Publications by authors named "Annemiek M E Walenkamp"

62 Publications

Cognitive Impairment in Long-Term Survivors of Testicular Cancer More Than 20 Years after Treatment.

Cancers (Basel) 2021 Nov 12;13(22). Epub 2021 Nov 12.

Department of Medical Oncology, University Medical Center Groningen and University of Groningen, 9728 NT Groningen, The Netherlands.

Background: Impaired cognition can be a late effect after treatment in long-term testicular cancer (TC) survivors, negatively affecting their daily life. However, little data is available beyond 20 years post-treatment. We assessed cognitive impairment in very long-term TC survivors after CT or RT and compared the results with stage I TC survivors and controls.

Methods: In this cross-sectional multicenter cohort study, we enrolled TC survivors (treated with orchiectomy followed by CT or RT or orchiectomy only)-with a follow-up duration ≥ 20 years-and age-matched healthy controls. Cognitive testing included the Auditory Verbal Learning Test, Letter Fluency Test, Category Fluency Test, and Trail Making Test. We used fasting blood samples to assess the presence of hypogonadism and measured cardiovascular aging parameters, including carotid pulse wave velocity (c-PWV) and advanced glycation end products (AGEs).

Results: We included 184 TC survivors (66 CT patients, 53 RT patients, and 65 orchiectomy-only patients) and 70 healthy controls. The median follow-up was 26 years (range: 20-42). TC survivors had a lower combined score of the cognitive tests (mean cumulative Z-score -0.85; 95% CI -1.39 to -0.33) compared to controls (mean 0.67; 95% CI -0.21 to 1.57, < 0.01). In univariate analysis, the presence of hypogonadism (β -1.50, < 0.01), high c-PWV (β -0.35, = 0.09), and high AGEs (β -1.27, = 0.02) were associated with lower cognitive scores, while only AGEs (β -1.17, = 0.03) remained a significant predictor in multivariate analysis (Model R2 0.31, < 0.01).

Conclusions: Long-term TC survivors performed worse on cognitive tests compared to controls. Physicians and patients should be informed about timely cardiovascular risk management and testosterone supplementation therapy during follow-up to reduce the risk of cognitive impairment.

Trial Registration: NCT02572934.
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http://dx.doi.org/10.3390/cancers13225675DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8616311PMC
November 2021

A Phase 2 Study of the Efficacy and Safety of Oral Selinexor in Recurrent Glioblastoma.

Clin Cancer Res 2021 Nov 2. Epub 2021 Nov 2.

Department of Oncology, Copehagen University Hospital, Rigshospitalet.

Purpose: Selinexor is an oral selective inhibitor of exportin-1 (XPO1) with efficacy in various solid and hematological tumors. We assessed intra-tumoral penetration, safety, and efficacy of selinexor monotherapy for recurrent glioblastoma.

Patients And Methods: Seventy-six adults with Karnofsky Performance Status{greater than or equal to}60 were enrolled. Patients undergoing cytoreductive surgery received up to three selinexor doses (twice weekly) pre-operatively (Arm A; N=8 patients). Patients not undergoing surgery received 50mg/m (Arm B, N=24), or 60mg (Arm C, N=14) twice weekly, or 80mg once weekly (Arm D; N=30). Primary endpoint was six-month progression-free survival rate (PFS6).

Results: Median selinexor concentrations in resected tumors from patients receiving pre-surgical selinexor was 105.4nM (range 39.7-291nM). In Arms B, C, and D, respectively, the PFS6 was 10% (95%CI, 2.79-35.9), 7.7% (95%CI, 1.17-50.6), and 17% (95%CI, 7.78-38.3). Measurable reduction in tumor size was observed in 19 (28%) and RANO-response rate overall was 8.8% (Arm B, 8.3% (95%CI, 1.0-27.0); C:7.7% (95%CI, 0.2-36.0); D:10% (95%CI, 2.1-26.5)), with one complete and two durable partial responses in Arm D. Serious adverse events (AEs) occurred in 26 (34%) patients; one (1.3%) was fatal. The most common treatment-related AEs were fatigue (61%), nausea (59%), decreased appetite (43%) and thrombocytopenia (43%), and were manageable by supportive care and dose modification. Molecular studies identified a signature predictive of response (AUC=0.88).

Conclusion: At 80mg weekly, single-agent selinexor induced responses and clinically relevant PFS6 with manageable side effects requiring dose reductions. Ongoing trials are evaluating safety and efficacy of selinexor in combination with other therapies for newly diagnosed or recurrent glioblastoma.
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http://dx.doi.org/10.1158/1078-0432.CCR-21-2225DOI Listing
November 2021

Home-based Physical Activity to Alleviate Fatigue in Cancer Survivors: A Systematic Review and Meta-analysis.

Med Sci Sports Exerc 2021 Dec;53(12):2661-2674

Department of General Practice and Elderly Care Medicine, University Medical Center Groningen, University of Groningen, Groningen, THE NETHERLANDS.

Purpose: Physical activity (PA) affects fatigue and mental health in cancer survivors favorably, but participation in PA interventions tends to be low. More participants may be reached by home-based PA owing to greater accessibility and self-monitoring. This systematic review therefore evaluated the effects of home-based PA of low to moderate intensity on symptoms of fatigue, depression, and anxiety among cancer survivors.

Methods: PubMed, CINAHL, PsycINFO, and Web of Science were systematically searched for randomized controlled trials. We included investigations of home-based PA interventions in adults treated curatively for cancer and evaluating fatigue, depression, or anxiety as outcomes. We performed a random-effect meta-analysis for the effects of PA interventions on fatigue in the short and long terms. Subgroup analyses were performed for the frequency of counseling. Standardized mean differences (SMD) and 95% confidence intervals are reported.

Results: Eleven articles comprising 1066 participants were included: 77% had a history of breast cancer; 14%, ovarian cancer; 4%, colorectal cancer; 4%, prostate cancer; and 1%, "other" cancer (not specified). Concerning the outcomes, nine articles reported on fatigue and two reported on depression or anxiety. Meta-analyses showed a significant effect of home-based PA on fatigue immediately after the intervention (SMD = 0.22 [0.06-0.37]), at 3 months' follow-up (SMD = 0.27 [0.04-0.51]), and at 6-9 months' follow-up (SMD = 0.31 [0.08-0.55]). PA interventions that used frequent counseling were associated with larger improvements in fatigue than those using no or infrequent counseling.

Conclusions: Home-based PA interventions can reduce fatigue among adult cancer survivors for up to 9 months, and frequent counseling may improve the benefits of these interventions.
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http://dx.doi.org/10.1249/MSS.0000000000002735DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8594505PMC
December 2021

The EGFRvIII transcriptome in glioblastoma, a meta-omics analysis.

Neuro Oncol 2021 Oct 5. Epub 2021 Oct 5.

UMC Utrecht, Utrecht, Netherlands.

Background: EGFR is among the genes most frequently altered in glioblastoma, with exons 2-7 deletions (EGFRvIII) being amongst its most common genomic mutations. There are conflicting reports about its prognostic role and it remains unclear whether and how it differs in signalling compared with wildtype EGFR.

