Jérémie Reeb

Double lumen bi-cava cannula for veno-venous extracorporeal membrane oxygenation as bridge to lung transplantation in non-intubated patient

Extracorporeal membrane oxygenation (ECMO) is used for refractory respiratory failure. Normally, ECMO is implanted in intubated patients as a last resort. We report the case of a non-intubated patient who benefited from veno-venous (VV) ECMO. A 35-year old cystic fibrosis man presented a severe respiratory decompensation with refractory hypercapnia. We opted for an ECMO instead of mechanical ventilation (MV). We implanted a double lumen bi-cava cannula (DLC) (Avalon Elite(TM)) in the right jugular vein. Before ECMO implantation, the patient presented refractory respiratory failure (pH = 7.1, PaO(2) = 83 mmHg, PaCO(2 )= 103 mmHg). We proposed that the patient be placed on the high emergency lung transplantation waiting list after failure to wean him from ECMO. This registration was effective 10 days after ECMO implantation. The patient was grafted the next day. Under ECMO, mean PaO(2), PaCO(2) and TCA were 80.6 ± 14.2, 53.8 ± 6.4 mmHg and 56.2 ± 9.7 s, respectively. The patient could eat, drink, talk and practice chest physiotherapy. The evolution was uneventful under ECMO. Weaning from ECMO was done in the operating theatre after transplantation. VV ECMO with DLC is safe and feasible in non-intubated patients. It avoids potential complications of MV, and allows respiratory assistance as bridge to transplantation.

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.

Mediastinal downstaging after induction treatment is not a significant prognostic factor to select patients who would benefit from surgery: the clinical value of the lymph node ratio

OBJECTIVES Multimodal management of N2 non-small-cell lung cancer is still a matter of debate. In particular, the place of surgery for persistent N2 after induction treatment is controversial and surgery is usually reserved for patients experiencing a mediastinal downstaging (pN1 and pN0). We aimed to evaluate whether there might exist subgroups of pN2 according to the lymph node ratio (LNR). METHODS Between 1996 and 2012, we retrospectively reviewed the data from 152 potentially resectable cN2 patients who underwent an induction treatment before surgery. RESULTS The median follow-up time was 32 months (2-112). The average age at the time of diagnosis was 58.52 ± 10.47 years. In univariate analysis, overall survival (OS) was significantly influenced by extracapsular spread (32 ± 5.33 vs 24 ± 12.73 months, P = 0.01), pN after surgery (65 ± 2.45 months for pN0, 44 ± 2.14 months for pN1 and 19 ± 1.72 months for pN2, P <0.0001) and LNR ≥ 1/3 (30 ± 3.77 months vs 16 ± 1.39 months, P <0.0001). When pN0 and pN1 patients were staged according to the LNR, the OS was divided by two for pN1 patients with an LNR ≥ 1/3 (48 ± 2.64 months vs 26 ± 5.65 months, P <0.001), whereas it decreased from 26 ± 0.87 to 15 ± 1.85 months (P <0.0001) for pN2 patients. OS was significantly better with adjuvant radio-chemotherapy than with chemotherapy or radiation therapy alone (P <0.0001). In multivariate analysis, mediastinal downstaging {Hazard Ratio (HR): 0.184 (95% confidence interval (CI): 0.084-0.403), P <0.0001} and LNR [HR: 0.359 (95% CI: 0.194-0.665], P = 0.001) remained significantly independent prognostic factors. CONCLUSIONS The LNR may potentially identify subgroups of pN+ patients and allow enhancement of adjuvant treatments. Because pN2 with a low LNR had an equivalent survival to pN1 with a high LNR, mediastinal downstaging does not seem to be a sufficient prognostic factor to exclude patients after induction treatment from surgery.

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.

