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Sections of human ganglioneuroblastoma (left) and neuroblastoma (right) double stained for CD31 (red) and a-SMA (green). Thin vessels showing flat, spindle-shaped endothelial cells and one layer of pericytes (left). MVP seen in vessels with enlarged endothelial cells and multiple layers of a-SMA ^ positive vascular mural cells (right). Magnification, Â100 (left and right).
Source publication
Tumor vasculature is disorganized and glomeruloid microvascular proliferation (MVP) has been identified as a poor prognosticator in some adult cancers. To determine the clinical significance of MVP, including glomeruloid MVP in neuroblastoma, we initially examined vessel architecture in tumor sections from 51 children diagnosed at Children's Memori...
Contexts in source publication
Context 1
... with no evidence of MVP (Fig. 1A-C). Immunohistochemistry showed a single layer of CD31-positive endothelial cells (Fig. 1B) and good coverage by a-SMA -positive pericytes (Fig. 1C). Similarly, blood vessels in the Schwannian stroma-rich ganglioneuroblastoma intermixed tumors were thin walled and MVP was not seen (CMH, n = 6; CHOP, n = 13; Fig. 1D-F and Fig. 2, ...
Context 2
... all four (100%) undifferentiated tumors had MVP. MVP was seen in 6 of the 11 (54.5%) differentiating neuroblastomas ( Fig. 1J-L) and 11 of the 16 (68.7%) poorly differentiated tumors (Fig. 1M-O). Both immunohistochemical and immunofluorescent staining with a-SMA revealed at least one but sometimes multiple layers of pericytes ( Fig. 1L and O and Fig. 2, right). In the CMH series, GMP was extensive in seven of the differentiating and poorly differentiated neuroblastomas, and staining with a-SMA revealed a prominent pericytic component ( Fig. 1L and O). In undifferentiated neuroblastoma tumors, a slightly different pattern of vasculature was noted characterized by continuous networks of MVP ...
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Citations
... These include vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), fibroblast growth factor-2 (FGF-2), transforming growth factor-alpha (TGF-α), platelet-derived growth factor A (PDGF-A), erythropoietin, and angiopoietin (61). High levels of expression of angiogenic factors are strongly associated with high risk and high stage NB, making them sensitive targets for anti-angiogenic therapy (62,63). Antiangiogenic agents include single-pathway inhibitors and multi-pathway inhibitors. ...
Background and Objective
Neuroblastoma (NB) is a common malignant tumor in children, and its treatment remains challenging. Precision medicine, as an individualized treatment strategy, aims to improve efficacy and reduce toxicity by combining unique patient- and tumor-related factors, bringing new hope for NB treatment. In this article, we review the evidence related to precision medicine in NB, with a focus on potential clinically actionable targets and a series of targeted drugs associated with NB.
Methods
We conducted an extensive search in PubMed, EMBASE, and Web of Science using key terms and database-specific strategies, filtered for time and language, to ensure a comprehensive collection of literature related to precision medicine in NB. The main search terms consisted of “neuroblastoma”, “precision medicine”, “pediatrics”, and “targeting”. The articles included in this study encompass those published from 1985 to the present, without restrictions on the type of articles.
Key Content and Findings
ALK inhibitors and MYCN inhibitors have been developed to interfere with tumor cell growth and dissemination, thereby improving treatment outcomes. Additionally, systematic testing to identify relevant driver mutations is crucial and can be used for diagnosis and prognostic assessment through the detection of many associated molecular markers. Furthermore, liquid biopsy, a non-invasive tumor detection method, can complement tissue biopsy and play a role in NB by analyzing circulating tumor DNA and circulating tumor cells to provide genetic information and molecular characteristics of the tumor. Recently, trials conducted by many pediatric oncology groups have shown the urgent need for new approaches to cure relapsed and refractory patients.
