[IHC, FISH, CISH, NGS in non-small cell lung cancer: What changes in the biomarker era?] / IHC, FISH, CISH, NGS dans les cancers bronchiques non à petites cellules : quelles évolutions dans l'ère des biomarqueurs ?

Lung cancer is the leading cause of cancer deaths in France, with about 30,000 deaths per year. The overwhelming majority (90 %) are tobacco-related. The prognosis is dark but great therapeutic advances have been made with the development of targeted therapies first and then immunotherapy afterwards. These medications are conditioned to the expression of biomarkers that require specific tools in routine to measure them. We will detail in this chapter several techniques of anatomopathology, cytogenetics and molecular biology necessary for the detection of biomarkers in lung cancers, and their applications in thoracic oncology in 2018.

[Bronchoscopic treatment of bronchopleural fistula]. / Traitement endoscopique des fistules bronchopleurales.

Bronchopleural fistula is an uncommon complication occurring especially following lung resection (pneumonectomy) and associated with high morbidity and mortality rates. The treatment is surgical but some studies reported bronchoscopic treatment. Localization and size of the fistula may indicate different endoscopic procedures. This overview described the different endoscopic procedures and their benefits.

[Mesothelioma and familial Mediterranean fever: A relationship?]. / Mésothéliome et fièvre méditerranéenne familiale : quelle relation ?

INTRODUCTION: The majority of pleural and peritoneal mesotheliomas are linked to asbestos exposure but, in around 20% of cases, no history of such exposure is found. Periodic disease is associated with recurrent serositis, which could favor the development of mesothelioma. CASE REPORT: We report a case of pleural mesothelioma in a 50-year-old Lebanese woman, with no detectable exposure to asbestos but suffering from periodic disease (familial Mediterranean fever) with recurrent episodes of serositis. DISCUSSION: Many cases of peritoneal mesothelioma in patients with FMF are reported in the literature. This is the second reported case of pleural mesothelioma associated with periodic disease. Because of the low incidence of both diseases, further publications are required to support the hypothesis of a causal link. It is important, therefore, that all cases of an association of periodic disease and mesothelioma are reported.

[Effect of tinzaparin on survival in non-small-cell lung cancer after surgery. TILT: tinzaparin in lung tumours]. / Effet de la tinzaparine sur la mortalité du cancer bronchique non à petites cellules opéré.

BACKGROUND: Experimental and clinical findings suggest that low molecular-weight heparins may improve overall survival in patients with cancer. The evidence is still limited and additional studies are needed to confirm these preliminary findings. METHODS: Patients with completely resected stage I, II or IIIA (T3N1) histologically confirmed non-small-cell lung cancer will be included in a prospective, controlled, randomized, multicenter open trial. Patients in the control group will receive usual postoperative care including chemotherapy when indicated. Patients in the experimental group will receive tinzaparin given subcutaneously as a daily 100 IU/kg dose for 90 days along with usual postoperative care. Patients will be followed-up for three to eight years. Main end-point is the overall survival. Five hundred and fifty patients are needed to demonstrate a 10% absolute increase in survival in the experimental group. EXPECTED RESULTS: A 10% absolute increase in the survival rate is expected in the patients receiving tinzaparin.

Total hip arthroplasty offset measurement: is C T scan the most accurate option?

BACKGROUND: Femoral offset is difficult to precisely evaluate with conventional X-ray techniques. Femoral offset characterizes the balance between body weight and the resistance provided by the abductor muscles. Total hip arthroplasties should respect this balance. HYPOTHESIS: Computed tomodensitometry (CT-scan) is more accurate than conventional X-ray to evaluate femoral offset. MATERIALS AND METHODS: Sixty-one patients who received unilateral total hip arthroplasties were prospectively included in the study. Femoral offset was measured by three-dimensional CT-scan reconstruction using the "Hip Plan" (Symbios) software. Offset was also determined with conventional X-ray and results were compared. This software can be used to measure leg length by frontal telemetry. It was developed for preoperative-planning of cementless femoral stem implants with modular necks of various lengths and angles. All pre- and postoperative measurements were made according to the same protocol. RESULTS: Femoral offset values in this study were very similar to anatomical values found in the literature. They were significantly higher than values obtained by conventional X-ray by an average of 8%. Implantation of hip replacements resulted in a significant increase in offset (1.88+/-4.71 mm) with a slight variation in leg length. Pre- and postoperative leg length increased slightly in the operated leg by an average of 1.66+/-5.63 mm. Seventeen percent of these femurs had high offset associated with small or average sized proximal medullary canals. This preoperative planning software made it possible to identify these difficulties and to adapt implant components using modular long 8 degrees varus necks to restore high offset. In most of these cases, only small femoral stems could be implanted because of the small size of the intramedullary femoral canal. These individual differences were identified with 3D CT-scan reconstruction and included in the preoperative planning. Moreover, leg length could also be evaluated with this method and included in the preplanning. DISCUSSION: Compared to conventional X-ray, measurements obtained with this preoperative planning method using 3D CT-scan reconstruction are easy to obtain and not dependent upon test conditions because the frame is placed on the femoral axis. Measurements are not influenced by position inconsistencies or if the hip is fixed in external rotation. The significant number of cases with above average offset confirms the importance of obtaining these measurements and the necessity of adapting the strategy in these cases by using lateralized stems, or, as in our series, modular necks to adjust femoral offset and neck angle. LEVEL OF EVIDENCE: Level III diagnostic prospective study.

