Increased expression of blood muscarinic receptors in patients with reflex syncope.

AIMS: Pathophysiology of reflex syncope is not fully understood but a vagal overactivity might be involved in this syncope. Previously, overexpression of muscarinic M2 receptors and acetylcholinesterase was found in particular in the heart and in lymphocytes of rabbits with vagal overactivity as well as in hearts of Sudden Infant Death Syndromes. The aim of this present study was to look at M2 receptor expression in blood of patients with reflex syncope. The second objective was to measure acetylcholinesterase expression in these patients. METHODS AND RESULTS: 136 subjects were enrolled. This monocenter study pooled 45 adults exhibiting recurrent reflex syncope compared with 32 healthy adult volunteers (18-50 years) and 38 children exhibiting reflex syncope requiring hospitalization compared with 21 controls (1-17 years). One blood sample was taken from each subject and blood mRNA expression of M2 receptors was assessed by qRT-PCR. Taking into account the non-symmetric distributions of values in both groups, statistical interferences were assessed using bayesian techniques. A M2 receptor overexpression was observed in adult and pediatric patients compared to controls. The medians [q1;q3] were 0.9 [0.3;1.9] in patients versus 0.2 [0.1;1.0] in controls; the probability that M2 receptor expression was higher in patients than in controls (Pr[patients>controls]) was estimated at 0.99. Acetylcholinesterase expression was also increased 0.7 [0.4;1.6] in patients versus 0.4 [0.2;1.1] in controls; the probability that acetylcholinesterase expression was higher in patients than in controls (Pr[patients>controls]) was estimated at 0.97. Both in adults and children, the expression ratio of M2 receptors over acetylcholinesterase was greater in the patient group compared with the control group. CONCLUSION: M2 receptor overexpression has been detected in the blood of both, adults and children, exhibiting reflex syncope. As in our experimental model, i.e. rabbits with vagal overactivity, acetylcholinesterase overexpression was associated with M2 receptor overexpression. For the first time, biological abnormalities are identified in vagal syncope in which only clinical signs are, so far, taken into account for differential diagnosis and therapeutic management. Further work will be needed to validate potential biomarkers of risk or severity associated with the cholinergic system.

Wide-volume versus helical acquisition in unenhanced chest CT: prospective intra-patient comparison of diagnostic accuracy and radiation dose in an ultra-low-dose setting.

OBJECTIVES: Diagnostic performance and potential radiation dose reduction of wide-area detector CT sequential acquisition ("wide-volume" acquisition (WV)) in unenhanced chest examination are unknown. This study aims to assess the image quality, the diagnostic performance, and the radiation dose reduction of WV mode compared with the classical helical acquisition for lung parenchyma analysis in an ultra-low-dose (ULD) protocol. METHODS: After Institutional Review Board Approval and written informed consent, 64 patients (72% men; 67.6 ± 9.7 years old; BMI 26.1 ± 5.3 kg/m2) referred for a clinically indicated unenhanced chest CT were prospectively included. All patients underwent, in addition to a standard helical acquisition (120 kV, automatic tube current modulation), two ULD acquisitions (135 kV, fixed tube current at 10 mA): one in helical mode and one in WV mode. Image noise, subjective image quality (5-level Likert scale), and diagnostic performance for the detection of 9 predetermined parenchymal abnormalities were assessed by two radiologists and compared using the chi-square or Fisher non-parametric tests. RESULTS: Subjective image quality (4.2 ± 0.7 versus 4.2 ± 0.8, p = 0.56), image noise (41.7 ± 8 versus 40.9 ± 8.7, p = 0.3), and diagnostic performance were equivalent between ULD WV and ULD helical. Radiation dose was significantly lower for the ULD WV acquisition (mean dose-length product 14.1 ± 1.3 mGy cm versus 15.8 ± 1.3, p < 0.0001). CONCLUSION: An additional 11% dose reduction is achieved with the WV mode in ULD chest CT with fixed tube current, with equivalent image quality and diagnostic performance when compared with the helical acquisition. KEY POINTS: • Image quality and diagnostic performance of ultra-low-dose unenhanced chest CT are identical between wide-volume mode and the reference helical acquisition. • Wide-volume mode allows an additional radiation dose reduction of 11% (mean dose-length product 14.1 ± 1.3 mGy cm versus 15.8 ± 1.3, p < 0.0001).

Prospective Trial on Probe-Based Confocal Laser Endomicroscopy for the Identification of the Distal Limit in Rectal Adenocarcinoma.