Conclusions
The purpose of this review is to summarize the latest advances in clinical treatment of NB, to better understand and focus on the development of promising treatment approaches, and to expedite the transition to the precision medicine clinical relevance in NB patients.
... It has been described that more aggressive risk groups display specific abnormal characteristics [35][36][37]. More recently, the description of a disorganized glomeruloid microvascular proliferation in poor outcome NB has been correlated to the hypothesis that angiogenesis could be regulated differently in Schwannian stroma-rich with a better prognosis than in stroma-poor NBs, which are associated with poor outcomes [38]. ...
Simple Summary
Neuroblastoma (NB) is the most common extracranial tumor in children. Despite the development of new therapeutic options, high-risk patients still have poor long-term survival. Distinguishing viable malignant tissue from necrotic areas and surrounding healthy tissue is pivotal during surgery. Variations in the tumor vascular architecture could guide surgeons to remove only viable tumor regions, achieving a safer and more efficient resection. In this paper, using histopathology scanned slides, we first examined variations in the vasculature density of different tumor regions, showing that viable and necrotic areas are associated with a distinct vascular signature. Then, we scanned an excised human NB specimen using a custom-made high-definition preclinical imaging device based on photoacoustic imaging, which is ideal for imaging vasculature, showing that the acquired images can differentiate macroscopic regions within the tumor.
Abstract
Despite aggressive treatments, the prognosis of high-risk NB remains poor. Surgical oncology needs innovative intraoperative devices to help surgeons discriminate malignant tissue from necrotic and surrounding healthy tissues. Changes within the tumor vasculature could be used intraoperatively as a diagnostic tool to guide surgical resection. Here, we retrospectively analyzed the mean vascular density (MVD) of different NB subtypes at diagnosis and after induction chemotherapy using scanned histological samples. One patient was prospectively enrolled, and an ex vivo photoacoustic imaging (PAI) scan was performed on two representative sections to assess its capacity to discriminate different tumor regions. We found that post-chemotherapy, viable areas of differentiating NBs and ganglioneuroblastomas are associated with higher MVD compared to poorly differentiated NBs. Early necrotic regions showed higher MVD than late necrotic and viable regions. Finally, calcified areas showed significantly lower MVD than any other histological component. The acquired PAI images showed a good high-resolution ex vivo 3D delineation of NB margins. Overall, these results suggest that a high-definition preclinical imaging device such as PAI could potentially be exploited to guide surgical resection by identifying different vasculature signatures.
... Analysis of clinical samples indicated that GMP is a defining histological trait of glioblastoma multiforme [36], and has been found in other tumors, such as neuroblastoma [37], as well as in breast cancer, where it was associated with p53 overexpression, BRCA1 germline mutations, and other markers of aggressive disease [38][39][40]. GMP has been proposed as a marker of poor prognosis in patients with melanomas, breast, endometrial, and prostate cancer [38,41]. ...
Simple Summary
Tumors rely on blood vessels to grow and metastasize. Malignant tumors can employ different strategies to create a functional vascular network. Tumor cells can use normal processes of vessel formation but can also employ cancer-specific mechanisms, by co-opting normal vessels present in tissues or by turning themselves into vascular cells. These different types of tumor vessels have specific molecular and functional characteristics that profoundly affect tumor behavior and response to therapies, including drugs targeting the tumor vasculature (antiangiogenic therapies). In this review, we discuss how vessels formed by different mechanisms affect the intrinsic sensitivity of tumors to therapy and, on the other hand, how therapies can affect tumor vessel formation, leading to resistance to drugs, cancer recurrence, and treatment failure. Potential strategies to avoid vessel-mediated resistance to antineoplastic therapies will be discussed.
