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Background Dabrafenib (D) and trametinib (T) improved survival in patients with BRAFV600mut melanoma. High plasma concentration of D (PCD) is weakly associated with adverse events (AE). We investigated the relationship between PCD/T and tumour control or AE. Methods We analysed PCD/T in patients treated with D + T for metastatic melanoma. We collected data of tumour response (RECIST 1.1) and AE (CTCAE 4.0) blinded to PCD/T results. Results We analysed 71 D and 58T assays from 34 patients. High inter-individual variability of PCD (median: 65.0 ng/mL; interquartile range (IQR) [4–945]) and of PCT (median: 8.6 ng/mL; IQR [5–39]) was observed. We found a weak relationship between PCD and progression-free survival, taking follow-up time into account (hazard ratio 0.991; 95%CI, 0.981 to 1.000; P = 0.06). However, no difference was observed between mean PCD/T of progressing patients (n = 21; 125 ± 183 ng/mL and 9.3 ± 3.6 ng/mL, respectively) and responders (complete, partial or stable response) (n = 13; 159 ± 225 ng/mL, P = 0.58 and 10.6 ± 24.4 ng/mL, P = 0.29, respectively). No significant relationship was found between PCD/T and most common AEs (fever, lymphopenia, CPK increase, and hepatic cytolysis), body mass index, or age. Mean CPT (n = 16) was significantly higher for female subjects (n = 18; 11.5 ± 4.8 ng/mL) than for male subjects (8.8 ng/mL ± 2.9, P = 0.01), but no difference was observed between sex and CPD (P = 0.32). Conclusion Our study showed a weak relationship between PCD and progression-free survival, but no relationship between PCD/T and AE was found. Monitoring PCD and PCT alone is unlikely to be useful in assessing response to treatment.

Background Non-small cell lung carcinoma (NSCLC) is a leading cause of cancer-related death and represents a major health burden worldwide. Current therapies for NSCLC include chemotherapy, immunotherapy, and targeted molecular agents such as tyrosine kinase inhibitors and epigenetic drugs such as DNA methyltransferase inhibitors. However, survival rates remain low for patients with NSCLC, especially those with metastatic disease. A major cause for therapeutic failure is drug resistance, highlighting the need for novel therapies and combination strategies. Given that epigenetic modulators such as protein arginine methyltransferases (PRMTs) are frequently overexpressed in cancers, PRMT inhibitors are a promising class of cancer therapeutics. We screened a library of epigenetic and anticancer drugs to identify compounds that would synergize with MS023, a type I PRMT inhibitor, in decreasing the viability of methylthioadenosine phosphorylase (MTAP)-negative NSCLC cells. Results Among 181 compounds, we identified PARP inhibitors (PARPi) as having a strong synergistic interaction with type I PRMT inhibition. The combination of MS023 and the PARP inhibitor BMN-673 (Talazoparib) demonstrated strong synergistic interaction at low nanomolar concentrations in MTAP-negative NSCLC cell lines A549, SK-LU-1 and HCC4006. The re-introduction of MTAP decreased the sensitivity of the combination therapy in A549. The combination therapy resulted in elevated γ-H2AX foci indicating increased DNA damage causing decreased cell viability. Lastly, the combination therapy was effective in PARPi resistant ovarian cancer cells, suggesting that type I PRMT inhibitors could mitigate PARPi resistance, thus potentially having an important clinical impact for cancer treatment. Conclusions These findings identify a novel cancer drug combination therapy, which is more potent than the separate single-agent therapies. Thus, combining PARP inhibitors and type I PRMT inhibitors represents a new therapeutic opportunity for MTAP-negative NSCLC and certain cancer cells resistant to PARP inhibitors.

