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Background The recently identified classical and basal-like molecular subtypes of pancreatic cancer impact on overall survival (OS). However, the added value of routine subtyping in both clinical practice and randomized trials is still unclear, as most studies do not consider clinicopathological parameters. This study examined the clinical prognostic value of molecular subtyping in patients with resected pancreatic cancer. Methods Subtypes were determined on fresh-frozen resected pancreatic cancer samples from three Dutch centres using the Purity Independent Subtyping of Tumours classification. Patient, treatment, and histopathological variables were compared between subtypes. The prognostic value of subtyping in (simulated) pre- and postoperative settings was assessed using Kaplan–Meier and Cox regression analyses. Results Of 199 patients with resected pancreatic cancer, 164 (82.4 per cent) were classified as the classical and 35 (17.6 per cent) as the basal-like subtype. Patients with a basal-like subtype had worse OS (11 versus 16 months (HR 1.49, 95 per cent c.i. 1.03 to 2.15; P = 0.035)) than patients with a classical subtype. In multivariable Cox regression analysis, including only clinical variables, the basal-like subtype was a statistically significant predictor for poor OS (HR 1.61, 95 per cent c.i. 1.11 to 2.34; P = 0.013). When histopathological variables were added to this model, the prognostic value of subtyping decreased (HR 1.49, 95 per cent c.i. 1.01 to 2.19; P = 0.045). Conclusion The basal-like subtype was associated with worse OS in patients with resected pancreatic cancer. Adding molecular classification to inform on tumor biology may be used in patient stratification.

Background The prognostic value of four proposed modifications to the 8th American Joint Committee on Cancer (AJCC) TNM staging system has yet to be evaluated. This study aimed to validate five proposed modifications. Methods Patients who underwent pancreatic ductal adenocarcinoma resection (2014–2016), as registered in the prospective Dutch Pancreatic Cancer Audit, were included. Stratification and prognostication of TNM staging systems were assessed using Kaplan–Meier curves, Cox proportional hazard analyses, and C-indices. A new modification was composed based on overall survival (OS). Results Overall, 750 patients with a median OS of 18 months (interquartile range 10–32) were included. The 8th edition had an increased discriminative ability compared with the 7th edition {C-index 0.59 (95% confidence interval [CI] 0.56–0.61) vs. 0.56 (95% CI 0.54–0.58)}. Although the 8th edition showed a stepwise decrease in OS with increasing stage, no differences could be demonstrated between all substages; stage IIA vs. IB (hazard ratio [HR] 1.30, 95% CI 0.80–2.09; p = 0.29) and stage IIB vs. IIA (HR 1.17, 95% CI 0.75–1.83; p = 0.48). The four modifications showed comparable prognostic accuracy (C-index 0.59–0.60); however, OS did not differ between all modified TNM stages (ns). The new modification, migrating T3N1 patients to stage III, showed a C-index of 0.59, but did detect significant survival differences between all TNM stages (p Conclusions The 8th TNM staging system still lacks prognostic value for some categories of patients, which was not clearly improved by four previously proposed modifications. The modification suggested in this study allows for better prognostication in patients with all stages of disease.

BACKGROUND & AIMS: Hepatocellular adenomas (HCA) rarely occur in males, and if so, are frequently associated with malignant transformation. Guidelines are based on small numbers of patients and advise resection of HCA in male patients, irrespective of size or subtype. This nationwide retrospective cohort study is the largest series of HCA in men correlating (immuno)histopathological and molecular findings with the clinical course.METHODS: Dutch male patients with available histological slides with a (differential) diagnosis of HCA between 2000 and 2017 were identified through the Dutch Pathology Registry (PALGA). Histopathology and immunohistochemistry according to international guidelines were revised by two expert hepatopathologists. Next generation sequencing (NGS) was performed to confirm hepatocellular carcinoma (HCC) and/or subtype HCA. Final pathological diagnosis was correlated with recurrence, metastasis and death.RESULTS: A total of 66 patients from 26 centers fulfilling the inclusion criteria with a mean (±SD) age of 45.0±21.6 years were included. The diagnosis was changed after expert revision and NGS in 33 of the 66 patients (50%). After a median follow-up of 9.6 years, tumor-related mortality of patients with accessible clinical data was 1/18 (5.6%) in HCA, 5/14 (35.7%) in uncertain HCA/HCC and 4/9 (44.4%) in the HCC groups (p=0.031). Four B-catenin mutated HCA were identified using NGS, which were not yet identified by immunohistochemistry and expert revision.CONCLUSIONS: Expert revision with relevant immunohistochemistry may help the challenging but prognostically relevant distinction between HCA and well-differentiated HCC in male patients. NGS may be more important to subtype HCA than indicated in present guidelines.

