Prognostic value of urinary prostate cancer antigen 3 (PCA3) during active surveillance of patients with low-risk prostate cancer receiving 5α-reductase inhibitors.

OBJECTIVES: To determine the clinical performance of the urinary prostate cancer antigen 3 (PCA3) test to predict the risk of Gleason grade re-classification amongst men receiving a 5α-reductase inhibitor (5ARI) during active surveillance (AS) for prostate cancer. PATIENTS AND METHODS: Patients with low-risk prostate cancer were enrolled in a prospective Phase II study of AS complemented with prescription of a 5ARI. A repeat biopsy was taken within the first year and annually according to physician and patient preference. In all, 90 patients had urine collected after digital rectal examination of the prostate before the first repeat biopsy. The PCA3 test was performed in a blinded manner at a central laboratory. RESULTS: Using a PCA3-test score threshold of 35, there was a significant difference (P < 0.001) in the risk of being diagnosed with Gleason ≥7 cancer during a median of 7 years of follow-up. Adjusted Cox regression and Kaplan-Meier analyses also showed a significantly higher risk of upgrading to Gleason ≥7 during follow-up for those with a higher PCA3-test score. CONCLUSION: The urinary PCA3 test predicted Gleason grade re-classification amongst patients receiving a 5ARI during AS for low-risk prostate cancer.

Prospective Evaluation of Nutritional Factors to Predict the Risk of Complications for Patients Undergoing Radical Cystectomy: A Cohort Study.

The objective of this study was to identify nutritional preoperative factors associated with complications after radical cystectomy (RC). We prospectively evaluated the Mini-Nutritional Assessment Score, body mass index (BMI), appetite, stool frequency, hydration, food intake, weight loss, albuminemia, and prealbuminemia of 144 patients who underwent RC between January 2011 and April 2014. Postoperative complications were defined as any adverse event reported in the patient's file up to 90 days after surgery. Each complication was classified according to the Clavien-Dindo and Memorial Sloan-Kettering Cancer Center systems. The adjusted relative risk (RR) computed through a Poisson regression model was used to identify nutritional risk factors associated with post-RC complications. A high BMI >27 kg/m2 was associated with higher risk of low-grade complications (RR:1.47 [95% CI,1.09-2.00]) at 7 days and a four-fold increased risk of cardiac complications at 7 and 90 days (RR:3.77 [1.15-12.32] and RR:3.28 [1.35-7.98]). Decreased appetite was associated with low-grade (RR:1.43 [1.03-1.99] complications within 90 days. Preoperative weight loss >3 kg was associated with high-grade (RR:2.49 [1.23-5.05]) and wound (RR:2.51 [1.23-5.10]) complications within 90 days. This study showed that preoperative nutritional status of patients may predict the occurrence of complications up to 90 days post-RC. Development of preoperative nutritional interventions may reduce the deleterious impact of RC on patients' health.

Outcome of ICU patients with Clostridium difficile infection.

INTRODUCTION: As data from Clostridium difficile infection (CDI) in intensive care unit (ICU) are still scarce, our objectives were to assess the morbidity and mortality of ICU-acquired CDI. METHODS: We compared patients with ICU-acquired CDI (watery or unformed stools occurring ≥ 72 hours after ICU admission with a stool sample positive for C. difficile toxin A or B) with two groups of controls hospitalized at the same time in the same unit. The first control group comprised patients with ICU-acquired diarrhea occurring ≥ 72 hours after ICU admission with a stool sample negative for C. difficile and for toxin A or B. The second group comprised patients without any diarrhea. RESULTS: Among 5,260 patients, 512 patients developed one episode of diarrhea. Among them, 69 (13.5%) had a CDI; 10 (14.5%) of them were community-acquired, contrasting with 12 (17.4%) that were hospital-acquired and 47 (68%) that were ICU-acquired. A pseudomembranous colitis was associated in 24/47 (51%) ICU patients. The median delay between diagnosis and metronidazole administration was one day (25th Quartile; 75th Quartile (0; 2) days). The case-fatality rate for patients with ICU-acquired CDI was 10/47 (21.5%), as compared to 112/443 (25.3%) for patients with negative tests. Neither the crude mortality (cause specific hazard ratio; CSHR = 0.70, 95% confidence interval; CI 0.36 to 1.35, P = 0.3) nor the adjusted mortality to confounding variables (CSHR = 0.81, 95% CI 0.4 to 1.64, P = 0.6) were significantly different between CDI patients and diarrheic patients without CDI. Compared to the general ICU population, neither the crude mortality (SHR = 0.64, 95% CI 0.34 to 1.21, P = 0.17), nor the mortality adjusted to confounding variables (CSHR = 0.71, 95% confidence interval (CI) 0.38 to 1.35, P = 0.3), were significantly different between the two groups. The estimated increase in the duration of stay due to CDI was 8.0 days ± 9.3 days, (P = 0.4) in comparison to the diarrheic population, and 6.3 days ± 4.3 (P = 0.14) in comparison to the general ICU population. CONCLUSIONS: If treated early, ICU-acquired CDI is not independently associated with an increased mortality and impacts marginally the ICU length of stay.

