Journal of Cachexia, Sarcopenia and Muscle

Prevalence and Prognostic Significance of Sarcopenia in Gynecologic Oncology: A Systematic Review and Meta‐Analysis

ABSTRACTBackgroundSarcopenia in gynaecologic oncology patients has garnered increasing attention, but its prevalence has not been comprehensively summarized. This study aims to integrate the prevalence of sarcopenia in this population through systematic evaluation and meta‐analysis, providing a reference for future clinical research.MethodsA computerized search of PubMed, Embase, The Cochrane Library, Web of Science and other databases was conducted to collect relevant literature on the prevalence of sarcopenia in gynaecologic oncology patients and its impact on prognosis, with a timeframe from the inception of the databases to July 2024. Two researchers independently screened the literature, extracted information and assessed the risk of bias. After evaluating the risk of bias, a meta‐analysis was performed using RevMan5.4 software. This systematic review was conducted using a previously published study protocol (PROSPERO: CRD42024565094).ResultsA total of 24 studies encompassing 4136 patients were included. The meta‐analysis revealed that the prevalence of sarcopenia in gynaecologic oncology patients was 38.8% (I2 = 96%, 95% CI [0.49–0.79], p < 0.001). Subgroup analysis indicated that the prevalence of sarcopenia was higher among patients with endometrial cancer or ovarian cancer, those over 60 years of age, individuals with a body mass index (BMI) greater than 25 kg/m2, those diagnosed using the psoas muscle index (PMI) and patients assessed at the L4 vertebra. Overall survival (OS) was significantly lower in patients with gynaecologic tumours combined with sarcopenia compared to those with gynaecologic tumours alone. However, no significant differences were observed in progression‐free survival (PFS), mortality or length of hospital stay.ConclusionSarcopenia has a high prevalence in gynaecologic oncology patients. Healthcare professionals should prioritize early screening and preventive measures for high‐risk patients.

Pancreatic Damage in Ovarian Cancer–Associated Cachexia Is Driven by Activin A Signalling

ABSTRACT Background Cancer‐associated cachexia (CAC) is a severe metabolic disorder characterized by involuntary weight loss, skeletal muscle atrophy and adipose tissue depletion. It is a major contributor to morbidity and mortality in the advanced stages of various cancers. However, the impact of CAC on the pancreas remains largely unexplored. Methods We used mice with constitutively active PI3K in oocytes, generated through a Cre‐inducible Pik3ca* knock‐in allele driven by Gdf9 ‐icre and performed histological and molecular analyses of the pancreas during cachexia development. Additionally, we examined pancreatic changes following ovariectomy and administration of Follistatin 288 (FST288). Results Mice that developed cachexia symptoms associated with granulosa cell tumour (GCT) growth exhibited significant pancreatic atrophy compared to controls (Cre+ vs. Cre− at PD83, p  < 0.0001), including reduced size of individual acinar cells (102.99 ± 12.19 μm 2 vs. 207.94 ± 24.85 μm 2 at PD83, p  < 0.0001) and acinar units (346.41 ± 169.22 μm 2 vs. 1193.59 ± 136.01 μm 2 at PD83, p  < 0.0001), despite comparable food intake between groups. Acinar cells exhibited a decrease in zymogen granules, reduced amylase expression and diminished amylase activity in both serum (0.29 ± 0.08 vs. 1.41 ± 0.40, p  < 0.001) and tissue (0.37 ± 0.14 vs. 1.05 ± 0.29, p  < 0.01). In contrast, pancreatic islets remained intact, as evidenced by histological analysis and preserved insulin expression. The pancreas of PD83 Cre+ mice also developed fibrosis and acinar cell death, characterized by elevated expression of collagen IV and α‐SMA, and TUNEL‐positive signals in acinar cells, respectively. Ovariectomy preserved body weight (2.66 ± 1.30 g for Cre+/OVX vs. 1.60 ± 0.97 g for Cre−) compared to Cre+ mice (−3.66 g) and maintained pancreatic function, suggesting that tumour‐derived factors from GCT contribute to the severity of cachexia. Acinar cells showed high expression of ACVR2B, leading to activation of downstream p‐SMAD3 signalling. Accordingly, activin A directly induced acinar cell atrophy in both ex vivo cultured pancreas (79.27 ± 19.03 μm 2 vs. 171.14 ± 27.01 μm 2 , p  < 0.0001) and 266‐6 acinar cells, as evidenced by reduced acinar cell size and decreased amylase production. Injection of FST288, an activin A inhibitor, rescued pancreatic acinar atrophy (252.95 ± 11.59 μm 2 in Cre+/FST288 vs. 97.25 ± 12.37 μm 2 in Cre+, p  < 0.001) without affecting GCT tumour size. Ex vivo culture of pancreas and 266‐6 acinar cells exposed to activin A confirmed that activin A directly induces pancreatic damage. Conclusions These findings demonstrate pancreatic damage occurs during CAC development and highlight the critical role of activin A in this process. Targeting activin A signalling may represent a promising therapeutic strategy to mitigate cachexia in cancer patients and preserve pancreatic function.