Introduction Le DRESS est une toxidermie severe rare et potentiellement fatale. La variabilite des presentations cliniques peut etre source d’errance diagnostique et de retard a la prise en charge. Le but de notre etude etait de decrire les caracteristiques du DRESS en population pediatrique. Materiel et methodes Etude retrospective multicentrique des cas de DRESS (Regiscar ≥ 3) chez des enfants ≤ 18 ans hospitalises entre 2000 et 2020. Resultats Nous avons inclus 53 cas, issus de 15 hopitaux francais. L’âge moyen etait de 8,6 ans avec une predominante feminine (54,7 %). Le DRESS survenait au cours d’une hospitalisation chez 11 enfants (20,8 %). Parmi les 90 molecules imputables, 57,8 % etaient des antibiotiques (AB), 21 % des antiepileptiques (AE). Le delai median d’apparition apres l’introduction etait de 13 jours (AB : 12, AE : 17). On notait un retard diagnostique median de 5 jours (jusqu’a 28). Un exantheme morbiliforme etait decrit dans 58,4 % des cas, une erythrodermie dans 26,4 %. La duree mediane de l’eruption etait de 20 jours (jusqu’a 90). Une fievre etait observee chez tous les enfants, un œdeme du visage chez 64,2 % et des adenopathies chez 67,9 %. Les organes touches etaient le foie (79,2 %), le rein (22,6 %), le poumon (20,8 %), la rate (13,2 %) et le systeme digestif (11,3 %). 83 % des enfants presentaient une hypereosinophilie > 500/mm3 (60,4 % > 1500/mm3). 17 (44,1 %) sur les 38 testes avaient une reactivation virale (PCR positive) : 7 HHV-6, 2 HHV-7, 4 Parvovirus B19, 2 EBV et 2 co-reactivations EBV-CMV. Pour le traitement du DRESS, 52,8 % des enfants ont eu une corticotherapie locale (duree mediane 8), 54,7 % une corticotherapie systemique (duree mediane 36,5 [min–max : 1 jour–11 mois]), 11,3 % des immunoglobulines intraveineuses et 3,8 % de la ciclosporine. La duree d’hospitalisation mediane etait de 11 jours. Des sequelles a long terme etaient observees chez 3 patients (5,7 %) : 1 HTA cortico-induite, 1 insuffisance corticotrope et 1 hyperpigmentation. Un enfant est decede d’un arret cardiorespiratoire sur myocardite. Vingt-cinq enfants (47,1 %) ont eu un bilan allergologique : 20 patch tests, 10 IDR, 3 pricks, 1 test de transformation lymphocytaire et 1 test de reintroduction. Quinze (60 %) avaient des tests positifs, 2 avaient une allergie a 2 molecules. Discussion Notre etude est la plus grande serie de DRESS pediatrique rapportee. Nos resultats sont concordants avec les cas publies (revues systematiques et cohortes retrospectives) et permettent de mieux preciser les caracteristiques clinicobiologiques du DRESS chez l’enfant. Les medicaments imputables sont frequemment des AB avec delai de survenue assez court ( Conclusion Le DRESS est mal connu des pediatres. Ce diagnostic doit etre systematiquement evoque chez l’enfant devant un exantheme cutane febrile des lors qu’un nouveau traitement a ete introduit dans les 12 dernieres semaines.

Targeting DNA hypermethylation, using nucleoside analogs, is an efficient approach to reprogram cancer cell epigenome leading to reduced proliferation, increased differentiation, recognition by the immune system, and ultimately cancer cell death. DNA methyltransferase inhibitors have been approved for the treatment of myelodysplastic syndromes, chronic myelomonocytic leukemia, and acute myelogenous leukemia. To improve clinical efficacy and overcome mechanisms of drug resistance, a second generation of DNA methyltransferase inhibitors has been designed and is currently in clinical trials. Although efficient in monotherapy against hematologic malignancies, the potential of DNA methyltransferase inhibitors to synergize with small molecules targeting chromatin or immunotherapy will provide additional opportunities for their future clinical application against leukemia and solid tumors.

Marine protected areas (MPAs) are a primary marine conservation strategy in the US territory of American Samoa, which has a goal to protect 20 percent of its coral reef area under “no-take” MPAs. T...

Background MRI can detect both inflammatory and structural lesions in the sacroiliac joints (SIJ) of patients with axial SpA. However, standard MRI sequences do not directly depict bone and the appearance of erosion may vary according to the presence/absence of inflammation. Consequently, further validation using an accepted gold standard, namely, computed tomography (CT), is essential. Objectives We aimed to assess the detection of structural lesions in the SIJ by MRI using CT as the gold standard. Methods CT scans from 44 patients (26 females, mean age 49.4 years, mean symptom duration 9.1 years) were reconstructed in the semicoronal plane parallel to the superior border of the sacrum, as for conventional MRI evaluation of the SIJ, and scoring of lesions by CT was confined to this plane. Structural lesions were scored in consecutive slices in SIJ quadrants (erosion, sclerosis) or SIJ halves (ankylosis) on a dichotomous basis (present/absent) using the same anatomical principles for defining SIJ quadrants as developed for the SPARCC MRI SIJ inflammation and structural scores. T1W MRI scans of the SIJ from the same cases conducted at the same time as CT were assessed independently for structural lesions (erosion, fat, backfill, ankylosis, sclerosis) blinded to CT assessments using the SPARCC method. Agreement between CT and MRI was assessed by kappa statistics. Sensitivity/specificity of MRI for CT lesions was calculated. The primary analysis was based on lesions detected concordantly by both readers at the level of the individual iliac/sacral joint surface (erosion, sclerosis) or the individual joint (ankylosis, backfill). Results With CT as gold standard and a lesion defined as being present when recorded in the same location on at least 1 coronal slice by both readers, MRI-defined ankylosis had 56.3% sensitivity and 100% specificity for CT ankylosis (Table). For erosion, sensitivity and specificity of MRI was 81.3% and 96.2%, and for sclerosis, sensitivity and specificity of MRI was 50% and 97%, respectively. Agreement between CT and MRI for erosion increased when the cut-off for presence of a lesion was set at 2 slices but only marginally for sclerosis, even when the cut-off for presence of a lesion was set at 3 slices. Lesions observed on CT corresponding to backfill on MRI were ankylosis, erosion, and sclerosis, in 66.7%, 66.7%, and 80% of backfill lesions, respectively. Conclusions Ankylosis and erosion on MRI correspond closely with the same type of lesion observed on CT. Both new bone formation and erosion are frequently evident on CT at locations where backfill is observed on MRI supporting the hypothesis that backfill is an intermediary tissue between erosion and ankylosis. Disclosure of Interest None declared

