Muscle Depletion Research Articles

Malnutrition in patients with advanced head and neck cancer: Exploring the Global Leadership Initiative on Malnutrition (GLIM) criteria, energy balance and health-related quality of life.

Head and neck cancer (HNC) involves several tumor locations, the most common of which are the oropharynx and oral cavity. Patients with HNC are at high risk of developing malnutrition. Together with treatment, the tumor location contributes to difficulties in eating and swallowing, which can lead to a negative energy balance and weight loss. This study aimed to examine malnutrition via the Global Leadership Initiative on Malnutrition (GLIM) criteria, explore the different combinations of the GLIM criteria, study changes in body energy content and evaluate health-related quality of life (HRQoL) in patients with locally advanced HNC. Malnutrition was diagnosed via the GLIM criteria. Body weight, muscle mass, body fat, C-reactive protein (CRP) levels, energy intake, use of enteral feeding tubes or parenteral nutrition were assessed, and HRQoL scales from the European Organization for Research and Treatment of Cancer (EORTC), including the Quality of Life Questionnaire-Core 30 (QLQ-C30) and the Quality of Life Questionnaire-Head and Neck 35 (QLQ-HN35), and the M.D. Anderson Dysphagia Inventory (MDADI) were completed at baseline, 6 weeks and at 3, 6 and 12 months after the start of treatment. Body composition was measured via dual-energy X-ray absorptiometry, and body energy content was calculated. Eighty patients were included. The prevalence of malnutrition varied over time and peaked at the end of treatment at 71%, and at this time, the most common combination of the GLIM criteria was weight loss + reduced food intake + inflammation (31%), followed by weight loss + reduced muscle mass + reduced food intake + inflammation (20%). At the end of treatment patients were in a negative energy balance, and compared to baseline, body weight, body fat, and muscle mass had decreased with 6.0% (p<0.0001), 5.9% (p<0.0001), and 8.0% (p<0.0001) respectively. At the 3-month follow-up, the reduction in muscle mass had ceased, despite a negative energy balance, and patients started to regain muscle mass. At 12 months body weight had decreased with 7.4% (p<0.0001), body fat with 18.9% (p<0.0001), and muscle mass with 2.4% (p<0.0001) compared to baseline. Patients with malnutrition reported significantly worse HRQoL on a majority of the 16 quality of life scales at all time points, except at the end of treatment, when no significant differences were found between malnourished and nonmalnourished patients. Patients with advanced HNC receiving combined treatment experience major nutritional problems, and malnutrition is common at the end of treatment. Inflammation-driven muscle depletion during treatment is challenging, but it seems possible to recover muscle mass after treatment. Patients with malnutrition reported worse HRQoL at all time points, except at the end of treatment, when all patients' quality of life was very negatively affected.

Evaluating sarcopenia and nutritional status in outpatients with liver cirrhosis: concordance of diagnostic methods.

malnutrition and sarcopenia are prevalent in individuals with cirrhosis, but their diagnosis remains challenging due to limited access to suitable methods across different levels of healthcare. This study aimed to identify the most effective method for diagnosing sarcopenia in outpatients with liver cirrhosis and to evaluate the concordance between subjective and objective diagnostic methods. patients aged ≥ 18 years with a diagnosis of cirrhosis (regardless of etiology) under outpatient care were included. Exclusion criteria were: a) neoplasia, b) acute liver failure, c) pregnancy/lactation, d) HIV infection, e) special situations requiring liver transplantation, and f) history of organ failure. Nutritional and sarcopenia assessments used subjective methods, including the Royal Free Hospital-Nutritional Prioritizing Tool (RFH-NPT), SARC-F, SARC-Calf, and RFH-Global Assessment (RFH-GA); and objective methods, including anthropometry, handgrip strength (HGS), the sit-and-stand test (15s), and appendicular skeletal muscle mass index (ASMI) by Dual-Energy X-ray Absorptiometry (DXA). Concordance between ASMI and traditional methods was analyzed. Significance was set at p < 0.05. a total of 45 patients were analyzed, with alcoholic liver disease being the most frequent etiology (44.4 %). The sit-and-stand test (15s) combined with muscle depletion by DXA diagnosed the most cases of sarcopenia (42.2 %). Moderate agreement was found between muscle depletion and isolated calf circumference (CC) (κ = 0.581; p < 0.001). our study suggests excluding SARC-F and SARC-CalF from sarcopenia screening in outpatients with cirrhosis. While ASMI remains the most reliable diagnostic method, CC may serve as a feasible alternative when DXA is unavailable.