A Novel Definition and Grading Diagnostic Criteria for Tumour‐Type‐Specific Comprehensive Cachexia Risk

ABSTRACT Background The existing diagnostic criteria for cancer cachexia do not meet clinical needs. We aimed to establish novel comprehensive evaluation scales for cachexia specific to patients with solid tumours. Methods This study included 12 651 patients (males: 6793 [53.7%]; females: 5858 [46.3%]; medium age: 58 [interquartile range:50/66] years; medium follow‐up duration: 24.16 [13.32/44.84] months; 4271 [33.8%] patients died; mean survival: 55.53 [95% confidence interval, 54.87/56.10] months; 3344 [26.4%], 4184 [33.1%] and 5123 [40.5%] patients with Stage I–II, III and IV tumour, respectively; derivation set: 10022, validation set: 2629 patients) with 14 types of solid tumours, including lung, gastric, liver, breast, oesophageal, cervical, bladder, pancreatic, prostate, ovarian, colorectal cancer, nasopharyngeal and endometrial carcinoma and cholangiocarcinoma, from an open and ongoing multicentre cohort study in China. Risk factors for cachexia, including tumour characteristics and nutritional parameters, were examined to develop diagnostic scales using Cox proportional hazards models and Kaplan–Meier analysis. Results Ten nutrition items (body mass index, weight loss, intake reduction, physical activity function, fatigue, handgrip strength, anorexia, albumin level, albumin/globulin ratio and neutrophil/lymphocyte ratio) with different weighted scores were identified to construct a nutrition‐weighted scoring scale (NWSS) for nutrition risk. Tumour type and tumour burden status (tumour‐node‐metastasis stage and radical or non‐radical tumour) were determined to construct a disease‐weighted scoring scale (DWSS) for disease risk. A lumped scale (5 × 5 matrix) established using a five‐grade classification of nutrition and disease risk was used to determine a five‐grade classification of comprehensive cachexia risk: A, no cachexia risk (reference; lowest disease and nutrition risks); B, cachexia risk (hazard ratio [HR] = 4.517 [4.033/5.058]); C, pre‐cachexia (HR = 9.755 [8.73/10.901], medium survival = 21.21 months); D, cachexia (HR = 16.901 [14.995/19.049], medium survival = 11.61 months); and E, refractory cachexia (HR = 31.879 [28.244/35.981], medium survival = 4.83 months, highest disease and nutrition risks) ( p  < 0.001). Patients in Categories A–D benefited from nutrition therapy and anti‐tumour treatments to varying degrees. Patients in Category E were clinically refractory to nutrition therapy without prolonged survival compared with patients without nutrition therapy (medium survival, pre‐hospitalization nutrition therapy vs. hospitalization nutrition therapy vs. without nutrition therapy, 2.89 [1.91/3.88] vs. 4.04 [3.21/4.88] vs. 5.89 [4.73/7.04] months, p  = 0.015) and anti‐tumour treatments without prolonged survival compared with patients receiving palliative care (medium survival, radical anti‐tumour treatments vs. adjuvant anti‐tumour treatments vs. palliative anti‐tumour treatments vs. and palliative care, 6.48 [4.42/8.53] vs. 6.48 [3.23/9.73] vs. 4.83 [4.22/5.44] vs. 2.70 [1.09/4.30] months, p  = 0.263). Conclusion We systematically developed a novel definition and grading diagnostic criteria for tumour‐type‐specific comprehensive cancer cachexia risk.