Methods: To better understand the oncogenic role of EGFRvIII, we leveraged four large datasets into one large glioblastoma transcriptome dataset (n=741) alongside 81 whole-genome samples from two datasets.

Results: The EGFRvIII/EGFR expression ratios differ strongly between tumours and ranges from 1% to 95%. Interestingly, the slope of relative EGFRvIII expression is near-linear, which argues against a more positive selection pressure than EGFR wildtype. An absence of selection pressure is also suggested by the similar survival between EGFRvIII positive and negative glioblastoma patients. EGFRvIII levels are inversely correlated with pan-EGFR (all wildtype and mutant variants) expression, which indicates that EGFRvIII has a higher potency in downstream pathway activation. EGFRvIII-positive glioblastomas have a lower CDK4 or MDM2 amplification incidence than EGFRvIII-negative (p=0.007), which may point towards crosstalk between these pathways. EGFRvIII-expressing tumours have an upregulation of 'classical' subtype genes compared to those with EGFR-amplification only (p=3.873e-6). Genomic breakpoints of the EGFRvIII deletions have a preference towards the 3' end of the large intron-1. These preferred breakpoints preserve a cryptic exon resulting in a novel EGFRvIII variant and preserve an intronic enhancer.

Conclusions: These data provide deeper insights into the complex EGFRvIII biology and provide new insights for targeting EGFRvIII mutated tumours.
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http://dx.doi.org/10.1093/neuonc/noab231DOI Listing
October 2021

The effects of molar activity on [F]FDOPA uptake in patients with neuroendocrine tumors.

EJNMMI Res 2021 Sep 8;11(1):88. Epub 2021 Sep 8.

Department of Nuclear Medicine and Molecular Imaging, University Medical Center Groningen, Medical Imaging Center, University of Groningen, Hanzeplein 1, 9700 RB, Groningen, The Netherlands.

Background: 6-[F]fluoro-L-3,4-dihydroxyphenyl alanine ([F]FDOPA) is a commonly used PET tracer for the detection and staging of neuroendocrine tumors. In neuroendocrine tumors, [F]FDOPA is decarboxylated to [F]dopamine via the enzyme amino acid decarboxylase (AADC), leading to increased uptake when there is increased AADC activity. Recently, in our hospital, a new GMP compliant multi-dose production of [F]FDOPA has been developed, [F]FDOPA-H, resulting in a higher activity yield, improved molar activity and a lower administered mass than the conventional method ([F]FDOPA-L).

Aims: This study aimed to investigate whether the difference in molar activity affects the [F]FDOPA uptake at physiological sites and in tumor lesions, in patients with NET. It was anticipated that the specific uptake of [F]FDOPA-H would be equal to or higher than [F]FDOPA-L.

Methods: We retrospectively analyzed 49 patients with pathologically confirmed NETs and stable disease who underwent PET scanning using both [F]FDOPA-H and [F]FDOPA-L within a time span of 5 years. A total of 98 [F]FDOPA scans (49 [F]FDOPA-L and 49 [F]FDOPA-H with average molar activities of 8 and 107 GBq/mmol) were analyzed. The SUVmean was calculated for physiological organ uptake and SUVmax for tumor lesions in both groups for comparison, and separately in subjects with low tumor load (1-2 lesions) and higher tumor load (3-10 lesions).

Results: Comparable or slightly higher uptake was demonstrated in various physiological uptake sites in subjects scanned with [F]FDOPA-H compared to [F]FDOPA-L, with large overlap being present in the interquartile ranges. Tumor uptake was slightly higher in the [F]FDOPA-H group with 3-10 lesion (SUVmax 6.83 vs. 5.19, p < 0.001). In the other groups, no significant differences were seen between H and L.

Conclusion: [18F]FDOPA-H provides a higher activity yield, offering the possibility to scan more patients with one single production. Minor differences were observed in SUV's, with slight increases in uptake of [F]FDOPA-H in comparison to [F]FDOPA-L. This finding is not a concern for clinical practice, but could be of importance when quantifying follow-up scans while introducing new production methods with a higher molar activity of [F]FDOPA.
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http://dx.doi.org/10.1186/s13550-021-00829-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8426426PMC
September 2021

Effects of supervised exercise during adjuvant endocrine therapy in overweight or obese patients with breast cancer: The I-MOVE study.

Breast 2021 Aug 15;58:138-146. Epub 2021 May 15.

Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands. Electronic address:

Background: Adjuvant endocrine therapy (ET) in patients with breast cancer (BC) increases the risk of becoming less physically active. Physical inactivity is associated with a higher risk of treatment-related side effects and mortality. This study investigated whether supervised exercise increased the proportion of patients adhering to the national physical activity (PA) guideline during adjuvant ET in overweight or obese BC patients.

Methods: This multicentre single-arm clinical trial included patients with BC participating in a 12-week supervised exercise intervention. An accelerometer measured moderate to vigorous PA (MVPA) at baseline (T0), after 12 (T1) and 26 weeks (T2). The primary endpoint was change in the proportion of patients with weekly ≥150 min of MVPA at T1 compared to T0. Secondary endpoints were adherence to PA guideline at T2, metabolic syndrome (MetS), body composition, health-related quality of life (HRQoL) and BC-specific functioning and symptoms, self-reported PA, self-efficacy, exercise motivation and satisfaction with life.

Results: 141 patients with a median age of 61 years and a mean BMI of 31.3 participated. Adherence to the PA guideline increased from 38.3% at T0, to 40.4% at T1 (p = .112) and 44.7% at T2 (p = .003). MetS, body composition, HRQoL, BC-specific functioning and symptoms (i.e. fatigue, dyspnoea), self-reported PA, self-efficacy, exercise motivation and satisfaction with life improved significantly over time.

Conclusions: Supervised exercise increased the proportion of BC patients adhering to the PA guideline over time. Furthermore, MetS, body composition, HRQoL and symptoms improved. Our findings highlight the clinical relevance of supervised exercise during ET in overweight BC patients.

Clinical Trial Information: (NCT02424292).
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http://dx.doi.org/10.1016/j.breast.2021.05.004DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8165430PMC
August 2021

Current Treatment Strategies and Future Directions for Extrapulmonary Neuroendocrine Carcinomas: A Review.

JAMA Oncol 2021 May;7(5):759-770

Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, Groningen, the Netherlands.

Importance: Patients with extrapulmonary neuroendocrine carcinomas (EPNECs) receive essentially the same treatment as those with small cell lung cancer (SCLC) despite differences in origin, clinical course, and survival. This SCLC-based approach is attributable to the rarity of EPNECs, which impedes the use of randomized clinical trials. However, neuroendocrine carcinomas are becoming more common because of the increasing use of systemic cancer therapy for adenocarcinomas. This treatment can transdifferentiate certain adenocarcinomas into neuroendocrine carcinomas. In addition, the treatment landscape for SCLC is slowly changing, potentially impacting the treatment paradigms for EPNECs.

