Southeast Netherlands Research Articles

Complex versus non-complex, should we adjust the antiplatelet strategy to the type of percutaneous coronary intervention? Results from a real world PCI population

Abstract Background/introduction Personalized dual antiplatelet treatment (DAPT) using risk stratification is key to minimize bleeding- and ischemic events after percutaneous coronary intervention (PCI). Known ischemic risk factors include complex procedures which are integrated in the recommendation for extended DAPT in patients with additional ischemic risk factors. Purpose We aimed to provide insight whether a complex PCI (CPCI) should be regarded as an individual risk factor, regardless of other risk factors, to adjust the antiplatelet strategy. Also, we determined the effect of DAPT duration and choice of P2Y12 inhibitor on outcomes. Methods We included patients from the South East (Zuid Oost) Netherlands Heart Registry (ZON-HR) and excluded patients using oral anticoagulants. This PCI registry prospectively collects baseline-, procedural- and follow-up data including medication use and the intended DAPT duration. Patients were stratified to non-CPCI or CPCI comprising of bifurcation lesions with two stents, venagraft PCI, chronic total occlusion (CTO) or ≥ 60mm stent. Analyses were conducted using Cox regression analysis. Multivariate analysis was performed to adjust for risk factors and baseline differences. Results We included 3691 patients (842 CPCI). Table 1 demonstrates the baseline characteristics and DAPT strategy. CPCI was more often required in patients with a high ischemic risk profile based on the extensiveness of atherosclerosis and comorbidities. Non-CPCI patients more often underwent PCI for acute coronary syndrome. Outcomes are presented in table 2. Compared to non-CPCI, CPCI increased the risk of major adverse cardiac and cerebral events (MACCE) in the second half of the year as opposed to bleeding events, which more often occurred in the first months after CPCI, driven by access site bleedings (73% in CPCI versus 56% in non-CPCI, p=0.01). All-cause mortality was higher during the overall follow-up period after a CPCI compared to non-CPCI. These findings remain significant when corrected for additional risk factors in both groups. In patients with CPCI, treatment with ticagrelor or prasugrel strongly reduced MACCE between 6-12 months when compared to clopidogrel (multivariate HR: 0.28, 95% CI: 0.08-0.98), but did not influence bleeding events or all-cause mortality. No effect of extended DAPT was observed. Conclusions A CPCI is an important ischemic risk factor that could be used for risk stratification to guide antiplatelet strategy. Treatment with ticagrelor or prasugrel strongly diminished the risk of MACCE without increasing the bleeding risk in patients with a CPCI. As the risk of MACCE increases between 6-12 months after PCI while the risk of bleeding events diminishes in this period, extended DAPT from 6 to 12 months could also be considered to provide extended protection.Table 1.Table 2

Undiagnosed Diabetes Mellitus is an important risk factor in secondary prevention after an acute coronary syndrome and warrants active screening

Abstract Background/Introduction Previous studies have shown that patients with Diabetes Mellitus (DM) undergoing percutaneous coronary intervention (PCI) for an acute coronary syndrome (ACS) have an increased ischemic risk compared to non-diabetics. This has led to the recommendation to take DM into account when considering extended dual antiplatelet therapy (DAPT) to prevent ischemic events. Although screening for DM can simply be conducted by measuring HbA1c values, the ACS guidelines do not yet recommend to screen for DM de novo. This may lead to undertreatment. Purpose We aimed to determine the ischemic risk of previously diagnosed DM and of DM de novo compared to patients without DM in a real world ACS population. Methods We included patients from the South East (Zuid Oost) Netherlands Heart Registry (ZON-HR) undergoing PCI for ACS without using oral anticoagulants and compared outcomes between DM and non-DM patients. In a subgroup of patients without previously diagnosed DM with available HbA1c measurements at baseline, we compared outcomes between patients with or without DM de novo (HbA1c ≥48 mmol/mol). All analyses were performed using Cox regression analysis. We used multivariate analysis to adjust for known ischemic risk factors. Results Of the 2406 patients included, 426 were previously diagnosed with DM. Additional ischemic risk factors, such as a history of myocardial infarction (MI), multivessel disease and kidney disease, were significantly more often present in patients with DM. Patients with DM showed numerically more major adverse cardiac and cerebral events (MACCE). However, this was not significant (HR: 1.24, 95% CI: 0.92-1.66). All-cause mortality was higher in patients with DM at 30 days (HR: 1.51, 95% CI 1.00-2.29) and 1 year (HR: 1.55, 95% CI 1.10-2.18), which remained significant at 1 year when corrected for additional risk factors. The HbA1c values at baseline were available in 387 patients without previously diagnosed DM. In this subgroup, 69 (18%) patients showed an elevated HbA1c level of ≥48 mmol/mol. Outcomes within this subgroup are presented in table 1. Patients with de novo DM showed significant more ischemic events after one month and one year follow-up compared to patients without DM de novo. Figure 1 depicts the survival from MACCE over time in these subgroups. Conclusion In our real world population of ACS patients undergoing PCI, we found no significant difference in ischemic risk between patients with previously diagnosed DM compared to non-DM. However, all-cause mortality was significant higher in DM patients. Active screening for DM resulted in a large proportion of patients with DM de novo who showed a major increase in ischemic risk. These results demonstrate the importance of screening for DM in ACS patients undergoing PCI.