Associations Between Body Composition and Intratumoural Immune Cells in Patients With Uterine Cervical Cancer

ABSTRACT Background In uterine cervical cancer (UCC), reduced muscle mass and radiodensity have been linked to unfavourable clinical outcomes. Our aim was to elucidate the associations between body composition (BC) and intratumoural immune cells in patients with UCC. Methods In this retrospective study, BC was analysed in 61 patients with UCC using staging computed tomography. The parameters of BC were skeletal muscle area (SMA), skeletal muscle radiodensity, visceral adipose tissue (VAT), subcutaneous adipose tissue (SAT) and intramuscular adipose tissue (IMAT). The radiodensities of VAT, SAT and IMAT were also estimated. Tumour specimens underwent histopathological analysis to quantify stromal and intratumoural CD45‐positive cells. Associations between body composition parameters and tumour immune cell infiltration were analysed using ANOVA. Results Patients with low muscle radiodensity (myosteatosis) had a lower proportion of stromal CD45‐positive cells than patients with normal muscle radiodensity (21.6% ± 21.90% vs. 34.85% ± 25.55%; p  = 0.04). High levels of SAT were associated with lower scores for tumour‐infiltrating CD45 cells ( p  = 0.03). High IMAT radiodensity was associated with lower stromal CD45 scores ( p  = 0.02). Conclusions Myosteatosis, high SAT and increased IMAT radiodensity were associated with reduced stromal and intratumoural immune cell infiltration in patients with UCC. These body composition parameters may serve as prognostic markers and should be explored in risk stratification.

Peripheral Thyroid Hormones, Inflammatory and Skeletal Muscle Indexes in Advanced Cervical Cancer Treated With Cemiplimab

ABSTRACT Background A low fT3/fT4 ratio has been associated with poorer prognosis in several diseases. Inflammatory indexes (IIs) and the skeletal muscle index (SMI) are established prognostic factors in various cancer types. However, their interplay and individual contributions to the prognosis of cervical cancer remain unclear. This study aimed to evaluate the impact of these biomarkers on survival outcomes in cervical cancer patients treated with innovative immunotherapy. Methods This retrospective study included 101 patients with cervical cancer treated with cemiplimab at 12 Italian oncology centres. Patients with thyroid comorbidities or missing fT3/fT4 ratio data were excluded. The primary endpoint was overall survival (OS) in relation to the fT3/fT4 ratio. Secondary endpoints included progression‐free survival (PFS) and correlations between the fT3/fT4 ratio, ECOG Performance Status, IIs and SMI. Results An optimal fT3/fT4 cutoff for OS prediction was identified at 0.29. Median OS was 10.9 months for patients with a low fT3/fT4 ratio, while it was not reached for those with high fT3/fT4 levels (HR = 2.70; 95% CI: 1.17–6.22; p  = 0.02). Multivariate analysis confirmed that both the fT3/fT4 ratio and ECOG PS independently influenced OS. Among the IIs analysed, the systemic inflammatory index (SII) demonstrated the strongest correlation with fT3/fT4 levels (OR = 3.82; 95% CI: 1.39–10.50; p  = 0.0092). Exploratory analysis also revealed significantly lower SMI values in patients with lower fT3/fT4 ratios ( p  = 0.034). Conclusions This study highlights the prognostic significance of the fT3/fT4 ratio, IIs, and SMI in cervical cancer patients treated with cemiplimab. Given the exploratory nature of these findings, further validation in larger, prospective cohorts is warranted to support their integration into clinical practice and the development of innovative prognostic tools.

