Are cytokines possible mediators of cancer cachexia?

The possible role of cytokines in the development of cancer cachexia was reviewed from the literature. Tumor necrosis factor (TNF)-alpha, interleukin (IL)-1, IL-6, interferon (IFN)-gamma and leukemia inhibitory factor (LIF) can elicit many but not all host changes seen in cancer cachexia, including loss of appetite, loss of body weight, and the induction of acute-phase protein synthesis. However, these cytokines are not always demonstrated in the circulation of the cancer patients. The inability to detect circulating cytokines may be due to their low rate of production, their short half-life and rapid clearance from plasma, or their mode of action (autocrine or paracrine). Different cytokines are induced to stimulate the same response. This is very different from hormonal regulation, where a hormone acts on a cell directly through a specific receptor without depending on other mediators. Specific antibodies including anti-IFN-gamma, anti-TNF and anti-IL-6 antibodies, as well as the cyclooxygenase inhibitor indomethacin, have been used to reverse cancer cachexia. Overlapping physiologic activities make it unlikely that a single substance is the sole cause of cancer cachexia. It is hoped that further investigation on other cytokines and their possible relationships with hormones will help to clarify the mechanisms of cancer cachexia in the near future.This work was supported by a grant from the Japan-Sweden Foundation in 1991.     

Incarceration and the acquired immunodeficiency syndrome: Autopsy results in Texas prison inmates

The Texas Department of Criminal Justice (TDCJ) houses many subjects with acquired immunodeficiency syndrome (AIDS) who receive medical care in a comprehensive AIDS treatment center. In this case-control autopsy survey, we compared pathological outcomes of TDCJ inmates treated at the center (n = 155) with nonincarcerated patients who died during the same period (n = 155). Using multiple regression analysis and a proportional hazards model, survival time in the prisoners was equivalent to that in the controls. With few exceptions, the prevalences of opportunistic viral, fungal, protozoal, and bacterial infections contributing to mortality were equivalent between groups. Mycobacterium tuberculosis was isolated more frequently in the inmates, and M avium intracellulare was isolated less frequently (P < .0001). The inmates had a higher prevalence of bacterial infection of the central nervous system (CNS) (9.1% v 1.4%; P < .006); half of all CNS bacterial infections were caused by M tuberculosis. Inmates had significantly lower prevalences of vacuolar myelopathy (P < .006) and severe wasting disease (P < .0009). We conclude that survival of prison inmates with AIDS treated in a comprehensive AIDS treatment center was equivalent to that of nonincarcerated subjects with AIDS. Prevalences of certain complications of AIDS differed in the inmates, showing that the prison environment influenced some of the underlying causes of AIDS morbidity and mortality.     

Skeletal muscle contractility is preserved in COPD patients with normal fat‐free mass

Aim: Peripheral muscle dysfunction often occurs in patients with chronic obstructive pulmonary disease (COPD). The muscle dysfunction may be caused by a loss of force‐generating capacity, resulting from a loss of muscle mass, as well as by other alterations in contractile properties of skeletal muscle. Methods: The maximal isometric voluntary strength and fatigability were determined in hand‐grip and quadriceps muscles from nine male COPD patients (FEV₁ 30–50% predicted) and control subjects matched for fat‐free mass (FFM), physical activity level and age. Contractile properties and fatigability of the quadriceps muscle were also studied with electrically evoked isometric contractions. Results: The maximal voluntary force (MVC) and fatigability of the handgrip muscle did not differ between the COPD patients and control subjects. Also the MVC of the quadriceps muscle and the rate of force rise, contraction time, force–frequency relationship and fatigability, as determined with electrically evoked contractions, were similar in patients with COPD and control subjects. Conclusion: Skeletal muscle strength, contractile properties and fatigability are preserved in patients with moderate COPD and a normal FFM and activity level. This suggests that skeletal muscle dysfunction does not take place during moderate COPD until cachexia and/or a decline in physical activity occur.     

Differential Diagnosis of Cachexia and Refractory Cachexia and the Impact of Appropriate Nutritional Intervention for Cachexia on Survival in Terminal Cancer Patients

Cancer cachexia subsequently shifts to refractory cachexia, however, it is not easy to properly differentiate them in clinical settings. Patients considered refractory cachexia may include cachectic patients with starvation. This study aimed to identify these cachectic patients and to evaluate the effect of nutritional intervention for them. Study subjects were terminal cancer patients admitted for palliative care and were judged refractory cachexia in the last five years. We retrospectively examined to find useful indices for identifying such cachectic patients and for evaluating the effect of nutritional intervention. Out of 223 patients in refractory cachexia, 26 were diagnosed cachexia with starvation after symptom management. Comparing before and one week after this management, Palliative Performance Scale (PPS) and transthyretin significantly improved (p < 0.0001, p = 0.0002, respectively) Then, we started nutritional intervention for these cachectic patients and divided into effective group (n = 17) and non-effective group (n = 9) using the criteria for cachexia. Comparing between the two groups, PPS significantly improved2 weeks after intervention in effective group (p = 0.006). Survival time was significantly longer in effective group (p = 0.008). PPS and transthyretin were useful for differential diagnosis of cachexia and refractory cachexia. PPS was useful for evaluating nutritional intervention for cachectic patients. Appropriate nutritional intervention improved survival.     

