Cancer incidence, stage shift and survival during the 2020 COVID-19 pandemic: A population-based study in Belgium.

The COVID-19 pandemic was associated with a profound decline in cancer diagnoses in 2020 in Belgium. Disruption in diagnostic and screening services and patient reluctance to visit health facilities led to fewer new cases and concerns that cancers may be diagnosed at more advanced stages and hence have poorer prognosis. Using data from mandatory cancer registration covering all of Belgium, we predicted cancer incidence, stage distribution and 1-year relative survival for 2020 using a Poisson count model over the preceding years, extrapolated to 2020 for 11 common cancer types. We compared these expected values to the observed values in 2020 to specifically quantify the impact of the COVID-19 pandemic, accounting for background trends. A significantly lower incidence was observed for cervical, prostate, head and neck, colorectal, bladder and breast cancer, with limited or no recovery of diagnoses in the second half of 2020 for these cancer types. Changes in stage distribution were observed for cervical, prostate, bladder and ovarian and fallopian tube tumours. Generally, changes in stage distribution mainly represented decline in early-stage than in late-stage tumours. One-year relative survival was lower than predicted for lung cancer and colorectal cancer. Stage shifts are hypothesised to result from alterations in access to diagnosis, potentially due to prioritisation of symptomatic patients, and patient reluctance to contact a physician. Since there were over 5000 fewer cancer diagnoses than expected by the end of 2020, it is critical to monitor incidence, stage distribution and survival for these cancers in the coming years.

Fluid flow as a driver of embryonic morphogenesis.

Fluid flow is a powerful morphogenic force during embryonic development. The physical forces created by flowing fluids can either create morphogen gradients or be translated by mechanosensitive cells into biological changes in gene expression. In this Primer, we describe how fluid flow is created in different systems and highlight the important mechanosensitive signalling pathways involved for sensing and transducing flow during embryogenesis. Specifically, we describe how fluid flow helps establish left-right asymmetry in the early embryo and discuss the role of flow of blood, lymph and cerebrospinal fluid in sculpting the embryonic cardiovascular and nervous system.

Impaired SMAD1/5 Mechanotransduction and Cx37 (Connexin37) Expression Enable Pathological Vessel Enlargement and Shunting.

OBJECTIVE: Impaired ALK1 (activin receptor-like kinase-1)/Endoglin/BMP9 (bone morphogenetic protein 9) signaling predisposes to arteriovenous malformations (AVMs). Activation of SMAD1/5 signaling can be enhanced by shear stress. In the genetic disease hereditary hemorrhagic telangiectasia, which is characterized by arteriovenous malformations, the affected receptors are those involved in the activation of mechanosensitive SMAD1/5 signaling. To elucidate how genetic and mechanical signals interact in AVM development, we sought to identify targets differentially regulated by BMP9 and shear stress. Approach and Results: We identify Cx37 (Connexin37) as a differentially regulated target of ligand-induced and mechanotransduced SMAD1/5 signaling. We show that stimulation of endothelial cells with BMP9 upregulated Cx37, whereas shear stress inhibited this expression. This signaling was SMAD1/5-dependent, and in the absence of SMAD1/5, there was an inversion of the expression pattern. Ablated SMAD1/5 signaling alone caused AVM-like vascular malformations directly connecting the dorsal aorta to the inlet of the heart. In yolk sacs of mouse embryos with an endothelial-specific compound heterozygosity for SMAD1/5, addition of TNFα (tumor necrosis factor-α), which downregulates Cx37, induced development of these direct connections bypassing the yolk sac capillary bed. In wild-type embryos undergoing vascular remodeling, Cx37 was globally expressed by endothelial cells but was absent in regions of enlarging vessels. TNFα and endothelial-specific compound heterozygosity for SMAD1/5 caused ectopic regions lacking Cx37 expression, which correlated to areas of vascular malformations. Mechanistically, loss of Cx37 impairs correct directional migration under flow conditions. CONCLUSIONS: Our data demonstrate that Cx37 expression is differentially regulated by shear stress and SMAD1/5 signaling, and that reduced Cx37 expression is permissive for capillary enlargement into shunts.

