High negative prediction for the Basel sarcoma score: Sonographic assessment of features suspicious of uterine sarcoma.

INTRODUCTION: In the management of uterine myomas, laparoscopic surgery with morcellation enables a minimal invasive procedure. Cases of unsuspected uterine sarcoma dissemination have been reported and led to regulative restrictions. To help to distinguish preoperatively myomas from sarcomas, we assessed the value of six sonographic criteria (Basel Sarcoma Score, BSS) in a prospective outpatient cohort of consecutive patients with uterine masses. MATERIAL AND METHODS: We prospectively evaluated all patients presenting with myoma-like masses planned for surgery with standardized ultrasound examination. BSS including the following criteria was investigated: rapid growth in past three months, high blood flow, atypical growth, irregular lining, central necrosis and oval solitary lesion. For each criterion, a score 0/1 was given. BSS (0-6) equals the sum of all given scores. Histological diagnosis was used as reference. RESULTS: Among 545 patients, 522 had the final diagnosis of myoma, 16 had peritoneal masses with sarcomatous components (PMSC), and seven had other malignancies. Median BSS for PMSC was 2.5 (range: 0-4) vs 0 for myomas (range: 0-3). The most common sonographic criteria leading to a false positive score in myomas were rapid growth in past three months and high blood flow. For the detection of sarcomatous masses with BSS threshold of >1, sensitivity was 93.8%, specificity 97.9%, and positive predictive value (PPV) and negative predictive value (NPV) were 57.7% and 99.8%, respectively (AUC 0.95). CONCLUSION: BSS can help distinguishing between myomas and sarcomatous masses, with high NPV. Caution is required when >1 criterion is present. As a simple tool, it could easily be integrated into routine myoma sonographic examination and help develop standardized assessment of uterine masses for better preoperative triage.

Evolution of impulsivity levels in relation to early cannabis use in violent patients in the early phase of psychosis.

BACKGROUND: Prevention of violent behaviors (VB) in the early phase of psychosis (EPP) is a real challenge. Impulsivity was shown to be strongly related to VB, and different evolutions of impulsivity were noticed along treatments. One possible variable involved in the relationship between VB and the evolution of impulsivity is cannabis use (CU). The high prevalence of CU in EPP and its relationship with VB led us to investigate: 1/the impact of CU and 2/the impact of early CU on the evolution of impulsivity levels during a 3-year program, in violent and non-violent EPP patients. METHODS: 178 non-violent and 62 violent patients (VPs) were followed-up over a 3 year period. Age of onset of CU was assessed at program entry and impulsivity was assessed seven times during the program. The evolution of impulsivity level during the program, as a function of the violent and non-violent groups of patients and CU precocity were analyzed with linear mixed-effects models. RESULTS: Over the treatment period, impulsivity level did not evolve as a function of the interaction between group and CU (coef. = 0.02, p = 0.425). However, when including precocity of CU, impulsivity was shown to increase significantly only in VPs who start consuming before 15 years of age (coef. = 0.06, p = 0.008). CONCLUSION: The precocity of CU in VPs seems to be a key variable of the negative evolution of impulsivity during follow-up and should be closely monitored in EPP patients entering care since they have a higher risk of showing VB.

Overlapping gene dependencies for PARP inhibitors and carboplatin response identified by functional CRISPR-Cas9 screening in ovarian cancer.

