Long term activity of vemurafenib in cancers with BRAF mutations: the ACSE basket study for advanced cancers other than BRAFV600-mutated melanoma.

BACKGROUND: BRAF inhibitors are approved in BRAFV600-mutated metastatic melanoma, non-small-cell lung cancer (NSCLC), Erdheim-Chester disease (ECD), and thyroid cancer. We report here the efficacy, safety, and long-term results of single-agent vemurafenib given in the AcSé vemurafenib basket study to patients with various BRAF-mutated advanced tumours other than BRAFV600-mutated melanoma and NSCLC. PATIENTS AND METHODS: Patients with advanced tumours other than BRAFV600E melanoma and progressing after standard treatment were eligible for inclusion in nine cohorts (including a miscellaneous cohort) and received oral vemurafenib 960 mg two times daily. The primary endpoint was the objective response rate (ORR) estimated with a Bayesian design. The secondary outcomes were disease control rate, duration of response, progression-free survival (PFS), overall survival (OS), and vemurafenib safety. RESULTS: A total of 98 advanced patients with various solid or haematological cancers, 88 with BRAFV600 mutations and 10 with BRAFnonV600 mutations, were included. The median follow-up duration was 47.7 months. The Bayesian estimate of ORR was 89.7% in hairy cell leukaemias (HCLs), 33.3% in the glioblastomas cohort, 18.2% in cholangiocarcinomas, 80.0% in ECD, 50.0% in ovarian cancers, 50.0% in xanthoastrocytomas, 66.7% in gangliogliomas, and 60.0% in sarcomas. The median PFS of the whole series was 8.8 months. The 12-, 24-, and 36-month PFS rates were 42.2%, 23.8%, and 17.9%, respectively. Overall, 54 patients died with a median OS of 25.9 months, with a projected 4-year OS of 40%. Adverse events were similar to those previously reported with vemurafenib. CONCLUSION: Responses and prolonged PFS were observed in many tumours with BRAF mutations, including HCL, ECD, ovarian carcinoma, gliomas, ganglioglioma, and sarcomas. Although not all cancer types responded, vemurafenib is an agnostic oncogene therapy of cancers.

Adjuvant management of operated uterine sarcomas: A single institution experience.

PURPOSE: The purpose of this study was to describe the adjuvant management of high grade uterine sarcoma and highlight prognostic factors for overall survival and progression-free survival. MATERIAL AND METHODS: Between 01/2000 and 01/2015, 91 patients undergoing surgery were presented at the multidisciplinary team meeting of our institution. The type of surgery, the anatomopathological features, adjuvant treatments, dates and sites of recurrence were collected. The prognostic value of the various factors was evaluated with the multivariate Cox model. RESULTS: A total of 50 women with uterine sarcoma were identified and lesions included 43 leiomyosarcomas (86%) and seven high grade sarcomas (14%). Eighteen patients received adjuvant pelvic radiotherapy (36%) and six adjuvant systemic therapy (12%). The median follow-up time was 63 months. Thirty-nine patients (78%) had a recurrence: 22 had only metastatic recurrence (58%), two had isolated pelvic recurrence (5%) and 15 had pelvic and metastatic recurrence (38%). Adjuvant radiotherapy was associated with survival without pelvic recurrence in univariate analysis (P=0.005, hazard ratio [HR]=0.15); age greater than 55 years and adjuvant radiotherapy were associated with metastatic free survival in multivariate analysis (P=0.015, HR=2.37, and P=0.013, HR=0.41 respectively) CONCLUSION: According to the results of our series, there is a benefit of radiotherapy after surgery in terms of local control of uterine sarcoma. It is necessary to identify the subgroup of patients who will benefit from an adjuvant radiotherapy in order to provide them with more optimal care.

Increased docosahexaenoic acid and n-3 polyunsaturated fatty acids in milk from mothers of small for gestational age preterm infants.

