High flow nasal oxygen in frail COVID-19 patients hospitalized in intermediate care units and non-eligible to invasive mechanical ventilation.

BACKGROUND: In COVID-19 patients, older age (sixty or older), comorbidities, and frailty are associated with a higher risk for mortality and invasive mechanical ventilation (IMV) failure. It therefore seems appropriate to suggest limitations of care to older and vulnerable patients with severe COVID-19 pneumonia and a poor expected outcome, who would not benefit from invasive treatment. HFNO (high flow nasal oxygen) is a non-invasive respiratory support device already used in de novo acute respiratory failure. The main objective of this study was to evaluate the survival of patients treated with HFNO outside the ICU (intensive care unit) for a severe COVID-19 pneumonia, otherwise presenting limitations of care making them non-eligible for IMV. Secondary objectives were the description of our cohort and the identification of prognostic factors for HFNO failure. METHODS: We conducted a retrospective cohort study. We included all patients with limitations of care making them non-eligible for IMV and treated with HFNO for a severe COVID-19 pneumonia, hospitalized in a COVID-19 unit of the pulmonology department of Lyon Sud University Hospital, France, from March 2020 to March 2021. Primary outcome was the description of the vital status at day-30 after HFNO initiation, using the WHO (World Health Organization) 7-points ordinal scale. RESULTS: Fifty-six patients were included. Median age was 83 years [76.3-87.0], mean duration for HFNO was 7.5 days, 53% had a CFS score (Clinical Frailty Scale) >4. At day-30, 73% of patients were deceased, one patient (2%) was undergoing HFNO, 9% of patients were discharged from hospital. HFNO failure occurred in 66% of patients. Clinical signs of respiratory failure before HFNO initiation (respiratory rate >30/min, retractions, and abdominal paradoxical breathing pattern) were associated with mortality (p = 0.001). CONCLUSIONS: We suggest that HFNO is an option in non-ICU skilled units for older and frail patients with a severe COVID-19 pneumonia, otherwise non-suitable for intensive care and mechanical ventilation. Observation of clinical signs of respiratory failure before HFNO initiation was associated with mortality.

PD-L1-expression patterns in large-cell neuroendocrine carcinoma of the lung: potential implications for use of immunotherapy in these patients: the GFPC 03-2017 "EPNEC" study.

BACKGROUND: Few data are available on programmed cell-death-protein-1-ligand-1 (PD-L1) expression on large-cell neuroendocrine carcinomas of the lung (LCNECs). We analyzed PD-L1 expression on tumor (TCs) and inflammatory cells (ICs) from LCNEC patients to assess relationships between this expression, clinical characteristics, and disease outcomes. METHODS: PD-L1 expression was determined by immunohistochemistry with monoclonal antibody 22C3 in consecutive LCNEC patients managed in 17 French centers between January 2014 and December 2016. RESULTS: After centralized review, only 68 out of 105 (64%) patients had confirmed LCNEC diagnoses. Median overall survival (OS) (95% CI) was 11 (7-16) months for all patients, 7 (5-10), 21 (10-not reached) and not reached months for metastatic, stage III and localized forms (p = 0.0001). Respectively, 11% and 75% of the tumor samples were TC+ and IC+, and 66% had a TC-/IC+ profile. Comparing IC+ versus IC- metastatic LCNEC, the former had significantly longer progression-free survival [9 (4-13) versus 4 (1-8) months; p = 0.03], with a trend towards better median OS [12 (7-18) versus 9.5 (4-14) months; p = 0.21]. Compared to patients with TC- tumors, those with TC+ LCNECs tended to have non-significantly shorter median OS [4 (1-6.2) versus 11 (8-18) months, respectively]. Median OS was significantly shorter for patients with TC+/IC- metastatic LCNECs than those with TC-IC+ lesions (2 versus 8 months, respectively; p = 0.04). CONCLUSION: TC-/IC+ was the most frequent PD-L1-expression profile for LCNECs, a pattern quite specific compared with non-small-cell lung cancer and small-cell lung cancer. IC PD-L1 expression seems to have a prognostic role.

Real-life efficacy of osimertinib in pretreated patients with advanced non-small cell lung cancer harboring EGFR T790M mutation.

