Nutritional and Metabolic Diseases

All Conditions

Symptoms and General Pathology

Neoplasms

Digestive System Diseases

Wasting Syndrome

Cachexia

Gastrointestinal Neoplasms

Digestive System Neoplasms

Syndrome

Weight Loss

Body Weight

Body Weight Changes

Thinness

Metabolic Diseases

Nutrition Disorders

Gastrointestinal Diseases

Central Nervous System Depressants

All Drugs and Chemicals

Anesthetics

Patients with cancer of digestive system requiring resection surgery will be included. They will have measure of height and weight, blood samples, skeletal muscle force, skeletal muscle index and muscle biopsy.

V1: Inclusion will be effectuated at the time of anaesthetic consultation V2: The day before and day of resection surgery about 1 month after V3: Follow-up at 1 month V4: Follow-up at 3 months V6: Follow-up at 6 months

Height and weight will be measured to estimate cachexia degree at the time of anaesthetic consultation. (V1)

Height and weight

Blood samples will be collected for measuring myostatin on blood at the time of anaesthetic consultation, the day before resection surgery, follow-ups at 1, 3 and 6 months. (V1, V2, V3, V4, V6)

Blood samples

Skeletal muscle force will be determined from Computerized Tomography (CT)-scan at the time of anaesthetic, follow-ups at 1, 3 and 6 months. (V1, V3, V4, V6)

Skeletal muscle force

Skeletal muscle index will be determined from Computerized Tomography (CT)-scan at the time of anaesthetic, follow-ups at 1, 3 and 6 months. (V1, V3, V4, V6)

Skeletal muscle index

Muscle biopsy will be performed during resection surgery under general anaesthesia. (V2)

Muscle biopsy

Karine ABBOUD, MD

Cancer cachexia is responsible for the death of approximately 20% of patients. Myostatin is a master negative regulator of skeletal muscle mass. If the role of myostatin in cancer cachexia is now well established in murine models, no study has focused on muscle expression of Myostatin in relation to the degree of cachexia. the hypothesize is that muscle Myostatin a biological marker of cachexia in patients with cancer of digestive system. The main objective is to compare skeletal muscle Myostatin messenger RiboNucleic Acid (mRNA) level as a function of cachexia in cancer of digestive system patients. Myostatin messenger RiboNucleic Acid (mRNA) level will be determined in a muscle sample taken during the resection under general anaesthesia. Skeletal muscle index will be determined before surgery, 3 and 6 months after surgery. Muscle strength of the lower and upper limbs will be determined before resection, at 1 month, 3 months and 6 months postoperatively. Blood sampling will also be performed on these 4 occasions.

Skeletal Muscle Expression of Myostatin and Cancer of Digestive System Associated Cachexia

Skeletal Muscle Expression of Myostatin and Cancer of Digestive System Associated Cachexia(MYOCAC Study)

Evaluate correlation between skeletal muscle force/index and degree myostatin. Skeletal muscle force/index will be determinated by skeletal muscle force/index results.

Degree myostatin will be determinated by blood samples with Enzyme Linked ImmunoSorbent Assay (ELISA) method.

Evaluate Correlation between skeletal muscle force and index before resection surgery to estimate the extent of cachexia-induced muscle dysfunction by results tests.

Evaluate correlation between level of myostatin muscular expression and degree myostatin.

Level of myostatin muscular expression will be determinated by muscle biopsy. Degree myostatin will be determinated by blood samples with Enzyme Linked ImmunoSorbent Assay (ELISA) method.

Determinate correlation between level of myostatin muscular expression and skeletal muscle force and index after resection surgery.

Analysis level of myostatin muscular expression and blood samples results according to cancer stage, neoadjuvant treatment and chemotherapy.

