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Purpose: To assess the preclinical efficacy, clinical safety and efficacy, and MTD of palbociclib plus nab-paclitaxel in patients with advanced pancreatic ductal adenocarcinoma (PDAC). Experimental Design: Preclinical activity was tested in patient-derived xenograft (PDX) models of PDAC. In the open-label, phase I clinical study, the dose-escalation cohort received oral palbociclib initially at 75 mg/day (range, 50‒125 mg/day; modified 3+3 design; 3/1 schedule); intravenous nab-paclitaxel was administered weekly for 3 weeks/28-day cycle at 100‒125 mg/m2. The modified dose–regimen cohorts received palbociclib 75 mg/day (3/1 schedule or continuously) plus nab-paclitaxel (biweekly 125 or 100 mg/m2, respectively). The prespecified efficacy threshold was 12-month survival probability of ≥65% at the MTD. Results: Palbociclib plus nab-paclitaxel was more effective than gemcitabine plus nab-paclitaxel in three of four PDX models tested; the combination was not inferior to paclitaxel plus gemcitabine. In the clinical trial, 76 patients (80% received prior treatment for advanced disease) were enrolled. Four dose-limiting toxicities were observed [mucositis (n = 1), neutropenia (n = 2), febrile neutropenia (n = 1)]. The MTD was palbociclib 100 mg for 21 of every 28 days and nab-paclitaxel 125 mg/m2 weekly for 3 weeks in a 28-day cycle. Among all patients, the most common all-causality any-grade adverse events were neutropenia (76.3%), asthenia/fatigue (52.6%), nausea (42.1%), and anemia (40.8%). At the MTD (n = 27), the 12-month survival probability was 50% (95% confidence interval, 29.9–67.2). Conclusions: This study showed the tolerability and antitumor activity of palbociclib plus nab-paclitaxel treatment in patients with PDAC; however, the prespecified efficacy threshold was not met. Trial Registration: Pfizer Inc (NCT02501902) Significance: In this article, the combination of palbociclib, a CDK4/6 inhibitor, and nab-paclitaxel in advanced pancreatic cancer evaluates an important drug combination using translational science. In addition, the work presented combines preclinical and clinical data along with pharmacokinetic and pharmacodynamic assessments to find alternative treatments for this patient population.

Lorlatinib is a third-generation, brain-penetrant anaplastic lymphoma kinase (ALK) and c-ros oncogene 1 (ROS1) tyrosine kinase inhibitor (TKI) with robust intracranial activity in patients with ALK- or ROS1-positive non-small cell lung cancer (NSCLC). Data from the ongoing open-label, single-arm, multicenter, phase-1/2 study of lorlatinib in patients with metastatic ALK- or ROS1-positive NSCLC were used to further investigate the potential brain penetration of lorlatinib. Patients received escalating lorlatinib doses (10-200 mg once daily or 35-100 mg twice daily) or the approved dosing (100 mg daily). Plasma was collected from all patients, and cerebrospinal fluid (CSF) was collected at baseline and during the study from 5 patients with suspected or confirmed leptomeningeal carcinomatosis or carcinomatous meningitis. For those 5 patients, lorlatinib concentrations ranged from 2.64 to 125 ng/mL in the CSF and from 12.7 to 457 ng/mL in the plasma; free plasma concentrations ranged from 4.318 to 155.385 ng/mL. The CSF/free plasma ratio was 0.77 (R

