Anti-cytokine strategies for the treatment of cancer-related anorexia and cachexia

Importance of the field: Cachexia is a syndrome characterized by body weight loss and metabolic abnormalities. It is a frequent feature of patients affected by chronic pathologies, including cancer. Neoplastic patients with cachexia show increased morbidity and mortality rates, benefit less from antineoplastic therapies, and have a poorer quality of life. Among the general mechanisms proposed to account for cachexia, anorexia and altered homeostasis of hormones and cytokines appear to play a major role.

Areas covered in this review: The present review will focus on anti-inflammatory drugs useful for the treatment of cancer-related anorexia and cachexia.

What the reader will gain: Molecules able to block cytokine production or biological activity are currently under evaluation. At present, none of them has been authorized for the clinical treatment of cancer-related anorexia and cachexia, since the few published clinical trials lead to contrasting results, and others are still pending.

Take home message: Considering the multifactorial pathogenesis of cancer-related anorexia and cachexia, combination protocols are probably the better choice. In this regard, anti-cytokine strategies should be pursued and included in the treatment of neoplastic patients, although cytokines modulate a number of processes.     

Development of Sarcopenia in Patients With Bladder Cancer: A Systematic Review

ObjectiveSarcopenia is known to influence cancer-related complications and overall survival. However, the effect of cancer treatment on the development or progression of sarcopenia is relatively unknown. The primary aim of this systematic review was to determine the prevalence and development of sarcopenia among people with bladder cancer.Data SourcesA systematic search was performed in PubMed, Web of Science, and EMBASE. Studies with ≥2 assessments of sarcopenia were eligible for inclusion. Five retrospective cohorts were included with a total of 438 participants. The baseline prevalence of sarcopenia across studies varied from 25% to 69% and post-treatment prevalence from 50% to 81%. The average loss of muscle mass was 2.2% to 10% during a time course of 3 to 12 months.ConclusionThe prevalence of sarcopenia markedly increased during cancer treatment in patients with bladder cancer. Further research into the effect of different treatment regimens on the development of sarcopenia, and how these changes might affect functional capacity and survival is needed.Implications for Nursing PracticeThe development of sarcopenia is important to understand because of its negative affect on quality of life, complications, and mortality. Further, understanding how sarcopenia develops during treatment could potentially strengthen nurses’ future care plans for patients with bladder cancer.     

Cancer cachexia,sarcopenia and biochemical markers in patients with advanced non-small cell lung cancer—chemotherapy toxicity and prognostic value

Purpose

Cancer cachexia and sarcopenia are frequently observed in cancer patients and associated with poor survival. The majority of studies of cancer cachexia and sarcopenia have been done in patients with solid tumors of different origins, and there are currently no good predictors of the benefit of chemotherapy or factors that predict survival in advanced cancer.The purpose of our prospective study was to evaluate prevalence of cachexia and sarcopenia using international consensus definition and criteria for diagnosis in patients with diagnosed advanced non-small cell lung cancer (NSCLC) stage IIIB and IV and their relation to chemotherapy toxicity and survival prediction. A secondary aim was to compare several biochemical markers (CRP, IL-6, protein, and albumin) with time to tumor progression in order to assess prognostic value or to guide a treatment.

Methods

Between December 2013 and April 2015, the prospective cohort study of 100 Caucasian patients with advanced NSCLC stage IIIB or IV, who were referred consecutively to Department for Respiratory Diseases “Jordanovac,” was evaluated. Anthropometric measurements and biochemical data (CRP, albumin, protein, IL-6, haemoglobin) together with body composition measurements (total muscle cross-sectional area, lumbar skeletal muscle index) were obtained for each patient before starting with platinum-doublet therapy. Skeletal muscle cross-sectional area at the third lumbar vertebra was measured by computerized tomography, and sarcopenia was defined using a previously published cutoff point. Toxicity was assessed after cycle 1 of treatment and time-to-tumor progression was determined prospectively.

