Adjuvant Use of PlasmaJet Device During Cytoreductive Surgery for Advanced-Stage Ovarian Cancer: Results of the PlaComOv-study, a Randomized Controlled Trial in The Netherlands.

OBJECTIVE: Standard surgical treatment of advanced-stage ovarian carcinoma with electrosurgery cannot always result in complete cytoreductive surgery (CRS), especially when many small metastases are found on the mesentery and intestinal surface. We investigated whether adjuvant use of a neutral argon plasma device can help increase the complete cytoreduction rate. PATIENTS AND METHODS: 327 patients with FIGO stage IIIB-IV epithelial ovarian cancer (EOC) who underwent primary or interval CRS were randomized to either surgery with neutral argon plasma (PlasmaJet) (intervention) or without PlasmaJet (control group). The primary outcome was the percentage of complete CRS. The secondary outcomes were duration of surgery, blood loss, number of bowel resections and colostomies, hospitalization, 30-day morbidity, and quality of life (QoL). RESULTS: Complete CRS was achieved in 119 patients (75.8%) in the intervention group and 115 patients (67.6%) in the control group (risk difference (RD) 8.2%, 95% confidence interval (CI) -0.021 to 0.181; P = 0.131). In a per-protocol analysis excluding patients with unresectable disease, complete CRS was obtained in 85.6% in the intervention group and 71.5% in the control group (RD 14.1%, 95% CI 0.042 to 0.235; P = 0.005). Patient-reported QoL at 6 months after surgery differed between groups in favor of PlasmaJet surgery (95% CI 0.455-8.350; P = 0.029). Other secondary outcomes did not differ significantly. CONCLUSIONS: Adjuvant use of PlasmaJet during CRS for advanced-stage ovarian cancer resulted in a significantly higher proportion of complete CRS in patients with resectable disease and higher QoL at 6 months after surgery. (Funded by ZonMw, Trial Register NL62035.078.17.) TRIAL REGISTRATION: Approved by the Medical Ethics Review Board of the Erasmus University Medical Center Rotterdam, the Netherlands, NL62035.078.17 on 20-11-2017. Recruitment started on 30-1-2018.

Evaluation of a nationwide Dutch guideline to detect Lynch syndrome in patients with endometrial cancer.

OBJECTIVE: In the Netherlands a nationwide guideline was introduced in 2016, which recommended routine Lynch syndrome screening (LSS) for all women with endometrial cancer (EC) <70 years of age. LSS consists of immunohistochemical (IHC) staining for loss of mismatch repair (MMR) protein expression, supplemented with MLH1 methylation analysis if indicated. Test results are evaluated by the treating gynaecologist, who refers eligible patients to a clinical geneticist. We evaluated the implementation of this guideline. METHODS: From the nation-wide pathology database we selected all women diagnosed with EC < 70 years of age, treated from 1.6.2016-1.6.2017 in 14 hospitals. We collected data on the results of LSS and follow up of cases with suspected LS. RESULTS: In 183 out of 204 tumours (90%) LSS was performed. In 41 cases (22%) MMR protein expression was lost, in 25 cases due to hypermethylation of the MLH1 promotor. One patient was known with a pathogenic MLH1 variant. The option of genetic counselling was discussed with 12 of the 15 remaining patients, of whom three declined. After counselling by the genetic counsellor nine patients underwent germline testing. In two no pathogenic germline variant was detected, two were diagnosed with a pathogenic PMS2 variant, and five with a pathogenic MSH6 variant, in concordance with the IHC profiles. CONCLUSION: Coverage of LSS was high (90%), though referral for genetic counselling could be improved. Gynaecologists ought to be aware of the benefits and possible drawbacks of knowing mutational status, and require training in discussing this with their patients.

Adjuvant VACcination against HPV in surgical treatment of Cervical Intra-epithelial Neoplasia (VACCIN study) a study protocol for a randomised controlled trial.

