Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

All Conditions

Uterine Cervical Neoplasms

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Cervical Diseases

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

The population is represented by women being admitted to the Gynecology Ward who are affected by cervical cancer.

Blood chemistry tests: neutrophil;lymphocyte; monocyte; platelet counts

Venous blood sample

biopsy

Carlo Ronsini, MD

Although significant advances in screening and treatment , cervical cancer is the fifth most common female cancer in Europe. Major prognostic factors for oncological outcome are used to categorise patients at high, intermediate and low risk groups and to define the type of radical hysterectomy according "Querleu-Morrow classification". The goal of this prospective observational study is to evaluate the association between several inflammatory markers and risk groups according European guidelines in women with cervical cancer Human Papillomavirus (HPV)-associated, in order to optimize the treatment.

European guidelines have proposed a risk stratification of patients basing on oncological risk. The type of radical hysterectomy (extent of parametrial resection and type according Querleu-Morrow classification) should be based upon the presence of prognostic risk factors.Major prognostic factors for oncological outcome as tumour size, maximum stromal invasion, Lymphovascular space invasion (LVSI) are used to categorise patients at high, intermediate and low risk for treatment failure. The investigators want to identify additional parameters to better define risk profiles. Systemic inflammation indices such as neutrophil to lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte to monocyte ratio (LMR) have shown prognostic value in solid tumors and several inflammatory conditions. Therefore, the primary endpoint of the present study is to assess the role of systemic inflammatory indices and risk groups stratification in patients with early cervical cancer.

CERvical Cancer The InFlammatory Index (CERTIFIKO)

CERvical Cance The InFlammatory Index as a Predictor of risK Stratification:an Observational Study

Anatomic pathology report of cell anaplasia in the sampled tumor

Anatomic pathology report of extent to which the cancer has spread

Anatomic pathology report of tissue types of cancer

an absolute value obtained from the ratio of neutrophils to lymphocytes

an absolute value obtained from the ratio of platelets to lymphocytes

an absolute value obtained from the ratio of lymphocytes to monocytes

University of Campania "Luigi Vanvitelli"

Principal Investigator

Endometrial Neoplasms

At least 18-year-old patients histologically diagnosed with endometrial cancer who will undergo surgical staging of disease after performing full-body CT-scan 30 days before the enrollment.

Blood chemistry tests: neutrophil; lymphocyte; monocyte; platelet counts.

Endometrial, adnexal, and lymphoid tissue samples.

Surgical staging of endometrial cancer

It is a prospective observational trial. Primary goal is identification of an association between alteration of systemic inflammation indices, such as neutrophil-to-lymphocyte ratio (NLR), platelet-t- lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (MRL) and patients risk classification according to European Guidelines.

The population is represented by all women being admitted to the Gynecology Ward, through Emergency, who are affected by endometrial cancer. Participants will undergo surgery, and freely express their consent to participate in the study.

Surgical treatment for endometrial cancer is class A radical hysterectomy according to Querleu-Morrow and bilateral adnexectomy with systematic pelvic lymphadenectomy. That allows the choice of adjuvant treatment, basing on anatomopathological risk information. Despite the standardization of adjuvant treatments, survival curves are heterogeneous in patients' responses. That is why European guide-lines have proposed a stratification of patients basing on oncological risk and molecular data (Microsatellite instability, aberrant P53, POLE gene mutation). The Investigators want to identify additional parameters to better define risk profiles. Systemic inflammation indices such as neutrophil-to-lymphocyte ratio (NLR), platelet-to-lymphocyte ratio (PLR) and lymphocyte-to-monocyte ratio (LMR) have shown prognostic value in several inflammatory conditions and solid tumors. Therefore, the Investigators have decided to explore their role also in recently diagnosed endometrial cancers, to find correlations with lymphovascular space invasion (LVSI), myometrial infiltration, histotype, and therefore with oncological risk classification. It is a prospective observational trial. Primary goal is identification of an association between alteration of systemic inflammation indices, such as neutrophil-to-lymphocyte ratio (NLR), platelet-t- lymphocyte ratio (PLR), lymphocyte-to-monocyte ratio (MRL) and patients risk classification according to European Guidelines.

The population is represented by all women being admitted to the Gynecology Ward, through Emergency, who are affected by endometrial cancer. Participants will undergo surgery, and freely express their consent to participate in the study.

