National multicentric evaluation of quality of pathology reports for rectal cancer in France in 2016.

The quality of pathologic assessment of rectal cancer specimens is crucial for treatment efficiency and survival. The Royal College of Pathologists (RCP) recommends evaluating the quality of the pathology report in routine practice using three quality indicators (QIs): the number of lymph nodes (LNs) analyzed (≥ 12), the rate of venous invasion (VI ≥ 30%), and peritoneal involvement (pT4a ≥ 10%). In this study, we evaluated the three QIs of the French national pathology reports and compared them with British guidelines and assessed the influence of neoadjuvant radiochemotherapy on QIs. From January 1 to December 31, 2016, all pathology reports for rectal adenocarcinoma were collected from French departments. Neoadjuvant radiochemotherapy included long-course radiotherapy with concomitant 5-FU-based chemotherapy. A total of 983 rectal cancer pathology reports were evaluated. A median of 15 LNs were analyzed and 81% of centers had ≥ 12 LNs. The rate of VI was 30% and 41% of centers had ≥ 30% VI. The rate of pT4a was 4% and 18% of centers reported ≥ 10% pT4a. None of the centers reached the threshold for the three QIs. All three QIs were lower after radiochemotherapy compared to surgery alone. In conclusion, in French routine practice, the values of two of the three QIs (LNs analyzed and VI) were globally in line with RCP guidelines. However, the rate of pT4a was very low, particularly after radiochemotherapy, suggesting its low value in rectal cancer.

Influence du score de Gleason des marges chirurgicales de prostatectomie totale sur la récidive biologique.

OBJECTIVES: The aim of this study was to assess the impact of the aggressiveness of cancer cells at the level of positive surgical margins (PSM) on the biochemical recurrence rate (BRR) by studying the Gleason score (GS) at this level. METHODS: We included all radical prostatectomy (RP) procedures performed from January 2007 to November 2011. All of the RP specimens with PSM were reviewed to determine the GS at the level of PSM. We compared the GS at PSM with BRR. RESULTS: A total of 658 RP were analysed, among which 16% had PSM. From the 101 patients with PSM included, 32% had biochemical recurrence (BR) with a median follow-up of 38 months. GS at PSM was significantly associated with earlier BR (P=0.008). Univariate analysis showed that GS at PSM (P=0.013), initial PSA (P<0.0001), pathologic GS (P<0.001), length of PSM (P=0.013), and seminal vesicle invasion (P<0.0001) were predictors of BR. Multivariate analysis confirmed that PSA greater than 10ng/mL and length of PSM greater than 3mm were independent prognostic factors for BR, but GS at the level of PSM was not. CONCLUSION: GS at PSM was not confirmed as an independent risk factor for BR. Initial PSA greater than 10ng/mL and length of PSM greater than 3mm were the sole independent predictors for BR. LEVEL OF PROOF: 4.

A reversed-phase high-performance liquid chromatographic method to analyze retinal isomers.

A high-performance liquid chromatographic (HPLC) procedure was developed to separate all-trans-, 13-cis-, 11-cis- and 9-cis-retinal isomers. Two reversed-phase Vydac C18 columns in series were used with an isocratic solvent system of 0.1 M ammonium acetate-acetonitrile (40:60, v/v) as mobile phase and all-trans-9-(4-methoxy-2,3,6-trimethylphenyl)-3,7-dimethyl-2,4,6,8-no natetraene-1-ol (TMMP) as internal standard. Prior to HPLC, the retinal isomers were efficiently extracted in their original isomeric conformation using dichloromethane-n-hexane in the presence of formaldehyde. This technique is suitable for the assay of 11-cis- and all-trans-retinal isomers in retina.

Effect of a cGMP-specific phosphodiesterase inhibitor on retinal function.