Background Computed tomography (CT) is considered the imaging benchmark for the assessment of certain structural lesions in the sacroiliac joints (SIJ) of patients with axial spondyloarthritis (axSpA). Availability of low dose radiation techniques may lead to more widespread use, potentially as a structural endpoint in clinical trials research. Objectives We aimed to validate a new CT-based scoring method, the CT Sacroiliac Structural Score (CT-SSS), for assessing structural lesions in the SIJ. Methods CT scans of the SIJ from 44 patients (26 females, mean age 49.4 years, mean symptom duration 9.1 years) were reconstructed in the semicoronal plane parallel to the superior border of the sacrum and scoring of lesions was confined to this plane. Structural lesions were scored in consecutive slices in SIJ quadrants (erosion, sclerosis) or SIJ halves (ankylosis) on a dichotomous basis (present/absent) using the same anatomical principles as developed for the SPARCC MRI SIJ inflammation and structural scores. The most anterior slice is defined as visible joint ≥1cm vertical height and when Results Scoring was feasible (5–10 minutes per scan) and both ankylosis (ICC=0.95) and erosion (ICC=0.81) were reliably scored (Table). Sclerosis was less reliably scored (ICC=0.39). Presence/absence of ankylosis was reliably detected irrespective of whether this was based on a single slice (κ=0.77) or 3 consecutive slices (κ=0.81). Reliable detection was lower for erosion (κ=0.50 for 1 or 3 slices) and sclerosis (κ=0.44 and 0.48 for 1 and 3 slices, respectively). Bland-Altman graphs illustrate reliability across the range of scores for ankylosis and erosion. Conclusions The CT-SSS method is feasible and reliable for scoring ankylosis and erosion with minimal calibration. Sclerosis requires further standardization and calibration. Disclosure of Interest None declared

MRCP is a non-invasive cholangiographic technique used in detection and characterization of bile ducts abnormalities. MRCP features of primary sclerosing cholangitis are randomly distributed annular strictures alternating with slightly dilated bile ducts. Secondary sclerosing processes including ascending, ischemic, caustic, AIDS-related, eosinophilic and autoimmune cholangitis can mimic PSC at MRCP.

Diffusion-weighted MR imaging of liver pathology: principles and clinical applications Due to ongoing technological advances, the range of clinical applications for diffusion-weighted MR imaging has expanded to now include abdominal pathology. Current applications for liver pathology include two main directions. First, oncologic imaging with detection, characterization and follow-up of lesions. Second, evaluation of diffuse liver diseases, including hepatic fibrosis. The diagnostic impact and role of diffusion-weighted MR imaging remain under investigation, but appear promising. Because of its short acquisition time, sensitivity, and additional information it provides, diffusion-weighted MR imaging should be included in routine liver imaging protocols.

Cystic lesions of the pancreas, with an estimated prevalence of 20%, frequently are incidental findings at imaging on asymptomatic patients. Pseudocysts, typically in a setting of pancreatitis, should first be excluded. Characterization of cystic tumors is more complicated. Still, it is important to differentiate between benign and malignant lesions. Multi-detector row CT and MRI allow characterization of such lesions in over 75% of cases. Indeterminate lesions should undergo endoscopic US with biopsy/aspiration and fluid analysis, especially for mucin producing tumors (rounded with thick enhancing wall). When imaging fails to fully characterize a lesion, follow-up may be proposed for lesions less than 3 cm in size, that are either unilocular with thin nonenhancing wall (simple cyst) or lobulated multilocular with thin nonenhancing wall (serous cystadenoma, isolated side branch IPMTP). Follow-up imaging shows that these tumors usually show very little change over time. Management is based on comparing estimated patient survival without treatment to surgical risks (morbidity, mortality, functional sequelae from the procedure).

