The natural history of breast carcinoma: what have we learned from screening?

BACKGROUND: The availability of breast carcinoma data from trials of mammographic screening provides an opportunity to study the natural history of breast carcinoma. METHODS: The Swedish Two-County study is a randomized, controlled trial of mammographic screening for breast carcinoma in which 77,080 women were randomized to receive an invitation to mammographic screening and 55,985 were randomized to receive no invitation. During the trial, a total of 2468 breast carcinoma cases were diagnosed. The authors examined the effect of screening on the pathologic attributes of the tumors diagnosed, mortality and survival from breast carcinoma, and the consequences of arresting tumor development by screening. RESULTS: Screening reduces mortality from breast carcinoma largely through its effect in detecting tumors at a smaller size, decreasing the probability of lymph node metastases, and reducing the opportunity for worsening of the grade of malignancy of the tumor. CONCLUSIONS: Breast carcinoma is not a systemic disease at its inception, but is a progressive disease and its development can be arrested by screening. The point at which the tumor's progression is arrested is crucial. Detection of small (<15 mm) and lymph node negative invasive tumors will save lives and confer an opportunity for less radical treatment. Tumor progression in the preclinical phase occurs more rapidly in women age <50 years, suggesting the need for a shorter screening interval for this group.     

Association between DQB1 and cervical cancer in patients with human papillomavirus and family controls

OBJECTIVE: The role of human leukocyte antigen (HLA) DQB1 alleles and human papillomavirus (HPV) as contributing factors to invasive cervical cancer was investigated. To overcome problems of misleading causal inferences common in traditional case-control studies, a family-based test, the transmission/disequilibrium test, was used. METHODS: Ninety-six patients with pathologically confirmed invasive cervical cancer were ascertained. Human papillomavirus types were determined in 80 patients, of whom 81.25% were HPV-positive, and 18.75% were HPV-negative. Deoxyribonucleic acid was extracted from samples, taken from patients and their parents, and sequenced to determine DQB1 genotypes. Nuclear family data were used to test whether the DQB1 locus is associated with invasive cervical cancer while controlling for high-risk HPV-positive patients. The transmission/disequilibrium test evaluates whether the frequency of transmission of parental marker alleles to their affected offspring deviates from the expected Mendelian frequency of 50%. RESULTS: The HLA DQB1 locus showed evidence for allelic association with invasive cervical cancer in high-risk HPV-positive patients (P = .006). The transmission/disequilibrium test showed that the DQB1*0303 allele was transmitted to high-risk HPV patients more often than expected by chance, chi2(1) = 8.0, P = .005 (P = .035 when correcting for multiple tests). Tests of association were negative when applied to all 96 patients, irrespective of HPV status. No significant differences were found in the distribution of the DQB1 alleles among HPV-positive patients compared with those who were HPV-negative, indicating that HLA alleles are not associated with susceptibility to HPV infection. CONCLUSION: These results suggest that the DQB1*0303 allele increases the risk for invasive cervical cancer in women who are HPV-positive.     

Behavioural effects of chronic haloperidol and risperidone treatment in rats

The therapeutic properties of typical antipsychotic drugs (APDs) such as haloperidol in schizophrenia treatment are mainly associated with their ability to block dopamine D2 receptors. This blockade is accompanied by side effects such as extrapyramidal symptoms (EPS). Atypical APDs such as risperidone have superior therapeutic efficacy possibly due to their activity at multiple receptors (in particular 5-HT2A receptors). Although the risk of EPS is significantly lower in atypical than in typical APDs, it is not negligible. To investigate and compare the behavioural profile and EPS-asssociated side effects of haloperidol and risperidone APD treatment we applied a multi-tiered, comprehensive behavioural phenotyping approach. Sprague-Dawley rats were treated chronically (28 days) with supratherapeutic EPS-inducing doses of haloperidol and risperidone using osmotic minipumps. Domains such as motor activity, exploration, memory, and anxiety were analysed together with EPS assessment ("early onset" vacuous chewing movements and catalepsy). Both APDs produced diminished motor activity and exploration, impaired working memory performances, and increased anxiety levels. These effects were more pronounced in haloperidol-treated animals. Chronic APD treatment also caused a time-course dependent elevation of EPS-like symptoms. Risperidone-treated animals showed a catalepsy-like phenotype, which differed to that of haloperidol-treated rats, indicating that processes other than the anticipated dopaminergic mechanisms are underlying this phenomenon. These EPS-related phenotypes are consistent with reported EPS-inducing D2 receptor occupancies of around 80%. Differences in the behavioural profile of haloperidol and risperidone, which were revealed by a comprehensive phenotyping strategy, are likely due to the unique receptor activation profiles of these APDs.     