Attributable risk estimation for adjusted disability multistate models: application to nosocomial infections.

Attributable risk has become an important concept in clinical epidemiology. In this paper, we suggest to estimate the attributable risk of nosocomial infections using a multistate approach. Recently, a multistate model (called progressive disability model in the literature) has been developed in order to take into consideration both the time-dependency of the risk factor (e.g., nosocomial infections) and the presence of competing risks (e.g., death and discharge) at each time point. However, this approach does not take into account the possible heterogeneity of the study population. In this paper, we investigate an extension of this model and suggest an adjusted disability multistate model including covariates in each transition. This new multistate model has led us to define the concepts of overall and profiled attributable risk. We use a classical semiparametric approach to estimate the model and the new attributable risk. A simulation study is investigated and we show, in particular, that neglecting the presence of covariates when estimating the model can lead to an important bias. The methodology developed in this paper is applied to data on ventilator-associated pneumonia in 12 French intensive care units.

Multiple-center evaluation of mortality associated with acute kidney injury in critically ill patients: a competing risks analysis.

INTRODUCTION: In this study, we aimed to assess the association between acute kidney injury (AKI) and mortality in critically ill patients using an original competing risks approach. METHODS: Unselected patients admitted between 1997 and 2009 to 13 French medical or surgical intensive care units were included in this observational cohort study. AKI was defined according to the RIFLE criteria. The following data were recorded: baseline characteristics, daily serum creatinine level, daily Sequential Organ Failure Assessment (SOFA) score, vital status at hospital discharge and length of hospital stay. Patients were classified according to the maximum RIFLE class reached during their ICU stay. The association of AKI with hospital mortality with "discharge alive" considered as a competing event was assessed according to the Fine and Gray model. RESULTS: Of the 8,639 study patients, 32.9% had AKI, of whom 19.1% received renal replacement therapy. Patients with AKI had higher crude mortality rates and longer lengths of hospital stay than patients without AKI. In the Fine and Gray model, independent risk factors for hospital mortality were the RIFLE classes Risk (sub-hazard ratio (SHR) 1.58 and 95% confidence interval (95% CI) 1.32 to 1.88; P < 0.0001), Injury (SHR 3.99 and 95% CI 3.43 to 4.65; P < 0.0001) and Failure (SHR 4.12 and 95% CI 3.55 to 4.79; P < 0.0001); nonrenal SOFA score (SHR 1.19 per point and 95% CI 1.18 to 1.21; P < 0.0001); McCabe class 3 (SHR 2.71 and 95% CI 2.34 to 3.15; P < 0.0001); and respiratory failure (SHR 3.08 and 95% CI 1.36 to 7.01; P < 0.01). CONCLUSIONS: By using a competing risks approach, we confirm in this study that AKI affecting critically ill patients is associated with increased in-hospital mortality.

Association between hypernatraemia acquired in the ICU and mortality: a cohort study.