Effect of sarcopenic obesity on treatment results in patients with malignant tumors of the gastrointestinal tract: systematic review

Background. Tumors of the gastrointestinal (GI) tract are characterized by high morbidity and poor prognosis. Over the past decade, sarcopenia (skeletal muscle depletion), myosteatosis, sarcopenic obesity were all shown to have negative prognostic effect in patients with various GI malignancies. However, the role of sarcopenic obesity (SO) in patients with GI tumors remains controversial. We have summarized clinical trial data on the effect of SO on treatment results in patients with malignant GI tumors who underwent surgical and/or drug antitumor treatment.Materials and methods. Thisstudy was conducted in comliance with the Preferred Reporting Itemsfor Systematic Review and Meta-Analyses (PRISMA) guidelines. PubMed and Cochrane Library databases were searched for relevant original studies published between January 2009 and December 2022 reporting postoperative complication rate and mortality, long-term survival and chemotherapy toxicity in SO patients with GI cancers.Results. Twenty four studies with 9,601 patients were included. The percentage of SO patients ranged from 2.6 to 51 %. Due to significant heterogeneity of SO determination methods and varying threshold values, the association between SO and outcomes of interest was inconsistent. SO was significantly associated with development of major postoperative complications in six studies. In contrast, three studies did not show any effect of SO on postoperative complications. Only two studies demonstrated that the mortality rate was significantly higher among patients with SO compared to those without SO. Four studies using multivariate analysis showed statistically significant effect of SO on long-term survival, one study – on disease-free survival. However, three trials contradicted this finding and reported that SO was not a negative prognostic factor of long-term survival in GI cancer patients. Three studies investigating SO effect on the outcomes of drug antitumor treatment showed negative effect of SO on chemotherapy toxicity.Conclusion. There is considerable heterogeneity in methods used to define SO in the literature, and current data is limited. Standardized terminology and deeper understanding of sarcopenic obesity pathophysiology is needed to further understand the effect of obesity and sarcopenia on clinical trajectory of patients with GI cancer.

Assessment of skeletal muscle dynamics and milk production across a 300-day lactation in multiparous dairy cattle

The objective of this study was to evaluate changes in longissimus dorsi muscle depth (LDD) across lactation (0 to 300 DIM) and identify the impact of low versus high muscle reserves immediately after parturition on body weight and body reserve changes as well as production variables across a 300-d lactation. Forty multiparous cows were classified as high muscle (HM; LDD > 5.0 cm; n = 18) or low muscle (LM; LDD ≤ 5.0 cm; n = 22) based on LDD measurements collected within 24 h of parturition. Body weights (BW) and ultrasound scans to assess LDD and back fat depth (BFD) were collected monthly from parturition until 300 DIM. Ultrasound scans captured and measured using available software. Blood samples were taken at 7, 150 and 300 DIM, and plasma was analyzed for markers of metabolic status by measuring insulin, nonesterified fatty acids (NEFA), creatinine, and 3-methylhistidine (3-MH). Milk yield was recorded daily and milk components were analyzed monthly. Data analysis was performed and the statistical models included the fixed effect of muscle group, time, their interaction, and the random effect of cow nested within muscle group with repeated measures using a first-order autoregressive covariance structure. Muscle group was not related with BW or BFD for any of the time points measured. Cows lost BW from 0 to 60 DIM and gained weight from 60 to 300 DIM. Similarly, BFD decreased between 0 to 90 DIM and increased BFD after 90 DIM until 300 DIM. A muscle group by time interaction was observed for LDD. The HM cows had more muscle at 0 DIM, indicative of treatment assignment (1.34 cm more), and 300 DIM (0.78 cm more) and tended to have more muscle at 60 DIM (0.66 cm more) compared with LM. After 240 DIM, both muscle groups began net accretion of muscle reserves until 300 DIM. No differences were observed for blood metabolites measured based on muscle group. However, there were significant time effects for creatinine, 3-MH, and NEFA concentrations, which reflected the observed changes in BFD and LDD measured in ultrasound scans. For statistical analysis of daily milk production, observations were grouped into 3 stages of lactation, early (0-60 DIM), mid (60-240 DIM), and late lactation (240-300 DIM). There was a muscle group by stage of lactation interaction, where in early and mid-lactation, HM cows produced, on average, 1.9 kg more milk/d; however, in late lactation, LM cows produced 1.8 kg more milk/d. Our results indicate that muscle reserves are depleted in early lactation, and accreted in late lactation, whereas BW and BFD started to increase by 90 DIM. Data also supports that cows with more extensive muscle depletion in early lactation had greater milk production, however, substantial muscle accretion in late lactation may result in reduced milk production.

Nutritional characterization of patients with oropharyngeal cancers: impact of human papillomavirus status.

