Ex Vivo Comparison of the Elastic Properties of Vascular Substitutes Used for Pulmonary Artery Replacement.

INTRODUCTION: Study aims were to evaluate the elastic properties of vascular substitutes frequently used for pulmonary artery (PA) replacement, and then to compare their compliance and stiffness indexes to those of human PA. METHODS: A bench-test pulsatile flow experiment was developed to perfuse human cadaveric vascular substitutes (PA, thoracic aorta, human pericardial conduit), bovine pericardial conduit, and prosthetic vascular substitutes (polytetrafluorethylene and Dacron grafts) at a flow and low pulsed pressure mimicking pulmonary circulation. Intraluminal pressure was measured. An ultrasound system with an echo-tracking function was used to monitor vessel wall movements. The diameter, compliance, and stiffness index were calculated for each vascular substitute and compared to the human PA at mean pressures ranging from 10 to 50 mmHg. RESULTS: The compliance of the PA and the thoracic aorta were similar at mean physiological pressures of 10 mmHg and 20 mmHg. The PA was significantly less compliant than the aorta at mean pressures above 30 mmHg (P = 0.017). However, there was no difference in stiffness index between the two substitutes over the entire pressure range. Compared to the PA, human pericardial conduit was less compliant at 10 mmHg (P = 0.033) and stiffer at 10 mmHg (P = 0.00038) and 20 mmHg (P = 0.026). Bovine pericardial conduit and synthetic prostheses were significantly less compliant and stiffer than the PA for mean pressures of 10, 20, and 30 mmHg. There were no differences at 40 and 50 mmHg. CONCLUSIONS: Allogenic arterial grafts appear to be the most suitable vascular substitutes in terms of compliance and stiffness for PA replacement.

What are the barriers to the completion of a home-based rehabilitation programme for patients awaiting surgery for lung cancer: a prospective observational study.

OBJECTIVES: Home-based rehabilitation programmes (H-RPs) could facilitate the implementation of pulmonary rehabilitation prior to resection for non-small cell lung cancer (NSCLC), but their feasibility has not been evaluated. The aim of this study was to identify determinants of non-completion of an H-RP and the factors associated with medical events occurring 30 days after hospital discharge. DESIGN: A prospective observational study. INTERVENTION: All patients with confirmed or suspected NSCLC were enrolled in a four-component H-RP prior to surgery: (i) smoking cessation, (ii) nutritional support, (iii) physiotherapy (at least one session/week) and (iv) home cycle-ergometry (at least three times/week). OUTCOMES: The H-RP was defined as 'completed' if the four components were performed before surgery. RESULTS: Out of 50 patients included, 42 underwent surgery (80% men; median age: 69 (IQR 25%-75%; 60-74) years; 64% Chronic Obstructive Pulmonary Disease (COPD); 29% type 2 diabetes). Twenty patients (48%) completed 100% of the programme. The median (IQR) duration of the H-RP was 32 (19; 46) days. Multivariate analysis showed polypharmacy (n=24) OR=12.2 (95% CI 2.0 to 74.2), living alone (n=8) (single vs couple) OR=21.5 (95% CI 1.4 to >100) and a long delay before starting the H-RP (n=18) OR=6.24 (95% CI 1.1 to 36.6) were independently associated with a risk of non-completion. In univariate analyses, factors associated with medical events at 30 days were H-RP non-completion, diabetes, polypharmacy, social precariousness and female sex. CONCLUSION: Facing multiple comorbidities, living alone and a long delay before starting the rehabilitation increase the risk of not completing preoperative H-RP. TRIAL REGISTRATION NUMBER: NCT03530059.

[Precision medicine: A major step forward in specific situations, a myth in refractory cancers?] / Médecine de précision : une avancée majeure dans des situations spécifiques, un mythe dans les cancers réfractaires ?

