ObjectiveSince the end of 2019, the coronavirus disease 2019 (COVID-19) virus has infected millions of people, of whom a significant group suffers from sequelae from COVID-19, termed long COVID. As... Show moreObjectiveSince the end of 2019, the coronavirus disease 2019 (COVID-19) virus has infected millions of people, of whom a significant group suffers from sequelae from COVID-19, termed long COVID. As more and more patients emerge with long COVID who have symptoms of fatigue, myalgia and joint pain, we must examine potential biomarkers to find quantifiable parameters to define the underlying mechanisms and enable response monitoring. The aim of this study is to investigate the potential added value of [F-18]FDG-PET/computed tomography (CT) for this group of long COVID patients. MethodsFor this proof of concept study, we evaluated [F-18]FDG-PET/CT scans of long COVID patients and controls. Two analyses were performed: semi-quantitative analysis using target-to-background ratios (TBRs) in 24 targets and total vascular score (TVS) assessed by two independent nuclear medicine physicians. Mann-Whitney U-test was performed to find significant differences between the two groups. ResultsThirteen patients were included in the long COVID group and 25 patients were included in the control group. No significant differences (P < 0.05) were found between the long COVID group and the control group in the TBR or TVS assessment. ConclusionAs we found no quantitative difference in the TBR or TVS between long COVID patients and controls, we are unable to prove that [F-18]FDG is of added value for long COVID patients with symptoms of myalgia or joint pain. Prospective cohort studies are necessary to understand the underlying mechanisms of long COVID. Show less
Chen, L.L.; Burgt, A. van de; Smit, F.; Audhoe, R.S.; Boer, S.M. de; Velden, F.H.P. van; Geus-Oei, L.F. de 2023
Objective Since the end of 2019, the coronavirus disease 2019 (COVID-19) virus has infected millions of people, of whom a significant group suffers from sequelae from COVID-19, termed long COVID.... Show moreObjective Since the end of 2019, the coronavirus disease 2019 (COVID-19) virus has infected millions of people, of whom a significant group suffers from sequelae from COVID-19, termed long COVID. As more and more patients emerge with long COVID who have symptoms of fatigue, myalgia and joint pain, we must examine potential biomarkers to find quantifiable parameters to define the underlying mechanisms and enable response monitoring. The aim of this study is to investigate the potential added value of [18F]FDG-PET/computed tomography (CT) for this group of long COVID patients.Methods For this proof of concept study, we evaluated [18F]FDG-PET/CT scans of long COVID patients and controls. Two analyses were performed: semi-quantitative analysis using target-to-background ratios (TBRs) in 24 targets and total vascular score (TVS) assessed by two independent nuclear medicine physicians. Mann–Whitney U-test was performed to find significant differences between the two groups.Results Thirteen patients were included in the long COVID group and 25 patients were included in the control group. No significant differences (P < 0.05) were found between the long COVID group and the control group in the TBR or TVS assessment.Conclusion As we found no quantitative difference in the TBR or TVS between long COVID patients and controls, we are unable to prove that [18F]FDG is of added value for long COVID patients with symptoms of myalgia or joint pain. Prospective cohort studies are necessary to understand the underlying mechanisms of long COVID. Show less
Standard molecular classification of endometrial cancers (EC) is now endorsed by the WHO and identifies p53-abnormal (p53abn) EC as the subgroup with the poorest prognosis and the most likely to... Show moreStandard molecular classification of endometrial cancers (EC) is now endorsed by the WHO and identifies p53-abnormal (p53abn) EC as the subgroup with the poorest prognosis and the most likely to benefit from adjuvant chemo(radio)therapy. P53abn EC are POLE wildtype, mismatch repair proficient and show abnormal immunohistochemical (IHC) staining for p53. Correct interpretation of routinely performed p53 IHC has therefore become of paramount importance. We aimed to comprehensively investigate abnormal p53 IHC patterns and their relation to clinicopathological