Objectives The efficacy of osimertinib in pretreated patients with advanced non-small cell lung cancer (NSCLC) harboring EGFR T790 M resistance mutation was demonstrated in clinical trials. However, data on efficacy of osimertinib in real world remain rare. Materials and methods This retrospective multicentric study analyzed T790M-positive advanced NSCLC patients enrolled in French early access program for osimertinib. Patients were pretreated with first- or second-generation EGFR tyrosine-kinase inhibitor and for a majority with chemotherapy. Primary endpoints were progression-free survival (PFS) and overall survival (OS) from osimertinib initiation. Results 205 patients (mean age, 69.5 years; female, 68.8%; adenocarcinoma, 97.5%, never-smokers, 71.5%) were analyzed. Osimertinib was used in second and third line in 18.0% and 82.0% of patients, respectively. Median PFS was 12.4 (95% CI, 10.1-15.1) months. In patients with and without cerebral metastasis, PFS was 9.7 (7.7-13.5) and 15.1 (12.0-17.1) months (p = 0.21), respectively. PFS in second and third line or more was 12.6 (6.7-17.5) and 12.4 (9.7-15.3) months, respectively. Median PFS in patients with EGFR exon 19 deletion and exon 21 mutation was 13.5 (10.1-16.0) and 9.7 (7.4-13.2) months, respectively (p = 0.049). Median OS since osimertinib initiation was 20.5 (16.9-24.3) months: 23.1 (18.6-27.8) and 18.0 (12.2-22.2) months in patients without and with cerebral metastasis (p = 0.11); 17.5 (11.6-27.8) and 21.7 (17.3-24.3) months as second or third line of treatment or more (p = 0.46), respectively. Median OS in patients with EGFR exon 19 deletion and exon 21 mutation was 23.1 (18.6-25.7) and 15.3 (11.6-21.7) months, respectively (p = 0.03). Osimertinib dosage was modified in 8.0% of patients and definitively discontinued for adverse events in 5.9%. Fifty patients benefited from rebiopsy (persistence of T790 M mutation, 44.7%; C797S mutation, 21.1%; cMET amplification, 8.0%). Conclusion In pretreated patients with T790M-mutated advanced NSCLC, the efficacy of osimertinib appears similar in real-world setting to that of clinical trials.

High-fidelity simulation self-training enables novice bronchoscopists to acquire basic bronchoscopy skills comparable to their moderately and highly experienced counterparts.

BACKGROUND: We sought to determine whether a self-training program on a high-fidelity flexible bronchoscopy (FB) simulator would allow residents who were novices in bronchoscopy to acquire competencies similar to those of experienced bronchoscopists as concerns the visualization of the bronchial tree and the identification of its anatomical elements. METHODS: We performed a prospective cohort study, categorizing bronchoscopists into three groups according to their experience level: novice (Group A, no FBs performed, n = 8), moderate (Group B, 30 ≤ FBs performed ≤200, n = 17) or high (Group C, > 200 FBs performed, n = 9). All were initially evaluated on their ability to perform on a high-fidelity FB simulator a complete visualization/identification of the bronchial tree in the least amount of time possible. The residents in Group A then completed a simulation-based self-training program and underwent a final evaluation thereafter. RESULTS: The median total procedure time for Group A fell from 561 s (IQR = 134) in the initial evaluation to 216 s (IQR = 257) in the final evaluation (P = 0.002). The visualization and identification scores for Group A also improved significantly in the final evaluation. Resultantly, the overall performance score for Group A climbed from 5.9% (IQR = 5.1) before self-training to 25.5% (IQR = 26.3) after (P = 0.002), thus becoming comparable to the overall performance scores of Group B (25.3%, IQR = 13.8) and Group C (22.2%, IQR = 5.5). CONCLUSIONS: Novice bronchoscopists who self-train on a high-fidelity simulator acquire basic competencies similar to those of moderately or even highly experienced bronchoscopists. High-fidelity simulation should be rapidly integrated within the learning curriculum and replace traditional, in-patient learning methods.

Lung cancer may increase serum procalcitonin level.

