Postoperative radiotherapy omission in selected patients with early breast cancer following preoperative breast MRI (PROSPECT): primary results of a prospective two-arm study.

BACKGROUND: Adjuvant breast radiotherapy as a standard component of breast-conserving treatment for early cancer can overtreat many women. Breast MRI is the most sensitive modality to assess local tumour burden. The aim of this study was to determine whether a combination of MRI and pathology findings can identify women with truly localised breast cancer who can safely avoid radiotherapy. METHODS: PROSPECT is a prospective, multicentre, two-arm, non-randomised trial of radiotherapy omission in patients selected using preoperative MRI and postoperative tumour pathology. It is being conducted at four academic hospitals in Australia. Women aged 50 years or older with cT1N0 non-triple-negative breast cancer were eligible. Those with apparently unifocal cancer had breast-conserving surgery (BCS) and, if pT1N0 or N1mi, had radiotherapy omitted (group 1). Standard treatment including excision of MRI-detected additional cancers was offered to the others (group 2). All were recommended systemic therapy. The primary outcome was ipsilateral invasive recurrence rate (IIRR) at 5 years in group 1. Primary analysis occurred after the 100th group 1 patient reached 5 years follow-up. Quality-adjusted life-years (QALYs) and cost-effectiveness of the PROSPECT pathway were analysed. This study is registered with the Australian New Zealand Clinical Trials Registry (ACTRN12610000810011). FINDINGS: Between May 17, 2011, and May 6, 2019, 443 patients with breast cancer underwent MRI. Median age was 63·0 years. MRI detected 61 malignant occult lesions separate from the index cancer in 48 patients (11%). Of 201 group 1 patients who had BCS without radiotherapy, the IIRR at 5 years was 1·0% (upper 95% CI 5·4%). In group 1, one local recurrence occurred at 4·5 years and a second at 7·5 years. In group 2, nine patients had mastectomy (2% of total cohort), and the 5-year IIRR was 1·7% (upper 95% CI 6·1%). The only distant metastasis in the entire cohort was genetically distinct from the index cancer. The PROSPECT pathway increased QALYs by 0·019 (95% CI 0·008-0·029) and saved AU$1980 (95% CI 1396-2528) or £953 (672-1216) per patient. INTERPRETATION: PROSPECT suggests that women with unifocal breast cancer on MRI and favourable pathology can safely omit radiotherapy. FUNDING: Breast Cancer Trials, National Breast Cancer Foundation, Cancer Council Victoria, the Royal Melbourne Hospital Foundation, and the Breast Cancer Research Foundation.

Effects of Performance-Based Training on Gait and Balance in Individuals With Incomplete Spinal Cord Injury.

OBJECTIVE: To determine changes in balance and gait following a task-specific, performance-based training protocol for overground locomotor training (OLT) in individuals with motor-incomplete spinal cord injury (iSCI). DESIGN: Convenience sample, prepilot and postpilot study. SETTING: Human performance research laboratory. PARTICIPANTS: Adults (N=15; 12 men and 3 women; mean age [y] ± SD, 41.5±16.9), American Spinal Injury Association Impairment Scale C or D, >6 months post-spinal cord injury. INTERVENTIONS: Two 90-minute OLT sessions per week over 12 to 15 weeks. OLT sessions were built on 3 principles of motor learning: practice variability, task specificity, and progressive overload (movement complexity, resistance, velocity, volume). Training used only voluntary movements without body-weight support, robotics, electrical stimulation, or bracing. Subjects used ambulatory assistive devices as necessary. MAIN OUTCOME MEASURES: Berg Balance Scale (BBS), Spinal Cord Injury Functional Ambulation Inventory (SCI-FAI) gait parameters, spatiotemporal measures of gait (step length, step width, percent stance, stance:swing ratio) from 7 participants who walked across a pressure-sensitive walkway. RESULTS: Fourteen participants completed the OLT protocol and 1 participant completed 15 sessions due to scheduled surgery. The BBS scores showed a mean improvement of 4.53±4.09 (P<.001). SCI-FAI scores showed a mean increase of 2.47±3.44 (P=.01). Spatiotemporal measures of gait showed no significant changes. CONCLUSION: This pilot demonstrated improvements in balance and selected gait characteristics using a task-specific, performance-based OLT for chronic iSCI.

Predicting outcomes within an innovative post-acute rehabilitation model for older adults.

