Improved boundary segmentation of skin lesions in high-frequency 3D ultrasound.

In this article, we propose a segmentation algorithm for skin lesions in 3D high-frequency ultrasound images. The segmentation is done on melanoma and Basal-cell carcinoma tumors, the most common skin cancer types, and could be used for diagnosis and surgical excision planning in a clinical context. Compared with previously proposed algorithms, which tend to underestimate the size of the lesion, we propose two new boundary terms which provide significant improvements of the accuracy. The first is a probabilistic boundary expansion (PBE) term designed to broaden the segmented area at the boundaries, which uses the feature asymmetry criterion. The second is a curvature dependent regularization (CDR), which aims at overcoming the tendency of standard regularization to shrink segmented areas. On a clinical dataset of 12 patients annotated by a dermatologist, the proposed algorithm has a comparable Dice index but increases the sensitivity by 26%. The proposed algorithm improves the sensitivity for all lesions, and the obtained sensitivity is close to that of the intra-observer variability.

[Long-term results of lung cancer surgery in octogenarians]. / Résultats à long terme de la chirurgie de résection pulmonaire pour cancer chez l'octogénaire.

INTRODUCTION: This retrospective study was undertaken to evaluate late results of lung cancer surgery in octogenerians. METHODS: All patients 80years old or more who underwent a lung resection for cancer from 2000 to 2010 at Lyon University Hospital were included. No patients were treated with video-assisted surgery. Wedge resections were excluded. RESULTS: Sixty-three patients (42 men, 21 women) were operated. The median age was 82years. Operative mortality was 4.7%. The rate of perioperative complications was 49%. The late survival was 34% at 5years. Five-year survival by nodal involvement was N0, 36%; N1, 29%; N2 20%, P<0.05. Patients with a squamous cell carcinoma (24) had a better long-term survival than patients with an adenocarcinoma (30), 33% and 25% respectively at 5years, P<0.05. The rate of recurrence was 33.9%. CONCLUSIONS: Surgical treatment of lung cancer in selected population of octogenerians is associated with satisfactory early and long-term results. Survival is influenced by nodal involvement and by the pathologic type of the cancer.

Thymoma associated with autoimmune diseases: 85 cases and literature review.

OBJECTIVES: To describe the clinical features, treatment, and outcome of autoimmune diseases (AD) in a cohort of patients with thymoma. DESIGN: Pathological records from three university hospitals, between 2005 and 2011, were reviewed to identify patients with thymoma. Patients with thymoma and AD were compared with patients with thymoma without AD. RESULTS: 47/85 (55%) cases of thymoma had AD, including myasthenia gravis (MG) (n=33), Hashimoto's thyroiditis (n=4), Isaac's syndrome (n=3), Morvan syndrome (n=2), pure red cell aplasia (n=2), systemic lupus (n=2), lichen planus (n=2), and one case of each following conditions: aplastic anemia, autoimmune hemolytic anemia, Good's syndrome, pemphigus, autoimmune hepatitis, Graves' disease, limbic encephalitis, and inflammatory myopathy. Six patients (7%) presented at least 2 ADs. The median duration of follow-up after surgery was 60 months (40-78 months). In 32 patients, the diagnosis of AD preceded the diagnosis of thymoma, in 9 patients, thymoma was diagnosed at the same time as the AD and 7 patients had been operated on when they developed an AD. We found a significative difference on the Masaoka stage between the MG patients and the patients who present another AD (p=0.028). No risk factor for developing an AD after thymectomy was identified. CONCLUSIONS: We describe here the long-term follow-up of a large series of AD related to thymoma. Our results confirm previous data concerning AD occurrence in patients with thymoma and suggest that preexisting autoimmunity is not a risk factor for developing autoimmune manifestations after thymectomy.

[Single French centre retrospective analysis of local control after high dose radiotherapy with or without chemotherapy and local control for Pancoast tumours]. / Analyse rétrospective monocentrique française du contrôle local des cancers bronchiques non à petites cellules de l'apex après radiothérapie de haute dose avec ou sans chimiothérapie.

