Epithelioid Haemangioendothelioma Observational Study

March 27, 2026 updated by: Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

The Evaluation of Cytokines and Hormones as Biomarkers for Epithelioid Haemangioendothelioma and Generation of Patient-derived Preclinical Models to Assess the Activity of Anticancer Agents and Validate Novel Therapeutic Targets

The EHE observational study was developed to obtain a high number of datas such as clinical presentation, natural history, and treatment outcomes, cto identificate cytokines and hormones as biomarkers and generate patient-derived preclinical models as a tool to assess the activity of anticancer agents and validate novel therapeutic targets

Study Overview

Status

Recruiting

Conditions

Detailed Description

Epithelioid hemangioendothelioma (EHE) is an ultra-rare (incidence rate < 1/1000.000), translocated, vascular soft tissue sarcoma. It shows a pick of incidence in the 4th decade of life, and it is more commonly diagnosed in females, with reported disease onset during pregnancy.

Two specific translocations have been identified in EHE, representing an hallmark in diagnosis today: the fusion of Transcriptional Co-activator with a PDZ-motif (TAZ) with Calmodulin Binding Transcription Activator 1 (CAMTA1) which is present in almost 90 % of cases, and the fusion of Yes-associated Protein (YAP) and Transcription Factor E3 (TFE3) genes (YAP-TFE3), which can be found in around 10% of the patients. YAP and TAZ are well-defined downstream effectors in the Hippo pathway. Forced activation of YAP/TAZ is thought to drive EHE and contribute to key aspects of the cancer phenotype, including metastasis and fibrosis.

Most of the times, EHE presents as multifocal or metastatic at diagnosis, with lung, liver and bone being the more commonly involved. The clinical course ranges from cases naturally stable over time to those highly aggressive and rapidly fatal. Pleural effusion, lymph node metastases and pathologic features (nuclear pleomorphism, mitotic figures and presence of necrosis) have been reported to be associated with a worse outcome, but biological and molecular predictors are still lacking. In particular, there is a subgroup of EHE presenting with serosal involvement, typically associated with chronic mild fever, weight loss, asthenia, anorexia, severe disease- related pain, (more responsive to anti-inflammatory pain killers that morphine), and dyspnoea which seems to perform very poorly. The biological basis sustaining this presentation is completely unknown.

As of today, there are no reports available in literature providing a comprehensive description of the peculiar EHE radiological features, both for primary and metastatic disease at different sites, and their potential prognostic role has not been explored. In addition, there are no published data to indicate the optimal routine follow-up policy of surgically treated EHE patients with localised disease and the routine follow-up schedules differ across institutions. The appropriate frequency of imaging in cases suffering of distant metastases is also left to be determined.

Also, the definition of radiological progression and the assessment of treatment response in EHE remain major challenges. The appearance or worsening of serosal effusion, the changes in serosal involvement and the limited increase in size over a short-time interval in slow-growing variants are not promptly captured by Response Evaluation Criteria for Solid Tumor (RECIST) definition for disease progression. This makes the use of such criteria unsatisfactory in this complex disease and could potentially lead to a delay in progression recognition and treatment start. Similarly, being frequently observed in EHE under treatment, improvement of serosal effusion, reduction in size <30%, and correlation between radiology and symptoms should be taken into account when assessing treatment response.

Surgery is the mainstay of care in the local setting. Active surveillance can be a reasonable strategy for patients with naturally stable or asymptomatic, slowly progressive disease, reserving medical treatment to symptomatic or progressive cases.

Data on conventional chemotherapy in advanced EHE are limited to case reports and single-institution experiences and suggest a limited role for the drugs commonly used in adult-type soft tissue sarcomas. Signs of activity have been reported with the use of anti-angiogenics, including pazopanib, sorafenib, bevacizumab, alone or in combination with chemotherapy, and apatinib. Due to the peculiar natural history of the disease, the value of antiangiogenics and/or immunomodulatory agents has also been explored, with responses described with sirolimus, thalidomide, interferon, and celecoxib.

In absence of any active treatment available, EHE is a neglected disease, and the identification of new potentially active compounds, especially for patients affected by the more aggressive EHE variant. To this end, it looks to be of major importance to identify what is behind disease progression, the "inflammatory-like" disease presentation, and the prevalence of the disease in the female young population.

Several lines of evidence have highlighted the significance of inflammation at the local and/or systemic level in human tumor pathobiology. Indeed, inflammation can influence tumor progression, metastasis and therapeutic outcome by establishing a tumor supportive immune microenvironment. These processes are mediated through a variety of cytokines and hormones that exert their biological actions either locally or distantly via systemic circulation.

