Prognosis of malignant pheochromocytoma and paraganglioma (MAPP-Prono study): an ENS@T retrospective study

Background Malignant pheochromocytoma and paraganglioma (MPP) are characterized by prognostic heterogeneity. Our objective was to look for prognostic parameters of overall survival in MPP patients. Patients and Methods Retrospective multicentric study of MPP characterized by a neck-thoraco-abdomino-pelvic CT or MRI at the time of malignancy diagnosis in European centers between 1998 and 2010. Results We included 169 patients from 18 European centers. Main characteristics of MPP patients were: primary pheochromocytoma in 53% of patients, tumor or hormone-related symptoms in 57% or 58% of cases, positive plasma or urine hormones in 81% of patients, identification of a mutation in SDHB in 42 % of cases. Metastatic sites included the bone (64%), lymph node (40%), lung (29%) and liver (26%); mean time between initial and malignancy diagnosis was 43 months (0-614). Median follow-up was 68 months and median survival 6.7 years. Using univariate analysis, better survival was associated with head and neck paraganglioma, age <40 years, metanephrines <5-fold the upper limits of the normal range and low proliferative index. In multivariate analysis, hypersecretion (Hazard Ratio 3.02[1.65-5.55]; p:0.0004) was identified as independent significant prognostic factors of worst overall survival. Conclusions Our results do not confirm SDHB mutations as a major prognostic parameter in MPP and suggest additional key molecular events involved in MPP tumor progression. Aside from SDHB mutation, the biology of aggressive MPP remains to be understood

Time Until Partial Response in Metastatic Adrenocortical Carcinoma Long-Term Survivors

A partial response (PR) has been proposed as a surrogate for overall survival in advanced adrenocortical carcinoma (ACC). The primary endpoint of the study was to characterize the time until a PR in patients with metastatic ACC treated with a standard therapy is achieved. Long-term survivors were selected to allow evaluation of delayed tumor response to mitotane. Records from patients with metastatic ACC that survived for &gt; 24 months were retrieved. Tumor response was analyzed according to the Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. Time until a tumor response, after treatment initiation or therapeutic plasma mitotane level, was analyzed. Sixty-eight patients were analyzed. The first-line systemic therapy was mitotane as a monotherapy (M) (n = 57) or cytotoxic polychemotherapy plus/minus mitotane (PC ± M) (n = 11). The second-line therapy was M (n = 2) or PC ± M (n = 41). Thirty-two PRs occurred in 30/68 patients (44.1%): this was obtained for 13 (40.6%) during M and during PC ± M for 19/32 responders (59.4%). PRs were observed within 6 months of starting M or PC ± M in 76.9 and 94.7% of responses, respectively, within 6 months of therapeutic plasma mitotane being first observed in 88.9% of responses with M and in 53.3% of responses with PC ± M. All PRs (but one) occurred within 1 year after initiating treatment. To conclude, Most patients with metastatic ACC and long survival times had PRs within the first 6 months of standard systemic therapy, and almost all within the first year. The absence of response after that period could be considered as a treatment failure. Maintenance of mitotane therapy in non-responders after 1 year should be questioned in future randomized trials

Caries prevalence and tooth loss in Hungarian adult population: results of a national survey

