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The erbb2 gene, which encodes the growth factor receptor HER2, is amplied and overexpressed in 1525 % of breast cancers, associated with poorer prognosis before the use of HER2 targeting agents. In patients with HER2-positive metastatic breast cancer, the addition of pertuzumab to trastuzumab and docetaxel signicantly improved the median overall survival to 56.5 months [1]. Prolonged survival combined with high neurotropism of HER2-amplied tumors results in increasing incidence of leptomeningeal metastases. Due to very limited options, this situation represents an emerging issue. The prognosis of breast cancer patients with meningeal carcinomatosis is very poor with a reported median survival of 4.5 months with high-dose intrathecal methotrexate [2]. Of crucial importance, comparison of HER2 statuses in cerebrospinal uid-derived tumor cells from patients with metastatic breast cancer with leptomeningeal carcinomatosis and corresponding archival primary tumors revealed a very concordance rate [3]. Furthermore, because of the high molecular weight of trastuzumab and pertuzumab, unable to cross the bloodbrain barrier, leptomeninges may be a sanctuary for cancer cells to monoclonal antibodies. Consequently, meningeal metastases may result from a pharmacokinetic limitation to treatment delivery rather than from a molecular resistance to HER2 blockade. The pulsatile administration of high doses of tyrosine kinase inhibitors is a potential way to obtain a very high plasma maximal concentration, resulting in active concentrations in the leptomeninges [4]. Lapatinib, a reversible dual tyrosine kinase inhibitor of EGFR and HER2, is active in patients with HER2-positive metastatic breast cancer. Because it has a small molecular weight and is lipophilic, we hypothesized that very high doses of lapatinib may circumvent the sanctuary effect in case of HER2-positive breast cancer with leptomeningeal metastases.

ROS1 tyrosine kinase inhibitors (TKIs) have showed activity and efficacy in -rearranged non-small cell lung cancer (NSCLC). In the clinical practice, besides the utilization of crizotinib, less is known about the best treatment strategies involving additional, new-generation TKIs for the sequential treatment of ROS1-positive NSCLC patients. A patient suffering from a -rearranged lung adenocarcinoma, after receiving cisplatin-pemetrexed chemotherapy, was treated with entrectinib, a new-generation ALK/ROS1/NTRK inhibitor. After 16 months, central nervous system (CNS) metastases appeared, without extra-cerebral disease progression. Stereotactic brain radiotherapy was performed and entrectinib was maintained, due to the global systemic disease control. Approximately one month after radiotherapy, thoracic and meningeal progressions were detected, the latter highly symptomatic with neurocognitive disorders, visual hallucinations and worsening of psycho-motor impairment. A lumbar puncture was positive for tumor cells and for an fusion. The administration of lorlatinib (a third-generation ALK/ROS1 inhibitor) prompted an extremely rapid improvement of clinical conditions, anticipating the positive results observed at radiologic evaluation that confirmed the disease response still ongoing after nine months since treatment start. With the expanding availability of targeted agents with differential activity on resistance mechanism and on CNS disease, choosing wisely the best treatment strategies is pivotal to assure the best clinical outcomes in oncogene-addicted NSCLC patients. Here we have reported lorlatinib reverted an almost fatal meningeal carcinomatosis developing during entrectinib in a ROS1-positive NSCLC patient.

Résumé Les cancers urothéliaux sont des cancers fréquents avec un pronostic péjoratif au stade métastatique. La chimiothérapie par MVAC dose-dense ou gemcitabine–cisplatine reste actuellement le standard en première intention. Chez les patients dont l’état général ou la fonction rénale ne permettent pas d’administrer du cisplatine, une combinaison par carboplatine–gemcitabine est considérée comme l’option la plus consensuelle actuellement. En cas d’échec d’une chimiothérapie de première ligne, aucun traitement n’a réellement montré d’efficacité importante même si la vinflunine a obtenu une autorisation dans cette indication. Actuellement, les espoirs se tournent essentiellement vers l’immunothérapie (les inhibiteurs de PD-1 et PD-L1) qui devrait radicalement changer la prise en charge de ces patients dans le futur. L’impact de l’administration de thérapies ciblées en fonction des anomalies moléculaires obtenues au cours d’une analyse extensive de génome des patients est également en cours d’évaluation.

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.

Résumé Le congrès Targeted Anticancer Therapies (TAT) s’est déroulé cette année du 2 au 4 mars à Paris. Encore une fois l’immunothérapie y était à l’honneur avec les anticorps anti-PD-1/PD-L1, les anticorps anti-CSF-1R, l’immunothérapie adoptive et le développement de combinaisons d’immunothérapies. Le challenge actuel reste de parvenir à identifier les patients susceptibles d’en retirer le plus grand bénéfice. Parmi les molécules prometteuses présentées par ailleurs, on peut citer les agents ciblant les cyclines dépendantes kinases (CDK) ou les empreintes épigénétiques ainsi que les inhibiteurs de PARP et des systèmes de réparation de l’ADN tels qu’ATR. Enfin, une troisième génération d’inhibiteurs de tyrosines-kinases (ITK) est actuellement en cours d’évaluation afin de contourner les résistances acquises aux premiers ITK ; comme le rociletinib actif sur la mutation de résistance T790M dans les cancers bronchiques. Sur le plan des techniques, le criblage moléculaire affirme son intérêt en routine clinique dans le cadre du développement de la médecine personnalisée avec les résultats de l’essai MOSCATO-01, et de nouveaux critères radiologiques et « radiomics » d’évaluation de la réponse tumorale sont en cours de validation pour s’adapter notamment à l’immunothérapie et aux thérapies ciblées.

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.