Unilateral inguinofemoral lymphadenectomy in patients with early-stage vulvar squamous cell carcinoma and a unilateral metastatic sentinel lymph node is safe.

OBJECTIVE: Optimal management of the contralateral groin in patients with early-stage vulvar squamous cell carcinoma (VSCC) and a metastatic unilateral inguinal sentinel lymph node (SN) is unclear. We analyzed patients who participated in GROINSS-V I or II to determine whether treatment of the contralateral groin can safely be omitted in patients with a unilateral metastatic SN. METHODS: We selected the patients with a unilateral metastatic SN from the GROINSS-V I and II databases. We determined the incidence of contralateral additional non-SN metastases in patients with unilateral SN-metastasis who underwent bilateral inguinofemoral lymphadenectomy (IFL). In those who underwent only ipsilateral groin treatment or no further treatment, we determined the incidence of contralateral groin recurrences during follow-up. RESULTS: Of 1912 patients with early-stage VSCC, 366 had a unilateral metastatic SN. Subsequently, 244 had an IFL or no treatment of the contralateral groin. In seven patients (7/244; 2.9% [95% CI: 1.4%-5.8%]) disease was diagnosed in the contralateral groin: five had contralateral non-SN metastasis at IFL and two developed an isolated contralateral groin recurrence after no further treatment. Five of them had a primary tumor ≥30 mm. Bilateral radiotherapy was administered in 122 patients, of whom one (1/122; 0.8% [95% CI: 0.1%-4.5%]) had a contralateral groin recurrence. CONCLUSION: The risk of contralateral lymph node metastases in patients with early-stage VSCC and a unilateral metastatic SN is low. It appears safe to limit groin treatment to unilateral IFL or inguinofemoral radiotherapy in these cases.

Prediction of response to anti-PD-1 therapy in patients with non-small-cell lung cancer by electronic nose analysis of exhaled breath.

BACKGROUND: Immune checkpoint inhibitors have improved survival outcome of advanced non-small-cell lung cancer (NSCLC). However, most patients do not benefit. Therefore, biomarkers are needed that accurately predict response. We hypothesized that molecular profiling of exhaled air may capture the inflammatory milieu related to the individual responsiveness to anti-programmed death ligand 1 (PD-1) therapy. This study aimed to determine the accuracy of exhaled breath analysis at baseline for assessing nonresponders versus responders to anti-PD-1 therapy in NSCLC patients. METHODS: This was a prospective observational study in patients receiving checkpoint inhibitor therapy using both a training and validation set of NSCLC patients. At baseline, breath profiles were collected in duplicate by a metal oxide semiconductor electronic nose (eNose) positioned at the rear end of a pneumotachograph. Patients received nivolumab or pembrolizumab of which the efficacy was assessed by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 at 3-month follow-up. Data analysis involved advanced signal-processing and statistics based on independent t-tests followed by linear discriminant and receiver operating characteristic (ROC) analysis. RESULTS: Exhaled breath data of 143 NSCLC patients (training: 92, validation: 51) were available at baseline. ENose sensors contributed significantly (P < 0.05) at baseline in differentiating between patients with different responses at 3 months of anti-PD-1 treatment. The eNose sensors were combined into a single biomarker with an ROC-area under the curve (AUC) of 0.89 [confidence interval (CI) 0.82-0.96]. This AUC was confirmed in the validation set: 0.85 (CI 0.75-0.96). CONCLUSION: ENose assessment was effective in the noninvasive prediction of individual patient responses to immunotherapy. The predictive accuracy and efficacy of the eNose for discrimination of immunotherapy responder types were replicated in an independent validation set op patients. This finding can potentially avoid application of ineffective treatment in identified probable nonresponders.

Margin status revisited in vulvar squamous cell carcinoma.

