11ß-HSD1 inhibition in men mitigates prednisolone-induced adverse effects in a proof-of-concept randomised double-blind placebo-controlled trial.

Glucocorticoids prescribed to limit inflammation, have significant adverse effects. As 11ß-hydroxysteroid dehydrogenase type 1 (11ß-HSD1) regenerates active glucocorticoid, we investigated whether 11ß-HSD1 inhibition with AZD4017 could mitigate adverse glucocorticoid effects without compromising their anti-inflammatory actions. We conducted a proof-of-concept, randomized, double-blind, placebo-controlled study at Research Unit, Churchill Hospital, Oxford, UK (NCT03111810). 32 healthy male volunteers were randomized to AZD4017 or placebo, alongside prednisolone treatment. Although the primary endpoint of the study (change in glucose disposal during a two-step hyperinsulinemic, normoglycemic clamp) wasn't met, hepatic insulin sensitivity worsened in the placebo-treated but not in the AZD4017-treated group. Protective effects of AZD4017 on markers of lipid metabolism and bone turnover were observed. Night-time blood pressure was higher in the placebo-treated but not in the AZD4017-treated group. Urinary (5aTHF+THF)/THE ratio was lower in the AZD4017-treated but remained the same in the placebo-treated group. Most anti-inflammatory actions of prednisolone persisted with AZD4017 co-treatment. Four adverse events were reported with AZD4017 and no serious adverse events. Here we show that co-administration of AZD4017 with prednisolone in men is a potential strategy to limit adverse glucocorticoid effects.

Design and rationale of the EMPA-VISION trial: investigating the metabolic effects of empagliflozin in patients with heart failure.

AIMS: Despite substantial improvements over the last three decades, heart failure (HF) remains associated with a poor prognosis. The sodium-glucose co-transporter-2 inhibitor empagliflozin demonstrated significant reductions of HF hospitalization in patients with HF independent of the presence or absence of type 2 diabetes mellitus in the EMPEROR-Reduced trial and cardiovascular mortality in the EMPA-REG OUTCOME trial. To further elucidate the mechanisms behind these positive outcomes, this study aims to determine the effects of empagliflozin treatment on cardiac energy metabolism and physiology using magnetic resonance spectroscopy (MRS) and cardiovascular magnetic resonance (CMR). METHODS AND RESULTS: The EMPA-VISION trial is a double-blind, randomized, placebo-controlled, mechanistic study. A maximum of 86 patients with HF with reduced ejection fraction (n = 43, Cohort A) or preserved ejection fraction (n = 43, Cohort B), with or without type 2 diabetes mellitus, will be enrolled. Participants will be randomized 1:1 to receive either 10 mg of empagliflozin or placebo for 12 weeks. Eligible patients will undergo cardiovascular magnetic resonance, resting and dobutamine stress MRS, echocardiograms, cardiopulmonary exercise tests, serum metabolomics, and quality of life questionnaires at baseline and after 12 weeks. The primary endpoint will be the change in resting phosphocreatine-to-adenosine triphosphate ratio, as measured by 31 Phosphorus-MRS. CONCLUSIONS: EMPA-VISION is the first clinical trial assessing the effects of empagliflozin treatment on cardiac energy metabolism in human subjects in vivo. The results will shed light on the mechanistic action of empagliflozin in patients with HF and help to explain the results of the safety and efficacy outcome trials (EMPEROR-Reduced and EMPEROR-Preserved).

Predicting post one-year durability of glucose-lowering monotherapies in patients with newly-diagnosed type 2 diabetes mellitus - A MASTERMIND precision medicine approach (UKPDS 87).