BACKGROUND: Understanding the provision of health services to community-dwelling older adults is of great importance due to regulatory changes within post-acute care. The aim of this study was to illustrate pathways by which older adults, within an innovative post-acute care delivery model, move to either independence or re-admission back into higher levels of care to maximize the value of rehabilitation delivery. METHODS: Clinical data specific to an episode of care (n = 30,001) provided to Medicare beneficiaries treated via a rehabilitation house-calls model of care in their homes and senior living communites were separated into training and test sets. Classification trees were fit on the training set's administrative and clinical variables. Descriptive statistics were calculated for the overall sample, patient characteristics, clinical characteristics, and clinical outcomes. RESULTS: Subjects were 83.3 years on average, 69.4% were female, and 62.2% were seen in their own homes while 37.8% were in senior living. The key variables predictive of progressing to independence were total number of visits, the presence of the Patient Specific Functional Scale (PSFS), PSFS score at discharge and change in PSFS. Prediction accuracy of the classification tree on the test set was 82.4%. CONCLUSIONS: Older adults progress to a higher degree of independence, instead of higher levels of care, via several distinct pathways within a rehabilitation house-calls model of care. A mix of service utilization and outcome variables are key predictors of each pathway and may be used to maximize the value of service delivery. Further examination of the predictors of outcome using administrative datasets drawn from different sub-sets of older adults across the post-acute care continuum is warranted.

Fatigability, oxygen uptake kinetics and muscle deoxygenation in incomplete spinal cord injury during treadmill walking.

PURPOSE: The purpose of the present study was to characterize hypothesized relationships among fatigability and cardiorespiratory fitness in individuals with chronic motor-incomplete SCI (iSCI) during treadmill walking. The theoretical framework was that exacerbated fatigability would occur concomitantly with diminished cardiorespiratory fitness in people with iSCI. METHODS: Subjects with iSCI (n = 8) and an able-bodied reference group (REF) (n = 8) completed a 6-min walking bout followed by a walking bout of 30-min or until volitional exhaustion, both at a self-selected walking speed. Fatigability was assessed using both perceived fatigability and performance fatigability measures. Pulmonary oxygen uptake kinetics (VO2 on-kinetics) was measured breath-by-breath and changes in deoxygenated hemoglobin/myoglobin concentration (∆[HHb]) of the lateral gastrocnemius was measured by near-infrared spectroscopy. Adjustment of VO2 and ∆[HHb] on-kinetics were modeled using a mono-exponential equation. RESULTS: Perceived fatigability and performance fatigability were 52% and 44% greater in the iSCI group compared to the REF group (p = 0.003 and p = 0.004). Phase II time constant (τp) of VO2 on-kinetics and ∆[HHb] ½ time during resting arterial occlusion were 55.4% and 16.3% slower in iSCI vs REF (p < 0.01 and p = 0.047, respectively). CONCLUSIONS: The results of the present study may suggest that compromised O2 delivery and/or utilization may have contributed to the severity of fatigability in these individuals with iSCI. The understanding of the extent to which fatigability and VO2 and Δ[HHb] on-kinetics impacts locomotion after iSCI will assist in the future development of targeted interventions to enhance function.

Outcomes of screening-detected ductal carcinoma in situ treated with wide excision alone.

BACKGROUND: Ductal carcinoma in situ (DCIS) is commonly identified on screening mammography. Standard treatment for localized DCIS is wide local excision (WLE) and adjuvant radiotherapy. This approach represents overtreatment in many cases, where the DCIS would never have become clinically significant, or where less intensive treatment would have been satisfactory. We reviewed the medium-term outcome of a cohort of screen detected DCIS patients treated mainly with WLE without radiotherapy. METHODS: All patients diagnosed with DCIS at NorthWestern BreastScreen between January 1994 and December 2005 were identified from a prospective database. Demographic, pathological, treatment, and outcome data were collected and analyzed. Survival and local recurrence (LR) rates were determined, and associations between various factors and recurrence were analyzed. RESULTS: A total of 422 patients were diagnosed with DCIS. There were 400 patients treated with WLE, and 27 of these received adjuvant radiotherapy. The 5- and 8-year overall and breast cancer specific survival rates were 96.1 and 91.3%, and 99.6 and 99.3%, respectively. The local recurrence rate was 15.4 and 17.1% at 5 and 8 years. Of 56 local recurrences, 34 had WLE after recurrence, 16 of which had adjuvant radiotherapy. No single factor was statistically significantly associated with local recurrence, although combining factors revealed groups where the LR rate was less than 5%. CONCLUSIONS: Breast cancer specific mortality was very low in this cohort of older patients with screen-detected DCIS. There was a moderate rate of local recurrence that could usually be salvaged with breast conservation. Decisions regarding adjuvant radiotherapy should take these findings into account.