Inflammatory Index as a Predictor for Endometrial Cancer: an Observational Study

Anatomic pathology report of tissue types that arise during the growth of cancer

Prognostic factor for recurrence and survival in endometrial cancer

Biomarker testing of genes and/or proteins

Medical Doctor

Respiratory Tract (Lung and Bronchial) Diseases

Skin and Connective Tissue Diseases

Lung Neoplasms

Breast Neoplasms

Collection of a venous blood sample to investigate metabolic changes in blood

Michiel Thomeer, prof. dr.

Kurt Baeten, dr.

This study aims to determine whether metabolic changes occur in blood plasma of cancer patients, and whether these changes can be used as a biomarker to detect cancer. These analyses will be done by means of nuclear magnetic resonance (NMR) spectroscopy.

Metabolic Changes as a Diagnostic Indicator for Cancer

Significant metabolic changes in blood between cancer patients \& control subjects

Ziekenhuis Oost-Limburg

Algemeen Ziekenhuis Vesalius

Ziekenhuis Maas en Kempen

Mariaziekenhuis Noord-Limburg

Hasselt University

prof. dr.

Respiratory Tract Neoplasms

Thoracic Neoplasms

Lung Diseases

Respiratory Tract Diseases

Subjects with lung cancer detected by a computed tomography (CT)-scan and referred to a positron emission tomography (PET)/CT-scan are included. The diagnosis of lung cancer is confirmed by means of an pathological biopsy or by a medical doctor specialized in oncology with respect to radiological or clinical data.

Intervention: a fasted venous blood sample is taken before PET-scan

The control group consists of subjects who were referred to the department Nuclear Medicine for an examination of the heart. This control group represents the average population, consists of healthy subjects and patients with non-cancer diseases and who did not undergo a PET/CT-scan.

Intervention: fasted venous blood sample

Michiel J Thomeer, MD, PhD

Lung cancer is the most common cancer in men and the fourth most common cancer in women worldwide. Until today no effective method permits the early detection of lung cancer. Consequently, lung cancer is often diagnosed owing to symptoms of advanced disease. To address this problem, detection methods with an improved sensitivity and specificity are urgently needed.

Over the past decade, accumulating evidence shows that the metabolism of cancer cells differs from that of normal cells. More specifically, the entire metabolism of cancer cells is reorganized or reprogrammed to increase anabolic reactions that induce cell growth and survival. Metabolic reprogramming during the development of cancer is driven by aberrant signaling pathways due to the activation of oncogenes and the loss of tumor suppressor genes. Furthermore, the microenvironment of the tumor plays a role in metabolic reprogramming. The altered cancer metabolism is characterized by an increased glycolysis, the production of lactate and the biosynthesis of macromolecules, such as proteins, lipids and nucleotides. Cancer cells have a high glycolytic rate and eliminate most of the glucose-derived carbon as lactate rather than oxidizing it completely via oxidative phosphorylation, a phenomenon known as the Warburg effect. The breakdown of glucose and other nutrients leads to a high energy production and provides the Krebs cycle with intermediates, which consequently are allocated to metabolic pathways that support biosynthesis. Metabolites are the end products of cellular metabolism and are therefore closely related to the observed phenotype. Disturbances in biochemical pathways which occur during the development of cancer consequently provoke changes in the metabolic phenotype. As a result, low-molecular weight metabolites are very attractive biomarkers for different cancer types. Nuclear magnetic resonance (NMR) spectroscopy enables the identification and quantitative analysis of complex mixtures of metabolites, as in plasma and serum, without an extended sample preparation.

The present study aims to determine the metabolic phenotype of lung cancer by means of proton (1H)-NMR spectroscopy. Once the phenotype determined (training cohort), this has to be validated by an independent cohort.

Subjects Subjects with lung cancer detected by a computed tomography (CT)-scan and referred to a positron emission tomography (PET)/CT-scan are included. The diagnosis of lung cancer is confirmed by means of an pathological biopsy or by a medical doctor specialized in oncology with respect to radiological or clinical data. The control group consists of subjects who were referred to the department Nuclear Medicine for an examination of the heart. This control group represents the average population, consists of healthy subjects and patients with non-cancer diseases and did not undergo a PET/CT-scan. Exclusion criteria are as follows: (1) not fasted for at least 6 hours, (2) poorly controlled diabetes (fasting plasma glucose concentration ≥ 200 mg/dl) in cancer patients, (3) medication intake at the day of blood sampling and (4) treatment or history of cancer in the preceding 5 years.

