Dose optimization of pancreatic enzyme replacement therapy is essential to mitigate muscle loss in patients with advanced pancreatic cancer and exocrine pancreatic insufficiency.

BACKGROUND & AIMS: Exocrine pancreatic insufficiency (EPI) contributes to malnutrition, marked by muscle loss during chemotherapy for advanced pancreatic cancer (aPC). Pancreatic enzyme replacement therapy (PERT) is recommended for patients with EPI; however, it's efficacy for attenuating muscle loss has not been demonstrated. We aimed to delineate the impact of PERT dose on muscle loss using a 7-year population-based cohort with aPC who were provided PERT at the discretion of their oncologist or dietitian according to clinical indications of EPI. METHODS: All patients treated with chemotherapy for aPC from 2013 to 2019 in Alberta, Canada (population ∼4.3 million) were included if they had computed tomography (CT) scans both prior to and 12 ± 4 weeks after chemotherapy initiation. Change in muscle area (cm2) was measured at 3rd lumbar level on repeated CT scans. Muscle loss was defined by measurement error (loss >2.3 cm2). Clinical and pharmaceutical data were retrieved from provincial registries. For patients who were dispensed PERT -8 to +6 weeks from chemo start (PERT users), estimated dose consumed per day was calculated as: (total dose dispensed) / (days, first to last dispensation). PERT users were categorized as high dose or low dose users according to the median estimated dose consumed. Non-users were classified as No PERT. Association between PERT use and muscle loss was analyzed with multivariable logistic regression. RESULTS: Among 210 patients, 81 (39%) were PERT users. Median estimated dose consumed per day of 75 000 USP lipase units defined the cutoff between low dose and high dose uses. There were no significant differences in baseline characteristics between high dose and low dose groups. Muscle loss was more prevalent among low dose compared to both high dose and No PERT groups (88% vs. 58% and 67%, p < 0.05). In the multivariable model predicting muscle loss, low dose PERT was independently associated with greater odds of muscle loss (OR 5.4, p = 0.004) vs. high dose, independent of tumour response, disease stage, and chemotherapy regimen. CONCLUSION: In patients with clinical indications of EPI during chemotherapy for aPC, low doses of PERT were insufficient to prevent muscle loss. Patients with EPI consuming higher doses of PERT had similar odds of muscle maintenance to patients without clinical indications of EPI. Provider education for optimal PERT dosing in patients with EPI should be prioritized, and resources must be allocated to support dose titration.

Call for standardization in assessment and reporting of muscle and adipose change using computed tomography analysis in oncology: A scoping review.

Investigators are increasingly measuring skeletal muscle (SM) and adipose tissue (AT) change during cancer treatment to understand impact on patient outcomes. Recent meta-analyses have reported high heterogeneity in this literature, representing uncertainty in the resulting estimates. Using the setting of palliative-intent chemotherapy as an exemplar, we aimed to systematically summarize the sources of variability among studies evaluating SM and AT change during cancer treatment and propose standards for future studies to enable reliable meta-analysis. Studies that measured computed tomography-defined SM and/or AT change in adult patients during palliative-intent chemotherapy for solid tumours were included, with no date or geographical limiters. Of 2496 publications screened by abstract/title, 83 were reviewed in full text and 38 included for extraction, representing 34 unique cohorts across 8 tumour sites. The timing of baseline measurement was frequently defined as prior to treatment, while endpoint timing ranged from 6 weeks after treatment start to time of progression. Fewer than 50% specified the actual time interval between measurements. Measurement error was infrequently discussed (8/34). A single metric (cm2 /m2 , cm2 or %) was used to describe SM change in 18/34 cohorts, while multiple metrics were presented for 10/34 and no descriptive metrics for 6/34. AT change metrics and sex-specific reporting were available for 10/34 cohorts. Associations between SM loss and overall survival were evaluated in 24 publications, with classification of SM loss ranging from any loss to >14% loss over variable time intervals. Age and sex were the most common covariates, with disease response in 50% of models. Despite a wealth of data and effort, heterogeneity in study design, reporting and statistical analysis hinders evidence synthesis regarding the severity and outcomes of SM and AT change during cancer treatment. Proposed standards for study design include selection of homogenous cohorts, clear definition of baseline/endpoint timing and attention to measurement error. Standard reporting should include baseline SM and AT by sex, actual scan interval, SM and AT change using multiple metrics and visualization of the range of change observed. Reporting by sex would advance understanding of sexual dimorphism in SM and AT change. Evaluating the impact of tissue change on outcomes requires adjustment for relevant covariates and concurrent disease response. Adoption of these standards by researchers and publishers would alter the current paradigm to enable meta-analysis of future studies and move the field towards meaningful application of SM and AT change to clinical care.