Routine HbA1c screening identifies de novo (pre)diabetes mellitus in 37% of ACS patients which comes with an even higher ischemic risk compared to known diabetes mellitus

Abstract Background Diabetes is a prominent risk factor for coronary artery disease (CAD). By exacerbating the progression of CAD, it puts these patients at increased risk of acute coronary syndrome (ACS) and recurrent ischemic events. It is therefore important to identify hyperglycaemic individuals and to treat them accordingly. However, in daily practice it is seen that a subsequent proportion of people with diabetes is undiagnosed. Purpose The aim of this research is to gain insight in the prevalence of patients with de novo (pre)diabetes, the treatment, and the risk of major adverse cardiac and cerebrovascular events (MACCE) compared to patients with known diabetes in an ACS cohort treated by percutaneous coronary intervention (PCI). Methods The Southeast Netherlands Heart Registry (ZON-HR) is an ongoing, multicentre registry collecting data of patients who underwent a PCI procedure. Of this cohort, patients presenting with ACS and measured HbA1c concentrations (on admission) were selected (N=1507). Patients with diagnosed diabetes are considered well-regulated when HbA1c <53 mmol/mol. Patients undiagnosed with diabetes were divided into three groups: HbA1c concentration <42 mmol/mol (normal), HbA1c 42-47 mmol/mol (pre-diabetes) and HbA1c ≥48 mmol/mol (diabetes). The rates of 30-day repeated myocardial infarction (MI), unplanned revascularisation, ischemic CVA, stent thrombosis, and cardiovascular mortality were determined, separately and combined as MACCE in patients with known diabetes compared to prediabetes and diabetes de novo. Results In the selected population, 28.5% of the patients were previously diagnosed with diabetes, which was well-regulated in only 30.2% of these patients. Of the patients not previously diagnosed, 23.1% and 14.4% had pre-diabetic and diabetic HbA1c concentrations, respectively. In 56.1% of patients with de novo diabetes, no glucose-lowering medication was prescribed at discharge (Table 1). At 30-day follow-up, de novo diabetes patients had increased rates of MACCE compared to patients with known diabetes (HR: 3.51, 95%CI 1.48-8.52) after multivariate analysis which corrected for differences at baseline (Figure 1). In addition, a significant increase in unplanned revascularisation (p=.014) and MI (p=.037) was found between de novo diabetes and known diabetes patients. Conclusions Almost half of the ACS patients in this cohort had either poorly regulated diabetes (305 patients) or was undiagnosed with (pre)diabetes while having an increased HbA1c concentration on admission (401 patients). Despite routine HbA1c screening, a subsequent part of these patients is not adequately treated for (pre)diabetes, especially the de novo diabetes patients. By this group, an even larger rate of MACCE was found, compared to the already established risk of diabetes in ACS. Therefore, active screening and treatment (as recommended in the guidelines) should get more attention to improve outcomes in these high-risk patients.Table 1:ACS population based on HbA1cFigure 1:Survival curves of 30D MACCE

Distribution and palaeoecology of scleractinian corals during the Maastrichtian (Late Cretaceous)