Observations: New information on tumorigenesis of EPNECs from different origins, either as a primary malignant tumor or after neuroendocrine differentiation from adenocarcinomas, demonstrates their biological similarity. Activated molecular pathways that appear to underlie the development of EPNECs are potentially targetable, and some of these targets, such as poly(adenosine diphosphate-ribose) polymerase, Wee1, and Aurora A kinase, are currently under investigation. Immune checkpoint inhibitors (ICIs) already constituted a new treatment modality for patients with SCLC and produced some promising results in patients with EPNECs.

Conclusions And Relevance: Although only moderately effective, the introduction of ICIs signifies the first new option in systemic treatment of SCLC in decades. To prove the value of ICIs and other new drugs for patients with EPNECs, these patients should be included in clinical trials independent of the primary tumor site. Furthermore, to optimize clinical decision-making for patients with EPNECs, experts from the neuroendocrine tumor board should collaborate with members from tumor site-specific boards, which will require patient referral to a center with EPNEC expertise.
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http://dx.doi.org/10.1001/jamaoncol.2020.8072DOI Listing
May 2021

Impact of depatuxizumab mafodotin on health-related quality of life and neurological functioning in the phase II EORTC 1410/INTELLANCE 2 trial for EGFR-amplified recurrent glioblastoma.

Eur J Cancer 2021 04 15;147:1-12. Epub 2021 Feb 15.

Department of Neurology, Brain Tumor Center at Erasmus MC Cancer Institute, University Medical Center Rotterdam, Rotterdam, the Netherlands. Electronic address:

Background: In the EORTC 1410/INTELLANCE 2 randomised, phase II study (NCT02343406), with the antibody-drug conjugate depatuxizumab mafodotin (Depatux-M, ABT-414) in patients with recurrent EGFR-amplified glioblastoma, the primary end-point (overall survival) was not met, and the drug had ocular dose-limiting toxicity. This study reports results from the prespecified health-related quality of life (HRQoL) and neurological deterioration-free survival (NDFS) exploratory analysis.

Patients And Methods: Patients (n = 260) were randomised 1:1:1 to receive either Depatux-M 1.25 mg/kg or 1.0 mg/kg intravenously every 2 weeks with oral temozolomide (TMZ) 150 mg/m, Depatux-M alone, or TMZ or oral lomustine (CCNU) 110 mg/m (TMZ/CCNU). HRQoL outcomes were recorded using the EORTC core Quality of Life QLQ-C30, and brain cancer-specific QLQ-BN20 questionnaires. Questionnaires were completed at baseline, weeks 8 and 16, and month 6, and changes from baseline to each time point were calculated. NDFS was defined as time to first deterioration in World Health Organisation performance status.

Results: Compliance with HRQoL was 88.1% at baseline and decreased to 37.9% at month 6. Differences from baseline between Depatux-M arms and TMZ/CCNU in global health/QoL status throughout treatment did not reach clinical relevance (≥10 points). Self-reported visual disorders deteriorated to a clinically relevant extent with Depatux-M arms versus TMZ/CCNU at all timepoints (mean differences range: 24.6-35.1 points). Changes from baseline for other HRQoL scales and NDFS were generally similar between treatment arms.

Conclusions: Depatux-M had no impact on HRQoL and NDFS in patients with EGFR-amplified recurrent glioblastoma, except for more visual disorders, an expected side-effect of the study drug.

Clinical Trial Registration: NCT02343406.
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http://dx.doi.org/10.1016/j.ejca.2021.01.010DOI Listing
April 2021

Data-driven prioritization and preclinical evaluation of therapeutic targets in glioblastoma.

Neurooncol Adv 2020 Jan-Dec;2(1):vdaa151. Epub 2020 Nov 5.

Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background: Patients with glioblastoma (GBM) have a dismal prognosis, and there is an unmet need for new therapeutic options. This study aims to identify new therapeutic targets in GBM.

Methods: mRNA expression data of patient-derived GBM ( = 1279) and normal brain tissue ( = 46) samples were collected from Gene Expression Omnibus and The Cancer Genome Atlas. Functional genomic mRNA profiling was applied to capture the downstream effects of genomic alterations on gene expression levels. Next, a class comparison between GBM and normal brain tissue was performed. Significantly upregulated genes in GBM were further prioritized based on (1) known interactions with antineoplastic drugs, (2) current drug development status in humans, and (3) association with biologic pathways known to be involved in GBM. Antineoplastic agents against prioritized targets were validated in vitro and in vivo.

Results: We identified 712 significantly upregulated genes in GBM compared to normal brain tissue, of which 27 have a known interaction with antineoplastic agents. Seventeen of the 27 genes, including and , have been clinically evaluated in GBM with limited efficacy. For the remaining 10 genes, , (, ), and play a role in GBM development. We demonstrated for the MAPK9 inhibitor RGB-286638 a viability loss in multiple GBM cell culture models. Although no overall survival benefit was observed in vivo, there were indications that RGB-286638 may delay tumor growth.

Conclusions: The MAPK9 inhibitor RGB-286638 showed promising in vitro results. Furthermore, in vivo target engagement studies and combination therapies with this compound warrant further exploration.
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http://dx.doi.org/10.1093/noajnl/vdaa151DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7764503PMC
November 2020

Comparison of 18F-DOPA Versus 68Ga-DOTATOC as Preferred PET Imaging Tracer in Well-Differentiated Neuroendocrine Neoplasms.

Clin Nucl Med 2021 Mar;46(3):195-200

From the Departments of Nuclear Medicine and Molecular Imaging.

Purpose: The aim of this study was to retrospectively compare 18F-FDOPA versus 68Ga-DOTATOC PET in lesion detection rates and laboratory tumor markers in patients with neuroendocrine neoplasms (NENs).

Patients And Methods: All patients with histologically proven NEN between May 2015 and February 2019 were included who underwent both 18F-DOPA and 68Ga-DOTATOC PET scans within 6 months from each other (mean, 75; median, 38; range, 2-168 days). All patients, except those with pancreatic NEN, received carbidopa before 18F-DOPA PET. Based on the number of lesions on both modalities, patients were divided into 3 categories: more lesions on 18F-DOPA (DOPA > DOTA), more lesions on 68Ga-DOTATOC (DOTA > DOPA), and equal number of lesions (DOPA = DOTA). Tumor markers chromogranin A, serotonin, and 5-hydroxyindoleacetic acid (5-HIAA) within a maximum of 3 months around either scan were retrieved from the patients' charts.

Results: 18F-DOPA revealed significantly more lesions compared with 68Ga-DOTATOC (611 vs 385, P < 0.05). Twenty-four patients were included in the DOPA > DOTA group with 16 small intestinal (SI) NENs, 3 large intestinal, 4 pancreatic, and 1 tumor of unknown origin (TUO). For the 9 patients in the DOTA > DOPA group, 4 were SI, 2 pancreatic, 1 lung, and 2 TUOs. Twelve patients in the DOPA = DOTA group had 6 pancreatic tumors, 3 SI, 1 ovarian, and 2 TUOs. Only serotonin and 5-HIAA showed significant higher values for DOPA > DOTA compared with DOTA > DOPA (mean 24 vs 4, P < 0.05, and 320 vs 81, P < 0.05, respectively). Cutoff values of 20 nmol/109 for serotonin, 185 μg/L for chromogranin A, and 200 nmol/L for 5-HIAA were found to include almost exclusively DOPA > DOTA patients.