IntroductionBenign liver tumours and cysts (BLTCs) comprise a heterogeneous group of cystic and solid lesions, including hepatic haemangioma, focal nodular hyperplasia and hepatocellular adenoma. Some BLTCs, for example, (large) hepatocellular adenoma, are at risk of complications. Incidence of malignant degeneration or haemorrhage is low in most other BLTCs. Nevertheless, the diagnosis BLTC may carry a substantial burden and patients may be symptomatic, necessitating treatment. The indications for interventions remain matter of debate. The primary study aim is to investigate patient-reported outcomes (PROs) of patients with BLTCs, with special regards to the influence of invasive treatment as compared with the natural course of the disease.Methods and analysisA nationwide observational cohort study of patients with BLTC will be performed between October 2021 and October 2026, the minimal follow-up will be 2 years. During surveillance, a questionnaire regarding symptoms and their impact will be sent to participants on a biannual basis and more often in case of invasive intervention. The questionnaire was previously developed based on PROs considered relevant to patients with BLTCs and their caregivers. Most questionnaires will be administered by computerised adaptive testing through the Patient-Reported Outcomes Measurement Information System. Data, such as treatment outcomes, will be extracted from electronic patient files. Multivariable analysis will be performed to identify patient and tumour characteristics associated with significant improvement in PROs or a complicated postoperative course.Ethics and disseminationThe study was assessed by the Medical Ethics Committee of the University Medical Center Groningen and the Amsterdam UMC. Local consultants will provide information and informed consent will be asked of all patients. Results will be published in a peer-reviewed journal.Study registrationNL8231—10 December 2019; Netherlands Trial Register.

BackgroundIdentification of metastatic pancreatic cancer (mPC) patients with the worst prognosis could help to tailor therapy. We evaluated readily available biomarkers for the prediction of 90-day mortality in a nationwide cohort of mPC patients.MethodsPatients with synchronous mPC were included from the Netherlands Cancer Registry (2015-2017). Baseline CA19-9, albumin, CRP, LDH, CRP/albumin ratio, and (modified) Glasgow Prognostic Score ((m)GPS composed of albumin and CRP) were evaluated. Multivariable logistic regression analyses were performed to identify predictors of 90-day mortality. Prognostic value per predictor was quantified by Nagelkerke's partial R-2.ResultsOverall, 4248 patients were included. Median overall survival was 2.2 months and 90-day mortality was 59.4% (n = 1629). All biomarkers predicted 90-day mortality in univariable analysis, and remained statistically significant after adjustment for clinically relevant factors and all other biomarkers (all p < 0.001). The prognostic value of the biomarkers combined was similar to WHO performance status. Patients who received chemotherapy had better outcomes than those who did not, regardless of biomarker levels.ConclusionsIn mPC patients, albumin, CA19-9, CRP, LDH, CRP/albumin ratio, and (m)GPS are prognostic for poor survival. Biomarkers did not predict response to chemotherapy. These readily available biomarkers can be used to better inform patients and to stratify in clinical trials.

Additional file 1.

This PhD thesis deals with the mass violence against Armenians in the Ottoman Empire during the reign of Sultan Abdülhamid II, in the years 1894-1897. This dramatic crisis in Armenian-Ottoman relations, despite the enormous interest it evoked contemporarily and more recently, has hitherto not been the subject of a separate monograph. Firstly the existing historiography of the incidents is scrutinised. It is demonstrated that there exists from the very beginning a dichotomy between an Armenian/western perspective that considers the events intentionally organized massacres by the Ottoman state of the Armenian civilian population, and an almost diametrically opposed Ottoman-Turkish narrative characterising the episode as an Armenian revolt. The origins and context of these strongly different historiographical traditions are investigated. Recent, more critical historical research on the issue is discussed and evaluated. Introductory chapters offer information on the social geography, history and ethnology of the area in which the violence took place and an outline of Armenian-Ottoman relations and the “Armenian Question” in the decades preceding the massacres. The research focuses on three topics: (1) An exhaustive survey and description of all incidents of violence and determination of a more reliable estimate of the number of victims on the basis of the death toll of individual incidents (2) Construction of a perpetrator profile and investigation of the motivation of the perpetrators (3) The issue of premeditation and the role of the various administrative levels of the Ottoman state.