Chronic lateral ankle instability surgical repairs: the long term prospective.

UNLABELLED: The present study sought to assess the clinical and radiological results and long-term joint impact of different techniques of lateral ankle ligament reconstruction. MATERIAL AND METHODS: A multicenter retrospective review was performed on 310 lateral ankle ligament reconstructions, with a mean 13-year-follow-up (minimum FU: 5 years). Male subjects (53%) and sports trauma (78%) predominated. Mean duration of instability was 92 months; mean age at surgery was 28 years. Twenty-eight percent of cases showed subtalar joint involvement. Four classes of surgical technique were distinguished: C1, direct capsular ligamentous complex reattachment; C2, augmented repair; C3, ligamentoplasty using part of the peroneus brevis tendon and C4, ligamentoplasty using the whole peroneus brevis tendon. Clinical and functional assessment used Karlsson and Good-Jones-Livingstone scores; radiologic assessment combined centered AP and lateral views, hindfoot weight-bearing Méary views and dynamic views (manual technique, Telos or self-imposed varus). RESULTS: The majority of results (92%) were satisfactory. The mean Karlsson score of 90 [19-100] (i.e., 87% good and very good results) correlated with the subjective assessment, and did not evolve over time. Postoperative complications (20%), particularly when neurologic, were associated with poorer results. Control X-ray confirmed the very minor progression in degenerative changes, with improved stability; there was, however, no correlation between functional result and residual laxity on X-ray. Unstable and painful ankles showed poorer clinical results and more secondary osteoarthritis. Analysis by class of technique found poorer results in C4-type plasties and poorer control of laxity on X-ray in C1-type tension restoration. DISCUSSION: The present results confirm the interest of lateral ankle ligamentoplasty in the management of instability and protection against secondary osteoarthritis, and of precise lesion assessment (CT-scan/MRI) to adapt surgery to the ligamentary and associated lesions. LEVEL OF EVIDENCE: Level IV. Retrospective therapeutic study.

[Arterial and venous thrombosis in lung cancer]. / Thrombose artérielle et veineuse et cancer bronchique.

We report the case of a 61-year old man in whom a deep venous thrombosis was the presenting feature of disseminated lung carcinoma. A few days later, an arterial thrombosis occurred necessitating amputation. Within a few weeks, the lung cancer progressed dramatically and the patient died. While the association between venous thrombosis and cancer is well known, the relationship between cancer and arterial thrombosis has been less explored. This observation allows discussion of the pathophysiological and clinical aspects of this association, as well as the implications for patient care.

[Bronchial carcinoma and actinomycosis: a dangerous trap]. / Cancer bronchique et actinomycose: un piège dangereux.

A 60 year old male patient was admitted to hospital with pulmonary and cerebral abscesses. A percutaneous lung biopsy under CT scanning showed actinomycosis. After 4 weeks antibiotic therapy with ceftriaxone and metronidazole there was an improvement in the pulmonary lesion but new cerebral lesions appeared. A neurosurgical cerebral biopsy showed evidence of metastatic squamous carcinoma, probably of pulmonary origin. The diagnosis had been delayed by the presence of the actinomycosis. His general condition did not permit anti-tumour treatment and the patient soon afterwards. In the presence of pulmonary actinomycosis an associated malignancy should be excluded.

Femoral offset: anatomical concept, definition, assessment, implications for preoperative templating and hip arthroplasty.

