Dynamical modeling of pro- and anti-inflammatory cytokines in the early stage of septic shock.

A dynamical model of the pathophysiological behaviors of IL18 and IL10 cytokines with their receptors is tested against data for the case of early sepsis. The proposed approach considers the surroundings (organs and bone marrow) and the different subsystems (cells and cyctokines). The interactions between blood cells, cytokines and the surroundings are described via mass balances. Cytokines are adsorbed onto associated receptors at the cell surface. The adsorption is described by the Langmuir model and gives rise to the production of more cytokines and associated receptors inside the cell. The quantities of pro and anti-inflammatory cytokines present in the body are combined to give global information via an inflammation level function which describes the patient's state. Data for parameter estimation comes from the Sepsis 48 H database. Comparisons between patient data and simulations are presented and are in good agreement. For the IL18/IL10 cytokine pair, 5 key parameters have been found. They are linked to pro-inflammatory IL18 cytokine and show that the early sepsis is driven by components of inflammatory character.

[Radiotherapy of maxillary sinus carcinoma: state of art]. / Radiothérapie des carcinomes des sinus maxillaires: l'état de l'art.

Maxillary sinus carcinomas are rare malignancies of the face, characterized by high local relapsing rate. Modalities of treatment are without consensus and respective roles of radiation therapy and surgery remain controversial. As those malignancies are often diagnosed at locally advanced stage, radiation therapy may frequently be used for patients having unresectable advanced disease. Nevertheless, surgery remains treatment of choice for more localized malignancies, in association with systematic postoperative radiotherapy. For those patients whose prognosis remains pejorative, it is necessary to precise the role of radiotherapy in first intention for inoperable tumors, to define necessity for nodal treatment performing and evaluate the place of neoadjuvant or concomitant chemotherapy in a multimodal strategy.

[Cancer chemotherapy of the upper aerodigestive tract]. / Chimiothérapie des cancers des voies aérodigestives supérieures.

Tumours of the upper aerodigestive tract represent the sixth most frequent kind of cancer in France and throughout the world. If the localised forms may be controlled in the long run in two thirds of cases by surgery or radiotherapy, only one third of locally advanced forms are accessible to a cure after association from radiotherapy and chemotherapy. Besides, with a median of survival less than six months, metastatic tumours present a catastrophic spontaneous prognosis among patients with a medical ground that is often heavily deteriorated by prolonged exposure to alcohol and tobacco. Thus, there is a necessity to implement adapted therapeutic strategies to each patient and based on satisfactory proof levels of effectiveness. Optimisation of existing chemotherapy protocols and development of new therapies, in particular of targeted therapies, remain an important objective in the hope to improve results of treatments in locally advanced and metastatic cancers of the oral cavity.

The use of computed tomography in radiotherapy treatment planning for breast cancer. How does conventional radiotherapy planning compare with virtual?

PURPOSE: To compare, in terms of ballistics and dosimetry, a conventional and a virtual simulation in 14 patients without changing the set-up. PATIENTS AND METHODS: 14 women with breast cancer were treated with postoperative radiotherapy from October 2003 to November 2004. Whole breast irradiation alone was indicated (50 Gy at International Committee on Radiation Units [ICRU] point in 25 fractions over 5 weeks) with, in some cases, an additional boost of 16 Gy to the tumor bed--that was not taken into account in this study. After CT scan, tangential fields were conventionally simulated using a Mecaserto Phebus-type simulator-CT scan. The planning target volume (PTV) was the clinical target volume (CTV) expanded with an additional margin of 1 cm in all directions but towards the skin. Both the lungs and the heart were delineated as organs at risk. Dosimetries were computed for the two beams arrangements i.e. 2D conventional and 3D virtual. RESULTS: The mean age of 14 women was 51.4 years (range 26-65). Laterality was the left breast for 6 patients and the right for 8. Few differences were noticeable in terms of gantry angles. The 3D medial fields were more medial with a mean of 8 mm (range 0-15). The 3D lateral fields were more posterior with a mean difference of 8 mm (range 0-25). The dosimetry analysis showed that, with regard to conventional simulations, at least 95% of the CTV received in all cases > 95% of the prescribed dose. However, in 8 out of 14 patients (57%), 15% of the PTV received < 95% of the prescribed dose. The ICRU 50 quality criterion that at least 95% of the PTV (PTV(95%)) should receive at least 95% of the prescribed dose was never met with conventional simulation. In the case of virtual simulation, the ballistics of the treatment were designed to meet the ICRU quality criterion and thus the PTV95% was higher here than with the conventional simulation by a mean of 17.6% +/- 9.7%. The percentage of CTV receiving a dose higher than 107% of the prescribed dose was 21.3% +/- 12% with conventional and 24% +/- 11% with virtual simulation. CONCLUSION: The high incidence of breast cancer, the essential role of radiotherapy in its treatment and the potential ensuing toxicity explain why so many studies are devoted to the improvements brought to the techniques of this treatment. The virtual planning of the treatment, however, comes up against many difficulties. The countering of the CTV is complex and necessitates a combination of clinical examination and imagery. The choice of margins around the CTV has not been standardised and is largely dependent both on the equipment used and the quality control methods.