BACKGROUND: The aim of this study is to describe the prevalence and outcomes of intensive care unit (ICU)-acquired hypernatraemia (IAH). METHODS: A retrospective analysis was performed on a prospectively collected database fed by 12 ICUs. Subjects are unselected patients with ICU stay >48 h. Mild and moderate to severe hypernatraemia were defined as serum sodium >145 and >150 mmol/L, respectively. IAH was hypernatraemia occurring >or=24 h after ICU admission in patients with normal serum sodium at ICU admission. RESULTS: Of the 8441 patients, 301 were excluded because they had hypernatraemia at ICU admission. Of the remaining 8140 patients, 901 (11.1%) experienced mild hypernatraemia, and 344 (4.2%) experienced moderate to severe hypernatraemia. Factors independently associated with IAH were male gender, severity at admission as assessed by the Simplified Acute Physiology Score version II (SAPS II), and organ failure or life-supporting treatment at ICU admission. Unadjusted hospital mortality was 15.2% in patients without hypernatraemia compared to 29.5% in patients with mild IAH and 46.2% in those with moderate to severe IAH (P < 0.0001). When any degree of IAH was handled as a time-dependent variable in a subdistribution hazard model, the subdistribution hazard ratio (SHR) for ICU mortality was 4.26 [95% confidence interval (CI), 3.74-4.84]. After stratification by centre and adjustment for confounders, both mild IAH and moderate to severe IAH were independently associated with mortality [SHR 2.03 (95% CI 1.73-2.39) and 2.67 (95% CI 2.19-3.26), respectively]. CONCLUSION: IAH is frequent and associated with mortality after adjustment on severity at ICU admission.

Neutrophil-to-lymphocyte Ratio as a Predictive Marker of Response to Abiraterone Acetate: A Retrospective Analysis of the COU302 Study.

BACKGROUND: The neutrophil-lymphocyte ratio (NLR) is an inexpensive and accessible prognostic marker for many cancers, including metastatic castration-resistant prostate cancer (mCRPC). OBJECTIVE: In this study, we assess the role of NLR as a predictive biomarker through a retrospective analysis of the pivotal COU302 study of abiraterone acetate (AA) as first-line therapy for men with asymptomatic or minimally symptomatic mCRPC. DESIGN, SETTING, AND PARTICIPANTS: The COU302 study randomized asymptomatic or minimally symptomatic men with mCRPC to receive AA plus prednisone or prednisone as first-line treatment. Baseline NLR, overall survival, radiographic progression-free survival, and prostate-specific antigen (PSA) progression-free survival were evaluated. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: Descriptive statistics, as well as Kaplan-Meier and Cox survival models were used to assess the effect of baseline NLR and changes in NLR on response to AA plus prednisone versus prednisone, with adjustment for important covariates. RESULTS AND LIMITATIONS: Among the 1082 patients who received treatment, baseline NLR values showed no significant differences according to baseline covariates except for albumin. Baseline variables were similar between dichotomous groups with an NLR cutoff of 2.5, except for a lower proportion of patients with >10 bone metastases in the NLR <2.5 group. Our survival results demonstrate that higher NLR values corresponded to poorer overall survival and PSA response to AA but not to placebo, which was confirmed in our adjusted regression models. No significant differences were seen in time to radiographic progression. In separate analyses, an increase or decrease in NLR by 2 from treatment baseline did not clearly signal subsequent lack of benefit with continued AA. CONCLUSIONS: Our results suggest that baseline NLR may be able to predict response to AA in men with asymptomatic mCRPC but that changes in NLR during treatment are insufficient to guide treatment. Further validation studies are warranted. PATIENT SUMMARY: In this report, we look at the ratio of circulating immune cells as a predictor of response to abiraterone acetate (AA), using data from a large trial. Our results suggest that this ratio derived from routinely obtained bloodwork can predict which patients respond better to AA.

Predicting the risk of documented ventilator-associated pneumonia for benchmarking: construction and validation of a score.