Conclusions: There is an advantage of carbidopa pretreated 18F-DOPA over 68Ga-DOTATOC PET, especially for large intestinal NENs with high levels of biomarkers. There seems to be a relationship between increased biomarker value and improved lesion detection rates with the 18F-DOPA PET scan, which requires further prospective analysis.
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http://dx.doi.org/10.1097/RLU.0000000000003447DOI Listing
March 2021

At the Bedside: Profiling and treating patients with CXCR4-expressing cancers.

J Leukoc Biol 2021 05 22;109(5):953-967. Epub 2020 Oct 22.

Polyphor Ltd, Allschwil, Switzerland.

The chemokine receptor, C-X-C chemokine receptor type 4 (CXCR4) and its ligand, C-X-C motif chemokine 12, are key mediators of hematopoietic cell trafficking. Their roles in the proliferation and metastasis of tumor cells, induction of angiogenesis, and invasive tumor growth have been recognized for over 2 decades. CXCR4 is a promising target for imaging and therapy of both hematologic and solid tumors. To date, Sanofi Genzyme's plerixafor is the only marketed CXCR4 inhibitor (i.e., Food and Drug Administration-approved in 2008 for stem cell mobilization). However, several new CXCR4 inhibitors are now being investigated as potential therapies for a variety of fluid and solid tumors. These small molecules, peptides, and Abs include balixafortide (POL6326, Polyphor), mavorixafor (X4P-001, X4 Pharmaceuticals), motixafortide (BL-8040, BioLineRx), LY2510924 (Eli Lilly), and ulocuplumab (Bristol-Myers Squibb). Early clinical evidence has been encouraging, for example, with motixafortide and balixafortide, and the CXCR4 inhibitors appear to be generally safe and well tolerated. Molecular imaging is increasingly being used for effective patient selection before, or early during CXCR4 inhibitor treatment. The use of radiolabeled theranostics that combine diagnostics and therapeutics is an additional intriguing approach. The current status and future directions for radioimaging and treating patients with CXCR4-expressing hematologic and solid malignancies are reviewed. See related review - At the Bench: Pre-Clinical Evidence for Multiple Functions of CXCR4 in Cancer. J. Leukoc. Biol. xx: xx-xx; 2020.
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http://dx.doi.org/10.1002/JLB.5BT1219-714RDOI Listing
May 2021

Vascular aging in long-term survivors of testicular cancer more than 20 years after treatment with cisplatin-based chemotherapy.

Br J Cancer 2020 11 14;123(11):1599-1607. Epub 2020 Sep 14.

Department of Medical Oncology, University Medical Centre Groningen and University of Groningen, Groningen, The Netherlands.

Background: Late effects of cisplatin-based chemotherapy in testicular cancer survivors (TCS) include cardiovascular morbidity, but little data is available beyond 20 years. The objective was to assess vascular damage in very long-term TCS.

Methods: TCS (treated with chemotherapy or orchiectomy only) and age-matched healthy controls were invited. Study assessment included vascular stiffness with ultrasound measurement of carotid-femoral pulse wave velocity (cf-PWV).

Results: We included 127 TCS consisting of a chemotherapy group (70 patients) and an orchiectomy group (57 patients) along with 70 controls. Median follow-up was 28 years (range: 20-42). The cf-PWV (m/s) was higher in TCS than in controls (geometrical mean 8.05 (SD 1.23) vs. 7.60 (SD 1.21), p = 0.04). The cf-PWV was higher in the chemotherapy group than in the orchiectomy group (geometrical mean 8.39 (SD 1.22) vs. 7.61 (SD 1.21), p < 0.01). In the chemotherapy group cf-PWV increased more rapidly as a function of age compared to controls (regression coefficient b 7.59 × 10 vs. 4.04 × 10; p = 0.03).

Conclusion: Very long-term TCS treated with cisplatin-based chemotherapy show increased vascular damage compatible with "accelerated vascular aging" and continue to be at risk for cardiovascular morbidity, thus supporting the need for intensive cardiovascular risk management.

Clinical Trial Registration: The clinical trial registration number is NCT02572934.
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http://dx.doi.org/10.1038/s41416-020-01049-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7686327PMC
November 2020

Corrigendum to "Dopamine and serotonin regulate tumor behavior by affecting angiogenesis" [Drug Resist. Updat. 17 (2014) 96-104].

Drug Resist Updat 2020 Dec 30;53:100717. Epub 2020 Jul 30.

Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands. Electronic address:

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http://dx.doi.org/10.1016/j.drup.2020.100717DOI Listing
December 2020

EGFR mutations are associated with response to depatux-m in combination with temozolomide and result in a receptor that is hypersensitive to ligand.

Neurooncol Adv 2020 Jan-Dec;2(1):vdz051. Epub 2019 Dec 9.

Departments of Neurology, Erasmus MC, Rotterdam, The Netherlands.

Background: The randomized phase II INTELLANCE-2/EORTC_1410 trial on EGFR-amplified recurrent glioblastomas showed a trend towards improved overall survival when patients were treated with depatux-m plus temozolomide compared with the control arm of alkylating chemotherapy only. We here performed translational research on material derived from this clinical trial to identify patients that benefit from this treatment.

Methods: Targeted DNA-sequencing and whole transcriptome analysis was performed on clinical trial samples. High-throughput, high-content imaging analysis was done to understand the molecular mechanism underlying the survival benefit.

Results: We first define the tumor genomic landscape in this well-annotated patient population. We find that tumors harboring EGFR single-nucleotide variations (SNVs) have improved outcome in the depatux-m + TMZ combination arm. Such SNVs are common to the extracellular domain of the receptor and functionally result in a receptor that is hypersensitive to low-affinity EGFR ligands. These hypersensitizing SNVs and the ligand-independent EGFRvIII variant are inversely correlated, indicating two distinct modes of evolution to increase EGFR signaling in glioblastomas. Ligand hypersensitivity can explain the therapeutic efficacy of depatux-m as increased ligand-induced activation will result in increased exposure of the epitope to the antibody-drug conjugate. We also identified tumors harboring mutations sensitive to "classical" EGFR tyrosine-kinase inhibitors, providing a potential alternative treatment strategy.

Conclusions: These data can help guide treatment for recurrent glioblastoma patients and increase our understanding into the molecular mechanisms underlying EGFR signaling in these tumors.
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http://dx.doi.org/10.1093/noajnl/vdz051DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7212878PMC
December 2019

The immune tumour microenvironment of neuroendocrine tumours and its implications for immune checkpoint inhibitors.

Endocr Relat Cancer 2020 09;27(9):R329-R343

Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Groningen, The Netherlands.

