Cancer-associated Cachexia Research Articles

Dissecting the importance and origin of circulating myokines in gastric cancer cachexia.

Some experimental data suggest that myokines may play an important role in developing cancer-associated cachexia (CAC), but their relevance in humans remains poorly explored. In our study, we tested the hypothesis that circulating myokines are associated with the pathogenesis of CAC in a model population of gastric cancer. A group of 171 treatment naïve patients with adenocarcinoma of the stomach were prospectively examined. Cachexia was defined as weight loss >5% or weight loss >2% with either BMI <20 kg/m2 or sarcopenia. A panel of 19 myokines was measured in portal and peripheral blood as well as tumour tissue and surrounding gastric mucosa. Moreover, a serum proteomic signature of cachexia was identified by a label-free quantitative proteomics with a nano LC-MS/MS system and stored in a ProteomeXchange database (PXD049334). One hundred (58%) patients were diagnosed with CAC. The concentrations of fatty acid-binding protein 3 (FABP3), follistatin-like 1 protein (FSTL-1), interleukin 6 (IL 6), and interleukin 8 (IL 8) were significantly higher in the peripheral blood of cachectic subjects, while leptin levels were lower. Of all the evaluated myokines, tumour tissues showed higher expression levels only for IL-15 and myostatin. However, the analysis of paired samples failed to demonstrate a decreasing concentration gradient between the portal and peripheral blood for any of the myokines, evidencing against their release by the primary tumour. Proteomic analysis identified 28 proteins upregulated and 24 downregulated in the peripheral blood of patients with cachexia. Differentially expressed proteins and 5 myokines with increased serum levels generated a significant protein-protein interaction network. Our study provides clinical evidence that some myokines are involved in the pathogenesis of cachexia and are well integrated into the regulatory network of circulating blood proteins identified among cachectic patients with gastric cancer.

A [18F]FDG PET based nomogram to predict cancer-associated cachexia and survival outcome: A multi-center study

ObjectivesCancer patients with cachexia face poor prognosis and shortened survival. Early diagnosis and accurate prognosis prediction remain challenging. This multi-center study aims to develop and externally validate a nomogram integrating [18F]fluoro-2-deoxy-D-glucose ([18F]FDG) PET findings and routine clinical biochemistry tests for predicting cancer-associated cachexia, while also assessing its potential prognostic value. Research Methods & ProceduresA retrospective analysis of 658 cancer patients (390 in the development cohort, 268 in the validation cohort) utilized [18F]FDG PET/CT data from two centers. Logistic regression identified organ-specific standardized uptake values (SUVs) and clinical variables associated with cancer-associated cachexia. Diagnostic accuracy, discriminative ability, and clinical effectiveness were assessed using area under the curve (AUC), calibration curve, and decision curve. Nomogram predictability for overall survival was evaluated through Cox regression and Kaplan–Meier curves. ResultsThe combined nomogram incorporating age (odds ratio [OR] = 1.893; P = 0.012), hemoglobin (OR = 2.591; P < 0.001), maximum SUV of the liver (OR = 3.646; P < 0.001), and minimum SUV of the subcutaneous fat (OR = 5.060; P < 0.001) achieved good performance in predicting cancer-associated cachexia (AUC = 0.807/0.726, development/validation). Calibration and decision curve analyses confirmed its clinical effectiveness. Kaplan–Meier curves analysis showed that overall survival can be categorized using the combined nomogram (P < 0.001). ConclusionCombining radiological information from clinical standard [18F]FDG PET data from cancer patients with biochemical results in their routine clinical blood tests through a well-constructed nomogram enables predicting cachexia and its effect on the prognosis of cancer patients.

A [18F]FDG pet based nomogram to predict cancer-associated cachexia and survival outcome: A multicenter study

A [18F]FDG pet based nomogram to predict cancer-associated cachexia and survival outcome: A multicenter study

A promising approach: Predicting cancer-associated cachexia risk with pet radiomics

A promising approach: Predicting cancer-associated cachexia risk with pet radiomics

Systemic Metabolic and Volumetric Assessment via Whole-Body [18F]FDG-PET/CT: Pancreas Size Predicts Cachexia in Head and Neck Squamous Cell Carcinoma.