Abstract Maastrichtian scleractinian corals from 94 localities in 26 Maastrichtian regions world-wide with strata of that age are taxonomically and palaeobiogeographically evaluated. A total of 205 taxa, belonging to 116 genera and 37 families, are included in the present study. Most coral taxa have been recorded from non-reefal environments. A significant majority of these taxa (genera = 70.7%; species = 75.6%) appear to have been endemic during the Maastrichtian. The Maastrichtian coral fauna is dominated by solitary and cerioid-plocoid forms (both accounting for 41 genera = 70%), having mainly medium- and large-sized corallites. The most diverse coral assemblages are those that have been recorded from arid (Jamaica: 63 species, Mexico: 29 species), warm-temperate (the Netherlands-Belgium: 32 species) and tropical regions (Iran: 27 species). The occurrence of Cunnolites polymorphus (Goldfuss) is newly recorded for the Netherlands (southern Limburg). Compared to the microstructural composition of the coral fauna of the lowermost Cretaceous (Berriasian; 91% of the species and 83% of the genera belonged to previously established microstructural groups), in the Maastrichtian, corals belonging to previously established microstructural groups were of minor importance (genera = 26%; species = 29.3%). The majority of Maastrichtian scleractinian taxa (both solitary and colonial) from the type area of the Maastrichtian Stage in the southeast Netherlands and northeast Belgium are illustrated.

Remarkable insights into modern bird origins from the Maastrichtian type area (north-east Belgium, south-east Netherlands)

Abstract For centuries, fossils from the Maastrichtian type locality and adjacent quarries have provided key evidence of vertebrate diversity during the latest Cretaceous, yet until recently the Maastrichtian type area had revealed no important insights into the evolutionary history of birds, one of the world’s most conspicuous groups of extant tetrapods. With the benefit of high-resolution micro-CT scanning, two important avian fossils from the Maastrichtian type area have now been examined in detail, offering profound, complementary insights into the evolutionary history of birds. The holotype specimens of these new taxa, Janavis finalidens Benito, Kuo, Widrig, Jagt and Field, 2022, and Asteriornis maastrichtensis Field, Benito, Chen, Jagt and Ksepka, 2020, were originally collected in the late 1990s, but were only investigated in detail more than twenty years later. Collectively, Janavis and Asteriornis provide some of the best evidence worldwide regarding the factors that influenced stem bird extinction and crown bird survivorship through the Cretaceous-Palaeogene transition, as well as insights into the origins of key anatomical features of birds such as an extensively pneumatised postcranial skeleton, a kinetic palate, and a toothless beak. Asteriornis also provides scarce evidence of a Cretaceous-aged divergence time calibration within the avian crown group, while together, Janavis and Asteriornis constitute the only documented co-occurrence of crown birds and non-neornithine avialans. Here, we review key insights into avian evolutionary history provided by these discoveries from the Maastrichtian stratotype, document undescribed and newly discovered Maastrichtian fossils potentially attributable to Avialae and provide the first histological data for the holotype of Asteriornis, illustrating its skeletal maturity at the time of its death.

Bryozoan assemblages of the Gulpen Formation (upper Campanian – upper Maastrichtian) in the Liège-Limburg area (Belgium, the Netherlands)

Abstract Renewed interest in bryozoan assemblages from the various members of the Gulpen Formation (upper Campanian–upper Maastrichtian) in the Liège-Limburg area (southeast Netherlands and northeast Belgium) during recent years has resulted in the discovery of a number of species previously unrecorded from the area. Nineteen species are here recorded from the Zeven Wegen, Vijlen, Lixhe and Lanaye members (Gulpen Formation) in the study area, occurring in three distinct assemblages. The vast majority of the bryozoan taxa belong to the order Cheilostomata; only two taxa are assigned to the order Cyclostomata. The species recorded here are Clinopora aff. costulata, Disporella obvallata, ‘Vincularia’ (sensu lato) marssoniana, Herpetopora laxata, Heteroconopeum ovatum, Wilbertopora aff. oxyteichos, Biaviculigera sacerdotalis, Semiflustrella britannica, Aechmellina anglica, Escharifora papyracea, Onychocella cyclostoma, Onychocella cylindrica, Onychocella matrona, Rhebasia disparilis, Stichomicropora sicksi, Coscinopleura elegans, Coscinopleura lamourouxi, Pachydermopora pachyderma and Beisselina aviculifera. While not previously recorded from the Liège-Limburg area, the bryozoan taxa identified from the Gulpen Formation are well known from coeval Cretaceous strata elsewhere in Europe, North America and Russia, highlighting their broad palaeobiogeographical distribution.