PARP inhibitors (PARPi) have revolutionized the therapeutic landscape of epithelial ovarian cancer (EOC) treatment with outstanding benefits in regard to progression-free survival, especially in patients either carrying BRCA1/2 mutations or harboring defects in the homologous recombination repair system. Yet, it remains uncertain which PARPi to apply and how to predict responders when platinum sensitivity is unknown. To shed light on the predictive power of genes previously suggested to be associated with PARPi response, we systematically reviewed the literature and identified 79 publications investigating a total of 93 genes. The top candidate genes were further tested using a comprehensive CRISPR-Cas9 mutagenesis screening in combination with olaparib treatment. Therefore, we generated six constitutive Cas9+ EOC cell lines and profiled 33 genes in a CRISPR-Cas9 cell competition assay using non-essential (AAVS1) and essential (RPA3 and PCNA) genes for cell fitness as negative and positive controls, respectively. We identified only ATM, MUS81, NBN, BRCA2, and RAD51B as predictive markers for olaparib response. As the major survival benefit of PARPi treatment was reported in platinum-sensitive tumors, we next assessed nine top candidate genes in combination with three PARPi and carboplatin. Interestingly, we observed similar dropout rates in a gene and compound independent manner, supporting the strong correlation of cancer cell response to compounds that rely on DNA repair for their effectiveness. In addition, we report on CDK12 as a common vulnerability for EOC cell survival and proliferation without altering the olaparib response, highlighting its potential as a therapeutic target in EOC.

Exposure to escalating olaparib does not induce acquired resistance to PARPi and to other chemotherapeutic compounds in ovarian cancer cell lines.

Poly (ADP­ribose) polymerase (PARP)­inhibitors (PARPi) such as olaparib and niraparib are currently used as a treatment option for BRCA­deficient tumors and also show efficacy in platinum­sensitive tumors. However, resistance to PARPi occurs in numerous patients and in particular acquired PARPi resistance presents a major obstacle in the treatment of these tumors. In the present study, it was investigated whether stepwise exposure of ovarian cancer cells to escalating concentrations of olaparib produced subcells with acquired resistance to PARPi and/or acquired cross­resistance to platinum compounds, paclitaxel, and doxorubicin. To this aim, the sensitivity of fourteen ovarian cancer cell lines, including nine with TP53­mutations and five carrying BRCA­mutations, to olaparib and niraparib was determined and a subset of seven cell lines was selected to investigate the potential of olaparib to produce resistance. It was identified that escalating olaparib did neither produce subcells with acquired PARPi­resistance nor did it produce acquired cross­resistance to platinum compounds, doxorubicin, and paclitaxel. This finding was independent of the cells' TP53 and BRCA mutation status. CRISPR­Cas9 mediated deletion of PARP1 did not affect sensitivity to PARPi, platinum compounds, doxorubicin, and paclitaxel. In addition, olaparib sensitivity correlated with niraparib sensitivity, but BRCA­mutated cells were not more sensitive to PARPi. Moreover, PARPi sensitivity associated with cross­sensitivity not only to platinum compounds but also to anthracylines, paclitaxel, and inhibitors of histone deacetylases. These in vitro data indicated that olaparib exposure is unlikely to produce an acquired resistance phenotype and that PARPi­sensitive ovarian cancer cells are also cross­sensitive to non­platinum and even to compounds not directly interacting with the DNA.

Vibrational Spectroscopy in Urine Samples as a Medical Tool: Review and Overview on the Current State-of-the-Art.

Although known since the first half of the twentieth century, the evolution of spectroscopic techniques has undergone a strong acceleration after the 2000s, driven by the successful development of new computer technologies suitable for analyzing the large amount of data obtained. Today's applications are no longer limited to analytical chemistry, but are becoming useful instruments in the medical field. Their versatility, rapidity, the volume of information obtained, especially when applied to biological fluids that are easy to collect, such as urine, could provide a novel diagnostic tool with great potential in the early detection of different diseases. This review aims to summarize the existing literature regarding spectroscopy analyses of urine samples, providing insight into potential future applications.

[L'état mental à risque : au-delà de la prévention de la psychose]. / The Clinical High-Risk State: Beyond the Prevention of Psychosis.

