Visceral fat and clinical outcome in patients receiving first-line chemotherapy with bevacizumab for metastatic colorectal cancer.

BACKGROUND: Visceral fat produces angiogenic factors such as vascular endothelial growth factor that promote tumoral growth. However, its influence on outcome for patients with advanced cancer treated with anti-angiogenic agents is controversial. AIMS: The aim of this study was to determine whether visceral fat volume, visceral fat area and body mass index are associated with outcome in patients receiving first-line bevacizumab-based treatment for metastatic colorectal cancer. METHODS: This multicenter prospective study included 103 patients with metastatic colorectal cancer who received first-line bevacizumab-based chemotherapy. Computed tomography was used to measure visceral fat volume and visceral fat area. Endpoints were tumoral response at 2 months, progression free survival and overall survival. RESULTS: Visceral fat volume and visceral fat area, but not body mass index, were significantly associated with better outcome. Using sex-specific median values progression free survival was significantly longer in patients with high visceral fat volume (13.2 versus 9.4 months; p = 0.0043). In the same way, high visceral fat volume and visceral fat area were associated with a significantly better overall survival: 31.3 versus 20.5 months (p = 0.0072) and 29.3 versus 20.5 months (p = 0.0078), respectively. By multivariate analysis, visceral fat volume was associated with longer progression free survival and overall survival. CONCLUSION: This study demonstrates that a high visceral fat volume is associated with better outcome in patients receiving first-line bevacizumab-based chemotherapy for metastatic colorectal cancer.

Is Glucagon Administration Compatible With FDG PET/MRI?

ABSTRACT: Digestive peristalsis generates many artifacts that limit the abdominal and pelvic MRI interpretation. Apart from the hypoglycemia treatment in patients with diabetes, glucagon analog is also indicated for the digestive peristalsis reduction to reduce MRI artifacts. However, its use in PET/MRI is not described, given the risk of interaction with the metabolism of FDG. To assess the importance of this interaction on the FDG PET images, we report FDG PET/MRI images obtained with and without glucagon analog injection.

Agreement between arterial and venous lactate in emergency department patients: a prospective study of 157 consecutive patients.

INTRODUCTION: In the emergency department (ED), lactate is routinely used for risk stratification. Whether venous or arterial lactate measured on blood gas is interchangeable is not known. We hypothesized that venous lactate can be used instead of arterial lactate for the evaluation of acute patients in the ED. PATIENTS AND METHODS: This was a prospective single-center study. All patients requiring a lactate measurement were enrolled and we simultaneously drew arterial and venous blood. We followed up all patients to hospital discharge. Our primary aim was to evaluate agreements between the two measurements using Bland and Altman plots with the report of bias (mean difference) and limits of agreements. We also aimed to determine the rate of misclassification (defined as one measurement<1.8 mmol/l and the other>2.2). Our secondary aim was to evaluate their respective prognostic value to predict in-hospital death or admission in the ICU longer than 72 h. RESULTS: The mean age of the 132 analyzed patients was 62 years (SD: 18 years), and 59% were men. The mean difference (bias) between arterial and venous lactate was -0.6 mmol/l (limits of agreement: -1.7 to 0.6 mmol/l). The rate of misclassification was 8% (95% confidence interval: 3-2%). Both methods present similar performances for the prediction of poor outcomes, with an area under the receiving operator characteristic curves of 0.67 for both. Results were similar when focused only on septic patients. CONCLUSION: Venous and arterial lactates do not agree well, and there is a high misclassification rate. Venous lactate does not appear to be interchangeable with arterial sampling.

Value of Contrast-Enhanced Ultrasound Quantification Criteria for Identifying Patients not Responding to Bevacizumab-Based Therapy for Colorectal Liver Metastases.

