Sarcopenia Predicts Early Dose-Limiting Toxicities and Pharmacokinetics of Sorafenib in Patients with Hepatocellular Carcinoma

BACKGROUND: Sorafenib induces frequent dose limiting toxicities (DLT) in patients with advanced hepatocellular carcinoma (HCC). Sarcopenia has been associated with poor performance status and shortened survival in cancer patients. PATIENTS AND METHODS: The characteristics of Child Pugh A cirrhotic patients with HCC receiving sorafenib in our institution were retrospectively analyzed. Sorafenib plasma concentrations were determined at each visit. Toxicities were recorded during the first month of treatment, and sarcopenia was determined from baseline CT-scans. RESULTS: Forty patients (30 males) were included. Eleven (27.5%) were sarcopenic. Eighteen patients (45%) experienced a DLT during the first month of treatment. Sarcopenic patients experienced significantly more DLTs than non-sarcopenic patients did (82% versus 31%, p = 0.005). Grade 3 diarrhea was significantly more frequent in sarcopenic patients than in non-sarcopenic patients (45.5% versus 6.9%, p = 0.01), but not grade 3 hand foot syndrome reaction (9% versus 17.2%, p = 1). On day 28, median sorafenib AUC (n = 17) was significantly higher in sarcopenic patients (102.4 mg/l.h versus 53.7 mg/l.h, p = 0.013). CONCLUSIONS: Among cirrhotic Child Pugh A patients with advanced HCC, sarcopenia predicts sorafenib exposure and the occurrence of DLT within the first month of treatment

Dorsal Root Ganglia Macrophages Maintain Osteoarthritis Pain

Pain is the major debilitating symptom of osteoarthritis (OA), which is difficult to treat. In OA patients joint tissue damage only poorly associates with pain, indicating other mechanisms contribute to OA pain. Immune cells regulate the sensory system, but little is known about the involvement of immune cells in OA pain. Here, we report that macrophages accumulate in the dorsal root ganglia (DRG) distant from the site of injury in two rodent models of OA. DRG macrophages acquired an M1-like phenotype, and depletion of DRG macrophages resolved OA pain in male and female mice. Sensory neurons innervating the damaged knee joint shape DRG macrophages into an M1-like phenotype. Persisting OA pain, accumulation of DRG macrophages, and programming of DRG macrophages into an M1-like phenotype were independent of Nav1.8 nociceptors. Inhibition of M1-like macrophages in the DRG by intrathecal injection of an IL4-IL10 fusion protein or M2-like macrophages resolved persistent OA pain. In conclusion, these findings reveal a crucial role for macrophages in maintaining OA pain independent of the joint damage and suggest a new direction to treat OA pain. SIGNIFICANCE STATEMENT: In OA patients pain poorly correlates with joint tissue changes indicating mechanisms other than only tissue damage that cause pain in OA. We identified that DRG containing the somata of sensory neurons innervating the damaged knee are infiltrated with macrophages that are shaped into an M1-like phenotype by sensory neurons. We show that these DRG macrophages actively maintain OA pain remotely and independent of joint damage. The phenotype of these macrophages is crucial for a pain-promoting role. Targeting the phenotype of DRG macrophages with either M2-like macrophages or a cytokine fusion protein that skews macrophages into an M2-like phenotype resolves OA pain. Our work reveals a mechanism that contributes to the maintenance of OA pain distant from the affected knee joint and suggests that dorsal root ganglia macrophages are a target to treat osteoarthritis chronic pain

A longitudinal study of muscle strength and function in patients with cancer cachexia

Purpose Patients with cancer frequently experience an involuntary loss of weight (in particular loss of muscle mass), defined as cachexia, with profound implications for independence and quality of life. The rate at which such patients’ physical performance declines has not been well established. The aim of this study was to determine the change in muscle strength and function over 8 weeks in patients with already established cancer cachexia, to help inform the design and duration of physical activity interventions applicable to this patient group. Methods Patients with thoracic and gastrointestinal cancer, with unintentional weight loss of >5% in 6 months or BMI < 20 plus 2% weight loss were included. Physical and functional assessments (baseline, 4 weeks, 8 weeks) included: isometric quadriceps and hamstring strength, handgrip, standing balance, 10m walk time and timed up and go. Results Fifty patients (32 male), mean ±SD age 65 ±10 years and BMI 24.9 ±4.3kg/m2 were recruited. Thoracic cancer patients had lower muscle strength and function (p0.05). Baseline variables did not differentiate between completers and non-completers (p>0.05). Conclusions More than a third of patients with established cancer cachexia in our study were stable over 8 weeks, suggesting a subgroup who may benefit from targeted interventions of reasonable duration. Better understanding the physical performance parameters which characterize and differentiate these patients has important clinical implications for cancer multidisciplinary team practice