Immunotherapy in the form of immune checkpoint inhibitors (ICIs) has transformed the treatment landscape in numerous types of advanced cancer. However, the majority of patients do not benefit from this treatment modality. Although data are scarce, in general, patients with low-grade neuroendocrine tumours (NETs) do not benefit from treatment with ICIs in contrast to patients with neuroendocrine carcinoma, in which a small subgroup of patients may benefit. Low- and intermediate-grade NETs predominantly lack factors associated with response to ICIs treatment, like immune cell infiltration, and have an immunosuppressive tumour metabolism and microenvironment. In addition, because of its potential influence on the response to ICIs, major interest has been shown in the tryptophan-degrading enzymes indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO). These enzymes work along the kynurenine pathway that deplete tryptophan in the tumour microenvironment. IDO and TDO are especially of interest in NETs since some tumours produce serotonin but the majority do not, which potentially deplete the precursor tryptophan. In this review, we summarize the current knowledge on the immune tumour microenvironment of neuroendocrine tumours and implications for treatment with immune checkpoint inhibitors. We also discuss (targetable) factors in the NET tumour microenvironment that potentially modulate the anti-cancer immune response.
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http://dx.doi.org/10.1530/ERC-20-0113DOI Listing
September 2020

Neuroendocrine tumours and their microenvironment.

Cancer Immunol Immunother 2020 Aug 8;69(8):1449-1459. Epub 2020 Apr 8.

Department of Medical Oncology, University Medical Centre Groningen, University of Groningen, DA11, PO Box 30.001, 9700 RB, Groningen, The Netherlands.

Tumours can escape the immune system by expressing programmed death-ligand-1 (PD-L1), which allows them to bind to PD-1 on T-cells and avoid recognition by the immune system. Regulatory T-cells (Tregs), indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) also play a role in immune suppression. Knowledge about the interaction of neuroendocrine tumours (NETs) with their immune microenvironment and the role of immunotherapy in patients with NET is scarce. Here, we investigated the immune microenvironment of serotonin-producing (SP) and non-serotonin-producing NETs (NSP-NETs). Tumours of 33 patients with SP-NET and 18 patients with NSP-NET were studied. Immunohistochemical analyses were performed for PD-L1, T-cells, IDO, TDO, mismatch repair proteins (MMRp) and activated fibroblasts. PD-L1 expression was seen in < 1% of tumour and T-cells. T-cells were present in 33% of NETs, varying between 1 and 10% T-cells per high power field. IDO was expressed in tumour cells in 55% of SP-NETs and 22% of NSP-NETs (p = 0.039). TDO was expressed in stromal cells in 64% of SP-NETs and 13% of NSP-NETs (p = 0.001). No tumours had loss of MMRp. TDO-expressing stromal cells also strongly expressed α-SMA and were identified as cancer-associated fibroblasts (CAFs). Factors that are associated with a response to checkpoint inhibitor treatment were absent or only present to a limited extent in the tumour microenvironment of NETs. The expression of IDO and TDO in a substantial part of NETs and the presence of CAFs suggest two mechanisms that could be responsible for the cold immune microenvironment, which should be explored to enhance anti-tumour immunity and clinical responses.
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http://dx.doi.org/10.1007/s00262-020-02556-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7347684PMC
August 2020

High hepatocyte growth factor expression in primary tumor predicts better overall survival in male breast cancer.

Breast Cancer Res 2020 03 18;22(1):30. Epub 2020 Mar 18.

Department of Medical Oncology, University of Groningen, University Medical Center Groningen, PO Box 30.001, 9700 RB, Groningen, The Netherlands.

Background: Breast cancer is rare in men, but management is focused on tumor characteristics commonly found in female breast cancer. The tumor microenvironment of male breast cancer is less well understood, and insight may improve male breast cancer management. The hepatocyte growth factor (HGF)/c-MET axis and the stromal cell-derived factor-1 (CXCL12)/C-X-C chemokine receptor type 4 (CXCR4) axis are prognostic in women with breast cancer. We aimed to investigate these factors in male breast cancer and correlate them with patient survival.

Methods: From 841 Dutch males with breast cancer who were enrolled in the EORTC 10085/TBCRC/BIG/NABCG International Male Breast Cancer Program (NCT01101425) and diagnosed between 1990 and 2010, archival primary tumor samples were collected. Tissue microarrays were constructed with 3 cores per sample and used for immunohistochemical analysis of HGF, c-MET, CXCL12, and CXCR4. Overall survival (OS) of the patients without metastases (M0) was analyzed using the Kaplan-Meier method. The value of the markers regarding OS was determined using univariable and multivariable Cox regression analyses, providing hazard ratios (HRs) and 95% confidence intervals (95% CIs).

Results: Of 720 out of 841 patients, sufficient tissue was available for analysis; 487 out of 720 patients had M0 disease. Patients with high HGF expression and high CXCL12 expression had a superior OS (low vs high expression of both markers, 7.5 vs 13.0 years, hazard ratio [HR] 0.64, 95% CI 0.49-0.84, P = 0.001 [HGF]; 9.1 vs 15.3 years, HR 0.63, 95% CI 0.45-0.87, P = 0.005 [CXCL12]). Multivariate analysis identified HGF as an independent predictor for OS (HR 0.64, 95% CI 0.47-0.88, P = 0.001).

Conclusions: HGF and CXCL12 tumor expression appear to identify male breast cancer patients with a relatively good prognosis. Possibly, this could support male breast cancer-specific management strategies in the future.
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http://dx.doi.org/10.1186/s13058-020-01266-xDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7081628PMC
March 2020

The Current Status of Immune Checkpoint Inhibitors in Neuro-Oncology: A Systematic Review.

Cancers (Basel) 2020 Mar 4;12(3). Epub 2020 Mar 4.

Department of Medical Oncology, University of Groningen, University Medical Center Groningen, 9700 RB Groningen, The Netherlands.

The introduction of immune checkpoint inhibitors (ICI), as a novel treatment modality, has transformed the field of oncology with unprecedented successes. However, the efficacy of ICI for patients with glioblastoma or brain metastases (BMs) from any tumor type is under debate. Therefore, we systematically reviewed current literature on the use of ICI in patients with glioblastoma and BMs. Prospective and retrospective studies evaluating the efficacy and survival outcomes of ICI in patients with glioblastoma or BMs, and published between 2006 and November 2019, were considered. A total of 88 studies were identified ( = 8 in glioblastoma and = 80 in BMs). In glioblastoma, median progression-free (PFS) and overall survival (OS) of all studies were 2.1 and 7.3 months, respectively. In patients with BMs, intracranial responses have been reported in studies with melanoma and non-small-cell lung cancer (NSCLC). The median intracranial and total PFS in these studies were 2.7 and 3.0 months, respectively. The median OS in all studies for patients with brain BMs was 8.0 months. To date, ICI demonstrate limited efficacy in patients with glioblastoma or BMs. Future research should focus on increasing the local and systemic immunological responses in these patients.
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http://dx.doi.org/10.3390/cancers12030586DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7139638PMC
March 2020

Quantitative Profiling of Platelet-Rich Plasma Indole Markers by Direct-Matrix Derivatization Combined with LC-MS/MS in Patients with Neuroendocrine Tumors.