OBJECTIVE: To determine the incidence of local recurrence of vulvar squamous cell carcinoma in relation to tumor- and/or precursor lesion free pathologic margins. METHODS: Consecutive patients with primary vulvar squamous cell carcinoma surgically treated in two Dutch expert centers between 2000 and 2010 were included. All pathology slides were independently reviewed by two expert gynecopathologists, and local recurrence was defined as any recurrent disease located on the vulva. Time to first local recurrence was compared for different subgroups using univariable and multivariable Cox-regression analyses. RESULTS: In total 287 patients with a median follow-up of 80months (range 0-204) were analyzed. The actuarial local recurrence rate ten years after treatment was 42.5%. Pathologic tumor free margin distance did not influence the risk on local recurrence (HR 1.03 (95% CI 0.99-1.06)), neither using a cutoff of eight, five, or three millimeters. Multivariable analyses showed a higher local recurrence rate in patients with dVIN and LS in the margin (HR 2.76 (95% CI 1.62-4.71)), in patients with dVIN in the margin (HR 2.14 (95% CI 1.11-4.12)), and a FIGO stage II or higher (HR 1.62 (95% CI 1.05-2.48)). CONCLUSIONS: Local recurrences frequently occur in patients with primary vulvar carcinoma and are associated with dVIN (with or without LS) in the pathologic margin rather than any tumor free margin distance. Our results should lead to increased awareness among physicians of an ongoing risk for local recurrence and need for life-long follow-up. Intensified follow-up and treatment protocols for patients with dVIN in the margin should be evaluated in future research.

A prospective multicenter trial on sentinel lymph node biopsy in patients with early-stage cervical cancer (SENTIX).

OBJECTIVE: Sentinel lymph node (SLN) biopsy has been increasingly used in the management of early-stage cervical cancer. It appears in guidelines as an alternative option to systematic pelvic lymphadenectomy. The evidence about safety is, however, based mostly on retrospective studies, in which SLN was combined with systematic lymphadenectomy. MATERIALS AND METHODS: SENTIX is a prospective multicenter trial aiming to prove that less-radical surgery with SLN is non-inferior to treatment with systematic pelvic lymphadenectomy. The primary end point is recurrence rate; the secondary end point is the prevalence of lower-leg lymphedema and symptomatic pelvic lymphocele. The reference recurrence rate was set up conservatively at 7% at 24 months after treatment. With a sample size of 300 patients treated per protocol, the trial is powered to detect a non-inferiority margin of 5% (90% power, p = 0.05) for recurrence rate, 30% reduction in the prevalence of symptomatic lymphocele or lower-leg lymphedema, with reference rates of 30% and 6% at 12 months (p = 0.025, Bonferroni correction). The patients eligible for SENTIX have stage IA1/LVSI+, IA2, IB1 (<2 cm for fertility sparing), with negative LN on pre-operative imaging. Intra-operatively, patients are excluded when there is a failure to detect SLN on both sides of the pelvis in cases of more advanced cancer (stage >IB1), or a positive intra-operative SLN assessment. The quality of SLN pathology evaluation will be assessed by central review. Three interim safety analyses are pre-planned when 30, 60, 150 patients complete 12 months' follow-up. CONCLUSIONS: The first patient was enrolled into the study in June 2016 and, by June 2018, 340 patients had been enrolled. The first analysis of secondary outcomes should be available in 2019 and the oncological outcome of 300 patients at the end of 2021. The trial is registered as a CEEGOG trial (CEEGOG CX-01), ENGOT trial (ENGOT-Cx 2), and at the ClinicalTrials.gov database (NCT02494063).

Early-life antibiotic exposure increases the risk of developing allergic symptoms later in life: A meta-analysis.