BACKGROUND: Cervical cancer is caused by Human Papilloma viruses (HPV) and is preceded by precursor stages: Cervical Intraepithelial Neoplasia (CIN). CIN is mostly found in women in their reproductive age and treated with a Loop Electrosurgical Excision Procedure (LEEP). The recurrence or residual disease rate after treatment is up to 17%. These women have a lifelong increased risk of recurrent CIN, cervical cancer and other HPV related malignancies. Furthermore, LEEP treatments are associated with complications such as premature birth. Limited data show that prophylactic HPV vaccination at the time of LEEP reduces recurrence rates, therefore leading to a reduction in repeated surgical interventions and side effect like preterm birth. The primary study objective is to evaluate the efficacy of the nonavalent HPV vaccination in women with a CIN II-III (high-grade squamous intraepithelial lesion (HSIL) lesion who will undergo a LEEP in preventing recurrent CIN II-III after 24 months. METHODS: This study is a randomised, double blinded, placebo controlled trial in 750 patients without prior HPV vaccination or prior treatment for CIN and with histologically proven CIN II-III (independent of their hrHPV status) for whom a LEEP is planned. Included patients will be randomised to receive either three injections with nonavalent (9 HPV types) HPV vaccine or placebo injections (NaCL 0.9%) as a comparator. Treatment and follow-up will be according the current Dutch guidelines. Primary outcome is recurrence of a CIN II or CIN III lesion at 24 months. A normal PAP smear with negative hrHPV test serves as surrogate for absence of CIN. At the start and throughout the study HPV typing, quality of life and cost effectiveness will be tested. DISCUSSION: Although prophylactic HPV vaccines are highly effective, little is known about the effectivity of HPV vaccines on women with CIN. Multiple LEEP treatments are associated with complications. We would like to evaluate the efficacy of HPV vaccination in addition to LEEP treatment to prevent residual or recurrent cervical dysplasia and decrease risks of repeated surgical treatment. TRIAL REGISTRATION: Medical Ethical Committee approval number: NL66775.078.18. Affiliation: Erasmus Medical Centre. Dutch trial register: NL 7938. Date of registration 2019-08-05.

Evaluation of effectiveness of the PlasmaJet surgical device in the treatment of advanced stage ovarian cancer (PlaComOv-study): study protocol of a randomized controlled trial in the Netherlands.

BACKGROUND: The most important goal for survival benefit of advanced stage ovarian cancer is to surgically remove all visible tumour, because complete cytoreductive surgery (CCS) has been shown to be associated with prolonged survival. In a remarkable number of women, CCS is very challenging. Especially in women with many small metastases on the peritoneum and intestinal surface, conventional CCS with electrosurgery is not able to be "complete" in removing safely all visible tumour. In this randomized controlled trail (RCT) we investigate whether the use of the PlasmaJet Surgical Device increases the rate of CCS, and whether this indeed leads to a longer progression free and overall survival. The main research question is: does the use of the PlasmaJet Surgical Device in surgery for advanced stage ovarian cancer result in an increased number of complete cytoreductive surgeries when compared with conventional surgical techniques. Secondary study objectives are: 30-day morbidity, duration of surgery, blood loss, length of hospitalisation, Quality of Life, disease-free survival, overall survival, percentage colostomy, cost-effectiveness. METHODS: The study design is a multicentre single-blinded superiority RCT in two university and nine non-university hospitals in The Netherlands. Three hundred and thirty women undergoing cytoreductive surgery for advanced stage ovarian carcinoma (FIGO Stage IIIB-IV) will be randomized into two arms: use of the PlasmaJet (intervention group) versus the use of standard surgical instruments combined with electrocoagulation (control group). The primary outcome is the rate of complete cytoreductive surgery in both groups. Secondary study objectives are: 30-day morbidity, duration of surgery, blood loss, length of hospitalisation, Quality of Life, disease-free survival, overall survival, percentage colostomy, cost-effectiveness. Quality of life will be evaluated using validated questionnaires at baseline, at 1 and 6 months after surgery and at 1, 2, 3 and 4 years after surgery. DISCUSSION: We hypothesize the additional value of the use of the PlasmaJet in CCS for advanced stage epithelial ovarian cancer. More knowledge about efficacy, side effects, recurrence rates, cost effectiveness and pathology findings after using the PlasmaJet Device is advocated. This RCT may aid in this void. TRIAL REGISTRATION: Dutch Trial Register NTR6624 . Registered 18 August 2017. Medical Ethical Committee approval number: NL62035.078.17 (Medical Ethical Committee Erasmus Medical Centre Rotterdam).

Protein C and S deficiency in severe infectious purpura of children: a collaborative study of 40 cases.

