Non-dioxin-like organic toxicant PCB153 modulates sphingolipid metabolism in liver progenitor cells: its role in Cx43-formed gap junction impairment.

The non-dioxin-like environmental toxicant 2,2',4,4',5,5'-hexachlorobiphenyl (PCB153), member of a group of persistent organic pollutants wide-spread throughout the environment, reduces gap junction intercellular communication (GJIC), an event possibly associated with tumor promotion. Since very few studies have investigated the signaling effectors and mode(s) of action of PCB153, and it is known that the gap junction (GJ) protein Cx43 can be regulated by the bioactive sphingolipid (SL) sphingosine 1-phosphate (S1P), this in vitro study mainly addresses whether SL metabolism is affected by PCB153 in rat liver epithelial WB-F344 cells. PCB153 treatment obtained significant changes in the S1P/ceramide (Cer) ratio, known to be crucial in determining cell fate. In particular, an increase in S1P at 30 min and a decrease of the bioactive lipid at 3 h were observed, whereas Cer level increased at 1 h and 24 h. Notably, a time-dependent modulation of sphingosine kinase (SphK), the enzyme responsible for S1P synthesis, and of its regulators, ERK1/2 and protein phosphatase PP2A, supports the involvement of these signaling effectors in PCB153 toxicity. Electrophysiological analyses, furthermore, indicated that the lipophilic environmental toxicant significantly reduced GJ biophysical properties, affecting both voltage-dependent (such as those formed by Cx43 and/or Cx32) and voltage-independent channels, thereby demonstrating that PCB153 may act differently on GJs formed by distinct Cx isoforms. SphK down-regulation alone induced GJIC impairment, and, when combined with PCB153, the acute effect on GJ suppression was additive. Moreover, after enzyme-specific gene silencing, the SphK1 isoform appears to be responsible for down-regulating Cx43 expression, while being the target of PCB153 at short-term exposure. In conclusion, we provide the first evidence of novel effectors in PCB153 toxic action in rat liver stem-like cells, leading us to consider SLs as potential markers for preventing GJIC deregulation and, thus, the tumorigenic action elicited by this environmental toxicant.

Betalains increase vitexin-2-O-xyloside cytotoxicity in CaCo-2 cancer cells.

Vitexin-2-O-xyloside (XVX) from Beta vulgaris var. cicla L. (BVc) seeds, betaxanthin (R1) and betacyanin (R2) fractions from Beta vulgaris var. rubra L. (BVr) roots were combined and tested for cytotoxicity in CaCo-2 colon cancer cells. XVX was the most cytotoxic molecule, but the combination of XVX with R1 and R2 significantly prolonged its cytotoxicity. Cytotoxicity was mediated by the intrinsic apoptotic pathway, as shown by an increase in Bcl2-like protein 4, cleaved Poly ADP-Ribosyl Polymerase 1 and cleaved Caspase 3 levels with a parallel decrease in anti-apoptotic protein B-cell leukemia/lymphoma 2 levels. R1 and R2, used alone or in combination, reduced oxidative stress triggered by H2O2 in CaCo-2 cells. Betalains dampened cyclooxygenase-2 and interleukin-8 mRNA expression after lipopolysaccharide induction in CaCo-2, showing an anti-inflammatory action. Our results support the use of a cocktail of R1, R2 and XVX as a chemopreventive tool against colon cancer.

Betacyanins enhance vitexin-2-O-xyloside mediated inhibition of proliferation of T24 bladder cancer cells.

Betacyanins (BC) were purified from beetroot (Beta vulgaris var. rubra L.) and tested, alone or in combination with vitexin-2-O-xyloside (XVX) from Beta vulgaris var. cicla L., for their ability to reduce the proliferation rate in T24 bladder cancer cells. Combination of BC and XVX exhibited a synergistic effect concerning the inhibition of proliferation in T24 cancer cells at 24 and 48 h but not after 72 h of incubation. The induction of apoptosis was evidenced by means of fluorescence activated cell sorting (FACS) analysis, as well as through the increase in caspase 3 and 8 activities. Using RTqPCR experiments, it was shown that the combination of XVX + BC was able to enhance the expression levels of pro-apoptotic BAX and downregulate anti-apoptotic BIRC5 (survivin), as well as pro-survival CTNNB1 (ß-catenin). The most evident effect of BC was the increase of the activity of caspase 8, leading to induction of extrinsic apoptosis. Moreover, XVX, BC and their combination showed no cytotoxic effect on normal human skin NCTC 2544 keratinocytes. These results demonstrated the efficacy and the mechanisms of the action of BC and XVX, extracted from edible plants, and suggested that a diet or a nutrition supplement, enriched with these bioactive molecules, could be used in the prevention of human bladder cancer.

