Observer-rated pain assessment instruments improve both the detection of pain and the evaluation of pain intensity in people with dementia.

BACKGROUND: Observer-rated pain assessment instruments for people with dementia have proliferated in recent years and are mainly effective in identifying the presence of pain. The objective of this study was to determine whether these tools can also be used to evaluate intensity of pain. METHOD: Quasi-experimental design. Cognitively intact [Mini Mental State Examination (MMSE) ≥ 24, n = 60] and impaired people (MMSE < 20, n = 65) in nursing home facilities took part in the study. Participants were observed at rest and during a movement protocol. Directly afterwards, the observer, blinded to cognitive status, completed three behavioural pain assessment instruments (Abbey Pain Scale, Pain Assessment in Advanced Dementia Scale (PAINAD), Non-communicative Patient's Pain Assessment Instrument (NOPPAIN) ], before interviewing the resident about pain self-report. RESULTS: Significant correlations were found between observer-rated and self-rated measures of pain and were stronger in persons with dementia than in cognitively intact adults. Discriminant function analysis (DFA) revealed: (1) that the use of observer-rated instruments improved recognition of the presence or absence of pain by up to 25.4% (in dementia) and 28.3% (in cognitively intact adults) above chance; and (2) the same instruments improved the classification of residents into the correct self-reported level of pain intensity by up to 42.5% (in dementia) and 34.1% (in cognitively intact adults) above chance. However, DFA also reveals a considerable rate of 'false alarms' for pain in cognitively intact and 'misses' in cognitively impaired people. CONCLUSIONS: The use of the Abbey Pain Scale, PAINAD or NOPPAIN improves both the recognition of pain presence/absence as well as rating pain severity in older people with impaired cognition.

A phase II trial of continuous 5-fluorouracil in recurrent or metastatic transitional cell carcinoma of the urinary tract.

AIMS: To assess the activity of a continuous infusion of 5-fluorouracil in patients with recurrent locally advanced or metastatic transitional cell carcinoma of the urinary tract. MATERIALS AND METHODS: Eight centres within the UK entered 50 patients into the study. Twenty-four weeks of continuously infused 5-fluorouracil, 300mg/m(2)/day through a mini-pump, were planned. The primary outcome was tumour response at 8 weeks after the start of treatment. RESULTS: The median age of the patients was 68 years and 37 (80.4%) had a World Health Organization performance status of 0 or 1. The overall response rate at 8 weeks, according to the response evaluation criteria in solid tumors (RECIST) criteria in 46 evaluable patients, was 15% (95% confidence interval 5-26%) and 20% (95% confidence interval 8-31%) when assessments at all time points were included. The median progression-free survival was 1.9 months (95% confidence interval 1.8-2.7 months) and the median overall survival was 6.5 months (95% confidence interval 4.1-8.5 months). The most frequent grade 3/4 toxicities were mucositis and diarrhoea (each in 6.5% of patients) and nausea/vomiting and hand-foot syndrome (each in 4.3% of patients). CONCLUSIONS: Continuous infusional 5-fluorouracil has activity in transitional cell carcinoma of the urinary tract. Prolonged fluoropyrimidine administration may be a useful component of future combination regimens for this disease, particularly in patients with poor renal function.

Bladder preservation in small cell carcinoma of the urinary bladder: an institutional experience and review of the literature.

