Nutritional and Metabolic Diseases

Symptoms and General Pathology

All Conditions

Neoplasms

Urinary Tract, Sexual Organs, and Pregnancy Conditions

Obesity

Endometrial Neoplasms

Overweight

Overnutrition

Nutrition Disorders

Body Weight

Uterine Neoplasms

Genital Neoplasms, Female

Urogenital Neoplasms

Uterine Diseases

Genital Diseases, Female

Genital Diseases

Urogenital Diseases

Female Urogenital Diseases

Pregnancy Complications

Female Urogenital Diseases and Pregnancy Complications

Potential participants will be identified in the Royal Surrey NHS Foundation trust - either seen here or referred here and receiving her treatment here for diagnosed endometrial cancer.

Patients diagnosed with endometrial cancer will be identified through the Gynaecological Oncology Multi-Disciplinary Team meeting or by the Gynaecological Oncology or Medical Oncology teams.

Blood sample will be collected on the day of the surgery when they are in the theatres and then repeated on day 1 post-operative in gynaecology ward and at 3/6 months post-surgery follow-up in clinic.

For the women undergoing chemotherapy, blood sample will be procured prior to commencing chemotherapy and after 3rd (with the blood test before the fourth cycle of chemotherapy) and 6th cycles of chemotherapy.

Blood and tissue sample collection from patients undergoing surgery for endometrial cancer and blood sample collection only from patients undergoing chemotherapy for endometrial cancer

Blood and tissue sample collection from patients with endometrial cancer

The number of women diagnosed with uterine cancer continues to rise each year. Since the early 1990s, there has been almost 55% rise in the United Kingdom (UK). 34% of endometrial cancer can be attributed to obesity. In the obese state, the function of adipose tissue deteriorates resulting in a state of chronic inflammation. Adipocytokine-related signalling pathways promote cancer development by causing inflammation, cell proliferation, DNA damage and by inhibiting apoptosis. The investigators postulate that adipocytokines levels are significantly different in uterine cancer patients of different weight categories and different grade/stage/ type of tumour.

Any woman attending the hospital with endometrial cancer and receiving treatment here will be invited to participate in the study. Consent will be sought to obtain 30mls (2 1/2 tablespoons) of venous blood at the time of surgery, on day 1 post-surgery and 3/6 months post-surgery during routine follow-up to check biomarker (adiponectin, leptin, tumour necrosis factor alpha, interleukin-6, Insulin-like growth factors 1 and 2) levels to see if the markers can be used to assess response to treatment. The investigators will also get consent to collect tissue - adipose tissue (after surgery) and uterine cancer tissue and lymph nodes (after histo-pathological evaluation) to assess for biomarkers. The investigators will also obtain blood samples from patients undergoing chemotherapy for advanced stage endometrial. All tissues procured will be anonymised and analysed at the oncology laboratory, Leggett building, University of Surrey and later correlated with patients' medical data as well as with tumour grade, stage and type. The investigators will also use archival tissue blocks stored at the same laboratory for analysis (previously consented for use in research). These are anonymised tissue and there is no link to patients' data.

The aim would be to ultimately find immuno-stimulatory/ suppressive biomarkers in order to develop novel diagnostic/ prognostic tools.

1. BACKGROUND

   Endometrial cancer is the most common malignancy of the female genital tract. It is the fourth most common cancer in the UK with around 9,500 new cases in 2017, current lifetime risk being 1 in 36 women. The number of women diagnosed with endometrial cancer continues to rise each year. Since the early 1990s, uterine cancer incidence rates have increased by almost three-fifths (55%) in the UK (2015-2017). The association between endometrial cancer and obesity is well documented. 7.5% of all cancers in women in UK are attributable to being overweight / obese (BMI ≥25 kg/m2). For endometrial cancer, this risk rises to 34%. A review of meta-analyses showed endometrial cancer risk is 16% higher per 5 kg- gained during adulthood, 29% higher per 10cm increase in hip circumference and 27% higher per 10cm increase in waist circumference. This higher endometrial cancer risk with raised BMI is present in both pre- and post-menopausal women. Moreover, patients who are obese tend to have a poorer outcome with more co-morbidities than their non-obese counterparts.

   In the overweight and obese state, the function of the adipose tissue deteriorates resulting in a state of chronic inflammation. In this inflammatory state, adipocytes and macrophages secrete several molecules, adipokines and inflammatory cytokines, which may promote tumour development and angiogenesis and stimulate adhesions and migration of cells.

   Most implicated adipocytokines in the tumorigenesis pathway are adiponectin, leptin, tumour necrosis factor-α (TNF-α), Interleukin-6 (IL-6) and Insulin-like growth factor 1 and 2 (IGF 1 and 2).