PURPOSE: To evaluate changes in tumor vascularization parameters based on contrast-enhanced ultrasound (CEUS) quantification criteria of at least one visible liver metastasis as an early predictor of non-response to chemotherapy, including bevacizumab for colorectal cancer (CRC) liver metastases. MATERIALS AND METHODS: This multicenter prospective study included patients who received first-line bevacizumab-based chemotherapy. Tumor enhancement measured using CEUS within one liver metastasis and in relation to the surrounding healthy liver was quantified within 8 days before the first infusion of bevacizumab (E0), 24 hours after the end of the first infusion of bevacizumab (E1), in the 24 hours before the 2nd and 3 rd infusion of bevacizumab on day 15 (E2) and day 30 (E3), respectively, and after 2 months of treatment (E4). Endpoints were tumor response using RECIST criteria at 2 months, progression-free survival (PFS) and overall survival (OS). RESULTS: Among the 137 patients included in this study, 109 were analyzed. Only CEUS parameters calculated in relation to healthy liver were significant. High wash-in and wash-out rates at baseline were significantly associated with a better tumor response. Increases over time E2-E0 and E3-E0 for peak enhancement were significantly associated with shorter progression-free survival. Increases over time E2-E0 and E3-E0 for peak enhancement and wash-in area under the curve were significantly associated with a shorter overall survival. CONCLUSION: This large study demonstrated that early dynamic changes in the vascularity of liver metastases evaluated by quantified CEUS are associated with outcome in patients receiving first-line bevacizumab-based treatment for metastatic CRC.

High-Sensitivity Cardiac Troponin T: a Preanalytical Evaluation.

BACKGROUND: Little is known about the effects of preanalytical conditions on high-sensitivity cardiac troponin T (hs-cTnT) concentrations. METHODS: Variations of hs-cTnT concentrations were evaluated under the following preanalytical conditions: 1) serum vs. lithium-heparin (Li-Hep) plasma, with or without separator gel; 2) centrifugation time (15-minutes vs. 10-minutes) and speed (1467 to 3756 g); 3) stability in Li-Hep plasma at room temperature and +4 degrees C for 4 days and at -80 degrees C for up to 12 months, for three concentrations; 4) four freeze-thaw cycles at -20 degrees C and -80 degrees C, for three concentrations. RESULTS: No significant changes were found regarding the type of blood collection tube, the centrifugation, and storage conditions. Minor decreases were observed after four freeze-thaw cycles at -20 degrees C (< 6.5%) and -80 degrees C (< 3.4%). CONCLUSIONS: High-sensitivity cardiac troponin T may be considered as not impacted by usual preanalytical conditions, thus strengthening its reliability in laboratory practice and clinical research.

Hemolysis indexes for biochemical tests and immunoassays on Roche analyzers: determination of allowable interference limits according to different calculation methods.

OBJECTIVES: To determine the hemolysis interference on biochemical tests and immunoassays performed on Roche Diagnostics analyzers, according to different maximum allowable limits. DESIGN AND METHODS: Heparinized plasma and serum pools, free of interferences, were overloaded by increasing amounts of a hemoglobin-titrated hemolysate. This interference was evaluated for 45 analytes using Modular(®) and Cobas(®) analyzers. For each parameter, the hemolysis index (HI) corresponding to the traditional ± 10% change of concentrations from baseline (± 10%Δ) was determined, as well as those corresponding to the analytical change limit (ACL), and to the reference change value (RCV). Then, the relative frequencies distribution (% RFD) of hemolyzed tests performed in a hospital laboratory over a 25-day period were established for each HI as allowable limit. RESULTS: Considering the ± 10%Δ, the analyte concentrations enhanced by hemolysis were: Lactate dehydrogenase (LDH), aspartate aminotransferase (AST), folate, potassium, creatine kinase, phosphorus, iron, alanine aminotransferase, lipase, magnesium and triglycerides, decreasingly. The analyte concentrations decreased by hemolysis were: Haptoglobin, high-sensitive troponin T and alkaline phosphatase. Over the 25-day period, the % RFD of tests impacted more than 10%Δ by hemolysis were < 7% for LDH; < 5% for AST, folates and iron; and < 1% for the other analytes. Considering the ACL, HI were lower, giving % RFD substantially increased for many analytes, whereas only four analytes remain sensitive to hemolysis when considering RCV. CONCLUSION: This study proposes new HI based on different allowable limits, and can therefore serve as a starting point for future harmonization of hemolysis interference evaluation needed in routine laboratory practice.