Background/Objectives: Cancer-associated cachexia in head and neck squamous cell carcinoma (HNSCC) is challenging to diagnose due to its complex pathophysiology. This study aimed to identify metabolic biomarkers linked to cachexia and survival in HNSCC patients using [18F]FDG-PET/CT imaging and machine learning (ML) techniques. Methods: We retrospectively analyzed 253 HNSCC patients from Vienna General Hospital and the MD Anderson Cancer Center. Automated organ segmentation was employed to quantify metabolic and volumetric data from [18F]FDG-PET/CT scans across 29 tissues and organs. Patients were categorized into low weight loss (LoWL; grades 0-2) and high weight loss (HiWL; grades 3-4) groups, according to the weight loss grading system (WLGS). Machine learning models, combined with Cox regression, were used to identify survival predictors. Shapley additive explanation (SHAP) analysis was conducted to determine the significance of individual features. Results: The HiWL group exhibited increased glucose metabolism in skeletal muscle and adipose tissue (p = 0.01), while the LoWL group showed higher lung metabolism. The one-year survival rate was 84.1% in the LoWL group compared to 69.2% in the HiWL group (p < 0.01). Pancreatic volume emerged as a key biomarker associated with cachexia, with the ML model achieving an AUC of 0.79 (95% CI: 0.77-0.80) and an accuracy of 0.82 (95% CI: 0.81-0.83). Multivariate Cox regression confirmed pancreatic volume as an independent prognostic factor (HR: 0.66, 95% CI: 0.46-0.95; p < 0.05). Conclusions: The integration of metabolic and volumetric data provided a strong predictive model, highlighting pancreatic volume as a key imaging biomarker in the metabolic assessment of cachexia in HNSCC. This finding enhances our understanding and may improve prognostic evaluations and therapeutic strategies.

GRP75 triggers white adipose tissue browning to promote cancer-associated cachexia

Cachexia, which affects 50–80% of cancer patients, is a debilitating syndrome that leads to 20% of cancer-related deaths. A key feature of cachexia is adipose tissue atrophy, but how it contributes to the development of cachexia is poorly understood. Here, we demonstrate in mouse models of cancer cachexia that white adipose tissue browning, which can be a characteristic early-onset manifestation, occurs prior to the loss of body weight and skeletal muscle wasting. By analysing the proteins differentially expressed in extracellular vesicles derived from cachexia-inducing tumours, we identified a molecular chaperone, Glucose-regulated protein 75 (GRP75), as a critical mediator of adipocyte browning. Mechanistically, GRP75 binds adenine nucleotide translocase 2 (ANT2) to form a GRP75–ANT2 complex. Strikingly, stabilized ANT2 enhances its interaction with uncoupling protein 1, leading to elevated expression of the latter, which, in turn, promotes adipocyte browning. Treatment with withanone, a GRP75 inhibitor, can reverse this browning and alleviate cachectic phenotypes in vivo. Overall, our findings reveal a novel mechanism by which tumour-derived GRP75 regulates white adipose tissue browning during cachexia development and suggest a potential white adipose tissue-centred targeting approach for early cachexia intervention.

Combined KRAS and TP53 mutation in patients with colorectal cancer enhance chemoresistance to promote postoperative recurrence and metastasis

The response of patients with colorectal cancer to chemotherapy is tightly correlated with their genomic variation. Among these, APC, TP53, KRAS, PIK3CA are the most frequently mutated genes in advanced colorectal cancer patients. However, the precise correlation between these mutations and the therapeutic effects of chemotherapy remains elusive. Here, we conducted genome sequencing to identify commonly mutated genes in colorectal cancer patients and comprehensively assessed their sensitivity to chemotherapy drugs by monitoring computer tomography (CT) scans and carcinoembryonic antigen (CEA) levels. Surprisingly, we discovered that the objective response rate to the standard first-line chemotherapy among patients harboring combined KRAS and TP53 mutations is dismal, and these patients are predisposed to recurrence and metastasis. Furthermore, advanced-stage patients with concurrent KRAS and TP53 mutations are susceptible to developing cancer-associated cachexia due to chemotherapy resistance or forced cessation of treatment. Our findings underscore the urgent need for the development of innovative and novel chemotherapeutic strategies to effectively manage colorectal cancer patients harboring combined KRAS and TP53 mutations.