<p>Abstract</p> <p>Background</p> <p>Oral health is basicly important for the well-being of people. Thus, it is strongly suggested to organize epidemiological surveys in order to gain representative data on oral condition of the given population. The purpose of the cross-sectional study was to determine the results on tooth loss and caries prevalence of Hungarian adults in different age groups.</p> <p>Methods</p> <p>Altogether 4606 persons (2923 women, 1683 men) participated in the study who were classified into different age groups: 19 [less than or equal to], 20–24, 35–44, 45–64, 65–74, [greater than or equal to]75 year olds. Probands were selected randomly from the population attending the compulsory lung screening examinations. The participants were examined by calibrated dentists, according to the WHO (1997) criteria. In order to produce representative data, the chosen localities for these examinations covered the capital, the largest towns, the villages, and case weights were used for the statistical evaluation.</p> <p>Results</p> <p>The mean values of DMF-T were found between 11.79±5.68 and 21.90±7.61 These values were significantly higher in women compared to men (p < 0.05). In all age groups the values of M were the highest. Except for the women in the groups of 35–44 and 45–64 year olds, these values showed an increasing tendency both in women and men by age (from 5.50±6.49, and 4.70±4.08 to 21.52±9.07 and 18.41±8.89 respectively). The values of D components reached the highest values in 45–64 year olds (4.54±2.12 and 4.22±2.81, by gender, respectively), then in the older age groups there was a high reduction in these values (in 65–74 year olds: 2.72±1.88 and 1.36±2.48; in 75 or more than 75 year olds: 1.05±1.41 and 1.03±1.76 by gender, respectively). The ratio of D and F values was the highest in the age group of 65–74 year olds (2.12), the lowest ratio could be calculated in 20–34 year olds (0.65).</p> <p>Data showed some decrease in caries experience in 35–44 years of age between 2000 and 2004. The prevalence of persons with 21 or more teeth had been increased from 65.6% to 73.1%. This positive tendency has not been occured in prevalence of edentulousness in this age group: the prevalence of edentulous persons changed from 1.4 to 1.9%. In 65–74 year olds the level of edentulousness became lower, from 25.9 to 14.8% and the prevalence of persons with 21 or more teeth is higher (22.6%) than it was in 2000 (13.0%).</p> <p>Conclusion</p> <p>Present data from Hungary show some slight decrease in caries experience between 35–44 years of age, although this positive tendency has not been occured in prevalence of edentulousness in this age group. A positive tendency could be experienced in the group of 65–74 year olds in edentulousness and in number of teeth, but further efforts are needed to reach a better situation.</p

Frequency and Risk Indicators of Tooth Decay among Pregnant Women in France: A Cross-Sectional Analysis

INTRODUCTION: Little is known on the prevalence of tooth decay among pregnant women. Better knowledge of tooth decay risk indicators during pregnancy could help to develop follow-up protocols for women at risk, along with better prevention strategies. The aim of this study was to assess the frequency of tooth decay and the number of decayed teeth per woman in a large sample of pregnant women in France, and to study associated risk indicators. METHODS: A secondary cross-sectional analysis of data from a French multicentre case-control study was performed. The sample was composed of 1094 at-term women of six maternity units. A dental examination was carried out within 2 to 4 days post-partum. Socio-demographic and behavioural characteristics were obtained through a standardised interview with the women. Medical characteristics were obtained from the women's medical records. Risk indicators associated with tooth decay were identified using a negative binomial hurdle model. RESULTS: 51.6% of the women had tooth decay. The mean number of decayed teeth among women having at least one was 3.1 (s.d. = 2.8). Having tooth decay was statistically associated with lower age (aOR = 1.58, 95%CI [1.03,2.45]), lower educational level (aOR = 1.53, 95%CI [1.06,2.23]) and dental plaque (aOR = 1.75, 95%CI [1.27,2.41]). The number of decayed teeth was associated with the same risk indicators and with non-French nationality and inadequate prenatal care. DISCUSSION: The frequency of tooth decay and the number of decayed teeth among pregnant women were high. Oral health promotion programmes must continue to inform women and care providers about the importance of dental care before, during and after pregnancy. Future research should also assess the effectiveness of public policies related to oral health in target populations of pregnant women facing challenging social or economic situations