International consensus statement on surgical education and training in an era of reduced working hours.

An international consensus statement has been developed as a reference on the key principles to be considered during discussions on surgical education and training and the delivery of surgical care in an era of restricted hours.

A mandatory intercalated degree programme: revitalising and enhancing academic and evidence-based medicine.

BACKGROUND: Recruitment of medical graduates to research careers is declining. Expansion of medical knowledge necessitates all graduates be equipped to critically evaluate new information. To address these challenges, a mandatory intercalated degree programme was introduced as part of curriculum reform. AIMS: To review the place on intercalated degrees, the methods available for learning about research and to analyse experience with a new university programme focusing on research. METHODS: A literature review followed by the analysis of experience with eight cohorts of students who had completed the new programme. RESULTS: A total of 1599 students completed the programme. Laboratory-based research was the most common choice followed by clinical research, population health, epidemiology, medical humanities and mental health. Also, 93% of students spent over 75% of their time undertaking research. Sixty-three students published their research, half as first authors. Students and coordinators support the programme. Learning about research during the postgraduate phase is variable and frequently left to individual choice. CONCLUSION: Intercalating an additional degree focusing on research can achieve a number of learning objectives but demands a level of maturity, autonomy and preparedness, not uniformly present in students undertaking a mandatory intercalated programme. A more realistic goal is the development of 'research-mindedness' amongst all students.

Assessing Motor Function in Congenital Muscular Dystrophy Patients Using Accelerometry.

BACKGROUND: When tested in a controlled clinic environment, individuals with neuromuscular-related symptoms may complete motor tasks within normal predicted ranges. However, measuring activity at home may better reflect typical motor performance. The accuracy of accelerometry measurements in individuals with congenital muscular dystrophy (CMD) is unknown. We aimed to compare accelerometry and manual step counts and assess free-living physical activity intensity in individuals with CMD using accelerometry. METHODS: Ambulatory pediatric CMD participants (n = 9) performed the 6-minute walk test in clinic while wearing ActiGraph GT3X accelerometer devices. During the test, manual step counting was conducted to assess concurrent validity of the ActiGraph step count in this population using Bland-Altman analysis. In addition, activity intensity of 6 pediatric CMD participants was monitored at home with accelerometer devices for an average of 7 days. Cut-point values previously validated for neuromuscular disorders were used for data analysis. RESULTS: Bland-Altman and intraclass correlation analyses showed no concurrent validity between manual and ActiGraph-recorded step counts. Fewer steps were recorded by ActiGraph step counts compared with manual step counts (411 ± 74 vs 699 ± 43, respectively; P = .004). Although improved, results were in the same direction with the application of low-frequency extension filters (587 ± 40 vs 699 ± 43, P = .03). ActiGraph step-count data did not correlate with manual step count (Spearman ρ = 0.32, P = .41; with low-frequency extension: Spearman ρ = 0.45, P = .22). Seven-day physical activity monitoring showed that participants spent more than 80% of their time in the sedentary activity level. CONCLUSIONS: In a controlled clinic setting, step count was significantly lower by ActiGraph GT3X than by manual step counting, possibly because of the abnormal gait in this population. Additional studies using triaxial assessment are needed to validate accelerometry measurement of activity intensity in individuals with CMD. Accelerometry outcomes may provide valuable measures and complement the 6-minute walk test in the assessment of treatment efficacy in CMD.

Measures of Clinical Meaningfulness and Important Differences.