Validation of dynamic contrast-enhanced ultrasound in predicting outcomes of antiangiogenic therapy for solid tumors: the French multicenter support for innovative and expensive techniques study.

OBJECTIVES: Dynamic contrast-enhanced ultrasound (DCE-US) has been used in single-center studies to evaluate tumor response to antiangiogenic treatments: the change of area under the perfusion curve (AUC), a criterion linked to blood volume, was consistently correlated with the Response Evaluation Criteria in Solid Tumors response. The main objective here was to do a multicentric validation of the use of DCE-US to evaluate tumor response in different solid tumor types treated by several antiangiogenic agents. A secondary objective was to evaluate the costs of the procedure. MATERIALS AND METHODS: This prospective study included patients from 2007 to 2010 in 19 centers (8 teaching hospitals and 11 comprehensive cancer centers). All patients treated with antiangiogenic therapy were eligible. Dynamic contrast-enhanced ultrasound examinations were performed at baseline as well as on days 7, 15, 30, and 60. For each examination, a perfusion curve was recorded during 3 minutes after injection of a contrast agent. Change from baseline at each time point was estimated for each of 7 fitted criteria. The main end point was freedom from progression (FFP). Criterion/time-point combinations with the strongest correlation with FFP were analyzed further to estimate an optimal cutoff point. RESULTS: A total of 1968 DCE-US examinations in 539 patients were analyzed. The median follow-up was 1.65 years. Variations from baseline were significant at day 30 for several criteria, with AUC having the most significant association with FFP (P = 0.00002). Patients with a greater than 40% decrease in AUC at day 30 had better FFP (P = 0.005) and overall survival (P = 0.05). The mean cost of each DCE-US was 180&OV0556;, which corresponds to $250 using the current exchange rate. CONCLUSIONS: Dynamic contrast-enhanced ultrasound is a new functional imaging technique that provides a validated criterion, namely, the change of AUC from baseline to day 30, which is predictive of tumor progression in a large multicenter cohort. Because of its low cost, it should be considered in the routine evaluation of solid tumors treated with antiangiogenic therapy.

Lapatinib plus capecitabine in patients with previously untreated brain metastases from HER2-positive metastatic breast cancer (LANDSCAPE): a single-group phase 2 study.

BACKGROUND: Brain metastases occur in 30-50% of patients with metastatic HER2-positive breast cancer. In the case of diffuse brain metastases, treatment is based on whole brain radiotherapy (WBRT). Few systemic options are available. We aimed to investigate the combination of lapatinib plus capecitabine for the treatment of previously untreated brain metastases from HER2-positive breast cancer. METHODS: In this single-arm phase 2, open-label, multicentre study, eligible patients had HER2-positive metastatic breast cancer with brain metastases not previously treated with WBRT, capecitabine, or lapatinib. Tretament was given in 21 day cycles: patients received lapatinib (1250 mg, orally) every day and capecitabine (2000 mg/m(2), orally) from day 1 to day 14. The primary endpoint was the proportion of patients with an objective CNS response, defined as a 50% or greater volumetric reduction of CNS lesions in the absence of increased steroid use, progressive neurological symptoms, and progressive extra-CNS disease. All responses had to be confirmed 4 weeks after initial response. Efficacy analyses included all patients who received the study drugs and were assessable for efficacy criteria. This trial is registered with ClinicalTrials.gov, number NCT00967031. FINDINGS: Between April 15, 2009, to Aug 2, 2010, we enrolled 45 patients, 44 (98%) of whom were assessable for efficacy, with a median follow-up of 21·2 months (range 2·2-27·6). 29 patients had an objective CNS response (65·9%, 95% CI 50·1-79·5); all were partial responses. Of all 45 treated patients, 22 (49%) had grade 3 or grade 4 treatment-related adverse events, of which the most common were diarrhoea in nine (20%) patients and hand-foot syndrome in nine (20%) patients. 14 (31%) patients had at least one severe adverse event; treatment was discontinued because of toxicity in four patients. No toxic deaths occurred. INTERPRETATION: The combination of lapatinib and capecitabine is active as first-line treatment of brain metastases from HER2-positive breast cancer. A phase 3 trial is warranted. FUNDING: GlaxoSmithKline-France and UNICANCER.