Purpose:To assess the preclinical efficacy, clinical safety and efficacy, and MTD of palbociclib plus nab-paclitaxel in patients with advanced pancreatic ductal adenocarcinoma (PDAC).Experimental Design:Preclinical activity was tested in patient-derived xenograft (PDX) models of PDAC. In the open-label, phase I clinical study, the dose-escalation cohort received oral palbociclib initially at 75 mg/day (range, 50‒125 mg/day; modified 3+3 design; 3/1 schedule); intravenous nab-paclitaxel was administered weekly for 3 weeks/28-day cycle at 100‒125 mg/m2. The modified dose–regimen cohorts received palbociclib 75 mg/day (3/1 schedule or continuously) plus nab-paclitaxel (biweekly 125 or 100 mg/m2, respectively). The prespecified efficacy threshold was 12-month survival probability of ≥65% at the MTD.Results:Palbociclib plus nab-paclitaxel was more effective than gemcitabine plus nab-paclitaxel in three of four PDX models tested; the combination was not inferior to paclitaxel plus gemcitabine. In the clinical trial, 76 patients (80% received prior treatment for advanced disease) were enrolled. Four dose-limiting toxicities were observed [mucositis (n = 1), neutropenia (n = 2), febrile neutropenia (n = 1)]. The MTD was palbociclib 100 mg for 21 of every 28 days and nab-paclitaxel 125 mg/m2 weekly for 3 weeks in a 28-day cycle. Among all patients, the most common all-causality any-grade adverse events were neutropenia (76.3%), asthenia/fatigue (52.6%), nausea (42.1%), and anemia (40.8%). At the MTD (n = 27), the 12-month survival probability was 50% (95% confidence interval, 29.9–67.2).Conclusions:This study showed the tolerability and antitumor activity of palbociclib plus nab-paclitaxel treatment in patients with PDAC; however, the prespecified efficacy threshold was not met.Trial Registration:Pfizer Inc (NCT02501902)Significance:In this article, the combination of palbociclib, a CDK4/6 inhibitor, and nab-paclitaxel in advanced pancreatic cancer evaluates an important drug combination using translational science. In addition, the work presented combines preclinical and clinical data along with pharmacokinetic and pharmacodynamic assessments to find alternative treatments for this patient population.

Supplementary Materials and Methods

Supplementary Table S3 from A Preclinical and Phase Ib Study of Palbociclib plus Nab-Paclitaxel in Patients with Metastatic Adenocarcinoma of the Pancreas

Purpose:Combined axitinib/pembrolizumab is approved for advanced renal cell carcinoma (aRCC). This exploratory analysis examined associations between angiogenic and immune-related biomarkers and outcomes following axitinib/pembrolizumab treatment.Patients and Methods:Prospectively defined retrospective correlative exploratory analyses tested biospecimens from 52 treatment-naïve patients receiving axitinib and pembrolizumab (starting doses 5 mg twice daily and 2 mg/kg respectively, every 3 weeks). Tumor tissue, serum, and whole blood samples were collected at baseline, at cycle 2 day 1 (C2D1), and end of treatment (EOT) for blood-based samples. Clinical outcomes were objective response rate (ORR) and progression-free survival (PFS).Results:Higher baseline tumor levels of CD8 showed a trend toward longer PFS (HR 0.4; P = 0.091). Higher baseline serum levels of CXCL10 (P = 0.0197) and CEACAM1 (P = 0.085) showed a trend toward better ORR and longer PFS, respectively. Patients for whom IL6 was not detected at baseline had longer PFS versus patients for whom it was detected (HR 0.4; P = 0.028). At C2D1 and/or EOT, mainly immune-related biomarkers showed any association with better outcomes. The genes CA9 (P = 0.084), HIF1A (P = 0.064), and IFNG (P = 0.073) showed trending associations with ORR, and AKT3 (P = 0.0145), DDX58 (P = 0.0726), GZMA (P = 0.0666), LCN2 (NGAL; P = 0.0267), and PTPN11 (P = 0.0287) with PFS.Conclusions:With combined axitinib/pembrolizumab treatment in patients with aRCC, mostly immune-related biomarkers are associated with better treatment outcomes. This exploratory analysis has identified some candidate biomarkers to consider in future prospective testing.