Muscle and Adipose Wasting despite Disease Control: Unaddressed Side Effects of Palliative Chemotherapy for Pancreatic Cancer.

Muscle and adipose wasting during chemotherapy for advanced pancreatic cancer (aPC) are associated with poor outcomes. We aimed to quantify the contributions of chemotherapy regimen and tumour progression to muscle and adipose wasting and evaluate the prognostic value of each tissue loss. Of all patients treated for aPC from 2013-2019 in Alberta, Canada (n = 504), computed-tomography (CT)-defined muscle and adipose tissue index changes (∆SMI, ∆ATI, cm2/m2) were measured for patients with CT images available both prior to and 12 ± 4 weeks after chemotherapy initiation (n = 210). Contributions of regimen and tumour response to tissue change were assessed with multivariable linear regression. Survival impacts were assessed with multivariable Cox's proportional hazards models. Tissue changes varied widely (∆SMI: -17.8 to +7.3 cm2/m2, ∆ATI: -106.1 to +37.7 cm2/m2) over 116 (27) days. Tumour progression contributed to both muscle and adipose loss (-3.2 cm2/m2, p < 0.001; -12.4 cm2/m2, p = 0.001). FOLFIRINOX was associated with greater muscle loss (-1.6 cm2/m2, p = 0.013) and GEM/NAB with greater adipose loss (-11.2 cm2/m2, p = 0.002). The greatest muscle and adipose losses were independently associated with reduced survival (muscle: HR 1.72, p = 0.007; adipose: HR 1.73, p = 0.012; tertile 1 versus tertile 3). Muscle and adipose losses are adverse effects of chemotherapy and may require regimen-specific management strategies.

Gingerols synergize with anthocyanins to induce antioxidant activity in vitro.

Oxidative stress caused by free radicals contributes to the pathogenesis of multiple chronic health conditions. Phytochemicals protect against oxidative stress; however, low bioavailability from dietary sources limits their health benefits. This study aimed to assess the effects of anthocyanins and gingerols' combination on the cellular antioxidant response of Caco-2 cells against oxidative stress. A strong synergism was observed for anthocyanin-gingerol (Ac-G) w/w combined ratios of 8:1 and 2:1 (dosages of (1 + 0.125) and (1 + 0.5) µg/mL) in the cellular antioxidant activity (CAA) and cytoprotective effects, with synergistic effect indicator (SE) values of 1.41 and 1.61, respectively. The synergism of Ac-G combinations promoted cellular antioxidant defense systems and cytoprotective effects by reducing the induced GPx enzyme activity, protecting SOD enzyme activity, reducing cellular ROS generation, increasing glutathione content, and inhibiting lipid peroxidation. Thus, Ac-G combinations showed potential in supporting the endogenous antioxidant systems to protect cells from oxidation and restore physiological redox status. The Ac-G formulation is a promising healthy option that can be developed into functional foods or nutraceutical products. Furthermore, it could help address the low bioavailability of these phenolics, as higher effects were achieved when combining the same doses.

Increased Expression of Hepatic Stearoyl-CoA Desaturase (SCD)-1 and Depletion of Eicosapentaenoic Acid (EPA) Content following Cytotoxic Cancer Therapy Are Reversed by Dietary Fish Oil.

Cancer treatment evokes impediments to liver metabolism that culminate in fatty liver. This study determined hepatic fatty acid composition and expression of genes and mediators involved in lipid metabolism following chemotherapy treatment. Female rats bearing the Ward colon tumor were administered Irinotecan (CPT-11) +5-fluorouracil (5-FU) and maintained on a control diet or a diet containing eicosapentaenoic acid (EPA) + docosahexaenoic acid (DHA) (2.3 g/100 g fish oil). Healthy animals provided with a control diet served as a reference group. Livers were collected one week after chemotherapy. Triacylglycerol (TG), phospholipid (PL), ten lipid metabolism genes, leptin, and IL-4 were measured. Chemotherapy increased TG content and reduced EPA content in the liver. Expression of SCD1 was upregulated by chemotherapy, while dietary fish oil downregulated its expression. Dietary fish oil down-regulated expression of the fatty acid synthesis gene FASN, while restoring the long chain fatty acid converting genes FADS2 and ELOVL2, and genes involved in mitochondrial ß-oxidation (CPT1α) and lipid transport (MTTP1), to values similar to reference animals. Neither leptin nor IL-4 were affected by chemotherapy or diet. Depletion of EPA is associated with pathways evoking enhanced TG accumulation in the liver. Restoring EPA through diet may pose a dietary strategy to attenuate chemotherapy-associated impediments in liver fatty acid metabolism.

