Receptor-mediated PLGA nanoparticles for glioblastoma multiforme treatment.

Glioblastoma multiforme is the most lethal type of brain tumor and the established therapy only extends patients survival to approximately one year. Its first-line treatment is based on of chemotherapy with the alkylating agent temozolomide (TMZ). As many other chemotherapeutic drugs, TMZ presents several limitations as high toxicity and low bioavailability. The delivery of TMZ using poly(lactic-co-glycolic acid) nanoparticles is proposed in this work. Stable nanoparticles functionalized with a OX26 type monoclonal antibody for transferrin receptor were developed, targeting the glioblastoma tumor cells, since these cells are known for overexpressing this receptor. The release profile of TMZ from the nanoparticles was studied mimicking physiological conditions, and targeted cellular internalization was also investigated. Two glioblastoma cell lines - U215 and U87 - were used to evaluate the in vitro cytotoxicity of the drug, showing that the prepared nanocarriers enhance the anticancer activity of TMZ. The functionalization with the monoclonal antibody for transferrin receptor proved to be advantageous in enhancing the cellular internalization in glioblastoma cells.

[What do virtual reality tools bring to child and adolescent psychiatry?] / Qu'apportent les outils de réalité virtuelle en psychiatrie de l'enfant et l'adolescent ?

Virtual reality is a relatively new technology that enables individuals to immerse themselves in a virtual world. It offers several advantages including a more realistic, lifelike environment that may allow subjects to "forget" they are being assessed, allow a better participation and an increased generalization of learning. Moreover, the virtual reality system can provide multimodal stimuli, such as visual and auditory stimuli, and can also be used to evaluate the patient's multimodal integration and to aid rehabilitation of cognitive abilities. The use of virtual reality to treat various psychiatric disorders in adults (phobic anxiety disorders, post-traumatic stress disorder, eating disorders, addictions…) and its efficacy is supported by numerous studies. Similar research for children and adolescents is lagging behind. This may be particularly beneficial to children who often show great interest and considerable success on computer, console or videogame tasks. This article will expose the main studies that have used virtual reality with children and adolescents suffering from psychiatric disorders. The use of virtual reality to treat anxiety disorders in adults is gaining popularity and its efficacy is supported by various studies. Most of the studies attest to the significant efficacy of the virtual reality exposure therapy (or in virtuo exposure). In children, studies have covered arachnophobia social anxiety and school refusal phobia. Despite the limited number of studies, results are very encouraging for treatment in anxiety disorders. Several studies have reported the clinical use of virtual reality technology for children and adolescents with autistic spectrum disorders (ASD). Extensive research has proven the efficiency of technologies as support tools for therapy. Researches are found to be focused on communication and on learning and social imitation skills. Virtual reality is also well accepted by subjects with ASD. The virtual environment offers the opportunity to administer controlled tasks such as the typical neuropsychological tools, but in an environment much more like a standard classroom. The virtual reality classroom offers several advantages compared to classical tools such as more realistic and lifelike environment but also records various measures in standardized conditions. Most of the studies using a virtual classroom have found that children with Attention Deficit/Hyperactivity Disorder make significantly fewer correct hits and more commission errors compared with controls. The virtual classroom has proven to be a good clinical tool for evaluation of attention in ADHD. For eating disorders, cognitive behavioural therapy (CBT) program enhanced by a body image specific component using virtual reality techniques was shown to be more efficient than cognitive behavioural therapy alone. The body image-specific component using virtual reality techniques boots efficiency and accelerates the CBT change process for eating disorders. Virtual reality is a relatively new technology and its application in child and adolescent psychiatry is recent. However, this technique is still in its infancy and much work is needed including controlled trials before it can be introduced in routine clinical use. Virtual reality interventions should also investigate how newly acquired skills are transferred to the real world. At present virtual reality can be considered a useful tool in evaluation and treatment for child and adolescent disorders.

First-line treatment with sunitinib for type 1 and type 2 locally advanced or metastatic papillary renal cell carcinoma: a phase II study (SUPAP) by the French Genitourinary Group (GETUG)†.

