beta1-integrin is dispensable for the induction of ErbB2 mammary tumors but plays a critical role in the metastatic phase of tumor progression.

Cross-talk between integrin receptors and activated growth factor receptors has been hypothesized to play a critical role in the initiation and progression of cancer. Despite in vitro evidence documenting the important role of integrin receptors in the regulation of cancer cell proliferation, the relative contribution of the integrin receptors to the initiation and progression of tumors remains unclear. Previous studies with a polyomavirus middle T mammary tumor model have indicated that targeted disruption of beta1-integrin in the mammary glands of these mice completely blocks tumor induction. To further explore the general significance of these observations, we have crossed these conditional beta1-integrin strains to a strain of mice carrying mouse mammary tumor virus/activated erbB2 (herein referred to as the NIC strain). In contrast to the tumor induction block in the polyomavirus middle T model, tumor onset in the beta1-integrin-deficient NIC mice was delayed by only 30 d and was 100% penetrant. This modest effect on tumor induction was not a result of inefficient excision, as all tumors were confirmed as beta1-integrin-null. Animals bearing beta1-integrin-deficient ErbB2 tumors exhibited significantly reduced tumor volume, which was associated with increased tumor cell apoptosis and a reduction in tumor angiogenesis. In addition, beta1-integrin-deficient tumors were compromised in their capacity to metastasize to the lung, a deficiency associated with abrogation of adhesion signaling. Taken together, these observations suggest that, although beta1-integrin is dispensable for the initiation of ErbB2 tumor induction, it plays a critical role in metastatic phase of tumor progression.

Severe SARS-CoV-2 pneumonia: Clinical, functional and imaging outcomes at 4 months.

INTRODUCTION: Given the pathophysiology of coronavirus disease 19 (COVID-19), persistent pulmonary abnormalities are likely. METHODS: We conducted a prospective cohort study in severe COVID-19 patients who had oxygen saturation<94% and were primarily admitted to hospital. We aimed to describe persistent gas exchange abnormalities at 4 months, defined as decreased diffusing capacity of the lungs for carbon monoxide (DLco) and/or desaturation on the 6-minute walk test (6MWT), along with associated mechanisms and risk factors. RESULTS: Of the 72 patients included, 76.1% required admission to an intensive care unit (ICU), while 68.5% required invasive mechanical ventilation (MV). A total of 39.1% developed venous thromboembolism (VTE). After 4 months, 61.4% were still symptomatic. Functionally, 39.1% had abnormal carbon monoxide test results and/or desaturation on 6MWT; high-flow oxygen, MV, and VTE during the acute phase were significantly associated. Restrictive lung disease was observed in 23.6% of cases, obstructive lung disease in 16.7%, and respiratory muscle dysfunction in 18.1%. A severe initial presentation with admission to ICU (P=0.0181), and VTE occurrence during the acute phase (P=0.0089) were associated with these abnormalities. 41% had interstitial lung disease in computed tomography (CT) of the chest. Four patients (5.5%) displayed residual defects on lung scintigraphy, only one of whom had developed VTE during the acute phase (5.5%). The main functional respiratory abnormality (31.9%) was reduced capillary volume (Vc<70%). CONCLUSION: Among patients with severe COVID-19 pneumonia who were admitted to hospital, 61% were still symptomatic, 39% of patients had persistent functional abnormalities and 41% radiological abnormalities after 4 months. Embolic sequelae were rare but the main functional respiratory abnormality was reduced capillary volume. A respiratory check-up after severe COVID-19 pneumonia may be relevant to improve future management of these patients.

[Different approaches to chest drainage in the management of primary spontaneous pneumothorax]. / Facteurs influençant la réussite du drainage pleural d'un premier épisode de pneumothorax spontané primitif.