Dietary EPA+DHA Mitigate Hepatic Toxicity and Modify the Oxylipin Profile in an Animal Model of Colorectal Cancer Treated with Chemotherapy.

Irinotecan (CPT-11) and 5-fluorouracil (5-FU) are commonly used to treat metastatic colorectal cancer, but chemotherapy-associated steatosis/steatohepatitis (CASSH) frequently accompanies their use. The objective of this study was to determine effect of CPT-11+5-FU on liver toxicity, liver oxylipins, and cytokines, and to explore whether these alterations could be modified by dietary eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in the form of fish oil (EPA+DHA). Tumor-bearing animals were administered CPT-11+5-FU and maintained on a control diet or a diet containing EPA+DHA (2.3 g/100 g). Livers were collected one week after chemotherapy for the analysis of oxylipins, cytokines, and markers of liver pathology (oxidized glutathione, GSSH; 4-hydroxynonenal, 4-HNE, and type-I collagen fiber). Dietary EPA+DHA prevented the chemotherapy-induced increases in liver GSSH (p < 0.011) and 4-HNE (p < 0.006). Compared with the tumor-bearing animals, ten oxylipins were altered (three/ten n-6 oxylipins were elevated while seven/ten n-3 oxylipins were reduced) following chemotherapy. Reductions in the n-3 fatty-acid-derived oxylipins that were evident following chemotherapy were restored by dietary EPA+DHA. Liver TNF-α, IL-6 and IL-10 were elevated (p < 0.05) following chemotherapy; dietary EPA+DHA reduced IL-6 (p = 0.09) and eotaxin (p = 0.007) levels. Chemotherapy-induced liver injury results in distinct alterations in oxylipins and cytokines, and dietary EPA+DHA attenuates these pathophysiological effects.

Higher subcutaneous adipose tissue radiodensity is associated with increased mortality in patients with cirrhosis.

Background & Aims: Association between sarcopenia and mortality in cirrhosis is well recognised; however, little is known about the clinical implications of adipose tissue radiodensity, indicative of biological features. This study aimed to determine an association between high subcutaneous adipose tissue (SAT) radiodensity and survival, compare the prevalence of high SAT radiodensity between healthy population and patients with cirrhosis, and identify an association between computed tomography (CT)-measured SAT radiodensity and histological characteristics. Methods: Adult patients with cirrhosis (n = 786) and healthy donors (n = 129) with CT images taken as part of the liver transplant (LT) assessment were included. Abdominal SAT biopsies (1-2 g) were harvested from the incision site at the time of LT from 12 patients with cirrhosis. Results: The majority of patients were male (67%) with a mean model for end-stage liver disease (MELD) score of 15 ± 8. SAT radiodensity above -83 HU in females (sub-distribution hazard ratio [sHR] 1.84, 95% CI 1.20-2.85, p = 0.006) and higher than -74 HU in males (sHR 1.51, 95% CI 1.05-1.18, p = 0.02) was associated with the highest mortality risk after adjusting for confounders in competing risk analysis. The frequency of high SAT radiodensity was 26% for those with cirrhosis, compared with 2% in healthy donors (p <0.001). An inverse correlation was found between SAT radiodensity and the mean cross-sectional area of SAT adipocytes (r = -0.67, p = 0.02). Shrunken, smaller adipocytes with expanded interstitial space were predominant in patients with high SAT radiodensity, whereas larger adipocytes with a thin rim of cytoplasm were observed in patients with low SAT radiodensity (744 ± 400 vs. 1,521 ± 1,035 µm2, p <0.001). Conclusion: High SAT radiodensity frequently presents and is associated with a higher mortality in cirrhosis. SAT morphological rearrangement in patients with high SAT radiodensity might indicate diminished lipid stores and alterations in tissue characteristics. Lay summary: Poor quality of subcutaneous adipose tissue (fat under the skin) is associated with higher mortality in patients with end-stage liver disease. Fat cells are smaller in patients with poor adipose tissue quality.

Alterations in hepatic fatty acids reveal depletion of total polyunsaturated fatty acids following irinotecan plus 5-fluorouracil treatment in an animal model of colorectal cancer.