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Supplementary Tables

Supplementary Figure 1

To analyze the efficacy and safety of lorlatinib in Asian and non-Asian patients with pretreated anaplastic lymphoma kinase (ALK)-positive, advanced non-small cell lung cancer (NSCLC) from a phase 1/2 study.In this ongoing phase 2 part of the trial, patients with ALK- or ROS1-positive, advanced NSCLC enrolled into six expansion cohorts (EXP1-6), based on ALK and ROS1 status and previous therapy, and received lorlatinib 100 mg once daily. The primary endpoint was objective tumor response and intracranial response. Post hoc analyses of activity were conducted in Asian and non-Asian (based on race) ALK-positive patients who received either previous crizotinib with or without chemotherapy (EXP2-3A) or at least one second-generation ALK tyrosine kinase inhibitor with any number of chemotherapy regimens (EXP3B-5). Analysis of safety (adverse events [AEs]) was in the phase 1 and 2 study population who started lorlatinib 100 mg once daily.17 Asian patients were enrolled in EXP2-3A and 53 in EXP3B-5; 33 non-Asian patients were enrolled in EXP2-3A and 73 in EXP3B-5. Objective response rates in the Asian and non-Asian subgroups were 82.4% (95% confidence interval [CI]: 56.6-96.2) and 63.6% (95% CI: 45.1-79.6) in EXP2-3A, and 47.2% (95% CI: 33.3-61.4) and 30.1% (95% CI: 19.9-42.0) in EXP3B-5, and median progression-free survival was 13.6 and 12.5 months (EXP2-3A) and 6.9 and 5.5 months (EXP3B-5). Lorlatinib exhibited antitumor activity across ALK resistance mutations, while no differences according to the EML4-ALK variant could be detected. The most common treatment-related AEs were hypercholesterolemia, hypertriglyceridemia, edema, and peripheral neuropathy in both Asian and non-Asian subgroups.Lorlatinib showed substantial overall and intracranial activity in pretreated patients with ALK-positive NSCLC in both Asian and non-Asian patients. AE profiles were similar between Asian and non-Asian patients.gov NCT01970865.

En 2003, 94,5 % des demandeurs d'asile maintenus en zone d'attente ont vu leur demande qualifiée de "manifestement infondée". Une épreuve de tri singulièrement inadaptée à des enfants, qui "ne devraient jamais se voir refuser l'accès à la procédure d'asile", estime le Haut Commissariat aux Réfugiés des Nations unies. Au lieu de quoi, rares sont les mineurs isolés qui "passent" les zones d'attente et accèdent, finalement, à la protection de l'enfance. La majorité est renvoyée au pays de départ., Martini Jean-François. Mineurs sans famille en zone d'attente. In: Hommes et Migrations, n°1251, Septembre-octobre 2004. Enfants sans frontières. pp. 23-31.

Development of a line of highly differentiated neuronal cells (GT1 cells) that secrete gonadotropin-releasing hormone (GnRH) has permitted studies on the signaling mechanisms involved in regulating secretion of GnRH. This study focused on the pathways coupling GnRH secretion to elevated levels of cyclic adenosine monophosphate (cAMP) in the GT1 cell line. Two mechanisms were examined: a direct action of increased cAMP by means of cyclic nucleotide-gated (CNG) cation channels and an indirect action through activation of cAMP-dependent protein kinase A (PKA). Patch-clamp experiments were carried out on two lines of GT1 cells in both the on-cell and excised patch configurations. Treatment of perifused GT1 cells with dopamine led to a substantial rise in cAMP levels, which resembled accumulation of intracellular cAMP in GT1 cells exposed to dopamine. GT1 cells were found to express the three CNG subunits present in olfactory neurons: CN2, CNG4.3, and CNG5. The cells possessed functional cAMP-gated cation channels. Activation of PKA did not seem to be required for increased cAMP to stimulate the release of GnRH. Indeed, inhibiting PKA activity was associated with increased basal GnRH secretion. PKA inhibited adenylyl cyclase activity, probably by suppressing the cellular expression of adenylyl cyclase V. Stimulation of GnRH release by increased cAMP seems to result from neuronal depolarization triggered by increased conductance of cations by cAMP-gated cation channels. Activation of PKA may be a negative-feedback means of lowering cAMP levels. The resultant oscillations in cAMP could provide a basis for timing the pulsatile release of GnRH. These findings can be tested in vivo by using transgenic methods to examine the role of cAMP signaling in regulating pulsatile GnRH release in the rat. Proc Natl Acad Sci U S A 2000;97:1861–1866