PURPOSE: Superior sulcus non-small cell lung cancer represents less than 5% of all lung cancers and is a challenge for the physicians because of clinical presentation, treatments related toxicities and poor prognosis. The aim of this preliminary retrospective report is to present outcomes of patients affected by a superior sulcus non-small cell lung cancer, treated by high dose radiotherapy (>60 Gy) with or with our chemotherapy. PATIENTS AND METHODS: All adult inoperable or unresectable patients (≥18 years) with a clinical and radiological diagnosis of superior sulcus non-small cell lung cancer treated in our department by radiotherapy with or without chemotherapy were retrospectively analysed. Primary endpoint was the local control. Overall survival, metastasis free survival and toxicity rates were also analysed and reported. RESULTS: From January 1999 to June 2009, 12 patients were treated by exclusive high-dose radiochemotherapy. Median age was 53 years (range: 33-64 years); mean follow-up time was 20 months (range: 2-75 months). Mean local control, overall survival and metastasis free survival were 20.2, 22 and 20 months, respectively. At the time of this analysis, seven patients died of cancer and three of them presented only a metastatic disease progression. One patient died of acute cardiac failure 36 months after the end of radiochemotherapy and was disease free. Treatment was well tolerated and any acute and/or late G3-4 toxicity was recorded (NCI-CTC v 3.0 score). CONCLUSION: This analysis confirms the interest of exclusive high-dose radiochemotherapy in treating inoperable superior sulcus non-small cell lung cancer patients, in achieving good local control and overall survival rates.

[Assessment of prognostic factors of thoracic synovial sarcoma]. / Evaluation des facteurs pronostiques du synovialosarcome thoracique.

INTRODUCTION: Synovial sarcoma is an uncommon tumour and thoracic involvement is rare and of varying location. Clinical characteristics are dominated by pain, with a slow progression over years. Pathological and immuno-histochemical characteristics are helpful in the diagnosis but a specific translocation between chromosomes X and 18 is crucial for confirmation. Extensive surgical resection is required for cure, combined with adjuvant radiotherapy in the presence of adverse prognostic factors. CASE REPORT: We report a case of synovial sarcoma of the chest wall, responsible for chronic local pain for several years, presenting as an acute pleuropneumonitis in a 21-year-old patient. In view of the large size of the tumour, associated with a high proliferation index (Ki-67), a surgical resection was performed, together with local adjuvant radiotherapy. CONCLUSION: This case report reviews synovial sarcoma and underlines the difficulties and requirements of both diagnostic strategy and therapeutic management. Among them, an initial systematic review of prognostic factors (tumour size, mitotic activity, proliferation index, SYT-SSX type fusion, histological grade) is crucial to determine the therapeutic options.

[Pulmonary metastases from Abrikossoff's tumour. Transformation capability of a benign granular cell tumour]. / Métastases pulmonaires d'une tumeur d'Abrikossoff. Transformation ou potentiel évolutif d'une tumeur bénigne à cellules granuleuses.

INTRODUCTION: Abrikossoff's tumour or granular cell tumour is usually benign involving multiple anatomical sites, most frequently the head, neck and airways. Occasional observations of aggressive malignant tumours have been reported, associated with a poor prognosis. CASE REPORT: We report the case of a mammary Abrikossoff's tumour, initially considered benign and treated solely by local surgery. Seven years later the tumour was responsible for the development of sub-cutaneous and pulmonary metastases. Local surgery was again the only treatment given in the absence of evidence for the effectiveness of alternative treatment with chemotherapy or radiotherapy. CONCLUSION: This original observation reports the case of a benign granular cell tumour that underwent malignant transformation after an interval of 7 years as indicated by the clinical progress and the cellular proliferation index Ki-67.

[Sweet's syndrome associated with squamous cell bronchial carcinoma. Neutrophilic dermatosis and non-small cell lung cancer]. / Syndrome de Sweet révélant un carcinome bronchique épidermoïde. Cancer bronchique et dermatose neutrophilique.