Fatty liver is a side effect of chemotherapy that limits the ability to treat colorectal cancer (CRC) patients in the most effective way. The aim of this study was to determine hepatic fatty acid composition and expression of genes involved in lipid metabolism at two time points following sequential chemotherapy treatment with Irinotecan (CPT-11)+5-fluorouracil (5-FU), agents commonly used to treat human colorectal cancer. Female Fischer 344 rats were provided a semi-purified AIN-76 basal diet with modified fat component. One cycle of chemotherapy consisted of CPT-11+5-FU and was initiated 2 weeks after tumor implantation (D0); a second cycle was given one week later. Two days after each cycle (Day 2 and Day 9), animals were euthanized, and livers collected. Triacylglycerol (TAG) and phospholipid (PL) fractions were isolated using thin layer chromatography and fatty acids (FAs) were quantified using gas chromatography. Expression of 44 lipid metabolism genes were analyzed by qPCR. Total liver TAG level was lowest after the second cycle D0 and D2 (P = 0.05) characterized by lower content of n-6 and n-3 polyunsaturated fatty acids (PUFAs). N-6 PUFAs significantly declined with subsequent treatments. Of 44 genes analyzed, 13 genes were altered with CPT-11+5-FU treatment. Expression of genes VLCAD and DGAT1, involved in fatty acid oxidation as well as DGAT1 in TAG synthesis, were significantly elevated after each cycle, whereas expression of genes ELOVL2 and FADS2, involved in fatty acid elongation and desaturation were significantly lower at D9 compared to D2 and D0 (P < 0.03). Hepatic total TAG PUFA was depleted, and genes involved in pathways of PUFA synthesis were down-regulated by chemotherapy treatment. This observation suggests impediments in lipid metabolism in the liver that could potentially impact peripheral availability of essential fatty acids.

Depletion of essential fatty acids in muscle is associated with shorter survival of cancer patients undergoing surgery-preliminary report.

Emerging studies are reporting associations between skeletal muscle abnormalities and survival in cancer patients. Cancer prognosis is associated with depletion of essential fatty acids in erythrocytes and plasma in humans. However the relationship between skeletal muscle membrane fatty acid composition and survival is unknown. This study investigates the relationship between fatty acid content of phospholipids in skeletal muscle and survival in cancer patients. Rectus abdominis biopsies were collected during cancer surgery from 35 patients diagnosed with cancer. Thin-layer and gas chromatography were used for quantification of phospholipid fatty acids. Cutpoints for survival were defined using optimal stratification. Median survival was between 450 and 500 days when patients had arachidonic acid (AA) eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) in muscle phospholipid below the cut-point compared to 720-800 days for patients above. Cox regression analysis revealed that low amounts of AA, EPA and DHA are risk factors for death. The risk of death remained significant for AA [HR 3.5 (1.11-10.87), p = 0.03], EPA [HR 3.92 (1.1-14.0), p = 0.04] and DHA [HR 4.08 (1.1-14.6), p = 0.03] when adjusted for sex. Lower amounts of essential fatty acids in skeletal muscle membrane is a predictor of survival in cancer patients. These results warrant investigation to restore bioactive fatty acids in people with cancer.

A 16-week randomized controlled trial of a fish oil and whey protein-derived supplement to improve physical performance in older adults losing autonomy-A pilot study.

BACKGROUND: Low functional capacity may lead to the loss of independence and institutionalization of older adults. A nutritional intervention within a rehabilitation program may attenuate loss of muscle function in this understudied population. OBJECTIVE: This pilot study assessed the feasibility for a larger RCT of a nutritional supplementation in older adults referred to an outpatient assessment and rehabilitation program. METHODS: Participants were randomized to receive a supplement (EXP: 2g fish oil with 1500 IU vitamin D3 1x/d + 20-30g whey protein powder with 3g leucine 2x/d) or isocaloric placebo (CTR: corn oil + maltodextrin powder) for 16 weeks. Handgrip and knee extension strength (using dynamometry), physical performance tests and plasma phospholipid n-3 fatty acids (using GCMS) were evaluated at weeks 0, 8 and 16; and lean soft tissue mass (using DXA), at weeks 0 and 16. RESULTS: Over 2 years, 244 patients were screened, 46 were eligible (18.9%), 20 were randomized, 10 completed the study (6 CTR, 4 EXP). Median age was 87 y (77-94 y; 75% women) and gait speed was 0.69 m/s; 55% had low strength, and all performed under 420m on the 6-minute walk test, at baseline. Overall self-reported compliance to powder and oil was high (96% and 85%) but declined at 16 weeks for fish oil (55%). The EXP median protein intake surpassed the target 1.2-1.5 g/kg/d, without altering usual diet. Proportions of plasma phospholipid EPA and DHA increased significantly 3- and 1.5-fold respectively, at week 8 in EXP, with no change in CTR. Participants were able to complete most assessments with sustained guidance. CONCLUSION: Because of low eligibility, the pilot study was interrupted and deemed non-feasible; adherence to rigorous study assessments and to supplements was adequate except for long-term fish oil. The non-amended protocol may be applied to populations with greater functional capacity. TRIAL REGISTRATION: ClinicalTrials.gov NCT04454359.