[Moderate preterm birth 34-37 weeks: Description of immediate neonatal causes and consequences in a level 2 maternity]. / Prématurité modérée 34-37SA : description des causes et conséquences néonatales immédiates dans une maternité de niveau 2.

OBJECTIVES: In France, 75% of annual preterm births happen between 34 and 36 weeks+6 days. This study's goal is to describe the main causes and short-term consequences. METHODS: Two hundred and ninety-seven computerized files of patients who gave birth between 34 and 36 weeks+6 days at the hospital Foch's maternity were analyzed retrospectively. Descriptive statistical analysis was done with XLSTAT 2008. RESULTS: Among the 6028 births, 4.9% happened between 34 and 36 weeks+6 days and 43.1% of these births were medically induced. The two main causes of induced late preterm birth were: pre-eclampsia (28.9%) and premature rupture of membranes (25%). In spontaneous deliveries, newborns less often require respiratory support at birth (17.2% vs 31%; P=0.02) and are significantly less likely to be hospitalized in neonatology (54% vs 72.3%; P<0.01). C-section rates (71.1% vs 17.75%; P<0.01) and post-partum hemorrhages' probability (10.2% vs 3%; P<0.01) are significantly higher than for medically induced deliveries. CONCLUSION: Better knowledge of late prematurity causes and consequences would help limit medically induced births after 34 weeks.

The etiology of low-grade gliomas: pathological and clinical considerations about radiation-induced low-grade gliomas.

The only environmental factor undoubtedly linked to an increased risk of brain tumors (including gliomas) is therapeutic X-rays. We aim to conduct a detailed study of radiation-induced low-grade gliomas, in order to better understand the pathogenesis of such gliomas. Furthermore, we want do prove whether or not there are significant differences, according to clinical features and biological behavior, between this type of tumor and general low-grade gliomas. We analyzed the existent literature of low-grade radiation-induced glioma case reports and other epidemiological reports based on the experience of the senior author. We were able to collect 20 cases of such gliomas. Demographic data and previous X-ray details, along with latency intervals of all patients are provided. The amount of radiation able to cause mutations is not necessarily very high, as tumors occur even after low doses of radiation (as 3-5 GY). The incidence of this kind of tumors may be underestimated and may rise in the future. Care must be taken when observing patients who were irradiated more than 10 years before, especially in the recent years in which access to radiosurgical and radiation therapies has increased in the general population for treating many cerebral pathologies. Radiation-induced low-grade gliomas appear to be different from general gliomas only in terms of age in which they occur. In terms of clinical and biological behavior, there seem to be no differences, even though exceptional cases are reported.

Contribution of Lymphoscintigraphy for Sentinel Lymph Node Biopsy in Women with Early Stage Endometrial Cancer: Results of the SENTI-ENDO Study.

BACKGROUND: This study was designed to evaluate detection rate and anatomical location of sentinel lymph node (SLN) at lymphoscintigraphy, to compare short and long lymphoscintigraphy protocols, and to correlate lymphoscintigraphic and surgical mapping of SLN in patients with early-stage endometrial cancer (EC). METHODS: Subanalysis of the prospective multicenter study Senti-endo performed from July 2007 to August 2009. Patients with stage I and II EC received four cervical injections of 0-2 mL of unfiltered technetium sulphur colloid the day before (long protocol) or the morning (short protocol) before surgery. SLN detection used a combined technetium/patent blue labeling technique, and all patients had a systematic bilateral pelvic lymphadenectomy. RESULTS: A total of 133 patients were enrolled in the study and 118 (94.5 %) underwent a lymphoscintigraphy. Of these 118 patients, 44 (37 %) underwent a short protocol and 66 (56 %) a long protocol (data on lymphoscintigraphy were not available in eight patients). Lymphoscintigraphic detection rate was 74.6 % (34 % for short protocol and 60.2 % for long protocol). No difference in the detection rate was observed according to lymphoscintigraphy protocol (p = 0.22), but a higher number of SLN was noted for the long protocol (p = 0.02). Aberrant drainage was noted on lymphoscintigraphy in 30.5 % of the patients. Paraaortic SLNs were exclusively detected using the long protocol. A poor correlation was noted between short (κ test = 0.24) or long lymphoscintigraphy (κ test = 0.3) protocol and SLN surgical mapping. CONCLUSIONS: Our study demonstrates that preoperative lymphoscintigraphy allowed a high SLN detection rate and that long lymphoscintigraphy protocol was associated with a higher detection of aberrant drainage especially in the paraaortic area.