and molecular features. Tumor material of 411 molecularly classified high-risk EC from consenting patients from the PORTEC-3 clinical trial were collected. p53 IHC was successful in 408 EC and was considered abnormal when the tumor showed a mutant expression pattern (including subclonal): overexpression, null or cytoplasmic. The presence of pathogenic mutations was determined by next generation sequencing (NGS). Abnormal p53 expression was observed in 131/408 (32%) tumors. The most common abnormal p53 IHC pattern was overexpression (n = 89, 68%), followed by null (n = 12, 9%) and cytoplasmic (n = 3, 2%). Subclonal abnormal p53 staining was observed in 27 cases (21%), which was frequently but not exclusively, associated with POLE mutations and/or MMRd (n = 22/27; p < 0.001). Agreement between p53 IHC and TP53 NGS was observed in 90.7%, resulting in a sensitivity and specificity of 83.6% and 94.3%, respectively. Excluding POLEmut and MMRd EC, as per the WHO-endorsed algorithm, increased the accuracy to 94.5% with sensitivity and specificity of 95.0% and 94.1%, respectively. Our data shows that awareness of the abnormal p53 IHC patterns are prerequisites for correct EC molecular classification. Subclonal abnormal p53 expression is a strong indicator for POLEmut and/or MMRd EC. No significant differences in clinical outcomes were observed among the abnormal p53 IHC patterns. Our data support use of the WHO-endorsed algorithm and combining the different abnormal p53 IHC patterns into one diagnostic entity (p53abn EC). Show less
Objectives: We have developed two Dutch questionnaires to assess the shared decision-making (SDM) process in oncology; the iSHAREpatient and iSHAREphysician. In this study, we aimed to determine:... Show moreObjectives: We have developed two Dutch questionnaires to assess the shared decision-making (SDM) process in oncology; the iSHAREpatient and iSHAREphysician. In this study, we aimed to determine: scores, construct validity, test-retest agreement (iSHAREpatient), and inter-rater (iSHAREpatient-iSHAREphysician) agreement. Methods: Physicians from seven Dutch hospitals recruited cancer patients, and completed the iSHAREphysician and SDM-Questionnaire-physician version. Their patients completed the: iSHAREpatient, nine-item SDM-Questionnaire, Decisional Conflict Scale, Combined Outcome Measure for Risk communication And treatment Decision-making Effectiveness, and five-item Perceived Efficacy in Patient-Physician Interactions. We formulated, respectively, one (iSHAREphysician) and 10 (iSHAREpatient) a priori hypotheses regarding correlations between the iSHARE questionnaires and questionnaires assessing related constructs. To assess test-retest agreement patients completed the iSHAREpatient again 1-2 weeks later. Results: In total, 151 treatment decision-making processes with unique patients were rated. Dimension and total iSHARE scores were high both in patients and physicians. The hypothesis on the iSHAREphysician and 9/10 hypotheses on the iSHAREpatient were confirmed. Test-retest and inter-rater agreement were >.60 for most items. Conclusions: The iSHARE questionnaires show high scores, have good construct validity, substantial test-retest agreement, and moderate inter-rater agreement. Practice implications: Results from the iSHARE questionnaires can inform both physician- and patient-directed efforts to improve SDM in clinical practice. Show less
Endometrial cancer is primarily treated with surgery. Adjuvant treatment strategies for endometrial cancer, such as external beam pelvic radiotherapy, vaginal brachytherapy, chemotherapy, and... Show moreEndometrial cancer is primarily treated with surgery. Adjuvant treatment strategies for endometrial cancer, such as external beam pelvic radiotherapy, vaginal brachytherapy, chemotherapy, and combined chemotherapy and radiotherapy, have been studied in several randomized trials. Adjuvant treatment is currently based on the presence of clinico-pathological risk factors. Low-risk disease is adequately managed with surgery alone. In high-intermediate risk endometrial cancer, adjuvant vaginal brachytherapy is recommended to maximize local control, with only mild side effects and without impact on quality of life. For high-risk endometrial cancer, recent large randomized trials support the use of pelvic radiotherapy, especially in stage I-II endometrial cancer with