[Role of immunotherapy in locally advanced non-small cell lung cancer]. / Place de l'immunothérapie dans le cancer bronchique non à petites cellules localement avancé.

Concomitant radiochemotherapy has been the standard of care for unresectable stage III non-small cell lung cancer (NSCLC), irrespective of histological sub-type or molecular characteristics. Currently, only 15-30 % of patients are alive five years after radiochemotherapy, and this figure remains largely unchanged despite multiple phase III randomised trials. In recent years, immune-checkpoint blockades with anti-PD-(L)1 have revolutionised the care of metastatic NSCLC, becoming the standard front- and second-line strategy. Several preclinical studies reported an increased tumour antigen release, improved antigen presentation, and T-cell infiltration in irradiated tumours. Immunotherapy has therefore recently been evaluated for patients with locally advanced stage III NSCLC. Following the PACIFIC trial, the anti-PD-L1 durvalumab antibody has emerged as a new standard consolidative treatment for patients with unresectable stage III NSCLC whose disease has not progressed following concomitant platinum-based chemoradiotherapy. Immunoradiotherapy therefore appears to be a promising association in patients with localised NSCLC. Many trials are currently evaluating the value of concomitant immunotherapy and chemoradiotherapy and/or consolidative chemotherapy with immunotherapy in patients with locally advanced unresectable NSCLC.

Preoperative MR imaging for ESMO-ESGO-ESTRO classification of endometrial cancer.

OBJECTIVE: To retrospectively investigate whether magnetic resonance imaging (MRI) findings could contribute to predict histologic type, tumor grade and lymphovascular space invasion (LVSI) to improve preoperative assessment of endometrial cancer using the European Society for Medical Oncology (ESMO) European Society for Radiotherapy & Oncology (ESTRO) and European Society of Gynecological Oncology (ESGO) classification. METHODS: Between January 2008 and August 2014, 104 women (mean age, 65±11 [SD] years; range, 32-84 years) with International Federation of Gynecology and Obstetrics (FIGO) stage I endometrial cancer underwent preoperative MRI of the pelvis. Two independent readers evaluated tumor heterogeneity and measured tumor size on T2-weighted, diffusion-weighted and T1-weighted images obtained after gadolinium chelate administration at 2minutes. The apparent diffusion coefficient (ADC) was generated from pixel ADC from the whole tumor volume. RESULTS: A short axis>24mm on MRI was associated with histopathologic type 2, grade 3 tumor and presence of LVSI (P<0.01). There were no significant differences in minimum, mean and maximum ADC between presence/absence of LVSI. In 9.1% women (9/99), the accuracy of the ESMO-ESGO-ESTRO classification with the inclusion of the MRI short-axis criterion was higher than that of the conventional ESMO classification to predict high-risk recurrence endometrial cancer (P=0.02). CONCLUSION: Tumor size reflects histologic type, tumor grade and LVSI in endometrial cancer. FIGO stage 1 endometrial cancer>24mm should be classified preoperatively in the high-intermediate or high-risk recurrence risk groups.

[Pain management in radiation oncology]. / Situations difficiles lors d'une irradiation : la douleur.

The goal of this article is to propose some practical means of pain management in radiation departments. Pain management in radiation oncology is difficult because of the high proportion of painful patients, underestimation by medical teams, and limited therapeutic options. Pain can cause mobilization difficulties, set-up errors, treatment interruption. According to procedure steps, a preventive attitude (for pre-radiation consultation) or an active attitude (for treatment) to quickly relieve the patient can be planned. This work is a brain storming about pain management. It is not a review about analgesic radiotherapy. The practical situations apply to patients to whom radiotherapy is indicated. Teamwork and anticipation are keywords to relieve patients. All proposed means are not always available for different reasons (time, finance, staff, training). The idea is to establish simple procedures that are appropriate to each center to fluidify acts, to optimize time for a successful irradiation.

Influence of atrial flutter ablation on right to left inter-atrial conduction.