The study aimed to test whether or not milk fatty acid composition in mothers of small for gestational age (SGA) infants is similar to that in mothers of adequate for gestational age (AGA) infants. Thirty three mothers of SGA preterm infants and 66 mothers of AGA preterm infants were included. Milk and plasma fatty acids were analyzed using capillary gas chromatography. Milk DHA (0.68 ±â€¯0.37 vs. 0.44 ±â€¯0.24; p < 0.01) was higher and n-6:n-3 PUFA ratio (12.0 ±â€¯4.64 vs. 16.0 ±â€¯6.32; p < 0.05) was lower in mothers of SGA infants. Plasma ARA and DHA were increased in mothers of SGA infants and decreased in their infants. Milk ARA or DHA was positively related to the correspondent fatty acid in plasma (r = 0.374, p = 0.010 for ARA and r = 0.690, p < 0.001 for DHA). Breast milk in mothers of preterm infants born SGA is enriched in DHA and n-3 PUFA. Breastfeeding SGA preterm infant with own mother's milk is recommended.

Postnatal RBC arachidonic and docosahexaenoic acids deficiencies are associated with higher risk of neonatal morbidities and mortality in preterm infants.

Arachidonic (AA) and docosahexaenoic (DHA) acids are essential for the health and development of the neonate. Red blood cell (RBC) fatty acids were analyzed in 583 very low birth weight (VLBW) infants and 274 term infants using capillary gas chromatography. VLBW infants exhibited significantly lower RBC AA (13.0 ± 0.89 vs. 13.5 ± 0.98) and DHA (3.77 ± 0.60 vs. 3.80 ± 0.62), but higher n6:n3 ratio (3.97 ± 0.46 vs. 3.63 ± 0.37) than term infants. In VLBW infants, DHA was lower in those born with small for gestational age (3.69 ± 0.57 vs. 3.86 ± 0.58) and those who suffered from neonatal sepsis (3.73 ± 0.60 vs. 3.86 ± 0.55). Both AA and DHA were significantly lower in infants who developed respiratory distress syndrome or intraventricular hemorrhage, and those who died during the hospital stay. VLBW infants had lower postnatal RBC AA and DHA levels than term infants did. These deficits are associated with higher risk of neonatal morbidities and mortality.

Multidisciplinary management of advanced ovarian cancer for an optimal therapeutic strategy.

The management of advanced ovarian cancer generally requires specialist multidisciplinary teamwork to achieve optimum outcomes. Preoperative computed tomography scans are the imaging modality of choice in determining the extent of disease and aiding in surgical planning. Histological classification is crucial to define various subtypes with their different behaviour and prognosis and to plan the best therapeutic strategy. Pathological prognostic factors, such as histological type, degree of differentiation, and FIGO stage must be described. To determine the ability to optimally cytoreduce advanced ovarian cancer, an experienced gynaecological oncologist needs to explore the entire upper abdomen and the pelvic and para-aortic lymph node regions to define the peritoneal cancer index (PCI). The final assessment is the completeness of cytoreduction (CC) score which is important in predicting prognosis and decision of post-surgical surgery. Ovarian cancer is the leading cause of death from gynaecologic cancers. Initial management is best provided by a specialist multidisciplinary team, including a radiologist, a pathologist, a gynaecologic oncologist, and a medical oncologist.

Selection of an early biomarker for vascular normalization using dynamic contrast-enhanced ultrasonography to predict outcomes of metastatic patients treated with bevacizumab.

