The review of randomization in the Canadian National Breast Screening Study: Is the debate over?

The randomization procedure in the Canadian National Breast Screening Study (NBSS) is assessed in this issue (see pages 193 to 199) by Drs. John C. Bailar III and Brian MacMahon. They conclude that although there was ample opportunity for the randomization process to be subverted, no evidence of subversion was found. This is unlikely to allay all concerns about randomization, because there are still puzzling differences between the arms of the NBSS in a number of baseline variables. For example, the existence of prior health claims for breast cancer for women who entered the NBSS in Manitoba has raised the possibility that subversion occurred. Although the question may never be resolved, one lesion is clear: randomization in clinical trials should be managed in a manner that makes subversion impossible. As for the clinical implications of the NBSS for women in their 40s, physicians may now look to the results of randomized trials that have been published more recently. A meta-analysis of these results suggests that screening mammography reduces deaths from breast cancer among women in their 40s, but continued follow-up over the next few years will be needed to settle the debate.     

Is the three year breast screening interval too long? Occurrence of interval cancers in NHS breast screening programme's north western region.

OBJECTIVE--To report the detection rate of interval cancers in women screened by the NHS breast screening programme. DESIGN--Detection of interval cancers by computer linkage of records held by the screening centres in the North Western Regional Health Authority with breast cancer registrations at the regional cancer registry. SETTING--North Western Regional Health Authority. SUBJECTS--137,421 women screened between 1 March 1988 and 31 March 1992 who had a negative screening result. RESULTS--297 invasive interval cancers were detected. The rate of detection of interval cancers expressed as a proportion of the underlying incidence was 31% in the first 12 months after screening, 52% between 12 and 24 months, and 82% between 24 and 36 months. CONCLUSION--The incidence of interval cancers in the third year after breast screening approaches that which would have been expected in the absence of screening and suggests that the three year interval between screens is too long.     

The review of randomization in the Canadian National Breast Screening Study: What does the verdict mean for clinicians?

What is the practising clinician to make of the review by Drs. John C. Bailar III and Brian MacMahon (see pages 193 to 199 of this issue) of the randomization procedure used in the Canadian National Breast Screening Study? Their conclusion that any flaws in randomization would not have affected the published data is reassuring. Nevertheless, the review has not resolved the controversy surrounding the recommendations for screening mammography for women aged 40-49. Recommendations must be based on strong evidence that the benefits of population-based testing outweigh the harms. The absence of such evidence for women aged 40-49 should not, however, preclude the use of mammography as a diagnostic test for women in their 40s whose clinical signs require follow-up. Mammography could also be considered for women whose family history or other factors suggest an increased risk for breast cancer, provided that the limitations and potential disadvantages of testing are explained.     

Chronological analysis of the species of Conus described during the 18th century

The 339 species-group names in the gastropod genus Conus proposed between 1758 and 1800 have been analyzed in chronological order, in order to (1) identify each nominal species, and (2) determine the correct name of each valid species. Additions and corrections are given to the author's series of papers on type specimens and identity of the described species of Conus. A table listing the 339 species-group names alphabetically indicates the present locations of the 124 known type specimens and the status of each name. At present, 123 valid species are recognized (118 Recent, 5 Tertiary), 159 names are synonyms of previously or simultaneously described species, 35 are nomina dubia, 19 are assigned to infrasubspecific rank, and 3 have been trandferred to genera in other families. Problems involving homonymy of 44 names have been resolved. The proportion of valid species to described species remained quite constant (about 80%) between 1758 and 1786, but then declined sharply to 40%. By 1800, although only 13% of all known species-group names in Conus had been introduced, they probably account for 25% of the known valid Recent species. Extension of the chronological study to species described through 1840 may establish the correct names of half the valid Recent species of Conus.     

Effect of breast self-examination techniques on the risk of death from breast cancer

