Objectives: Programmed death-ligand 1 (PD-L1) is the only approved predictive biomarker for immunotherapy in non-small cell lung cancer (NSCLC). However, predictive PD-L1 immunohistochemistry is... Show moreObjectives: Programmed death-ligand 1 (PD-L1) is the only approved predictive biomarker for immunotherapy in non-small cell lung cancer (NSCLC). However, predictive PD-L1 immunohistochemistry is subject to interobserver variability. We hypothesized that a pathologist's personality influences the interobserver variability and diagnostic accuracy of PD-L1 immunoscoring.& nbsp;Materials and Methods: Seventeen pathologists performed PD-L1 immunoscoring on 50 resected NSCLC tumors in three categories (< 1%;1-49%;>= 50%). Also, the pathologists completed a certified personality test (NEO-PI-r), assessing five personality traits: neuroticism, extraversion, openness, altruism and conscientiousness.& nbsp;Results: The overall agreement among pathologists for a series of 47 tumors was substantial (kappa = 0.63). Of these, 23/47 (49%) tumors were entirely negative or largely positive, resulting in a kappa value of 0.93. The remaining 24/47 (51%) tumors had a PD-L1 score around the cutoff value, generating a kappa value of 0.32. Pathologists with high scores for conscientiousness (careful, diligent) had the least interobserver variability (r = 0.6, p = 0.009). Also, they showed a trend towards higher sensitivity (74% vs. 68%, p = 0.4), specificity (86% vs. 82%, p = 0.3) and percent agreement (83% vs. 79%, p = 0.3), although not significant. In contrast, pathologists with high scores for neuroticism (sensitive, anxious) had significantly lower specificity (80% vs. 87%, p = 0.03) and percent agreement (78% vs. 85%, p = 0.03). Also, a trend towards high interobserver variability (r =-0.3, p = 0.2) and lower sensitivity (68% vs. 74%, p = 0.3) was observed, although not significant. Pathologists with relatively high scores for conscientiousness scored fewer tumors PD-L1 positive at the >= 1% cut-off (r =-0.5, p = 0.03). In contrast, pathologists with relatively high scores for neuroticism score more tumors PD-L1 positive at > 1% (r = 0.6, p = 0.017) and >= 50% cut-offs (r = 0.6, p = 0.009).& nbsp;Conclusions: This study is the first to demonstrate the impact of a pathologist's personality on the interobserver variability and diagnostic accuracy of immunostaining, in the context of PD-L1 in NSCLC. Larger studies are needed for validation of these findings. Show less
The studies in this thesis contribute to more accurate risk assessment and prognosis prediction for DCIS and to better response evaluation of IBC treatment.For the Ductal Carcinoma In Situ (DCIS)... Show moreThe studies in this thesis contribute to more accurate risk assessment and prognosis prediction for DCIS and to better response evaluation of IBC treatment.For the Ductal Carcinoma In Situ (DCIS) studies, unbiased cohorts were used within the international Grand Challenge PRECISION consortium, funded by Cancer Research UK and KWF Dutch Cancer Society. DCIS is graded as low-, intermediate-, or high-grade depending on how abnormal the DCIS-cells look like. However, we showed that pathologists often disagree on grade. To overcome this limitation, we found that almost all DCIS scored as non-high-grade by the majority of pathologists express the estrogen receptor (ER) and are negative for the growth factor receptor HER2, whereas high-grade DCIS is mixed in expression for ER and HER2. We also provided insights in the recurrence risks of DCIS after treatment. See also https://cancergrandchallenges.org/teams/precision.The studies on Invasive Breast Cancer (IBC) were performed on a hospital-based cohort. We found for example substantial variation in tumour response evaluation for HER2-positive IBC after pre-operative chemotherapy due to different guidelines used. For accurate outcome analysis, reducing such variation is mandatory. Therefore, we are working on reaching international consensus of response evaluation. Show less
Rutgers, J.J.; Banki, T.; Kamp, A. van der; Waterlander, T.J.; Scheijde-Vermeulen, M.A.; Heuvel-Eibrink, M.M. van den; ... ; Krijger, R.R. de 2021
Background Histopathological classification of Wilms tumors determines treatment regimen. Machine learning has been shown to contribute to histopathological classification in various malignancies... Show moreBackground Histopathological classification of Wilms tumors determines treatment regimen. Machine learning has been shown to contribute to histopathological classification in various malignancies but requires large numbers of manually annotated images and thus specific pathological knowledge. This study aimed to assess whether trained, inexperienced observers could contribute to reliable annotation of Wilms tumor components for classification performed by machine learning. Methods Four inexperienced observers (medical students) were trained in histopathology of normal kidneys and Wilms tumors by an experienced observer (pediatric pathologist). Twenty randomly selected scanned Wilms tumor-slides (from n = 1472 slides) were annotated, and annotations were independently classified by both the inexperienced observers and two experienced pediatric pathologists. Agreement between the six observers and for each tissue element was measured using kappa statistics (kappa). Results Pairwise interobserver agreement between all inexperienced and experienced observers was high (range: 0.845-0.950). The interobserver variability for the different histological elements, including all vital tumor components and therapy-related effects, showed high values for all kappa-coefficients (> 0.827). Conclusions Inexperienced observers can be trained to recognize specific histopathological tumor and tissue elements with high interobserver agreement with experienced observers. Nevertheless, supervision by experienced pathologists remains necessary. Results of this study can be used to facilitate more rapid progress for supervised machine learning-based algorithm development in pediatric pathology and beyond. Show less