Objectives This article aims to contextualize and review interventions for patients with a clinical high-risk (CHR) state for psychosis. Method This review explores the literature on the CHR state and focuses more precisely on the development of its defining criteria, the evolution of CHR patients, the main interventions studied so far, and the clinical services implemented to date. Results The CHR criteria were developed from observations on the prodrome of psychotic disorders to prevent or delay the onset of psychosis. These criteria help defining three distinct groups of patients who seek help because of significant distress and functional impairments. The diagnostic evaluation remains a critical step that represents a challenge for clinicians. A significant proportion of CHR patients will not develop a psychotic disorder. And the course can be unfavorable even if there is no conversion to a psychotic disorder. In order to improve the clinical conditions of CHR patients, several interventions have been developed and studied. They fall into two main categories: psychosocial approaches and pharmacotherapy. Clinical initiatives to assess and provide support to these patients have emerged around the world, including in Switzerland, in France, and in Canada. The implementation and the integration of these services within existing health care system are influenced by several factors, including the organization of health care structures. Knowing that only a small proportion of CHR patients will progress to a psychotic disorder, it is relevant to offer these interventions in non-stigmatizing and youth-friendly places. These services would possibly be distinct from first-episode psychosis programs. Conclusion Interventions for CHR patients go well beyond the prevention of psychosis. They meet legitimate clinical needs. We must think about how to deploy them adequately in the most appropriate places.

[Rapid tranquilisation in adults†: algorithm proposed for psychopharmacological treatment]. / Agitation aiguë chez l'adulte†: proposition d'un algorithme de traitement psychopharmacologique.

Acute treatment of agitation in psychiatry is one of the urgent situations for which management recommendations are needed. Various existing international recommendations have been evaluated and adapted to our clinical practice and to the drugs available in Switzerland in order to propose a uniform management strategy in our hospital. This strategy includes a treatment choice algorithm with different options depending on the clinical situation and the possible route of administration. Dose recommendations for the oral and intramuscular routes, certain pharmacokinetic parameters, as well as risks of interactions and important warnings are also included in this clinical recommendation.

Le traitement aigu de l'agitation en psychiatrie fait partie des situations urgentes pour lesquelles des recommandations de prise en charge sont nécessaires. Diverses recommandations internationales existantes ont été évaluées et adaptées à notre pratique clinique ainsi qu'aux médicaments disponibles en Suisse afin de proposer une stratégie de prise en charge uniformisée au sein de notre hôpital. Cette stratégie inclut un algorithme de choix de traitement avec différentes options selon la situation clinique et la voie d'administration possible. Des recommandations de doses pour les voies orale et intramusculaire, certains paramètres pharmacocinétiques, ainsi que les risques d'interactions et des mises en garde importantes figurent également dans cette recommandation clinique.

Moderating role of cannabis use between insight and depression in early psychosis.

BACKGROUND: A high level of insight in first episode psychosis (FEP) is positively correlated to important prognostic factors such as medication adherence and functional outcome but is associated with increased depression level and suicidal behavior. AIMS: This is the first study questioning the potential moderating role of cannabis use in the relationship between insight and depression one year after a FEP. METHOD: In this prospective observational study, we enrolled 214 FEP patients who had provided informed consent and been referred to a specialized early psychosis program and followed for 36 months. A series of multivariate regression models were used. Baseline insight, medication adherence and cannabis use (level of use on a continuum) were entered as independent variables, while the PANSS (positive and negative), the MADRS and the SOFAS scores after one year were alternately selected as the dependent variable. RESULTS: We found a three-way interaction term between cannabis use, insight and medication adherence on depression level one year after the entry into the program. A high level of insight was significantly associated with higher MADRS scores in patients with high cannabis use, while depression decreased in high-insight patients with low cannabis use. CONCLUSIONS: Cannabis use continuation during the year following a first episode psychosis may play a significant role in the development or the maintenance of post-psychotic depression in patients who present with high level of insight and adherence to medication, stressing the need for specific therapeutic strategies in this subgroup of patients.

Unfolded protein response, a link between endometrioid ovarian carcinoma and endometriosis: A pilot study.