Results

One hundred patients with advanced lung cancer were recruited: 67 were male and median age was 64 years. The median time to disease progression was 187 days. The prevalence of cachexia and sarcopenia in study cohort was 69 and 47 %, respectively. CRP, IL-6, and albumin concentration in cachectic compared to non-cachectic patients demonstrated statistically significant difference (p?=?0.020, p?=?0.040, p?=?0.003). Cachexia and sarcopenia were not found to be predictors of chemotoxicity nor was time to tumor progression. On the contrary, albumin concentration with established cutoff point of 37.5 g/L was clearly proved as the predictive factor of both chemotoxicity (OR (95 % CI)?=?0.85; p?<?0.001) and survival (HR (95 % CI)?=?0.55).

Conclusions

Albumin level has been shown to be more important predictive marker of chemotherapy toxicity and survival than cachexia and sarcopenia are. This approach in clinical settings can be used to guide the choice of oncologic treatment.

     

Cardiac cachexia

Chronic heart failure (CHF) remains an important and increasing public health care problem. It is a complex syndrome affecting many body systems. Body wasting (i.e., cardiac cachexia) has long been recognised as a serious complication of CHF. Cardiac cachexia is associated with poor prognosis, independently of functional disease severity, age, and measures of exercise capacity and cardiac function. Patients with cardiac cachexia suffer from a general loss of fat tissue, lean tissue, and bone tissue. Cachectic CHF patients are weaker and fatigue earlier, which is due to both reduced skeletal muscle mass and impaired muscle quality. The pathophysiologic alterations leading to cardiac cachexia remain unclear, but there is increasing evidence that metabolic, neurohormonal and immune abnormalities may play an important role. Cachectic CHF patients show raised plasma levels of epinephrine, norepinephrine, and cortisol, and they show high plasma renin activity and increased plasma aldosterone level. Several studies have also shown that cardiac cachexia is linked to raised plasma levels of tumour necrosis factor alpha and other inflammatory cytokines. The degree of body wasting is strongly correlated with neurohormonal and immune abnormalities. The available evidence suggests that cardiac cachexia is a multifactorial neuroendocrine and metabolic disorder with a poor prognosis. A complex imbalance of different body systems may cause the development of body wasting.     

Therapeutic considerations of sarcopenia in heart failure patients

Introduction: Sarcopenia is a common feature, and affects 20–47% of patients with heart failure (HF). Sarcopenia is also an independent predictor of impaired functional capacity, even after adjusting for clinical relevant variables, which is associated with adverse outcome in patients with HF.

Areas covered: Several different pathophysiological pathways are involved in sarcopenic processes including altered nutrient intake and absorption, hormonal factor, inflammatory processes, oxidative stress, cellular proteolysis, and unhealthy lifestyle. Nutritional therapy, physical activity and/or exercise training have been associated with improved muscle mass or physical performance in HF. Few studies reported beneficial effects for muscle mass and physical performance, in those who received angiotensin-converting enzyme (ACE) inhibitors, or/and beta-blocker. In addition, testosterone, selective androgen receptor modulators, ghrelin agonist and myostatin inhibitors are currently under study as possible future therapeutic options.

Expert commentary: Regular and adequate level of physical activity and/or exercise training, and sufficient nutritional intake or special nutritional supplementation may represent the best strategy for prevention or delay of sarcopenia and worsening physical performance in patients with HF. Maximal tolerated dosages of standard therapies for HF such as ACE-inhibitors or beta-blockers are first-line strategy, however it is difficult to recommend other pharmacological agents as part of routine treatment of sarcopenia.     

Muscle wasting associated co-morbidities,rather than sarcopenia are risk factors for hospital mortality in critical illness

BackgroundLow skeletal muscle mass on intensive care unit admission is related to increased mortality. It is however unknown whether this association is influenced by co-morbidities that are associated with skeletal muscle loss. The aim of this study was to investigate whether sarcopenia is an independent risk factor for hospital mortality in critical illness in the presence of co-morbidities associated with muscle wasting.MethodsData of 155 patients with abdominal sepsis were retrospectively analyzed. Skeletal muscle area was assessed using CT-scans at the level of vertebra L3. Demographic and clinical data were retrieved from electronic patient files. Sarcopenia was defined as a muscle area index below the 5th percentile of the general population. Uni- and multivariable analyses were performed to assess the association between sarcopenia and hospital mortality, correcting for age and comorbidities.ResultsThe prevalence of sarcopenia was higher in patients that did not survive until hospital discharge. However, it appeared that this relation was confounded by the presence of chronic renal insufficiency and cancer. These were independent risk factors for hospital mortality, whereas sarcopenia was not.ConclusionIn critically ill patients with abdominal sepsis, muscle wasting associated co-morbidities rather than sarcopenia were risk factors for hospital mortality.     