The Prognostic Value of Sarcopenia in Clinical Outcomes in Cervical Cancer: A Systematic Review and Meta‐Analysis

ABSTRACTBackgroundSarcopenia is a condition characterized by inadequate muscle and function decline and is often associated with ageing and cancer. It is established that sarcopenia and muscle loss occurred during treatment are associated with the clinical outcomes of patients with cancer. This systematic review and meta‐analysis aims to evaluate the association between sarcopenia at pretreatment and during treatment and overall survival or disease progression in patients with cervical cancer.MethodsThe Web of Science, Embase, Medline and Cochrane Library databases were searched until 4 July 2024. Studies evaluating the prognostic effect of muscle mass at pretreatment or muscle change during treatment on survival or disease progression for patients with cervical cancer were included. Study quality was evaluated with the Newcastle–Ottawa Scale (NOS). Forest plots and summary effect models were used to show the effect size of sarcopenia on clinical outcomes.ResultsThe search strategy yielded 1721 studies in four databases. Eleven and seven studies were included in the quantitative analysis of pretreatment sarcopenia and muscle change on clinical outcomes, respectively. A total of 1907 patients underwent pretreatment muscle assessment, but 1016 were monitored for muscle changes; however, none of the studies involved measures of muscle strength or function. Meta‐analysis showed a significant association between pretreatment sarcopenia and OS [hazard ratio (HR) 1.58, 95% confidence interval (CI): 1.16–2.14, p = 0.003] and PFS (HR 1.63, 95%CI 1.16–2.29, p = 0.005) according to data of univariate analysis. In the meta‐analysis of the multivariate data, pretreatment sarcopenia remained associated with poor OS (HR 3.09, 95% CI: 2.07–4.61, p < 0.00001) and PFS (HR: 1.55, 95%CI 1.06–2.28, p = 0.03). Additionally, muscle loss was significantly associated with OS (HR 5.18, 95%CI 3.54–7.56, p < 0.00001) and PFS (HR 2.62, 95%CI 1.63–4.22, p < 0.00001). Subgroup analysis showed that the association between pretreatment sarcopenia and OS, as well as PFS, was influenced by muscle mass measurements and cut‐off values, whereas muscle loss consistently predicted worse OS and PFS when stratified by varying degrees of reduction. The NOS scores of all included studies were ≥ 6.ConclusionsPretreatment sarcopenia and muscle change during treatment are significantly associated with both overall survival and disease progression. Therefore, muscle assessment and monitoring should be conducted for appropriate diagnosis and intervention to improve clinical outcomes in patients with cervical cancer.

Association of malignant ascites with systemic inflammation and muscle loss after treatment in advanced‐stage ovarian cancer

AbstractBackgroundMalignant ascites is prevalent in advanced‐stage ovarian cancer and may facilitate identification of the drivers of muscle loss. This study aimed to evaluate the association of ascites with changes in systemic inflammation and muscle after treatment of advanced‐stage ovarian cancer.MethodsWe evaluated 307 patients with advanced‐stage (III/IVA) ovarian cancer who underwent primary debulking surgery and adjuvant platinum‐based chemotherapy between 2010 and 2019. The changes in skeletal muscle index (SMI) and radiodensity (SMD) were measured using pre‐surgery and post‐chemotherapy portal‐venous phase contrast‐enhanced computed tomography scans at L3. Systemic inflammation was measured using albumin levels, prognostic nutritional index (PNI), neutrophil‐lymphocyte ratio (NLR), and platelet‐lymphocyte ratio (PLR). Primary endpoint was the changes in SMI and SMD after treatment. Linear regression analysis was used to test associations between muscle change and other covariates. Mediation analysis was used to determine the mediator.ResultsThe median (range) age was 53 (23–83) years. The median duration (range) of follow‐up was 5.2 (1.1–11.3) years. Overall, 187 (60.9%) patients had ascites. The changes in muscle and systemic inflammatory markers after treatment were significantly different between patients with and without ascites (SMI: −3.9% vs. 2.2%, P < 0.001; SMD: −4.0% vs. −0.4%, P < 0.001; albumin: −4.4% vs. 2.1%, P < 0.001; PNI: −8.4% vs. −0.1%, P < 0.001; NLR: 20.6% vs. −29.4%, P < 0.001; and PLR: 1.7% vs. −19.4%, P < 0.001). The changes in SMI and SMD were correlated with the changes in albumin, PNI, NLR, and PLR (all P < 0.001). In multiple linear regression, ascites and NLR changes were negatively while albumin change was positively correlated with SMI change (ascites: β = −3.19, P < 0.001; NLR change: β = −0.02, P = 0.003; albumin change: β = 0.37, P < 0.001). Ascites and NLR changes were negatively while PNI change was positively correlated with SMD change (ascites: β = −1.28, P = 0.02; NLR change: β = −0.02, P < 0.001; PNI change: β = 0.11, P = 0.04). In mediation analysis, ascites had a direct effect on SMI change (P < 0.001) and an indirect effect mediated by NLR change (indirect effects = −1.61, 95% confidence interval [CI]: −2.22 to −1.08) and albumin change (indirect effects = −2.92, 95% CI: −4.01 to −1.94). Ascites had a direct effect on SMD change (P < 0.001) and an indirect effect mediated by NLR change (indirect effects = −1.76, 95% CI: −2.34 to −1.22) and PNI change (indirect effects = −2.00, 95% CI: −2.79 to −1.36).ConclusionsMalignant ascites was associated with enhanced systemic inflammation and muscle loss after primary debulking surgery and adjuvant chemotherapy in advanced‐stage ovarian cancer. The association between ascites and muscle loss may be mediated by systemic inflammation.