OBJECTIVE: To measure the effect of breast self-examination (BSE) technique and frequency on the risk of death from breast cancer. DESIGN: Case-control study nested within the Canadian National Breast Screening Study (NBSS). SETTING: The Canadian NBSS, a multicentre randomized controlled trial of screening for breast cancer in Canadian women. SUBJECTS: The case subjects were 163 women who had died from breast cancer and 57 women with distant metastases. Ten control subjects matched by 5-year age group, screening centre, year of enrolment and random allocation group were randomly selected for each case subject. EXPOSURE MEASURES: Self-reported BSE frequency before enrolment in the NBSS, annual self-reports of BSE frequency during the program and annual objective assessments of BSE technique. OUTCOME MEASURES: Odds ratios (ORs) associated with BSE practice were estimated by conditional multiple logistic regression modelling, which permitted control of covariates. RESULTS: Relative to women who, when assessed 2 years before diagnosis, examined their breasts visually, used their finger pads for palpation and examined with their 3 middle fingers, the OR for death from breast cancer or distant metastatic disease for women who omitted 1, 2 or 3 of these components was 2.20 (95% confidence interval [CI] 1.30 to 3.71, p = 0.003). The OR for women who omitted 1 of the 3 components was 1.82 (95% CI 1.00 to 3.29, p = 0.05), for those who omitted 2 of the 3 components, 2.84 (95% CI 1.44 to 5.59, p = 0.003), and for those who omitted all 3 components, 2.95 (95% CI 1.19 to 7.30, p = 0.02). The results remained unchanged after adjustment for potential confounders. CONCLUSION: The results, obtained with the use of prospectively collected data, suggest that the performance of specific BSE components may reduce the risk of death from breast cancer.     

全数字化X线摄影联合MR动态增强检查诊断早期乳腺癌的临床价值研究

目的：分析早期乳腺癌的全数字X线摄影与MRI影像学表现,评价全数字X线摄影联合MRI检查在早期乳腺癌诊断中的临床价值。方法：回顾性分析2009年10月至2012年5月在我院经穿刺或手术病理证实为早期乳腺癌的42例患者的临床资料,术前均行数字X线及动态增强MR检查,比较两种方法单独使用和联合使用的诊断乳腺癌的准确率。结果：全数字化X线摄片诊断早期乳腺癌的准确率为69．0％（29／42）,动态增强MR检查为95．2％（40／42）,两者比较差异有统计学意义（P〈0．05）;两者联合使用诊断早期乳腺癌的准确率为97．6％（41／42）。结论：动态增强MR检查对早期乳腺癌的诊断价值明显优于全数字X线摄影,但后者对微小钙化显示较好,两者联合可提高诊断正确率,尤其对多腺体型和致密型乳腺的早期乳腺癌的检出具有重要的价值。     

全数字化X线摄影联合MR 动态增强检查诊断早期乳腺癌的 临床价值研究

摘要目的：分析早期乳腺癌的全数字X 线摄影与MRI影像学表现,评价全数字X 线摄影联合MRI 检查在早期乳腺癌诊断中的 临床价值。方法：回顾性分析2009 年10 月至2012 年5月在我院经穿刺或手术病理证实为早期乳腺癌的42例患者的临床资料, 术前均行数字X线及动态增强MR 检查,比较两种方法单独使用和联合使用的诊断乳腺癌的准确率。结果：全数字化X 线摄片 诊断早期乳腺癌的准确率为69.0%(29/42),动态增强MR 检查为95.2%(40/42),两者比较差异有统计学意义(P<0.05);两者联合使 用诊断早期乳腺癌的准确率为97.6%(41/42)。结论：动态增强MR 检查对早期乳腺癌的诊断价值明显优于全数字X线摄影,但后 者对微小钙化显示较好,两者联合可提高诊断正确率,尤其对多腺体型和致密型乳腺的早期乳腺癌的检出具有重要的价值。     

Sensitivity analyses comparing outcomes only existing in a subset selected post-randomization, conditional on covariates, with application to HIV vaccine trials

In many experiments, researchers would like to compare between treatments and outcome that only exists in a subset of participants selected after randomization. For example, in preventive HIV vaccine efficacy trials it is of interest to determine whether randomization to vaccine causes lower HIV viral load, a quantity that only exists in participants who acquire HIV. To make a causal comparison and account for potential selection bias we propose a sensitivity analysis following the principal stratification framework set forth by Frangakis and Rubin (2002, Biometrics58, 21-29). Our goal is to assess the average causal effect of treatment assignment on viral load at a given baseline covariate level in the always infected principal stratum (those who would have been infected whether they had been assigned to vaccine or placebo). We assume stable unit treatment values (SUTVA), randomization, and that subjects randomized to the vaccine arm who became infected would also have become infected if randomized to the placebo arm (monotonicity). It is not known which of those subjects infected in the placebo arm are in the always infected principal stratum, but this can be modeled conditional on covariates, the observed viral load, and a specified sensitivity parameter. Under parametric regression models for viral load, we obtain maximum likelihood estimates of the average causal effect conditional on covariates and the sensitivity parameter. We apply our methods to the world's first phase III HIV vaccine trial.     