Abstract
Blood vessels in tumors are formed through a variety of different mechanisms, each generating vessels with peculiar structural, molecular, and functional properties. This heterogeneity has a major impact on tumor response or resistance to antineoplastic therapies and is now emerging as a promising target for strategies to prevent drug resistance and improve the distribution and efficacy of antineoplastic treatments. This review presents evidence of how different mechanisms of tumor vessel formation (vasculogenesis, glomeruloid proliferation, intussusceptive angiogenesis, vasculogenic mimicry, and vessel co-option) affect tumor responses to antiangiogenic and antineoplastic therapies, but also how therapies can promote alternative mechanisms of vessel formation, contributing to tumor recurrence, malignant progression, and acquired drug resistance. We discuss the possibility of tailoring treatment strategies to overcome vasculature-mediated drug resistance or to improve drug distribution and efficacy.
... TMZ is the standard therapy for patients with malignant glioma with myelosuppression as the main toxicity. Angiogenesis is a significant regulator of glioblastoma growth and tumor vascularity correlates with high-risk disease [24,25]. Rh-ES is an endogenous broad-spectrum angiogenesis inhibitor, which could inhibit VEGF, cyclin D1, metalloproteinases, c-myc, integrins, and even Wnt signaling, thus inhibiting endothelial cell proliferation and migration, suppressing tumor vascularization and blocking the nutrition and oxygen supply to tumor cells [26][27][28]. ...
Background:
The optimal chemotherapeutics of recurrent disseminated glioblastoma has yet to be determined. We analyzed the efficacy and safety of recombinant human endostatin (rh-ES) combined with temozolomide and irinotecan in patients with recurrent disseminated glioblastoma.
Methods:
We retrospectively reviewed 30 adult patients with recurrent disseminated glioblastoma treated with this combination chemotherapy at Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University of China from November 2009 to August 2018. Temozolomide was given orally at 200 mg/m2 daily for 5 days and rh-ES was administrated 15 mg/d daily for 14 days of each 28-day treatment cycle. Irinotecan was given intravenously every 2 weeks on a 28-day cycle at 340 mg/m2 or 125 mg/m2 depending on antiepileptic drugs. Primary endpoint was progression-free survival (PFS) at 6 months (6 m-PFS).
Results:
The 6 m-PFS was 23.3%. The median PFS was 3.2 months. The overall survival rate (OS) at 12 months was 28.6%. The median OS was 6.9 months. Six out of 30 (20%) patients demonstrated partial radiographic response and 11 (36.7%) remained stable. The PFS of the 6 patients who got partial response was 5.8, 6.3, 6.9, 13.6, 15.8 and 16.6 months, respectively, and the median time interval of first response was 4 (range, 2.0-6.6) months. The most common adverse events were hematologic toxicities and gastrointestinal effects. The Grade ≥ 3 adverse event was hematologic toxicities. The adverse events were manageable.
Conclusions:
Rh-ES, in combination with cytotoxic drugs, was an alternative effective regimen with manageable toxicities in treatment of recurrent disseminated glioblastoma.
... TMZ is the standard therapy for patients with malignant glioma with myelosuppression as the main toxicity. Angiogenesis is a signi cant regulator of glioblastoma growth and tumor vascularity correlates with high-risk disease [24][25]. Rh-ES is an endogenous broad-spectrum angiogenesis inhibitor, which could inhibit VEGF, cyclin D1, metalloproteinases, c-myc, integrins, and even Wnt signaling, thus inhibiting endothelial cell proliferation and migration, suppressing tumor vascularization and blocking the nutrition and oxygen supply to tumor cells [26-28]. ...
