Conclusions

Neoplastic cachexia is a complex and multifactori-al syndrome that can affect drug efficacy, mainly in elderly cancer patients, due to organ insufficiencies and comorbidities. The use of antitumoural drugs in this phase of disease, particularly in elderly patients, is extremely cumbersome because of the clear implications on the quality of residual life. Furthermore, in such patients, problems related to obtaining an accurate clinical picture make it difficult to elaborate guidelines for...

Physical Values

The energy values of a single food or nutrient can be directly measured by determining the amount of heat released upon its ignition and total combustion in a bomb calorimeter (Fig. 1). The values obtained with this direct measurement for different foods and nutrients are reported in Table 1 3 . These values do not correspond to the amount of energy utilisable by the body, since they do not take into consideration the amount lost by digestive and metabolic processes, i.e. excretion in the...

Anabolic Androgenic Steroids and Other Anabolic Steroids

Anabolic steroids are analogues of testosterone that can increase lean body mass 107, 108 and increase weight and activity in hypogonadal males 109, 110 . Although a proportion of cancer patients may be hypogonadal 111 , the role of these drugs and how they should be combined with other modalities (e.g. physical therapy, nutrition and anti-inflammatory anti-catabolic therapies) in cancer cachexia is currently unclear. As with other anabolic agents there has been some concern that tumour growth...

Factors Other Than Cytokines

In addition to humoural factors, tumour-derived molecules have also been suggested as mediators of cancer cachexia. Firstly, cancer cells are capable of constitutively producing cytokines. These may act on cancer cells in an autocrine manner or on supporting tissues, such as fibroblasts and blood vessels, to produce an environment conducive to cancer growth 31 . While tumour-produced cytokines may have a more important role in the anorexia-cachexia syndrome, several compounds produced by the...

Leptin and Immune Function

Initially described as an antiobesity hormone, lep-tin has subsequently been shown also to influence haematopoiesis, thermogenesis, reproduction, angiogenesis and immune response. Circulating levels of this adipocyte-derived hormone are proportional to fat mass, but may be lowered rapidly by fasting. Impaired cell-mediated immunity and reduced levels of leptin are both features of low body weight in humans. There is enough reported evidence to suggest a role for leptin in linking nutritional...

Treatment of Weight Loss and Cachexia in the Elderly

Numerous studies have shown that weight loss is associated with an increase in mortality 1-4 . Treating weight loss in the elderly can ameliorate many medical conditions. For example, rehabilitation time following post-hip fractures has been shown to decrease with nutritional supplementation 5 . In hospitalised geriatric patients, nutritional supplementation resulted in improvement in serum protein, nutritional status, and decreased mortality 6 . In a subset of geriatric inpatients, low serum...

Introduction

Extreme loss of body tissue in association with severe illness has been observed by physicians since ancient Greek times. The term 'cachexia' was the label for a 'signum mali ominis' in various, mostly fatal, diseases. Observing the chronicity of the course of a disease, cachexia was recognised as a severe complication indicating end-stage disease and poor quality of life. As modern treatment helps to prevent early death for an increasing number of chronic diseases, growing interest is focussed...

Pineal Gland and Cancer

In cancer patients, the function of the pineal gland and the circadian secretion of pineal hormones are frequently disrupted 4-8 . Animal and in vitro models have shown that melatonin inhibits the growth of several tumours, such as breast cancer MCF7 9, 10 and prostatic cancer 11, 12 . Chemical pinealectomy increased the growth of experimental tumours in animals. Recent experimental evidence in animal models of cancer showed that exposure to light during the dark phase of an alternating...

Additional Approaches

Glutamine is an amino acid with various physiological effects (e.g. metabolic, immune and gut integrity) and supplementation in cancer patients has recently been reviewed extensively 74 . The specific role of immune-modifying nutritional supplementation in surgery has recently been reviewed 75, 76 . There have been suggestions that patients with upper gastrointestinal cancer undergoing surgery may benefit from this approach however, further studies are needed to characterise this intervention....

Patient Eligibility

Inclusion criteria were as follows 18-80 years histologically confirmed tumour of any site at advanced stage, especially cancers inducing early cachexia (head and neck and gastrointestinal cancers) loss of at least 5 of their ideal (or pre-ill-ness) body weight in the last 3 months (early 'clinical' or overt cachexia) and or with abnormal values of proinflammatory cytokines, ROS, and antioxidant enzymes predictive of the onset of clinical cachexia any antineoplastic therapy with curative or...

References

Torun B, Viteri FE (1988) Protein-energy malnutrition. In Shils ME, Young VR (eds) Modern nutrition in health and disease, 7th edn. Lea & Febiger, Philadelphia, pp 746-773 2. Scevola D (1993) La cachessia nelle malattie infettive e neoplastiche. Edizioni Medico Scientifiche, Pavia 3. Watson RR (1994) Nutrition and AIDS. CRC Press, Boca Raton 4. Anonymous (1986) WHO Working group on the use and interpretation of anthropometric indicators of nutritional status. Bull World Health Organ 64...

Support of Energy Balance

The best way to improve energy balance is apparently to control tumour progression, which attenuates the metabolic abnormalities induced by the tumour and or tumour-host interactions. When cure cannot be achieved, an obvious next option is to increase nutritional intake by oral nutritional support or artificial nutrition (Fig. 3). A number of studies have tried to achieve this, particularly on a short-term basis. However, few positive effects were reported in terms of anthropometric measures,...

Transcriptional Factors

At the moment there are few studies describing the involvement of different transcriptional factors in muscle wasting. Penner et al. 45 reported an increase in NFkB and AP-1 transcription factors during sepsis in experimental animals. Recent data from our laboratory do not support an involvement of NFkB in skeletal muscle during cancer cachexia (unpublished data). However, tumour burden results in a significant increase in the binding activity of AP-1. Interestingly, inhibition of NFkB is not...