BACKGROUND: Dynamic contrast-enhanced ultrasonography (DCE-US) has been used for evaluation of tumor response to antiangiogenic treatments. The objective of this study was to assess the link between DCE-US data obtained during the first week of treatment and subsequent tumor progression. PATIENTS AND METHODS: Patients treated with antiangiogenic therapies were included in a multicentric prospective study from 2007 to 2010. DCE-US examinations were available at baseline and at day 7. For each examination, a 3 min perfusion curve was recorded just after injection of a contrast agent. Each perfusion curve was modeled with seven parameters. We analyzed the correlation between criteria measured up to day 7 on freedom from progression (FFP). The impact was assessed globally, according to tumor localization and to type of treatment. RESULTS: The median follow-up was 20 months. The mean transit time (MTT) evaluated at day 7 was the only criterion significantly associated with FFP (P = 0.002). The cut-off point maximizing the difference between FFP curves was 12 s. Patients with at least a 12 s MTT had a better FFP. The results according to tumor type were significantly heterogeneous: the impact of MTT on FFP was more marked for breast cancer (P = 0.004) and for colon cancer (P = 0.025) than for other tumor types. Similarly, the differences in FFP according to MTT at day 7 were marked (P = 0.004) in patients receiving bevacizumab. CONCLUSION: The MTT evaluated with DCE-US at day 7 is significantly correlated to FFP of patients treated with bevacizumab. This criterion might be linked to vascular normalization. AFSSAPS NO: 2007-A00399-44.

A new laparoscopic method of bowel radio-protection before pelvic chemoradiation of locally advanced cervix cancers.

BACKGROUND: Chemoradiation therapy (CRT) has become the mainstay of locally advanced cervical carcinomas (LACC). However, the price to pay is a significant rate of both early and late colo-rectal toxicities, which may impact on survivors' quality of life. To reduce the incidence of such complications, we suggest a simple technique of pelvic radioprotection. MATERIALS AND METHODS: An omental flap is created which is placed to fill the Douglas pouch to both increase the space between rectum and uterine cervix and prevent small bowel to fall in and to be exposed to radiation. In addition, a long sigmoid loop is retracted and fixed in the left paracolic gutter to prevent its irradiation as well. RESULTS: From May 2011 to May 2012, 51 successive LACC patients were offered this procedure in addition of a laparoscopic staging. All but 2 with too small an omentum benefitted from omentoplasty, while sigmoidopexy was performed in all but one patient with a long and free sigmoid loop. No immediate adverse effect was observed. The volume of retro-uterine omental flap averaged 7.17 ± 3.79 cm(3). Sequential measurements of the utero-rectal space throughout CRT duration showed a real and durable increase in the distance between these organs, resulting in a drop in the dose of irradiation to recto-sigmoid. With 10 ± 4.5-month median follow-up, we did not observe any rectal or small bowel early or late adverse effects of CRT. CONCLUSIONS: Although this series is preliminary, this simple procedure, feasible by laparoscopy (or laparotomy), seems effective to prevent recto-sigmoid as well as small bowel from radio-induced complications due to pelvic CRT.

Organized breast screening: Answers to recurring controversies.

The reduction in mortality specifically from breast cancer, demonstrated in the major meta-analyses in the 1980s resulted in public health breast cancer screening programs being set up in many countries, including France. Recent publications have challenged the usefulness of screening, by insisting in particular on the negative effects of overdiagnosis and the lack of any significant impact on mortality. From analysis of the literature and particularly independent reviews published in 2012, we provide some answers for doctors faced with the legitimate concerns of women. These studies confirm that screening in the right age group reduces specific mortality by at least 20% at a cost of overdiagnosis estimated at between 1 and 15%.

[Anti-Hu antibody syndrome: diagnostic and therapeutic difficulties]. / Syndrome des anticorps anti-Hu: difficultés diagnostiques et thérapeutiques.

INTRODUCTION: Anti-Hu antibody syndrome is a paraneoplastic syndrome usually associated with small cell lung carcinoma which induces various symptoms, particularly neurological ones. CASE REPORT: We describe the case of a 49-year old woman with a small cell lung carcinoma who initially experiences a spontaneous regression but then developed neurological symptoms associated with severe autonomic dysfunction manifesting as chronic intestinal pseudo-obstruction and leading finally to hemodynamic failure. CONCLUSION: Anti-Hu antibody syndrome remains a rare entity. Its diagnosis must be considered in the face of neurologic symptoms associated with small cell lung cancer.

Quality indicators in ovarian cancer surgery: report from the French Society of Gynecologic Oncology (Societe Francaise d'Oncologie Gynecologique, SFOG).

