Pierre Mordant

Emergency circulatory support in refractory cardiogenic shock patients in remote institutions: a pilot study (the cardiac-RESCUE program)

AIMS Temporary circulatory support with extracorporeal membrane oxygenation (ECMO) is often the only alternative for supporting patients with refractory cardiogenic shock (RCS). In practice, this strategy is limited to a small minority of patients hospitalized in tertiary-care centres with ECMO programs. The cardiac-RESCUE program was designed to test the feasibility of providing circulatory support distant from specialized ECMO centres, for RCS patients in remote locations. METHODS AND RESULTS From January 2005 to December 2009, hospitals without ECMO facilities throughout the Greater Paris area were invited to participate. One hundred and four RCS cases were assessed and 87 consecutively eligible patients (mean age 46 ± 15 years, 41% following cardiac arrest) had ECMO support instituted locally and were enrolled into the program. Local initiation of ECMO support allowed successful transfer to the tertiary-care centre in 75 patients. Of these, 32 patients survived to hospital discharge [overall survival rate 36.8%, 95% confidence interval (CI) 27.4-46.2]. Independent predictors for in-hospital mortality included initiation of ECMO during cardiopulmonary resuscitation [hazard ratio (HR) = 4.81, 95% CI 2.25-10.30, P < 0.001] and oligo-anuria (HR = 2.48, 95% CI 1.29-4.76, P = 0.006). After adjusting for other confounding factors, in-hospital mortality was not statistically different from that of 123 consecutive patients who received ECMO at our institution during the same period (odds ratio 1.48, 95% CI 0.72-3.00, P = 0.29). CONCLUSION Offering local ECMO support appears feasible in a majority of RCS patients hospitalized in remote hospitals. In this otherwise lethal situation, our pilot experience suggests that over one-third of such patients can survive to hospital discharge.

Experience of extracorporeal membrane oxygenation as a bridge to lung transplantation in France

BACKGROUND Extracorporeal membrane oxygenation (ECMO) is increasingly used as a bridge to lung transplantation (LTx). However, data concerning this approach remain limited. METHODS We retrospectively reviewed the medical records of all patients in France who received ECMO as a bridge to LTx from 2007 to 2011. Post-transplant survival and associated factors were assessed by the Kaplan-Meier method and the Cox model. RESULTS Included were 36 patients from 11 centers. Indications for LTx were cystic fibrosis (CF) in 20 (56%), pulmonary fibrosis (PF) in 11 (30%), and other diagnoses in 5 (14%). ECMO was venovenous for 27 patients (75%) and venoarterial for 9 (25%). Mean follow-up was 17 months. Bridging to LTx was achieved in 30 patients (83%); however, only 27 patients (75%) survived the LTx procedure, and 20 (56%) were discharged from hospital. From ECMO initiation, 2-year survival rates were 50.4% overall, 71.0% for CF patients, 27.3% for PF patients, and 20.0% for other patients (p < 0.001). From LTx, 2-year survival rates were 60.5% overall, 71.0% for CF patients, 42.9% for PF patients, and 33.0% for other patients (p = 0.04). CONCLUSIONS Our study confirms that the use of ECMO as a bridge to LTx in France could provide a medium-term survival benefit for LTx recipients with critical conditions. Survival differed by underlying respiratory disease. Larger studies are needed to further define the optimal use of ECMO.

Dependence on Phosphoinositide 3-Kinase and RAS-RAF Pathways Drive the Activity of RAF265, a Novel RAF/VEGFR2 Inhibitor, and RAD001 (Everolimus) in Combination