   Adipocytokine related signalling pathways are important in the development of an inflammatory microenvironment for tumours. This process is thought to increase the risk of endometrial cancer by inducing cell proliferation and preventing cell apoptosis. Adiponectin, the most abundant adipokine, has been suggested to have anti-angiogenic, anti-inflammatory, and anti-apoptotic properties. Raised leptin levels in obese state promotes inflammation by stimulating the production of IL-6, TNFα as well as IL-1 and IL-126. Leptin and adiponectin secretion are counter-regulated in vivo. A study by Luhn et. al. has shown adiponectin to have inverse relationship with the risk of endometrial cancer and leptin to have a direct correlation.

   Also, in an inflammatory environment, macrophages secrete potent proinflammatory cytokines such as TNF-α and IL-6, which are known to activate numerous transcription factors that regulate the expression of genes involved in immune responses, anti-apoptosis, angiogenesis, and metastasis. The mechanisms of tumorigenesis are thought to be involved are free-radical production that cause DNA damage and impaired DNA repair.

   Research have further suggested that systemic levels of insulin-like growth factor (IGF) is dysregulated in obesity either due to increased IGF production or by down-regulation of IGF binding protein (IGFBP) production. IGF 1 is a growth and proliferation promotor and has inhibitory effects on cell death and is a major contributor in many neoplastic transformations.

   The above biomarkers are physiologically interrelated and are likely to reflect a more restricted number of underlying biological pathways. Possibly, they work in a synergistic capacity to modulate the risk of developing endometrial cancer. If specific patterns of cytokine expression were found to be predictive of adverse outcome, then the specific receptors may be targeted as a therapeutic option for endometrial cancer11. No study so far has looked at all these markers together in the serum and tissue samples of the same endometrial cancer patients to give a more wholesome idea about their effect on tumour genesis, progression and outcome. Therefore, this study is designed to assess the prognostic significance of these six biomarkers in the blood and tissue of endometrial cancer patients and co-relating the levels with their BMI and tumour type, after adjusting for age, parity, smoking status, menopausal status, use of hormone replacement therapy (HRT)/ hormonal contraception, and prevalence of diabetes and hypertension.
2. RATIONALE

   Development of novel biomarkers for a variety of uses including diagnosis, treatment monitoring and prognostication is on the Cancer Reform Strategy agenda and actively encouraged by the National Cancer Research Institute and Medical Research Council.

   Understanding how adipocytokines influence endometrial cancer risk may help to elucidate biological mechanisms important for the observed obesity-endometrial cancer association.
3. THEORITICAL FRAMEWORK

   As the incidence of endometrial cancer continues to rise there is a health need for a better diagnostic and prognostic approach.

   Studying the different biomarker levels in blood and cancer tissue will enable us to look for new targets that may be useful in the treatment and prognostication of this cancer.

   Also, if the levels of these markers change significantly post-treatment, the investigators can investigate if it will be possible to use these markers to assess response to treatment as follow-up for risk of recurrence forms an important part of the treatment protocol.
4. RESEARCH QUESTIONS / OBJECTIVES:

   To assess the relationship between the endometrial cancer and blood and tissue biomarkers in patients referred for endometrial cancer management to Royal Surrey NHS Foundation trust and to correlate with obesity and tumour characteristics.
5. STUDY DESIGN and METHODS of DATA COLLECTION AND DATA ANALYSIS

   5.1. Study design

   All patients being referred to the Royal Surrey NHS Foundation trust with diagnosed uterine cancer will be given the research information leaflet.

   Initially, an invitation letter will be sent alongside the patients' clinic appointment letter to inform them of the study and give them time for preliminary consideration of the study.

   Patients will then be approached in the outpatients' clinics after the initial consultation by the clinician. They will be given a participant information leaflet detailing the study rationale, methodology and analysis. Patients who agree to participate in the study will be asked to sign a consent form after explanation.

   Demographic data will be collected at the same time to correlate various risk factors associated with the development of uterine cancer. This data will be collected by:
   * A short patient interview (10 minutes)
   * Patients' medical notes Data from the interview will be directly entered into an existing departmental database for Gynaecological oncology which is password protected and stored on NHS computers. A copy of the data proformas from the interview will be filed in a secure room within the University department to allow for source data verification.

   Participants will then have 30mls (2 ½ tablespoons) of venous blood taken on the day of the surgery.

   Tissue samples from the participants undergoing hysterectomy will be collected as follows: the PI will collect any fresh tissue (adipose tissue) directly from theatre before fixing as it is not needed for establishing diagnosis and the uterine cancer tissue and lymph node will be collected by the PI after histo-pathological examination from the histo-pathology department after the diagnosis is established. All tissue processing will adhere to Human Tissue Authority (HTA) guidelines and will be performed at the Oncology laboratory at Leggett building at University of Surrey.