Measures of clinical significance have been in use for several decades as a means of interpreting clinical findings and patient-reported outcomes. The most common of these measures is the minimal clinically important difference. With the rise in popularity of measurements of clinical significance, several common misconceptions have arisen that may impact their interpretation and application to clinical practice. The purpose of this article is to present a schema for understanding measurement of clinical significance and use this to highlight the reasons why misuse and misinterpretation have occurred. A new measure of clinical significance is then defined that is intended to be resistant to these issues. Clinical significance has long been a topic of importance to researchers looking to make their findings interpretable and has been quantified in diverse ways.1 Recently, there has been rapidly increasing interest in and use of an assortment of minimal (clinically) important difference measures. The range of their use is illustrated by the publications of reviews and meta-analyses in pain relief,2 cognitive interventions for dementia,3 and CT densitometry for patients with chronic obstructive pulmonary disease.4 Consensus has not been reached for how clinical significance should be defined. Despite this, current methods fall into 2 distinct approaches. The first estimates measurement error levels, and the other quantifies the ability of the instrument to predict clinical outcomes of interest. The conceptual differences between the 2 approaches have not been clearly delineated in the literature. Further, additional conceptual and practical issues exist for measures using the second approach because it has not previously been framed as a clinical prediction problem. It is the aim of this paper to develop a framework to guide researchers in the use of clinical importance measures and to introduce a new methodology for predicting clinically meaningful change. We first propose 2 types of clinical significance measures relating to what we call the Detection and Clinical Prediction Problems. Next, we discuss weaknesses of existing measures of clinical prediction within this unifying framework. Finally, we define a new measure of clinical significance using predictive values and demonstrate its use with simulated data.

Left Ventricular Function Before and After Aerobic Exercise Training in Women With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) is a chronic debilitating illness. The effects of vigorous aerobic exercise training (AET) on heart function in PAH are poorly understood. METHODS: Eighteen women with PAH (aged 56.2 ± 8.8 yr, body mass index: 28.8 ± 7.3 kg/m) underwent 10 wk of vigorous AET. Cardiac function was observed at rest and peak exercise using bioelectrical impedance cardiography before and after the AET. Cardiac function was observed in a small PAH subset (n = 7) for 10 wk before beginning the AET. A cohort of sedentary women (n = 19) served as healthy controls. RESULTS: Left ventricular ejection fraction (48 ± 9.2 vs 61.5 ± 13.3%, P = .034) and the systemic vascular resistance index (2258 ± 419.1 vs 2939 ± 962.4 dyn·sec/cm·m, P = .008) were lower at supine rest in the baseline PAH group versus the healthy group, as were peak exercise heart rate (140 ± 13.3 vs 170 ± 13.8 beats/min, P < .001) and systemic vascular resistance index (828 ± 141.1 vs 824 ± 300.9 dyn·sec/cm·m, P = .050) after controlling for age and heart rate. Systemic vascular resistance index measured at peak exercise decreased in the PAH group after AET (828 ± 141.1 vs 766 ± 139.6 dyn·sec/cm·m, P = .020). Left ventricular early diastolic filling ratio worsened in the PAH subset prior to AET (95.9 ± 19.4 vs 76.2 ± 18.9%, P = .043) and remained unchanged after AET. CONCLUSION: Vigorous AET was not associated with significant declines in left ventricular systolic or diastolic function in women with PAH. Aerobic exercise training may be beneficial for reducing afterload and may preserve left ventricular diastolic function.

Effect of overground locomotor training on ventilatory kinetics and rate of perceived exertion in persons with cervical motor-incomplete spinal cord injury.

Study design: Pre-post, pilot study. Objectives: To characterize ventilatory (VE) responses to exercise following warm-up walking in individuals with chronic incomplete spinal cord injury (iSCI) during constant work rate (CWR) exercise. Secondarily, to investigate VE and tidal volume (VT) variability, and ratings of perceived exertion (RPE) before and after overground locomotor training (OLT). Setting: Research laboratory. Methods: A 6-min CWR walking bout at preferred pace was used as a warm-up followed by 6 min of rest and a second 6-min CWR bout at above preferred walking pace. The second CWR bout was analyzed. Breath-by-breath ventilatory data were examined using a curvilinear least squares fitting procedure with a mono-exponential model. VE and VT variability was calculated as the difference between the observed and predicted values and RPE was taken every 2 min. Results: Participants (n = 3, C4-C5) achieved a hyperpneic response to exercise in VE and VT. OLT resulted in faster ventilatory kinetics and reductions of 24 and 29% for VE and VT variability, respectively. A 30% reduction in RPE was concurrent with the reductions in ventilatory variability. Conclusions: OLT may improve ventilatory control during CWR in patients with cervical motor-iSCI. These data suggest that in some participants with iSCI, ventilation may influence RPE during walking. Future research should investigate mechanisms of ventilatory variability and its implications in walking performance in patients with iSCI.

Predictors of surgical margin status in breast-conserving surgery within a breast screening program.