This study systematically reviewed and quantified the relationship between exposure to antibiotics during the first 2 years of life and the risk of allergies/atopies including hay fever, eczema, food allergy, positive skin prick testing (SPT), or elevated allergen-specific serum/plasma immunoglobulin (Ig) E levels later in life. PubMed and Web of Science databases were searched for observational studies published from January 1966 through November 11, 2015. Overall pooled estimates of the odds ratios (ORs) were obtained using fixed or random-effects models. Early-life exposure to antibiotics appears to be related to an increased risk of allergic symptoms of hay fever, eczema, and food allergy later in life. The summary OR for the risk of hay fever (22 studies) was 1.23, 95% confidence interval (CI):1.13-1.34; I2 : 77.0%. The summary OR for the risk of eczema (22 studies) was 1.26, 95% CI: 1.15-1.37; I2 : 74.2%, and the summary OR for food allergy (3 studies) was 1.42, 95% CI: 1.08-1.87; I2 : 80.8%. However, no association was found for antibiotics exposure early in life and objective atopy measurements including positive SPT or elevated allergen-specific serum/plasma IgE levels.

NOACs replace VKA as preferred oral anticoagulant among new patients: a drug utilization study in 560 pharmacies in The Netherlands.

BACKGROUND: In 2012, around 400.000 patients in the Netherlands were treated with Vitamin K Antagonists (VKA) for thromboembolic diseases. Since 2011, non-VKA oral anticoagulants (NOACs) are available. NOACs do not require frequent INR monitoring which benefits patients, but also imposes a risk of reduced therapy adherence. The objective of this study is to describe uptake and patient adherence of NOACs in The Netherlands until October 2016. METHODS: Prescription data for 247.927 patients across 560 pharmacies were used to describe patient profiles, uptake of NOACs among new naive patients and switch between VKA and NOACs, and calculate therapy adherence as the Proportion of Days Covered (PDC). RESULTS: During the studied period the share of NOACs in oral anticoagulants has grown to 57% of prescriptions to new patients. More than 70% of new NOAC users were new naive patients and around 26% switched from VKA. The overall share of NOACs among starters is largest in the group of patients of 50-80 years. Calculated compliance rate for NOAC patients shows that 88% of all users are adherent with a PDC higher than 80%. CONCLUSIONS: NOAC have overtaken VKA as the major treatment prescribed to new oral anticoagulant patients, and the number of starters on VKA is decreasing. Patients are generally adherent to NOACs during the implementation phase, the period that the medication is used. Fear for inadherence by itself does not need to be a reason for not prescribing NOACs instead of VKA.

Use of oral immunosuppressive drugs in the treatment of atopic dermatitis in the Netherlands.

BACKGROUND: Although atopic dermatitis (AD) is a very common skin disease, data on the percentage of patients with really difficult-to-treat AD are scarce. From socio-economic perspective, it is important to have more insight into these numbers, as new very effective, but expensive, treatment options will be available in the near future for difficult-to-treat AD. Estimating the number of patients with AD using oral immunosuppressive drugs can give an impression of the percentage of difficult-to-treat patients in the total AD population. OBJECTIVE: To give an overview of the use of oral immunosuppressive drugs in patients with AD in the Netherlands. METHODS: Prescription data of oral immunosuppressive drugs in the Netherlands were extracted from a pharmaceutical database (NControl) containing data of 557 million prescriptions and 7.2 million patients. An algorithm, based on the WHO Anatomical Therapeutic Chemical (ATC) codes, was used to identify patients with AD. The prescription of oral immunosuppressive drugs in patients with AD between 1 January 2012 and 1 January 2017 was evaluated. RESULTS: Based on the algorithm, 65 943 patients with AD were selected. 943 patients with AD (1.4%) used cyclosporine A, methotrexate, azathioprine or mycophenolic acid. Methotrexate was most commonly used, followed by azathioprine and cyclosporine A. A switch in medication was rarely seen. In the evaluation period, a decrease in the prescription of cyclosporine A was seen, together with an increase in the prescription of methotrexate. In 31% of the patients who stopped treatment, the discontinuation took place within the first months of treatment. CONCLUSION: In this study population, 1.4% of the patients with AD used oral immunosuppressive drugs for their eczema in a 5-year period. Methotrexate was the most commonly used systemic drug in the Netherlands for the treatment of AD.

