KRAS and BRAF mutations are prognostic biomarkers in patients undergoing lung metastasectomy of colorectal cancer.

BACKGROUND: We evaluated KRAS (mKRAS (mutant KRAS)) and BRAF (mBRAF (mutant BRAF)) mutations to determine their prognostic potential in assessing patients with colorectal cancer (CRC) for lung metastasectomy. METHODS: Data were reviewed from 180 patients with a diagnosis of CRC who underwent a lung metastasectomy between January 1998 and December 2011. RESULTS: Molecular analysis revealed mKRAS in 93 patients (51.7%), mBRAF in 19 patients (10.6%). In univariate analyses, overall survival (OS) was influenced by thoracic nodal status (median OS: 98 months for pN-, 27 months for pN+, P<0.0001), multiple thoracic metastases (75 months vs 101 months, P=0.008) or a history of liver metastases (94 months vs 101 months, P=0.04). mBRAF had a significantly worse OS than mKRAS and wild type (WT) (P<0.0001). The 5-year OS was 0% for mBRAF, 44% for mKRAS and 100% for WT, with corresponding median OS of 15, 55 and 98 months, respectively (P<0.0001). In multivariate analysis, WT BRAF (HR: 0.005 (95% CI: 0.001-0.02), P<0.0001) and WT KRAS (HR: 0.04 (95% CI: 0.02-0.1), P<0.0001) had a significant impact on OS. CONCLUSIONS: mKRAS and mBRAF seem to be prognostic factors in patients with CRC who undergo lung metastasectomy. Further studies are necessary.

Systematic lymph node dissection in lung metastasectomy of renal cell carcinoma: an 18 years of experience.

BACKGROUND: Pulmonary metastasectomy of renal cell carcinomas (RCC) remains controversial. Thoracic lymph node involvement (LNI) is a known prognostic factor. The aim of our analysis is to evaluate whether patients with LNI, and particularly N2 patients, should be excluded from surgical treatment. METHODS: We retrospectively reviewed data from 122 patients who underwent operations at two French thoracic surgery departments between 1993 and 2011 for RCC lung metastases. RESULTS: The population consisted of 38 women and 84 men; the average age at time of metastasectomy was 63.3 years (min: 43, max: 82). LNI was identified as a prognostic factor using univariate and multivariate analysis (median survival: 107 months vs. 37 months, P = 0.003; HR = 0.384 (0.179; 0.825), P = 0.01, respectively). Although differences in survival between metastases at the hilar and mediastinal locations were not significant (median survival: 74 months vs. 32 months, respectively, P = 0.75), length of survival time was associated with disease-free interval less than 12 months (median survival: 23 months vs. 94 months, P < 0.0001; HR = 3.081 (1.193; 7.957), P = 0.02). CONCLUSION: Although LNI has an adverse effect on survival; long-term survival can be achieved in pN+ patients. Consequently, these patients should not be excluded from surgery. Systematic lymphadenectomy should be performed to obtain more accurate staging and to determine appropriate adjuvant treatment.

Impact of adjuvant radiotherapy and chemotherapy on thymoma.

PURPOSE: Thymoma is a rare tumour. The most common treatment for thymoma is surgical resection, while the use of radiotherapy and chemotherapy remains controversial. PATIENTS AND METHODS: We conducted a monocentric observational study of 31 patients diagnosed with thymoma from June 2004 to July 2020 at cancer centre in Strasbourg, France. We analysed the outcomes of the patients. RESULTS: The 2- and 5- year locoregional relapse-free survival rates were 96.3% (95% confidence interval [CI]: 76.5-99.5%) and 68.0% (95% CI: 43.8-83.5%), respectively. Radiotherapy and chemotherapy significantly improved local tumour control (P=0.0008 and 0.04, respectively), while a larger initial tumour size significantly worsened local control rates (P=0.04). The 5- and 10-year overall survival rates were 87.1% (95% CI: 69.2-95%) and 81.7% (95% CI: 60.3-92.2%), respectively. The median overall survival was not reached, and no favourable factor was retrieved. For relapsed patients, the median overall survival after relapse was 115 months. CONCLUSION: Despite the inherent limitations of retrospective studies with a limited patient sample size, we demonstrated that chemotherapy and radiotherapy in addition to surgery were effective in achieving local control and contributed to improving patient outcomes in thymoma. Notably, an aggressive treatment strategy at the time of relapse resulted in favourable outcomes for retreated patients.