The prognostic impact of BMI in patients with HR+/HER2− advanced breast cancer: a study of the SONABRE registry

PurposeThis study determines the prognostic impact of body mass index (BMI) in patients with hormone receptor-positive/human epidermal growth factor receptor-2-negative (HR+/HER2−) advanced (i.e., metastatic) breast cancer (ABC).MethodsAll patients with HR+/HER2− ABC who received endocrine therapy +—a cyclin-dependent kinase 4/6 inhibitor as first-given systemic therapy in 2007–2020 in the Netherlands were identified from the Southeast Netherlands Advanced Breast Cancer (SONABRE) registry (NCT03577197). Patients were categorised as underweight (BMI: < 18.5 kg/m2), normal weight (18.5–24.9 kg/m2), overweight (25.0–29.9 kg/m2), or obese (≥ 30.0 kg/m2). Overall survival (OS) and progression-free survival (PFS) were compared between BMI classes using multivariable Cox regression analyses.ResultsThis study included 1456 patients, of whom 35 (2%) were underweight, 580 (40%) normal weight, 479 (33%) overweight, and 362 (25%) obese. No differences in OS were observed between normal weight patients and respectively overweight (HR 0.99; 95% CI 0.85–1.16; p = 0.93) and obese patients (HR 1.04; 95% CI 0.88–1.24; p = 0.62). However, the OS of underweight patients (HR 1.45; 95% CI 0.97–2.15; p = 0.07) tended to be worse than the OS of normal weight patients. When compared with normal weight patients, the PFS was similar in underweight (HR 1.05; 95% CI 0.73–1.51; p = 0.81), overweight (HR 0.90; 95% CI 0.79–1.03; p = 0.14), and obese patients (HR 0.88; 95% CI 0.76–1.02; p = 0.10).ConclusionIn this study among 1456 patients with HR+/HER2− ABC, overweight and obesity were prevalent, whereas underweight was uncommon. When compared with normal weight, overweight and obesity were not associated with either OS or PFS. However, underweight seemed to be an adverse prognostic factor for OS.

The Maastrichtian type area (Netherlands–Belgium): a synthesis of 250+ years of collecting and ongoing progress in Upper Cretaceous stratigraphy and palaeontology

Abstract Cretaceous limestones near Maastricht (SE Netherlands) have been quarried at least since Roman times. In the late eighteenth century, scientific interest developed in their macrofossil content and specimens were illustrated for the first time. Amongst the early discoveries was a partial skull of a large predatory vertebrate that would play an important role in the emergence of modern palaeontology and our understanding of the concept of extinction. After decades of scientific debate, this animal was recognized as a large extinct marine relative of monitor lizards (varanoids) and named Mosasaurus. A detailed lithostratigraphy of Upper Cretaceous (Santonian–Maastrichtian) rocks was established in the Maastrichtian type area during the mid-1970s, which resulted in a renewed interest in fossil hunting by professional and amateur palaeontologists alike. During recent decades, both micro- and macrofossils have enabled a refinement of biozonations, correlations within the basin and with sections elsewhere, a greater insight into taphonomic processes and updated taxonomic interpretations. A new age model and chemostratigraphical framework is the most recent addition, permitting the placement of geoheritage in a larger frame and intensifying outreach to the public, including also virtual and augmented reality and hands-on experience to visitors of museum and (disused) quarries alike.

The initial hormone receptor/HER2 subtype is the main determinator of subtype discordance in advanced breast cancer: a study of the SONABRE registry

PurposeThe hormone receptor (HR) and human epidermal growth factor receptor 2 (HER2) are the main parameters in guiding systemic treatment choices in breast cancer, but can change during the disease course. This study aims to evaluate the biopsy rate and receptor subtype discordance rate in patients diagnosed with advanced breast cancer (ABC).MethodsPatients diagnosed with ABC in seven hospitals in 2007–2018 were selected from the SOutheast Netherlands Advanced BREast cancer (SONABRE) registry. Multivariable logistic regression analyses were performed to identify factors influencing biopsy and discordance rates.ResultsOverall, 60% of 2854 patients had a biopsy of a metastatic site at diagnosis. One of the factors associated with a reduced biopsy rate was the HR + /HER2 + primary tumor subtype (versus HR + /HER2- subtype: OR = 0.68; 95% CI: 0.51–0.90). Among the 748 patients with a biopsy of the primary tumor and a metastatic site, the overall receptor discordance rate was 18%. This was the highest for the HR + /HER2 + primary tumor subtype, with 55%. In 624 patients with metachronous metastases, the HR + /HER2 + subtype remained the only predictor significantly related to a higher discordance rate, irrespective of prior (neo-)adjuvant therapies (OR = 7.49; 95% CI: 3.69–15.20).ConclusionThe HR + /HER2 + subtype has the highest discordance rate, but the lowest biopsy rate of all four receptor subtypes. Prior systemic therapy was not independently related to subtype discordance. This study highlights the importance of obtaining a biopsy of metastatic disease, especially in the HR + /HER2 + subtype to determine the most optimal treatment strategy.