AIMS: Primary small cell carcinoma (SCC) of the urinary bladder is rare, accounting for less than 1% of all primary bladder malignancies. Metastases are often present at the time of diagnosis, prognosis is poor and there is no established optimum treatment strategy. Small cell carcinoma of the lung (SCLC) shares many clinicopathological features with SCC of the bladder, and there is good evidence supporting the use of combination chemotherapy in SCLC. In addition, consolidation thoracic irradiation and prophylactic cranial irradiation (PCI) both increase 3-year absolute survival by 5.4% in SCLC patients with limited disease and a complete response to chemotherapy. Therefore, we adopted a similar staging and treatment strategy for SCC of the bladder. We report our clinical experience using this strategy, and review published studies. MATERIALS AND METHODS: All cases of SCC of the bladder referred to Velindre Hospital between 1998 and 2005 were identified and data collected retrospectively on demographic details, stage, performance status, treatment and response to treatment. For the review, the electronic databases MEDLINE, EMBASE and Cancerlit were searched, along with hand searching of journals, relevant books and review papers. RESULTS: Seven patients were identified. In total, six out of seven had platinum-based chemotherapy. Four patients received consolidation radiotherapy (CRT) to the bladder after a complete response to chemotherapy, and none have locally relapsed to date. The three patients with limited disease remain alive and disease free 14, 30 and 36 months after diagnosis. CONCLUSIONS: Combined modality therapy using platinum-based combination chemotherapy and consolidation radiotherapy may provide effective local control and allow a bladder-preserving approach to the management of SCC of the bladder. The role of PCI is controversial, and should be discussed with patients on an individual basis.

Detection of individual differences in radiation-induced apoptosis of peripheral blood lymphocytes in normal individuals, ataxia telangiectasia homozygotes and heterozygotes, and breast cancer patients after radiotherapy.

Quantification of radiation-induced apoptosis in peripheral blood lymphocytes (PBLs) has been proposed as a possible screening test for cancer-prone individuals and also for the prediction of normal tissue responses after radiotherapy. We have used the TUNEL assay (terminal transferase nick-end labeling) 24 h after irradiation with 4 Gy at high dose rate to assess interindividual differences in radiation-induced apoptosis between (1) a panel of normal individuals, (2) ataxia telangiectasia (AT) homozygotes and heterozygotes, and (3) breast cancer patients who had received radiotherapy 8-13 years ago, including a number of patients who had suffered adverse responses to radiation. With this protocol, we show clear differences in radiation-induced apoptosis between individuals, and good reproducibility in the assay. In agreement with previous reports using EBV-transformed lymphoblasts, we show a very poor induction of apoptosis in AT homozygotes and a reduced level in AT heterozygotes compared to normal individuals. A similar reduced level compared to normal individuals was seen in the breast cancer patients. Despite a wide range of values in the breast cancer patients and good reproducibility on repeat samples, there was no correlation of rates of apoptosis with the severity of breast fibrosis, retraction or telangiectasia. The reduced rate of apoptosis observed in the breast cancer cases may be associated with genetic predisposition to breast cancer; however, we conclude that assays of lymphocyte apoptosis are unlikely to be of use in predicting normal tissue tolerance to radiotherapy.

Relationship between in vitro chromosomal radiosensitivity of peripheral blood lymphocytes and the expression of normal tissue damage following radiotherapy for breast cancer.