Drainage of primary spontaneous pneumothorax (PSP) may be managed by different techniques and with different types of drain. It is mainly performed in the pneumology department or in the emergency department. The aim of the study was to evaluate the factors that influence the success of PSP drainage. This retrospective, monocentric study performed in University Hospital of Toulouse, included patients with a first episode of PSP requiring drainage. The primary outcome was the rate of success according to the techniques of drainage. Data on the size of the drain (>14F or<14F), the drainage technique (small bore catheter or chest tube drainage) and the drainage department (pneumology or emergency) were collected. One hundred and twenty-four patients had a drainage between 2014 and 2016: the late recurrence free success rate was 59% (n=73). Compared with emergency, drainage in pneumology increased the success rate threefold regardless of the drainage technique (P=0.0001) The success rate was similar whatever the technique used (Seldinger or classic technique) (P=0.31). Success and complications rates were similar whether the drain was large (>14F) or small (<14F) (respectively P=0.99 and P=0.58). In our study, the drainage of PSP in the pneumology department, with a small caliber inserted by the Seldinger technique, was associated with a significantly higher success rate.

[Pulmonary vein stenosis after radiofrequency ablation for atrial fibrillation]. / Sténose des veines pulmonaires après radiofréquence pour fibrillation atriale.

INTRODUCTION: Pulmonary vein stenosis is a rare condition with a high mortality. With the advent of radiofrequency ablation for atrial fibrillation a new cause of pulmonary vein stenosis has emerged. OBSERVATIONS: We report two cases of severe pulmonary vein stenosis. In the first case the diagnosis was obtained rapidly and balloon angioplasty with stent implantation was performed in the two left pulmonary veins. Recurrent occlusion occurred within the stents, extensive pulmonary infiltrates resembling pulmonary venous infarction developed and the patient died. In the second case the diagnosis was missed initially because the clinical picture suggested thrombo-embolic disease or infection. Balloon angioplasty with stent implantation was performed later. Restenosis occurred after 18 months. These two cases illustrate the frequency with which percutaneously inserted venous prostheses thombose. CONCLUSIONS: Clinicians should be familiar with the possibility of the development of pulmonary vein stenosis after radiofrequency ablation for atrial fibrillation. Pulmonary vein stenosis remains a difficult condition to manage. The pulmonary infarction should probably be considered as an urgent indication for surgical resection or even transplantation.

Thrombotic microangiopathy in a sirolimus-treated renal transplant patient receiving gemcitabine for lung cancer.

BACKGROUND: Many etiologies lead to thrombotic microangiopathy (TMA), amongst which are antineoplastic chemotherapies. Gemcitabine, a nucleoside analogue, has been approved for the treatment ofbladder and advanced non-small cell lung carcinomas (NSCLC). The reported incidence of gemcitabine-associated TMA in the literature is low, ranging from 0.015-0.31%. METHODS: Herein, we describe the first reported case of gemcitabine-induced TMA in a renal transplant patient. This occurred in a 54-year-old male transplant recipient undergoing sirolimus-based immunosuppression. In February 2005, he was diagnosed to have NSCLC, for which he received dual chemotherapy, including carboplatin and gemcitabine. After the third cycle he developed TMA. RESULTS: On admission, he presented with weakness, edema, normal blood pressure, leucopenia (2440/mm3), thrombopenia (11,000/mm3), hemolytic anemia with hemoglobin at 8 g/dl, schistocytes between 18-33% per hundred, increase in lactate dehydrogenase at 600 IU/l (N <380), and decreased haptoglobin at 0.29 g/l. Renal function was stable: serum creatinine was 1.3 mg/dl, albuminemia 30 g/l, proteinuria was present at 3 g/l in association with microscopic hematuria, and sirolimus trough level was 6.4 ng/ml. Treatment included infusions of fresh frozen plasma, withdrawal of sirolimus, which was replaced by mycophenolate mofetil, and suspension of chemotherapy. He fully recovered from TMA within 4 weeks. The concomitant use of sirolimus, which inhibits vascular endothelial growth factor, plus gemcitabine may have resulted in TMA.

[General practice management of obstructive sleep apnea in the Midi-Pyrénées]. / Prise en charge du syndrome d'apnées obstructives du sommeil en médecine générale en Midi-Pyrénées.