INTRODUCTION: Serum procalcitonin (PCT) is a biomarker used routinely to diagnose infections. Some malignancies are usual false positives for PCT. However, its value and behavior in the setting of lung cancers are poorly known. The objective of this study was to assess PCT positivity in a lung cancer cases series. METHOD: Between November 2011 and September 2012, all cases of newly diagnosed lung cancer with a pre-antineoplastic PCT assay and no patent signs of infection were included in the study. All PCT levels were assessed by immunofluorescent assay in a single laboratory. RESULTS: Eighty-nine patients were included (70.8% male; mean age 62; small-cell cancer 20.2%; stage IV cancer 60.7%). Overall, PCT was positive in 42%. A neuroendocrine component, having 2 or more metastatic sites, having a pleura or a liver metastasis, and being positive for CRP were all significantly associated with positive PCT in univariate analysis. In multivariate analysis, only the presence of a neuroendocrine component remained strongly associated with a positive PCT (AOR=7.24 [CI=95% 1.91-27.51]; P=0.004). Finally, baseline PCT levels <0.5 µg/l were found in 43% of NSCLC with a neuroendocrine component, vs. 9% of cancers with other histology (P=0.0001). CONCLUSION: Lung cancer may cause false positives for procalcitonin, particularly in cases of neuroendocrine cancers or in the presence of multiple metastases. These results should be taken into account for PCT-based decisional algorithms.

Assessment of palliative care for advanced non-small-cell lung cancer in France: a prospective observational multicenter study (GFPC 0804 study).

INTRODUCTION: Few studies assessed, in real life, symptoms, specific interventions and factors influencing palliative care (PC) initiation for patients with advanced non-small-cell lung cancer (NSCLC). The objective of this study was to examine, in a prospective cohort of advanced NSCLC patients, PC use and factors associated with early (≤3 months after diagnosis) PC initiation. METHODS: It was an observational multicenter study. Each center included 10 consecutive patients with PC initiation. RESULTS: 514 patients were enrolled by 39 centers (age: 62.3 ± 10.7 years, performance status: 0/1; 68.6% cases). At baseline, the most frequent symptoms concerned pain (43.6%), malnutrition (37%) and psychological disorders (25.3%). Specific interventions were infrequent for pain control and malnutrition, but were more numerous for psychological and social problems and terminal care. Median time between diagnosis and PC initiation was 35 [13-84] days, median PC duration was 4.2 [0.6-9.3] months. Median overall survival was 8.6 [6.6-10.7] months; median survival after PC initiation was 3.6 [3.2-4.5] months. In multivariate analysis, only PS ≥2 was linked to early PC. CONCLUSION: This study showed that early PC initiation is not a standard for patients with advanced NSCLC.

Primary lung adenocarcinoma occurring in a PTEN related syndrome (Cowden's disease): routine EGFR sequencing also highlights two rare somatic mutations S768I and V769L.

Cowden's syndrome is a rare autosomal dominant disorder that has been linked to germline mutations in the phosphatase and TENsin homolog (PTEN) gene. PTEN is a tumour suppressor gene that negatively regulates the PI3K-AKT-mTOR pathway. Cowden's syndrome is a multi-system disease with increased risks for a number of malignancies but very rarely for lung cancer. A systematic follow-up chest CT scan was performed to a 42 year's old female, light smoker. It showed a 20mm opacity of the left upper pulmonary lobe. Differential diagnose with benign tumours (such as hamartoma) was carefully searched. Procedures led to the diagnosis of a primitive lung adenocarcinoma. EGFR sequencing shows two rare somatic mutations (S768I and V769L). Lack of expression of PTEN is a non-sufficient condition leads to lung cancer formation alone. Nevertheless, it increases cell oncogenic potential. PTEN lacking in non small cell lung cancer is a frequent issue. It could be an alternative mechanism of non-efficacy of EGFR-TKI in cells with a sensitizing EGFR mutation. This case report, a very rare entity: a patient with a PTEN germline mutation and a lung adenocarcinoma harbouring two concomitant rare somatic mutations of EGFR. This observation comforts PTENs role in lung oncogenesis.

Life-threatening disseminated tuberculosis as a complication of treatment by infliximab for Crohn's disease: report of two cases, including cerebral tuberculomas and miliary tuberculosis.