   The participants will have a repeat blood test (30mls) on day 1 post-surgery and at their 3 or 6 months routine post-surgery follow up appointment.

   For those participants who are recommended chemotherapy, the investigators will also ask consent to collect demographic data at the time of consultation and baseline blood sample (30mls venous blood) before commencing chemotherapy and after 3rd and 6th chemotherapy cycles to assess any changes in the biomarkers that may correlate with progression or regression of disease.

   The investigators will also obtain archival tissue blocks (of uterine cancer patients consented from a previous study for use during an appropriate ethics committee approved research) to help increase the number of recruitments for this study. Their demographic data with identification log will be made available to the PI only to assess for correlation between their data and the tissue diagnosis during analysis.

   5.2. Sample analysis

   ELISA will be used to assay bio-marker levels in blood samples.

   For tissue analysis the investigators will set up a tissue microarray (TMA). This will allow more uniform staining of the sample for immunohistochemistry with no inter-specimen variation of the staining method. Each case will be reviewed, and the area of interest (tumour) will be marked on the slide and cores from the areas of interest will be used to create the microarray block. Sections can then be cut from the microarray block and slides prepared for immune staining. The advantage of using this method is that the samples are subjected to the same conditions while being stained and the same part of a tumour can be reliably stained for several markers. Tissue sections from the TMA will be used for immune-staining and the expression of the markers of interest will be scored. Clinical data which is available on the cases will then be correlated with the histological and immunohistochemical scores and statistical analysis will be carried out.

   5.3. Data analysis

   Standard statistical analytical tools will be used to analyse the data. Relation between different variables will be sought with odds ratio, confidence interval and significance with P value (\<0.05 significant). The Mann-Whitney U test will be used to assess differential expression of immune markers between tissue types -blood and tumour tissue. Correlation with clinical characteristics will be determined using univariate log-rank and multivariable Cox proportional hazards adjusting for age, stage, grade and histology.
6. SAMPLE AND RECRUITMENT

Potential participants will be identified in the Royal Surrey NHS Foundation trust - either seen here or referred here and receiving her treatment here for diagnosed endometrial cancer.

6.1. Sample size

The investigators will aim to recruit 30-60 patients with diagnosed endometrial cancer in the study. This sample size will also include archived tissue sample (formerly consented and stored in Leggett building, University of Surrey, for use in future ethical research).

6.2. Recruitment

All patients seen or referred with endometrial cancer at the Royal Surrey Oncology Department will be invited to participate in the study.

Patients will not receive any payments for participation in the study. The investigators aim to obtain all information and samples at the time of routine visits.

6.2.1. Sample identification

Patients diagnosed with endometrial cancer will be identified through the Gynaecological Oncology Multi-Disciplinary Team meeting or by the Gynaecological Oncology or Medical Oncology teams.

6.2.2. Consent

Written consent will be obtained after the patient has received the participant information leaflet and had the opportunity to discuss and ask questions about the study. Enough time will be given for the purpose. Patients must all have capacity to consent. Consent will be undertaken by clinicians on the Gynaecological Oncology team. If necessary, a translator or language line can be used.

Consent will also be taken for use of samples (anonymised and stored in Leggett building, University of Surrey following all regulations by HTA) for use in future research.

Adipocytokines in Endometrial Cancer

Adipocytokines and Their Relationship to Obesity and Endometrial Cancer

All personal information will be anonymised so that researchers except the Principal Investigator (PI) will be blinded to this information. At all times, the NHS Code of Confidentiality will be followed. Only the PI will have access to the 'key' to the patient identifiers connecting the samples to the clinical data of the patients which will be stored in a secured encrypted database on a NHS computer.

Levels of adiponectin and leptin in serum will be measured by ELISA in ng/mL and in the tissues by immunohistochemistry

Levels of adiponectin and leptin in serum will be measured by ELISA in ng/mL

Levels of cytokines- tumour necrosis factor alpha (TNFα) and interleukin 6 (IL-6) will be measured in serum by ELISA in pg/mL and in the tissues by immunohistochemistry

Levels of cytokines - tumour necrosis factor alpha (TNFα) and interleukin 6 (IL-6) will be measured in serum by ELISA in pg/mL

Levels of Insulin like growth factors 1 and 2 (IGF 1 and 2) will be measured in serum by ELISA in ng/mL and in the tissues by immunohistochemistry

Levels of Insulin like growth factors 1 and 2 (IGF 1 and 2) will be measured in serum by ELISA in ng/mL

Levels of biomarkers in serum and tissue will be correlated with obesity (WHO classification of BMI) after adjusting for confounding factors like age, parity, menopause, use of HRT/ hormonal contraception, smoking, diabetes and hypertension, using statistical tools like univariate log-rank and multivariable Cox proportional hazards analysis.

