[Resistance to anti-EGFR through the successive and cumulative acquisition of two new oncogenic addictions: BRAF and ALK]. / Résistance aux anti-EGFR via l'acquisition successive et cumulée de deux nouvelles addictions oncogénique BRAF et ALK.

Targeted therapies are the standard first-line treatment for metastatic lung adenocarcinoma with certain molecular abnormalities. These abnormalities are particularly common in Southeast Asia and French Polynesia. A 51-year-old Tahitian female non-smoker was diagnosed in 2018 with stage IV lung adenocarcinoma harboring a p.L858R EGFR mutation. She received gefitinib as first-line treatment. Due to locoregional progression and the presence of a resistance mutation (p.T790M of EFGR), she received osimertinib as second-line treatment, after which chemotherapy was proposed as 3rd-line treatment. An additional biopsy detected not only the previously known EGFR mutation, but also a BRAF p.V600E mutation. Following disease progression during chemotherapy, the patient received targeted therapies combining dabrafenib, trametinib and osimertinib. Due to a dissociated response after four months of treatment, a 5th line of paclitaxel bevacizumab was initiated. Subsequent to additional progression and given the ALK rearrangement shown on the re-biopsy, 6th-line treatment with alectinib was proposed. As the response was once again dissociated, a final line was proposed before stopping active treatments due to their toxicity and overall deterioration in the patient's state of health. This exceptional case is characterized by resistance to anti-EGFR through the successive and cumulative acquisition of two new oncogene addictions. The authors underline the importance of re-biopsy at each progression, leading (if at all feasible) to yet around round of targeted therapy.

[Severe adult asthma and treatment adherence: Results of the FASE-CPHG study]. / Asthme sévère de l'adulte et observance : résultats de l'étude FASE-CPHG.

INTRODUCTION: Data on severe asthma in France are scarce. The aim of this study was to evaluate adherence to asthma treatments and its determinants in a population of severe asthmatics. METHODS: From May 2016 to June 2017, the French Collège des Pneumologues des Hôpitaux Généraux organized a large-scale prospective, cross-sectional, multicenter study on this topic; 1502 patients with severe asthma were included. RESULTS: The average number of substantive treatments was 2.5±1.1. Assessed by self-questionnaire in 1289 patients, overall adherence was 64.8%, in good agreement with the findings of the pneumologist in charge (p<0.0001). Control of asthma according to the GINA criteria was more successful in compliant patients (p<0.01). In univariate analysis, the most compliant participants were frequent exacerbator patients (p=0.02), those with nasal polyposis (p=0.01) and those receiving an anticholinergic agent (p<0.01), anti-IgE biotherapy (p<0.0001) or oral corticosteroids (p<0.01). The least compliant participants were younger (p<0.0001), active smokers (p<0.001), with shorter average disease duration (24.2±15.7 vs 29.1±18.7 years, p<0.0001) and a lower number of substantive asthma treatments (2.2±1 vs 2.6±1, p<0.0001). In multivariate analysis, age, length of disease and anti-IgE treatment were the only factors affecting therapeutic compliance. CONCLUSION: In this large-scale study of severe asthmatic patients, 64.8% were compliant according to the MMAS-4© self-administered questionnaire and appeared to be better monitored according to the criteria defined in our study. Overall, adherence was more satisfactory among older patients and those whose disease had been evolving over a long period of time or were receiving anti-IgE biotherapy.

[Physical activity in severe asthma: Results of the FASE-CPHG Study]. / Activité physique et asthme sévère : résultats de l'étude FASE-CPHG.

INTRODUCTION: Data on physical activity in severe asthma are scarce. From May 2016 to June 2017, 1502 adult patients with severe asthma visiting a pulmonologist practicing in one of the 104 non-academic hospitals participating in the study were included in this prospective, cross-sectional, multicenter study, provided they gave consent. Physical activity was classified according to 4 levels: 1 (no activity), 2 (occasional), 3 (regular), or 4 (frequent). Clinical and therapeutic parameters were described according to these levels. RESULTS: Respectively, 440, 528, 323, and 99 patients had physical activity of level 1, 2, 3, and 4. The percentage of patients with controlled asthma increased with physical activity. Treatment adherence did not differ with physical activity. Percentages of obese patients, patients with FEV1 <60%, and patients with anxiety, depressive syndrome, gastro-esophageal reflux disease, arterial hypertension, diabetes, obstructive sleep apnoea-hypopnoea syndrome, and osteoporosis decreased with physical activity. Respiratory rehabilitation was offered to only 5% of patients. CONCLUSIONS: In this large study, physical activity is associated with disease control in severe asthma and with less comorbidity. Its practice should be encouraged and respiratory rehabilitation offered more often.

