and microradiography. RESULTS: Lesions in Groups B and E progressed by 64% and 61%, respectively, while those in Groups C and F progressed by only 19% and 23% respectively. CONCLUSIONS: Both 10-day and 7-day pH-cycling models were suitable for studying carious lesion progression in primary teeth (the demineralising and remineralising solutions of the 10-day cycling model contained 0.25ppm F). A pea-sized portion (0.32g) of 500ppm F toothpaste slowed down the demineralisation progression better than a half-pea-sized portion.

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.

Effect of fluoridated milk on progression of root surface lesions in vitro under pH cycling conditions.

The aim of this study was to assess the effect of milk with 0, 2.5 or 5 ppm F on progression and remineralization of caries-like root surface lesions using a pH cycling model. The root surface lesions were created utilizing a partially saturated lactic acid buffer at pH 4.6. Longitudinal sections were cut through the lesion and analyzed using polarized light microscopy (PLM) and microradiography (MRG). The sections were then coated with an acid resistant varnish, except the outer natural surface that would be exposed to water, milk or fluoridated milk and cycled in a de- and remineralizing system for 2 weeks. The lesions were characterized again by PLM and MRG after treatment. A significant reduction in lesion progression was found by PLM and MRG after treatment with either non-fluoridated or fluoridated milk when compared to the control group. Using quantitative MRG, mineral change and distribution in the lesions were recorded. A possible protective effect of fluoridated milk on root surface caries was supported by a reduction in the progression of the lesions and an increase in the mineral within the lesion.

Effect of smear layer on root demineralization adjacent to resin-modified glass ionomer.

The cariostatic effect of resin-modified glass ionomer (RMGI) on secondary root caries is well-documented. However, this beneficial effect may be dependent upon the mode of cavity surface treatment. To investigate this relationship, we studied 4 cavity surface treatments prior to the placement of RMGI: no treatment (None), polyacrylic acid (PAA), phosphoric acid (H(3)PO(4)), and Scotchbond Multi-Purpose adhesive (SMP) as a control. Specimens were aged for two weeks in synthetic saliva, thermocycled, and subjected to an artificial caries challenge (pH 4.4). Polarized light microscopy (PLM) and microradiography (MRG) showed significantly less demineralization with the H(3)PO(4) cavity surface treatment as revealed by ANOVA and Tukey's multiple comparisons (p < or = 0.05). Dentin fluoride profiles determined by electron probe microanalysis (EPMA) supported PLM and MRG findings. It may be concluded that removal of the smear layer with phosphoric acid provides significantly enhanced resistance to secondary root caries formation adjacent to RMGI restorations.

In situ evaluation of sodium hexametaphosphate-containing dentifrices.

The purpose of this investigator-blinded, five-treatment, crossover human intraoral study was to evaluate the effects of two experimental dentifrice formulations containing either stannous fluoride (SnF(2)) or sodium fluoride (NaF) packaged with sodium hexametaphosphate in a dual-phase delivery system on demineralization-remineralization using an in situ model system. The experimental dentifrice formulations' ability to alter demineralization-remineralization was compared to a series of three controls: SnF(2)-positive control, NaF-positive control and no-fluoride placebo-negative control. The single-section crown model, developed at the University of Iowa, was used to assess the fluoride efficacy of two experimental products versus the placebo containing no fluoride and positive controls. The results of the current in situ study suggest a clinical level of anticaries activity for the experimental SnF(2) and NaF dentifrice formulations that was as good as either of the positive controls, when evaluated using polarized light microscopy. This supports the conclusion that the use of the sodium hexametaphosphate ingredient does not interfere with the normal fluoride activity of these toothpastes. In addition, the experimental SnF(2) product was numerically better than both the NaF and placebo controls at preventing demineralization of sound root surfaces.

The effect of fluoridated and non-fluoridated rewetting agents on in vitro recurrent caries.

OBJECTIVE: This study examined the in vitro caries inhibiting potential of fluoridated and non-fluoridated rewetting agents that are applied to acid-etched enamel and dentine before the use of a water-free, dentine adhesive. MATERIALS AND METHODS: Twelve caries-free premolars were divided into three groups of four teeth each. 2 x 3 x 1.5 mm cavities were prepared on the mesial and distal surfaces of each tooth, with half of the cavosurface margin in enamel and half in root dentine. In Group I (control), One-Step (Bisco, Schaumburg, USA) was applied without etching or rewetting agents. In Group II, cavities were acid-etched, rinsed, dried, and rewetted with Aqua-Prep (Bisco), a non-fluoridated rewetting agent, and then bonded with One-Step. Treatment for Group III was similar to Group II, except that Aqua-Prep F (Bisco), a fluoridated rewetting agent was used. Bonded cavities were restored with a non-fluoride-containing flowable composite (AEliteFlo, Bisco). Artificial carious lesions were induced in these specimens, from which multiple 100+/-20 microm thick longitudinal sections were prepared, yielding 16 specimens per group for evaluation with polarised light microscopy (PLM) and microradiography (MRG). Representative sections were processed for transmission electron microscopy (TEM) examination and scanning transmission electron microscopy/energy dispersive X-ray (STEM/EDX) analyses. RESULTS: The differences in demineralisation of dentine among the groups were not statistically significant for 'relative' lesion depth (p > 0.05, ANOVA, Student-Neuman-Keuls test), but highly significant for 'relative' lesion area (p < 0.001). Wall lesions were consistently present in Group I, while inhibition zones were invariably observed in Group III. 87.5% of Group II specimens exhibited neither wall lesion nor inhibition zone. TEM showed that remnant dentine apatite crystallites within the inhibition zones in Group III were larger and denser than those present within the corresponding wall lesions. STEM/EDX analyses confirmed the presence of calcium, phosphorus and fluorine in these plate-like crystallites. CONCLUSION: When used with a water-free, single-bottle dentine adhesive, a non-fluoridated rewetting agent is able to reduce, but cannot completely prevent recurrent caries. The use of a fluoridated rewetting agent is useful under the situation when microleakage occurs, by providing the additional benefit of fluoride-induced demineralisation inhibition.