[Prostate cancer and disseminated intravascular coagulation: review of the literature]. / Cancer de prostate et coagulation intravasculaire disséminée: une revue de la littérature.

Disseminated intravascular coagulation is a rare complication of prostatic cancer evolution. Occurring on hormonorefractory phase, it remains most often infraclinic. Cases of acute, severe intravascular disseminated coagulation at first presentation are life-threatening because of hemorragic and thrombotic complications, justifying emergency medical treatment. In the light of a review of literature, we insist on epidemiological features, physiopathology and therapeutics of intravascular disseminated coagulation. In spite of a pejorative prognosis, this could help to achieve a period of remission.

[Favorable outcome of gemcitabine-induced acute respiratory distress syndrome]. / Syndrome de détresse respiratoire aiguë à la gemcitabine d'évolution favorable.

Gemcitabine is a new important drug used to treat solid tumors including non-small cell lung cancer, pancreatic, bladder and breast cancers. Myelosuppression is the most common adverse effect. Pulmonary toxicity is rare and usually mild and self-limiting with acute dyspnea. Severe pneumonitis and potentially fatal acute respiratory distress syndrome (ARDS) have been described in patients treated for a non-small cell lung cancer. We report a case of gemcitabine-induced ARDS in a 72-year old patient treated with gemcitabine and cisplatin for a bladder cancer without lung metastasis. Administration of high doses of corticosteroids led to a prompt symptomatic improvement.

Leukotriene B4 level in neutrophils from allergic and healthy subjects stimulated by low concentration of calcium ionophore A23187. Effect of exogenous arachidonic acid and possible endogenous source.

Peripheral blood neutrophils from patients with allergic rhinitis and from normal subjects were incubated for 5 min at 37 degrees C with 0.15 microM calcium ionophore A23187 in the absence or presence of exogenous arachidonic acid (2.5 to 10 microM). In neutrophils from allergic patients, the leukotriene B4 (LTB4) level was significantly increased by exogenous arachidonic acid in a concentration-dependent manner (16.2 +/- 4.2 and 38.1 +/- 6.8 pmol/5 min per 2 X 10(6) cells in the absence and presence of 10 microM arachidonic acid, respectively; P less than 0.005; n = 8). The LTB4 level in neutrophils from healthy subjects was only 0.97 +/- 0.17 pmol/5 min per 2 x 10(6) cells (n = 5) and was not enhanced by exogenous arachidonate. When cells from allergic patients were challenged in the presence of exogenous [1-14C]arachidonic acid, released LTB4 was radiolabeled and the incorporated radioactivity increased with the labeled arachidonate concentration. Labeled LTB4 was never detectable after incubating neutrophils from normal donors with exogenous labeled arachidonate. When neutrophils were incubated with [1-14C]arachidonate for 1 h, the different lipid pools of the two cell populations were labeled but both types of neutrophils produced unlabeled LTB4 in response to ionophore stimulation. The hydrolysis of choline and ethanolamine phospholipids into diacyl-, alkenylacyl- and alkylacyl-species revealed that solely the alkylacyl-subclass of phosphatidylcholine was unlabeled. We conclude (i) that neutrophils from allergic patients stimulated by low ionophore concentration produce more LTB4 than neutrophils from healthy subjects and incorporate exogenous arachidonate, (ii) that endogenous arachidonate converted to LTB4 by the 5-lipoxygenase pathway may provide only from 1-O-alkyl-2-arachidonoyl-glycero-3-phosphocholine.