BACKGROUND: Based on registries, the European experience has been that <50% of patients are treated according to protocols and/or benefit from the minimum required surgery for ovarian cancer. The French Cancer Plan 2009-2013 considers the definition of qualitative indicators in ovarian cancer surgery in France. This endeavour was undertaken by the French Society of Gynaecologic Oncology (SFOG) in partnership with the French National College of Obstetricians and Gynecologists and all concerned learned societies in a multidisciplinary mindset. METHODS: The quality indicators for the initial management of patients with ovarian cancer were based on the standards of practice determined from scientific evidence or expert consensus. RESULTS: The indicators were divided into structural indicators, including material (equipment), human (number and qualification of staff), and organizational resources, process indicators, and outcome indicators. CONCLUSIONS: The enforcement of a quality assurance programme in any country would undoubtedly promote improvement in the quality of care for ovarian cancer patients and would result in a dramatic positive impact on their survival. Such a policy is not only beneficial to the patient, but is also profitable for the healthcare system.

Unbalanced bone remodeling in Tunisian patients with inflammatory bowel diseases.

BACKGROUND: Bone loss is an ignored complication in inflammatory bowel diseases. Its underling mechanisms are not fully elucidated. OBJECTIVES: To investigate bone turnover in patients with inflammatory bowel diseases. METHODS: The study included 67 patients with inflammatory bowel diseases and 54 age- and sex-matched healthy subjects. Urinary degradation products of C-terminal telopeptide of type I collagen, serum osteocalcin, parathyroid hormone, 25 hydroxy vitamin D and interleukin-6 were assessed. Bone mineral density was measured by dual energy-X-ray absorptiometry and osteoporosis was defined as T score < -2.5 SD. RESULTS: Patients showed significantly higher levels of C-terminal telopeptide of type I collagen and interleukin-6 and lower levels of 25 hydroxy vitamin D. Serum osteocalcin and parathyroid hormone were in normal range. In multivariate analysis, urinary degradation products of C-terminal telopeptide of type I collagen were associated with disease activity (p=0.04) and osteocalcin was associated with parathyroid hormone (p=0.04). Urinary degradation products of Cterminal telopeptide of type I collagen and interleukin-6 were significantly increased in inflammatory bowel disease patients with osteoporosis. No association was found between osteoporosis and serum osteocalcin, parathyroid hormone and 25 hydroxy vitamin D. CONCLUSION: Bone resorption rate is increased and is associated with osteoporosis in inflammatory bowel disease patients. Inflammation, malnutrition, and hypovitaminosis D may contribute to the bone loss.

Pure flat epithelial atypia: is there a place for routine surgery?

PURPOSE: To determine whether it is appropriate to routinely undertake surgery if flat epithelial atypia (FEA) or pure flat epithelial atypia (pFEA) is found on large-core biopsy. PATIENTS AND METHODS: Between 2005 and 2010, 1678 large-core biopsy procedures were carried out, which led to 136 FEA sites being identified, 63 of which across 59 patients were pFEA (four patients had two sites of pFEA each). Forty-eight patients underwent further surgical excision, equating to 52 excised sites of pFEA. RESULTS: Of the 52 operated sites, there were 20 benign lesions (38%), 26 borderline lesions (56%), and three ductal carcinomas in situ (6%). The rate of histologic underestimation was put at 3.8%. Of the three cases that were underestimated, one was discarded because the definitive histology was not representative of the site from which microcalcifications had initially been taken. The other two cases that were underestimated were found in patients with an increased individual risk of breast cancer. CONCLUSION: In patients with no personal or first-degree family history of breast cancer, after complete or subtotal excision under radiology of the radiological lesion, and while excluding images fitting BI-RADS 5, annual monitoring may be offered as an alternative to surgical excision in view of the absence of underestimation found in our study.

Clinical utility and economic viability of a 3T MRI in an anti-cancer centre: The experience of the centre Oscar Lambret.

This paper will try and describe the installation of a 3T MRI in an anti-cancer centre. Functional sequences become indispensable in the assessment of targeted treatments. It is only possible to carry out these treatments on a routine basis in acceptable examination times with 3T. The technical constraints are overcome with third generation MRI and the improvement of the spatial resolution in examination times reduced by 30 to 50% increases patient comfort. Nevertheless, the financial constraints represent a major handicap. It is not possible to obtain an economic balance with rates based on the cost and depreciation of 1.5T imagers that are half the price.