Explainable machine learning model for predicting skeletal muscle loss during surgery and adjuvant chemotherapy in ovarian cancer

AbstractBackgroundSkeletal muscle loss during treatment is associated with poor survival outcomes in patients with ovarian cancer. Although changes in muscle mass can be assessed on computed tomography (CT) scans, this labour‐intensive process can impair its utility in clinical practice. This study aimed to develop a machine learning (ML) model to predict muscle loss based on clinical data and to interpret the ML model by applying SHapley Additive exPlanations (SHAP) method.MethodsThis study included the data of 617 patients with ovarian cancer who underwent primary debulking surgery and platinum‐based chemotherapy at a tertiary centre between 2010 and 2019. The cohort data were split into training and test sets based on the treatment time. External validation was performed using 140 patients from a different tertiary centre. The skeletal muscle index (SMI) was measured from pre‐ and post‐treatment CT scans, and a decrease in SMI ≥ 5% was defined as muscle loss. We evaluated five ML models to predict muscle loss, and their performance was determined using the area under the receiver operating characteristic curve (AUC) and F1 score. The features for analysis included demographic and disease‐specific characteristics and relative changes in body mass index (BMI), albumin, neutrophil‐to‐lymphocyte ratio (NLR), and platelet‐to‐lymphocyte ratio (PLR). The SHAP method was applied to determine the importance of the features and interpret the ML models.ResultsThe median (inter‐quartile range) age of the cohort was 52 (46–59) years. After treatment, 204 patients (33.1%) experienced muscle loss in the training and test datasets, while 44 (31.4%) patients experienced muscle loss in the external validation dataset. Among the five evaluated ML models, the random forest model achieved the highest AUC (0.856, 95% confidence interval: 0.854–0.859) and F1 score (0.726, 95% confidence interval: 0.722–0.730). In the external validation, the random forest model outperformed all ML models with an AUC of 0.874 and an F1 score of 0.741. The results of the SHAP method showed that the albumin change, BMI change, malignant ascites, NLR change, and PLR change were the most important factors in muscle loss. At the patient level, SHAP force plots demonstrated insightful interpretation of our random forest model to predict muscle loss.ConclusionsExplainable ML model was developed using clinical data to identify patients experiencing muscle loss after treatment and provide information of feature contribution. Using the SHAP method, clinicians may better understand the contributors to muscle loss and target interventions to counteract muscle loss.

