Increase in emergency department visits related to cannabis reported using syndromic surveillance system.

BACKGROUND: Cannabis is illegal in France but, as in many countries, legalization is under debate. In the United States, an increase of emergency department (ED) visits related to cannabis exposure (CE) in infants and adults was reported. In France, a retrospective observational study also suggested an increase of CE in children under 6 years old. This study only included toddlers and the data sources used did not allow repeated analysis for monitoring. METHODS: Our study aimed to evaluate the trend in visits for CE in ED in patients younger than 27 years old in Southern France. A cross-sectional study using the Electronic Emergency Department Abstracts (EEDA) included in the national Syndromic Surveillance System. CE visits were defined using International Classification of Disease (ICD-10). RESULTS: From 2009 to 2014, 16 EDs consistently reported EEDA with <5% missing diagnosis code. Seven hundred and ninety seven patients were admitted for CE including 49 (4.1%) children under 8 years old. From 2009-11 to 2012-14, the rate of CE visits increased significantly across all age groups. The highest increase was in the 8-14 years old (+144%; 1.85-4.51, P < 0.001) and was also significant in children under 8 (0.53-1.06; P = 0.02). Among children under 8, hospitalization rate (75.5% vs. 16.8%; P < 0.001) and intensive care unit admissions (4.1% vs. 0.1%; P < 0.001) were higher compared with patients older than 8 years. CONCLUSION: These trends occurred despite cannabis remaining illegal. EEDA could be useful for monitoring CE in EDs.

Travel-associated and autochthonous Zika virus infection in mainland France, 1 January to 15 July 2016.

During summer 2016, all the conditions for local mosquito-borne transmission of Zika virus (ZIKV) are met in mainland France: a competent vector, Aedes albopictus, a large number of travellers returning from ZIKV-affected areas, and an immunologically naive population. From 1 January to 15 July 2016, 625 persons with evidence of recent ZIKV infection were reported in mainland France. We describe the surveillance system in place and control measures implemented to reduce the risk of infection.

Impact of KRAS codon subtypes from a randomised phase II trial of selumetinib plus docetaxel in KRAS mutant advanced non-small-cell lung cancer.

BACKGROUND: Selumetinib (AZD6244, ARRY-142886)+docetaxel increases median overall survival (OS) and significantly improves progression-free survival (PFS) and objective response rate (ORR) compared with docetaxel alone in patients with KRAS mutant, stage IIIB/IV non-small-cell lung cancer (NSCLC; NCT00890825). METHODS: Retrospective analysis of OS, PFS, ORR and change in tumour size at week 6 for different sub-populations of KRAS codon mutations. RESULTS: In patients receiving selumetinib+docetaxel and harbouring KRAS G12C or G12V mutations there were trends towards greater improvement in OS, PFS and ORR compared with other KRAS mutations. CONCLUSION: Different KRAS mutations in NSCLC may influence selumetinib/docetaxel sensitivity.

First-line bevacizumab plus taxane-based chemotherapy for locally recurrent or metastatic breast cancer: safety and efficacy in an open-label study in 2,251 patients.

BACKGROUND: First-line bevacizumab combined with chemotherapy significantly improves efficacy versus chemotherapy alone in human epidermal growth factor receptor 2 (HER2)-negative locally recurrent or metastatic breast cancer (LR/mBC). This large, open-label study further assesses first-line bevacizumab with taxane-based chemotherapy in routine oncology practice. PATIENTS AND METHODS: Patients with HER2-negative LR/mBC, Eastern Cooperative Oncology Group (ECOG) performance status (PS) of zero to two and no prior chemotherapy for LR/mBC received bevacizumab 10 mg/kg every 2 weeks or 15 mg/kg every 3 weeks plus taxane-based chemotherapy (or other non-anthracycline chemotherapy) until disease progression, unacceptable toxicity or patient withdrawal. The primary end point was safety; time to progression (TtP) was a secondary end point. RESULTS: Median follow-up in 2251 treated patients was 12.7 months. Median age was 53 years and 94% of patients had ECOG PS of zero or one. Bevacizumab was most commonly administered with single-agent paclitaxel (35%), single-agent docetaxel (33%) or taxane-based combination therapy (10%). The most frequent grade ≥3 adverse event (AE) was neutropenia (5.4%). Grade ≥3 AEs previously associated with bevacizumab included hypertension (4.4%), arterial/venous thromboembolism (3.2%), proteinuria (1.7%) and bleeding (1.4%). No new bevacizumab safety signals were observed. Median TtP was 9.5 months (95% confidence interval 9.1-9.9). CONCLUSIONS: The study population in ATHENA was more representative of general oncology practice than populations enrolled into randomised trials, although there may have been some bias towards younger, fitter patients. The safety and efficacy of bevacizumab-taxane therapy in this large study were consistent with results from randomised first-line trials.

