Momar Diouf

Is stenting as "a bridge to surgery" an oncologically safe strategy for the management of acute, left-sided, malignant, colonic obstruction? A comparative study with a propensity score analysis.

Objective and Background:Self-expanding metallic stent (SEMS) insertion has been suggested as a promising alternative to emergency surgery for left-sided malignant colonic obstruction (LMCO). However, the literature on the long-term impact of SEMS as “a bridge to surgery” is limited and contradictory. Methods:From January 1998 to June 2011, we retrospectively identified patients operated on for LMCO with curative intent. The primary outcome criterion was overall survival. Short-term secondary endpoints included the technical success rate and overall success rate and long-term secondary endpoints included 5-year overall survival, 5-year cancer-specific mortality, 5-year disease-free survival, the recurrence rate, and mean time to recurrence. Patients treated with SEMS were analyzed on an intention-to-treat basis. Overall survival was analyzed after using a propensity score to correct for selection bias. Results:There were 48 patients in the SEMS group and 39 in the surgery-only group. In the overall population, overall survival (P = 0.001) and 5-year overall survival (P = 0.0003) were significantly lower in the SEMS group than in the surgery-only group, and 5-year cancer-specific mortality was significantly higher in the SEMS group (48% vs 21%, respectively (P = 0.02)). Five-year disease-free survival, the recurrence rate, and the mean time to recurrence were better in the surgery-only group (not significant). For patients with no metastases or perforations at hospital admission, overall survival (P = 0.003) and 5-year overall survival (30% vs 67%, respectively, P = 0.001) were significantly lower in the SEMS group than in the surgery-only group. Conclusions:Our study results suggest worse overall survival of patients with LMCO with SEMS insertion compared with immediate surgery.

EGFR activation is a potential determinant of primary resistance of hepatocellular carcinoma cells to sorafenib

Sorafenib is currently the medical treatment of reference for hepatocellular carcinoma (HCC), but it is not known whether sorafenib is equally active in all HCC. Here, our aim was to explore intrinsic differences in the response of HCC cells to sorafenib, to identify potential mechanisms leading to primary resistance to this treatment. We analyzed a panel of six human HCC cell lines and compared the activity of the main oncogenic kinase cascades, their clonogenic potential, proliferation and apoptosis upon exposure to sorafenib. We report that HCC cells present important differences in their response to sorafenib, and that some cell lines are more resistant to the actions of sorafenib than others. We identify the activated epidermal growth factor receptor (EGFR) as a parameter that promotes the resistance of HCC cells to sorafenib. In resistant cells, the efficacy of sorafenib was increased when EGFR was inhibited, as was demonstrated using two chemical inhibitors (erlotinib or gefitinib), a monoclonal antibody directed against EGFR (cetuximab), and RNA interference directed against EGFR. A combination of EGFR inhibitors and sorafenib affords a better control over HCC proliferation, most likely through an improved blockade of the RAF kinases. Our findings therefore confirm the importance of RAF kinases as therapeutic targets in HCC, and identify EGFR as a determinant of the sensitivity of HCC cells to sorafenib. Our findings bear possible implications for the improvement of the efficacy of sorafenib in HCC, and might be useful for the identification of predictive biomarkers in this context.

Effect of postoperative antibiotic administration on postoperative infection following cholecystectomy for acute calculous cholecystitis: a randomized clinical trial.

IMPORTANCE Ninety percent of cases of acute calculous cholecystitis are of mild (grade I) or moderate (grade II) severity. Although the preoperative and intraoperative antibiotic management of acute calculous cholecystitis has been standardized, few data exist on the utility of postoperative antibiotic treatment. OBJECTIVE To determine the effect of postoperative amoxicillin plus clavulanic acid on infection rates after cholecystectomy. DESIGN, SETTING, AND PATIENTS A total of 414 patients treated at 17 medical centers for grade I or II acute calculous cholecystitis and who received 2 g of amoxicillin plus clavulanic acid 3 times a day while in the hospital before and once at the time of surgery were randomized after surgery to an open-label, noninferiority, randomized clinical trial between May 2010 and August 2012. INTERVENTIONS After surgery, no antibiotics or continue with the preoperative antibiotic regimen 3 times daily for 5 days. MAIN OUTCOMES AND MEASURES The proportion of postoperative surgical site or distant infections recorded before or at the 4-week follow-up visit. RESULTS An imputed intention-to-treat analysis of 414 patients showed that the postoperative infection rates were 17% (35 of 207) in the nontreatment group and 15% (31 of 207) in the antibiotic group (absolute difference, 1.93%; 95% CI, -8.98% to 5.12%). In the per-protocol analysis, which involved 338 patients, the corresponding rates were both 13% (absolute difference, 0.3%; 95% CI, -5.0% to 6.3%). Based on a noninferiority margin of 11%, the lack of postoperative antibiotic treatment was not associated with worse outcomes than antibiotic treatment. Bile cultures showed that 60.9% were pathogen free. Both groups had similar Clavien complication severity outcomes: 195 patients (94.2%) in the nontreatment group had a score of 0 to I and 2 patients (0.97%) had a score of III to V, and 182 patients (87.8%) in the antibiotic group had a score of 0 to I and 4 patients (1.93%) had a score of III to V. CONCLUSIONS AND RELEVANCE Among patients with mild or moderate calculous cholecystitis who received preoperative and intraoperative antibiotics, lack of postoperative treatment with amoxicillin plus clavulanic acid did not result in a greater incidence of postoperative infections. TRIAL REGISTRATION clinicaltrials.gov Identifier: NCT01015417.

