Effects of S-pindolol in mouse pancreatic and lung cancer cachexia models.

BACKGROUND: It is known that S-pindolol attenuates muscle loss in animal models of cancer cachexia and sarcopenia. In cancer cachexia, it also significantly reduced mortality and improved cardiac function, which is strongly compromised in cachectic animals. METHODS: Here, we tested 3 mg/kg/day of S-pindolol in two murine cancer cachexia models: pancreatic cancer cachexia (KPC) and Lewis lung carcinoma (LLC). RESULTS: Treatment of mice with 3 mg/kg/day of S-pindolol in KPC or LLC cancer cachexia models significantly attenuated the loss of body weight, including lean mass and muscle weights, leading to improved grip strength compared with placebo-treated mice. In the KPC model, treated mice lost less than half of the total weight lost by placebo (-0.9 ± 1.0 vs. -2.2 ± 1.4 g for S-pindolol and placebo, respectively, P < 0.05) and around a third of the lean mass lost by tumour-bearing controls (-0.4 ± 1.0 vs. -1.5 ± 1.5 g for S-pindolol and placebo, respectively, P < 0.05), whereas loss of fat mass was similar. In the LLC model, the gastrocnemius weight was higher in sham (108 ± 16 mg) and S-pindolol tumour-bearing (94 ± 15 mg) mice than that in placebo (83 ± 12 mg), whereas the soleus weight was only significantly higher in the S-pindolol-treated group (7.9 ± 1.7 mg) than that in placebo (6.5 ± 0.9). Grip strength was significantly improved by S-pindolol treatment (110.8 ± 16.2 vs. 93.9 ± 17.1 g for S-pindolol and placebo, respectively). A higher grip strength was observed in all groups; whereas S-pindolol-treated mice improved by 32.7 ± 18.5 g, tumour-bearing mice only show minimal improvements (7.3 ± 19.4 g, P < 0.01). CONCLUSIONS: S-pindolol is an important candidate for clinical development in the treatment of cancer cachexia that strongly attenuates loss of body weight and lean body mass. This was also seen in the weight of individual muscles and resulted in higher grip strength.

Effect of Cancer-Related Cachexia and Associated Changes in Nutritional Status, Inflammatory Status, and Muscle Mass on Immunotherapy Efficacy and Survival in Patients with Advanced Non-Small Cell Lung Cancer.

Immune checkpoint inhibitor (ICI)-based immunotherapy has significantly improved the survival of patients with advanced non-small cell lung cancer (NSCLC); however, a significant percentage of patients do not benefit from this approach, and predictive biomarkers are needed. Increasing evidence demonstrates that cachexia, a complex syndrome driven by cancer-related chronic inflammation often encountered in patients with NSCLC, may impair the immune response and ICI efficacy. Herein, we carried out a prospective study aimed at evaluating the prognostic and predictive role of cachexia with the related changes in nutritional, metabolic, and inflammatory parameters (assessed by the multidimensional miniCASCO tool) on the survival and clinical response (i.e., disease control rate) to ICI-based immunotherapy in patients with advanced NSCLC. We included 74 consecutive patients. Upon multivariate regression analysis, we found a negative association between IL-6 levels (odds ratio (OR) = 0.9036; 95%CI = 0.8408-0.9711; p = 0.0025) and the miniCASCO score (OR = 0.9768; 95%CI = 0.9102-0.9999; p = 0.0310) with the clinical response. As for survival outcomes, multivariate COX regression analysis found that IL-6 levels and miniCASCO-based cachexia severity significantly affected PFS (hazard ratio (HR) = 1.0388; 95%CI = 1.0230-1.0548; p < 0.001 and HR = 1.2587; 95%CI = 1.0850-1.4602; p = 0.0024, respectively) and OS (HR = 1.0404; 95%CI = 1.0221-1.0589; p < 0.0001 and HR = 2.3834; 95%CI = 1.1504-4.9378; p = 0.0194, respectively). A comparison of the survival curves by Kaplan-Meier analysis showed a significantly lower OS in patients with cachexia versus those without cachexia (p = 0.0323), as well as higher miniCASCO-based cachexia severity (p = 0.0428), an mGPS of 2 versus those with a lower mGPS (p = 0.0074), and higher IL-6 levels (>6 ng/mL) versus those with lower IL-6 levels (≤6 ng/mL) (p = 0.0120). In conclusion, our study supports the evidence that cachexia, with its related changes in inflammatory, body composition, and nutritional parameters, is a key prognostic and predictive factor for ICIs. Further larger studies are needed to confirm these findings and to explore the potential benefit of counteracting cachexia to improve immunotherapy efficacy.