Vascular access for extracorporeal life support: tips and tricks

In thoracic surgery, extracorporeal life support (ECLS) techniques are performed to (I) provide a short to mid term extracorporeal mechanical support; (II) realize the gas exchanges; and (III)-depending the configuration of the circuit-substitute the failed heart function. The objective of this review is to describe the rational of the different ECLS techniques used in thoracic surgery and lung transplantation (LTx) with a specific attention to the vascular access. Venovenous extracorporeal membrane oxygenation (VV ECMO) is the most common ECLS technique used in thoracic surgery and represents the best strategy to support the lung function. VV ECMO needs peripheral vascular access. The selection between his double-site or single-site configuration should be decided according the level of O2 requirements, the nosological context, and the interest to perform an ECLS ambulatory strategy. Venoarterial (VA) ECMO uses peripheral and/or central cannulation sites. Central VA ECMO is mainly used in LTx instead a conventional cardiopulmonary bypass (CPB) to decrease the risk of hemorrhagic issues and the rate of primary graft dysfunction (PGD). Peripheral VA ECMO is traditionally realized in a femoro-femoral configuration. Femoro-femoral VA ECMO allows a cardiocirculatory support but does not provide an appropriate oxygenation of the brain and the heart. The isolated hypercapnic failure is currently supported by extracorporeal CO2 removal (ECCO2R) devices inserted in jugular or subclavian veins. The interest of the Novalung (Novalung GmbH, Hechingen, Germany) persists due to his central configuration indicated to bridge to LTx patients suffering from pulmonary hypertension. The increasing panel of ECLS technologies available in thoracic surgery is the results of a century of clinical practices, engineering progress, and improvements of physiological knowledges. The selection of the ECLS technique-and therefore the vascular access to implant the device-for a given nosological context trends to be defined according an evidence-based medicine.

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 (41.58–98.42) vs 24 months (1.15–46.86), P = 0.001] and OS [101 vs 55 months (49.77–60.23), P = 0.004]. However, this benefit was only significant in cases of KRAS exon 2 codon 12 mutations [median OS: 101 months (83.97–118.02) vs 60 months (53–66.99), P < 0.001; median LRRFS: 76 months (64.62–87.38) vs 44 months (35.27–52.73), 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.

Bronchial complications after lung transplantation are associated with primary lung graft dysfunction and surgical technique

BACKGROUND After lung transplantation, bronchial complications are one of the major concerns for surgeons and physicians. In the era of evolving immunosuppressive regimens and surgical approaches, we have reassessed risk factors for bronchial complications after lung transplantation. METHODS We undertook a retrospective study of all consecutive lung transplantations performed at a single center from 2004 to 2014. We monitored the incidence of symptomatic bronchial complications. Demographic data of donors and recipients were also studied. Our objective was to evaluate the impact of 3 subsequent immunosuppressive regimens (including the use of induction therapy), and of a technical modification of bronchial anastomosis on the incidence of airway complications. RESULTS We performed 270 consecutive lung transplantations during the study period. On multivariate analysis, bronchial complications were not directly associated with the different immunosuppressive regimens. In subgroup analysis, when comparing different immunosuppressive regimens, primary graft dysfunction within 72 hours (odds ratio [OR] = 2.55; p = 0.08), lung infection within the first month (OR = 2.96; p = 0.039), diabetes before transplantation (OR = 2.66; p = 0.11) and chronic obstructive pulmonary disease (OR = 2.20; p = 0.04) appeared as major risk factors (c-index = 0.77 on multivariate analysis). The use of a modified bronchial suture technique was associated with fewer bronchial complications (OR = 0.47; p = 0.059) (c-index = 0.71 on multivariate analysis). CONCLUSIONS The mode of immunosuppression had no influence on airway complications. We were able to reproduce the beneficial effect of a modified suture technique.

Microparticles: A new insight into lung primary graft dysfunction?

Lung transplantation is the only life-saving treatment for end stage respiratory disease. The immediate outcome is still hampered by primary graft dysfunction. The latter is a form of acute lung injury occurring within the 30min following the unclamping of the pulmonary artery that prompts ischemia reperfusion injury. Severe forms may need prolonged mechanical ventilation and extra-corporeal membrane oxygenation. Overall, primary graft dysfunction accounts for at least one third of the deaths during the first post-operative month. Despite increasing experience and knowledge on the underlying cellular events, there is still a lack of an early marker of ischemia reperfusion graft injuries. Microparticles are plasma membrane vesicles that are released from damaged or stressed cells in biological fluids and remodeling tissues, among which the lung parenchyma during acute or chronic injury. We recently evidenced alveolar microparticles as surrogate markers of strong ischemia injury in ex-vivo reperfusion experimental models. We propose herein new insights on how microparticles may be helpful to evaluate the extent of lung ischemia reperfusion injuries and predict the occurrence of primary graft dysfunction.