Shear Stress and VE-Cadherin.

Objective- Vascular fusion represents an important mechanism of vessel enlargement during development; however, its significance in postnatal vessel enlargement is still unknown. During fusion, 2 adjoining vessels merge to share 1 larger lumen. The aim of this research was to identify the molecular mechanism responsible for vascular fusion. Approach and Results- We previously showed that both low shear stress and DAPT ( N-[ N-(3,5-difluorophenacetyl)-L-alanyl]- S-phenylglycine t-butyl ester) treatment in the embryo result in a hyperfused vascular plexus and that increasing shear stress levels could prevent DAPT-induced fusion. We, therefore, investigated vascular endothelial-cadherin (VEC) phosphorylation because this is a common downstream target of low shear stress and DAPT treatment. VEC phosphorylation increases after DAPT treatment and decreased shear stress. The increased phosphorylation occurred independent of the cleavage of the Notch intracellular domain. Increasing shear stress rescues hyperfusion by DAPT treatment by causing the association of the phosphatase vascular endothelial-protein tyrosine phosphatase with VEC, counteracting VEC phosphorylation. Finally, Src (proto-oncogene tyrosine-protein kinase Src) inhibition prevents VEC phosphorylation in endothelial cells and can rescue hyperfusion induced by low shear stress and DAPT treatment. Moesin, a VEC target that was previously reported to mediate endothelial cell rearrangement during lumenization, relocalizes to cell membranes in vascular beds undergoing hyperfusion. Conclusions- This study provides the first evidence that VEC phosphorylation, induced by DAPT treatment and low shear stress, is involved in the process of fusion during vascular remodeling.

Scar-free cutaneous wound healing in the leopard gecko, Eublepharis macularius.

Cutaneous wounds heal with two possible outcomes: scarification or near-perfect integumentary restoration. Whereas scar formation has been intensively investigated, less is known about the tissue-level events characterising wounds that spontaneously heal scar-free, particularly in non-foetal amniotes. Here, a spatiotemporal investigation of scar-free cutaneous wound healing following full-thickness excisional biopsies to the tail and body of leopard geckos (Eublepharis macularius) is provided. All injuries healed without scarring. Cutaneous repair involves the development of a cell-rich aggregate within the wound bed, similar to scarring wounds. Unlike scar formation, scar-free healing involves a more rapid closure of the wound epithelium, and a delay in blood vessel development and collagen deposition within the wound bed. It was found that, while granulation tissue of scarring wounds is hypervascular, scar-free wound healing conspicuously does not involve a period of exuberant blood vessel formation. In addition, during scar-free wound healing the newly formed blood vessels are typically perivascular cell-supported. Immunohistochemistry revealed widespread expression of both the pro-angiogenic factor vascular endothelial growth factor A and the anti-angiogenic factor thrombospondin-1 within the healing wound. It was found that scar-free wound healing is an intrinsic property of leopard gecko integument, and involves a modulation of the cutaneous scar repair program. This proportional revascularisation is an important factor in scar-free wound healing.

Breast cancer incidence, stage distribution, and treatment shifts during the 2020 COVID-19 pandemic: a nationwide population-level study.

