Publications by authors named "Annelies Janssens"

76 Publications

Immunoglobin G/total antibody testing for SARS-CoV-2: A prospective cohort study of ambulatory patients and health care workers in two Belgian oncology units comparing three commercial tests.

Eur J Cancer 2021 Feb 27;148:328-339. Epub 2021 Feb 27.

Multidisciplinary Oncologic Centre Antwerp (MOCA), Antwerp University Hospital, Wilrijkstraat 10, Edegem, B-2650, Belgium; Center for Oncological Research (CORE), Integrated Personalised and Precision Oncology Network (IPPON), University of Antwerp, Universiteitsplein 1, Wilrijk, B-2610, Belgium.

Background: Coronavirus disease (COVID-19) is interfering heavily with the screening, diagnosis and treatment of cancer patients. Better knowledge of the seroprevalence and immune response after Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) infection in this population is important to manage them safely during the pandemic.

Methods: 922 cancer patients, 100 non-cancer patients and 94 health care workers (HCW) attending the Multidisciplinary Oncology Unit of Antwerp University Hospital from 24th of March 2020 till 31st of May 2020, and the Oncology Unit of AZ Maria Middelares Hospital, Ghent, from 13th of April 2020 till 31st of May 2020 participated in the study. The Alinity® (A; Abbott) and Liaison® (D; DiaSorin) commercially available assays were used to measure SARS-CoV-2 IgG, while total SARS-CoV-2 Ig was measured by Elecsys® (R; Roche).

Results: In the overall study population IgG/total SARS-CoV-2 antibodies were found in respectively 32/998 (3.2%), 68/1020 (6.7%), 37/1010 (3.7%) and of individuals using the A, D or R test. Forty-six out of 618 (7.4%) persons had a positive SARS-CoV-2 polymerase chain reaction (RT-PCR) test. Seroprevalence in cancer patients (A:2.2%, D:6.2%, R:3.0%), did not significantly differ from that in non-cancer patients (A:1.1%, D:5.6%, R:0.0%), but was lower than the HCW (A:13%, D:12%, R:12%; respectively Fisher's exact test p = 0.00001, p = 0.046, p = 0.0004). A positive SARS-CoV-2 RT-PCR was found in 6.8% of the cancer patients, 2.3% of the non-cancer patients and 28.1% of the HCW (Fisher's exact test p = 0.0004). Correlation between absolute values of the different Ig tests was poor in the cancer population. Dichotomising a positive versus negative test result, the A and R test correlated well (kappa 0.82 p McNemar test = 0.344), while A and D and R and D did not (respectively kappa 0.49 and 0.57; result significantly different p McNemar test = <0.0001 for both). The rate of seroconversion (>75%) and median absolute antibody levels (A: 7.0 versus 4.7; D 74.0 versus 26.6, R: 16.34 versus 7.32; all >P Mann Whitney U test = 0.28) in cancer patients and HCW with a positive RT-PCR at least 7 days earlier did not show any differences. However, none (N = 0/4) of the patients with hematological tumours had seroconversion and absolute antibody levels remained much lower compared to patients with solid tumours (R: 0.1 versus 37.6, p 0.003; D 4.1 versus 158, p 0.008) or HCW (all p < 0.0001).

Conclusion: HCW were at high risk of being infected by SARS-CoV-2 during the first wave of the pandemic. Seroprevalence in cancer patients was low in the study period. Although Ig immune response in cancer patients with solid tumours does not differ from healthy volunteers, patients with hematological tumours have a very poor humoral immune response. This has to be taken into account in future vaccination programmes in this population. SARS-CoV-2 antibody tests have divergent results and seem to have little added value in the management of cancer patients.
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http://dx.doi.org/10.1016/j.ejca.2021.02.024DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7914028PMC
February 2021

Real-World Treatment Patterns, Epidermal Growth Factor Receptor (EGFR) Testing and Outcomes in EGFR-Mutated Advanced Non-small Cell Lung Cancer Patients in Belgium: Results from the REVEAL Study.

Drugs Real World Outcomes 2021 Mar 12. Epub 2021 Mar 12.

Department of Pulmonology, Cliniques Universitaires Saint-Luc, Université Catholique de Louvain, Brussels, Belgium.

Background: Treatment of patients with epidermal growth factor receptor-mutated (EGFRm) non-small cell lung cancer (NSCLC) continues to evolve expeditiously.

Objectives: This retrospective study investigated real-world treatment patterns and EGFR mutation testing in patients with EGFRm advanced NSCLC in Belgium.

Methods: Data were extracted from medical records of adults diagnosed with EGFRm locally advanced/metastatic NSCLC between 1 September 2015 and 31 December 2017. Patients were followed retrospectively from diagnosis until 1 September 2018, end of clinical activity or death. Data on demographics, patient outcomes and disease characteristics, treatment patterns and EGFR mutation testing at diagnosis and progression were analyzed descriptively.

Results: A total of 141 patients were enrolled. At diagnosis, median age was 69 years, 63.1% were female, 88.7% had metastatic disease, 94.3% had adenocarcinoma histology, 76.6% had ECOG 0/1, 70.9% had common EGFR mutations and 29.1% had only rare mutations. In first line, 73.8% of patients received first/second-generation EGFR-tyrosine kinase inhibitors (1G/2G EGFR-TKIs), while 21.9% received other systemic treatments. Among 61 patients progressing on and discontinuing a first 1G/2G EGFR-TKI, 45 (73.8%) received subsequent systemic treatment while 16 (26.2%) did not; 20 (32.8%) received osimertinib. Among 65 patients progressing on a first 1G/2G EGFR-TKI, 47 (72.3%) were tested for T790M, of whom 25 (53.2%) were positive.

Conclusion: These real-world data from Belgium show that a substantial fraction of patients with EGFRm NSCLC do not receive 1G/2G EGFR-TKIs in first line and do not receive subsequent systemic treatment after progression on 1G/2G EGFR-TKIs. Only a third receive osimertinib upon progression on 1G/2G EGFR-TKIs. These observations should be considered in first-line treatment decisions.