UNLABELLED: BACKGROUND OBJECTIVE: Femoral offset is supposed to influence the results of hip replacement but little is known about the accurate method of measure and the true effect of offset modifications. MATERIAL AND METHODS: This article is a collection of independent anatomic, radiological and clinical works, which purpose is to assess knowledge of the implications of femoral offset for preoperative templating and total hip arthroplasty. RESULTS: There is a strong correlation between femoral offset, abductors lever arm and hip abductor strength. Hip lateralization is independent of the femoral endomedullary characteristics. The abductors lever arm is highly correlated to the gluteus medius activation angle. There were correlations between femoral offset and endomedullary shape. The hip center was high and medial for stovepipe metaphysis while it was lower and lateralized for champagne - flute upper femur. A study was performed to compare the femoral offset measured by X-ray and CT-scan in 50 patients, demonstrated that plain radiography underestimates offset measurement. The 2D templating cannot appreciate the rotation of the lower limb. Taking into account the horizontal plane is essential to obtain proper 3D planning of the femoral offset. A randomized study was designed to compare femoral offset measurements after hip resurfacing and total hip arthroplasty. This study underlined hip resurfacing reduced the femoral offset, while hip replacement increased offset. However, the reduction of femoral offset after hip resurfacing does not affect the function. A pilot study was designed to assess the results of 120 hip arthroplasties with a modular femoral neck. This study showed that the use of a modular collar ensures an easier restoration of the femoral offset. A cohort of high offset stems (Lubinus 117 degrees) was retrospectively assessed. The survival rate was slightly lower that the standard design reported in the Swedish register. Finally, the measurement of offset and leg length was assessed with the help of computer assistance. The software changed the initial schedule (obtained by templating) in 29%. CONCLUSION: Therefore, femoral offset restoration is essential to improve function and longevity of hip arthroplasty. CT-scan is more accurate than plain radiography to assess femoral offset. Hip resurfacing decreases offset without effect on function. Modular neck and computer assistance may improve intraoperative calculation and reproduction of femoral offset. Increasing offset with a standard cemented design may decrease long-term fixation. Level IV: Retrospective or historical series.

[Pericarditis: a giant cell arteritis manifestation]. / La péricardite: une manifestation de la maladie de Horton.

INTRODUCTION: Temporal arteritis is a vasculitis in which inflammatory manifestations mainly involve the external carotid artery area but not exclusively. Through a clinical observation and a review of the literature, we suggest that inflammatory pericarditis could represent a manifestation of temporal arteritis. EXEGESIS: A 75-year-old-woman was admitted for progressive physical deterioration which had been evolving for three months, associated with fever, frontotemporal cephalalgia and severe biological inflammatory syndrome. Chest X-ray reveals a cardiomegaly and suggests a pericarditis, which was rapidly confirmed by echocardiogram. Temporal artery biopsy concludes to the diagnosis of a giant cell arteritis. Steroids treatment is prescribed, leading to a rapid regression of the inflammatory state and the pericarditis without relapse after 6 months of follow-up. CONCLUSION: Only prospective studies on systematic echocardiography when faced with the diagnosis of giant cell arteritis, whatever clinical symptoms, will enable to appreciate the prevalence and prognosis value of this manifestation. Moreover, temporal artery analysis seems to be justified when faced with a sub-acute or chronic "idiopathic" inflammatory pericarditis occurring in the elderly patient. Physiopathogeny is unknown but some hypothesis can be proposed: inflammatory cytokines storm, immune complexes deposition, giant cell vasculitis of pericardial arteries or inflammatory interstitial lesion of the pericardium with or without granuloma.

[Computer-assisted positioning of the acetabular cup for total hip arthroplasty based on joint kinematics without prior imaging: preliminary results with computed tomographic assessment]. / Positionnement de la cupule d'une prothèse totale de hanche par navigation sans image basée sur la cinématique articulaire: Premiers résultats avec evaluation tomodensitométrique de l'orientation des implants.