BACKGROUND: Intraoperative decision of the level of distal resection in rectal cancer is often imprecise, based exclusively on digital examination and pretherapeutic imaging. DESIGN: Prospective, single institution, nonrandomized trial ( ClinicalTrial.gov identification no. NCT01887509) to evaluate the contribution of probe-based confocal laser endomicroscopy (pCLE) to establish the optimal resection margin of rectal adenocarcinoma. The primary outcome was the concordance in the identification of lower tumor margins between pCLE and histopathology. For each patient, pCLE examination was performed on nonneoplastic and neoplastic aspects of the distal tumor margin, before and after neoadjuvant chemoradiation, or preceding surgery, if chemoradiation was not required. Biopsies were taken at the same locations. The intraclass correlation coefficient was determined. RESULTS: Twenty-one patients were enrolled. Thirteen patients completed the full study. Six patients completed imaging only before chemoradiation. Two patients retracted their consent after inclusion. A total of 134 videos and corresponding histopathology samplings were analyzed. The sensitivity and specificity of in vivo pCLE interpretation were 0.915 (95% confidence interval [CI] = 0.840-0.970) and 0.736 (95% CI = 0.657-0.821), respectively. The sensitivity and specificity of the blinded pCLE reinterpretation were 0.930 (95% CI = 0.858-0.980) and 0.688 (95% CI = 0.600-0.770), respectively. No deep layer tumor infiltration was encountered in the samplings with superficial healthy layers. The intraclass correlation coefficient for in vivo pCLE interpretation and blinded pCLE reinterpretation were 0.747 (95% CI = 0.257-0.993) and 0.766 (95% CI = 0.280-0.995), respectively. CONCLUSIONS: This supports the concordance between pCLE and histopathology in identifying the "tumor-free" limit of a rectal tumor preceding resection.

Upper and lower gastrointestinal endoscopies in patients over 85 years of age: Risk-benefit evaluation of a longitudinal cohort.

After age 85, upper and lower gastrointestinal (GI) endoscopy may be indicated in 5% to 10% of inpatients, but the risk-benefit ratio is unknown. We studied patients older than 85 years undergoing upper and lower GI endoscopy.We analyzed a retrospective cohort of inpatients older than 85 years between 2004 and 2012, all explored by upper and complete lower GI endoscopy. Initial indications, including iron deficiency anemia (IDA), other anemias, GI bleeding, weight loss, and GI symptoms, were noted, as were endoscopy or anesthesia complications, immediate endoscopic diagnosis, and the ability to modify the patients' therapeutics. Deaths and final diagnosis for initial endoscopic indication were analyzed after at least 12 months.We included 55 patients, 78% women, with a median age, reticulocyte count, hemoglobin, and ferritin levels of 87 (85-99), 56 (24-214) g/L, 8.6 (4.8-12.9) g/dL, and 56 (3-799) µg/L, respectively. IDA was the most frequent indication for endoscopy (60%; n = 33). Immediate diagnoses were found in 64% of the patients (n = 35), including 25% with GI cancers (n = 14) and 22% with gastroduodenal ulcers or erosions (n = 12). Cancer diagnosis was associated with lower reticulocyte count (45 vs. 60 G/L; P = .02). Among the 35 diagnoses, 94% (n = 33) led to modifications of the patients' therapeutics, with 29% of the patients deciding on palliative care (n = 10). No endoscopic complications lead to death. Follow-up of >12 months was available in 82% (n = 45) of the patients; among these patients, 40% (n = 27) died after an average 24 ±â€Š18 months. Cancer diagnosis was significantly associated with less ulterior red cell transfusion (0% vs. 28%; P = .02) and fewer further investigations (6.7% vs. 40%; P = .02).Upper and complete lower GI endoscopy in patients older than 85 years appears to be safe, and enables a high rate of immediate diagnosis, with significant modifications of therapeutics. GI cancers represented more than one-third of the endoscopic diagnoses.

Low Accuracy of Computed Tomography and Positron Emission Tomography to Detect Lung and Lymph Node Metastases of Colorectal Cancer.

BACKGROUND: Minimally invasive surgery, stereotactic radiotherapy, and radiofrequency ablation are commonly proposed in the case of pulmonary colorectal-metastasis as alternatives to conventional open surgery. Preoperative imaging assessment by computed tomography (CT) scan and fluorodeoxyglucose positron emission tomography (FDG-PET) are critical to guide oncologic radical treatment. Our aim was to investigate the accuracy of CT and FDG-PET for the evaluation of the number of pulmonary colorectal metastases and thoracic lymph nodal involvement (LNI). METHODS: Patients who underwent lung surgical resection for pulmonary colorectal metastases from 2004 to 2014 were analyzed. Concordance between histology, CT scan, and FDG-PET findings were assessed. RESULTS: Data of 521 patients were analyzed. Of those, FDG-PET was performed in 435 (83.5%). A moderate agreement between both CT scan (kappa index: 0.42) and FDG-PET (kappa index: 0.42) findings and the histologically proven number of metastases was observed. The number of histologically proven metastases was correctly discriminated in 61.7% of cases with CT scan and in 61.8% of cases with FDG-PET. Multiple metastases were discovered in 20.9% of clinical single metastasis cases with CT scan, and in 24.4% of those cases with FDG-PET. One hundred fifty patients (29.1%) presented with pathologic LNI. A poor agreement was observed between LNI and CT scan findings (kappa index: 0.02), and a weak agreement was observed concerning LNI and FDG-PET findings (kappa index: 0.39). CONCLUSIONS: Computed tomography and FDG-PET have limitations if the objective is to detect all malignant nodules and to discriminate the LNI in cases of pulmonary metastases of colorectal cancer.