Trial Registration: ClinicalTrials.gov: NCT03761901-December 3, 2018.
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http://dx.doi.org/10.1007/s40801-021-00243-wDOI Listing
March 2021

Cancer-Associated Fibroblasts as a Common Orchestrator of Therapy Resistance in Lung and Pancreatic Cancer.

Cancers (Basel) 2021 Feb 27;13(5). Epub 2021 Feb 27.

Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, B2610 Antwerp, Belgium.

Cancer arises from mutations accruing within cancer cells, but the tumor microenvironment (TME) is believed to be a major, often neglected, factor involved in therapy resistance and disease progression. Cancer-associated fibroblasts (CAFs) are prominent and key components of the TME in most types of solid tumors. Extensive research over the past decade revealed their ability to modulate cancer metastasis, angiogenesis, tumor mechanics, immunosuppression, and drug access through synthesis and remodeling of the extracellular matrix and production of growth factors. Thus, they are considered to impede the response to current clinical cancer therapies. Therefore, targeting CAFs to counteract these protumorigenic effects, and overcome the resistance to current therapeutic options, is an appealing and emerging strategy. In this review, we discuss how CAFs affect prognosis and response to clinical therapy and provide an overview of novel therapies involving CAF-targeting agents in lung and pancreatic cancer.
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http://dx.doi.org/10.3390/cancers13050987DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7956441PMC
February 2021

The tele-transition of toxicity management in routine oncology care during the severe acute respiratory syndrome (SARS-CoV-2) pandemic.

Br J Cancer 2021 04 9;124(8):1366-1372. Epub 2021 Feb 9.

Department of Oncology, Antwerp University Hospital Antwerp, Antwerp, Belgium.

Background: Telehealth modalities were introduced during the SARS-CoV-2 pandemic to assure continuation of cancer care and maintain social distance.

Methods: This is a retrospective cohort analysis of our telehealth expansion programme. We adapted two existing patient-reported outcome (PRO) telemonitoring tools that register and (self-)manage toxicities to therapy, while screening for SARS-CoV-2-related symptoms. Outpatients from a tertiary cancer centre were enrolled. The adapted PRO interface allowed for uniform registration of SARS-CoV-2-related symptoms and effective triage of patients at home where we also implemented systematic throat washings, when available.

Results: Three hundred and sixty patients registered to the telemonitoring systems from March 13 to May 15, 2020. Four prespecified SARS-CoV-2 alarms resulted in three patients with positive PCR testing. Other Covid-19 symptoms (fever 5× and cough 2×) led to pretreatment triage resulting in 1 seroconversion after initial negative testing. One of the 477 throat washings proved positive.

Conclusions: The rapid adoption of an amended PRO (self-)registrations and toxicity management system was feasible and coordinated screening for Covid-19. Continued clinical cancer care was maintained, with significant decreased waiting time. The systemic screening with throat washings offered no real improvement.
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http://dx.doi.org/10.1038/s41416-020-01235-3DOI Listing
April 2021

Caspr2 autoantibody-associated Morvan syndrome predating thymoma relapse by 30 months.

Lung Cancer 2021 03 13;153:117-119. Epub 2021 Jan 13.

Department of Neurology, Antwerp University Hospital, Edegem, Belgium.

Morvan's syndrome (MoS) is a rare autoimmune disorder characterized by central nervous system involvement, autonomic dysfunction and peripheral nerve hyperexcitability. MoS is believed to be caused by autoantibodies targeting contactin-associated protein 2 (Caspr2), a subunit of the neuronal voltage-gated potassium channel (VGKC) complex, usually in association with thymoma, less commonly with other malignancies. This case highlights an exceptional case of severe sleep disturbances and behavioural changes due to MoS, in a patient who would present with and be treated successfully for a second relapse of thymoma 30 months later. Originally he suffered from ocular myasthenia, another autoimmune disorder, which led to diagnosis of his original thymoma and first relapse.
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http://dx.doi.org/10.1016/j.lungcan.2021.01.012DOI Listing
March 2021

Evaluation of mediastinoscopy in mediastinal lymph node staging for non-small-cell lung cancer.

Interact Cardiovasc Thorac Surg 2021 Jan;32(2):270-275

Department of Thoracic and Vascular Surgery, Antwerp University Hospital, Antwerp, Belgium.

Objectives: The purpose of this study was to assess the quality of video-assisted cervical mediastinoscopy (VACM) in the staging of non-small-cell lung cancer (NSCLC) at the Antwerp University Hospital with a focus on test effectiveness indicators, morbidity and unforeseen pN2 results.

Methods: All consecutive VACM workups of cases of NSCLC performed between January 2010 and December 2015 were included to assess overall test quality and effectiveness. Quality assurance was performed in accordance with the recommendations of the European Society of Gastrointestinal Endoscopy and European Society of Thoracic Surgeons (ESTS) where appropriate.

Results: A total of 168 video-assisted cervical mediastinoscopies were included. A total of 91.7% of the procedures were performed in accordance with the ESTS guideline. An unforeseen pN2 staging was identified in 10 anatomical lung resections (8.6%). Statistical analysis showed no significant association between VACM performed in accordance with the ESTS guideline and the presence of pN2 positive lymph nodes [χ2 (1) = 0.61; P = 0.57] and no association between VACM performed in accordance with the ESTS guideline and overall futile thoracotomy [χ2 (1) = 0.76; P = 0.50]. Calculations revealed a sensitivity of 81.8 [95% confidence interval (CI) 69.1-90.9], specificity of 100%, positive predictive value of 100%, negative predictive value of 91.9% (95% CI 86.6-95.2) and diagnostic accuracy of 94.1% (95% CI 89.33-97.11).

Conclusions: Overall, 91.7% of the VACM were performed in accordance with the ESTS guideline. This process resulted in a sensitivity of 81.8%, a negative predictive value of 91.9% and an unforeseen pN2 rate of 8.6%.
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http://dx.doi.org/10.1093/icvts/ivaa263DOI Listing
January 2021

Coping Strategy Influences Quality of Life in Patients With Advanced Lung Cancer by Mediating Mood.

