Causes and Ways of Death in Patients With Head and Neck Cancer.

Importance: There is limited literature on the exact causes and ways of death in patients with head and neck cancer. To provide optimal care, especially in the palliative phase, more information on this is needed. Objective: To provide insights into the causes and ways of death among patients with head and neck cancer. Design, Setting, and Participants: This retrospective cohort study included a consecutive population of patients who received a diagnosis of primary squamous cell carcinoma of the head and neck between January 2006 and December 2013 who were treated in the Erasmus MC. Patient data were merged with nonpublic microdata from Statistics Netherlands. Follow-up time was specified as the date of diagnosis until death or December 3, 2019, whichever came first. The data were checked and reanalyzed in November 2023. Main outcomes and Measures: Causes (eg, head and neck cancer, other cancer) and ways (eg, natural death, suicide) of death. Results: A total of 1291 patients (59.2%; 342 women [26.5%]) died during follow-up (median [IQR] follow-up, 2.7 [1.2-5.6] years). The main cause of death was head and neck cancer (557 [43.1%]), followed by the competing cause of other cancers (344 [26.6%]). In total, 240 patients (18.6%) received palliative sedation and 70 patients (5.4%) euthanasia. Compared with patients with head and neck cancer as the underlying cause of death, lower odds ratios (ORs) were observed for receiving palliative sedation (OR, 0.32 vs 0.07; 95% CI, 0.22-0.46 vs 0.03-0.12) and euthanasia (OR, 0.22 vs 0.01; 95% CI, 0.11-0.41 vs 0-0.107) in patients with other causes of death. Patients with a middle and high income had higher ORs for receiving palliative sedation (OR, 1.46 vs 1.86; 95% CI, 1.05-2.04 vs 1.22-2.85) or euthanasia (OR, 2.25 vs 3.37; 95% CI, 1.18-4.3, 1.6-7.12) compared with low-income patients. Retired patients had lower ORs for receiving palliative sedation or euthanasia compared with employed patients (OR, 0.56 vs 0.44; 95% CI, 0.39-0.8 vs 0.24-0.82). Conclusion and Relevance: The results of this cohort study suggest that more than half of the patients died of competing causes and palliative sedation and euthanasia were more common in patients with head and neck cancer as the underlying cause of death. Patients with a higher socioeconomic status had higher odds of receiving palliative sedation and euthanasia. These insights may support health care professionals in providing patient-centered care, especially for patients in the palliative phase.

Prognostic model for overall survival of head and neck cancer patients in the palliative phase.

BACKGROUND: Patients with head and neck squamous cell carcinoma (HNSCC) enter the palliative phase when cure is no longer possible or when they refuse curative treatment. The mean survival is five months, with a range of days until years. Realistic prognostic counseling enables patients to make well-considered end-of-life choices. However, physicians tend to overestimate survival. The aim of this study was to develop a prognostic model that calculates the overall survival (OS) probability of palliative HNSCC patients. METHODS: Patients diagnosed with incurable HNSCC or patients who refused curative treatment for HNSCC between January 1st 2006 and June 3rd 2019 were included (n = 659). Three patients were lost to follow-up. Patients were considered to have incurable HNSCC due to tumor factors (e.g. inoperability with no other curative treatment options, distant metastasis) or patient factors (e.g. the presence of severe comorbidity and/or poor performance status).Tumor and patients factors accounted for 574 patients. An additional 82 patients refused curative treatment and were also considered palliative. The effect of 17 candidate predictors was estimated in the univariable cox proportional hazard regression model. Using backwards selection with a cut-off P-value < 0.10 resulted in a final multivariable prediction model. The C-statistic was calculated to determine the discriminative performance of the model. The final model was internally validated using bootstrapping techniques. RESULTS: A total of 647 patients (98.6%) died during follow-up. Median OS time was 15.0 weeks (95% CI: 13.5;16.6). Of the 17 candidate predictors, seven were included in the final model: the reason for entering the palliative phase, the number of previous HNSCC, cT, cN, cM, weight loss in the 6 months before diagnosis, and the WHO performance status. The internally validated C-statistic was 0.66 indicating moderate discriminative ability. The model showed some optimism, with a shrinkage factor of 0.89. CONCLUSION: This study enabled the development and internal validation of a prognostic model that predicts the OS probability in HNSCC patients in the palliative phase. This model facilitates personalized prognostic counseling in the palliative phase. External validation and qualitative research are necessary before widespread use in patient counseling and end-of-life care.

