Symptoms and General Pathology

All Conditions

Death

Joerg Faber, Univ.-Prof. Dr. med.

Philipp S Wild, Univ.-Prof. Dr. med. MSc

Hiltrud Merzenich, Dr. oec. troph.

Due to remarkable advances in childhood cancer therapy the 10-year survival rate increased to over 80% and late sequelae come to the fore. Childhood cancer survivors (CCS) suffer from significant excess in mortality risk associated with treatment-related complications at least for 25 years after the initial cancer diagnosis. In particular, the prevalence of cardiovascular disease seems to be elevated compared to the general population. The CVSS study is a multi-disciplinary cooperation project between the Institute for Medical Biostatistics, Epidemiology and Informatics (IMBEI) and the German Childhood Cancer Registry (GCCR), the Preventive Cardiology and Preventive Medicine and the Pediatric Hematology and Oncology all at the University Medical Center of the Johannes Gutenberg University Mainz. The central element is a thorough clinical cardiovascular examination of all patients, which permits detecting subclinical disease. Therapy data will be extracted retrospectively from various sources. The study intends to describe the current situation of a cohort of approximately 1000 CCS in Germany aged 24 to 49 years with respect to cardiovascular health. The role of risk factors (treatment related and classic cardiovascular risk factors), as well as related predisposing genetic factors is investigated. The results will contribute to recommendations to improve follow-up care.

blood, serum, plasma, DNA, RNA, urine, tear fluid

Cardiac and Vascular Late Sequelae in Long-term Survivors of Childhood Cancer (CVSS)

Cardiac and Vascular Late Sequelae in Long-term Survivors of Childhood Cancer (CVSS): a Multidisciplinary Clinical, Epidemiological and Genetic Approach

"late" is defined as 5 years or more after diagnosis of cancer

Univ. Prof. Dr. med. Joerg Faber, Center for Pediatrics, Hematology, Oncology and Hemostaseology

Univ. Prof. Dr. med. Philipp S. Wild, MSc, Preventive Cardiology and Preventive Medicine, Center for Cardiology, Clinical Epidemiology, CTH

Dr. oec. troph. Hiltrud Merzenich, Insitute for Medical Biometry, Epidemiology and Informatics (IMBEI)

CVSS study

interdisciplinary cooperation

Neoplasms

Respiratory Tract (Lung and Bronchial) Diseases

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Skin and Connective Tissue Diseases

Digestive System Diseases

Heart and Blood Diseases

Immune System Diseases

Lung Neoplasms

Carcinoma

Prostatic Neoplasms

Breast Neoplasms

Inflammation

Carcinoma, Hepatocellular

Thromboembolism

Thrombosis

Embolism

Embolism and Thrombosis

Vascular Diseases

All Drugs and Chemicals

Anticoagulants

Antineoplastic Agents

Coagulants

Anti-Infective Agents

Amino Acids

Immunomodulating Agents

Rivaroxaban

Palbociclib

Factor Xa Inhibitors

Antithrombins

Antithrombin III

Protease Inhibitors

Serine Proteinase Inhibitors

HIV Protease Inhibitors

Enzyme Inhibitors

Protein Kinase Inhibitors

Serine

Cancer patients without any incidence of thromboembolism will be included if they are non-carriers of the targeted gene-related polymorphism (GRP).

Cancer patients without any incidence of thromboembolism will be included if they are carriers of the targeted gene-related polymorphism.

Cancer patients with incidence of thromboembolism will be included if they are carriers of the targeted gene-related polymorphism.

Cancer patients with incidence of thromboembolism will be included if they are carriers of the targeted gene-related polymorphism and will be subjected to Palbociclib treatment.

Cancer patients with incidence of thromboembolism will be included if they are carriers of the targeted gene-related polymorphism and will be subjected to anti-coagulant treatment.

Palbociclib will be administered at a dose of 125 mg oral on a 21/7 cycle.