BACKGROUND: Breast-conserving surgery (BCS) requires clear surgical margins to minimize local recurrence. We sought to identify groups of patients at higher risk of involved margins who might benefit from preoperative counselling and/or more generous excision at the first operation. METHODS: We reviewed demographic, clinical, radiological and pathological records of all women diagnosed with ductal carcinoma in situ (DCIS) or invasive cancer (IC) through a population-based breast screening program in Melbourne, Australia between 1994 and 2005. RESULTS: A total of 2,160 women were diagnosed with DCIS or IC. We excluded 199 who had mastectomy (TM) as initial procedure or had missing data. Three hundred and thirteen had a diagnostic biopsy. Of 1,648 women who had BCS after a preoperative diagnosis of DCIS or IC, 13.5% had involved margins, 16.6% had close (1 mm) margins. Of the patients, 281/1,648 (17.1%) underwent re-excision, of whom 93 (33.1%) had residual disease identified. Mammographic microcalcifications (P < 0.0001), absence of a mammographic mass (P = 0.002), presence of DCIS (P < 0.0001), high tumour grade (P < 0.0001), large size (P < 0.0001), multifocal disease (P < 0.0001) and lobular histology (P = 0.005) were associated with involved margins. Microcalcifications (odds ratio [OR] 1.97), large size (OR 4.22) and multifocal disease (OR 2.85) were independently associated with involved margins. Residual disease was associated with involved margins (P < 0.0001), presence of DCIS (P = 0.05) and large tumour size (P = 0.01). CONCLUSION: After BCS, patients with mammographic microcalcifications, larger tumour size and multifocal tumours are more likely to have involved margins. Patients with involved margins, large tumour size and/or a DCIS component are more likely to have residual disease on re-excision.

Uptake of adjuvant breast cancer treatments recommended by multi-disciplinary meetings.

BACKGROUND: Adjuvant therapy for breast cancer is routinely discussed and recommended in multi-disciplinary meetings (MDMs). Current literature explores how treatments received by patients differ from national guidelines; however, it does not explore whether treatment is concordant with MDMs. This study provides an Australian perspective on the uptake of MDM recommendations and reasons for non-concordance. METHODS: A retrospective cohort study of patients with breast cancer presented at The Royal Melbourne Hospital MDM in 2010 and 2014 to investigate the concordance between MDM recommendations and treatment received. RESULTS: The study group comprised 441 patients (161 from 2010 and 280 from 2014). A total of 375 patients were included in the analyses. Overall, 82% of patients had perfect concordance between recommended and received treatment for all modes of adjuvant therapy. Concordance to endocrine therapy was higher for invasive cancers than ductal carcinoma in situ (97% versus 81%, P < 0.0001). Concordance to radiotherapy was high and did not differ according to type of cancer or surgery (ranging from 88 to 91%). Concordance to chemotherapy recommendations was high overall (92%) and did not vary with nodal status. Women aged over 65 years were least likely to be recommended for adjuvant therapy but most likely to concordant with the recommendation. CONCLUSIONS: Uptake of MDM-recommended treatments is high. There is a minority of patients in whom MDM recommendations are not followed, highlighting that there are extra steps between recommendations at an MDM and decisions with patients. More attention to this issue is appropriate, and the reasons for non-concordance warrant further study.

A new surgical education and training programme.

Educating and training tomorrow's surgeons has evolved to become a sophisticated and expensive exercise involving a wide range of learning methods, opportunities and stakeholders. Several factors influence this process, prompting those who provide such programmes to identify these important considerations and develop and implement appropriate responses. The Royal Australasian College of Surgeons embarked on this course of action in 2005, the outcome of which is the new Surgical Education and Training programme with the first intake to be selected in 2007 and commence training in 2008. The new programme is competency based and shorter than any designed previously. Implicitly, it recognizes in the curriculum and assessment development and processes, the nine roles and their underpinning competencies identified as essential for a surgeon. It is an evolution of the previous programme retaining that which has been found to be satisfactory. There will be one episode of selection directly into the candidate's specialty of choice and those accepted will progress in an integrated and seamless fashion, provided they meet the clinical and educational requirements of each year. The curriculum and assessment in the basic sciences include both generic and specially aligned components from the commencement of training in each of the nine surgical specialties. Born of necessity and developed through extensive research, discussion and consensus, the implementation of this programme will involve many challenges, particularly during the transition period. Through cooperation, commitment and partnerships, a more efficient and better outcome will be achieved for trainees, their trainers and their patients.