Clin Lung Cancer 2021 Mar 18;22(2):e146-e152. Epub 2020 Sep 18.

University Hospital Antwerp, Department of Thoracic Oncology, Edegem, Belgium.

Introduction: Patients with advanced lung cancer experience high physical symptom burden with substantial psychological distress. Depressive and anxiety symptoms are common and associated with worse quality of life (QoL). Early palliative care (EPC) addresses the complex supportive care needs improving QoL and mood. The mechanisms of EPC are uncertain. We examined whether and how coping strategy, a primary component of EPC, influenced QoL in these patients.

Materials And Methods: We conducted a multicenter cross-sectional study of patients with advanced lung cancer. A total of 125 patients completed assessments of QoL (QLQ-C15-PAL), depressive and anxiety symptoms (HADS), and coping (brief COPE questionnaire). The data were analyzed by descriptive statistics. To determine whether and how coping strategy influences QoL, correlations and logistic regressions were performed.

Results: Positive reframing correlates significantly with global QoL (r = 0.25, P < .01), emotional well-being (r = 0.33, P < .01), pain (r = -0.30, P < .01), fatigue (r = -0.22, P < .01), loss of appetite (r = -0.22, P < .01) and nausea (r = -0.24, P < .01). Self-blame correlates significantly with worse emotional well-being (r = -0.19, P < .05) and insomnia (r = 0.19, P < .05). Using a 4-step logistic regression model, it was found that anxiety and depressive symptoms fully mediated the relationship between positive reframing and QoL.

Conclusions: Patients with advanced lung cancer using positive reframing as coping strategy, experience higher QoL. The mechanism behind it seems that positive reframing goes along with less anxiety and depressive symptoms leading to a better QoL. Self-blame leads to more insomnia and worse emotional well-being. Providing skills to cope effectively could impact QoL in these patients.
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http://dx.doi.org/10.1016/j.cllc.2020.09.010DOI Listing
March 2021

Gender effects on quality of life and symptom burden in patients with lung cancer: results from a prospective, cross-cultural, multi-center study.

J Thorac Dis 2020 Aug;12(8):4253-4261

Center for Clinical Studies, University Hospital Regensburg, Regensburg, Germany.

Background: Lung cancer causes impairment of health-related quality of life (QoL), but little is known about gender aspects in QoL and symptom burden of lung cancer patients. The aim of this study was to investigate gender differences in QoL as assessed by the European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30 and the updated lung cancer module.

Methods: In a prospective, international, cross-cultural, multicenter study that was undertaken to update the lung cancer-specific module EORTC QLQ-LC13, patients filled in the core questionnaire EORTC QLQ-C30 and the updated lung cancer module. Gender differences were calculated for all QoL scores using ANCOVAs that controlled for known and suspected confounders. Comparisons with historic data were drawn.

Results: A total of 200 patients (82 female and 118 male, median age 65 years) were recruited. With the exception of coughing (estimated marginal means: women 33.86 and men 43.52, P=0.022) and diarrhea (estimated marginal means: women 26.01 and men 17.93, P=0.038) there were no significant QoL gender differences. Fatigue was the most pronounced symptom in both, men and women, outpacing typical respiratory symptoms. Quite generally, our sample of lung cancer patients showed considerably worse QoL in all scores when compared to EORTC reference data (lung cancer and combined cancer diagnoses, mean differences up to 13.70 and 21.54 score points, respectively) and to a German norm reference sample (up to 35.37 score points).

Conclusions: This study adds to the literature in showing that the typical QoL gender difference effect (women doing worse than men) may not be generalizable across all patient samples.
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http://dx.doi.org/10.21037/jtd-20-1054DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7475557PMC
August 2020

Pharmacological properties of TRPM3 isoforms are determined by the length of the pore loop.

Br J Pharmacol 2020 Aug 11. Epub 2020 Aug 11.

Laboratory of Endometrium, Endometriosis and Reproductive Medicine, Department of Development and Regeneration, KU Leuven, Leuven, Belgium.

Background And Purpose: Transient receptor potential melastatin 3 (TRPM3) is a non-selective cation channel that plays a pivotal role in the peripheral nervous system as a transducer of painful heat signals. Alternative splicing gives rise to several TRPM3 variants. The functional consequences of these splice isoforms are poorly understood. Here, the pharmacological properties of TRPM3 variants arising from alternative splicing in the pore-forming region were compared.

Experimental Approach: Calcium microfluorimetry and patch clamp recordings were used to compare the properties of heterologously expressed TRPM3α1 (long pore variant) and TRPM3α2-α6 (short pore variants). Furthermore, site-directed mutagenesis was done to investigate the influence of the length of the pore loop on the channel function.

Key Results: All short pore loop TRPM3α variants (TRPM3α2-α6) were activated by the neurosteroid pregnenolone sulphate (PS) and by nifedipine, whereas the long pore loop variant TRPM3α1 was insensitive to either compound. In contrast, TRPM3α1 was robustly activated by clotrimazole, a compound that does not directly activate the short pore variants but potentiates their responses to PS. Clotrimazole-activated TRPM3α1 currents were largely insensitive to established TRPM3α2 antagonists and were only partially inhibited upon activation of the μ opioid receptor. Finally, by creating a set of mutant channels with pore loops of intermediate length, we showed that the length of the pore loop dictates differential channel activation by PS and clotrimazole.

Conclusion And Implications: Alternative splicing in the pore-forming region of TRPM3 defines the channel's pharmacological properties, which depend critically on the length of the pore-forming loop.
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http://dx.doi.org/10.1111/bph.15223DOI Listing
August 2020

SARS-CoV-2 and cancer: Are they really partners in crime?

Cancer Treat Rev 2020 Sep 11;89:102068. Epub 2020 Jul 11.

Multidisciplinary Oncologic Centre Antwerp (MOCA), Antwerp University Hospital, Wilrijkstraat 10, Edegem B-2650, Belgium; Center for Oncological Research (CORE), Integrated Personalized and Precision Oncology Network (IPPON), University of Antwerp, Universiteitsplein 1, Wilrijk B-2610, Belgium.