Regulation of Skeletal Muscle Satellite Cell Differentiation by Omega-3 Polyunsaturated Fatty Acids: A Critical Review.

Skeletal muscle is composed of multinuclear cells called myofibres, which are formed by the fusion of myoblasts during development. The size of the muscle fiber and mass of skeletal muscle are altered in response to several pathological and physiological conditions. Skeletal muscle regeneration is primarily mediated by muscle stem cells called satellite cells (SCs). In response to injury, these SCs replenish myogenic progenitor cells to form new myofibers to repair damaged muscle. During myogenesis, activated SCs proliferate and differentiate to myoblast and then fuse with one another to form muscle fibers. A reduced number of SCs and an inability to undergo myogenesis may contribute to skeletal muscle disorders such as atrophy, cachexia, and sarcopenia. Myogenic regulatory factors (MRF) are transcription factors that regulate myogenesis and determines whether SCs will be in the quiescent, activated, committed, or differentiated state. Mitochondria oxidative phosphorylation and oxidative stress play a role in the determination of the fate of SCs. The potential activation and function of SCs are also affected by inflammation during skeletal muscle regeneration. Omega-3 polyunsaturated fatty acids (PUFAs) show promise to reduce inflammation, maintain muscle mass during aging, and increase the functional capacity of the muscle. The aim of this critical review is to highlight the role of omega-3 PUFAs on the myogenic differentiation of SCs and pathways affected during the differentiation process, including mitochondrial function and inflammation from the current body of literature.

Myokines in treatment-naïve patients with cancer-associated cachexia.

Cancer-associated cachexia is a complex metabolic syndrome characterized by weight loss and systemic inflammation. Muscle loss and fatty infiltration into muscle are associated with poor prognosis in cancer patients. Skeletal muscle secretes myokines, factors with autocrine, paracrine and/or endocrine action, which may be modified by or play a role in cachexia. This study examined myokine content in the plasma, skeletal muscle and tumor homogenates from treatment-naïve patients with gastric or colorectal stages I-IV cancer with cachexia (CC, N = 62), or not (weight stable cancer, WSC, N = 32). Myostatin, interleukin (IL) 15, follistatin-like protein 1 (FSTL-1), fatty acid binding protein 3 (FABP3), irisin and brain-derived neurotrophic factor (BDNF) protein content in samples was measured with Multiplex technology; body composition and muscle lipid infiltration were evaluated in computed tomography, and quantification of triacylglycerol (TAG) in the skeletal muscle. Cachectic patients presented lower muscle FSTL-1 expression (p = 0.047), higher FABP3 plasma content (p = 0.0301) and higher tumor tissue expression of FABP3 (p = 0.0182), IL-15 (p = 0.007) and irisin (p = 0.0110), compared to WSC. Neither muscle TAG content, nor muscle attenuation were different between weight stable and cachectic patients. Lumbar adipose tissue (AT) index, visceral AT index and subcutaneous AT index were lower in CC (p = 0.0149, p = 0.0455 and p = 0.0087, respectively), who also presented lower muscularity in the cohort (69.2% of patients; p = 0.0301), compared to WSC. The results indicate the myokine profile in skeletal muscle, plasma and tumor is impacted by cachexia. These findings show that myokines eventually affecting muscle wasting may not solely derive from the muscle itself (as the tumor also may contribute to the systemic scenario), and put forward new perspectives on cachexia treatment targeting myokines and associated receptors and pathways.

Fish oil supplementation and maintaining muscle mass in chronic disease: state of the evidence.

