Nutritional and Metabolic Diseases

Symptoms and General Pathology

All Conditions

Neoplasms

Nervous System Diseases

Rare Diseases

Obesity

Malnutrition

Sarcoma

Sarcopenia

Neoplasms, Connective and Soft Tissue

Neoplasms by Histologic Type

Nutrition Disorders

Atrophy

Muscular Atrophy

Neuromuscular Manifestations

Neurologic Manifestations

Pathological Conditions, Anatomical

Soft Tissue Sarcoma

Subgroup of patients with available preoperative CT/MRI scans will be detected and body composition measurements will be assessed min order to detect nutrition-related syndromes

The cross section of the third lumbar vertebrae in the CT scan images of the patients will be analyzed for assessment of body composition parameters including skeletal muscle area (SMA), muscle radiation attenuation (MRA), visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT)

Measurement of body composition with computed tomography (CT)

GLIM criteria (Global Leadership Initiative on Malnutrition) will be applied to assess malnutrition

GLIM malnutrition criteria

EWGSOP2 criteria (Writing Group for the European Working Group on Sarcopenia in Older People 2) will be followed to determine the diagnosis of sarcopenia

EWGSOP2 sarcopenia criteria

The European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) consensus criteria from 2018 will be applied to assess sarcopenic obesity

ESPEN-EASO criteria for sarcopenic obesity

Prognostic Nutritional Index is diagnostic test based on serum albumin level and total lymphocyte count

Prognostic Nutritional Index (PNI)

The high-sensitivity modified Glasgow prognostic score (Hs-mGPS) is an inflammation-based score consisted of C-reactive protein level and serum albumin

The high-sensitivity modified Glasgow prognostic score

Manuel Ramanović, M.D.

Nada Rotovnik Kozjek, M.D. PhD

Marko Novak, M.D.

Andraž Perhavec, M.D. PhD

Taja Jordan, M.D. PhD

This is a retrospective, observational study in consecutive patients operated on for primary RPS in the Institute of Oncology Ljubljana (Slovenia) between September 1999 and June 2020. This study aims to investigate the impact of preoperatively assessed body composition parameters on the perioperative outcomes of patients operated on for primary RPS. The impact of preoperative malnutrition, sarcopenia, sarcopenic obesity and myosteatosis to the oncologic and postoperative outcome in patients operated on for primary RPS will be examined. Additionally, the aim is to evaluate the prognostic role of preoperative immune and inflammatory markers (serum albumin level, C-reactive protein, neutrophil to lymphocyte ratio, platelet to lymphocyte ratio, high-sensitivity modified Glasgow prognostic score) and prognostic nutritional index in primary RPS patients undergoing surgery. Patient outcome will be evaluated in terms of overall survival (OS), local-recurrence free survival (LRFS), postoperative intrahospital length of stay, overall and major postoperative morbidity.

Retroperitoneal sarcomas (RPS) are rare neoplasms of mesenchymal origin with estimated crude incidence of 0.3 cases per 100000 inhabitants per year. The most common histologic subtypes are well-differentiated and dedifferentiated liposarcoma and leiomyosarcoma, accounting for 42% and 26% of cases, respectively. RPS are optimally managed in multidisciplinary settings in specialized sarcoma centers. Surgical resection with an adequate margin of normal tissue is the cornerstone of curative therapy and en bloc surgical resection of localized tumors is the recommended surgical approach. This "extended" surgical approach (including resection of adjacent organs), is optimal for reducing local recurrence and improving overall survival.

Cancer patients undergoing surgical treatment face number of challenges which negatively impact their nutritional status. Patients are usually in catabolic state, which together with ongoing proteolysis and lipolysis as well as decreased protein synthesis contribute to development of cancer - associated cachexia. Most important nutritional disorders in these patients are malnutrition, sarcopenia, cancer cachexia. On the other side, often under-recognized, sarcopenic obesity is gaining attention in clinical and research settings.

The association of malnutrition and poor postoperative outcome has been demonstrated in patients with various cancer locations. Malnourished patients reportedly have longer length of postoperative stay (LOS), higher rates of 30-day mortality, infection rate, sepsis, reoperation, increased number of cardiopulmonary complications. Diagnostic process of malnutrition has been a topic of debate considering inconsistency in diagnostic methodology and criteria. Global Leadership Initiative on Malnutrition (GLIM) addressed this problem and recommended a new diagnostic scheme for malnutrition, in form of consensus report incorporating previous finding and recommendations from world leading clinical nutrition societies. To our knowledge, no study validated GLIM criteria in patients with primary RPS.