Healthcare Use during the Last Six Months of Life in Patients with Advanced Breast Cancer.

Simple SummaryIn the last decades, new treatment options for advanced (breast) cancer have resulted in increased use of health care resources near the end of life. We assessed health care use near the end of life of patients with advanced breast cancer (ABC). In this study, we have shown that ICU admission, and CPR occurred rarely during the last six months of life of ABC patients. However, hospital admissions occurred often, especially in patients who received new chemotherapy within 30 days of end of life. Those patients were also more likely to die in the hospital. However, death was most often due to disease progression. To improve quality of life near the end of life of advanced breast cancer patients, it is vital to develop tools to help clinicians identify those patients who will benefit from chemotherapy at the end of life.New treatment options in cancer have resulted in increased use of health care resources near the end of life. We assessed health care use near the end of life of patients with advanced breast cancer (ABC). From the Southeast Netherlands Breast cancer (SONABRE) registry, we selected all deceased patients diagnosed with ABC in Maastricht University Medical Center between January 2007 and October 2017. Frequency of health care use in the last six months of life was described and predictors for health care use were assessed. Of 203 patients, 76% were admitted during the last six months, 6% to the intensive care unit (ICU) and 2% underwent cardiopulmonary resuscitation (CPR). Death in hospital occurred in 25%. Nine percent of patients received a new line of chemotherapy ≤30 days before death, which was associated with age <65 years and <1 year survival since diagnosis of metastases. In these patients, the hospital admission rate was 95%, of which 79% died in the hospital, mostly due to progressive disease (80%). In conclusion, the frequency of ICU-admission, CPR or a new line of chemotherapy ≤30 days before death was low. Most patients receiving a new line of chemotherapy ≤30 days before death, died in the hospital.

An unusual conchorhynch from the upper Maastrichtian of the southeast Netherlands and the distinction between nautiloid and ammonoid conchorhynchs (Mollusca, Cephalopoda)

A single, atypical conchorhynch (calcitic tip of a cephalopod lower jaw), recovered from the uppermost Meerssen Member (Maastricht Formation, upper Maastrichtian) at the former ENCI-HeidelbergCement Group quarry, south of Maastricht, is described as a new parataxon, Conchorhynchus illustris sp. nov. The specimen can be differentiated from all previous conchorhynch records on account of its large size, elongated shape and, in particular, of the structure of its apical part which is smooth and forwardly elongated. During the Late Cretaceous, conchorhynchs formed part of the jaw apparatus of nautilids and of two ammonoid suborders, Phylloceratina and Lytoceratina. Since conchorhynchs are most often found separated from jaws, establishing to which group of cephalopods their bearer belonged can be complicated. Here, for the first time, we propose a set of morphological criteria to differentiate clearly between nautiloid and ammonoid conchorhynchs. Although Conchorhynchus illustris sp. nov. is distinct from all currently known nautilid conchorhynchs, the sum of its morphological features is indicative of assignment to that cephalopod group. The upper portion of the Maastricht Formation in the Maastricht area (Nekum and Meerssen members) has yielded internal and external moulds of shells of the nautilid Eutrephoceras and the hercoglossid Cimomia. The new conchorhynch type described herein most likely belonged to one of these shell-based taxa. Judging from its unusual shape, the feeding strategy of its bearer must have differed from that of modern nautilids, in that it held and pierced prey rather than crushed sturdy shells.

The implementation of CDK 4/6 inhibitors and its impact on treatment choices in HR+/HER2- advanced breast cancer patients: A study of the Dutch SONABRE Registry.