Tumor necrosis factor α antagonist therapies represent an increased risk of reactivation of tuberculosis. We report two cases of life-threatening disseminated tuberculosis in patients undergoing treatment with infliximab for Crohn's disease including one case of a patient with cerebral tuberculomas. We discuss the implication of tumor necrosis factor α in the genesis of tuberculosis infection and the features of tuberculosis under infliximab. Tuberculosis screening and eventually preventive chemotherapy should become the standard of care for individual undergoing tumor necrosis factor α antagonist therapies.

Epidemiology and treatment costs of bone metastases from lung cancer: a French prospective, observational, multicenter study (GFPC 0601).

INTRODUCTION: The aim of this prospective, observational, multicenter study was to examine the epidemiology and management costs of bone metastatic disease (BMD) in patients with lung cancer. METHODS: The analysis included all patients with BMD from lung cancer diagnosed between May 2006 and May 2007 in 40 centers. We analyzed their management and the direct costs of BMD from the health care provider's perspective, using a Markov model. Skeletal-related event (SRE) was defined as pathological fractures, spinal cord compression, or hypercalcemia (clinical SRE [cSRE]) for an initial analysis; a second analysis included palliative radiotherapy and surgery (therapeutic SRE [tSRE]). RESULTS: Among the 554 patients enrolled (62 ± 11 years, 76.5% males, 69.3% performance status 0/1, 91% non-small cell lung cancer), 24.7% had a cSRE and 26.7% a tSRE at baseline and 9% and 39% during follow-up, respectively; 81.8% received at least one chemotherapy cycle. The median survival time was 5.8 months, and the 1- and 2-year survival rates were 22% and 7%, respectively; there was no significant difference in overall survival between the patients with and without SRE at enrollment. The main BMD treatments were opiate therapy (77.7%), biphosphonates (52.3%), radiotherapy (42.1%), and surgery (9.2%). The mean monthly BMD treatment costs in euros were €190, €374, and €4672 for asymptomatic patients, symptomatic patients, and patients with SRE, respectively. The average first-year BMD management cost in euros was €3999 ± 4135 (95% confidence interval: 374-15,886), and 49.5% of this cost was attributable to patients with SRE. CONCLUSIONS: This analysis confirms the poor prognosis of BMD from lung cancer and underlines the burden of SRE in overall treatment costs.

Oral vinorelbine and cisplatin with concurrent radiotherapy after induction chemotherapy with cisplatin and docetaxel for patients with locally advanced non-small cell lung cancer: the GFPC 05-03 study.

INTRODUCTION: The aim of this multicenter phase II trial was to evaluate the combination of oral vinorelbine and cisplatin with radiotherapy (RT) after cisplatin-docetaxel induction chemotherapy (CT) in patients with locally advanced non-small cell lung cancer (NSCLC). PATIENTS AND METHODS: Patients with previously untreated, inoperable, histologically or cytologically confirmed stage IIIA or IIIB NSCLC, with performance status ≤ 1 and weight loss ≤ 10% received two cycles of induction CT with cisplatin (75 mg/m) and docetaxel (75 mg/m) every 3 weeks. Patients with a tumor response or stabilization continued to receive cisplatin (80 mg/m) and oral vinorelbine (40 mg/m) on days 1 and 8 for two cycles, with concomitant thoracic RT (2 Gy/d, 5 d/wk, and total dose 66 Gy). RESULTS: Fifty-six patients were enrolled. All patients (n = 38) who received CT-RT were assessable for the tumor response. There were no complete responses. In the intent-to-treat analysis, the response rates were 32.1% after induction CT and 41.1% after CT-RT. The median progression-free and overall survival times were 9.2 months (95% confidence interval: 7-14) and 20.8 months (95% confidence interval: 13.7-24.1), respectively. Adverse effects of RT-CT were grades 3 to 4 neutropenia (four patients) and grade 3 esophageal toxicity (one patient). No treatment-related deaths occurred. CONCLUSION: The oral vinorelbine-cisplatin combination with concurrent RT is feasible and has a favorable risk-benefit ratio in stage IIIA/IIIB NSCLC.