INTRODUCTION: Obstructive sleep apnoea syndrome (OSAS) is a significant public health problem. In the French care system general practitioners have an important role to play in its management especially in the field of early diagnosis. METHODS: The first part of this work is a descriptive case-control study looking at health resource usage of OSAS patients treated with continuous positive airway pressure (CPAP) in the MidiPyrénées area. The second part is a descriptive study which involved by interviewing 100 general practitioners settled in the area in order to evaluate their knowledge and their practice regarding OSAS. Results were compared with a previous study (1) performed in 2002 with similar methodology. RESULTS: Our results confirm that OSAS remains to a large extent undiagnosed (mean OSAS patients was less than 6 per physician) and underline the close connection between OSAS and cardiovascular diseases. A low degree of knowledge concerning the symptoms, main complications and treatment of OSAS was observed in this group of physicians. There was, however a relative improvement in the answers compared to the study performed in 2002. Two or more complications were mentioned by 67% of practitioners (33% in 2002) and only 13% of them were unable to identify at least one possible complication of OSAS (50% in 2002). CONCLUSION: This study confirms the impact on health of OSAS, characterized by a higher consumption of various medications than in non OSAS patients. Knowledge of OSAS remains low in general practitioner population in France. An important effort has to be made to improve learning of this disease by continuous medical training and during initial medical course.

[Use of endobronchial ultrasound in the management of cryptogenic haemoptysis]. / Apport de l'échoendoscopie radiaire dans la prise en charge de l'hémoptysie cryptogénique.

Currently about 50% of cases of haemoptysis are thought to be cryptogenic. Haemorrhage from the pulmonary arterial system is rare and usually due to aneurysms or pseudoaneurysms, the radiological diagnosis of which is often difficult. We report here the case of a patient admitted with a heavy haemoptysis in whom the thoracic CT scan did not reveal the diagnosis. Bronchoscopy with endobronchial ultrasound showed a vascular malformation of a branch of the pulmonary artery allowing a radiological embolisation. This case underlines the importance of bronchoscopy and the role of ultrasound in the diagnosis of haemoptysis, considered ideopathic, complicating vascular malformations.

Management of acute exacerbations of chronic obstructive pulmonary disease (COPD). Guidelines from the Société de pneumologie de langue française (summary).

Chronic obstructive pulmonary disease (COPD) is the chronic respiratory disease with the most important burden on public health in terms of morbidity, mortality and health costs. For patients, COPD is a major source of disability because of dyspnea, restriction in daily activities, exacerbation, risk of chronic respiratory failure and extra-respiratory systemic organ disorders. The previous French Language Respiratory Society (SPLF) guidelines on COPD exacerbations were published in 2003. Using the GRADE methodology, the present document reviews the current knowledge on COPD exacerbation through 4 specific outlines: (1) epidemiology, (2) clinical evaluation, (3) therapeutic management and (4) prevention. Specific aspects of outpatients and inpatients care are discussed, especially regarding assessment of exacerbation severity and pharmacological approach.

[Exacerbations of COPD: An audit of emergency department practice in France]. / Exacerbations de BPCO: Audit de pratique dans les services d'urgences en France.

INTRODUCTION: Exacerbations of COPD are potentially serious events, the recognition and treatment of which appear to be poorly understood by both patients and doctors. The aim of this study is to describe, on the basis of two case histories, the management of exacerbations of COPD in emergency departments, to compare it with the current guidelines and to evaluate the extent of use of non-invasive ventilation in decompensated COPD. METHODS: The study took place between February and June 2004. Two case histories describing one moderate and one severe exacerbation with respiratory failure were written by the authors of the study and submitted to an emergency physician in a university hospital and a district hospital in each region. RESULTS: 110 questionnaires were returned from 20 university hospitals and 25 district hospitals. Only 38% of the episodes were identified correctly. 20% of doctors did not regard dyspnoea as a clinical sign of an exacerbation. 22% of doctors never prescribed bronchodilators, even in severe cases. Finally, non-invasive ventilation (NIPV) was used for only 9% of the moderate and 56% of the severe exacerbations. DISCUSSION: This study, although limited by certain factors, illustrates a number of points in need of improvement in the recognition and treatment of exacerbations of COPD in emergency departments, the use of NIPV, and the collaboration between emergency physicians, intensivists and respiratory physicians.