AIMS: Predicting likely durability of glucose-lowering therapies for people with type 2 diabetes (T2D) could help inform individualised therapeutic choices. METHODS: We used data from UKPDS patients with newly-diagnosed T2D randomised to first-line glucose-lowering monotherapy with chlorpropamide-glibenclamide-basal insulin or metformin. In 2339 participants who achieved one-year HbA1c values <7.5% (<59 mmol/mol)-we assessed relationships between one-year characteristics and time to monotherapy-failure (HbA1c ≥ 7.5% or requiring second-line therapy). Model validation was performed using bootstrap sampling. RESULTS: Follow-up was median (IQR) 11.0 (8.0-14.0) years. Monotherapy-failure occurred in 72%-82%-75% and 79% for those randomised to chlorpropamide-glibenclamide-basal insulin or metformin respectively-after median 4.5 (3.0-6.6)-3.7 (2.6-5.6)-4.2 (2.7-6.5) and 3.8 (2.6- 5.2) years. Time-to-monotherapy-failure was predicted primarily by HbA1c and BMI values-with other risk factors varying by type of monotherapy-with predictions to within ±2.5 years for 55%-60%-56% and 57% of the chlorpropamide-glibenclamide-basal insulin and metformin monotherapy cohorts respectively. CONCLUSIONS: Post one-year glycaemic durability can be predicted robustly in individuals with newly-diagnosed T2D who achieve HbA1c values < 7.5% one year after commencing traditional monotherapies. Such information could be used to help guide glycaemic management for individual patients.

Lixisenatide in type 1 diabetes: A randomised control trial of the effect of lixisenatide on post-meal glucose excursions and glucagon in type 1 diabetes patients.

AIMS: The GLP1 agonist lixisenatide is glucagonostatic and reduces post-prandial blood glucose (PPBG) in type 2 diabetes. This study investigates its impact in type 1 diabetes (T1D). METHODS: In a blinded, crossover trial, 25 patients with T1D were randomised to 4 weeks adjunctive treatment with lixisenatide (L) or placebo (P), with a 4-week washout period. The primary outcome was percentage of 3 hours PPBG in target (4-10 mmol/L) assessed by CGM before and after treatment. Participants also underwent post-treatment standardised mixed meal test (MMT, n = 25) and hyperinsulinaemic hypoglycaemic clamp (n = 15). RESULTS: PPBG CGM readings in target were similar between L vs P (Mean % ± SE, breakfast 45.4 ± 6.0 vs 44.3 ± 6.0, P = .48, lunch 45.5 ± 5.8 vs 50.6 ± 5.3, P = .27 and dinner 43.0 ± 6.7 vs 47.7 ± 5.6, P = .30). HbA1C was similar between L vs P (64.7 ± 1.6 vs 64.1 ± 1.6 mmol/mol, P = .30). Prandial insulin fell after lixisenatide (dose change -0.7 ± 0.6 vs +2.4 ± 0.7 units/d, P = .004), but basal insulin dose was similar between groups. The post-MMT glucose area under the curve (AUC) was lower with L than P (392.0 ± 167.7 vs 628.1 ± 132.5 mmol/L × min, P < .001), as was the corresponding glucagon AUC (140.0 ± 110.0 vs 304.2 ± 148.2 nmol/L × min, P < .001). Glucagon and counter-regulatory hormone values at a blood glucose of 2.4 mmol/L during the hypoglycaemic clamp were similar between L and P. CONCLUSION: In T1D, PPBG values were not altered by adjunctive lixisenatide although prandial insulin dose fell. Glucose and glucagon level during an MMT were significantly lower after lixisenatide, without affecting counter-regulatory response during hypoglycaemia.

Time-varying risk of microvascular complications in latent autoimmune diabetes of adulthood compared with type 2 diabetes in adults: a post-hoc analysis of the UK Prospective Diabetes Study 30-year follow-up data (UKPDS 86).