BACKGROUND: Papillary renal cell carcinoma (PRCC), type 1 and type 2, represents 10%-15% of renal cell carcinomas (RCC). There is no standard first-line treatment of metastatic PRCC (mPRCC). Anti-angiogenics have shown activity in retrospective studies but no prospective studies in pure papillary histology have been reported, but one with foretinib. PATIENTS AND METHODS: A prospective phase II study evaluated sunitinib in first-line treatment of mPRCC. The primary end point was overall response rate (ORR). Secondary end points were progression-free survival (PFS) and overall survival (OS). RESULTS: Fifteen and 46 patients, respectively, with type 1 and type 2 mPRCC were enrolled. Using the MSKCC scoring system: 12 (20%), 33 (55%) and 9 (15%) patients were, respectively, in the favourable, intermediate or poor risk group and 7 undetermined. Median follow-up is 51.4 months. In type 1, 2 patients 13% [95% confidence interval (CI) 0.1-30.5] had a partial response (PR), 10 had stable disease (SD) with 5 (33%) ≥12 weeks. In type 2, 5 patients 11% (95% CI 1.9-20.3) had a PR, 25 had SD with 10(22%) ≥12 weeks. Median PFS was 6.6 months (95% CI 2.8-14.8) in type 1 and 5.5 months (95% CI 3.8-7.1) in type 2. Median OS was 17.8 (95% CI 5.7-26.1) and 12.4 (95% CI 8.2-14.3) months, respectively, in type 1 and 2. Safety was as expected with sunitinib for metastatic RCC. CONCLUSION: Sunitinib showed activity in treatment of type 1 and 2 mPRCC but lower than in clear-cell mRCC. Both PFS and OS are longer in type I PRCC. Sunitinib represents an acceptable option in first-line treatment of mPRCC.

A phase II study of lenalidomide in platinum-sensitive recurrent ovarian carcinoma.

BACKGROUND: Lenalidomide has dual antiangiogenic and immunomodulatory properties and confirmed antitumor activity in hematologic malignancies. A phase II study investigating the safety and efficacy of continuous lenalidomide in recurrent ovarian cancer patients was initiated. PATIENTS AND METHODS: Patients with histologically confirmed epithelial ovarian, fallopian tube or primary peritoneal carcinoma, with asymptomatic recurrence 6 months after prior therapy were treated with continuous oral lenalidomide (20 mg/day). The primary end point was to evaluate efficacy according to the rate of disease control at 4 months. Secondary objectives were progression-free survival (PFS) and safety. RESULTS: Most of the 45 patients enrolled and treated had serous histology (78%) and a single line of prior chemotherapy (73%). Median platinum-free interval (PFI) was 11.3 months (range 6.9-56.8). Clinical benefit at 4 months was 38% [95% confidence interval (CI) 23% to 53%]. A 59% disease control rate was reported in patients with a PFI >12 months versus 24% with PFI of 6-12 months (P = 0.023). Four patients had RECIST partial responses and 21 had stable disease. CA125 responses were reported in eight patients, including one complete response. Median PFS was 3.4 months (95% CI 2.4-4.4). Most frequent toxicity was hematologic, notably grade 3-4 neutropenia in 29% of patients, along with fatigue (69%), gastrointestinal toxicity (constipation 53%, abdominal pain 49%, diarrhea 38%, nausea/vomiting 36%) and thrombosis (11%). Eight patients withdrew due to related toxicity. CONCLUSIONS: Lenalidomide shows interesting efficacy in late recurrent ovarian cancer patients. Toxicity was mainly hematologic, gastrointestinal and venous thrombosis. Future studies will evaluate combination of lenalidomide with chemotherapy agents. CLINICALTRIALSGOV: NCT01111903.

Development of a geriatric vulnerability score in elderly patients with advanced ovarian cancer treated with first-line carboplatin: a GINECO prospective trial.