A complex network of cytokines mediates immunoregulatory responses in the pathogenesis of endometriosis. RANTES (regulated upon activation, normal T cell expressed and secreted) is a chemoattractant for monocytes and T cells. Endometriotic lesions express RANTES, and its concentration in peritoneal fluid correlates with the severity of endometriosis. We investigated the influence of IL-1beta, a potent macrophage cytokine, on RANTES production in endometriotic stromal cells and determined the region of the RANTES promoter responsible for IL-1beta action. RANTES mRNA was induced 5-fold in endometriotic stromal cells, and the conditioned medium RANTES protein concentrations were 12-fold higher in IL-1beta-treated endometriotic stromal cells vs. untreated controls (P < 0.05). IL-1beta activated the full-length (-940 bp) RANTES promoter as well as a truncated 456-bp 5'-flanking construct by 2-fold. Mutagenesis of a nuclear factor-kappaB response element at -30 bp abolished the IL-1beta effect, whereas mutation of a nearby TNF response element did not affect the IL-1beta induction. An IL-1beta time-course Western assay revealed a rapid diminution of IkappaB (endogenous inhibitor of nuclear factor-kappaB) in endometriotic stromal cells. Overexpression of IkappaB in endometriotic stromal cells inhibited the IL-1beta response of the RANTES gene promoter. Transcription of RANTES mRNA is up-regulated by IL-1beta via a nuclear factor-kappaB response element in the proximal RANTES gene promoter. These results demonstrate a feed-forward regulatory loop in the pathogenesis of endometriosis by which IL-1beta produced from activated macrophages can lead to further macrophage recruitment via RANTES production in endometriotic stromal cells.

We asked whether the antiangiogenic action of 16K human PRL (hPRL), in addition to blocking mitogeninduced vascular endothelial cell proliferation, involved activation of programmed cell death. Treatment with recombinant 16K hPRL increased DNA fragmentation in cultured bovine brain capillary endothelial (BBE) and human umbilical vein endothelial (HUVE) cells in a time- and dose-dependent fashion, independent of the serum concentration. The activation of apoptosis by 16K hPRL was specific for endothelial cells, and the activity of the peptide could be inhibited by heat denaturation, trypsin digestion, and immunoneutralization, but not by treatment with the endotoxin blocker, polymyxin-B. 16K hPRL-induced apoptosis was correlated with the rapid activation of caspases 1 and 3 and was blocked by pharmacological inhibition of caspase activity. Caspase activation was followed by inactivation of two caspase substrates, poly(ADP-ribose) polymerase (PARP) and the inhibitor of caspase-activated deoxyribonuclease (DNase) (ICAD). Furthermore, 16K hPRL increased the conversion of Bcl-X to its proapoptotic form, suggesting that the Bcl-2 protein family may also be involved in 16K hPRL-induced apoptosis. These findings support the hypothesis that the antiangiogenic action of 16K hPRL includes the activation of programmed cell death of vascular endothelial cells. (Molecular Endocrinology 14: 1536‐ 1549, 2000)

Recently, we have demonstrated that ischemic preconditioning (IP) both limits infarct size and decreases internucleosomal DNA fragmentation in rat hearts in vivo, and that there was a direct correlation between myocardial infarct size and DNA fragmentation even after IP. In this study, we examined the ability of IP to attenuate processing and activation of caspase-1 and caspase-3, and cleavage of poly(ADP-ribose) polymerase (PARP), after prolonged ischemia and reperfusion using the same in vivo animal model. Rats that underwent IP and controls (Ctrl) were subjected to 30 min of left coronary artery occlusion followed by 180 min of reperfusion. IP was accomplished by five 5-min cycles of ischemia, each followed by 5 min of reperfusion. The amount of soluble nucleosomes was measured by enzyme-linked immunosorbent assay. Cleavage of caspases-1 and -3, and of one of their substrates PARP, was analyzed by Western blotting. Nucleosomal DNA fragmentation was significantly reduced in ischemic left ventricular (LV) tissue obtained from IP compared with Ctrl animals. The proforms of caspases-1 and -3, and the active form of PARP were not cleaved in the nonischemic LV region of both IP and Ctrl hearts. In contrast, the proform of caspase-3 and the active form of PARP were cleaved in the ischemic LV region of Ctrl hearts, while processing of caspase-1 was increased. Cleavages of caspases-1 and -3, and inactivation of PARP were prevented by IP. The results of this study indicate that IP attenuates both internucleosomal DNA fragmentation and caspases processing, and suggest that the prevention of caspases activation by IP may be important steps in protecting the heart against ischemia/reperfusion injury in vivo.