BACKGROUND: Latent autoimmune diabetes of adulthood (LADA) differs in clinical features from type 2 diabetes. Whether this difference translates into different risks of complications remains controversial. We examined the long-term risk of microvascular complications in people enrolled in the UK Prospective Diabetes Study (UKPDS), according to their diabetes autoimmunity status. METHODS: We did a post-hoc analysis of 30-year follow-up data from UKPDS (UKPDS 86). UKPDS participants with diabetes autoantibody measurements available and without previous microvascular events were included. Participants with at least one detectable autoantibody were identified as having latent autoimmune diabetes, and those who tested negative for all autoantibodies were identified as having type 2 diabetes. The incidence of the primary composite microvascular outcome (first occurrence of renal failure, renal death, blindness, vitreous haemorrhage, or retinal photocoagulation) was compared between adults with latent autoimmune diabetes and those with type 2 diabetes. The follow-up ended on Sept 30, 2007. Baseline and updated 9-year mean values of potential confounders were tested in Cox models to adjust hazard ratios (HRs). UKPDS is registered at the ISRCTN registry, 75451837. FINDINGS: Among the 5028 participants included, 564 had latent autoimmune diabetes and 4464 had type 2 diabetes. After median 17·3 years (IQR 12·6-20·7) of follow-up, the composite microvascular outcome occurred in 1041 (21%) participants. The incidence for the composite microvascular outcome was 15·8 (95% CI 13·4-18·7) per 1000 person-years in latent autoimmune diabetes and 14·2 (13·3-15·2) per 1000 person-years in type 2 diabetes. Adults with latent autoimmune diabetes had a lower risk of the composite outcome during the first 9 years of follow-up than those with type 2 diabetes (adjusted HR 0·45 [95% CI 0·30-0·68], p<0·0001), whereas in subsequent years their risk was higher than for those with type 2 diabetes (1·25 [1·01-1·54], p=0·047). Correcting for the higher updated 9-year mean HbA1c seen in adults with latent autoimmune diabetes than in those with type 2 diabetes explained entirely their subsequent increased risk for the composite microvascular outcome (adjusted HR 0·99 [95% CI 0·80-1·23], p=0·93). INTERPRETATION: At diabetes onset, adults with latent autoimmune diabetes have a lower risk of microvascular complications followed by a later higher risk of complications than do adults with type 2 diabetes, secondary to worse glycaemic control. Implementing strict glycaemic control from the time of diagnosis could reduce the later risk of microvascular complications in adults with latent autoimmune diabetes. FUNDING: European Foundation for the Study of Diabetes Mentorship Programme (AstraZeneca).

Simulating the impact of targeting lower systolic blood pressure and LDL-cholesterol levels on type 2 diabetes complication rates.

AIMS: There are few data available on the incremental benefits of risk factor modification in type 2 diabetes mellitus (T2DM). We simulated the potential benefits of achieving lower systolic blood pressure (SBP) and LDL-cholesterol targets. METHODS: We used the UKPDS Outcomes Model v2.0 to estimate 10-year event rates for complications using baseline data from 5717 participants with T2DM in the Trial Evaluating Cardiovascular Outcomes with Sitagliptin Study. All risk factor values were held constant over 10 years. In separate analyses, different levels of SBP between 160 and 120 mm Hg and LDL-cholesterol between 5.0 and 1.0 mmol/l were imposed on the cohort. Cumulative relative risk reductions (CRRR) at each 10 mm Hg and 1.0 mmol/l decrements respectively were compared using Kruskal-Wallis tests. RESULTS: CRRRs for each 10 mm Hg SBP decrement from 160 mm Hg were 2.2%, 4.5%, 7.0% and 10.0% for myocardial infarction (MI); 12.5%, 24.8%, 35.6% and 44.9% for stroke; 5.4%, 10.9%, 16.2% and 20.9% for blindness; 7.4%, 14.7%, 21.6% and 27.4% for amputation, respectively. CRRRs for each 1.0 mmol/l LDL-cholesterol decrement from 5.0 mmol/l were 16.9%, 30.8%, 41.2% & 51.0% for MI; 9.2%, 19.7%, 29.6% & 38.8% for stroke (p < 0.001 in all cases). CONCLUSIONS: These simulated outcomes illustrate the potential benefits of targeting progressively lower SBP and LDL-cholesterol values.

Sentinel node biopsy using a magnetic tracer versus standard technique: the SentiMAG Multicentre Trial.

