BACKGROUND:Everolimus (Afinitor®) plus exemestane are indicated for hormone receptor-positive, HER2/neu-negative metastatic breast cancer (MBC), in menopausal women without symptomatic visceral disease after recurrence or progression following aromatase inhibitors. But everolimus efficacy as late treatment has not been explored.METHODS:Sixty-three MBC patients progressing under hormonotherapy (HT; n = 30) or after chemotherapy (CT; n = 32) received everolimus plus HT (EHT) and were analyzed for safety, efficacy and overall survival (OS). This cohort was compared with our previous 530 MBC patients stratified by line (PMID 21852136).RESULTS:The median duration of EHT was 27.8 weeks at 5-10 mg/day until clinical progression or toxicity. Median OS was not reached (median follow-up 18 months). Twelve-month survival was 100, 79 and 49% for patients treated with 0 (n = 13), 1-2 (n = 18) and >3 CT (n = 32), respectively. Median time-to-treatment failure was 6.4 months. In 62 EHT patients randomly matched 1:7 with 421 previous patients for age and number of CT, OS improved compared with patients receiving a new CT (p = 0.062). In patients pretreated with <2 CT, EHT gave a better OS than in those with a new CT (p = 0.026).CONCLUSIONS:These results may support the use of EHT whatever the number of previous lines.

Aim: Everolimus (Afinitor®) is indicated for the treatment of hormone receptor-positive, HER2/neu negative MBC, combined with exemestane, in postmenopausal women without symptomatic visceral disease after recurrence or progression following a non-steroidal aromatase inhibitor. However late patients after several lines may also benefit from new therapies, and we report here our experience on MBC patients pre-treated by a median of 3 CT and 2 HT lines at metastatic stage.

Le pronostic du cancer de l'œsophage est sombre; aussi, depuis de nombreuses années, différents traitements préopératoires ont été réalisés au cours d'essais de phase II ou d'essais randomisés afin d'améliorer la survie. Après la radiothérapie, la chimiothérapie, ce sont les chimioradiothérapies qui semblent amener une lueur d'espoir, en particulier ces 5 dernières années. Mais la contrepartie de cela n'est-elle pas une augmentation de la morbidité et la mortalité pré- et postopératoire? À la lecture des différentes publications, et pour la grande majorité, on ne constate pas de répercussion de ces traitements. Il faut poursuivre nos efforts par des essais randomisés tenant compte des études récentes de phase II au sein d'équipes pluridisciplinaires.Prognosis of œsophageal cancer is poor. There have been phase II–III trials of postoperative chemotherapy with the aim of improving survival. Chemoradiotherapy seems more promising than both chemotherapy and radiotherapy alone. In contrast, better results obtained with chemoradiotherapy were associated with an increase in morbidity and mortality, and finally overall survival was uncommonly improved. It is necessary to implement new multidisciplinary randomised trial.

Nous avons rapporté dans un travail antérieur (2009) l'intérêt de l'ampullectomie endoscopique (AE) comme traitement de première intention des ampullomes bénins et ampullocarcinomes T1N0 avec 90% de résection curatrice Ro. Notre taux de pancréatite aigue (PA) était faible (6,6%) à priori corrélé avec un taux d'intubation pancréatique élevé (83,3%) mais avec trop peu d'évènements pour pouvoir conclure statistiquement. Le taux de PA généralement rapporté après AE varie de 18 à 21%. Le but de cette étude sur une série rétrospective plus large était de déterminer si l'intubation pancréatique systématique après AE diminue le risque de PA.

Borassus aetihiopum MART (Arecaceae) is a plant used in traditional herbal medicine for the treatment of various diseases (bronchitis, laryngitis, antiseptic). In particular, their male inflorcscences were reported to exhibit cicatrizing, antiseptic and fungicidal properties. In the present study, the biological activity of E2F2, an apolar extract from Borassus aethiopum male inflorescence was investigated on colon cancer HT29 cells. Phytochemical screening was carried according to methodology for chemical analysis for vegetable drugs. Cells proliferation was determined by the MTT assay and cells cycle distribution was analysed by using laser flow cytometer (Beckman coulter). The cytoskeleton organisation was examined under a laser scanning confocal microscope (Zess). Preliminary phytochemical analysis of E2F2 extract revealed the presence of sterols, triterpenes and saponosids. E2F2 extract (1 microg and 100 microg mL(-1)) significantly inhibited cell proliferation by blocking cell population in G0/G1 phase. Flow Cytometric analysis of E2F2-treated HT29 cells showed that hypoploïd cell population (sub G1 phase) increased with processing time exposures. Immunofluorescence confocal analysis revealed a disrupt actin microfilaments network in E2F2 treated-cells with a significant reduction in actin stress fibres and appearance of a random, non-oriented distribution of focal adhesion sites. These data indicate that E2F2 extract has anti-proliferative and pro-apoptotic activities. Further studies are required to unravel the mechanisms of action of E2F2 extract.

