Dordrecht Hospital

Overall survival (OS) of patients with stage IV large cell neuroendocrine carcinoma (LCNEC) is poor and optimal systemic treatment is unknown. Here, we describe clinical outcomes per treatment strategy of patients with stage IV LCNEC, including stratification by immunohistochemical (IHC) protein RB1 (pRb) status. Clinical data were obtained from all patients with LCNEC (2019-2022) in the Netherlands Cancer Registry (NCR). Central pathology review and IHC pRb staining were performed when tumor material was available. OS was calculated from time of diagnosis of stage IV until death, last OS update was April 2024. In total 269/530 patients (51 %) received systemic treatment, and 132 samples were eligible for pathology review. In 88/132 (67 %) the diagnosis LCNEC was confirmed (other diagnoses: SCLC (34 %), NSCLC NOS (34 %)). The median OS of all panel-reviewed LCNEC patients was 7.4 months. Patients treated with chemo-immunotherapy had a numerically, but not statistically significant different survival compared to chemotherapy (median OS 9.6 months versus OS of 6.5 months; HR 0.71, 95 % CI 0.42-1.2). This was different from the real-world LCNEC patients, where a benefit of immunotherapy was observed (median OS 10.7 months versus OS of 6.7 months; HR 0.53, 95 % CI 0.4-0.72). In real-world half of patients with stage IV LCNEC do not receive systemic treatment. Accurate diagnosing LCNEC is challenging and therefore introduces bias (i.e. other diagnoses as SCLC instead of LCNEC) in real-world cohorts, which in turn has impact on analysis of treatment outcomes. Patients with panel-reviewed LCNEC have a poor prognosis and no statistically significant improvement was observed with chemo-immunotherapy.

AimsDifferentiated or HPV‐independent vulvar intraepithelial neoplasia (dVIN) can progress rapidly to invasive cancer and accurate pathological diagnosis is essential to facilitate appropriate interventions. Histological similarities of dVIN with non‐neoplastic lesions, however, often make the diagnosis less reproducible. We investigated among a diverse group of pathologists whether the diagnostic agreement improves with the use of p53 immunohistochemistry (IHC) interpreted using the pattern‐based schema.Methods and resultsFifty haematoxylin–eosin (HE) stained archival slides (30 dVIN and 20 non‐dysplastic vulvar lesions) were selected and p53‐IHC was performed. Twenty‐four board‐certified pathologists from eight countries first assessed the HE slides alone, and after a washout period, re‐evaluated them alongside the p53‐IHC slides. During both rounds, slides were diagnosed as dVIN, favour dVIN, favour no‐VIN or no‐VIN. p53‐IHC was scored as wild‐type or mutant (diffuse, basal, cytoplasmic or null). Kappa (κ) statistics and McNemar's test were used for statistical analyses. Overall diagnostic agreement for dVIN saw a significant increase in the Kappa value (κ = 0.6 vs. κ = 0.4, P = 0.002) when HE and p53‐IHC slides were assessed together compared with histology assessment alone, although the level of agreement remained moderate. For p53‐IHC assessment, overall agreement was substantial (κ = 0.7). Diagnoses changing from no‐VIN/favour no‐VIN to dVIN correlated significantly with the identification of a p53‐mutant pattern (P < 0.001).ConclusionsOur findings indicate that p53‐IHC is a robust ancillary tool that can be reproducibly interpreted by pathologists with varying experience levels and supports the routine use of p53‐IHC in cases where dVIN is considered in the differential diagnosis.

AimUse of immunomodulating therapeutics for immune‐mediated inflammatory diseases may cause disease‐drug‐drug interactions (DDDIs) by reversing inflammation‐driven alterations in the metabolic capacity of cytochrome P450 enzymes. European Medicine Agency (EMA) and US Food and Drug Administration (FDA) guidelines from 2007 recommend that the DDDI potential of therapeutic proteins should be assessed. This systematic analysis aimed to characterize the available DDDI trials with immunomodulatory drugs, experimental evidence for a DDDI risk and reported DDDI risk information in FDA/EMA approved drug labelling.MethodFor this systematic review, the EMA list of European Public Assessment Reports of human medicine was used to select immunomodulating monoclonal antibodies (mAbs) and tyrosine kinase inhibitors (TKIs) marketed after 2007 at risk for a DDDI. Selected drugs were included in PubMed and Embase searches to extract reported interaction studies. The Summary of Product Characteristics (SPCs) and the United States Prescribing Information (USPIs) were subsequently used for analysis of DDDI risk descriptions.ResultsClinical interaction studies to evaluate DDDI risks were performed for 12 of the 24 mAbs (50%) and for none of the TKIs. Four studies identified a DDDI risk, of which three were studies with interleukin‐6 (IL‐6) neutralizing mAbs. Based on (non)clinical data, a DDDI risk was reported in 32% of the SPCs and in 60% of the USPIs. The EMA/FDA documentation aligned with the DDDI risk potential in 35% of the 20 cases.ConclusionThis systematic review reinforces that the risk for DDDI by immunomodulating drugs is target‐ and disease‐specific. Drug labelling information designates the greatest DDDI risk to mAbs that neutralize the effects of IL‐6, Tumor Necrosis Factor alfa (TNF‐α) and interleukin‐1 bèta (IL‐1β) in diseases with systemic inflammation.