[Multicenter Ozurdex® assessment for diabetic macular edema: MOZART study]. / Étude rétrospective du traitement par Ozurdex® dans l'œdème maculaire diabétique: MOZART study.

PURPOSE: To evaluate the efficiency and safety of intravitreal implant of 0.7mg dexamathasone in visual impairment due to diabetic macular edema (DME). MATERIALS AND METHODS: This was a retrospective, multicenter, study. Seventy-four patients, with a mean age of 65 years, followed for at least 6 months (mean follow-up: 9.8 months) were included in 5 French eye clinics (P 1.5 collective). The mean systolic blood pressure was 138mmHg and the mean HbA1c was 7.2%. We monitored 2 systemic parameters: blood pressure and glycemic balance. Best-corrected visual acuity (BCVA), central retinal thickness (CRT, Spectralis OCT), intraocular pressure (IOP) and cataract progression are studied at baseline and then at 1, 2, 4 and 6 months. RESULTS: The average CRT decrease was: 239µm at month 2 (M2) and 135µm at month 6 (M6). The mean improvement from baseline of BCVA is 8.5 letters at M2 and 7.6 letters at M6. A gain greater than 15 letters is found in 27% of patients at M6. For naive patients the BCVA is 71 letters versus 60 letters (P<0.05). Patients with a baseline CRT <500mmHg have a BCVA of 66 letters versus 57 letters (P<0.05). The mean rate injections was 1.2 at 6 months with an average of 5.4 months for reinjection. Ocular hypertension greater than 25mmHg, managed by topical treatment, is observed in 13.4% of patients. No glaucoma surgery was necessary. CONCLUSION: Dexamethasone has an anatomical and functional effectiveness in the treatment of DME. Outcomes for naive patients and lower CRT suggest that the duration of diabetes mellitus and previous treatments are negative factors of recovery. Side effects are rare and manageable. Ozurdex(®) seems to be a treatment for visual impairment due to DME with a favorable safety profile. Patient follow-up must be adapted to half-life of the product with a control before M1 (intraocular pressure) and before M5 (DME recurrence, BCVA).

[Anatomical and functional prognosis of secondary retinal detachments after sutureless macular surgery]. / Pronostic anatomique et fonctionnel des décollements de rétine secondaires après chirurgie maculaire sans suture.

PURPOSE: To evaluate the incidence, characteristics and risk factors for rhegmatogenous complications of transconjunctival sutureless 23-gauge vitrectomy (TSV) in macular surgery. The results were correlated with those reported in the literature. METHODS: Multicentric retrospective study of a cohort of patients undergoing macular surgery by 23-gauge TSV between January 2009 and June 2010. RESULTS: Four hundred and seventy-four patients divided into: epiretinal membrane (MEM) (n=279), vitreomacular traction (n=65) and idiopathic macular hole n=130. Forty-three percent of patients were pseudophakic. Posterior vitreous detachment (PVD) was absent in 60% of cases and was therefore systematically performed intraoperatively. It was seen that 1.7% of patients developed retinal tears and 2.7% retinal detachment with a higher incidence in the vitreomacular traction (VMT) group and the group in which the PVD was performed intraoperatively. Rhegmatogenous lesions were localized mainly in the inferior retina in the macular hole group. DISCUSSION: Results are consistent with the TSV literature. Their location does not appear to be related to the sclerotomies or handedness as in 20-gauge surgery, probably due to sclerotomy trocars. Localization of rhegmatogenous lesions in the inferior retina in macular hole surgery suggests a role of gas in this subgroup. In addition to instrument-retinal touch, the performance of a surgical PVD represents a major independent risk factor for retinal detachment (RD). CONCLUSION: Even with limited macular surgery, it is essential to check the retinal periphery for 360 degrees, especially for VMT and intraoperative PVD, and especially inferiorly in the case of gas tamponnade.