Centre Hospitalier Universitaire de Saint Etienne

Gland and Hormone Related Diseases

Musculoskeletal Diseases

Nervous System Diseases

Rare Diseases

Pheochromocytoma

Cushing Syndrome

Muscular Diseases

Endocrine System Diseases

Hyperaldosteronism

Neuromuscular Diseases

Paraganglioma

Neuroendocrine Tumors

Neuroectodermal Tumors

Neuroectodermal Tumors, Primitive

Neoplasms, Germ Cell and Embryonal

Neoplasms by Histologic Type

Neoplasms, Nerve Tissue

Adrenocortical Hyperfunction

Adrenal Gland Diseases

Cushing's Syndrome

Paragangliomas 1

Neuroendocrine Tumor

Neuroepithelioma

Hyperadrenalism

Coagulants

Hemostatics

Anesthetics, General

Patients with Cushing's syndrome treated medically prior to adrenalectomy

Patients with PPGL treated medically prior to adrenalectomy

Patients with Conn's syndrome treated medically prior to adrenalectomy

Patients will have muscle biopsies taken at time of surgery under general anaesthetic. Open biopsies from the operation field (abdominal wall) will be taken by the surgical team without extending or making new skin incisions. Briefly, muscle samples (approximately 0.5cm3) are excised and haemostasis secured. The muscle biopsies will be snap frozen and stored at -80°C for the analysis of pathways relevant to muscle homeostasis using biochemical and molecular techniques.

Mark J Griffiths, MB BS

Endocrine diseases including Cushing's syndrome and phaeochromocytoma/paraganglioma (PPGL) but not Conn's syndrome are associated with muscle wasting and weakness. The study's aim is to identify epigenetic determinants of muscle homeostasis in these conditions following medical treatment and adrenalectomy. This is an observational pilot study that will recruit 66 patients from 3 diagnostic groups: Cushing's syndrome (16), PPGL (20) and Conn's syndrome (30). Indices of muscle bulk and strength will be assessed at diagnosis and at outpatient follow-up 6-9 weeks after adrenalectomy. At these times blood and urine will be collected and a muscle biopsy taken from the operation site at the time of surgery. Pathway analysis in these samples will identify potentially novel signalling pathways contributing to muscle wasting via prolonged exposure to high levels of corticosteroid and catecholamines. This will highlight commonalities and differences in pathogenesis of muscle wasting from a variety of different causes. Finally, it will inform identification of novel therapies for muscle atrophy.

Muscle wasting and weakness is important because it accounts for a large proportion of the disability associated with disease and normal aging. The annual economic cost in the USA alone has been estimated at $1.8 billion.

The investigators have studied muscle wasting associated with chronic and acute illness, finding a marked dissociation between wasting and disease severity. This indicated that epigenetic and genetic factors may contribute to individual susceptibility to wasting. To analyse factors controlling muscle mass, the investigators have developed a novel clinical model of muscle loss. Hence, in patients undergoing aortic surgery, a large insult is imposed on patients with a background of a disease that leads to muscle wasting (reduced cardiac function). As the timing of the insult is known, the investigators can follow muscle wasting longitudinally. Our recent work using this model has characterised novel muscle signalling pathways that mediate muscle breakdown. Specifically, the investigators found that 50% of patients undergoing cardiac surgery lose significant muscle mass (\>10% in the "wasters" group) in the 7 days after uncomplicated surgery, which correlated with loss of strength 7-9 Expression of microRNAs (miRNAs) from imprinted loci (C19MC miRNAs and miR-675) in muscle biopsy samples was strongly associated with subsequent muscle wasting and weakness. Furthermore, expression of these miRNA in myoblasts and animal models confirms their effects on muscle and suggests modes of action through transforming growth factor signalling pathways, ribosome assembly and mitochondrial function. Finally, metabolomic analysis of plasma samples from these patients suggested that exposure to higher levels of active intrinsic corticosteroid, a known cause of sarcopenia, was correlated with muscle loss. Acute muscle wasting (ICU acquired weakness) is associated with high levels of corticosteroids, owing to a defect in deactivation, and shock which is countered with high doses of catecholamines. The investigators will measure miR expression, and longitudinal muscle bulk and strength in patients undergoing adrenalectomy at SBH.

Group 1: Cushing's syndrome caused by very elevated levels of corticosteroids, associated with severe wasting.

Group 2: Phaeochromocytoma and paraganglioma (PPGL) caused by very elevated levels of catecholamines, associated with moderate wasting.

Group 3: Conn's syndrome caused by elevated mineralocorticoid, not associated with muscle wasting (Control group) All patients will be assessed at diagnosis, after medical treatment and after completed reversal of the defect after surgery. Various measures of focal and global strength and function will be recorded alongside measures of muscle bulk. A muscle biopsy from the wound site will be taken at surgery.