Tumor necrosis factor biologics beyond psoriasis in dermatology

Introduction: TNF-α is a cytokine essential for immune response and its receptors has been shown to be dysregulated in a variety of diseases including psoriasis vulgaris. There are a number of TNF-α inhibitors approved for psoriasis, however there is a growing body of literature supporting their use in a wide variety of dermatological conditions.

Areas covered: The use of biologic TNF-α antagonists in conditions for which they have not yet been approved by the FDA (‘off-label’ uses) and the literature that supports the most appropriate agents and conditions for use. A PubMed/MEDLINE search was performed with the keywords ‘TNFα antagonist’, ‘biologic therapy’, ‘off-label’ and ‘unapproved’. The list of references and citing articles of the articles retrieved were also used as sources. This complete list was evaluated for inclusion, based on relevance to the proposed goal of this review.

Expert opinion: There are a large number of conditions for which biologic antagonists of TNFα are effective, beyond those already approved by the FDA. The various agents vary in their efficacy in treatment, with infliximab consistently the most effective, particularly in granulomatous diseases. Although effectiveness varies among these conditions, biologic antagonists of TNF-α are promising for the treatment of these diseases.     

Familial Hemolytic Jaundice Complicated by Acute Purulent Cholecystitis

Objective: Our aim was to explore how differing attitudes, expectations, and experiences among people with obesity (PwO) and healthcare providers (HCPs) might have an impact on effectively implementing current obesity treatment guidelines.

Methods: Online surveys were conducted among 3,008 adult PwO (BMI≥30 by self-reported height and weight) and 606 HCPs.

Results: PwO with weight loss ≥ 10% during the previous three years were more likely to have been diagnosed with obesity and to have discussed a weight loss plan with an HCP. However, only 21% believe HCPs have a responsibility to actively contribute to their obesity treatment. Further, HCPs tend not to effectively communicate the diagnosis of obesity, its nature as a serious and chronic disease, the full range of treatment options, and obesity’s implications for health and quality of life.

Regarding treatment goals, HCPs more often focus on BMI reduction, while PwO’s goals focus on improved functioning, energy, and appearance. HCPs also tend to underestimate their patients’ motivation to address their obesity. Twenty-eight percent of HCPs ‘completely agreed’ that losing weight was a high priority for PwO, whereas more than half of PwO ‘completely agreed’ that losing weight was a high priority for them. When asked how their HCP could better support them, PwO most often expressed a desire for helpful resources, as well as assistance with specific and realistic goal-setting to improve health.

Conclusions: HCPs can more effectively implement obesity treatment guidelines by more clearly and proactively communicating with PwO about their diagnosis, health implications of obesity, desired treatment goals, and the full range of treatment options. HCPs should understand that most PwO believe that managing their disease is solely their own responsibility. HCPs can also encourage more effective conversations by better appreciating their patients’ motivation and treatment goals.     

Updates in the management and treatment of HCV genotype 3, what are the remaining challenges?

ABSTRACT

Introduction: Chronic hepatitis C (CHC) genotype-3 (G-3) infection is the next most prevalent genotype with 54.3 million patients globally. It is associated with an increasing risk of fibrosis, liver-related events, hepatocellular carcinoma, and overall mortality. G-3 infection may have a negative impact on histological and clinical outcomes in CHC patients. In addition, its characteristic features of steatosis and metabolic abnormalities may add more difficulty in the disease management.

Area covered: Fortunately, the landscape of management has been drastically changed in the past decade with the blooming of all oral direct antiviral agents (DAAs). The extremely high efficacy, high safety, short treatment duration, low adverse effects, and easy dosing of DAAs provide an excellent exploration of medical therapeutics in human history. The review consisted of the updated management of CHC G-3, and also touched upon what are the remaining challenges currently. Some challenges and unmet needs were also raised in a clinical setting, including treatment barriers, clinical outcomes, and metabolic abnormalities.