BACKGROUND: The first COVID-19 wave in 2020 necessitated temporary suspension of non-essential medical services including organized cancer screening programs in Belgium. This study assessed the impact of the pandemic on breast cancer (BC) incidence, stage at diagnosis, and management in Belgium in 2020. METHODS: All Belgian residents diagnosed with in situ or invasive BC in 2015-2020 in the nationwide, population-based cancer registry database were included. Incidence trends for 2015-2019 were extrapolated to predict incidence and stage distribution for 2020 and compared with the observed values. National healthcare reimbursement data were used to examine treatment strategies. Exact tumor diameter and nodal involvement, extracted from pathology reports, were analyzed for 2019 and 2020. RESULTS: 74,975 tumors were selected for analysis of incidence and clinical stage. Invasive BC incidence declined by -5.0% in 2020, with a drop during the first COVID-19 wave (Mar-Jun; -23%) followed by a rebound (Jul-Dec; +7%). Predicted and observed incidence (in situ + invasive) was not different in patients < 50 years. In the 50-69 and 70 + age groups, significant declines of -4.1% and - 8.4% respectively were found. Excess declines were seen in clinical stage 0 and I in Mar-Jun, without excess increases in clinical stage II-IV tumors in Jul-Dec. There was no increase in average tumor diameter or nodal involvement in 2020. Patients diagnosed in Mar-Jun received significantly more neoadjuvant therapy, particularly neoadjuvant hormonal therapy for patients with clinical stage I-II BC. CONCLUSIONS: BC incidence decline in 2020 in Belgium was largely restricted to very early-stage BC and patients aged 50 and over. Delayed diagnosis did not result in an overall progression to higher stage at diagnosis in 2020. Observed treatment adaptations in Belgium were successful in prioritizing patients for surgery while preventing tumor progression in those with surgical delay. Continuation of monitoring BC incidence and stage in the future is crucial.

Quality of surgery and treatment and its association with hospital volume: A population-based study in more than 5000 Belgian ovarian cancer patients.

BACKGROUND: Different sets of quality indicators are used to identify areas for improvement in ovarian cancer care. This study reports transparently on how (surgical) indicators were measured and on the association between hospital volume and indicator results in Belgium, a country setting without any centralisation of ovarian cancer care. METHODS: From the population-based Belgian Cancer Registry, patients with a borderline malignant or invasive epithelial ovarian tumour diagnosed between 2014 and 2018 were selected and linked to health insurance and vital status data (n = 5119). Thirteen quality indicators on diagnosis and treatment were assessed and the association with hospital volume was analysed using logistic regression adjusted for case-mix. RESULTS: The national results for most quality indicators on diagnosis and systemic therapy were around the predefined target value. Other indicators showed results below the benchmark: genetic testing, completeness of staging surgery, lymphadenectomy with at least 20 pelvic/para-aortic lymph nodes removed, and timely start of chemotherapy after surgery (within 42 days). Ovarian cancer care in Belgium is dispersed over 100 hospitals. Lower volume hospitals showed poorer indicator results compared to higher volume hospitals for lymphadenectomy, staging, timely start of chemotherapy and genetic testing. In addition, surgery for advanced stage tumours was performed less often in lower volume hospitals. CONCLUSIONS: The indicators that showed poorer results on a national level were also those with poorer results in lower-volume hospitals compared to higher-volume hospitals, consequently supporting centralisation. International benchmarking is hampered by different (surgical) definitions between countries and studies.

Impact of the COVID-19 Pandemic on Incidence and Observed Survival of Malignant Brain Tumors in Belgium.

(1) Background: This study evaluates the impact of the COVID-19 pandemic on the incidence, treatment, and survival of adults diagnosed with malignant brain tumors in Belgium in 2020. (2) Methods: We examined patients aged 20 and older with malignant brain tumors (2004-2020) from the Belgian Cancer Registry database, assessing incidence, WHO performance status, vital status, and treatment data. We compared 2020 incidence rates with projected rates and age-standardized rates to 2015-2019. The Kaplan-Meier method was used to assess observed survival (OS). (3) Results: In 2020, there was an 8% drop in age-specific incidence rates, particularly for those over 50. Incidence rates plunged by 37% in April 2020 during the first COVID-19 peak but partially recovered by July. For all malignant brain tumors together, the two-year OS decreased by four percentage points (p.p.) in 2020 and three p.p. in 2019, compared to that in 2015-2018. Fewer patients (-9 p.p.) with glioblastoma underwent surgery, and the proportion of patients not receiving surgery, radiotherapy, or systemic therapy increased by six percentage points in 2020. (4) Conclusions: The COVID-19 pandemic profoundly impacted the diagnosis, treatment strategies, and survival of brain tumor patients in Belgium during 2020. These findings should guide policymakers in future outbreak responses, emphasizing the need to maintain or adapt (neuro)-oncological care pathways and promote informed decision making when care capacity is limited.