[Combined chemotherapy and radiation therapy for intracranial germinomas. The Val-de-Grace hospital experience]. / Intérêt de la chimiothérapie néoadjuvante dans le traitement des séminomes purs intracérébraux: expérience de l'hôpital du Val-de-Grâce.

Optimal management of intracranial germinomas remains controversial. Focal irradiation to the primary tumor followed by prophylactic craniospinal radiotherapy represents the traditional treatment resulting in excellent long-term survival but potential late effects. To decrease late effects related to extensive fields of radiotherapy, combined chemotherapy and irradiation has been tested with reduced volumes and doses of radiation therapy. We report our experience about four patients successfully treated by neoadjuvant chemotherapy with carboplatin and etoposide followed by radiotherapy delivering 26 to 36 Gy to the whole brain and 36 to 50 Gy to the initial tumor volume.

[Comparison of classic simulation and virtual simulation in breast irradiation: prospective study on 14 patients]. / Comparaison simulation classique-simulation virtuelle au cours d'une irradiation mammaire: étude prospective sur 14 patientes.

PURPOSE: To compare conventional 2D simulation and virtual simulation on 14 patients with breast cancer. PATIENTS AND METHODS: Patients were simulated for treatment using standard procedure. They subsequently underwent CT scan in the treatment position. The CTV was defined as breast tissue. The PTV was obtained by adding a 3D margin of 1 cm around CTV. Organs at risk (lungs and heart) were outlined. Ballistics and dose distribution obtained with the two planning methods were compared. RESULTS: With conventional simulation, 95% of CTV received 95% of the dose prescribed. Virtual simulation significantly improved dosimetric coverage of PTV without increasing irradiation volume of lung and heart. In 2D simulation, using three slices allowed optimisation by adjusting wedge angle. The five-slice plan was a much better predictor of the maximum dose regions when compared to the three-slice plan. Using entire CT data didn't give any benefit. CONCLUSION: Variations in CTV delineation and PTV definition limit interest of virtual simulation. In classic simulation, a 5 CT slice-plan can be used to optimise dose distribution.

Flow cytometry analysis of T lymphocytes in sarcoidosis.

To examine the immunologic alterations in patients with sarcoidosis we characterized the cell cycle phase of T lymphocytes that were collected from peripheral blood and from bronchoalveolar lavage fluid. T-cell DNA and RNA contents were measured at the single cell level using flow cytometry after staining with the metachromatic fluorochrome acridine orange. T-enriched lymphocyte suspensions were obtained from peripheral blood and from bronchoalveolar lavage in 17 patients with histologically-proved sarcoidosis (10 patients, stage I and 7 patients, stage II) and in 4 patients with acute extrinsic hypersensitivity pneumonitis (AEHP). The percentages of cells in the S + (GS + M) phase in the peripheral blood of the patients with sarcoidosis did not differ from those of healthy control subjects. With bronchoalveolar lavage, however, elevated numbers of T cells in the S + (G2 + M) phase were found in the patients with AEHP and in those with stage II sarcoidosis when compared to patients with stage I sarcoidosis. The cellular RNA content of T lymphocytes from the peripheral blood showed a typical bimodal distribution without difference between patients and control subjects. Conversely, T lymphocytes obtained by bronchoalveolar lavage from patients with AEHP and sarcoidosis had a homogeneous low RNA content which differed from that of T lymphocytes from the blood from that of in vitro phytohemagglutinin-stimulated lymphocytes. These findings provide a new approach to the study of the mechanisms of local T-cell activation in sarcoidosis.