Is pneumonectomy after induction chemotherapy for non-small cell lung cancer a reasonable procedure? A multicenter retrospective study of 228 cases.

INTRODUCTION: Pneumonectomy (PN) after induction chemotherapy (CT) for non-small cell lung cancer is controversial because high-mortality rates are still reported. METHODS: This multicenter retrospective study included all patients treated by induction CT then PN between January 1993 and April 2006 in four General and Thoracic Surgery Departments. Postoperative mortality and morbidity and long-term outcomes were studied. RESULTS: The study considered 228 patients. Doublets with cisplatin and vinorelbine or gemcitabine were used in 66% of cases. pTNM stages (World Health Organization, 1997) were 0 (2%), I (16%), II (25%), IIIA (29%), IIIB (16%), and IV (12%). The postoperative morbidity rate was 37% (84 of 228 patients). The independent risk factors identified for postoperative morbidity were chronic obstructive pulmonary disease, more than four cycles of induction CT or an association of cisplatin, and an old cytotoxic molecule, extended PN, and extended anesthesia time. Postoperative mortality rates were 5.3% at 30 days (12 of 228 patients) and 9.2% at 90 days (21 of 228 patients). The independent risk factors identified for operative mortality were chronic obstructive pulmonary disease, manual suture of the stump, and pTNM stage higher than IIIA. The 90-day mortality rates were 10.3% (12 of 117) for right PN and 8.2% (9 of 111) for left PN (p = 0.65). The overall survival (OS) rates were 68% at 1 year, 39% at 3 years, and 32% at 5 years. CONCLUSIONS: Induction CT was not found to compromise short- or long-term outcomes after PN in non-small cell lung cancer. The right or left PN performed by experienced surgeons after induction CT seems to be a reasonable procedure in case of tumor local extension.

[A difficult end of life]. / Une fin de vie difficile.

The law specifies how a doctor may write a medical certifcate and how a patient or his beneficiaries can obtain his medical records. It's important for a doctor to know this rules. A 56 years old patient was referred to our hospital for pulmonary adenocarcinoma cT2N2M1, the clinical stage was IV. The patient underwent radiotherapy and chemotherapy. During the treatment, the relations with the family were difficult. The patient refuse to accept the doctors tell his son any information and get married with his companion in secret. After patient's death, the son and the wife asked for many medical certificates. The doctors turned down so the son asked for the patient medical records. This observation asks the question of the medical certificates: how and when write them, which are obligatories? Moreover, how should a patient or his beneficiaries obtain medical records?

[Confidentiality in medical practice: tell no one]. / Le secret médical à tout prix?...

Medical confidentiality is sometimes difficult to impose on patient's families, especially in the field of oncology. Here, we describe the case of a 54-years-old woman with a T1N0M0 lung adenocarcinoma. After the diagnosis was made, she advised the medical team not to inform her family about her disease. Although the patient was aware of the high-risk of relapse, she was lost of follow-up after first-line treatment. Five years later, she presented with multi-metastatic recurrence and had to be admitted in an intensive-care unit for severe respiratory failure due to tumor progression. She kept refusing to inform her family, which in the end was contacted by the patient's sister, a few hours before her death. This observation highlights the absolute inviolability of medical confidentiality and led the French Association of Young Pneumologist to initiate a multi-disciplinary symposium on ethical problems raised by the management of patients with lung cancer.

[A difficult diagnosis]. / Un diagnostic difficile...

The patient information and obtaining their consent before any therapeutic constitute a basis for medicine exercise. However, there are situations where the physician may be in default. In that case, concepts of benefit/risk balance, of clear and appropriate information, and of legal liability for medico-surgical staff takes all their magnitude. That was the case in our observation, with a 69 years old patient with history of smoking, presenting a suspicious lung opacity which will require, following an agreement by multidisciplinary meeting, an exploration by thoracotomy despite an acceptable but altered respiratory function, as a result of a post-smoking broncho-emphysema. The non-malignant character of the suspected lesion raise questions about the risks involved, the benefit/risk balance, and the legal risk scopes of the medicosurgical staff as defined in the Cancer programme framework.

[Family mesotheliomas: genetic interaction with environmental carcinogenic exposure?]. / Mésothéliomes familiaux : une composante génétique associée aux risques environnementaux?