Protein Metabolism in Diabetes Mellitus

Proteins are one of the major body fuels however, despite the large size of the protein pool, only about 15-20 of daily calorie consumption is accounted for by protein oxidation, while fat accounts for about 30 and carbohydrates for 50 or more. There is no 'storage' form for amino acids - in contrast to glycogen and triglycerides, which are the storage forms for glucose and free fatty acids, respectively. Body proteins are not a fuel reservoir in themselves instead, protein molecules have...

Leptin and Congenital Leptin Deficiency

Congenital leptin deficiency due to mutations in the leptin gene or receptor is a rare, but treatable, cause of severe early-onset obesity and various endocrine disturbances in both rodents and humans 74, 75 . According to the lypostatic theory, a state of 'perceived starvation' might exist in these subjects and results in a chronic stimulation of excessive food intake 39 . Leptin therapy has shown to have dramatically beneficial effects on weight, fat mass and appetite, hyperinsulinaemia and...

Hydroxy BetaMethylbutyrate Arginine and Glutamine

Hydroxy-beta-methylbutyrate (HMB) is a leucine derivative, which, in common with arginine and glutamine, may favourably modulate protein turnover. The combination had already shown activity in weight-losing patients with acquired immunodeficiency syndrome 69 and has recently been tested against an isonitrogenous non-essential amino acid control supplement in weight-losing cancer patients (n 32). After 4 weeks of administration, patients receiving the experimental supplement had increased their...

Height and Body Weight

Unclothed measurements must be taken using an anthropometer and weight scales. Body weight is the most obvious index of nutritional status, but, taken alone, it is not an accurate measurement. Actual body weight must be compared with ideal body weight (IBW) and other anthropometric parameters. For example, patients with ascites and or oedema may have a normal body weight but severe malnutrition. Several approaches are used for estimating the IBW. One simple method consists of measuring body...

Anticytokine and Antiinflammatory Agents

Pentoxifylline and hydrazine sulphate both appear to modulate TNF but contemporary evidence does not support their use in weight-losing cancer patients 127-130 . Thalidomide and melatonin 131-134 are two agents for which there is some early evidence of clinical benefit. Melatonin has been studied in combination with chemotherapy and may modulate efficacy and toxicity 135 . Along with thalidomide it is a candidate for further study. Neither agent can currently be recommended for routine use in...

The Spectrum of Malnutrition

Hunger and malnutrition remain among the most devastating problems facing the majority of the world's poor and needy, and continue to dominate the health of the world's poorest nations. Nearly 30 of humanity - infants, children, adolescents, adults and older persons in the developing world - are currently suffering from one or more of the multiple forms of malnutrition. This remains a continuing travesty of the recognised fundamental human right to adequate food and nutrition, and freedom from...

Dietary Records and Diaries

The most widely used technique for the assessment of food intake is keeping a record of food consumption 31 . Ideally, food should be weighed before and after preparation, records kept during the meal, and leftovers weighed again 31 . This technique produces data that can be expressed in quantitative terms, be converted into nutrients, and serve as the basis of clinical and biochemical research 31 . Investigators working with the elder ly prefer the record system even if the food intake can be...

Pathogenesis

A complex imbalance of different body systems may cause the development of body wasting, with alterations in the body composition. Available evidence suggests that metabolic, neurohormonal, and immune abnormalities play an important role in the pathophysiology of cardiac cachexia. Pittman and Cohen, in 1964, proposed increased catabolism (protein loss) and reduced anabolism due to cellular hypoxia as the principal pathogenic factor 14 . Currently, several further mechanisms are thought to be...

Brain Functional Proinflammatory Stimulatory and Antiinflammatory Inhibitory Cytokine Balance

Data continue to accumulate that cytokine positive and negative feedback systems and a balance between stimulatory and inhibitory cytokines may be pivotal for an appropriate modulation of cellular responses in the brain. An unopposed proinflammatory cytokine response cascade could aggravate the magnitude of neurological and neu-ropsychiatric manifestations and may influence wasting and cachexia 36 . This relevant concept that focuses on the temporal profile of proinflam-matory and...

Concluding Remarks and Future Research

The weight-losing cancer patient suffers from a substantial loss of fat tissue. This is accompanied by profound changes in lipid metabolism, affecting almost all metabolic pathways involved in fat accretion mobilisation in the adipocyte. Many of these changes are triggered by cytokines, TNF-a in particular. Until very recently, adipose tissue was considered exclusively as a fat reservoir however, recent studies have demonstrated that the adipocyte is a key cell in the regulation of body weight,...

History of the Energy Value of Foods

Most of the fundamental work on the energy value of foods was carried out by the pioneer scientists Rubner (in Germany) and his pupil Atwater (in USA) at the end of the nineteenth century. Rubner measured the heats of combustion of a number of different proteins, fats, and carbohydrates in a bomb calorimeter and also studied the heat of combustion of urine passed by a dog, a man, a boy, and a baby. He realised that the heat of combustion of protein in a bomb calorimeter was greater than its...

Proinflammatory Cytokines and the Acute Phase Response

Among the specific causes of CACS, there is evidence of a chronic, low-grade, tumour-induced activation of the host immune system that shares numerous characteristics with the acute-phase response found after major traumatic events and septic shock. The latter is characterised by an increased production of cytokines 27, 28 high levels of catecholamine, cortisol, and glucagon 27, 29-31 increased peripheral amino-acid mobilisation and hepatic amino acid uptake 27, 32 increased hepatic...

Cachexia and Infectious Diseases

Malnutrition, particularly that related to micronu-trients (vitamins, trace minerals, essential amino acids, polyunsaturated fatty acids), is certainly one of the most easily preventable causes of death and disability. The 1995 World Health Organization (WHO) bulletin shows population-attributable risk for child deaths in 52 developing countries due to interaction between malnutrition and infectious disorders 16 . Malnutrition is a common complication of HIV infection and plays a significant...