BACKGROUND: The SentiMAG Multicentre Trial evaluated a new magnetic technique for sentinel lymph node biopsy (SLNB) against the standard (radioisotope and blue dye or radioisotope alone). The magnetic technique does not use radiation and provides both a color change (brown dye) and a handheld probe for node localization. The primary end point of this trial was defined as the proportion of sentinel nodes detected with each technique (identification rate). METHODS: A total of 160 women with breast cancer scheduled for SLNB, who were clinically and radiologically node negative, were recruited from seven centers in the United Kingdom and The Netherlands. SLNB was undertaken after administration of both the magnetic and standard tracers (radioisotope with or without blue dye). RESULTS: A total of 170 SLNB procedures were undertaken on 161 patients, and 1 patient was excluded, leaving 160 patients for further analysis. The identification rate was 95.0 % (152 of 160) with the standard technique and 94.4 % (151 of 160) with the magnetic technique (0.6 % difference; 95 % upper confidence limit 4.4 %; 6.9 % discordance). Of the 22 % (35 of 160) of patients with lymph node involvement, 16 % (25 of 160) had at least 1 macrometastasis, and 6 % (10 of 160) had at least a micrometastasis. Another 2.5 % (4 of 160) had isolated tumor cells. Of 404 lymph nodes removed, 297 (74 %) were true sentinel nodes. The lymph node retrieval rate was 2.5 nodes per patient overall, 1.9 nodes per patient with the standard technique, and 2.0 nodes per patient with the magnetic technique. CONCLUSIONS: The magnetic technique is a feasible technique for SLNB, with an identification rate that is not inferior to the standard technique.

Long-term survival of women with basal-like ductal carcinoma in situ of the breast: a population-based cohort study.

BACKGROUND: Microarray gene-profiling of invasive breast cancer has identified different subtypes including luminal A, luminal B, HER2-overexpressing and basal-like groups. Basal-like invasive breast cancer is associated with a worse prognosis. However, the prognosis of basal-like ductal carcinoma in situ (DCIS) is still unknown. Our aim was to study the prognosis of basal-like DCIS in a large population-based cohort. METHODS: All 458 women with a primary DCIS diagnosed between 1986 and 2004, in Uppland and Västmanland, Sweden were included. TMA blocks were constructed. To classify the DCIS tumors, we used immunohistochemical (IHC) markers (estrogen-, progesterone-, HER2, cytokeratin 5/6 and epidermal growth factor receptor) as a surrogate for the gene expression profiling. The association with prognosis was examined for basal-like DCIS and other subtypes using Kaplan-Meier survival analyses and Cox proportional hazards regression models. RESULTS: IHC data were complete for 392 women. Thirty-two were basal-like (8.2%), 351 were luminal or HER2-positive (89.5%) and 9 unclassified (2.3%). Seventy-six women had a local recurrence of which 34 were invasive. Another 3 women had general metastases as first event. Basal-like DCIS showed a higher risk of local recurrence and invasive recurrence 1.8 (Confidence interval (CI) 95%, 0.8-4.2) and 1.9 (0.7-5.1), respectively. However, the difference was not statistically significant. Also, no statistically significant increased risk was seen for triple-negative or high grade DCIS. CONCLUSIONS: Basal-like DCIS showed about a doubled, however not statistically significant risk for local recurrence and developing invasive cancer compared with the other molecular subtypes. Molecular subtyping was a better prognostic parameter than histopathological grade.

Mammographic features of breast cancers at single reading with computer-aided detection and at double reading in a large multicenter prospective trial of computer-aided detection: CADET II.