Multiple forms of phosphodiesterase have been reported in many tissues. Phosphodiesterase 6, a cGMP-specific phosphodiesterase, is described as a photoreceptor cell-specific phosphodiesterase. Phosphodiesterase 6 is known to play a crucial role in visual function. A novel phosphodiesterase inhibitor, GF248 (5["(propoxy),7'(4-morpholino)-phenacyl],[1-methyl-3 propyl]pyrazolo[4,3d]pyrimidin-7-one), has been described to be a very potent cGMP-specific phosphodiesterase inhibitor. In the present study, we compared the potency of GF248 and other known cGMP-specific phosphodiesterase inhibitors on phosphodiesterase 5 and phosphodiesterase 6. GF248 displayed an IC50 of 2 and 5 nM for phosphodiesterase 5 and phosphodiesterase 6, respectively. Thereafter, we assessed the effect of GF248 on retinal function, using an ex vivo model of isolated retina electroretinogram recording. Exposure of retina to GF248 resulted in a dose-dependent decrease in electroretinogram amplitude (PIII and b-waves), with no marked modification of PIII and b-wave implicit time. Among other phosphodiesterase inhibitors, DMPPO (1,3-dimethyl-6-(2-propoxy-5-methanesulfonylamidophenyl)pyrazol ol[3,4d]-pyrimidin-4-(5H)-one) and dipyridamole, cGMP-specific phosphodiesterase inhibitors, and IBMQ (1-isobutyl-3-methylimidazol[1,5a]quinoxalin-4-(5H)one), a nonselective phosphodiesterase inhibitor, altered retinal function but less potently than GF248, consistent with their in vitro phosphodiesterase 6 inhibition. Phosphodiesterase 3- and phosphodiesterase 4-selective inhibitors, cilostamide and rolipram, respectively, did not affect retinal function at 10 micromol l(-1). Our conclusion from these data is that GF248, a potent phosphodiesterase 6 inhibitor, could interfere with visual transduction by cGMP accumulation.

Protective effect of a specific PAF antagonist on vincristine-induced experimental retinopathy.

The alkaloid vincristine displays considerable toxicity, particularly for the retina. This type of retinopathy being an inflammatory disease, we measured the effects of a new hetrazepine platelet activating factor antagonist, BN 50730, on a vincristine-induced retinopathy in the rat. Retinal impairments were established by recording several parameters of the electroretinogram obtained from isolated retina. Our results indicate that 1) the increase in PIII duration induced by vincristine is significantly reduced by BN 50730 administration 2) the decrease in the amplitude of the PIII/b wave ratio caused by vincristine is partially inhibited by treatment with BN 50730. These experiments suggest that platelet activating factor is implicated in vincristine retinopathy and demonstrate the therapeutic effect of a specific antagonist of the mediator.

Inhibition of platelet-activating factor-induced retinal impairments by cholera and pertussis toxins.

Platelet-activating factor (PAF) has been shown to alter the trans-retinal potential recorded from light-stimulated isolated retina. In the present study, we investigated the effect of cholera and pertussis toxins on PAF-induced impairment of the electroretinogram (ERG). Administered alone, 2 x 10(-7) M PAF induced a very marked and rapid drop in the b-wave amplitude. When 75 micrograms/l of cholera toxin was coadministered with PAF in the perfusion solution, no b-wave drop was observed, suggesting that the effect of PAF on retinal function was mediated by GTP-binding protein (G protein). Similarly, a low dose of pertussis toxin (5 micrograms/l) was sufficient to antagonize the action of PAF on the ERG. Our results suggest that the irreversible and deleterious effect of PAF on ERG is mediated by a G protein mechanism, located in the neural retina.

Antioxidant effect of a Ginkgo biloba extract (EGb 761) on the retina.