OBJECTIVES: : To build and validate a ventilator-associated pneumonia risk score for benchmarking. The rate of ventilator-associated pneumonia varies widely with case-mix, a fact that has limited its use for measuring intensive care unit performance. METHODS: : We studied 1856 patients in the OUTCOMEREA database treated at intensive care unit admission by endotracheal intubation followed by mechanical ventilation for >48 hrs; they were allocated randomly to a training data set (n = 1233) or a validation data set (n = 623). Multivariate logistic regression was used. Calibration of the final model was assessed in both data sets, using the Hosmer-Lemeshow chi-square test and receiver operating characteristic curves. MEASUREMENTS AND MAIN RESULTS: : Independent risk factors for ventilator-associated pneumonia were male gender (odds ratio = 1.97, 95% confidence interval = 1.32-2.95); SOFA at intensive care unit admission (<3 [reference value], 3-4 [2.57, 1.39-4.77], 5-8 [7.37, 4.24-12.81], >8 [5.81 (3.2-10.52)], no use within 48 hrs after intensive care unit admission of parenteral nutrition (2.29, 1.52-3.45), no broad-spectrum antimicrobials (2.11, 1.46-3.06); and mechanical ventilation duration (<5 days (); 5-7 days (17.55, 4.01-76.85); 7-15 days (53.01, 12.74-220.56); >15 days (225.6, 54.3-936.7). Tests in the training set showed good calibration and good discrimination (area under the curve-receiver operating characteristic curve = 0.881), and both criteria remained good in the validation set (area under the curve-receiver operating characteristic curve = 0.848) and good calibration (Hosmer-Lemeshow chi-square = 9.98, p = .5). Observed ventilator-associated pneumonia rates varied across intensive care units from 9.7 to 26.1 of 1000 mechanical ventilation days but the ratio of observed over theoretical ventilator-associated pneumonia rates was >1 in only two intensive care units. CONCLUSIONS: : The ventilator-associated pneumonia rate may be useful for benchmarking provided the ratio of observed over theoretical rates is used. External validation of our prediction score is needed.

Omega-3 Fatty Acids Survey in Men under Active Surveillance for Prostate Cancer: from Intake to Prostate Tissue Level.

Dietary omega-3 fatty acids (ω3), particularly long-chain ω3 (LCω3), have protective effects against prostate cancer (PCa) in experimental studies. Observational studies are conflicting, possibly because of the biomarker used. This study aimed at evaluating associations between grade reclassification and ω3 levels assessed in prostatic tissue, red blood cells (RBC), and diet. We conducted a validation cross-sectional study nested within a phase II clinical trial. We identified 157 men diagnosed with low-risk PCa who underwent a first active surveillance repeat prostate biopsy session. Fatty acid (FA) intake was assessed using a food frequency questionnaire and their levels measured in prostate tissue and RBC. Associations were evaluated using logistic regression. At first repeat biopsy session, 39 (25%) men had high-grade PCa (grade group ≥2). We found that high LCω3-eicosapentaenoic acid (EPA) level in prostate tissue (odds ratio (OR) 0.25; 95% (confidence interval (CI) 0.08-0.79; p-trend = 0.03) was associated with lower odds of high-grade PCa. Similar results were observed for LCω3 dietary intake (OR 0.30; 95% CI 0.11-0.83; p-trend = 0.02) but no association for RBC. LCω3-EPA levels in the target prostate tissue are inversely associated with high-grade PCa in men with low-risk PCa, supporting that prostate tissue FA, but not RBC FA, is a reliable biomarker of PCa risk.

Metabolic Imaging of Prostate Cancer Reveals Intrapatient Intermetastasis Response Heterogeneity to Systemic Therapy.

Although intrapatient heterogeneity of prostate cancer (PCa) has recently been characterized via genomic and transcriptomic studies, the heterogeneity of systemic treatment responses has yet to be reported or imaged. Our objective was to evaluate the intrapatient intermetastasis response to systemic treatment among patients with metastatic PCa. We evaluated the metabolic response for each individual metastatic lesion (n=165) in 15 patients with metastatic PCa who underwent 18F-fluorodeoxyglucose positron emission tomography/computed tomography before and at least 3 mo after initiation of a systemic therapy that did not change in that period. Intermetastasis heterogeneity was defined as opposite metabolic responses for at least two metastases from the same compartment (bone or soft tissue) between the two time points. We found intrapatient intermetastasis response heterogeneity in 40% of the cases in our retrospective series. Our results suggest that systemic therapies can induce heterogeneous responses among individual metastases in patients with PCa, supporting the polyclonal evolution of PCa in advanced disease. Molecular imaging may thus be useful in identifying clinical resistance early after therapy initiation and could also allow targeted biopsy of resistant clones for molecular analysis. PATIENT SUMMARY: Systemic therapies can lead to heterogeneous responses in individual metastases of prostate cancer in a patient. Molecular imaging may be useful for identifying heterogeneity and could allow targeted biopsy for molecular analysis or therapy.