Rupture of the gastrocnemius muscle at its distal musculotendinous junction: conservative treatment and outcomes in 11 dogs.

CASE HISTORY: Medical records from three veterinary referral centres and a university veterinary teaching hospital in Australia and the USA were reviewed to identify dogs with a diagnosis of distal gastrocnemius musculotendinous junction rupture (DGMJR) that were treated without surgery between 2007 and 2020. CLINICAL AND IMAGING FINDINGS: All dogs (n = 11) presented with unilateral, pelvic limb lameness and bruising, swelling or pain on palpation at the distal musculotendinous junction. The diagnosis was confirmed with ultrasound or MRI in six dogs; radiographs were used to excluded stifle and tarsus pathology in four dogs; and five dogs were diagnosed on physical examination findings. TREATMENT AND OUTCOME: All dogs were managed conservatively, either with complete confinement alone (n = 10; median 9 weeks), external coaptation alone (n = 1), or a combination of both (n = 4). Sporting dogs (n = 7) were completely confined (median 22 weeks) for longer periods than companion dogs (n = 3; median 5 weeks).A good to excellent outcome was achieved for all cases in this cohort. The seven sporting dogs achieved an excellent outcome; returning to their previous level of sport, with complete resolution of lameness and recovery of a normal tibiotarsal stance. The four companion dogs achieved a good outcome; returning to their previous level of activity but with persistently increased tibiotarsal standing angle compared to the contralateral limb. CLINICAL RELEVANCE: Conservative treatment represents a viable treatment option for dogs with a rupture of the gastrocnemius muscle at its distal musculotendinous junction.

Mediastinal histoplasmosis with cardiac involvement in a cat.

Histoplasmosis is the second most common fungal infection reported among domestic felines in the United States. Dissemination of the organism after inoculation is common and affected organ systems include the respiratory tract, gastrointestinal tract, reticuloendothelial organs, skeletal system, integument, and ocular system. However, histoplasmosis presenting as a discrete granulomatous mass identified on echocardiogram has never been reported in the veterinary literature. Here, we describe the first case of feline histoplasmosis presenting as a granuloma with cardiac involvement. The patient, a 6-year-old male neutered domestic longhair feline, was referred for tachypnea and dyspnea. A mass in the cranial mediastinum abutting the heart was diagnosed via two-dimensional echocardiography. Cytology of fine needle aspirates from the mass revealed round yeast structures consistent with Histoplasma spp. The patient was treated with oral fluconazole therapy, and subsequent rechecks have shown marked improvement in clinical parameters, lesion size, and antigen concentrations.

The Safer Anaesthesia from Education (SAFE)® paediatric anaesthesia course: educational impact in five countries in East and Central Africa.