INTRODUCTION: Sweet's syndrome, one of the neutrophilic dermatoses, is idiopathic in most cases. In 10-20% of cases it is paraneoplastic, associated with a solid tumour or haematological malignancy. An association with carcinoma of the bronchus has been only rarely described. CASE REPORT: We report the case of a 56 year old man who presented with Sweet's syndrome two months before the diagnosis of a squamous cell carcinoma of the bronchus. The dermatosis responded well to corticosteroids. The progress of the tumour was favourable, with stabilisation following 3 courses of chemotherapy and local radiotherapy. DISCUSSION: This case report updates this rare association and underlines the importance of undertaking appropriate thoracic investigations in the presence of this dermatosis. A paraneoplastic secretion of interleukin-8, GM-CSF and/or G-CSF by the bronchial tumour cells facilitating the recruitment of neutrophils, particularly in the skin, may account for the pathophysiology of this condition.

[Gastropleural fistula presenting with a pyopneumothorax in pregnancy]. / Pyopneumothorax révélant une fistule gastropleurale.

INTRODUCTION: Gastropleural fistula has only rarely been described in the literature, typically presenting with evidence of left-sided pleural infection. CASE REPORT: The diagnosis may be suggested by the occurrence of chest pain and repeated vomiting with the diagnosis confirmed by microbiological examination of the pleural fluid and appropriate radiological investigations. The fistula occurs most frequently after abdominal or anterior thoracic surgery. Generally, surgical repair should be performed urgently but in the case that we describe occurring during pregnancy, surgery was delayed for 10 weeks until a caesarean section could be performed. CONCLUSION: In the presence of left-sided basal pleuritic chest pain in the context of a possible gap in the diaphragm the diagnosis of gastropleural fistula should be considered. Treatment is usually a medico-surgical emergency.

Arf, Sec7 and Brefeldin A: a model towards the therapeutic inhibition of guanine nucleotide-exchange factors.

GEFs (guanine nucleotide-exchange factors), which stimulate GDP dissociation from small G-proteins, are pivotal regulators of signalling pathways activated by small G-proteins. In the case of Arf proteins, which are major regulators of membrane traffic in the cell and have recently been found to be involved in an increasing number of human diseases, GDP/GTP exchange is stimulated by GEFs that carry a catalytic Sec7 domain. Recent structural results captured snapshots of the exchange reaction, revealing that Sec7 domains secure Arf-GDP to membranes before nucleotide exchange takes place, taking advantage of a built-in structural device in Arf proteins that couples their affinity for membranes to the nature of the bound nucleotide. One of the Arf-Sec7 intermediates was trapped by BFA (Brefeldin A), an uncompetitive inhibitor of Arf activation that has been instrumental in deciphering the molecular principles of membrane traffic at the Golgi. BFA targets a low-affinity Arf-Sec7 intermediate of the exchange reaction. It binds at the Arf-GDP/Sec7 interface, thus freezing the complex in an abortive conformation that cannot proceed to nucleotide dissociation. In the cell, this results in the specific inhibition of Arf1 by a subset of its GEFs, and the efficient and reversible block of membrane traffic at the Golgi. The mechanism of BFA leads to the concept of 'interfacial inhibition', in which a protein-protein interaction of therapeutic interest is stabilized, rather than impaired, by a drug. Up-regulated activity of small G-proteins is involved in various human diseases, making their GEFs attractive candidates to interrupt specifically the corresponding signalling pathway. Interfacial inhibitors are proposed as an alternative to competitive inhibitors that may be explored for their inhibition.

Long-term results of intrathoracic chemohyperthermia (ITCH) for the treatment of pleural malignancies.