Background: The optimal chemotherapeutics of recurrent disseminated glioblastoma has yet to be determined. We analyzed the efficacy and safety of recombinant human endostatin (rh-ES) combined with temozolomide and irinotecan in patients with recurrent disseminated glioblastoma. Methods: We retrospectively reviewed 30 adult patients with recurrent disseminated glioblastoma treated with this combination chemotherapy at Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University of China from November 2009 to August 2018. Temozolomide was given orally at 200mg/m 2 daily for 5 days and rh-ES was administrated 15 mg/d daily for 14 days of each 28-day treatment cycle. Irinotecan was given intravenously every 2 weeks on a 28-day cycle at 340 mg/m 2 or 125 mg/m 2 depending on antiepileptic drugs. Primary endpoint was progression-free survival (PFS) at 6 months (6m-PFS). Results: The 6m-PFS was 23.3%. The median PFS was 3.2 months. The overall survival rate (OS) at 12 months was 28.6%. The median OS was 6.9 months. Six out of 30 (20%) patients demonstrated partial radiographic response and 11 (36.7%) remained stable. The PFS of the 6 patients who got partial response was 5.8, 6.3, 6.9, 13.6, 15.8 and 16.6 months, respectively, and the median time interval of first response was 4 (range, 2.0-6.6) months. The most common adverse events were hematologic toxicities and gastrointestinal effects. The Grade ≥ 3 adverse event was hematologic toxicities. The adverse events were manageable. Conclusions: Rh-ES, in combination with cytotoxic drugs, was an alternative effective regimen with manageable toxicities in treatment of recurrent disseminated glioblastoma.
... TMZ is the standard therapy for patients with malignant glioma with myelosuppression as the main toxicity. Angiogenesis is a signi cant regulator of glioblastoma growth and tumor vascularity correlates with high-risk disease [24][25]. Rh-ES is an endogenous broad-spectrum angiogenesis inhibitor, which could inhibit VEGF, cyclin D1, metalloproteinases, c-myc, integrins, and even Wnt signaling, thus inhibiting endothelial cell proliferation and migration, suppressing tumor vascularization and blocking the nutrition and oxygen supply to tumor cells [26-28]. ...
Background: The optimal chemotherapeutics of recurrent disseminated glioblastoma has yet to be determined. We analyzed the efficacy and safety of recombinant human endostatin (rh-ES) combined with temozolomide and irinotecan in patients with recurrent disseminated glioblastoma. Methods: We retrospectively reviewed 30 adult patients with recurrent disseminated glioblastoma treated with this combination chemotherapy at Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University of China from November 2009 to August 2018. Temozolomide was given orally at 200mg/m2 daily for 5 days and rh-ES was administrated 15 mg/d daily for 14 days of each 28-day treatment cycle. Irinotecan was given intravenously every 2 weeks on a 28-day cycle at 340 mg/m2 or 125 mg/m2 depending on antiepileptic drugs. Primary endpoint was progression-free survival (PFS) at 6 months (6m-PFS). Results: The 6m-PFS was 23.3%. The median PFS was 3.2 months. The overall survival rate (OS) at 12 months was 28.6%. The median OS was 6.9 months. Six out of 30 (20%) patients demonstrated partial radiographic response and 11 (36.7%) remained stable. The PFS of the 6 patients who got partial response was 5.8, 6.3, 6.9, 13.6, 15.8 and 16.6 months, respectively, and the median time interval of first response was 4 (range, 2.0-6.6) months. The most common adverse events were hematologic toxicities and gastrointestinal effects. The Grade ≥3 adverse event was hematologic toxicities. The adverse events were manageable. Conclusions: Rh-ES, in combination with cytotoxic drugs, was an alternative effective regimen with manageable toxicities in treatment of recurrent disseminated glioblastoma.
... TMZ is the standard therapy for patients with malignant glioma with myelosuppression as the main toxicity. Angiogenesis is a signi cant regulator of glioblastoma growth and tumor vascularity correlates with high-risk disease [24][25]. Rh-ES is an endogenous broad-spectrum angiogenesis inhibitor, which could inhibit VEGF, cyclin D1, metalloproteinases, c-myc, integrins, and even Wnt signaling, thus inhibiting endothelial cell proliferation and migration, suppressing tumor vascularization and blocking the nutrition and oxygen supply to tumor cells [26-28]. ...