Intracranial metastases account for up to 35% of intracranial tumors in adult. They can involve any part of the central nervous system: brain, meninges and cranial nerves. Any systemic tumor can metastasize to the brain; the most common primaries include lung, breast and melanoma. Imaging plays a major role in the evaluation and management of patients with metastatic brain tumors. This article discusses optimal CT and MR imaging protocols and describes imaging features and distinguishing characteristics of cerebral and meningeal metastases.

EURATOM has been supporting R&D on the back-end of the fuel cycle for several decades. At present, the research activities in this area comprise work on Partitioning and Transmutation (P&T) of long-lived radionuclides in nuclear waste and on geological disposal. Societal and public involvement issues associated with waste management and local democracy and governance issues associated principally with site selection are also investigated in the programme. Research projects on the back-end of the fuel cycle are partly funded by the European Commission in the Euratom Fifth Framework Programme (FP5) (1998-2002) and Sixth Framework Programme (FP6) (2002-2006). The R&D activities in FP6 represent a continuation of the FP5 effort in this field, but with larger and fewer projects to improve the co-ordination and the integration of the research community in this area. Nonetheless, in addition to the scientific and technical issues, there are also important strategic and political considerations that will fashion the way future support is provided at the European Union level. This is having an important influence on the planning of the Seventh Euratom Framework Programme.

A high speed trainset consists of a power car (or power cars) and trailer cars. Each car has its own processor which communicates via a network in the train. For dependability, most of data (objects) in memory are replicated on each processor. To design applications in the context of distributed systems, a simple and portable method consists in utilizing the Distributed Shared Memory (for short DSM) paradigm. On a group of Sun Workstations, an evaluation model has been implemented consisting in a set of hierarchical software layers to offer a DSM with two consistency criteria, namely sequential consistency and causal consistency. On top of this DSM, the application layer implements a typical train application software namely door management. In this train application software, focus was put on portability, dependability and safety issues.

Introduction Parotid duct sialocele is a salivary cavity arising at the expense of the parotid duct. Many cases of parotid sialocele have been published, but very few cases of parotid duct sialocele have been reported. Case report We report a case of post-traumatic parotid duct sialocele that was assessed by MR sialography. The parotid duct was catheterized via the oral cavity and the catheter was left in place for ten days. No recurrence was observed. Discussion Published cases of parotid duct sialocele are rare, as only seven cases were identified in the literature. Several treatment options are available for sialocele involving the parotid gland or parotid duct. Subcutaneous injection of botulinum toxin is commonly used, with good results. Parotid duct catheterization has also been reported, mainly for parotid gland sialoceles. To the best of our knowledge, apart from the present case, the use of this technique for parotid duct sialocele has only been reported once before. This technique is minimally invasive, with very low morbidity and good results.

Acute lymphoblastic leukemia (ALL) represents approximately 25% of all pediatric cancers diagnosed every year. In about 80% of cases, pediatric patients will attain an event-free 5-year survival. Unfortunately, patients who are resistant to treatment or who relapse have a poor prognosis. Hence, novel therapeutic approaches are necessary to increase survival rates. Epigenetic alterations, such as DNA methylation and histone modifications, are involved in disease development, progression, and in particular, resistance to treatment. These reversible alterations represent additional targets in ALL. Recently, we discovered candidate epigenetic drugs in FDA-approved drug libraries. We hypothesize that one drug in particular, the cardiac glycoside proscillaridin A, has both epigenetic and anti-cancerous properties in preclinical models of ALL and can therefore be repositioned for the treatment of the disease. To test our hypothesis, we treated two ALL cell lines Nalm-6 (pre-B ALL) and Molt-4 (T-ALL) in vitro with clinically relevant concentrations of proscillaridin A and analyzed cell growth, cell cycle, gene expression and chromatin modifications. We observed dose-dependent growth inhibition in all cell lines, with IC50 values of 3.0 and 2.3 nM in Nalm-6 and Molt-4, respectively. Our results using BrdU staining indicate a block in the G2/M phase of the cell cycle. By western blot, we detected a reduction in histone acetylation levels and in histone modifying enzymes CBP and Tip60, as well as the c-myc oncogene. These promising results illustrate the perspective of using the cardiac glycoside proscillaridin A as a novel epigenetic drug for the treatment of relapsed or refractory ALL. Citation Format: Gregory Armaos, Simon Jacques-Ricard, Elodie Da Costa, Annie Beaudry, Noël J-M Raynal. Proscillaridin A effects on chromatin modifications and oncogene degradation in acute lymphoblastic leukemia. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4526.