Cancer-associated cachexia - understanding the tumour macroenvironment and microenvironment to improve management.

Cachexia is a devastating, multifactorial and often irreversible systemic syndrome characterized by substantial weight loss (mainly of skeletal muscle and adipose tissue) that occurs in around 50-80% of patients with cancer. Although this condition mainly affects skeletal muscle (which accounts for approximately 40% of total body weight), cachexia is a multi-organ syndrome that also involves white and brown adipose tissue, and organs including the bones, brain, liver, gut and heart. Notably, cachexia accounts for up to 20% of cancer-related deaths. Cancer-associated cachexia is invariably associated with systemic inflammation, anorexia and increased energy expenditure. Understanding these mechanisms is essential, and the progress achieved in this area over the past decade could help to develop new therapeutic approaches. In this Review, we examine the currently available evidence on the roles of both the tumour macroenvironment and microenvironment in cancer-associated cachexia, and provide an overview of the novel therapeutic strategies developed to manage this syndrome.

The atypical ß-blocker S-oxprenolol reduces cachexia and improves survival in a rat cancer cachexia model.

BACKGROUND: Beta-blockers and selected stereoisomers of beta-blockers, like bisoprolol and S-pindolol (ACM-001), have been shown to be effective in preclinical cancer cachexia models. Here, we tested the efficacy of stereoisomers of oxprenolol in two preclinical models of cancer cachexia-the Yoshida AH-130 rat model and the Lewis lung carcinoma (LLC) mouse model. METHODS AND RESULTS: In the Yoshida AH130 hepatoma rat cancer cachexia model and compared with placebo, 50 mg/kg/d S-oxprenolol (HR: 0.49, 95% CI: 0.28-0.85, P = 0.012) was superior to 50 mg/kg/d R-oxprenolol (HR: 0.83, 95% CI 0.38-1.45, P = 0.51) in reducing mortality (= reaching ethical endpoints). Combination of the three doses (12.5, 25 and 50 mg/kg/d) that had a significant effect on body weight loss in the S-oxprenolol groups vs the same combination of the R-oxprenolol groups lead to a significantly improved survival of S-oxprenolol vs R-oxprenolol (HR: 1.61, 95% CI: 1.08-2.39, P = 0.0185). Interestingly, there is a clear dose dependency in S-oxprenolol-treated (5, 12.5, 25 and 50 mg/kg/d) groups, which was not observed in groups treated with R-oxprenolol. A dose-dependent attenuation of weight and lean mass loss by S-oxprenolol was seen in the Yoshida rat model, whereas R-oxprenolol had only had a significant effect on fat mass. S-oxprenolol also non-significantly reduced weight loss in the LLC model and also improved muscle function (grip strength 428 ± 25 and 539 ± 37 g/100 g body weight for placebo and S-oxprenolol, respectively). However, there was only a minor effect on quality of life indicators food intake and spontaneous activity in the Yoshida model (25 mg/kg/S-oxprenolol: 11.9 ± 2.5 g vs placebo: 4.9 ± 0.8 g, P = 0.013 and also vs 25 mg/kg/d R-oxprenolol: 7.5 ± 2.6 g, P = 0.025). Both enantiomers had no effects on cardiac dimensions and function at the doses used in this study. Western blotting of proteins involved in the anabolic/catabolic homoeostasis suggest that anabolic signalling is persevered (IGF-1 receptor, Akt) and catabolic signalling is inhibited (FXBO-10, TRAF-6) by S-pindolol, but not he R-enantiomer. Expression of glucose transporters Glut1 and Glut 4 was similar in all groups, as was AMPK. CONCLUSIONS: S-oxprenolol is superior to R-oxprenolol in cancer cachexia animal models and shows promise for a human application in cancer cachexia.