The Spectrum of Malnutrition/Cachexia/Sarcopenia in Oncology According to Different Cancer Types and Settings: A Narrative Review

Nutritional status in oncological patients may differ according to several modifiable and non-modifiable factors. Knowledge of the epidemiology of malnutrition/cachexia/sarcopenia may help to manage these complications early in the course of treatment, potentially impacting patient quality of life, treatment intensity, and disease outcome. Therefore, this narrative review aimed to critically evaluate the current evidence on the combined impact of tumor- and treatment-related factors on nutritional status and to draw some practical conclusions to support the multidisciplinary management of malnutrition in cancer patients. A comprehensive literature search was performed from January 2010 to December 2020 using different combinations of pertinent keywords and a critical evaluation of retrieved literature papers was conducted. The results show that the prevalence of weight loss and associated symptoms is quite heterogeneous and needs to be assessed with recognized criteria, thus allowing a clear classification and standardization of therapeutic interventions. There is a large range of variability influenced by age and social factors, comorbidities, and setting of cures (community-dwelling versus hospitalized patients). Tumor subsite is one of the major determinants of malnutrition, with pancreatic, esophageal, and other gastroenteric cancers, head and neck, and lung cancers having the highest prevalence. The advanced stage is also linked to a higher risk of developing malnutrition, as an expression of the relationship between tumor burden, inflammatory status, reduced caloric intake, and malabsorption. Finally, treatment type influences the risk of nutritional issues, both for locoregional approaches (surgery and radiotherapy) and for systemic treatment. Interestingly, personalized approaches based on the selection of the most predictive malnutrition definitions for postoperative complications according to cancer type and knowledge of specific nutritional problems associated with some new agents may positively impact disease course. Sharing common knowledge between oncologists and nutritionists may help to better address and treat malnutrition in this population.     

The possible role of TNF-α and IL-2 in inducing tumor-associated metabolic alterations

This study was conducted to investigate the role of tumor necrosis factor- (TNF-) and interleukin-2 (IL-2) in inducing cancer cachexia, and the results were compared with those obtained from our previous study on Fisher 344 rats with methylcholanthrene-induced sarcoma. Three groups of male Fisher 344 rats received one of the following regimens: 4×10⁴ IU of human recombinant TNF- per rat per day subcutaneously (sc) for 5 consecutive days (n=5), 3.5×10⁵ U human recombinant IL-2 per rat per day sc for 14 consecutive days (n=5), or normal saline (n=5). The activities of both phosphoenolpyruvate carboxykinase (PEPCK) and malic enzyme (ME) were increased slightly in the IL-2 group. Furthermore, LPL activity was significantly increased in the adipose tissue of the TNF group and in the cardiac muscle of the IL-2 group, but not in that of the TNF group. These results show that there is a significant difference between the metabolic alterations seen in the tumor-bearing state and those induced by either TNF- or IL-2 alone. Thus, it is unlikely that IL-2 or TNF- is the sole mediator of cancer cachexia in this tumor and rat model.     

癌性恶病质代谢的研究现状

恶病质是癌症病人死亡的常见原因之一。与单纯性饥饿引起的营养不良不同．它的主要代谢改变是葡萄糖合成率的变化，糖异生、糖酵解增加，脂肪动员和氧化加速．蛋白质合成减少。     

Cancer cachexia: drugs in the patent literature

Background: The therapeutic approach to the neoplastic patient with cachexia is very frustrating for the physician. Indeed, we can say that a cure for cancer cachexia does not exist. Numerous therapeutic strategies have been tested in the last few decades with discouraging or at least conflicting results. Methods: Drugs patented for the treatment of cancer cachexia are evaluated and discussed. Results: New drugs such as ghrelin splice variant, small-molecule melanocortin-4 receptor antagonists and selective androgen receptor modulators have been discovered, evaluated with promising results, and patented. It is expected that soon they will be tested in humans through adequate clinical trials in experimental studies. Other compounds such as retinoid X receptor agonists, the inhibitor of LPS-induced TNF-α factor (LIPAF) protein, novel inhibitors of TNF-α production or release and tumour cytotoxic factor II need to be tested first in experimental models of cancer cachexia. Conclusion: With the recent discovery of new, effective drugs, it seems that a new scenario is opening up in the therapy of cancer cachexia.