Expert commentary: There is a pressing need for management of G-3 infection because of its large patient burden and poor clinical outcomes than other genotypes. Further investigation is warranted in terms of its treatment barriers and clinical outcomes.     

Biologics for the treatment of adult-onset still’s disease

ABSTRACT

Introduction: Adult-onset Still’s disease (AOSD) is a systemic inflammatory disorder of unknown etiology, and approximately 60–70% of patients develop a chronic form. Up to 20–30% of patients who are refractory to conventional therapy need biologic agents. Recently, anti-cytokine biologic agents according to pathophysiology have resulted in significant progress in the treatment of AOSD.

Area Covered: Due to rarity and heterogeneous features of the disease, treatment of AOSD is not based on the controlled study but on case-based retrospective data. Here, we review the current status of the pathogenesis, limitations of therapeutic guidelines and outcome measures, utility of biologic agents, and future perspectives for treatment.

Expert opinion: IL-1 inhibitors are more effective for systemic manifestations and IL-6 inhibitors for both joint disease and systemic features. Anti-TNF agents would be useful for patients with the pure rheumatoid subgroup. Systemic manifestations respond rapidly, but arthritis shows rather slow response. Clinical response must be obtained within 2 to 3 months, and biologics with different mechanisms of action are required for non-responders. For patients in prolonged remission, we need to try tapering of biologics. Randomized controlled studies, new therapeutic agents, and composite biomarkers are required to improve the outcome of patients with AOSD.     

Optimizing treatment of metastatic colorectal cancer patients with anti-EGFR antibodies: overcoming the mechanisms of cancer cell resistance

Introduction: A number of anti-EGFR monoclonal antibodies (mAbs) have been recently developed for the treatment of refractory metastatic colorectal cancer (mCRC). These mAbs, blocking ligand/receptor interactions, exert their biological activity via multiple mechanisms, including inhibition of cell cycle progression, potentiation of cell apoptosis, inhibition of angiogenesis, tumor cell invasion and metastasis and, potentially, induction of immunological effector mechanisms.

Areas covered: Cetuximab is an anti-EGFR mAb currently used in mCRC treatment. Despite the evidence of efficacy of cetuximab in the treatment of mCRC patients, the observation of low response rates was the proof of concept of resistance to anti-EGFR mAbs treatment. An increasing number of molecular alterations have been more recently hypothesized to be involved in resistance to anti-EGFR mAbs in CRC: mutations in BRAF, NRAS and PIK3CA, loss of expression of PTEN and, now, activation of HER2 signaling through HER2 gene amplification and/or increased heregulin stimulation.

Expert opinion: This review focuses on the development of new strategies such as combination with other agents blocking alternative escape pathways, cancer cell prioritization hyperactivating EGFR pathway, combination with immune system, development of nanotech devices to increase efficacy of antibody-based therapy and overcome the mechanisms of cancer cell resistance.     

Cogan’s syndrome: new therapeutic approaches in the biological era

Introduction: Cogan’s syndrome (CS) is a rare autoimmune disease, characterized by ocular and vestibulo-auditory involvement. Treatment of CS could be challenging, and the only evidence-based data comes from case reports or series.

Areas covered: There have recently been several reports of new treatment strategy involving the use of biological disease-modifying anti-rheumatic drugs such as TNFα inhibitors, anti-CD20 or anti-IL6 receptor antibodies, in cases resistant to first- or second-line drugs.

Expert commentary: Corticosteroids are the cornerstone of CS therapy at disease onset and during acute phases of the disease. Conventional immunosuppressive therapy, such as methotrexate, could be used in relapsing patients or as a glucocorticoid sparing agent, but efficacy is often modest. The anti-TNFα monoclonal antibody Infliximab appears to be the most frequently used, leading to an improvement in hearing loss in 89% of the cases and allow corticosteroid tapering in 86% of the patients. The appropriate timing of Infliximab treatment has yet to be thoroughly investigated, but it seems to be more effective when started at an early stage of the disease. Efficacy of others anti-TNFα agents is controversial. Rituximab and Tocilizumab are a safe option, but results on hearing loss have still to be confirmed on larger patients’ cohorts.     