Local Breast Cancer Spatial Patterning: A Tool for Community Health Resource Allocation to Address Local Disparities in Breast Cancer Mortality

Despite available demographic data on the factors that contribute to breast cancer mortality in large population datasets, local patterns are often overlooked. Such local information could provide a valuable metric by which regional community health resources can be allocated to reduce breast cancer mortality. We used national and statewide datasets to assess geographical distribution of breast cancer mortality rates and known risk factors influencing breast cancer mortality in middle Tennessee. Each county in middle Tennessee, and each ZIP code within metropolitan Davidson County, was scored for risk factor prevalence and assigned quartile scores that were used as a metric to identify geographic areas of need. While breast cancer mortality often correlated with age and incidence, geographic areas were identified in which breast cancer mortality rates did not correlate with age and incidence, but correlated with additional risk factors, such as mammography screening and socioeconomic status. Geographical variability in specific risk factors was evident, demonstrating the utility of this approach to identify local areas of risk. This method revealed local patterns in breast cancer mortality that might otherwise be overlooked in a more broadly based analysis. Our data suggest that understanding the geographic distribution of breast cancer mortality, and the distribution of risk factors that contribute to breast cancer mortality, will not only identify communities with the greatest need of support, but will identify the types of resources that would provide the most benefit to reduce breast cancer mortality in the community.     

A Standardized Reference Data Set for Vertebrate Taxon Name Resolution

Taxonomic names associated with digitized biocollections labels have flooded into repositories such as GBIF, iDigBio and VertNet. The names on these labels are often misspelled, out of date, or present other problems, as they were often captured only once during accessioning of specimens, or have a history of label changes without clear provenance. Before records are reliably usable in research, it is critical that these issues be addressed. However, still missing is an assessment of the scope of the problem, the effort needed to solve it, and a way to improve effectiveness of tools developed to aid the process. We present a carefully human-vetted analysis of 1000 verbatim scientific names taken at random from those published via the data aggregator VertNet, providing the first rigorously reviewed, reference validation data set. In addition to characterizing formatting problems, human vetting focused on detecting misspelling, synonymy, and the incorrect use of Darwin Core. Our results reveal a sobering view of the challenge ahead, as less than 47% of name strings were found to be currently valid. More optimistically, nearly 97% of name combinations could be resolved to a currently valid name, suggesting that computer-aided approaches may provide feasible means to improve digitized content. Finally, we associated names back to biocollections records and fit logistic models to test potential drivers of issues. A set of candidate variables (geographic region, year collected, higher-level clade, and the institutional digitally accessible data volume) and their 2-way interactions all predict the probability of records having taxon name issues, based on model selection approaches. We strongly encourage further experiments to use this reference data set as a means to compare automated or computer-aided taxon name tools for their ability to resolve and improve the existing wealth of legacy data.     

Diagnosing breast carcinoma in young women.

OBJECTIVE--To assess the individual and combined diagnostic accuracy of clinical examination, mammography, and fine needle aspiration biopsy in young women with breast cancer. DESIGN--Analysis based on case notes of patients presenting with breast cancer during 1971-89. SETTING--A combined breast clinic. PATIENTS--Consecutive series of 81 women aged less than 36 with histologically proved breast cancer presenting with a discrete mass over 19 years. MAIN OUTCOME MEASURES--Results of clinical examination, xeromammography or conventional mammography, fine needle aspiration biopsy, and examination of tissue removed by surgery. RESULTS--The clinical diagnosis was correct in 47 women and radiography in 35. Fine needle aspiration biopsy was correct in 47 of the 63 women in whom it was successfully performed. Fine needle aspiration was significantly more accurate than mammography (78% v 45%, p less than 0.01). Ten (16%) patients had negative results on clinical examination, mammography, and fine needle aspiration. CONCLUSION--Mammography alone seems inadequately sensitive to detect breast cancer in young patients. When all investigations give negative results excision biopsy is the only way of obtaining a definitive diagnosis.     

Subgroup-Based Adaptive (SUBA) Designs for Multi-arm Biomarker Trials

Targeted therapies based on biomarker profiling are becoming a mainstream direction of cancer research and treatment. Depending on the expression of specific prognostic biomarkers, targeted therapies assign different cancer drugs to subgroups of patients even if they are diagnosed with the same type of cancer by traditional means, such as tumor location. For example, Herceptin is only indicated for the subgroup of patients with HER2+ breast cancer, but not other types of breast cancer. However, subgroups like HER2+ breast cancer with effective targeted therapies are rare, and most cancer drugs are still being applied to large patient populations that include many patients who might not respond or benefit. Also, the response to targeted agents in humans is usually unpredictable. To address these issues, we propose subgroup-based adaptive (SUBA), designs that simultaneously search for prognostic subgroups and allocate patients adaptively to the best subgroup-specific treatments throughout the course of the trial. The main features of SUBA include the continuous reclassification of patient subgroups based on a random partition model and the adaptive allocation of patients to the best treatment arm based on posterior predictive probabilities. We compare the SUBA design with three alternative designs including equal randomization, outcome-adaptive randomization, and a design based on a probit regression. In simulation studies, we find that SUBA compares favorably against the alternatives.     