Sarcopenia is clinical syndrome characterized by generalized skeletal muscle mass loss, loss of strength and function (performance). Sarcopenia has been associated with lower survival rate and proved to be an independent predictor of survival in patients with breast cancer, pancreatic adenocarcinoma, hepatocellular carcinoma, and melanoma. There is a lack of studies investigating the impact of sarcopenia on survival and postoperative outcome in patients with soft-tissue sarcoma (STS), including retroperitoneal sarcoma. Similarly to malnutrition diagnosis, there is an evident inconsistency and confusion in diagnostic criteria and tools used to define and characterize sarcopenia in clinical practice and research. However, recently the European Working Group on Sarcopenia in Older People (EWGSOP2) published updated findings in form of Revised European Consensus. The Working Group proposed new recommendation, among which are those related to establishing specific cut-off points for body composition (primarily skeletal muscle quantity and quality) measures that identify and characterize sarcopenia.

Sarcopenic obesity (SO) is co-existence of sarcopenia and excess adiposity. Recent expert consensus of The European Society for Clinical Nutrition and Metabolism (ESPEN) and the European Association for the Study of Obesity (EASO) will be followed for definition and diagnostic criteria for SO.

Myosteatosis is ectopic adipose tissue infiltration in skeletal muscle. Intermuscular adipose tissue can be quantified using CT scans by low muscle radiodensity. CT-derived myosteatosis contributes to impaired glucose metabolism, including insulin resistance, type 2 diabetes mellitus, and inflammation. Additionally, it may increase the risk for dyslipidemia. Myosteatosis may predict oncologic and postoperative outcome in primary RPS patients.

Patients with primary RPS are in a great risk for malnutrition, sarcopenia and cachexia for the number of reasons: requirement for demanding abdominal surgery in their management, catabolic tumor effects, long period before diagnosis of RPS and tumor size (approximately 15 cm). Due to their rarity, it is still unclear how preoperative nutritional status and body composition impact outcome of patients with primary RPS.

STUDY DESIGN DATA COLLECTION Patient's histories including the anaesthetician's preoperative reports, surgeon's operative reports, hospital records, and follow-up data will be collected. Paper and electronic data archive of Institute of Oncology Ljubljana Patient Data Information System will be used.

The following preoperative clinical data will be acquired: age, sex, preoperative weight, height, significant weight loss, appetite loss and weakness. CT reports will be also acquired for analysis as well as histopathological diagnosis (subtype), stage, grade and tumor size.

The preoperative laboratory data, including absolute counts of leukocytes, neutrophils, lymphocytes, monocytes and platelets, CRP, and albumin levels will be assessed. Data will be deidentified and whenever possible all measures to conceal patient identifiers and maintain patient confidentiality will be taken.

STATISTICAL CONSIDERATIONS The data will be presented using appropriate summary statistics: mean, median, standard deviation for continuous variables and percentages and frequencies for categorical variables. Kaplan-Meier method will be used for survival curves analysis and differences between survival rates compared using the log-rank test. The independent prognostic variables for survival (OS and LRFS) will be identified using Cox proportional hazard model (hazard ratio, 95% confidence interval, p value).

ETHICS The study was approved by Slovenian National Medical Ethics Committee, Institute of Oncology Ljubljana Review Board and Institute of Oncology Ljubljana Ethical Committee. The need to obtain informed consent from participants was waived.

Influence of Nutritional Status on Oncologic and Operative Outcome in Patients Operated for Retroperitoneal Sarcoma

Influence of Body Composition, Nutritional Status and Inflammatory Markers on Survival and Postoperative Outcome in Patients Operated on for Primary Retroperitoneal Sarcoma: Report From Institute of Oncology Ljubljana

Complications graded by Clavien-Dindo Complication Classification System

A postoperative local recurrence will be defined by biopsy-proven or radiographic evidence of local recurrent disease

Overall survival (OS) will be defined as the time between the date of the operation to the date of death from any cause or last follow-up (according to medical records and using telephone contacts)

Time interval from the date of operation to the date of discharge. Body composition parameters may predict the length of hospital stay

Complication grade 3 or higher according to Clavien-Dindo Complication Classification System

