Mitochondrial Activity and Myosteatosis in the Cachexia of Cancers of the Upper Aerodigestive Tract
试验速览
- 阶段
- 不适用
- 发起方
- 入组人数
- 60
- 试验地点
- 1
- 主要终点
- ATP / Oxygen ratio
研究概览
简要总结
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.
详细描述
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.
研究设计
- 研究类型
- Observational
- 观察模型
- Other
- 时间视角
- Retrospective
入排标准
- 年龄范围
- 18 Years 至 80 Years（Adult, Older Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •For the Cancer Group (K + Group):
- •Active cancer of the upper aerodigestive tract
- •Eligible for surgery treatment decided by CPR
- •Age ≥ 18 years or Age ≤ 80 years
- •For the control Group (K- Group):
- •No active cancer or a history of cancer less than 5 years old - Head and neck surgery for any reason except cancer
- •Absence of cachexia, defined by a weight loss> 5% over the last 6 months
- •Age ≥ 18 years or Age ≤ 80 years
排除标准
- •For groups K + and K-:
- •Presence of another obvious etiology of undernutrition
- •A history of heart failure, respiratory failure (requiring long-term oxygen therapy) or chronic renal disease (MDRD clearance <60 ml / min), moderate, severe or very severe COPD (HAS classification), insulin-dependent diabetes , Coronary artery disease
- •Age <18 years or Age >80 years
- •Protected persons and pregnant and / or nursing women
- •For the group K-:
- •Posterior diagnosis of cancer in the case of anatomo-pathological analysis (eg thyroidectomy, parotidectomy)
结局指标
主要结局
ATP / Oxygen ratio
时间窗: at day 1
The ratio of ATP produced by mitochondria and oxygen consumed by muscle mitochondria
次要结局
- Study of muscle proteolytic activity(at day 1)
- Study of enzymatic mitochondrial activity(at day 1)
- Study of the activity of muscle lipases(at day 1)
- Study of the muscular lipid infiltration(at day 1)
- Study of the mobilization of the muscular lipid droplets(at day 1)
- Study of myosteatosis(at day 1)
- Study of the activity of signaling pathways of protein anabolism(at day 1)
- Study of the activity of the signaling pathway of insulin in the muscle(at day 1)
- Evaluation of the preoperative metabolic and nutritional plasma status of patients(at day 1)