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Lerner L.,AVEO Oncology One Broadway 14th Floor Cambridge | Tao J.,AVEO Oncology One Broadway 14th Floor Cambridge | Liu Q.,AVEO Oncology One Broadway 14th Floor Cambridge | Nicoletti R.,AVEO Oncology One Broadway 14th Floor Cambridge | And 14 more authors.
Journal of Cachexia, Sarcopenia and Muscle | Year: 2015

Background: Cancer associated cachexia affects the majority of cancer patients during the course of the disease and thought to be directly responsible for about a quarter of all cancer deaths. Current evidence suggests that a pro-inflammatory state may be associated with this syndrome although the molecular mechanisms responsible for the development of cachexia are poorly understood. The purpose of this work was the identification of key drivers of cancer cachexia that could provide a potential point of intervention for the treatment and/or prevention of this syndrome. Methods: Genetically engineered and xenograft tumour models were used to dissect the molecular mechanisms driving cancer cachexia. Cytokine profiling from the plasma of cachectic and non-cachectic cancer patients and mouse models was utilized to correlate circulating cytokine levels with the cachexia phenotype. Results: Utilizing engineered tumour models we identified MAP3K11/GDF15 pathway activation as a potent inducer of cancer cachexia. Increased expression and high circulating levels of GDF15 acted as a key mediator of this process. In animal models, tumour-produced GDF15 was sufficient to trigger the cachexia phenotype. Elevated GDF15 circulating levels correlated with the onset and progression of cachexia in animal models and in patients with cancer. Inhibition of GDF15 biological activity with a specific antibody reversed body weight loss and restored muscle and fat tissue mass in several cachectic animal models regardless of their complex secreted cytokine profile. Conclusions: The combination of correlative observations, gain of function, and loss of function experiments validated GDF15 as a key driver of cancer cachexia and as a potential therapeutic target for the treatment and/or prevention of this syndrome. © 2015 The Authors. Journal of Cachexia, Sarcopenia and Muscle published by John Wiley & Sons Ltd on behalf of the Society of Sarcopenia, Cachexia and Wasting Disorders.


Trutschnigg B.,McGill Nutrition and Performance Laboratory | Kilgour R.D.,McGill Nutrition and Performance Laboratory | Kilgour R.D.,Concordia University at Montréal | Morais J.A.,McGill Nutrition and Performance Laboratory | And 5 more authors.
Journal of Geriatric Oncology | Year: 2013

Objective: Few studies have focused on the metabolic profiling of patients with advanced cancer and the relationship with nutritional and inflammatory characteristics, which have important diagnostic, treatment and prognostic implications, particularly in the elderly. Our objective was to determine differences in energy expenditure during rest and activity, body composition, nutrition, and inflammatory markers between healthy elderly females and those with advanced cancer. Materials and Methods: Twenty elderly (74.8 ± 6.7. years) females (9 with solid malignancies, 11 healthy) were evaluated for energy expenditure using indirect calorimetry at rest and throughout a 6-min walk test (6MWT). Body composition (dual-energy x-ray absorptiometry); nutritional intake (3-day 24-h food recall); and markers of nutrition and inflammation (complete blood count, albumin and C-reactive protein) were also measured. Results: Compared to healthy controls, patients with cancer had similar energy expenditures, but significantly lower (p < 0.05) respiratory quotients at rest. During the 6MWT, the group with cancer walked shorter distances at slower speeds (p < 0.001), consumed less oxygen (p < 0.05), and trended toward an increased oxygen cost while walking. The patients with cancer ingested fewer calories and presented with higher levels of inflammatory markers (p < 0.05). No differences in body composition were observed. Conclusion: Early signs of cachexia (i.e. reduced caloric intake, inflammation and greater fat metabolism) may be present in older patients with cancer, along with poorer levels of functional capacity, compared to healthy controls. Timely recognition of these signs may allow therapeutic interventions to better prevent or delay nutritional and functional demise in elderly patients with cancer. © 2012 Elsevier Inc.