A prevalent case of malnutrition will be considered if a patient fulfills the Global Leadership Initiative on Malnutrition (GLIM) criteria. GLIM proposed 5 diagnostic criteria to assess malnutrition and includes 3 phenotypic (weight loss, low body mass index and reduced muscle mass) and 2 etiologic (reduced food intake/assimilation, and inflammation/disease burden) criteria. To diagnose malnutrition at least 1 phenotypic criterion and 1 etiologic criterion should be present

A prevalent case of sarcopenia will be considered if a patient fulfills the diagnostic criteria defined by European Working Group on Sarcopenia in Older People (EWGSOP2)

Skeletal muscle area (SMA) area will be measured by using preoperative computed tomography (CT) scans at lumbar (L3) vertebral level and recorded as cm\^2 using standard Hounsfield Unit thresholds of - 29 to + 150. SMA at the third lumbar spine level has been established as a good indicator of whole-body muscle mass.

Muscle radiation attenuation (MRA) will be assessed using CT scans at lumbar (L3) vertebral level and recorded as mean Hounsfield unit (HU) of each pixel within a region of interest. MRA reflects muscle composition, including the degree of intramuscular fat accumulation, important to define the presence of myosteatosis

Visceral adipose tissue (VAT) area will be measured by using preoperative computed tomography (CT) scans at lumbar (L3) vertebral level and recorded as cm\^2 using standard Hounsfield Unit thresholds of -150 to -50

Subcutaneous adipose tissue (SAT) area will be measured by using preoperative computed tomography (CT) scans at lumbar (L3) vertebral level and recorded as cm\^2 using standard Hounsfield Unit thresholds of -190 to -30.

Visceral-to-subcutaneous adipose tissue ratio will be calculated by dividing the visceral adipose tissue area by the subcutaneous adipose tissue area.

Neutrophil to lymphocyte ratio (NLR): calculated as the absolute neutrophil count divided by the absolute lymphocyte count.

Platelet to Lymphocyte Ratio (PLR): calculated as the absolute platelet count divided by the absolute lymphocyte count.

Systemic immune inflammation index (SII): based on absolute platelet, neutrophil and lymphocyte count and calculated according to following formula:

SII =(platelet count×neutrophil count)/(lymphocyte count)

The high-sensitivity modified Glasgow prognostic score (Hs-mGPS) will be defined as numeric value 0 - 2 according to following criteria based on C-reactive protein (CRP) and serum albumin levels:

Score 0: CRP level ≤ 0.3 mg/dl and albumin ≥ 3.5 g/dl, Score 1: CRP level \> 0.3 mg/dl and albumin ≥ 3.5 g/dl, Score 3: CRP level \> 0.3 mg/ dl and albumin \< 3.5 g/dl.

The prognostic nutrition index (PNI) will be calculated based on previously published and validated formula:

PNI =10× serum albumin (g/dl)+0.005× lymphocyte count (per mm\^3)

Institute of Oncology Ljubljana

Digestive System Diseases

Stomach Neoplasms

Esophageal Neoplasms

Neoplasms, Adipose Tissue

Gastrointestinal Neoplasms

Digestive System Neoplasms

Gastrointestinal Diseases

Stomach Diseases

Stomach Cancer

Esophageal Cancer

Myosteatosis

Yannick Deswysen, MD

Nicolas Lanthier, PhD

The aim of this project is to study the presence of cancer-associated adipocytes in oesogastric cancers and their possible links with myosteatosis. This research project has a retrospective component, the aim of which is to analyse the body component based on imaging in patients with oesogastric neoplasia in order to determine the incidence of myosteatosis and to study the relationship with oncological and prognostic data. The second part of the project is prospective and will collect biological material (skeletal muscle, adipose tissue, tumour, blood) for histological, molecular and genomic analyses and will analyse muscle function in patients with oesogastric cancer. It will address the role of adipocytes in the tumour microenvironment of oesogastric cancer, focusing on their interactions with the observed muscle myosteatosis and prognosis. In the future, it will help to identify signalling pathways, targets and patients who could benefit from appropriate treatment.

Oesophageal and gastric cancer pose a significant challenge to caregivers, both in terms of the complexity of its presentation and its treatment. At diagnosis, patients often present with malnutrition associated with sarcopenia, which has a significant impact on morbidity and mortality. Although loss of muscle mass has received much attention in cancer, muscle quality, particularly the accumulation of fat in muscle named "myosteatosis", may be considered as a better predictor of a patient's physical condition and ability to recover from cancer treatments. Studying the tumor microenvironment is essential to understanding the mechanisms underlying disease progression. Cancer-associated adipocytes (CAA), a major component of this tumor microenvironment, provide an interface for dialogue with the tumor through the secretion of pro-inflammatory cytokines, metalloproteases and the release of free fatty acids. They have been described as capable of stimulating tumor progression, particularly in breast cancer. However, their presence in oesogastric cancer and possible links with myosteatosis have not been described.