Assessment of pharmacogenetic tests: presenting measures of clinical validity and potential population impact in association studies.

The progressing discovery of genetic variants associated with drug-related adverse events has raised expectations for pharmacogenetic tests to improve drug efficacy and safety. To further the use of pharmacogenetics in health care, tests with sufficient potential to improve efficacy and safety, as reflected by good clinical validity and population impact, need to be identified. The potential benefit of pharmacogenetic tests is often concluded from the strength of the association between the variant and the adverse event; measures of clinical validity are generally not reported. This paper describes measures of clinical validity and potential population health impact that can be calculated from association studies. We explain how these measures are influenced by the strength of the association and by the frequencies of the variant and the adverse event. The measures are illustrated using examples of testing for HLA-B*5701 associated with abacavir-induced hypersensitivity and SLCO1B1 c.521T>C (*5) associated with simvastatin-induced adverse events.

Pharmacogenomics of inhaled corticosteroids and leukotriene modifiers: a systematic review.

BACKGROUND: Pharmacogenetics studies of anti-inflammatory medication of asthma have expanded rapidly in recent decades, but the clinical value of their findings remains limited. OBJECTIVE: To perform a systematic review of pharmacogenomics and pharmacogenetics of inhaled corticosteroids (ICS) and leukotriene modifiers (LTMs) in patients with asthma. METHODS: Articles published between 1999 and June 2015 were searched using PubMed and EMBASE. Pharmacogenomics/genetics studies of patients with asthma using ICS or LTMs were included if ≥1 of the following outcomes were studied: lung function, exacerbation rates or asthma symptoms. The studies of Single Nucleotide Polymorphisms (SNPs) that had been replicated at least once were assessed in more detail. RESULTS: In total, 59 publications were included in the systematic review: 26 addressed LTMs (including two genomewide Genome-Wide association studies [GWAS]) and 33 addressed ICS (including four GWAS). None of the GWAS reported similar results. Furthermore, none of the SNPs assessed in candidate gene studies were identified in a GWAS. No consistent reports were found for candidate gene studies of LTMs. In candidate gene studies of ICS, the most consistent results were found for rs28364072 in FCER2. This SNP was associated with all three outcomes of poor response, and the largest effect was reported with the risk of exacerbations (hazard ratio, 3.95; 95% CI, 1.64-9.51). CONCLUSION AND CLINICAL RELEVANCE: There is a lack of replication of genetic variants associated with poor ICS or LTM response. The most consistent results were found for the FCER2 gene [encoding for a low-affinity IgE receptor (CD23)] and poor ICS response. Larger studies with well-phenotyped patients are needed to assess the clinical applicability of ICS and LTM pharmacogenomics/genetics.

Volume-controlled versus short drainage after inguinofemoral lymphadenectomy in vulvar cancer patients: A Dutch nationwide prospective study.

OBJECTIVE: Inguinofemoral lymphadenectomy for patients with vulvar squamous cell carcinoma is associated with a high incidence of postoperative wound complications, which may be influenced by inguinal drain management. The aim of this nationwide prospective study (MAMBO: Morbidity And Measurement of the BOdy) was to assess the feasibility and the incidence of complications after volume-controlled versus short drainage. METHODS: The MAMBO study consisted of two observational studies in all eight oncology centers in the Netherlands, conducted between 2012 and 2016. In the first study, the drain was removed when the production was <30ml/24h, except in the first 48h, and after a maximum of 28days (MAMBO-IA). In the second study, the drain was removed five days postoperatively regardless of production (MAMBO-IB). We assessed the complications within eight weeks after surgery using logistic regression to compare the incidence of one or more complications between the two drainage protocols, adjusting for possible confounders. RESULTS: We included 77 patients (139 groins) for volume-controlled drainage and 64 patients (112 groins) for short drainage. Volume-controlled drainage was associated with significant less lymphocele formation. Moreover, we found no difference in wound infection or primary wound breakdown. The estimated incidence of one or more complications was 46% per groin after volume-controlled drainage versus 75% after short drainage, (RD 29% (95% CI 8, 49) p=0.006). CONCLUSIONS: This prospective study shows that volume-controlled drainage is associated with significantly less complications compared to short drainage. We therefore recommend volume-controlled drainage after inguinofemoral lymphadenectomy in patients with vulvar squamous cell carcinoma.