There is an urgent need to improve access to safe surgical and anaesthetic care for children living in many low- and middle-income countries. Providing quality training for healthcare workers is a key component of achieving this. The 3-day Safer Anaesthesia from Education (SAFE)® paediatric anaesthesia course was developed to address the specific skills and knowledge required in this field. We undertook a project to expand this course across five East and Central African countries (Ethiopia, Kenya, Malawi, Uganda and Zambia) and train local faculty. This study reports the outcomes from course evaluation data, exploring the impact on knowledge, skills and behaviour change in participants. Eleven courses were conducted in a 15-month period, with 381 participants attending. Fifty-nine new faculty members were trained. Knowledge scores (0-50 scale) increased significantly from mean (SD) 37.5 (4.7) pre-course to 43.2 (3.5) post-course (p < 0.0001). Skills scores (0-10 scale) increased significantly from 5.7 (2.0) pre-course to 8.0 (1.5) post-course (p < 0.0001). One hundred and twenty-six participants in Malawi, Uganda and Zambia were visited in their workplace 3-6 months later. Knowledge and skills were maintained at follow-up, with scores of 41.5 (5.0) and 8.3 (1.4), respectively (p < 0.0001 compared with pre-course scores). Content analysis from interviews with these participants highlighted positive behaviour changes in the areas of preparation, peri-operative care, resuscitation, management of the sick child, communication and teaching. This study indicates that the SAFE paediatric anaesthesia course is an effective way to deliver training, and could be used to help strengthen emergency and essential surgical care for children as a component of universal health coverage.

Predictors of community-associated Staphylococcus aureus, methicillin-resistant and methicillin-susceptible Staphylococcus aureus skin and soft tissue infections in primary-care settings.

Skin and soft tissue infections (SSTIs) due to Staphylococcus aureus have become increasingly common in the outpatient setting; however, risk factors for differentiating methicillin-resistant S. aureus (MRSA) and methicillin-susceptible S. aureus (MSSA) SSTIs are needed to better inform antibiotic treatment decisions. We performed a case-case-control study within 14 primary-care clinics in South Texas from 2007 to 2015. Overall, 325 patients [S. aureus SSTI cases (case group 1, n = 175); MRSA SSTI cases (case group 2, n = 115); MSSA SSTI cases (case group 3, n = 60); uninfected control group (control, n = 150)] were evaluated. Each case group was compared to the control group, and then qualitatively contrasted to identify unique risk factors associated with S. aureus, MRSA, and MSSA SSTIs. Overall, prior SSTIs [adjusted odds ratio (aOR) 7·60, 95% confidence interval (CI) 3·31-17·45], male gender (aOR 1·74, 95% CI 1·06-2·85), and absence of healthcare occupation status (aOR 0·14, 95% CI 0·03-0·68) were independently associated with S. aureus SSTIs. The only unique risk factor for community-associated (CA)-MRSA SSTIs was a high body weight (⩾110 kg) (aOR 2·03, 95% CI 1·01-4·09).

A clinically applicable molecular-based classification for endometrial cancers.

BACKGROUND: Classification of endometrial carcinomas (ECs) by morphologic features is inconsistent, and yields limited prognostic and predictive information. A new system for classification based on the molecular categories identified in The Cancer Genome Atlas is proposed. METHODS: Genomic data from the Cancer Genome Atlas (TCGA) support classification of endometrial carcinomas into four prognostically significant subgroups; we used the TCGA data set to develop surrogate assays that could replicate the TCGA classification, but without the need for the labor-intensive and cost-prohibitive genomic methodology. Combinations of the most relevant assays were carried forward and tested on a new independent cohort of 152 endometrial carcinoma cases, and molecular vs clinical risk group stratification was compared. RESULTS: Replication of TCGA survival curves was achieved with statistical significance using multiple different molecular classification models (16 total tested). Internal validation supported carrying forward a classifier based on the following components: mismatch repair protein immunohistochemistry, POLE mutational analysis and p53 immunohistochemistry as a surrogate for 'copy-number' status. The proposed molecular classifier was associated with clinical outcomes, as was stage, grade, lymph-vascular space invasion, nodal involvement and adjuvant treatment. In multivariable analysis both molecular classification and clinical risk groups were associated with outcomes, but differed greatly in composition of cases within each category, with half of POLE and mismatch repair loss subgroups residing within the clinically defined 'high-risk' group. Combining the molecular classifier with clinicopathologic features or risk groups provided the highest C-index for discrimination of outcome survival curves. CONCLUSIONS: Molecular classification of ECs can be achieved using clinically applicable methods on formalin-fixed paraffin-embedded samples, and provides independent prognostic information beyond established risk factors. This pragmatic molecular classification tool has potential to be used routinely in guiding treatment for individuals with endometrial carcinoma and in stratifying cases in future clinical trials.