Open versus percutaneous instrumentation in thoracolumbar fractures: magnetic resonance imaging comparison of paravertebral muscles after implant removal.

OBJECTIVE Percutaneous instrumentation in thoracolumbar fractures is intended to decrease paravertebral muscle damage by avoiding dissection. The aim of this study was to compare muscles at instrumented levels in patients who were treated by open or percutaneous surgery. METHODS Twenty-seven patients underwent open instrumentation, and 65 were treated percutaneously. A standardized MRI protocol using axial T1-weighted sequences was performed at a minimum 1-year follow-up after implant removal. Two independent observers measured cross-sectional areas (CSAs, in cm2) and region of interest (ROI) signal intensity (in pixels) of paravertebral muscles by using OsiriX at the fracture level, and at cranial and caudal instrumented pedicle levels. An interobserver comparison was made using the Bland-Altman method. Reference ROI muscle was assessed in the psoas and ROI fat subcutaneously. The ratio ROI-CSA/ROI-fat was compared for patients treated with open versus percutaneous procedures by using a linear mixed model. A linear regression analyzed additional factors: age, sex, body mass index (BMI), Pfirrmann grade of adjacent discs, and duration of instrumentation in situ. RESULTS The interobserver agreement was good for all CSAs. The average CSA for the entire spine was 15.7 cm2 in the open surgery group and 18.5 cm2 in the percutaneous group (p = 0.0234). The average ROI-fat and ROI-muscle signal intensities were comparable: 497.1 versus 483.9 pixels for ROI-fat and 120.4 versus 111.7 pixels for ROI-muscle in open versus percutaneous groups. The ROI-CSA varied between 154 and 226 for open, and between 154 and 195 for percutaneous procedures, depending on instrumented levels. A significant difference of the ROI-CSA/ROI-fat ratio (0.4 vs 0.3) was present at fracture levels T12-L1 (p = 0.0329) and at adjacent cranial (p = 0.0139) and caudal (p = 0.0100) instrumented levels. Differences were not significant at thoracic levels. When adjusting based on age, BMI, and Pfirrmann grade, a significant difference between open and percutaneous procedures regarding the ROI-CSA/ROI-fat ratio was present in the lumbar spine (p < 0.01). Sex and duration of instrumentation had no significant influence. CONCLUSIONS Percutaneous instrumentation decreased muscle atrophy compared with open surgery. The MRI signal differences for T-12 and L-1 fractures indicated less fat infiltration within CSAs in patients who received percutaneous treatment. Differences were not evidenced at thoracic levels, where CSAs were smaller. Fat infiltration was not significantly different at lumbar levels with either procedure in elderly patients with associated discopathy and higher BMI. In younger patients, there was less fat infiltration of lumbar paravertebral muscles with percutaneous procedures.

Epidermal growth factor receptor mutations are linked to skip N2 lymph node metastasis in resected non-small-cell lung cancer adenocarcinomas.

Objectives: The impact of skip N2 metastases (i.e. N2 lymph node metastases without N1) on survival in surgically resected non-small lung cancer remains an intriguing and rarely investigated topic. The goal of our study was to elucidate (i) skip N2 influence on overall survival (OS) and time to recurrence (TTR) in patients with resected lung adenocarcinoma and (ii) its link with epidermal growth factor receptor ( EGFR ) and v-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog ( KRAS ) mutations. Methods: A retrospective analysis of 279 consecutive patients with lung pN2 adenocarcinoma, operated in two institutions between 2003 and 2013, was conducted. OS and TTR were calculated using the Kaplan-Meier method. Crude and multivariable-adjusted comparisons by skip N2 for OS and TTR were performed using the Cox method with shared frailty (accounting for the within-centre correlation). Associations between skip N2 metastasis, clinicopathological characteristics and EGFR and KRAS mutations were investigated using the Fisher exact test and Cramér's V -test. Results: The mean age at the time of surgery was 63 years (±12), and the median follow-up time was 36 months (min 3; max 101). Skip N2 was observed in 54 patients (19%). EGFR mutations were observed in 38 patients (14%); KRAS mutations were seen in 86 patients (31%). Patients with skip N2 metastasis were predominantly non-smokers ( P = 0.001), underwent segmentectomy or limited resections ( P = 0.004) and were not submitted to adjuvant therapy ( P = 0.022). Moreover, there was a correlation between EGFR mutations and skip N2 (Cramér's V : 0.25, P < 0.001). Indeed, EGFR mutations were significantly more frequent in skip N2 tumours (33%) compared with non-skip tumours (10%), P < 0.001. No correlation between skip N2 and KRAS mutations was observed (Cramér's V : 0.05, P = 0.46). The multivariable-adjusted model showed a significant skip N2 protective effect on OS (hazard ratio, HR 0.503; P = 0.014; 95% confidence interval, CI: 0.291-0.8704) but not on TTR (HR 0.788; P = 0.446; 95% CI: 0.427-1.454). Conclusions: In our series, lung adenocarcinoma skip N2 metastasis demonstrated a favourable prognosis. The presence of EGFR mutations could have significance in the better survival and in the specific anatomic pathway of lymphatic metastases exhibited by skip N2 tumours.