Prehypertension among adults in Great Tunis region (Tunisia): A population-based study.

PURPOSE: The present study aimed to determine the prevalence of prehypertension (preHTN) and its cardiometabolic profile in Tunisians, and to estimate the risk for coronary heart disease (CHD) according to blood pressure status. PATIENTS AND METHOD: This cross-sectional study was conducted in 2004-2005, and used a two-stage cluster sampling method to select a representative sample of the Great Tunis population. A total of 2712 individuals (1228 men and 1484 women), aged 35 to 69 years were included. Definition and classification of hypertension (HTN) was performed according to guidelines from the Joint National Committee on prevention, detection, evaluation and treatment of high blood pressure (JNC-7) report. RESULTS: The prevalence of preHTN and HTN was 56.8% and 25.0% in males, and 43.1% and 36.1% in females, respectively. Subjects with preHTN and those with HTN showed higher prevalence of diabetes, dyslipidemia, obesity and abdominal obesity than the normotensive (NT) group. The metabolic syndrome (MetS) was found in 8.0%, 17.8% and 53.8% of NT, preHT and HTN subjects, respectively. The risk of developing CHD within 10 years, as predicted by the Framingham-Anderson model, was above 15% for 3.9%, 31.1% and 65.0% among NT, preHTN and HTN subjects, respectively. In multivariate analysis, preHTN was associated with age (OR [95% CI], 1.02 [1.01-1.03]; P<0.01), male gender (2.51 [1.89-3.23]; P<0.001), obesity (2.36 [1.71-3.26]; P<0.01), abdominal obesity (1.53 [1.14-2.06]; P<0.01) and smoking (0.70 [0.53-0.92]; P<0.01). CONCLUSION: PreHTN is very common in Tunisians. It is associated with a higher prevalence of cardiometabolic risk factors and confers a higher risk for subsequent CHD. These findings support the recommendations of lifestyle modification for preHTN patients.

[Management of pregnant women with advanced cervical cancer: About five cases observed in Lille from 2002 till 2009. Evaluation of practices referring to the new French recommendations of 2008]. / Cancer du col utérin invasif et grossesse : cinq cas observés à Lille de 2002 à 2009. Évaluation des pratiques en référence aux recommandations françaises.

PURPOSE: An update on the management of invasive cervical cancer (from stage IB) diagnosed during pregnancy with reference to the recent French guidelines. PATIENTS AND METHODS: We retrospectively analyzed patients for whom invasive cervical cancer was diagnosed during pregnancy and managed jointly by Jeanne-de-Flandres and Roubaix maternity and by Oscar-Lambret cancer center between 2002 and 2009. RESULTS: Five patients were included: four stage IB1, and one stage IB2. Five pregnancies resulted in the birth of six alive children. Three patients received neoadjuvant chemotherapy during pregnancy. One patient had a laparoscopic pelvic lymphadenectomy in first trimester. Two laparoscopic extraperitoneal paraortic lymphadenectomy have been made. The mean time of survey is 47.5 months (12-94 months). One patient died of her cancer. CONCLUSION: The diagnosis of cervical cancer during pregnancy involves the same therapeutic guidelines in the absence of pregnancy. The laparoscopic pelvic lymphadenectomy (up to 20 to 24 weeks of gestation) is crucial in the therapeutic treatment for tumors less than 4cm. Neoadjuvant chemotherapy is used during pregnancy for patients refusing medical termination of pregnancy.

Plasma fatty acids profile and estimated elongase and desaturases activities in Tunisian patients with the metabolic syndrome.