The training cohort consists of 80 subject with lung cancer and 80 controls. The validation cohort consist of 250 subject with lung cancer and 250 controls.

Blood sampling and processing Fasting venous blood samples (BD Vacutainer® LH 17 I.U. 10 ml tube) are collected and stored at 4°C within 5 to 10 minutes. Around 8 hours after blood collection, blood samples are transported on crushed ice to the central laboratory and centrifuged at room temperature (swinging bucket centrifuge, 1600 g, 15 minutes). Subsequently, 4 plasma aliquots of 500 µl are transferred into sterile cryovials and stored at -80°C until examination within 6 months. When subjects give permission to store their biological material, 3 aliquots are stored at the University Biobank Limburg (UBiLim) for biomedical research purposes.

Prior to NMR analysis, plasma aliquots are thawed and homogenized using a vortex mixer. After centrifugation at 13000 g for 4 minutes at 4°C (fixed rotor Eppendorf centrifuge 5415 R, Hamburg, Germany), plasma aliquots are diluted in deuterium oxide (D2O, 99.9%, Cambridge Isotope Laboratories Inc, Andover, USA) containing 180 µg/µl trimethylsilyl-2,2,3,3-tetradeuteropropionic acid (TSP, 98%, Cambridge Isotope Laboratories Inc, Andover, USA) as a chemical shift reference. Finally, the prepared plasma samples are transferred into a 5 mm NMR tube and analyzed.

1H-NMR analyses and assignment of present resonances The 1H-NMR spectra are recorded on a 400 Megahertz (MHz) NMR spectrometer (Varian/Agilent, Nuclear Magnetic Resonance Instruments, Palo Alto, California, USA) with a magnetic field strength of 9.4 Tesla at 294 K. Slightly T2- weighted spectra are acquired using a Carr-Purcell-Meiboom-Gill (CPMG) pulse sequence to attenuate signals of macromolecules, such as proteins and polysaccharides. Additionally, water suppression is performed in order to allow optimal detection and quantification of low-molecular weight metabolites. The 1H-NMR spectra are phased manually, baseline corrected and referenced to the TSP resonance at 0.015 parts per million (ppm). The assignment of the present 1H-NMR resonances occurs by means of spiking experiments. A reference plasma sample is alternately spiked with 34 known metabolites with a concentration of 1 mg compound per 100 µl plasma. The obtained chemical shifts are double checked with Chenomx NMR suite software (Version 7.5, Chenomx Inc., Edmonton, Alberta, Canada). Finally, 1H-NMR spectra are divided in 112 spectral regions, which are integrated and normalized relative to the total integrated area of all spectral regions, irrespective of the remaining water, TSP, fructose and glucose resonances. The end result corresponds to 110 normalized integration regions (all integration regions except those of water and TSP).

Statistical analysis At first, the integration values of all 110 spectral regions are analyzed by means of a student t-test with correction for multiple testing by Benjamini-Hochberg to identify those which differ significantly between lung cancer patients and controls (IBM SPSS Version 20.0, Chicago, Illinois, USA). Secondly, multivariate statistical analyses are performed using SIMCA-P+ (Version 12.0, Umetrics, Umea, Sweden) to investigate whether the metabolic composition of blood plasma allows to discriminate between lung cancer patients and controls. An unsupervised principal component analysis (PCA) was performed to identify intrinsic clusters and outliers within the dataset. After the removal of outliers (detected by a Hotelling's T2 range plot), an orthogonal partial least squares discriminant analysis (OPLS-DA), an extension of partial least squares discriminant analysis (PLS-DA) with an integrated orthogonal signal correction filter, is performed to remove variability not relevant to class separation. The predicted classification is expressed as specificity (the percentage of controls that are actually classified as controls) and sensitivity (the percentage of lung cancer patients that are actually classified as lung cancer patients). The outcome of using the integration values of the significantly different spectral regions, obtained by the student t-test with correction for multiple testing by Benjamini-Hochberg, is compared to the outcome in which the integration values of all 110 spectral regions were used.

Plasma is used to determine the metabolic profile by NMR spectroscopy

LC-NMR Study Biomarkers to Detect Lung Cancer

Search for Biomarkers to Detect Lung Cancer by Means of a NMR Spectroscopic Analysis of Blood Plasma

Plasma: metabolic phenotype by NMR spectroscopy

Time between date of diagnosis and date of death

Time between date of diagnosis and date of disease progression

Subtype of histology, eg adenocarcinoma vs squamous, vs large cell,...