The outbreak of the SARS-CoV-2 pandemic has overwhelmed health care systems in many countries. The clinical presentation of the SARS-CoV-2 varies between a subclinical or flu-like syndrome to that of severe pneumonia with multi-organ failure and death. Initial reports have suggested that cancer patients may have a higher susceptibility to get infected by the SARS-CoV-2 virus but current evidence remains poor as it is biased by important confounders. Patients with ongoing or recent cancer treatment for advanced active disease, metastatic solid tumors and hematological malignancies are at higher risk of developing severe COVID-19 respiratory disease that requires hospitalization and have a poorer disease outcome compared to individuals without cancer. However it is not clear whether these are independent risk factors, or mainly driven by male gender, age, obesity, performance status, uncontrolled diabetes, cardiovascular disease and various other medical conditions. These often have a greater influence on the probability to die due to SARS-CoV-2 then cancer. Delayed diagnosis and suboptimal cancer management due to the pandemic results in disease upstaging and has considerable impact cancer on specific death rates. Surgery during the peak of the pandemic seems to increase mortality, but there is no convincing evidence that adjuvant systemic cancer therapy and radiotherapy are contraindicated, implicating that cancer treatment can be provided safely after individual risk/benefit assessment and some adaptive measures. Underlying immunosuppression, elevated cytokine levels, altered expression of the angiotensin converting enzyme (ACE-2) and TMPRSS2, and a prothrombotic status may fuel the effects of a SARS-CoV-2 in some cancer patients, but have the potential to be used as biomarkers for severe disease and therapeutic targets. The rapidly expanding literature on COVID-19 should be interpreted with care as it is often hampered by methodological and statistical flaws.
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http://dx.doi.org/10.1016/j.ctrv.2020.102068DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7351667PMC
September 2020

Prescreening for COVID-19 in patients receiving cancer treatment using a patient-reported outcome platform.

ESMO Open 2020 06;5(3):e000817

Department of Medical Oncology, MOCA, University Hospital Antwerp (UZA), Antwerp, Belgium; Department of Molecular Imaging, Pathology, Radiotherapy & Oncology (MIPRO), Center for Oncological Research (CORE), Antwerp University, Antwerp, Belgium.

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http://dx.doi.org/10.1136/esmoopen-2020-000817DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7307523PMC
June 2020

The Zinc-Finger Domain Containing Protein ZC4H2 Interacts with TRPV4, Enhancing Channel Activity and Turnover at the Plasma Membrane.

Int J Mol Sci 2020 May 18;21(10). Epub 2020 May 18.

Laboratory of Ion Channel Research, VIB-KU Leuven Center for Brain & Disease Research, 3000 Leuven, Belgium.

The Ca-permeable Transient Receptor Potential channel vanilloid subfamily member 4 (TRPV4) is involved in a broad range of physiological processes, including the regulation of systemic osmotic pressure, bone resorption, vascular tone, and bladder function. Mutations in the gene are the cause of a spectrum of inherited diseases (or TRPV4-pathies), which include skeletal dysplasias, arthropathies, and neuropathies. There is little understanding of the pathophysiological mechanisms underlying these variable disease phenotypes, but it has been hypothesized that disease-causing mutations affect interaction with regulatory proteins. Here, we performed a mammalian protein-protein interaction trap (MAPPIT) screen to identify proteins that interact with the cytosolic N terminus of human TRPV4, a region containing the majority of disease-causing mutations. We discovered the zinc-finger domain-containing protein ZC4H2 as a TRPV4-interacting protein. In heterologous expression experiments, we found that ZC4H2 increases both the basal activity of human TRPV4 as well as Ca responses evoked by ligands or hypotonic cell swelling. Using total internal reflection fluorescence (TIRF) microscopy, we further showed that ZC4H2 accelerates TRPV4 turnover at the plasma membrane. Overall, these data demonstrate that ZC4H2 is a positive modulator of TRPV4, and suggest a link between TRPV4 and ZC4H2-associated rare disorders, which have several neuromuscular symptoms in common with TRPV4-pathies.
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http://dx.doi.org/10.3390/ijms21103556DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7278933PMC
May 2020

Gain of channel function and modified gating properties in TRPM3 mutants causing intellectual disability and epilepsy.

Elife 2020 05 19;9. Epub 2020 May 19.

Laboratory of Endometrium, Endometriosis and Reproductive Medicine, Department of Development and Regeneration, Leuven, Belgium.

Developmental and epileptic encephalopathies (DEE) are a heterogeneous group of disorders characterized by epilepsy with comorbid intellectual disability. Recently, two de novo heterozygous mutations in the gene encoding TRPM3, a calcium permeable ion channel, were identified as the cause of DEE in eight probands, but the functional consequences of the mutations remained elusive. Here we demonstrate that both mutations (V990M and P1090Q) have distinct effects on TRPM3 gating, including increased basal activity, higher sensitivity to stimulation by the endogenous neurosteroid pregnenolone sulfate (PS) and heat, and altered response to ligand modulation. Most strikingly, the V990M mutation affected the gating of the non-canonical pore of TRPM3, resulting in large inward cation currents via the voltage sensor domain in response to PS stimulation. Taken together, these data indicate that the two DEE mutations in TRPM3 result in a profound gain of channel function, which may lie at the basis of epileptic activity and neurodevelopmental symptoms in the patients.
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http://dx.doi.org/10.7554/eLife.57190DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7253177PMC
May 2020

Cancer in the time of COVID-19: expert opinion on how to adapt current practice.

Eur Respir J 2020 05 14;55(5). Epub 2020 May 14.

Dept of Pulmonology and Thoracic Oncology, Antwerp University Hospital, Edegem, Belgium.

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http://dx.doi.org/10.1183/13993003.00959-2020DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7163694PMC
May 2020

Psychometric properties of the updated EORTC module for assessing quality of life in patients with lung cancer (QLQ-LC29): an international, observational field study.

Lancet Oncol 2020 05 23;21(5):723-732. Epub 2020 Mar 23.