Introduction: Whereas neoadjuvant chemo(radio)therapy is increasingly used in pancreatic cancer, it is currently not recommended for other periampullary (non-pancreatic) cancers. This has important implications for the relevance of the preoperative diagnosis for pancreatoduodenectomy. This retrospective multicentre cohort study aimed to determine the frequency of clinically relevant misdiagnoses in patients undergoing pancreatoduodenectomy for pancreatic or other periampullary cancer. Methods: Data from all consecutive patients who underwent a pancreatoduodenectomy between 2014 and 2018 were obtained from the prospective Dutch Pancreatic Cancer Audit. The preoperative diagnosis as concluded by the multidisciplinary team (MDT) meeting was compared with the final postoperative diagnosis at pathology to determine the rate of clinically relevant misdiagnosis (defined as missed pancreatic cancer or incorrect diagnosis of pancreatic cancer). Results: In total, 1244 patients underwent pancreatoduodenectomy of whom 203 (16%) had a clinically relevant misdiagnosis preoperatively. Of all patients with a final diagnosis of pancreatic cancer, 13% (87/ 679) were preoperatively misdiagnosed as distal cholangiocarcinoma (n = 41, 6.0%), ampullary cancer (n = 27, 4.0%) duodenal cancer (n = 16, 2.4%), or other (n = 3, 0.4%). Of all patients with a final diagnosis of periampullary (non-pancreatic) cancer, 21% (116/565) were preoperatively incorrectly diagnosed as pancreatic cancer. Accuracy of preoperative diagnosis was 84% for pancreatic cancer, 71% for distal cholangiocarcinoma, 73% for ampullary cancer and 73% for duodenal cancer. A prediction model for the preoperative likelihood of pancreatic cancer (versus other periampullary cancer) prior to pancreatoduodenectomy demonstrated an AUC of 0.88. Discussion: This retrospective multicentre cohort study showed that 16% of patients have a clinically relevant misdiagnosis that could result in either missing the opportunity of neoadjuvant chemotherapy in patients with pancreatic cancer or inappropriate administration of neoadjuvant chemotherapy in patients with non-pancreatic periampullary cancer. A preoperative prediction model is available on www.pancreascalculator.com. (c) 2021 The Authors. Published by Elsevier Ltd. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background: The aim of this survey was to gain insights in the current surgical management and pathological assessment of pancreatoduodenectomy with portal–superior mesenteric vein resection (VR). Methods: A systematic literature search was performed to identify international expert surgeons (N = 150) and pathologists (N = 40) who published relevant studies between 2009 and 2019. These experts and Dutch surgeons (N = 17) and pathologists (N = 20) were approached to complete an online survey. Results: Overall, 76 (46%) surgeons and 37 (62%) pathologists completed the survey. Most surgeons (71%) estimated that preoperative imaging corresponded correctly with intraoperative findings of venous involvement in 50–75% of patients. An increased complication risk following VR was expected by 55% of surgeons, mainly after Type 4 (segmental resection-venous conduit anastomosis). Most surgeons (61%) preferred Type 3 (segmental resection-primary anastomosis). Most surgeons (75%) always perform the VR themselves. Standard postoperative imaging for patency control was performed by 54% of surgeons and 39% adjusted thromboprophylaxis following VR. Most pathologists (76%) always assessed tumor infiltration in the resected vein and only 54% of pathologists always assess the resection margins of the vein itself. Variation in assessment of tumor infiltration depth was observed. Conclusion: This international survey showed variation in the surgical management and pathological assessment of pancreatoduodenectomy with venous involvement. This highlights the lack of evidence and emphasizes the need for research on imaging modalities to improve patient selection for VR, surgical techniques, postoperative management and standardization of the pathological assessment.