Low L3 skeletal muscle index associated with the clinicopathological characteristics and prognosis of ovarian cancer: a meta‐analysis

AbstractSarcopenia is a syndrome characterized by progressive loss of skeletal muscle mass, strength and function, which is one of the most important clinical features of cancer malnutrition, representing a poor prognostic indicator in oncology. Sarcopenia is commonly assessed by measuring the skeletal muscle index (SMI) of the third lumbar spine (L3) using computed tomography (CT). The primary aim of this meta‐analysis was to study the association between low SMI and comprehensive clinicopathological characteristics as well as prognosis in patients with ovarian cancer. Data were searched in PubMed, EMBASE and Cochrane databases from inception to 10 June 2022. Studies evaluating the prognostic effect of SMI on ovarian cancer survival or chemotherapy‐related side effects were included. The risk of bias and study quality were assessed via the Newcastle–Ottawa Scale (NOS). The search strategy yielded 1286 hits in all three databases combined. Thirteen studies were included for qualitative and quantitative analysis, comprising 1814 patients. Our meta‐analysis revealed the significant association between low SMI and progression‐free survival (PFS) [P = 0.02; hazard ratio (HR): 1.40, 95% confidence interval (CI): 1.06–1.85], as well as 5‐year overall survival (OS) [P = 0.02; odds ratio (OR): 1.35, 95% CI: 1.05–1.74]. Low SMI was also obviously associated with body mass index (BMI) < 25 (P < 0.00001; OR: 5.08, 95% CI: 3.54–7.30), FIGO stage (P = 0.02; OR: 1.62, 95% CI: 1.06–2.45) and R0 cytoreduction (P = 0.04;OR: 1.34, 95% CI: 1.01–1.79). There was no correlation between low SMI and histological types, pathological grades and chemotherapy‐related toxicity. The quality of the evidence was relatively high according to NOS. Our meta‐analysis indicated that sarcopenia assessed by SMI was associated with poor clinical characteristics and adverse prognosis in patients with ovarian cancer. Consensus should be reached on standardized cut‐off values for defining sarcopenia in patients with ovarian cancer.

Autocrine activin A signalling in ovarian cancer cells regulates secretion of interleukin 6, autophagy, and cachexia

AbstractBackgroundThe majority of patients with advanced cancer develop cachexia, a weight loss syndrome that severely reduces quality of life and limits survival. Our understanding of the underlying mechanisms that cause the condition is limited, and there are currently no treatment options that can completely reverse cachexia. Several tumour‐derived factors and inflammatory mediators have been suggested to contribute to weight loss in cachectic patients. However, inconsistencies between studies are recurrent. Activin A and interleukin 6 (IL‐6) are among the best studied factors that seem to be important, and several studies support their individual role in cachexia development.MethodsWe investigated the interplay between activin A and IL‐6 in the cachexia‐inducing TOV21G cell line, both in culture and in tumours in mice. We previously found that the human TOV21G cells secrete IL‐6 that induces autophagy in reporter cells and cachexia in mice. Using this established cachexia cell model, we targeted autocrine activin A by genetic, chemical, and biological approaches. The secretion of IL‐6 from the cancer cells was determined in both culture and tumour‐bearing mice by a species‐specific ELISA. Autophagy reporter cells were used to monitor the culture medium for autophagy‐inducing activities, and muscle mass changes were evaluated in tumour‐bearing mice.ResultsWe show that activin A acts in an autocrine manner to promote the synthesis and secretion of IL‐6 from cancer cells. By inhibiting activin A signalling, the production of IL‐6 from the cancer cells is reduced by 40–50% (up to 42% reduction on protein level, P = 0.0048, and 48% reduction on mRNA level, P = 0.0308). Significantly reduced IL‐6 secretion (P < 0.05) from the cancer cells is consistently observed when using biological, chemical, and genetic approaches to interfere with the autocrine activin A loop. Inhibiting activin signalling also reduces the ability of the cancer cells to accelerate autophagy in non‐cancerous cells (up to 43% reduced autophagy flux, P = 0.0006). Coherent to the in vitro data, the use of an anti‐activin receptor 2 antibody in cachectic tumour‐bearing mice reduces serum levels of cancer cell‐derived IL‐6 by 62% (from 417 to 159 pg/mL, P = 0.03), and, importantly, it reverses cachexia and counteracts loss of all measured muscle groups (P < 0.0005).ConclusionsOur data support a functional link between activin A and IL‐6 signalling pathways and indicate that interference with activin A‐induced IL‐6 secretion from the tumour has therapeutic potential for cancer‐induced cachexia.

