Association of location of BRCA1 and BRCA2 mutations with benefit from olaparib and bevacizumab maintenance in high-grade ovarian cancer: phase III PAOLA-1/ENGOT-ov25 trial subgroup exploratory analysis.

BACKGROUND: In the phase III PAOLA-1 study, the addition of maintenance olaparib to bevacizumab in patients with newly diagnosed high-grade ovarian cancer (HGOC) resulted in prolonged progression-free survival (PFS), particularly for homologous recombination deficiency-positive tumors, including those with a BRCA mutation (BRCAm). The magnitude of benefit from olaparib and bevacizumab according to the location of mutation in BRCA1/BRCA2 remains to be explored. PATIENTS AND METHODS: Patients with advanced-stage HGOC responding after platinum-based chemotherapy + bevacizumab received maintenance therapy bevacizumab (15 mg/kg q3w for 15 months) + either olaparib (300 mg b.i.d. for 24 months) or placebo. PFS was analyzed in the subgroup of patients with BRCA1m/BRCA2m according to mutation location in the functional domains of BRCA1 [Really Interesting Gene (RING), DNA-binding domain (DBD), or C-terminal domain of BRCA1 (BRCT)] and BRCA2 [RAD51-binding domain (RAD51-BD); DBD]. RESULTS: From 806 randomized patients, 159 harbored BRCA1m (19.7%) and 74 BRCA2m (9.2%). BRCA1m in RING, DBD, and BRCT domains was detected in 18, 40, and 33 patients, and BRCA2m in RAD51-BD and DBD in 36 and 13 patients, respectively. After a median follow-up of 25.5 months, benefit from maintenance olaparib + bevacizumab was observed irrespective of location of BRCAm. The benefit was particularly high for those with BRCA1m located in the DBD, with 24-month PFS estimated to be 89% and 15% [olaparib + bevacizumab versus placebo + bevacizumab hazard ratio = 0.08 (95% confidence interval 0.02-0.28); interaction P = 0.03]. In BRCA2m patients, 24-month PFS rates for those with mutations located in the DBD were 90% and 100% (olaparib + bevacizumab versus placebo + bevacizumab), respectively. CONCLUSIONS: Advanced-stage BRCA-mutated HGOC patients reported PFS benefit from maintenance olaparib and bevacizumab regardless of mutation location. The benefit is particularly high for patients with mutations located in the DBD of BRCA1. Mutations located in the DBD of BRCA2 are also associated with excellent outcome.

Influence of outer-layer finite-size effects on the dewetting dynamics of a thin polymer film embedded in an immiscible matrix.

In capillary-driven fluid dynamics, simple departures from equilibrium offer the chance to quantitatively model the resulting relaxations. These dynamics in turn provide insight on both practical and fundamental aspects of thin-film hydrodynamics. In this work, we describe a model trilayer dewetting experiment elucidating the effect of solid, no-slip confining boundaries on the bursting of a liquid film in a viscous environment. This experiment was inspired by an industrial polymer processing technique, multilayer coextrusion, in which thousands of alternating layers are stacked atop one another. When pushed to the nanoscale limit, the individual layers are found to break up on time scales shorter than the processing time. To gain insight on this dynamic problem, we here directly observe the growth rate of holes in the middle layer of the trilayer films described above, wherein the distance between the inner film and solid boundary can be orders of magnitude larger than its thickness. Under otherwise identical experimental conditions, thinner films break up faster than thicker ones. This observation is found to agree with a scaling model that balances capillary driving power and viscous dissipation with a no-slip boundary condition at the solid substrate/viscous environment boundary. In particular, even for the thinnest middle-layers, no finite-size effect related to the middle film is needed to explain the data. The dynamics of hole growth is captured by a single master curve over four orders of magnitude in the dimensionless hole radius and time, and is found to agree well with predictions including analytical expressions for the dissipation.

Evaluation of morphological representative sample sizes for nanolayered polymer blends.