Formoterol reduces muscle wasting in mice undergoing doxorubicin chemotherapy.

Background: Even though doxorubicin (DOX) chemotherapy promotes intense muscle wasting, this drug is still widely used in clinical practice due to its remarkable efficiency in managing cancer. On the other hand, intense muscle loss during the oncological treatment is considered a bad prognosis for the disease's evolution and the patient's quality of life. In this sense, strategies that can counteract the muscle wasting induced by DOX are essential. In this study, we evaluated the effectiveness of formoterol (FOR), a ß2-adrenoceptor agonist, in managing muscle wasting caused by DOX. Methods and results: To evaluate the effect of FOR on DOX-induced muscle wasting, mice were treated with DOX (2.5 mg/kg b.w., i.p. administration, twice a week), associated or not to FOR treatment (1 mg/kg b.w., s.c. administration, daily). Control mice received vehicle solution. A combination of FOR treatment with DOX protected against the loss of body weight (p<0.05), muscle mass (p<0.001), and grip force (p<0.001) promoted by chemotherapy. FOR also attenuated muscle wasting (p<0.01) in tumor-bearing mice on chemotherapy. The potential mechanism by which FOR prevented further DOX-induced muscle wasting occurred by regulating Akt/FoxO3a signaling and gene expression of atrogenes in skeletal muscle. Conclusions: Collectively, our results suggest that FOR can be used as a pharmacological strategy for managing muscle wasting induced by DOX. This study provides new insights into the potential therapeutic use of FOR to improve the overall wellbeing of cancer patients undergoing DOX chemotherapy.

Lack of Synergy Between ß-Agonist Treatment and a Blockage of Sarcoplasmic Calcium Flow in a Rat Cancer Cachexia Model.

BACKGROUND: During cancer cachexia, both skeletal muscle and adipose tissue losses take place. The use of ß2-agonists, formoterol in particular, has proven to be very successful in the treatment of the syndrome in pre-clinical models. The object of the present research was to study the effects of a combination of formoterol and dantrolene, an inhibitor of the ryanodine receptor 1 (RyR1), on body weight loss and cachexia in tumour-bearing animals. METHODS: Rats were separated into two groups: controls (C) and tumour bearing (TB). TB group was further subdivided into four groups: untreated (saline as a vehicle), treated with Formoterol (TF) (0,3 mg/kg body weight in saline, subcutaneous (s.c.), daily), treated with Dantrolene (TD) (5 mg/kg body weight in saline, subcutaneous (s.c.), daily), and double-treated treated (TFD) with Formoterol (0,3 mg/kg body weight, subcutaneous (s.c.), daily) and Dantrolene (5 mg/kg body weight, subcutaneous (s.c.), daily). 7 days after tumour transplantation, muscle weight, grip force, and total physical activity were specified in all experimental groups. RESULTS: While formoterol had, as in previous studies, a very positive effect in reducing muscle weight loss, dantrolene had no effects, neither on skeletal muscle nor on any of the parameters studied. Finally, the combined treatment (formoterol and dantrolene) did not result in any significant benefit on the action of the ß2-agonist. CONCLUSION: It is concluded that, in the preclinical cachectic model used, no synergy exists between ß2-agonist treatment and the blockade of sarcoplasmic-calcium flow.

[Map of ethics conflicts in chronic patient's hospitalization]. / Mapa de conflictos éticos en hospitalización de pacientes crónicos.

