Nijmegen, Netherlands
Nijmegen, Netherlands

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Mellema W.W.,VU University Amsterdam | Masen-Poos L.,Robert Bosch GmbH | Smit E.F.,VU University Amsterdam | Hendriks L.E.L.,Maastricht University | And 15 more authors.
Lung Cancer | Year: 2015

OBJECTIVES: As suggested by in-vitro data, we hypothesize that subtypes of KRAS mutated non-small cell lung cancer (NSCLC) respond differently to chemotherapy regimens. METHODS: Patients with advanced NSCLC and known KRAS mutation, treated with first-line platinum-based chemotherapy, were retrieved from hospital databases. Primary objective: to investigate overall response rate (ORR), progression free survival (PFS) and overall survival (OS) between different types of platinum-based chemotherapy per type of KRAS mutation. RESULTS: 464 patients from 17 hospitals, treated between 2000 and 2013, were included. The majority of patients had stage IV disease (93%), had a history of smoking (98%) and known with an adenocarcinoma (91%). Most common types of KRAS mutation were G12C (46%), G12V (20%) and G12D (10%). Platinum was combined with pemetrexed (n=334), taxanes (n=68) or gemcitabine (n=62). Patients treated with taxanes had a significant improved ORR (50%) compared to pemetrexed (21%) or gemcitabine (25%; p<0.01). Patients treated with bevacizumab in addition to taxanes (n=38) had the highest ORR (62%). The PFS was significantly improved in patients treated with taxanes compared to pemetrexed (HR=0.72, p=0.02), but not OS (HR=0.87, p=0.41). In patients with G12V, significantly improved ORR (p<0.01) was observed for taxanes, but not PFS or OS. Patients with G12C or G12D mutation had comparable ORR, PFS and OS in all treatment groups. CONCLUSION: KRAS mutated NSCLC patients treated with taxane-based chemotherapy had best ORR. Response to chemotherapy regimens was different in types of KRAS mutation. Especially patients with G12V had better response to taxane treatment. © 2015 Elsevier Ireland Ltd. All rights reserved.


PubMed | Canisius Wilhemina Hospital, St Antonius Hospital, Erasmus Medical Center, Elisabeth TweeSteden Hospital and 2 more.
Type: Journal Article | Journal: Acta obstetricia et gynecologica Scandinavica | Year: 2016

Women with postmenopausal bleeding and endometrial thickness >4 mm undergo endometrial sampling to exclude endometrial cancer. The aim of this study is to investigate the relative risk of developing endometrial cancer in a prospective cohort after initial work-up for postmenopausal bleeding showing reassuring histology or insufficient sampling.All women presenting with postmenopausal bleeding were prospectively included from January 2009 to April 2011. Follow-up data were collected from patient charts and PALGA (Dutch Pathology Registry). Hazard ratios for endometrial cancer were determined by calculating standardized incidence ratios.A total of 668 women were included and 568 women were available for follow-up [median follow-up time 47 (range 7-63) months]. Women who presented with postmenopausal bleeding, endometrial thickness >4 mm and hyperplasia without atypia on biopsy at the first presentation showed a significantly increased risk (standardized incidence ratio 17.15, 95% confidence interval 1.96-61.93) of being diagnosed with endometrial cancer during the first four years of follow up compared with the age-specific population. All women that developed endometrial cancer after initial reassuring histology presented with recurrent postmenopausal bleeding. None of the women with endometrial thickness >4 mm and no or insufficient sample for histology at the first presentation developed endometrial cancer during the follow up.Although in general, women with endometrial hyperplasia without atypia are considered to have a low risk for cancer, we observed a significant long-term risk of endometrial cancer after postmenopausal bleeding. Whether additional diagnostics or a more stringent follow-up regimen would be cost-effective, needs to be studied.