Oropharyngeal squamous cell carcinoma (OPSCC) of human papillomavirus (HPV)-positive status is increasing relative to HPV-negative disease. Nutritional features of OPSCC patients according to HPV status is unclear. Canadian and Spanish patients with OPSCC were assessed for body mass index (BMI), weight loss grade (WLG), and computed tomography-defined skeletal muscle index (SMI). Chi-square, t-test, Mann-Whitney-U, Kruskal-Wallis tests were conducted to compare HPV positive and negative groups. Overall survival (OS) was assessed by univariable Kaplan-Meier and Cox proportional hazard methods. No differences in BMI, WLG, SMI, and adipose tissue index between the 308 (Canada) and 134 (Spain) patients according to HPV status; hence cohorts were pooled (n = 442). HPV-positive patients (n = 317) were overweight/obese (72.8%), had WLG of 0/1 (59.6%) and high SMI (83.4%) while HPV-negative patients were normal/underweight (61.5%), had high WLG 3/4 (50.8%), and moderate/severe SMI depletion (46.9%) (p < 0.003). These overall differences notwithstanding, there was crossover i.e. 35% of HPV-positive patients had high WLG and/or moderate/severe muscle depletion and 29% of HPV-negative patients had minimal weight loss and high SMI. HPV-negative patients had a higher risk of mortality (HR 3.78, 95% CI 2.70-5.29, P < 0.001) and this difference was retained after multivariable adjustment for WLG, SMI, age, disease stage, and planned treatment (HR 3.30, 95% CI 2.17-5.02, P < 0.001). Nutrition features of patients with OPSCC did not differ between Canada and Spain. Distinctive nutrition features exist in patients according to HPV status. The high heterogeneity of individual nutritional profiles invites an individualized approach to nutrition care.

Integrating Muscle Depletion with Barcelona Clinic Liver Cancer Staging to Predict Overall Survival in Hepatocellular Carcinoma

Background: Muscle depletion (MD) is a critical factor that influences clinical outcomes in patients with hepatocellular carcinoma (HCC). Although its role in cancer prognosis is recognized, its integration into widely used prognostic systems remains underexplored. This study aimed to evaluate the prognostic impact of MD on overall survival (OS) in HCC patients and to improve existing noninvasive prognostic models by incorporating MD-related metrics. Methods: A retrospective analysis was conducted on 1072 HCC patients treated at Taipei Tzu Chi Hospital between January 2006 and December 2016. All patients had follow-up data and computed tomography (CT) scans at vertebral level L3 for MD evaluation. Independent prognostic factors for OS were identified using Cox proportional hazards models, and the predictive performance of various prognostic models was assessed through the area under the receiver operating characteristic curve (AUROC). Results: The key independent predictors of OS in HCC patients included hepatitis B virus infection, hepatitis C virus infection, liver cirrhosis, tumor size, serum alpha-fetoprotein levels, and MD-related metrics (psoas muscle-to-spine ratio, psoas muscle-to-vertebral ratio, and myosteatosis). Among existing models, the Barcelona Clinic Liver Cancer (BCLC) stage, the Child–Turcotte–Pugh (CTP) class, and the albumin–bilirubin (ALBI) grade demonstrated robust predictive performance for OS. However, incorporating MD significantly improved the predictive accuracy of these models, with the MD–BCLC model showing the highest AUROC (0.804, 95% CI: 0.777–0.832, p &lt; 0.001). Conclusions: MD is an independent and significant prognostic predictor for patients with HCC. Integrating MD metrics into established systems, particularly the BCLC staging system, markedly improves OS prediction, providing a more comprehensive tool for clinical decision-making in the management of HCC.

Gender-Specific Malnutrition and Muscle Depletion in Gastric and Colorectal Cancer: Role of Dietary Intake in a Jordanian Cohort.

This study aimed to assess malnutrition and muscle mass depletion risk in gastrointestinal cancer patients, exploring the differences between gastric and colorectal cancer, with a focus on gender0specific variations and dietary intake. It also examined whether muscle depletion mediates the relationship between dietary intake and malnutrition risk. A sample of 100 Jordanian pre-operative gastrointestinal cancer patients (60 male, 40 female) with gastric or colorectal cancer were assessed for malnutrition risk using the malnutrition universal screening tool (MUST) and for muscle depletion using fat-free mass index (FFMI) and mid-upper arm muscle area (MUAMA). The study found that 80% (95% CI: 0.708-0.873) of patients were at high risk of malnutrition, with over 60% experiencing severe muscle loss. Gastric cancer patients showed higher, though not statistically significant, malnutrition risk (90.2% vs. 72.9%) and muscle depletion compared to colorectal cancer patients. Advanced cancer stages were associated with significantly higher risk of malnutrition and muscle depletion. Significant gender-specific differences in muscle depletion via FFMI (p = 0.012) and via MUAMA (p = 0.028) were also noted, especially in females with gastric cancer. Additionally, males exhibited a significantly higher malnutrition risk (p < 0.001) based on cancer stage. Patients' dietary intake was significantly (p < 0.001) below the recommended levels for energy, protein, carbohydrates, fiber, and essential fatty acids, which was associated with higher malnutrition risk, muscle depletion, low BMI (<18.5 kg/m2), and significant weight loss (>10%). Low dietary intake was strongly linked to increased malnutrition risk and muscle depletion, with muscle loss partially mediating (b = 0.4972, p < 0.0001) the relationship between poor dietary intake and malnutrition risk. Additionally, higher muscle mass was protective against malnutrition (OR = 16.0, 95% CI: 1.706-150.507), and cancer type was a significant predictor of malnutrition risk (OR = 14.4, 95% CI: 1.583-130.867). Malnutrition risk and significant muscle loss are common in GI cancer patients, highlighting the urgent need for tailored nutrition care plans and lifestyle modifications.