Levels of biomarkers in serum and tissue will be correlated with tumour grade/ stage and type after adjusting for BMI, age, parity, menopause, use of HRT/ hormonal contraception, smoking, diabetes and hypertension, using statistical tools like univariate log-rank and multivariable Cox proportional hazards analysis.

Levels of adiponectin and leptin in serum will be measured by ELISA in ng/mL to measure change from baseline levels

Levels of cytokines - tumour necrosis factor alpha (TNFα) and interleukin 6 (IL-6) will be measured in serum by ELISA in pg/mL to measure change from baseline

Levels of tumour necrosis factor alpha (TNFα) and interleukin 6 (IL-6) will be measured in serum by ELISA in pg/mL to measure change from baseline levels

Levels of Insulin like growth factors 1 and 2 (IGF 1 and 2) will be measured in serum by ELISA in ng/mL to measure change from baseline

Levels of Insulin like growth factors 1 and 2 (IGF 1 and 2) will be measured in serum by ELISA in ng/mL to measure change from baseline levels

Royal Surrey County Hospital NHS Foundation Trust

GRACE Group

University of Surrey

Immune System Diseases

Necrosis

Hypersensitivity

Insulin Resistance

Hyperinsulinism

Metabolic Diseases

Glucose Metabolism Disorders

Hypoglycemic Agents

All Drugs and Chemicals

Insulin

Insulin, Globin Zinc

Metformin

Tablet of 500 mg metformin, oral every 12 hours (total metformin dose of 1 g/day) for 3 months.

Tablet of 500 mg oral placebo every 12 hours for 3 months.

Placebo

Maria L Evia-Viscarra, M.D.

Edel R Rodea-Montero, Statistician

Evelia Apolinar-Jiménez, Nutrition

Leticia M García-Morales, M.D.

Constanza Leaños-Pérez, M.D.

Mireya Figueroa-Barrón, Chemestry

Dolores Sánchez-Fierros, Chemestry

Nathalie Muñoz-Noriega, Nutrition

Juan G Reyes-García, M.D.

The purpose of this study is to compare serum concentrations of inflammatory cytokines, interleukin 6 (IL-6), High-sensitivity C-reactive protein (hs-CRP), adiponectin, and tumour necrosis factor alpha (TNFα), before and after three months treatment with metformin in obese adolescents with insulin resistance (IR).

The increased prevalence of obesity in pediatric patients is a public health problem particularly because of the difficulties involved with changing lifestyles. Current studies of obese children and adolescents show increased insulin resistance (IR) and chronic inflammatory states. These conditions increase the risk of disability and/or premature death.

The current treatment schemes for obese children are conservative and are focused on changing their lifestyles (exercise and dietary plans). However, metabolic conditions, such as IR, dyslipidemia, and inflammatory processes, are perpetuated.

Metformin is a biguanide that is used for adolescents with diabetes mellitus and polycystic ovarian syndrome. Several clinical trials with metformin for obese pediatric patients have observed decreases in IR, decreases in weight, and improvements in lipid metabolism.

Adipose tissue is not only an energy repository, but also plays an immunological role by the secretion of cytokines. Both overweight adults and adolescents show decreases in adiponectin levels and increases in tumor necrosis factor alpha (TNFα) and interleukin 6 (IL-6). IL-6 can stimulate the production of high-sensitivity C-reactive protein (hs-CRP), which is considered to be a risk marker for the development of cardiovascular disease.

Adipokines in Obese Adolescents With Insulin Resistance

Inflammatory Mediators in Obese Adolescents With Insulin Resistance Following Metformin Treatment: Controlled Randomized Clinical Trial

Change from baseline in Adiponectin after 3 months of treatment.

Change from baseline in High-sensitivity C-reactive protein after 3 months of treatment.

Change from baseline in Interleukin 6 after 3 months of treatment.

Change from baseline in Tumour necrosis factor alpha after 3 months of treatment.

Change from baseline in Fasting plasma glucose after 3 months of treatment.

Change from baseline in Fasting insulin after 3 months of treatment.

Change from baseline in Body Mass Index after 3 months of treatment.

Change from baseline in Waist circumference after 3 months of treatment.