There is no standard treatment for patients with pleural malignancies. The aim of this prospective study was to investigate the toxicity and long-term results of a multimodality treatment consisting of surgery and intrathoracic chemohyperthermia (ITCH) for the treatment of patients with pleural malignancies. From January 1990 to August 2000, 24 patients with mesothelioma (n=17), fibrosarcoma (n=3), pleural adenocarcinoma (n=3) and thymoma (n=1) were included. The mesothelioma stages were T1 or T2 in 10 cases, and T3 or T4 in seven cases. After cytoreductive surgery, ITCH was carried out for over 60 min, at inflow temperatures less than 45 degrees C, either with mitomycin C (n=7) or cisplatin (n=5) or both (n=12). One patient died from major thoracic air leaks after major decortication and pleurectomy. Seven patients had complications, one pleural clotting necessitating reoperation. After a median follow-up of 89 months, the overall 1-year and 5-year survival rates were 74 and 27%, respectively. For T1 and T2 mesothelioma patients, the median survival was 41.3 months, and for T3 and T4 tumours, it was 4.5 months (P=0.001). The fibrosarcoma patients are alive with no evidence of recurrence at 24, 43 and 54 months. In the conclusion, the combination of surgery with ITCH with mitomycin and/or cisplatin is relatively safe. This procedure may offer unexpected long-term survival in a selected group of patients (T1 and T2 mesothelioma patients and fibrosarcoma patients).

[Neoadjuvant chemoradiotherapy and peroperative radiotherapy for non-small-cell lung cancer of the apex. A study of 5 cases]. / Chimio-radiothérapie néoadjuvante et radiothérapie per-opératoire dans les carcinomes non à petites cellules (CBNPC) de l'apex. Etude dur 5 cas.

The management of superior sulcus tumors with Pancoast 's syndrome is not well defined, especially in view of their low frequency. Even if surgery performed by "en bloc" resection of the tumor and the chest wall is recommended, neoadjuvant treatment could have a potential benefit on the resecability and pain control. We report five cases of Pancoast tumors (NSCLC), treated by radiotherapy and chemotherapy before surgery. Four tumors was on stage IIIb. A regimen with radiotherapy (50 Gy) and chemotherapy (cisplatinum + etoposide) was initially performed. Four tumors were resected, with 2 complete pathologic responses and good control on pain. Three patients received radiotherapy during surgery. No toxic reaction was observed. This regimen may be discussed with locally advanced tumors and poor prognosis.

Phosphorylation by PKA of a site unique to B-Raf kinase.

The Raf kinases serve as central intermediates to relay signals from Ras to ERK. Cell-specific effects of these signals on growth, differentiation and survival can be observed due to the recruitment of different isoenzymes of the Raf family. The in vitro phosphorylation of a site unique to B-Raf (Ser429) has been proposed to be responsible for the negative regulation of the isoenzyme by Akt. Using phosphopetide mapping and site-directed mutagenesis we showed that Ser429 is phosphorylated upon cAMP elevation in PC12 cells and proposed that PKA is a major kinase phosphorylating the B-Raf-specific site in vivo.

Differential subcellular distribution and transcriptional activity of sigmaE3, sigmaE4, and sigmaE3-4 isoforms of the rat estrogen receptor-alpha.

E3, E4, and E3-4 are naturally occurring estrogen receptor (ER) isoforms, generated through differential splicing of the ERalpha primary transcript and abundantly expressed in embryonic rat pituitary. Studies in COS cells transfected with full-length ERalpha or its three splice variants fused to green fluorescent protein (GFP), revealed a different subcellular localization for each isoform. In the absence of estradiol, full-length ERalpha-GFP was predominantly nuclear, and E3-GFP and E4-GFP were present both in cytoplasm and nucleus, whereas E3-4-GFP was predominantly cytoplasmic. Upon hormone treatment, a dramatic redistribution of full-length ERalpha-GFP and E3-GFP, from a diffuse to punctate pattern, occurred within the nucleus. In contrast, the distribution of E4-GFP and E3-4-GFP was unaffected. Nuclear fractionation studies showed that full-length ER-alpha and E3 displayed the same hormone-induced ability to tether to nuclear matrix, whereas nuclear E4 appeared to remain loosely associated to functional nuclear constituents. When cotransfected with an estrogen-inducible reporter plasmid (VIT-TK-CAT) in ER-negative (CHO k1) and ER-positive pituitary (GH4 C1) cells, E3-4 exhibited a very weak estrogen-dependent transactivation activity, whereas E3 had an inhibitory effect on full-length ER action. Conversely, E4 displayed estrogen-independent transcriptional activity in ER-negative cells, and in ER-positive cells, enhanced the estrogen-induced gene expression as efficiently as full-length ERalpha. In a gel mobility shift assay, phosphorylated E4 was able to form a specific complex with a consensus ERE, while E3 and E3-4 never did bind by themselves. The observed inhibitory action of E3 on estrogen-dependent transcription would rather involve protein-protein interactions such as formation of heterodimers with full-length ERalpha, as suggested by immunoprecipitation followed by Western blotting. These data suggest that E3 and E4 may play a physiologically relevant role as negative or constitutively positive modulators of transcription, in the developing rat pituitary.