The added value of quality of life (QoL) for prognosis of overall survival in patients with palliative hepatocellular carcinoma

BACKGROUND & AIMS Several prognostic classifications (PCs) have been developed for use in palliative care in patients with hepatocellular carcinoma (HCC). We have recently suggested that CLIP combined with WHO PS has the greatest discriminative power. We evaluated the prognostic value of quality of life (QoL) data and whether the latter could improve classification of palliative HCC patients. METHODS This was a reanalysis from the CHOC trial with an evaluation of the discriminative power for overall survival (OS) of the established CLIP/GRETCH/BCLC/BoBar prognostic systems alone and then in association with each of the following groups of parameters: selected clinical factors, QoL as continuous variables, dichotomized QoL, selected clinical factors and continuous QoL, selected clinical factors and dichotomized QoL. Baseline QoL was assessed using the EORTC QLQ-C30. Discriminative power was evaluated with the Harrells C-index and net reclassification improvement. RESULTS Quality of life was available in 79% of the patients (n=271). Univariate analysis revealed that better role functioning (HR=0.991 [0.987-0.995]) and better physical functioning (0.991 [0.984-0.997]) scores were associated with longer survival. In contrast, poorer score for fatigue (1.011 [1.006-1.015]) and diarrhoea (1.008 [1.002-1.013]) were associated with shorter survival. After adjustment for clinical and sociodemographic variables, only better role functioning score (0.993 [0.988-0.998]) was associated with longer survival. Adding oedema, hepatomegaly, fatigue and diarrhoea QoL scales to CLIP resulted in the best performance. CONCLUSIONS Our results confirm that QoL scales are independent prognostic factors of OS in palliative HCC patients. Incorporation of QoL data improved all the studied PCs.

Ability of stroke volume variation measured by oesophageal Doppler monitoring to predict fluid responsiveness during surgery

BACKGROUND The objective of this study was to test whether non-invasive assessment of respiratory stroke volume variation (ΔrespSV) by oesophageal Doppler monitoring (ODM) can predict fluid responsiveness during surgery in a mixed population. The predictive value of ΔrespSV was evaluated using a grey zone approach. METHODS Ninety patients monitored using ODM who required i.v. fluids to expand their circulating volume during surgery under general anaesthesia were studied. Patients with a preoperative arrhythmia, right ventricular failure, frequent ectopic beats, or breathing spontaneously were excluded. Haemodynamic variables and oesophageal Doppler indices [peak velocity (PV), stroke volume (SV), corrected flow time (FTc), cardiac output (CO), ΔrespSV, and respiratory variation of PV (ΔrespPV)] were measured before and after fluid expansion. Responders were defined by a >15% increase in SV after infusion of 500 ml crystalloid solution. RESULTS SV was increased by ≥15% after 500 ml crystalloid infusion in 53 (59%) of the 90 patients. ΔrespSV predicted fluid responsiveness with an area under the receiver-operating characteristic (AUC) curve of 0.91 [95% confidence interval (95% CI): 0.85-0.97, P<0.0001]. The optimal ΔrespSV cut-off was 14.4% (95% CI: 14.3-14.5%). The grey zone approach identified 12 patients (14%) with a range of ΔrespSV values between 14% and 15%. FTc was not predictive of fluid responsiveness (AUC 0.49, 95% CI: 0.37-0.62, P=0.84). CONCLUSIONS ΔrespSV predicted fluid responsiveness accurately during surgery over a ΔrespSV range between 14% and 15%. In contrast, FTc did not predict fluid responsiveness.