One of the key epigenetic determinants of muscle wasting in acute and chronic conditions is micro-RNA (miR-) 424, which targets ribosome synthesis and function as well as insulin sensitivity. The promotor for its' large non-coding RNA precursor contains a steroid responsive region. Therefore overall, the investigators expect miR-424 expression to be correlated with muscle wasting across the 3 patient groups. Mi-RNA profiles will be generated in patient blood and muscle samples: our previous studies have shown that muscle expression of selected mi-RNA is a strong predictor of the response to injury and in patients with chronic respiratory failure (COPD) corresponding circulating levels can be measured in contemporaneous blood samples.

A predictive biomarker (miR expression in blood) would allow a personalised approach to clinical trials for anti-muscle atrophy therapies. The miRNA profiles in blood associated with muscle wasting are likely to be useful predictive biomarkers for several conditions associated with sarcopenia, as evidenced by previous miRNA sets associating with muscle phenotype in COPD and in patients undergoing cardiac surgery.

Pathway analysis will identify potentially novel signalling pathways contributing to muscle wasting via prolonged exposure to high levels of corticosteroid or increased inflammatory sensitivity. This will highlight commonalities and differences in pathogenesis of muscle wasting from a variety of different causes. Finally, it will inform identification of novel therapies for muscle atrophy.

Insensitivity to insulin is a hallmark of many acute and chronic diseases, and a feature of metabolic syndrome. The investigators will be able to determine the potential role of high circulating levels of miR-424, which could constitute a novel therapeutic approach to type 2 diabetes. Similarly, owing to the multi-system insult of cardiac surgery our patient cohorts suffered acute kidney injury and systemic inflammation requiring vasopressors. These data have been collected and could be mined in the future to identify epigenetic determinants and pathways associated with these outcomes.

Abdominal wall muscle biopsy Blood and urine

Metabolic Myopathy in Endocrinopathy

Prospective Observational Study of Metabolic Myopathy in Cushing's Syndrome or Pheochromocytoma Patients Undergoing Adrenalectomy

RFcsa will be calculated using B-mode ultrasound (US) at pre-determined time points

Hand-held dynamometry will be assessed in both hands (the maximum of 3 attempts)

The test will be conducted using a Lafayette Manual Muscle Tester. Joint knee moment (torque) and strength will be measured.

SPPB is a measure of patients' functional status: scores range from 0 (worst performance) to 12 (best performance).

Lying and standing vital capacity will be measured using a hand held spirometer

Indices of body composition will be measured by electrical impedance.

Pixel intensity is a measure of muscle quality measured by B mode ultrasound

Unbiased RNA sequencing of plasma samples and targetted qPCR for micro RNAs

Mass spectroscopy based unbiased metabolic screen in plasma

Imperial College London

Queen Mary University of London

Barts & The London NHS Trust

Pancreatic Neoplasms

Endocrine Gland Neoplasms

Pancreatic Diseases

Pancreatic Cancer

Gastrointestinal Agents

Pancrelipase

Pancreatin

During the surgical resection for the pancreatic cancer a muscle tissue biopsy sample will be performed.

During surgical resection for patients with benign right upper quadrant pathology, a muscle tissue biopsy sample will be performed.

During surgical resection, to enter the abdominal cavity, anterior muscle groups such as the rectus abdominous muscle. This group of muscle is divided. During division, muscle fibers are released from fascial group and discarded off the operative field. This will be the target for specimen collection.

Muscle Tissue Biopsy Sample

Andrew Judge, PhD

The relationship between myopenia, nutritional status, and long-term oncologic outcomes remains poorly characterized in patients with anatomically resectable pancreatic cancer (PC). The investigators want to look at muscle properties in pancreatic cancer patients to determine possible therapeutic options toward better nutritional status. Patients with benign right upper quadrant pathology will be utilized as controls for the study.

The researchers hypothesize that improving cancer cachexia in PC will improve the quality of life and ultimately increase overall survival. The long term goal of is to identify areas of intervention to prevent and/or improve cachectic events in PC in order to significantly improve clinical outcomes. The first step in this long term goal is to fully characterize cachexia in the condition of PC. This research is to understand and modify the local response within skeletal muscle leading to a clinically relevant persistent wasting and to understand and interrupt the systemic stimulus produced by the tumor local environment resulting in these muscle specific mechanisms.