PubMed | Robert Bosch GmbH, Gelre hospital, Canisius Wilhemina hospital, Ziekenhuis groep Twente and 13 more.
Type: Journal Article | Journal: Lung cancer (Amsterdam, Netherlands) | Year: 2015

As suggested by in-vitro data, we hypothesize that subtypes of KRAS mutated non-small cell lung cancer (NSCLC) respond differently to chemotherapy regimens.Patients with advanced NSCLC and known KRAS mutation, treated with first-line platinum-based chemotherapy, were retrieved from hospital databases.to investigate overall response rate (ORR), progression free survival (PFS) and overall survival (OS) between different types of platinum-based chemotherapy per type of KRAS mutation.464 patients from 17 hospitals, treated between 2000 and 2013, were included. The majority of patients had stage IV disease (93%), had a history of smoking (98%) and known with an adenocarcinoma (91%). Most common types of KRAS mutation were G12C (46%), G12V (20%) and G12D (10%). Platinum was combined with pemetrexed (n=334), taxanes (n=68) or gemcitabine (n=62). Patients treated with taxanes had a significant improved ORR (50%) compared to pemetrexed (21%) or gemcitabine (25%; p<0.01). Patients treated with bevacizumab in addition to taxanes (n=38) had the highest ORR (62%). The PFS was significantly improved in patients treated with taxanes compared to pemetrexed (HR=0.72, p=0.02), but not OS (HR=0.87, p=0.41). In patients with G12V, significantly improved ORR (p<0.01) was observed for taxanes, but not PFS or OS. Patients with G12C or G12D mutation had comparable ORR, PFS and OS in all treatment groups.KRAS mutated NSCLC patients treated with taxane-based chemotherapy had best ORR. Response to chemotherapy regimens was different in types of KRAS mutation. Especially patients with G12V had better response to taxane treatment.


PubMed | Martini Hospital, Robert Bosch GmbH, VieCuri Medical Center Noord Limburg, Canisius Wilhemina Hospital and 10 more.
Type: Journal Article | Journal: JAMA oncology | Year: 2016

This is the first randomized placebo-controlled evaluation of a medical intervention for the prevention of trastuzumab-related cardiotoxic effects.To determine as the primary end point whether angiotensin II antagonist treatment with candesartan can prevent or ameliorate trastuzumab-related cardiotoxic effects, defined as a decline in left ventricular ejection fraction (LVEF) of more than 15% or a decrease below the absolute value 45%.This randomized, placebo-controlled clinical study was conducted between October 2007 and October 2011 in 19 hospitals in the Netherlands, enrolling 210 women with early breast cancer testing positive for human epidermal growth factor receptor 2 (HER2) who were being considered for adjuvant systemic treatment with anthracycline-containing chemotherapy followed by trastuzumab.A total of 78 weeks of candesartan (32 mg/d) or placebo treatment; study treatment started at the same day as the first trastuzumab administration and continued until 26 weeks after completion of trastuzumab treatment.The primary outcome was LVEF. Secondary end points included whether the N-terminal of the prohormone brain natriuretic peptide (NT-proBNP) and high-sensitivity troponin T (hs-TnT) can be used as surrogate markers and whether genetic variability in germline ERBB2 (formerly HER2 or HER2/neu) correlates with trastuzumab-related cardiotoxic effects.A total of 206 participants were evaluable (mean age, 49 years; age range, 25-69 years) 103 in the candesartan group (mean age, 50 years; age range, 25-69 years) and 103 in the placebo group (mean age, 50 years; age range, 30-67 years). Of these, 36 manifested at least 1 of the 2 primary cardiac end points. There were 3.8% more cardiac events in the candesartan group than in the placebo group (95% CI, -7% to 15%; P=.58): 20 events (19%) and 16 events (16%), respectively. The 2-year cumulative incidence of cardiac events was 0.28 (95% CI, 0.13-0.40) in the candesartan group and 0.16 (95% CI, 0.08-0.22) in the placebo group (P=.56). Candesartan did not affect changes in NT-proBNP and hs-TnT values, and these biomarkers were not associated with significant changes in LVEF. The Ala1170Pro homozygous ERBB2 genotype was associated with a lower likelihood of the occurrence of a cardiac event compared with Pro/Pro+Ala/Pro genotypes in multivariate analysis (odds ratio, 0.09; 95% CI, 0.02-0.45; P=.003).The findings do not support the hypothesis that concomitant use of candesartan protects against a decrease in left ventricular ejection fraction during or shortly after trastuzumab treatment in early breast cancer. The ERBB2 germline Ala1170Pro single nucleotide polymorphism may be used to identify patients who are at increased risk of trastuzumab-related cardiotoxic effects.clinicaltrials.gov Identifier: NCT00459771.