Cuidado de enfermagem para enfermeiros docentes na perspectiva da complexidade

O cuidado de enfermagem complexo é condição essencial para a compreensão do ser humano como singular e multidimensional. Assim, objetivou-se conhecer o significado do cuidado de enfermagem para enfermeiros docentes, na perspectiva da complexidade. Trata-se de uma pesquisa qualitativa, realizada com sete enfermeiros docentes deum curso de enfermagem de nível superior da região central do Rio Grande do Sul, Brasil. Os dados foram coletados no mês de novembro de 2011, por meio do grupo focal, a partir de três encontros, sistematizados com temáticas que contemplassem o objetivo deste estudo. Para a análise de dados, foi utilizada a análise textual discursiva. Os resultados evidenciaram o cuidado de enfermagem como construção singular que vai além de um cuidado técnico-prescritivo, pontual e linear. Conclui-se que o cuidado de enfermagem não pode ser concebido como açãoreducionista, mas como construção singular, que envolve interações, reflexões e autoconhecimento

Habitat and Scale Shape the Demographic Fate of the Keystone Sea Urchin Paracentrotus lividus in Mediterranean Macrophyte Communities

Demographic processes exert different degrees of control as individuals grow, and in species that span several habitats and spatial scales, this can influence our ability to predict their population at a particular life-history stage given the previous life stage. In particular, when keystone species are involved, this relative coupling between demographic stages can have significant implications for the functioning of ecosystems. We examined benthic and pelagic abundances of the sea urchin Paracentrotus lividus in order to: 1) understand the main life-history bottlenecks by observing the degree of coupling between demographic stages; and 2) explore the processes driving these linkages. P. lividus is the dominant invertebrate herbivore in the Mediterranean Sea, and has been repeatedly observed to overgraze shallow beds of the seagrass Posidonia oceanica and rocky macroalgal communities. We used a hierarchical sampling design at different spatial scales (100 s, 10 s and <1 km) and habitats (seagrass and rocky macroalgae) to describe the spatial patterns in the abundance of different demographic stages (larvae, settlers, recruits and adults). Our results indicate that large-scale factors (potentially currents, nutrients, temperature, etc.) determine larval availability and settlement in the pelagic stages of urchin life history. In rocky macroalgal habitats, benthic processes (like predation) acting at large or medium scales drive adult abundances. In contrast, adult numbers in seagrass meadows are most likely influenced by factors like local migration (from adjoining rocky habitats) functioning at much smaller scales. The complexity of spatial and habitat-dependent processes shaping urchin populations demands a multiplicity of approaches when addressing habitat conservation actions, yet such actions are currently mostly aimed at managing predation processes and fish numbers. We argue that a more holistic ecosystem management also needs to incorporate the landscape and habitat-quality level processes (eutrophication, fragmentation, etc.) that together regulate the populations of this keystone herbivore

Body Composition, Symptoms, and Survival in Advanced Cancer Patients Referred to a Phase I Service

Background: Body weight and body composition are relevant to the outcomes of cancer and antineoplastic therapy. However, their role in Phase I clinical trial patients is unknown. Methods: We reviewed symptom burden, body composition, and survival in 104 patients with advanced cancer referred to a Phase I oncology service. Symptom burden was analyzed using the MD Anderson Symptom Assessment Inventory(MDASI); body composition was evaluated utilizing computerized tomography(CT) images. A body mass index (BMI)$25 kg/m 2 was considered overweight. Sarcopenia, severe muscle depletion, was assessed using CT-based criteria. Results: Most patients were overweight (n = 65, 63$25 kg/m 2. Sarcopenic patients were older and less frequently African-American. Symptom burden did not differ among patients classified according to BMI and presence of sarcopenia. Median (95% confidence interval) survival (days) varied according to body composition: 215 (71–358) (BMI,25 kg/m 2; sarcopenic), 271 (99–443) (BMI,25 kg/m 2; non-sarcopenic), 484 (286–681) (BMI$25 kg/m 2; sarcopenic); 501 d (309–693) (BMI$25 kg/m 2; non-sarcopenic). Higher muscle index and gastrointestinal cancer diagnosis predicted longer survival in multivariate analysis after controlling for age, gender, performance status, and fat index. Conclusions: Patients referred to a Phase I clinic had a high frequency of sarcopenia and a BMI$25 kg/m 2, independent o