6826 Mevalonate Treatment Worsened Hypocholesterolemia During Prolonged Sepsis Without Affecting Adrenal And Muscle Function

Abstract Disclosure: L. De Bruyn: None. S. Derde: None. F. Van Beek: None. S. Vander Perre: None. I. Derese: None. L. Pauwels: None. G. Van den Berghe: None. L. Langouche: None. Introduction: Sepsis is hallmarked by an immediate and sustained reduction in total-, HDL- and LDL-cholesterol (-C), associated with illness severity and a potential contributor to the development of adrenal failure and muscle weakness. The underlying mechanisms that might be involved in sepsis-induced hypocholesterolemia are multifactorial and partly understood. We hypothesized that treatment with the cholesterol precursor mevalonate might improve cholesterol availability, thereby improving adrenal gland and skeletal muscle function. Our hypothesis was tested in a validated and clinically relevant mouse model of prolonged sepsis. Methods: In a catheterized mouse model of cecal ligation and puncture-induced, fluid resuscitated and antibiotics treated polymicrobial abdominal sepsis (5 d), septic mice received continuous infusion with either mevalonate (78 mg/d) or placebo solution, whereas healthy mice served as controls (N=50). Plasma total-C (HDL- + LDL-C), CORT and total bile acids were measured, in addition to ex vivo muscle force and adrenocortical cholesterol ester content. Gene expression markers of inflammation (Tnf-α, Il-6) were measured in the adrenal gland, as well as hepatic mRNA expression of cholesterol synthesis enzymes (Hmgcs1, Hmgcr, Fdft1). Metabolites of the mevalonate pathway (mevalonic acid, squalene, lanosterol, desmosterol and (7-dehydro) cholesterol) were quantified in the liver with LC-MS. Results: The sepsis-induced reduction in plasma total-C was further decreased in mevalonate-treated septic mice (26±3 mg/dL) as compared with placebo (53±3 mg/dL) and healthy controls (108±3 mg/dL) (p&amp;lt;0.0001). Metabolites of the mevalonate pathway were all increased in the liver after mevalonate treatment (p&amp;lt;0.01), whereas hepatic cholesterol content was decreased as compared with placebo (p&amp;lt;0.05). Also, gene expression markers of cholesterol synthesis enzymes were further decreased in the liver of mevalonate-treated septic mice as compared with placebo (p&amp;lt;0.05). In the context of the unexpected further reduction in plasma total-C, no additional effect on plasma CORT, total bile acids, and sepsis-induced loss of muscle force and depletion in adrenocortical cholesterol ester content was observed. In addition, the sepsis-induced rise in markers of adrenal inflammation (Tnf-α, Il-6) was not further affected by mevalonate treatment. Conclusion: Mevalonate treatment further reduced the sepsis-induced hypocholesterolemia in prolonged septic mice, potentially due to increased feedback inhibition on hepatic cholesterol biosynthesis, but without further affecting adrenal and muscle function. Other therapies such as substitution with bovine serum HDL-C are currently investigated to improve altered cholesterol availability during sepsis. Presentation: 6/2/2024

MANEJO NUTRICIONAL DA RESISTÊNCIA À INSULINA NA SÍNDROME DE OVÁRIO POLICÍSTICO

Introduction: Polycystic Ovary Syndrome (PCOS) is the most common hormonal disorder among women during the ovulation and menstrual periods. Its origin is still unknown; however, the treatment of the disease involves changes in dietary habits and physical activity practices. Reducing carbohydrate intake has positive effects on PCOS, as this low carbohydrate consumption allows for depletion of muscle and hepatic glycogen stores. Objective: To evaluate the nutritional management of insulin resistance in PCOS. Materials and Methods: Literature reviews were conducted focusing on the last cinco years, using the PubMed, Scielo, and Virtual Health Library (BVS) databases. Result: A hypocaloric diet showed improvements in metabolic rates, menstrual cycle, weight loss, and insulin resistance parameters. Conclusion: Although there is no specific diet for women with insulin resistance and polycystic ovary syndrome, the results of studies have shown that low-calorie diets in conjunction with physical activity can influence the reduction of anthropometric measurements of patients, and therefore assist in the treatment of PCOS and insulin resistance.