In recent years, high-throughput sequencing techniques have been developed for cancerology and many clinical trials are currently structured around biomarkers that can guide specific treatment choices. This approach is characteristic of precision medicine, which is actually a concept initiated several decades ago with, for example, retinoic acid in promyelocytic leukemia. This paper will review the different types of molecular alterations and « -omics ¼ biological analyses, bioinformatics tools, coupled drug/biomarkers already validated, the ethical issues of whole genomic sequencing of an individual as part of an inclusion in a clinical trial and finally the first results of precision medicine trials. The AcSé crizotinib program, supported by the Inca (french Cancer National Institute), is emblematic of a success of this personalized medicine illustrated by 4 points: the discovery of a cohort of patients with lung cancer with a ROS1 rearrangement characteristic of a sensitivity to crizotinib, a rapid availability of this innovation through the implementation of a temporary recommendation for use (ANSM), the obtention of a conditional marketing authorization by the pharmaceutical industry and finally, financial assumption of responsibility by French social security (HAS), despite preliminary and non-comparative data. In the case of cancers refractory to standard chemotherapy, and regarding our system of access to drugs illustrated by the PROFILER clinical trial, this approach allows the access to a therapeutic drug targeting specific biomarkers only in 7% of patients included. This does not bode well for efficient treatment and even less for survival. Allowing patients to be included in trials that identify molecular targets by molecular screening, and not being able to propose the drug of interest is a traumatic event for those patients who live in the hope of an immediate future. In refractory disease we must rethink precision medicine in a more humanistic vision for our patients and not only in a dimension of medico-industrial promotion. The implementation of a new multi-drug/multi-molecular target program could address this issue.

Unusually prolonged pemetrexed cytotoxicity in a patient with a lung adenocarcinoma: a case report.

BACKGROUND: We describe a case of pemetrexed toxicities related to reabsorption by an ileal neobladder, which caused prolonged hematotoxicity and nephrotoxicity. CASE PRESENTATION: A 59-year-old white man was diagnosed with metastatic wild-type adenocarcinoma of the upper lobe of his right lung. After a first cycle of cisplatin and pemetrexed, he had unusually prolonged aplasia and acute kidney injury. The prolonged aplasia was caused by pemetrexed reabsorption by the ileal mucosa of the neobladder as pemetrexed was eliminated renally in an active form and is partly lipophilic. CONCLUSIONS: Pemetrexed may be reabsorbed by the ileal mucosa of the neobladder because of its hydrophobic structure and renal excretion in its active form. Acute urinary retention may maintain this phenomenon. Published data excluded a potential role for cisplatin in this toxicity; furthermore, we could not assess pemetrexed concentrations in the blood or urine as these assay techniques are not validated. Thus, care is needed when giving chemotherapy to patients with a neobladder.

Feasibility of Real-Time Intraprocedural Temperature Control during Bone Metastasis Thermal Microwave Ablation: A Bicentric Retrospective Study.

PURPOSE: To evaluate feasibility of using a thermocouple for temperature monitoring during microwave (MW) ablation of metastatic bone disease. MATERIALS AND METHODS: This retrospective study comprised 16 patients (8 men with mean age 63 y and 8 women with mean age 59 y) with 18 bone metastases treated with MW ablation using a thermocouple between March 2012 and October 2015. The mean maximum tumor size was 29.5 mm. MW ablation power was set between 15 W and 40 W and applied for 1-6 minutes. Thermocouple placements were as follows: epidural space (n = 7 cases), nerve roots (n = 9 cases), pleura (n = 1), and pericardium (n = 1). The procedure was considered technically successful when the MW and the thermocouple probes were accurately placed and thermoablation was initiated. Clinical success was defined as a 50% visual analog scale score decrease at 1 month as assessed by the operators. RESULTS: Mean MW ablation time was 4.3 minutes with a mean energy of 30 W. Procedural success was 100%. In 16 cases with neural structure monitoring, temperature did not increase > 43°C. In 8 cases, MW ablation had to be discontinued because of temperature reaching 42°C. Efficacy of the procedure in regard to pain was achieved in 17 of 18 ablation sessions at 1 month. CONCLUSIONS: Use of a thermocouple during bone MW ablation is a feasible technique and may be a potentially useful tool to help avoid nontarget ablation surrounding tumors.

Selection criteria for intensive care unit referral of lung cancer patients: a pilot study.

The decision-making process for the intensity of care delivered to patients with lung cancer and organ failure is poorly understood, and does not always involve intensivists. Our objective was to describe the potential suitability for intensive care unit (ICU) referral of lung cancer in-patients with organ failures. We prospectively included consecutive lung cancer patients with failure of at least one organ admitted to the teaching hospital in Grenoble, France, between December 2010 and October 2012. Of 140 patients, 121 (86%) were evaluated by an oncologist and 49 (35%) were referred for ICU admission, with subsequent admission for 36 (73%) out of those 49. Factors independently associated with ICU referral were performance status ⩽2 (OR 10.07, 95% CI 3.85-26.32), nonprogressive malignancy (OR 7.00, 95% CI 2.24-21.80), and no explicit refusal of ICU admission by the patient and/or family (OR 7.95, 95% CI 2.39-26.37). Factors independently associated with ICU admission were the initial ward being other than the lung cancer unit (OR 6.02, 95% CI 1.11-32.80) and an available medical ICU bed (OR 8.19, 95% CI 1.48-45.35). Only one-third of lung cancer patients with organ failures were referred for ICU admission. The decision not to consider ICU admission was often taken by a non-intensivist, with advice from an oncologist rather than an intensivist.