In August 2017, cyclin‐dependent kinase 4/6 (CDK4/6) inhibitors combined with endocrine therapy have been reimbursed in the Netherlands for patients with hormone receptor positive (HR+), HER2 negative (HER2−) advanced breast cancer (ABC). This study evaluates the implementation of CDK4/6 inhibitors and changes in treatment choices in the Netherlands. All patients diagnosed with HR+/HER2− ABC in 2009 to 2018 in seven hospitals were selected from the Southeast Netherlands Advanced Breast cancer (SONABRE) registry. The 2‐year cumulative use of CDK4/6 inhibitors since reimbursement date (August 2017) was assessed using competing‐risk methodology in two cohorts. The first cohort included patients with ABC diagnosis between August 2017 and December 2018. The second cohort included patients with ABC diagnosis between 2009 and August 2017, and still alive on August 1, 2017. In addition, treatment choices in the first three lines of therapy in calendar years 2009 to 2018 were evaluated for the total study population. Among patients diagnosed since August 2017 (n = 214), 50% (95% confidence interval [CI] = 43‐57) received CDK4/6 inhibitors within 2 years beyond diagnosis. Of eligible patients diagnosed before August 2017 (n = 417), 31% (95% CI = 27‐36) received CDK4/6 inhibitors within 2 years following reimbursement. Another 20% of both cohorts are still CDK4/6 inhibitor naïve and on first‐line therapy. The use of chemotherapy decreased in first two lines of therapy between 2009 and 2018 (first‐line: 29%‐13%; second‐line: 26%‐19%). The implementation rate of CDK4/6 inhibitors since reimbursement is currently 50% within 2 years beyond diagnosis and is expected to increase further. The implementation of targeted therapy decreased the use of chemotherapy as first‐line therapy.

P14.33 Preoperative Lactate Dehydrogenase levels as a predictor of venous thromboembolism development in glioblastoma patients

Abstract BACKGROUND Venous thromboembolism (VTE) is a common complication in patients with glioblastoma. Despite high incidence of up to 30% per year, concerns about bleeding complications have limited the use of primary anticoagulant prophylaxis. Finding a suitable biomarker to assess the risk of occurrence is therefore of utmost clinical interest. We performed an exploratory study of preoperative routinely used haematological markers as predictor for the development of VTE in glioblastoma patients. MATERIAL AND METHODS Data was retrospectively collected from an existing database of 307 patients diagnosed with glioblastoma by the Oncology Network South-East Netherlands (OnzoZON) between 2006 and 2020. Collected preoperative haematological markers included: haemoglobin, platelets, lactate dehydrogenase, neutrophils, lymphocytes, albumin and derived ratios. In addition, type and date of VTE were retrieved from medical records. Receiver operating curve was used to identify the optimal cut-off values of the preoperative haematological markers. Univariate and multivariate logistic regression analyses were performed to predict VTE for each haematologic marker independently. Variables included in the multivariate analyses were age, gender, type of surgery, Karnofsky performance score, MGMT status, weight, height and BMI, already available from the primary database. RESULTS In the total dataset, 45 patients (15%) suffered from a VTE, most common pulmonary embolism (51%) followed by deep vein thrombosis (31%). Mean time from diagnosis until VTE was 4.3 months (SD = 5.5). Preoperative haemoglobin value was available for analyses in 265 patients, platelets value in 226, lactate dehydrogenase in 98, neutrophils in 133, lymphocytes in 133 and albumin in 56 patients. A preoperative lactate dehydrogenase value &amp;gt; 243 U/L was found to increase the risk of VTE in both univariate and multivariate analysis (P &amp;lt;0.05). Seventeen out of 98 patients of whom lactate dehydrogenase level was available suffered from a VTE, most common pulmonary embolism (59%), followed by deep vein thrombosis (29%) and cerebral venous sinus thrombosis (12%). An elevated lactate dehydrogenase in serum increased the odds for getting a VTE by 3.2 (1.1–9.4). None of the other investigated haematological markers or ratios were found to be significantly correlated with the occurrence of VTE in our study. CONCLUSION Glioblastoma initiates locally haemostatic abnormalities, that propagate systemically though circulating mediators. Our exploratory analysis shows for the first time that preoperative lactate dehydrogenase levels might aid clinicians in identifying patients at risk for a venous thromboembolism. Ultimately this could lead to preventive measures and patient education, but larger and prospective validation of these findings is warranted.

Carbon isotope trends in north-west European mosasaurs (Squamata; Late Cretaceous)

The carbon stable isotope composition (δ13C) of tooth enamel in mosasaurid squa-mates reflects aspects of their diet and diving behaviour. Here we present new δ13C data for such marine squamates from the Maastrichtian of Denmark and compare these with results obtained in previous studies from the lower-latitude type area of the Maastrichtian Stage (latest Cretaceous; 72.1–66.0 Ma) in the south-east Nether-lands and north-east Belgium. For the Danish samples, there is a weak correlation between mosasaur body size and δ13C values, with larger-sized taxa having lower δ13C values, comparable to what has previously been observed for mosasaurs from the Maastrichtian type area.