Prognostic significance of blood lactate and lactate clearance in trauma patients.

BACKGROUND: Lactate has been shown to be a prognostic biomarker in trauma. Although lactate clearance has already been proposed as an intermediate endpoint in randomized trials, its precise role in trauma patients remains to be determined. METHODS: Blood lactate levels and lactate clearance (LC) were calculated at admission and 2 and 4 h later in trauma patients. The association of initial blood lactate level and lactate clearance with mortality was tested using receiver-operating characteristics curve, logistic regression using triage scores, Trauma Related Injury Severity Score as a reference standard, and reclassification method. RESULTS: The authors evaluated 586 trauma patients (mean age 38±16 yr, 84% blunt and 16% penetrating, mortality 13%). Blood lactate levels at admission were elevated in 327 (56%) patients. The lactate clearance should be calculated within the first 2 h after admission as LC0-2 h was correlated with LC0-4 h (R=0.55, P<0.001) but not with LC2-4 h (R=0.04, not significant). The lactate clearance provides additional predictive information to initial blood lactate levels and triage scores and the reference score. This additional information may be summarized using a categorical approach (i.e., less than or equal to -20 %/h) in contrast to initial blood lactate. The results were comparable in patients with high (5 mM/l or more) initial blood lactate. CONCLUSIONS: Early (0-2 h) lactate clearance is an important and independent prognostic variable that should probably be incorporated in future decision schemes for the resuscitation of trauma patients.

Concordance between transcutaneous and arterial measurements of carbon dioxide in an ED.

BACKGROUND: Transcutaneous carbon dioxide pressure (PtcCO(2)) has been suggested as a noninvasive surrogate of arterial carbon dioxide pressure (PaCO(2)). Our study evaluates the reliability of this method in spontaneously breathing patients in an emergency department. PATIENTS AND METHODS: A prospective, observational study was performed in nonintubated dyspneic patients who required measurement of arterial blood gases. Simultaneously and blindly to the physicians in charge, PtcCO(2) was measured using a TOSCA 500 monitor (Radiometer, Villeurbanne, France). Agreement between PaCO(2) and PtcCO(2) was assessed using the Bland-Altman method. RESULTS: Forty-eight patients (mean age, 65 years) were included, and 50 measurements were done. Eleven (23%) had acute heart failure; 10 (21%), pneumonia; 7 (15%), acute asthma; and 7 (15%), exacerbation of chronic obstructive pulmonary disease. Median PaCO(2) was 42 mm Hg (range, 17-109). Mean difference between PaCO(2) and PtcCO(2) was 1 mm Hg with 95% limits of agreement of -3.4 to +5.6 mm Hg. All measurement differences were within 5 mm Hg, and 32 (64%) were within 2 mm Hg. CONCLUSION: Transcutaneous carbon dioxide pressure accurately predicts PaCO(2) in spontaneously breathing patients.

Concordance between capnography and capnia in adults admitted for acute dyspnea in an ED.

BACKGROUND: End-tidal carbon dioxide pressure (etCO(2)) is widely used in anaesthesia and critical care in intubated patients. The aim of our preliminary study was to evaluate the feasibility of a simple device to predict capnia in spontaneously breathing patients in an emergency department (ED). PATIENTS AND METHODS: This study was a prospective, nonblind study performed in our teaching hospital ED. We included nonintubated patients with dyspnea (> or =18 years) requiring measurement of arterial blood gases, as ordered by the emergency physician in charge. There were no exclusion criteria. End-tidal CO(2) was measured by an easy-to-use device connected to a microstream capnometer, which gave a continuous measurement and graphical display of the etCO(2) level of a patient's exhaled breath. RESULTS: A total of 43 patients (48 measurements) were included, and the majority had pneumonia (n = 12), acute cardiac failure (n = 8), asthma (n = 7), or chronic obstructive pulmonary disease exacerbation (n = 6). Using simple linear regression, the correlation between etCO(2) and Paco(2) was good (R = 0.82). However, 18 measurements (38%) had a difference between etCO(2) and Paco(2) of 10 mm Hg or more. The mean difference between the Paco(2) and etCO(2) levels was 8 mm Hg. Using the Bland and Altman matrix, the limits of agreement were -10 to +26 mm Hg. CONCLUSION: In our preliminary study, etCO(2) using a microstream method does not seem to accurately predict Paco(2) in patients presenting to an ED for acute dyspnea.