Ghrelin and Weight Loss in Obesity

Obesity is a chronic disease that is causally related to serious medical illnesses such as type 2 diabetes mellitus, hypertension, hyperlipidaemia, sleep apnoea and orthopaedic complications. Based on evidence of the potent orexigenic action of ghrelin, its levels were at first expected to be increased in obesity. On the contrary, ghrelin levels turned out to be inversely related to body mass index. At present, the exact peripheral signals leading to a reduced ghrelin secretion in obesity have...

Albumin Pool Size Secretion Metabolism Nutritional and Hormonal Regulation

The concentration of serum albumin is the compounded result of synthesis, catabolism, changes in intra extravascular distribution, and hydration state. Normal plasma albumin concentration reflects the intravascular portion of the pool, which is about 40 of the total 11 . The total albumin pool (intra- plus extravascular) in a healthy adult human subject is about 200 grams. The extravascular pool is composed of one pool with a faster half life ( 6 h), likely located in organs with discontinuous...

Iron

A reduction in the plasma iron is considered an important host response to microbial infection. However, a number of T-cell and phagocyte abnormalities follow Fe deficiency 71 . Characteristic changes include reduced inflammatory responses such as the DTH reaction, impairments in neutrophil and macrophage cytotoxic activity, reductions in lymphocyte proliferation, T-cell numbers, cytokine release, antibody production, and lymphoid tissue atrophy. Whitley et al. 72 noted decreased allograft...

Criteria for Considering Patients as Responders High Responders or Nonresponders

The patients were considered as 'high responders' if the following changes occurred after treatment - Improvement of clinical response plus improvement of PS, or improvement of clinical response plus stability of PS, or stability of clinical response plus improvement of PS - Improvement of at least three nutritional functional variables with stability of the other variables - Improvement of three or more laboratory variables (including at least proinflammatory cytokines and ROS) independently...

Cytokines and Insulin Resistance

In addition to their well-known anorectic and hypermetabolic effects, cytokines appear to be involved in obesity-related disorders such as insulin resistance and vascular diseases 65 . Epidemiological findings support the hypothesis that the metabolic syndrome, type II diabetes and cardiovascular diseases have an inflammatory component mediated by cytokines 66, 67 . Thus, overweight and obese children as well as adults have elevated serum levels of C-reactive protein, IL-6 and TNF-a, which are...

Mechanisms of Malnutrition in Chronic Pancreatitis

Malnutrition and weight loss in patients with chronic pancreatitis mainly result from maldigestion and abdominal pain (Fig. 1). The loss of aci- Fig.1. Malnutrition in patients with chronic pancreatitis. Modified from 83 Fig.1. Malnutrition in patients with chronic pancreatitis. Modified from 83 nar cells causes insufficient secretion of lipase, col-ipase, amylase, and proteases, which results in maldigestion of lipid, carbohydrates, and protein. Of these nutrients, fat maldigestion is the most...

Pentoxifylline

Pentoxifylline decreases TNF-a production by suppressing TNF-a mRNA transcription 140 . Studies using pentoxifylline to treat cancer- and HIV-associated cachexia demonstrated that it did not improve appetite, weight, or sense of well-being 141-143 . It may have even have an adverse effect on the course of opportunistic infections. Sathe and Sarai 144, 145 found that pentoxi-fylline treatment led to impairment in TNF-a secretion and, thereby, increased the mycobacterial load in macrophages of...

Experience with an Ambulatory Physical Activity Meter

We are currently undertaking pilot work with an advanced physical activity meter (Fig. 2), the activPAL professional 'physical activity logger' (PAL Technologies, Glasgow, Scotland). This records the time that is spent lying sitting, standing and stepping. In addition it will display the number of up-down down-up transitions, the stepping cadence and estimated energy expenditure. From this estimated energy expenditure it is possible to derive an estimated PAL (the estimated energy expenditure...

Causes of Malnutrition in the Elderly

The major causes of weight loss, as determined by several large studies, are summarised in Table 1. In Table 1. Diagnostic spectrum of involuntary weight loss. (Modified from 3 ) Table 1. Diagnostic spectrum of involuntary weight loss. (Modified from 3 ) aOther medical diagnoses neurologic, infectious, alcohol, medication, renal, inflammatory disease n, number of patients aOther medical diagnoses neurologic, infectious, alcohol, medication, renal, inflammatory disease n, number of patients...

The Ubiquitin Proteasome System

Proteins degraded by the ubiquitin proteasome system are first conjugated to multiple molecules of ubiquitin, a 76-amino acid, 8.5-kDa residue that is highly conserved and present in the cytoplasm of all eukaryotic cells 6 . Ubiquitinated proteins are degraded by the proteolytic 26s proteasome, the catalytic core of which is the 20s proteasome, a barrel-shaped particle consisting of four stacked rings with seven subunits in each ring. This complex and tightly regulated process takes place...

Influence of Nutritional Status on Immune Response

A survey of the literature shows that most nutritional deficits lead to suppressed immune responses. This is not surprising, since anabolic and catabolic pathways in the immune system require the same sort of building blocks and energy sources as other physiological activities. Caloric restriction is another area of emerging interest, with important implications for human health. In general, moderate caloric restriction appears to have beneficial effects on longevity and disease resistance....

Energy Distribution Among Nutrients

The choice of foods according to their energy value represents the basis for building-up the energy-controlled dietary regimens that are required under different conditions, such as reduction of body weight (in overweight or obese patients), increased energy demand during recovery from illness or surgery, or high-level physical activity 11,12 . Fig. 2. Metabolic products of carbohydrate fermentation by colon microflora Table 2. Distribution of foods according to the four energy categories3...