Rivaroxaban will be administered at a dosage of 15 mg intravenously twice a day for 21 days, followed by 20 mg once daily for the subsequent 21 days.

diagnostics of patients' carriers or not of the risk allele(s)

Nehman Makdissy, Professor

Malak Naboulsi, MD

David Wehbe, MD

Samar Hamoui, PhD

Fida Ayoubi, PhD

Noha Ibrahim, PhD

Nadine Ghotme, PhD

Christelle Rahme, MD, MSc

Elisa Makdessi, MSc

Bassam Bou Deleh, MSc

Joelle Moustafa, MSc

Maria Mouawad, MSc

This study aims to assess biomarkers and their related polymorphisms in the context of cancer-associated thromboembolism, with a particular focus on their interaction with the immune system. The roles of immune checkpoints, inflammatory and angiogenesis factors, as well as circulating immune cells will be elucidated. Additionally, our investigation extends to the exploration of long non-coding RNAs (LncRNAs) and genes associated with the coagulation vascular system. Initially, these aspects will be evaluated in the context of colorectal cancer, with the intention to expand our research to other solid tumors.

The identification of these biomarkers and genetic factors holds the potential to revolutionize therapeutic approaches for patients with cancer-associated thromboembolism, shedding light on their chemotherapy resistance. The effectiveness of combining immunotherapy with targeted inhibitors like Palbociclib and anticoagulants such as Rivaroxaban, among other potential interventions, will be assessed.

This study aims to make significant contributions to the understanding of these critical aspects, ultimately leading to the development of more effective treatment strategies for cancer patients.

Cancer, especially solid tumors, remains a significant global health challenge despite ongoing advancements in risk factor identification and targeted therapies. Among the various complexities of cancer treatment, the relationship between cancer and thromboembolism, characterized by arterial and venous thrombosis, has attracted attention due to its significant impact on patient outcomes.

Cancer cells activate the coagulation system, leading to prothrombotic disorders in the vascular wall and promoting tumor progression. Patients with cancer, particularly those undergoing systemic chemotherapy, face an increased risk of thromboembolism due to abnormal blood clotting mechanisms.

Recent research has emphasized the importance of identifying novel biomarkers for risk assessment, prognosis determination, and treatment selection in cancer. Among these biomarkers, long non-coding RNAs (LncRNAs) and those of the vascular coagulation system have emerged as pivotal players in cancer development and progression. However, their role as prognostic and predictive biomarkers for cancer risk and treatment response remains relatively unexplored.

Understanding the complex interplay between cancer, immune responses, and thromboembolism is crucial. Immunological subsets, including central immune effector T cells (CD8+, CD25+), NK cells, and macrophages, have been linked to cancer prognosis. Furthermore, therapies that modulate the immune system, such as immunotherapy and cell-based therapies, hold promise for improving cancer treatment outcomes.

Most notably, these therapies exhibit immunomodulatory effects, triggering immunogenic cell death and preventing immunosuppression. However, their efficacy may be compromised in cases of cancer associated with clotting abnormalities within the circulatory system. Progenitor cells, including stem cells and endothelial progenitor cells (EPCs), are emerging as potential players in cancer therapy, offering new avenues for research.

Among the innovative approaches is the assessment of circulating immune and endothelial progenitor cells (termed "CIEs"), which may play significant roles in the mechanisms underlying cancer-associated thromboembolism. Understanding the relationship between these cells, inflammatory and angiogenic factors, immune checkpoint, and cancer progression could pave the way for improved cancer risk assessment and treatment strategies.

This study seeks to contribute to our understanding of the intricate connections between LncRNA, coagulation-related biomarkers, thromboembolism, immune responses, and cancer, using solid tumors as a representative example. By shedding light on these complex interactions, this study aims to identify potential biomarkers that can guide risk assessment and treatment decisions, ultimately improving the management of cancer patients.