Cancer cachexia (CC) is a devastating condition affecting up to 80% of cancer patients, diminishing quality of life and contributing to increased mortality. Cancer cachexia is a complex metabolic syndrome characterized by the loss of skeletal muscle mass and weakness. The muscle pathology of cancer cachexia is not only related to muscle atrophy but also to disruptions to the contractile apparatus of the muscle. While physiologic disruptions in muscle sarcomere and myofiber membrane integrity have been observed despite the lack of injury, the totality of the muscle specific mechanisms contributing to these phenotypes have not been described, nor investigated in the context of pancreatic cancer (PC) where cachexia is a significant clinical problem. Therefore, delineating specific mechanisms of muscle catabolism in PC is critical to developing clinical therapies to control wasting and improve patient quality of life, clinical outcomes and long-term survival.

A variety of tumor promoting and inflammatory cell signaling pathways have been implicated in cancer cachexia, whereby pro-inflammatory cytokines have been implicated as a driving force. Remarkably, approximately half of all patients with PC demonstrate a measurable acute phase response, which is associated with poor clinical outcomes. Importantly, systemic elevations of these inflammatory mediators are due to a complex local interplay between the developing tumor and the immune system which subsequently leads to a systemic chronic inflammatory state. PC appears to manipulate the immune system to promote its survival at the expense of nutritional stores which results in cachexia. Therefore, understanding of the local and systemic inflammatory response in PC and its relation to muscle specific mechanisms is crucial to developing effective therapies for cancer cachexia.

PC associated cachexia results in a significant therapeutic dilemma. Local approaches such as surgery for curative intent encounter a high recurrence rate which is indicative of the systemic nature of even very early-stage disease. Therefore, systemic therapies are necessary for long-term survival. Unfortunately, effective chemotherapies are only offered to patients with good clinical parameters such as nutritional status. In other words, if the patient is too weak, they are not offered effective therapies for the risk of causing more harm than good.

The Role of Muscle Cachexia in Pancreatic Cancer

To look at the extent of ultrastructural abnormalities in the skeletal muscle by histologic examination of muscle biopsies

2) identify the growth and atrophy-related transcription factors associated with the muscle pathology and 3) identify the genome-wide gene networks and biological process associated with skeletal muscle pathology in surgically resected PC patients and healthy control patients by RT-PCR and histologic staining of tissues for transcriptional factors associated with cachexia.

RT-PCR of RNA from biopsied muscle tissues

Clinical assessment at treatment follow-up

Clinical assessment at treatment follow-up and radiographic measurements of muscle groups on routine surveillance for cancer recurrence or advancement

Pathologic specimen at time of resection to determine extent of pathologic stage which is routine

Noted at pathologic assessment and part of routine examination

The V Foundation for Cancer Research

National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)

University of Florida

Carcinoma

Colorectal Neoplasms

Intestinal Neoplasms

Colonic Diseases

Intestinal Diseases

Rectal Diseases

Anesthetics, Local

The exercise regime consists of 10 sessions of exercise against a constant load, each lasting 60 seconds, separated by 60 seconds of recovery eliciting 90% maximal heart rate. The 6 sessions are held over a 2 week period.

Exercise programme

muscle biopsy under local anaesthetic taken from the thigh, again for analysis and storage 3 times: before, during and after the exercise programme

Tamas Hickish, FRCP

This pilot study looks to explore the biological effects of exercise on cancer and muscle cells using a two week exercise program (HIThigh intensity training) on 20 patients with newly diagnosed and operable colorectal cancer following diagnosis and prior to surgery. Maximal oxygen uptake will also be measured. The aim of this pilot is to assess the feasibility of recruiting participants to and carrying out a two week preoperative exercise program in patients with colorectal cancer.

Patients undergoing investigation for symptoms of colorectal cancer presenting to the hospital will undergo standard diagnostic procedures. Once resectable nonmetastatic cancer has been diagnosed (i.e. cancer that has not spread beyond the bowel), is amenable to surgical resection as decided by the colorectal multidisciplinary and if the patient fulfills the selection criteria, they will be asked if they wish to participate in the study. They will be given information regarding the study at the time of diagnosis. If they give their consent then a formal consenting process will take place at the next routine appointment.

