Monitoring of plasma concentrations of dabrafenib and trametinib in advanced BRAFV600mut melanoma patients.

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: 65.0ng/mL; interquartile range (IQR) [4-945]) and of PCT (median: 8.6ng/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±183ng/mL and 9.3±3.6ng/mL, respectively) and responders (complete, partial or stable response) (n=13; 159±225ng/mL, P=0.58 and 10.6±24.4ng/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±4.8ng/mL) than for male subjects (8.8ng/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.

Experimental and computational diagnosis of the fluxional nature of a benzene-1,3,5-tricarboxamide-based hydrogen-bonded dimer.

Precise characterization of the hydrogen bond network present in discrete self-assemblies of benzene-1,3,5-tricarboxamide monomers derived from amino-esters (ester BTAs) is crucial for the construction of elaborated functional co-assemblies. For all ester BTA dimeric structures previously reported, ester carbonyls in the side chain acted as hydrogen bond acceptors, yielding well-defined dimers stabilized by six hydrogen bonds. The ester BTA monomer derived from glycine (BTA Gly) shows a markedly different self-assembly behaviour. We report herein a combined experimental and computational investigation aimed at determining the nature of the dimeric species formed by BTA Gly. Two distinct dimeric structures were characterized by single-crystal X-ray diffraction measurements. Likewise, a range of spectroscopic and scattering techniques as well as molecular modelling were employed to diagnose the nature of dynamic dimeric structures in toluene. Our results unambiguously establish that both ester and amide carbonyls are involved in the hydrogen bond network of the discrete dimeric species formed by BTA Gly. The participation of roughly 4.5 ester carbonyls and 1.5 amide carbonyls per dimer as determined by FT-IR spectroscopy implies that several conformations coexist in solution. Moreover, NMR analysis and modelling data reveal rapid interconversion between these different conformers leading to a symmetric structure on the NMR timescale. Rapid hydrogen bond shuffling between conformers having three (three), two (four), one (five) and zero (six) amide carbonyl groups (ester carbonyl groups, respectively) as hydrogen bond acceptors is proposed to explain the magnetic equivalence of the amide N-H on the NMR timescale. When compared to other ester BTA derivatives in which only ester carbonyls act as hydrogen bond acceptors, the fluxional behaviour of the hydrogen-bonded dimers of BTA Gly likely originates from a larger range of energetically favorable conformations accessible through rotation of the BTA side chains.

Probing halogen-halogen interactions in solution.

Halogen-halogen interactions are a particularly interesting class of halogen bonds that are known to be essential design elements in crystal engineering. In solution, it is likely that halogen-halogen interactions also play a role, but the weakness of this interaction makes it difficult to characterize or even simply detect. We have designed a supramolecular balance that allows detecting BrBr interactions between CBr3 groups in solution and close to room temperature. The sensitivity and versatility of the chosen platform have allowed accumulating consistent data. In halogenoalkane solvents, we propose estimates for the free energy of these weak halogen bond interactions. In toluene solutions, we show that the interactions between Br atoms and the solvent aromatic groups dominate over the BrBr interactions.

[Nasal polyposis and olfactory function: results of the surgical treatment]. / La polypose nasosinusienne et l'odorat: intérêt de la chirurgie.

INTRODUCTION: Hyposmia is a common cause of functional complaint in patients with nasal polyposis. The aim of the current study was to report the olfactory functional results after sinus surgery. MATERIALS AND METHODS: A systematic review of the scientific literature was achieved in the Pubmed database. RESULTS: Overall, 10 series published between 1989 and 2013, involving 959 patients, were selected. The surgery for nasal polyposis, adjuvant medical treatment, may allow olfactory improvement. The results are even better than surgery is as wide as possible and the evolutionary stage is low.

[Diagnosis and therapeutic pathways in head and neck cancers]. / Parcours de soins du patient présentant un carcinome epidermoïdes des voies aéro-digestives supérieures.