Exploring Cancer-Associated Thromboembolism Prognosis Biomarkers and Polymorphisms

Unveiling Prognosis Cancer-Associated Thromboembolism Biomarkers and Their Related Polymorphisms: Exploring Their Involvement With Immune Circulating Cells and Therapeutic Reversibility

The outcome measure of VTE including DVT, PE, and other thromboembolic events will be assessed by : (1) Clinical Assessment: Clinical symptoms such as swelling and pain in the lower limbs, tenderness behind the lower leg and/or medial thigh, and supplementary evaluation with color ultrasound of the veins in both lower limbs (lower extremity venography); (2) Imaging: CT pulmonary arteriography (CTPA) will be employed in conjunction with related clinical manifestations such as dyspnea and shortness of breath for diagnosing PE; (3) Laboratory Criteria: Diagnostic criteria will also consider laboratory parameters, including elevated D-dimer levels (\> 1000 ng/mL), increased fibrinogen levels (\> 700 mg/dL), and shortened activated partial thromboplastin time (aPTT) (\< 20 sec).

The assessment of cancer progression will be conducted using the standardized TNM staging system and applying the Response Evaluation Criteria (RECIST) guideline (ver. 1.1). Clinical parameters, laboratory tests indicative of cancer progression (including tumor markers and histopathological analysis), and relevant imaging modalities (e.g., CT, MRI, or PET scans) will be employed to evaluate the extent of primary tumor growth, lymph node involvement, and the presence of distant metastases. Progression-Free Survival (PFS), a key primary clinical endpoint for assessing cancer progression, will be calculated as the duration (in months) from the date of enrollment in the study until the tumor progresses, new lesions appear, or until the participant's death from any cause. Cancer progression will be determined based on RECIST guidelines, considering an increase in tumor size or the appearance of new lesions according to imaging assessments and clinical evaluations.

The objective of this outcome is to identify and characterize novel biomarkers associated with thromboembolism and cancer progression. Specifically, the assessment will focus on Long Non-Coding RNAs (LncRNAs) such as CDKN2B and CDKN2B-AS1, and markers related to the vascular coagulation system including ACE, PAI-1, FXIII, and Prothrombin. This identification process will involve collecting biological samples (e.g., blood, tissue) from enrolled patients at the time of study enrollment. The assessment will analyze and evaluate the expression and polymorphisms of the studied genes (CDKN2B, CDKN2B-AS1, ACE, PAI-1, FXIII, and Prothrombin) using quantitative PCR (qPCR), with Ct (Cycle threshold) as the common unit of measure for all genes. This comprehensive assessment aims to enhance our understanding of the molecular signatures linked to thromboembolism and cancer progression, illuminating potential diagnostic and therapeutic avenues for improved patient outcomes.

This primary outcome assesses treatment response in patients undergoing Palbociclib therapy for controlling cancer progression and thromboembolism. The evaluation will employ RECIST criteria to measure the percentage change in tumor size, indicative of treatment effectiveness.

Analysis of overall survival and progression-free survival rates among groups

The objective of this secondary outcome is to examine genetic variants, with a specific focus on the rs1333049 G\>C polymorphism within the CDKN2B-AS1 gene. The screening for polymorphism(s) will be determined by genotyping analysis using TaqMan PCR-based genotyping for SNP identification.

Monitoring and reporting of adverse events related to the Palbociclib and Rivaroxaban treatment regimen.

This outcome aims to comprehensively assess immune cell populations involved in the immune response, including T cells, B cells, natural killer (NK) cells, dendritic cells (DCs), and macrophages. The objective is to characterize changes in immune cell subsets over time, providing insights into the immune response dynamics. The assessment will involve immunophenotyping using flow cytometry to quantify and analyze the different immune cell populations. The unit of measure for this assessment will be the percentage of change of T cells, B cells, NK cells, DCs, and macrophages in the total population. The percentage of change will be determined up to a period of 60 months relatively to their levels at the diagnostic time.

This outcome focuses on assessing the levels of cytokines secreted by immune cells, including interferons (IFNs), interleukins (ILs), and tumor necrosis factor (TNF). The objective is to understand cytokine dynamics and their role in the immune response. The assessment will involve cytokine profiling by flow cytometry or ELISA. The levels of IFNs, ILs, and TNF will be measured as a percentage of change over a period of 60 months, relative to their levels at the diagnostic time. This standardized approach of using a common unit of measure will enable a comprehensive and unified evaluation of cytokine variations, providing critical insights into the immune response dynamics throughout the study duration.