Survival before and after the introduction of pertuzumab and T-DM1 in HER2-positive advanced breast cancer, a study of the SONABRE Registry

PurposeImmediate and proper implementation of a new and more potent therapy is important to ensure that the patient achieves the best possible outcome. This study aimed to examine whether the real-world overall survival (OS) has improved in patients with human epidermal growth factor receptor 2-positive (HER2 +) advanced breast cancer (ABC) since the market release of pertuzumab and T-DM1. Furthermore, we aimed to assess the implementation and survival rates per hormone receptor (HR) subtype.Patients and methodsWe included 493 systemically treated patients consecutively diagnosed with HER2 + ABC in 2008–2017 from the SOutheast Netherlands Advanced BREast cancer (SONABRE) Registry. Median OS was obtained using the Kaplan–Meier method and differences between periods (2008–2012 versus 2013–2017) were tested using multivariable Cox proportional hazards regression modeling. The 3-year implementation rates were estimated for any HER2-targeted therapy, pertuzumab, and T-DM1 by using the competing risk method and calculated from the date of diagnosis of ABC to start of HER2-targeted therapy of interest.ResultsThe median OS in 2008–2012 versus 2013–2017 was 28.3 versus 39.7 months in all patients (adjusted hazard ratio (adjHR) 0.85, 95%CI 0.66–1.08), 29.9 versus 36.3 months in patients with HR + /HER2 + disease (adjHR 0.97, 95%CI 0.72–1.32), and 22.7 versus 40.9 months in patients with HR-/HER2 + disease (adjHR 0.59, 95%CI 0.38–0.92). Any HER2-targeted therapy was used in 79% of patients in 2008–2012 and in 84% in 2013–2017. The use of pertuzumab and T-DM1 in 2013–2017 was 48% and 29%, respectively. For patients diagnosed with HR + /HER2 + and HR-/HER2 + disease, implementation rates in 2013–2017 were , respectively, 77% and 99% for any HER2-targeted therapy, 38% and 69% for pertuzumab, and 24% and 40% for T-DM1.ConclusionThe survival of patients with HER2 + ABC improved since the introduction of pertuzumab and T-DM1. There is room for improvement in implementation of these HER2-targeted therapies, especially in patients with HR + /HER2 + disease.

Direct Medical Costs of Advanced Breast Cancer Treatment: A Real-World Study in the Southeast of The Netherlands

ObjectivesPolicy makers increasingly seek to complement data from clinical trials with information from routine care. This study aims to provide a detailed account of the hospital resource use and associated costs of patients with advanced breast cancer in The Netherlands. MethodsData from 597 patients with advanced breast cancer, diagnosed between 2010 and 2014, were retrieved from the Southeast Netherlands Advanced Breast Cancer Registry. Database lock for this study was in October 2017. We report the observed hospital costs for different resource categories and the lifetime costs per patient, adjusted for censoring using Lin’s method. The relationship between patients’ characteristics and costs was studied using multivariable regression. ResultsThe average (SE) lifetime hospital costs of patients with advanced breast cancer were €52 709 (405). Costs differed considerably between patient subgroups, ranging from €29 803 for patients with a triple-negative subtype to €92 272 for patients with hormone receptor positive and human epidermal growth factor receptor 2 positive cancer. Apart from the cancer subtype, several other factors, including age and survival time, were independently associated with patient lifetime costs. Overall, a large share of costs was attributed to systemic therapies (56%), predominantly to a few expensive agents, such as trastuzumab (15%), everolimus (10%), and bevacizumab (9%), as well as to inpatient hospital days (20%). ConclusionsThis real-world study shows the high degree of variability in hospital resource use and associated costs in advanced breast cancer care. The presented resource use and costs data provide researchers and policy makers with key figures for economic evaluations and budget impact analyses.

Palaeozoic micro-pelmatozoan thecae from the bedload of the River Maas (province of Limburg, the Netherlands)

In the Netherlands, Late Palaeozoic pelmatozoans – that is, stalked echinoderms – are known from building stones and cobbles in rivers, but there are no in-situ carbonate rocks from which they might be collected. Unsurprisingly, most recognisable specimens are columnals and pluricolumnals. Two small thecae, collected in the mid-1970s from silexite cobbles in the bedload of the River Maas in the Venlo-Tegelen area (province of Limburg, south-east Netherlands) are exceptional finds. One specimen, the diplobathrid camerate crinoid Rhodocrinites sp., has an unsculptured theca and some minor differences of form, yet otherwise satisfies the diagnosis of this genus. The other, the pentremitid blastoid Doryblastus? sp. is rather poorly preserved, yet is the first blastoid to be recorded from the Netherlands. Either or both of these specimens may be juveniles, particularly the blastoid. They are unlikely to be coeval, coming from separate cobbles and being of slightly different preservation. Their provenance from silexite cobbles suggest they originated from Lower Carboniferous (Tournaisian-Visean = Mississippian) carbonates in the southern Ardennes (south-central Belgium).