Signaling pathways mediating the antiangiogenic action of 16K human (h)PRL include inhibition of vascular endothelial growth factor (VEGF)-induced activation of the mitogen-activated protein kinases (MAPK). To determine at which step 16K hPRL acts to inhibit VEGF-induced MAPK activation, we assessed more proximal events in the signaling cascade. 16K hPRL treatment blocked VEGF-induced Raf-1 activation as well as its translocation to the plasma membrane. 16K hPRL indirectly increased cAMP levels; however, the blockade of Raf-1 activation was not dependent on the stimulation of cAMP-dependent protein kinase (PKA), but rather on the inhibition of the GTP-bound Ras. The VEGF-induced tyrosine phosphorylation of the VEGF receptor, Flk-1, and its association with the Shc/Grb2/Ras-GAP (guanosine triphosphatase-activating protein) complex were unaffected by 16K hPRL treatment. In contrast, 16K hPRL prevented the VEGF-induced phosphorylation and dissociation of Sos from Grb2 at 5 min, consistent with inhibition by 16K hPRL of the MEK/MAPK feedback on Sos. The inhibition of Ras activation was paralleled by the increased phosphorylation of 120 kDa proteins comigrating with Ras-GAP. Taken together, these findings show that 16K hPRL inhibits the VEGF-induced Ras activation; this antagonism represents a novel and potentially important mechanism for the control of angiogenesis.

La nouvelle législation relative aux étrangers , dite «loi Pasqua», est appliquée depuis dix-huit mois. Un premier bilan fait apparaître un certain nombre de dysfonctionnements. En particulier, les problèmes rencontrés par les couples binationaux illustrent parfaitement les aspects pernicieux de cette réforme., Martini Jean-François, Rodier Claire. Couples mixtes : le parcours du combattant. In: Hommes et Migrations, n°1185, mars 1995. Histoires de familles. pp. 45-48.

L’aide sociale a l’enfance a pour mission de proteger les mineurs, tous les mineurs, y compris s’ils sont etrangers et isoles. Pourtant, a travers toute la France, des conseils generaux arguent de leur afflux et des depenses induites pour ne plus les prendre en charge. Paris, qui en recoit le plus, n’est donc pas un cas isole. Tous en appellent a la responsabilite de l’Etat. Au risque d’un jeu dangereux autour des politiques migratoires et au detriment des mineurs.

To examine the respective effects of reduced food intake and of uremia on the growth defect in uremic rats, we have studied the expression of GH receptors in three groups of male rats: Group 1, rats fed ad libitum; Group 2, food-restricted to be pair-fed with uremic rats; Group 3, uremic rats. Animals were studied for a time period of 9 days starting 1 week after surgery (sham operation in rats of Groups 1 and 2, 5/6 nephrectomy in rats of Group 3). The gain in body length and weight of pair-fed controls and of uremic rats was comparable and significantly lower than that of rats fed ad libitum. IGF-1 plasma levels were low in rats of groups 2 and 3. Low food intake (50% that of rats fed ad libitum) resulted in a reduced number of GH receptors in liver membranes and a low plasma level of GH-binding protein (GHBP); GH receptor gene expression in the liver, as analyzed by Northern blots, was not significantly lower in normal food-restricted animals. In uremic rats, the low level of GH binding to liver membranes was comparable to that found in pair-fed controls; but the level of GHBP activity was normal, not different from the values found in rats fed ad libitum. However, expression of the liver GHBP mRNA was reduced in uremic rats. In uremia, the GH receptor dysfunction is not only at a transcriptional level but also at a post-transcriptional level. These findings suggest that uremia, as such, is not primarily responsible for the growth failure.(ABSTRACT TRUNCATED AT 250 WORDS)

L’identification de l’etranger est devenue un enjeu determinant dans un contexte de controle strict de l’entree et du sejour sur le territoire national. Apporter la preuve qu’un jeune est majeur revet donc, pour l’administration, une telle importance, qu’elle n’hesite pas a recourir a des methodes d’analyse plus que contestables.