Pediatric neuroblastoma is one of the most common extra cranial cancers in children. Despite an improvement in survival with the currently available therapies, neuroblastoma with an amplification of the transcription factor MYCN have a very poor prognosis. New therapeutic approaches must be developed to increase the survival of patients. One such approach is epigenetic drug therapy. Neuroblastoma, like many other pediatric cancers, contains several epigenetic alterations at the level of DNA methylation and histone modifications. In a screening of FDA approved drugs, we discovered some molecules having characteristics of epigenetic drugs that were unknown until now. Our study seeks to demonstrate the efficacy of these molecules in the treatment of neuroblastoma cell lines. Following preliminary tests, one of the molecules approved by the FDA stood out: disulfiram, a medication approved for the treatment of chronic alcoholism. We treated neuroblastoma cell lines (MYCN amplified: IMR-32, N91 and SK-N-DZ; MYCN non-amplified: SK-N-AS and SK-N-SH) for 48 hours with disulfiram at clinically relevant concentrations (from 10 nM to 50 μM). Our results demonstrate a 50% growth inhibition (IC50) of 50nM for the cell lines tested. In addition, after analysis by flow cytometry, we found a cell cycle block in G2/M. We also observed a decrease in the transcription factor MYCN and a reduction in acetylation of several histone marks by Western blots analysis. Further studies are underway to determine the mechanism of action of disulfiram and we also plan on doing RNA sequencing and ChIP sequencing. This study will evaluate the efficacy of disulfiram alone as well as in combination with other epigenetic drugs, such as DNA methyltransferase inhibitor decitabine, for the treatment of neuroblastoma. Citation Format: Simon Jacques-Ricard, Noel Raynal, Gregory Armaos, Elodie Da Costa, Annie Beaudry. New epigenetic mechanism of disulfiram targeting chromatin remodeling in neuroblastoma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3200.

4512Background: Although genotype-phenotype correlations have been described for different subtypes of renal cell carcinoma (RCC), it is unknown if DNA methylation profiles correlate with morpholog...

Digestive haemorrhage following supramesocolic abdominal surgery (cephalic duodenopancreatectomy, cholecystectomy, total oesogastrectomy) is a rare but serious complication, which can be life-threatening. Improvement in scanning techniques has made it possible to modify the diagnostic strategy and improve the therapeutic management of the patients. The aim of this iconographic review is to recall the causes of digestive haemorrhage following supramesocolic surgery and to illustrate the dominant role of tomodensitometry in diagnosing it and in planning and controlling the efficacy of endovascular treatment.

3D Virtual Environments, used to visualize complex data, are emerging in different domains. Among interaction tasks that have been defined for this kind of applications, the evaluation of an elementary task like the pointing task can simplify the determination of an appropriate technique used to perform the task in this environment. We detail and discuss results of a user experimentation conducted according to a composite approach, which aims at assessing performance, comfort of techniques and satisfaction of users for a 3D pointing task.

Sequential algorithms design and operating system principles have always been fundamental courses in any computer science curriculum. Protocols are now a well established discipline, and parallelism and concurrency issues are becoming more and more popular in academic courses. Along these guidelines distributed algorithms have now emerged as a proper topic of computer science; studying them demands some prerequisite on algorithms, parallelism and protocols but they cannot themselves be reduced to these three domains.In this paper we present elements for a course on the design of distributed algorithms performing common operating system services. The fundamental aspects of this course lie in teaching the students that no global state can be instantaneously caught because of the asynchronism of the processes and message transmission delays. We state basis problems addressed during the lecture (mutual exclusion, rendezvous implementation, snapshot computation, network traversals and distributed evaluation of predicates) and present how students are faced with distributed problems in practical classes, using a distributed memory parallel machine to implement their solutions.

Between 1970 and 1986, 166 patients with T1 or T2 epidermoid carcinomas of the mobile tongue were treated by iridium 192 implantation (70 T1N0, 83 T2N0, 13 T1-2 N1-3). Five-year actuarial survival was 52% for T1N0, 44% for T2aN0, and 8% for or T1-2 N1-3. Cause specific survivals were 90%, 71%, and 46%, respectively. Local control was 87% for both T1N0 and T2N0, and 69% for T1-2 N1-3. Seven of 23 failures were salvaged by surgery, increasing local control to 96% for T1 and 90% for T2. Thirty-six patients developed a minor or moderate necrosis (16% T1, 28% T2). Half of these involved bone but only five required surgical intervention. Both local control (LC) and necrosis (nec) increased with increasing dose but improvement beyond 65 Gy is minimal (less than or equal to 60 Gy: LC = 78% nec = 13%; 65 Gy: LC = 90% nec = 29%; greater than or equal to 70 Gy: LC = 94% nec = 23%). For N0 patients, neck management consisted of surveillance (n = 78), elective neck dissection followed with external irradiation for pathologically positive nodes (n = 72), or irradiation (n = 3). Clinically positive nodes (13 patients) were managed by either neck dissection followed by external irradiation if pathologically positive (n = 10) or irradiation alone (n = 3). Regional control was 79% for N0 patients, improving to 88% after surgical salvage, and was 9/13 for N1-3 patients. We recommend that T1 and T2 carcinomas of the mobile tongue be treated by iridium 192 implantation to deliver 65 Gy. Mandibular necrosis should be reduced by using an intra-oral lead-lined dental mold.