Electrophysiological effects of corticosteroids on the retinal pigment epithelium.

PURPOSE: As corticosteroids appear to intervene in pathogenesis of central serous chorioretinopathy, ion transport changes within the retinal pigment epithelium (RPE) might be involved. Electrophysiological responses to corticosteroid administration were recorded in vivo and in vitro. METHODS: Clinical study: The standing ocular potential was recorded during intravenous (IV) infusion of glucose 5% and glucose 5% + prednisolone 0.2% in 14 patients with relapsing multiple sclerosis. The results were compared with a control group receiving two successive identical glucose 5% infusions. In vitro study: Native tissue explants (RPE + choroid, porcine, and bovine) were placed in a Ussing-type chamber. After baseline determination of the transepithelial potential (PD), short circuit current (I(sc)) and transepithelial resistance (R(t)), the effect of apical hydrocortisone (HC) 10(-4) M was determined. RESULTS: Clinical study: A significant rise of the standing potential was found after glucose infusion (P = 0.005), whereas no change was detected after IV glucose + prednisolone (P = 0.695). In vitro study: In the porcine RPE, the mean baseline PD and I(sc) were significantly reduced (both P: = 0.012) after applying apical 10(-4) HC. R(t) was also significantly reduced (P = 0.01). The same type of response, observed in bovine RPE, was reduced in low chloride/low bicarbonate conditions. CONCLUSIONS: Corticosteroids modified electrophysiological parameters representing RPE function in vivo. The existence of an RPE-specific effect was confirmed in vitro. Further work is required to link the observed ion transport changes to a reduction of apical, subretinal fluid absorption.

[Atypical cerebral lymphoma with ocular onset: report of a case]. / Lymphome cérébral atypique à révélation oculaire: à propos d'un cas.

A 72 year-old woman is hospitalized and explored in the neurological department because of dementia discovered after a vitrectomy performed to treat a relapsing chronic uveitis. MRI examination shows atypical hyperintense white matter lesions on T2 weighted images related to Lyme disease. Worsening of clinical status, despite appropriate medical treatment and apparition of enhanced nodules MR images rules out the diagnosis of lyme disease and is attributed to brain metastases. The search for primitive tumor is not contributive and a brain biopsy is performed. It discloses a B cells non-hodgkin lymphoma. This case report stresses two points: first, a lymphoma must be one of the diagnosis to evocate if imaging shows an enhancing nodule, or extensive hypersignal of the white matter, second: it emphasizes the value of vitreous analysis searching for lymphoma during chronic uveitis associated to neurological symptoms.

[Fuchs' uveitic syndrome in a patient with ocular toxoplasmosis]. / Syndrome uvéitique de Fuchs chez une patiente porteuse d'une toxoplasmose oculaire.

We report a case of Fuchs' uveitic syndrome associated with toxoplasmic chorioretinis scars, and a positive Desmonts' coefficient. This allows us to emphasize ocular toxoplasmosis as a main association to be searched for clinically. In the cases in which this association is found, it would be warranted, if a high level of specific antitoxoplasmic antibodies is demonstrated in aqueous humor, to consider toxoplasmosis as one of the potential etiopathogenic factors of the Fuchs' uveitic syndrome.

[Biological perspectives]. / Perspectives biologiques.

The tumour biology of non-small cell bronchial cancer integrates recent developments and a dynamic schema of the phenomena of tumour progression and diffusion of the metastatic disease. There is no leap of known biological disruption between Stage II and Stage III. The latter is defined by anatomical criteria and is a transition in the continuum of the natural history of these cancers. The moto for the tumour progression is the genotypic instability and phenotypic diversification. Metastatic microscopic disease constitutes the first cause of failure in the treatment of Stage III non-small cell bronchial cancer. Among prognostic factors for survival emphasis is placed on the alterations of p53 expression, different types of aneuploidy, anomalies of the expression of cellular adhesion molecules and finally, tumour diversification towards a metastatic phenotype.