Drugs

It is important that every underweight patient at risk for malnutrition undergoes intense nutritional support in order to improve the prognosis of the underlying disease as well as the quality of life. The patient's ability to maintain his or her weight at close to ideal or normal levels may be aided by the prescription of appetite-stimulating drugs (Table 2), such as cyproheptadine 63, 64 , medroxyprogesterone acetate (MPA) 65, 66 , megestrol acetate (MA) 67-69 , insulin-like growth factor-1...

The Challenge of Nutritional Intervention Trials in Cancer Cachexia

In general, trials of clinical nutrition begin with the observation that a particular disease and or its treatment are associated with adverse clinical outcomes. It is also observed that, during the course of this disease, patients demonstrate deteriorating nutritional status. The hypothesis is then derived that disease-related deterioration in nutritional status may contribute to the overall adverse clinical outcomes. The challenge in clinical trials is to develop a nutritional intervention of...

Neuroendocrine Tumors

Neuroendocrine tumours (NET) constitute a heterogeneous group of neoplasms that originate from endocrine glands, such as the pituitary, parathyroids, and adrenals, as well as endocrine islets within glandular tissue (thyroid or pancreatic) and cells dispersed between exocrine cells, such as the endocrine cells of the digestive and respiratory tracts 31 . NET can be divided into four groups (a) carcinoid tumours, (b) islet cell tumours, (c) chromaffin cell tumours (PHs and paragangliomas), and...

Proinflammatory Cytokines

Immune response results in a variety of metabolic adjustments that are mediated by cytokines of leukocytic origin. Among cytokines released during an immune response, IL-1, TNF-a and IL-6 are the major mediators of intermediary metabolism. These cytokines act in concert to decrease food intake, increase resting energy expenditure, gluco-neogenesis, glucose oxidation, and hepatic synthesis of fatty acids and acute-phase proteins, decrease fatty acid uptake by adipocytes and alter the...

Folate

Folate is the generic name for folic acid-related compounds. They are mainly involved in thymi-dine synthesis. There seem to be no age-related changes in folate metabolism. Folate is ubiquitous in nature and is present in nearly all natural foods. Deficiencies are characterised by anaemia (mega-loblastic), depression and dermatological lesions 56 . Alcohol and drug intake increase the risk of deficiency. Folate deficiency can occur within a few days of insufficient intake 54 . This deficiency...

Fibronectin

Fibronectins (FNs) are high molecular weight gly-coproteins found in plasma, on cell surfaces, and in extracellular matrices 89 . Cell FN (cFN) and plasma FN (pFN) are two different products of a single gene 90 . cFN is synthesised by fibroblasts and other cell types, which secrete it into the extracellular matrix, where it assembles in a fibrillar form. In contrast, pFN is synthesised by hepa-tocytes and circulates as a soluble molecule in plasma 91 . Both forms are disulphide-linked dimers of...

Nutritional Support

Nutritional support seems to be an easy way of improving the nutritional status in cachectic heart-failure patients. However, non-surgical studies with such patients are rare, and perioperative studies evaluating the effect of nutritional support on mortality have yielded contradictory results 8, 88 . In a non-surgical study, intensive nutritional support led to an increase in the amount of lean tissue 89 . Another study demonstrated no significant effect on the clinical status of heart failure...

PBlockers

Wasting in cancer patients is multifactorial, but is caused, at least in part, by increased p(1)- and p(2)-adrenoceptor activity, as well as elevated basal metabolic rate and altered host metabolism 172-174 . Weight gain in response to p-blocker therapy in the hypertensive population may be attributable to decreased resting energy expenditure, inhibition of lipolysis, and decreased insulin sensitivity 175, 176 . p-Blocker therapy has also been shown to reverse excess protein catabolism after...

Tube Feeding

Tube feeding has been indicated in persons with neuromuscular diseases (with impaired swallowing or gag reflex), postoperative patients, individuals who are unable to eat, and patients using ventilators. Feeding-tube-associated side effects include aspiration, diarrhoea, and vomiting 21 . Numerous studies have been aimed at determining the benefits of tube feeding 22 . Mitchell et al. found no evidence that tube feeding prolonged survival, especially if dysphagia is the main indication 23 ....

Impairment of the Immune System

Immunodepression is a key feature of patients with CACS. The severity of immunodepression is related to stage of disease and severity of cachexia. Several of our studies demonstrated that the immune system of cancer patients shows an impaired blastic response to mitogens. The reduced proliferative response to mitogens (such as PHA, anti-CD3 antibody and recombinant IL-2) of peripheral blood mononuclear cells (PBMCs) isolated from cancer patients has to be considered as an index of more complex...

Nutritional Supplementation

Rolls and Dimeo found that even healthy elderly men consumed significant less baseline energy compared to young men 13-16 . Roberts et al. found that healthy elderly men had both a short-term (7 weeks) and a long-term (6 months) impairment in adjusting their food intake after an episode of either overfeeding or underfeeding. Encouraging the elderly to take in extra food (with verbal prompts, physical assistance, or appetite stimulants) at mealtime over a period of 4-6 weeks, then allowing them...

Conclusions and Future Steps

Both chronic inflammation and protein-energy malnutrition, together also referred to as MICS, are involved in engendering the commonly encountered wasting syndrome in CKD population. Hypoalbuminaemia is a marker of MICS and a strong outcome-predictor in these patients. The wasting syndrome in CKD patients per se is a chronic and slowly progressive condition that worsens over time in both pre-dialysis 54, 55 and dialysis patients 191 . Hence, a state of 'cachexia in slow motion' can be described...