[Precarious parturients and readmission: pilot study at the Lariboisière-Fernand-Widal Hospital Group in Paris]. / Parturientes précaires et réhospitalisation : étude pilote au groupe hospitalier Lariboisière-Fernand-Widal de Paris.

OBJECTIVES: We wondered whether pregnant women with social handicap benefited from readmissions which could have been prevented, and if there was a selection of patients? PATIENTS AND METHOD: This is a retrospective study of 127 pregnant women with social handicap having given natural childbirth in a public health establishment. The research was based on analysis of data from DRG's (PMSI), legislation and other documents. RESULTS: Between mid March 2007 and mid June 2009, 27 of the 127 pregnant women with social handicap have benefited from 35 readmissions. There were 171.5 ± 255.1 days between readmissions. There was no second readmission on the same day for the same patient. According to the criteria of the Appropriateness Evaluation Protocol (AEPf), none of the readmissions were considered avoidable. No parturient was readmitted for non-medical reasons. Readmitted patients presented low to severe social handicaps and had 79.6 % more coded diagnosis compared to their first hospitalization. This service plays its public service role to fight against social exclusion. DISCUSSION AND CONCLUSION: This pilot study provides encouraging results but also underlines the limits of our approach. We nevertheless wished to explore whether this low resource intensive initiative could make interesting indicators emerge, which seems to be the case.

Four-year clinical and neuroradiological follow-up of a papillary tumor of the pineal region.

Papillary tumor of the pineal region (PTPR) is a rare variety of CNS neoplasms and, since its first definition in 2003, only 64 cases have been described. PTPR is a primary neoplasm morphologically characterized by papillary structure staining for cytokeratin, transthyretin, neurone-specific enolase and S-100 protein. We report on a case of about 4 years' clinical history and neuroradiological follow-up of PTPR, in a 47-year-old Indian patient, with the aim of increasing the knowledge of its natural history. We describe through CT and MRI scans the natural evolution of this neoplasm, enhancing changes and morphologic structures involved, together with the final surgical treatment and pathological details. A mean growth rate average was calculated for this kind of lesion. In conclusion, the inexorable progressive growing nature of this tumor leads us to advocate an aggressive attitude among neurosurgeons and radiotherapists, with a precocious surgical approach when the suspicion rises.

[Sentinel lymph node detection in patients with early-stage breast cancer: which site of injection in 2011?]. / Détection du ganglion sentinelle chez les patientes atteintes d'un cancer du sein à un stade précoce : quel site d'injection en 2011 ?

Sentinel lymph node (SLN) mapping and biopsy have emerged as the technique of choice for axillary staging of breast cancer. Several methods have been developed to identify SLNs, including peritumoral or periareolar injection of blue dye or technetium colloid. The optimal site for injection of mapping tracers is controversial in SLN. The peritumoral injection provides information on the deep lymphatic drainage and the internal mammary chain. The advantages of periareolar injection are simplicity, the ability to perform it in non-palpable tumors, and the potential enhancement of uptake via the subareolar lymphatic plexus. The results of multiinstitutional study have indicated that superficial injection (periareolar or peritumoral) is associated with a better identification rate and an equal false-negative rate compared to deep peritumoral (PT) injection. However, the false-negative rate of periareolar injection has not been formally demonstrated.

Safety and feasibility of the adjunct of local chemotherapy with biodegradable carmustine (BCNU) wafers to the standard multimodal approach to high grade gliomas at first diagnosis.