One hundred and ten patients with Stage II epidermoid carcinomas of the mobile tongue were treated by interstitial irradiation (Group I: 85 patients) or external irradiation to the primary and the regional lymphatics followed by an interstitial boost (Group II: 25 patients). The neck was managed by either an elective neck dissection (43 patients) completed by external irradiation in 13 patients with pathological specimen or close follow-up (40 patients) with therapeutic neck dissection for relapses (7 patients) in Group I. Primary local control was 88% in Group I and 36% in Group II. Regional control was 91 in Group I and 5 6 in Group II for patients whose primary tumor was controlled. Five-year absolute disease-free survival (DFS) was 42% in Group I and 24% in Group II, but there was an imbalance in the distribution of larger tumors favoring Group I. There were 30 radiation-induced complications and four patients required corrective surgery. This retrospective analysis showed better results in patients whose primary was treated by interstitial irradiation alone which has the extra advantage of preserving salivary function.

From 1970 to 1986, 117 patients with T1 (47) or T2 (70) epidermoid carcinomas of the floor of the mouth (SCC) were treated by iridium-192 implantation (192 Ir). The dose was prescribed according to the Paris System and varied over those years. Follow-up information was available on 116 patients. There were 46 T1N0, 47 T2N0, and 23 T2N1-3. Neck management varied for the 93 N0 patients consisting of surveillance (24 T1, 17 T2) or elective neck dissection (22 T1:all pN-, 30 T2: 20 pN-, 10 pN+). Cause specific survival rates were 94% for T1N0, 61.5% for T2N0, and 28% for T2N1-3 at 5 years. Primary local control was 93.5%, 74.5%, and 65%, respectively, and 98%, 79%, and 65% after salvage. Patients with gingival extension or a tumor size over 3 cm (T2b) had a local control of 50% (9/18) and 58% (15/26), respectively. Nodal control was 93.5% for Stage I, 85% for Stage II, and 48% for T2N1-3 patients. There was no difference in nodal control with regard to treatment policy for Stage I-II patients. There were few complications including three deaths: two from surgery and one from 192 Ir. Nodal status, tumor size defined as T1, T2a (less than or equal to 3 cm), T2b (greater than 3 cm), and gingival extension were the only independent prognostic factors. The management of T1N0 and T2N0 SCC by 192 Ir to a dose of 65 or 70 Gy, using the Paris System, is recommended for lesions 3 cm or less and without gingival extension.

This paper presents the process of ANDRA for the characterization of backfilling materials for a deep radioactive waste disposal in crystalline rocks. The experimental programme was developed in collaboration with the CEA/DRDD; the main objective was to build a comprehensive methodology of characterization, applied to the French Ca-smectite clay, ldFo-Card clay selected from several French deposits. For this programme specific experimental facilities are needed adapted to this kind of material. The main results concerning thermal, hydraulic and radioelement transfer properties are presented for pure Fo-Ca clay, or used in mixtures with different components such as sand, graphite or talc. Hydraulic properties of Fo-Ca and Na-bentonite MX-80 are compared and discussed.

e13556 Background: The combination of epigenetic drug decitabine with genistein, a natural isoflavone, produces synergistic responses in preclinical studies with particular activity shown in lung c...

This paper presents two Compare&Swap protocols that, with respect to omission failures, are (1) fault-tolerant and (2) gracefully degrading, respectively. It shows that fault-tolerance and graceful degradation are close but distinct concepts, and that graceful degradation is inherently more costly than fault-tolerance. These Compare&Swap protocols are derived from consensus protocols proposed by Jayanti et al. (1999).

Multicast communications are of primary importance for multimedia real-time applications where participants are required to exchange real-time audio and video information over a communication network. This flow of information must preserve the causal dependency even though part of the information can be lost or discarded if it violates the timing constraints imposed by a real-time interaction. As it is, a causal order communication mode concerns distributed systems without real-time delivery constraints and assumes unpredictable but finite messages transmission delays and, hence, protocols implementing this communication mode do not cope with real-time issues. We first propose a communication abstraction to cope with unreliable communication networks with real-time delivery constraints: messages have a lifetime, /spl Delta/, after which their contents can no longer be used, moreover some of them can be lost. Secondly, we propose a protocol imposing /spl Delta/-causal order in the case of one-to-one and one-to-many (multicast) communications.