This study aimed to determine plasma fatty acids pattern and to estimate desaturases activities in Tunisian subjects with metabolic syndrome (MetS). A total of 1975 adults were randomly selected from the Great Tunis region (Tunisia). MetS was defined according to the International Diabetes Federation criteria. Saturated and monounsaturated fatty acids levels and delta 9 desaturase activity were increased, but polyunsaturated fatty acids (PUFA) levels and delta 5 desaturase activity were decreased in patients with MetS. Using multivariate analysis, MetS was found inversely associated with PUFA; compared to first quartile, multi-adjusted odd ratios (95% confidence interval) of MetS were 0.80 (0.54-1.17), 0.47 (0.27-0.81) and 0.32 (0.15-0.68) for second, third and fourth quartiles of PUFA, respectively. Altered fatty acids pattern in MetS is likely related to both dietary and metabolic changes.

[Comparison between electronic zoom and geometric magnification of clusters of microcalcifications on digital mammography]. / Comparaison entre le zoom numérique et l'agrandissement géométrique dans l'étude des foyers de microcalcifications en mammographie numérique.

PURPOSE: With the advent of digital mammography with electronic zoom capabilities, we have sought to determine the need for geometric magnification for the evaluation of clusters of microcalcifications. PATIENTS AND METHODS: Eighty-eight clusters of microcalcifications were reviewed by two experienced radiologists using electronic zoom (ZOOM) and geometric magnification (MAG). The following criteria were evaluated: image quality, shape and number of microcalcifications, size and shape of the clusters. The clusters were classified based on malignancy risk using the BI-RADS criteria. Histological results from macrobiopsy or surgery as well as 2 year follow-up were used as reference for statistical analysis. RESULTS: Sensitivity (100% for MAG and 90% for ZOOM), specificity (52% versus 39%), positive predictive value (51% versus 44%) and negative predictive value (100% versus 88%) were superior for geometric magnification compared to electronic zoom irrespective of the reviewer but without reaching statistical significance. However, image quality was significantly superior with geometric magnification (p<<0.05). In addition, reviewers were more confident in their interpretation of geometric magnification images. CONCLUSION: Geometric magnification remains necessary in routine clinical practice for the characterization of microcalcifications and BI-RADS classification.

The metabolic syndrome: prevalence, main characteristics and association with socio-economic status in adults living in Great Tunis.

AIMS: This study aimed to determine the prevalence of the metabolic syndrome (MetS) and its association with socio-economic status in the population of Great Tunis. METHODS: The study included 2712 subjects (1228 men and 1484 women), aged 35-70 years and living in the Great Tunis region, all of whom were recruited between March 2004 and June 2005. The sample was weighted by using the inverse of the response rate according to governorate, district and gender. The MetS was defined according to the National Cholesterol Education Program-Adult Treatment Panel III. RESULTS: In the studied population, the overall prevalence of the MetS was 31.2%, and it was significantly more frequently seen in women than in men (37.3% vs 23.9%, respectively; P<0.001), as were abdominal obesity (69% vs 21.6%, respectively; P<0.001), high blood pressure (50.3% vs 43.1%, respectively; P<0.001) and low HDL cholesterol (40.6% vs 33.6%, respectively; P<0.001), the most common characteristics of the MetS. Also, the prevalence of the MetS increased with age in both genders, but more so in women. In those aged greater than 55 years, the prevalence of MetS was 56.7% in women and 30.7% in men. An inverse relationship was observed between level of education and prevalence of the MetS in women, with the highest prevalence being in illiterate women and the lowest in those who were university graduates. CONCLUSION: The prevalence of the MetS is markedly high within the population of Great Tunis and especially in women. As these findings predict future increases in cardiovascular disease in these populations, substantial efforts need to be made to fight against obesity and sedentary lifestyles to ameliorate the expected poor health outcomes.

[Upper abdomen cytoreduction in advanced ovarian carcinoma: techniques and results]. / Chirurgie sus-mésocolique des cancers de l'ovaire: techniques et résultats.

Upper abdomen cytoreduction is an important and challenging surgery that should be considered only if a macroscopically complete cytoreduction is expected. Techniques of the main procedures are addressed herein, as well as their respective morbidity and indications. Given its complexity, this surgery should be reserved to specialized teams, working in specialized centers.