PURPOSE OF THE STUDY: Most navigation systems for computer-assisted total hip arthroplasty (THA) require prior computed tomography (CT) or acquisition of multiple bone landmarks on the pelvis. In order to avoid these problems, we developed a computer-assisted navigation system without CT based on a kinematic approach to the hip joint. The principle is to orient the cup in relation to the cone describing the hip joint range of motion. The purpose of this work was to analyze preliminary results. MATERIAL AND METHODS: Eighteen primary THA were implanted with the system (16 women, two men, mean age 68 +/- 7.8 years, age range 54-83 years, 18 degenerative hip disease). Two optoelectronic captors were fixed percutaneously on the pelvis and the distal femur. The acetabulum was prepared first followed by the femur using reamers and broaches of increasing size. The last broach placed in the femur was equipped with a large head adapted to the newly prepared acetabulum. The range of hip motion was recorded to determine the maximal range of motion cone. The acetabular cup was thus positioned in order the prosthesis range of motion included entirely the maximal range of motion of the hip joint. RESULTS: One patient fell three weeks after implantation causing posterior dislocation; there was no recurrence. The Postel-Merle-d'Aubligné score improved from 8 +/- 2.9 (range 3-12) preoperatively to 17 +/- 0.8 (range 16-18) at last follow-up. None of the patients complained about the captor insertion and there were no cases of hematoma or fracture. Operative time was 35-40 minutes longer for the first four cases and was progressively reduced 15-20 minutes for the last four cases. Mean leg length discrepancy was 5.6 +/- 7.5 mm (range 0-25) before implantation and 0.6 +/- 3 mm (range -5 to 10 mm) at last follow-up. CT-scan measurements revealed a mean anteversion of the femoral implant of 18.2 +/- 8.5 degrees (range 0-31). Anatomic anteversion of the cup (measured from the pelvis landmark and thus independently of the position of the pelvis) was 24.7 +/- 8.8 degrees (range 12-40). The sum of the femoral and anatomic acetabular anteversions was 43 +/- 13.1 degrees (range 22-71). Anteversions were 16 degrees for the cup and 16 degrees for the stem for the one case of dislocation. CONCLUSION: This method can be used in routine without lengthening operative time significantly. It safely controls leg length and helps position the cup. This study demonstrated that there is no ideal position for the cup which can be used for all patients. Because of the wide range of inclination and anteversion figures, half of the cases were outside the safety zone recommended by Lewinnek.

ATP-induced apoptosis of thymocytes is mediated by activation of P2 X 7 receptor and involves de novo ceramide synthesis and mitochondria.

Thymocytes were reported to undergo apoptosis in the presence of extracellular ATP through the activation of the purinergic receptors P2 X 1R, P2 X 7R or both. We investigated the identity of the P2 X R and the signaling pathways involved in ATP-mediated apoptosis. Apoptosis elicited by ATP was prevented by inhibition of P2 X 7R, or in thymocytes bearing a mutated P2 X 7R, and reproduced with a P2 X 7R agonist, but not with a P2 X 1R agonist. Stimulation of thymocytes with either ATP or a P2 X 7R agonist was found to stimulate a late de novo ceramide synthesis and mitochondrial alterations. Inhibition of either processes attenuated apoptosis. Interestingly, stimulation with either ATP or a P2 X 1R agonist induced an early ceramide accumulation and a weak caspases-3/7 activation that did not lead to apoptosis. In conclusion, de novo ceramide generation and mitochondrial alterations, both resulting from P2 X 7R activation, were implicated in ATP-induced thymocyte apoptosis.

Sciatica caused by epidural gas. Four case reports.

We report four cases of sciatica caused by gas in the epidural space with no other abnormality. Only 21 similar cases have been reported. Clinical features are identical to those of common sciatica, and plain radiographs are often uninformative. Computed tomography shows a low-density epidural collection displacing the nerve root.

Deoxygenation of sickle cells stimulates Syk tyrosine kinase and inhibits a membrane tyrosine phosphatase.

Polymerization of hemoglobin S in sickle red cells, in deoxygenated conditions, is associated with K+ loss and cellular dehydration. It was previously reported that deoxygenation of sickle cells increases protein tyrosine kinase (PTK) activity and band 3 tyrosine phosphorylation and that PTK inhibitors reduce cell dehydration. Here, the study investigates which PTKs are involved and the mechanism of their activation. Deoxygenation of sickle cells induced a 2-fold increase in Syk activity, measured by autophosphorylation in immune complex assays, but had no effect on Lyn. Syk was not stimulated by deoxygenation of normal red cells, and stimulation was partly reversible on reoxygenation of sickle cells. Syk activation was independent of the increase in intracellular Ca++ and Mg2+ associated with deoxygenation. Lectins that promote glycophorin or band 3 aggregation did not activate Syk. In parallel to Syk stimulation, deoxygenation of sickle cells, but not of normal red cells, decreased the activity of both membrane-associated protein tyrosine phosphatase (PTPs) and membrane protein thiol content. In vitro pretreatment of Syk immune complexes with membrane PTP inhibited Syk autophosphorylation. It is suggested that Syk activation in vivo could be mediated by PTP inhibition, itself resulting from thiol oxidation, as PTPs are known to be inhibited by oxidants. Altogether these data indicate that Syk could be involved in the mechanisms leading to sickle cell dehydration.

Effects of PKC alpha activation on Ca2+ pump and K(Ca) channel in deoxygenated sickle cells.