Visser N.C.M.,Radboud University Nijmegen | Bulten J.,Radboud University Nijmegen | van der Wurff A.A.M.,St Elisabeth Hospital | Boss E.A.,Maxima Medical Center | And 14 more authors.
BMC Cancer | Year: 2015

Background: Endometrial carcinoma is the most common gynaecologic malignancy in industrialised countries and the incidence is still rising. Primary treatment is based on preoperative risk classification and consists in most cases of hysterectomy with bilateral salpingo-oophorectomy. In patients with serous and clear cell histology a complete surgical staging is mandatory. However, in routine clinical practice final histology regularly does not correspond with the preoperative histological diagnosis. This results in both over and under treatment. Methods/Design: The aim of this multicentre, prospective cohort study is to select a panel of prognostic biomarkers to improve preoperative diagnosis of endometrial carcinoma in order to identify those patients that need extended surgery and/or additional treatment. Additionally, we will determine whether incorporation of cervical cytology and comorbidity could improve this preoperative risk classification. All patients treated for endometrial carcinoma in the participating hospitals from September 2011 till December 2013 are included. Patient characteristics, as well as comorbidity are registered. Patients without preoperative histology, history of hysterectomy and/or endometrial carcinoma or no surgical treatment including hysterectomy are excluded. The preoperative histology and final pathology will be reviewed and compared by expert pathologists. Additional immunohistochemical analysis of IMP3, p53, ER, PR, MLH1, PTEN, beta-catenin, p16, Ki-67, stathmin, ARID1A and L1CAM will be performed. Preoperative histology will be compared with the final pathology results. Follow-up will be at least 24 months to determine risk factors for recurrence and outcome. Discussion: This study is designed to improve surgical treatment of endometrial carcinoma patients. A total of 432 endometrial carcinoma patients were enrolled between 2011 and 2013. Follow-up will be completed in 2015. Preoperative histology will be evaluated systematically and background endometrium will be classified. This is the first study incorporating immunohistochemistry, cervical cytology and comorbidity to define the optimal panel of prognostic biomarkers that contribute in clinical decision making in the management of endometrial carcinoma. Trial registration: Netherlands Trial Register number NTR3503. © 2015 Visser et al.


Visser N.C.M.,Radboud University Nijmegen | Bulten J.,Radboud University Nijmegen | van der Wurff A.A.M.,St Elisabeth Hospital | Boss E.A.,Maxima Medical Center | And 15 more authors.
BMC Cancer | Year: 2015

Background: Endometrial carcinoma is the most common gynaecologic malignancy in industrialised countries and the incidence is still rising. Primary treatment is based on preoperative risk classification and consists in most cases of hysterectomy with bilateral salpingo-oophorectomy. In patients with serous and clear cell histology a complete surgical staging is mandatory. However, in routine clinical practice final histology regularly does not correspond with the preoperative histological diagnosis. This results in both over and under treatment. Methods/Design: The aim of this multicentre, prospective cohort study is to select a panel of prognostic biomarkers to improve preoperative diagnosis of endometrial carcinoma in order to identify those patients that need extended surgery and/or additional treatment. Additionally, we will determine whether incorporation of cervical cytology and comorbidity could improve this preoperative risk classification. All patients treated for endometrial carcinoma in the participating hospitals from September 2011 till December 2013 are included. Patient characteristics, as well as comorbidity are registered. Patients without preoperative histology, history of hysterectomy and/or endometrial carcinoma or no surgical treatment including hysterectomy are excluded. The preoperative histology and final pathology will be reviewed and compared by expert pathologists. Additional immunohistochemical analysis of IMP3, p53, ER, PR, MLH1, PTEN, beta-catenin, p16, Ki-67, stathmin, ARID1A and L1CAM will be performed. Preoperative histology will be compared with the final pathology results. Follow-up will be at least 24months to determine risk factors for recurrence and outcome. Discussion: This study is designed to improve surgical treatment of endometrial carcinoma patients. A total of 432 endometrial carcinoma patients were enrolled between 2011 and 2013. Follow-up will be completed in 2015. Preoperative histology will be evaluated systematically and background endometrium will be classified. This is the first study incorporating immunohistochemistry, cervical cytology and comorbidity to define the optimal panel of prognostic biomarkers that contribute in clinical decision making in the management of endometrial carcinoma. Trial registration: Netherlands Trial Register number NTR3503. © Visser et al. 2015.