To compare the results of the measurement of femoral torsion using the axial measurement method on three-dimensional (3D) volumetric reconstructions of computed tomography images AMM(CT), the biplanar measurement method on 3D volumetric reconstructions of computed tomography images BMM(CT) and a reference standard using the axial measurement method on stereolithographic bone models AMM (SBM). Ex vivo study. Three-dimensional volumetric reconstructions of computed tomography images and stereolithographic bone models from 23 femurs of 14 dogs with hind limb lameness presented for orthopedic evaluation. Three-dimensional volumetric reconstructions of computed tomography images and stereolithographic bone models of each femur were created from computed tomography data. Femoral torsion was measured using the AMM (CT) and the BMM (CT) and compared with a reference standard, the AMM (SBM). No differences were noted among the measurement methods (P=.0863). Median measurement of femoral torsion using the AMM (CT) was 34.2°, the BMM (CT) was 36.7°, and the AMM (SBM) was 32.3°. No differences existed among the AMM (CT), the BMM (CT), and the AMM (SBM). Both AMM (CT) and BMM (CT) can be used to measure femoral torsion in dogs with orthopedic disease.

This case describes a dog with severe epistaxis due to an infection with Leishmania infantum. The dog was hypovolemic and anaemic at presentation. Standard treatment with sedation and application of gauzes with epinephrine was unsuccessful. The bleeding was temporarily controlled by applying two balloon catheters in the right nasal passage under general anaesthesia. The bleeding recurred after one of the catheters got displaced. Ultimately, the right common carotid artery was ligated, after which right-sided epistaxis did not recur.

AimsThymic tumours are rare in routine pathology practice. Although the World Health Organization (WHO) classification describes a number of well‐defined categories, the classification remains challenging. The aim of this study was to investigate the reproducibility of the WHO classification among a large group of international pathologists with expertise in thymic pathology and by using whole slide imaging to facilitate rapid diagnostic turnover.Methods and resultsThree hundred and five tumours, consisting of 90 biopsies and 215 resection specimens, were reviewed with a panel‐based virtual microscopy approach by a group of 13 pathologists with expertise in thymic tumours over a period of 6 years. The specimens were classified according to the WHO 2015 classification. The data were subjected to statistical analysis, and interobserver concordance (Fleiss kappa) was calculated. All cases were diagnosed within a time frame of 2 weeks. The overall level of agreement was substantial (κ = 0.6762), and differed slightly between resection specimens (κ = 0.7281) and biopsies (κ = 0.5955). When analysis was limited to thymomas only, and they were grouped according to the European Society for Medical Oncology Clinical Practice Guidelines into B2, B3 versus A, AB, B1 and B3 versus A, AB, B1, B2, the level of agreement decreased slightly (κ = 0.5506 and κ = 0.4929, respectively). Difficulties arose in distinguishing thymoma from thymic carcinoma. Within the thymoma subgroup, difficulties in distinction were seen within the B group.ConclusionsAgreement in diagnosing thymic lesions is substantial when they are assessed by pathologists with experience of these rare tumours. Digital pathology decreases the turnaround time and facilitates access to what is essentially a multinational resource. This platform provides a template for dealing with rare tumours for which expertise is sparse.

Before the construction of a car park in 2007 a flooded medieval church with graveyard was excavated a few kilometres south of the town of Dordrecht. Part of the roof of a medieval village church emerged. On the exterior of this church part of the original slating had been preserved. The wood of the roof was dendrochronologically dated around 1350. The church was lost during the St Elizabeth flood of 1421. It concerns an original, extremely rare combination of roof boards with slate. The high-pitched roof boards were supported by rafters and through spur ties and slabs they stood on the masonry by means of ashlar pieces. Behind the rafters and (presumably existing) trusses, counter braces ran in a V-shaped pattern. The slates are different in shape, but the covering shows most resemblance to that of the Rhine slates. An XRF analysis by RCE Amersfoort appears to indicate that the slates came from Fumay in northern France, a well-known quarry for slate.