Variations in vertebral muscle mass and muscle quality in adult patients with different types of cancer

Assessment of malnutrition-related muscle depletion with computed tomography (CT) using skeletal muscle index (SMI) and muscle radiation attenuation (MRA) at the third lumbar vertebra is well validated. However, SMI and MRA values at other vertebral locations and interchangeability as parameters in different types of cancer are less known. We aimed to investigate whether adult patients with different types of cancer show differences in SMI and MRA at all vertebral levels. We retrospectively analyzed CT images from 203 patients:120 with head and neck cancer, esophageal cancer, or lung cancer (HNC/EC/LC) and 83 with melanoma (ME). Univariate and multivariate linear regression analyses determined the association between SMI (cm²/m2) and MRA (Hounsfield units) and cancer type at each vertebral level (significance corrected for multiple tests, P ≤ 0.002). The multivariate analyses included age, sex, cancer stage, comorbidity, CT protocol, and body mass index (BMI) (MRA analyses). SMI was lower in the HNC/EC/LC group versus the ME group at all vertebral levels, except C4 through C6 in the multivariate analyses. Female sex was associated with lower SMI at almost all levels. MRA was similar at most vertebral levels in both cancer groups but was lower at C1 through C4, T7, and L5 in the multivariate analyses. Use of contrast fluid and BMI were associated with higher MRA at all vertebral levels except T8 to T9 and C1 to C2, respectively. SMI, but not MRA, was lower in HNC/EC/LC patients than in ME patients at most vertebral levels. This indicates that low muscle mass presents itself across the various vertebral muscle areas. MRA may less consistently mark muscle depletion in malnourished patients.

Assessing cachexia in obesity: contradiction or perfectly possible?

Existing definitions of clinically important weight loss in patients with cancer do not specifically address weight loss in patients who are obese at presentation. This review explores the clinical impact of weight loss and depletion of the skeletal muscle mass (i.e., criteria defining cancer cachexia), in patients with obesity. Overweight and obese BMI values are shown by many recent studies to pose a survival advantage in patients with cancers of advanced stage, when compared with BMI in normal and underweight ranges. The classification of cancer-associated weight loss has evolved, and current grading schemes evaluate the impact of weight across the range of BMI values. Weight loss is associated with mortality in patients with BMI more than 30 kg/m 2 , however this is to a much lesser degree than in patients with lower BMI values. Diagnostic imaging permits the precise assessment of skeletal muscle index (SMI) in patients with cancer, and it has been clearly shown that while usually quite muscular, obese patients can have profound muscle depletion (i.e., sarcopenia), independent of the presence of weight loss. Muscle depletion associates strongly with mortality in obese patients, as well as with complications of cancer surgery and systemic therapy. It would seem contradictory to diagnose concurrent obesity and cachexia, as these terms represent opposite ends of the weight spectrum. Weight loss can occur in anyone with cancer, however its priority for clinical management may be lesser in obese versus low body weight individuals. Sarcopenic obesity is strongly associated with a poor clinical outcome and deserves further research, diagnosis in clinical practice, and new strategies for mitigation.

Association of sarcopenia with severe chemotherapy toxicities and survival in patients with advanced gastric cancer.

Sarcopenia or skeletal muscle depletion is a poor prognostic factor for gastric cancer (GC). However, existing cutoff values of skeletal muscle index (SMI) for defining sarcopenia have been found to have limitations when clinically applied. This study aimed to determine the optimal cutoff for SMI to predict severe toxicities of chemotherapy and overall survival (OS) in patients with advanced GC. Patients with metastatic gastric adenocarcinoma who received first-line palliative chemotherapy between January 2014 and December 2021 at Queen Mary Hospital, Hong Kong, were included in this study. The SMI was determined via a pre-chemotherapy computed tomography scan. Optimal cutoff points of SMI were identified by recursive partitioning analysis. Univariate and multivariate analyses evaluating risk factors of severe chemotherapy toxicities and OS were also performed. A total of 158 patients (male: 108 (68.4%), median age: 65.3) were included. The SMI cutoff to define low SMI was ≤33 cm2/m2 for males and ≤28 cm2/m2 for females; 30 patients (19.0%) had low SMI. Patients with low SMI had a higher incidence of hematological toxicities (63.3% vs 32.0%, P = .001) and non-hematological toxicities (66.7% vs 36.7%, P = .003). Multivariable analysis indicated that low SMI and low serum albumin (≤28 g/L) were independent predictive factors of hematological toxicity, while low SMI and neutrophil-lymphocyte ratio ≥5 were predictive factors of non-hematological toxicity. Moreover, patients with low SMI had a significantly shorter OS (P = .011), lower response rate to chemotherapy (P = .045), and lower utilization of subsequent lines of treatment (P < .001). Using pre-chemotherapy SMI cutoff (≤33 cm2/m2 for males and 28 cm2/m2 for females) one can identify individuals with a higher risk of severe chemotherapy toxicities and worse prognosis.