Disinfection by-products exposure and intra-uterine growth restriction: Do genetic polymorphisms of CYP2E1or deletion of GSTM1 or GSTT1 modify the association?

BACKGROUND: Exposure to disinfection by-products (DBPs) during pregnancy was associated with reduced foetal growth. Genetic susceptibility might play a role, especially for genes encoding for the Cytochrome P450 (CYP2E1) and Glutathione S-Transferase (GST) enzymes, involved in metabolism and activation of DBPs. Few epidemiological studies evaluated these gene-environment interactions and their results were never replicated. OBJECTIVE: This study aims to examine interactions between trihalomethanes (THM) or haloacetic acids (HAA) exposure and genetic polymorphisms on small for gestational age (SGA) neonates by investigating single nucleotide polymorphisms (SNPs) in CYP2E1 gene and GSTM1 and GSTT1 deletions in mothers-children pairs. METHODS: A population-based case-control study of 1549 mothers and 1455 children was conducted on SGA and THM/HAA exposure. DNA was extracted from blood or saliva cells. Targeted SNPs and deletions were genotyped. Statistical interaction between SNPs/deletions and THMs or HAAs in utero exposure with regard to SGA occurrence was evaluated by unconditional logistic regression with control of potential confounders. RESULTS: Previously reported positive modification of the effect of THM uterine exposure by mothers or newborns CYP2E1 rs3813867 C allele or GSTM1 deletion was not replicated. However interactions with CYP2E1 rs117618383 and rs2515641 were observed but were not statistically significant after correction for multiple testing. CONCLUSIONS: Previous positive interactions between THMs exposure and CYP2E1 and GSTM1 were not replicated but interactions with other CYP2E1 polymorphisms are reported.

Phase II Drug-Metabolizing Polymorphisms and Smoking Predict Recurrence of Non-Muscle-Invasive Bladder Cancer: A Gene-Smoking Interaction.

Cigarette smoking is the most important known risk factor for urinary bladder cancer. Selected arylamines in cigarette smoke are recognized human bladder carcinogens and undergo biotransformation through several detoxification pathways, such as the glutathione S-transferases (GST), and uridine-diphospho-glucuronosyltransferases (UGT) pathways. GSTM1 deletion status and UGT1A1*28 rs8175347 genotypes were assessed in 189 non-muscle-invasive bladder cancers (NMIBC) patients with pTa (77.2%) and pT1 (22.8%) tumors and a mean follow-up of 5.6 years, to investigate whether two common functional polymorphisms in GSTM1 and UGT1A1 genes and smoking history are associated with recurrence-free survival of patients with NMIBC. Most patients were current (48.7%) or previous (35.4%) cigarette smokers and 15.9% never smoked. Tumor recurrence occurred in 65.1% of patients, at a median time of 12.9 months. Upon multivariate analysis, previous and current smokers approximately tripled their risk of recurrences [HR = 2.76; 95% confidence interval (CI), 1.03-7.40 and HR = 2.93; 95% CI, 1.08-7.94, respectively]. When adjusted for age, smoking status, stage, grade, gender, and presence of carcinoma in situ, carriers of GSTM1 (+/- and -/-) and UGT1A1*28/*28 alleles were significantly at risk of NMIBC recurrence (HR = 10.05; 95% CI, 1.35-75.1 and HR = 1.91; 95% CI, 1.01-3.62, respectively). Compared with nonsmokers with UGT1A1*1/*1 and *1/*28 genotypes, previous and current smokers homozygous for the UGT1A1*28 allele demonstrated a risk of recurrence of 4.95 (95% CI, 1.02-24.0) and 5.32 (95% CI, 2.07-13.7), respectively. This study establishes a connection between GSTM1, UGT1A1, and tobacco exposure as prognostic markers of NMIBC recurrence in bladder cancer patients. These findings warrant validation in larger cohorts.

