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.

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.

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.

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.

Effects of fluoride on caries development and progression using intra-oral models.

This paper reviews the use of intra-oral model systems to help elucidate the role of fluoride and its mechanism of action in caries prevention. The intra-oral models currently in use were found to be of three general types. The most widely used system has consisted of a removable appliance that relies on the use of dacron gauze or a recessed sample to enhance plaque formation. Similarly, the banding model of Ogaard requires the presence of orthodontic band material to produce a plaque accumulation niche for demineralization, while the crown single-section technique relies mainly on placement of the sections in plaque-retentive areas (below contact points). In general, the models may be used for the assessment of food cariogenicity, an evaluation of de- and re-mineralization, and measurement of fluoride incorporation into enamel or root substrates. On evaluation of lesion initiation and progression in vivo, it is apparent that few non-destructive in vivo techniques are available that offer the sensitivity of laboratory-based analysis. Thus, the use of intra-oral models that allow lesion formation and progression to occur in the oral environment, but can be measured with the sensitivity of in vitro techniques, has been extremely important. Although the magnitude of the fluoride dose, the longevity of fluoride in the oral environment, and the time required for remineralization are different from those found in vitro, it is apparent that the presence of fluoride in the aqueous phase is now thought to be of primary importance. Mechanistically, the presence of fluoride will both inhibit demineralization by acid and promote remineralization under more neutral conditions. Thus, one of fluoride's major contributions is to affect the rates of lesion formation and progression. It was concluded that low-concentration fluoride agents with a high frequency of application would best fulfill the above needs.

The use of saturated DCPD in remineralization of artificial caries lesions in vitro.

Dicalcium phosphate dihydrate (DCPD) may play a significant role in the caries lesion since it is a stable calcium phosphate phase under acidic conditions. The reaction of DCPD and fluoride, forming fluorapatite (FAP), may provide a potentially promising treatment regimen for remineralization of caries lesions in vivo. The purpose of this study was to determine whether a two-step DCPD and inorganic wash with fluoride can remineralize artificial caries-like lesions in vitro. We used the single-section technique to facilitate quantitation of the same tissue before and after the experimental regimen. The two-step remineralizing treatment was repeated three times and consisted of a two-minute saturated DCPD treatment (pH 2.1) followed by a 24-hour inorganic wash. Lesion parameters were recorded before and after treatment by the taking of polarized light photomicrographs of each section after imbibition in several media. The changes in the tissue following treatment were expressed as a percent change in the area of the initial pre-treatment lesion. Significant reductions (p < 0.02) in lesion pore volume were observed in all aqueous media examined. In the lesions after imbibition in quinoline, remineralization was also apparent from the significant increase in the area of the dark zone following treatment. This two-step DCPD treatment appears to remineralize artificial caries-like lesions effectively, but additional work is needed to determine whether it affords any protection against subsequent cariogenic challenges.

An intra-oral single-section demineralization/remineralization model.

This paper reviews the use of our intra-oral crown single-section model for the evaluation of in situ demineralization and remineralization. The model uses normal, healthy adults who are in need of a gold crown. A slot is placed in the working crown which can hold 3-4 single sections. A typical experiment would use an enamel lesion, root lesion, and sound root section which are characterized with polarized light microscopy and/or microradiography prior to insertion in the crown. After the experimental regimen, the sections are removed and re-characterized for any changes. The model has been used to evaluate mineral changes from the use of fluoride dentifrices and rinses, chewing gum, and food sequencing. The advantages of the model system are the before-and-after measurements on the same section, a natural plaque formation, interaction with saliva, episodic demineralization and remineralization, no bulky appliances, and the use of reasonable time frames. This model, therefore, reduces the artificiality of the in situ study to a great extent and appears to be a useful predictor of demineralization/remineralization interactions.

Comparison of artificial white spots by microradiography and polarized light microscopy.

This work compared lesions produced by three artificial caries systems with natural white spot lesions using both polarized light microscopy and microradiography. The three systems employed were the acidified gelatin gel, diphosphonate surface dissolution inhibitor, and a partially saturated buffer system. When we compared the natural white spot lesions with the artificial caries-like lesions, we found that the acidified gel system reproduced the classical histological zones most frequently. All systems showed a radiopaque surface layer overlying a radiolucent body of the lesion. This radiopaque layer could not be equated with the negatively birefringent surface zone seen in polarized light.

In vitro interactions between the surfaces of enamel white spots and calcifying solutions.

The treatment of white spot enamel lesions with a saturated DCPD solution followed by a high fluoride topical application appeared to produce a surface coating consisting mainly of spherical particles that filled in the honeycombed-etched surface of the untreated enamel white spot. The conditions used in these pilot studies were not ideal to take advantage of the DCPD and fluoride reaction to form FAP. Additional study is warranted on the solution composition and application time along with identification of the reaction products formed.

Seeded growth of calcium phosphates: effect of different calcium phosphate seed material.

Seed crystals of OCP, TCP, and HAP are effective nucleators of DCPD in stable supersaturated solutions under conditions in which DCPD is the predominant phase. The crystals will grow with the second-order kinetics (TCa = 5.0 X 10(-3)M, Tp = 1.0 X 10(-2)M [pH, 5.60]) characteristic of DCPD. TCP is the least efficient, DCPD growth taking place only after an initial induction period. In all instances, the rate of DCPD crystallization is proportional to the square of the supersaturation with respect to DCPD, and the reaction is surface controlled. Scanning electron micrographs show an amorphous or microcrystalline precursor to the development of the characteristic platelets of DCPD. In stable supersaturated calcium phosphate solutions at a physiologic pH (TCa = 1.4 X 10(-3)M, Tp = 8.0 X 10(-4)M [pH, 7.40]), only OCP and HAP seed crystals are effective nucleators. The efficiency of OCP as a nucleator adds further evidence for its participation as a precursor in the precipitation of HAP under these conditions.