Radiation injuries of the gastrointestinal tract in Hodgkin's disease: the role of exploratory laparotomy and fractionation. A study of 19 cases observed in a series of 134 patients treated at the Institut Gustave Roussy from 1972 to 1982.

Out of 134 patients irradiated below the diaphragm to a dose of 40 Gy for Hodgkin's disease at the Institut Gustave-Roussy, 19 (14%) were subsequently found to present with radiation injuries of the gastrointestinal tract. Since five patients presented with two different injuries, 24 radiolesions were observed. Most of them (17 out of 24) were gastric or duodenal. Twelve (out of 24) were ulcers. Nine patients required surgery. A complete cure of the radiation injuries was obtained in 15 out of 19 patients. Sex, age, stage, histology or initial chemotherapy were not found to play a role in the occurrence of radiation damage. On the contrary, the role of a previous exploratory laparotomy appeared important; for the patients who underwent laparotomy and irradiation, the complication rate was 23%. For the patients treated by irradiation alone, the complication rate was 7% (p less than 0.01). Fractionation was found to be another important parameter: for 52 patients treated using 3 weekly fractions of 3.3 Gy, the complication rate was 25%, compared to 8% (p less than 0.01) for 76 patients treated using 4 weekly fractions of 2.5 Gy. Combining these two factors, we found a 42% complication rate for the group of patients who underwent laparotomy and who were treated by means of 3 fractions of 3.3 Gy per week, whereas patients irradiated using 4 weekly fractions of 2.5 Gy, without any previous laparotomy, had only a 5% complication risk (p less than 0.001).

Increased plasma levels of atrial natriuretic factor, renin activity, and leukotriene C4 in chronic obstructive pulmonary disease.

We studied atrial natriuretic factor (ANF), plasma renin activity (PRA), and plasma levels of leukotrienes (LTs) B4 and C4 in 23 patients with COPD undergoing right cardiac catheterization for suspected pulmonary hypertension. Hemodynamic measurements together with concomitant ANF levels (both in venous and pulmonary artery blood and right atrial and pulmonary artery plasma levels of LTC4 and LTB4, were determined at rest (T0), after 30 min of breathing oxygen (3 L/min) (T1), and after 30 min recovering and breathing air (T2). Patients with effective exacerbation or definitive evidence of left ventricular disease, hypertension, arrhythmias, or vasodilator or diuretic therapy were excluded. Increased levels of ANF, both in peripheral venous blood (117 +/- 65 pg/ml) and the pulmonary artery (153 +/- 75 pg/ml), were found in patients with COPD, with or without pulmonary hypertension. Levels of LTC4 were also significantly increased (366 +/- 406 pg/ml) when compared with our control values. No correlations among ANF, LTC4 values, functional tests, and hemodynamic measurements were found. Brief increased levels of oxygen did not modify ANF or LTC4 plasma levels, either in patients with or without pulmonary hypertension.

Long-term results of surgical treatment for gastroesophageal reflux in asthmatic patients.

We report the long-term results of surgical repair of gastroesophageal reflux in 44 asthmatic patients who underwent surgery more than five years earlier (mean = 7.9 +/- 1.5 years). The severe asthma was associated with clinically evident reflux, and repair was attempted by surgical technique Nissen transabdominal gastropexy, with the following results: total cure, 11 cases (25 percent); marked improvement, 7 (16 percent); moderate improvement, 11 (25 percent); no improvement, 15 (34 percent). Cure was attained in intrinsic asthma with a predominance of nocturnal crises, associated with nocturnal tracheitis and with significant reflux, objective signs of which had appeared before the beginning of the asthma. Other results concerned asthmas complicated secondarily by GER in which it was impossible to determine whether the reflux was only a complication, without effect on the respiratory illness, or exacerbating the asthma. The question of surgery in these patients should be considered with care, being reserved for cases of severe asthma, poorly controlled by antiasthmatic drugs, and complicated by a severe reflux that encompasses ulcerative esophagitis.