Abstract B002: Tumor-secreted PTHrP facilitates pancreatic cancer cachexia by regulation of de novo lipogenesis pathway

Abstract Pancreatic cancer is associated with one of the highest and most severe forms of cancer- associated cachexia amongst solid tumors. In an effort to further our understanding of the molecular etiology of pancreatic cancer-associated cachexia, we have developed mouse models to study adipose tissue wasting during Pancreatic Ductal Adenocarcinoma (PDAC) progression. In these pursuits, we have identified a pro-cachectic factor, PTHrP, that is produced and secreted by PDAC tumor cells and directly signals to adipocytes to facilitate wasting. Genetic deletion and pharmacological inhibition of PTHrP significantly extended the survival of tumor-bearing animals and dramatically reduced cachectic phenotypes in these animals, manifesting as decreased adipose and muscle tissue wasting. Mechanistic studies have shown crosstalk between tumor-cell derived PTHrP and adipose tissue PTH1R that drives the cachectic phenotype. Finally, bulk RNA sequencing analysis in PTHrP-driven cachectic models point towards a role for reduced de novo lipogenesis and adipogenesis in cachectic adipose depots, suggesting potential rewiring of the metabolic profile of white adipose tissue in tumor-bearing mice with higher PTHrP expression. Citation Format: Nikita Bhalerao, Jessica Peura, Yamini Ogoti, Calvin Johnson, Qingbo Chen, Ekaterina Korobkina, Faith Keller, Maximillan Wengyn, Robert Norgard, Richard Kremmer, Emma Watson, Marcus Ruscetti, David Guertin, Jason R Pitarresi. Tumor-secreted PTHrP facilitates pancreatic cancer cachexia by regulation of de novo lipogenesis pathway [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research; 2024 Sep 15-18; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2024;84(17 Suppl_2):Abstract nr B002.

1823P Significance of skeletal muscle measurement in cancer-associated cachexia screening

1823P Significance of skeletal muscle measurement in cancer-associated cachexia screening

Low-dose orthotopic cancer implantation permits measurement of longitudinal functional changes associated with cachexia.

Progressive functional decline is a key element of cancer-associated cachexia. Major barriers to translating preclinical therapies into the clinic include lack of cancer models that accurately mimic functional decline, which develops over time, and use of nonspecific measures, like grip strength, as surrogates for physical function. In this study, we aimed to extend the survival and longevity of a cancer model, to investigate cachexia-related function at the basic science level. Survival extension studies were performed by testing multiple cell lines, dilutions, and vehicle-types in orthotopic implantation of K-rasLSL.G12D/+; Trp53R172H/+; Pdx-1-Cre (KPC)-derived cells. One hundred twenty-eight animals in this new model were assessed for cachexia syndrome phenotype using a battery of anatomical, biochemical, and behavioral techniques. We extended the survival of the KPC orthotopic model to 8-9 wk postimplantation using a relatively low 100-cell dose of DT10022 KPC cells (P < 0.001). In this low-dose orthotopic (LO) model, progressive muscle wasting was detected in parallel to systemic inflammation; skeletal muscle atrophy at the fiber level was detected as early as 3 wk postimplantation compared with controls (P < 0.001). Gait speed in LO animals declined as early as 2 wk postimplantation, whereas grip strength change was a late event. Principal component and regression analyses revealed distinct cachectic and noncachectic animal populations, which we leveraged to show that the gait speed decline was specific to cachexia (P < 0.01), whereas grip strength decline was not (P = 0.19). Gait speed represents an accurate surrogate for cachexia-related physical function as opposed to grip strength.NEW & NOTEWORTHY Previous studies of cancer-induced cachexia have been confounded by the relatively rapid death of animal subjects. Using a lower dose of cancer cells in combination with a battery of behavioral, structural, histological, and biochemical techniques, we show that gait speed is actually the best indicator of functional decline due to cachexia. Future studies are required to define the underlying physiological basis of these findings.

Detection of cancer-associated cachexia in lung cancer patients using whole-body [18F]FDG-PET/CT imaging: A multi-centre study.