Outcomes of lung transplantation for pleuroparenchymal fibroelastosis: A French multicentric retrospective study.

BACKGROUND: Pleuroparenchymal fibroelastosis (PPFE) has no currently available specific treatment. Benefits of lung transplantation (LT) for PPFE are poorly documented. METHODS: We conducted a nation-wide multicentric retrospective study in patients who underwent lung or heart-lung transplantation for chronic end-stage lung disease secondary to PPFE between 2012 and 2022 in France. RESULTS: Thirty-one patients were included. At transplantation, median age was 48 years [IQR 35-55]. About 64.5% were women. Twenty-one (67.7%) had idiopathic PFFE. Sixteen (52%) had bilateral LT, 10 (32%) had single LT, 4 (13%) had lobar transplantation and one (3%) had heart-lung transplantation. Operative mortality was 3.2%. Early mortality (<90 days or during the first hospitalization) was 32%. Eleven patients (35.5%) underwent reoperation for hemostasis. Eight (30.8%) experienced bronchial complications. Mechanical ventilation time was 10 days [IQR 2-55]. Length of stay in intensive care unit and hospital were 34 [IQR 18-73] and 64 [IQR 36-103] days, respectively. Median survival was 21 months. Post-transplant survival rates after 1, 2, and 5 years were 57.9%, 42.6% and 38.3% respectively. Low albuminemia (p = 0.046), FVC (p = 0.021), FEV1 (p = 0.009) and high emergency lung transplantation (p = 0.04) were associated with increased early mortality. Oversized graft tended to be correlated to a higher mortality (p = 0.07). CONCLUSION: LT for PPFE is associated with high post-operative morbi-mortality rates. Patients requiring high emergency lung transplantation with advanced disease, malnutrition, or critical clinical status experienced worse outcomes. GOV IDENTIFIER: NCT05044390.

Effect of Treatment of Residual Disease After Immunotherapy-Based Combinations on Complete Response Rate of Patients With Metastatic Renal Cell Carcinomas.

INTRODUCTION: Immune checkpoint inhibitor (ICI)-based combinations have revolutionized the management of first-line metastatic renal cell carcinoma (mRCC) by improving patient survival. Large phase 3 randomized trials assessing ICI-based combinations have reported complete response (CR) rates of 10% to 18% in the first-line setting. However, there is a scarcity of data about the effect of treatment of residual disease regarding CR rates improvement. MATERIALS AND METHODS: We included retrospectively all consecutive mRCC patients treated in first-line setting at the Institut de Cancérologie Strasbourg Europe with an ICI-based combination involving ICI or TKI, either alone or with added local treatment of residual disease. Patients were characterized according to IMDC risk. Radiologic response was defined according to RECIST v1.1. RESULTS: We enrolled 80 mRCC patients treated with ICI-based combinations between May 2015 and May 2022. The median age was 63 years. Regarding IMDC risk, there were 12 favourable (15%), 50 intermediate (63%), and 18 poor-risk (22%) patients. Forty-seven patients (59%) received ICI + ICI, 24 (30%) received ICI + TKI, and 9 (11%) received another ICI-based therapy. In total, 8 achieved CR (10%), 36 patients (45%) achieved partial response, 23 (29%) achieved stable disease and 12 achieved progressive disease (15%) as the best response with systemic therapy alone. By adding local treatment of residual disease, 11 additional patients (14%) achieved radiological NED. Residual disease resected sites included kidney (n = 6), lymph nodes (n = 5), lung metastases (n = 2) and liver metastases (n = 1). CONCLUSIONS: The resection of residual disease after first-line ICI-based therapy is associated with improved CR rate (CR + NED) in patients with mRCC. These results need to be validated in prospective trial. PATIENT SUMMARY: In recent years, the advent of immunotherapy has radically changed the management of patients with metastatic kidney cancer. Approximately 10% to 18% of these patients using immune checkpoint inhibitor (ICI)-based combinations no longer have detectable disease on CT scans (complete response). There are currently few data on the use of treatment of residual disease to increase the number of patients in complete response. In this retrospective study, the complete response rate with ICI-based treatment was 10%. When local treatment was added, the number of patients with a complete response increased to 24%. This strategy could increase the number of patients with a prolonged complete response in the future.