The aim of the present study was to analyze the expression profile of unfolded protein response (UPR) genes in endometrioid ovarian carcinoma and to evaluate its possible involvement in the neoplastic progression of endometriosis. An experimental retrospective pilot study was conducted on women with a diagnosis of endometrioid ovarian carcinoma at FIGO stage IA, ovarian endometriotic cysts or healthy subjects without a previous diagnosis of endometriosis. The expression profiles of UPR genes (ATF6, GRP78, CHOP and XBP1) were compared among ovaries with endometrioid ovarian cancer, endometriotic ovarian cysts, healthy contralateral ovaries and eutopic and healthy endometrial tissues. A significantly higher expression of ATF6 and GRP78 was detected in the affected ovaries in comparison with the healthy contralateral ovaries, while CHOP and XBP1 exhibited a significantly lower expression. XBP1 was overexpressed in endometrial tissues and its expression gradually decreased in endometriosis cysts and endometrioid ovarian carcinoma. These results support the hypothesis that alterations in the UPR genes CHOP and XBP1 are involved in the neoplastic progression of endometrioid ovarian cancer and are acquired following ovarian localization of ectopic endometrial cells.

Early changes of blood lipid levels during psychotropic drug treatment as predictors of long-term lipid changes and of new onset dyslipidemia.

BACKGROUND: Cardiovascular diseases and dyslipidemia represent a major health issue in psychiatry. Many psychotropic drugs can induce a rapid and substantial increase of blood lipid levels. OBJECTIVE: This study aimed to determine the potential predictive power of an early change of blood lipid levels during psychotropic treatment on long-term change and on dyslipidemia development. METHODS: Data were obtained from a prospective study including 181 psychiatric patients with metabolic parameters monitored during the first year of treatment and with adherence ascertained. Blood lipid levels (ie, total cholesterol [TC], low-density lipoprotein cholesterol [LDL-C], high-density lipoprotein cholesterol [HDL-C], non-high-density lipoprotein cholesterol [non-HDL-C], and fasting triglycerides [TGs]) were measured at baseline and after 1, 3, and/or 12 months of treatment. RESULTS: Receiver-operating characteristic analyses indicated that early (ie, after 1 month of psychotropic treatment) increases (≥5%) for TC, LDL-C, TG, and non-HDL-C and decrease (≥5%) for HDL-C were the best predictors for clinically relevant modifications of blood lipid levels after 3 months of treatment (≥30% TC, ≥40% LDL-C, ≥45% TG, ≥55% non-HDL-C increase, and ≥20% HDL-C decrease; sensitivity 70%-100%, specificity 53%-72%). Predictive powers of these models were confirmed by fitting longitudinal multivariate models in the same cohort (P ≤ .03) as well as in a replication cohort (n = 79; P ≤ .003). Survival models showed significantly higher incidences of new onset dyslipidemia (TC, LDL-C, and non-HDL-C hypercholesterolemia, HDL-C hypocholesterolemia, and hypertriglyceridemia) for patients with early changes of blood lipid levels compared to others (P ≤ .01). CONCLUSION: Early modifications of blood lipid levels following prescription of psychotropic drugs inducing dyslipidemia should therefore raise questions on clinical strategies to control long-term dyslipidemia.

Hypovitaminosis D and "small burden" uterine fibroids: Opportunity for a vitamin D supplementation.

The aim of this study was to evaluate the effect of vitamin D supplementation in women with hypovitaminosis D and "small burden" uterine fibroids.This study focused on 208 women diagnosed with uterine fibroids and concomitant hypovitaminosis D, from January to December 2014. One hundred eight women of the initial study population were diagnosed with "small burden" uterine fibroids. Among them, those who underwent a proper vitamin D supplementation constituted the "study group" (n = 53), while women who spontaneously refused the therapy or did not perform it properly, constituted the "control group" (n = 55). The characteristics of uterine fibroids, the fibroid-related symptoms, and the vitamin D serum levels were evaluated 12 months after the initial diagnosis.In women with uterine fibroids, a negative correlation emerged between the baseline 25-hydroxy-cholecalciferol (25-OH-D3) concentration and both the volume of the largest fibroid (r = -0.18, P = 0.01) and the total volume of fibroids (r = -0.19, P = 0.01). No correlation was found between the baseline 25-OH-D3 levels and the number of fibroids per patient (r = -0.10, P = 0.16). In women of the "study group," a significant increase in the 25-OH-D3 serum level was observed after 12 months of supplementation, and a lower rate of surgical or medical treatment due to the "progression to extensive disease" was reported (13.2% vs 30.9%, P = 0.05).Supplementation therapy with 25-OH-D3 restores normal vitamin D serum levels in women with "small burden" fibroids. In these women, vitamin D supplementation seems to reduce the progression to an extensive disease, and thus the need of conventional surgical or medical therapy.