Double-blind, randomised, placebo-controlled study of two concentrations of azelastine eye drops in seasonal allergic conjunctivitis or rhinoconjunctivitis.

This double-blind, randomised, placebo-controlled study was carried out to assess the efficacy and safety of 0.025% and 0.05% azelastine eye drops twice daily administered for 14 days to patients with seasonal allergic conjunctivitis or rhinoconjunctivitis. A total of 278 patients were recruited and 226 patients were evaluable for per protocol analysis. The target parameter was the response rate. Four eye symptoms, including the main symptom (itching) were recorded by patients in diaries and eight symptoms were assessed by physicians before and after seven and 14 days of treatment. Severity of symptoms was measured on a four-point scale. The response rates for itching (improvement of at least one score point within the first three days) according to patient assessment were 43% for placebo, 52% for 0.025% and 56% for 0.05% azelastine (NS). However, a more objective assessment of the three main eye symptoms by physicians showed a concentration-dependent improvement in response rate compared with placebo (a decrease of > or = 3 points from a baseline total score of > or = 6), which reached statistical significance for 0.05% azelastine on Day 7 (p < 0.002). In the evaluable patient population, the scores of the three main eye symptoms as well as of all eight recorded eye symptoms, as assessed by the physician, were significantly (p < 0.05) lower in the 0.05% azelastine eye drops group in comparison with the placebo group at Day 7. Inefficacy was the cause of withdrawal in five and three patients on 0.025% and 0.05% azelastine, respectively, and in six patients on placebo. Adverse drug effects, mainly a mild, transient irritation and a bitter or unpleasant taste, were reported by 14% (0.025%), 20% (0.05%) and 15% (placebo) of the patients. No serious side-effects occurred. Azelastine eye drops are effective and well tolerated at a concentration of 0.05% for the treatment of seasonal allergic conjunctivitis.

Phosphatidylethanolamine methyltransferase and cAMP, cGMP phosphodiesterases in lymphocytes and monocytes in sarcoidosis.

Among the various hypotheses proposed to explain immune cell defect in sarcoidosis, we examined thoroughly that of Faguet who described abnormalities of signal transmission at lymphocyte membrane level. Phosphatidylethanolamine methyltransferase and cAMP cGMP phosphodiesterases were studied in blood lymphocytes and monocytes from 8 subjects with sarcoidosis disease. Phosphatidylethanolamine methyltransferase (PMT1) plays an important regulatory role in membrane signal transmission. cAMP and cGMP phosphodiesterases (PDE) regulate cytoplasmic cyclic nucleotide levels and so participate in the modulation of the cell cycle. We observed a decreased PMT1 activity in lymphocytes and monocytes and a decreased cAMP and cGMP PDE activities in monocytes. It is not now possible to say if these abnormalities are primary or secondary. Whatever the origin of this dysfunctioning, these results evoke simultaneous disturbances of membrane signal transmission and cell cycle in monocytes and membrane abnormalities in lymphocytes. These abnormalities could explain some immune cell defects in sarcoidosis disease.

Activity of cyclic AMP phosphodiesterase and methyltransferases in leukocyte membranes from allergic patients.

Cyclic AMP metabolism and methylation of phospholipids are central events which occur at the membrane level. Since a dysfunction of cell membranes seems to characterize some allergic diseases, we investigated cyclic AMP phosphodiesterase and methyltransferase activities in leukocyte membrane fractions obtained from healthy volunteers and from allergic patients. The allergic group presented a significantly decreased methyltransferase activity compared with a control group, whereas cyclic AMP phosphodiesterase and noradrenaline (NA)-stimulated methyltransferase were found to be increased with respect to the control group. A significant correlation has been found between cyclic AMP phosphodiesterase and NA-stimulated methyltransferase with both control and allergic subjects, which suggests close relationships between these two enzymes within the cell membrane.

Phosphatidyl ethanolamine methylation in membrane from bronchoalveolar lavage mononuclear cells, in asthmatic patients: a new marker of macrophage activity.