Activation of phosphatidylinositol-3-kinase (PI3K)-AKT and Kirsten rat sarcoma viral oncogene homologue (KRAS) can induce cellular immortalization, proliferation, and resistance to anticancer therapeutics such as epidermal growth factor receptor inhibitors or chemotherapy. This study assessed the consequences of inhibiting these two pathways in tumor cells with activation of KRAS, PI3K-AKT, or both. We investigated whether the combination of a novel RAF/vascular endothelial growth factor receptor inhibitor, RAF265, with a mammalian target of rapamycin (mTOR) inhibitor, RAD001 (everolimus), could lead to enhanced antitumoral effects in vitro and in vivo. To address this question, we used cell lines with different status regarding KRAS, PIK3CA, and BRAF mutations, using immunoblotting to evaluate the inhibitors, and MTT and clonogenic assays for effects on cell viability and proliferation. Subcutaneous xenografts were used to assess the activity of the combination in vivo. RAD001 inhibited mTOR downstream signaling in all cell lines, whereas RAF265 inhibited RAF downstream signaling only in BRAF mutant cells. In vitro, addition of RAF265 to RAD001 led to decreased AKT, S6, and Eukaryotic translation initiation factor 4E binding protein 1 phosphorylation in HCT116 cells. In vitro and in vivo, RAD001 addition enhanced the antitumoral effect of RAF265 in HCT116 and H460 cells (both KRAS mut, PIK3CA mut); in contrast, the combination of RAF265 and RAD001 yielded no additional activity in A549 and MDAMB231 cells. The combination of RAF and mTOR inhibitors is effective for enhancing antitumoral effects in cells with deregulation of both RAS-RAF and PI3K, possibly through the cross-inhibition of 4E binding protein 1 and S6 protein. Mol Cancer Ther; 9(2); 358–68

Which metastasis management allows long-term survival of synchronous solitary M1b non-small cell lung cancer?

UNLABELLED OBJECTIVES; Patients with extrathoracic synchronous solitary metastasis and non-small cell lung cancer (NSCLC) are rare. The effectiveness of both tumour sites resection is difficult to evaluate because of the high variability among clinical studies. We reviewed our experience regarding the management and prognosis of these patients. METHODS The charts of 4668 patients who underwent lung cancer surgery from 1983 to 2006 were retrospectively reviewed. We analysed the epidemiology, treatment, pathology and prognostic characteristics of those with extrathoracic synchronous solitary metastasis amenable to lung cancer surgery on a curative intend. RESULTS There were 94 patients (sex ratio M/F 3.2/1, mean age 56 years). Surgery included pneumonectomy (n = 27), lobectomy (n = 65) and exploratory thoracotomy (n = 2). Pathology revealed adenocarcinomas (n = 57), squamous cell carcinoma (n = 20), large cell carcinoma (n = 14) and other NSCLC histology (n = 3). Lymphatic extension was N0 (n = 46), N1 (n = 17) and N2 (n = 31). Metastasis involved the brain (n = 57), adrenal gland (n = 12), bone (n = 14), liver (n = 5) and skin (n = 6). Sixty-nine metastases were resected. Five-year survival rate was 16% (median 13 months). Induction therapy, adenocarcinoma, N0 staging and lobectomy were criteria of better prognosis, but metastasis resection was not. CONCLUSIONS These results suggest that extrathoracic synchronous solitary metastasis of pN0 adenocarcinoma may achieve long-term survival in the case of lung resection with or without metastasis resection. This pattern may reflect a specific tumour biology whose solitary metastasis benefits both from surgical or non-surgical treatment.

Clinical review: Intrapericardial fibrinolysis in management of purulent pericarditis

Purulent pericarditis (PP) is a potentially life-threatening disease. Reported mortality rates are between 20 and 30%. Constrictive pericarditis occurs over the course of PP in at least 3.5% of cases. The frequency of persistent PP (chronic or recurrent purulent pericardial effusion occurring despite drainage and adequate antibiotherapy) is unknown because this entity was not previously classified as a complication of PP. No consensus exists on the optimal management of PP. Nevertheless, the cornerstone of PP management is complete eradication of the focus of infection. In retrospective studies, compared to simple drainage, systematic pericardiectomy provided a prevention of constrictive pericarditis with better clinical outcome. Because of potential morbidity associated with pericardiectomy, intrapericardial fibrinolysis has been proposed as a less invasive method for prevention of persistent PP and constrictive pericarditis. Experimental data demonstrate that fibrin formation, which occurs during the first week of the disease, is an essential step in the evolution to constrictive pericarditis and persistent PP. We reviewed the literature using the MEDLINE database. We evaluated the clinical efficacy, outcome, and complications of pericardial fibrinolysis. Seventy-four cases of fibrinolysis in PP were analysed. Pericarditis of tuberculous origin were excluded. Among the 40 included cases, only two treated by late fibrinolysis encountered failure requiring pericardiectomy. No patient encountered clinical or echocardiographic features of constriction during follow-up. Only one serious complication was described. Despite the lack of definitive evidence, potential benefits of fibrinolysis as a less invasive alternative to surgery in the management of PP seem promising. Early consideration should be given to fibrinolysis in order to prevent both constrictive and persistent PP. Nevertheless, in case of failure of fibrinolysis, pericardiectomy remains the primary option for complete eradication of infection.