The identification, priorization and anticipation of the ethics conflicts, allow the Healthcare Ethics Committees (HEC) a better approach to them, as well as the adoption of measures to prevent its appearance and/or its mitigation. For this purpose, we set ourselves the objective of knowing what they are in the present, how important they are, and what would be the future scenario to face. An qualitative structure research was made whit two focal groups whit the participation of nurses, nurse auxiliary and doctors from the hospitalization area, they also answer a future ethics conflicts Decalogue. The results were tested after by their importance level (Relevance-Frequency-Consistency). The medium age of the participants was 34,7 +- 15,4, whit a medium experience at work of 11,7 +- 15,4 years. A total of 40 ethics conflicts was identify grouped in 5 risk areas: professional, assistance, social, organizational and legal. From there 21 results the more important, between them we find patient abandonment, inexistence of internal performance protocols, patient and relatives false expectations waiting for non-assistance care, unnecessary care at the end of the life, lack of rules for family / caregivers, and ignorance of legality. The more important ethical dilemmas for the future identified by the personal will be patients in abandonment, the lack of sociohealth resources, conflicts with family / caregivers situation and lack of information for decision making at the end of the life. The ethical conflicts between the personal from a chronic patients hospital and the relatives/caregivers was identifying, the most important were prioritized, and futures were anticipated. In these scenarios, we highlight abandonment as the most important. A map of ethics conflicts is a good tool to identify risk areas for ethics conflicts, we see the difference between the ethics conflicts found in other kind of hospitals. The map of ethics conflicts need to be update periodically to keep the validity.

Mapa de conflictos éticos en hospitalización de pacientes crónicos / Map of ethics conflicts in chronic patient's hospitalization

La identificación, priorización y anticipación de los conflictos éticos, permite a los Comités de Ética Asistencial (CEA) un mejor abordaje de los mismos, así como la adopción de medidas para evitar su aparición y/o mitigación. Para este cometido, nos planteamos como objetivo conocer cuáles eran en el presente, que importancia tenían, y cuál sería el escenario futuro al que enfrentarse. Se realizó una investigación cualitativa estructurada con 2 grupos focales compuestos por personal de enfermería, auxiliares de enfermería y médicos del área de Hospitalización, que contestaron además a un decálogo de conflictos éticos futuros. Los datos obtenidos se evaluaron posteriormente según su nivel de importancia (Relevancia-Frecuencia-Consistencia). La edad media del personal fue de 34,7 ± 15,4, con una experiencia laboral media de 11,7 ± 15,4 años. Se identificaron 40 conflictos éticos agrupados en 5 áreas de riesgo: profesional, asistencial, social, organizacional y legal. De ellos 21 resultaron ser los de la mayor importancia, entre los cuales se encuentran el abandono de los pacientes, inexistencia de protocolos de actuación internos, falsas expectativas de los pacientes y familiares que esperan cuidados no asistenciales, los cuidados innecesarios al final de la vida, la falta de normas para familiares/cuidadores, y el desconocimiento de la legalidad. Los dilemas éticos más importantes identificados por el personal a los que podría enfrentarse en el futuro serían los pacientes en situación de abandono, la escasez de recursos socio-sanitarios, los conflictos con familiares/cuidadores y la falta de información para la toma de decisiones al final de la vida. Se identificaron los conflictos entre el personal de un hospital de pacientes crónicos y los familiares/cuidadores, se priorizaron los más importantes, y se anticiparon los futuros. En estos escenarios, destacamos el abandono como el de mayor importancia. Un mapa de conflictos es una herramienta útil para identificar áreas de riesgo de conflicto ético, observamos diferencia respecto a conflictos éticos en hospitales de otras características. La realización de los mapas de conflicto debe hacerse periódicamente para mantener su validez

The identification, priorization and anticipation of the ethics conflicts, allow the Healthcare Ethics Committees (HEC) a better approach to them, as well as the adoption of measures to prevent its appearance and/or its mitigation. For this purpose, we set ourselves the objective of knowing what they are in the present, how important they are, and what would be the future scenario to face. An qualitative structure research was made whit two focal groups whit the participation of nurses, nurse auxiliary and doctors from the hospitalization area, they also answer a future ethics conflicts Decalogue. The results were tested after by their importance level (Relevance-Frequency-Consistency). The medium age of the participants was 34,7 ± 15,4, whit a medium experience at work of 11,7 ± 15,4 years. A total of 40 ethics conflicts was identify grouped in 5 risk areas: professional, assistance, social, organizational and legal. From there 21 results the more important, between them we find patient abandonment, inexistence of internal performance protocols, patient and relatives false expectations waiting for non-assistance care, unnecessary care at the end of the life, lack of rules for family / caregivers, and ignorance of legality. The more important ethical dilemmas for the future identified by the personal will be patients in abandonment, the lack of socio-health resources, conflicts with family / caregivers situation and lack of information for decision making at the end of the life. The ethical conflicts between the personal from a chronic patients hospital and the relatives/caregivers was identifying, the most important were prioritized, and futures were anticipated. In these scenarios, we highlight abandonment as the most important. A map of ethics conflicts is a good tool to identify risk areas for ethics conflicts, we see the difference between the ethics conflicts found in other kind of hospitals. The map of ethics conflicts need to be update periodically to keep the validity

A small Cretaceous crocodyliform in a dinosaur nesting ground and the origin of sebecids.