Vigano A.,McGill Nutrition and Performance Laboratory | Piccioni M.,McGill Nutrition and Performance Laboratory | Piccioni M.,Concordia University at Montréal | Trutschnigg B.,McGill Nutrition and Performance Laboratory | And 5 more authors.
The Lancet Oncology | Year: 2010

Male hypogonadism is commonly diagnosed on the basis of subphysiological concentrations of androgen hormones, and is associated with many symptoms present in advanced cancer. Androgen deficiency might be an important cause of muscle wasting in both cancer cachexia and sarcopenia. We did a systematic review of the clinical association of male hypogonadism in advanced cancer. We searched PubMed, Medline, and Embase for publications on the relation between male hypogonadism and functional status, nutritional status, body composition, symptoms, and quality of life in patients with advanced cancer. Of 381 publications identified, six original articles were included. We found no definitive association between nutritional, functional, or quality-of-life characteristics and male hypogonadism. Possible associations between male hypogonadism and weight loss, low albumin, low-body cell mass index, low-peripheral fat and muscle mass, higher inflammation, higher pain, higher opioid consumption, worse scores for anxiety, depression, and emotional and functional well-being need to be confirmed by better designed studies. There is no clear epidemiological data to indicate whether male hypogonadism is independently associated with clinical and biological sequelae of cancer cachexia, such as higher inflammation, fatigue, and body wasting. Standardised kits sensitive to low concentrations of free-testosterone or bioavailable testosterone are needed to diagnose androgen deficiency in women. A clearer epidemiology of androgen deficiencies in advanced cancer will help determine which patients should receive testosterone-replacement therapy for alleviating cancer cachexia symptoms and improving quality of life. © 2010 Elsevier Ltd.


Vigano A.L.,McGill Nutrition and Performance Laboratory | Vigano A.L.,McGill University | Di Tomasso J.,McGill University | Kilgour R.D.,Concordia University at Montréal | And 5 more authors.
Journal of the Academy of Nutrition and Dietetics | Year: 2014

Cancer cachexia (CC) is a syndrome characterized by wasting of lean body mass and fat, often driven by decreased food intake, hypermetabolism, and inflammation resulting in decreased lifespan and quality of life. Classification of cancer cachexia has improved, but few clinically relevant diagnostic tools exist for its early identification and characterization. The abridged Patient-Generated Subjective Global Assessment (aPG-SGA) is a modification of the original Patient-Generated Subjective Global Assessment, and consists of a four-part questionnaire that scores patients' weight history, food intake, appetite, and performance status. The purpose of this study was to determine whether the aPG-SGA is associated with both features and clinical sequelae of cancer cachexia. In this prospective cohort study, 207 advanced lung and gastrointestinal cancer patients completed the following tests: aPG-SGA, Edmonton Symptom Assessment System, handgrip strength, a complete blood count, albumin, apolipoprotein A and B, and C-reactive protein. Ninety-four participants with good performance status as assessed by the Eastern Cooperative Oncology Group Performance Status completed additional questionnaires and underwent body composition testing. Of these, 68 patients tested for quadriceps strength and completed a 3-day food recall. Multivariable regression models revealed that higher aPG-SGA scores (≥9 vs 0 to 1) are significantly associated (P<0.05) with the following: unfavorable biological markers of cancer cachexia, such as higher white blood cell counts (10.0 vs 6.7×109/L; lower hemoglobin (115.6 vs 127.7 g/L), elevated C-reactive protein (42.7 vs 18.2 mg/L [406.7 vs 173.3 nmol/L]); decreased anthropometric and physical measures, such as body mass index (22.5 vs 27.1); fat mass (14.4 vs 26.0 kg), handgrip (24.7 vs 34.9 kg) and leg strength; an average 12% greater length of hospital stay; a dose reduction in chemotherapy; and increased mortality. Given its association with the main features of cancer cachexia and its ease of use, the aPG-SGA appears to be a useful tool for detecting and predicting outcomes of cancer cachexia. Additional research is required to determine what impact the aPG-SGA has on quality of care when used in the clinical setting. © 2014 Academy of Nutrition and Dietetics.


PubMed | McGill Nutrition and Performance Laboratory
Type: Journal Article | Journal: Journal of geriatric oncology | Year: 2013