The size of representative microstructural samples obtained from atomic force microscopy is addressed in this paper. The case of an archetypal one-dimensional nanolayered polymer blend is considered. Image analysis is performed on micrographs obtained through atomic force microscopy, yielding statistical data concerning morphological properties of the material. The variability in terms of microstructural morphology is due to the thermomechanical processing route. The statistical data is used in order to estimate sample size representativity, based on an asymptotic relationship relating the inherent point variance of the indicator function of one material phase to the statistical, size-dependent, ensemble variance of the same function. From the study of nanolayered material systems, the statistical approach was found to be an effective mean for discriminating and characterizing multiple scales of heterogeneity.

The detection of blood group phenotypes using paper diagnostics.

BACKGROUND AND OBJECTIVES: Paper biodiagnostics for blood typing are novel, cheap, fast and easy to use. Agglutinated red blood cells cannot travel through the porous structure of paper, indicating a positive antibody-antigen interaction has occurred. Conversely, non-agglutinated blood can disperse and wick through the paper structure with the ease to indicate a negative result. This principle has been demonstrated to detect blood group phenotypes: ABO and RhD. However, typing for red blood cell antigens such as Rh, Kell, Duffy and Kidd has not yet been explored on paper. MATERIALS AND METHODS: Two paper testing methods - an elution and a direct flow-through method - were investigated to detect red blood cell antigens excluding the ABO system and RhD. Antigens explored include the following: C, c, E, e, K, k, Fy(a), Fy(b), Jk(a), Jk(b), M, N, S and s, P1, Le(a) and Le(b). The variables tested include the following: reaction time and reagent concentration. The importance of antibody type/structure for successful agglutination on paper was confirmed. RESULTS: Some blood group phenotypes showed less agglutination due to weaker antibody-antigen interactions. Most blood groups with antibodies available as IgM, such as C, c, E, e, K and k, and Jk(a) and Jk(b), and P1, were successful using both methods. However, other blood groups, especially those with antibodies only available as polyclonal antibodies, were unsuccessful and require further scrutiny. CONCLUSION: Paper can be used as an alternative blood grouping diagnostic tool for selected blood group phenotypes.

Dataset for facilitating the calculation of aspect ratio of fibrillated cellulose suspensions based on gel point data.

This article describes data related to the research paper "Simplification of gel point characterization of cellulose nano and microfiber suspensions" [1]. The characterization of fibrillated celluloses that include cellulose nano and microfibrils (CMNFs) is a challenge for their production on an industrial scale, requiring easy techniques that control their quality and reproducibility. Gel point is a convenient parameter commonly used to estimate the aspect ratio (AR) of CMNFs. However, this estimation requires many sedimentation experiments, which are tedious and time consuming. The dataset includes all information related to the traditional experiments and to the simplified experiments for estimating gel point and AR based on only one sedimentation experiment. The full data set is useful to select the initial concentration to carry out the experimentation. This dataset also includes the information for the validation of the proposed simplified methodology and shows that the errors are lower than 7% for the gel point calculation and of 3% for the AR estimation. A larger databased of nanocellulose suspensions can be built with the reuse of this data to allow the estimation of nanocellulose properties in a future.

SEED: An Operational Numerical Tool for Dosimetric Reconstruction in Case of External Radiological Overexposure.

ABSTRACT: In the event of a radiological accident involving external exposure of one or more victims and potential high doses, it is essential to know the dose distribution within the body in order to sort the victims according to the severity of the irradiation and then to take them to the most suitable medical facilities. However, there are currently few techniques that can be rapidly deployed on field and capable of characterizing an irradiation. Therefore, a numerical simulation tool has been designed. It can be implemented by a doctor/physicist pairing, projected within a limited time as close as possible to the irradiation accident and emergency response teams. Called SEED (Simulation of External Exposures & Dosimetry), this tool (dedicated to dose reconstruction in case of external exposure) allows a rapid modeling of the irradiation scene and a visual exchange with the victims and witnesses of the event. The user can navigate in three dimensions in the accident scene thanks to a graphical user interface including a "first person" camera. To validate the performance of the SEED tool, two dosimetric benchmarking exercises were performed. The first consisted in comparing the dose value provided by SEED to that given by a reference calculation code: MCNPX. The purpose of the second validation was to perform an experiment irradiating a physical dummy equipped with dosimeters and to reconstruct this irradiation using SEED. These two validation protocols have shown satisfactory results with mean difference less than 2% and 12% for the first and second exercises, respectively. They confirm that this new tool is able to provide useful information to medical teams in charge of dosimetric triage in case of a major external exposure event.