This outcome aims to evaluate the presence and distribution of TILs within the tumor microenvironment. The objective is to understand the role of TILs in the immune response against the tumor. The assessment will involve analyzing tissue samples for TIL presence and distribution by immunohistochemistry (IHC) or flow cytometry.

This outcome focuses on investigating the expression of immune checkpoint molecules, specifically programmed cell death protein 1 (PD-1) and cytotoxic T-lymphocyte-associated protein 4 (CTLA-4). The objective is to understand the role of immune checkpoints in regulating the immune response. The assessment will involve evaluating immune checkpoint expression using techniques such as flow cytometry or PCR. The levels of PD-1 and CTLA-4 expression will be measured in the percentage of change over a period of 60 months, relative to their levels at the diagnostic time. Utilizing a standardized common unit of measure ensures a uniform assessment, allowing for a comprehensive understanding of the immune checkpoint dynamics and their impact on the immune response throughout the study's duration.

This outcome aims to assess alterations in angiogenic factors, with a specific focus on Vascular Endothelial Growth Factor (VEGF), in relation to treatment and study outcomes. VEGF is a key regulator of angiogenesis and is associated with tumor vascularization. The serum concentrations of VEGF-A/C will be measured by ELISA, providing valuable insights into the angiogenic processes linked to the immune response and their potential impact on treatment outcomes.

Haykel Hospital

Lebanese University

Principal Investigator, Professor

Gland and Hormone Related Diseases

Diseases and Abnormalities at or Before Birth

Nutritional and Metabolic Diseases

Rare Diseases

Adenoma

Hyperplasia

Hyperaldosteronism

Adrenal Hyperplasia, Congenital

Adrenogenital Syndrome

Syndrome

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Adrenocortical Hyperfunction

Adrenal Gland Diseases

Endocrine System Diseases

Disorders of Sex Development

Congenital Abnormalities

Urogenital Abnormalities

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Male Urogenital Diseases

Genetic Diseases, Inborn

Metabolism, Inborn Errors

Steroid Metabolism, Inborn Errors

Metabolic Diseases

Gonadal Disorders

Congenital Adrenal Hyperplasia

21-hydroxylase Deficiency

Hyperadrenalism

Vasoconstrictor Agents

Respiratory System Agents

Channel Blockers

Natriuretic Agents

Antihypertensive Agents

Epinephrine

Amiloride

Spironolactone

Racepinephrine

Epinephryl borate

Eplerenone

Mineralocorticoid Receptor Antagonists

Mineralocorticoids

Hormones

Hormone Antagonists

Diuretics

Diuretics, Potassium Sparing

Sodium Channel Blockers

Patients who undergo medical treatment, in view of bilateral PA, or unilateral PA not keen for surgery, or indeterminate (lack of localisation on tests)

Patients with unilateral PA who underwent adrenalectomy

Adrenalectomy for unilateral adrenal hyperplasia / adenoma

Adrenalectomy

Troy Puar, MRCP (UK)

Majority of patients with hypertension have primary hypertension (without an underlying cause). Secondary hypertension (due to an underlying disease) is important to recognize, as treatment can lead to cure of hypertension. Primary aldosteronism (PA) is the most common cause of secondary hypertension, and can be found in 5-10% of patients locally.

PA is caused by excessive release of a hormone (aldosterone) from the adrenal glands, which can be unilateral (one gland) or bilateral (both glands). Distinction between two is crucial as unilateral disease is treated with the aim of cure by surgery, and bilateral disease is treated by medication.

It has been shown that excess aldosterone has other harmful effects in addition to hypertension, such as directly affecting the heart, blood vessels, kidneys, diabetes and quality of life. This is supported by studies showing reversal of these effects after treatment for PA. In addition, improvements after surgery appears to be superior to medical treatment, although studies have found variable results.

Hence, the investigators aim to accurately subtype patients with PA into unilateral or bilateral disease and study the post-treatment response after both surgery and medicine with regards to the effects on blood pressure, cardiovascular, renal, metabolic and quality of life.