Unresolved inflammation: ‘immune tsunami’ or erosion of integrity in immune-privileged and immune-responsive tissues and acute and chronic inflammatory diseases or cancer

Introduction: Unresolved inflammation is loss of balance between two biologically opposing arms of acute inflammation, ‘Yin’ (tumoricidal) and ‘Yang’ (tumorigenic) processes that cause disruption of protective mechanisms of immune system.

Areas covered: Hypothesis: Unresolved inflammation-induced exaggerated expression of apoptotic and/or wound healing mediators lead to fundamental erosion (‘immune tsunami’ or ‘immune meltdown’) of integrity in tissues that are naturally immune-responsive (immune surveillance); or immune-privileged (immune tolerance). ‘Immune tsunami’ refers to end results of acute or chronic immune dysfunction leading to inflammatory diseases or cancer. Acute inflammatory diseases including drug-induced cancer cachexia, would fit features of ‘immune meltdown’ that are otherwise described for end results of age-associated diseases. Pathogens induce rapid destruction of vascular integrity, gain access to tissues and cause excessive expression of apoptotic factors leading to multiple organ failure (MOF). Significant disruptions of immunological barriers and response shifts lead to chronic neurodegenerative and autoimmune diseases, tumor growth, malignancies and angiogenesis and loss of natural immune response balances.

Expert opinion: Strategies to promote (stabilize) inherent properties of innate immune cells (‘tumoricidal’ versus ‘tumorigenesis’) that would influence polarization of adaptive immune (T or B) cells are key in reducing or preventing incidence of inflammatory and vascular diseases or cancer during aging process.     

Pharmacotherapy of haemophilia A

Introduction: Haemophilia A is due to factor VIII (FVIII) deficiency. The main treatment is replacement therapy with FVIII concentrates. However, these concentrates carried a high risk of blood-borne viral infections and still have a high risk of inducing anti-FVIII inhibitors.

Areas covered: An overview of products available and therapeutic options for haemophilia A management in order to help in decision making. A literature search using Medline with the keywords: ‘haemophilia’, ‘factor VIII’, ‘therapy’, ‘inhibitor’, ‘concentrate’, ‘bleeding’, ‘prophylaxis’, ‘on demand’, ‘plasma-derived’, ‘recombinant’, ‘coagulation factors’, ‘immunotolerance’ was performed. The years 1960 – 2010 are included.

Expert opinion: Progress in management of patients with haemophilia A has allowed increased life expectancy and quality of life. There is evidence that prophylaxis prevents or, at least, slows down arthropathy development when started early in childhood. FVIII concentrates have achieved high levels of blood-borne pathogen safety. However, treatment is frequently complicated by development of FVIII-neutralizing inhibitors, which prevent control of bleeding and predispose to a high morbidity and mortality risk. Bypassing agents are effective in bleeding treatment in a high percentage of cases. Prophylaxis with bypassing agents and their use in combination are offering opportunities in management of inhibitor patients. More evidence is necessary to understand how to prevent and manage this complication.     

The alternate effects of anti-TNFα therapeutics and their role in mycobacterial granulomatous infection in Crohn’s disease

Introduction: Crohn’s disease is an inflammatory bowel disease that has been debated to be associated with bacterial triggers such as Mycobacterium avium subspecies paratuberculosis (MAP). Standard treatment of Crohn’s disease (CD) patients includes a family of immunomodulators and biologics such as Anti-Tumor Necrosis Factor alpha (Anti-TNFα). This cytokine in particular has been known to play vital roles in fighting microbial infections through formation and maintenance of granulomas.

Areas covered: This perspective is focused on elucidating the negative effects of using Anti-TNFα therapeutic agents as a treatment option in CD patients who are more likely suspected to have MAP infection, and the role of other immunomodulators in MAP infection.

Expert commentary: While treatment with Anti-TNFα is beneficial to reduce inflammation and to provide short term relief to the patients, it also compromises the immune system causing susceptibility to microbial infection. More than 50% of CD patients have shown no response to Anti-TNFα treatment which indicates a demand for introducing novel CD treatment in combination with antibiotics as a future CD treatment plan.     