1121 Background: Metastatic breast cancer (MBC) is an incurable disease in most cases; then treatment is palliative, to prolong overall survival (OS) and control clinical symptoms. Progressively the figures obtained have improved with time. However, the optimal duration of therapy is unknown. Few authors have considered the treatment globally versus for each line and fewer have demonstrated the interest of chemotherapy (CT) after the third line. The aim of this study was to assess tumoral response and OS of patients treated with more than 3 lines of treatment, for each line given. We selected recent patients treated during "taxanes/anti-aromatase era (TAA)" corresponding to an important progress in breast cancer therapy. METHODS Our metastatic database recorded 590 patients with MBC. Among these patients, 530 received at least one line of CT and 383 an hormonotherapy (HT). TAA was defined from December 31th, 1993, as from this date they became available for the french patients. RESULTS Median OS survival was globally 34.1 months and was calculated for each line given; 226 patients received >3 lines of CT (an increased proportion in comparison with more ancient patients) with a median OS per line rather constant, around 11 months for these late lines. Median OS of women treated with >3 lines of HT was 28 months however, only 70 patients were concerned. Clinical benefit after the third line of CT was obtained for 29.2 to 36.6% of patients and approximately 50% had a progressive disease. Total duration of CT was 11.7 months versus 20.6 months without CT. CONCLUSIONS As the number of available drugs increases, these results support the use of more than 3 lines of CT with a quantifiable benefit in tumoral response and OS. It appears that each line can contribute to a longer survival, when the patient is able to receive it.

e11574 Background: Panitumumab is an antiboby targeting the epidermal growth factor receptor (EGFR) to which a role has been suggested in TNBC. Consequently, we evaluated the combination of a standard chemotherapy (FEC100 followed by T) with panitumumab as neoadjuvant therapy of operable TNBC. Methods: 58 patients with stage II-IIIA disease were prospectively included in this multicentre pilot study. Systemic therapy (ST) consisted of 4 cycles of FEC100 (500/100/500 mg/m2) q.3 weeks followed by 4 cycles of T (100 mg/m2) q.3 weeks, in combination with panitumumab (9mg/kg) for 8 cycles q.3 weeks. All patients underwent surgery at completion of ST. Complete pathologic response (pCR) was the primary endpoint (Sataloff : J Am Coll Surg 1995 ; Chevallier : Am J Clin Oncol 1993), with toxicity and biologic ancillary studies as secondary endpoints. Results: Patients characterisctics are as follows : mean age 50 [38-64] ; T2 : 81%, T3 : 19% (mean tumor size : 42 mm [25-80]) ; N0 : 73% and N1 : 27%; invasive ductal carcinoma : 87%; Scarff-Bloom-Richardson Grade III : 56%, grade II : 44%. The median number of cycles was : FEC 100 : 4 [4-4], T : 4 [2-4], Panitumumab : 8 [4-8]. Preliminary results on 17 patients showed a pCR of 65% (Sataloff) and 53% (Chevallier) with an overall clinical response rate of 80% (47% CR). Conservative surgery was performed in 87% of cases. Skin toxicity was the main side-effect : grade II : 69%, grade III : 19%. Neutropenia grade IV : 27%, febrile neutropenia : 7%, infection : 0%. Hand-foot syndrome grade III : 12%. Ungueal toxicity grade III : 6%, grade II : 12%. Conclusions: These preliminary results suggest that panitumumab in combination with FEC100 followed by T appears efficacious with acceptable toxicity in the neoadjuvant therapy of operable TNBC. Updated results on 40 patients will be presented at the meeting.

Abstract Background: Panitumumab is an antibody targeting the epidermal growth factor receptor (EGFR) to which a role has been suggested in TNBC. Consequently, we evaluated the combination of a standard chemotherapy (FEC 100 followed by T) with panitumumab as neoadjuvant therapy of oprable TNBC. Methods: 60 patients with stage II-IIIA disease were prospectively included in this multicentre pilot study. Systemic therapy (ST) consisted of 4 cycles of FEC 100 (500/100/500 mg/m2) q.3 weeks followed by 4 cycles of T (100 mg/m2) q.3 weeks, in combination with panitumumab (9 mg/kg) for 8 cycles q.3 weeks. All patients underwent surgery at completion of ST. Complete pathologic response (pCR) was the primary endpoint (Sataloff/J Am Coll Surg 1995; Chevallier: Am J Clin Oncol 1993), with toxicity and biologic ancillary studies as secondary endpoints. Results: Patients characteristics are as follows: mean age 47 [27-72]; T2: 74%, T3: 26%, (mean tumor size: 40 mm [20-120]); N0: 65%, N1: 28% and N2: 7%; invasive ductal carcinoma: 96%; Scarff-Bloom-Richardson Grade III: 72%, grade II: 28%. The median number of cycles was: FEC 100: 4 [2-4], T: 4 [0-4], Panitumumab: 7 [1-8]. Pathological response showed a pCR according to Sataloff's classification of 57.1% [95% IC: 40.7−73.5] and according to Chevallier's classification of 51.4% [95% IC: 34.8−68.0] with an overall clinical response rate of 60% (29% CR) [95% IC: 43.8−76.2]. Conservative surgery was performed in 79% of cases. Skin toxicity was the main side-effect: Cutaneous toxicity grade IV: 12%, grade III: 26%, grade II: 23%. No ocular complications have been reported. Neutropenia grade IV: 23.7%; febrile neutropenia: 4.2%. Infection: 0%. Hand-foot syndrome grade III: 4%. Ungueal toxicity grade IV: 2.5%, grade II: 25 .5%. Conclusions: These results suggest that Panitumumab in combination with FEC100 followed by T appears efficacious with acceptable toxicity in the neoadjuvant therapy of operable TNBC. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P3-14-01.