We studied, in 40 children (mean age: 52 months) with severe infectious purpura, the relationships between protein C (PC) and protein S (PS) levels, and shock, disseminated intravascular coagulation (DIC) and outcome. We determined, on admission, PC antigen (ELISA) and activity (chromogenic test), and total PS (ELISA). Results were expressed as % of normal adult values. Statistical analysis was performed with SAS. Thirty children were in shock, 20 had DIC. All children with DIC, and 10 without DIC were in shock. Of 20 children who were in shock and had DIC, 7 died and 3 had an amputation. PC antigen was significantly decreased in shock children (p less than 0.05), in children with DIC (p less than 0.0005), and in non-survivors (p less than 0.05). PC activity was significantly decreased in shock children (p less than 0.05), in children with DIC (p less than 0.0005), and in non-survivors (p less than 0.005). Total PS was not decreased in shock children, but was significantly decreased in children with DIC (p less than 0.005), and in non-survivors (p less than 0.005). We conclude that PC and PS levels were decreased in our children, and that PC levels were significantly decreased in the presence of shock, DIC, and fatal outcome. PC and antithrombin III (AT III) supplementation, should be evaluated in children with severe infectious purpura with shock and DIC.

[Beta 2 agonists in infants and young children with a wheeze: often ineffective]. / beta 2-sympathicomimetica bij zuigelingen en peuters met een piepende ademhaling: vaak ineffectief.

Wheezing is a common symptom in infants and young children, for which the treatment of choice is beta 2-agonists. However, the efficacy of beta 2-agonists in children aged 2 years and younger is not evidence based. Approximately 60% of wheezy infants do not have asthma, but a transient condition related to airway obstruction that is associated with coughing, wheezing and/or stuffiness: so-called infant asthma. In infants, beta 2-agonists may make the airways more compliant, resulting in more severe airway obstruction. In addition to this, beta 2-agonists increase the metabolism and cause ventilation-perfusion mismatch in the lung which may lead to a decrease in the oxygen saturation. Since it is unclear which infants will benefit from beta 2-agonists, a trial treatment is justified and this should be critically evaluated. Beneficial clinical effects of beta 2-agonists are a reduction in breathing frequency, reduction in or disappearance of retractions or the use of accessory respiratory muscles during breathing and possibly an increase in oxygen saturation. beta 2-agonists are effective and safe for the treatment of asthma. However, there is no basis for continuing the treatment in the case of infants and young children with an airway obstruction unless there is a clinically favourable effect.

[Negative effects of passive smoking on the (unborn) child]. / Nadelige effecten van passief roken op het (ongeboren) kind.

The negative effects of passive smoking on the health of the foetus or child continue to receive little attention, despite the large volume of research in this area. Passive smoking during pregnancy is associated with low birth weight, a reduction in head circumference at birth, and a far higher incidence of sudden infant death syndrome. Exposure to cigarette smoke also leads to a decreased lung function, an increased risk of severe infections, including respiratory syncytial virus bronchiolitis, meningococcal disease and middle ear infections. There is no association between passive smoking and the development of allergic asthma, but passive smoking does cause an increase in the prevalence of respiratory symptoms in children with or without asthma. Finally, there is a relation between passive smoking and behavioural disorders including attention deficit/hyperactivity disorder (ADHD). Passive smoking before birth seems even more harmful than after birth. A causal relationship is suggested in most studies, or has been proven by animal experiments. A decreased birth weight in general increases the risk of developing chronic diseases as an adult, such as hypertension, cardiovascular disease and type 2 diabetes mellitus. This extensive knowledge about the adverse health effects of smoke exposure in (unborn) children deserves greater attention in the counselling of pregnant women, and in anti-smoking campaigns.

Exhaled nitric oxide predicts asthma relapse in children with clinical asthma remission.