Congenital Partial Lipodystrophy Type 1 Dunningam Syndrome

This LD variety was first described by Dunningam in 1974 32 in females belonging to two families in Scotland. An autosomal dominant transmission of the disease was reported in five families. To date, some 200 cases of the disease have been reported, with a higher prevalence in females. Atrophy of the subcutaneous fat layer usually manifests at puberty, involving the arms, legs, and buttocks. The subcutaneous adipose tissue of the face, neck, and intra-abdominal area may be preserved, giving...

Body Mass Index

A more recent approach to the evaluation of nutritional status refers to body mass index (BMI). It affords a more accurate measurement, as follows body weight (kg) height2 (m2). The reference table (Table 11) includes only five classes 0 < 20 kg m2, weight deficit N 20-24.9 kg m2, normal 1 25-29.9 kg m2, mild weight excess 2 30-39.9 kg m2, obesity 3 > 40 kg m2, severe obesity. Table 11. Body mass index values of the body classes Table 11. Body mass index values of the body classes Recently...

Congenital Generalised Lipodystrophy Berardinelli Seip Syndrome or Lipoatrophic Diabetes

Congenital generalised lipodystrophy (CGLD) is an autosomal recessive, transmitted disease characterised by a pronounced loss of subcutaneous and visceral fat tissue manifested since birth. The condition is associated with acromegalic traits (Fig. 2), accelerated growth with normal hGH Fig. 2. A patient with congenital lipodystrophy or lipoatrophic diabetes. There is evidence of a pronounced loss of subcutaneous fat, acromegaloid aspect, and phlebomegaly (for details, see Table 3, patient GF)...

Anticytokine Approaches to CAC Treatment

Proinflammatory cytokines such as IL-1, IL-6, and particularly, TNF-a have a prominent role in the pathogenesis of CAC. The specific neutralisation of these factors with antibodies in animal models of cachexia suggests that an anticytokine approach is worth pursuing, while taking into account that no single cytokine is responsible for all abnormalities found in CAC. However, in chronic human diseases such as cancer, the long-term administration of anticytokine antibodies could be of no...

Main Proposed Brain Mechanisms in Wasting and Cachexia

Multiple models have been proposed mediated either by the pathophysiological process itself (e.g. a tumour, chronic infections) or by host-derived chemical factors. The following brief description focuses on 'mediator mechanisms' in wasting and cachexia that can affect brain function directly or indirectly. It is accepted that, in many cases, the magnitude of anorexia does not have a relationship with the severity of wasting and cachexia and degree of malnutrition. Here, metabolic abnormalities...

Short Bowel Syndrome

Short bowel syndrome is a malabsorptive state of the small intestine resulting from intestinal resec tion. When more than 75 of the small intestine is resected, a clinical syndrome usually occurs. Its major features are diarrhoea, malabsorption, and malnutrition. The severity of this disease depends on the length and site of residual intestine, as well as other factors. In addition, adaptation of the residual intestine following resection may compensate the impaired absorbing function to some...

Administration of Melatonin in Cancer Associated Cachexia

To investigate the in vivo relationships between cancer cachexia, TNF, and melatonin, our Institution carried out a randomised clinical trial in 1994 in advanced-stage cancer patients with progressive disease after standard treatment 53 . This randomised, open-label study enrolled 100 patients with metastatic solid tumours who had not responded to previous conventional antitu-mour treatment and or who were not eligible to receive other effective standard forms of treatment. Exclusion criteria...

Patients and Methods Study Design

An open non-randomised phase II study was designed according to the Simon two-stage design for P1 - P0 0.20 considering P0 (i.e. non-effective treatment) as a total response of < 40 of patients and P1 (i.e. effective treatment) as a total response of at least 60 of patients, the treatment should be considered effective if at least 21 out of 39 patients are 'responders'. The study was approved by the Ethical Committee of the Policlinico Universitario, University of Cagliari, and written...

Palliative Nutritional Endpoints and Decision Making

A careful multidimensional evaluation is the basis for treatment decisions for patients with advanced illness, such as cancer, suffering from anorexia, cachexia and related symptoms (see also Chp. 9.11 'Eating-related Distress of Patients with Advanced, Incurable Cancer and Their Partners'). In order to prioritise anorexia cachexia in the present (and often rapidly fluctuating) context, the patient should be assessed considering concurring physical (anorexia, fatigue, asthenia, body image,...

Biochemical Parameters of Nutrition in the Elderly

The epidemiological findings suggest that intakes of particular vitamins are related to the incidence of chronic diseases 53 so vitamin requirements and metabolism should be studied more closely. Vitamins that act as antioxidants appear to have a role in preventing coronary artery disease and cancer 53 . Current work is focusing on the actions of vitamins as related to immune function, the formation of cataracts, and the development of osteoporosis, all associated with ageing 53 . The Food and...

Effects on Metabolism and Energy Expenditure

As already mentioned, most of the effects of thyroid hormones (TH) are exerted on energy metabolism, including protein, carbohydrate, and lipid metabolism 18 . The stimulation of energy metabolism and heat production is reflected by the increased basal metabolic rate (BMR), increased appetite, heat intolerance and slightly elevated basal body temperature that occur during TS. Despite the increased food intake, a state of chronic caloric and nutritional inadequacy often ensues, depending on the...

Social Causes of Weight Loss

In developing countries, malnutrition takes on different forms of multiple or partial deficiencies, ranging from simple undernourishment to denutrition and cachexia. High rates of malnutrition persist, in spite of progress in the production, preservation, and distribution of food, and in sanitary measures and education. UNO, FAO, WHO and UNICEF data collected in the 1990s (Table 2) show that 20 of the popu- Table 2. Prevalence of undernourishment in developing countries (source FAO) Countries...