Background: The optimal chemotherapeutics of recurrent disseminated glioblastoma has yet to be determined. We analyzed the efficacy and safety of temozolomide and irinotecan combined with recombinant human endostatin (rh-ES) in patients with recurrent disseminated glioblastoma. Methods: We retrospectively reviewed 30 adult patients with recurrent disseminated glioblastoma treated with this combination chemotherapy at Department of Neuro-Oncology, Sanbo Brain Hospital, Capital Medical University of China from November 2009 to August 2018. Temozolomide was given orally 200mg/m2 for 5 days in each 28-day cycle (5/28d). Irinotecan was administrated 125 mg/m2 for patients not receiving enzyme-inducing antiepileptic drugs (EIAEDs) or 340 mg/m2 for patients receiving EIAEDs on day 1 and day 15; rh-ES was administrated 15 mg/d, daily for 14 days of each 28-day treatment cycle. Primary endpoint was progression-free survival at 6 months (6m-PFS). Results: The 6m-PFS was 23.3%. The median PFS was 3.2 months. The overall survival rate (OS) at 12 months was 28.6%. The median OS was 6.9 months. Six out of 30 (20%) patients demonstrated partial radiographic response and 11/30 (36.7%) remained stable. The PFS of the 6 patients who got partial response was 5.8, 6.3, 6.9, 13.6, 15.8, 16.6 months, respectively, and the median time interval of first response was 4 (range, 2.0-6.6) months. The most common adverse events were hematologic toxicity and gastrointestinal reactions. The Grade ≥3 adverse event was hematologic toxicity. The adverse events were manageable. Conclusions: Rh-ES, in combination with cytotoxic drugs, was an alternative effective regimen with manageable toxicity in treatment of recurrent disseminated glioblastoma.
... In neuroblastoma, a high vascular index is associated with increased disseminated disease, amplification of MYCN, unfavorable histology, and overall poor prognosis (2). Increased microvascular proliferation and other specific vascular morphological patterns are associated with even poorer prognosis, highlighting the pivotal role of angiogenesis in determining the clinical behavior of neuroblastoma (3,4). The VEGF family is a key regulator of angiogenesis in neuroblastoma and high VEGF expression at the time of diagnosis is associated with poor outcome (5). ...
... We also identified tumors with large areas of differentiating neuroblasts, a phenotype similar to that in MYCN-driven GEM models of neuroblastoma harboring constitutive activation of ALK, and in which reduced VEGFR signaling has been reported (31,41,42). Clinically, differentiated neuroblastoma displays low vascularity (2,3), partly due to the release of strong antiangiogenic factors that directly antagonize the effect of VEGF (43,44). Additionally, in differentiating, Schwannian-stroma poor neuroblastoma, VEGF-mediated cross-talk between differentiating neuroblasts and endothelial cells has been identified, which mimics normal vascular maturation in the developing nervous system (45). ...
Childhood neuroblastoma is a hypervascular tumor of neural origin, for which antiangiogenic drugs are currently being evaluated; however, predictive biomarkers of treatment response, crucial for successful delivery of precision therapeutics, are lacking. We describe an MRI-pathologic cross-correlative approach using intrinsic susceptibility (IS) and susceptibility contrast (SC) MRI to noninvasively map the vascular phenotype in neuroblastoma Th-MYCN transgenic mice treated with the vascular endothelial growth factor receptor inhibitor cediranib. We showed that the transverse MRI relaxation rate R2* (second−1) and fractional blood volume (fBV, %) were sensitive imaging biomarkers of hemorrhage and vascular density, respectively, and were also predictive biomarkers of response to cediranib. Comparison with MRI and pathology from patients with MYCN-amplified neuroblastoma confirmed the high degree to which the Th-MYCN model vascular phenotype recapitulated that of the clinical phenotype, thereby supporting further evaluation of IS- and SC-MRI in the clinic. This study reinforces the potential role of functional MRI in delivering precision medicine to children with neuroblastoma.