Our patient was refered to hospital for a malignant mesthelioma 22 years after the prior diagnosis of a mesothelioma in his brother. Their family history included others cancers. No exposure to asbestos was documented in brother's history. Literature is rich with family mesothelioma reports. Most of them are linked to an occupationnal asbestos exposure. But, some studies suggest that family genetic factors are involved in the development of mesothelioma: (genetically transmitted mesotheliomas in Turkish families in Cappadoce, family clustering of cancers including mesotheliomas, inhibition of tumor suppressor genes (INK4A, p53, Nf2...), a small proportion of mesothelioma among asbestosis exposed workers. Many studies suggest an interaction between genetic and environment. A genetic predisposition could lead to an increased susceptibility to carcinogenic factors.

An open multicenter phase II trial of weekly docetaxel for advanced-stage non-small-cell lung cancer in elderly patients with significant comorbidity and/or poor performance status: The GFPC 02-02b study.

CONTEXT: The objective of this study was to evaluate the feasibility and activity of weekly docetaxel monotherapy in frail elderly patients with advanced-stage non-small-cell lung cancer, selected on the basis of their precise age, general condition, and number of comorbid disorders (Charlson score). METHODS: Analysis of the response rate, toxicity, quality of life, median survival and 1-year survival rates after 1-3 six-week cycles of docetaxel 30mg/m(2) weekly. RESULTS: Fifty patients were enrolled and 42 were assessable. Five patients (10%, [3.7-22.6]) had objective responses, 14 (28%, [16.9-41.6]) had stable disease, and 23 (46%, [32.6-52.8]) progressed. The main grade 3-4 toxicity was fatigue (30%). Quality of life remained stable during treatment. The median survival time was 4.3 months, and the 1-year survival rate was 21.8%. CONCLUSION: In frail elderly patients selected on the basis of their age, general condition and comorbidity, weekly docetaxel monotherapy has acceptable toxicity and does not negatively affect quality of life. In contrast, it has only moderate activity.

Preoperative chemotherapy does not increase complications after nonsmall cell lung cancer resection.

BACKGROUND: Neoadjuvant chemotherapy before resection of nonsmall cell lung cancer seems to increase survival, mainly in the early stage. Risks of postoperative complications after chemotherapy and surgery remain controversial. Here we review our experience with patients treated in one thoracic surgery center. METHODS: Patients undergoing resection for nonsmall cell lung cancer after induction chemotherapy between January 1993 and March 2002 were reviewed. Data collected included age, sex, preoperative forced expiratory volume in 1 second (FEV1), hemoglobin, and arterial oxygen pressure tension (PaO2), postoperative complications, and global survival. The main objectives were postoperative mortality and morbidity. Postoperative mortality and morbidity were defined as complications or deaths occurring within 30 days after surgery. Predictive morbidity factors were identified by univariate and multivariate analysis and overall survival by the Kaplan-Meier method. RESULTS: In all, 114 patients were reviewed. Different induction chemotherapies were used, mainly cisplatin with vinorelbine or gemicitabine. Postoperative mortality was 2 of 114, 1 of 27 after pneumonectomy, and there were no deaths after lobectomy. Complications occurred in 29% of patients (33 of 114), usually infectious pneumonia and anemia requiring transfusion. Preoperative FEV1, hemoglobin, and PaO2 are not associated with morbidity in univariate or multivariate analysis. CONCLUSIONS: Preoperative chemotherapy does not increase postoperative mortality and morbidity after nonsmall cell lung cancer surgery, performed exclusively by thoracic surgeons.

[Combinations of platinum salts and gemcitabine in the treatment of non-small-cell lung cancer]. / Les associations sels de platine-gemcitabine dans les traitements des cancers bronchiques non à petites cellules.

Actually gemcitabine is a main drug in the treatment of non small cell lung cancer (NSCLC). The doublet gemcitabine and cisplatin is a standard treatment, widely used in the world. The review of the literature, and specially several recent randomised phase III trial in stage IV NSCLC demonstrates the reproducibility of the results, and a manageable toxicity which allows its use in preoperative setting in stages I, II and resectable III. The carboplatin-gemcitabine doublet is under investigation.