PURPOSE: To evaluate the mammographic features of breast cancer that favor lesion detection with single reading and computer-aided detection (CAD) or with double reading. MATERIALS AND METHODS: The Computer Aided Detection Evaluation Trial II study was approved by the ethics committee, and all participants provided written informed consent. A total of 31,057 women were recruited from three screening centers between September 2006 and August 2007. They were randomly allocated to the double reading group, the single reading with CAD group, or the double reading and single reading with CAD group at a ratio of 1:1:28, respectively. In this study, cancers in the women whose mammograms were read with both single reading with CAD and double reading were retrospectively reviewed. The original mammograms were obtained for each case and reviewed by two of three experienced breast radiologists in consensus. The method of detection was noted. The size and predominant mammographic feature of the cancer were recorded, as was the breast density. CAD marking data were reviewed to determine if the cancer had been correctly marked. RESULTS: A total of 227 cancers were detected in 28,204 women. A total of 170 cases were recalled with both reading regimens. Lesion types were masses (66%), microcalcifications (25%), parenchymal deformities (6%), and asymmetric densities (3%). The ability of the reading regimens to correctly prompt the reader to recall cases varied significantly by lesion type (P < .001). More parenchymal deformities were recalled with double reading, whereas more asymmetric densities were recalled with single reading with CAD. There was no difference in the ability of either reading regimen to prompt the reader to correctly recall masses or microcalcifications. CAD correctly prompted 100% of microcalcifications, 87% of mass lesions, 80% of asymmetric densities, and 50% of parenchymal deformities. CAD correctly marked 93% of spiculated masses compared with 80% of ill-defined masses (P = .054). There was a significant trend for cancers detected with double reading to occur only in women with a denser mammographic background pattern (P = .02). Size had no effect on lesion detection. CONCLUSION: Readers using either single reading with CAD or double reading need to be aware of the strengths and weaknesses of reading regimens to avoid missing the more challenging cancer cases.

Incorporation of a genetic factor into an epidemiologic model for prediction of individual risk of lung cancer: the Liverpool Lung Project.

The Liverpool Lung Project (LLP) has previously developed a risk model for prediction of 5-year absolute risk of lung cancer based on five epidemiologic risk factors. SEZ6L, a Met430IIe polymorphic variant found on 22q12.2 region, has been previously linked with an increased risk of lung cancer in a case-control population. In this article, we quantify the improvement in risk prediction with addition of SEZ6L to the LLP risk model. Data from 388 LLP subjects genotyped for SEZ6L single-nucleotide polymorphism (SNP) were combined with epidemiologic risk factors. Multivariable conditional logistic regression was used to predict 5-year absolute risk of lung cancer with and without this SNP. The improvement in the model associated with the SEZ6L SNP was assessed through pairwise comparison of the area under the receiver operating characteristic curve and the net reclassification improvements (NRI). The extended model showed better calibration compared with the baseline model. There was a statistically significant modest increase in the area under the receiver operating characteristic curve when SEZ6L was added into the baseline model. The NRI also revealed a statistically significant improvement of around 12% for the extended model; this improvement was better for subjects classified into the two intermediate-risk categories by the baseline model (NRI, 27%). Our results suggest that the addition of SEZ6L improved the performance of the LLP risk model, particularly for subjects whose initial absolute risks were unable to discriminate into "low-risk" or "high-risk" group. This work shows an approach to incorporate genetic biomarkers in risk models for predicting an individual's lung cancer risk.

Use of lung cancer risk models in planning research and service programs in CT screening for lung cancer.

Computed tomography screening for lung cancer is now being tested in a number of international trials. The long-term success of the approach in the future National Screening Programme is dependent upon identifying populations at sufficient risk of lung cancer that the benefit-harm ratio of the intervention is likely to be high. There are a number of lung cancer risk prediction models currently available. We review these, and demonstrate, using the Liverpool Lung Project risk prediction model as a case study, the potential for use of a risk prediction model in the design of a randomized trial of lung cancer screening and in the planning of a service screening program.

Increasing participant recruitment into large-scale screening trials: experience from the CADET II study.

OBJECTIVES: Multicentre randomized trials frequently encounter difficulties in meeting their recruitment targets, resulting in extension of the trial and delays in implementation of the findings. We report on recruitment strategies implemented in a randomized evaluation of computer-aided detection in women attending routine screening in the UK Breast Screening Programme. SETTING: The target population for the trial was identified from an existing NHS database of women aged 50-70 invited for routine mammography in Coventry, Manchester and Nottingham, UK. Women were asked to consent to their mammograms being randomly allocated (in a ratio of 28:1:1) to one of three film-reading protocols. Trial information was mailed to women, along with the invitation to attend screening, and informed consent was obtained at the mammography appointment. Several strategies were implemented to increase recruitment rates. RESULTS: Recruitment rate increased significantly over time in the study (P < 0.0010 in all centres) with an overall acceptance rate of 46% of those attending screening. Mailing of the trial information sheet separate from the screening invitation in Coventry and Nottingham increased the recruitment rate, even after adjustment for the trend over time and for socioeconomic status of the attendees (P < 0.001). Extension of recruitment to mobile screening units in Nottingham, and the presence of an additional member of staff also improved recruitment (P < 0.001). Simplification of the trial information sheet had little effect. Increases in recruitment rate were not attributable to socioeconomic status of the attendees. CONCLUSIONS: In multicentre trials, monitoring of local recruitment protocols is required to ensure that each centre can maximize accrual targets.