Extracorporeal Membrane Oxygenation for Acute Respiratory Distress Syndrome After Pneumonectomy.

BACKGROUND: Postpneumonectomy acute respiratory distress syndrome (ppARDS) is a life-threatening condition with a disastrous prognosis. This study assessed the efficacy of venovenous extracorporeal membrane oxygenation (VV-ECMO) in adult patients with unresponsive severe ppARDS. METHODS: We retrospectively reviewed data of all patients treated with VV-ECMO for ppARDS from January 2009 to December 2015. We calculated the Sequential Organ Failure Assessment score before ECMO insertion and monitored the subsequent mechanical ventilation settings. The primary end point was hospital survival. The secondary end point was the ability to achieve a protective ventilatory strategy allowing lung recovery on ECMO. RESULTS: VV-ECMO was indicated in 8 ppARDS patients for refractory hypoxemia (median partial pressure of arterial oxygen/fraction of inspired oxygen: 68 [range, 60 to 75] mm Hg). Median Sequential Organ Failure Assessment before ECMO was 15 (range, 12 to 17), predicting a mortality rate greater than 80%. Median duration of ECMO was 9.5 (range, 5 to 16) days. Tidal volumes and plateau pressures both decreased on ECMO (pre-ECMO tidal volume: 412 [range, 250 to 450 mL] vs ECMO tidal volume: 277 [range, 105 to 367 mL], p = 0.0156; pre-ECMO plateau pressure: 34 [range, 32 to 40] cm H2O vs ECMO plateau pressure: 24.5 [range, 23.3 to 27.3] cm H2O, p = 0.0195). ECMO could be weaned in 7 patients (87.5%). Hospital survival was 50%. CONCLUSIONS: Hospital survival was better than predicted before ECMO insertion. In severe and refractory ppARDS, VV-ECMO allows lung recovery and therefore increased survival.

Perioperative bevacizumab improves survival following lung metastasectomy for colorectal cancer in patients harbouring v-Ki-ras2 Kirsten rat sarcoma viral oncogene homologue exon 2 codon 12 mutations†.

OBJECTIVES: The role of perioperative chemotherapy (POC) and targeted therapies in lung metastasectomy for colorectal cancer (CRC) is still subject to debate. We aimed to evaluate whether POC and targeted therapies were associated with different outcomes according to the mutational status. METHODS: We reviewed data from 223 patients who underwent pulmonary metastasectomy for CRC from 1998 to 2015 and for whom the V-Ki-ras2 Kirsten sarcoma viral oncogene homologue (KRAS) and V-raf Murine sarcoma viral oncogene homologue B1 (BRAF) mutational statuses were known. RESULTS: A total of 167 patients (74%) underwent POC: 62 (37%) received neoadjuvant therapy, 59 (35%) were in the adjuvant setting and 46 (28%) were in both the neoadjuvant and adjuvant settings. POC did not significantly influence either the loco-regional recurrence free survival (LRRFS) (P = 0.21) or the overall survival (OS) (P = 0.29). Furthermore, in cases of adjuvant chemotherapy, outcomes were not significantly different in cases of neoadjuvant chemotherapy or both neoadjuvant and adjuvant treatment (P = 0.26 for OS, P = 0.14 for LRRFS). For patients with KRAS mutation, perioperative bevacizumab was associated with a significant improvement in both LRRFS [70 months (41.58­98.42) vs 24 months (1.15­46.86), P = 0.001] and OS [101 vs 55 months (49.77­60.23), P = 0.004]. However, this benefit was only significant in cases of KRAS exon 2 codon 12 mutations [median OS: 101 months (83.97­118.02) vs 60 months (53­66.99), P < 0.001; median LRRFS: 76 months (64.62­87.38) vs 44 months (35.27­52.73), P < 0.001]. CONCLUSION: Perioperative bevacizumab appears to be beneficial in patients with exon 2 codon 12 KRAS mutations who have undergone lung metastasectomy for CRC.

Zenith Bifurcated Iliac Side Branch Device: Mid-term Results and Assessment of Risk Factors for Intraoperative Thrombosis.