Patterns of fluoride intake from birth to 36 months.

OBJECTIVES: Dental fluorosis prevalence has increased in the United States, Canada, and other nations due to the widespread availability of fluoride in many forms, with fluoride ingestion during the first three years of life appearing most critical in fluorosis etiology. With few contemporary studies of fluoride ingestion in this age group, the purpose of this paper is to describe patterns of estimated fluoride ingestion from birth to 36 months of age from water, dentifrice, and dietary fluoride supplements and combined. METHODS: Repeated responses to separate series of questions about water intake, use of fluoride dentifrice, and use of fluoride supplements were collected by questionnaire as part of the longitudinal Iowa Fluoride Study and used to estimate fluoride intake. Estimated intake is reported by source and combined at different ages. Effects of subject age and other covariates on fluoride intake were assessed using regression methods appropriate for the analysis of correlated data. RESULTS: For most children, water fluoride intake was the predominant source, especially through age 12 months. Combined daily fluoride intake increased through 9 months, was lower at 12 and 16 months, and increased again thereafter. Mean intake per unit body weight (bw) was about 0.075 mg F/kg bw through 3 months of age, 0.06 mg F/kg bw at 6 and 9 months, 0.035 mg F/kg bw at 12 and 16 months, and 0.043 mg F/kg bw from 20-36 months. Depending on the threshold chosen (e.g., 0.05 or 0.07 mg F/kg bw), variable percentages of the children exceeded the levels, with percentages greatest during the first 9 months. Regression analyses showed fluoride intake (mg F/kg bw) from 1.5-9 months to decrease with increasing child's age, mother's age, and mother's education, with a complex three-way interaction among these factors. From 12-20 months, fluoride intake increased with increasing child age and decreased with increasing mother's age. No statistically significant relationships were found for fluoride intake from 24-36 months. CONCLUSIONS: There is considerable variation in fluoride intake across ages and among individuals. Longitudinal studies may be necessary to fully understand the relationships between fluoride ingestion over time and development of fluorosis.

Laser-matrix-fluoride effects on enamel demineralization.

Laser and fluoride have been shown to inhibit enamel demineralization. However, the role of organic matrix and their interactions remains unclear. This study investigated the interaction among CO2 laser irradiation, fluoride, and the organic matrix on the demineralization of human enamel. Twenty-four molars were selected and cut into halves. One half of each tooth was depleted of its lipid and protein. The other half served as a matched control. Each tooth half had two window areas, treated with a 2.0% NaF gel. All left windows then received a laser treatment. Next, the tooth halves were subjected to a four-day pH-cycling procedure that created caries-like lesions. Tooth sections were cut from the windows, and microradiographs were used for quantification of the demineralization. The combined fluoride-laser treatment led to 98.3% and 95.1% reductions in mineral loss for enamel with and without organic matrix, respectively, when compared with sound enamel.

In vitro evaluation of fluoride-releasing restorative materials for sealing the root canals of overdenture abutments.

PURPOSE: The purpose of this study was to evaluate the ability of newer fluoride-releasing restorative materials to protect the root surface from acid attack. MATERIALS AND METHODS: The materials used were glass-ionomer cement (GIC), resin-modified glass-ionomer cement (RM-GIC), and a compomer (Comp). A composite resin (CR) was used as the control. The restored teeth were stored in deionized, distilled water for 14 days and subjected to 300 thermocycles (55 degrees C and 5 degrees C). The teeth were cycled in a demineralizing solution (pH 5.0 or 4.0) for 6 hours and in a remineralizing solution (pH 7.0) for 17 hours for 10 days. The depths of lesions created by acid challenge were measured at the interface of the tooth and the restorative material and then at a distance of 50, 100, and 300 microns from the tooth-restoration margin using polarized light microscopy and contact microradiography. RESULTS: At pH 4.0, there was significant difference in the depth at the interface between the tooth and the restorative material (P < .001). The GIC and RM-GIC were protective, and the lesion depths were significantly shallower than for Comp or CR. The protective effect varied depending on the distance from the interface of the tooth and the restorative material. At pH 5.0, the GIC and RM-GIC had no lesions at the interface, while the Comp and the CR had lesions (P < .001). CONCLUSION: Fluoride-releasing glass-ionomer cement seems to be an appropriate material to seal the root canals of overdenture abutments, because it has an inhibiting effect on demineralization at the cavity wall in vitro.