Describes a shore based monitoring system used in Mediterranean Sea within the framework of a European Acoustic Tomographic program. The main features of the listening station are: self governing, continuous real time processing to verify the working conditions of acoustic sources, and data storage at a very good accuracy. Moreover, the monitoring station is operated by remote control via a telephonic modem. >

Multimedia real-time collaborative applications or groupware real-time applications require participants to exchange real-time audio and video information over a communication network. This flow of information must preserve the causal dependency even though part of the information can be lost or can be discarded if it violates the tinting constraints imposed by a real-time interaction. In this paper we propose a communication abstraction to cope with unreliable communication networks with real-time delivery constraints: messages have a lifetime, /spl Delta/, after which their contents can no longer be used, moreover some of them can be lost. This new abstraction, called /spl Delta/-causal order, requires to deliver as much messages as possible within their lifetime in such a way that these deliveries respect causal order. An efficient protocol is proposed in the case of one-to-one communications. A variation of this protocol weld suited to broadcast communications is also shown.

Targeting epigenetic pathways to induce tumor suppressor gene reactivation is a promising approach for cancer therapy. Epigenetic drugs produce impressive responses in some patients; however, treatment options are limited to a small number of drugs. We screened drug libraries for epigenetic activity using a live cell-based assay. We found that around 1% of US-FDA approved drugs have significant epigenetic activity detected by GFP reactivation of a DNA methylated and silenced promoter in colon cancer cells. Newly identified drugs, most prominently cardiac glycosides, induced tumor suppressor gene reactivation and showed selective anticancer apoptosis induction. These drugs did not change DNA methylation or histone acetylation globally but induced gene reactivation and cancer cell killing through calcium signaling leading to nuclear exclusion of chromatin repressors. Our data identify new epigenetic drugs that can be rapidly repurposed for cancer clinical trials and raise questions about the safety of commonly used medications. Citation Format: Noël J. Raynal, Justin T. Lee, Youjun Wang, Judith Garriga, Gabriel Malouf, Sarah Dumont, Elisha J. Dettman, Vazganush Gharibyan, Saira Ahmed, Woonbok Chung, Wayne E. Childers, Magid Abou-Gharbia, Ryan A. Henry, Andrew Andrews, Jaroslav Jelinek, Ying Cui, Stephen B. Baylin, Donald L. Gill, Jean-Pierre J. Issa. Discovery of new epigenetic drugs among FDA-approved drug libraries. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 380. doi:10.1158/1538-7445.AM2014-380

Concepts of group (to structure processes) and causality (to structure sendings and deliveries of messages) are of major importance in the design of distributed systems. Mixing both concepts, the ISIS system defined causal multicast in overlapping groups. This paper presents a simple and efficient protocol that implements such causal multicasts. It compares favourably with the ISIS protocol as it uses only one vector of integers (size of this vector being the total number of groups) to timestamp messages. This low cost in the size of timestamps is obtained by using (sometimes) additional resynchronization messages. It is shown that there is a trade-off between the "as early as possible delivery time" criterium and the "as small as possible timestamps size" criterium for timestamp-based protocols implementing causal order.

This is a retrospective analysis of 233 evaluable patients with stage I-II squamous cell carcinoma of the oral cavity treated by definitive branchytherapy. Minimum follow-up is 3 years. Treatment of neck was chosen by a multidisciplinary team, according to age, medical status and availability for regular follow-up. One hundred and ten patients (47%) underwent elective neck dissection (END); 28 (25%) had positive nodes and received neck irradiation post-operatively. One hundred and twenty three patients (53%) were regularly followed up only, with therapeutic neck dissection (TND) reserved for cases of node relapses. In the END group, there were 19 neck relapses (17%): 12/60 (20%) in patients with mobile tongue carcinoma and 7/50 (14%) in patients with floor of the mouth carcinoma. Salvage treatment was successful in 9/19 (47%) cases. In the TND group, there were 21 neck relapses (17%): 16/82 (20%) in patients with mobile tongue carcinoma and 5/41 (10%) in patients with floor of the mouth carcinoma. Salvage treatment was successful in 13/21 (62%) cases. Ten-year survival is 37% for the END group and 31% for the TND group. Tumour stage and infiltration into underlying tissues increased the probability of neck relapse and death. Furthermore, a multivariate analysis showed that patients treated in the TND group had a higher probability of death than patients treated in the END group (p less than 0.04).