Hospital Infantil de Mexico Federico Gomez

Hospital Regional de Alta Especialidad del Bajio

Pediatrics Endocrinology

Total

Age, Categorical

Age Continuous

Sex: Female, Male

Mexico

Region of Enrollment

During the recruitment phase, 83 children who were diagnosed with obesity and acanthosis nigricans were evaluated. Of these, 45 did not have the insulin concentration values (\>15 µU/mL) required to biochemically define Insulin Resistance.

M.D. Maria L. Evia-Viscarra

Adiponectin

High-sensitivity C-reactive Protein

Interleukin 6

Tumour Necrosis Factor Alpha

Fasting Plasma Glucose

Fasting Insulin

Body Mass Index

Waist Circumference

Overall Study

Digestive System Diseases

Gland and Hormone Related Diseases

Rare Diseases

Adenocarcinoma

Pancreatic Neoplasms

Carcinoma

Neoplasms, Glandular and Epithelial

Neoplasms by Histologic Type

Gastrointestinal Neoplasms

Digestive System Neoplasms

Endocrine Gland Neoplasms

Gastrointestinal Diseases

Pancreatic Diseases

Endocrine System Diseases

Pancreatic Cancer

Patients with Adenocarcinoma will be included. They will have blood sample at the inclusion visit and at 3 months, 6 months, 9 months and 12 months after.

Patient with no adenocarcinoma will be included. They will have blood sample at the inclusion visit.

Blood sample

Nicolas WILLIET, MD

Jean-Marc PHELIP, MD-PhD

Lea SABAN-ROCHE, MD

Jean-Marc PHELIP, MD PhD

This study is about pancreatic cancer. If the diagnostic cancer is done at an early stage (\<2cm), the chances of recovery are very good.

But the main problem is there is not any detections means for this cancer. Sadly, when there is a cancer diagnostic , it's already too late in the majority of cases, because the cancer is in an advanced case.

Today, there is no any effective means of detection... Blood markers can be a simple means of early detection

The purpose of this study is to establish a sero-library in a case-control cohort to assess several potentially useful serum biomarkers, such as adiponectin in the early diagnosis of pancreatic cancer.

SERum-bank for PANcreatic Cancer

Measure by blood sample result Serum adiponectin concentration threshold for which the specificity will be 100% for the diagnosis of pancreatic cancer with a sensitivity of 80%.

Measure by blood sample result Threshold for Comparison of diagnostic performance compared to serum adiponectin concentration

Tumor response and progression rates defined according to RECIST v1.1 criteria according to a serum threshold of the prognostic biomarker to be identified by logistic regression analyzes.

Measure by blood sample result Serum adiponectin concentration to correlate with cancer progression or not.

Centre Hospitalier Universitaire de Saint Etienne

Heart and Blood Diseases

Inflammation

Syndrome

Metabolic Syndrome

Microvascular Angina

Abdominal Obesity Metabolic Syndrome

Anti-Inflammatory Agents

Antirheumatic Agents

Analgesics

Gastrointestinal Agents

Etanercept

Anti-Inflammatory Agents, Non-Steroidal

Analgesics, Non-Narcotic

Immunosuppressive Agents

Immunologic Factors

Steven K Grinspoon, MD

Metabolic syndrome is associated with increased inflammatory cytokines and reduced adiponectin, that may be mediated in part by TNF production from abdominal fat. We reasoned that an anti-TNF agent would reduce C-reactive protein (CRP) and increase adiponectin, improving the inflammatory milieu associated with metabolic syndrome.

Screening visit 1:

Fifty six patients will be randomized to receive etanercept or identical placebo. During the screening visit, after informed consent is obtained, subjects will undergo a medical history and physical exam, which will include vital signs, weight, abdominal girth measurements and an evaluation for signs of underlying infection. A purified protein derivative (PPD) of 5 tuberculin units (TU) (0.1 milliliter of 5 TU/0.1 ml solution) will be intradermally placed to test for the presence of tuberculosis (TB). Fasting blood work will include a complete blood count (CBC), glucose, insulin, a cholesterol panel, and urine pregnancy test. Subjects will be shown what a subcutaneous injection entails using placebo. Patients will be selected based on their laboratory results, abdominal girth measurements and PPD negativity 48 hrs after placement.

Screening visit 2:

Subjects will return 48 hours after their first screening visit for evaluation of their PPD test. In the event of a positive PPD, subjects will be excluded from the study, and their primary care physicians will be notified of their test result.

Day 1 visit:

Subjects will report to Massachusetts General Hospital (MGH) or Massachusetts Institute of Technology (MIT) Clinical Research Center (GCRC) after an overnight fast. Fasting blood work will be obtained to test for CRP, adiponectin, IL-6, TNF-alpha, TNF-alpha receptor 1, TNF-alpha receptor 2, free fatty acids, glucose, insulin and a cholesterol panel, and CBC. A urine pregnancy test will be done. Patients will be asked to recall the food they consumed over the past 24 hours. A bionutritionist will measure height, weight, waist, hip, chest, arm, neck and thigh circumference. Subjects will be instructed to practice adequate birth control throughout the study. Serum will be stored for etanercept antibody testing.