BACKGROUND: Cancers of uppers aero-digestives tracts represent, infrequency, the 5th cancer in the French population. Most of them (about 70%) are diagnosed at an advanced stage (stage III or IV) while they are associated with a poor prognosis (only 40% five year survival). The objective of our study was to analyze the care pathway of patients with cancers of uppers aero-digestives tracts in order to target efforts to improve the survival of these patients. METHODS: It was a descriptive and retrospective study, on medical files, on the health care pathway of patients with cancers of uppers aero-digestives tracts cared in the Head and Neck surgery department of Val de Grâce in Paris and Percy in Clamart between January 2004 and December 2006. The patients were adults with squamous cell carcinoma of uppers aero-digestives tracts. RESULTS: One hundred thirty-eight files of patients were analyzed. Fifty-five percent of patients were diagnosed at an advanced stage. On average patients have waited two months and twenty-one days before consulting a doctor for the first time. The time interval between the specialist consultation and the start of treatment was on average 7 weeks. The overall 5-year survival rate was 61%. CONCLUSION: Squamous cell carcinoma of uppers aero-digestives tracts remains serious and has a poor diagnosis, even in a population with a high social-cultural level. The long time interval before the first consultation may be reduced by improving health education among the general practitioner (primary and secondary prevention), and by establishing health care public campaigns. This would allow earlier diagnosis, more conservative therapeutic opportunities and therefore a better prognosis.

[Diffusion-weighted MR imaging of liver pathology: principles and clinical applications]. / Imagerie par résonance magnétique de diffusion (IRMD) en pathologie hépatique: principe et applications cliniques.

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.

[Management of ear, nose, and throat diseases in district hospital centers in Madagascar]. / Prise en charge de la pathologie ORL dans les centres hospitaliers de district à Madagascar.

The purpose of this report is to describe the experience of a specialized medico-surgical ENT team sent to hospital centers in Atalaha and Tulear, Madagascar by a nonprofit organization called "Terre rouge" from the Reunion Island. In three separate short-term missions, a total of 93 patients received care. Discussion focuses on the particular pathological, cultural, and pedagogical features of the Island and on the resources that were deployed during the missions. Providing ENT care in district hospitals in Madagascar requires adaptation to the difficult climatic conditions, poor hospital facilities (infrastructure, equip ment, and personnel), and advanced stage of diseases. To ensure continuous access to ENT care, it will be necessary to provide practical and didactic training for healthcare personnel in the country.

[Post-traumatic carotid cavernous fistula: report of two cases]. / Fistule carotido-caverneuse post-traumatique: à propos de deux cas.

Carotid cavernous fistula (CCF) is an abnormal communication between the cavernous sinus and the carotid arterial system. The authors reported the clinical presentation and therapeutic procedure of two cases. The physician has to be aware of this diagnosis when a patient is referred for a posttraumatic exophthalmia. The medical behaviour is multidisciplinary (ENT, ophthalmologist, radiologist and neurosurgeon). The imaging of choice is the angiography but angio-MRI and angio-CT can help to confirm the diagnosis. The endovascular embolization is the treatment of choice. It presents an acceptable risk of complication and a low risk of failure. In this paper the authors report 2 posttraumatic CCF cases treated with success by endovascular embolization.

[Cataract surgery and its impact on balance and autonomy in elderly]. / Incidence d'une chirurgie de la cataracte sur l'équilibre et l'autonomie du sujet âgé.

PURPOSE: Cataract is a major cause of visual impairment among elderly. Cataract surgery improves visual afferencies and can have an impact on balance. The present study assessed the impact of cataract surgery upon balance and autonomy in elderly. We realized clinical examinations and objective tests the day before surgery and 2-months later. METHODS: The initial cohort consisted of 66 patients that had to undergo a cataract surgery. Their mean age was 79 +/- 0.5. For logistic reasons, only 33 patients have been completely evaluated before and after surgery. Each patient underwent a history and examination that have assessed autonomy, walking, visual and then cochleo-vestibular functions including bone vibratory test and dynamic computerized posturography (Equitest). RESULTS: After 2 months, cataract surgery had no incidence on balance. The fear of falling has stayed the same whereas the number of falls has been noticeably reduced by surgery. The overall score of Equitest has shown an increase in visual dependence after surgery. Although cataract surgery has no incidence on autonomy, it may improve the quality of life among older people by leisure activities recovery. CONCLUSION: An early physical rehabilitation facilitated by visual improvement after surgery can also prevent visual dependence and autonomy loss. We recommend vestibular rehabilitation in elderly with major visual dependence.