BACKGROUND: Nitric oxide in exhaled air (FE(NO)) is a marker of eosinophilic airway inflammation. A study was undertaken to determine whether FE(NO) predicts asthma relapse in asymptomatic asthmatic children in whom inhaled corticosteroids are discontinued. METHODS: Forty children (21 boys) of mean age 12.2 years on a median dose of 400 mug budesonide or equivalent (range 100-400) were included. FE(NO) was measured before and 2, 4, 12, and 24 weeks after withdrawal of steroids. A relapse was defined as more than one exacerbation per month, or need for beta agonist treatment on 4 days per week for at least 2 weeks, or diurnal peak flow variability of >20%. FE(NO) measurements were performed online with an expiratory flow of 50 ml/s. RESULTS: Nine patients relapsed. Two and 4 weeks after withdrawal of steroids geometric mean FE(NO) in children who were about to relapse was higher than in those who did not relapse: 35.3 ppb v 15.7 ppb at 2 weeks (ratio 2.3; 95% CI 1.2 to 4.1; p = 0.01) and 40.8 ppb v 15.9 ppb at 4 weeks (ratio 2.6; 95% CI 1.3 to 5.1). An FE(NO) value of 49 ppb at 4 weeks after discontinuation of steroids had the best combination of sensitivity (71%) and specificity (93%) for asthma relapse. CONCLUSION: FE(NO) 2 and 4 weeks after discontinuation of steroids in asymptomatic asthmatic children may be an objective predictor of asthma relapse.

Blue rubber-bleb naevus syndrome: report of a case with consumption coagulopathy complicated by manifest thrombosis.

Blue rubber-bleb naevus (BRBN) syndrome is a rare disorder characterized by subcutaneous and gastrointestinal haemangiomas. The latter may lead to bleeding complications. A case is reported in which a process of chronic intravascular coagulation resulted in serious thrombotic complications. In the presence of a chronic consumption coagulopathy, it remains uncertain whether antiplatelet drugs are of prophylactic antithrombotic value.

Streptokinase treatment for femoral artery thrombosis after arterial cardiac catheterisation in infants and children.

Data on 205 children who underwent retrograde arterial catheterisation were studied to assess the frequency of femoral artery thrombosis and the safety and efficacy of systemic streptokinase treatment for this complication. In 29 (14%) a transarterial balloon dilatation was performed. In 15 (7.3%) patients impaired arterial perfusion due to vascular spasm with or without thrombus formation was seen in the cannulated leg after catheterisation. Despite heparinisation, signs of impaired arterial circulation persisted in nine patients (4.4% of the total). In these patients femoral artery thrombosis was strongly suspected. Six (53%) of these had undergone a balloon dilatation. Therefore in this study the risk of femoral artery thrombosis developing was 12 times greater after transarterial balloon dilatation than after arterial catheterisation without dilatation (20.6% v 1.7%). Systemic infusion of streptokinase was started in all patients with femoral artery thrombosis. Arterial perfusion became normal in all patients, though in one this was delayed. Haematological monitoring showed lengthening of the thrombin time and a decrease of the fibrinogen concentration during streptokinase treatment. There were no serious complications. Systemic infusion of streptokinase is a safe and useful treatment in children with persistent femoral artery thrombosis after arterial cardiac catheterisation.

Adverse health effects of prenatal and postnatal tobacco smoke exposure on children.

Parents who choose to smoke are possibly not aware of, or deny, the negative effects of passive smoking on their offspring. This review summarises a wide range of effects of passive smoking on mortality and morbidity in children. It offers paediatricians, obstetricians, specialists in preventive child health care, general practitioners, and midwives an approach to promote smoking cessation in smoking parents before, during, and after pregnancy.

The effect of heparin in arterial catheters on the coagulation in preterm infants.

The coagulation of 16 healthy preterm infants (control infants) was compared with 15 ventilated preterm infants (study infants) receiving 0.5 ml/hr of a solution containing 5 IU/ml heparin intra-arterially in order to keep a radial artery catheter patent. A venous sample was obtained in both groups, in the study group a sample from the arterial catheter was also taken. Both the heparin dependent (APTT, thrombin time) and the heparin independent coagulation factors (AT-III, Clotting Factors I, II, V and VII) were not different between the venous samples of both groups. The arterial samples showed a significantly elevated APTT and thrombin time compared with venous samples, especially when the heparin level in the sample was higher than 0.1 IU/ml. These elevations are due to heparin in the sample from the arterial line as the venous sample in the same patient did not show any heparin effect. The heparin non-dependent factors were not different between venous and arterial samples. We conclude that a solution containing 5 IU/ml heparin given at a rate of 0.5 ml/hr does not influence coagulation in preterm infants. Determination of heparin independent coagulation factors can be done in both venous samples and samples taken from the arterial catheter, in these arterial samples the heparin dependent factors can be influenced by the heparin present in the catheters.