Single reading with computer-aided detection for screening mammography.

BACKGROUND: The sensitivity of screening mammography for the detection of small breast cancers is higher when the mammogram is read by two readers rather than by a single reader. We conducted a trial to determine whether the performance of a single reader using a computer-aided detection system would match the performance achieved by two readers. METHODS: The trial was designed as an equivalence trial, with matched-pair comparisons between the cancer-detection rates achieved by single reading with computer-aided detection and those achieved by double reading. We randomly assigned 31,057 women undergoing routine screening by film mammography at three centers in England to double reading, single reading with computer-aided detection, or both double reading and single reading with computer-aided detection, at a ratio of 1:1:28. The primary outcome measures were the proportion of cancers detected according to regimen and the recall rates within the group receiving both reading regimens. RESULTS: The proportion of cancers detected was 199 of 227 (87.7%) for double reading and 198 of 227 (87.2%) for single reading with computer-aided detection (P=0.89). The overall recall rates were 3.4% for double reading and 3.9% for single reading with computer-aided detection; the difference between the rates was small but significant (P<0.001). The estimated sensitivity, specificity, and positive predictive value for single reading with computer-aided detection were 87.2%, 96.9%, and 18.0%, respectively. The corresponding values for double reading were 87.7%, 97.4%, and 21.1%. There were no significant differences between the pathological attributes of tumors detected by single reading with computer-aided detection alone and those of tumors detected by double reading alone. CONCLUSIONS: Single reading with computer-aided detection could be an alternative to double reading and could improve the rate of detection of cancer from screening mammograms read by a single reader. (ClinicalTrials.gov number, NCT00450359.)

Variable size computer-aided detection prompts and mammography film reader decisions.

INTRODUCTION: The purpose of the present study was to investigate the effect of computer-aided detection (CAD) prompts on reader behaviour in a large sample of breast screening mammograms by analysing the relationship of the presence and size of prompts to the recall decision. METHODS: Local research ethics committee approval was obtained; informed consent was not required. Mammograms were obtained from women attending routine mammography at two breast screening centres in 1996. Films, previously double read, were re-read by a different reader using CAD. The study material included 315 cancer cases comprising all screen-detected cancer cases, all subsequent interval cancers and 861 normal cases randomly selected from 10,267 cases. Ground truth data were used to assess the efficacy of CAD prompting. Associations between prompt attributes and tumour features or reader recall decisions were assessed by chi-squared tests. RESULTS: There was a highly significant relationship between prompting and a decision to recall for cancer cases and for a random sample of normal cases (P < 0.001). Sixty-four per cent of all cases contained at least one CAD prompt. In cancer cases, larger prompts were more likely to be recalled (P = 0.02) for masses but there was no such association for calcifications (P = 0.9). In a random sample of 861 normal cases, larger prompts were more likely to be recalled (P = 0.02) for both mass and calcification prompts. Significant associations were observed with prompting and breast density (p = 0.009) for cancer cases but not for normal cases (P = 0.05). CONCLUSIONS: For both normal cases and cancer cases, prompted mammograms were more likely to be recalled and the prompt size was also associated with a recall decision.

Matrix metalloproteinase single-nucleotide polymorphisms and haplotypes predict breast cancer progression.