Le vieillissement n'est pas une maladie. Toutefois, avec l'âge, l'incidence des cancers augmente. La prise en charge des personnes âgées atteintes de cancer a ses spécificités « techniques » qui aboutissent à décider ou non, à appliquer ou non et à ajuster ou non les traitements du cancer de la façon la plus individuelle qui soit. Cela sous-entend une approche globale et pluridisciplinaire du malade âgé atteint de cancer. Parmi les acteurs de soins, les psycho-oncologues auront à explorer le monde bien vaste et encore peu connu des comportements des personnes âgées atteintes de cancer et leur retentissement sur la maladie et les résultats des traitements et sur la qualité de vie des patients. C'est ce qu'attend « l'onco-un peu psychologue » du « psycho-un peu oncologue »…

We investigated, for the first time, the expression of I- and L-FABP in two very rare hereditary lipid malabsorption syndromes as compared with normal subjects. Abetalipoproteinemia (ABL) and Anderson's disease (AD) are characterized by an inability to export alimentary lipids as chylomicrons that result in fat loading of enterocytes. Duodeno-jejunal biopsies were obtained from 14 fasted normal subjects, and from four patients with ABL and from six with AD. Intestinal FABP expression was investigated by immuno-histochemistry, western blot, ELISA and Northern blot analysis. In contrast to normal subjects, the cellular immunostaining for both FABPs was clearly decreased in patients, as the enterocytes became fat-laden. In patients with ABL, the intestinal contents of I- (60.7 +/- 13.38 ng/mg protein) and L-FABP (750.3 +/- 121.3 ng/mg protein) are significantly reduced (50 and 35%, P < 0.05, respectively) as compared to normal subjects (I-135.3 +/- 11.1 ng, L-1211 +/- 110 ng/mg protein). In AD, the patients also exhibited decreased expression (50%, P < 0.05; I-59 +/- 11.88 ng, L-618.2 +/- 104.6 ng/mg protein). Decreased FABP expression was not associated with decreased mRNA levels. The results suggest that enterocytes might regulate intracellular FABP content in response to intracellular fatty acids, which we speculate may act as lipid sensors to prevent their intracellular transport.

The effect of leptin on glucose transport was studied in rat jejunal mucosa in Ussing chambers. Leptin was added in the luminal or the serosal compartment before the tissues were challenged with 1, 10, or 50 mmol/l glucose. In response to 10 mmol/l glucose, the increase in short-circuit current (DeltaIsc) reached 26.8 +/- 2.1 microA/cm(2). Luminal addition of leptin dramatically decreased glucose-induced Isc (90.5% for 10 nmol/l leptin). Inhibition was maximal after 5 min and dose dependent (IC(50) = 0.13 nM). Western blot analysis showed that rapid inhibition of glucose-induced Isc by leptin was associated with a parallel decrease in the abundance of sodium-glucose transporter-1 in brush border membranes. Inhibition by luminal leptin of DeltaIsc was prevented by inhibitor of conventional protein kinase C isoforms. Serosal addition of leptin did not decrease glucose-induced Isc within 5 min and reached maximum after 10 min. The effect of leptin from serosal side was blocked by cholecystokinin (CCK) receptor-2 receptor antagonist YM022. Altogether, these data demonstrate that luminal leptin induces rapid inhibition of glucose entry into enterocyte. The slower action of leptin on the serosal side of mucosa seems indirect and is likely mediated by endogenous CCK. They demonstrate that gut leptin is a major regulator of rapid intestinal glucose transport.

The stomach was reported to synthesize and secrete leptin mainly in the gastric lumen. Gastric leptin release is markedly increased after food intake, by vagal cholinergic stimulation and by cholecystokinin and secretin. Here we show that human gastric MKN‐74 cells produce leptin that increases upon challenge with cholecystokinin, insulin, glucocorticoids and all‐trans retinoic acid through activation of the leptin gene promoter. In addition, we demonstrate that forskolin and BRL37344 which increased cAMP levels, fail to affect the activity of leptin gene promoter in MKN74 expressing β3‐adrenoceptor cells but, induce a 2‐fold decrease in this activity in adipose 3T3‐L1 cells. These data described for the first time, similarities and more interestingly, differences in the regulation of the leptin gene promoter in gastric cells as compared to adipocytes.