Denosumab and osteonecrosis of the jaws - the pharmacology, pathogenesis and a report of two cases.

Denosumab (Amgen, Thousand Oaks, California, USA) is a new bone antiresorptive agent used in patients with osteoporosis or metastatic cancer to the bones. As with the bisphosphonates that are used as antiresorptive medications, denosumab has been associated with osteonecrosis of the jaws (ONJ). Over the past two years there has been an increase in the literature describing ONJ in patients receiving agents such as denosumab. Due to promising study results that demonstrate the effectiveness of denosumab in avoiding skeletal complications related to osteoporosis and metastatic bone disease, more patients will receive denosumab in the future. It is reported that this has the potential to become a comparable challenge to bisphosphonate related osteonecrosis of the jaws (BRONJ) for clinicians. This article describes the management of two patients that developed ONJ while receiving denosumab, reviews the incidence of ONJ associated with denosumab, and contrasts the pharmacokinetics of denosumab and the bisphosphonates. The importance of avoiding interventional dental treatment until denosumab has been withdrawn for six months cannot be overstated.

Psychological outcomes in critically ill patients receiving renal replacement therapy: a matched-pairs analysis.

We conducted a single-centre observational study over five years to assess the impact of renal replacement therapy on the psychological health of survivors of critical illness. We hypothesised that the added burden of renal replacement would increase the prevalence and severity of anxiety, depression and stress reactions in these patients, compared with matched pairs (matched for age, sex and APACHE II score) who did not receive renal replacement. Participants completed postal questionnaires. A total of 342 patients with acute kidney injury received renal replacement. One hundred and seventy-nine (52.3%) survived to hospital discharge, and 161 (47.1%) were alive at 90 days. Seventy-seven (47.8% of survivors) completed questionnaires. We found 77 matches for the Hospital Anxiety and Depression Scale analysis and 72 for the Impact of Events Scale analysis. Clinically relevant symptoms of psychiatric morbidity were common, with anxiety and depression affecting 49 (63.6%) patients and stress reactions affecting 24 (33.3%) patients. Mean scores (95% CI) were 11.4 (9.6-13.2) and 20.1 (15.7-24.6), respectively. On multivariate analysis, we found no significant differences between renal replacement patients and controls, in either the frequency or severity of these symptoms.

Bilateral symmetry of breast tissue composition by magnetic resonance in young women and adults.

BACKGROUND: Some reports suggest that there is a slightly higher frequency of breast cancer in the left breast compared with the right in middle-aged women. The reasons for this association are unknown. The water and fat content of both breasts was compared using magnetic resonance (MR). Breast water by MR reflects fibro-glandular tissue and is strongly positively correlated with percent mammographic density, a strong risk factor for breast cancer. METHODS: Magnetic resonance was used to measure fat and water content of the breast in 400 young women aged 15-30 years and a random sample of 100 of their mothers. All MR examinations were carried out using a 1.5T MR system, and 45 contiguous slices were obtained in the sagittal plane. One reader identified the breast tissue in the image, and subsequently, fat and water content was calculated using a three-point Dixon technique. Left- and right-sided images were read independently in random order. RESULTS: In young women, mean percent water was on average 0.84 % higher in the right compared with the left breast (p < 0.001) and total breast water was on average 6.42 cm(3) greater on the right side (p < 0.001). In mothers, there were no significant differences in any breast measure between right and left sides. CONCLUSION: The small differences in breast tissue composition in young women are unlikely to be associated with large differences in breast cancer risk between sides. The reported excess of left-sided breast cancer in older women is unlikely to be explained by differences in breast tissue composition.