Epitope mapping of mAbs to denatured human testicular ACE (CD143).

Angiotensin I-converting enzyme (ACE; CD143) has two homologous enzymatically active domains (N and C) and plays a crucial role in blood pressure regulation and vascular remodeling. A wide spectrum of monoclonal antibodies (mAbs) to different epitopes on the N and C domains of human ACE have been used to study different aspects of ACE biology. In this study, we characterized a set of nine mAbs, developed against the C domain of human ACE, which recognize the denatured forms of ACE and thus are suitable for the detection and quantification of somatic ACE (sACE) and testicular ACE (tACE) using Western blotting and immunohistochemistry on paraffin-embedded human tissues. The epitopes for these mAbs were defined using species cross-reactivity, phage display library screening, Western blotting and ACE mutagenesis. Most of the mAbs recognized common/overlapping region(s) on both somatic and testicular forms of human ACE, whereas mAb 4E10 was relatively specific for the testicular isoform and mAb 5B9 mainly recognized the glycan attached to Asn 731. This set of mAbs is useful for identifying even subtle changes in human ACE conformation because of denaturation. These mAbs are also sensitive tools for the detection of human sACE and tACE in biological fluids and tissues using proteomic approaches. Their high reactivity in paraffin-embedded tissues provides opportunities to study changes in the pattern of ACE expression and glycosylation (particularly with mAb 5B9) in different tissues and cells.

[Embryonal germ cells and germ cell tumors]. / Embryonale Keimzellen und Keimzelltumoren.

Testicular germ cell tumors comprise of group of pluripotent tumors including seminomas and nonseminomas, arise from intratubular germ cell neoplasia and originate from the primordial germ cells/ gonocytes. Many well characterized markers of embryonic stem cells including CD9, PODXL and centromere-specific histone-H3-like protein CENPA are consistently expressed in TGCTs. In embryonic stem cells, pluripotency and self renewal capacities are provided by a network of OCT3/4, NANOG and SOX2. In testicular germ cell tumors, pluripotency genes OCT3/4 und NANOG are upregulated both, in seminomas and non-seminomas, while SOX2 is differentially upregulated in embryonal carcinomas only. Similar to embryonic stem cells, most histological elements of type II GCTs are sensitive to chemotherapy and irradiation. Furthermore, all invasive TGCTs show a consistent gain of the short arm of chromosome 12, as found in ES cells upon extensive in vitro culturing. Moreover, the genetic constitution of testicular germ cell tumors can also be linked to characteristics of embryonic stem cells, likely related to their specific inability to repair DNA damage and their high sensitivity to apoptotic cell death. In conclusion, testicular germ cell tumors represent embryonic cancers found in adults. Both the seminomas and nonseminomas have their specific population of stem cells representative of the primordial germ cells/gonocytes and for embryonic stem cells, respectively.

[Expression of angiotensin I converting enzyme in pulmonary hypertension]. / Expression des Angiotensin converting enzyme (ACE) bei pulmonaler Hypertonie.