Quality of Life Department, European Organisation for Research and Treatment of Cancer, Brussels, Belgium.

Background: The European Organisation for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire-Lung Cancer 13 (QLQ-LC13) assesses quality of life (QOL) in patients with lung cancer and was the first EORTC module developed for use in international clinical trials. Since its publication in 1994, major treatment advances with possible effects on QOL have occurred. These changes called for an update of the module and its international psychometric validation. We aimed to investigate the scale structure and psychometric properties of the updated lung cancer module, QLQ-LC29, in patients with lung cancer.

Methods: This international, observational field study was done in 19 hospitals across 12 countries. Patients aged older than 18 years with a confirmed diagnosis of lung cancer and no other previous primary tumour, and who were mentally fit with sufficient language skills to understand and complete the questionnaire were included. Patients were asked during a hospital visit to fill in the paper versions of the core questionnaire EORTC QLQ-C30 plus QLQ-LC29, and investigators selected half of these patients to complete the questionnaire again 2-4 weeks later. Our primary aim was to assess the scale structure and psychometric properties of EORTC QLQ-LC29. We analysed scale structure using confirmatory factor analysis; reliability using Cronbach's α value (internal consistency) and intra-class coefficient (test-retest reliability); sensitivity using independent t tests stratified by Karnofsky performance status; and responsiveness to change over time by ANOVA. This study is registered with ClinicalTrials.gov, NCT02745691.

Findings: Between April 12, 2016, and Sept 26, 2018, 523 patients with a confirmed diagnosis of either non-small-cell lung cancer (n=442) or small-cell lung cancer (n=81) were recruited. Confirmatory factor analysis provided a solution composed of five multi-item scales (coughing, shortness of breath, fear of progression, hair problems, and surgery-related symptoms) plus 15 single symptom or side-effect items: χ=370·233, root mean square error of approximation=0·075, and comparative-fit index=0·901. Cronbach's α for internal consistencies of all multi-item scales were above the threshold of 0·70. Intra-class coefficients for test-retest reliabilities ranged between 0·82 and 0·97. Three (shortness of breath, fear of progression, and hair problems) of the five multi-item scales showed responsiveness to change over time (p values <0·05), as did nine of 15 single symptom items. Four (coughing, shortness of breath, fear of progression, and surgery-related symptoms) of the five multi-item scales and ten of the 15 single symptom items were sensitive to known group differences (ie, lower vs higher Karnofsky performance status).

Interpretation: Results determined the psychometric properties of the updated lung cancer module, which is ready for use in international clinical studies.

Funding: EORTC Quality of Life Group.
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http://dx.doi.org/10.1016/S1470-2045(20)30093-0DOI Listing
May 2020

Nivolumab and anti-HCV activity, a case report.

Acta Clin Belg 2020 Mar 17:1-5. Epub 2020 Mar 17.

Department of Gastroenterology and Hepatology, Antwerp University Hospital (UZA), Antwerp, Belgium.

Exhaustion of antigen-specific T-cells in order to escape immune destruction is frequently seen in chronic viral infection and different types of cancer. Blockade of overexpressed negative co-stimulatory pathways, a process known as immune checkpoint modulation, is a promising novel therapy that could improve the treatment of liver diseases with features of T cell exhaustion. We present a case of a 54-year-old hepatitis C virus (HCV) positive patient with an acute flare of hepatitis during nivolumab treatment for a stage IV lung carcinoma, an anti-programmed death-1 (PD-1) immunotherapy. Retrospective testing of HCV RNA documented infection more than 6 months ago. Nivolumab treatment was associated with an alanine aminotransferase (ALT) flare reaching a peak value of 663 U/L, along with bilirubin levels of 0.74 mg/dL and no signs of coagulopathy. The assumption of a nivolumab-associated autoimmune hepatitis led to the interruption of the immune checkpoint inhibitor treatment. However, a subsequent 1-log decrease of HCV RNA load was noticed, which raised the possibility of an immune reconstitution against the HCV-infected hepatocytes with cell lysis. Liver biopsy specimen demonstrated no evidence for autoimmune liver disease or fibrosis. Clinical evolution was favorable and serum transaminases returned to normal levels and HCV RNA load increased to baseline values following nivolumab cessation. The current case suggests an anti-HCV activity of anti-PD-1 treatment in the setting of concomitant HCV viremia and lung carcinoma.
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http://dx.doi.org/10.1080/17843286.2020.1741897DOI Listing
March 2020

Local treatment of stage IIIA-N2 nonsmall cell lung cancer: surgery and/or radiotherapy.

Curr Opin Oncol 2020 01;32(1):54-62

University of Antwerp, Antwerp.

Purpose Of Review: Controversy exists regarding the optimal treatment of patients with stage IIIA-N2 nonsmall cell lung cancer because of its heterogeneity. Patients are at risk for both local and distant disease relapse after primary local treatment. However, there may be a window of opportunity for surgery, if mediastinal downstaging has been obtained after induction therapy. This manuscript reviews the outcome of patients treated by neo-adjuvant chemotherapy (NA-C) followed by surgery, compared with patients treated with either definitive sequential or concurrent chemoradiotherapy (cCRT), illustrated by a single-centre retrospective case series.

Recent Findings: Of 53 eligible patients, 19 received NA-C and underwent surgical resection, whilst 20 and 14 received concurrent or sequential definitive CRT, respectively. A significant difference in progression-free survival favouring NA-C followed by surgery over both CRT modalities was found. However, this translated only in an overall survival benefit in comparison with sequential definitive CRT. A trend for better outcome was observed in selected surgical patients with single-level mediastinal involvement and complete resection.

Summary: Our case series results are consistent with the present standard of care of CRT, which restricts surgical resection to carefully selected patients. Immunotherapy will likely change the treatment paradigm.
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http://dx.doi.org/10.1097/CCO.0000000000000596DOI Listing
January 2020

Prognostic Understanding and Quality of Life in Patients With Advanced Lung Cancer: A Multicenter Study.

Clin Lung Cancer 2019 05 13;20(3):e369-e375. Epub 2018 Dec 13.