During this appointment the patient will have the opportunity to ask questions. A member of the study team will explain the study in detail, answer any questions potential participants (and their partners/ carers) have. The patient is free to refuse participation or withdraw from the study at any time without this affecting their care, this is explained in the information and will be discussed further at the time of informed consent. If the patient agrees to participate in the trial, following the provision of informed consent and before embarking on the exercise programme they will need to fill in two questionnaires, the International Physical Activity Questionnaire (Long) and Dietary Intervention in Primary Care Questionnaire (DINE). They will be counseled to try and maintain their normal exercise level and their calorie intake. Blood samples will also be taken, analyzed and stored for further analysis including possible genetic analysis at a later stage before starting the exercise regime. They will have a muscle biopsy under local anaesthetic taken from the thigh, again for analysis and storage.

Participants will undergo an initial assessment of their baseline exercise ability and oxygen absorption using an upright exercise bike with concurrent ECG readings and breath analysis. The two week preoperative exercise regime will be planned depending on the patient's operation date. The exercise regime consists of 10 sessions of exercise against a constant load, each lasting 60s, separated by 60s of recovery eliciting 90% maximal heart rate.

The 6 sessions are held over a 2 week period. Each patients exercise ability and oxygen absorption will be remeasured at the end of the 2 week period and a second sample of blood taken for comparison. During the operation a sample of adipose tissue near the tumour site will be taken separately to the main sample. A muscle biopsy from the thigh will also be taken at the same time. As a standard of clinical care all patients are reviewed in the outpatient setting 6 weeks postoperatively. When patients attend this follow up appointment a final blood test and muscle biopsy (under local anaesthetic) will be taken to assess the longer term effects of the exercise program. Patient consent will be sought for this separately although it will be discussed at the initial introduction to the study.

Patients are free to withdraw from the study at any time and if there are any adverse events or concerns regarding the continuation of the study for a patient then they will be withdrawn.

EDICT - Exercise inDuced Changes In Colorectal Cancer Tissues

Clinical and Biological Effects of a Preoperative Exercise Programme in Colorectal Tumour and Skeletal Muscle Tissues (Exercise inDuced Changes In Colorectal Cancer Tissues)

To assess the feasibility of carrying out a two week preoperative exercise program in patients with colorectal cancer and to assess the effects of preoperative exercise on the proliferation of colorectal cancer cells by measuring the change in the percentage of cells staining positive for Ki67 (a measure of cell proliferation).

Measuring changes in molecular markers for the effects of exercise and/or diet on AMPK/mTOR signalling pathway (phosphorylated 4EBP1 (P4EBP1), phosphorylated protein kinase B (PPKB/AKT), and phosphorylated AMPK (PAMPK).

Measuring changes in AKT expression normal colonic tissue - Intensity of AKT1/AKT2 staining, or AKT phosphorylation, a marker of insulin receptor signalling in cells.

Assessing Apoptosis index - Percentage of tumour cells staining positive for DNA fragmentation, a marker of cells undergoing apoptosis and therefore cell death.

Measuring changes in molecular markers that may mediate or modify exercise/dietary effects in tumour tissues (IR, IGF1R, p53 and its transcriptional target p21, ER, progesterone receptor, tumor necrosis factor-alpha converting enzyme and TIMP3).

Assessing gene expression profiles focusing on gene associated with insulin resistance.

Assessing the 11 gene signature that help to predict maximal oxygen uptake gain in patients before and after exercise

Cortisol levels to evaluate levels of biological stress.

Postoperative complications up to 30 days postoperatively

Moderator variables including state of motivational readiness for exercise, weight change, depression and anxiety

The Royal Bournemouth Hospital

Skin and Connective Tissue Diseases

Breast Neoplasms

Breast Diseases

Skin Diseases

Acute Graft Versus Host Disease

Antineoplastic Agents

Antirheumatic Agents

Anti-Infective Agents

Paclitaxel

Albumin-Bound Paclitaxel

Cyclophosphamide

Epirubicin

Tubulin Modulators

Antimitotic Agents

Immunosuppressive Agents

Immunologic Factors

Antineoplastic Agents, Alkylating

Alkylating Agents

Anti-Bacterial Agents

Antibiotics, Antitubercular

Enzyme Inhibitors

Woman with early breast cancer receiving a first cycle of epirubicin-cyclphosphamide