Diethyl sinapate-grafted cellulose nanocrystals as nature-inspired UV filters in cosmetic formulations.

Inspired by nature's photoprotection mechanisms, we report an effective UV-blocking nanomaterial based on diethyl sinapate-grafted cellulose nanocrystals (CNC-DES). The colloidal stability and UV-blocking performance of CNC-DES in aqueous glycerol (a common humectant in petroleum-free cosmetic formulations) and in a commercially available moisturizing cream were studied. Grafting the water-insoluble DES onto CNCs renders it dispersible in these water-based formulations, thanks to the excellent water-dispersibility of CNC nanoparticles. Glycerol dispersions containing 0.1 to 1.5 wt% CNC-DES display very high UV-blocking activity owing to the anti-UV DES moieties anchored onto CNCs. A facial cream blended with 1.5 wt% CNC-DES exhibits an SPF of 5.03, which is higher than a commercially available sunscreen with the same active ingredient concentration (SPF = 3.84). DPPH radical scavenging assay also showed the antioxidant potential of CNC-DES, albeit coinciding with a significant reduction in antioxidant activity after grafting DES onto CNCs. Cytotoxicity measurements revealed the CNC-DES not to cause significant cytotoxicity to murine fibroblast cells after 24 h of exposure. Overall, CNC-DES exhibits strong anti-UV and antioxidant properties and is water-dispersible, biocompatible, non-greasy, and lightweight. This study demonstrates the exceptional potential of DES-grafted CNCs as nature-inspired UV filters in the next generation of cosmetic formulations, including those for sensitive skins.

cis and trans elements differ among mouse strains with high and low extrahepatic complement factor B gene expression.

Factor B (Bf), an enzyme of the alternative pathway of complement activation, is one of four major histocompatibility complex (MHC) class III genes. To ascertain the genetic mechanism for tissue-specific constitutive and regulated expression of Bf, we sequenced the regulatory regions 5' of the gene from mice of different H-2 MHC haplotypes and assessed trans-acting factors, specific DNA binding nucleoproteins, in liver and kidney. Striking tissue-specific differences in constitutive expression of Bf were demonstrated in mice of H-2f or H-2z haplotypes when compared with H-2d or H-2u (kidney and intestinal Bf in H-2d or H-2u much greater than H-2f or H-2z). These differences correlated with a point nucleotide substitution 3 bp downstream of the upstream Bf initiation site that affects interaction with a DNA binding protein. This and additional cis differences localize the sequence substitutions responsible for previously identified restriction fragment length polymorphisms among inbred mouse strains and also reveal two previously unrecognized polymorphisms generated by SmaI and HinfI digestion. Evidence for differences in trans was found in a comparison of DNA binding nucleoproteins from kidney, but not liver, of B10.PL when compared with B10.M. These data, together with the high degree of sequence homology between human and mouse Bf 5' flanking regions, should prompt a search for polymorphic restriction sites and cis binding elements in the Bf promoter that could serve as markers of human MHC-associated renal pathology and variants in local MHC class III gene expression.

A mutation in the surfactant protein B gene responsible for fatal neonatal respiratory disease in multiple kindreds.

To determine the molecular defect accounting for the deficiency of pulmonary surfactant protein B (SP-B) in full-term neonates who died from respiratory failure associated with alveolar proteinosis, the sequence of the SP-B transcript in affected infants was ascertained. A frameshift mutation consisting of a substitution of GAA for C in codon 121 of the SP-B cDNA was identified. The three affected infants in the index family were homozygous for this mutation, which segregated in a fashion consistent with autosomal recessive inheritance of disease. The same mutation was found in two other unrelated infants who died from alveolar proteinosis, one of whom was also homozygous, and in the parents of an additional unrelated, affected infant, but was not observed in 50 control subjects. We conclude that this mutation is responsible for SP-B deficiency and neonatal alveolar proteinosis in multiple families and speculate that the disorder is more common than was recognized previously.