Subjects will then undergo an insulin modified frequently sampled intravenous (IV) glucose tolerance test (FSIGT) as initially developed by Bergman et al.

Dual energy x-ray absorptiometry (DEXA) (Hologic QDR 4500) will be used to determine whole body and regional fat. The technique has a precision error (1 SD) of 3% for whole body fat and 1.5% for lean mass. Subjects will also undergo a single thin-slice CT scan of the abdomen at L4 vertebral body to determine visceral and subcutaneous fat area.

Indirect calorimetry for the measurement of resting energy expenditure indirect calorimetry using the Deltatrac instrument (Sensormedics, Anaheim, CA) will be carried out.

Drug administration:

Patients will be given a total of either etanercept 50 mg subcutaneously or placebo subcutaneously at the GCRC at the end of their visit. They will receive this in two injections of 25 mg each, one given immediately following the other, at different body sites. Etanercept will be supplied as a sterile, white, preservative-free, lyophilized powder. The pharmacy will reconstitute it with 1 mL of the supplied sterile bacteriostatic water for injection (BWFI), United States Pharmacopeia (USP) (containing 0.9% benzyl alcohol). Each vial of etanercept contains 25 mg etanercept, 40 mg mannitol, 10 mg sucrose, and 1.2 mg tromethamine. Subjects will receive the 50 mg dose of etanercept or placebo once a week, given as two 25 mg injections, one immediately following the other, at different body sites, at each of their ensuing three visits to the GCRC, on Visit Day 8, Visit Day 15 and Visit Day 22. Subjects will be monitored for 30 minutes after the injection of study drug at each visit. The skin injection site will be observed and their vital signs will be taken. If a subject has a significant exposure to varicella virus during the study, transient termination of the study will be considered.

Day 8 visit, Day 15 visit, Day 22 visit:

Subjects will report to MGH or MIT Clinical Research Center after an overnight fast. Each subject will undergo a history and physical exam to assess for safety and compliance. Fasting blood work will be obtained. A bionutritionist will measure subjects' height, weight, hip and waist circumference and calculate a waist to hip ratio. They will receive 50 mg of either etanercept or placebo, given as two 25 mg doses subcutaneously, at different body sites.

Day 25 visit:

Subjects will report to MGH or MIT Clinical Research Center after an overnight fast. Each subject will undergo a history and physical exam to assess for safety and compliance. Blood work, a urine pregnancy test and 24 hour food recall will be collected, identical to that on Day 1 visit. Anthropomorphic measurements will be the same as the Day 1 visit. Subjects will undergo an intravenous glucose tolerance test (IVGTT) identical to that on the Day 1 visit. Subjects will undergo a DEXA, bioelectric impedance analysis (BIA), and CT, and indirect calorimetry identical to those on the Day 1 visit. No study drug will be administered at this visit.

Effects of Tumor Necrosis Factor (TNF)-Alpha Antagonism in Patients With Metabolic Syndrome

Massachusetts General Hospital

National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)

Polycystic Ovary Syndrome

Cysts

Ovarian Cysts

Ovarian Diseases

Adnexal Diseases

Gonadal Disorders

Androgens

Testosterone

Women with polycystic ovaries, oligo or anovulation and hyperandrogenism.

Women with polycystic ovaries and oligo or anovulation without hyperandrogenism

Women with normal ovaries, oligo or anovulation and hyperandrogenism

Total testosterone, bioavailable testosterone, Free androgen index, Total cholesterol, LDL Cholesterol, HDL Cholesterol, Triglycerides, insulinemia, OGTT, HOMA index, Adiponectin, C Reactive Protein

Blood samples, transvaginal ultrasound

Paula S Mereshian, MD

Carolina Fux Otta, MD

Marta Fiol de Cuneo, MD

Polycystic ovary syndrome (PCOS) is a very frequent endocrine disease of women in reproductive age, with an estimated prevalence of 5 to 10 % according to the studied population. In 2003 a committee of experts joined in Rotterdam under the auspice of the American Society for Reproductive Medicine and the European Society for Human Reproduction and Embryology, defined diagnostic criteria. It should include unless two of the following: menstrual irregularities; excess of male hormones (clinic or biochemical) and polycystic ovaries under ultrasound examination; giving rise to four subgroups or phenotypes:

1- Women with polycystic ovaries, hyperandrogenism and oligoamenorrhea . 2. Women with normal ovaries, hyperandrogenism and oligoamenorrhea. 3- Women with polycystic ovaries, oligoamenorrhea without hyperandrogenism. 4- Women with polycystic ovaries, hyperandrogenism with normal menses. PCOS shares components of Metabolic Syndrome for the high prevalence of insulin resistance (abdominal obesity, impaired glucose tolerance, type 2 diabetes, hypertension, endothelial dysfunction, impaired lipid profile and probably cardiovascular disease). All these findings lead us to assume that women with PCOS could have an increased risk of developing cardiovascular disease. Nevertheless it is premature to assume that every PCOS phenotype has the same cardiac and metabolic risk factors. So, it is important to evaluate the endocrine and metabolic characteristic in different phenotypes of PCOS to prevent the co morbidities that predispose to cardiovascular disease. And of course to avoid unnecessary measures in groups that could not show increased risk.

Polycystic ovary syndrome (PCOS) is a very frequent endocrine disease of women in reproductive age, with an estimated prevalence of 5 to 10 % according to the studied population.

Its cause remains not fully understood. PCOS is characterized by hyperandrogenism, chronic anovulation and / or polycystic ovaries. Patients, in a high percentage of cases show obesity, hirsutism, acne, menstrual irregularities and infertility. Clinically and biologically PCOS is a heterogeneous disorder with a not yet clear pathogenesis. Therefore, discussions on its definition and diagnosis still subsist. Seventy years ago Stein and Leventhal published their findings in 7 women with amenorrhea, hirsutism, acne, obesity and polycystic appearance of their ovaries. Since then, diagnostic criteria for PCOS suffered multiple modifications.

In 1990 a group of experts under the auspices of the National Institutes of Health (NIH) considered affected by PCOS every woman with hyperandrogenism and chronic anovulation; after having excluded other specific diseases that mimic that clinic like Cushing's syndrome, androgen secreting tumors and congenital adrenal hyperplasia (NIH criteria). The presence of polycystic ovaries under ultrasound exploration was considered controversial criteria and was not included for diagnosis. In May 2003 a new committee of experts joined in Rotterdam under the auspice of the American Society for Reproductive Medicine (ASRM) and the European Society for Human Reproduction and Embryology (ESHRE), included polycystic ovaries by ultrasound to the physiologic abnormalities for diagnosis. Thus, diagnosis should include unless two of the following: oligo or anovulation; hyperandrogenism (clinic or biochemical) and polycystic ovaries under ultrasound examination.

Rotterdam consensus widened the definition already proposed by NIH in 1990 giving rise to four subgroups or phenotypes:

1- Women with polycystic ovaries, hyperandrogenism and oligoamenorrhea. 2. Women with normal ovaries, hyperandrogenism and oligoamenorrhea. 3- Women with polycystic ovaries, oligoamenorrhea without hyperandrogenism. 4- Women with polycystic ovaries, hyperandrogenism with normal menses. This new criteria increase de prevalence, diversity and also controversy about PCOS. Some authors like Franks accept that the new consensus gave significant advances in the etiological knowledge of the syndrome. Others, like Azziz, proposed that is premature to include ovulating women and the ones with no clear evidence of androgens excess. In the last subgroups is no clear if they have an increased risk of cardiovascular and / or metabolic diseases.

The clinical heterogeneity of the syndrome is the product of a multifaceted process; where converge genetic and environmental influences. Many hypotheses try to explain the primary defect; but insulin resistance (IR) seems the most suitable according to most of studies. IR is present in 60 to 70 % of patients independently of obesity. Compensatory hyperinsulinism has a fundamental role in the pathology of PCOS. In vitro insulin stimulates androgen synthesis in ovary theca cells, acting on its own receptor and inhibits hepatic synthesis of sex hormone binding globulin (SHBG), increasing free testosterone. It also leads to the amplification of LH induced expression of cytochrome P450c 17 alfa (a limiting enzyme in androgen synthesis).

PCOS shares components of Metabolic Syndrome for the high prevalence of IR (abdominal obesity, impaired glucose tolerance, type 2 diabetes, hypertension, endothelial dysfunction, impaired lipid profile and probably cardiovascular disease). Dunaif and Sam using NIH criteria for PCOS diagnosis suggested a sole entity called XX syndrome. Central adiposity seems to play an important role in the development of this metabolic phenotype trough the production of many cytokines and adipocytes derived proteins, known as "adipocytokines". Failures on its regulation could contribute to the development of IR. The late one for itself or trough metabolic disturbances is associated with endothelial dysfunction and atherosclerosis.