risk factors. For women with serous cancers and those with stage III disease, chemoradiation increased both recurrence-free and overall survival, while GOG-258 showed similar recurrence-free survival compared with six cycles of chemotherapy alone, but with better pelvic and para-aortic nodal control with combined chemotherapy and radiotherapy. Recent molecular studies, most notably the work from The Cancer Genome Atlas (TCGA) project, have shown that four endometrial cancer molecular classes can be distinguished; POLE ultra-mutated, microsatellite instable hypermutated, copy-number-low, and copy-number-high. Subsequent studies, using surrogate markers to identify groups analogous to TCGA sub-classes, showed that all four endometrial cancer sub-types are found across all stages, histological types, and grades. Moreover, the molecular sub-groups have proved to have a stronger prognostic impact than histo-pathological tumor characteristics. This introduces an new era of molecular classification based diagnostics and treatment approaches. Integration of the molecular factors and new therapeutic targets will lead to molecular-integrated adjuvant treatment including targeted treatments, which are the rationale of new and ongoing trials. This review presents an overview of current adjuvant treatment strategies in endometrial cancer, highlights the development and evaluation of a molecular-integrated risk profile, and briefly discusses ongoing developments in targeted treatment. Show less
The ongoing threat of viral infections and the emergence of antiviral drug resistance warrants a ceaseless search for new antiviral compounds. Broadly-inhibiting compounds that act on elements... Show moreThe ongoing threat of viral infections and the emergence of antiviral drug resistance warrants a ceaseless search for new antiviral compounds. Broadly-inhibiting compounds that act on elements shared by many viruses are promising antiviral candidates. Here, we identify a peptide derived from the cowpox virus protein CPXV012 as a broad-spectrum antiviral peptide. We found that CPXV012 peptide hampers infection by a multitude of clinically and economically important enveloped viruses, including poxviruses, herpes simplex virus-1, hepatitis B virus, HIV-1, and Rift Valley fever virus. Infections with non-enveloped viruses such as Coxsackie B3 virus and adenovirus are not affected. The results furthermore suggest that viral particles are neutralized by direct interactions with CPXV012 peptide and that this cationic peptide may specifically bind to and disrupt membranes composed of the anionic phospholipid phosphatidylserine, an important component of many viral membranes. The combined results strongly suggest that CPXV012 peptide inhibits virus infections by direct interactions with phosphatidylserine in the viral envelope. These results reiterate the potential of cationic peptides as broadly-acting virus inhibitors. Show less
Approximately 15–20% of women with endometrial cancer have high-risk disease features and are at increased risk of distant metastases. Standard treatment after surgery is pelvic radiotherapy to... Show moreApproximately 15–20% of women with endometrial cancer have high-risk disease features and are at increased risk of distant metastases. Standard treatment after surgery is pelvic radiotherapy to reduce the risk of recurrence. In the international PORTEC-3 trial we have investigated the added value of adjuvant chemotherapy during and after radiotherapy in terms of efficacy, toxicity and quality of life. It was found that both overall and recurrence-free survival were significantly improved with the addition of chemotherapy to radiotherapy, especially for women with more advanced disease (stage 3) or with serous histological type. This comes however at the expense of increased and more serious toxicity and an impaired quality of life during and in the first 6 months after treatment. About 25% of women treated with chemotherapy still reported tingling and numbness of hands and/or feet at 2 years after treatment. It is therefore important to discuss the benefits and costs of the addition of chemotherapy in shared decision making, for which the results discussed in this thesis provide valuable information. Currently molecular analysis of the PORTEC-3 tissue samples is done to evaluate which patients benefit most from added chemotherapy. Show less