[Identity vigilance and implementation of transfusion software in hospitals]. / Identitovigilance et intégration de l'informatique transfusionnelle dans les établissements de santé.

In hospitals, patients' identity mismatch is the cause of serious incidents during transfusion or other healthcare processes. With a wider use of healthcare software, new dysfunctions and risks may occur in case of ID mismatch between different software and for transfusion between blood bank and hospital. Four critical stages are to be considered when using software management of hospital care: initial patients' identification, modifications of identification data during hospital stay and then synchronization of all different software, proper use of patient's identification means by hospital staff and share of patient's identification data with others such as the Etablissement français du sang (EFS) for transfusional purposes. Perpignan Hospital has put in place an identity vigilance group whose role is to enforce a safe patients' identification policy. It has to inform and train hospital staff, make sure that all software requiring patients' ID are correctly synchronized, especially when sharing data with EFS and monitor improvement with a surveillance system. As transfusion care is one of the more patients' ID sensitive, particularly when computer assisted, haemovigilance officers are highly involved in identity vigilance.

[Imaging of incidental cystic lesions of the pancreas]. / Imagerie des lésions kystiques du pancréas de découverte fortuite.

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).

Direct evidence to support the immunosurveillance concept in a human regressive melanoma.

The concept of immunosurveillance against cancer has been an extensively debated question over the last decades. Multiple indirect arguments have supported the view that the immune system may control, at least in certain cases, malignant cell growth while direct demonstration is still lacking in the human. In an attempt to address this issue, we have selected a study model, namely spontaneously regressive melanoma. In previous series of experiments, the variability of T cell receptors (TCRs) in the lymphocytes infiltrating a regressive tumor lesion was investigated. Results demonstrated that clonal T cell populations, precisely defined through their V-D-J junctional sequences, were amplified in situ. One clone was predominant, expressing the V beta 16 variable gene segment. A specific anti-V beta 16 TCR mAb was generated here to purify and functionally characterize the corresponding cells. A tumor-infiltrating lymphocyte-derived V beta 16+ T cell line was developed using this reagent. These in vitro cultured cells were found to express the in vivo predominant TCR sequence exclusively and to display an HLA-B14-restricted cytotoxic activity against the autologous tumor cells. Immunohistochemical experiments, performed with the anti-V beta 16 mAb, showed that the corresponding CTLs are present in the tumor area, some of them being closely opposed to the melanoma cells. Together, these studies demonstrate the existence of a local adaptive immune response clinically associated to tumor regression, thus strongly supporting the validity of the immunosurveillance concept in certain human tumors.

[Imaging of intracranial metastases in adults]. / Imagerie des métastases intracrâniennes chez l'adulte.

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.

Characterization and evolution of napin-encoding genes in radish and related crucifers.

Three cDNA clones, encoding napin storage proteins from radish, were isolated and sequenced. They fall into two classes differing in the size of the primary translation product. Sequences of the two classes are very well conserved and they display an organization very similar to that of the homologous genes from rapeseed and Arabidopsis which have previously been described. On the basis of hybridization intensity and the number of restriction fragments, we estimate that the radish napin multigene family is represented by eight to twelve members. The use of probes specific to each subfamily demonstrates that they contribute to a similar extent to the production of napin mRNA. Analysis of the sequence data suggests that the napin ancestral genes are probably derived from successive duplication and divergence of a protogene. Comparing other available napin sequences with those of radish reveals intriguing features. Comparison of the coding sequences shows that the homology between the radish and rapeseed sequences is much higher than that between each of the four members of the Arabidopsis gene family. This would suggest that the duplications which gave rise to the different members occurred independently in the two groups of species after separation of Arabidopsis from the Brassica lineage. However, similar comparison carried out on the 3' -noncoding sequences does not support this hypothesis, but shows that slightly different duplicated genes probably already existed in the common ancestor to the three genera. This paradox can be resolved by assuming that, within each genus, coding sequences for napin-encoding genes have been considerably homogenized as a result of concerted evolution.

The Arabidopsis thaliana cDNA sequencing projects.