Controlled donation after circulatory death lung transplantation: Results of the French protocol including in situ abdominal normothermic regional perfusion and ex vivo lung perfusion.

BACKGROUND: The French national protocol for controlled donation after circulatory determination of death (cDCD) includes normothermic regional perfusion (NRP) in case of abdominal organ procurement and additional ex-vivo lung perfusion (EVLP) before considering lung transplantation (LT). METHODS: We made a retrospective study of a prospective registry that included all donors considered for cDCD LT from the beginning of the program in May 2016 to November 2021. RESULTS: One hundred grafts from 14 donor hospitals were accepted by 6 LT centers. The median duration of the agonal phase was 20 minutes [2-166]. The median duration from circulatory arrest to pulmonary flush was 62 minutes [20-90]. Ten lung grafts were not retrieved due to prolonged agonal phases (n = 3), failure of NRP insertion (n = 5), or poor in situ evaluation (n = 2). The remaining 90 lung grafts were all evaluated on EVLP, with a conversion rate of 84% and a cDCD transplantation rate of 76%. The median total preservation time was 707 minutes [543-1038]. Seventy-one bilateral LTs and 5 single LTs were performed for chronic obstructive pulmonary disease (n = 29), pulmonary fibrosis (n = 21), cystic fibrosis (n = 15), pulmonary hypertension (n = 8), graft-versus-host disease (n = 2), and adenosquamous carcinoma (n = 1). The rate of PGD3 was 9% (n = 5). The 1-year survival rate was 93.4%. CONCLUSION: After initial acceptance, cDCD lung grafts led to LT in 76% of cases, with outcomes similar to those already reported in the literature. The relative impacts of NRP and EVLP on the outcome following cDCD LT should be assessed prospectively in the context of comparative studies.

[Updated indications and contraindications in 2022 for lung transplantation in France]. / Transplantation pulmonaire en France : actualisation des indications et contre-indications en 2022.

Lung transplantation (LTx) is the last-resort treatment for end-stage respiratory insufficiency, whatever its origin, and represents a steadily expanding field of endeavor. Major developments have been impelled over the years by painstaking efforts at LTx centers to improve donor and recipient selection, and multifaceted attempts have been made to meet the challenges raised by surgical management, perioperative care, and long-term medical complications. The number of procedures has increased, leading to improved post-LTx prognosis. One consequence of these multiple developments has been a pruning away of contraindications over time, which has, in some ways, complicated the patient selection process. With these considerations in mind, the Francophone Pulmonology Society (Société de Pneumology de Langue Française [SPLF]) has set up a task force to produce up-to-date working guidelines designed to assist pulmonologists in managing end-stage respiratory insufficiency, determining which patients may be eligible for LTx, and appropriately timing LTx-center referral. The task force has examined the most recent literature and evaluated the risk factors that continue to limit patient survival after LTx. Ideally, the objectives of LTx are to prolong life while improving quality of life. The guidelines developed by the task force apply to a limited resource and are consistent with the ethical principles described below.

[Approaches to the pre-operative functional assessment of patients with lung cancer and preoperative rehabilitation]. / Bilan fonctionnel préopératoire du cancer bronchique et réhabilitation préopératoire.

Surgery is the best treatment for early lung cancer but requires a preoperative functional evaluation to identify patients who may be at a high risk of complications or death. Guideline algorithms include a cardiological evaluation, a cardiopulmonary assessment to calculate the predicted residual lung function, and identify patients needing exercise testing to complete the evaluation. According to most expert opinion, exercise tests have a very high predictive value of complications. However, since the publication of these guidelines, minimally-invasive surgery, sublobar resections, prehabilitation and enhanced recovery after surgery (ERAS) programmes have been developed. Implementation of these techniques and programs is associated with a decrease in postoperative mortality and complications. In addition, the current guidelines and the cut-off values they identified are based on early series of patients, and are designed to select patients before major lung resection (lobectomy-pneumonectomy) performed by thoracotomy. Therefore, after a review of the current guidelines and a brief update on prehabilitation (smoking cessation, exercise training and nutritional aspects), we will discuss the need to redefine functional criteria to select patients who will benefit from lung surgery.