COX2 Selective Inhibitors Celecoxib Rofecoxib and Valdecoxib

COX-2 is a bifunctional enzyme possessing both cyclo-oxygenase and peroxidase activities. Selective COX-2 inhibitors inhibit PG biosynthesis (anti-COX-2 activity) but do not, or only partially, affect the peroxidase activity of COX, which can generate proximate carcinogens. In experimental animals, selective inhibitors of COX-2 such as cele-coxib reduce the formation of head and neck, col-orectal, stomach, lung, breast and prostate tumours. In addition to preventing tumorigenesis, selective...

Magnesium

Animal studies have associated magnesium (Mg) deficiency with increases in thymic cellularity and inflammatory cells (especially eosinophils). Magnesium deficits also elevate plasma concentrations of inflammatory cytokines such as IL-1, IL-6 and TNF-a. Conversely, Mg deficiency decreased concentrations of acute-phase molecules 71 . Complement activity depends on an optimum Mg concentration range. In vitro T-cell-mediated lysis of target cells is directly propor tional to Mg concentration, an...

Atherosclerotic Cardiovascular Disease

Cachexia, by virtue of MICS, may predispose CKD patients to atherosclerotic cardiovascular disease 24, 49, 51 . Dialysis patients with coronary heart disease often have hypoalbuminaemia and elevated levels of acute-phase reactants 24 . Moreover, progression of carotid atherosclerosis during dialysis may be related to IL-6 levels 137 . It should be noted that the cascade of inflammatory factors leading to an acute-phase reaction is counter-regulated by various anti-inflammatory cytokines, such...

Creactive protein

C-reactive protein (CRP) is an acute-phase protein that is a very sensitive index of inflammation. Its serum level increases as much as 1000-fold during the acute phase of inflammation 65-68 . Structurally, it is a planar pentamer of identical subunits, expressed and synthesised almost exclusively in the liver by the hepatocytes. Its normal concentrations, using a sensitive assay, normally range between 0 and 2.5 mg l. Besides being an index of inflammation, CRP concentrations have been...

Enteral Feeding

In general there are three indications for enteral feeding 10 (1) patients with neuromuscular disease may have impaired swallowing or gag reflexes (2) patients with hypermetabolic states, such as those induced by cancer or cachexia, may be unable to meet their nutritional needs by eating alone (3) patients who are unable to eat, such as those who are ventilator-dependent, postoperative, or have tumours of the upper gastrointestinal tract. In the elderly, the most common indication for enteral...

Proteolysis Inducing Factor

Proteolysis-inducing factor (PIF) is a 24-kDa sul-phated glycoprotein secreted by cachexia-induc-ing murine and human tumours 29 . Administration of PIF to normal mice causes atrophy of skeletal muscle by an inhibition of protein synthesis and an increase of protein degradation 30 . The increased protein degradation arises from an increased expression of the ubiquitin-proteasome proteolytic pathway 31 . As with TNF-a 24 , upregulation of the pathway involves the transcription factor NF-kB 32 .

Thyroid Disorders Thyrotoxicosis

The term thyrotoxicosis (TS) refers to the biochemical and physiological manifestations of excessive quantities of thyroid hormones. TS may be due to sustained hormone overproduction (hyperthyroidism) or to excessive circulating hormone levels not associated with hyperthyroidism (Table 1). The effects of TS on the major organ systems are the same regardless of the underlying origin, and weight loss is a common feature in the presence of intermediate and severe TS. Table 1. Classification of...

Definition and Diagnosis

Cachectic heart-failure patients are weaker and fatigue earlier, which is due to both reduced skeletal muscle mass and impaired muscle quality. A simple and fast applicable definition of 'clinical cardiac cachexia' is the following in CHF patients without signs of other primary cachectic states (e.g. cancer, thyroid disease, or severe liver disease), cardiac cachexia can be diagnosed when weight loss of > 6 of the previous normal weight is observed over a period of > 6 months 4 . The...

Cold Exposure

This condition involves the immediate activation of the orthosympathetic system, with the consequent, immediate functional activation of brown adipocytes via the innervation and the neuro-adipocytic junctions described above. In a matter of hours, activated adipocytes exercise their ther-mogenic function by synthesising new mitochondria and UCP1 in the course of a few days new cells develop, giving rise to a new tissue organisation characterised by an increased number of vessels and nerves 59,...

Metabolic Factors

Relevant comments in other chapters of this book relate to the biochemical and metabolic derangements and tumour-derived products including lipid-mobilising factors and proteolysis-inducing factors that have been implicated in the development and or progression of wasting and cachexia in animal models and humans 4, 15 . Through a variety of mechanisms, cytokines can also contribute to the metabolic dysregulation and insulin resistance in wasting and cachexia 3,4,16 . Factors that induce...

Selenium

Selenium (Se) deficiency is associated with suppression of a large number of immunological endpoints including resistance to infection, antibody synthesis, cytotoxicity, cytokine secretion and lymphocyte proliferation, and is also associated with a high incidence of cancer. Conversely, experimental Se supplementation increases the most important immune parameters, suggesting that this element has adjuvant properties. In a recent paper, we demonstrated that SeO2 was effective in inducing a...

Mini Nutritional Assessment MNA

The Mini Nutritional Assessment (MNA) is a rapidly administered, simple tool for evaluating the nutritional status of older persons. It consists of 18 items 38 and can be administered by a healthcare professional in less than 15 minutes. It involves a general assessment of health, a dietary assessment, anthropometric measurements, and a subjective self-assessment by the patient (Table 2). The results of the MNA test classify the patient as well nourished, at risk for malnutrition, or...

R

Consider treatable causes (MEALS ON WHEELS) Consider orexigenic drugs (appetite stimulants) Stop drugs that cause anorexia or substitute where possible Reversible Causes of Protein-Energy Malnutrition in Nursing Homes The MEALS ON WHEELS Mnemonic* M edications (eg, digoxin, theophylline, antipsychotics) E motional problems (depression) A norexia tardive (nervosa) Alcoholism L ate-life paranoia S wallowing disorders O ral problems N osocomial infections (tuberculosis, Helicobacter pylori,...