Multidisciplinary Oncology Center Antwerp, Antwerp Hospital University, Edegem, Belgium.

Introduction: Communication about the palliative setting remains a barrier for many physicians because they are afraid to harm the patient by giving bad news. We sought to determine whether this a valid concern; the influence of prognostic understanding on patients' quality of life (QoL); and which factors influence this relationship.

Methods: The present multicenter, cross-sectional study used a questionnaire to measure patients' prognostic understanding, QoL, mood, and coping strategy.

Results: We surveyed 125 patients with advanced lung cancer. Prognostic understanding correlated significantly with emotional well-being (r = -0.20; P = .01) and pain (r = 0.43; P = .00) but not with anxiety (r = 0.12, P = .12) or depression (r = 0.05; P = .29). Patients with anxiety (r = -0.23; P = .01) and patients with depressive feelings (r = -0.63; P = .00) experienced poorer QoL. Four in 10 patients reported feelings of anxiety and/or depression. Positive reframing as a coping strategy was associated with a better QoL (r = 0.25; P = .00).

Conclusion: Prognostic understanding was related to poorer emotional well-being and more pain but does not affect mood. Four in 10 patients reported feelings of anxiety and/or depression, which were associated with a poorer QoL. A holistic approach seems necessary when physicians communicate about the palliative setting.
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http://dx.doi.org/10.1016/j.cllc.2018.11.011DOI Listing
May 2019

Δ-tetrahydrocannabivarin impairs epithelial calcium transport through inhibition of TRPV5 and TRPV6.

Pharmacol Res 2018 10 28;136:83-89. Epub 2018 Aug 28.

Laboratory of Ion Channel Research, VIB Center for Brain & Disease Research, Leuven, Belgium; Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium. Electronic address:

Compounds extracted from the cannabis plant, including the psychoactive Δ-tetrahydrocannabinol (THC) and related phytocannabinoids, evoke multiple diverse biological actions as ligands of the G protein-coupled cannabinoid receptors CB1 and CB2. In addition, there is increasing evidence that phytocannabinoids also have non-CB targets, including several ion channels of the transient receptor potential superfamily. We investigated the effects of six non-THC phytocannabinoids on the epithelial calcium channels TRPV5 and TRPV6, and found that one of them, Δ-tetrahydrocannabivarin (THCV), exerted a strong and concentration-dependent inhibitory effect on mammalian TRPV5 and TRPV6 and on the single zebrafish orthologue drTRPV5/6. Moreover, THCV attenuated the drTRPV5/6-dependent ossification in zebrafish embryos in vivo. Oppositely, 11-hydroxy-THCV (THCV-OH), a product of THCV metabolism in mammals, stimulated drTRPV5/6-mediated Ca uptake and ossification. These results identify the epithelial calcium channels TRPV5 and TRPV6 as novel targets of phytocannabinoids, and suggest that THCV-containing products may modulate TRPV5- and TRPV6-dependent epithelial calcium transport.
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http://dx.doi.org/10.1016/j.phrs.2018.08.021DOI Listing
October 2018

Monitoring EGFR TKI resistance in real time using ddPCR-based liquid biopsy: a case report.

J Clin Pathol 2018 08 31;71(8):754-756. Epub 2018 May 31.

Phase I - Early Clinical Trials Unit - Oncology Department, Antwerp University Hospital (UZA), Edegem, Belgium.

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http://dx.doi.org/10.1136/jclinpath-2018-205210DOI Listing
August 2018

Imaging of urgencies and emergencies in the lung cancer patient.

Insights Imaging 2018 Aug 11;9(4):463-476. Epub 2018 Apr 11.

Department of Radiology, University Hospital Antwerp and University of Antwerp, Wilrijkstraat 10, 2650, Edegem, Belgium.

Lung cancer patients often experience potentially life-threatening medical urgencies and emergencies, which may be a direct or indirect result of the underlying malignancy. This pictorial review addresses the most common thoracic, neurological and musculoskeletal medical emergencies in lung cancer patients, including superior vena cava syndrome, pulmonary embolism, spontaneous pneumothorax, cardiac tamponade, massive haemoptysis, central airway obstruction, oesophagorespiratory fistula, malignant spinal cord compression, carcinomatous meningitis, cerebral herniation and pathological fracture. Emphasis is placed on imaging findings, the role of different imaging techniques and a brief discussion of epidemiology, pathophysiology and therapeutic options. Since early diagnosis is important for adequate patient management and prognosis, radiologists have a crucial role in recognising and communicating these urgencies and emergencies.

Teaching Points: • Multiplanar multidetector computed tomography is the imaging examination of choice for thoracic urgencies and emergencies. • Magnetic resonance imaging is the imaging modality of choice for investigating central nervous system emergencies. • Urgencies and emergencies can be the initial manifestation of lung cancer. • Radiologists have a crucial role in recognising and in communicating these urgencies/emergencies.
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http://dx.doi.org/10.1007/s13244-018-0605-6DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6108967PMC
August 2018

Mutations in the voltage-sensing domain affect the alternative ion permeation pathway in the TRPM3 channel.

J Physiol 2018 06 25;596(12):2413-2432. Epub 2018 Apr 25.

Laboratory of Experimental Gynecology and G-PURE, KU Leuven, Department of Development and Regeneration, Herestraat 49 box 611, B-3000, Leuven, Belgium.

Key Points: Mutagenesis at positively charged amino acids (arginines and lysines) (R1-R4) in the voltage-sensor domain (transmembrane segment (S) 4) of voltage-gated Na , K and Ca channels can lead to an alternative ion permeation pathway distinct from the central pore. Recently, a non-canonical ion permeation pathway was described in TRPM3, a member of the transient receptor potential (TRP) superfamily. The non-canonical pore exists in the native TRPM3 channel and can be activated by co-stimulation of the endogenous agonist pregnenolone sulphate and the antifungal drug clotrimazole or by stimulation of the synthetic agonist CIM0216. Alignment of the voltage sensor of Shaker K channels with the entire TRPM3 sequence revealed the highest degree of similarity in the putative S4 region of TRPM3, and suggested that only one single gating charge arginine (R2) in the putative S4 region is conserved. Mutagenesis studies in the voltage-sensing domain of TRPM3 revealed several residues in the voltage sensor (S4) as well as in S1 and S3 that are crucial for the occurrence of the non-canonical inward currents. In conclusion, this study provides evidence for the involvement of the voltage-sensing domain of TRPM3 in the formation of an alternative ion permeation pathway.