Comparison of digital image analysis and visual scoring of KI-67 in prostate cancer prognosis after prostatectomy.

BACKGROUND: The tumor proliferative index marker Ki-67 was shown to be associated with clinically significant outcomes in prostate cancer, but its clinical application has limitations due to lack of uniformity and consistency in quantification. Our objective was to compare the measurements obtained with digital image analysis (DIA) versus virtual microscopy (visual scoring (VS)). METHODS: To do so, we compared the measurement distributions of each technique and their ability to predict clinically useful endpoints. A tissue microarray series from a cohort of 225 men who underwent radical prostatectomy was immunostained for Ki-67. The percentage of Ki-67 positive nuclei in malignant cells was assessed both by VS and DIA, and a H-score was calculated. The distribution and predictive ability of these scoring methods to predict biochemical recurrence (BCR) and death from prostate cancer (DPCa) were compared using Mann-Whitney test and C-index. RESULTS: The measurements obtained with VS were similar to the DIA measurements (p = 0.73) but dissimilar to the H-score (p < 0.001). Cox regression models showed that Ki-67 was associated with BCR (HR 1.46, 95 % CI 1.10-1.94) and DPCa (HR 1.26, 95 % CI 1.06-1.50). C-indexes revealed that Ki-67 was a better predictor of DPCa (0.803, 0.8059 and 0.789; VS, DIA and H-score, respectively) than of BCR (0.625, 0.632 and 0.604; VS, DIA and H-score, respectively). CONCLUSION: The measurement distributions and the predictive abilities of VS and DIA were similar and presented the same predictive behaviour in our cohort, supporting the role of Ki-67 proliferative index as an important prognostic factor of BCR and DPCa in prostate cancer post RP. VIRTUAL SLIDES: The virtual slide(s) for this article can be found here: http://www.diagnosticpathology.diagnomx.eu/vs/6656878501536663.

Attributable mortality of ventilator-associated pneumonia: respective impact of main characteristics at ICU admission and VAP onset using conditional logistic regression and multi-state models.

PURPOSE: Methods for estimating the excess mortality attributable to ventilator-associated pneumonia (VAP) should handle VAP as a time-dependent covariate, since the probability of experiencing VAP increases with the time on mechanical ventilation. VAP-attributable mortality (VAP-AM) varies with definitions, case-mix, causative microorganisms, and treatment adequacy. Our objectives here were to compare VAP-AM estimates obtained using a traditional cohort analysis, a multistate progressive disability model, and a matched-cohort analysis; and to compare VAP-AM estimates according to VAP characteristics. METHODS: We used data from 2,873 mechanically ventilated patients in the Outcomerea database. Among these patients from 12 intensive care units, 434 (15.1%) experienced VAP; of the remaining patients, 1,969 (68.5%) were discharged alive and 470 (16.4%) died. With the multistate model, VAP-AM was 8.1% (95% confidence interval [95%CI], 3.1-13.1%) for 120 days' complete observation, compared to 10.4% (5.6-24.5%) using a matched-cohort approach (2,769 patients) with matching on mechanical ventilation duration followed by conditional logistic regression. VAP-AM was higher in surgical patients and patients with intermediate (but not high) Simplified Acute Physiologic Score II values at ICU admission. VAP-AM was significantly influenced by time to VAP but not by resistance of causative microorganisms. Higher Logistic Organ Dysfunction score at VAP onset dramatically increased VAP-AM (to 31.9% in patients with scores above 7). CONCLUSION: A multistate model that appropriately handled VAP as a time-dependent event produced lower VAP-AM values than conditional logistic regression. VAP-AM varied widely with case-mix. Disease severity at VAP onset markedly influenced VAP-AM; this may contribute to the variability of previous estimates.