PURPOSE OF REVIEW: Providing eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), in the form of fish oils, to benefit muscle is an emerging area of interest. The aim of this work was to evaluate the current literature that has assessed muscle mass as an outcome during a fish oil intervention in any chronic disease. RECENT FINDINGS: The vast majority of studies published in the last 3 years (12 of 15) have been conducted in the oncological setting, in patients undergoing treatment for cancers of the gastrointestinal tract, breast, head and neck, lung, cervix, and hematological cancers. Three studies were conducted in patients with chronic obstructive pulmonary disease (COPD). Fish oil was provided as part of nutrient mixtures in 12 studies and as capsules in three studies. SUMMARY: Overall, the evidence for an effect of fish oil supplementation on muscle mass in patients with cancer undergoing treatment and in COPD remains unequivocal and reveals limited new knowledge in the area of fish oil supplementation in the cancer setting. Recent literature continues to provide mixed evidence on the efficacy of fish oil on muscle mass and function. The present review highlights challenges in comparing and interpreting current studies aimed at testing fish oil supplementation for muscle health.

N - 3 fatty acids during chemotherapy: toward a higher level of evidence for clinical application.

PURPOSE OF REVIEW: Recommendations for intakes of n - 3 fatty acids (FAs) in patients who are receiving chemotherapy for cancer are based on weak evidence. This review highlights themes within the emergent literature to suggest improvements in the design of studies that provide n - 3 FA supplements concurrent with cytotoxic agents. RECENT FINDINGS: Following earlier research in animal models and human pilot studies, recent human studies have evaluated the effect of providing n - 3 FAs during delivery of single agent and multiagent chemotherapy regimens for breast and gastro-intestinal cancers. Regimens were based on platinum compounds, fluoropyrimidines or both, and a variety of additional agents. Tumor location and stage, supplement dose and duration, and endpoints were dissimilar across studies. Overall, the recent research continues to support the safety and tolerability of n - 3 FA supplementation with chemotherapy and provides additional evidence, albeit weak, for enhanced tumor response, maintenance of weight and muscle, and reduction in inflammation and toxicities in the host across multiple cancer sites and chemotherapy regimens. SUMMARY: The barriers to implementation in practice remain small study sizes, variations in supplement dosage and methodology, and differences in primary endpoints. Randomized, blinded trials with a justifiable sample size, adequate doses, monitored compliance and measures of clinically important endpoints are required to move these findings to a higher level of evidence for implementation into clinical practice.

Deficits in Muscle Strength and Physical Performance Influence Physical Activity in Sarcopenic Children After Liver Transplantation.

Sarcopenia is a muscle disease characterized by reduced skeletal muscle mass (SMM), muscle strength, and physical performance. Reduced SMM has been identified in children after liver transplantation (LT), but no information related to muscle strength/physical performance or lifestyle factors contributing to sarcopenia is available. We hypothesized that sarcopenia, as determined by measures of SMM, muscle strength, and physical performance, is highly prevalent in children after LT and is related to poor diet quality (DQ) and physical inactivity. A cross-sectional study in post-LT children (n = 22) and age-matched healthy controls (n = 47) between the ages of 6 and 18 years examining body composition (dual energy X-ray absorptiometry and multiple skinfold), measures of muscle strength (handgrip, sit-to-stand, and push-ups), physical performance (6-minute walk test and stair climb test), diet (3-day food intake), and physical activity (accelerometer) was conducted. Low muscle strength/physical performance and SMM (SMM z scores ≤-1.5) were defined by values 2 standard deviations below the mean values for age- and sex-matched controls. Sarcopenia occurred in 36% of children who underwent LT, and they had significantly lower scores for muscle strength (sit-to-stand and push-up tests) and physical performance (stair climb test) than controls (P < 0.05). Deficits in physical performance in children with sarcopenia were predominantly revealed by longer stair climbing times (P = 0.03), with no differences in other muscle tests. Low SMM, muscle strength, and physical performance were associated with a lower amount of time spent in fairly and very active physical activity, but no associations with DQ were found. Sarcopenia is highly prevalent in children after LT and is related to lower moderate-to-vigorous physical activity. Development of effective rehabilitation strategies to treat sarcopenia are needed in post-LT children.

Lipid is heterogeneously distributed in muscle and associates with low radiodensity in cancer patients.