Peripheral blood samples Adrenal vein blood samples (during adrenal vein sampling) Adrenal tissue (post-adrenalectomy)

Prospective Study Assessing Blood Pressure and Other Outcomes Post-treatment in Patients With Primary Aldosteronism

Prospective Study Assessing Blood Pressure, Cardiovascular, Endothelial and Other Outcomes poSt-surgical and Medical Treatment in Patients With Primary Aldosteronism

Blood pressure assessed by 24hr ambulatory BP

Use of antihypertension medications as expressed in daily defined dosages and total number of medications

change in serum creatinine, calculated GFR, albuminuria (prevalence and severity)

Proportion of patients reaching normal BP (ambulatory /home BP \<135/85 or clinic BP \<140/90)

Proportion of patients with cure of PA after adrenalectomy

Changi General Hospital

Heart Diseases

Arrhythmias, Cardiac

Metabolic Syndrome

Insulin Resistance

Hyperinsulinism

Glucose Metabolism Disorders

No interventions are planned

Mariana Mirabel, MD, PhD

Cardio-oncology is an emerging field. Most of the data available have been issued from either retrospective analysis, industry data or pharmacovigilance data. These data sources include a number of bias.

CONFUCIUS is a single tertiary centre prospective registry including all patients who have been referred for cardio-oncology assessemnt.

The objectives are to provide a comprehensive vue of cardoi-oncology, enable to detect early signals of cardiotoxicity and enhance ancillary projetcts aiming at specific populations (e.g., type of cancer) and/or drugs.

Cardio-Oncology Registry

Cardio-Oncologie: étude Pilote évaluant la faisabilité, Utilité Concrète, Interdisciplinaire d'Une Unité Spécialisée

Number of patients with cardiotoxicity in a cohort of patients referred to a cardio-oncology clinic

Correlation of cardio-toxicity overall, and in predefined subgroups; statistical associatoin with outcomes.

Correlation between the use of cardiovascular drugs and the number of patients with cardiotoxicity.

Correlation between underlying cardioascular profile and the number of patients with cardiotoxicity.

Correlation between incident arrhythmias and cancer drugs

Correlation between biomarkers with use of artificial intelligence and the number of patients with cardiotoxicity.

Adherence to oncology treatment plan as stated in the multidisciplinary team meeting in patients with cardio-oncology assessment compared to matched patients with no cardio-oncology assessment within our institution; outcomes.

Assess cardiovascular outcomes (cardiovascular death, admission for heart failure, acute coronary syndrome, stroke).

Correlation between any adverse event, oncology treatment, and outcomes.

Correlation of any behaviour treatment (exercice, rehabilitation, nutrition consultation) and the number of patents with cardiotoxocity.

Correlation between oncology treatments, cardiovascular therapies, behaviour therapies and the number of patients with metabolic disorders (diabetes or dyslipidemia).

European Georges Pompidou Hospital

MD, PhD, Assosiate Professor

Nervous System Diseases

Behaviors and Mental Disorders

ACTH-Secreting Pituitary Adenoma

Pituitary ACTH Hypersecretion

Pituitary Diseases

Hypothalamic Diseases

Brain Diseases

Central Nervous System Diseases

Pituitary Neoplasms

Endocrine Gland Neoplasms

Quality of Life

ACTH-secreting Pituitary Adenoma

Anti-Inflammatory Agents

Hydrocortisone

Hydrocortisone 17-butyrate 21-propionate

Hydrocortisone acetate

Hydrocortisone hemisuccinate

Blood sample 24hrs urinary cortisol and salivary cortisol, urinary labstick test, EKG, cardiac ultrasound, cardiac CT-scan, arterial and venous US ophthalmology examination spine X-Ray bone densitometry QoL questionnaires (SF-36, QoLCushing, Beck BDI-II)

Exams and questionnaires

Jerome Bertherat, MD, PhD

This study aims at investigating the complications of Cushing's disease in "de novo" patients. A series of investigations will assay before treatment and every year thereafter during a 3 years follow-up period the various complications of the disease. These investigations will determine the presence and severity of cardiovascular, metabolic, and bone complications as well as the Quality of Life. Outcome of these complications after treatment, especially after pituitary surgery will be monitored, as well as cortisol levels.