Atypical response to erlotinib in a patient with metastatic lung adenocarcinoma: a case report.

INTRODUCTION: Tyrosine kinase inhibitors are widely prescribed in thoracic oncology and have excellent responses as a first-line treatment for locally advanced or metastatic lung cancer with epidermal growth factor receptor mutations. The side effects of tyrosine kinase inhibitors are mostly gastrointestinal and dermatological, and are usually resolved after symptomatic treatment. However, new complications have now arisen due to increased use of these drugs. Here we report a side effect of erlotinib that has not been described previously: that is, metastatic lung tumor nodules were transformed into cysts, which ruptured the pleura and were responsible for bilateral life-threatening pneumothorax. CASE PRESENTATION: We report the case of a 35-year-old Caucasian woman with metastatic adenocarcinoma and a deletion in epidermal growth factor receptor exon 19 (del E746-A750). She was treated with erlotinib for metastatic lung adenocarcinoma. Treatment with erlotinib resulted in the replacement of pulmonary tumor nodules with air-containing cysts. These cysts ruptured in the pleura causing a life-threatening bilateral pneumothorax. To the best of our knowledge, this tumor-cystic response after erlotinib therapy has not been previously described. CONCLUSIONS: Tyrosine kinase inhibitors are widely prescribed in thoracic oncology, and managing toxicities must be optimal in order to improve adherence. Transformation of pulmonary nodules into cysts must be known and clinicians should be aware of this potential complication, which can lead to life-threatening pneumothorax.

Prognostic impact of paraneoplastic cushing's syndrome in small-cell lung cancer.

INTRODUCTION: Paraneoplastic Cushing's syndrome (CushingPS) in small-cell lung cancer is rare but severe. METHODS: We studied 383 patients with small-cell lung cancer diagnosed between 1998 and 2012. Among them, 23 patients had CushingPS, 56 had other paraneoplastic syndrome (OtherPS), and 304 had no paraneoplastic syndrome (NoPS). RESULTS: After comparison of the three groups, we observed that CushingPS patients had more extensive disease: 82.6% versus 67.8% versus 53.3% (p = 0.005), respectively, with more than two metastatic sites: 63.2% versus 15.8% and 24.1% (p ≤ 0.001), a higher World Health Organization performance status (2-4): 73.9% versus 57.1% versus 43.7% (p = 0.006), greater weight loss (≥10%): 47.8% versus 33.9% versus 16.4% (p ≤ 0.001), reduced objective response to first-line treatment: 47.6% versus 74.1% versus 71.1% (p = 0.04), and poorer sensitivity to first-line treatment: 19% versus 38.9% versus 48.6% (p = 0.01). NoPS patients, with World Health Organization performance status of 3-4, had extensive disease at diagnosis, with response, sensitivity to first-line treatment, and survival similar to the CushingPS group. At relapse, the CushingPS group had no objective response to second-line treatment versus 25% versus 42.8% in OtherPS and NoPS groups, respectively (p = 0.005). The median survival of CushingPS patients was 6.6 months versus 9.2 months for OtherPS and 13.1 months for NoPS patients (p ≤ 0.001). CushingPS is a prognostic factor of death (hazard ratio, 2.31; p ≤ 0.001). CONCLUSION: CushingPS is the worst form of the paraneoplastic syndromes with particularly extensive tumors. Reduced objective response and sensitivity to first-line treatment and no response to second-line treatment suggest starting palliative care early at first line and exclusively at relapse.

On the relevance of a testing algorithm for the detection of ROS1-rearranged lung adenocarcinomas.