Improved Stability of Proline-Derived Direct Thrombin Inhibitors through Hydroxyl to Heterocycle Replacement

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The process of evidence-based practice in radiology: an introduction

EBP can be used by radiologists to assess imaging modalities using the recognized “Ask, Search, Appraise, Apply, and Evaluate” steps. The technology assessment framework is also a useful tool to stratify an imaging modality according to its technical and diagnostic performance. It can also be used to assess its therapeutic and diagnostic impact as part of the “Evaluate” step of EBP. We have described how these two processes can be combined and used in a synergistic way. While its format may appear unorthodox compared to conventional research methodology (i.e., aims, methods, results, and conclusion), it is a practical and readily interpreted way of bridging the gap between EBP and primary research. An example of its application entitled “Combining ‘Evidence-Based Practice’ and ‘Technology Assessment’ Methods to Develop Departmental Imaging Protocols: Should FDG PET Be Routinely Used in the Preoperative Assessment of Patients With Colorectal Liver Metastases?” is published in this issue. Further details of this process and its potential impact on technology assessment, education, ethics, and radiology literature has been considered in a recent Radiology special series (11).     

DBA/2J (Mls-1a) B-cell differentiation in BALB.xid recipients

Studies of superantigens (SAg) have focused primarily on their impact on CD4+ T cells, largely bypassing the impact of the sequelae of this interaction upon the antigen-presenting cell (APC). Sequelae of SAg-induced CD4+ T-cell activation include the 'bathing' of the SAg-presenting cell with cytokines that promote the differentiation of the APC. In this report, the SAg-induced differentiation of Mls+ DBA/2J B cells was studied in vivo by their transplantation into B-cell-defective BALB.xid recipients. Rapid, high-level serum immunoglobulin M (IgM) production was noted shortly after transfer, disappearing by 3 weeks. Donor B cells, as evidenced after their chemical and genetic impairment and by the use of an IgM allotype-disparate donor-recipient combination, contributed to this transient IgM production. These results clarify a discrepancy in the literature regarding donor B-cell contribution to IgM production and illustrate a model system to utilize SAg to study B-lymphocyte diversity.     

Unrestricted principal components analysis of brain electrical activity: Issues of data dimensionality,artifact, and utility

Summary Principal components analysis (PCA) was performed on the 1536 spectral and 2944 evoked potential (EP) variables generated by neurophysiologic paradigms including flash VER, click AER, and eyes open and closed spectral EEG from 202 healthy subjects aged 30 to 80. In each case data dimensionality of 1500 to 3000 was substantially reduced using PCA by magnitudes of 20 to over 200. Just 20 PCA factors accounted for 70% to 85% of the variance. Visual inspection of the topographic distribution of factor loading scores revealed complex loadings across multiple data dimensions (time-space and frequency-space). Forty-two non-artifactual factors were successful in classifying age, gender, and a separate group of 60 demented patients by linear discriminant analysis. Discrimination of age and gender primarily involved EP derived factors, whereas dementia primarily involved EEG derived factors. Thirty-eight artifactual factors were identified which, alone, could not discriminate age but were relatively successful in discriminating gender and dementia. The need to parsimoniously develop real neurophysiologic measures and to objectively exclude artifact are discussed. Unrestricted PCA is suggested as a step in this direction.Acknowledgements: This work was supported in part by NIA program project PO1AG049853 to M. Albert and the Mental Retardation Program Project P30HD18655 to J.J. Volpe. We thank our qEEG technologists Adele Mirabella, Susan Katz, Ellen Belles, and Marianne McGaffigan as well as our research secretaries for their unflagging support.     

Circadian and sleep/wake dependent aspects of subjective alertness and cognitive performance

Circadian and sleep/wake dependent processes underlying variations in subjective alertness and cognitive performance were assessed in a constant routine protocol and in a protocol in which the sleep/wake cycle was uncoupled from the output of the endogenous circadian pacemaker. In the latter protocol, the contribution of a sleep/wake dependent process and a circadian process to alertness and performance were separated by folding the data at either the period of the sleep/wake cycle or at the period of the endogenous circadian body temperature rhythm. This analysis revealed that prior wakefulness within a range of 0-18 h significantly reduced alertness and performance and that the circadian rhythm of core body temperature paralleled the circadian rhythm of alertness and performance. During the first 16 h of the constant routine protocol, which coincided with the subjects' habitual period of wakefulness, alertness and performance remained at a stable level. The latter finding was explained by assuming that during our usual waking day the circadian system counteracts the detrimental effects of increasing duration of prior wakefulness.