BACKGROUND: Two previous GINECO elderly specific studies in advanced ovarian cancer (AOC) patients highlighted the prognostic value of geriatric covariates for overall survival (OS). PATIENTS AND METHODS: This open-label prospective trial was designed to identify the impact of geriatric covariates on OS in AOC patients ≥70 years treated with first-line carboplatin. RESULTS: Geriatric covariates of the 111 patients included median age 79 years (≥80 years: 41%); performance status (PS) ≥2: 47%; ≥3 major comorbidities: 24%; ≥4 comedications: 68%; activities of daily living (ADL) score <6: 55%; instrumental activities of daily living (IADL) score <25: 69%; Hospital Anxiety and Depression Scale (HADS) >14: 37%. The median OS was 17.4 months. Overall, 74% of patients completed the six planned chemotherapy cycles. Grade 3-4 haematological toxic effects were frequent (50%) but manageable. Grade 3-4 non-haematological toxicities included fatigue (15%), anorexia (12%), infections (9%) and thrombosis (2%). A survival score = exp(0.327*GVS) was developed, where the geriatric vulnerability score (GVS) is the sum of the following (each assigned a value of one): albuminaemia <35 g/l; ADL score <6; IADL score <25; lymphopaenia <1 G/l; and HADS >14. With a cut-off ≥3, GVS discriminated two groups with significantly different OS, treatment completion, severe adverse events and unplanned hospital admissions rates. CONCLUSIONS: The GVS is a valuable tool for identifying vulnerable patients when treating an elderly AOC population.

Accelerated Caco-2 cell permeability model for drug discovery.

INTRODUCTION: By culturing Caco-2 cells according to a new and optimized protocol, it has been possible to accelerate the cell culture process in such a way that the cells can be used for experiments after only 6 days. The accelerated Caco-2 model has been compared to the traditional model (requiring 21-25 days of culture) in terms of tightness of the junctions, ability to rank chemical compounds for apparent permeability, active efflux and to discriminate P-gp substrates. METHODS AND RESULTS: In the new protocol, Caco-2 cells were cultured with the classical Caco-2 medium supplemented with puromycin. The initial cell seeding density was increased two times compared to the traditional procedure and the presence of a low concentration of puromycin in the culture medium reduced the Caco-2 permeability of mannitol. Bi-directional studies were performed with known P-gp substrates (rhodamine 123, digoxin and saquinavir) and with a total of 20 marketed drugs covering a wide range of physicochemical characteristics and therapeutic indications. Strong correlations were obtained between the apparent permeability in absorptive (Papp A→B) or secretory (Papp B→A) of the drugs in the accelerated model and in the traditional models and comparable efflux ratios were observed in the two studied models. DISCUSSION: The new protocol reduces costs for screening and leads to higher throughput compared to traditional Caco-2 cell models. This accelerated model provides short time-feedback to the drug design during the early stage of drug discovery.

Weekly combination of topotecan and gemcitabine in early recurrent ovarian cancer patients: a French multicenter phase II study.

OBJECTIVES: The aim of this phase II study was to assess the benefits of a weekly administration of topotecan and gemcitabine in patients with ovarian carcinoma having relapsed after platinum/taxane-based first-line chemotherapy. METHODS: Seventy-seven patients with progression of disease /=2 cycles administered). The only major severe toxicity was neutropenia grades 3 (17%) and 4 (6%). Approximately 60% of the patients received the complete schedule of treatment, dose interruptions/delays being mainly due to moderate thrombocytopenia or neutropenia. The objective response rate was 14%, the values for patients having relapsed within 6 (n=30) and 6-12 (n=36) months being 7% and 20%, respectively. Median durations of response were 4.9 and 6.4 months and clinical benefit rates including stabilizations reached 63% and 69% in patients having relapsed within 6 or 6-12 months, respectively. Corresponding median overall survival was 7.5 and 15.6 months. Symptoms and pain were reduced in 64% and 39% of the patients concerned, respectively. CONCLUSION: In early relapse ovarian cancer, weekly combination of gemcitabine and topotecan has a modest objective response rate. However, a high proportion of patients experienced stable disease and symptom control leading to acceptable quality of life.

First-line bevacizumab combined with reduced dose interferon-alpha2a is active in patients with metastatic renal cell carcinoma.