PURPOSE: Polymorphisms within the promoter region of several matrix metalloproteinase (MMP) genes have been linked to alterations in the level of transcription. We hypothesized that an individual's MMP genotype and haplotype will influence breast tumor progression and help predict prognosis. EXPERIMENTAL DESIGN: This study has evaluated the association between single-nucleotide polymorphisms (SNP) in the promoter regions of MMP-1, MMP-3, MMP-7, MMP-9, MMP-12, and MMP-13 and metastatic spread of breast cancer in 128 lymph node-negative and 93 lymph node-positive patients. The study cohort was of mixed ethnicity, with Caucasian patients comprising 65%. Associations between genotype and lymph node status were estimated by logistic regression and with overall survival using the method of Kaplan-Meier and log-rank test. Associations between haplotype and lymph node status were also investigated. RESULTS: The data show a significant and independent association of the C/T genotype for MMP-9 [mixed ethnicities odds ratio 3.6, 95% confidence interval (95% CI) 1.2-11.1; Caucasian odds ratio 9.1, 95% CI 1.7-48.4] and the 2G/2G genotype for MMP-1 (mixed ethnicities odds ratio 3.9, 95% CI 1.7-9.4; Caucasian odds ratio 2.6, 95% CI 1.0-6.9) with lymph node-positive disease. MMP-1 2G/2G was associated with reduced survival (hazard ratio 3.1, 95% CI 1.1-8.7), although this is dependent on lymph node status. Two haplotypes, driven by the MMP-1 2G allele, were significantly associated with lymph node-positive disease and survival. CONCLUSIONS: These results suggest that MMP single-nucleotide polymorphisms influence breast cancer behavior and that the MMP-1 2G/2G genotype increases the risk of lymph node metastasis and predicts poor prognosis.

Lymph node status and breast cancer-related lymphedema.

OBJECTIVE: This study examines the association between nodal positivity and risk of developing breast cancer-related lymphedema (BCRL) in patients who underwent axillary lymph node dissection (ALND). SUMMARY BACKGROUND DATA: The pathophysiology of BCRL is poorly understood. It has been assumed that one of the factors predisposing to the development of BCRL is nodal positivity, although retrospective series have produced contradictory findings. As these studies have included treatment regimens known to cause BCRL, such as axillary radiotherapy, any relationship between nodal positivity and the development of BCRL remains speculative. METHODS: A total of 212 patients who had undergone ALND for invasive breast cancer had arm volume measurements preoperatively, and at intervals postoperatively. No patient received axillary radiotherapy. Arm volumes were obtained by measuring serial arm circumferences every 4 cm up the arm and then calculated by using the formula for the volume of a truncated cone. Robust regression techniques were used to analyze the effects of node positivity, age, preoperative body mass index, and wound infection on arm volume excess. RESULTS: In all, 64 of 212 (30%) patients were node positive. Contrary to previous assumptions, positive node status was significantly inversely associated with arm volume after adjusting for tumor size, time since operation, and allowing for correlated observations within subjects. Furthermore, the number of positive nodes also correlated inversely with arm volume. CONCLUSION: These results are counterintuitive to the conventional understanding of the pathophysiology of BCRL. A possible explanation is that patients who develop disease in axillary lymph nodes and subsequently undergo ALND have more time and ability to develop lymphatic collaterals, which may provide adequate lymphatic drainage following surgery, thereby reducing the risk of developing BCRL.

Avoiding bias from aggregate measures of exposure.

BACKGROUND: Sometimes in descriptive epidemiology or in the evaluation of a health intervention policy change, proportions exposed to a risk factor or to an intervention are used as explanatory variables in log-linear regressions for disease incidence or mortality. AIM: To demonstrate how estimates from such models can be substantially inaccurate as estimates of the effect of the risk factor or intervention at individual level. To show how the individual level effect can be correctly estimated by excess relative risk models. METHODS: The problem and solution are demonstrated using data on prostate-specific antigen testing and prostate cancer incidence.

Overdiagnosis, sojourn time, and sensitivity in the Copenhagen mammography screening program.