Few studies have focused on the metabolic profiling of patients with advanced cancer and the relationship with nutritional and inflammatory characteristics, which have important diagnostic, treatment and prognostic implications, particularly in the elderly. Our objective was to determine differences in energy expenditure during rest and activity, body composition, nutrition, and inflammatory markers between healthy elderly females and those with advanced cancer.Twenty elderly (74.86.7years) females (9 with solid malignancies, 11 healthy) were evaluated for energy expenditure using indirect calorimetry at rest and throughout a 6-min walk test (6MWT). Body composition (dual-energy x-ray absorptiometry); nutritional intake (3-day 24-h food recall); and markers of nutrition and inflammation (complete blood count, albumin and C-reactive protein) were also measured.Compared to healthy controls, patients with cancer had similar energy expenditures, but significantly lower (p<0.05) respiratory quotients at rest. During the 6MWT, the group with cancer walked shorter distances at slower speeds (p<0.001), consumed less oxygen (p<0.05), and trended toward an increased oxygen cost while walking. The patients with cancer ingested fewer calories and presented with higher levels of inflammatory markers (p<0.05). No differences in body composition were observed.Early signs of cachexia (i.e. reduced caloric intake, inflammation and greater fat metabolism) may be present in older patients with cancer, along with poorer levels of functional capacity, compared to healthy controls. Timely recognition of these signs may allow therapeutic interventions to better prevent or delay nutritional and functional demise in elderly patients with cancer.


News Article | November 4, 2016
Site: www.eurekalert.org

Montreal, November 4, 2016 - About one third of cancer patients die because of cachexia - an involuntary weight loss, characterized primarily by muscle wasting and metabolic changes, which cannot be addressed or treated solely with increased food intake. A study by researchers at the McGill University Health Centre (MUHC), published in Clinical Nutrition, aims to save patient lives by giving doctors a practical tool to easily diagnose cachexia before it becomes irreversible. Cachexia is a serious health condition that goes beyond simple weight loss. Clinicians and scientists have been trying to better understand and treat this condition for many years. It is often associated with poor responses to oncological treatments, increased hospitalizations, and has been shown to be a major burden to family caregivers. It is still largely overlooked and untreated in many oncology centres. Patients with this condition eventually experience a decline of their overall health to a point where it cannot be reversed by eating more or taking nutritional supplements. Despite recent advancements in research, cachexia remains very difficult to alleviate or treat. "We are losing many cancer patients, not because of their cancer, but because their bodies have undergone important metabolic changes. In other words, they have simply stopped functioning correctly. In severe stages of cachexia, weight loss becomes very important and nutrients can no longer be absorbed or used properly by cancer patients," explains Dr. Antonio Vigano, lead author of the paper and Director of the Cancer Rehabilitation Program and Cachexia Clinic of the MUHC. "Cachexia gets worse with time and the longer we wait to address it, the harder it is to treat. Effectively diagnosing cachexia when still in its early stages can make an enormous difference for a cancer patient's prognosis and quality of life. In order to save more lives, we need practical and accessible tools that can be effectively used by clinicians in their routine practice to identify patients with cachexia." The tool developed to diagnose cachexia is composed of five routinely available clinical measures and laboratory tests, which could be available to doctors within the next few years or sooner. The researchers also hope the tool can be applied to other patients who are losing weight from chronic diseases, such as acquired immunodeficiency syndrome (AIDS), chronic obstructive pulmonary disease, multiple sclerosis, chronic heart failure, tuberculosis and many more. Dr. Vigano's team at the McGill Nutrition and Performance Laboratory (MNUPAL) is also participating in studies aiming at developing treatments for cachexia. However, he insists, these treatments will only be useful if doctors can diagnose cachexia and understand the severity of each case. "Research is still needed to understand all the causes of cachexia. Unless we can talk the same language in terms of what type of patients we are treating and the severity of their condition, it is often very difficult to make substantial progress," he states. The study "Use of routinely available clinical, nutritional and functional criteria to classify cachexia in advanced cancer patients" was co-written by Vigano AAL, Morais JA, Ciutto L, Rosenthall L, Di Tomasso, J, Khan S, Olders H, Borod M, Kilgour RD.. Clinical Nutrition (2016), http://dx. The Research Institute of the McGill University Health Centre (RI-MUHC) is a world-renowned biomedical and healthcare research centre. The Institute, which is affiliated with the Faculty of Medicine of McGill University, is the research arm of the McGill University Health Centre (MUHC) - an academic health centre located in Montreal, Canada, that has a mandate to focus on complex care within its community. The RI-MUHC supports over 460 researchers and close to 1,300 research trainees devoted to a broad spectrum of fundamental, clinical and health outcomes research at the Glen and the Montreal General Hospital sites of the MUHC. Its research facilities offer a dynamic multidisciplinary environment that fosters collaboration and leverages discovery aimed at improving the health of individual patients across their lifespan. The RI-MUHC is supported in part by the Fonds de recherche du Québec - Santé (FRQS). rimuhc.ca

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