BACKGROUND: The aim of this study is to evaluate the short- and mid-term results of the Zenith bifurcated iliac side branch device (ZBIS) in the treatment of common iliac artery (CIA) aneurysms, and to assess risk factors for intraoperative internal iliac artery (IIA) thrombosis. METHODS: All patients who underwent endovascular treatment of either an isolated CIA aneurysm or an aortoiliac aneurysm using the ZBIS device in the departments of vascular surgery of Strasbourg (France) and Lausanne (Switzerland) between January 2010 and December 2014 were retrospectively collected. RESULTS: Thirty-one implantations were performed: 30 patients underwent 31 endovascular CIA aneurysm treatments with the ZBIS device. Mean operative time was 188 min. Technical success was obtained in 26 implantations (84%). In 5 implantations (16%), the final angiogram revealed an IIA thrombosis. Thirty-day mortality was 3.2%. Thirty-day morbidity was 13.3%. Mean follow-up was 15 months. Overall survival was 96% at 1 year and 89% at 2 years. In intention-to-treat analysis, primary patency of the internal iliac side branch was 84% at 1 year and 76% at 2 years (5 peroperative IIA occlusions and 1 late occlusion). Freedom from reintervention was 89% at 1 and 2 years. One case of type III endoleak and 2 cases of type II endoleaks were identified. Only type III endoleak required an additional intervention with a covered stent. Aneurysm diameter decreased in 15 implantations (48%) and remained stable in 16 implantations (52%). Clinical, radiological, and peroperative parameters were analyzed to identify risk factor for intraoperative thrombosis of the internal iliac side branch. Notion of intraoperative difficulties (any additional procedure that was not initially planned and increasing the operating time) appeared as a risk factor in multivariate analysis (P < 0.01, standard deviation 1.27, odds ratio 30.6). CONCLUSIONS: The main findings of our study is that the procedure can be difficult to perform in particular conditions and can lead to peroperative failure in these cases, highlighting the need for adequate patients screening. When technical success is obtained, outcomes can be considered as satisfactory.

Increased Extravascular Lung Water and Plasma Biomarkers of Acute Lung Injury Precede Oxygenation Impairment in Primary Graft Dysfunction After Lung Transplantation.

BACKGROUND: After lung transplantation (LT), early prediction of grade 3 pulmonary graft dysfunction (PGD) remains a research gap for clinicians. We hypothesized that it could be improved using extravascular lung water (EVLWi) and plasma biomarkers of acute lung injury. METHODS: After institutional review board approval and informed consent, consecutive LT recipients were included. Transpulmonary thermodilution-based EVLWi, plasma concentrations of epithelial (soluble receptor for advanced glycation endproducts [sRAGE]) and endothelial biomarkers (soluble intercellular adhesion molecule-1 and endocan [full-length and cleaved p14 fragment]) were obtained before and after LT (0 [H0], 6, 12, 24, 48 and 72 hours after pulmonary artery unclamping). Grade 3 PGD was defined according to the International Society for Lung and Heart Transplantation definition, combining arterial oxygen partial pressure (PaO2)/inspired fraction of oxygen (FiO2) ratio and chest X-rays. Association of clinical risk factors, EVLWi and biomarkers with grade 3 PGD was analyzed under the Bayesian paradigm, using logistic model and areas under the receiver operating characteristic curves (AUCs). RESULTS: In 47 LT recipients, 10 developed grade 3 PGD, which was obvious at H6 in 8 cases. Clinical risk factors, soluble intercellular adhesion molecule-1 and endocan (both forms) were not associated with grade 3 PGD. Significant predictors of grade 3 PGD included (1) EVLWi (optimal cutoff, 13.7 mL/kg; AUC, 0.74; 95% confidence interval [CI], 0.48-0.99), (2) PaO2/FiO2 ratio (optimal cutoff, 236; AUC, 0.68; 95% CI, 0.52-0.84), and (3) sRAGE (optimal cutoff, 11 760 pg/mL; AUC, 0.66; 95% CI, 0.41-0.91) measured at H0. CONCLUSIONS: Immediate postreperfusion increases in EVLWi and sRAGE along with impaired PaO2/FiO2 ratios were early predictors of grade 3 PGD at or beyond 6 hours and may trigger early therapeutic interventions.

KRAS exon 2 codon 13 mutation is associated with a better prognosis than codon 12 mutation following lung metastasectomy in colorectal cancer.

INTRODUCTION: The utilization of molecular markers as routinely used biomarkers is steadily increasing. We aimed to evaluate the potential different prognostic values of KRAS exon 2 codons 12 and 13 after lung metastasectomy in colorectal cancer (CRC). RESULTS: KRAS codon 12 mutations were observed in 116 patients (77%), whereas codon 13 mutations were observed in 34 patients (23%). KRAS codon 13 mutations were associated with both longer time to pulmonary recurrence (TTPR) (median TTPR: 78 months (95% CI: 50.61-82.56) vs 56 months (95% CI: 68.71-127.51), P = 0.008) and improved overall survival (OS) (median OS: 82 months vs 54 months (95% CI: 48.93-59.07), P = 0.009). Multivariate analysis confirmed that codon 13 mutations were associated with better outcomes (TTPR: HR: 0.40 (95% CI: 0.17-0.93), P = 0.033); OS: HR: 0.39 (95% CI: 0.14-1.07), P = 0.07). Otherwise, no significant difference in OS (P = 0.78) or TTPR (P = 0.72) based on the type of amino-acid substitutions was observed among KRAS codon 12 mutations. MATERIALS AND METHODS: We retrospectively reviewed data from 525 patients who underwent a lung metastasectomy for CRC in two departments of thoracic surgery from 1998 to 2015 and focused on 150 patients that had KRAS exon 2 codon 12/13 mutations. CONCLUSIONS: KRAS exon 2 codon 13 mutations, compared to codon 12 mutations, seem to be associated with better outcomes following lung metastasectomy in CRC. Prospective multicenter studies are necessary to fully understand the prognostic value of KRAS mutations in the lung metastases of CRC.