BACKGROUND AND PURPOSE: There is a need for rapid and reliable tests for the prediction of normal tissue responses to radiotherapy, as this could lead to individualization of patient radiotherapy schedules and thus improvements in the therapeutic ratio. Because the use of cultured fibroblasts is too slow to be practicable in a clinical setting, we evaluated the predictive role of assays of lymphocyte chromosomal radiosensitivity in patients having radiotherapy for breast cancer. MATERIALS AND METHODS: Radiosensitivity was assessed using a micronucleus (MN) assay at high dose rate (HDR) and low dose rate (LDR) on lymphocytes irradiated in the G(0) phase of the cell cycle (Scott D, Barber JB, Levine EL, Burril W, Roberts SA. Radiation-induced micronucleus induction in lymphocytes identifies a frequency of radiosensitive cases among breast cancer patients: a test for predispostion? Br. J. Cancer 1998;77;614-620) and an assay of G(2) phase chromatid radiosensitivity ('G(2) assay') (Scott D, Spreadborough A, Levine E, Roberts SA. Genetic predisposition in breast cancer. Lancet 1994; 344: 1444). In a study of acute reactions, blood samples were taken from breast cancer patients before the start of radiotherapy, and the skin reaction documented. 116 patients were tested with the HDR MN assay, 73 with the LDR MN assay and 123 with the G(2) assay. In a study of late reactions, samples were taken from a series of breast cancer patients 8-14 years after radiotherapy and the patients assessed for the severity of late effects according to the'LENT SOMA' scales. 47 were tested with the HDR assay, 26 with the LDR assay and 19 with the G(2) assay. For each clinical endpoint, patients were classified as being normal reactors or 'highly radiosensitive patients' (HR patients (Burnet NG. Johansen J, Turesson I, Nyman J. Describing patients' normal tissue reactions: Concerning the possiblity of individualising radiotherapy dose presciptions based on potential predictive assays of normal tissue radiosensitivity. Int. J. Cancer 1998;79:606-613)). RESULTS: The HR patients could be identified in some of the assays. For example, for acute skin reactions, 9/123 patients were judged as HR; they had significantly higher G(2) scores than normal reactors (P=0.004). For the late reactions, the mean HDR MN scores were higher for the 4/47 patients who had severe telangiectasia (P=0.042) and the 8/47 patients had severe fibrosis (P=0.055). However, there were no trends towards increased chromosomal radiosensitivity with the micronucleus scores at HDR or LDR, or with G(2) chromosomal radiosensitivity. CONCLUSIONS: While these results support the concept of using lymphocytes to detect elevated sensitivity to radiotherapy (as an alternative to fibroblasts), these assays are unlikely to be of assistance for the prediction of normal tissue effects in the clinic in their present form.

Heritability of chromosomal radiosensitivity in breast cancer patients: a pilot study with the lymphocyte micronucleus assay.

Of breast cancer patients, 30% are sensitive in a lymphocyte assay of radiation-induced chromosome damage (micronucleus induction) compared with 10% of healthy controls. Twenty-two first-degree relatives of 11 sensitive patients had an average micronucleus yield significantly higher than that of 68 controls. This suggests that radiosensitivity in this assay may be an inherited characteristic associated with predisposition to breast cancer.

Heritability of cellular radiosensitivity: a marker of low-penetrance predisposition genes in breast cancer?

Many inherited cancer-prone conditions show an elevated sensitivity to the induction of chromosome damage in cells exposed to ionizing radiation, indicative of defects in the processing of DNA damage. We earlier found that 40% of patients with breast cancer and 5%-10% of controls showed evidence of enhanced chromosomal radiosensitivity and that this sensitivity was not age related. We suggested that this could be a marker of cancer-predisposing genes of low penetrance. To further test this hypothesis, we have studied the heritability of radiosensitivity in families of patients with breast cancer. Of 37 first-degree relatives of 16 sensitive patients, 23 (62%) were themselves sensitive, compared with 1 (7%) of 15 first-degree relatives of four patients with normal responses. The distribution of radiosensitivities among the family members showed a trimodal distribution, suggesting the presence of a limited number of major genes determining radiosensitivity. Segregation analysis of 95 family members showed clear evidence of heritability of radiosensitivity, with a single major gene accounting for 82% of the variance between family members. The two alleles combine in an additive (codominant) manner, giving complete heterozygote expression. A better fit was obtained to a model that includes a second, rarer gene with a similar, additive effect on radiosensitivity, but the data are clearly consistent with a range of models. Novel genes involved in predisposition to breast cancer can now be sought through linkage studies using this quantitative trait.

A correlation between residual radiation-induced DNA double-strand breaks in cultured fibroblasts and late radiotherapy reactions in breast cancer patients.