Anthropometric indicators as screening tools for sarcopenia in older adult women

ObjectiveTo investigate the association between sarcopenia and different anthropometric indicators, and identify the best indicator to discriminate sarcopenia in community-dwelling older adult women.MethodData from 173 older adult women (≥60 years), living in Lafaiete Coutinho, a small-sized city in northeastern Brazil, were analyzed. Sarcopenia was defined based on the European consensus on definition and diagnosis using three components: muscle mass, muscle strength and performance. The association between sarcopenia and anthropometric indicators (body mass index, corrected arm muscle area and calf perimeter) was tested using the binary logistic regression technique.ResultsThe adjusted regression model indicated that all anthropometric indicators were inversely associated with sarcopenia, and an increase by one unit in body mass index, corrected arm muscle area or calf circumference decreased the probability of sarcopenia in older adult women by approximately 85%, 16% and 72%, respectively.ConclusionAll the studied anthropometric indicators can be used as discriminators of sarcopenia in an older adult women population. To this end body mass index exhibited better sensitivity and calf circumference better specificity. The results of the study may improve nursing practice and that of other healthcare professionals, enabling sarcopenia screening in older adult women from simple and low-cost anthropometric indicators.     

Sarcopenia in patients with colorectal cancer: A comprehensive review

Colorectal cancer(CRC)is the third most commonly diagnosed cancer globally and the second cancer in terms of mortality.The prevalence of sarcopenia in patients with CRC ranges between 12%-60%.Sarcopenia comes from the Greek“sarx”for flesh,and“penia”for loss.Sarcopenia is considered a phenomenon of the aging process and precedes the onset of frailty(primary sarcopenia),but sarcopenia may also result from pathogenic mechanisms and that disorder is termed secondary sarcopenia.Sarcopenia diagnosis is confirmed by the presence of low muscle quantity or quality.Three parameters need to be measured:muscle strength,muscle quantity and physical performance.The standard method to evaluate muscle mass is by analyzing the tomographic total cross-sectional area of all muscle groups at the level of lumbar 3rd vertebra.Sarcopenia may negatively impact on the postoperative outcomes of patients with colorectal cancer undergoing surgical resection.It has been described an association between sarcopenia and numerous poor short-term CRC outcomes like increased perioperative mortality,postoperative sepsis,prolonged length of stay,increased cost of care and physical disability.Sarcopenia may also negatively impact on overall survival,disease-free survival,recurrence-free survival,and cancerspecific survival in patients with non-metastatic and metastatic colorectal cancer.Furthermore,patients with sarcopenia seem prone to toxic effects during chemotherapy,requiring dose deescalations or treatment delays,which seems to reduce treatment efficacy.A multimodal approach including nutritional support(dietary intake,high energy,high protein,and omega-3 fatty acids),exercise programs and anabolic-orexigenic agents(ghrelin,anamorelin),could contribute to muscle mass preservation.Addition of sarcopenia screening to the established clinical-pathological scores for patients undergoing oncological treatment(chemotherapy,radiotherapy or surgery)seems to be the next step for the best of care of CRC patients.     

New pharmacotherapy options for noninfectious posterior uveitis

Introduction: Noninfectious posterior uveitis is a leading cause of visual impairment. Although conventional immunosuppressive agents have been successfully used, these are nonspecific and their long-term use may induce significant adverse effects. The purpose of this article is to identify recent advances and future therapeutic options in noninfectious posterior uveitis.

Areas covered: A MEDLINE database search was conducted through May 2014 using the terms: uveitis, treatment, intravitreal and corticosteroid, biological. To provide ongoing and future perspectives in treatment options, also clinical trials as registered at ClinicalTrials.gov were included.

Expert opinion: For individuals who do not respond to conventional immunotherapy, two major lines of treatments can be identified as focus in recent years: i) the intraocular application of anti-inflammatory drugs and ii) the introduction of new agents, for example, biologicals and small-molecule inhibitors. Whereas intravitreal treatments have the beauty of avoiding systemic side effects, new agents are gaining increased importance because of their highly targeted molecular effects. Even when current treatment strategies are still hampered by the paucity of randomized controlled trials, promising progress and continuous efforts are undertaken to close this gap. Still, a critical evaluation of new agents has to be made because ‘new’ agents are almost exclusively based on experience in other autoimmune disorders.