The gray zone of the qualitative assessment of respiratory changes in inferior vena cava diameter in ICU patients

IntroductionTransthoracic echocardiography (TTE) is a useful tool for minimally invasive hemodynamic monitoring in the ICU. Dynamic indices (such as the inferior vena cava distensibility index (dIVC)) can be used to predict fluid responsiveness in mechanically ventilated patients. Although quantitative use of the dIVC has been validated, the routinely used qualitative (visual) approach had not been assessed before the present study.MethodsQualitative and quantitative assessments of the dIVC were compared in a prospective, observational study. After operators with differing levels in critical care echocardiography had derived a qualitative dIVC, the last (expert) operator performed a standard, numeric measurement of the dIVC (referred to as the quantitative dIVC). Two groups of patients were separated into two groups: group (dIVC < 18%) and group (dIVC ≥ 18%).ResultsIn total, 114 patients were assessed for inclusion, and 97 (63 men and 34 women) were included. The mean sensitivity and specificity values for qualitative assessment of the dIVC by an intensivist were 80.7% and 93.7%, respectively. A qualitative evaluation detected all quantitative dIVCs >40%. Most of the errors concerned quantitative dIVCs of between 15% and 30%. In the dIVC <18% group, two qualitative evaluation errors were noted for quantitative dIVCs of between 0 and 10%. The average of positive predictive values and negative predictive values for qualitative assessment of the dIVC by residents, intensivists and cardiologists were 83%, 83%, and 90%; and 92%, 94%, and 90%, respectively. The Fleiss kappa for all operators was estimated to be 0.68, corresponding to substantial agreement.ConclusionThe qualitative dIVC is a rather easy and reliable assessment for extreme numeric values. It has a gray zone between 15% and 30%. The highest and lowest limitations of the gray area are rather tedious to define.Despite reliability of the qualitative assessment when it comes to extreme to numerical values, the quantitative dIVC measurement must always be done within a hemodynamic assessment for intensive care patients. The qualitative approach can be easily integrated into a fast hemodynamic evaluation by using portable ultrasound scanner for out-of-hospital patients.

Could baseline health-related quality of life (QoL) predict overall survival in metastatic colorectal cancer? The results of the GERCOR OPTIMOX 1 study

BackgroundHealth-related quality of life (QoL) has prognostic value in many cancers. A recent study found that the performance of prognostic systems for metastatic colorectal cancer (mCRC) were improvable. We evaluated the independent prognostic value of QoL for overall survival (OS) and its ability to improve two prognostic systems’performance (Köhne and GERCOR models) for patients with mCRC.MethodsThe EQ-5D questionnaire was self-completed before randomization in the OPTIMOX1, a phase III trial comparing two strategies of FOLFOX chemotherapy which included 620 previously untreated mCRC patients recruited from January 2000 to June 2002 from 56 institutions in five countries. The improvement in models’ performance (after addition of QoL) was studied with Harrell’s C-index and the net reclassification improvement.ResultsOf the 620 patients, 249 (40%) completed QoL datasets. The Köhne model could be improved by LDH, mobility and pain/discomfort; the C-index rose from 0.54 to 0.67. The associated NRI for 12-month death was 0.23 [0.05; 0.46]. Mobility and pain/discomfort could be added to the GERCOR model: the C-index varied from 0.63 to 0.68. The NRI for 12 months death was 0.35 [0.12; 0.44].ConclusionsMobility and pain dimensions of EQ5D are independent prognostic factors and could be useful for staging and treatment assignment of mCRC patients. Presented at the 2011 ASCO Annual Meeting (#3632).

Outcome Implication of Aortic Valve Area Normalized to Body Size in Asymptomatic Aortic StenosisCLINICAL PERSPECTIVE