Atopic dermatitis characteristics and medication-use patterns in school-age children with AD and asthma symptoms.

BACKGROUND: Atopic dermatitis (AD) and asthma often coexist. Both diseases can have a major impact on the lives of children with AD and their caregivers. AIM: To investigate the association of patient characteristics, comorbidities and impact of AD on children who have both asthma and AD. METHODS: Children with AD (n = 140) were selected from a larger cohort of children with a reported use of asthma medication. The Children's Dermatology Life Quality Index (CDLQI) was used to assess Quality of Life (QoL), and the Self-Assessed Eczema Area and Severity Index (SA-EASI) was used to measure AD severity. Characteristics assessed included: age, sex, and the number and type of atopic comorbidities. Medication use for AD was defined using the total number of AD prescriptions, the number of different topical AD prescriptions and the highest potency topical corticosteroid (TCS) used. Determinants of AD severity and QoL were evaluated using Spearman rank tests. RESULTS: The following factors were most strongly associated with a lower QoL: characteristics of AD lesions (Spearman Rs = 0.61-0.69, P < 0.01), a higher SA-EASI score (Rs = 0.54, P < 0.01) and a larger number of different topical AD prescriptions (Rs = 0.38, P < 0.01). The following factors were correlated with more severe AD: age (Rs = -0.36, P < 0.01), larger number of different TCS preparations used (Rs = 0.27, P < 0.05) and larger number of TCS prescriptions (Rs = 0.25, P < 0.05). CONCLUSION: In children with asthma and AD, the number of TCS preparations used is associated with lower QoL and increased AD severity.

Molecular imaging in ovarian cancer.

Ovarian cancer has a high mortality and novel-targeted treatment strategies have not resulted in breakthroughs for this disease. Insight into the molecular characteristics of ovarian tumors may improve diagnosis and selection of patients for treatment with targeted therapies. A potential way to achieve this is by means of molecular imaging. Generic tumor processes, such as glucose metabolism ((18)F-fluorodeoxyglucose) and DNA synthesis ((18)F-fluorodeoxythymidine), can be visualized non-invasively. More specific targets, such as hormone receptors, growth factor receptors, growth factors and targets of immunotherapy, can also be visualized. Molecular imaging can capture data on intra-patient tumor heterogeneity and is of potential value for individualized, target-guided treatment selection. Early changes in molecular characteristics during therapy may serve as early predictors of response. In this review, we describe the current knowledge on molecular imaging in the diagnosis and as an upfront or early predictive biomarker in patients with ovarian cancer.

Cost-effectiveness of pharmacogenetic-guided dosing of warfarin in the United Kingdom and Sweden.

We aimed to assess the cost-effectiveness of pharmacogenetic-guided dosing of warfarin in patients with atrial fibrillation (AF) in the United Kingdom and Sweden. Data from EU-PACT, a randomized controlled trial in newly diagnosed AF patients, were used to model the incremental costs per quality-adjusted life-year (QALY) gained by pharmacogenetic-guided warfarin dosing versus standard treatment over a lifetime horizon. Incremental lifetime costs were £26 and 382 Swedish kronor (SEK) and incremental QALYs were 0.0039 and 0.0015 in the United Kingdom and Sweden, respectively. The corresponding incremental cost-effectiveness ratios (ICERs) were £6 702 and 253 848 SEK per QALY gained. The ICER was below the willingness-to-pay threshold of £20 000 per QALY gained in 93% of the simulations in the United Kingdom and below 500 000 SEK in 67% of the simulations in Sweden. Our data suggest that pharmacogenetic-guided dosing of warfarin is a cost-effective strategy to improve outcomes of patients with AF treated with warfarin in the United Kingdom and in Sweden.