An evaluation of transcutaneous carbon dioxide partial pressure monitoring during apnea testing in brain-dead patients.

BACKGROUND: Diagnosis of brain death usually requires an arterial carbon dioxide partial pressure (Paco2) of 60 mmHg during the apnea test, but the increase in Paco2 is unpredictable. The authors evaluated whether transcutaneous carbon dioxide partial pressure (Ptcco2) monitoring during apnea test can predict that a Paco2 of 60 mmHg has been reached. METHODS: The authors compared Ptcco2 measured with a transcutaneous ear sensor (V-Sign Sensor, Sentec Digital Monitoring System; SENTEC-AG, Therwil, Switzerland) and Paco2 obtained from arterial blood gas measurements in 32 clinically brain-dead patients. RESULTS: In the first 20 patients, the mean Paco2-Ptcco2 gradient was 0.7 +/- 3.6 mmHg at baseline and 8.7 +/- 7.1 mmHg after 20 min of apnea. Using receiver operating characteristic curve analysis (area under the curve: 0.983 +/- 0.013), the best threshold value of Ptcco2 to predict that a Paco2 of 60 mmHg had been reached was 60 mmHg (positive predictive value: 1.00 [0.93-1.00]). In the following 12 patients investigated with use of this Ptcco2 target value of 60 mmHg, the mean duration of the apnea test (11 +/- 4 vs. 20 +/- 0 min; P < 0.001), hypercapnia (74.0 +/- 4.9 vs. 98.3 +/- 20.0 mmHg; P < 0.001), acidosis (pH: 7.18 +/- 0.06 vs. 7.11 +/- 0.08; P < 0.001), and decrease in arterial oxygen partial pressure (-47 +/- 44 vs. -95 +/- 89; P < 0.05) at the end of the test were reduced as compared with the 20-min apnea test group. CONCLUSION: During the apnea test in brain-dead patients, a Ptcco2 of 60 mmHg accurately predicts that a Paco2 of 60 mmHg has been reached. This may allow a reduction in the duration of the apnea test and consecutively limit occurrence of complications.

Early hypocalcemia in severe trauma.

OBJECTIVES: We tested the hypothesis that colloid-induced hemodilution can induce hypocalcemia in the early phase of severe trauma resuscitation and tried to assess other potential causative factors of that hypocalcemia. DESIGN: Prospective cohort. SETTING: Level I academic trauma center. PATIENTS: Consecutive severe trauma patients (n = 212, mean Injury Severity Score 34) resuscitated in the prehospital phase without any blood transfusion. INTERVENTIONS: At admission, ionized calcium (corrected to an arterial pH = 7.40) was measured. MEASUREMENTS AND MAIN RESULTS: Hypocalcemia was defined as a value <1.15 mmol/L and severe hypocalcemia as a value <0.9 mmol/L. A normal ionized calcium concentration was observed in 56 (26%) patients, a mild ionized hypocalcemia (1.05 +/- 0.06 mmol/L) in 135 (64%) patients, and a severe ionized hypocalcemia (0.77 +/- 0.10 mmol/L) in 21 (10%) patients. There were significant correlations between ionized calcium concentration with the amount of infused colloid (R = .658, p < .001) and arterial pH (R = .760, p < 0.001) but not with the amount of infused crystalloid (R = .007, not significant). Despite taking into account hemodilution, arterial pH, binding of calcium to lactates, and colloids, some patients had marked differences (>15%) between calculated and observed ionized calcium, and these patients had more severe trauma and more frequently had acidosis and/or prehospital cardiac arrest. Using the TRISS methodology, survival was not significantly different from that expected in this trauma population. CONCLUSION: Hypocalcemia frequently occurs on arrival at the hospital in severe trauma patients, and colloid-induced hemodilution and severe shock and/or ischemia-reperfusion appear to be important causative factors.