We studied angiotensin I converting enzyme (ACE) expression in lung tissue from patients with different forms of pulmonary hypertension (PH) in comparison with that from morphologically normal lung specimens. ACE antigen expression was analysed by immunohistochemistry in morphologically normal lung tissue from 33 patients (19 males, 32-77 years; 14 females, 34-93 years) and compared to that in specimens from 94 patients (67 males, 30-97 years; 27 females: 27-90 years) with different clinically proven forms of PH (according to Venedig classification). Type specific vessel expression pattern as described for normal lung tissue was generally intensified in arteries, arterioles and capillaries of the lung specimens with PH. Specimens with PH due to left heart disease and chronic obstructive pulmonary disease (COPD) showed only very weak or no augmented arterial ACE expression, while PH due to collagenoses or interstitial lung disease showed significantly higher ACE expression. In human PH there is--comparable to animal models--a raised ACE expression in pulmonary lung vessels, with differences between the various forms of PH. These differences in ACE expression may be relevant for subtly differentiated therapeutic anti-ACE therapy regimes.

Epidemiologic surveillance system implemented in the Hautes-Alpes District, France, during the Winter Olympic Games, Torino 2006.

Some of the competitions of the Olympic Winter Games in Torino, 10 to 26 February 2006, were organised in France near the city of Briançon, in the department of Hautes-Alpes. An epidemiologic surveillance system was set up by the local health authorities. The goals were to detect in a timely fashion any phenomenon which could justify prevention or sanitary control action, and to guide interventions in the case of outbreak or environmental pollution. Surveillance was implemented from 30 January to15 March 2006 in the Briançon area. Mortality was tracked using by analysing the number and cause of deaths. A sentinel network of general practitioners was set up and reported the frequency of acute gastroenteritis, influenza-like illness and measles. Medical laboratories provided data about the analyses they undertook. Hospital emergency department and emergency ambulance service activities were followed up. Statutory notification diseases and toxic effects of carbon monoxide surveillances were reinforced. Analysed data were transmitted daily to the health authorities. A French/English report was sent weekly to all participants. The participation rate was close to 100%, and data transmission deadlines were respected. No adverse health event was identified. The strong acceptability of this surveillance system comes from its good understanding by the participants. This surveillance, structured around routine and ad-hoc systems, allowed the establishment of the foundations of a network to be used in case of outbreak or environmental pollution.

Epidemiologic surveillance system implemented in the Hautes-Alpes District, France, during the Winter Olympic Games, Torino 2006.

Some of the competitions of the Olympic Winter Games in Torino, 10 to 26 February 2006, were organised in France near the city of Briancon, in the department of Hautes-Alpes. An epidemiologic surveillance system was set up by the local health authorities. The goals were to detect in a timely fashion any phenomenon which could justify prevention or sanitary control action, and to guide interventions in the case of outbreak or environmental pollution. Surveillance was implemented from 30 January to 15 March 2006 in the Briancon area. Mortality was tracked using by analysing the number and cause of deaths. A sentinel network of general practitioners was set up and reported the frequency of acute gastroenteritis, influenza-like illness and measles. Medical laboratories provided data about the analyses they undertook. Hospital emergency department and emergency ambulance service activities were followed up. Statutory notification diseases and toxic effects of carbon monoxide surveillances were reinforced. Analysed data were transmitted daily to the health authorities. A French/English report was sent weekly to all participants. The participation rate was close to 100%, and data transmission deadlines were respected. No adverse health event was identified. The strong acceptability of this surveillance system comes from its good understanding by the participants. This surveillance, structured around routine and ad-hoc systems, allowed the establishment of the foundations of a network to be used in case of outbreak or environmental pollution.

Measles outbreak in the Provence-Alpes-Côte d'Azur region, France, January-July 2003.