Cancer-associated cachexia (CAC) is a metabolic syndrome contributing to therapy resistance and mortality in lung cancer patients (LCP). CAC is typically defined using clinical non-imaging criteria. Given the metabolic underpinnings of CAC and the ability of [18F]fluoro-2-deoxy-D-glucose (FDG)-positron emission tomography (PET)/computer tomography (CT) to provide quantitative information on glucose turnover, we evaluate the usefulness of whole-body (WB) PET/CT imaging, as part of the standard diagnostic workup of LCP, to provide additional information on the onset or presence of CAC. This multi-centre study included 345 LCP who underwent WB [18F]FDG-PET/CT imaging for initial clinical staging. A weight loss grading system (WLGS) adjusted to body mass index was used to classify LCP into 'No CAC' (WLGS-0/1 at baseline prior treatment and at first follow-up: N=158, 51F/107M), 'Dev CAC' (WLGS-0/1 at baseline and WLGS-3/4 at follow-up: N=90, 34F/56M), and 'CAC' (WLGS-3/4 at baseline: N=97, 31F/66M). For each CAC category, mean standardized uptake values (SUV) normalized to aorta uptake (<SUVaorta>) and CT-defined volumes were extracted for abdominal and visceral organs, muscles, and adipose-tissue using automated image segmentation of baseline [18F]FDG-PET/CT images. Imaging and non-imaging parameters from laboratory tests were compared statistically. A machine-learning (ML) model was then trained to classify LCP as 'No CAC', 'Dev CAC', and 'CAC' based on their imaging parameters. SHapley Additive exPlanations (SHAP) analysis was employed to identify the key factors contributing to CAC development for each patient. The three CAC categories displayed multi-organ differences in <SUVaorta>. In all target organs, <SUVaorta> was higher in the 'CAC' cohort compared with 'No CAC' (P<0.01), except for liver and kidneys, where <SUVaorta> in 'CAC' was reduced by 5%. The 'Dev CAC' cohort displayed a small but significant increase in <SUVaorta> of pancreas (+4%), skeletal-muscle (+7%), subcutaneous adipose-tissue (+11%), and visceral adipose-tissue (+15%). In 'CAC' patients, a strong negative Spearman correlation (ρ=-0.8) was identified between <SUVaorta> and volumes of adipose-tissue. The machine-learning model identified 'CAC' at baseline with 81% of accuracy, highlighting <SUVaorta> of spleen, pancreas, liver, and adipose-tissue as most relevant features. The model performance was suboptimal (54%) when classifying 'Dev CAC' versus 'No CAC'. WB [18F]FDG-PET/CT imaging reveals groupwise differences in the multi-organ metabolism of LCP with and without CAC, thus highlighting systemic metabolic aberrations symptomatic of cachectic patients. Based on a retrospective cohort, our ML model identified patients with CAC with good accuracy. However, its performance in patients developing CAC was suboptimal. A prospective, multi-centre study has been initiated to address the limitations of the present retrospective analysis.

Role of the sympathetic nervous system in cancer-associated cachexia and tumor progression in tumor-bearing BALB/c mice

BackgroundAdipose and muscle tissue wasting outlines the cachectic process during tumor progression. The sympathetic nervous system (SNS) is known to promote tumor progression and research suggests that it might also contribute to cancer-associated cachexia (CAC) energetic expenditure through fat wasting.MethodsWe sympathectomized L5178Y-R tumor-bearing male BALB/c mice by intraperitoneally administering 6-hydroxydopamine to evaluate morphometric, inflammatory, and molecular indicators of CAC and tumor progression.ResultsTumor burden was associated with cachexia indicators, including a 10.5% body mass index (BMI) decrease, 40.19% interscapular, 54% inguinal, and 37.17% visceral adipose tissue loss, a 12% food intake decrease, and significant (p = 0.038 and p = 0.0037) increases in the plasmatic inflammatory cytokines IL-6 and IFN-γ respectively. Sympathectomy of tumor-bearing mice was associated with attenuated BMI and visceral adipose tissue loss, decreased interscapular Ucp-1 gene expression to basal levels, and 2.6-fold reduction in Mmp-9 relative gene expression, as compared with the unsympathectomized mice control group.ConclusionThe SNS contributes to CAC-associated morphometric and adipose tissue alterations and promotes tumor progression in a murine model.

Leveraging real-world data to predict cancer cachexia stage, quality of life, and survival in a racially and ethnically diverse multi-institutional cohort of treatment-naïve patients with pancreatic ductal adenocarcinoma.