Outcome of endoscopy-negative iron deficiency anemia in patients above 65: A longitudinal multicenter cohort.

After the age of 65 years, iron deficiency anemia (IDA) requires the elimination of digestive neoplasia and is explored with upper and lower gastrointestinal (GI) endoscopy. However, such explorations are negative in 14% to 37% of patients. To further evaluate this issue, we evaluated the outcomes of patients aged over 65 years with endoscopy-negative IDA.We retrospectively analyzed the outcomes of in-patients over the age of 65 years with IDA (hemoglobin <12 g/dL and ferritin <70 µg/L) who had negative complete upper and lower GI endoscopies in 7 tertiary medical hospitals. Death, the persistence of anemia, further investigations, and the final diagnosis for IDA were analyzed after at least 12 months by calling the patients' general practitioners and using hospital records.Between 2004 and 2011, 69 patients (74% women) with a median age of 78 (interquartile range (IQR) 75-82) years and hemoglobin and ferritin levels of 8.4 (IQR 6.8-9.9) g/dL and 14 (IQR 8-27) µg/L, respectively, had endoscopy-negative IDA, and 73% of these patients received daily antithrombotics. After a follow-up of 41 ±â€Š22 months, 23 (33%) of the patients were dead; 5 deaths were linked with the IDA, and 45 (65%) patients had persistent anemia, which was significantly associated with death (P = 0.007). Further investigations were performed in 45 patients; 64% of the second-look GI endoscopies led to significant changes in treatment compared with 25% for the capsule endoscopies. Conventional diagnoses of IDA were ultimately established for 19 (27%) patients and included 3 cancer patients. Among the 50 other patients, 40 (58%) had antithrombotics.In endoscopy-negative IDA over the age of 65 years, further investigations should be reserved for patients with persistent anemia, and second-look GI endoscopy should be favored. If the results of these investigations are negative, the role of antithrombotics should be considered.

Epidermal growth factor receptor and v-Ki-ras2 Kirsten rat sarcoma viral oncogen homologue-specific amino acid substitutions are associated with different histopathological prognostic factors in resected non-small-cell lung cancer.

OBJECTIVES: Epidermal growth factor receptor (mEGFR) and v-Ki-ras2 Kirsten rat sarcoma viral oncogen homologue (mKRAS) mutations are the two main oncogenic drivers in resected non-small-cell lung cancer (NSCLC). We aimed to evaluate the correlation between histopathological prognostic factors and these mutations in resected NSCLC. METHODS: We retrospectively reviewed data from 841 patients who underwent a surgical resection with a curative intent for NSCLC between 2007 and 2012. RESULTS: KRAS mutations were observed in 255 patients (32%) and mEGFR in 103 patients (12%). A correlation was observed between mKRAS patients and lymph node involvement [Cramer's V: 0.451, P < 0.001, OR: 7.5 (95% CI: 5.3-10.7), P < 0.001]. Otherwise, a correlation was observed between mKRAS and the risk of harbouring 2 N2 stations [Cramer's V: 0.235, P = 0.02, OR: 3.04 (95% CI: 1.5-6.3), P = 0.004]. High lymph node ratio and angioinvasion were also significantly more frequent in mKRAS [Cramer's V: 0.373, P < 0.001, OR: 6.37 (95% CI: 3.9-10.5), P < 0.001; and Cramer's V: 0.269, P < 0.001, OR: 3.25 (95% CI: 2.4-4.4), P < 0.001, respectively]. Skip N2 and microscopic N2 were significantly more frequent in mEGFR [Cramer's V: 0.459, P < 0.001, OR: 18 (95% CI: 5.6-57.8), P < 0.001; and (Cramer's V: 0.45, P < 0.001 OR: 21.14 (95% CI: 9.2-48.3), P < 0.001, respectively]. CONCLUSIONS: We observed a correlation between mKRAS and negative histopathological prognostic factors and between mEGFR and positive prognostic factors. One can wonder whether histopathological prognostic factors are only clinical reflections of molecular alterations.

Specific KRAS amino acid substitutions and EGFR mutations predict site-specific recurrence and metastasis following non-small-cell lung cancer surgery.