BACKGROUND: Low muscle radiodensity is associated with mortality in a variety of cancer types. Biochemical and morphological correlates are unknown. We aimed to evaluate triglyceride (TG) content and location as a function of computed tomography (CT)-derived measures of skeletal muscle radiodensity in cancer patients. METHODS: Rectus abdominis (RA) biopsies were collected during cancer surgery from 75 patients diagnosed with cancer. Thin-layer chromatography and gas chromatography were used for quantification of TG content of the muscle. Axial CT images of lumbar vertebra were used to measure muscle radiodensity. Oil Red O staining was used to determine the location of neutral lipids in frozen muscle sections. RESULTS: There was wide variation in RA radiodensity in repeated measures (CV% ranged from 3 to 55% based on 10 serial images) as well as within one slice (CV% ranged from 6 to 61% based on 10 subregions). RA radiodensity and total lumbar muscle radiodensity were inversely associated with TG content of RA (r = -0.396, P < 0.001, and r = -0.355, P = 0.002, respectively). Of the total percentage area of muscle staining positive for neutral lipid, 54 ± 17% was present as extramyocellular lipids (range 23.5-77.8%) and 46 ± 17% (range 22.2-76.5%) present as intramyocellular lipid droplets. CONCLUSIONS: Repeated measures revealed wide variation in radiodensity of RA muscle, both vertically and horizontally. Low muscle radiodensity reflects high level of TG in patients with cancer. Non-uniform distribution of intramyocellular and extramyocellular lipids was evident using light microscopy. These results warrant investigation of mechanisms resulting in lipid deposition in muscles of cancer patients.

Screening for Pediatric Malnutrition at Hospital Admission: Which Screening Tool Is Best?

BACKGROUND: Identifying children at malnutrition risk on admission to hospital is considered best practice; however, nutrition screening in pediatric populations is not common. The aim of this study was to determine which screening tool is able to identify children with malnutrition on admission to hospital. METHODS: A nurse administered 2 pediatric nutrition screening tools, Screening Tool for Risk on Nutritional Status and Growth (STRONGkids) and Pediatric Nutrition Screening Tool (PNST) to patients admitted to medicine and surgery units (n = 165). The Subjective Global Nutritional Assessment (SGNA) was then completed by a dietitian, blinded to the results of the screens. Sensitivity, specificity, and κ were calculated for both screening tools against the SGNA. A receiver operating characteristic (ROC) curve assessed alternate cutoffs for each tool. Length of hospital stay (LOS) was used to assess prospective validity. RESULTS: Using the recommended cutoffs, the sensitivity of STRONGkids was 89%, specificity 35%, and κ 0.483. The sensitivity of PNST was 58%, specificity 88%, and κ 0.601. Using adjusted cutoffs, PNST's sensitivity improved to 87%, specificity 71%, and κ 0.681, and STRONGkids specificity improved to 61%, sensitivity 80%, and κ 0.5. Children identified at nutrition risk had significantly longer LOS (P < 0.05). CONCLUSION: This study showed neither tool was appropriate for clinical use based on published cutoffs. By adjusting the cutoffs using ROC curve analysis, both tools improved overall agreement with the SGNA without significantly impacting the prospective validity. PNST with adjusted cutoffs is the most appropriate for clinical use in this population.

Meeting Minimum ESPEN Energy Recommendations Is Not Enough to Maintain Muscle Mass in Head and Neck Cancer Patients.

The relationship between dietary intake and body composition changes during cancer treatment has not been well characterized. The aim of this study was to compare dietary intake at diagnosis and end of treatment in relation to changes in muscle mass and adiposity in head and neck cancer (HNC) patients. Dietary intakes (three-day food record) and body composition using computed tomography (CT) were assessed at diagnosis (baseline) and after treatment completion (post-treatment). Skeletal muscle (SM) loss was explored as a consequence of energy and protein intake in relation to the minimum and maximum European Society of Parenteral and Enteral Nutrition (ESPEN) guidelines. Higher energy intakes (kcal/kg/day) and increases in energy intake (%) from baseline to post-treatment were correlated with attenuated muscle loss (r = 0.62, p < 0.01; r = 0.47, p = 0.04, respectively). Post-treatment protein intake demonstrated a weak positive correlation (r = 0.44, p = 0.05) with muscle loss, which did not persist when controlling for covariates. Meeting minimum ESPEN energy guidelines (25 kcal/kg/day) did not attenuate SM loss, whereas intakes >30 kcal/kg/day resulted in fewer participants losing muscle. Greater baseline adiposity correlated with greater SM loss (p < 0.001). Energy intakes of 30 kcal/kg/day may be required to protect against SM loss during treatment in HNC patients. The influence of adiposity on SM loss requires further exploration.

Immunohistochemical phenotyping of T cells, granulocytes, and phagocytes in the muscle of cancer patients: association with radiologically defined muscle mass and gene expression.