[Retinochoroidal involvement of type II membranoproliferative glomerulonephritis. An angiographic study with indocyanine green]. / Atteinte rétinochoroïdienne dans les glomérulonéphrites membrano-prolifératives de type II (GNMP II). Une étude angiographique au vert d'indocyanine.

PURPOSE: Type II measangiocapillary glomerulonephritis is related to dense deposits within the glomerular basal membrane and the basal membrane of the pigment epithelium (Bruch's membrane). Being a vasculitis, an angiographic study by indocyanine green (ICG) could possibly enlarge the semiologic features of this disease. METHODS: The indocyanine green angiographic changes in 3 patients with predialitic renal failure due to type II measangiocapillary glomerulonephritis (MCGN II) (dense deposit disease) are reported. A complete ophthalmologic examination, electroretinography, electro-oculography, fluorescein and indocyanine green angiography (ICG) were performed for each patient. RESULTS: Abnormal hyperfluorescent dots were seen on the same part of the fundus on both fluorescein and ICG angiography, though these locations were different for each of the three patients. These results seem to link the deposits to vascular changes within the choriocapillaris, which opposes them to drusen encountered in age related macular degeneration (ARMD). It appears that the choriocapillary lesions could be similar to the glomerular disease. CONCLUSION: Beyond the diagnostic challenges related to the nephrologic disease, it is known that subretinal neovascularization occurs in some cases of MCGN II, although the pathophysiologic mechanism of the deposits is probably not the same as in ARMD. Therefore, ICG angiography should be performed when MCGN II is first known, serving as an initial examination for further follow-up.

Cytokeratins as serum markers in lung cancer: a comparison of CYFRA 21-1 and TPS.

We examined two recently described cytokeratin markers, CYFRA 21-1 (cytokeratin fragment recognized by KS 19-1 and BM 19-21 antibodies) and TPS (specific M3 epitope of the tissue polypeptide antigen), in 405 lung cancer patients (91 small-cell and 314 non-small-cell lung cancers) and 59 patients presenting with nonmalignant pulmonary disease. Sensitivity-specificity relationship, as analyzed by receiver operating characteristic curves, demonstrated a higher accuracy of CYFRA 21-1 in comparison with TPS in both small-cell and non-small-cell lung cancers. Thresholds of 3.6 ng/ml and 140 U/L for CYFRA 21-1 and TPS respectively gave a 90% to 95% specificity. Sensitivity of CYFRA 21-1 was the highest in squamous-cell carcinomas (0.61) and the lowest in small-cell lung cancers (0.36), whereas sensitivity of TPS did not vary significantly according to histology (overall sensitivity, 0.40). In non-small-cell lung cancers, both serum CYFRA 21-1 and serum TPS distributions varied significantly according to Mountain's stage of the disease, nodal status, tumor status, and performance status, inasmuch as the worse each above-mentioned variable became, the higher the median and interquartile serum marker level was. Neither CYFRA 21-1 nor TPS was able to accurately discriminate between stage IIIa (marginally resectable) and stage IIIb (unresectable) non-small-cell lung cancers, however. In both small-cell and non-small-cell lung cancers, univariate survival analyses demonstrated that either a CYFRA 21-1 level over 3.6 ng/ml or a TPS level over 140 U/L significantly indicated a poor survival rate. In the whole population, taking into account other significant variables, Cox's model analysis demonstrated that a poor performance index, an advanced stage of the disease, the presence of metastases, elevated serum lactate dehydrogenase, and high serum CYFRA 21-1 (odds ratio, 1.74; 95% confidence interval, [1.33-2.27] were independent prognostic variables. We concluded that CYFRA 21-1 is a significant determinant of survival. Other applications of cytokeratin markers in lung cancer are still limited.

Lung cancer chemotherapy. Response-survival relationship depends on the method of chest tumor response evaluation.