Background—Current guidelines define severe aortic stenosis in patients with aortic valve area normalized to body surface area (AVA/BSA) <0.6 cm2/m2; yet, this cutoff has never been validated. Moreover, it is not known whether AVA normalization to other body size indexes allows improved outcome prediction. We aim to test the value of AVA normalized to body size for outcome prediction in asymptomatic aortic stenosis. Methods and Results—We included 289 patients with asymptomatic aortic stenosis, preserved ejection fraction, and AVA<1.3 cm2 at diagnosis. The outcome measure was the occurrence of aortic valve replacement or all-cause death or during follow-up. AVA was normalized to BSA, height, weight, and body mass index. For each normalized index, patients in the lowest tertile were at high risk of events whereas outcome was similar for the other tertiles. High risk of events was observed with AVA/BSA <0.4 cm2/m2 (adjusted hazard ratio [HR], 3.42 [2.09–5.60]), AVA/height <0.45 cm2/m (adjusted HR, 3.99 [2.42–6.60]), AVA/weight <0.01 cm2/kg (adjusted HR, 3.37 [2.07–5.49]), and AVA/body mass index <0.029 cm2/kg per meter square (adjusted HR, 3.23 [1.99–5.24]). Mortality risk was high with AVA/height <0.45 cm2/m (adjusted HR, 2.18 [1.28–3.71]), followed by AVA/BSA <0.40 cm2/m2 (adjusted HR, 1.84 [1.09–3.11]), AVA/weight <0.01 cm2/kg (adjusted HR, 1.78 [1.07–2.98]), and AVA/body mass index <0.029 cm2/kg per meter square (adjusted HR, 1.75 [1.04–2.93]). AVA/height showed better predictive performance than AVA/BSA with improved reclassification and better discrimination (net reclassification improvement: 0.33 versus 0.28; integrated discrimination improvement: 0.10 versus 0.08; C statistic: 0.67 versus 0.65), whereas AVA/weight and AVA/body mass index showed lower predictive capacity. Conclusions—Among AVA normalization methods, AVA/height <0.45 cm2/m followed by AVA/BSA <0.40 cm2/m2 seem as robust parameters for defining high risk in asymptomatic aortic stenosis. The prognostic value of AVA/height deserves future research.

Evaluation of cardiac output by 5 arterial pulse contour techniques using trend interchangeability method

AbstractCardiac output measurement with pulse contour analysis is a continuous, mini-invasive, operator-independent, widely used, and cost-effective technique, which could be helpful to assess changes in cardiac output. The 4-quadrant plot and the polar plot have been described to compare the changes between 2 measurements performed under different conditions, and the direction of change by using different methods of measurements. However, the 4-quadrant plot and the polar plot present a number of limitations, with a risk of misinterpretation in routine clinical practice. We describe a new trend interchangeability method designed to objectively define the interchangeability of each change of a variable. Using the repeatability of the reference method, we classified each change as either uninterpretable or interpretable and then as either noninterchangeable, in the gray zone or interchangeable. An interchangeability rate can then be calculated by the number of interchangeable changes divided by the total number of interpretable changes. In this observational study, we used this objective method to assess cardiac output changes with 5 arterial pulse contour techniques (Wesselings method, LiDCO, PiCCO, Hemac method, and Modelflow) in comparison with bolus thermodilution technique as reference method in 24 cardiac surgery patients. A total of 172 cardiac output variations were available from the 199 data points: 88 (51%) were uninterpretable, according to the first step of the method. The second step of the method, based on the 84 (49%) interpretable variations, showed that only 18 (21%) to 30 (36%) variations were interchangeable regardless of the technique used. None of pulse contour cardiac output technique could be interchangeable with bolus thermodilution to assess changes in cardiac output using the trend interchangeability method in cardiac surgery patients. Future studies may consider using this method to assess interchangeability of changes between different methods of measurements.

Optimal Cut Points for Quality of Life Questionnaire-Core 30 (QLQ-C30) Scales: Utility for Clinical Trials and Updates of Prognostic Systems in Advanced Hepatocellular Carcinoma

BACKGROUND Health-related quality of life (QoL) has been validated as a prognostic factor for cancer patients; however, to be used in routine practice, QoL scores must be dichotomized. Cutoff points are usually based on arbitrary percentile values. We aimed to identify optimal cutoff points for six QoL scales and to quantify their added utility in the performance of four prognostic classifications in patients with hepatocellular carcinoma (HCC). METHODS We reanalyzed data of 271 patients with advanced HCC recruited between July 2002 and October 2003 from 79 institutions in France in the CHOC trial, designed to assess the efficacy of long-acting octreotide. QoL was assessed with the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire-Core 30 (QLQ-C30). The scores ranged from 0 to 100. Identification of optimal cutoff points was based on the method of Faraggi and Simon [Stat Med 1996;15:2203-2213]. Improvement in the performance of prognostic classifications was studied with Harrells C-index, the net reclassification improvement (NRI), and integrated discrimination improvement (IDI). RESULTS We found that optimal cutoff points were 50 for global health, 58.33 for physical functioning, 66.67 for role functioning, 66.67 for fatigue, 0 for dyspnea, and 33.33 for diarrhea. The addition of QoL and clinical factors improved the performance of all four prognostic classifications, with improvement in the range of 0.02-0.09 for the C-index, 0.24-0.78 for 3-month NRI, and 0.02-0.10 for IDI. CONCLUSION These cutoff values for QoL scales can be useful to identify HCC patients with very poor prognosis and thus improve design of clinical trials and treatment adjustment for these patients.