A new ophiacanthid brittle star (Echinodermata, Ophiuroidea) from sublittoral crinoid and seagrass communities of late Maastrichtian age in the southeast Netherlands.

A new species of brittle star, Ophiomitrella floorae, is recorded from the lower two meters of the Gronsveld Member (Maastricht Formation), of late Maastrichtian age (c. 66.7 Ma). These relatively fine-grained biocalcarenites reflect shallow-water deposition in a sheltered setting with a relatively firm sea floor and clear waters, under middle sublittoral and subtropical conditions. Associated echinoderm taxa comprise more robust, sturdy-plated ophiomusaid and ophiodermatid brittle stars and numerous bourgueticrinine sea lilies. The new brittle star described herein belongs to a family whose present-day members are predominantly restricted to bathyal depths. Its small size and the exceptional preservation of a single articulated specimen partially wrapped around the stalk of a bourgueticrinine suggest that O. floorae n. sp. was probably epizoic and specifically associated with stalked crinoids.

An economic evaluation of eribulin for advanced breast cancer treatment based on the Southeast Netherlands advanced breast cancer registry

Background: In 2013, eribulin was reimbursed under a coverage with evidence development (CED) as third or later chemotherapy line for advanced breast cancer (ABC) patients in the Netherlands because of uncertain cost effectiveness. In 2016, the final decision of reimbursing eribulin was taken without considering the evidence collected during CED research. We analysed the cost effectiveness of eribulin versus non-eribulin chemotherapy, using real-world data.Methods: A three health states (progression-free, progressed disease, dead) partitioned survival model was developed. The SOuth East Netherlands Advanced BREast Cancer (SONABRE) registry informed the effectiveness and costs inputs. Health state utility values were obtained from the literature. Incremental cost-effectiveness ratio (ICER) between the eribulin and matched non-eribulin chemotherapy was estimated. Deterministic and probabilistic sensitivity analyses and scenario analyses were performed. The financial risk (i.e., the expected value of perfect information (EVPI) plus the expected monetary loss (eML) associated with reimbursing eribulin) and budget impact associated with reimbursing eribulin were calculated.Results: Eribulin led to higher health benefits (0.07 quality-adjusted life year (QALY)) and costs (€15,782) compared with non-eribulin chemotherapy. This resulted in an ICER of €239,338. At a €80,000 per QALY threshold, the risk of reimbursing eribulin was €10,516 per patient (EVPI €9, eML €10,507). Scaled up to the Dutch population, the estimated annual budget impact was €1.9 million and the annual risk of reimbursing eribulin was €2.9 million.Conclusion: From a Dutch societal perspective, eribulin is not cost effective when considering its list price as third and later chemotherapy line for ABC patients.

Variability of cost trajectories over the last year of life in patients with advanced breast cancer in the Netherlands.

In breast cancer patients, treatment at the end of life accounts for a major share of medical spending. However, little is known about the variability of cost trajectories between patients. This study aims to identify underlying latent groups of advanced breast cancer patients with similar cost trajectories over the last year before death. Data from deceased advanced breast cancer patients, diagnosed between 2010 and 2017, were retrieved from the Southeast Netherlands Advanced Breast Cancer (SONABRE) Registry. Costs of hospital care over the last twelve months before death were analyzed, and the variability of longitudinal patterns between patients were explored using group-based trajectory modeling. Descriptive statistics and multinomial logistic regression were applied to investigate differences between the identified latent groups. We included 558 patients. Over the last twelve months before death, mean hospital costs were €2,255 (SD = €492) per month. Costs increased over the last five months and reached a maximum of €3,614 in the last month of life, driven by hospital admissions, while spending for medication declined over the last three months of life. Based on patients' individual cost trajectories, we identified six latent groups with distinct longitudinal patterns, of which only two showed a marked increase in costs over the last twelve months before death. Latent groups were constituted of heterogeneous patients, and clinical characteristics explained membership only to a limited extent. The average costs of advanced breast cancer patients increased towards the end of life. However, we uncovered several latent groups of patients with divergent cost trajectories, which did not reflect the overall increasing trend. The mechanisms underlying the variability in cost trajectories warrants further research.