Stage shift and relative survival for head and neck cancer during the 2020 COVID-19 pandemic: a population-based study of temporal trends.

Objective: During the first wave of the COVID-19 pandemic in 2020, non-essential health services were suspended in Belgium, and the public was ordered to socially isolate. Underdiagnosis of cancer during this period was reported worldwide. Certain risk factors for head and neck cancer (HNC) overlap with those for COVID-19 incidence and mortality, making underdiagnosis and subsequent stage shift of this potentially rapidly progressing cancer a major concern. We aimed to analyze incidence, clinical stage at presentation, and survival of patients diagnosed with HNC in 2020 in Belgium, considering recent temporal trends. Methods: Using population-based data from the Belgian Cancer Registry (BCR), we extrapolated 2017-2019 trends in incidence, clinical stage, and 1-year relative survival (1yRS) of HNC to create an expected value for 2020 and compared this to the observed value. Results: There were 9.5% fewer HNCs diagnosed in 2020, compared to the predicted incidence. Underdiagnosis was larger for males (-11.8%), patients aged 50-64 (-11.2%) and 65-79 (-11.1%), and for oral cavity cancer (-17.6%). Shifts to more advanced stages were observed in larynx and oropharynx tumors and for (male) patients aged 80+. A 2.4 percentage point decline in 1yRS was observed, relative to the increasing trends in 1yRS (2017-2019). Conclusion: The COVID-19 pandemic led to underdiagnosis of HNC, resulting in shifts to more advanced stage at presentation in certain subgroups. A stage shift can be expected for the 9.5% of tumors not yet diagnosed at the end of 2020. HNC patients diagnosed in 2020 suffered higher than expected mortality.

Association between hospital volume and outcomes in invasive ovarian cancer in Belgium: A population-based study.

OBJECTIVES: To study the association between hospital volume and outcomes in patients with invasive epithelial ovarian cancer (EOC). METHODS: This study included 3988 patients diagnosed with invasive EOC between 2014 and 2018, selected from the population-based database of the Belgian Cancer Registry (BCR), and coupled with health insurance and vital status data. The associations between hospital volume and observed survival since diagnosis were assessed with Cox proportional hazard models, while volume associations with 30-day post-operative mortality and complicated recovery were evaluated using logistic regression models. RESULTS: Treatment for EOC was very dispersed with half of the 100 centres treating fewer than six patients per year. The median survival of patients treated in centres with the highest-volume quartile was 2.5 years longer than in those with the lowest-volume quartile (4.2 years versus 1.7 years). When taking the case-mix of hospitals into account, patients treated in the lowest volume centres had a 47% higher hazard to die than patients treated in the highest volume centres (HR: 1.47, 95% CI: 1.11-1.93, p = 0.006) over the first five years after incidence. A similar association was found when focussing on the surgical volume of the hospitals and considering only operated patients with invasive EOC. Lastly, the 30-day post-operative mortality decreased significantly with increasing surgical volume. CONCLUSIONS: The large dispersion of care and expertise within Belgium and the volume-outcome associations observed in this study support the implementation of the concentration of care for patients with invasive EOC in reference centres.

Blood vessel formation during tail regeneration in the leopard gecko (Eublepharis macularius): The blastema is not avascular.