Generation of a functional liver tissue mimic using adipose stromal vascular fraction cell-derived vasculatures.

One of the major challenges in cell implantation therapies is to promote integration of the microcirculation between the implanted cells and the host. We used adipose-derived stromal vascular fraction (SVF) cells to vascularize a human liver cell (HepG2) implant. We hypothesized that the SVF cells would form a functional microcirculation via vascular assembly and inosculation with the host vasculature. Initially, we assessed the extent and character of neovasculatures formed by freshly isolated and cultured SVF cells and found that freshly isolated cells have a higher vascularization potential. Generation of a 3D implant containing fresh SVF and HepG2 cells formed a tissue in which HepG2 cells were entwined with a network of microvessels. Implanted HepG2 cells sequestered labeled LDL delivered by systemic intravascular injection only in SVF-vascularized implants demonstrating that SVF cell-derived vasculatures can effectively integrate with host vessels and interface with parenchymal cells to form a functional tissue mimic.

First reflections: third-year dentistry students' introduction to reflective practice.

INTRODUCTION: To develop both professionally and personally, health professionals need to build essential skills in reflective practice. Educators generally agree that these skills should be developed as part of curricula for health professional students. The aims were to introduce reflective practice to third-year dentistry students and to evaluate the students' self-perceived reflective skills before and after their reflective activities. MATERIALS AND METHODS: Using a written questionnaire, third-year dentistry students' perceptions of reflective practice were gathered before and after their first clinic placement. Students also completed two reflective writing pieces about their clinical placements. RESULTS: The students' reflective writing pieces were allocated into one of the three categories: non-reflector, reflector and critical reflector. Content analysis of students' perceptions of reflective practice revealed nine themes. Eight main themes emerged from students' suggestions for improving their reflective abilities. DISCUSSION AND CONCLUSION: Issues around the assessment of reflective writing are discussed, and students' suggestions for improving their reflective abilities are presented.

Germline mutations in CDH1 are infrequent in women with early-onset or familial lobular breast cancers.

BACKGROUND: Germline mutations in CDH1 are associated with hereditary diffuse gastric cancer; lobular breast cancer also occurs excessively in families with such condition. METHOD: To determine if CDH1 is a susceptibility gene for lobular breast cancer in women without a family history of diffuse gastric cancer, germline DNA was analysed for the presence of CDH1 mutations in 318 women with lobular breast cancer who were diagnosed before the age of 45 years or had a family history of breast cancer and were not known, or known not, to be carriers of germline mutations in BRCA1 or BRCA2. Cases were ascertained through breast cancer registries and high-risk cancer genetic clinics (Breast Cancer Family Registry, the kConFab and a consortium of breast cancer genetics clinics in the United States and Spain). Additionally, Multiplex Ligation-dependent Probe Amplification was performed for 134 cases to detect large deletions. RESULTS: No truncating mutations and no large deletions were detected. Six non-synonymous variants were found in seven families. Four (4/318 or 1.3%) are considered to be potentially pathogenic through in vitro and in silico analysis. CONCLUSION: Potentially pathogenic germline CDH1 mutations in women with early-onset or familial lobular breast cancer are at most infrequent.

Adiposity changes after a 1-year aerobic exercise intervention among postmenopausal women: a randomized controlled trial.