Genetic variation in uncontrolled childhood asthma despite ICS treatment.

Genetic variation may partly explain asthma treatment response heterogeneity. We aimed to identify common and rare genetic variants associated with asthma that was not well controlled despite inhaled corticosteroid (ICS) treatment. Data of 110 children was collected in the Children Asthma Therapy Optimal trial. Associations of genetic variation with measures of lung function (FEV1%pred), airway hyperresponsiveness (AHR) to methacholine (Mch PD20) and treatment response outcomes were analyzed using the exome chip. The 17q12-21 locus (containing ORMDL3 and GSMDB) previously associated with childhood asthma was investigated separately. Single-nucleotide polymorphisms (SNPs) in the 17q12-21 locus were found nominally associated with the outcomes. The strongest association in this region was found for rs72821893 in KRT25 with FEV1%pred (P=3.75*10(-5)), Mch PD20 (P=0.00095) and Mch PD20-based treatment outcome (P=0.006). No novel single SNPs or burden tests were significantly associated with the outcomes. The 17q12-21 region was associated with FEV1%pred and AHR, and additionally with ICS treatment response.

A genome-wide association study identifies variants in KCNIP4 associated with ACE inhibitor-induced cough.

The most common side effect of angiotensin-converting enzyme inhibitor (ACEi) drugs is cough. We conducted a genome-wide association study (GWAS) of ACEi-induced cough among 7080 subjects of diverse ancestries in the Electronic Medical Records and Genomics (eMERGE) network. Cases were subjects diagnosed with ACEi-induced cough. Controls were subjects with at least 6 months of ACEi use and no cough. A GWAS (1595 cases and 5485 controls) identified associations on chromosome 4 in an intron of KCNIP4. The strongest association was at rs145489027 (minor allele frequency=0.33, odds ratio (OR)=1.3 (95% confidence interval (CI): 1.2-1.4), P=1.0 × 10(-8)). Replication for six single-nucleotide polymorphisms (SNPs) in KCNIP4 was tested in a second eMERGE population (n=926) and in the Genetics of Diabetes Audit and Research in Tayside, Scotland (GoDARTS) cohort (n=4309). Replication was observed at rs7675300 (OR=1.32 (1.01-1.70), P=0.04) in eMERGE and at rs16870989 and rs1495509 (OR=1.15 (1.01-1.30), P=0.03 for both) in GoDARTS. The combined association at rs1495509 was significant (OR=1.23 (1.15-1.32), P=1.9 × 10(-9)). These results indicate that SNPs in KCNIP4 may modulate ACEi-induced cough risk.

Improved outcomes due to changes in organization of care for patients with ovarian cancer in the Netherlands.

OBJECTIVES: Objectives of this study were to evaluate the effect of changes in patterns of care, for example centralization and treatment sequence, on surgical outcome and survival in patients with epithelial ovarian cancer (EOC). METHODS: Patients diagnosed with FIGO stage IIB-IV EOC (2004-2013) were selected from the Netherlands Cancer Registry. Primary outcomes were surgical outcome (extent of macroscopic residual tumor after surgery) and overall survival. Changes in treatment sequence (primary debulking surgery and adjuvant chemotherapy (PDS+ACT) or neo-adjuvant chemotherapy and interval debulking surgery (NACT+IDS)), hospital type and annual hospital volume were also evaluated. RESULTS: Patient and tumor characteristics of 7987 patients were retrieved. Most patients were diagnosed with stage III-IV EOC. The average annual case-load per hospital increased from 8 to 28. More patients received an optimal cytoreduction (tumor residue≤1cm) in 2013 (87%) compared to 2004 (55%, p<0.001). Complete cytoreduction (no macroscopic residual tumor), registered since 2010, increased from 42% to 52% (2010 and 2013, respectively, p<0.001). Optimal/complete cytoreduction was achieved in 85% in high volume (≥20 cytoreductive surgeries annually), 80% in medium (10-19 surgeries) and 71% in small hospitals (<10 surgeries, p<0.001). Within a selection of patients with advanced stage disease that underwent surgery the proportion of patients undergoing NACT+IDS increased from 28% (2004) to 71% (2013). Between 2004 and 2013 a 3% annual reduction in risk of death was observed (HR 0.97, p<0.001). CONCLUSION: Changes in pattern of care for patients with EOC in the Netherlands have led to improvement in surgical outcome and survival.

