Can we expand active surveillance criteria to include biopsy Gleason 3+4 prostate cancer? A multi-institutional study of 2,323 patients

ObjectiveTo test the expandability of active surveillance (AS) to Gleason score 3+4 cancers by assessing the unfavorable disease risk in a large multi-institutional cohort.Materials and methodsWe performed a retrospective analysis including 2,323 patients with localized Gleason score 3+4 prostate cancer who underwent a radical prostatectomy between 2005 and 2013 from 6 academic centers. We analyzed the rates of biopsy downgrading/upgrading and advanced stage in the overall cohort by employing standardized AS criteria (using biopsy Gleason score 3+4).ResultsThe final pathologic Gleason score was 3+3 = 6 in 8%, 3+4 = 7 in 67%, 4+3 = 7 in 20%, and 8 to 10 in 5% cases. The overall rate of unfavorable disease (upgrading or advanced stage or both) was 46%. In multivariable analysis, prostate-specific antigen (PSA) level>10 ng/ml, PSA density (PSAD) >0.15 ng/ml/g, clinical stage >T1, and>2 positive cores were predictors of unfavorable disease. According to the AS criteria used, the risk of unfavorable disease ranged from 30% to 42%. In patients without any risk factor (PSA level≤10 ng/ml, PSAD ≤0.15 ng/ml/g, T1c, and≤2 positive cores), the unfavorable disease rate was 19%. The main limitations of this study are the retrospective design and nonstandardization of pathologic assessment between centers.ConclusionsApproximately half of patients with biopsy Gleason score 3+4 cancer have unfavorable disease at final pathology. Nevertheless, expanding AS eligibility to these patients may be acceptable provided adherence to strict selection criteria leading to a<20% risk of unfavorable disease. Future tools for selection such as magnetic resonance imaging, early rebiopsy, and serum markers may be especially beneficial in this group of patients.     

Carotid Intima-Media Thickness and Plaque in Cardiovascular Risk Assessment

Carotid intima-media thickness (CIMT) has been shown to predict cardiovascular (CV) risk in multiple large studies. Careful evaluation of CIMT studies reveals discrepancies in the comprehensiveness with which CIMT is assessed—the number of carotid segments evaluated (common carotid artery [CCA], internal carotid artery [ICA], or the carotid bulb), the type of measurements made (mean or maximum of single measurements, mean of the mean, or mean of the maximum for multiple measurements), the number of imaging angles used, whether plaques were included in the intima-media thickness (IMT) measurement, the report of adjusted or unadjusted models, risk association versus risk prediction, and the arbitrary cutoff points for CIMT and for plaque to predict risk. Measuring the far wall of the CCA was shown to be the least variable method for assessing IMT. However, meta-analyses suggest that CCA-IMT alone only minimally improves predictive power beyond traditional risk factors, whereas inclusion of the carotid bulb and ICA-IMT improves prediction of both cardiac risk and stroke risk. Carotid plaque appears to be a more powerful predictor of CV risk compared with CIMT alone. Quantitative measures of plaques such as plaque number, plaque thickness, plaque area, and 3-dimensional assessment of plaque volume appear to be progressively more sensitive in predicting CV risk than mere assessment of plaque presence. Limited data show that plaque characteristics including plaque vascularity may improve CV disease risk stratification further. IMT measurement at the CCA, carotid bulb, and ICA that allows inclusion of plaque in the IMT measurement or CCA-IMT measurement along with plaque assessment in all carotid segments is emerging as the focus of carotid artery ultrasound imaging for CV risk prediction.     

Relationship between right portal and biliary systems based on reclassification of the liver

BACKGROUND: Although the anatomy of the right portal and biliary systems and their interrelationships must be understood to safely and satisfactorily perform left-sided resection of hilar cholangiocarcinoma or right-lobe living donor liver transplantation, the anatomies of the right portal and biliary systems are extremely difficult to understand. METHODS: A total of 60 patients with normal liver underwent computed tomography during both portography and cholangiography to evaluate relationships between the right biliary and portal systems based on reclassification of the liver to divide the right liver into 3 segments. RESULTS: All ventral and posterior ducts constantly join medially to the anterior portal trunk. In contrast, some dorsal ducts join the ventral duct medially and others join the posterior duct lateral to the anterior trunk. CONCLUSIONS: Reclassification of the liver to divide the right liver into 3 segments facilitates an understanding of relationships between the right portal and biliary systems.     

Predicting progression to dementia in persons with mild cognitive impairment using cerebrospinal fluid markers

Introduction

We aimed to determine the added value of cerebrospinal fluid (CSF) to clinical and imaging tests to predict progression from mild cognitive impairment (MCI) to any type of dementia.

When no treatment is the best treatment: Active surveillance strategies for low risk prostate cancers

Although the incidence of prostate cancer is rising due to PSA screening and increased life expectancy, the metastatic potential of low-grade, organ-confined disease remains low. An increasing number of studies suggest that radical treatment in such cases confers little or no survival benefit at a significant cost to morbidity. Active surveillance is a promising management approach of such low-risk cancers: eligible patients are selected based on clinical and pathological findings at diagnosis and are regularly monitored with digital rectal examinations, PSA testing and biopsies. Treatment, however, is deferred until and unless there is evidence of disease progression. This is a key difference from watchful waiting, where treatment is avoided until and unless there are symptoms. The purpose of this work is to review the rationale and evidence behind active surveillance and to offer an overview of current active surveillance strategies and outcomes.     