AIM: Among physicians there is still a reluctant attitude in the employment of combined treatment with surgery and intraoperative placement of carmustina 7.7 mg wafers (Gliadel®), followed by standard adjuvant treatment with radiotherapy and concomitant and subsequent chemiotherapy with temozolomide (TMZ), for supratentorial high grade gliomas at first diagnosis. To determine the safety and feasibility of this multimodality sequential adjuvant therapy, we reviewed our single-institution experience, in the light to provide more insights on this continuous multi-stage chemotherapy approach to such a challenging disease as glioblastoma multiforme. METHODS: From February 2006 to January 2008, 32 patients were treated at our institution for cerebral supratentorial high grade glioma with surgery and intraoperative placement of carmustine wafers. No postsurgical complications could be observed. After a median time of 4,8 weeks all patients began adjuvant concomitant radiotherapy with a mean of 60 Gy and TMZ chemotherapy 75 mg/m2 during which weekly hematologic assessments were performed. After 3 to 6 weeks patients commenced adjuvant TMZ, administered 5 days every 28, 200 mg/m2 for not less than 12 cycles. A contrast-enhanced magnetic resonance imaging (MRI) was routinely performed. Median follow-up after surgery was of 6.5 months, ranging from 4 to 23 months. RESULTS: The mean presurgical KPS was of 80 (range: from 60 to 100), and it remained unmodified after adjuvant therapies even at suspension of steroids. In 4 cases there was a radiologic evidence of progression of the disease and the necessity of steroids, with a progression-free survival (PFS) of 6, 8, 9,5 and 13,6 months. One case died 14 months after first operation. All other patients are still alive. CONCLUSION: The integration of local chemiotherapy with carmustine wafers and the standard adjuvant regimen with radiotherapy and concomitant chemiotherapy appears to be safe and feasible, without any adjunctive complication. Promising results on the efficacy require more follow up to be quantified.

[Clinicopathological and genomics predictors of response to neoadjuvant chemotherapy in breast cancer]. / Prédicteurs clinicopathologiques et génomiques de la réponse à la chimiothérapie néoadjuvante dans les cancers du sein.

Breast cancer is a frequent and heterogeneous disease. The choice of systemic treatments such as chemotherapy is based on predicting factors of response that did not much evolve. Preoperative chemotherapy provides an opportunity to directly assess tumor response to therapy. Predictors based on mathematical models could optimize those treatments. To go on this way, three different concepts have been developed to predict the preoperative chemotherapy complete response. Predictors based on clinical and pathological variables are specific of a tumor. They combine into mathematical models variables that have been previously identified as predicting the preoperative chemotherapy complete response. Predictors based on gene expression profile have been developed from groups of patients who received preoperative chemotherapy. They integrate multigene information to predict the tumor behaviour in front of several cytotoxic agents. Those predictors developed for each type of drug characterize the genetic chemoresistance of a tumor. In the same time, predictors of chemosensitivity developed from cell lines of diverse human cancer appeared. The authors established a genetic profile involved into chemoresistance and extrapolated the drug sensitivity for another type of cancer which was not represented, as breast cancer. All those predictors seem interesting but evolution of patients' characteristics and treatments induces a perpetual reassessment to optimize our predictive abilities.

Sarcoma metastatic to the brain: a series of 35 cases and considerations from 27 years of experience.

The authors report their 27-year experience regarding 35 cases of supratentorial brain metastasis from sarcoma treated in a single institution: these included ten osteosarcomas, seven leiomyosarcomas, five Ewing sarcomas, four malignant fibrous histiocytomas, three alveolar soft-part sarcomas (ASPS), two rhabdomyosarcomas, one liposarcoma, and three unclassified sarcomas. The first 15 cases of the series have already been described in a previous publication. Median survival after craniotomy was 9.8 months (range: 4-24). In patients with preoperative Karnofsky performance score (KPS) > 60 it was 12.8 months (range: 6.5-24 months) versus 5.4 months for those patients with a KPS < or = 60 (P = 0.01). Eight patients had more than one lesion, six of which were treated in the last ten years. Of the three patients with ASPS, the first two were alive at 15 and 20 months (before being lost to follow-up) whereas the third patient is alive at 24 month follow-up. The authors conclude that surgery is more effective in treating selected patients with sarcoma metastatic to the brain, and that patients with metastasis from ASPS have good prognosis when submitted to surgical treatment. The complete removal of all brain metastases "en bloc" and a KPS > 60 are associated with the best prognosis. Finally, it seems that surgical indications for multiple brain metastases from sarcoma have increased during the last ten years.