En juin 2008, un jeune ghaneen est interpelle par la police. Il dit avoir seize ans et s'etre enfui a la suite de l'assassinat de ses parents au Ghana. Pour justifier de sa minorite, il presente la copie d'un certificat de son ancien etablissement scolaire. Il subit neanmoins une expertise osseuse qui conclut que son âge serait d'au moins 21 ans. Le prefet prend un arrete de reconduite a la frontiere contre lui. Un premier juge annule cette mesure en estimant que sa demande d'asile n'a pas ete prise en compte. Le prefet fait appel. La cour administrative d'appel de Douai lui donne raison : le jeune ne peut justifier qu'il a tente de deposer une demande d'asile. Mais entre-temps, une deuxieme expertise a ete ordonnee. Resultat : «l'âge de l'interesse se situerait entre 16 ans et 18 ans». Le jeune ne sera pas reconduit a la frontiere mais place sous la protection de l'aide sociale a l'enfance par le juge des enfants (1).

La Belgique vient d'etre durement condamnee par la Cour europeenne des droit de l'Homme pour avoir enferme pendant deux mois dans un centre pour etranger en situation irreguliere, puis renvoye dans son pays d'origine, Tabitha, une petite Congolaise de cinq ans. Qualifies de traitement inhumain et degradant par la Cour, la detention et le refoulement de cette enfant sont intervenus alors qu'elle tentait, avec l'aide de son oncle, de rejoindre, via Bruxelles, sa mere residant au Canada en qualite de refugiee (1).

Parti de mobilisations ponctuelles autour de lyceens sans papiers, le Reseau education sans frontieres (RESF) est devenu un reseau national reunissant militants individuels, etablissements scolaires, syndicats, associations. Dans l’entretien ci-dessous, Brigitte Wieser, militante de la premiere heure du Reseau parisien, revient sur le demarrage, la structuration et l’avenir de ce mouvement de solidarite sans precedent.

Les differentes declarations de principe sur le droit a la formation ne semblent avoir aucun effet des lors qu’il s’agit de jeunes etrangers. Les mineurs entres en France en dehors des procedures legales et auxquels est refuse l’acces aux formations en apprentissage sont maintenus « en sursis » sur le territoire francais. Alors que, dans leur immense majorite, un retour dans leur pays d’origine est illusoire, la reglementation actuelle ne leur donne aucune possibilite de se construire un avenir en France.

Si l’accueil dans les etablissements scolaires est le meme pour tous, Francais et etrangers, un dispositif specifique a toutefois ete mis en place pour les « eleves nouvellement arrives » qui ont besoin d’une remise a niveau scolaire. Sont ainsi designes des jeunes francophones ou non francophones qui n’ont pas une maitrise suffisante des apprentissages scolaires pour s’inserer immediatement dans le cursus ordinaire. En theorie, ce dispositif s’adresse a des eleves de nationalite francaise ou etrangere. Dans la pratique, il ne concerne que ces derniers.

Dans un rapport parlementaire sur la police publie en novembre 2000, le depute (PS) de l’Isere Louis Mermaz n’hesitait pas a qualifier les zones d’attente d’« horreur de la Republique ». Pourtant, la France y enferme des mineurs, qu’ils soient arrives seul en France ou accompagnes par un membre de leur famille, au mepris des droits les plus elementaires reconnus par la Convention internationale sur les droits de l’enfant.

Martini Jean-François. Le pèlerin de 1885, journalisme d'apostolat, journalisme de combat. In: Espaces Temps, 2, 1976. pp. 50-63.