Adipose mass redistribution

Body composition changes with advancing age Accurate body composition information is considered to be more difficult to obtain in the elderly than in younger age groups for a variety of reasons 12 . Several methods are available for assessing body composition, but it is questionable whether some of them can be used in an older population. In clinical practice, anthropometry cannot adequately estimate nutritional status, and measuring fat mass (FM) and fat-free mass (FFM) is recommended....

Drug Therapy

The optimal therapeutic approach to anorexia should be aimed at counteracting its pathophysio-logic mechanisms. Therefore, considering their involvement in anorexia, cytokines represent the ideal therapeutic target. A series of animal studies support this approach by showing that intrahypo-thalamic IL-1 blockade results in amelioration of anorexia and improves food intake 48, 62 . In humans, cytokine therapeutic targeting is achieved by the use of agents that interfere with their synthesis and...

Robinson D

Clinical Hematology Oncology, Centocor, Malvern, PA, USA Department of Medical and Surgical Sciences, Department of Clinical and Surgical Sciences (Surgery), The University of Edinburgh, Royal Psychiatric Clinic, San Raffaele Hospital, Department of Cardiology, Charit , Campus IRCCS S. Matteo Polyclinic, University of Pavia, Department of Surgery, Section of Plastic Surgery, IRCCS Maugeri Foundation, University of Pavia, Department of Geriatrics, Nutrition, Bone Marrow and Blood Stem Cell...

Molecular Mechanisms of Transdifferentiation

Energy expenditure via activation of the orthosympathetic system is essential for the energy balance indeed, mice lacking all p receptors (1, 2 and 3), though not exhibiting changes in the amount of food intake or in motor activity, become precociously and massively obese 66 . These mice exhibit a complete and early transformation of BAT into WAT, in line with the observations that absence of BAT results in obesity and that ectopic UCP1 expression in WAT makes mice resistant to obesity. These...

Cytokine Model in Brain Responses

In various clinical conditions, 'blood circulating' and 'organ tissue' cytokines could cooperate and this has implications for an integrative cytokine involvement in disease. Thus, proinflammatory cytokines produced and released within brain can interact with cytokines from systemic origin to modulate metabolic outputs and neuropsychiatric manifestations associated with wasting and cachexia. The simultaneous up-regulation of cytokines in peripheral organs and brain regions in response to a...

Positive Energy Balance Overweight and Obesity

When the energy balance is positive, the adipose organ prevalently undergoes an increment in its white component. White adipocytes become hypertrophic and subsequently hyperplastic (likely due to a close causal relationship). In fact, it has been suggested that adipocytes are unable to expand beyond a given maximum volume, or 'critical size', which is genetically determined and specific for each depot 77 . Adipocytes that have reached the critical size trigger an increase in cell number 78-80 ....

Introduction Background

Cancer cachexia is a major symptom burden for patients with cancer. Cachexia occurs in up to one half of all patients diagnosed with cancer 1 and is more frequent in patients with lung and upper-gastrointestinal cancer. Cancer cachexia results from the interaction of the host and the tumour. However, the nature of this interaction is incompletely understood 2-5 , including the dynamics of the host response (activation of the systemic inflammatory response, metabolic, immune and neuroendocrine...

Role of Hypothalamic Neuroimmune Interactions

The mechanisms by which cytokines negatively influence energy intake are currently under investigation. As proposed by Inui, cytokines may play a pivotal role in long-term inhibition of feeding by mimicking the hypothalamic effect of excessive negative-feedback signalling 53 . This could be done by inhibition of the NPY AgRP orexigenic network as well as by persistent stimulation of the Recent data suggested that hypothalamic sero-tonergic neurotransmission may be critical in linking cytokines...

Cyclic Plasma Perfusion

Anaemia-inducing substance (AIS) is a protein of approximately 50000 molecular weight that is secreted by malignant tumour tissue and depresses erythrocyte and immunocompetent cell functions. Ishiko and et al. reported enhanced AIS activity and lipolytic activity as the tumours grew and suggested that AIS is one of the substances involved in the enhanced lipolytic activity seen in advanced-tumour-bearing rabbits 198 . AIS can be removed by cyclic plasma perfusion adsorption in animal studies...

Isolation and Structure of Proteolysis Inducing Factor

Initial attempts to purify a lipid mobilising factor (LMF) from the MAC16 tumour, using anion exchange chromatography, revealed the presence of a 24-kDa band on Western blotting, detected using serum from mice bearing the MAC16 tumour 9 . Antibodies to the 24-kDa material were not present in the serum of mice bearing the MAC13 tumour, which is histologically similar to the MAC16 tumour but which does not induce cachexia. A similar 24k-Da band on Western blots was detected using serum from...

Ponalrestat

Lipoprotein lipase (LPL) is a key regulatory enzyme responsible for the hydrolysis of triglyceride (TG)-rich lipoproteins. The reduction in LPL activity is observed in tumour-bearing animals and cancer patients with cachexia, suggesting an involvement of LPL in inducing cancer cachexia 192 . Kawamura et al. demonstrated that tumour-induced cachexia in mice is inhibited by ponalre-stat 193-195 . This suggests that ponalrestat, a LPL-activating agent, has a therapeutic potential for the treatment...

Protein

In order to block protein loss, it is necessary to administrate amino acids in quantities of 1.5-2 g kg day, as well as a sufficient amount (< 0.7 g kg) of essential amino acids. Selective mixtures of branched-chain amino acids are useful in treating patients with associated liver diseases and a tendency to encephalopathy. The administration of nutritional supplements reduces the length of hospitalisation and rehabilitation, as well as the mortality rate. Early and aggressive nutritional...