BACKGROUND: In patients with untreated metastatic renal cell carcinoma (mRCC), progression-free survival (PFS) was longer with bevacizumab + interferon (IFN)-alpha than IFN + placebo (AVOREN trial). In this hypothesis-generating study, subgroup analysis was carried out to determine the effect of IFN dose reduction. PATIENTS AND METHODS: A total of 649 patients received IFN 9 MIU s.c. three times weekly plus bevacizumab 10 mg/kg or placebo every 2 weeks until disease progression. The IFN dose was reduced to 6 or 3 MIU with the development of IFN-attributed toxicity. Differences between treatment arms in PFS, response rate and tolerability were analysed in the reduced-dose group. RESULTS: IFN dose was reduced in 131 patients in the bevacizumab + IFN arm and 97 patients in the IFN + placebo arm during the trial. PFS rates in the bevacizumab + reduced-dose IFN group were comparable with the total population (Kaplan-Meier estimates of event-free rate at 1 year: 0.524 versus 0.427). Bevacizumab + reduced-dose IFN was well tolerated, with substantial decreases in the rate of adverse events following dose reduction. CONCLUSION: This retrospective subgroup analysis suggests that the dose of IFN can be reduced to manage side-effects while maintaining efficacy in patients with mRCC receiving bevacizumab + IFN.

[Systemic infection due to implanted leads of a cardiac pacemaker. Apropos of a case and review of the literature]. / Infection systémique sur sondes endocavitaires de stimulateur cardiaque. A propos d'un cas et revue de la littérature.

Systemic infection related to transvenous pacemaker-leads are rare, but their diagnosis is difficult. We report the observation of a 78-year-old patient whose recurrent Staphylococcus aureus septicemias linked to endocarditis related to an endovascular lead only on a third observation, characterized by an infectious bone localization. Transoesophageal echocardiography appears as the reference diagnostic method. The treatment lies in the surgical ablation of the pacing system and a prolonged antibiotic therapy. The heavy mortality caused by these pathologies leads us to reconsider the interest of a prophylaxis, particularly for elderly patients.

Serum cholesterol and impulsivity in personality disorders.

Decreased serum cholesterol has been associated with impulsive aggressive behaviors. This study was designed to explore the relationship between serum cholesterol levels and measures of impulsive aggression in personality disordered patients. Forty-two personality disordered patients (14 borderline personality disorder, 28 other personality disorders) were included. Fasting serum cholesterol was measured by standard enzymatic assay. An ANOVA was performed with factors of gender and diagnosis, looking at two-way interactions between the factors and serum cholesterol. Patients with borderline personality disorder were found to have significantly lower serum cholesterol than non-borderline personality disorders. A significant interaction effect was also seen between gender and diagnosis with the male patients having lower cholesterol levels. This study suggests there may be a relationship between borderline personality disorder and low serum cholesterol.

d,l-fenfluramine response in impulsive personality disorder assessed with [18F]fluorodeoxyglucose positron emission tomography.

Reduced serotonergic activity has been associated with impulsive aggression in personality disordered patients in metabolite and pharmacologic challenge studies. This study used positron emission tomography to explore whether reduced serotonergic function occurs in critical brain regions such as orbital frontal and cingulate cortex that, may play a role in modulating aggression. Six impulsive-aggressive patients and five healthy volunteers were evaluated for changes in regional glucose metabolism after administration of the serotonergic releasing agent d,l-fenfluramine (60 mg, p.o.) or placebo. Volunteers demonstrated increases in orbital frontal and adjacent ventral medial frontal cortex, cingulate, and inferior parietal cortex, whereas impulsive-aggressive patients showed no significant increases in glucose metabolism after fenfluramine in any region. Compared with volunteers, patients showed significantly blunted metabolic responses in orbital frontal, adjacent ventral medial and cingulate cortex, but not in inferior parietal lobe. These results are consistent with reduced serotonergic modulation of orbital frontal, ventral medial frontal, and cingulate cortex in patients with impulsive-aggressive personality disorders.

Co-detection of Helicobacter pylori and of its resistance to clarithromycin by PCR.