OBJECTIVE: We examined the effects of an aerobic exercise intervention on adiposity outcomes that may be involved in the association between physical activity and breast cancer risk. DESIGN: This study was a two-centre, two-armed, randomized controlled trial. The 1-year-long exercise intervention included 45 min of moderate-to-vigorous aerobic exercise five times per week, with at least three of the sessions being facility based. The control group was asked not to change their activity and both groups were asked not to change their diet. SUBJECTS: A total of 320 postmenopausal, sedentary, normal weight-to-obese women aged 50-74 years who were cancer-free, nondiabetic and nonhormone replacement therapy users were included in this study. MEASUREMENTS: Anthropometric measurements of height, weight and waist and hip circumferences; dual energy X-ray absorptiometry measurements of total body fat; and computerized tomography measurements of abdominal adiposity were carried out. RESULTS: Women in the exercise group exercised a mean of 3.6 days (s.d.=1.3) per week and 178.5 min (s.d.=76.1) per week. Changes in all measures of adiposity favored exercisers relative to controls (P<0.001). The mean difference between groups was: -1.8 kg for body weight; -2.0 kg for total body fat; -14.9 cm(2) for intra-abdominal fat area; and -24.1 cm(2) for subcutaneous abdominal fat area. A linear trend of greater body fat loss with increasing volume of exercise was also observed. CONCLUSION: A 1-year aerobic exercise program consistent with current public health guidelines resulted in reduced adiposity levels in previously sedentary postmenopausal women at higher risk of breast cancer.

Mammographic density, lobular involution, and risk of breast cancer.

In this review, we propose that age-related changes in mammographic density and breast tissue involution are closely related phenomena, and consider their potential relevance to the aetiology of breast cancer. We propose that the reduction in mammographic density that occurs with increasing age, parity and menopause reflects the involution of breast tissue. We further propose that age-related changes in both mammographic density and breast tissue composition are observable and measurable phenomena that resemble Pike's theoretical construct of 'breast tissue ageing'. Extensive mammographic density and delayed breast involution are both associated with an increased risk of breast cancer and are consistent with the hypothesis of the Pike model that cumulative exposure of breast tissue to hormones and growth factors that stimulate cell division, as well as the accumulation of genetic damage in breast cells, are major determinants of breast cancer incidence.

Germline E-cadherin mutations in familial lobular breast cancer.

BACKGROUND: The cell surface glycoprotein E-cadherin (CDH1) is a key regulator of adhesive properties in epithelial cells. Germline mutations in CDH1 are well established as the defects underlying hereditary diffuse gastric cancer (HDGC) syndrome, and an increased risk of lobular breast cancer (LBC) has been described in HDGC kindreds. However, germline CDH1 mutations have not been described in patients with LBC in non-HDGC families. This study aimed to investigate the frequency of germline CDH1 mutations in patients with LBC with early onset disease or family histories of breast cancer without DGC. METHODS: Germline DNA was analysed in 23 women with invasive lobular or mixed ductal and lobular breast cancers who had at least one close relative with breast cancer or had themselves been diagnosed before the age of 45 years, had tested negative for a germline BRCA1 or BRCA2 mutation, and reported no personal or family history of diffuse gastric cancer. The full coding sequence of CDH1 including splice junctions was amplified using PCR and screened for mutations using DHPLC and sequencing. RESULTS: A novel germline CDH1 truncating mutation in the extracellular portion of the protein (517insA) was identified in one woman who had LBC at the age of 42 years and a first degree relative with invasive LBC. CONCLUSIONS: Germline CDH1 mutations can be associated with invasive LBC in the absence of diffuse gastric cancer. The finding, if confirmed, may have implications for management of individuals at risk for this breast cancer subtype. Clarification of the cancer risks in the syndrome is essential.

BMP4 promotes formation of primitive vascular networks in human embryonic stem cell-derived embryoid bodies.