Body composition measures as a determinant of alpelisib-related toxicity.

e13093 Background: Body composition has emerged as an important prognostic factor in patients treated with cancer. Severe depletion of skeletal muscle, sarcopenia, has been associated with poor performance status and worse oncological outcomes. We studied patients with metastatic breast cancer receiving alpelisib, to determine if sarcopenia and additional body composition measures accounting for muscle and adiposity are associated with toxicity. Methods: A retrospective observational analysis was conducted, including 38 women with metastatic breast cancer and a PIK3CA mutation, treated with alpelisib as advanced line of therapy. Sarcopenia was determined by measuring skeletal muscle cross-sectional area at the third lumbar vertebra using computerized tomography. Various body composition metrics were assessed along with drug toxicity, dose reductions, treatment discontinuation, and hospitalizations. Results: Sarcopenia was observed in half of the patients (n=19, 50%), spanning normal weight, overweight, and obese individuals. Among the body composition measures, lower skeletal muscle density (SMD) was associated with an increased risk of treatment-related hyperglycaemia (P=0.03). Additionally, lower visceral adipose tissue (VAT) was associated with alpelisib-induced rash (P=0.04) and hospitalizations (P=0.04). Notably, alpelisib treatment discontinuation was not impacted by alpelisib toxicity. Conclusions: Body composition measures, specifically SMD and VAT may provide an opportunity to identify patients at higher risk for severe alpelisib related hyperglycemia, and cutaneous toxicity. These findings suggest the potential use of body composition assessment to predict toxicity, allowing for personalized therapeutic observation and intervention.

Association between Muscle Mass Index and Neurological Outcomes of Patients with Out-of-Hospital Cardiac Arrest.

Muscle mass depletion is associated with unfavorable outcomes in many diseases. However, its relationship with cardiac arrest outcomes has not been explored. This retrospective single-center study determined the relationship between muscle mass depletion and the neurological outcomes of patients with out-of-hospital cardiac arrest (OHCA) by measuring muscle mass at various locations. Adult patients with OHCA, who were treated with target temperature management, and who underwent abdominal or chest computed tomography (CT) within 3 months of the cardiac arrest were included. Skeletal muscle index (SMI) was measured at the third lumbar vertebra (L3) level, psoas muscle, fourth thoracic vertebra (T4) level, and pectoralis muscle. The Youden index was used to determine a low SMI based on sex-specific cutoff values. The outcome variables were "good neurological outcome" and "survival" at hospital discharge. Multivariable analyses revealed that patients with low T4 SMI level were significantly associated with good neurological outcomes at hospital discharge (odds ratio = 0.26, 95% confidence interval: 0.07-0.88, p = 0.036). However, no significant differences were observed between good neurological outcomes and low SMI at the L3 level and psoas and pectoralis muscles; SMIs were not associated with survival at hospital discharge. T4 level SMI depletion was inversely associated with good neurological outcomes in patients with OHCA. Thoracic muscle depletion may be crucial for predicting the neurological outcomes in patients with OHCA and further investigation in larger prospective study is warranted.

Skeletal Muscle Mass Index Reduction Rate as a Prognostic Indicator for Patients Undergoing Pancreatectomy for Pancreatic Cancer.

There have been many studies on skeletal muscle depletion before surgery, and skeletal muscle depletion is a known risk factor for poor prognosis. However, reports on the association between changes in skeletal muscle mass and prognosis after surgery for pancreatic cancer are very few. The data of 137 patients who underwent pancreatectomy for pancreatic cancer between 2005 and 2022 were reviewed. Muscle areas were measured at the third lumbar vertebral level, and skeletal muscle mass index (SMI) reduction rates were calculated. Patients were divided into two groups using receiver operating characteristic (ROC) curve analysis based on the SMI reduction rate with a cutoff of 14% reduction rate. The clinicopathological factors, overall survival (OS), and recurrence-free survival (RFS) were compared between the two groups. Survival rates were analyzed both univariately and multivariately to clarify the factors associated with poor prognosis after pancreatectomy. A total of 102 patients met the inclusion criteria. SMI reduction rate ≥14% significantly correlated with advanced age and higher incidence of postoperative complications. In the multivariate Cox regression analysis, preoperative prognostic nutritional index (PNI) <40 and SMI reduction rate ≥14% were significantly associated with poor OS. Tumor size ≥3.0 cm, preoperative neutrophile-lymphocyte ratio ≥3.0, and SMI reduction rate ≥14% were significantly associated with poor RFS. The rate of skeletal muscle mass reduction after pancreatic surgery is an independent prognostic factor for survival in patients with pancreatic cancer.