Clin Chem 2019 11 24;65(11):1388-1396. Epub 2019 Sep 24.

Department of Laboratory Medicine, University Medical Center Groningen, University of Groningen, Groningen, the Netherlands;

Background: Currently, several indole markers are measured separately to support diagnosis and follow-up of patients with neuroendocrine tumors (NETs). We have developed a sensitive mass spectrometry method that simultaneously quantifies all relevant tryptophan-related indoles (tryptophan, 5-hydroxytryptophan, serotonin, 5-hydroxyindoleacetic acid) in platelet-rich plasma. Direct-matrix derivatization was used to make the chemical properties of the indoles uniform and to improve the analytical sensitivity and specificity of the assay.

Methods: In situ derivatization was performed directly in platelet-rich plasma with propionic anhydride at an ambient temperature. The derivatized indoles were extracted by online solid-phase extraction and eluted to the analytical column for separation followed by mass spectrometric detection. The method was validated according to international guidelines. Platelet-rich plasma samples from 68 healthy individuals and 40 NET patients were analyzed for tryptophan, 5-hydroxytryptophan, serotonin, and 5-hydroxyindoleacetic acid.

Results: The method reproducibly quantified relevant indoles in 8.5 min, including online sample cleanup. Intra- and interassay imprecision, evaluated at 3 different concentrations, ranged from 2.0% to 12% and 1.9% to 13%, respectively. The limit of quantification was sufficient to measure endogenous concentrations of all 4 indoles. Healthy individuals and NET patients had different concentrations of 5-hydroxytryptophan, serotonin, and 5-hydroxyindoleacetic acid, but tryptophan concentrations were the same.

Conclusions: Direct-matrix derivatization in combination with LC-MS/MS is a powerful tool for the simultaneous quantification of all tryptophan-related indoles in platelet-rich plasma. Simultaneous profiling of relevant indoles improves the biochemical characterization and follow-up of NETs.
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http://dx.doi.org/10.1373/clinchem.2019.305359DOI Listing
November 2019

Serotonin and Dopamine Receptor Expression in Solid Tumours Including Rare Cancers.

Pathol Oncol Res 2020 Jul 2;26(3):1539-1547. Epub 2019 Sep 2.

Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, Box 30.001, 9700 RB, Groningen, The Netherlands.

In preclinical studies serotonin stimulates and dopamine inhibits tumour growth and angiogenesis. Information regarding serotonin and dopamine receptor (5-HTR and DRD) expression in human cancers is limited. Therefore, we screened a large tumour set for receptor mRNA overexpression using functional genomic mRNA (FGmRNA) profiling, and we analysed protein expression and location of 5-HTR1B, 5-HTR2B, DRD1, and DRD2 with immunohistochemistry in different tumour types. With FGmRNA profiling 11,756 samples representing 43 tumour types were compared to 3,520 normal tissue samples to analyse receptor overexpression. 5-HTR2B overexpression was present in many tumour types, most frequently in uveal melanomas (56%). Receptor overexpression in rare cancers included 5-HTR1B in nasopharyngeal carcinoma (17%), DRD1 in ependymoma (30%) and synovial sarcoma (21%), and DRD2 in astrocytoma (13%). Immunohistochemistry demonstrated high 5-HTR2B protein expression on melanoma and gastro-intestinal stromal tumour cells and endothelial cells of colon, ovarian, breast, renal and pancreatic tumours. 5-HTR1B expression was predominantly low. High DRD2 protein expression on tumour cells was observed in 48% of pheochromocytomas, and DRD1 expression ranged from 14% in melanoma to 57% in renal cell carcinoma. In conclusion, 5-HTR1B, 5-HTR2B, DRD1, and DRD2 show mRNA overexpression in a broad spectrum of common and rare cancers. 5-HTR2B protein is frequently highly expressed in human cancers, especially on endothelial cells. These findings support further investigation of especially 5HTR2B as a potential treatment target.
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http://dx.doi.org/10.1007/s12253-019-00734-wDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7297821PMC
July 2020

Interlesional Heterogeneity of Metastatic Neuroendocrine Tumors Based on 18F-DOPA PET/CT.

Clin Nucl Med 2019 Aug;44(8):612-619

From the Departments of Medical Oncology.

Purpose: Neuroendocrine tumors (NETs) can produce neuroendocrine amines resulting in symptoms. Selecting the most active amine-producing tumor lesions for local treatment might be beneficial for patients with metastatic small intestinal NET. Tumor burden correlates with catecholamine pathway activity. We analyzed interlesional heterogeneity with F-DOPA PET scans in patients with small intestinal NET and investigated if lesions with substantially higher F-DOPA uptake could be identified.

Methods: In this retrospective, observational study, the F-DOPA uptake was calculated by dividing SUVpeak of the lesion by the SUVmean of the background organ. The magnitude of heterogeneity between lesions within a patient was calculated by dividing the lesion with the highest by the one with the lowest F-DOPA uptake. Lesions with a higher F-DOPA uptake than the upper inner or outer fence (>1.5 or 3 times the interquartile range above the third quartile) were defined as lesions with mild or extreme high F-DOPA uptake, respectively, and presence of these was determined in patients with 10 lesions or more.

Results: F-DOPA was detected over 680 lesions in 38 patients, of which 35 were serotonin producing. F-DOPA uptake varied with a median of 8-fold up to 44-fold between lesions within a patient. In 12 of 20 evaluable patients, lesions with mild high F-DOPA uptake were found, and in 5, lesions with extreme high F-DOPA uptake.

Conclusions: F-DOPA-PET showed considerable heterogeneity in F-DOPA uptake between tumor lesions and identified lesions within patients with mild or extreme high F-DOPA uptake.
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http://dx.doi.org/10.1097/RLU.0000000000002640DOI Listing
August 2019

Epidermal growth factor receptor (EGFR) amplification rates observed in screening patients for randomized trials in glioblastoma.

J Neurooncol 2019 Aug 4;144(1):205-210. Epub 2019 Jul 4.

Department of Neurology, Erasmus MC Cancer Institute, Rotterdam, The Netherlands.

Purpose: Epidermal growth factor receptor (EGFR) amplification has been reported to occur in ~ 50% of glioblastomas (GBMs). We are conducting several global studies that require central testing for EGFR amplification during screening, representing an opportunity to confirm the frequency of amplification in GBM in a large cohort and to evaluate whether EGFR amplification differs by region of the world.

Methods: EGFR amplification was measured by fluorescence in situ hybridization during screening for therapeutic trials of an EGFR antibody-drug conjugate: two Phase 2/3 global trials (INTELLANCE-1, INTELLANCE-2), and a Japanese Phase 1/2 trial (INTELLANCE-J). We evaluated the proportion of tumor tissue samples harboring EGFR amplification among those tested and differences in amplification frequency by geography.