Stage of the lung tumor, defined by the TNM classification

Immune System Diseases

Blood and Lymph Conditions

Rare Diseases

Hypersensitivity

Lymphoma

Lymphosarcoma

Anti-Infective Agents

All Drugs and Chemicals

Antihypertensive Agents

Nitric Oxide Donors

Vasodilator Agents

Hydrogen Peroxide

Nitroprusside

Acetylcholine

Breast cancer or lymphoma patients currently undergoing anthracycline-based chemotherapy treatment. Patients are eligible if they have completed at least 1 cycle of chemotherapy. Free of known clinical cardiovascular disease.

Individuals with history of breast cancer or lymphoma (1-5 years removed from last date of chemotherapy) who have a treatment history of anthracycline-based chemotherapy. Free of known clinical cardiovascular disease.

Individuals with no history of caner or chemotherapy. Free of known clinical cardiovascular disease

Continuously monitored for 5-30 minutes via finger photoplesmography

Arterial blood pressure

Assessment of carotid artery cross sectional area and intima-media thickness. Assessment of brachial artery diameter

Vascular Ultrasound

Evaluation of oxidative stress via serum lipid hydroperoxide

Assessed non-invasively in the forearm skin via Laser Doppler flowmetry in response to locally delivered acetylcholine (ACh) and sodium nitroprusside (SNP) via iontophoresis.

Skin microcirculatory blood flow

The overall goal of this project is to determine the effects of anti-cancer chemotherapy on reflex control of blood pressure and vascular function. Recent data have demonstrated that cardiovascular disease-related mortality is the 2nd cause of morbidity and mortality for 7-year cancer survivors treated with chemotherapy. This anti-cancer treatment-mediated cardiotoxicity is a progressive process that begins at the molecular level, progresses to myocardial injury and left ventricular dysfunction, cumulating as heart failure and cardiovascular disease-related mortality. In parallel to these cardiac-specific changes, chemotherapy has also been shown to increase the risk for vascular-related abnormalities. However, the impact of adjuvant treatments on the function and structure of the peripheral vascular system remains poorly understood. With normal aging, two of the most important vascular adaptations to arteries, which strongly contribute to the increased risk of vascular-related and general cardiovascular disease, are an increase in large artery stiffness and dysfunction of the vascular endothelium. Therefore, the overall goal of this project is to determine the effects of anthracycline-based chemotherapy on large and small artery function and structure. The central hypothesis is that this type of cancer therapy results in negative vascular consequences as determined by non-invasive evaluation of spontaneous blood pressure control, carotid artery stiffness, and vascular endothelium-dependent vasodilation.

This observational study is designed to increase our understanding of the vascular changes that occur during and following anti-cancer chemotherapy and provide insight into new methods that will decrease cardiovascular disease risk in those treated for cancer.

Cancer remains one of the leading causes of death in modern society. Breast cancer is a prevalent type of cancer in most societies, but due to increasing rates of detection coupled with advanced therapies, of the ≈230,000 people newly diagnosed each year with breast cancer, approximately 90% are expected to live beyond 5 years. Despite the trend in improved cancer-related morality, cancer survivors are at a significantly increased risk for cardiovascular disease (CVD) morbidity and mortality. As such, approximately $800 million is spent annually in providing cardiovascular care for female cancer survivors alone. In a recent study, Daher et al. (2012) reported a Framingham Risk Score of 8.4 and a 10-year risk of general CVD of 7.6% in men and women cancer survivors older than 30 yrs. More importantly, they also determined that the mean vascular age of cancer survivors was 8 years greater than their chronological age, suggesting that sub-clinical manifestation of CVD may be present within the vasculature of some cancer survivors.

