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Ovarian cancer (OC) is a heterogeneous disease usually diagnosed at a late stage. Experimental in vitro models that faithfully capture the hallmarks and tumor heterogeneity of OC are limited and hard to establish. We present a protocol that enables efficient derivation and long-term expansion of OC organoids. Utilizing this protocol, we have established 56 organoid lines from 32 patients, representing all main subtypes of OC. OC organoids recapitulate histological and genomic features of the pertinent lesion from which they were derived, illustrating intra- and interpatient heterogeneity, and can be genetically modified. We show that OC organoids can be used for drug-screening assays and capture different tumor subtype responses to the gold standard platinum-based chemotherapy, including acquisition of chemoresistance in recurrent disease. Finally, OC organoids can be xenografted, enabling in vivo drug-sensitivity assays. Taken together, this demonstrates their potential application for research and personalized medicine.A biobank of ovarian cancer organoids recapitulates the histopathological and molecular hallmarks of patient tumors and provides a resource for preclinical research.

Bladder cancer is a common malignancy that has a relatively poor outcome. Lack of culture models for the bladder epithelium (urothelium) hampers the development of new therapeutics. Here we present a long-term culture system of the normal mouse urothelium and an efficient culture system of human bladder cancer cells. These so-called bladder (cancer) organoids consist of 3D structures of epithelial cells that recapitulate many aspects of the urothelium. Mouse bladder organoids can be cultured efficiently and genetically manipulated with ease, which was exemplified by creating genetic knockouts in the tumor suppressors Trp53 and Stag2. Human bladder cancer organoids can be derived efficiently from both resected tumors and biopsies and cultured and passaged for prolonged periods. We used this feature of human bladder organoids to create a living biobank consisting of bladder cancer organoids derived from 53 patients. Resulting organoids were characterized histologically and functionally. Organoid lines contained both basal and luminal bladder cancer subtypes based on immunohistochemistry and gene expression analysis. Common bladder cancer mutations like TP53 and FGFR3 were found in organoids in the biobank. Finally, we performed limited drug testing on organoids in the bladder cancer biobank.

Background Bladder cancer is one of the most common cancer types worldwide. Generally, research relies on invasive sampling strategies. Methods Here, we generate bladder cancer organoids directly from urine (urinoids). In this project, we establish 12 urinoid lines from 22 patients with non-muscle and muscle-invasive bladder tumours, with an efficiency of 55%. Results The histopathological features of the urinoids accurately resemble those of the original bladder tumours. Genetically, there is a high concordance of single nucleotide polymorphisms (92.56%) and insertions & deletions (91.54%) between urinoids and original tumours from patient 4. Furthermore, these urinoids show sensitivity to bladder cancer drugs, similar to their tissue-derived organoid counterparts. Genetic analysis of longitudinally generated tumoroids and urinoids from one patient receiving systemic immunotherapy, identify alterations that may guide the choice for second-line therapy. Successful treatment adaptation was subsequently demonstrated in the urinoid setting. Conclusion Therefore, urinoids can advance precision medicine in bladder cancer as a non-invasive platform for tumour pathogenesis, longitudinal drug-response monitoring, and therapy adaptation.

Seminoma is a subclass of human testicular germ cell tumors (TGCT), the most frequently observed cancer in young men with a rising incidence. Here we describe the identification of a novel gene predisposing specifically to seminoma formation in a vertebrate model organism. Zebrafish carrying a heterozygous nonsense mutation in Leucine-Rich Repeat Containing protein 50 (lrrc50 also called dnaaf1), associated previously with ciliary function, are found to be highly susceptible to the formation of seminomas. Genotyping of these zebrafish tumors shows loss of heterozygosity (LOH) of the wild-type lrrc50 allele in 44.4% of tumor samples, correlating with tumor progression. In humans we identified heterozygous germline LRRC50 mutations in two different pedigrees with a family history of seminomas, resulting in a nonsense Arg488* change and a missense Thr590Met change, which show reduced expression of the wild-type allele in seminomas. Zebrafish in vivo complementation studies indicate the Thr590Met to be a loss-of-function mutation. Moreover, we show that a pathogenic Gln307Glu change is significantly enriched in individuals with seminoma tumors (13% of our cohort). Together, our study introduces an animal model for seminoma and suggests LRRC50 to be a novel tumor suppressor implicated in human seminoma pathogenesis.