The goal of this research was to estimate the overdiagnosis at the first and second screens of the mammography screening program in Copenhagen, Denmark. This study involves a mammography service screening program in Copenhagen, Denmark, with 35,123 women screened at least once. We fit multistate models to the screening data, including preclinical incidence of progressive cancers and nonprogressive (i.e., overdiagnosed) cancers. We estimated mean sojourn time as 2.7 years (95% confidence interval [CI] 2.2-3.1) and screening test sensitivity as 100% (95% CI 99.8-100). Overdiagnosis was estimated to be 7.8% (95% CI 0.3-26.5) at the first screen and 0.5% (95% CI 0.02-2.1) at the second screen. This corresponds to 4.8% of all cancers diagnosed among participants during the first two invitation rounds and following intervals. A modest overdiagnosis was estimated for the Copenhagen screening program, deriving almost exclusively from the first screen. The CIs were very broad, however, and estimates from larger datasets are warranted.

Evaluation of nonlinear regression approaches to estimation of insulin sensitivity by the minimal model with reference to Bayesian hierarchical analysis.

Minimal model analysis of intravenous glucose tolerance test (IVGTT) glucose and insulin concentrations offers a validated approach to measuring insulin sensitivity, but model identification is not always successful. Improvements may be achieved by using alternative settings in the modeling process, although results may differ according to setting, and care must be exercised in combining results. IVGTT data (12 samples, regular test) from 533 men without diabetes was modeled by the traditional nonlinear regression (NLR) approach, using five different permutations of settings. Results were evaluated with reference to the more robust Bayesian hierarchical (BH) approach to model identification and to the proportion of variance they explained in known correlates of insulin sensitivity (age, BMI, blood pressure, fasting glucose and insulin, serum triglyceride, HDL cholesterol, and uric acid concentration). BH analysis was successful in all cases. With NLR analysis, between 17 and 35 IVGTTs were associated with parameter coefficients of variation (PCVs) for minimal model parameters S(I) (insulin sensitivity) and S(G) (glucose effectiveness) of >100%. Systematic use of each different approach in combination reduced this number to five. Mean (interquartile range) S(I)(NLR) was then 3.14 (2.29-4.63) min(-1).mU(-1).l x 10(-4) and 2.56 (1.74-3.83) min(-1).mU(-1).l x 10(-4) for S(I)(BH) (correlation 0.86, P < 0.0001). S(I)(NLR) explained, on average, 10.6% of the variance in known correlates of insulin sensitivity, whereas S(I)(BH) explained 8.5%. In a large body of data, which BH analysis demonstrated could be fully identified, use of alternative modeling settings in NLR analysis could substantially reduce the number of analyses with PCVs >100%. S(I)(NLR) compared favorably with S(I)(BH) in the proportion of variance explained in known correlates of insulin sensitivity.

Overdiagnosis and overtreatment of breast cancer: estimates of overdiagnosis from two trials of mammographic screening for breast cancer.

Randomised controlled trials have shown that the policy of mammographic screening confers a substantial and significant reduction in breast cancer mortality. This has often been accompanied, however, by an increase in breast cancer incidence, particularly during the early years of a screening programme, which has led to concerns about overdiagnosis, that is to say, the diagnosis of disease that, if left undetected and therefore untreated, would not become symptomatic. We used incidence data from two randomised controlled trials of mammographic screening, the Swedish Two-county Trial and the Gothenburg Trial, to establish the timing and magnitude of any excess incidence of invasive disease and ductal carcinoma in situ (DCIS) in the study groups, to ascertain whether the excess incidence of DCIS reported early in a screening trial is balanced by a later deficit in invasive disease and provide explicit estimates of the rate of 'real' and non-progressive 'overdiagnosed' tumours from the study groups of the trials. We used a multistate model for overdiagnosis and used Markov Chain Monte Carlo methods to estimate the parameters. After taking into account the effect of lead time, we estimated that less than 5% of cases diagnosed at prevalence screen and less than 1% of cases diagnosed at incidence screens are being overdiagnosed. Overall, we estimate overdiagnosis to be around 1% of all cases diagnosed in screened populations. These estimates are, however, subject to considerable uncertainty. Our results suggest that overdiagnosis in mammography screening is a minor phenomenon, but further studies with very large numbers are required for more precise estimation.