The definition and scientific study of cardiotoxicity has, to date, primarily focused solely on the myocardial injury related to adjuvant cancer therapy and the National Cancer Institute has defined it as "toxicity that affects the heart" (http://www.cancer.gov/dictionary/). However, cancer survivors are also at risk for vascular-related abnormalities. Despite this risk, the impact of adjuvant treatments on the function and structure of the peripheral vascular system is still poorly understood. With normal aging, two of the most important vascular adaptations to arteries, which strongly contribute to the increased risk of vascular-related and general CVD, are an increase in large artery stiffness and dysfunction of the vascular endothelium \[15, 16\]. In subjects receiving anthracycline chemotherapy, Chaosuwannaki et al. (2010), Miza-Stec et al. (2013), and Draft et al. (2013) independently demonstrated significant increases in aortic stiffness 4-6 mo following treatment. Likewise, carotid intima-media thickness has been shown to increase within 6 mo of treatment with chemotherapy. This is critical given that arterial stiffness and intima-media thickness both are independently associated with increased risk of cardiovascular disease. In addition, carotid artery stiffness is a key determinant of the sympathetic baroreflex sensitivity in older men and women. This information suggests that decreases in baroreflex sensitivity may be occurring following chemotherapy treatment, which is important given it is a primary mechanism through which the autonomic nervous system regulates arterial blood pressure and that a low baroreflex sensitivity is associated with cardiovascular morbidity and mortality. Specific Aim 1 will address this question.

The vascular endothelium is the first physiological barrier encountered by intravenously administered chemotherapy. Unfortunately, the effects of adjuvant therapy on endothelial function have primarily been studied in childhood cancer survivors or following a single treatment session. Chow et al. (2006) observed a decreased brachial artery flow-mediated dilation (FMD), a measurement of endothelial-dependent dilation, ≈20 mo following anthracycline-based chemotherapy. Similarly, Vaughn et at. (2008) demonstrated a decreased FMD in long-term survivors of testicular cancer. In addition, several reports have demonstrated a decrease in arterial reactivity to various biological vasodilators (e.g., sodium nitroprusside, acetylcholine) following acute chemotherapy and radiation. In contrast to these studies, Jones et al. (2007) reported no difference in FMD in breast cancer patients ≈20 mo post-treatment compared to healthy controls. Increasing our understanding of the effects of chemotherapy on endothelial function is essential, especially since it can be the initial step in the development of cardiovascular disease.

Recently, the skin microcirculation has been used as a model circulation to evaluate the changes in vascular health in a variety of diseases including hypertension, renal disease, diabetes, atherosclerosis, coronary artery disease, and heart failure. This work has been facilitated, in part, by its easy accessibility and high responsiveness to biological vasodilators. Given the paucity of information on endothelial health in cancer patients undergoing anthracycline chemotherapy evaluation of the skin microcirculation provides a non-invasive and useful method of increasing our understanding of cardiotoxicity. Specific Aim 2 will address this problem.

Specific Aim 1: Evaluate the changes in spontaneous blood pressure control and arterial stiffness in patients treated with anthracycline-based chemotherapy.

Hypothesis 1a: Spontaneous baroreflex sensitivity will be significantly decreased in cancer patients and cancer survivors treated with anthracycline-based chemotherapy.

Hypothesis 1b: Changes in baroreflex control of blood pressure will be related to increases in carotid artery stiffness and cardiac changes in left ventricular ejection time.

Specific Aim 2: Evaluate the changes in macrovascular and microvascular vascular function.

Hypothesis 2a: Treatment with anthracycline-based chemotherapy will significantly decrease endothelium-dependent vasodilation in both the large brachial artery and the small microvascular capillaries in the skin.

Hypothesis 2b: Changes in vascular function will be associated with molecular markers of endothelial function and oxidative stress.

The Effects of Anthracycline-based Chemotherapy on Peripheral Vascular Function

The Effects of Anthracycline-based Chemotherapy on Spontaneous Baroreflex Sensitivity, Carotid Artery Stiffness, and Endothelial-dependent Vascular Function.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
CERvical Cancer The InFlammatory Index (CERTIFIKO)	NCT05673252	Cervical Cancer	Venous blood sa... biopsy	18 Years -	University of Campania "Luigi Vanvitelli"
Inflammatory Index as a Predictor for Endometrial Cancer: an Observational Study	NCT05657483	Endometrial Neo... Inflammatory Re...	Venous blood sa... Surgical stagin...	18 Years -	University of Campania "Luigi Vanvitelli"
Metabolic Changes as a Diagnostic Indicator for Cancer	NCT02362776	Breast Cancer Lung Cancer	Venous blood sa...	-	Hasselt University
LC-NMR Study Biomarkers to Detect Lung Cancer	NCT02024113	Lung Cancer	Venous blood sa...	18 Years -	Hasselt University
The Effects of Anthracycline-based Chemotherapy on Peripheral Vascular Function	NCT03062878	Breast Cancer Lymphoma Chemotherapy Ef...	Arterial blood ... Vascular Ultras... Venous blood sa... Skin microcircu...	21 Years -	Kansas State University

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