BACKGROUND AND PURPOSE: Prediction of late normal tissue reactions to radiotherapy would permit tailoring of dosage to each patient. Measurement of residual DNA double strand breaks using pulsed field gel electrophoresis (PFGE) shows promise in this field. The aim of this study was to test the predictive potential of PFGE in a group of retrospectively studied breast cancer patients. MATERIALS AND METHODS: Thirty nine patients, treated uniformly for breast cancer 9-15 years previously, with excision of the tumour and radiotherapy to the breast and drainage areas, were assessed clinically using the LENT SOMA scale, and a 5-mm punch biopsy taken from the buttock. Fibroblast cell strains were established and used to study residual DNA double strand breaks, using PFGE. RESULTS: There were significant correlations between the DNA assay results and the fibrosis score (r(s) = 0.46; P = 0.003), the combined fibrosis and retraction score (r(s) = 0.45, P = 0.004) and the overall LENT score (r(s) = 0.43; P = 0.006). Using polychotomous logistic regression, the fibroblast DNA assay result was an independent prognostic factor for fibrosis severity. CONCLUSIONS: There is a relationship between residual radiation-induced DNA damage in fibroblasts and the severity of the late normal tissue damage seen in the patients from whom the cells were cultured.

Lack of correlation between residual radiation-induced DNA damage, in keratinocytes assayed directly from skin, and late radiotherapy reactions in breast cancer patients.

PURPOSE: To study the relationship between the severity of late reactions to radiotherapy in breast cancer patients, and the extent of residual radiation-induced DNA damage, using a rapid assay of keratinocytes obtained directly from skin biopsies. METHODS AND MATERIALS: A review was made of 32 patients with breast cancer, treated uniformly by radiotherapy between 1983 and 1988, following breast-conserving surgery. Their late radiotherapy reactions were scored (9-14 years post-radiotherapy) using a modified LENT SOMA scale, and a 5-mm buttock skin punch biopsy was obtained. Intact skin was irradiated at room temperature, and after allowing 24 h for repair, the tissue was disaggregated and the cells processed for pulsed field gel electrophoresis (PFGE). Residual DNA damage was expressed as the fraction of DNA released (FDR) following 150 Gy. RESULTS: Studies using flow cytometry on disaggregated breast skin showed that over 90% of the cells were keratinocytes. The PFGE assay was robust with low background FDRs in unirradiated skin samples (mean 3.2%) and a wide range of FDRs following irradiation from 11.5% to 26.6%. No correlation was found between the FDR at 150 Gy (FDR 150) and any of the late reaction scores or retrospective acute reaction scores. There was, however, a borderline significant correlation for family history and FDR 150 (p = 0.059). CONCLUSION: Rapid measurement of residual DNA damage in irradiated differentiated keratinocytes, the predominant cell population in skin biopsies, showed no correlation with the severity of symptomatic early or documented late reactions in a retrospectively studied group of 32 breast cancer patients.

Increased chromosomal radiosensitivity in breast cancer patients: a comparison of two assays.

PURPOSE: It has been shown previously that sensitivity to the induction of chromosome damage by ionizing radiation is, on average, higher in G2 or G0 lymphocytes of breast cancer patients than of normal healthy controls. The authors suggested that elevated chromosomal radiosensitivity may be a marker for breast cancer predisposition. To investigate whether the G0 micronucleus assay is a true surrogate for the more demanding G2 metaphase assay, both tests have now been performed on the same blood samples from 80 patients. METHODS: For the G0 micronucleus assay, cells were exposed to 3.5 Gy 137Cs gamma-rays 6 h before mitogenic stimulation, treated with cytochalasin B at 24 h post-stimulation and harvested at 90 h. For the G2 assay, at 72 h after stimulation cells were given 0.5 Gy X-rays and harvested 90 min later. RESULTS: Previous observations were confirmed, now with much larger numbers of donors, in that approximately 40% of breast cancer patients showed elevated sensitivity in the G2 assay (135 patients, 105 normals) and 25% in the G0 assay (130 patients, 68 normals). However, there was no correlation between G2 and G0 sensitivity for the 80 patients tested (r = -0.001, p = 0.99). Most of the sensitive patients were either G2 or G0 sensitive, with only 4% sensitive in both assays. CONCLUSIONS: The results suggest that different mechanisms of chromosomal radiosensitivity operate in G2 and G0 cells and that, in general, each chromosomally radiosensitive patient is defective in only one such mechanism, possibly via mutation (or polymorphism) of a single gene. Such mutations may confer cancer predisposition, of low penetrance, in a substantial proportion of patients.