[Meningococcemia without meningitis: A report of two cases]. / Méningococcémie sans méningite: à propos de deux observations.

INTRODUCTION: Meningococcemia without meningitis is an often under recognized clinical form of invasive Neisseria meningitidis infection. CASE REPORTS: We report two unusual cases of invasive meningococcal disease who presented with meningococcemia without distinct signs of meningitis or severe sepsis manifestation. In both cases, confirmation of the diagnosis is provided by meningococcal PCR performed on blood or skin lesion biopsy. CONCLUSION: Clinical recognition of this entity is crucial for early antibiotic treatment and to avoid delayed diagnosis and potentially dangerous complications.

Rearrangement of proximal 11q13 band in a CMML in acute transformation.

Fluorescence in situ hybridization (FISH) was performed on bone marrow cells thought to contain a t(7;11)(p22;q13) from a patient with chronic myelomonocytic leukemia in transformation. FISH analysis using a panel of 10 probes previously mapped to 11q13 revealed a cytogenetically undetected complex rearrangement that involved chromosomes 7 and 11 as well as a chromosome 3 at band p24. Two distinct translocation breakpoints, both proximal to the BCL1 locus, were found in chromosome 11 that perforce separate it into three subregions. The two breakpoints appear distinct from the two previously described ones which involved the FAU and GSTP1 genes. Our observations add to the involvement of proximal 11q13 in myeloid malignancies.

Phase I study of vinorelbine and carboplatin in advanced non-small cell lung cancer.

Thirty-one patients with previously untreated advanced non-small cell lung cancer were included in a Phase I study to determine the optimal dose of Carboplatin (CBDCA) which preserves the best Navelbine (NVB) dose-intensity. NVB was administered at a 30-mg/m2 fixed-dose on days 1-8/q 3 weeks, whereas CBDCA doses were planned to be escalated from 275 to 400 mg/m2 on day 1/q 3 weeks for six successive groups of patients. The toxicity limiting dose of CBDCA in the combination was 350 mg/m2 on day 1/q 3 weeks because of repetitive Grade IV neutropenia, and the optimal dose of CBDCA was 325 mg/m2 on day 1/q3 weeks, offering a 86.4% NVB and a 92.6% CBDCA relative dose-intensity for the first 9 weeks. Responses were observed at each step. This study demonstrates the feasibility and the efficacy of the NVB-CBDCA combination. It suggests that dose-intensity calculation can be helpful to determine the recommended dose for Phase II studies of new drug combinations.

Phase II study of alternating doses of vinorelbine in combination with cisplatin for non-small cell lung cancer (NSCLC): a disappointing experience.

UNLABELLED: In both Phase III trials of vinorelbine-cisplatin (VP) versus single-agent vinorelbine, the received vinorelbine dose intensities were 18.8 and 21.1 mg/m2 per week in the VP arms. Vinorelbine was administered at the weekly dose of 30 mg/m2. A new structure of the vinorelbine-cisplatin regimen delivering alternating doses of vinorelbine (35 mg/m2 on weeks 1, 3, 5 and 17.5 mg/m2 on weeks 2 and 4) was reported to increase the vinorelbine dose intensity in patients with non-small cell lung cancer (NSCLC). To further analyze the ability of such an alternating vinorelbine schedule to enhance vinorelbine delivery, a Phase II study of VP was conducted in NSCLC patients using the previously published alternating doses of vinorelbine for 6 cycles. Cisplatin was administered on weeks 1, 5 and every 6 weeks thereafter, at a dose of 75 mg/m2 in the first 14 patients and at a dose of 100 mg/m2 in the 18 remaining patients. The intended vinorelbine dose intensity was 26.25 mg/m2 per week. The median delivered dose intensities of vinorelbine calculated during the first 8-week period were: all patients, 17.9 mg/m2 per week; patients treated with cisplatin 75 mg/m2, 18.1 mg/m2 per week; patients receiving cisplatin 100 mg/m2, 17.9 mg/m2 per week; naive patients 18.2 mg/m2 per week and previously treated patients. 13.2 mg/m2 per week. Reductions and delays in the vinorelbine treatment mostly occurred on weeks 3 and 7, which are times of high-dose treatments (35 mg/m2) according to the protocol. The partial response rate was 34% (95% C.I. = 26-42%). Median survival was 21 weeks. The main toxicities were febrile neutropenia (nine patients, including two septic deaths) and constipation Grades 3 and 4 (five patients). CONCLUSION: The use of alternating doses of vinorelbine within the VP regimen did not lead to higher vinorelbine delivered dose intensities than those reported with a standard weekly 30 mg/m2 administration.