Woman with early breast cancer receiving a first cycle of paclitaxel

Epirubicin-cyclophosphamide

Chemotherapy treatments such as epirubicin-cyclophosphamid or paclitaxel lead to severe off-target side effects such as skeletal muscle deconditioning. To date, three different studies investigated skeletal muscle decontioning in breast cancer patients, through long term protocols including all chemotherapy cycle treatment, and highlighted both structural alterations and impaired cellular processes. However, no study is currently availbale on the acute effect of one single chemotherapy administration in breast cancer patients skeletal muscle tissue. Our study is therefore dedicated to the investigation of the acute effect of the first dose administration of both Epuribicin/cyclophosphamide and Paclitaxel chemotherapies on skeletal muscle of breast cancer patients.

Chemotherapy treatments such as epirubicin-cyclophosphamid or paclitaxel lead to severe off-target side effects such as skeletal muscle deconditioning. Resulting from a global perturbation of the muscle homeostasis, skeletal muscle is characterized by both structural and functional alterations that will translate into a decrease in muscle mass and/or force as well as an increase in muscle fatigability. These maladaptations result in a reduced quality of life and an increased treatment-related toxicity, ultimately leading to an increased mortality risk.To date, three different studies investigated skeletal muscle decontioning in breast cancer patients, through long term protocols including all chemotherapy cycle treatment, and highlighted both structural alterations and impaired cellular processes. However, no study is currently availbale on the acute effect of one single chemotherapy administration in breast cancer patients skeletal muscle tissue.Our study is therefore dedicated to the investigation of the acute effect of the first dose administration of both Epuribicin/cyclophosphamide and Paclitaxel chemotherapies on skeletal muscle of breast cancer patients. Our study will particularly explore cellular mechanisms of muscle decontioning, such as protein turnover, mitochondrial homeostasis and fatty infiltrations.

Acute Effects of Chemotherapy Administration on Skeletal Muscle of Breast Cancer Patients: the PROTECT-06 Study

Change From Baseline in Western Blots measurements of protein expression levels

Change From Baseline in Cross-Sectional Area (CSA) measurements

Change From Baseline in Western Blots measurments of protein expression levels

Change From Baseline in Western Blot measurement of protein expression levels

Change From Baseline in quantity of muscle mass measured by bioelectrical impedance analysis

Change From Baseline in the maximal isometric strength of the knee with force transducer

Change From Baseline in ultrasonography measurement

Change From Baseline in FACT-G auto-questionnaire measurement

Change From Baseline in FAACT auto-questionnaire measurement

Change From Baseline in GPAQ auto-questionnaire measurement

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Skeletal Muscle Expression of Myostatin and Cancer of Digestive System Associated Cachexia	NCT03172403	Cancer of Diges...	Height and weig... Blood samples Skeletal muscle... Skeletal muscle... Muscle biopsy	40 Years - 80 Years	Centre Hospitalier Universitaire de Saint Etienne
Metabolic Myopathy in Endocrinopathy	NCT05456997	Cushing Syndrom... Pheochromocytom... Conns Syndrome Metabolic Myopa...	Muscle biopsy	18 Years -	Barts & The London NHS Trust
The Role of Muscle Cachexia in Pancreatic Cancer	NCT02515513	Pancreas Cancer	Muscle Tissue B...	18 Years - 80 Years	University of Florida
EDICT - Exercise inDuced Changes In Colorectal Cancer Tissues	NCT02056691	Colorectal Canc...	Exercise progra... Muscle biopsy	18 Years -	The Royal Bournemouth Hospital
Skeletal Muscle Expression of Myostatin and Cancer of Digestive System Associated Cachexia	NCT03172403	Cancer of Diges...	Height and weig... Blood samples Skeletal muscle... Skeletal muscle... Muscle biopsy	40 Years - 80 Years	Centre Hospitalier Universitaire de Saint Etienne
Acute Effects of Chemotherapy Administration on Skeletal Muscle of Breast Cancer Patients: the PROTECT-06 Study	NCT05128617	Breast Cancer	Epirubicin-cycl... Paclitaxel	18 Years -	Institut de cancérologie Strasbourg Europe

Spots Global Cancer Trial Database for muscle biopsy