Our aim was to develop a rapid molecular test based on polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) and making it possible to detect Helicobacter pylori directly from gastric biopsy samples, and to test its susceptibility to clarithromycin. A 629-bp fragment of the 23S rRNA gene of H. pylori was amplified by PCR and the mutations responsible for clarithromycin resistance were detected with Bsa1 and Bbs1 restriction endonucleases. Thirty-five gastric samples were tested in parallel by standard microbiologic methods (culture and clarithromycin susceptibility testing with E-test strips) and by PCR-RFLP. The 10 culture-negative samples were also PCR-negative. Sixteen out of the 25 culture-positive samples (64%) were PCR-positive. RFLP analysis could be done in 12 cases and the results were in agreement with those of the E-test: susceptibility in five cases, resistance in seven (six A2144G mutations and one A2143G mutation).

[Management of caustic burns of the esophagus in children]. / Prise en charge des brûlures caustiques de l'oesophage chez l'enfant.

The authors describe their therapeutic approach to caustic burns of the esophagus in pediatric patients. Initially, early endoscopic evaluation is carried out under general anesthesia using a stiff tube then a fiberoptic endoscope. During this procedure, severity of esophageal damage is determined: stage I: mild burn requiring no treatment; stages II and III: severe burn with a risk of subsequent esophageal stricture requiring insertion of a nasogastric stent. A repeat endoscopy is performed after approximately 25 days to evaluate healing. If healing has occurred, the nasogastric tube is removed and dynamic esophagography is performed 2 to 7 days later. Patients with strictures should be treated with repeated endoscopic dilatation at gradually increasing intervals. Surgery is indicated only in patients with complications or multiple strictures after failure of dilatation; trans-mediastinal colon esophagoplasty with removal of the burned esophagus is the method of choice.

[Chaotic aspect of heart rate and blood pressure in diabetic patients]. / Aspect chaotique de la fréquence cardiaque et de la pression artérielle chez le sujet diabétique.

We applied a simplified version of the method suggested by Sugihara-May (Nature 1990: 344: 734-41) to study the control of heart rate (HR) in subjects with diabetes mellitus. The method aims to predict the future of an observation, if a series of observations on the same phenomenon is available. The method quantifies the fact that the series is predictable more or less longtime in the future. A random series is only shortly predictable in the future. HR and blood pressure were measured from beat to beat (by the Finapres system) for about 0.5 hours in 11 subjects with diabetes mellitus and normal blood pressure (group D) and in 10 controls subjects (group N). The subjects were sitting in a temperature-controlled quiet room, isolated from all external stimuli. The 2 groups were matched for age, and had the same weight and height. No difference was observed in mean-value and standard deviation (SD) of BP and HR between the 2 groups. Groups N/D: SBP = 112 +/- 11/123 +/- 11 mmHg, NS; DBP = 64 +/- 9/67 +/- 12 mmHg, NS; HR = 70 +/- 10/69 +/- 7 b/min, NS. Standard deviation of PAS = 5.5 +/- 1.6/5.7 +/- 1.9 mmHg, NS and SD of DBP = 3.5 +/- 0.9/3.4 +/- 1.2 mmHg, NS. The SD of HR (3.0 +/- 0.5/2.3 +/- 1.0 b/min in groups N/D) was somewhat lower in diabetics than in control subjects but the difference was not significant.(ABSTRACT TRUNCATED AT 250 WORDS)

[Ingestion of caustics by children. Report of 23 deep lesions. Therapeutic attitude and long-term results]. / Ingestion de caustiques chez l'enfant. A propos de 23 brûlures graves. Attitude thérapeutique et résultats à long terme.

In children, 23 caustic injuries of oesophagus with deep lesions (second or third degree of burn) were treated in pediatric ENT department (Pr ANDRIEU--Rouen) during a 19 years long period. Endoscopy in emergency, nasogastric tube for stent and repeated dilatations were the bases of the treatment. 14 second degree burns and 7 third degree burns were complicated of 9 stenosis and one death. The mean duration of total treatment was 43 months. The mean number of dilatations was 38 months. 4 stenosis were definitely cured. 8 children had normal feeding. Mean following was 8 years with good long term results.