Abstract 1006: Pathological PERK/ATF4 Activation In Vascular Smooth Muscle Cells Drives Abdominal Aortic Aneurysm Development

Introduction: Abdominal aortic aneurysms (AAA) are characterized by vascular smooth muscle cell (VSMC) apoptosis leading to pathological aortic remodeling. Activation of the endoplasmic reticulum (ER) stress response has been linked to VSMC dysfunction but the driving factors behind ER stress activation and its role on AAA development remains poorly defined. The epigenetic enzyme, MLL1, plays a critical role in establishing cellular phenotype and regulating gene expression. We examine the MLL-mediated epigenetic regulation of the ER stress response in VSMCs during AAA development and establish the ER stress pathways as a novel target in the treatment AAAs. Methods: Single-cell sequencing was conducted on human AAA and control tissue samples. For our murine model, C57BL/6 mice were injected with an AAV encoding a PCSK9 gain-of-function mutation and then fed a saturated fat-enriched diet and infused with AngII (1 μg/kg/min) with or without 4-PBA (20mg/kg/day). Mice with vascular smooth muscle cell-specific knockout of PERK (PERK SMKO ) underwent tamoxifen injection. AAA maximum diameters were quantified and VSMCs were isolated. Eif2a, Atf4 , and Chop gene expression was examined. Apoptosis was quantified by Annexin V staining. Results: Using single-cell RNA sequencing of human aortic tissue, we identified EIF2A, ATF4 , and CHOP were profoundly upregulated in aneurysmal VSMCs as well as two murine AAA models. Mechanistically, TNFα signaling in VSMCs leads to activation of MLL1 which trimethylates histone 3 lysine 4 (H3K4me3) at NF-κB binding sites on the EIF2A and ATF4 gene promoters thereby upregulating the ER stress response and driving VSMC apoptosis. Both In vivo pharmacological inhibition of the PERK/eIF2A/ATF4 ER stress response via 4-PBA injection and vascular smooth muscle depletion of PERK (PERK SMKO ) inhibited AAA formation resulting with in significant reduction in VSMC apoptosis, elastin fragmentation, and inflammatory cytokine infiltration. Conclusions: Taken together, our results identify MLL1-mediated activation of the PERK/eIF2A/ATF4 ER stress response as a critical regulator of VSMC apoptosis in AAA formation and suggest inhibition of ER stress response as a mechanistic target for the management of AAAs.

The impact of skeletal muscle index at the third lumbar spine on nosocomial deterioration and short-term prognosis in acute pancreatitis: a retrospective observational study.

To investigate the impact of the third lumbar skeletal muscle index (L3-SMI) assessed by CT on the in-hospital severity and short-term prognosis of acute pancreatitis. A total of 224 patients with severe acute pancreatitis admitted to Yantaishan Hospital from January 2021 to June 2022 were selected as the subjects. Based on the in-hospital treatment outcomes, they were divided into a mortality group of 59 cases as well as a survival group of 165 cases. Upon admission, general information such as the Acute Physiology and Chronic Health Evaluation II (APACHE II) score, along with the abdominal CT images of each patient, were analyzed. The L3-SMI was calculated, and the Modified CT Severity Index (MCTSI) and Balthazar CT grade were used to assess the severity of in-hospital complications of acute pancreatitis. The evaluation value of L3-SMI for the prognosis of severe acute pancreatitis was analyzed, as well as the factors influencing the prognosis of severe acute pancreatitis. No statistically significant differences in gender, age, BMI, etiology, duration of anti-inflammatory drug use, and proportion of surgical patients between the survival and mortality groups were observed. But the mortality group showed higher proportions of patients with an elevated APACHE II score upon admission, mechanical ventilation, and renal replacement therapy, compared to the survival group, with statistically significant differences (P < 0.001). Furthermore, the mortality group had higher MCTSI scores (6.42 ± 0.69) and Balthazar CT grades (3.78 ± 0.45) than the survival group, with statistically significant differences (P < 0.001). The mortality group also had a lower L3-SMI (39.68 ± 3.25) compared to the survival group (42.71 ± 4.28), with statistically significant differences (P < 0.001). L3-SMI exhibited a negative correlation with MCTSI scores and Balthazar CT grades (r = -0.889, -0.790, P < 0.001). Logistic regression analysis, with mortality of acute pancreatitis patients as the dependent variable and MCTSI scores, Balthazar CT grades, L3-SMI, APACHE II score upon admission, mechanical ventilation, and renal replacement therapy as independent variables, revealed that MCTSI scores and L3-SMI were risk factors for mortality in acute pancreatitis patients (P < 0.001). Logistic regression analysis using the same variables confirmed that all these factors were risk factors for mortality in acute pancreatitis patients. This study confirmed that diagnosing muscle depletion using L3-SMI is a valuable radiological parameter for predicting in-hospital severity and short-term prognosis in patients with acute pancreatitis.

Pretransplant Malnutrition, Particularly With Muscle Depletion Is Associated With Adverse Outcomes After Kidney Transplantation.