[Evolution of surgical operations for female for stress urinary incontinence in gynaecology departments of Parisian public hospitals between 2002 and 2006]. / Evolution des interventions chirurgicales pour incontinence urinaire d'effort dans les services de chirurgie gynécologique de l'Assistance publique des Hôpitaux de Paris entre 2002 et 2006.

OBJECTIVE: To appreciate the evolution of the current surgical practice for female for stress urinary incontinence (SUI) in the gynaecologic surgery departments of Parisian public hospitals in three different periods of 12 months (2002-2003, 2003-2004, and 2006). PATIENTS AND METHODS: The 16 departments were surveyed by postal questionnaire about their surgical practice for the treatment of female SUI. The number, the type of operation, the type of suburethral tapes and their surgical routes were detailed. RESULTS: The participation rate in the survey was 87.5% (14/16) for the first two studied periods and 75% (12/16) for the last one. The number of SUI procedure decreases between the three periods (586, 505, and 263 procedures, respectively; p<0.001). Suburethral slings represent the technique of choice for SUI (86.2% in 2002-2003; 92.7% in 2003-2004, and 98.1% in 2006). Other practices are exceptional. The transobturator approach has widely progressed and became the preferred one in 2006 (31.1%; 64.5%; 95.4% in 2006; p<0.001). No transobturator route was privileged. TVT procedures have decreased between the three studied periods (48.3%, 36.5%, and 4.6% in 2006; p<0.001). TVT-O is the preferred sling in 2006 (120/258, 46.5% of suburethral tapes). DISCUSSION AND CONCLUSION: Suburethral tape placement is nowadays the main surgical treatment for female SUI amongst members in gynaecology departments in Parisian public hospitals. The transobturator approach is preferred.

How to set up a microsurgical laboratory on small animal models: organization, techniques, and impact on residency training.

Microsurgical training is mandatory for the optimal education of modern neurosurgeons. Even though this is a widely acknowledged statement and a lot of institutions around the world practice training in laboratory, the recent literature lacks tip and tricks on how to start a laboratory from scratch, what would be a convenient anesthesia, and what kind of exercises are appropriate. We present our experience in 16 microsurgical training courses settled up at our institutions. Two hundred eleven rodents were dissected. We will describe the organization of the laboratory and of the training courses and we will discuss its practical impact on the residency program.

Prenatal evaluation of a scrotal mass using a high-frequency probe in the diagnosis of inguinoscrotal hernia.

Whereas inguinal hernia is a common pediatric disease, fetal inguinal hernia is rarely diagnosed because intra-abdominal pressure usually occurs only after birth. We report a case of prenatal diagnosis of a scrotal mass at 35 weeks' gestation. The initial differential diagnosis included hydrocele, testicular teratoma and testicular torsion, but inguinoscrotal hernia was considered the most likely diagnosis when further ultrasound imaging using a high-frequency probe demonstrated bowel loop movements around the mesenteric artery. This diagnosis was confirmed postnatally.

High cervical neurenteric cyst; acute post-traumatic rupture and respiratory failure: a case report.

The neuroenteric cyst is a rare developmental lesion originating from incomplete formation of the primitive neuroenteric canal. We report on the difficult management of an acute post-traumatic rupture of a cervical neuroenteric cyst. A 35-year-old male patient came to our observation after a spinal injury incurred during a football match. The patient immediately demonstrated tetraplegia and respiratory failure and was operated on. After two weeks the patient died of cardiopulmonary failure. High cervical neurenteric cysts, even those representing benign lesions, can produce dramatic results after a spinal injury.

Hemangioblastoma of the filum terminale. Case report and review of the literature.