Sentinel nodes in vulvar cancer: Long-term follow-up of the GROningen INternational Study on Sentinel nodes in Vulvar cancer (GROINSS-V) I.

OBJECTIVE: In 2008 GROINSS-V-I, the largest validation trial on the sentinel node (SN) procedure in vulvar cancer, showed that application of the SN-procedure in patients with early-stage vulvar cancer is safe. The current study aimed to evaluate long-term follow-up of these patients regarding recurrences and survival. METHODS: From 2000 until 2006 GROINSS-V-I included 377 patients with unifocal squamous cell carcinoma of the vulva (T1, <4 cm), who underwent the SN-procedure. Only in case of SN metastases an inguinofemoral lymphadenectomy was performed. For the present study follow-up was completed until March 2015. RESULTS: Themedian follow-up was 105 months (range 0­179). The overall local recurrence ratewas 27.2% at 5 years and 39.5% at 10 years after primary treatment, while for SN-negative patients 24.6% and 36.4%, and for SN-positive patients 33.2% and 46.4% respectively (p = 0.03). In 39/253 SN-negative patients (15.4%) an inguinofemoral lymphadenectomy was performed, because of a local recurrence. Isolated groin recurrence rate was 2.5% for SN-negative patients and 8.0% for SN-positive patients at 5 years. Disease-specific 10-year survival was 91% for SN-negative patients compared to 65% for SN-positive patients (p b .0001). For all patients, 10-year disease-specific survival decreased from 90% for patients without to 69% for patients with a local recurrence (p b .0001).

ST13 polymorphisms and their effect on exacerbations in steroid-treated asthmatic children and young adults.

BACKGROUND: The clinical response to inhaled corticosteroids (ICS) is associated with single nucleotide polymorphisms (SNPs) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS. METHODS: We performed a meta-analysis of three cohort studies: Pharmacogenetics of Asthma Medication in Children: Medication with Anti-Inflammatory effects (n = 357, age: 4-12 years, the Netherlands), BREATHE (n = 820, age: 3-22 years, UK) and Paediatric Asthma Gene Environment Study (n = 391, age: 2-16 years, UK). Seventeen genes were selected based on a role in the glucocorticoid signalling pathway or a reported association with asthma. Two outcome parameters were used to reflect exacerbations: hospital visits and oral corticosteroid (OCS) use in the previous year. The most significant associations were tested in three independent validation cohorts; the Childhood Asthma Management Programme (clinical trial, n = 172, age: 5-12 years, USA), the Genes- environment and Mixture in Latino Americans II- study (n = 745, age: 8-21, USA) and the Pharmacogenetics of adrenal suppression cohort (n = 391, age: 5-18, UK) to test the robustness of the findings. Finally, all results were meta-analysed. RESULTS: Two SNPs in ST13 (rs138335 and rs138337), but not in the other genes, were associated at a nominal level with an increased risk of exacerbations in asthmatics using ICS in the three cohorts studied. In a meta-analysis of all six studies, ST13 rs138335 remained associated with an increased risk of asthma-related hospital visits and OCS use in the previous year; OR = 1.22 (P = 0.013) and OR = 1.22 (P = 0.0017), respectively. CONCLUSION AND CLINICAL RELEVANCE: A novel susceptibility gene, ST13, coding for a cochaperone of the glucocorticoid receptor, is associated with exacerbations in asthmatic children and young adults despite their ICS use. Genetic variation in the glucocorticoid signalling pathway may contribute to the interindividual variability in clinical response to ICS treatment in children and young adults.