Results: EGFR was amplified in 54% of 3150 informative cases screened for INTELLANCE-1 and -2, consistent with historic controls, but was significantly lower in patients from Asia versus the rest of the world (35% vs. 56%, P < 0.0030). The independent INTELLANCE-J trial validated this finding (33% amplified of 153 informative cases).

Conclusions: EGFR amplification occurs less frequently in patients from Asia than elsewhere. Further study is required to understand biological differences to optimize treatment in glioblastoma.
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http://dx.doi.org/10.1007/s11060-019-03222-yDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8082754PMC
August 2019

Serial FLT PET imaging to discriminate between true progression and pseudoprogression in patients with newly diagnosed glioblastoma: a long-term follow-up study.

Eur J Nucl Med Mol Imaging 2018 12 21;45(13):2404-2412. Epub 2018 Jul 21.

Department of Medical Oncology, University of Groningen, University Medical Centre Groningen, P.O. Box 30.001, 9700 RB, Groningen, The Netherlands.

Purpose: Response evaluation in patients with glioblastoma after chemoradiotherapy is challenging due to progressive, contrast-enhancing lesions on MRI that do not reflect true tumour progression. In this study, we prospectively evaluated the ability of the PET tracer F-fluorothymidine (FLT), a tracer reflecting proliferative activity, to discriminate between true progression and pseudoprogression in newly diagnosed glioblastoma patients treated with chemoradiotherapy.

Methods: FLT PET and MRI scans were performed before and 4 weeks after chemoradiotherapy. MRI scans were also performed after three cycles of adjuvant temozolomide. Pseudoprogression was defined as progressive disease on MRI after chemoradiotherapy with stabilisation or reduction of contrast-enhanced lesions after three cycles of temozolomide, and was compared with the disease course during long-term follow-up. Changes in maximum standardized uptake value (SUV) and tumour-to-normal uptake ratios were calculated for FLT and are presented as the mean SUV for multiple lesions.

Results: Between 2009 and 2012, 30 patients were included. Of 24 evaluable patients, 7 showed pseudoprogression and 7 had true progression as defined by MRI response. FLT PET parameters did not significantly differ between patients with true progression and pseudoprogression defined by MRI. The correlation between change in SUV and survival (p = 0.059) almost reached the standard level of statistical significance. Lower baseline FLT PET uptake was significantly correlated with improved survival (p = 0.022).

Conclusion: Baseline FLT uptake appears to be predictive of overall survival. Furthermore, changes in SUV over time showed a tendency to be associated with improved survival. However, further studies are necessary to investigate the ability of FLT PET imaging to discriminate between true progression and pseudoprogression in patients with glioblastoma.
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http://dx.doi.org/10.1007/s00259-018-4090-4DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6208814PMC
December 2018

False-positive findings on 6-[18F]fluor-l-3,4-dihydroxyphenylalanine PET (F-FDOPA-PET) performed for imaging of neuroendocrine tumors.

Eur J Endocrinol 2018 Aug 6;179(2):125-133. Epub 2018 Jun 6.

Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.

Background/aim: PET with 6-[18F]fluor-l-3,4-dihydroxyphenylalanine (F-FDOPA) has been shown to be a useful imaging tool with a high sensitivity for the visualization of neuroendocrine tumors (NETs). F-FDOPA uptake in tumors other than NETs has been suggested previously, but data on this phenomenon are limited. We therefore studied the non-physiological, false-positive uptake of F-FDOPA in a large population of patients with a NET or with a high clinical suspicion of harboring a NET.

Patients And Methods: Retrospective single-center study among adult patients in whom F-FDOPA PET scintigraphy was performed between January 2004 and December 2014. The original scan report was compared with the original pathology report corresponding with the F-FDOPA PET-positive lesion. In case this was inconsistent with the diagnosis of a NET, both the scan and the pathology slides were reassessed. Specimens of these non-NET tissues were immunohistochemically stained for AADC.

Results: 1070 F-FDOPA PET scans from 705 patients were evaluated. Focal or multiple F-FDOPA-avid lesions were described in 709 F-FDOPA PET scans (66%). Histology of these F-FDOPA PET-positive lesions was present in 508 (72%) cases. In seven cases, the histopathology was not compatible with NET but showed squamous cell carcinoma of the cervix, multiple myeloma (two cases), hepatocellular carcinoma, Schwannoma, adrenocortical carcinoma and a skeletal myxoid chondrosarcoma, with positive immunohistochemical staining for AADC in 67%.

Conclusions: Pathological uptake of F-FDOPA does not always indicate the presence of a NET. The possibility of F-FDOPA uptake by tumor types other than NETs, although rare, should be considered.
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http://dx.doi.org/10.1530/EJE-18-0321DOI Listing
August 2018

Self-monitoring physical activity with a smartphone application in cancer patients: a randomized feasibility study (SMART-trial).

Support Care Cancer 2018 Nov 21;26(11):3915-3923. Epub 2018 May 21.

Department of Medical Oncology, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713, GZ, Groningen, the Netherlands.

Purpose: Evidence accumulates that an active lifestyle positively influences cancer treatment outcome. A "smartphone application" (app) such as "RunKeeper," to self-monitor physical activity (PA) might be helpful. This study aimed to examine whether using RunKeeper to increase self-reported PA is feasible in cancer patients and to evaluate patients' opinion about using RunKeeper in a 12-week program.

Methods: Adult patients (n = 32), diagnosed with cancer, were randomized between usual care (n = 16) or a 12-week intervention with instructions to self-monitor PA with RunKeeper (n = 16). Changes in PA were determined with the Physical Activity Scale for the Elderly (PASE) at baseline (T0), 6 weeks (T1), and 12 weeks (T2). Usability and patients' experiences were tested at T2 with the System Usability Scale (SUS) and a semi-structured interview.

Results: Patient mean age was 33.6 years. Between T0 and T1, an increase in PA of 51% (medium estimated effect size r = 0.40) was found in PASE sum score in the intervention group compared with usual care. In addition, total minutes of PA increased with 46% (r = 0.37). These effects decreased over time (T2). Sedentary time decreased with 19% between T0 and T1 and 27% between T0 and T2. Usability was rated "good" and most patients found RunKeeper use helpful to improve PA.

Conclusions: Self-monitoring PA with RunKeeper was safe and feasible in cancer patients. The RunKeeper use resulted in an increase in PA after 6 weeks. RunKeeper usability was rated good and can be used to study PA in cancer patients.

Trial Registration: NCT02391454.
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http://dx.doi.org/10.1007/s00520-018-4263-5DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6182373PMC
November 2018

Response to Alwardat comments on our systematic review entitled: "Predictors of adherence to exercise interventions during and after cancer treatment: A systematic review".

Psychooncology 2018 04;27(4):1354

Department of Medical Oncology, University Medical Center Groningen, Groningen, The Netherlands.

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http://dx.doi.org/10.1002/pon.4652DOI Listing
April 2018

CXCR4 Ligands: The Next Big Hit?

J Nucl Med 2017 09;58(Suppl 2):77S-82S

Pharmaceutical Radiochemistry, Technische Universität München, Munich, Germany; and.