At inclusion the following will be investigated and recorded :

* demographic and personal medical history.
* Familial medical history related to osteoporosis, cardiovascular disorders and thromboembolism.
* Current medical treatment.
* Physical examination.
* Assessment of basal 24hrs urinary cortisol and salivary cortisol.

  - At baseline (i.e. before specific treatment of Cortisol excess):
* physical examination,
* routine biology,
* HbA1C, fasting glucose and oral glucose load,
* cholesterol, triglyceride, HDL \& LDL,
* coagulation and fibrinolysis investigation,
* 24hrs urinary cortisol and salivary cortisol, urinary labstick test.
* EKG, cardiac ultrasound, cardiac CT-scan, arterial and venous US,
* ophthalmology examination,
* spine X-Ray, bone densitometry,
* QoL questionnaires (SF-36, QoLCushing, Beck BDI-II).

Every year during a 3 years follow-up the following will be investigated :

* Current medical treatment.
* Physical examination.
* Assessment of basal routine biology,
* HbA1C, fasting glucose,
* cholesterol, triglyceride, HDL \& LDL,
* coagulation and fibrinolysis investigation,
* 24hrs urinary cortisol and salivary cortisol, urinary labstick test.
* EKG, cardiac ultrasound, cardiac CT-scan (if abnormal initially), arterial and venous US,
* ophthalmology examination, bone densitometry,
* QoL questionnaires (SF-36, QoLCushing, Beck BDI-II).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Cardiac and Vascular Late Sequelae in Long-term Survivors of Childhood Cancer (CVSS)	NCT02181049	Childhood and A...		24 Years - 49 Years	Johannes Gutenberg University Mainz
Cardiac and Vascular Late Sequelae in Long-term Survivors of Childhood Cancer (CVSS)	NCT02181049	Childhood and A...		24 Years - 49 Years	Johannes Gutenberg University Mainz
Exploring Cancer-Associated Thromboembolism Prognosis Biomarkers and Polymorphisms	NCT06065592	Cancer Solid Tumor Thromboembolism Cardiovascular ... Immune System D... Inflammatory Di... Colon Cancer Breast Cancer Prostate Cancer Hepatocellular ... Lung Cancer Chemotherapy Immunotherapy	Palbociclib Rivaroxaban SNP	18 Years -	Lebanese University
Prospective Study Assessing Blood Pressure and Other Outcomes Post-treatment in Patients With Primary Aldosteronism	NCT03174847	Primary Aldoste... Primary Aldoste... Primary Aldoste...	Adrenalectomy Mineralocortico...	21 Years - 80 Years	Changi General Hospital
Cardio-Oncology Registry	NCT04407780	Cancer Cardiac Disease Metabolic Syndr... Arrhythmia Heart Diseases	No intervention...	18 Years -	European Georges Pompidou Hospital
Cushing's Disease Complications	NCT02568982	Cushing's Disea...	Exams and quest...	18 Years -	Assistance Publique - Hôpitaux de Paris
Omega 3 FA Supplements as Augmentation in the Treatment of Depression	NCT01803711	Major Depressio... Cancer Diabetes Cardiovascular ...	Desvenlafaxine Omega 3 Fatty a... Placebo (for Om...	18 Years -	UConn Health
Safety and Tolerability Study of APN01 (Recombinant Human Angiotensin Converting Enzyme 2)	NCT00886353	Pulmonary Disea... Cardiovascular ... Kidney Diseases Cancer Diseases	APN01 Placebo	18 Years -	Apeiron Biologics
Prospective Study Assessing Blood Pressure and Other Outcomes Post-treatment in Patients With Primary Aldosteronism	NCT03174847	Primary Aldoste... Primary Aldoste... Primary Aldoste...	Adrenalectomy Mineralocortico...	21 Years - 80 Years	Changi General Hospital
Exploring Cancer-Associated Thromboembolism Prognosis Biomarkers and Polymorphisms	NCT06065592	Cancer Solid Tumor Thromboembolism Cardiovascular ... Immune System D... Inflammatory Di... Colon Cancer Breast Cancer Prostate Cancer Hepatocellular ... Lung Cancer Chemotherapy Immunotherapy	Palbociclib Rivaroxaban SNP	18 Years -	Lebanese University

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