Phosphatidyl ethanolamine methylation was compared in alveolar macrophage membrane from asthmatic and control subjects. Phosphatidyl ethanolamine methylase activity was determined by measuring the incorporation of (3H) methyl group from (3H) adenosyl methionine into membrane phospholipids. (3H) methyl group incorporation was significantly higher in macrophages from asthmatic patients. This result is consistent with macrophage membrane activation and could signify: a membrane phospholipid pool regeneration after allergenic or toxic disturbance or an enzymatic activation by inflammatory mediators.

[Treatment of non-Hodgkin's lymphomas in adults, stages III and IV with favorable histology : abstention or therapeutic aggressiveness?]. / Le traitement des lymphomes non hodgkiniens de l'adulte stades III et IV d'histologie favorable : abstention ou agressivité thérapeutique?

Within the inhomogeneous group of non Hodgkin's lymphomas, the natural history of lymphomas with favorable histologies, stages III and IV is uncommon; survival can be long, but the relapse rate is high, and finally the ten-year survival rate is poor. In order to improve these results, various proposals have been made. Presently, two main attitudes can be defined. The first one is based on data showing a better survival rate when a complete remission has been obtained; consequently, a very aggressive treatment scheme (for example an association of chemotherapy--including Adriamycin--and total body irradiation) is proposed. The second attitude is based on favorable results obtained by a "deferred treatment", the patients being treated only when the disease is symptomatic. Actually, the review of the literature shows that these two attitudes are complementary rather than antagonistic. For a young adult patient, essentially if histology is more "intermediate" than really "favorable" and if the patient presents with bulky tumoral masses, aggressive treatment must be proposed, because it is the only attitude able to achieve complete remission and therefore able to provide chances of long term survival. For an older patient, essentially with a very favorable histology and without any symptoms such an aggressive therapy appears too risky. "Light" treatments and occasionally "deferred treatment" can be proposed in these cases.

A comparison of flunisolide inhaler and beclomethasone dipropionate inhaler in bronchial asthma.

Ninety-nine patients, who had never previously taken inhaled steroids were enrolled in a randomized, single-blind, parallel study, the aim of which was to compare the efficacy and safety of flunisolide inhalation, 500 mcg twice daily, with beclomethasone dipropionate inhaler 100 mcg four times daily for the treatment of chronic asthma. The treatment period was for 6 weeks. The patients were examined clinically at entry, week 3 and week 6 and both treatment groups showed a marked improvement in almost all parameters during the course of the study. Flunisolide was statistically significantly superior to beclomethasone dipropionate for wheezing at week 6, coughing at week 6 and chest tightness at weeks 3 and 6. The number of asthma attacks per day decreased significantly more with flunisolide treatment than with beclomethasone dipropionate. The over-all evaluation of efficacy by both doctors and patients also showed flunisolide to be superior to beclomethasone dipropionate. In several other parameters there was a trend shown favouring flunisolide, and beclomethasone dipropionate did not show a superiority over flunisolide in any efficacy parameter. Both drugs were well-tolerated, with unpleasant taste being the most frequent complaint in the flunisolide group. No patient in either group withdrew from the study because of adverse events. In this study, flunisolide inhaler was more effective than beclomethasone dipropionate inhaler for the treatment of chronic asthma exhibited by patients who had never been treated with inhaled steroids.

[Chiasmal radionecrosis after irradiation of the sella turcica using a conventional dosage. Contribution of magnetic resonance imaging]. / Radionécrose chiasmatique après irradiation de la selle turcique à doses conventionnelles. Apport de l'imagerie par résonance magnétique.

A 47 year-old man developed rapid visual loss, visual field defects and memory disturbances after radiotherapy with conventional doses for a pituitary metastasis from a renal carcinoma. CT and MRI did not show recurrent tumour, pituitary apoplexy or empty sella. Eventually, T2-weighted MRI images showed abnormal high signals in the optic chiasm, the left mesial temporal lobe and the right inferior frontal lobe, supporting the diagnosis of delayed radionecrosis. The role of chemotherapy associated with radiotherapy is discussed.