BACKGROUND: We aimed to evaluate whether EGFR mutations (mEGFR) and KRAS amino acid substitutions can predict first site of recurrence or metastasis after non-small-cell lung cancer (NSCLC) surgery. METHODS: Data were reviewed from 481 patients who underwent thoracic surgery for NSCLC between 2007 and 2012. RESULTS: Patients with KRAS G12C developed significantly more bone metastases compared with the remainder of the cohort (59% vs 16%, P<0.0001). This was confirmed in multivariate analysis (MA) (odds ratio (OR): 0.113 (95% confidence interval (CI): 0.055-0.231), P<0.0001). Significantly, more patients with mEGFR developed liver and brain metastases compared with the remainder of the cohort (30% vs 10%, P=0.006; 59% vs 1%, P<0.0001, respectively). These were confirmed in MA (OR: 0.333 (95% CI: 0.095-0.998), P=0.05; OR: 0.032 (95% CI: 0.008-0.135), P<0.0001, respectively). Patients with KRAS G12V developed significantly more pleuro-pericardial metastases compared with the remainder of the cohort (94% vs 12%, P<0.0001). This was confirmed in MA (OR: 0.007 (95% CI: 0.001-0.031), P<0.0001). Wild-type patients developed significantly more lung metastases (35% vs 10%, P<0.0001). This was confirmed in MA (OR: 0.383 (95% CI: 0.193-0.762), P=0.006). CONCLUSION: Epidermal growth factor receptor mutation and KRAS amino acid substitutions seem to predict site-specific recurrence and metastasis after NSCLC surgery.

Impact of EGFR mutations and KRAS amino acid substitution on the response to radiotherapy for brain metastasis of non-small-cell lung cancer.

BACKGROUND: Our study aimed to evaluate response rate (RR) to brain metastasis radiotherapy (RT), depending on the genomic status of non-small-cell lung cancer. MATERIAL & METHODS: We retrospectively reviewed 1971 non-small-cell lung cancer files of patients with EGFR and KRAS testing and focused on 157 patients who had undergone RT for brain metastasis. RESULTS: A total of 16 patients (10.2%) harbored EGFR mutations (mEGFR) and 45 patients (28.7%) KRAS (mKRAS). In univariate analysis, RR was significantly higher for mEGFR compared with wild-type EGFR/KRAS (odds ratio [OR]: 4.96; p = 0.05) or mKRAS (OR: 1.81; p = 0.03). In multivariate analysis, KRAS G12V or G12C status was associated with both poor RR (OR: 0.1; p < 0.0001) and overall survival (OR: 3.41; p < 0.0001). CONCLUSION: mEGFR are associated with higher RR to brain RT than wild-type EGFR/RAS or mKRAS.

Prognostic value of the KRAS G12V mutation in 841 surgically resected Caucasian lung adenocarcinoma cases.

BACKGROUND: Identifying patients who will experience lung cancer recurrence after surgery remains a challenge. We aimed to evaluate whether mutant forms of epidermal growth factor receptor (EGFR) and Kirsten rat sarcoma viral oncogene homolog (KRAS) (mEGFR and mKRAS) are useful biomarkers in resected non-small cell lung cancer (NSCLC). METHODS: We retrospectively reviewed data from 841 patients who underwent surgery and molecular testing for NSCLC between 2007 and 2012. RESULTS: mEGFR was observed in 103 patients (12.2%), and mKRAS in 265 (31.5%). The median overall survival (OS) and time to recurrence (TTR) were significantly lower for mKRAS (OS: 43 months; TTR: 19 months) compared with mEGFR (OS: 67 months; TTR: 24 months) and wild-type patients (OS: 55 months; disease-free survival (DFS): 24 months). Patients with KRAS G12V exhibited worse OS and TTR compared with the entire cohort (OS: KRAS G12V: 26 months vs COHORT: 60 months; DFS: KRAS G12V: 15 months vs COHORT: 24 months). These results were confirmed using multivariate analyses (non-G12V status, hazard ratio (HR): 0.43 (confidence interval: 0.28-0.65), P<0.0001 for OS; HR: 0.67 (0.48-0.92), P=0.01 for TTR). Risk of recurrence was significantly lower for non-KRAS G12V (HR: 0.01, (0.001-0.08), P<0.0001). CONCLUSIONS: mKRAS and mEGFR may predict survival and recurrence in early stages of NSCLC. Patients with KRAS G12V exhibited worse OS and higher recurrence incidences.

The intrathoracic lymph node ratio seems to be a better prognostic factor than the level of lymph node involvement in lung metastasectomy of colorectal carcinoma.