From 1961 to 1974, 245 patients with unilateral "operable" breast cancer (25% T1, 56% T2, 19% T3) were treated with breast conservation and irradiation at the Gustave Roussy Institute (1961-1969) or at the Henri Mondor Hospital (1970-1974). The minimum follow-up is 15 years. Most patients with T greater than 3 cm underwent radiation therapy with the tumor in place, while the greater part of patients with T less than 3 cm received radiation therapy after tumorectomy. The breast and draining lymph node areas received widefield telecobalt irradiation to 45 Gy. The dose to the tumor site was boosted using iridium-192 implantation. Additional irradiation was given to the internal mammary and lower axillary nodes using an electron beam. The 15 years NED survival rate was 63%, 51% and 26% for T1, T2 and T3 tumors, respectively. The NED survival for T less than or equal to 1 cm was 86%. The local recurrence rate was 8, 12 and 19% for T1, T2 and T3 tumors, respectively. Of the patients with local recurrence, 85% underwent surgical salvage. Complications were rare. Cosmetic results were satisfactory in most patients including the T3 group. The proportion of breasts conserved among patients living NED at 15 years, was 97, 88 and 93% for T1, T2 and T3 tumors, respectively. In 1980, after almost 20 years experience using breast conserving techniques, we modified our treatment policies in close collaboration with our surgical team, hel cbye extending the indications for tumorectomy and associating routine surgical exploration of the lower axilla.

Forty-eight patients with T1 or T2 epidermoid carcinomas of the base of tongue were treated at the Henri Mondor Hospital between 1971 and 1981. Forty-one patients received moderate dose 60Co external beam irradiation (mean: 48.6 Gy) to the primary tumor and regional nodes, followed by an interstitial iridium 192 implant to the primary tumor (mean: 32 Gy). This completed the treatment for the 30 node negative patients, but those with clinically positive nodes were managed by either an additional electron beam boost to the involved nodes or a neck dissection. Seven tumors were treated exclusively by implantation to the base of tongue (mean: 63 Gy). Five-year crude disease-free survival is 50% with 35% of patients dying of recurrent disease. Definitive local control for T1 lesions is 85% (11/13) and for T2 is 71% (25/35). A dose response effect was observed with local control of 79% (26/33) obtained with a combined dose greater than or equal to 75 Gy, but only 50% (4/8) for less than or equal to 70 Gy. For N0 patients definitive regional control is 97% and for N1-3 is 89%. Minor or moderate soft tissue ulceration was observed in 12 patients, including 3 cases that progressed to osteonecrosis. None required surgical intervention. No correlation exists between necrosis and tumor size or total dose.

From 1970 to 1979, a group of 50 patients was treated for squamous cell carcinoma of the penis by interstitial irradiation using an afterloading technique and iridium 192 wires. The group included 9 patients with T1 tumors, 27 with T2 tumors, and 14 with T3 tumors. Forty-five patients presented with no metastatic inguinal nodes (N0), 3 patients with N1 nodes, and 2 patients had N3 nodes. After treatment, 11 patients (1 T1, 6 T2 and 4T3) developed local recurrences; 10 of these 11 patients underwent penile amputation which controlled the tumor in 7 of the patients. One patient refused amputation. Three patients developed post-therapeutic necrosis which necessitated partial amputation in 2 cases. Eight patients developed post-therapeutic urethral stenosis, which required surgical treatment in three of the cases. Overall, at their last follow-up examinations, 74% of the patients were free of disease with conservation of penile morphology and function. Most patients without metastatic nodes (37/45) at diagnosis did not receive prophylatic treatment of the groin. Two of these patients developed delayed metastatic nodes; one was successfully salvaged. All 5 patients presenting with metastatic nodes at diagnosis died, four with uncontrolled regional disease. Twenty-one percent of the patients died of their disease. We advocate interstitial irradiation using iridium 192 wires for the treatment of non-infiltrating or moderately infiltrating squamous cell carcinoma of the penis in which the largest dimension does not exceed 4 cm. Pre-implant circumcision and regular long-term follow-up are necessary. More extensive tumors are better managed surgically. When regular follow-up can be assured, it is reasonable to forgo prophylactic treatment of the inguinal nodes in patients presenting without groin metastasis.

From January 1970 to November 1982, 70 patients with carcinoma of the pinna were treated by interstitial irradiation. An afterloading technique with Iridium 192 wires was used. One patient recurred and had a total pinnectomy followed by 60 Gy external radiation. This patient was alive without evidence of disease at 134 months. Three patients who had tumors greater than 4 cm in size at presentation developed late necrosis which required subsequent total pinnectomy. Cosmetic results were assessed in 55 patients and were good with few late sequelae (in 78% of cases (3646) when the tumor measured less than 4 cm, but only in 19 when the tumor measured more than 4 cm). We advocate interstitial Iridium 192 irradiation for treatment of pinna tumors smaller than 4 cm. None of 39 patients with squamous cell carcinoma had biopsy proven cervical lymph node metastasis at the time of diagnosis. Four patients with squamous cell carcinoma (439: 10%) later developed a regional nodal metastasis after treatment of the pinna. All four relapsed in the parotid region and were managed by partial parotidectomy and neck dissection followed by external irradiation. One of these four patients died from uncontrolled cervical node disease. In our opinion, when regular follow-up is dependable, it is reasonable to save treatment of the cervical nodes for those patients who relapse with involved metastatic cervical nodes.