The G protein-coupled protein receptor C-X-C chemokine receptor 4 (CXCR4) is an attractive target for cancer diagnosis and treatment, as it is overexpressed in many solid and hematologic cancers. Binding of its ligand, C-X-C chemokine ligand 12 (CXCL12), results in receptor internalization and activation of several signal transduction pathways, such as phosphoinositide 3-kinase/protein kinase B, which are critical in cell proliferation, angiogenesis, development of metastasis, and survival. Also, the CXCR4-CXCL12 axis is involved in the interaction between hematopoietic stem cells (as well as hematologic and solid tumor cells) and their protective microenvironment. This interaction can be disrupted by CXCR4 antagonists. This concept is being used clinically to harvest hematopoietic stem or progenitor cells from bone marrow and to sensitize cancer cells to conventional chemotherapy and radiotherapy, and the potential to overcome tumor microenvironment-driven immunosuppression is being explored. This review focuses on new strategies for improvement of cancer treatment by targeting of the CXCR4-CXCL12 interaction. Because of its critical role in cancer, many peptidic and nonpeptidic ligands with different modes of antagonistic activity against the CXCR4-CXCL12 axis have been developed, with some of them reaching clinical trials. Molecular imaging with recently developed radiolabeled CXCR4 ligands could facilitate the selection of patients who might benefit from directed targeted therapy, including CXCR4-directed endoradiotherapy.
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http://dx.doi.org/10.2967/jnumed.116.186874DOI Listing
September 2017

Treatment outcome of patients with recurrent glioblastoma multiforme: a retrospective multicenter analysis.

J Neurooncol 2017 Oct 20;135(1):183-192. Epub 2017 Jul 20.

Department of Medical Oncology, Cancer Center Amsterdam, VU University Medical Center, P.O. Box 7057, 1007 MB, Amsterdam, The Netherlands.

Glioblastoma multiforme (GBM) universally recurs with dismal prognosis. We evaluated the efficacy of standard treatment strategies for patients with recurrent GBM (rGBM). From two centers in the Netherlands, 299 patients with rGBM after first-line treatment, diagnosed between 2005 and 2014, were retrospectively evaluated. Four different treatment strategies were defined: systemic treatment (SYST), re-irradiation (RT), re-resection followed by adjuvant treatment (SURG) and best supportive care (BSC). Median OS for all patients was 6.5 months, and median PFS (excluding patients receiving BSC) was 5.5 months. Older age, multifocal lesions and steroid use were significantly associated with a shorter survival. After correction for confounders, patients receiving SYST (34.8%) and SURG (18.7%) had a significantly longer survival than patients receiving BSC (39.5%), 7.3 and 11.0 versus 3.1 months, respectively [HR 0.46 (p < 0.001) and 0.36 (p < 0.001)]. Median survival for patients receiving RT (7.0%) was 9.2 months, but this was not significantly different from patients receiving BSC (p = 0.068). Patients receiving SURG compared to SYST had a longer PFS (9.0 vs. 4.3 months, respectively; p < 0.001), but no difference in OS was observed. After adjustments for confounders, patients with rGBM selected for treatment with SURG or SYST do survive significantly longer than patients who are selected for BSC based on clinical parameters. The value of reoperation versus systemic treatment strategies needs further investigation.
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http://dx.doi.org/10.1007/s11060-017-2564-zDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5658463PMC
October 2017

Web-Based Tailored Psychoeducation for Breast Cancer Patients at the Onset of the Survivorship Phase: A Multicenter Randomized Controlled Trial.

J Pain Symptom Manage 2017 10 13;54(4):466-475. Epub 2017 Jul 13.

Department of Medical Oncology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands. Electronic address:

Context: Many breast cancer patients have unmet informational and psychosocial needs after treatment completion. A psychoeducational intervention may be well suited to support these patients.

Objectives: The purpose of this multicenter randomized controlled trial was to examine the effectiveness of a web-based tailored psychoeducational program (ENCOURAGE) for breast cancer patients, which aims to empower patients to take control over prevailing problems.

Methods: Female breast cancer patients from two hospitals in The Netherlands who recently completed (neo-)adjuvant chemotherapy were randomly assigned to standard care or 12-week access to the ENCOURAGE program providing fully automated information problem-solving strategies, resources, and services for reported problems. At six and 12 weeks, patients completed self-report questions on optimism and control over the future (primary outcome), feelings of being informed, and acceptance of the illness. At baseline and 12 weeks, distress and quality of life questionnaires were completed.

Results: About 138 patients were included. Almost all patients (67 of 69) visited ENCOURAGE as requested. No differences between the control and intervention group were observed for primary and secondary outcomes. An unplanned subgroup analysis showed that in clinically distressed patients (N = 57 at baseline; 41%), use of the ENCOURAGE program increased optimism and control over the future at 12 weeks more than in patients in the control group (Cohen's d = 0.65).

Conclusion: Although the effectiveness was not demonstrated, a subgroup of women treated for breast cancer can probably be supported by the program. The results of the present study are a starting point for further development and use of the program.
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http://dx.doi.org/10.1016/j.jpainsymman.2017.07.009DOI Listing
October 2017

Web-based information and support for patients with a newly diagnosed neuroendocrine tumor: a feasibility study.

Support Care Cancer 2017 07 9;25(7):2075-2083. Epub 2017 Feb 9.

Department of Medical Oncology, University Medical Center Groningen, University of Groningen, DA11, PO Box 30.001, 9700 RB, Groningen, The Netherlands.

Purpose: Patients with a neuroendocrine tumor (NET) frequently experience physical and psychosocial complaints. Novel strategies to provide information to optimize supportive care in these patients are of interest. The aim of this study was to examine whether the use of a web-based system consisting of self-screening of problems and care needs, patient education, and self-referral to professional health care is feasible in NET patients and to evaluate their opinion on this.

Methods: Newly diagnosed NET patients were randomized between standard care (n = 10) or intervention with additional access to the web-based system (n = 10) during 12 weeks. Patients completed questionnaires regarding received information, distress, quality of life (QoL), and empowerment. The intervention group completed a semi-structured interview to assess patients' opinion on the web-based system.

Results: The participation rate was 77% (20/26 invited patients) with no dropouts. The use of the web-based system had a negative effect on patients' perception and satisfaction of received information (range Cohen's d -0.88 to 0.13). Positive effects were found for distress (Cohen's d 0.75), global QoL (subscale European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, Cohen's d 0.46), resolving problems with social functioning and finding information (subscales EORTC QLQ-GINET 21, Cohen's d 0.69, respectively, 1.04), and feeling informed (subscale empowerment questionnaire, Cohen's d 0.51). The interview indicated that the web-based system was of additional value to standard care.

Conclusions: Use of this web-based system is feasible. Contradictory effects on informing and supporting NET patients were found and should be subject of further research.

Trial Registration: NCT01849523.
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http://dx.doi.org/10.1007/s00520-017-3598-7DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5445166PMC
July 2017
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