OBJECTIVES: Data on thoracic lymph node involvement (LNI) in lung metastasis of colorectal cancer (CRC) are conflicting, with a 5-year overall survival (OS) ranging from 6 to 40%. We aimed to evaluate whether there are subgroups of patients according to the lymph node ratio (LNR). METHODS: We retrospectively reviewed the data from 106 patients who underwent a thoracic procedure for CRC lung metastasis with pathologically proven thoracic LNI. RESULTS: In the univariate analysis, the median OS was significantly poorer for a pN2 location of LNI (26 vs 16 months, P = 0.04), LNR ≥50% (30 vs 17 months, P = 0.005), high preoperative CEA (32 vs 16 months, P = 0.02), hepatic metastases (27 vs 11 months, P <0.0001) and disease-free survival < 24 months (32 vs 17 months, P = 0.05). When pN1 and pN2 patients were staged according to the LNR, the median OS was significantly better for an LNR <50% (27 vs 17 months for pN1, 32 vs 12 months for pN2, P = 0.01). In the multivariate analysis, a high preoperative CEA [hazard ratio (HR): 2.256 (1.051-4.841), P = 0.04], pN1 status [HR: 0.337 (0.162-0.7), P = 0.004] and the absence of hepatic metastases [HR: 0.395 (0.180-0.687), P = 0.02] remained significant prognostic factors. There was an upward trend for patients with LNR <50% [HR: 0.565 (0.296-1.082), P = 0.08]. Otherwise, low LNR was significantly associated with a decreased risk of loco-regional recurrence (HR: 0.36, 95% confidence intervals: 0.14-0.96, P = 0.04). CONCLUSIONS: The LNR seems to be a more reliable prognostic factor than LNI for CRC lung metastasis. Prospective studies are necessary.

The prothrombotic paradox of severe obesity after cardiac surgery under cardiopulmonary bypass.

BACKGROUND: Obesity is suggested to reduce postoperative bleeding in patients undergoing cardiac surgery with cardiopulmonary bypass (CPB) but perioperative hemostasis variations have not been studied. Therefore, we investigated the effects of severe obesity (body mass index [BMI] ≥35kg/m(2)) on chest tube output (CTO) and hemostasis in patients undergoing cardiac surgery with CPB. MATERIALS AND METHODS: We prospectively investigated 2799 consecutive patients who underwent coronary and/or valve surgery using CPB between 2008 and 2012. 204 patients (7.3%) presented a severe obesity. RESULTS: In the severe obesity group, the 6-h and 24-h CTO were significantly reduced by -21.8% and -14.8% respectively (P<0.0001) compared with the control group. A significant reduction of the mean number of red blood cell units transfused at 24h was observed in the severe obesity groups (P=0.01). On admission to the intensive care unit, a significant increase of platelet count (+9.2%; P<0.0001), fibrinogen level (+12.2%; P<0.0001) and prothrombin time (+4.1%; P<0.01) and a significant decrease of the activated partial thromboplastin time (-4.2%; P<0.01) were observed in the severe obesity group compared with the control group. In multivariate analysis, severe obesity was significantly associated to a decreased risk of excessive bleeding (24-h CTO >90th percentile; Odds ratio: 0.37, 95% CI: 0.17 to 0.82). No significant differences were observed regarding postoperative thromboembolic events between the two groups. CONCLUSIONS: Severe obesity is associated with a prothrombotic postoperative state that leads to a reduction of postoperative blood loss in patients undergoing cardiac surgery with CPB.

Plasma fibrinogen level on admission to the intensive care unit is a powerful predictor of postoperative bleeding after cardiac surgery with cardiopulmonary bypass.

INTRODUCTION: Evidence regarding the behavior of fibrinogen levels and the relation between fibrinogen levels and postoperative bleeding is limited in cardiac surgery under cardiopulmonary bypass (CPB). To evaluate perioperative fibrinogen levels as a predictor of postoperative bleeding in patients undergoing cardiac surgery with CPB. MATERIALS AND METHODS: In this prospective, single-center, observational cohort study of 1956 patients following cardiac surgery with CPB, fibrinogen level was measured perioperatively. Excessive bleeding group was defined as patients with a 24-h chest tube output (CTO) exceeded the 90th percentile of distribution. RESULTS: The median 24-h CTO was 728.6±431.1ml. A total of 189 patients (9.7%) were identified as having excessive bleeding. At admission to the intensive care (Day 0), the fibrinogen levels were 2.5±0.8g/l and 2.1±0.8g/l in the control and excessive bleeding groups, respectively (P<0.0001). The fibrinogen level on Day 0 was significantly correlated with the 24-h CTO (rho=-0.237; P<0.0001). Multivariate analysis demonstrated that the fibrinogen level at Day 0 was the best perioperative standard laboratory test to predict excessive bleeding (P=0.0001; odds ratio, 0.5), whereas preoperative fibrinogen level was not a predictor. Using receiver operating characteristics curve analyses, the best Day 0 fibrinogen level cutoff to predict postoperative bleeding was 2.2g/l. CONCLUSIONS: In this large prospective study, the fibrinogen level upon admission to the intensive care unit after CPB predicted the risk of postoperative bleeding. Our data add to the concern regarding the fibrinogen level threshold that might require fibrinogen concentrate infusion to reduce postoperative blood loss.