AIMS: Ablation of the atrial isthmus between the tricuspid annulus and the inferior vena cava changes P-wave morphology during low lateral right atrial pacing. For better understanding of the mechanism of this alteration, the sequence of activation of the inter-atrial septum and the left atrium were compared before and after ablation of the isthmus between the inferior vena cava and the tricuspid annulus. METHODS AND RESULTS: In 13 patients, left atrial mapping was performed using a duodecapolar electrode catheter advanced to the far distal coronary sinus. The inter-atrial septum was mapped using a right atrial duodecapolar electrode catheter. Conduction times were measured during low lateral right atrial pacing from the pacing artefact and during sinus rhythm from the earliest right atrial electrogram to every intra-cardiac electrogram before and after the ablation. During low lateral right atrial pacing, isthmus ablation resulted in a significant delay in every left atrial lead. Changes were maximal at the posterior aspect of the left atrium and minimal at its anterior aspect. No significant change was discernible on the inter-atrial septum. During sinus rhythm, atrial activations remained unchanged. CONCLUSION: Electrocardiographic changes of P-wave morphology result from alteration in the sequence of left atrial activation rather than that of the inter-atrial septum.

[Radiofrequency ablation of intranodal tachycardia]. / Traitement par radiofréquence des tachycardies intranodales.

The first radical approach to the treatment of atrioventricular nodal reentrant tachycardia was surgical dissection of the perinodal region. This technique has been replaced by the delivery of radiofrequency energy by an ablation catheter to the region of the atrioventricular node. The aim of this report is to describe the authors' experience of atrioventricular nodal application of radiofrequency current. The study comprised 53 cases (32 women and 21 men, mean age 46 +/- 17 years) with frequent attacks of reciprocating tachycardia. Endocavitary electrophysiological investigation confirmed the intranodal reentrant mechanism. The region of application of the radiofrequency current was located radiologically and then the precise site determined by the recording of nodal electrical activity. The appearance of junctional rhythm during the procedure was also used as a means of identification of the zone of ablation. Dual conduction persisted after ablation in 35 patients. However, no episode of tachycardia could be induced after the procedure. The AH interval increased during application of radiofrequency current in 3 cases but this abnormality regressed in the 2 months following the procedure. Recurrences of nodal reentrant tachycardia were observed in 14 cases (26%), 24 hours to 2 months after ablation. The rate of recurrence was significantly higher in patients who did not have a junctional rhythm during application of the radiofrequency current (62% vs 4%, p < 0.05). The number of recurrences was also greater in the group of patients with persistence of slow intranodal conduction after the radiofrequency ablation (p < 0.04). A second session of radiofrequency ablation was undertaken in 14 patients and a third session was required for 2 of them.(ABSTRACT TRUNCATED AT 250 WORDS)

[Ablation of accessory pathways by radiofrequency current. Towards a simplified approach of Wolff-Parkinson-White syndrome?]. / Ablation des voies accessoires par courant de radiofrquence. Vers une approche simplifiée du syndrome de Wolff-Parkinson-White?

From December 1990 to April 1992, 41 consecutive patients (22 men and 19 women with an average age of 35 +/- 16 years -6-72) underwent ablation of accessory atrioventricular conduction pathways (Bundles of Kent) for poorly tolerated and/or medically resistant supraventricular tachycardias. In 33 cases, the arrhythmia was a paroxysmal SVT, in 7 cases atrial fibrillation, and in 1 patient incessant junctional tachycardia causing left ventricular dysfunction. The Wolff-Parkinson-White syndrome was apparent in 30 patients and concealed in 11 cases. The location of the Kent bundle was left lateral in 22 cases (53.7%), posterior paraseptal in 9 cases (21.9%), right lateral in 5 cases (12.2%) and anterior paraseptal in 5 cases (12.2%). The Kent bundles were ablated by radiofrequency currents in 38 cases (92.7%); in 2 patients (4.9%) in whom radiofrequency could not be used (increased impedance) high energy electrical shock was successful. In one patient (2.4%), it was not possible to suppress the Kent bundle. A single session of radiofrequency ablation was sufficient in 33 cases: 7 cases (17.5%) required 2 (4) or 3 (3) sessions. The average number of sites of application per patient was 8.8 +/- 8.8. The duration and intensity were respectively 32.2 +/- 9.3 (5-60) seconds and 25 +/- 15 (20-30) watts. With an average follow-up of tachycardia or of ventricular preexcitation have been observed in the 40 patients. In addition, in 36 patients, electrophysiological control studies confirmed the initial result with absence of any disturbance of nodohisian conduction.(ABSTRACT TRUNCATED AT 250 WORDS)

Transfer of IgG from serum to lachrymal fluid in chickens.