French Endocrine Society Guidance on endocrine side-effects of immunotherapy

The management of cancer patients has changed due to the considerably more frequent use of immune checkpoint inhibitors (ICPI). However, the use of ICPI has a risk of side-effects, particularly endocrine toxicity. Since the indications for ICPI are constantly expanding due to their efficacy, it is important that endocrinologists and oncologists know how to look for this type of toxicity and how to treat it when it arises. In view of this, the French Endocrine Society initiated the formulation of a consensus document on ICPI-related endocrine toxicity. In this paper, we will introduce data on the general pathophysiology of endocrine toxicity, we will then outline expert opinion focusing primarily on methods for screening, management and monitoring for endocrine side-effects in patients treated by ICPI. We will then look in turn at endocrinopathies that are induced by ICPI including dysthyroidism, hypophysitis, primary adrenal insufficiency and fulminant diabetes. In each chapter, expert opinion will be given on the diagnosis, management and monitoring for each complication. These expert opinions will also discuss the methodology for categorizing these side-effects in oncology using \u27Common terminology criteria for adverse events\u27 (CTCAE) and the difficulties in applying this to endocrine side-effects in the case of these anti-cancer therapies. This is shown in particular by certain recommendations that are used for other side-effects (high-dose corticosteroids, contra-indicated in ICPI for example), and that cannot be considered as appropriate in the management of endocrine toxicity, as it usually does not require ICPI withdrawal or high dose glucocorticoid intake

Molecular Targets of Mitotane in Adrenocortical Carinoma

Le mitotane, ou o,p’DDD, médicament historique dérivé d’un insecticide, reste le traitement de référence du corticosurrénalome (CS), tumeur rare et de mauvais pronostic. Le mitotane exerce un effet anti-sécrétoire associé à un effet anti-tumoral dont les mécanismes d’action sous-jacents sont mal compris et ses cibles moléculaires restent inconnues. Néanmoins, de nombreux arguments semblent désigner la mitochondrie comme organite cible du mitotane. Dans ce travail de thèse, nous nous sommes intéressés à l’impact mitochondrial du mitotane par des approches complémentaires sur plusieurs modèles expérimentaux. Nous avons ainsi pu mettre en évidence une inhibition sélective des complexes I et IV de la chaîne respiratoire, une fission du réseau mitochondrial ou encore une activation de la biogenèse mitochondriale. Ces données nous ont permis d’identifier les mitochondrial-associated membranes (MAM) et le transducéosome comme organites cibles du mitotane. Parallèlement, en réévaluant le rôle potentiel du métabolite acide o,p’DDA, nous avons pu exclure son implication dans l’action cytotoxique du mitotane. Nous avons également démontré que le mitotane libre, non lié aux lipoprotéines, était le plus actif in vitro et pouvait ainsi être celui responsable de l’action pharmacologique in vivo. L’ensemble de ces résultats apportent une meilleure compréhension des mécanismes d’action du mitotane et devrait permettre d’identifier des facteurs prédictifs de réponse à ce traitement pour une meilleure prise en charge des patients atteints de CS.Mitotane is o,p’DDD, an historic drug derived from an insecticide and represents the treatment of choice for adrenocortical carcinoma (ACC), a rare adrenal tumor associated with bad prognosis. Mitotane is responsible for an inhibition of steroidogenesis associated with an antitumoral effect but its exact molecular mechanisms of action remain unclear and its molecular target remains unknown. However, mitochondria could be an organite targeted by mitotane. In this study we evaluated mitochondrial impact of mitotane using complementary approaches on several experimental models. We showed a mitotane-induced selective inhibition of respiratory chain complexes I and IV, an increased fission of the mitochondrial network and an activation of the mitochondrial biogenesis. These data helped us to identify mitochondrial-associated membranes (MAM) and so-called transduceosome as targeted organites of mitotane. We also reevaluated the potential role of the acid metabolite o,p’DDA and excluded its implication in the cytotoxic action of mitotane. Finally, we demonstrated that free mitotane which is not linked to lipoproteins is more efficient in vitro and could be therefore responsible for pharmacological action in vivo. Altogether, these results allow to better understand mitotane mechanisms of action and should help to identify predictive markers of response to mitotane for a better care of patients with ACC