[Intra-vascular lymphoma presenting with respiratory symptoms]. / Lymphome intravasculaire à présentation pulmonaire.

INTRODUCTION: Intra-vascular large cell lymphoma is a rare disease characterised by the proliferation of malignant cells within small blood vessels. CASE REPORT: We report a case of intra-vascular lymphoma presenting with unexplained dyspnoea, hypoxaemia and associated neurological symptom. The diagnosis was made by liver biopsy but the patient ultimately died. CONCLUSIONS: Earlier diagnosis with transbronchial biopsy might have improved the prognosis by allowing more prompt treatment.

[Acquired right-to-left shunt with normal right heart pressure]. / Shunts intra-cardiaques droits-gauches acquis à pressions cardiaques droites normales.

Intracardiac right-to-left shunting through a patent ovale foramen (POF) despite normal right-sided pressures is an uncommon cause of dyspnea with posture worsening in adults. We report herein 6 cases which sum up etiological circumstances, diagnostic workup and management of this syndrome. The main reported etiopathologic mechanism is consistent with a change in the internal configuration of the right atria leading to preferential blood flow from inferior vena cava through patent foramen ovale. The treatment lies on surgical closure of the septal defect, which can now be performed using a noninvasive percutaneous procedure.

[Chronic necrotizing pulmonary aspergillosis and ankylosing spondylarthritis]. / Aspergillose pulmonaire nécrosante chronique et spondylarthrite ankylosante.

Fibro-bullous disease is a late complication of ankylosing spondylarthritis. Its radiologic features frequently mimics tuberculosis or excavated neoplasm. About 50 to 65% of patients with ankylosing spondylarthritis have chronic aspergillus colonization of their airways. Pulmonary aspergillosis infection occurs in 10 to 30% during evolution. We report two cases of patients with spondylarthritis who developed chronic necrotizing pulmonary aspergillosis. Diagnosis was based on serology, mycologic examination of expectoration and in one case on histology obtain by transbronchial biopsies. Pulmonary complications due to aspergillus species frequently reveal an associated fibro-bullous disease in patients with ankylosing spondylarthritis. This can be reported to diminished chest wall movements in such patients. Treatment is based on administration of anti-fungal drugs. In case of medical treatment failure, thoracic surgery may be indicated.

[Granulomatous pneumocystis pneumonia]. / Pneumocystose à forme granulomateuse.

INTRODUCTION: Granulomatous pneumocystis pneumonia (PCP) is a rarity whose presentation may be misleading. CASE REPORT: We report the case of a patient suffering from chronic lymphatic leukaemia presenting with acute respiratory insufficiency, with a fatal outcome, due to granulomatous PCP. Broncho-alveolar lavage (BAL) remained negative and the diagnosis could only be made later by open lung biopsy. CONCLUSION: Although infrequent, granulomatous PCP should be recognised because in this situation the standard investigation (BAL) may be negative. New, more sensitive, methods of investigation such as the polymerase chain reaction (PCR) may permit earlier diagnosis.

[An unusual mediastinal mass]. / Une masse médiastinale atypique.

INTRODUCTION: Primary mediastinal tumors are rare diseases including a broad spectrum of pathologies ranging from the well-known, such as lymphoma, thymoma or germ-line tumors to some very unusual presentations. CASE REPORT: We describe a solitary mediastinal mass compressing the bronchial and vascular system in a patient suffering from chronic dyspnea. Diagnosis, obtained by means of a CT-guided biopsy, was a melanoma without any sign of a primary cutaneous lesion which harbored the BRAF V600E mutation. CONCLUSIONS: An exclusive mediastinal presentation of a malignant melanoma is exceptional and, in the context of BRAF mutation needs to be considered and diagnosed given the potential therapeutic impact.