An improved abrasive enamel microsampling device.

An improved enamel abrasive microsampling technique with an electronic preset counter and comparator has been designed. In vivo enamel microsamples were obtained from 30 incisors and premolars. The results showed low coefficients of variations for both enamel fluoride concentrations and depths of microsamples in vivo.

Topical fluoride application and lesion progression in vitro.

The objectives of this investigation were to study the effects of topical fluoride application on white spot enamel and the effect that this application would have on a second acid exposure (lesion progression). Artificial white spot lesions of approximately 200 micron were created with an acidified gel technique, central control sections were removed, and the remaining tooth halves were randomly paired, with one half serving as an untreated control while the other received a single four-minute application of 1.23% (w/v) fluoride solution of either NH4F, Na2SnF6, APF, or TiF4. Both tooth halves were sectioned following progression and examined with polarized light microscopy. Lesion depth, internal pore volume, and presence, size and shape of dark zones were determined. The considerable variation among progressed lesions revealed no significant benefit from any topical fluoride treatment.

A model for producing caries-like lesions in enamel and dentin using oral bacteria in vitro.

Subsurface enamel lesions and root surface caries-like lesions were consistently produced in vitro using Streptococcus mutans FA1 cultured in thioglycollate broth containing 3.5% w/v dextrose and 2% w/v gelatin. When viewed in polarized light and after imbibition in water, the enamel lesions had a negatively birefringent surface zone and positively birefringent body of the lesion. Those lesions produced after six weeks, after imbibition in quinoline, exhibited a dark zone. The root surface caries-like lesions exhibited a less-radiolucent surface zone above a heavily demineralized body of the lesion. However, no reactionary dentin was seen in the in vitro lesions.

The effect of polyvalent metal ion mordanting on caries-like lesion progression in enamel.

The ability of metal ion mordanting followed by APF application to inhibit the progression of caries-like lesions was compared with APF treatment alone. The progression of the lesion was investigated in vitro using an acidified gel system, and the lesions were compared using polarized light microscopy. Both ferric and zirconyl pre-treatments, but not titanium, were shown to inhibit lesion progression to a greater extent than did APF. This inhibition was thought to be due to the presence of an amorphous-type coating similar to those produced on sound enamel by metal ion mordanting.

Root hard-tissue demineralization rate measured by 125I absorptiometry: comparison with lesion-depth measurements.

The aim of the present study was to compare demineralization of root hard tissue, monitored by 125I absorptiometry, with lesion-depth measurements under polarized light microscopy. The intact roots of ten human molars, which had not been exposed to the oral environment, were divided into 39 cementum/dentin blocks and exposed to a buffer solution of pH 4.5 containing 2.2 mmol/L calcium and inorganic phosphate. After demineralization for 3.5, 7, 14, and 21 days, transmission measurements by 125I absorptiometry were performed, and one block from each tooth was taken out of the solution for lesion-depth measurement. The results showed a high degree of correlation (r = 0.952) between lesion depth and change in transmission, with a more rapid increase initially in both variables. A linear relationship with the square root of time was found. Conversion of transmission data to lesion-depth data was possible when this caries model system was used on cementum dentin blocks.

An in vitro evaluation of the prevention of caries on overdenture abutments.

Teeth prepared as overdenture abutments are susceptible to caries, and it has been shown that brushing by itself is not sufficient to prevent this process. This study evaluated the preventive effect of a remineralization gel which has a low fluoride concentration and compared its effects with those of a phosphate fluoride gel (Karigel), which has a much higher concentration of fluoride. Twenty extracted anterior teeth from patients aged 50 to 70 years were prepared as for overdenture abutments. Each tooth was sectioned into three fragments. An acidified gel system was used to produce artificial caries lesions on the occlusal and root surfaces of each fragment. One fragment of each tooth was treated with the remineralizing gel, the second fragment with a high-fluoride gel, and the third fragment served as the control. Ten teeth were removed at two weeks and again at four weeks, and were sectioned and prepared for histological examination. The depth of the lesions was measured from standardized photomicrographs by means of a sonic digitizer. The conclusions were: (1) Lesions on the occlusal tended to be deeper than those on the root surfaces at four weeks but not at two weeks; and (2) the high-fluoride gel was more protective than the low-fluoride remineralizing solution at both time periods on the occlusal but not on the root surface.

An in vitro evaluation of artificial caries-like lesions on restored overdenture abutments.

An acidified dialyzed gelatin gel system was used to determine the caries resistance of a variety of restorative materials used to obturate the canal orifice of overdenture abutment teeth. The restorative materials used were Tytin, Tytin + Copalite, P30 + Scotchbond, Fuji Ionomer-Type II, and Miracle Mix. Polarized light microscopy and microradiography were used to examine the caries-like lesions adjacent to the restorations. The lesions formed in the Fuji Ionomer-Type II and Miracle Mix groups appeared arrested at the wall adjacent to the restoration, and did not penetrate apically down the wall as did those associated with the other restorative materials. The mean depths of lesions adjacent to Fuji Ionomer-Type II and Miracle Mix restorations were significantly less than those of Tytin, Tytin + Copalite, or P30 + Scotchbond.