Extracorporeal life support in thoracic surgery

The use of extracorporeal life support (ECLS) techniques is increasing in the setting of general thoracic surgery, lung transplantation (LTx) and cardiorespiratory failure. Depending on the technique used, ECLS can provide a shortto mid-term extracorporeal mechanical support, help in carbon dioxide (CO2) clearance, aid in oxygen (O2) enrichment and provide cardiocirculatory support. The objective of the ECLS techniques is to supply the failing respiratory and/or cardiocirculatory system(s) to facilitate recovery (bridge to recovery), transplantation (bridge to transplantation), change to another ECLS device or configuration (bridge to bridge) or change of care strategy (bridge to decision). ‘ECLS’ is a generic term that includes all extracorporeal mechanical cardiorespiratory support techniques. In thoracic surgery, the commonly used ECLS techniques are (i) extracorporeal membrane oxygenation (ECMO), (ii) pumpless interventional lung assist device ‘Novalung’ (Xenios AG, Heilbron, Germany) and (iii) extracorporeal CO2 removal (ECCO2R). From a clinical standpoint, ‘ECLS’ and ‘ECMO’ are two separate terms; ‘ECLS’ provides cardiorespiratory support, whereas ‘ECMO’ is limited only to respiratory support. In this article, we will use the term ‘ECLS’ as the generic term for all extracorporeal mechanical techniques available. The physiology of the ECLS is based on 4 cardinal points: (i) oxygenation depends on the ECLS blood flow; (ii) CO2 clearance depends on the gas flow through the membrane (sweep gas flow); (iii) providing haemodynamic support by an injection at a systemic arterial site and (iv) maintaining optimal oxygenation to the vital organs (brain, heart and lungs) by an ECLS inflow directed to the right atrium. This editorial aims at summarizing the rationale behind the main ECLS techniques used in thoracic surgery, clinical indications and results of ECLS.

KRAS-specific amino acid substitutions are associated with different responses to chemotherapy in advanced non-small cell lung cancer

&NA; Emerging evidence is highlighting different behaviors of non–small‐cell lung cancer according to KRAS amino acid substitutions (AAS). We have shown that, in a large sample of 1190 patients, response to chemotherapy differs according to KRAS AAS in non–small‐cell lung cancer. This supports the use of different chemotherapy regimens according to KRAS AAS. Background: Emerging data highlight different clinical behaviors according to KRAS amino acid substitutions (AASs) in patients with non–small‐cell lung cancer (NSCLC). We aimed to evaluate whether different KRAS AASs were associated with different responses to chemotherapy. Patients and Methods: We retrospectively reviewed data from 1190 patients with KRAS mutations who underwent first‐line platinum‐based chemotherapy for stage IV NSCLC. The response to different chemotherapy regimens was evaluated using the Response Evaluation Criteria In Solid Tumors criteria (v 1.1). Overall survival and time to progression (TTP) were secondary endpoints. Results: Taxane was associated with the best response in the entire cohort (odds ratio, 2.52; 95% confidence interval [CI], 1.82‐3.48; P < .001), especially in G12V patients (odds ratio, 2.15; 95% CI, 1.05‐4.41; P = .036). Taxane was associated with improved TTP in the entire cohort (hazard ratio [HR], 0.31; 95% CI, 0.26‐0.38; P < .001), especially in G13D patients (HR, 0.47; 95% CI, 0.22‐1.01; P = .054). Pemetrexed was associated with the worst TTP in the entire cohort, particularly in G12V patients, who had the worst response rates (HR, 0.55; 95% CI, 0.30‐0.99; P = .049). No impact on overall survival was observed according to different chemotherapy regimens and AASs. Conclusion: KRAS‐specific AAS appears to induce different responses to chemotherapy regimens after first‐line platinum‐based chemotherapy in advanced NSCLC.