OBJECTIVES: ROS1 proto-oncogene translocations define a new molecular subgroup in non-small cell lung cancers (NSCLC) and are associated with a response to the MET/ALK inhibitor, crizotinib. These rearrangements are described in 0.9-1.7% NSCLC, in wild-type EGFR, KRAS and ALK ("triple negative") lung adenocarcinomas. Rapid and efficient identification of these alterations is thus becoming increasingly important. MATERIALS AND METHODS: In this study, 121 triple negative lung adenocarcinomas were screened by both IHC with the ROS1 D4D6 antibody, and FISH using two commercially available ROS1 break-apart probes. To address a possible cross-reactivity of the ROS1 antibody with other protein kinase receptors, we screened 80 additional cases with known EGFR, KRAS, PI3KCA, BRAF, HER2 mutations or ALK-rearrangement. RESULTS: We diagnosed 9 ROS1-rearranged adenocarcinomas, with both a positive FISH result (51-87% rearranged nuclei) and a positive IHC staining (2+/3+ cytoplasmic staining). Only one of the ROS1-positive FISH cases was characterized by a classical split pattern, the others showed a variant pattern, most commonly involving a loss of the 5' telomeric probe. Considering a positivity threshold of 2+ stained cells, the sensitivity of the ROS1 D4D6 antibody compared to FISH was 100% and the specificity 96.9%, as two HER2-mutated tumors were positive with D4D6 antibody, without any translocation in FISH. All the ROS1-positive cases were at an advanced stage, arising in never or light smokers. They were mainly solid cribriform and acinar adenocarcinomas, with signet ring cells noted in 5 cases, and calcifications in 3 cases. One positive case was an invasive mucinous carcinoma. CONCLUSION: Our results show that a screening algorithm based on an IHC detection of ROS1 fusion proteins, confirmed if positive or doubtful by a ROS1 break-apart FISH assay, is pertinent in advanced "triple negative" lung adenocarcinomas, since the prevalence of ROS1-positive cases in this selected population reaches 7.4% in our series.

Primary extraosseous Ewing sarcoma of the lung in children.

We report a case of primary extraosseous Ewing sarcoma (EES) of the lung in a four-year-old child. In the literature, there are only a few case reports of EES located in the thorax.

Outcomes in recurrent small-cell lung cancer after one to four chemotherapy lines: a retrospective study of 300 patients.

Standard treatment of small-cell lung cancer (SCLC) is a combination of etoposide and platinum for patients with extensive disease, associated with radiotherapy for patients with limited disease (LD). Therapeutic strategies for relapse, although well characterized, are disappointing. Between 1997 and 2009, 300 patients were treated for SCLC at Grenoble University Hospital. We analyzed patients' characteristics and outcomes at different treatment steps, to determine prognostic factors and propose subsequent treatment strategies according to "sensitive", "resistant" or "refractory" status established after first-line treatment (L1). The median patient age was 63.2 years, 46.3% had LD, and 23% were female. The objective response rate (ORR) to first-line chemotherapy was 73% [CI(95%): 67.6-77.9] and median survival was 13 months. After L1, comparison between "refractory" and "sensitive" groups showed more extensive disease (76.6% vs. 34.3%, p=0.003), poorer Performance Status (PS 0-1: 48.4% vs. 67.8%, p=0.008), more endocrine paraneoplastic syndrome (18.7% vs. 8.4%, p=0.03) and more composite histology (17.2% vs. 4.9%, p=0.004) in "refractory" patients. After second line (L2), ORR was 55.8% [CI(95%): 45.2-66.0] in "sensitive", 18.2% [CI(95%): 8.2-32.7] in "resistant", and 14.7% [CI(95%): 4.9-31.0] in "refractory" groups; with partial response only for the last two groups. After L3 and L4, ORR was 24.0% [CI(95%): 14.9-35.2] in "sensitive", 9.1% [CI(95%): 11.2-29.2] in "resistant" with partial response only. No response was observed for "refractory". After L1, the median survival was respectively 23, 10 and 6.4 months for "sensitive", "resistant" and "refractory" groups (p<0.001). Multivariate analysis showed that LD and classical SCLC histology were positive predictors of belonging to the "sensitive" group. Positive factors for survival were sensitivity to L1, PS 0-1, LD, Charlson score <4, no endocrine paraneoplastic syndrome and no occupational exposure. Limited disease is the major predictive factor for sensitivity to treatments and survival. Factors linked to the patients' clinical presentation also impact on survival. With currently recommended drugs, the "sensitivity" of the patient determined by the response to L1 indicates that it is pointless to treat "sensitive" with L4, "resistant" with L3 and "refractory" with L2, except for a few selected patients after multidisciplinary group discussion.