Radiation-induced micronucleus induction in lymphocytes identifies a high frequency of radiosensitive cases among breast cancer patients: a test for predisposition?

Enhanced sensitivity to the chromosome-damaging effects of ionizing radiation is a feature of many cancer-predisposing conditions. We previously showed that 42% of an unselected series of breast cancer patients and 9% of healthy control subjects showed elevated chromosomal radiosensitivity of lymphocytes irradiated in the G2 phase of the cell cycle. We suggested that, in addition to the highly penetrant genes BRCA1 and BRCA2, which confer a very high risk of breast cancer and are carried by about 5% of all breast cancer patients, there are also low-penetrance predisposing genes carried by a much higher proportion of breast cancer patients, a view supported by recent epidemiological studies. Ideally, testing for the presence of these putative genes should involve the use of simpler methods than the G2 assay, which requires metaphase analysis of chromosome damage. Here we report on the use of a simple, rapid micronucleus assay in G0 lymphocytes exposed to high dose rate (HDR) or low dose rate gamma-irradiation, with delayed mitogenic stimulation. Good assay reproducibility was obtained, particularly with the HDR protocol, which identified 31% (12 out of 39) of breast cancer patients compared with 5% (2 out of 42) of healthy controls as having elevated radiation sensitivity. In the long term, such cytogenetic assays may have the potential for selecting women for intensive screening for breast cancer.

Developing a rural primary care practice network.

Establishing and managing a primary care practice in rural communities is particularly challenging. Many rural practices are closing, and relatively few new practices are initiated independently. The integrated health system can provide at least part of the solution to the lack of physicians in the rural setting. The following article describes the objectives, methods, and results of an integrated health system's development of a rural primary care provider network.

Absence of mutations in the ATM gene in breast cancer patients with severe responses to radiotherapy.

The effectiveness of cancer radiotherapy is compromised by the small proportion (approximately 5%) of patients who sustain severe normal tissue damage after standard radiotherapy treatments. Predictive tests are required to identify these highly radiosensitive cases. Patients with the rare, recessively inherited, cancer-prone syndrome ataxia-telangiectasia (A-T) sustain extremely severe normal tissue necrosis after radiotherapy and their cultured cells are also highly radiosensitive. Clinically normal carriers (heterozygotes) of the A-T gene have an increased risk of breast cancer, account for approximately 4% of all breast cancer cases and show a modest increase in cellular radiosensitivity in vitro. It has been suggested that a substantial proportion of highly radiosensitive (HR) breast cancer patients may be A-T heterozygotes, and that screening for mutations in the A-T gene could be used as a predictive test. We have tested this hypothesis in a group of cancer patients who showed adverse reactions to radiotherapy. Sixteen HR breast cancer patients showing mainly acute reactions (and seven HR patients with other cancers) were tested for ATM mutations using the restriction endonuclease fingerprinting assay. No mutations typical of those found in obligate A-T heterozygotes were detected. If the estimate that 4% of breast cancer cases are A-T gene carriers is correct, then ATM mutations do not confer clinical radiosensitivity. These early results suggest that screening for ATM mutations in cancer patients may not be of value in predicting adverse reactions.

Research, prevention, and quality assurance in traumatic brain injury: a public hospital perspective.

The following recommendations are made: increased Medicaid reimbursement for head injury patients to public hospitals that provide care to disproportionately large numbers of these unemployed, uninsured patients, develop comprehensive federal control legislation concerning gun control, develop violence prevention programs such as curricula to combine public health and criminal justice approach, develop trauma registry for neurologic injuries (brain and spinal cord), enforce the use of seat belts and cycle helmets, develop practice guidelines for traumatic brain-injured patients, continue research into the mechanisms and management of brain swelling, neuronal regrowth and transplantations, and other mechanisms to overcome neurologic deficits as well as continue research on post-traumatic syndrome, which results from minor head injuries yet causes significant morbidity and costs, and establish comprehensive rehabilitation and habilitation programs to include physical, cognitive, and behavioral approaches and support systems (eg, "halfway house").