A phase II study of Navelbine (vinorelbine) in the treatment of non-small-cell lung cancer.

Navelbine (vinorelbine, NVB) is the first semisynthetic 5'-nor-vinca-alkaloid selected for clinical trial. NVB has been shown to have a good level of activity against different experimental solid tumors in animals, with low neurotoxicity. In the phase II study, 78 patients with an inoperable non-small-cell lung cancer (NSCLC) were treated with NVB at a weekly dose of 30 mg/m2. No patient had previously received chemotherapy. Twenty-three of the 78 eligible patients showed a partial response (29.4% with a 95% confidence limits: 19.5-39.5). Eight patients were not evaluable and the percentage of partial response were 32.8% in the evaluable patients group. The median response duration was 34 weeks, and the median survival time for the overall population reached 33 weeks. Grade 3-4 leukopenia was seen in 12.5% of cycles. No thrombocytopenia occurred. At the dosage schedule used, NVB seems a very promising agent in the treatment of NSCLC.

Paraneoplastic Raynaud's phenomenon.

A testicular tumour could be diagnosed by the occurrence of a Raynaud's phenomenon complicated by severe digital arteritis. The arteritis rapidly regressed under prostacyclin therapy. Such vascular manifestations are frequent in testicular carcinoma, but they usually develop after chemotherapy. To our knowledge, this is the first case where they preceded the diagnosis and specific treatment of a tumour of the testis.

Lymphoma developing in a patient with rheumatoid arthritis taking methotrexate.

We report one case of non-Hodgkin lymphoma in a patient, with a 30-year history of rheumatoid arthritis, taking low dose methotrexate weekly over a 10-month period. The mild immunosuppression that occurs with methotrexate therapy probably places patients with rheumatoid arthritis at added risk of developing lymphoproliferative diseases, but coincidence cannot be excluded.

Subacute cutaneous lupus erythematosus associated with Hodgkin's disease.

Simultaneous occurrence of subacute cutaneous lupus erythematosus and malignancy has rarely been reported. We report the first case of subacute cutaneous lupus erythematosus associated with Hodgkin's disease. Although our case does not fulfill the criteria of paraneoplastic process, a relationship between the two disorders might be suggested by their simultaneous occurrence and in view of the cases of disseminated lupus erythematosus associated with lymphoma reported so far. The different hypotheses are discussed.

[Prognostic factors of small cell bronchial carcinomas]. / Facteurs pronostiques des carcinomes bronchiques a petites cellules.

Prognostic factors in small cell lung carcinoma have a great importance with regard to the interpretation of treatment results. The main prognostic factors are the extent of the disease, performance status, age and sex. Other factors are discussed.

[Cardiovascular manifestations of Cogan syndrome. Apropos of a case]. / Manifestations cardiovasculaires du syndrome de Cogan. A propos d'un cas.

The authors describe a case of Cogan's syndrome in a patient with ulcerative colitis complicated by several cardiovascular manifestations including bilateral coronary ostial stenosis, rapidly progressive aortic regurgitation and aneurysm of the thoracic aorta, thrombosis of the common iliac artery and pericardial symphysis. This rare form of inflammatory arteritis, the diagnosis of which is usually made on the finding of associated ocular and auditory involvement, is distinct from other types of angiitis by the predisposition to severe cardiovascular complications which influence the vital prognosis. The differential diagnosis with more common collagen diseases with cardiovascular complications is discussed.