Several investigations have recently shown that the retina is very sensitive to oxygenated free radicals (O2-, OH.) at the origin of the membrane phospholipids peroxidation. Peroxy radical (ROO.) release is responsible for the induction of electrophysiological disturbances leading to retinopathy development. As Ginkgo biloba extract (EGb 761, IPSEN, France) was reported to scavenge primary (O2-, OH.) and secondary (ROO.) free radicals, we evaluated its antioxidant effect on retinas of albino rats submitted to different types of aggressors. On isolated rat retina, EGb 761 given orally significantly protected against lipoperoxidation induced by a mixture of ferrous sulfate and sodium ascorbate added to the perfusion solution. With EGb 761, the decrease of the b-wave ERG amplitude was less pronounced and the retina survival was increased. EGb 761 was also effective against ischaemia-reperfusion disorders due to occlusion of the central retinal artery or by intraocular hypertony. Like other antioxidants such as superoxide dismutase tested on these models, EGb 761 significantly attenuated, according to a dose-response effect, the free-radical injury. EGb 761 reduces the decrease of the b-wave amplitude, the oedema, necrosis and ion homeostasis disturbances. Xenobiotics are also responsible for the retinotoxicity partly due to free radicals and PAF release. We noted an EGb 761 dose-dependent protective effect against acute and chronic chloroquine toxicity to the retina. The deleterious effect of chloroquine was characterized by a delayed b-wave and an asymmetry of the signal with slow declining b-wave. After EGb 761 treatment, the ERG aspect was partially normal. In conclusion, EGb 761, by its general free-radical scavenger properties, is an antioxidant that inhibits or reduces the functional and morphological retina impairments observed after lipoperoxide release.

Prevention of chloroquine-induced electroretinographic damage by a new platelet-activating factor antagonist, BN 50730.

Chloroquine retinopathy is a severe toxic retinal impairment which may result in loss of vision by alterations of the retinal pigment epithelium and photoreceptors. Currently, there is no specific treatment for this retinopathy. Platelet-activating factor (PAF) is known to modulate retinal function and is one of the major immunomediators of the retina. In order to test the possible involvement of PAF in chloroquine-induced retinopathy and the effectiveness of PAF antagonists in the prevention of this condition, we investigated the effects of BN 50730, a specific PAF antagonist, on the electroretinogram (ERG) of the isolated rat retina exposed to chloroquine. When retinas from normal rats were perfused with chloroquine (10(-6) M), a marked and rapid decrease in b-wave amplitude was observed. In contrast, chloroquine had no effect on the b-wave of the retina isolated from animals pretreated with the PAF antagonist BN 50730 (30 mg/kg/day, i.p., for 5 days). The results obtained indicate that (i) chloroquine is a toxic drug for retinal function, (ii) PAF plays a key role in the mediation of chloroquine retinopathy and (iii) PAF antagonists may constitute valuable agents for the treatment of this retinal impairment.

Inhibition of vincristine-induced retinal impairments by a specific PAF antagonist.

The alkaloid vincristine is widely used for its anti-leukemic and anti-tumor activity. However, the drug also displays considerable toxicity, particularly for the retina. Indeed, vincristine has been shown to induce alteration of photoreceptor outer segments in animals and impairment of scotopic vision in man. This type of retinopathy is an inflammatory disease in which PAF may be implicated and for which specific PAF antagonist may have a therapeutic role. Thus, we measured the effects of a new hetrapezine derived PAF antagonist, BN 50730, on a vincristine-induced retinopathy in the rat. Retinal impairments were established by recording several parameters of the electroretinogram (ERG) obtained from isolated retina. Our results indicate that, first, the increase in PIII duration induced by vincristine is significantly reduced by BN 50730 administration and, second, the decrease in the value of the PIII/b wave ratio caused by vincristine is partially inhibited by treatment with BN 50730. These experiments suggest that PAF is implicated in vincristine retinopathy and demonstrate the therapeutic effect of a specific antagonist of the mediator.

Protective effect of Ginkgo biloba extract (EGB 761) on free radical-induced changes in the electroretinogram of isolated rat retina.