Effects of overground locomotor training on the ventilatory response to volitional treadmill walking in individuals with incomplete spinal cord injury: a pilot study.

INTRODUCTION: Although there has been substantial emphasis on the neuromuscular and cardiovascular adaptations following rehabilitation, pulmonary adaptations in individuals with incomplete SCI (iSCI) in response to locomotor training have been less frequently studied. In healthy individuals, effective transition from rest to work is accomplished by a hyperpneic response, which exhibits an exponential curve with three phases. However, the degree to which our current understanding of exercise hyperpnea can be applied to individuals with iSCI is unknown. The purpose of this case series was to characterize exercise hyperpnea during a rest to constant work rate (CWR) transition before and after 12-15 weeks of overground locomotor training (OLT). CASE PRESENTATION: Six subjects with cervical motor incomplete spinal cord injury participated in 12-15 weeks of OLT. Subjects were trained in 90-min sessions twice a week. All training activities were weight-bearing and under volitional control without the assistance of body-weight support harnesses, robotic devices or electrical stimulation. Six minutes of CWR treadmill walking was performed at self-selected pace with cardiorespiratory analysis throughout the tests before and after OLT. Averaged group data for tidal volume, breathing frequency or VE showed no difference before and after training. VE variability was decreased by 46.7% after OLT. DISCUSSION: CWR VE from rest to work was linear throughout the transition. Following OLT, there was a substantial reduction in VE variability. Future research should investigate the lack of a phasic ventilatory response to exercise, as well as potential mechanisms of ventilatory variability and its implications for functional performance.

Mastectomy with tears: breast cancer surgery in the early nineteenth century.

BACKGROUND: By the early nineteenth century, breast cancer was better understood and surgical treatment was emerging as a more favoured option although anaesthesia had yet to be discovered. Many questions would have arisen for a woman advised to have surgery, including possible alternatives, what the operation would entail, pain and risks involved and the competence, ethical and professional behaviour of the surgeon. This paper addresses these questions in the context of the contemporary environment, focusing in particular on the personal experiences of the women involved. METHODS: A review of the surviving personal letters and information regarding three women who had breast surgery, and of the contemporary surgical writings on breast cancer, training of surgeons, ethical and professional expectations and the concurrent status of women in society. RESULTS: Surgical training was in its infancy and the first pronouncements on medical ethics had just been published. Pain, bleeding and infection presented formidable challenges and carried significant risks. Women were frequently devoid of information, suffered a loss of their dignity and were progressively stripped of their authority. CONCLUSIONS: Breast cancer surgery was accompanied by enormous emotional and physical distress and significant risks from bleeding and infection. Although efforts were being made to give women a greater voice and autonomy in society, their position when receiving health care remained largely a submissive one. Lack of information, feelings of vulnerability, helplessness and loss of control occurred. The public perception of detachment most likely accounted for the occasional negative stigma then associated with the surgical profession.

Validation of a Clinical-Grade Assay to Measure Donor-Derived Cell-Free DNA in Solid Organ Transplant Recipients.

The use of circulating cell-free DNA (cfDNA) as a biomarker in transplant recipients offers advantages over invasive tissue biopsy as a quantitative measure for detection of transplant rejection and immunosuppression optimization. However, the fraction of donor-derived cfDNA (dd-cfDNA) in transplant recipient plasma is low and challenging to quantify. Previously reported methods to measure dd-cfDNA require donor and recipient genotyping, which is impractical in clinical settings and adds cost. We developed a targeted next-generation sequencing assay that uses 266 single-nucleotide polymorphisms to accurately quantify dd-cfDNA in transplant recipients without separate genotyping. Analytical performance of the assay was characterized and validated using 1117 samples comprising the National Institute for Standards and Technology Genome in a Bottle human reference genome, independently validated reference materials, and clinical samples. The assay quantifies the fraction of dd-cfDNA in both unrelated and related donor-recipient pairs. The dd-cfDNA assay can reliably measure dd-cfDNA (limit of blank, 0.10%; limit of detection, 0.16%; limit of quantification, 0.20%) across the linear quantifiable range (0.2% to 16%) with across-run CVs of 6.8%. Precision was also evaluated for independently processed clinical sample replicates and is similar to across-run precision. Application of the assay to clinical samples from heart transplant recipients demonstrated increased levels of dd-cfDNA in patients with biopsy-confirmed rejection and decreased levels of dd-cfDNA after successful rejection treatment. This noninvasive clinical-grade sequencing assay can be completed within 3 days, providing the practical turnaround time preferred for transplanted organ surveillance.