Myosteatosis in Oeso-gastric Cancer: Clinical Impacts

Muscle fat infiltration measured by analysis of tissue density based on a CT scan in L3 with the help of body component analysis software

Determining the presence and impact of tumor-associated adipocytes

Cliniques universitaires Saint-Luc- Université Catholique de Louvain

Wasting Syndrome

Cachexia

Syndrome

Body Weight

Weight Loss

Body Weight Changes

Thinness

Metabolic Diseases

Group K +: cancer of the upper aerodigestive tract with or without cachexia

Group K-: absence of cancer and absence of cachexia

The MYOMEC study includes the inclusion of healthy patients (to form a control group

carcinological surgery

cervical surgery

Patrick LACARIN

Stéphane WALRAND

Laura MONTRIEUL

Loss of muscle mass (scientific term: cachexia) affects about 80% of patients with advanced cancer and impacts their prognosis by decreasing tolerance and response to treatment, decreasing quality of life and survival. The prognosis in these patients depends directly on the importance of the loss of muscle mass. Preserving it is therefore an essential therapeutic objective. It is therefore important to understand perfectly the mechanism of this muscular loss. The accumulation of fat in the muscle (scientific term: myosteatosis) could be a mechanism responsible for this loss of muscle mass. It is indeed a hypothesis proved on animal models. Moreover, it has recently been shown that more the cancer patient loses weight, more his muscle contains fat. This lets think that this deposit of fat in the muscle would be directly related to the loss of muscle mass. All of these observations could not be clearly established in humans and investigators are seeking by this study to illuminate these mechanisms at the human level. A better understanding of these mechanisms would allow investigator to set up targeted treatments against the accumulation of fat in the muscle, which would significantly improve the quality of life of patients with cancer of the aerodigestive pathways and their chances of recovery.

The MYOMEC study includes the inclusion of healthy patients (to form a control group) but also patients with cancer of the upper aero-digestive tract. The study will be divided into two parts: clinical examination and nutritional evaluation the day before surgery at the time of the participants' admission to hospital and then the biological samples during surgery. The nutritional examination consists in collecting the morphological data of the patient, namely:

Its weight, size, calculation of the body mass index Tests of muscular strength (wearing weight of 1, 2 and 3 kilos) Measurement of the percentage of fat mass and lean mass (Impedancemetry)

In this study, participants benefit from the following investigations:

* Clinical examination complete with elaboration of the clinical nutritional status, realized the day before the surgical intervention in hospitalization.
* Elaboration of the radiological nutritional status by a complementary analysis of the scanner envisaged in the balance of extension of the disease
* Performing surgical site sampling during surgery without additional invasive procedure and under general anesthesia. It will be realized:

A muscle biopsy of the sterno-cleido-mastoid muscle (neck muscle) (maximum volume 5 mm3), A tumor biopsy (maximum volume 5mm3). A blood sample (maximum volume 5ml)

No invasive procedure, supplemental examination or additional consultation is required for the whole off-set study for the extensive muscular percutaneous biopsy regarding which additional patient agreement will be required. No additional follow-up is required when participating in this study. Participation in this study does not entail any particular constraint or additional treatment. The duration of the patient's participation is defined as follows: from the date of the preoperative consultation or from the consultation of announcement until his / her discharge from hospital. The exclusion period defined in this study extends from the date of inclusion of the patient to the date of the surgical procedure, during which time the patient can not participate in another clinical research protocol.

Malnutrition is characterized by a negative energy balance due to a deep skeletal muscular loss, which is itself secondary to the reduction of intake and metabolic abnormalities aggravating the loss of weight. Sarcopenia is defined as the loss of muscle mass, the consequences of which are a decrease in muscle strength and physical performance .Cachexia, identified in many chronic diseases (renal insufficiency, heart failure, diabetes, COPD), is the result of an imbalance between proteolysis and proteogenesis and can be defined as a multifactorial syndrome characterized by a weight loss resulting mainly from a loss of lean mass, in particular muscle mass, which is not reversible by an adequate nutritional contribution and which leads to functional abnormalities.