Compliance, hysteresis, and collapsibility of human small airways.

We tested the hypothesis that airway wall dimensions are important determinants for the mechanical properties of airways. Lung tissue was obtained from 31 smokers with different degrees of chronic obstructive pulmonary disease (COPD) who were operated on for a solitary lung lesion. Segments of small airways (n = 35) were mounted on cannulas in an organ bath and inflated and deflated cyclically between +15 and -15 cm H(2)O. For each airway this was done at baseline, after methacholine, and after isoprenaline. Specific compliance (sCdyn), specific hysteresis (seta), and pressure at which the airways collapsed (Pcol) were calculated from each recording. Airway wall dimensions were measured morphometrically. Lung function parameters of airflow obstruction were correlated to sCdyn, seta, and Pcol. At baseline, after methacholine, and after isoprenaline sCdyn was 0.059, 0.052, and 0. 085 cm H(2)O(-)(1), seta was 13.5, 12.9, and 7.1%, and Pcol was -3.4, -3.5, and -1.9 cm H(2)O, respectively. Differences between sCdyn, seta, and Pcol after methacholine and after isoprenaline were highly significant (p < 0.001). Of all dimensions studied, smooth muscle area, but not total wall area, was the most important determinant for sCdyn and for seta after methacholine. Specific hysteresis at baseline correlated to residual volume as a fraction of total lung capacity (RV/TLC) (r = 0.5, p = 0.05) and, in the presence of methacholine, to FEV(1)/FVC (r = -0.68, p = 0.02) and RV/TLC (r = 0. 5, p = 0.05). We conclude that, in this study, smooth muscle area and smooth muscle tone, but not total wall area, are determinants for compliance, hysteresis, and collapsibility of isolated airways obtained from smokers.

Exhaled nitric oxide measurements with dynamic flow restriction in children aged 4-8 yrs.

Fractional exhaled nitric oxide concentration (FENO) depends on exhalation flow; however, children often are unable to perform controlled flow procedures. Therefore, a device was developed for off-line FENO sampling, with dynamic flow restriction (DFR). The authors compared off-line with on-line FENO, assessed feasibility, and obtained normal values for FENO in children aged 4-8 yrs. Subjects inhaled nitric oxide (NO)-free air and exhaled into the device, where DFR kept exhalation flow constant at 50 mL x s(-1). Dead space air was discarded. Exhaled air was collected in a 150 mL mylar balloon. On-line measurements were performed and values compared with off-line FENO in 19 adult volunteers. Seventy-nine children performed off-line sampling. All samples were analysed with a chemiluminescence NO-analyser. Normal values were obtained in 34 healthy children. There was an excellent correlation between on- and off-line values. Bland and Altman plots showed good agreement between on- and off-line FENO. Seventy-four out of 79 children were able to perform a correct off-line procedure. Geometric mean+/-SEM FENO in healthy children was 4.9+/-1.2 parts per billion (ppb) for male children and 7.6+/-1.1 ppb for female children. It can be concluded that off-line fraction of exhaled nitric oxide measurements with dynamic flow restriction are feasible in young children and correspond to on-line values.

Bronchodilation in infants with malacia or recurrent wheeze.

BACKGROUND: Controversy remains regarding the effectiveness of bronchodilators in wheezy infants. AIMS: To assess the effect of inhaled beta(2) agonists on lung function in infants with malacia or recurrent wheeze, and to determine whether a negative effect of beta(2) agonists on forced expiratory flow (V'(maxFRC)) is more pronounced in infants with airway malacia, compared to infants with wheeze. METHODS: We retrospectively analysed lung function data of 27 infants: eight with malacia, 19 with recurrent wheeze. Mean (SD) age was 51 (18) weeks. Mean V'(maxFRC) (in Z score) was assessed before and after inhalation of beta(2) agonists. RESULTS: Baseline V'(maxFRC) was below reference values for both groups. Following inhalation of beta(2) agonists the mean (95% CI) change in mean V'(maxFRC) in Z scores was -0.10 (-0.26 to 0.05) and -0.33 (-0.55 to -0.11) for the malacia and wheeze group, respectively. CONCLUSIONS: In infants with wheeze, inhaled beta(2) agonists caused a significant reduction in mean V'(maxFRC). Infants with malacia were not more likely to worsen after beta(2) agonists than were infants with recurrent wheeze.