The retina is a tissue particularly rich in polyunsaturated fatty acids and thus highly sensitive to lipid peroxidation initiated by oxygenated free radicals. By recording the electroretinogram (ERG) b wave amplitude on isolated rat retina, the authors have investigated the anti-oxidant properties of Ginkgo biloba extract (EGB 761). Two groups of rats were used: one group was treated with EGB 761 at a dose of 100 mg/kg/day per os for 10 days; the other one of untreated animals served as a control. At the end of the treatment (10 days), rats were sacrificed, one retina isolated and perfused in order to record ERG. Lipid peroxidation was induced by adding a mixture of (FeSO4 + Na ascorbate) to the perfusion solution. In the untreated rats a 50% decrease in ERG was observed after only 55 min. Such a delay in the decrease and subsequent maintenance of ERG b wave amplitude confirm that the anti-oxidant properties of EGB 761 can protect the retina against lipoperoxidation.

Effects of platelet-activating factor on electrophysiology of isolated retinas and their inhibition by BN 52021, a specific PAF-acether receptor antagonist.

The effects of (R)PAF-acether have been tested on the isolated rat retina model. Results indicate that (R)PAF-acether inhibits the electrophysiological response (electroretinogram) elicited on isolated retina by a brief light flash. Immediately after the administration of (R)PAF-acether, an irreversible decrease of the electroretinogram b-wave amplitude is observed. This effect is dose-dependent (2 X 10(-11) M, 2 X 10(-9) M, 2 X 10(-7) M) and partially inhibited by simultaneous administration of Ginkgolide B (BN 52021; 2 X 10(-5) M). These results suggest the existence of (R)PAF-acether-specific receptors inside the retina.

Effects of PAF-acether on electrophysiological response of isolated retina.

Results of experiments performed on rat isolated retina indicate that platelet-activating factor (PAF) is able to inhibit the functional response of the retina electroretinogram (ERG) recorded in response to a brief light flash. In the presence of PAF, the ERG b-wave amplitude decreases according to a dose-dependent (2.10(-11) M; 2.10(-9) M; 2.10(-7) M) process. This effect is partially inhibited by the simultaneous administration of a Ginkgo biloba extract (GBE, 10 mg/l) or Ginkgolide B (BN 52021, 2.10(-5)M). The authors interpret these results with reference to the main mechanism of the membrane signal triggered by PAF, namely the activation of phosphatidylinositol cycle with the formation of inositol-triphosphate, the inhibition of the light-induced response of the retina by administration of inositol-triphosphate, and the antagonistic effect of GBE and BN 52021 on specific PAF-receptors demonstrated on other models. Thus specific PAF-receptors may exist at the level of the retina, which suggests that they are also present in the brain.

[Effect of Ginkgo biloba extract on the electrophysiology of the isolated retina from a diabetic rat]. / Effet de l'extrait de Ginkgo biloba sur l'électrophysiologie de la rétine isolée de rat diabétique.

The purposes of the experimental work presented here were to ascertain that diabetes causes impairment of the visual function and to test the protective properties of Ginkgo biloba extract against this impairment. The experimental method selected was the isolated albino rat retina maintained in survival by perfusion. Retinal function was evaluated by electroretinographic recording in response to a light stimulus. The rats were made diabetics by injection of alloxan. After one month of diabetes the electroretinogram amplitude was significantly decreased in diabetic rats as compared with control animals. This decrease in amplitude was more pronounced after 2 months of diabetes, which confirmed that retinal function was worse. In rats treated with Ginkgo biloba extract, after 2 months of diabetes the electroretinograms had a significantly greater amplitude that that observed in untreated rats. These results are attributed to the specific role played by free oxygenated radicals on the retina of diabetic rats and to the free radical scavenger property of Ginkgo biloba extract.

Experimental study of the retinal toxicity of hemoglobinic iron.