We have previously shown that a pretreatment with phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C (PKC), reduced deoxygenation-induced K+ loss and Ca2+ uptake and prevented cell dehydration in sickle anemia red blood cells (SS cells) (H. Fathallah, E. Coezy, R.-S. De Neef, M.-D. Hardy-Dessources, and F. Giraud. Blood 86: 1999-2007, 1995). The present study explores the detailed mechanism of this PMA-induced inhibition. The main findings are, first, the detection of PKC alpha and PKC zeta in normal red blood cells and the demonstration that both isoforms are expressed at higher levels in SS cells. The alpha-isoform only is translocated to the membrane and activated by PMA and by elevation of cytosolic Ca2+. Second, PMA is demonstrated to activate Ca2+ efflux in deoxygenated SS cells by a direct stimulation of the Ca2+ pump. PMA, moreover, inhibits deoxygenation-induced, charybdotoxin-sensitive K+ efflux in SS cells. This inhibition is partly indirect and explained by the reduced deoxygenation-induced rise in cytosolic Ca2+ resulting from Ca2+ pump stimulation. However, a significant inhibition of the Ca2+-activated K+ channels (K(Ca) channels) by PMA can also be demonstrated when the channels are activated by Ca2+ plus ionophore, under conditions in which the Ca2+ pump is operating near its maximal extrusion rate, but swamped by Ca2+ plus ionophore. The data thus suggest a PKC alpha-mediated phosphorylation both of the Ca2+ pump and of the K(Ca) channel or an auxiliary protein.

[Various functions of human erythrocyte membrane lipids]. / Róznorodne funkcje lipidów blony plazmatycznej erytrocytów czlowieka.

The major phospholipid classes of the human red blood cell membrane are: phosphatidylcholine, phosphatidylethanolamine, phosphatidylserine and sphingomyelin. These phospholipids are distributed asymmetrically across the two halves of the lipid bilayer. This asymmetry appears to be generated and maintained by an ATP-dependent translocation of aminophospholipids from outer to inner leaflet, and by the interaction of phospholipids with skeletal proteins. The phosphoinositides account for 3-4% of total erythrocyte membrane phospholipid. They play an important role in signal transduction and are involved in other various membrane functions.

Inhibition of deoxygenation-induced membrane protein dephosphorylation and cell dehydration by phorbol esters and okadaic acid in sickle cells.

Deoxygenation (DO) of sickle cell anemia red blood cells (SS cells) induces membrane permeabilization to Ca2+, Na+, and K+ and cell dehydration mostly through the activation of the Ca(2+)-dependent K+ channels. We show that DO of both SS cells and normal red blood cells was accompanied by a nonspecific dephosphorylation of membrane proteins. After treatment with a protein kinase C activator (phorbol myristate acetate) or a phosphoprotein phosphatase inhibitor (okadaic acid), the level of membrane protein phosphorylation in deoxygenated cells was maintained higher or equal, respectively, to that of the oxygenated controls. We found that these drugs in SS cells (1) inhibited by 40% the DO-stimulated net Ca2+ uptake, without affecting the DO-stimulated Ca2+ influx, suggesting that they activated the Ca2+ efflux; (2) slightly increased the DO-induced Na+ uptake and decreased the DO-induced K+ loss; and (3) prevented the DO-induced cell dehydration. Both drugs are known to stimulate both phosphorylation and activity of the Ca pump and of the Na/H antiport. Inhibition of SS cell dehydration might be due to an activation of the Ca pump preventing [Ca2+]i elevation responsible for the stimulation of the K+ channels and/or to an activation of the Na/H exchange resulting in cell water gain.

[Myeloma with intrathoracic tumor expression]. / Myélome à expression tumorale intrathoracique.

We report a case of a patient of 58 years old who suffered from a left apical opacity occurring in a context of deterioration in general health. Subsequent clinical developments were dominated by the ophthalmic disease and a frontal syndrome. The radiological work-up showed tumoral lesions which had developed from the first rib, from the structures at the base of the cranium and the frontal area and were associated with multiple lacunae of the cranial vault. There was evidence of hyperproteinaemia, and an IgG gamma monoclonal gammopathy, a significant medullary plasmocytosis with morphological anomalies of the plasmocytes leading to a diagnosis of myeloma with a plasmocytoma of the rib and the retro-orbital area. Thoracic disease associated with this pathology is common but mainly present as osteolytic lesions. The occurrence of intrathoracic plasma cell tumours is rarer as are orbital manifestations. In spite of treatment which can frequently lead to an objective response, the prognosis of this disorder remains gloomy.