[The congenital central hypoventilation syndrome (CCHS): a late presentation]. / Le syndrome d'hypoventilation alvéolaire central congénital (CCHS): un cas de révélation tardive.

BACKGROUND: The congenital central hypoventilation syndrome (CCHS) or Ondine's curse is a rare autosomal dominant disease, characterized by disorders of the autonomic nervous system, with abnormal ventilatory responses to hypercapnia and hypoxia. PHOX2B has been identified as the major gene causing CCHS. It results from polyalanine repeat expansion mutations. It typically presents in the newborn period but some cases have been described in adults (late onset CCHS) reflecting the variable penetrance of PHOX2B mutations. CASE REPORT: A 48 year-old woman presented, after ovarian cyst surgery, with severe hypoventilation requiring intubation. Arterial blood gases revealed a PaO2 of 6.6kPa (50mmHg), a PaCO2 of 10kPa (80mmHg) and a pH of 7.22. The past medical history revealed nocturnal symptoms for a few years. These included apnoeas, fitful sleep and awakening with headaches. Physical examination, pulmonary function tests, lung tomography and magnetic resonance imaging of the brainstem were all normal. Polysomnography revealed numerous central and obstructive apnoeas and hypopnoeas, with severe hypoxaemia and hypercapnia. Hypoxic and hypercapnic stimulation tests showed no adaptation of the ventilatory responses. Genetic analysis showed a heterozygous five alanine expansion mutation of the 20-residue polyalanine tract in exon 3 of the PHOX2B gene. CONCLUSION: The diagnosis of late onset CCHS should be considered in patients with unexplained hypoventilation, and physiological evaluation should be undertaken to document the abnormal ventilatory responses. The presence of a PHOX2B mutation confirms the diagnosis.

[Characteristics of sleep apnea syndrome in a cohort of patients with acromegaly]. / Caractéristiques du syndrome d'apnées du sommeil dans une cohorte de patients acromégales.

INTRODUCTION: Sleep apnoea syndrome (SAS) has a prevalence of between 40 and 80 % in patients with acromegaly. The objective of our study was to focus on the occurrence of SAS and its relation with acromegalic characteristics in this population as well as to study patients' comorbidities. METHODOLOGY: This study was retrospective, monocentric and related to a cohort of 106 acromegalic patients of whom 55 patients had performed ventilatory polygraphic recordings looking for SAS in addition to assessment of comorbidities. RESULTS: Within the screened patients, 42 had sleep apnoea syndrome with a majority of them having severe SAS. In this population, SAS was associated with hypertension, diabetes and a longer duration of acromegaly but acromegaly control was not a risk factor. Patients with severe SAS were older (mean 64 years) than the ones without SAS (47 years) (P=0.01). CONCLUSION: SAS prevalence is twenty times higher in the acromegalic population than for the normal population, even more so if patients are diabetic, hypertensive, older and if acromegaly has had a long evolution. Knowing this high prevalence, systematic screening for SAS may be justified in this population.

[Education of patients with sleep apnea syndrome: Feasibility of a phone coaching procedure. Phone-coaching and SAS]. / Faisabilité du "coaching" téléphonique dans l'appareillage du syndrome d'apnée du sommeil. Coaching téléphonique et SAS.

INTRODUCTION: The most commonly used treatment for obstructive sleep apnea syndrome (OSA) is the application of continuous positive airway pressure (CPAP) during sleep. However compliance with this treatment is frequently below 70%. METHODS: The main aim of this study was to evaluate the feasibility of an educational intervention (EI) delivered in phone calls made to OSA patients (n=66) treated with CPAP by a home care provider (SADIR). The educational intervention consisted of five sessions of telephone based counseling intervention by appropriately trained staff delivered on day 3, 10, 30, 60 and 90 after initiation of treatment. Secondary objectives were to compare, using a case-control design, CPAP compliance of OSA patients (n=133) with or without EI. RESULTS: Ninety-eight percent of patients accepted the intervention to participate in the study. Fifty-seven patients (86%) received the full intervention program and 44 patients (66%) strictly respected the pre-defined timings per protocol. A higher adherence to CPAP at six months was observed in the EI group compared to patient without EI (94% versus 81%) (P<0.05). CPAP compliance at three months was 54minutes higher in the EI group compared to the control group (4h39±2h17 and 3h45±2h45 respectively) but this difference was not statistically significant. CONCLUSION: An educational intervention dispensed by phone is applicable and would have an impact on CPAP compliance. Its efficacy on long-term compliance has to be confirmed in a larger group using a randomized procedure.