[Progressive paralysis of the diaphragm following intra-abdominal chemotherapy]. / Paralysie diaphragmatique progressive consécutive à une chimiothérapie intra-abdominale.

INTRODUCTION: In patients presenting with intra-abdominal tumor and peritoneal carcinomatosis, cytoreductive surgery associated with hyperthermic chemotherapy may offer improved survival. We describe a case of diaphragmatic paralysis following that kind of procedure. CASE REPORT: A 60-year-old woman presented with respiratory insufficiency following cytoreductive surgery and intra-abdominal hyperthermic chemotherapy performed for pseudomyxoma intraperitonei. Pulmonary function assessment demonstrated a restrictive pattern. Three successive chest CT-scans demonstrated a thinning diaphragm muscle. Respiratory insufficiency eventually led to the death of our patient. CONCLUSION: We conclude in favor of a muscular degeneration of the diaphragm consecutive to the combined effect of cytoreductive surgery and intraperitoneal chemotherapy. Owing to the unusual nature of this complication, we did not consider it as a hypothesis at an early point in this patient's management. We think physicians should be aware of such a complication in order to consider it in a timely way. We recommend performing a biopsy of the diaphragm for pathology examination to assess muscular degeneration.

[Extracorporeal life support in thoracic surgery: What are the indications and the pertinence?] / Support extracorporel en chirurgie thoracique : quelles indications et quels intérêts ?

INTRODUCTION: In thoracic surgery, extracorporeal life support (ECLS) technologies are used in cases of severe and refractory respiratory failure or as intraoperative cardiorespiratory support. The objectives of this review are to describe the rationale of ECLS techniques, to review the pulmonary diseases potentially treated by ECLS, and finally to demonstrate the efficacy of ECLS, using recently published data from the literature, in order to practice evidence based medicine. STATE OF THE ART: ECLS technologies should only be undertaken in expert centers. ECLS allows a protective ventilatory strategy in severe ARDS. In the field of lung transplantation, ECLS may be used successfully as a bridge to transplantation, as intraoperative cardiorespiratory support or as a bridge to recovery in cases of severe primary graft dysfunction. In general thoracic surgery, ECLS technology seems to be safe and efficient as intraoperative respiratory support for tracheobronchial surgery or for severe respiratory insufficiency, without significant increase in perioperative risk. PERSPECTIVE: The indications for ECLS are going to increase. Future improvements both in scientific knowledge and bioengineering will improve the prognosis of patients treated with ECLS for respiratory failure. Multicenter randomized controlled trials will refine the indications for ECLS and improve the global care strategies for these patients. CONCLUSION: ECLS is an efficient therapeutic strategy that will improve the prognosis of patients suffering from, or exposed to, the risks of severe respiratory failure.

Structure of the reovirus outer capsid and dsRNA-binding protein sigma3 at 1.8 A resolution.

The crystallographically determined structure of the reovirus outer capsid protein sigma3 reveals a two-lobed structure organized around a long central helix. The smaller of the two lobes includes a CCHC zinc-binding site. Residues that vary between strains and serotypes lie mainly on one surface of the protein; residues on the opposite surface are conserved. From a fit of this model to a reconstruction of the whole virion from electron cryomicroscopy, we propose that each sigma3 subunit is positioned with the small lobe anchoring it to the protein mu1 on the surface of the virion, and the large lobe, the site of initial cleavages during entry-related proteolytic disassembly, protruding outwards. The surface containing variable residues faces solvent. The crystallographic asymmetric unit contains two sigma3 subunits, tightly associated as a dimer. One broad surface of the dimer has a positively charged surface patch, which extends across the dyad. In infected cells, sigma3 binds dsRNA and inhibits the interferon response. The location and extent of the positively charged surface patch suggest that the dimer is the RNA-binding form of sigma3.