Neutrophil lymphocyte ratio significantly improves the Framingham risk score in prediction of coronary heart disease mortality: Insights from the National Health and Nutrition Examination Survey-III

Background

Neutrophil lymphocyte ratio (NLR) has been shown to predict cardiovascular events in several studies. We sought to study if NLR predicts coronary heart disease (CHD) in a healthy US cohort and if it reclassifies the traditional Framingham risk score (FRS) model.

Methods

We performed post hoc analysis of National Health and Nutrition Examination Survey-III (1998–94) including subjects aged 30–79 years free from CHD or CHD equivalent at baseline. Primary endpoint was death from ischemic heart disease. NLR was divided into four categories: < 1.5, ≥ 1.5 to < 3.0, 3.0–4.5 and > 4.5. Statistical analyses involved multivariate Cox proportional hazards models as well as discrimination, calibration and reclassification.

Results

We included 7363 subjects with a mean follow up of 14.1 years. There were 231 (3.1%) CHD deaths, more in those with NLR > 4.5 (11%) compared to NLR < 1.5 (2.4%), p < 0.001. Adjusted hazard ratio of NLR > 4.5 was 2.68 (95% CI 1.07–6.72, p = 0.035). There was no significant improvement in C-index (0.8709 to 0.8713) or area under curve (0.8520 to 0.8531) with addition of NLR to FRS model. Model with NLR was well calibrated with Hosmer–Lemeshow chi-square of 8.57 (p = 0.38). Overall net reclassification index (NRI) was 6.6% (p = 0.003) with intermediate NRI of 10.1% (p < 0.001) and net upward reclassification of 5.6%. Absolute integrated discrimination index (IDI) was 0.003 (p = 0.039) with relative IDI of 4.3%.

Conclusions

NLR can independently predict CHD mortality in an asymptomatic general population cohort. It reclassifies intermediate risk category of FRS, with significant upward reclassification. NLR should be considered as an inflammatory biomarker of CHD.     

Predictors of unfavourable repeat biopsy results in men participating in a prospective active surveillance program

Background

Active surveillance (AS) protocols for low-risk prostate cancer (PCa) generally include repeat prostate biopsies at predefined follow-up intervals.

Objective

To study the outcome of routinely obtained 1-yr repeat biopsies and factors predicting reclassification to higher risk, to contribute to risk stratification for men on AS.

Design, setting, and participants

We analysed men with low-risk PCa (clinical stage ≤T2, prostate-specific antigen (PSA) ≤10 ng/ml, PSA density <0.2 ng/ml per millilitre, one or two positive biopsy cores, and Gleason score ≤6) who had been included in a prospective AS protocol.

Interventions

PSA was measured 3-monthly and the first volume-dependent repeat biopsy was scheduled 1 yr after diagnosis, independent of PSA doubling time (PSA-DT). Reclassification to higher risk disease on repeat biopsy was defined as Gleason score ≥7 or ≥3 positive cores.

Measurements

We analysed whether baseline patient characteristics and PSA-DT were associated with reclassification to more aggressive PCa on repeat biopsy.

Results and limitations

A first repeat biopsy was taken in 757 patients after median follow-up of 1.03 yr. The results of repeat biopsies were favourable (no or low-risk PCa) in 594 patients (78.5%) and led to reclassification of risk in 163 (21.5%). Analysis showed that reclassification to higher risk was significantly influenced by the number of initial positive cores (two vs one) (odds ratio [OR]: 1.8; p = 0.002) and higher PSA density (OR: 2.1; p = 0.003). The outcome was not significantly influenced by age, clinical stage, total number of biopsy cores, or PSA. Adding PSA-DT at time of repeat biopsy to the model showed PSA-DT <3 yr to be significantly associated with reclassification to higher risk (OR: 1.7; p = 0.015). Data on tumour involvement per biopsy core were not available.

Conclusions

Clinical features at baseline and during follow-up in our AS cohort are significantly associated with short-term reclassification to higher risk on repeat biopsy. These characteristics can potentially be used for risk stratification of men with PCa who are apparently at favourable risk.

Trial registration

The current program is registered at the Dutch Trial Register with identification number ID NTR1718 (http://www.trialregister.nl/trialreg/admin/rctview.asp?TC=1718).     

Improving risk classification of critical illness with biomarkers: A simulation study

Purpose

Optimal triage of patients at risk for critical illness requires accurate risk prediction, yet few data on the performance criteria required of a potential biomarker to be clinically useful exists.

Materials and Methods

We studied an adult cohort of nonarrest, nontrauma emergency medical services encounters transported to a hospital from 2002 to 2006. We simulated hypothetical biomarkers increasingly associated with critical illness during hospitalization and determined the biomarker strength and sample size necessary to improve risk classification beyond a best clinical model.

Results

Of 57?647 encounters, 3121 (5.4%) were hospitalized with critical illness and 54?526 (94.6%) without critical illness. The addition of a moderate-strength biomarker (odds ratio, 3.0, for critical illness) to a clinical model improved discrimination (c statistic, 0.85 vs 0.8; P < .01) and reclassification (net reclassification improvement, 0.15; 95% confidence interval, 0.13-0.18) and increased the proportion of cases in the highest-risk category by + 8.6% (95% confidence interval, 7.5%-10.8%). Introducing correlation between the biomarker and physiological variables in the clinical risk score did not modify the results. Statistically significant changes in net reclassification required a sample size of at least 1000 subjects.

Conclusions

Clinical models for triage of critical illness could be significantly improved by incorporating biomarkers, yet substantial sample sizes and biomarker strength may be required.