Comparison of blue dye and isotope with blue dye alone in breast sentinel node biopsy.

BACKGROUND: Sentinel lymph node biopsy (SNB) is rapidly gaining acceptance as an alternative to axillary dissection (AD) in patients with early breast cancer. Debate continues regarding the optimum technique for sentinel node (SN) mapping. We have used our series of 364 SNBs to compare two different techniques. METHODS: A retrospective review of patients undergoing SNB by surgeons in our breast service. Overall results were analysed, with particular attention to those having blue dye alone and those having blue dye in combination with radio-labelled colloid. SNs were analysed using haematoxylin-eosin and immunohistochemical staining. RESULTS: SN identification rates were similar: 96% for dye alone and 89% for dye and colloid in combination. Twenty-one per cent of SN mapped with dye alone contained metastases, compared to 30% with dye and colloid in combination. The false-negative rate was correspondingly higher in the dye alone group (21 vs 2.8%). CONCLUSION: SNB using dye and colloid in combination was significantly superior to dye alone in this series. We advocate using both dye and colloid for intraoperative SN mapping.

Prostatic adenocarcinoma with urothelial (transitional cell) carcinoma features.

Prostatic adenocarcinoma and urothelial carcinoma (transitional cell carcinoma) may coexist in the prostate. However, a carcinoma with mixed features has not been recognized. Four cases, three surgical pathology cases and one autopsy case of prostatic adenocarcinoma with urothelial carcinoma features, were retrospectively found in a urological pathology teaching file maintained from 1984 to 1993. Subsequently, 181 consecutive cases of radical prostatectomy from 1994 to 1999 were reviewed, and two prostatic adenocarcinoma areas with features of urothelial carcinoma were identified. Areas with urothelial carcinoma features were identified in the intraductal component of the carcinoma in five cases and in the invasive component in three cases. The intraductal carcinoma with urothelial carcinoma areas usually merged with regions of prostatic adenocarcinoma with a papillary or cribriform pattern. All prostatic adenocarcinomas having areas with urothelial carcinoma features were of high stage, and five of six cases had ductal features. The urothelial carcinoma component displayed a positive reactivity for thrombomodulin and negative or weaker reactivity for PAP and PSA than the prostatic adenocarcinoma component in the same tumor. Excluding the case noted at autopsy, all patients died of the disease within 3 years. Urothelial carcinoma features were usually associated with ductal carcinoma of high stage. Areas of prostatic adenocarcinoma with urothelial carcinoma features should be considered histopathologically as areas of mixed carcinoma of the prostate. Prostatic adenocarcinoma with areas of urothelial carcinoma features may pose a difficult differential diagnosis problem with urothelial carcinoma, especially with small biopsies with focal weak immunoreactivity for PAP, PSA, and thrombomodulin.

Surgical management of ductal carcinoma in situ in Australia in 1995.

BACKGROUND: In the present paper we describe the presentation and management of ductal carcinoma in situ (DCIS) of the breast in women in Australia in 1995. This representative, national data set provides a historical comparator for studies examining DCIS management that follow. METHODS: Surgeons identified by population-based cancer registries as having treated a new diagnosis of DCIS between 1 April and 30 September 1995 completed a questionnaire on the presentation and management of each case. RESULTS: Two hundred and five surgeons supplied treatment details on 418 DCIS tumours in 415 women. Half of all tumours were detected at Breast Screen clinics and a further 25% were detected at other mammography centres. Twenty-six percent of tumours were palpable at presentation, 33% were multifocal and 55% were high grade (including comedocarcinoma). Breast conserving therapy (BCT) rather than mastectomy was utilized in 260 (62%)of cases. Tumours that were of low grade, small in size and not multifocal were more likely to be treated by BCT. Surgeons seeing six or moreDCIS cases in the 6-month period were more likely to utilize BCT. Of the conservatively treated cases, 22% were referred for a radiation oncology consultation. The most common reasons for treating DCIS with mastectomy were that the tumour was too extensive or multifocal (63%), it extended to margins of the specimen (42%), or patient concerns about recurrence (34%). CONCLUSIONS: In 1995 the majority of DCIS was treated with breast conserving surgery alone. Surgeons treating more DCIS cases were more likely to perform conservative surgery than surgeons treating only one DCIS case in the study period.