Nearly 30000 Arabidopsis thaliana EST (Expressed Sequence Tags) have been produced by a French-American consortium. Despite redundancy, these sequences tag about half of the expected Arabidopsis genes. Approximately 40% of the non-redundant EST can be assigned a putative function by simple homology search. This programme allowed the identification of a large number of genes which would have been very difficult to isolate by other classical techniques. It considerably stimulated many areas of plant biology by the rapid discovery a large number of genes, by revealing multigene families and by allowing the analysis of differential expression of the different members. Finally this programme facilitated construction of physical maps of the chromosomes and opened the way for complete sequencing of the Arabidopsis genome and comparative mapping of the major plant crops.

The Arabidopsis thaliana cDNA sequencing projects.

Nearly 30000 Arabidopsis thaliana EST (Expressed Sequence Tags) have been produced by a French and an American consortium. Despite redundancy these sequences tag about half the expected Arabidopsis genes. Approximately 40% of the non-redundant EST can be assigned a putative function by simple homology search. This programme allowed the identification of a large number of genes which would have been very difficult to isolate by other classical techniques. It considerably stimulated many areas of plant biology by the rapid discovery a large number of genes, by revealing multigene families and by allowing the analysis of differential expression of the different members. Finally this programme facilitated construction of physical maps of the chromosomes and opened the way for complete sequencing of the Arabidopsis genome and comparative mapping of the major plant crops.

The distribution of T-DNA in the genomes of transgenic Arabidopsis and rice.

Almost all the nuclear genes of four Gramineae (maize, wheat, barley, rice) and pea are located in DNA fractions covering only a 1-2% GC range and representing between 10 and 25% of the different genomes. These DNA fractions comprise large gene-rich regions (collectively called the 'gene space') separated by vast gene-empty, repeated sequences. In contrast, in Arabidopsis thaliana, genes are distributed in DNA fractions covering an 8% GC range and representing 85% of the genome. Here, we investigated the integration of a transferred DNA (T-DNA) in the genomes of Arabidopsis and rice and found different patterns of integration, which are correlated with the different gene distributions. While T-DNA integrates essentially everywhere in the Arabidopsis genome, integration was detected only in the gene space, namely in the gene-rich, transcriptionally active, regions of the rice genome. The implications of these results for the integration of foreign DNA are discussed.

Definitive radiation treatment for early stage carcinoma of the soft palate and uvula: the indications for iridium 192 implantation.

From 1971 to 1984 59 T1 and T2 carcinomas of the soft palate and uvula were treated definitively by irradiation at the Henri Mondor hospital. Included are ten patients previously irradiated to the oropharyngeal area for either a carcinoma of the soft palate or another malignancy. Sixteen patients were treated by external irradiation alone, 14 by Iridium 192 implantation, and 29 by a combination of the two. Two techniques of implantation were used: the guide gutter technique (33 patients) and the plastic tube technique (10 patients). Clinically negative neck nodes (51/59) either received prophylactic telecobalt therapy (39/51) or were surveilled (12/51). Clinically involved nodes (8/59) were managed either by external irradiation alone (4/8) or combined with neck dissection (4/8). Local failure was 25% (4/16) after exclusive telecobalt therapy, 18% (5/19) after combined telecobalt therapy and implantation, and 0% (0/14) after Iridium 192 implantation alone. No local failures were seen with the plastic tube technique (0/10) as compared to 15% (5/33) for guide gutters. Only two nodal failures were observed (2/59: 3%). Crude 5-year disease-free survival was 33%. Severe complications were limited to one osteonecrosis, one soft tissue necrosis, and one partial palatal incompetence. Salivary impairment was reduced when implantation was used for part or all of the treatment. We recommend 45 Gy external radiation followed by 30 Gy from Iridium 192 implantation using the plastic tube method unless there has been prior oropharyngeal irradiation, in which case we give 60 Gy from implantation alone. For clinically negative neck nodes, we recommend 45 Gy prophylactic external neck irradiation. For clinically positive lymph nodes, this should be followed by either a 25 to 30 Gy boost to the involved nodes or a neck dissection.

Iridium 192 implantation of T1 and T2 carcinomas of the mobile tongue.

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.