The vasculature develops primarily through two processes, vasculogenesis and angiogenesis. Although much work has been published on angiogenesis, less is known of the mechanisms regulating the de novo formation of the vasculature commonly called vasculogenesis. Human embryonic stem cells (hESC) have the capability to produce all of the cells of the body and have been used as in vitro models to study the molecular signals controlling differentiation and vessel assembly. One such regulatory molecule is bone morphogenetic protein-4 (BMP4), which is required for mesoderm formation and vascular/hematopoietic specification in several species. However, hESC grown in feeder-free conditions and treated with BMP4 differentiate into a cellular phenotype highly expressing a trophoblast gene profile. Therefore, it is unclear what role, if any, BMP4 plays in regulating vascular development in hESC. Here we show in two National Institutes of Health-registered hESC lines (BG02 and WA09) cultured on a 3D substrate of Matrigel in endothelial cell growth medium-2 that the addition of BMP4 (100 ng/ml) for 3 days significantly increases the formation and outgrowth of a network of cells reminiscent of capillary-like structures formed by mature endothelial cells (P<0.05). Analysis of the expression of 45 genes by quantitative real time-polymerase chain reaction on a low-density array of the entire culture indicates a rapid and significant downregulation of pluripotent and most ectodermal markers with a general upregulation of endoderm, mesoderm, and endothelial markers. Of the genes assayed, BMPR2 and RUNX1 were differentially affected by exposure to BMP4 in both cell lines. Immunocytochemistry indicates the morphological structures formed were negative for the mature endothelial markers CD31 and CD146 as well as the neural marker SOX2, yet positive for the early vascular markers of endothelium (KDR, NESTIN) and smooth muscle cells (alpha-smooth muscle actin [alpha SMA]). Together, these data suggest BMP4 can enhance the formation and outgrowth of an immature vascular system.

Dietary fat and breast cancer risk revisited: a meta-analysis of the published literature.

Animal experiments and human ecological studies suggest that dietary fat intake is associated with a risk of breast cancer, but individual-based studies have given contradictory results. We have carried out a meta-analysis of this association to include all papers published up to July 2003. Case-control and cohort studies that examined the association of dietary fat, or fat-containing foods, with risk of breast cancer were identified. A total of 45 risk estimates for total fat intake were obtained. Descriptive data from each study were extracted with an estimate of relative risk and its associated 95% confidence interval (CI), and were analysed using the random effects model of DerSimonian and Laird. The summary relative risk, comparing the highest and lowest levels of intake of total fat, was 1.13 (95% CI: 1.03-1.25). Cohort studies (N=14) had a summary relative risk of 1.11 (95% CI: 0.99-1.25) and case-control studies (N=31) had a relative risk of 1.14 (95% CI 0.99-1.32). Significant summary relative risks were also found for saturated fat (RR, 1.19; 95% CI: 1.06-1.35) and meat intake (RR, 1.17; 95% CI 1.06-1.29). Combined estimates of risk for total and saturated fat intake, and for meat intake, all indicate an association between higher intakes and an increased risk of breast cancer. Case-control and cohort studies gave similar results.

The detection of change in mammographic density.

Mammographic density is associated with risk of breast cancer, and factors that change density may also change risk. There has, however, been little research into how change in serial mammograms is best detected. The purpose of the work described here was to examine the effects of different reading conditions on the detection of change in mammographic features. Mammograms were selected from women who had participated in a randomized controlled trial of screening for breast cancer. We selected two age-matched groups of subjects, one had undergone menopause after entry (n = 202) and another who had not (n = 202). Serial mammograms from these subjects were then measured four times using a computer-assisted method under different conditions: (a) films were randomized; (b) subjects were randomized (i.e., pairs of films from individuals were read one after the other), but the order of films was random and unknown to the reader; (c) subjects were randomized, and the order of films was sequential and known to the reader; and (d) subjects were randomized, and the order of films was random and unknown to the reader, but both films in each pair were read simultaneously on separate computer screens. The mean effect of the menopause on change in the mammographic measures of total, dense and nondense areas, percent density, and the associated variances were then compared. With one exception, all of the randomization and viewing methods confirmed a change in all mammographic measures at menopause and produced very similar overall results, suggesting that mammographic density is a robust measure. Compared with randomization of all films, the method in which subjects were randomized and paired films read one after the other in random and unknown order was associated with a slightly smaller mean difference and achieved a substantial reduction in variability, suggesting that it is the most sensitive method of randomization and viewing for the detection of change.