The recent FLAME trial has demonstrated improved local control of intermediate to high-risk prostate cancer after focal dose escalation of the visible tumor. To visualize the tumor, MRI... Show moreThe recent FLAME trial has demonstrated improved local control of intermediate to high-risk prostate cancer after focal dose escalation of the visible tumor. To visualize the tumor, MRI examinations were taken in which prostate tissue characteristics were visualized. Since this treatment strategy improves the clinical outcome of the patient, a technical analysis of the FLAME dataset is useful for the further optimization of focal dose escalation strategies.Delineation of the prostate tumor appeared to be performed differently in the participating radiotherapy departments. Considering the impact on the realized tumor dose, this analysis demonstrated the need for guidelines of tumor delineation on MRI. Due to the complex nature of the treatment plans, in addition a prediction model was developed, which identified patients for which a higher tumor dose could be planned.The application of MRI was also investigated for ‘dose painting by numbers’, in which MRI values are translated to prescription dose without interference of manual tumor delineations. Dose prescription based on MRI appeared robust to daily patient variations, a prerequisite for further development of ‘dose painting by numbers’. However, because of the absence of significant tumor changes during the treatment course, MRI was considered not suitable for early adaptive treatment. Show less
This thesis focuses on renal involvement in ANCA-associated vasculitis (AAV), also named as ANCA-associated glomerulonephritis (AAGN). The studies mainly focus on clinico- and histopathologic... Show moreThis thesis focuses on renal involvement in ANCA-associated vasculitis (AAV), also named as ANCA-associated glomerulonephritis (AAGN). The studies mainly focus on clinico- and histopathologic parameters that are predictive for renal outcome. Predictive parameters for renal relapse in the native kidney are the histopathological classification of AAGN and interstitial infiltrates. The histopathological classification of AAGN is validated and the interobserver variability is investigated. It shows that this classification is predictive for renal outcome regarding the focal and sclerotic class, but needs more refinement for the crescentic and mixed class. The interobserver agreement between pathologists for this classification was moderate. Regarding renal transplantation, this thesis shows that this is a viable treatment option in patients with end-stage renal failure due to AAGN. The risk of renal disease recurrence in the renal graft is low, but once it has occurred, the risk of graft loss is considerable. In addition, this thesis presents an optimized assay for detecting anti-plasminogen autoantibodies in patients with AAV. The presence of these autoantibodies is validated in a cohort. The detection of these autoantibodies is important, because their presence seem to have a predictive value for renal outcome. This thesis also gives an overview of the clinical presentation, diagnosis and management of AAV. Show less
Eschbach, S.J.; Gijtenbeek, M.; Geloven, N. van; Oepkes, D.; Haak, M.C. 2019
Background and purposeAccurate delineation of the primary tumour is vital to the success of radiotherapy and even more important for successful boost strategies, aiming for improved local control... Show moreBackground and purposeAccurate delineation of the primary tumour is vital to the success of radiotherapy and even more important for successful boost strategies, aiming for improved local control in oesophageal cancer patients. Therefore, the aim was to assess delineation variability of the gross tumour volume (GTV) between CT and combined PET-CT in oesophageal cancer patients in a multi-institutional study.Materials and methodsTwenty observers from 14 institutes delineated the primary tumour of 6 cases on CT and PET-CT fusion. The delineated volumes, generalized conformity index (CIgen) and standard deviation (SD) in position of the most cranial/caudal slice over the observers were evaluated. For the central delineated region, perpendicular distance between median surface GTV and each individual GTV was evaluated as in-slice SD.ResultsAfter addition of PET, mean GTVs were significantly smaller in 3 cases and larger in 1 case. No difference in CIgen was observed (average 0.67 on CT, 0.69 on PET-CT). On CT cranial-caudal delineation variation ranged between 0.2 and 1.5 cm SD versus 0.2 and 1.3 cm SD on PET-CT. After addition of PET, the cranial and caudal variation was significantly reduced in 1 and 2 cases, respectively. The in-slice SD was on average 0.16 cm in both phases.ConclusionIn some cases considerable GTV delineation variability was observed at the cranial-caudal border. PET significantly influenced the delineated volume in four out of six cases, however its impact on observer variation was limited. Show less
This thesis presents the identification of new targets for therapeutic treatment of chondrosarcoma, tumours that are highly insensitive to conventional chemo- and radiation thearapy. A relatively... Show moreThis thesis presents the identification of new targets for therapeutic treatment of chondrosarcoma, tumours that are highly insensitive to conventional chemo- and radiation thearapy. A relatively new array technique to identify active kinases in chondrosarcoma cell cultures was used, which identified Src inhibitor dasatinib as a potential target in chondrosarcoma treatment. Subsequently, growth of the majority of chondrosarcoma cell cultures was inhibited by dasatinib. In addition to dasatinib, CDK inhibitor Flavoperidol, Aurorakinase inhibitor AZD1152 and AKT inhibitor Enzastaurin were identified as candidates for therapeutic intervention in chondrosarcomas. Moreover, the use of selective COX-2 inhibition was evaluated preclinically. In vitro, chondrosarcoma cell viability was inhibited by celecoxib, a selective COX-2 inhibitor. Also in a grade II and III chondrosarcoma xenograft mouse model an anti- tumourigenic effect of celecoxib was found, since tumor size was negatively correlated to celecoxib serum levels. The results described in this thesis have led to a better understanding of molecular events that are important in the growth of conventional chondrosarcoma. In addition, new targets were identified, which are expected to lead to the implementation of new therapy modalities for patients that have inoperable or metastatic chondrosarcoma. Show less