Estrogen signaling is mediated via several receptor proteins. In addition to the classical ERα and ERβ, the membrane-bound G-protein coupled estrogen receptor (GPER) mediates both the genomic and non-genomic effects of estrogen and has been implicated in the development of other tumors such as breast cancer. Interestingly, GPER stimulation activates YAP and TAZ as key effectors of the Hippo pathway. Insulin-like growth factor-1(IGF-1) has also been shown to regulate GPER expression and function, suggesting a crosstalk between growth factors and ERs The availability of translatable preclinical models of human EHE, able to properly recapitulate tumor biology and response to treatment of the clinical tumors, appears instrumental for the development of innovative and effective treatments. Patient-derived xenograft (PDX) models preserve the original histomorphological and molecular characteristics of the originating clinical tumors. We previously demonstrated the consistency between preclinical data obtained on PDXs of different soft-tissue sarcoma histotypes (solitary fibrous tumor, epithelioid sarcoma and dedifferentiated liposarcoma) and clinical results concerning the activity of several cytotoxic and molecularly targeted drugs, providing novel insight into the antitumor effect of different combinations that was instrumental to design novel clinical trials.

MicroRNAs (miRNAs) are small non-coding RNAs that negatively regulate gene expression at the post-transcriptional level. Their proven deregulation in several types of human cancer, and the possibility to be reliably detected in both tissue and blood specimens, have prompted the assessment of miRNAs as novel cancer biomarkers21. No information is currently available on miRNA expression and function in EHE.

Study Type

Observational

Enrollment (Estimated)

50

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Locations

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

  • Adult
  • Older Adult

Accepts Healthy Volunteers

No

Sampling Method

Non-Probability Sample

Study Population

We plan to include at least 50 patients (range: 50-70) in 36 months, followed by a follow up time of 3 years.68 including The Royal Marsden Hospital.

Description

Inclusion Criteria:

  • Histological diagnosis of EHE according to 2020 WHO classification, performed on biopsy or surgical specimen
  • Signed informed consent
  • Adequate patient compliance to treatment or follow up
  • No age limit

Exclusion Criteria:

  • Impossibility to ensure adequate compliance

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Cohorts and Interventions

Group / Cohort
Group A
Patients newly diagnosed with advanced EE starting active surveillance
Group B
Patients with new diagnosis of advanced, evolving EE, worthy of medical treatment
Group C
Patients with a previous diagnosis of advanced EE, already under active surveillance
Group D
Patients with a previous diagnosis of advanced EE with ongoing medical treatment
Group E
Patients with localized EHE

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Demographic description
Time Frame: Through study completion, an average of 1 year
To provide a demographic description of the population affected by advanced EHE
Through study completion, an average of 1 year
Patient status
Time Frame: Through study completion, an average of 1 year
To provide a description of clinical presentation, natural history, and treatment pattern in patients with advanced EHE
Through study completion, an average of 1 year
Tumor-related symptoms
Time Frame: Through study completion, an average of 1 year
To provide a description of tumour-related symptoms and their changes over time
Through study completion, an average of 1 year
Tumor-related pain
Time Frame: Through study completion, an average of 1 year
To provide a tumor-related pain assessment
Through study completion, an average of 1 year
Clinical prognosis
Time Frame: Through study completion, an average of 1 year
To prospectively identify clinical prognostic and predictive factors
Through study completion, an average of 1 year
radiological features
Time Frame: Through study completion, an average of 1 year
To describe the radiological features of the disease (group A, B, C, D, E)
Through study completion, an average of 1 year
correlation between radiological features and outcome
Time Frame: Through study completion, an average of 1 year
To correlate radiologic features with the outcome and the tested plasma levels of the cytokines and hormones (group A, B, C, D, E)
Through study completion, an average of 1 year
radiological response and systemic treatment
Time Frame: Through study completion, an average of 1 year
To assess radiologic response to systemic treatments by basing on RECIST 1.1 assessment (group B, D).
Through study completion, an average of 1 year

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Investigators

  • Principal Investigator: Silvia Stacchiotti, Fondazione IRCCS Istituto Nazionale dei Tumori, Milano

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (Actual)

February 25, 2021

Primary Completion (Estimated)

February 1, 2028

Study Completion (Estimated)

December 1, 2028

Study Registration Dates

First Submitted

March 20, 2024

First Submitted That Met QC Criteria

November 6, 2024

First Posted (Actual)

November 8, 2024

Study Record Updates

Last Update Posted (Actual)

April 1, 2026

Last Update Submitted That Met QC Criteria

March 27, 2026

Last Verified

March 1, 2026

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • POEM (Alias Study Number)

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

NO

Drug and device information, study documents

Studies a U.S. FDA-regulated drug product

No

Studies a U.S. FDA-regulated device product

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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