Cancers of the ENT sphere represent about 15% of all cancers in men and 2% in women. They mainly concern subjects between 45 and 70 years of age with a predominant role of ethylo-tobacco poisoning. Patients with upper aero-digestive tract cancers are particularly prone to malnutrition on the part of the tumor itself but also on the context (ethylo-tobacco intoxication, sedentary behavior, poor general condition), tumor localization involving reduction of intake (Mechanical obstruction, anorexia, pain), but also after treatment (chemotherapy, radiotherapy, surgery).

Cancer cachexia affects approximately 80% of patients with advanced cancer and impacts their prognosis by increasing morbidity and mortality, decreased tolerance and response to treatment , decreased quality of life and decreased survival. Its prognosis depends on the extent of the loss of muscle mass. It is generally reported for a patient with a weight loss superior than 5% of its initial weight over the last 6 months, with 3 stages described: Pre-cachexia stage, clean cachexia stage, refractory cachexia stage. It is characterized, among other things, by the development of systemic inflammation and tumor cell lines and tumor cells from cancer patients have been shown to produce pro-inflammatory cytokines ( IL-6, IL-8).

The loss of skeletal muscle mass, up to 75% in severe malnutrition is related to an acceleration of muscle catabolism and an alteration of muscle protein anabolism, mediated by large tumor signals and leads to a decrease in performans status, decrease in overall survival, increase in susceptibility to toxicity of chemotherapy, and increase in exposure to long-term hospital stays.

This muscular loss is the result of an increase in proteolysis phenomen but also of a decrease in protein synthesis. The main proteolytic pathways are the calpain-calcium-dependent pathway, the lysosomal pathway and the ubiquitin-proteasome-ATP pathway. Several studies have shown the activation of these proteolytic pathways in cancer cachexia . Among these proteolytic pathways, the ubiquitin-proteasome-ATP-dependent pathway appears to be the most involved in cancer cachexia .This proteolytic pathway is mediated by 2 ubiquitin ligases specific for skeletal muscle, MAF-Box and MURF1, which are largely overexpressed in many models of muscular atrophy and cancer cachexia . On the other hand, the growth factor IGF1 is a known anabolic factor which activates the proteosynthesis via the signaling pathway PI3K / Akt / mTOR . The decrease in IGF1 expression in skeletal muscle is observed in experimental models of cancer cachexia . Studies have shown that certain factors of tumor origin may contribute to cancer cachexia in some animal models.

2 factors have particularly attracted the attention of scientists in recent years, the ZAG factor (Zinc alpha 2 glycoprotein), a veritable lipid mobilization factor in humans , overexpressed in the liver and adipose tissue and PIF (proteoglycan identified in mouse murine adenocarcinoma tumor cells which would be responsible for muscle wasting induced by the activation of the ubiquitin-proteasome-ATP-dependent proteolytic pathway . More recent work suggests that Myostatin and Activin A, two members of the TGFβ superfamily, may contribute to cachexia, particularly muscular atrophy, induced by certain cancers.

Adipose loss is an early syndrome in the development of cancer cachexia and is negatively correlated with patient life expectancy . Early studies on this adipose melt revealed a lack of storage of triglycerides in adipose tissue . The storage of triglycerides is achieved by the action of lipoprotein lipase. It predominantly exists in adipose tissue and hydrolyzes lipoproteins circulating in the blood, thus allowing the capture of fatty acids by adipocytes and storage of adipose reserves . The development of the tumor would induce a decrease in the gene expression and activity of lipoprotein lipase via the action of inflammatory cytokines . However, current research seems to demonstrate that the adipose melt observed in cancer cachexia is mostly explained by an increase in lipolysis (shown indirectly by an increase in plasma fatty acid concentration in cachectic patients with gastrointestinal cancer). .

Lipolysis, via hormone-sensitive lipase (LHS) and monoglyceride lipase (MGL), allows the hydrolysis of triglycerides into diglycerides and diglycerides into monoglycerides themselves degraded into free fatty acids and glycerol. Adipose tissue-specific triglyceride lipase (TGLA) has recently been discovered and has a role that is redundant to that of LHS. Studies of Cao et al. showed that the activation of LHS by catecholamines could constitute a mechanism of regulation of lipolysis during cancer cachexia. . An alteration of TGLA and LHS would also be responsible for an accumulation of DAG and TAG in the muscle of cancerous mice . A recent study showed that the invalidation of TGLA and LHS in 2 models of cachexia induced by injection of Lewis pulmonary carcinoma cells or B16 melanoma cells induced resistance to the development of cachexia by limiting adipose and muscular loss . Systemic inflammation developed during cancerous cachexia could also induce an increase in insulin resistance via TNFalpha . TNFalpha could inhibit the expression of perilipin A, a protein expressed on the surface of adipocyte lipid droplets , which plays a major role in the integrity of adipose tissue since it limits the access of enzymes involved in lipolysis to the lipid droplet . A decrease in the expression of perilipin A would induce an increase in lipolysis. In addition, a study by Stephens et al. in 2011 concluded that the number and size of intramuscular lipid droplets are increased in the presence of cancer and also increase with weight loss / adipose fat loss in other body compartments .