BACKGROUND: Inflammation is a recognized contributor to muscle wasting. Research in injury and myopathy suggests that interactions between the skeletal muscle and immune cells confer a pro-inflammatory environment that influences muscle loss through several mechanisms; however, this has not been explored in the cancer setting. This study investigated the local immune environment of the muscle by identifying the phenotype of immune cell populations in the muscle and their relationship to muscle mass in cancer patients. METHODS: Intraoperative muscle biopsies were collected from cancer patients (n = 30, 91% gastrointestinal malignancies). Muscle mass was assessed histologically (muscle fiber cross-sectional area, CSA; µm2) and radiologically (lumbar skeletal muscle index, SMI; cm2/m2 by computed tomography, CT). T cells (CD4 and CD8) and granulocytes/phagocytes (CD11b, CD14, and CD15) were assessed by immunohistochemistry. Microarray analysis was conducted in the muscle of a second cancer patient cohort. RESULTS: T cells (CD3+), granulocytes/phagocytes (CD11b+), and CD3-CD4+ cells were identified. Muscle fiber CSA (µm2) was positively correlated (Spearman's r = > 0.45; p = < 0.05) with the total number of T cells, CD4, and CD8 T cells and granulocytes/phagocytes. In addition, patients with the smallest SMI exhibited fewer CD8 T cells within their muscle. Consistent with this, further exploration with gene correlation analyses suggests that the presence of CD8 T cells is negatively associated (Pearson's r = ≥ 0.5; p = <0.0001) with key genes within muscle catabolic pathways for signaling (ACVR2B), ubiquitin proteasome (FOXO4, TRIM63, FBXO32, MUL1, UBC, UBB, UBE2L3), and apoptosis/autophagy (CASP8, BECN1, ATG13, SIVA1). CONCLUSION: The skeletal muscle immune environment of cancer patients is comprised of immune cell populations from the adaptive and innate immunity. Correlations of T cells, granulocyte/phagocytes, and CD3-CD4+ cells with muscle mass measurements indicate a positive relationship between immune cell numbers and muscle mass status in cancer patients. Further exploration with gene correlation analyses suggests that the presence of CD8 T cells is negatively correlated with components of muscle catabolism.

Clinical and biological characterization of skeletal muscle tissue biopsies of surgical cancer patients.

BACKGROUND: Researchers increasingly use intraoperative muscle biopsy to investigate mechanisms of skeletal muscle atrophy in patients with cancer. Muscles have been assessed for morphological, cellular, and biochemical features. The aim of this study was to conduct a state-of-the-science review of this literature and, secondly, to evaluate clinical and biological variation in biopsies of rectus abdominis (RA) muscle from a cohort of patients with malignancies. METHODS: Literature was searched for reports on muscle biopsies from patients with a cancer diagnosis. Quality of reports and risk of bias were assessed. Data abstracted included patient characteristics and diagnoses, sample size, tissue collection and biobanking procedures, and results. A cohort of cancer patients (n = 190, 88% gastrointestinal malignancies), who underwent open abdominal surgery as part of their clinical care, consented to RA biopsy from the site of incision. Computed tomography (CT) scans were used to quantify total abdominal muscle and RA cross-sectional areas and radiodensity. Biopsies were assessed for muscle fibre area (µm2 ), fibre types, myosin heavy chain isoforms, and expression of genes selected for their involvement in catabolic pathways of muscle. RESULTS: Muscle biopsy occurred in 59 studies (total N = 1585 participants). RA was biopsied intraoperatively in 40 studies (67%), followed by quadriceps (26%; percutaneous biopsy) and other muscles (7%). Cancer site and stage, % of male participants, and age were highly variable between studies. Details regarding patient medical history and biopsy procedures were frequently absent. Lack of description of the population(s) sampled and low sample size contributed to low quality and risk of bias. Weight-losing cases were compared with weight stable cancer or healthy controls without considering a measure of muscle mass in 21 out of 44 studies. In the cohort of patients providing biopsy for this study, 78% of patients had preoperative CT scans and a high proportion (64%) met published criteria for sarcopenia. Fibre type distribution in RA was type I (46% ± 13), hybrid type I/IIA (1% ± 1), type IIA (36% ± 10), hybrid type IIA/D (15% ± 14), and type IID (2% ± 5). Sexual dimorphism was prominent in RA CT cross-sectional area, mean fibre cross-sectional area, and in expression of genes associated with muscle growth, apoptosis, and inflammation (P < 0.05). Medical history revealed multiple co-morbid conditions and medications. CONCLUSIONS: Continued collaboration between researchers and cancer surgeons enables a more complete understanding of mechanisms of cancer-associated muscle atrophy. Standardization of biobanking practices, tissue manipulation, patient characterization, and classification will enhance the consistency, reliability, and comparability of future studies.