Resection of adrenal metastases from non-small cell lung cancer: a multicenter study.

BACKGROUND: In recent case reports and limited series, adrenalectomy was recommended for an isolated adrenal metastasis from non-small cell lung cancer (NSCLC). METHODS: We retrospectively studied patients with a solitary adrenal metastasis from NSCLC who had undergone potentially curative resection in eight centers. RESULTS: Forty-three patients were included. Their adrenal gland metastasis was discovered synchronously with NSCLC in 32 patients, and metachronously in 11. It was homolateral to the NSCLC in 31 patients and contralateral in 12 (p < 0.01). Median survival was 11 months, and 3 patients survived more than 5 years. There was no difference between the synchronous and metachronous groups regarding recurrence rate or survival. Survival was not affected by the homolateral location of the metastasis, the histology of the NSCLC, TNM stage, any adjuvant and neoadjuvant treatment, or, in the metachronous group, a disease-free interval exceeding 6 months. CONCLUSIONS: We confirm the possibility of long-term survival after resection of isolated adrenal metastasis from NSCLC, but no clinical or pathologic criteria were detected to identify patients amenable to potential cure.

Interaction between the serotoninergic and dopaminergic systems in d-fenfluramine-induced activation of c-fos and jun B genes in rat striatal neurons.

To test for the relative contributions of the dopaminergic and serotoninergic systems in the striatum to the effects of d-fenfluramine, an indirect serotonin receptor agonist, we assessed the expression of Fos/Jun proteins induced by d-fenfluramine given alone or in the presence of dopaminergic or serotoninergic agents. To determine the neuronal targets of d-fenfluramine in the striatum, we identified the phenotypes of striatal neurons in which d-fenfluramine induced Fos expression. Our results demonstrated that d-fenfluramine evokes nuclear expression of Fos/Jun B proteins in the striatum, and that the Fos expression was dose-dependent and accompanied by transient induction of c-fos mRNA. Fos expression was blocked by p-chloroamphetamine, a serotoninergic neurotoxin. Pretreatment with SCH 23390, a D1-dopamine receptor antagonist, led to a marked decrease in Fos/Jun B expression in the caudoputamen, but not in the cortex, whereas pretreatment with methiothepin, a nonselective serotonin 5-HT1 receptor antagonist, blocked Fos expression completely in the cortex and only partially in the caudoputamen. The expression of Fos/Jun B in the striatum occurred mainly in dynorphin-containing neurons and in a subpopulation of striatal interneurons that exhibited NADPH-diaphorase activity. Most of the enkephalin-containing neurons of the striatum did not show Fos/Jun B staining. These results suggest that the mechanism by which d-fenfluramine induces c-fos and jun B expression in the rat caudoputamen depends at least in part on activation of the dopaminergic system by serotonin.

Effect of PRL on MAPK activation: negative regulatory role of the C-terminal part of the PRL receptor.