Sebecosuchia was a group of highly specialized cursorial crocodyliforms that diversified during the Cretaceous and persist until the end of the Miocene. Their unique combination of cranial and post-cranial features indicates that they were active terrestrial predators that occupied the apex of the Late Cretaceous terrestrial ecosystems, even competing with theropod dinosaurs. Here, we report the discovery of the earliest sebecid worldwide, and the first from Eurasia, Ogresuchus furatus gen. et sp. nov., based on a semi-articulate specimen located in a titanosaurian sauropod nesting ground. The new taxon challenges current biogeographical models about the early dispersal and radiation of sebecid crocodylomorphs, and suggests an origin of the group much earlier than previously expected. Moreover, the new taxon suggests a potential convergent evolution between linages geographically isolated. Taphonomic evidences suggest that Ogresuchus died almost in the same place where fossilized, in a dinosaur nesting area. Biometric and morphologic observations lead to speculate that Ogresuchus could easily predate on sauropod hatchlings.

Differential structural features in soleus and gastrocnemius of carnitine-treated cancer cachectic rats.

Muscle wasting is associated with chronic diseases and cancer. Elucidation of the biological mechanism involved in the process of muscle mass loss and cachexia may help identify therapeutic targets. We hypothesized that l-carnitine treatment may differentially revert muscle fiber atrophy and other structural alterations in slow- and fast-twitch limb muscles of rats bearing the Yoshida ascites hepatoma. In soleus and gastrocnemius of tumor-bearing rats (108 AH-130 Yoshida ascites hepatoma cells inoculated intraperitoneally) with and without treatment with l-carnitine (1 g/kg body weight for 7 days, intragastric), food intake, body and muscle weights, fiber typing and morphometry, morphological features, redox balance, autophagy and proteolytic, and signaling markers were explored. Levels of carnitine palmitoyl transferase were also measured in all the study muscles. l-Carnitine treatment ameliorated the atrophy of both slow- and fast-twitch fibers (gastrocnemius particularly), muscle structural alterations (both muscles), and attenuated oxidative stress, proteolytic and signaling markers (gastrocnemius). Despite that carnitine palmitoyl transferase-1 levels increased in both muscle types in a similar fashion, l-carnitine ameliorated muscle atrophy and proteolysis in a muscle-specific manner in cancer-induced cachexia. These data reveal the need to study muscles of different fiber type composition and function to better understand whereby l-carnitine exerts its beneficial effects on the myofibers in muscle wasting processes. These findings also have potential clinical implications, since combinations of various exercise and muscle training modalities with l-carnitine should be specifically targeted for the muscle groups to be trained.

The animal cachexia score (ACASCO).

BACKGROUND: None of the published studies involving cancer cachexia experimental models have included a measure of the severity of the syndrome like the scoring system previously developed for human subjects. The aim of the present investigation was to define and validate a cachexia score usable in both rat and mouse tumor models. METHODS: In order to achieve this goal, we included in the study one rat model (Yoshida AH-130ascites hepatoma) and two mouse models (Lewis lung carcinoma and Colon26 carcinoma). The Animal cachexia score (ACASCO) includes five components: (a) body and muscle weight loss, (b) inflammation and metabolic disturbances, (c) physical performance, (d) anorexia, and (e) quality of life measured using discomfort symptoms and behavioral tests. RESULTS: Using the ACASCO values, three cut-off values were estimated by applying hierarchical cluster analysis. Four groups were originally described, one exactly below the observed mean, a second exactly over the mean, and two other groups adjusted to every cue (inferior and superior). The three cut-off values were estimated through maximization of the classification function. This was accomplished by using a similarity matrix based on the metric properties of the variables and assuming multinormal distribution. The results show that the four groups were: no cachexia, mild cachexia, moderate cachexia and advanced cachexia. CONCLUSIONS: The results obtained allow us to conclude that the score could be very useful as an endpoint in pre-clinical studies involving therapeutic strategies for cancer cachexia. The potential usefulness of ACASCO relates to the primary endpoint in pre-clinical cancer cachexia drug evaluations.