Nutritional Status and Postoperative Outcome After Pneumonectomy for Lung Cancer

BACKGROUND The influence of nutritional status on outcome after major lung resection remains controversial. Nutritional assessment is not included as a major recommendation in lung cancer guidelines. The purpose of this study was to assess the nutritional status of patients referred for pneumonectomy and to assess the predictive value of malnutrition in determining the surgical outcome. METHODS This study was a multicenter observational trial. The eligibility criterion for participants was pneumonectomy for lung cancer. Criteria for group classification according to nutritional status were albumin and transthyretin levels. Predicted outcomes were major infectious and noninfectious complications and 90-day mortality. Univariate analysis identified independent variables for the predictive model of age, sex, induction chemotherapy, extended resections, treatment side, smoking, and malnutrition. Predictive variables were then included in a logistic regression model. RESULTS Between January 2010 and December 2011, 86 (mean age, 61.5 years) consecutive patients referred for pneumonectomy (left side, n = 58; right side, n = 28) at 4 thoracic surgery centers were included. The malnutrition group included 33 patients (39%) and the normal nutritional status group included 53 patients. Univariate analysis elected malnutrition, recent active smoking, and extended resection to be included in a multivariate analysis. Multivariate analysis identified malnutrition, recent smoking, and extended resection as predictive variables for major complications and mortality. CONCLUSIONS The frequency of malnutrition detected by biological markers was dramatically high. Malnutrition, as well as recent active smoking and extended resection, is a predictive factor for infectious complications and mortality after pneumonectomy. Nutritional assessment with appropriate markers should be considered before pneumonectomy.

Impella and extracorporeal membrane oxygenation: a demanding combination.

We report the case of a 34-year-old woman admitted in our institution for cardiogenic shock related to acute myocarditis. Initial hemodynamic instability required mechanical ventilation and peripheral venoarterial extracorporeal membrane oxygenation (ECMO). Secondary acute pulmonary edema after ECMO implantation required emergency left ventricular decompression with a percutaneous Impella Recover LP 5.0. After a short period of improvement, an unexpected technical problem led to the Impella Recover LP 5.0 arrest. The clinical situation quickly worsened, and the patient finally died. This case highlights the usefulness of Impella pump to unload left cardiac chambers but also its technical challenge when used in a patient on ECMO.

Bioluminescent orthotopic mouse models of human localized non-small cell lung cancer: feasibility and identification of circulating tumour cells.

Background Preclinical models of non-small cell lung cancer (NSCLC) require better clinical relevance to study disease mechanisms and innovative therapeutics. We sought to compare and refine bioluminescent orthotopic mouse models of human localized NSCLC. Methods Athymic nude mice underwent subcutaneous injection (group 1-SC, n = 15, control), percutaneous orthotopic injection (group 2-POI, n = 30), surgical orthotopic implantation of subcutaneously grown tumours (group 3-SOI, n = 25), or transpleural orthotopic injection (group 4-TOI, n = 30) of A549-luciferase cells. Bioluminescent in vivo imaging was then performed weekly. Circulating tumour cells (CTCs) were searched using Cellsearch® system in SC and TOI models. Results Group 2-POI was associated with unexpected direct pleural spreading of the cellular solution in 53% of the cases, forbidding further evaluation of any localized lung tumour. Group 3-SOI was characterized by high perioperative mortality, initially localized lung tumours, and local evolution. Group 4-TOI was associated with low perioperative mortality, initially localized lung tumours, loco regional extension, and distant metastasis. CTCs were detected in 83% of nude mice bearing subcutaneous or orthotopic NSCLC tumours. Conclusions Transpleural orthotopic injection of A549-luc cells in nude mouse lung induces localized tumour, followed by lymphatic extension and specific mortality, and allowed the first time identification of CTCs in a NSCLC mice model.