Myosteatosis, a pathological fatty deposit in skeletal muscle, is another characteristic of body composition, in addition to low muscle mass, which is associated with the poor prognosis of the cancer disease, in particular a decrease in overall survival and it has recently been shown that the muscle of cancer patients contains all the more adipose tissue that severe weight loss . Several studies have shown that myosteatosis is associated with an increase in insulin resistance and therefore a decrease in proteolysis via the inhibition of insulin transport of amino acids. The fat content of the muscle may be indirectly and non-invasively studied on the basis that the adipose tissue typically attenuates the radiation applied thereto. . The value of the attenuation measurements are determined by the rate at which the radiation passes through the tissue and is expressed in Hounsfield units (HU). Muscle and adipose tissue attenuation values were defined between -190 and -30 HU .

The weakening of the radiation in the muscle was correlated well with the fat content of the muscles. . Thus, the HU values defined by the CT scan may reflect the degree of intramuscular adipose tissue and are used to categorize the muscle of normal or exposed to myosteatosis . Low muscle mass and weakening of the radiation in muslce testify of high degree of myostaatosis and were identified as an independent prognostic factor for overall survival and mortality in cancer patients, respectively. . The comparison of muscle metabolism in obese and normoponded subjects showed an abolition of protein synthesis in response to insulin especially in muscle mitochondria in overweight subjects. Interestingly, muscle protein renewal was inversely correlated with fat mass. Such an observation raises the question of the possibility of a deleterious effect of fat mass on protein synthesis. The hypothesis of this lipotoxicity was confirmed by a work carried out in the rat which showed that the synthesis of the muscle proteins is slowed down when there is infiltration of fat into the muscle

At the cellular level, metabolism is governed by the mitochondria which provides 90% of our energy in the form of ATP. This energy is synthesized within oxidative phosphorylation, which consists of 2 entities (the respiratory chain and ATP synthase) and which allows the conversion, in water and ATP, of the reduced equivalents resulting from dehydrogenation reactions (and Decarboxylation) of energetic nutrients, in the presence of dioxygen (O2) and ADP, according to chemosmotic coupling theory . The decoupling of oxidative phosphorylation may be involved in involuntary weight loss. The work of Romestaing et al. Showed that weight loss following the development of a steatosis was associated with a decrease in the ATP / O2 ratio . Mitochondrial dysfunctions could therefore have a direct effect on the protein degradation observed during cancer cachexia. In addition, systemic inflammation caused by the development of the tumor can also affect mitochondrial bioenergetics.

The works of Hochwald et al. were among the first to suggest an alteration of muscle mitochondrial metabolism by demonstrating a decrease in ATP concentration in the gastrocnemius of rats with MCA sarcoma . The recent works of Constantinou and col. confirmed this hypothesis by demonstrating in vivo by 31P nuclear magnetic resonance (NMR) a reduction in the rate of synthesis of ATP on the lower limb of mice with Lewis pulmonary carcinoma compared to its healthy mice . This work suggested a decrease in the ability to synthesize ATP during cancerous cachexia through decoupling proteins such as UCP3 . This decrease in ATP synthesis could also be explained by alterations in the functioning of the mitochondrial respiratory chain .

Julienne and col. in 2012 studied the mitochondrial activity of skeletal muscles in murine models of cancer cachexia based on the ATP / Oxygen ratio and concluded that muscular mitochondrial oxidative capacities were reduced by decreasing the activity of complex IV, responsible for muscle loss and accumulation of free fatty acids in muscle (myosteatosis) since less oxidized by mitochondria. They also observed that the expression of MURF1 and MAF-Box (proteolytically active ligases) was increased in the muscle of rats with cancers .