Mediators of cachexia in cancer patients.

Alterations in amino acid and protein metabolism-particularly in skeletal muscle-are a key feature of cancer that contributes to the cachexia syndrome. Thus, skeletal muscle protein turnover is characterized by an exacerbated rate of protein degradation, promoted by an activation of different proteolytic systems that include the ubiquitin-proteasome and the autophagic-lysosomal pathways. These changes are promoted by both hormonal alterations and inflammatory mediators released as a result of the systemic inflammatory response induced by the tumor. Other events, such as alterations in the rate of myogenesis/apoptosis and decreased regeneration potential also affect skeletal muscle in patients with cancer. Mitochondrial dysfunction also contributes to changes in skeletal muscle metabolism and further contributes to the exacerbation of the cancer-wasting syndrome. Different inflammatory mediators-either released by the tumor or by the patient's healthy cells-are responsible for the activation of these catabolic processes that take place in skeletal muscle and in other tissues/organs, such as liver or adipose tissues. Indeed, white adipose tissue is also subject to extensive wasting and "browning" of some of the white adipocytes into beige cells; therefore increasing the energetic inefficiency of the patient with cancer. Recently, an interest in the role of micromRNAs-either free or transported into exosomes-has been related to the events that take place in white adipose tissue during cancer cachexia.

Therapeutic strategies against cancer cachexia.

Cancer cachexia has two main components: anorexia and metabolic alterations. The main changes associated with the development of this multi-organic syndrome are glucose intolerance, fat depletion and muscle protein hypercatabolism. The aim of this paper is to review the more recent therapeutic approaches designed to counteract the wasting suffered by the cancer patient with cachexia. Among the most promising approaches we can include the use of ghrelin agonists, beta-blockers, beta-adrenergic agonists, androgen receptor agonists and anti-myostatin peptides. The multi-targeted approach seems essential in these treatments, which should include the combination of both nutritional support, drugs and a suitable program of physical exercise, in order to ameliorate both anorexia and the metabolic changes associated with cachexia. In addition, another very important and crucial aspect to be taken into consideration in the design of clinical trials for the treatment of cancer cachexia is to staging cancer patients in relation with the degree of cachexia, in order to start as early as possible this triple approach in the course of the disease, even before the weight loss can be detected.

Cancer cachexia, a clinical challenge.

PURPOSE OF REVIEW: The aim of this article is to review the metabolic background of the cachectic syndrome and to analyze the recent therapeutic approaches designed to counteract the wasting suffered by the cancer patient with cachexia. RECENT FINDINGS: The main changes associated with the development of this multiorganic syndrome are glucose intolerance, fat depletion and muscle protein hypercatabolism. Among the most promising approaches for the treatment of cachexia include the use of ghrelin agonists, beta-blockers, beta-adrenergic agonists, androgen receptor agonists and antimyostatin peptides. The multitargeted approach seems essential in these treatments, which should include the combination of both nutritional support, drugs and a suitable program of physical exercise, in order to ameliorate both anorexia and the metabolic changes associated with cachexia. In addition, another very important aspect for the design of clinical trials for the treatment of cancer cachexia is to staging cancer patients in relation with the degree of cachexia, in order to start as early as possible, this triple approach in the course of the disease, even before weight loss can be detected. SUMMARY: Cancer cachexia has two main components: anorexia and metabolic alterations and both have to be taken into consideration for the treatment of the syndrome.

Development and Pilot Test of a New Set of Good Practice Indicators for Chronic Nonmalignant Pain Management.