Ovarian cancer ascites induces skeletal muscle wasting in vitro and reflects sarcopenia in patients

AbstractBackgroundCachexia‐associated skeletal muscle wasting or ‘sarcopenia’ is highly prevalent in ovarian cancer and contributes to poor outcome. Drivers of cachexia‐associated sarcopenia in ovarian cancer remain elusive, underscoring the need for novel and better models to identify tumour factors inducing sarcopenia. We aimed to assess whether factors present in ascites of sarcopenic vs. non‐sarcopenic ovarian cancer patients differentially affect protein metabolism in skeletal muscle cells and to determine if these effects are correlated to cachexia‐related patient characteristics.MethodsFifteen patients with an ovarian mass and ascites underwent extensive physical screening focusing on cachexia‐related parameters. Based on computed tomography‐based body composition imaging, six cancer patients were classified as sarcopenic and six were not; three patients with a benign condition served as an additional non‐sarcopenic control group. Ascites was collected, and concentrations of cachexia‐associated factors were assessed by enzyme‐linked immunosorbent assay. Subsequently, ascites was used for in vitro exposure of C2C12 myotubes followed by measurements of protein synthesis and breakdown by radioactive isotope tracing, qPCR‐based analysis of atrophy‐related gene expression, and NF‐κB activity reporter assays.ResultsC2C12 protein synthesis was lower after exposure to ascites from sarcopenic patients (sarcopenia 3.1 ± 0.1 nmol/h/mg protein vs. non‐sarcopenia 5.5 ± 0.2 nmol/h/mg protein, P < 0.01), and protein breakdown rates tended to be higher (sarcopenia 31.2 ± 5.2% vs. non‐sarcopenia 20.9 ± 1.9%, P = 0.08). Ascites did not affect MuRF1, Atrogin‐1, or REDD1 expression of C2C12 myotubes, but NF‐κB activity was specifically increased in cells exposed to ascites from sarcopenic patients (sarcopenia 2.2 ± 0.4‐fold compared with control vs. non‐sarcopenia 1.2 ± 0.2‐fold compared with control, P = 0.01). Protein synthesis and breakdown correlated with NF‐κB activity (rs = −0.60, P = 0.03 and rs = 0.67, P = 0.01, respectively). The skeletal muscle index of the ascites donors was also correlated to both in vitro protein synthesis (rs = 0.70, P = 0.005) and protein breakdown rates (rs = −0.57, P = 0.04).ConclusionsAscites of sarcopenic ovarian cancer patients induces pronounced skeletal muscle protein metabolism changes in C2C12 cells that correlate with clinical muscle measures of the patient and that are characteristic of cachexia. The use of ascites offers a new experimental tool to study the impact of both tumour‐derived and systemic factors in various cachexia model systems, enabling identification of novel drivers of tissue wasting in ovarian cancer.

Muscle loss during primary debulking surgery and chemotherapy predicts poor survival in advanced‐stage ovarian cancer