FGF9 and FGF18 in idiopathic pulmonary fibrosis promote survival and migration and inhibit myofibroblast differentiation of human lung fibroblasts in vitro

Idiopathic pulmonary fibrosis (IPF) is characterized by an accumulation of extracellular matrix proteins and fibroblasts in the distal airways. Key developmental lung signaling pathways are reactivated in IPF. For instance, fibroblast growth factor 9 (FGF9) and FGF18, involved in epithelial-mesenchymal interactions, are critical for lung development. We evaluated the expression of FGF9, FGF18, and FGF receptors (FGFRs) in lung tissue from controls and IPF patients and assessed their effect on proliferation, survival, migration, and differentiation of control and IPF human lung fibroblasts (HLFs). FGF9, FGF18, and all FGFRs were present in the remodeled alveolar epithelium close to the fibroblast foci in IPF lungs. FGFR3 was generally detected in fibroblast foci by immunohistochemistry. In vitro, HLFs mainly expressed mesenchyme-associated FGFR isoforms (FGFR1c and FGFR3c) and FGFR4. FGF9 did not affect fibroblast proliferation, whereas FGF18 inhibited cell growth in control fibroblasts. FGF9 and FGF18 decreased Fas-ligand-induced apoptosis in control but not in IPF fibroblasts. FGF9 prevented transforming growth factor β1-induced myofibroblast differentiation. FGF9 and FGF18 increased the migratory capacities of HLF, and FGF9 actively modulated matrix metalloproteinase activity. In addition, FGFR3 inhibition by small interfering RNA impacted p-ERK activation by FGF9 and FGF18 and their effects on differentiation and migration. These results identify FGF9 as an antiapoptotic and promigratory growth factor on HLF, maintaining fibroblasts in an undifferentiated state. The biological effects of FGF9 and FGF18 were partially driven by FGFR3. FGF18 was a less potent molecule. Both growth factors likely contribute to the fibrotic process in vivo.

Long-Term Survival of Patients With pN2 Lung Cancer According to the Pattern of Lymphatic Spread

BACKGROUND N2 involvement has dramatic consequences on the prognosis and management of patients with non-small cell lung cancer (NSCLC). N2-NSCLC may present with or without N1 involvement, constituting non-skip (pN1N2) and skip (pN0N2) diseases, respectively. As the prognostic impact of this subclassification is still a matter of debate, we analyzed the prognosis of pN2 patients according to the pN1-involvement and the number of N2-stations concerned. METHODS The medical records of consecutive patients who underwent surgery for pN2-NSCLC in 2 French centers between 1980 and 2009 were prospectively collected and retrospectively reviewed. Patients undergoing induction therapy, exploratory thoracotomy, incomplete mediastinal lymphadenectomy, or incomplete resections were excluded. The prognoses of pN1N2 and pN0N2 patients were first compared, and then deciphered according to the number of N2 stations involved (single-station: 1S, multi-station: 2S). RESULTS All together, 871 patients underwent first-line complete surgical resection for pN2-NSCLC during the study period, including 258 pN0N2 (29.6%) and 613 pN1N2 (70.4%) patients. Mean follow-up was 72.8±48 months. Median, 5- and 10-year survivals were, respectively, 30 months, 34%, and 24% for pN0N2 and 20 months, 21%, and 14% for pN1N2 patients (p<0.001). Multivariate analysis revealed 3 different prognostic groups; ie, favorable in pN0N2-1S disease, intermediate in pN0N2-2S and pN1N2-1S diseases, and poor in pN1N2-2S disease (p<0.001). CONCLUSIONS Among pN2 patients, the combination of N1 involvement (pN0N2 vs pN1N2) and number of involved N2 stations (1S vs 2S) are independent prognostic factors. These results might be taken into consideration to sub-classify the heterogeneous pN2-NSCLC group of patients.