A new DRB1 * 1202 allele (DRB1 * 12022) found in association with DQA1 * 0102 and DQB1 * 0602 in two Black narcoleptic subjects

The nucleotide sequence data reported in this paper have been submitted to the GenBank nucleotide sequence database and have been assigned the accession number L34353. The name listed for this sequence has been officially assigned by the WHO Nomenclature Committee in August 1994. This follows the agreed policy that subject to the conditions stated in the most recent Nomenclature Report (Bodmer et al 1994), names will be assigned to new sequences as they are identified. Lists of such new names will be published in the following WHO Nomenclature Report     

Mammography: a surgeon's experience.

Most reports advocating mammography have been written by radiologists rather than by clinicians who are frequently confronted by women with breast complaints. The value of mammography in managing patients with breast problems was studied by reviewing its role in 1026 breast consultations; there were 129 patients with cancer. Mammography was performed in 95 patients. The procedure hastened the diagnosis of one comedocarcinoma, and in another patient was suspicious 3 years before she presented with a locally advanced lesion. It missed six cancers. In seven patients it recognized clinically obvious cancers, though in one of these it had given negative results 10 months before the patient presented with a lesion 15 cm in diameter. It also falsely suggested the possibility of cancer in 28 women. In the other 52 patients the clinical diagnosis of a benign condition was usually fairly evident. The morbidity caused by mammography does not seem to have been widely appreciated, no doubt because of the hope that clinically unrecognized cancers would be found by it. Most breast problems can be diagnosed without mammography.     

A newHLA-DRB1 * 13 allele (DRB1 * 1318) with a shortDRB1*08 sequence

The nucleotide sequence data reported in this paper have been submitted to the EMBL/GenBank nucleotide sequence database and have been assigned the accession number Z48631. The name listed for this sequence was officially assigned by the WHO Nomenclature Committee in November 1994. This follows the agreed policy that, subject to the conditions stated in the most recent Nomenclature Report (Bodmer et al. 1994), names will be assigned to new sequences as they are identified. Lists of such new names will be published in the following WHO Nomenclature Report     

The role of various modalities in breast imaging

Background: Breast cancer is the most common type of cancer in women worldwide. Mammography is considered the "gold standard" in the evaluation of the breast from an imaging perspective. Apart from mammography, ultrasound examination and magnetic resonance imaging are being offered as adjuncts to the preoperative workup. Recently, other new modalities like positron emission tomography, 99mTc-sestamibi scintimammography, and electrical impedance tomography (EIT) are also being offered. However, there is still controversy over the most appropriate use of these new modalities. Based on the literature, this review evaluates the role of various modalities used in the screening and diagnosis of breast cancer. Methods and Results: Based on relevant literatures this article gives an overview of the old and new modalities used in the field of breast imaging. A narrative literature review of all the relevant papers known to the authors was conducted. The search of literatures was done using pubmed and ovid search engines. Additional references were found through bibliography reviews of relevant articles. It was clear that though various new technics and methods have emerged, none have substituted mammography and it is still the only proven screening method for the breast as of date. Conclusion: From the literature it is clear that apropos modern radiology's impact on diagnosis, staging and patient follow-up, only one imaging technique has had a significant impact on screening asymptomatic individuals for cancer i.e.; low-dose mammography. Mammography is the only screening test proven in breast imaging. Positron emission tomography (PET) also plays an important role in staging breast cancer and monitoring treatment response. As imaging techniques improve, the role of imaging will continue to evolve with the goal remaining a decrease in breast cancer morbidity and mortality. Progress in the development and commercialisation of EIT breast imaging system will definitely help to promote other systems and applications based on the EIT and similar visualization methods. Breast ultrasound and breast magnetic resonance imaging (MRI) are frequently used adjuncts to mammography in today's clinical practice and these techniques enhance the radiologist's ability to detect cancer and assess disease extent, which is crucial in treatment planning and staging.     

Does genetic counseling have any impact on management of breast cancer risk?