Prolactin induces cell proliferation and cell differentiation through well-known MAPK Erk, and JAK2/STAT5 pathways depending on the cell line. The aim of the present study was to delineate the functional domains of the PRL receptor involved in PRL induced MAPK regulation. Using various PRL-R mutants of the cytoplasmic domain we found, that the membrane proximal domain is necessary for PRL induced MAPK activation and that the C-terminal part of the receptor exerts a negative regulatory role. A pharmacological approach, using different types of inhibitors, provided evidence that PRL induced MAPK activation requires both a MEK dependent pathway and a PI3K dependent pathway. The negative regulation induced by the carboxy-terminal part of the receptor involves a combination of tyrosine phosphatases and serine/threonine phosphatases as concluded from the actions of the phosphatase inhibitors: pervanadate, PAO and okadaic acid. The mechanism by which these phosphatases are recruited or are induced by the last 141 cytoplasmic residues of the receptor remains to be determined. Finally the negative regulatory role of the carboxy-terminal part of the receptor, first demonstrated in the present study, is discussed in terms of the regulation of different effects of PRL on growth and differentiation.

Pulmonary mucormycosis in a diabetic patient.

We present the case of a 54 year-old male from Moldavia with diabetes mellitus (type II diabetic), admitted to hospital in January 1999, with ketoacidosis and consolidation of the lower left lobe. The diagnosis of mucormycosis was confirmed by identification of large, nonseptate hyphae of the order Mucorales. A strain of Rhizopus oryzae (Rhizopus arrhizus) was isolated from culture on sabouraud medium. The patient was treated by systemic amphotericin B, associated with surgical debridement (lobectomy). The treatment with amphotericin B was stopped after ten days and the patient was completely asymptomatic and returned to Moldavia. Mucormycoses are rare, and tend to be encountered in individuals with predisposing factors such as malignant blood disorders (immunocompromised patients) or diabetes mellitus. Prognosis is poor, resembling infection with Aspergillus, despite aggressive treatment as in the present case. The gravity of the condition can be accounted for by the thrombotic and necrosing nature of the fungal invasion of lung vessels.

The in vivo modulation of dopamine synthesis by calcium ions: influences on the calcium independent release.

To investigate the contribution of the dopamine (DA) synthesis to both the calcium-dependent and the carrier-mediated, mechanisms of DA release in the striatum, anaesthetized rats were locally superfused in the striatum with a push pull cannula supplied with an artificial CSF containing tritiated tyrosine. DA, dihydroxyphenylacetic acid (DOPAC) and their respective specific activity were measured in effluent and used to evaluate changes in the DA synthesizing rate. Excluding calcium ions from the CSF only partially reduced spontaneous DA release (70%) still leaving a possible carrier-mediated DA release. This effect was not additive with a local superfusion with 0.1 mM a-methyl-p-tyrosine, a blocker of DA synthesis, suggesting that synthesis could already be reduced by calcium-free superfusion. Local superfusion with 100 microM cadmium in the presence or not of calcium ions, increased the DA release (220 and 350%, respectively), simultaneously reducing DA synthesis. Local application of 1 microM calcium ionophore (A23187) was without effect on the basal release of DA but enhanced DA synthesis and increased the amphetamine-evoked and carrier-mediated amine release. We conclude that DA synthesis can be a modulatory process of the firing-independent and carrier-mediated amine release while it weakly affects the classical calcium-dependent release.

Heterogeneous distribution of polyamines in temporal lobe epilepsy.

Polyamine contents were determined in human temporal lobe epilepsy. In the seven patients studied, stereoelectroencephalography (SEEG) located the epileptogenic focus in Ammon's horn and neuropathological findings were limited to hippocampal gliosis and sclerosis. Each polyamine exhibited a specific regional distribution. The most important variations were observed for spermidine and spermine while putrescine levels varied less. The regional variation was predominant in middle > posterior > anterior parts of the temporal lobe. Spermine contents and the spermidine/spermine (SPD/SPM) index varied especially in the middle and posterior parts of the hippocampus. Metabolic SPD/SPM index and spermidine levels were found to be drastically increased in almost all limbic parts when compared to neocortical regions. The opposite was observed for spermine. The heterogeneous distribution of polyamines was compared to abnormal electrical activities recorded by SEEG: SPD/SPM index and spermidine levels were sharply increased in seizure onset areas and high levels of spermine were detected in temporal cortex propagation areas. The presently reported heterogeneity of polyamine contents might contribute to modulate differentially the local control of excitability in human temporal epilepsy.