Adiponectin is exclusively secreted in adipose tissue and could inhibit the expression of vascular endothelial adhesion molecules induced by TNF-alfa. So, it could be an anti atherogenic effect of adiponectin. In obese subjects and those with type 2 diabetes and IR (whom has a high incidence of coronary atherosclerosis) it was found low plasma levels of adiponectin. Recent studies propose low serum levels of adiponectin as an early marker for metabolic risk in women with PCOS.

C Reactive Protein (CRP), a low grade inflammation marker, has been suggested as an independent predictor of cardiovascular event in women; even more relevant than LDL cholesterol. Those facts have been reassured in the recent publication of Reynolds risk score which adds to the classical ATP III´s Framingham score; the usage of CRP in women, increasing its prognostic value. Higher levels of CRP have been described in women with PCOS compared with normal controls.

All these findings lead us to assume that women with PCOS have an increased risk of developing cardiovascular disease. As there is no universally accepted definition for PCOS, studies that show an association between PCOS and cardiovascular disease are of relative value. Legro stated that "It is premature to assume that every PCOS phenotype has the same cardiac and metabolic risk factors".

So, it is important to evaluate the endocrine and metabolic characteristic in different phenotypes of PCOS to prevent the co morbidities that predispose to cardiovascular disease. And of course to avoid unnecessary measures in groups that could not show increased risk.

Evaluation of Endocrine and Metabolic Parameters in the New Diagnostic Phenotypes of Polycystic Ovary Syndrome

Descriptive, Transversal Study of Evaluation of Cardiovascular Risks Factors and Prevalence of Metabolic Syndrome in the Different Phenotypes of Women With Polycystic Ovary Syndrome

Fundación Florencio Fiorini

Universidad Nacional de Córdoba

Carolina Fux Otta

Rectal Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Intestinal Diseases

Rectal Diseases

Level of serum adipokines will be measured with flow cytometry

serum adipokines

Cihad Tatar, MD

Cihad Tatar

Husnu Sevik, MD

It has been shown that adipokines (resistin, leptin, adiponectin) secreted from adipose tissue and proinflammatory cytokines such as IL-6, TNF-a are associated with the risk of developing colorectal cancer. However, the role of these factors in predicting clinical response to neoadjuvant therapy in rectal cancers is unknown. In this study, the role of serum adipokine levels before neoadjuvant therapy in predicting clinical response in patients with rectal cancer is investigated. For this purpose, blood will be drawn from patients with rectal cancer who will receive neoadjuvant therapy, serum adipokines will be studied and clinical response to neoadjuvant therapy will be compared.

The Role of Serum Adipokines in Predicting Response to Neoadjuvant Therapy in Patients With Rectal Cancer

The Adiponectin, Adipsin, Leptin, Resistin levels will be measured with flow cytometric analysis.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Adipocytokines in Endometrial Cancer	NCT04697264	Endometrial Can... Obesity	Blood and tissu...	-	University of Surrey
Adipokines in Obese Adolescents With Insulin Resistance	NCT01410604	Obesity	Metformin Placebo	9 Years - 18 Years	Hospital Regional de Alta Especialidad del Bajio
SERum-bank for PANcreatic Cancer	NCT04374175	Adenocarcinoma	Blood sample	18 Years -	Centre Hospitalier Universitaire de Saint Etienne
Effects of Tumor Necrosis Factor (TNF)-Alpha Antagonism in Patients With Metabolic Syndrome	NCT00111956	Metabolic Syndr...	Etanercept Placebo	18 Years - 55 Years	National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Adipokines in Obese Adolescents With Insulin Resistance	NCT01410604	Obesity	Metformin Placebo	9 Years - 18 Years	Hospital Regional de Alta Especialidad del Bajio
Evaluation of Endocrine and Metabolic Parameters in the New Diagnostic Phenotypes of Polycystic Ovary Syndrome	NCT00784615	Polycystic Ovar...	Blood samples, ...	18 Years - 35 Years	Universidad Nacional de Córdoba
Adipokines in Obese Adolescents With Insulin Resistance	NCT01410604	Obesity	Metformin Placebo	9 Years - 18 Years	Hospital Regional de Alta Especialidad del Bajio
SERum-bank for PANcreatic Cancer	NCT04374175	Adenocarcinoma	Blood sample	18 Years -	Centre Hospitalier Universitaire de Saint Etienne
The Role of Serum Adipokines in Predicting Response to Neoadjuvant Therapy in Patients With Rectal Cancer	NCT04598984	Rectal Cancer S...	serum adipokine...	18 Years -	Istanbul Training and Research Hospital

Spots Global Cancer Trial Database for adiponectin

Every month we try and update this database with for adiponectin cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for adiponectin

Every month we try and update this database with for adiponectin cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for adiponectin cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.