Introduction/BackgroundAim To compare oncological outcomes in patients with early stage high-intermediate or high-risk endometrial cancer undergoing surgical staging by laparotomy, conventional laparoscopy or robot-assisted laparoscopy.MethodologyPatients who underwent staging surgery for stage I-II (FIGO 2009), high-intermediate or high-risk endometrial cancer between 2015 and 2021 were identified in the Netherlands Cancer Registry. Five-year disease-free survival and overall survival were calculated using the Kaplan-Meier method, and differences between groups were evaluated using log-rank testing. Survival analyses were also stratified by histological subtype. The effect of surgical modality on the risk of recurrence and all-cause death was assessed by performing Cox regression analysis with inverse probability treatment weighting.ResultsIn total 941 patients met the inclusion criteria of whom 399 (42.4%) underwent staging surgery by laparotomy, 273 (29.0%) by laparoscopy and 269 (28.6%) by robot-assisted laparoscopy. Baseline characteristics were generally comparable across the three groups. No difference in disease-free survival (75.0% vs 71.2% vs 79.0% p = 0.35) or overall survival (72.7% vs 72.3% vs 71.2% p=0.98) was observed between patients after laparotomy, laparoscopy or robot-assisted laparoscopy respectively. Sub-analyses based on histologic subtype also showed comparable disease-free survival and overall survival between surgical approaches. After correcting for possible confounders by means of inverse probability treatment weighting there was no significantly increased risk of recurrence or risk of death of all cause after laparoscopy or robot-assisted laparoscopy compared to laparotomy.ConclusionLaparoscopic and robot-assisted laparoscopic staging surgery in women with early stage high-intermediate or high-risk endometrial cancer seem a safe alternative to laparotomic staging surgery.DisclosuresThe authors declare that they have no relevant or material financial interests that relate to the research described in this abstract.Abstract 834 Figure 1

Purpose: Our aim was to analyze grading variation between pathology laboratories and between pathologists within individual laboratories using nationwide real-life data. Methods: We retrieved synoptic (n = 13,397) and narrative (n = 29,377) needle biopsy reports from the Dutch Pathology Registry and prostate-specific antigen values from The Netherlands Cancer Registration for prostate cancer patients diagnosed between January 2017 and December 2019. We determined laboratory-specific proportions per histologic grade and unadjusted odds ratios (ORs) for International Society of Urological Pathologists Grades 1 vs. 2–5 for 40 laboratories due to treatment implications for higher grades. Pathologist-specific proportions were determined for 21 laboratories that consented to this part of analysis. The synoptic reports of 21 laboratories were used for analysis of case-mix correction for PSA, age, year of diagnosis, number of biopsies and positive cores. Results: A total of 38,321 reports of 35,258 patients were included. Grade 1 ranged between 19.7% and 44.3% per laboratory (national mean = 34.1%). Out of 40 laboratories, 22 (55%) reported a significantly deviant OR, ranging from 0.48 (95% confidence interval (CI) 0.39–0.59) to 1.54 (CI 1.22–1.93). Case-mix correction was performed for 10,294 reports, altering the status of 3/21 (14%) laboratories, but increasing the observed variation (20.8% vs. 17.7%). Within 15/21 (71%) of laboratories, significant inter-pathologist variation existed. Conclusion: Substantial variation in prostate cancer grading was observed between and within Dutch pathology laboratories. Case-mix correction did not explain the variation. Better standardization of prostate cancer grading is warranted to optimize and harmonize treatment.

Samenvatting Polyarteritis nodosa (PAN) is een zeldzame vasculitis van de middelgrote en kleine arteriën. Meestal is er sprake van betrokkenheid van meerdere orgaansystemen, met name perifere zenuwen, huid, het gastro-intestinale systeem, spieren en nieren. Deze aandoening kan zich ook beperken tot één orgaansysteem. We beschrijven een casus van een 32-jarige man met linkszijdige scrotalgie en echografisch verdachte bilaterale testislaesies. Tumormarkers waren niet verhoogd. Er werd beiderzijds een radicale inguinale orchidectomie verricht. Histopathologisch onderzoek toonde geen maligniteit, maar PAN. De incidentie van PAN is slechts 1–8 gevallen per miljoen inwoners in Europa, maar toch is het van belang om benigne afwijkingen differentieel diagnostisch te overwegen, zeker bij bilaterale testisafwijkingen. Eerst dient enkelzijdige of partiële orchidectomie overwogen te worden vanwege de zeldzaamheid van bilaterale testistumoren en het belang van fertiliteitsbehoud.