[Initiation of long-term non-invasive ventilation at home: current practices and expected issues. Surveys from the CasaVNI working party]. / Mise en route d'une ventilation non invasive : pratiques actuelles et évolutions attendues. Enquêtes du groupe de travail CasaVNI.

INTRODUCTION: At the initiative of the Antadir Federation, the expert group CasaVNI has undertaken a study of the current situation and the medium term outlook of the initiation of long term non-invasive ventilation (NIV) in France and other countries. METHODS: Three surveys have been undertaken: (1) the first concerning the modalities of installation and surveillance of long-term NIV in France, (2) a second concerning the same modalities in other countries, (3) a third concerning the current prevalence and expected incidence of long-term NIV over the next few years. RESULTS: The initiation of long-term NIV takes place in hospital in the majority of cases (France 76%, elsewhere 79%) and the surveillance mainly at a day hospital (France 59%, elsewhere 43%). Despite the interrogation of many sources, the working party has been unable to determine the exact incidence and prevalence of patients receiving long-term NIV in France. CONCLUSION: With regard to the initiation of long-term NIV, clinical studies and guidelines are still necessary to validate the alternatives that will permit a response to the increasing demand while maintaining high standards.

Integrin-linked kinase has a critical role in ErbB2 mammary tumor progression: implications for human breast cancer.

Elevated expression of the integrin-linked kinase (ILK) has been observed in a variety of cancers and has been further correlated with poor clinical outcome. Here, we show that mammary epithelial disruption of ILK results in a profound block in mammary tumor induction. Consistent with these observations, inhibition of ILK function in ErbB2-expressing cells with small molecule inhibitor or RNA interference resulted in profound block in their in vitro invasive properties due to the induction of apoptotic cell death. The rare ILK-deficient tumors that eventually arose overcame this block in tumor induction by an upregulation of ErB3 phosphorylation. These observations provide direct evidence that ILK has a critical role in the initiation phase of ErbB2 tumor induction.

Allosteric effects of G protein overexpression on the binding of beta-adrenergic ligands with distinct inverse efficacies.

Allosteric models of G protein-coupled receptors predict that G protein influences the spontaneous isomerization between inactive (R) and active (R*) conformations. Since inverse agonists have been proposed to preferentially bind to the inactive and uncoupled form(s), changes in the G protein content should influence the binding properties of these ligands. To test this hypothesis, we systematically assessed the effect of G proteins on the binding of beta(2)-adrenergic ligands with distinct levels of inverse efficacy. Recombinant baculoviruses encoding the human beta(2)-adrenoreceptor (beta(2)AR) were expressed alone or in combination with G protein subunits in Sf9 cells. Coexpression with the G protein alpha s beta 1 gamma 2 did not influence the relative efficacy of the ligands to inhibit the adenylyl cyclase but induced considerable decrease in number of sites detected by [(3)H]ICI 118551, [(3)H]propranolol, and (125)I-cyanopindolol. This loss was proportional to the inverse efficacy of the ligand used as the radiotracer in the assay. The addition of Gpp(NH)p inhibited the effects of G protein overexpression indicating that the G proteins acted allosterically. Consistent with this notion, Western blot analysis revealed that coexpression with the G proteins was not accompanied by a loss of immunoreactive beta(2)AR. Such allosteric effects of the G proteins were also observed in mammalian cells expressing endogenous level of G proteins indicating that the phenomenon is not unique to overexpression systems. Taken together, these results demonstrate that the apparent receptor number detected by radiolabeled inverse agonists is affected by the content in G proteins as a result of their influence on R/R* isomerization.