At the end of May 2003, the Marseilles Hospital Centre's virology laboratory informed the French public heath institute of 5 cases of confirmed measles among young adults living in Marseilles. An investigation was conducted, consulting different community and hospital health services, to determine the virus circulation in the Provence-Alpes-Côte d'Azur (PACA) region by the southern interregional epidemiological cell. The investigation identified 259 cases: 183 clinical, 74 serologically confirmed and 2 epidemiologically linked cases. The first cases were identified during the first six months of 2003, with a peak in April. This outbreak of measles in the PACA region was favoured by poor vaccination coverage, which created groups of susceptible population. The real number of cases was probably higher than the number identified. This investigation has outlined the limitations of the measles surveillance system in France: the sentinel network had not detected any case for this period. France needs to reach the WHO objective of measles elimination by 2010 and the surveillance tools used must be those already used in the most countries that are furthest advanced in the elimination process. To reach this goal, the Direction Générale de la Santé has nominated a working group to be in charge of proposing a national plan to interrupt indigenous measles transmission in France.

Measles outbreak in the Provence - Alpes - Côte d'Azur region, France, January - July 2003.

At the end of May 2003, the Marseilles Hospital Centre's virology laboratory informed the French public heath institute of 5 cases of confirmed measles among young adults living in Marseilles. An investigation was conducted, consulting different community and hospital health services, to determine the virus circulation in the Provence-Alpes-Côte d'Azur (PACA) region by the southern interregional epidemiological cell. The investigation identified 259 cases: 183 clinical, 74 serologically confirmed and 2 epidemiologically linked cases. The first cases were identified during the first six months of 2003, with a peak in April. This outbreak of measles in the PACA region was favoured by poor vaccination coverage, which created groups of susceptible population. The real number of cases was probably higher than the number identified. This investigation has outlined the limitations of the measles surveillance system in France: the sentinel network had not detected any case for this period. France needs to reach the WHO objective of measles elimination by 2010 and the surveillance tools used must be those already used in the most countries that are furthest advanced in the elimination process. To reach this goal, the Direction Générale de la Santé has nominated a working group to be in charge of proposing a national plan to interrupt indigenous measles transmission in France.

[Angiotensin converting enzyme (ACE, CD143) in the regular pulmonary vasculature]. / Angiotensin-I-converting-Enzym (ACE, CD143) in regelrechtem humanem Lungengewebe.

Angiotensin I converting enzyme (ACE, CD143) is an endothelial transmembrane Zn2+-dipeptidylpeptidase. By formation of angiotensin II and degrading bradykinin it acts as a vasoconstrictor. We examined endothelial ACE expression in human pulmonary vessels in specimens from 20 female and 19 male patients (age: 34-76 years) by immunohistochemistry. In all specimens, capillary endothelial cells showed the strongest expression, followed by those in arterioles and arteries. Venules and veins showed next to no staining. The differences in staining intensities were significant ( P<0.001). Sex affected neither the expression intensity nor the expression pattern. Summarizing, we demonstrate the existence of a vessel-type specific ACE expression pattern for pulmonary vessels. The nearly exclusive endothelial ACE expression in capillaries and arterial vessels points to ACE as an immunohistochemical marker for these vessels in normal lung tissue.

Reappraisal of thromboangiitis obliterans--a pathological contribution.

Thromboangiitis obliterans (TAO), the Winiwarter-Buerger disease, is a vasoocclusive disease of unknown etiology which typically affects medium-sized extremital vessels of young male smokers. While the diagnosis of TAO is largely based on patients' presentation and clinical criteria, pathological substrates have been poorly defined and repeatedly disputed. Comparing the histology and immunohistochemistry of TAO especially with those of arteriosclerosis obliterans (ASO) and thromboembolism in two larger studies, we recently identified several features with significant meaning for the differential diagnosis. The unique tissue appearance of TAO is in favor of a general disorder of minute vessels indicating periarteritis rather than pure endarteritis, whereas an inflammatory reaction directed to the internal elastic lamina corresponds with the severity of disease. Since TAO or its syndromic equivalent is probably more common than currently diagnosed, the presented pathological criteria may help to identify latent cases, the overlap with ASO, and untypical organ involvement of TAO.

Monoclonal antibodies to denatured human ACE (CD 143), broad species specificity, reactivity on paraffin sections, and detection of subtle conformational changes in the C-terminal domain of ACE.