Kidney transplant centers lack consistent diagnostic malnutrition tools. The Academy of Nutrition and Dietetics and American Society of Parenteral Nutrition Adult Malnutrition Criteria (AMC) is the widely accepted and utilized tool by Registered Dietitian Nutritionists (RDNs) to diagnose malnutrition. In this single-center, retrospective observational study, we evaluated the outcomes of prekidney transplant malnutrition based on Academy of Nutrition and Dietetics and American Society of Parenteral Nutrition AMC, as well as the individual components of the AMC, on posttransplant outcomes including length of stay, delayed graft function (DGF), early readmission, cardiovascular events, acute rejection, death-censored graft failure, and death. Bivariable and multivariable logistic regression models were used to assess the association of malnutrition or its components with outcomes of interest. A total of 367 recipients were included, of whom 36 (10%) were malnourished (23 moderately and 13 severely) at pretransplant evaluation. In adjusted models, pretransplant malnutrition was significantly associated with increased risk for early readmission (adjusted odds ratio 2.86; 95% confidence interval: 1.14-7.21; P = 0.03) and with DGF (adjusted odds ratio 8.33; 95% confidence interval: 1.07-64.6; P = 0.04). Muscle depletion was also associated with an increased risk for readmission and with DGF. Fat depletion and reduced functionality in the adjusted model were only associated with increased risk for readmission. Malnutrition could be an important consideration for selecting kidney transplant recipients because it was associated with poor clinical outcomes. A multidisciplinary approach with the involvement of RDNs to outline a nutrition intervention plan may help mitigate some of the poor outcomes.

Body composition measures as a determinant of Alpelisib related toxicity

BackgroundBody composition has emerged as an important prognostic factor in patients treated with cancer. Severe depletion of skeletal muscle, sarcopenia, has been associated with poor performance status and worse oncological outcomes. We studied patients with metastatic breast cancer receiving alpelisib, to determine if sarcopenia and additional body composition measures accounting for muscle and adiposity are associated with toxicity.MethodsA retrospective observational analysis was conducted, including 38 women with metastatic breast cancer and a PIK3CA mutation, treated with alpelisib as advanced line of therapy. Sarcopenia was determined by measuring skeletal muscle cross-sectional area at the third lumbar vertebra using computerized tomography. Various body composition metrics were assessed along with drug toxicity, dose reductions, treatment discontinuation, hospitalizations, time to treatment failure and overall survival.ResultsSarcopenia was observed in half of the patients (n = 19, 50%), spanning normal weight, overweight, and obese individuals. Among the body composition measures, lower skeletal muscle density (SMD) was associated with an increased risk of treatment-related hyperglycaemia (P = 0.03). Additionally, lower visceral adipose tissue (VAT) was associated with alpelisib-induced rash (P = 0.04) and hospitalizations (P = 0.04). Notably, alpelisib treatment discontinuation was not impacted by alpelisib toxicity.ConclusionBody composition measures, specifically SMD and VAT may provide an opportunity to identify patients at higher risk for severe alpelisib related hyperglycemia, and cutaneous toxicity. These findings suggest the potential use of body composition assessment to caution toxicity risk, allowing for personalized therapeutic observation and intervention.

Abstract 3083: Unveiling the role of chemotherapy-resistant, slow-cycling cancer cells in driving cancer cachexia

Abstract Cancer cachexia, a systemic disease marked by substantial, involuntary weight loss, predominantly affecting muscle and adipose tissue, manifests in patients with advanced-stage cancer. The emergence of cancer cachexia poses significant challenges to cancer treatment, diminishing the efficacy of anticancer medications, and the resultant muscle loss adversely impacts the daily lives of patients, diminishing the overall quality of life. Notably, cancer cachexia is implicated in 30-40% of cancer-related deaths, underscoring the pivotal need to comprehend its underlying principles and propose apt interventions to enhance both survival rates and the well-being of cancer patients. Based on our previous findings, cancer cells exhibiting a slow cell cycle, resistant to widely employed clinical chemotherapy agents, exhibit the formation of proinflammatory tumor microenvironment. The escalation of systemic inflammatory cytokines has long been suggested as a potential mechanism contributing to cancer cachexia. Building upon these insights, we hypothesized that slow-cycling cancer cells (SCCs) featuring resistance to chemotherapy are pivotal contributors to cancer cachexia. We investigated the impact of drug-resistant SCCs on the loss of differentiated myotubes and lipid droplets in vitro and muscle and fat loss in in vivo conditions. Interestingly, these cells induced more severe muscle and fat losses. Upon scrutinizing this cell population, we found the overexpression of a particular membrane protein, Protein A. The increase of this Protein A enhanced the release of exosomes from the cell through a novel mechanism distinct from its classical functions, consequently amplifying the release of inflammatory substances originating from cancer cells. In summary, our study elucidates that chemotherapy-resistant cancer cells, characterized by a slow cell cycle, intensify the secretion of inflammatory substances in a manner contingent upon the overexpression of a membrane protein A, which leads to the depletion of muscle and fat located in the distal peripheral regions. Citation Format: Jaebeom Cho, Ho-Young Lee. Unveiling the role of chemotherapy-resistant, slow-cycling cancer cells in driving cancer cachexia [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 3083.