Pure 125I-radiolabeled chicken IgG was inoculated intravenously into 2-week old chickens. Radioactivity in lachrymal fluid samples was first detected 10 minutes postinoculation (PI). Radioactivity levels declined up to day 20 PI, when they reached marginal levels. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) followed by autoradiography of lachrymal fluid samples, taken daily for 16 days, showed the presence of radioactive polypeptides in the same positions as their stained control counterparts at molecular weights corresponding to heavy and light chains of immunoglobulins. Radiolabeled IgG also was detected in serum samples of the inoculated chickens. SDS-PAGE followed by autoradiography of lachrymal samples taken until day 16 PI showed similar results. These results demonstrate that transfer of IgG from serum to lachrymal fluid does occur in chickens.

Progestin treatment depresses estrogen receptor but not cathepsin D levels in needle aspirates of benign breast disease.

We studied the effect of a progestin (lynestrenol) on estrogen receptors (ER) and cathepsin D (cath-D) levels immunochemically in successive fine needle aspirates of benign breast disease. Fibrocystic disease was the main pathology (43 out of 47 patients). Thirty-one patients were treated with 10 mg of lynestrenol daily from the fifth to the twenty-fifth day of the menstrual cycle for 1 to 3 months. Sixteen untreated patients were used as controls. Lynestrenol significantly decreased the percentage of ER stained cells. This is in agreement with the antiestrogenic effect of progestin and, for the first time, indicates that in vivo progestin may decrease the stimulatory effect of estrogens on mammary cells by decreasing their estrogen receptor content. No effect of progestin on cath-D level was found throughout the whole population. However, this level varied more between aspirates of each patient in the treated group than in the control group, suggesting heterogeneity in patient responses to progestin. Since cath-D may have a role in carcinogenesis, clinical follow-up of these patients and more detailed studies are required to determine whether this progestin-challenge test has any value for detecting high risk mastopathies and for predicting effectiveness of treatment.

Pharmacologic modulation of picryl chloride-induced contact dermatitis in the mouse.

A biphasic response of ear swelling was observed 2 h and 24 h after application of the antigen to picryl chloride-sensitized Balb/c mice. A platelet-activating factor (PAF) antagonist, BN 52063, or the anti-inflammatory drug, betamethasone, applied topically or injected subcutaneously, inhibited in a dose-dependent fashion the antigen-induced increase in ear thickness observed after 24 h. In addition, BN 52063 and betamethasone presented a synergistic effect when administered in vivo simultaneously and subcutaneously. Indomethacin administered subcutaneously at the time of the antigen challenge significantly potentiated the early swelling phase and inhibited the late one. In contrast, the inhibitors of histamine and serotonin, ketotifen and methysergide, respectively, modulated mostly the early, and to a lower extent the late phase when administered at the time of antigen challenge. In contrast, none of these drugs inhibited the late phase reaction when administered 4 h after the antigen. A significant eosinophil and mononuclear-cell ear infiltrate was observed following topical application of the antigen, a phenomenon that was markedly reduced by either BN 52063 or betamethasone. These results demonstrate the effectiveness of PAF antagonists, either alone or in association with glucocorticosteroids, in experimental CD, the modulation of the infiltration of eosinophils and mononuclear cells possibly explaining part of the inhibitory action of these drugs.

Modulation of leucocyte activation in the early phase of the rabbit burn injury.

Previous studies in burned patients have shown an early enhanced polymorphonuclear leucocyte (PMN) generating capacity for superoxide radical (O2.-), for the arachidonic acid (AA) lipoxygenase metabolite leukotriene B4 (LTB4) and for platelet activating factor-acether (PAF). These findings have been confirmed on a burn injury rabbit model. As we have suggested a pivotal role for an exaggerated initial (less than 36-48 h) neutrophil stimulation leading to a later (greater than 72 h) immuno-depression and anergy, we tried to modulate the early phase by drug therapy. A Ginkgo biloba extract (IPS200) injected i.v. in burned rabbits greatly reduced O2.- and LTB4 generation on A23187 challenge. IPS200 includes flavonoids and other polyphenols, inhibiting either arachidonic acid metabolism or PAF receptors, and may thus exert their modulating effect on PMN function in thermal injury.

Inhibition of platelet aggregation by manoalide: preliminary results.

Manoalide (MND), a sesterterpenoid first isolated from the marine sponge Luffariela variabilis and later synthesized by Japanese chemists, exhibits anti-inflammatory activity and directly inactivates bee and snake venom phospholipase A2. We investigated the effects of MND on platelet aggregation induced by PAF-acether, arachidonic acid (AA), ADP and thrombin. Rabbit platelet aggregation was inhibited by MND in a dose-dependent manner. MND also inhibited the aggregation induced by AA and ADP but not that induced by thrombin. Since this marine natural product is also a potent inhibitor of lipoxygenase in human polymorphonuclear neutrophils, MND appears to be a useful tool for determining the role of phospholipase A2 in biological processes.