Fonteyn E.M.R.,Radboud University Nijmegen | Fonteyn E.M.R.,Canisius Wilhemina Hospital | Schmitz-Hubsch T.,University of Bonn | Verstappen C.C.P.,Canisius Wilhemina Hospital | And 14 more authors.
European Neurology | Year: 2013

In a previous retrospective study, we demonstrated that falls are common and often injurious in dominant spinocerebellar ataxias (SCAs) and that nonataxia features play an important role in these falls. Retrospective surveys are plagued by recall bias for the presence and details of prior falls. We therefore sought to corroborate and extend these retrospective findings by means of a prospective extension of this fall study. 113 patients with SCA1, SCA2, SCA3 or SCA6, recruited from the EuroSCA natural history study, were asked to keep a fall diary in between their annual visits to the participating centres. Additionally, patients completed a detailed questionnaire about the first three falls, to identify specific fall circumstances. Relevant disease characteristics were retrieved from the EuroSCA registry. 84.1% of patients reported at least one fall during a time period of 12 months. Fall-related injuries were common and their frequency increased with that of falls. The presence of nonataxia symptoms was associated with a higher fall frequency. This study confirms that falls are a frequent and serious complication of SCA, and that the presence of nonataxia symptoms is an important etiological factor in its occurrence. © 2012 S. Karger AG, Basel.


Bertholeta J.W.M.,Canisius Wilhemina Hospital | Joosten J.J.A.,Westfriesgasthuis | Keemers-Gelsa M.E.,Canisius Wilhemina Hospital | van den Wildenberga F.J.H.,Canisius Wilhemina Hospital | Barendregta W.B.,Canisius Wilhemina Hospital
Interactive Cardiovascular and Thoracic Surgery | Year: 2011

Much controversy exists regarding the management of chest tubes following pulmonary lobectomy. The objective of this study was to analyse the effect of a new chest tube management protocol on clinical features, such as postoperative air leak, drain characteristics, 30-day postoperative complications and length of hospital stay. We retrospectively analysed 133 patients who underwent pulmonary lobectomy, from January 2005 to December 2008. A new chest tube protocol was introduced on 1 January 2007 and included placement of a single chest tube and early conversion to water seal. The chest tube was removed when air leak had resolved and (non-chylous) fluid drainage was <400 ml/day. The results of patients in the old (n=68) and the new protocol (n=65) were compared. In the new protocol group the median duration of air leak and duration of chest tube drainage declined significantly. Also the length of hospital stay decreased significantly to a median of eight days. The number of reinterventions and 30-day morbidity and mortality rates did not differ significantly. Our data suggest that placement of a single chest tube and early conversion to water seal decreases the duration of air leak and chest tube drainage and length of hospital stay. © 2011 Published by European Association for Cardio-Thoracic Surgery.


te Riele M.G.E.,Radboud University Nijmegen | Verrips A.,Canisius Wilhemina Hospital
Cerebellum | Year: 2014

Hypomagnesaemia is common among hospitalised patients and is often under-recognised. Chronic alcohol abuse and alcohol withdrawal are known causes for severe hypomagnesaemia. Hypomagnesaemia can present with cardiac arrhythmias, seizures and other neurological symptoms, among which ataxia. We present a 57-year-old man with a history of chronic alcohol abuse who developed a subacute cerebellar syndrome with hypertension after alcohol withdrawal. A severe hypomagnesaemia of 0.19 mmol/L (normal values 0.70–1.10) was found. MRI showed diffuse, T2 hyperintense lesions in and swelling of the cerebellum. Symptoms, hypertension and MRI abnormalities significantly improved rapidly after intravenous magnesium supplementation. Hypomagnesaemia can cause a subacute, cerebellar syndrome and hypertension. Symptoms, hypertension and MRI abnormalities can be reversed with rapid magnesium supplementation. MRI abnormalities are similar to those caused by vascular endothelial dysregulation seen in posterior reversible encephalopathy syndrome (PRES). A similar case was recently described. We confirm that magnesium is likely to be involved in the pathophysiology of PRES. © 2014, Springer Science+Business Media New York.

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