OBJECTIVES: This study was designed to address the current relative void of valid measures by developing evidence-based quality indicators for pain management of chronic nonmalignant pain. METHODS: We performed a 10-year literature search to identify guidelines and review articles on chronic pain management to identify evidence-based recommendations for the different conditions associated to chronic pain. A complementary search of indicators and indicator-related articles was also performed. Then, we built new indicators or adapted existing ones to cover all the evidence-based recommendations we found. The resulting set was pilot tested for feasibility, reliability (kappa), and usefulness to identify quality problems, using the Lot Quality Acceptance method (α ≤ 0.05 and ß ≤ 0.01) for 75% (40% threshold) and 95% (70% threshold) compliance standards, and estimates with binomial exact 95% confidence intervals. We reviewed clinical records from a primary care center, a medium-size hospital (250 beds), and a large hospital (500 beds). RESULTS: Forty-six indicators were developed (6 general and 40 condition specific). Thirty-three were feasible in primary care and/or hospitals. Feasible indicators were also reliable (most kappa > 0.7). Regarding compliance, 4 quality indicators obtained compliance levels over 60%, addressing pharmacological treatment, multimodal approach, and appropriate use of neuro-image tests, while 16 obtained compliance scores under 15% (6 with 0% compliance). CONCLUSIONS: The created set has tested to be feasible, reliable, and useful, with the capacity to serve as the baseline for developing the necessary strategies to improve the management of chronic nonmalignant pain, by monitoring and evaluating quality of care.

Inter-tissue communication in cancer cachexia.

Cachexia is a systemic condition that occurs during many neoplastic diseases, such as cancer. Cachexia in cancer is characterized by loss of body weight and muscle and by adipose tissue wasting and systemic inflammation. Cancer cachexia is often associated with anorexia and increased energy expenditure. Even though the cachectic condition severely affects skeletal muscle, a tissue that accounts for ~40% of total body weight, it represents a multi-organ syndrome that involves tissues and organs such as white adipose tissue, brown adipose tissue, bone, brain, liver, gut and heart. Indeed, evidence suggests that non-muscle tissues and organs, as well as tumour tissues, secrete soluble factors that act on skeletal muscle to promote wasting. In addition, muscle tissue also releases various factors that can interact with the metabolism of other tissues during cancer. In this Review, we examine the effect of non-muscle tissues and inter-tissue communication in cancer cachexia and discuss studies aimed at developing novel therapeutic strategies for the condition.

Effects of the beta2 agonist formoterol on atrophy signaling, autophagy, and muscle phenotype in respiratory and limb muscles of rats with cancer-induced cachexia.

Muscle mass loss and wasting are characteristic features of patients with chronic conditions including cancer. Beta-adrenoceptors attenuate muscle wasting. We hypothesized that specific muscle atrophy signaling pathways and altered metabolism may be attenuated in cancer cachectic animals receiving treatment with the beta2 agonist formoterol. In diaphragm and gastrocnemius of tumor-bearing rats (intraperitoneal inoculum, 108 AH-130 Yoshida ascites hepatoma cells, 7-day study period) with and without treatment with formoterol (0.3 mg/kg body weight/day/7days, subcutaneous), atrophy signaling pathways (NF-κB, MAPK, FoxO), proteolytic markers (ligases, proteasome, ubiquitination), autophagy markers (p62, beclin-1, LC3), myostatin, apoptosis, muscle metabolism markers, and muscle structure features were analyzed (immunoblotting, immunohistochemistry). In diaphragm and gastrocnemius of cancer cachectic rats, fiber sizes were reduced, levels of structural alterations, atrophy signaling pathways, proteasome content, protein ubiquitination, autophagy, and myostatin were increased, while those of regenerative and metabolic markers (myoD, mTOR, AKT, and PGC-1alpha) were decreased. Formoterol treatment attenuated such alterations in both muscles. Muscle wasting in this rat model of cancer-induced cachexia was characterized by induction of significant structural alterations, atrophy signaling pathways, proteasome activity, apoptotic and autophagy markers, and myostatin, along with a significant decline in the expression of muscle regenerative and metabolic markers. Treatment of the cachectic rats with formoterol partly attenuated the structural alterations and atrophy signaling, while improving other molecular perturbations similarly in both respiratory and limb muscles. The results reported in this study have relevant therapeutic implications as they showed beneficial effects of the beta2 agonist formoterol in the cachectic muscles through several key biological pathways.