The Future

Clinical experience suggests introduction of the routine control of lipid metabolism in the clinical treatment of HIV patients. This will protect patients from side effects of therapies that compromise their quality of life and the functions of organs, such as the pancreas and heart, that are targets in lipid disorders. Guidelines must be proposed in which the clinical examination of HIV patients includes assessment of body shape and body composition, and laboratory evaluation of blood lipids...

The Functional Impact of Cancer Cachexia

Many of the consequences of cachexia are likely to impact on patient function but as yet this has not been studied in detail. There is, however, a considerable body of knowledge about the importance of weight loss in relation to clinical end-points and treatment variables. Scott 37 studied patients with inoperable non-small-cell lung cancer -about 40 had at least 5 weight loss and almost 80 an elevated CRP. Weight-losing patients had a significantly lower KPS and overall QoL and greater fatigue...

Exercise

Exercise training is a therapeutic option that has been probably underevaluated so far. Moderate exercise training improves exercise capacity by reversing muscular metabolic abnormalities and atrophy as well as impaired blood flow and neurohormonal abnormalities 102 . Pathophysiological , skeletal-muscle cytochrome c oxidase activity is increased with long-term training, and this is associated with reduced local expression of pro-inflammatory cytokines 103 . Exercise training may therefore help...

Central Cytokines

Glia cells and neurons in various brain areas express proinflammatory cytokines and cytokine receptors 9, 10 . Acute and chronic CNS diseases (e.g., meningitis, encephalitis, multiple sclerosis, Alzheimer's disease, stroke and brain tumours) stimulate CNS cytokine production 11, 12 . Cytokines produced within the blood-brain barrier (BBB) can act directly on neural circuitries controlling energy balance, and intracerebroven-tricular (ICV) administration of proinflammatory cytokines presumably...

Small Intestine

Creamer examined the structure of the mucosa of the small intestine in five patients with malignancy that arose outside the GI tract 36 . He concluded that 'weight loss and ill health' were associated Fig. 1. The putative influence of non-gastrointestinal (GI) tumour on the regulation of brain and GI-tract activity, as these relate to gastric emptying and small bowel absorption. NTS, nucleus of the solitary tract with an abnormal small-intestinal mucosa. As shown in Fig. 2, the changes were...

Hypothalamus and Pituitary Disorders

Hypothalamic and or pituitary disorders can result from different kinds of lesions, most com monly tumours, trauma, congenital brain defects, infections or inflammation, radiation therapy, vascular damage or malformation, familiar disorders, granulomatoses. In addition, they can originate from the hypothalamus or from suprahypothalamic structures and secondarily cause pituitary dysfunction, or take origin directly in the pituitary gland, most commonly when pituitary tumours develop 36 .

Corticosteroids

Corticosteroids, an important palliative intervention for patients with advanced cancer, stimulate appetite. Multiple randomised, placebo-controlled trials of corticosteroids, at a variety of doses and schedules, have tested their appetite-stimulating properties (Table 1) 7-11 . Corticosteroids consis tently improve appetite, though short-lived (4-8 weeks), without measurable increase in weight gain. In general, treatment with corticosteroids is associated with an improvement in overall sense...

Refining Oral Nutritional Support

For any oral nutritional supplement to be effective it must be consumed and unfortunately patients with advanced cancer frequently demonstrate anorexia, early satiety and alteration in taste and food preference. These obstacles to increasing oral nutritional intake suggest that appetite and desire for food will often need to be improved if an oral nutritional supplement is to have any chance of benefit. This could be particularly important in patients also receiving anti-cancer therapies, which...

Palliative Symptom and Syndrome Management

Eating-related symptoms encompass a wealth of possible symptoms, which can be individually very different in severity and predominance. Their management follows multidimensional principles. For palliative treatment of anorexia, the progestins are still the most effective drugs, but with limited effects on other nutritional endpoints. It remains to be discussed with the patient, whether the pure improvement of the sensation of appetite is a meaningful endpoint considering the side-effects and...

Energy Values from the Food Composition Tables

These values represent the average calculations derived from the chemical composition of food, which can vary according to the sample and the method used, resulting in possible differences among the various tables applied by different countries. However, the differences are generally small and acceptable for evaluating the actual intake of food energy in a mixed diet. For carbohydrates, a value of 3.75 Kcal g, when expressed as monosaccharides (corresponding to the physical value), is used. In...

Superficial

The superficial fat (areolar fat) consistently lines the skin and follows the skin displacements. It can be considered a part of the skin, as it is responsible for the terminal vascularisation of the skin itself. Histologically it has a lobular pattern and a vertical orientation, being located within connective arches (retinacula cutis). Its mean dimensions are 0.5-1.0 cm per unit. It is firmly anchored both to the undersurface of the skin and to the fascia superficialis these septa are able to...

Nitrogen Metabolism and Dietary Protein Characteristics

Nitrogen balance data measured after adaptation to different protein levels over periods of several days is the usual approach to measure nitrogen retention 2, 44 . Diets containing poor quality proteins are associated with an increase in nitrogen losses, due to the inefficient utilisation of indispensable amino acids in turn linked to unbalanced amino acid composition. The (relative) lack of essential amino acids generates the ineffective utilisation of dietary nitrogen. Furthermore, besides...

Nutrients Deficiency and Diarrhoea

Under physiological conditions, each nutrient is absorbed at a specific site of the small intestine. The majority of carbohydrates, proteins, and fats are normally absorbed within the first 150 cm of small bowel. Folic acid, calcium, magnesium, iron, vitamin C, and fat-soluble vitamins (A, D, E, and K) are also absorbed in the proximal intestine. Thus, resection of the proximal intestine means a reduction in the absorption area for these nutrients. In addition, the loss of intestinal lactase,...