Two new mouse monoclonal antibodies (mAbs) were generated to denatured human angiotensin-converting enzyme (ACE, CD143). The clones 2E2 and 3C5, each of the IgG1 kappa chain isotype, detect ACE with high sensitivity, respectively, at 20 ng and 2 ng of protein per lane in Western blotting. They both recognize different epitopes on the C-domain of ACE located between amino acid residues 740 and 992. In formalin-fixed and paraffin-embedded human tissues, immunohistochemistry revealed all known expression sites of ACE, e.g. the epithelial brush borders of proximal kidney tubules, epithelial cells of epididymis, endothelial cells, activated macrophages as well as germ cells during spermatogenesis. In contrast to other mAbs to denatured human ACE, mAbs 2E2 and 3C5 demonstrate cross-reactivity with a broad spectrum of animal species such as monkey, rat, rabbit, cattle, dog, cat, and guinea pig. In addition, mAb 2E2 recognized mouse ACE in Western blotting and on paraffin sections. Our findings suggest that mAbs 2E2 and 3C5 are useful for identifying even subtle changes in ACE conformation resulting from denaturation. These mAbs are also sensitive tools for the detection of minimal amounts of ACE in biological fluids and tissues using proteomics approaches. Their reactivity in routinely processed tissues of various species may prove useful for correlation of ACE expression in animal models to human diseases.

Isoforms of angiotensin I-converting enzyme in the development and differentiation of human testis and epididymis.

Angiotensin I-converting enzyme (ACE; CD143, Kininase II, EC 3.4.15.1) is known to be crucial for male fertility in animal models. We therefore studied its testicular (tACE) and somatic (sACE) isoforms in foetal and adult human testis and epididymis using monoclonal antibodies and cRNA probes. During spermatogenesis, tACE was found only in differentiating germ cells and was the only isoform within the seminiferous tubules of adult men. Although tACE mRNA was present in spermatocytes, tACE protein was initially found in post-meiotic step 3 spermatids and increased markedly during further differentiation. The enzyme was strictly confined to the adluminal membrane site of elongating spermatids and was localized at the neck and midpiece region of released and ejaculated spermatozoa. In contrast, sACE was expressed heterogeneously in Leydig cells and endothelial cells of the testicular interstitium, and homogeneously along the luminal surface of epithelial cells lining the ductuli efferents, corpus and cauda of epididymis, and vas deferens. The cell- and site-restricted pattern of sACE corresponded to that found in foetal tissues except an additional and transient expression of sACE in foetal germ cells and foetal Sertoli cells. Our study documents for the first time in humans the regulation and unique cellular distribution of ACE isoforms during the ontogenesis of the lower male genital tract.

[Effects of sociomedical risk factors on the progression of ovarian cancer]. / Auswirkungen soziomedizinischer Risikofaktoren auf den Verlauf des Ovarialkarzinoms.

INTRODUCTION: The potential prognostic influence of sociomedical risk factors probably on ovarian cancer patient prognosis has yet not been intensively investigated. This study was to determine whether the general psychologic constitution has an influence on patient survival after primäry surgery and in how far it correlates to sociobiologic factors. METHOD: 695 long-term followed ovarian carcinoma patients were studied. The median follow-up was 4.8 years with a range of 63 days to 18.7 years. Tumor-associated death was recorded in 219 patients. The prognostic influence of sociomedical risk factor was determined by age and stage corrected survival analysis. RESULTS: The variables "genetic or hereditary risk", "hormone replacement therapy" and "use of tobacco or alcohol" had no significant influence on survival. However, the variables "psychic disorders" and "parity" were found to be of strong prognostic influence, alone and in combination. Patients showing psychic disorders had a clearly worse prognosis (p < 0,001), as well as those of higher parity (p < 0,001). DISCUSSION: This newly described link between patients' psychological constitution and course of disease suggests psychotherapeutic support to be helpful for ovarian carcinoma patients. Risk factors, furthermore, may have an opposite effect on both cancer incidence and prognosis. The latter is discussed on the background of an ovarian carcinogenesis threshold model.