AbstractBackgroundSarcopenia is commonly observed in patients with advanced‐stage epithelial ovarian cancer (EOC). However, the effect of body composition changes—during primary debulking surgery (PDS) and adjuvant platinum‐based chemotherapy—on outcomes of patients with advanced‐stage EOC is unknown. This study aimed to evaluate the association between body composition changes and outcomes of patients with stage III EOC treated with PDS and adjuvant platinum‐based chemotherapy.MethodsPre‐treatment and post‐treatment computed tomography (CT) images of 139 patients with stage III EOC were analysed. All CT images were contrast‐enhanced scans and were acquired according to a standardized protocol. The skeletal muscle index (SMI), skeletal muscle radiodensity (SMD), and total adipose tissue index were measured using CT images obtained at the L3 vertebral level. Predictors of overall survival were identified using Cox regression models.ResultsThe median follow‐up was 37.9 months. The median duration between pre‐treatment and post‐treatment CT was 182 days (interquartile range: 161–225 days). Patients experienced an average SMI loss of 1.8%/180 days (95% confidence interval: −3.1 to −0.4; P = 0.01) and SMD loss of 1.7%/180 days (95% confidence interval: −3.3 to −0.03; P = 0.046). SMI and SMD changes were weakly correlated with body mass index changes (Spearman ρ for SMI, 0.15, P = 0.07; ρ for SMD, 0.02, P = 0.82). The modified Glasgow prognostic score was associated with SMI loss (odds ratio: 2.42, 95% confidence interval: 1.03–5.69; P = 0.04). The median time to disease recurrence was significantly shorter in patients with SMI loss ≥5% after treatment than in those with SMI loss <5% or gain (5.4 vs. 11.2 months, P = 0.01). Pre‐treatment SMI (1 cm2/m2 decrease; hazard ratio: 1.08, 95% confidence interval: 1.03–1.11; P = 0.002) and SMI change (1%/180 days decrease; hazard ratio: 1.04, 95% confidence interval: 1.01–1.08; P = 0.002) were independently associated with poorer overall survival. SMD, body mass index, and total adipose tissue index at baseline and changes were not associated with overall survival.ConclusionsSkeletal muscle index decreased significantly during treatment and was independently associated with poor overall survival in patients with stage III EOC treated with PDS and adjuvant platinum‐based chemotherapy. The modified Glasgow prognostic score might be a predictor of SMI loss during treatment.

Development of ovarian tumour causes significant loss of muscle and adipose tissue: a novel mouse model for cancer cachexia study

AbstractBackgroundCancer‐associated cachexia (CAC) is a complex syndrome of progressive muscle wasting and adipose loss with metabolic dysfunction, severely increasing the morbidity and mortality risk in cancer patients. However, there are limited studies focused on the underlying mechanisms of the progression of CAC due to the complexity of this syndrome and the lack of preclinical models that mimics its stagewise progression.MethodsWe characterized the initiation and progression of CAC in transgenic female mice with ovarian tumours. We measured proposed CAC biomarkers (activin A, GDF15, IL‐6, IL‐1β, and TNF‐α) in sera (n = 6) of this mouse model. The changes of activin A and GDF15 (n = 6) were correlated with the decline of bodyweight over time. Morphometry and signalling markers of muscle atrophy (n ≥ 6) and adipose tissue wasting (n ≥ 7) were assessed during CAC progression.ResultsCancer‐associated cachexia symptoms of the transgenic mice model used in this study mimic the progression of CAC seen in humans, including drastic body weight loss, skeletal muscle atrophy, and adipose tissue wasting. Serum levels of two cachexia biomarkers, activin A and GDF15, increased significantly during cachexia progression (76‐folds and 10‐folds, respectively). Overactivation of proteolytic activity was detected in skeletal muscle through up‐regulating muscle‐specific E3 ligases Atrogin‐1 and Murf‐1 (16‐folds and 14‐folds, respectively) with decreasing cross‐sectional area of muscle fibres (P < 0.001). Muscle wasting mechanisms related with p‐p38 MAPK, FOXO3, and p‐AMPKα were highly activated in concurrence with an elevation in serum activin A. Dramatic fat loss was also observed in this mouse model with decreased fat mass (n ≥ 6) and white adipocytes sizes (n = 6) (P < 0.0001). The adipose tissue wasting was based on thermogenesis, supported by the up‐regulation of uncoupling protein 1 (UCP1). Fibrosis in adipose tissue was also observed in concurrence with adipose tissue loss (n ≥ 13) (p < 0.0001).ConclusionsOur novel preclinical CAC mouse model mimics human CAC phenotypes and serum biomarkers. The mouse model in this study showed proteolysis in muscle atrophy, browning in adipose tissue wasting, elevation of serum activin A and GDF15, and atrophy of pancreas and liver. This mouse line would be the best preclinical model to aid in clarifying molecular mediators of CAC and dissecting metabolic dysfunction and tissue atrophy during the progression of CAC.