In a previous study we found that tumor responses as assessed by CT scan and fiberoptic bronchoscopy are sometimes discordant. We hypothesize that the response-survival relationship might vary according to the method of tumor response assessment. In a multivariate analysis of survival using the landmark method, we evaluated the prognostic significance of tumor response assessed by CT scan or fiberoptic bronchoscopy together with bronchial tumor location and histology of bronchial biopsies at restaging. A total of 133 lung cancer patients (50 small cell lung cancers and 83 non-small cell lung cancers) were entered in controlled chemotherapy trials and prospectively evaluated for chest tumor response by CT scan and fiberoptic bronchoscopy (FOB). Only 106 patients were fully evaluable for response by both methods. For these patients, a statistical concordance was observed between the two tests (kappa = 0.271; p < 0.001). There was a significant correlation between response and survival whatever the test used. However, only CT scan evaluation resulted in a classification showing that the more unfavorable the response stage was, the worse the survival became with no intersection between survival curves. Cox's hazard model demonstrated that CT-evaluated progression, proximal bronchial location at second FOB (intermediate, main bronchus or trachea) and positive histologic status at restaging were all prognostic determinants of poor survival. In conclusion, CT-evaluated response led to the best response-survival relationship as this method classified patients into four groups with different outcomes. Fiberoptic bronchoscopy should be avoided in patients who were found to have no endobronchial lesion during the pretreatment staging. For patients with pretreatment assessable endobronchial lesions, the decision of a second FOB depends on the results of CT restaging: FOB is probably unnecessary in patients for whom progression is disclosed by CT scan. In patients for whom CT scan discloses tumor response or stabilization, bronchial tumor location and histology of bronchial biopsies at second FOB are independent prognostic factors.

[Evaluation of tumor response during chemotherapy of bronchial cancer]. / Evaluation de la réponse tumorale au cours de la chimiothérapie du cancer bronchique.

Chemotherapy of lung cancer is still an experimental approach requiring careful evaluation. Tumour response (marker of anticancer activity) is not perfectly correlated to survival (marker of chemotherapy efficacy), but its evaluation remains a milestone inasmuch as reporting a wrong tumour response rate might lead to the rejection of active new treatments. This review deals with the method of tumour response measurements and its use during a chemotherapy protocol. Recommendations drawn from the analysis of the literature are: 1) to assess and classify all lesions which can be identified at the beginning of the treatment; 2) to define the target lesions, mainly the ones which can be bidimensionally measured; 3) to use the World Health Organization recommendations for reporting the overall response; 4) to confirm complete response by negative rebiopsies; 5) to avoid second fiberoptic bronchoscopy to patients with stable or progressive disease on CT-scan, and finally; 6) to assess response quality by evaluating response duration and improvement of quality of life.

Chest tumor response during lung cancer chemotherapy. Computed tomography vs fiberoptic bronchoscopy.

Tumor response is one of the most important criteria in the analysis of chemotherapy. A chest computed tomographic (CT) scan and fiberoptic bronchoscopy (FOB) might give different results, as they analyze different aspects of the effects of chemotherapy on lung cancer. The response of the chest tumor in 103 patients with stage III or IV lung cancer (35 with small-cell lung cancer [SCLC] and 68 with non-small-cell lung cancer [NSCLC]) who prospectively entered chemotherapy trials was studied in order to determine the concordance between the chest CT scan and FOB. The chest CT scan allowed an assessment of tumor response in almost all patients, whereas FOB was not able to evaluate this response in 15 of the 103. The frequency of an evaluable endobronchial lesion did not depend on histology (SCLC, 97 percent; NSCLC, 93 percent; chi 2 = 0.85; not significant [NS]) or tumor T classification (T1-2, 83 percent; T3, 94 percent; T4, 97 percent; chi 2 = 1.49; NS). Tumor location in the bronchial airway did not differ when SCLC and NSCLC were compared. Thus, it is not possible to predict a subgroup of patients in whom FOB may be optional. In the group of 88 patients who were evaluable for response using both FOB and CT scan, a statistical concordance of the response classification was observed. The response was overevaluated by CT scan in 22 patients for whom data obtained by FOB appeared to be critical in the evaluation of tumor response. The concordance of response data obtained when the 2 methods were used was lower in NSCLC in comparison with SCLC. Thus, the use of FOB in the analysis of tumor response might be important, especially for NSCLC, inasmuch as FOB modulates the CT-evaluated response.