Hemangioblastomas of the filum terminale are particularly rare tumors. The authors present the case of a 62-year-old woman with a 6 month history of low-back-pain, who underwent surgery for the removal of an hemangioblastoma affecting the cauda at L2-L3 level. This highly vascularized tumour is tightly adherent to the filum terminale and hence is a very challenging pathology to remove. Histologically it consisted in vascular structures interposed to a network of capillary-like vessels, surrounded by stromal cells. MRI, angiography with pre-surgical embolization, and radical surgery represent the focal points in the diagnosis and treatment of these tumours. The most relevant literature has been carefully reviewed.

Effect of pinching-evoked pain on jaw-stretch reflexes and exteroceptive suppression periods in healthy subjects.

OBJECTIVE: To investigate the influence of conditioning cutaneous nociceptive inputs by a new "pinch" model on the jaw-stretch reflex and the exteroceptive suppression periods (ES1 and ES2) in jaw muscles. METHODS: The jaw-stretch reflex was evoked with the use of a custom-made muscle stretcher and electrical stimuli were used to evoke an early and late exteroceptive suppression period (ES1 and ES2) in the jaw-closing muscles. Electromyographic (EMG) activity was recorded bilaterally from the masseter and temporalis muscles. These brainstem reflexes were recorded in 19 healthy men (28.8+/-1.1 years) during three different conditions: one painful clip applied to the earlobe; one painful clip applied to the nostril, and four painful clips applied simultaneously to the earlobe, nostril, eyebrow, and lower lip. Pain intensity induced by the application of the clips was scored continuously by the subjects on a 100mm visual analogue scale (VAS). RESULTS: The highest VAS pain scores were evoked by placement of four clips (79+/-0.5mm). There was no significant modulation of the jaw-stretch reflex (ANOVAs: P=0.929), the ES1 (P=0.298) or ES2 (P=0.082) in any of the three painful conditions. CONCLUSIONS: Intense and tonic cutaneous pain could be elicited by this new "pinch" pain model; however, there was no significant modulation on either excitatory or inhibitory brainstem reflex responses. SIGNIFICANCE: The novel observation that high-intensity pinch stimuli applied to the craniofacial region fail to modulate two different brainstem reflexes is in contrast to other experimental pain studies documented facilitation of the jaw-stretch reflexes or inhibition of exteroceptive suppression periods. The clinical implication of the present findings is that only some craniofacial pain conditions could be expected to show perturbation of the brainstem reflex responses.

Brain metastasis from prostate cancer. Report of 13 cases and critical analysis of the literature.

Brain metastasis from prostate carcinoma occurs very rarely. We describe 13 patients with single brain metastasis from prostatic cancer. Total removal of the lesions was performed in ten patients. Three patients underwent stereotactic biopsy. All patients were treated with postoperative whole brain radiotherapy (WBRT). Eight patients died for systemic disease after a mean time of 9.2 months with a diagnosis of metastasis. Five patients are still alive at 20, 14, 11, 7 and 6 months, respectively. Even if brain metastasis from prostate cancer is often a terminal event with death occurring within few months from diagnosis, we suggest the same protocol (surgery and/or radiosurgery plus postoperative WBRT) usually adopted to treat brain metastasis from other primitive tumours. A non specific neurological symptomatology and a possible normal dosage of serum specific antigen may contribute to a delay in diagnosis. However, considering the rarity of brain metastasis from prostate carcinoma, standard brain MRI follow-up in men with prostatic cancer does not seem to be necessary yet.

Central nervous system mesenchymal chondrosarcoma.

Central nervous system mesenchymal chondrosarcomas are rare malignant tumors that constitute a separate entity from the classical chondrosarcoma and myxoid variant. Clinical behaviour of central nervous system chondrosarcomas is still unknown. We describe two rare examples of intracranial mesenchymal chondrosarcoma with a review of the literature, in an attempt to clarify the clinical characteristics, prognosis and treatment of choice of these unusual tumors. Among the 55 reported cases, 23 had postoperative radiotherapy. Although there is no statistical significance according to the Log-Rank test (p=0.7), the patients treated with radiation therapy seem to have a better chance of survival. Patients who had adjuvant chemotherapy (only 5) showed survival times similar to those patients who had none. Although clinical behaviour of central nervous system chondrosarcomas remains to be defined, data from our series as well as literature show that radical removal is the best therapeutic choice. In addition, patients treated with postoperative radiotherapy seem to show a trend toward increased survival.