Unique among amniotes, many lizards are able to self-detach (autotomize) their tail and then regenerate a replacement. Tail regeneration involves the formation of a blastema, an accumulation of proliferating cells at the site of autotomy. Over time, cells of the blastema give rise to most of the tissues in the replacement tail. In non-amniotes capable of regenerating (such as urodeles and some teleost fish), the blastema is reported to be essentially avascular until tissue differentiation takes place. For tail regenerating lizards less is known. Here, we investigate neovascularization during tail regeneration in the leopard gecko (Eublepharis macularius). We demonstrate that the gecko tail blastema is not an avascular structure. Beginning with the onset of regenerative outgrowth, structurally mature (mural cell supported) blood vessels are found within the blastema. Although the pattern of blood vessel distribution in the regenerate tail differs from that of the original, a hierarchical network is established, with vessels of varying luminal diameters and wall thicknesses. Using immunostaining, we determine that blastema outgrowth and tissue differentiation is characterized by a dynamic interplay between the pro-angiogenic protein vascular endothelial growth factor (VEGF) and the anti-angiogenic protein thrombospondin-1 (TSP-1). VEGF-expression is initially widespread, but diminishes as tissues differentiate. In contrast, TSP-1 expression is initially restricted but becomes more abundant as VEGF-expression wanes. We predict that variation in the neovascular response observed between different regeneration-competent species likely relates to the volume of the blastema. J. Morphol. 278:380-389, 2017. © 2017 Wiley Periodicals, Inc.

Erythro-myeloid progenitors can differentiate from endothelial cells and modulate embryonic vascular remodeling.

Erythro-myeloid progenitors (EMPs) were recently described to arise from the yolk sac endothelium, just prior to vascular remodeling, and are the source of adult/post-natal tissue resident macrophages. Questions remain, however, concerning whether EMPs differentiate directly from the endothelium or merely pass through. We provide the first evidence in vivo that EMPs can emerge directly from endothelial cells (ECs) and demonstrate a role for these cells in vascular development. We find that EMPs express most EC markers but late EMPs and EMP-derived cells do not take up acetylated low-density lipoprotein (AcLDL), as ECs do. When the endothelium is labelled with AcLDL before EMPs differentiate, EMPs and EMP-derived cells arise that are AcLDL+. If AcLDL is injected after the onset of EMP differentiation, however, the majority of EMP-derived cells are not double labelled. We find that cell division precedes entry of EMPs into circulation, and that blood flow facilitates the transition of EMPs from the endothelium into circulation in a nitric oxide-dependent manner. In gain-of-function studies, we inject the CSF1-Fc ligand in embryos and found that this increases the number of CSF1R+ cells, which localize to the venous plexus and significantly disrupt venous remodeling. This is the first study to definitively establish that EMPs arise from the endothelium in vivo and show a role for early myeloid cells in vascular development.

Arteriovenous malformations in hereditary haemorrhagic telangiectasia: looking beyond ALK1-NOTCH interactions.

Hereditary haemorrhagic telangiectasia (HHT) is characterized by the development of arteriovenous malformations--enlarged shunts allowing arterial flow to bypass capillaries and enter directly into veins. HHT is caused by mutations in ALK1 or Endoglin; however, the majority of arteriovenous malformations are idiopathic and arise spontaneously. Idiopathic arteriovenous malformations differ from those due to loss of ALK1 in terms of both location and disease progression. Furthermore, while arteriovenous malformations in HHT and Alk1 knockout models have decreased NOTCH signalling, some idiopathic arteriovenous malformations have increased NOTCH signalling. The pathogenesis of these lesions also differs, with loss of ALK1 causing expansion of the shunt through proliferation, and NOTCH gain of function inducing initial shunt enlargement by cellular hypertrophy. Hence, we propose that idiopathic arteriovenous malformations are distinct from those of HHT. In this review, we explore the role of ALK1-NOTCH interactions in the development of arteriovenous malformations and examine a possible role of two signalling pathways downstream of ALK1, TMEM100 and IDs, in the development of arteriovenous malformations in HHT. A nuanced understanding of the precise molecular mechanisms underlying idiopathic and HHT-associated arteriovenous malformations will allow for development of targeted treatments for these lesions.