The functional consequences of vitreous hemorrhage on the retina were studied using a rabbit experimental model. The repartition of hemoglobinic iron inside the retina was assessed after the intravitreous injection of 59Fe-labeled erythrocytes. Electroretinographic studies were performed both in vivo after the intravitreous injection of labeled blood and in vitro on albino rat isolated retina treated with Fe ions. Results indicate that hemoglobinic iron migrates from the vitreous to the retina and inside the retinal tissue from ganglion cells to deeper layers. It is also demonstrated that hemoglobinic iron has a significant functional toxicity on the retina.

An automatic stimulus generation system for electroretinogram capture and processing.

An automated system is presented for on-line capture and processing of the analog signal obtained in response to light or X-ray stimulation of isolated rat retina maintained in survival by perfusion. The most important part of the system is a microcomputer Apple II (48 K Europlus) equipped with interface boards. Basic and assembler programs automatically deliver light or X-ray stimulation every 5 min. Data capture and data processing are carried out following each retinal response. Calculated parameters of the ERG, and 200 values obtained after sampling of an ERG are placed in a data file on a floppy disc. One hundred ERGs can be stored in this way.

Electrophysiological consequences of leukotrienes applied on isolated rat retina.

Scotopic vision is the result of a cascade of light-dependent biochemical events in rod outer segments (ROS) involving mainly a cGMP-modulation of sodium current. This modification of ionic currents induces changes of membrane potential which generates electroretinographic (ERG) waves. As (i) ERG disturbances are commonly recorded in hypoxic and inflammatory retinal diseases (ii) leukotrienes (LTs), a very potent mediators of inflammation, disturb ionic exchanges in several artificial or natural membrane systems, we undertook the investigation of the effects of LTs on ERG record in mammalian isolated retina. LTB4, LTC4 and LTD4, all induced a dose-dependent marked reduction of the b wave amplitude of ERG. This effect is correlated with a significant decrease in the survival time of the retina. The analysis of the modification of ERG indicates that LTs exhibit a real toxic effect since b wave is mainly affected while P III wave is unchanged. Comparatively with other nervous cells, this phenomenon may be attributed to an increase in Na+ permeability of ROS. It is suggested that LTs may be involved in the development of inflammatory or ischemic retinal diseases.

Effects of leukotrienes on the electroretinographic profile of the isolated rat retina.

The isolated retina represents an excellent membrane model since it provides a specific electrophysiological response that is easy to quantify. Therefore the authors have tested the effects of B4, C4 and D4 leukotrienes on this model. In the presence of leukotrienes, electrical response generally decreases and survival duration of the isolated retina is generally shortened. No significant difference between the effects of the three tested products has been found. These results are discussed in relation to, on the one hand, the mechanism of intraretinal generation of its electrophysiological signal and, on the other hand, the leukotrienes' role in inflammatory diseases of the retina.

[Effects of oxygenated free radicals on the electrophysiological activity of the isolated retina of the rat]. / Effets des radicaux libres oxygénés sur l'activité électrophysiologique de la rétine isolée de rat.

Particularly rich in polyunsaturated fatty acids, the retina constitutes an excellent model for testing the functional consequences of membrane lipoperoxidation. The effects could be quantified by measuring the amplitude of the electroretinogram which represents the characteristic response of the retina to its physiological stimulus (light photons). The authors report results obtained on isolated rat retina maintained in survival by perfusion. The membrane lipid peroxidation is induced by the non enzymatic catalytic system (Fe2+ + ascorbate). In the presence of such a system, the amplitude of the b-wave of the electroretinogram rapidly decreases and the survival time is notably shortened. These results are discussed with regards to the mechanism generating the electroretinogram and the specific role played by the disk membrane and plasmic membrane of the rod outer segment. Finally, the authors test the radical scavenger properties of a Ginkgo biloba extract. The results indicate that such an extract develops an antiperoxidative effect probably connected with its flavonoid composition. With this extract the survival time of the isolated retina is significantly increased and this result could be related to the retinal cell membrane disorders observed in diabetes.