Association of polymorphisms in the beta-2 adrenergic receptor gene with fracture risk and bone mineral density.

UNLABELLED: Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms influence receptor function. We show that these polymorphisms are not associated with fracture risk or bone mineral density in the UCP, Rotterdam Study, and GEFOS cohorts. INTRODUCTION: Signaling through the beta-2 adrenergic receptor (B2AR) on the osteoblast influences bone remodeling in rodents. In the B2AR gene, three polymorphisms are known to influence receptor function in vitro and in vivo (rs1042713, rs1042714, and rs1800888). We examined the role of these polymorphisms in the B2AR gene on human bone metabolism. METHODS: We performed nested case-control studies to determine the association of these polymorphisms with fracture risk in the Utrecht Cardiovascular Pharmacogenetics (UCP) cohort and in three cohorts of the Rotterdam Study. We also determined the association of these polymorphisms with bone mineral density (BMD) in the GEFOS Consortium. UCP contains drug-dispensing histories from community pharmacies linked to national registrations of hospital discharges in the Netherlands. The Rotterdam Study is a prospective cohort study investigating demographics and risk factors of chronic diseases. GEFOS is a large international collaboration studying the genetics of osteoporosis. Fractures were defined by ICD-9 codes 800-829 in the UCP cohort (158 cases and 2617 unmatched controls) and by regular X-ray examinations, general practitioner, and hospital records in the Rotterdam Study (2209 cases and 8559 unmatched controls). BMD was measured at the femoral neck and lumbar spine using dual-energy X-ray absorptiometry in GEFOS (N = 32,961). RESULTS: Meta-analysis of the two nested case-control studies showed pooled odds ratios of 0.98 (0.91-1.05, p = 0.52), 1.04 (0.97-1.12, p = 0.28), and 1.16 (0.83-1.62, p = 0.38) for the associations between rs1042713, rs1042714, and rs1800888 per minor allele and fractures, respectively. There were no significant associations of the polymorphisms and BMD in GEFOS. CONCLUSION: In conclusion, polymorphisms in the beta-2 adrenergic receptor gene are not associated with fracture risk or BMD.

A panel of regulated proteins in serum from patients with cervical intraepithelial neoplasia and cervical cancer.

We developed a discovery-validation mass-spectrometry-based pipeline to identify a set of proteins that are regulated in serum of patients with cervical intraepithelial neoplasia (CIN) and squamous cell cervical cancer using iTRAQ, label-free shotgun, and targeted mass-spectrometric quantification. In the discovery stage we used a "pooling" strategy for the comparative analysis of immunodepleted serum and revealed 15 up- and 26 down-regulated proteins in patients with early- (CES) and late-stage (CLS) cervical cancer. The analysis of nondepleted serum samples from patients with CIN, CES, an CLS and healthy controls showed significant changes in abundance of alpha-1-acid glycoprotein 1, alpha-1-antitrypsin, serotransferrin, haptoglobin, alpha-2-HS-glycoprotein, and vitamin D-binding protein. We validated our findings using a fast UHPLC/MRM method in an independent set of serum samples from patients with cervical cancer or CIN and healthy controls as well as serum samples from patients with ovarian cancer (more than 400 samples in total). The panel of six proteins showed 67% sensitivity and 88% specificity for discrimination of patients with CIN from healthy controls, a stage of the disease where current protein-based biomarkers, for example, squamous cell carcinoma antigen (SCCA), fail to show any discrimination. Additionally, combining the six-protein panel with SCCA improves the discrimination of patients with CES and CLS from healthy controls.