Abstract: Transient receptor potential (TRP) channels are cationic channels involved in a broad array of functions, including homeostasis, motility and sensory functions. TRP channel subunits consist of six transmembrane segments (S1-S6), and form tetrameric channels with a central pore formed by the region encompassing S5 and S6. Recently, evidence was provided for the existence of an alternative ion permeation pathway in TRPM3, which allows large inward currents upon hyperpolarization independently of the central pore. However, very little knowledge is available concerning the localization of this alternative pathway in the native TRPM3 channel protein. Guided by sequence homology with Shaker K channels, in which mutations in S4 can create an analogous 'omega' pore, we performed site-directed mutagenesis studies and patch clamp experiments to identify amino acid residues involved in the formation of the non-canonical pore in TRPM3. Based on our results, we pinpoint four residues in S4 (W982, R985, D988 and G991) as crucial determinants of the properties of the alternative ion permeation pathway.
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http://dx.doi.org/10.1113/JP274124DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6002228PMC
June 2018

Patient-reported outcome measures (PROMs) in the management of lung cancer: A systematic review.

Lung Cancer 2017 11 23;113:140-151. Epub 2017 Sep 23.

Faculty of Medicine and Health Care, Antwerp University, Universiteitsplein 1, 2610 Antwerpen, Belgium; Multidisciplinary Oncological Center Antwerp (MOCA), Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium; Department of Pulmonology & Thoracic Oncology, Antwerp University Hospital, Wilrijkstraat 10, 2650 Edegem, Belgium. Electronic address:

Lung cancer is often associated with a poor quality of life, as reflected by patient-reported outcome measures (PROMs). The aim of this paper is to describe and compare the PROMs that are available. In this manuscript, we review the impact of PROMs on the management of lung cancer. Quality of the study and risk of bias were assessed using the appraisal tools recommended by the Dutch Cochrane Center. Out of 51 studies included in this review, ten instruments were identified and categorized as either generic, cancer- or lung cancer-specific. PROMs are primarily applied in scientific research to compare the therapy outcomes and in drug development to support labeling claims. The interest for the routine use of PROMs in daily practice is growing, which has positive effects on the communication with the patient, mutual decision making and the monitoring and managing of the patient. Besides that, PROMs have an independent prognostic value for survival in lung cancer and economic evaluations can be conducted using their results. Electronic platforms simplify the implementation of PROMs in the daily clinic. The EORTC QLQ-C30 and its lung cancer-specific module QLQ-LC13 are the most frequently used instruments in lung cancer patients. PROMs have the potential to improve the quality of care with a proper implementation in the routine practice. PROMS are needed to value and understand the experience of the patient.
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http://dx.doi.org/10.1016/j.lungcan.2017.09.011DOI Listing
November 2017

Externalizing Problem Behavior in Adolescence: Parenting Interacting With DAT1 and DRD4 Genes.

J Res Adolesc 2017 06 13;27(2):278-297. Epub 2016 Jun 13.

KU Leuven.

This study extends previous gene-by-environment (G × E) research through design and methodological advances and examines alternative hypotheses of diathesis stress, vantage sensitivity, and differential susceptibility. In a sample of 984 adolescents and their parents, we examined whether effects of parental support, proactive, punitive, harsh punitive, and psychological control on externalizing problem behavior are moderated by adolescents' genotype for the dopamine transporter (DAT1) or receptor D4 (DRD4) gene. Results provided evidence for main effects of parenting behavior and DRD4, and multiple interaction effects of which one survived Bonferroni correction. Adolescents carrying a long DRD4 variant were more susceptible to the effects of parental proactive control on aggression, for better and for worse. Critical considerations were made regarding the complexity of G × E research.
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http://dx.doi.org/10.1111/jora.12271DOI Listing
June 2017

Recurrent dysphasia due to nivolumab-induced encephalopathy with presence of Hu autoantibody.

Lung Cancer 2017 07 10;109:74-77. Epub 2017 May 10.

Department of Thoracic Oncology, Antwerp University Hospital, Edegem, Belgium; Center for Oncological Research, University of Antwerp, Antwerp, Belgium.

A 58-year-old man was being treated for squamous non-small-cell lung cancer with nivolumab. At the 17th of biweekly administrations he presented with global dysphasia, dysarthria and myoclonus in the right upper extremity. MRI showed multiple T2/FLAIR hyperintense lesions in the left hemisphere; lumbar puncture showed lymphocytic pleiocytosis in the CSF without identifiable pathogens. Hu antibodies were present in serum and CSF. Nivolumab was discontinued and corticosteroids were administered. The neurological symptoms gradually improved; MRI showed complete remission of cerebral lesions. After rechallenge with nivolumab his symptoms and cerebral lesions recurred, proving the causal relationship with nivolumab. After tapering of corticosteroids, a second relapse occurred.
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http://dx.doi.org/10.1016/j.lungcan.2017.05.002DOI Listing
July 2017

Malignant pleural mesothelioma: single-institution experience of 101 patients over a 15-year period.

Acta Chir Belg 2017 Jun;117(3):157-163

a Department of Thoracic and Vascular surgery , Antwerp University Hospital , Antwerp , Belgium.

Background: Malignant pleural mesothelioma (MPM) is a rare but aggressive neoplasm that typically originates from the mesothelial surfaces of the pleural cavity. Exposure to asbestos is the principal etiological agent of MPM. The disease is characterized by difficult stage classification and limited consensus on therapeutic approach. We have evaluated the experience with MPM in the Antwerp University Hospital over the past 15 years.