Despite there being an increasing literature on the impact of cancer genetic counseling on risk perception and mental health, there is a lack of data describing impact on risk management. Genetic counseling and testing for cancer predisposition genes aims to improve the future health of those at high risk through appropriate surveillance and screening. However, management of breast cancer risk in women with a family history of this disease is an area of controversy. Counseling services may recommend specific risk management options to women, who then rely on their local screening service to make provision. This study investigated the impact of genetic counseling on management of breast cancer risk in women attending Cancer Family Clinics. A total of 293 women attending four genetic clinics were enrolled. Rates of breast self-examination, clinical breast examination, mammography, biopsy, detected cancers, and other screenings were documented. Participants' perceived benefits and barriers to mammography were assessed along with cancer worry. Results show that rates of mammography, clinical breast examination, and breast self-examination were increased following clinic attendance (p < 0.001). Women in the under 35 age-group had limited access to screening. Rates for biopsy and detected cancers were low. Women reported positive attitudes to mammography, with few reported barriers. Contrary to previous studies, there was no evidence that anxiety about breast cancer impedes uptake of health surveillance methods. Genetic counseling had a positive impact on management of breast cancer risk. Whether this translates into future health gains remains to be established.     

Cw * 1505: a novel HLA-C allele isolated from a B * 7301 haplotype

The nucleotide sequence data reported in this paper have been submitted to the EMBL database and have been assigned the accession number X78343. The name Cw ^*1505 was officially assigned by the WHO Nomenclature Committee in May 1994. This follows the agreed policy that, subject to the conditions stated in the most recent Nomenclature Report (The WHO Nomenclature Committee 1992), names will be assigned to new sequences as they are identified. Lists of such new names will be published in he following WHO Nomenclature Report     

A new DRB1 allele (DRB1 * 0811) identified in Native Americans

The nucleotide sequence data reported here have been submitted to the Genome Sequence Database and have been assigned the accession number L32810. The name DRB1 ^*0811 was officially assigned by the WHO Nomenclature Committee in March 1994. This follows the policy that, subject to the conditions stated in the most recent Nomenclature Report (Bodmer et al. 1992), names will be assigned to new sequences as they are identified. Lists of such new names will be published in the following WHO Nomenclature Report     

Preventive health care, 1999 update: 3. Follow-up after breast cancer

OBJECTIVE: To make recommendations to physicians who provide follow-up care for women who have been treated for early-stage breast cancer. OPTIONS: Combination of blood tests, bone scans, liver echography and chest radiography for detection of distant disease; physical examination with or without mammography for detection of contralateral breast cancer; and physical examination with or without mammography for detection of ipsilateral recurrent disease after breast-conserving therapy. OUTCOMES: Survival, disease recurrence and quality-of-life measures for distant disease, local recurrence of disease and disease in the contralateral breast. EVIDENCE: A MEDLINE search for relevant articles published between January 1966 and January 1998 with the MeSH terms "breast neoplasms" and "neoplasm recurrence" (local and distant) with limits to "human" was done. A subsequent MEDLINE search using the MeSH terms "breast neoplasms," "neoplasm recurrence," "local/diagnosis" and "mammography" was done to address issues of mammography. The literature search was reviewed by a medical librarian and 2 breast cancer specialists to ensure completeness. BENEFITS, HARMS AND COSTS: Breast cancer is the most common cancer in Canadian women and is the second leading cause of death after lung cancer. Even with early-stage breast cancer, recurrence after treatment for primary breast cancer is frequent. Traditionally, follow-up has been felt to facilitate early detection and improve survival. Randomized controlled trials (RCTs) have shown that routine screening (blood tests and diagnostic imaging) for distant disease does not alter survival or quality of life over routine physical examination. In an underpowered secondary analysis of RCT data, the detection of contralateral breast cancer did not affect survival. However, there have been no RCTs examining the role of mammography and physical examination and their effect on survival in the detection of contralateral breast cancer. The sensitivity and specificity of mammography after local excision and radiotherapy is unknown. There have been no RCTs examining the role of mammography or physical examination, or both, and their effect on survival in the detection of ipsilateral breast recurrence. VALUES: The strength of evidence was evaluated using the methods of the Canadian Task Force on Preventive Health Care. A high value was placed on interventions that changed survival. When evidence was available, high value was also placed on interventions that affected quality of life. RECOMMENDATIONS: There is good evidence not to include blood work and diagnostic imaging as part of screening for distant disease (grade E recommendation). There is no evidence to suggest that mammography decreases mortality by detecting ipsilateral disease in the conservatively treated breast; however, there is indirect evidence that it may be beneficial (grade C recommendation). There is no direct evidence to suggest that physical examination or mammography, or both, should be used to detect contralateral breast cancer; however, there is indirect evidence that it may be beneficial (grade C recommendation). VALIDATION: The findings of this analysis were reviewed through an iterative process by the members of the Canadian Task Force on Preventive Health Care.