Significance
This study shows that functional MRI predicts response to vascular-targeted therapy in a genetically engineered murine model of neuroblastoma.
... MVP was also described in other solid tumors. Several studies, notably in breast or lung carcinomas (3,4), melanomas (5), and neuroblastomas (6), MVP has been identified as a marker of a poor prognosis. To a lesser degree, endothelial cell hypertrophy (ECH), also termed "endothelial hyperplasia", defined by a turgescent endothelium but without endothelial cells stratification, was reported to be strongly correlated with a shorter survival in patients with oligodendroglioma (7). ...
... In gliomas, MVP is one of the major histopathological features used for WHO grading, allowing for the classification of tumors as glioblastoma or anaplastic oligodendrogliomas (2), albeit showing only a modest reproducibility (20). In a few extra-cerebral tumors, MVP was also found to correlate with a shorter survival (3,4,6,21). In a study including 793 patients with melanoma, breast, endometrium, and prostate cancer, Straume et al demonstrated that MVP occurred in 12%-23% of cases and was significantly associated with patient survival or clinical recurrence (21). ...
Microvascular proliferation (MVP) is a hallmark of glioblastoma. Endothelial cell hypertrophy (ECH), also known as endothelial hyperplasia, is correlated with a shorter survival of patients with gliomas. However, the prognostic value of these 2 morphological features has not been studied in meningiomas. The aim of this study was to evaluate the prognostic value of angiogenesis in meningiomas, most notably ECH, MVP, and microvascular density, which were evaluated using immunohistochemistry with antibodies against CD34 and CD105 (a marker of neovascularization) in a series of 139 meningiomas. ECH, MVP, and CD105 immunoreactivity were significantly correlated with higher histological grades (p < 0.0001, p = 0.0004, and p = 0.0003, respectively). ECH and MVP but not CD105 immunoreactivities were significantly correlated with a shorter progression-free survival time (PFS) (p = 0.017, p = 0.021, and p = 0.137, respectively). In Cox multivariate analysis, ECH was an independent predictor of shorter PFS (p = 0.028). Therefore, ECH and MVP are markers of shorter PFS in meningiomas and are significantly correlated with grade. These findings give insight into the use of anti-angiogenic therapies. Further studies are needed to determine whether these markers could allow us to identify patients who could benefit from anti-angiogenic therapies.
... In many aspects, tumour vessels are different from normal vessels; they are dilated, tortuous and poorly covered by pericytes (Carmeliet and Jain, 2000;Bergers and Benjamin, 2003). In NB, conflicting results have been reported with regard to the prognostic impact of angiogenesis (Canete et al, 2000;Peddinti et al, 2007;Jakovljevic et al, 2011;Tadeo et al, 2013Tadeo et al, , 2016. ...
Background:
Although survival for neuroblastoma patients has dramatically improved in recent years, a substantial number of children in the high-risk subgroup still die.
Methods:
We aimed to define a subgroup of ultra-high-risk patients from within the high-risk cohort. We used advanced morphometric approaches to quantify and characterise blood vessels, reticulin fibre networks, collagen type I bundles, elastic fibres and glycosaminoglycans in 102 high-risk neuroblastomas specimens. The Kaplan-Meier method was used to correlate the analysed elements with survival.
Results:
The organisation of blood vessels and reticulin fibres in neuroblastic tumours defined an ultra-high-risk patient subgroup with 5-year survival rate <15%. Specifically, tumours with irregularly shaped blood vessels, large sinusoid-like vessels, smaller and tortuous venules and arterioles and with large areas of reticulin fibres forming large, crosslinking, branching and haphazardly arranged networks were linked to the ultra-high-risk phenotype.
Conclusions:
We demonstrate that quantification of tumour stroma components by morphometric techniques has the potential to improve risk stratification of neuroblastoma patients.British Journal of Cancer advance online publication, 14 July 2016; doi:10.1038/bjc.2016.210 www.bjcancer.com.