Methods: A database was created with all patients diagnosed with or treated for a MPM between 2001 and 2015. A total of 101 patients were included on which different survival analyses were performed combined with a reproduction of demographic, clinical, histologic and therapeutic data, and these were compared to literature data.

Results: Vast majority of our 101 patients were male (80%) with a median age of 66 years at diagnosis with predominantly epitheloid histology (81%). Overall median survival was 18.3 months and overall 1-, 2- and 5-year survival rates were 68%, 37% and 7%, respectively. Kaplan-Meier analysis showed a non-significant difference in survival between the several best (b) TNM-stages (p = .356). A significant difference in survival was observed in patients undergoing surgery versus no surgery (p = .008), between the different histological types (p < .0001) and treatment with chemotherapy alone versus chemotherapy with surgery (p < .0001). Smoking at diagnosis and epitheloid histology have been identified as significant prognostic factors in the multivariate Cox regression model (HR 3.13 and 0.53, respectively).

Conclusion: Descriptive and survival analysis of our patient database confirmed the limitations of the current staging system and were concordant with literature regarding MPM.
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http://dx.doi.org/10.1080/00015458.2016.1272253DOI Listing
June 2017

Adolescent externalizing behaviour, psychological control, and peer rejection: Transactional links and dopaminergic moderation.

Br J Dev Psychol 2017 09 24;35(3):420-438. Epub 2017 Mar 24.

Parenting and Special Education Research Group, Faculty of Psychology and Educational Sciences, KU Leuven, Belgium.

This study investigated (1) reciprocal links among parental psychological control, peer rejection, and adolescent externalizing (aggressive and rule-breaking behaviour), and (2) the moderating effect of an adolescent genetic factor (biologically informed polygenic score for dopamine signalling). Three-year longitudinal data from 1,116 adolescents (51% boys; M age = 13.79) and their parents included psychological measures (adolescent-reported psychological control, peer-reported rejection, and parent-reported aggressive and rule-breaking behaviour). Cross-lagged analyses showed bidirectional effects between psychological control and both aggressive and rule-breaking behaviour and a unidirectional effect of peer rejection on both forms of problem behaviour over time. Multigroup structural equation modelling revealed genetic moderation only for rule-breaking behaviour: for adolescents with intermediate levels of dopamine signalling significant environmental effects were present, whereas adolescent effects of rule-breaking behaviour on psychological control were significant for adolescents with both intermediate and high profiles and effects on peer rejection only for adolescents with high dopamine profiles. Statement of contribution What is already known on this subject? Parental psychological control is related to adolescent externalizing problems. Experiencing peer rejection reinforces aggressive and rule-breaking behaviour. Single-gene studies show that dopaminergic genes influence externalizing problems directly or in interaction with the environment. What does this study add? Parental psychological control and adolescent aggressive and rule-breaking behaviour exacerbate one another longitudinally. Longitudinal associations between peer rejection and both subtypes of externalizing behaviour are unidirectional. With a polygenic approach, dopaminergic moderation is present for rule-breaking behaviour only.
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http://dx.doi.org/10.1111/bjdp.12184DOI Listing
September 2017

Addressing the Palliative Setting in Advanced Lung Cancer Should Not Remain a Barrier: A Multicenter Study.

Clin Lung Cancer 2017 07 20;18(4):e283-e287. Epub 2017 Jan 20.

Department of Thoracic Oncology, Antwerp University Hospital, Edegem, Belgium.

Background: Implementation of early palliative care (EPC) into daily oncology practice remains difficult. One of the barriers preventing oncologists from starting EPC is open communication about the palliative setting. The aim of this study was to investigate the relevance of this communication barrier.

Patients And Methods: In this cross-sectional multicenter study, 106 patients with advanced thoracic cancer were issued a questionnaire to survey 3 dimensions of interest: illness understanding, observation of conversation regarding prognosis and end-of-life (EoL) care, and information preferences of the patients.

Results: Only 45% of subjects were aware that their treatment was not curative. When comparing presumed treatment goals between patients who were aware that their treatment could not cure them and patients likely to think that their treatment could cure them, 39% of the former chose quality of life versus 9% of the latter, whereas 36% of the former chose cure versus 13% of the latter (χ = 17.7, P = .001). Seventy-five percent never had a conversation about EoL care. More than 50% found a discussion about prognosis and EoL care to be very important.

Conclusion: This study reveals the existence of a communication barrier and underlines the importance of sustained emphasis with regard to the palliative intent of the treatment. Patients who are aware that they could not be cured were more aware of the primary goal of their treatment, namely quality of life. Most patients did not discuss prognosis and EoL care despite their wish for such a communication.
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http://dx.doi.org/10.1016/j.cllc.2017.01.001DOI Listing
July 2017

O-Methylguanine-DNA methyltransferase (MGMT): A drugable target in lung cancer?

Lung Cancer 2017 05 18;107:91-99. Epub 2016 Jul 18.

Thoracic Oncology, Antwerp University Hospital and Antwerp University, Wilrijkstraat 10, 2650, Edegem, Belgium.

This manuscript addresses the role of O-methylguanine-DNA methyltransferase (MGMT) as a biomarker in the oncogenesis of cancer and the opportunity of turning this gene into a drugable target in neuroendocrine tumours of the lung. Studies in brain tumours conclude that MGMT promoter methylation is considered a strong predictive factor for a favourable outcome for treatment with temozolomide, e.g. alkylating agent. We conducted a systematic review of MGMT in non-small cell lung cancer (NSCLC), small-cell lung cancer (SCLC) and other pulmonary neuroendocrine tumours (NETs) to evaluate whether MGMT is a prognostic and/or predictive factor to select patients with lung cancer who can benefit from treatment with temozolomide. In NSCLC MGMT promoter methylation is not a prognostic and predictive factor, hence temozolomide has no place. In SCLC and NET patients with a MGMT promoter methylation benefit of temozolomide has to be confirmed.Temozolomide can be considered a 'personalized' treatment if the predictive role of MGMT is further confirmed.
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http://dx.doi.org/10.1016/j.lungcan.2016.07.014DOI Listing
May 2017