Cancerous cachexia affects about 80% of patients with advanced cancer and increases their prognosis by increasing their morbidity and mortality. It is defined as a loss of lean mass especially muscular resulting from an imbalance between proteolysis and proteogenesis. It has been shown that the presence of cancer in the murine model favors the development of myosteatosis, which is linked, among other things, to alteration of muscle lipases and a decrease in mitochondrial activity, the consequence of which is a decrease Of the oxidation by the latter of free fatty acids which would consequently accumulate in the muscle of mice suffering from cancer. It is known that this myosteatosis then induced is responsible for an insulin resistance participating in a decrease in proteogenesis and therefore in weight loss.

The main objective here is to confirm this same hypothesis in humans by studying the influence of cachexia on muscle mitochondrial activity as a marker of myosteatosis in patients with cancer of the upper air-digestive tract, cachectic or not, and non-cachectic controls.

Patients will be recruited from ENT and Cervico-facial Surgery at CHU Gabriel Montpied in Clermont-Ferrand.

Inclusion of patients in 2 groups:

* Group K +: cancer of the upper aerodigestive tract with or without cachexia
* Group K-: absence of cancer and absence of cachexia The recruitment arrangements for the K + group will be made through a Multidisciplinary Consultation Meeting (RCP), the decision of which is an exclusive or non-exclusive surgery. Before the protocol is realized, during the preoperative consultation, an information sheet is given to the patient and an informed consent in 2 copies is signed after a period of reflection of the patient of 7 days.

At inclusion, the day before the surgery, patients benefit from a dual general and nutritional evaluation:

* Collection of epidemiological data: age, medical and surgical history (cardiac insufficiency, renal insufficiency, respiratory insufficiency, COPD, coronary artery disease), ethyl intoxication (gram / day), tobacco poisoning (package / year), usual treatment, tumor characteristics for group K+ (histological type, location, tumor stage, nature of treatment), indication and nature of surgery for group K-, pre-operative renutrition program for K + group (food supplements, enteral or parenteral feeding )
* Clinical nutritional evaluation: bodyweight (kg), weight loss in the last 6 months (kg), height (m), body mass index (BMI in kg / m²) (NPH), Short Physical Performance Battery (SPPB), muscle strength measurement by dynamometry (Newton), Impedancemetry (Kyle index, Janssen index)
* Myostéatosic and nutritional morphological evaluation by, respectively, Hounsfield Unit and Muscular Mass Index at L3 level (cm² / m²) by abdominal tomodensitometry for the K + group (carried out in the cancer extension imaging balance)

Patients will benefit from 4 organic samples during the planned surgery (carcinological surgery for Group K +, cervical surgery for Group K-):

* Carrying out a muscle biopsy of the SCOM muscle with a total volume of about 300 mg, without resorting to an additional invasive act. This sampling is immediately divided into 6 samples and placed in a liquid nitrogen tank for transport to the place of storage. It will then be frozen at -80 ° C.
* Carrying out a blood sample according to the following conditions: 1 dry tube, 1 EDTA tube and 2 dry tubes for biochemistry The dry tube and the EDTA tube will be immediately put in ice for transport to the storage site. It will then be immediately centrifuged and then frozen at -80 ° C. The two dry tubes for biochemistry will be transmitted to the laboratory of biochemistry of the CHU Gabriel-Montpied.
* Carrying out a tumor biopsy with a total volume of approximately 200 mg without resorting to an additional invasive procedure. This sampling is immediately divided into 4 samples and placed in a liquid nitrogen tank for transport to the place of storage. It is then frozen at -80 ° C (only for K + Group).

Mitochondrial Activity and Myosteatosis in the Cachexia of Cancers of the Upper Aerodigestive Tract

The ratio of ATP produced by mitochondria and oxygen consumed by muscle mitochondria

(Expression of cytochrome c oxidase, citrate synthase, HAD, complexes 1, 2 and 3 of the mitochondrial respiratory chain)

(Muscular ceramide concentration, DAG and TAG)

myosteatosis (Computed tomography in L3 for quantification in Hounsfield units)

(phosphorylation rate of mTOR and EiF2alpha)

(Expression of MURF1 and MAF-box ligases)

(Insulinemia, Fasting Glycemia, Hepatic and Lipid Assessment, CRP, Albumin, Pre-albumin, Blood Ionogram, Inflammatory Markers)

University Hospital, Clermont-Ferrand

Colonic Neoplasms

Colorectal Neoplasms

Intestinal Neoplasms

Colonic Diseases

Intestinal Diseases

Michał Pędziwiatr, MD, PhD

So far, the impact of sarcopenia has been analysed only in patients undergoing traditional surgical procedures (laparotomy) or those with metastatic spread. As the ERAS protocol combined with minimally invasive access decreases postoperative metabolic disorders, it seems possible that it can limit the deleterious impact of sarcopenia as well. The aim of this study was to investigate whether the use of ERAS protocol in colorectal cancer patients influences the postoperative risk due to sarcopenia.