Attachment, Neurobiology, and Mentalizing along the Psychosis Continuum.

In this review article, we outline the evidence linking attachment adversity to psychosis, from the premorbid stages of the disorder to its clinical forms. To better understand the neurobiological mechanisms through which insecure attachment may contribute to psychosis, we identify at least five neurobiological pathways linking attachment to risk for developing psychosis. Besides its well documented influence on the hypothalamic-pituary-adrenal (HPA) axis, insecure attachment may also contribute to neurodevelopmental risk through the dopaminergic and oxytonergic systems, as well as bear influence on neuroinflammation and oxidative stress responses. We further consider the neuroscientific and behavioral studies that underpin mentalization as a suite of processes potentially moderating the risk to transition to psychotic disorders. In particular, mentalization may help the individual compensate for endophenotypical impairments in the integration of sensory and metacognitive information. We propose a model where embodied mentalization would lie at the core of a protective, resilience response mitigating the adverse and potentially pathological influence of the neurodevelopmental cascade of risk for psychosis.

Importance of early weight changes to predict long-term weight gain during psychotropic drug treatment.

BACKGROUND: Psychotropic drugs can induce substantial weight gain, particularly during the first 6 months of treatment. The authors aimed to determine the potential predictive power of an early weight gain after the introduction of weight gain-inducing psychotropic drugs on long-term weight gain. METHOD: Data were obtained from a 1-year longitudinal study ongoing since 2007 including 351 psychiatric (ICD-10) patients, with metabolic parameters monitored (baseline and/or 1, 3, 6, 9, 12 months) and with compliance ascertained. International Diabetes Federation and World Health Organization definitions were used to define metabolic syndrome and obesity, respectively. RESULTS: Prevalences of metabolic syndrome and obesity were 22% and 17%, respectively, at baseline and 32% and 24% after 1 year. Receiver operating characteristic analyses indicated that an early weight gain > 5% after a period of 1 month is the best predictor for important long-term weight gain (≥ 15% after 3 months: sensitivity, 67%; specificity, 88%; ≥ 20% after 12 months: sensitivity, 47%; specificity, 89%). This analysis identified most patients (97% for 3 months, 93% for 12 months) who had weight gain ≤ 5% after 1 month as continuing to have a moderate weight gain after 3 and 12 months. Its predictive power was confirmed by fitting a longitudinal multivariate model (difference between groups in 1 year of 6.4% weight increase as compared to baseline, P = .0001). CONCLUSION: Following prescription of weight gain-inducing psychotropic drugs, a 5% threshold for weight gain after 1 month should raise clinician concerns about weight-controlling strategies.

Laparoscopic Treatment of Sclerosing Stromal Tumor of the Ovary in a Woman With Gorlin-Goltz Syndrome: A Case Report and Review of the Literature.

Gorlin-Goltz syndrome is a rare hereditary multisystemic disease. Multiple basal cell carcinomas, odontogenic keratocysts, and skeletal abnormalities are the main clinical manifestations of the syndrome, but several organs can be involved. Moreover, this condition is associated with the development of various benign and malignant tumors, even in the genital tract. This report describes a rare association between Gorlin-Goltz syndrome and the sclerosing stromal tumor of the ovary. Because the ultrasound and magnetic resonance imaging patterns of this tumor can be similar to those of a malignant neoplasm, prompt surgical intervention and histological confirmation of diagnosis is mandatory; however, this is a benign lesion and thus can be approached with a laparoscopic fertility-sparing surgery. Gynecologists should be aware of this possible association to provide appropriate counseling for these women, and to take a fertility-sparing laparoscopic approach whenever possible.