Electrophysiological action of bepridil on atrioventricular accessory pathways.

The electrophysiologic properties of bepridil, a calcium channel blocker with additional effects on fast response tissues, were investigated in 10 patients with atrioventricular accessory pathways. Seven patients had Wolff-Parkinson-White syndrome, and three had concealed atrioventricular pre-excitation. A dose of 4 mg/kg was administered intravenously over five minutes. Bepridil increased the AH interval and the functional refractory period of the atrioventricular node. The effective refractory periods of the right atrium and right ventricle were also increased. Bepridil prolonged refractoriness in the accessory pathway both in the anterograde and retrograde direction. After bepridil administration it was impossible to induce reciprocating tachycardia electrically in two patients because of conduction block in the normal pathway. On the other hand, the zone of tachycardia was often increased after bepridil. Nevertheless, the heart rate during tachycardia was slowed by depression of conduction in both the normal and accessory pathways. The findings of this study provide a basis for the antiarrhythmic action of bepridil in patients with atrioventricular accessory pathways.

Effects of intravenous sotalol in patients with atrioventricular accessory pathways.

Effects of intravenous injection of 0.6 mg/kg sotalol, a beta-blocking agent with additional class III properties, were studied by means of electrophysiologic techniques in 14 patients, seven with the Wolff-Parkinson-White syndrome and seven with concealed atrioventricular (AV) accessory pathways. Sotalol brought about a significant increase in the retrograde effective refractory period of the anomalous pathway, whereas changes in the antegrade effective refractory period were more variable. In five of nine patients with electrically induced reciprocating tachycardia sotalol prevented the initiation of sustained reentry. In most cases the suppression of the circus movement was the result of the development of AV nodal block. Thus our data support the use of sotalol for the treatment of tachycardias incorporating anomalous AV conduction pathways.

Electrophysiologic effects of cibenzoline in humans related to dose and plasma concentration.

The electrophysiologic effects of a new antiarrhythmic agent, cibenzoline, were investigated in 25 patients with an average age of 62 years. The compound was administered intravenously, as a bolus given over 2 minutes, then as a slow infusion over 40 minutes. Each subject was randomly allocated to receive one of the following four doses: 1.55 mg/kg (six patients), 1.8 mg/kg (six patients), 2.2 mg/kg (six patients), or 2.6 mg/kg (seven patients). Plasma cibenzoline concentrations at these doses were 378 +/- 80,525 +/- 194, 618 +/- 72, and 731 +/- 196 ng/ml, respectively. Administration of 1.55 mg/kg cibenzoline significantly shortened the sinus cycle (60 msec on average; p less than 0.025) and increased intraatrial (+8 msec; p less than 0.05) and His-Purkinje conduction times (HV interval + 13 msec; p less than 0.001). At 1.80 mg/kg, prolongation occurred in the HV interval (+9 msec; p less than 0.02), the duration of the QRS complex (+20 msec; p greater than 0.05), and the QT interval (+18 msec; p less than 0.025). At the higher doses these changes became more marked (maximum increase: HV = +16 msec, p less than 0.001; QRS + 25 msec; p less than 0.001; QT + 26 msec, p less than 0.05), and additional effects on atrioventricular nodal conduction time (AH interval + 17 msec; p less than 0.05) and atrial (+20 msec; p less than 0.05) and ventricular (+10 msec; p greater than 0.05) effective refractory periods were observed. Prolongation of the QRS duration was the effect that correlated best with plasma cibenzoline levels (r = 0.47; p less than 0.05).(ABSTRACT TRUNCATED AT 250 WORDS)

Bundle branch reentrant tachycardia treated by electrical ablation of the right bundle branch.

A 66 year old man presented with multiple episodes of tachycardia. Some had QRS complexes with a right bundle branch block configuration identical to those of sinus beats. The onset of the tachycardia was preceded by premature His bundle depolarizations. There was a His potential before each QRS complex of the tachycardia. Atrial activity was dissociated. Occasionally the appearance of sinus beats with a left bundle branch block pattern announced a tachycardia with an identical configuration and atrioventricular dissociation. His bundle activity occurred before the QRS complex and was followed by a right bundle branch deflection. A reentrant mechanism within the bundle branch system was invoked. One 200 J shock was delivered through an electrode catheter to the site of the right bundle branch. The postprocedure course was uneventful (follow-up 10 months).