In patients with prostate cancer, metastases mostly develop in bone, lung, liver, pleura and adrenal glands. Prostate carcinoma metastases to the ureter are very rare, and the peritoneum is an even rarer site of prostate metastases. We present two cases of ureteral metastases of prostate cancer, of which one patient also developed malignant ascites and peritoneal metastases. An overview of the literature on these metastatic sites is also provided. Both patients presented with hydronephrosis and a ureteral mass. Biopsies of the masses were taken, which showed the presence of prostate carcinoma metastases. The first patient was treated with chemotherapy but was diagnosed with progressive disease and died 3 years later. The second patient was diagnosed with pathology-confirmed peritoneal metastases 8 months later. He died 2 years after presentation with hydronephrosis.

The aim of this study was to investigate the association between the immunohistochemical expression of hypoxia-inducible factor (HIF)-1α and HIF-2α and dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) parameters Ktrans and kep in prostate cancer. Therefore, 15 patients with biopsy-confirmed prostate cancer underwent a pre-operative 3T DCE-MRI scan. Immunohistochemical analysis of HIF-1α and HIF-2α, and of CD31 for microvessel density (MVD) was performed. Tumor areas were delineated on whole-mount histopathological sections. Nuclear HIF expression was correlated with the quantitative DCE-MRI parameters Ktrans and kep, MVD and Gleason score. HIF expression was highly heterogeneous within tumors and between patients. Pronounced expression of HIF-2α was present, while HIF-1α expression was more limited. Larger tumors showed higher HIF-2α expression (P=0.041). A correlation between HIF-2α and Ktrans p5th was found (r=0.30, P=0.02), but no differences in Ktrans, kep and MVD were observed for different levels of HIF expression. HIF expression was not associated with Gleason score. In conclusion, in this whole-mount prostate cancer study, larger prostate tumors showed frequently high HIF-2α expression, suggesting that larger tumors are clinically most relevant. However, HIF-1α and HIF-2α were not correlated with DCE-MRI parameters. Given the pronounced expression of HIF-2α and independence of Gleason score, HIF expression may function as a biomarker to guide boost dose prescription.

ObjectivesAlmost 10% of ovarian cancer (OC) patients carry a somatic pathogenic variant (PV) in one of the ovarian cancer (OC) predisposition genes (e.g. BRCA1/2) and might respond to PARP inhibition. Without somatic testing these patients are denied effective treatment.MethodsTo implement tumor testing of ovarian cancer predisposition genes the 523 gene panel (TSO500, Illumina) was validated in a cohort of 48 formalin-fixed paraffin-embedded archival samples with known mutation status. Blind data analysis was performed for mutational status using Franklin Genoox software (Franklin) and an in-house built Copy Number Variation (CNV) analysis. BRCA1 MLPA analysis was performed for all mutation negative samples.ResultsThe validation cohort consisted of ovarian (n=40), breast (n=6) and pancreas (n=2) samples of which 44 were known to contain a germline mutation and 3 a somatic mutation. After blinded data analysis, a PV was detected in 35 cases (BRCA1/2, BRIP1, RAD51C) and a variant of unknown significance in 6 cases (BRCA1/2, BRIP1, RAD51D). Exon deletions in BRCA1 were detected in 5 cases. The known molecular defect was identified in 46/48 (96%). Two CNVs (4%) were missed, a tandem duplication inclusing CHEK2 and loss of RAD51D.ConclusionsTSO500 mutation analysis can be reliably used to detect PVs in OC predisposition genes, however, CNV analysis remains challenging. Therefore, the tumor first workflow where the tumor test is performed first to guide treatment might not identify all carriers of a germline PV. However, with Dutch nationwide implementation, this universal workflow leads to genetic testing of a higher proportion of OC patients.