The prospective observation with post-hoc analysis of 171 consecutive colorectal cancer patients was performed. In all patients 16-item ERAS protocol was applied.

Contrast-enhanced CT scan was performed preoperatively. From each scan one CT image at the level of L3 vertebra was transferred in Digital Imaging and Communications in Medicine format (DICOM) and anonymised. Firstly, the threshold range between -29 and +150 Hounsfield units was set to semi-automatically outline muscle areas, - 150 to - 50 was used for visceral adipose tissue areas, and -190 to -30 was used for subcutaneous and intermuscular adipose tissue areas. Secondly, the software calculated the surface area (cm2) of each tissue. The L3 skeletal muscle area (rectus abdominis, external and internal obliques, transversus abdominis, quadratus lumborum, psoas, erector spinae) normalized for patient height was used to calculate skeletal muscle index (SMI) (cm2/m2).

According to Martin et al. sarcopenia was defined as a SMI \<41 cm2/m2 in women, \<43 cm2/m2 in men with a BMI \<25 kg/m2, and \<53 cm2/m2 in men with a BMI \>25 kg/m2 (10). To assess for myosteatosis the mean radiodensity of a L3 psoas muscle was measured. The cut-off for patients with BMI \<25 kg/m2 was \<41 Hounsfield units and \<33 Hounsfield units for patients with BMI ≥25 kg/m2.

For the purposes of further analysis the entire group of patients was divided into subgroups depending on the presence of sarcopenia or myosteatosis.

ERAS in Colorectal Surgery Diminishes the Negative Impact of Sarcopenia on Short Term Outcomes

Enhanced Recovery After Surgery Protocol (ERAS) in Colorectal Surgery Diminishes the Negative Impact of Sarcopenia on Short Term Outcomes

tolerating at least 800 ml of clear water/fluids and 1 oral nutritional supplement within the first 24h postoperative hours

walking at least 100 m without assistance, at least 6h out of bed (sitting, walking)

no need for opioid drug administration (any kind, dosage or administration route)

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Influence of Nutritional Status on Oncologic and Operative Outcome in Patients Operated for Retroperitoneal Sarcoma	NCT05631379	Retroperitoneal... Body Compositio... Malnutrition Sarcopenia Sarcopenic Obes... Myosteatosis	Measurement of ... GLIM malnutriti... EWGSOP2 sarcope... ESPEN-EASO crit... Prognostic Nutr... The high-sensit...	18 Years -	Institute of Oncology Ljubljana
Myosteatosis in Oeso-gastric Cancer: Clinical Impacts	NCT06419244	Esophageal Canc... Gastric Cancer Myopenia Adipose Tissue ...	Myosteatosis	18 Years -	Cliniques universitaires Saint-Luc- Université Catholique de Louvain
Mitochondrial Activity and Myosteatosis in the Cachexia of Cancers of the Upper Aerodigestive Tract	NCT03111771	Cancer of Upper... Cachexia	carcinological ... cervical surger...	18 Years - 80 Years	University Hospital, Clermont-Ferrand
Myosteatosis in Oeso-gastric Cancer: Clinical Impacts	NCT06419244	Esophageal Canc... Gastric Cancer Myopenia Adipose Tissue ...	Myosteatosis	18 Years -	Cliniques universitaires Saint-Luc- Université Catholique de Louvain
ERAS in Colorectal Surgery Diminishes the Negative Impact of Sarcopenia on Short Term Outcomes	NCT02618811	Sarcopenia Colonic Neoplas...		18 Years -	Jagiellonian University
Influence of Nutritional Status on Oncologic and Operative Outcome in Patients Operated for Retroperitoneal Sarcoma	NCT05631379	Retroperitoneal... Body Compositio... Malnutrition Sarcopenia Sarcopenic Obes... Myosteatosis	Measurement of ... GLIM malnutriti... EWGSOP2 sarcope... ESPEN-EASO crit... Prognostic Nutr... The high-sensit...	18 Years -	Institute of Oncology Ljubljana

Spots Global Cancer Trial Database for myosteatosis

Every month we try and update this database with for myosteatosis 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.