Cancer-associated cachexia (CC) is a progressive syndrome characterized by unintentional weight loss, muscle atrophy, fatigue, and poor outcomes that affects most patients with pancreatic ductal adenocarcinoma (PDAC). The ability to identify and classify CC stage along its continuum early in the disease process is challenging but critical for management. The main objective of this study was to determine the prevalence of CC stage overall and by sex and race and ethnicity among treatment-naïve PDAC cases using clinical, nutritional, and functional criteria. Secondary objectives included identifying the prevalence and predictors of higher symptom burden, supportive care needs, and quality of life (QoL), and examining their influence on overall survival (OS). A population-based multi-institutional prospective cohort study of patients with PDAC was conducted between 2018 and 2021 by the Florida Pancreas Collaborative. Leveraging patient-reported data and laboratory values, participants were classified at baseline into four stages [non-cachexia (NCa), pre-cachexia (PCa), cachexia (Ca), and refractory cachexia (RCa)]. Multivariate regression, Kaplan Meier analyses, and Cox regression were conducted to evaluate associations. CC stage was estimated for 309 PDAC cases (156 females, 153 males). The overall prevalence of NCa, PCa, Ca, and RCa was 12.9%, 24.6%, 54.1%, and 8.4%, respectively. CC prevalence across all CC stages was highest for males and racial and ethnic minorities. Criteria differentiated NCa cases from other groups, but did not distinguish PCa from Ca. The most frequently reported symptoms included weight loss, fatigue, pain, anxiety, and depression, with pain significantly worsening over time. The greatest supportive care needs included emotional and physical domains. Males, Black people, and those with RCa had the worst OS. Using clinical, nutritional, and functional criteria, nearly one-quarter of the PDAC cases in our diverse, multi-institutional cohort had PCa and 62.5% had Ca or RCa at the time of diagnosis. The PCa estimate is higher than that reported in prior studies. We recommend these criteria be used to aid in CC classification, monitoring, and management of all incident PDAC cases. Findings also highlight the recommendation for continued emotional support, assistance in alleviating pain, and supportive care needs throughout the PDAC treatment journey.

KLF10: a point of convergence in cancer cachexia.

Cancer-associated cachexia is a wasting syndrome entailing loss in body mass and a shortened life expectancy. There is currently no effective treatment to abrogate this syndrome, which leads to 20-30% of deaths in patients with cancer. While there have been advancements in defining signaling factors/pathways in cancer-induced muscle wasting, targeting the same in the clinic has not been as successful. Krüppel-like factor 10 (KLF10), a transcription factor implicated in muscle regulation, is regulated by the transforming growth factor-beta signaling pathway. This review proposes KLF10 as a potential convergence point of diverse signaling pathways involved in muscle wasting. KLF10 was discovered as a target of transforming growth factor-beta decades ago but more recently it has been shown that deletion of KLF10 rescues cancer-induced muscle wasting. Moreover, KLF10 has also been shown to bind key atrophy genes associated with muscle atrophy in vitro . There is an elevated need to explore targets in cachexia, which will successfully translate into the clinic. Investigating a convergence point downstream of multiple signaling pathways might hold promise in developing effective therapies for cachexia.

The role of interleukin-6 family cytokines in cancer cachexia.

Cachexia is a wasting syndrome that manifests in more than half of all cancer patients. Cancer-associated cachexia negatively influences the survival of patients and their quality of life. It is characterized by a rapid loss of adipose and skeletal muscle tissues, which is partly mediated by inflammatory cytokines. Here, we explored the crucial roles of interleukin-6 (IL-6) family cytokines, including IL-6, leukemia inhibitory factor, and oncostatin M, in the development of cancer cachexia. These cytokines have been shown to exacerbate cachexia by promoting the wasting of adipose and muscle tissues, activating mechanisms that enhance lipolysis and proteolysis. Overlapping effects of the IL-6 family cytokines depend on janus kinase/signal transducer and activator of transcription 3 signaling. We argue that the blockade of these cytokine pathways individually may fail due to redundancy and future therapeutic approaches should target common downstream elements to yield effective clinical outcomes.

Defining and Addressing Research Priorities in Cancer Cachexia through Transdisciplinary Collaboration.

For many patients, the cancer continuum includes a syndrome known as cancer-associated cachexia (CAC), which encompasses the unintended loss of body weight and muscle mass, and is often associated with fat loss, decreased appetite, lower tolerance and poorer response to treatment, poor quality of life, and reduced survival. Unfortunately, there are no effective therapeutic interventions to completely reverse cancer cachexia and no FDA-approved pharmacologic agents; hence, new approaches are urgently needed. In May of 2022, researchers and clinicians from Moffitt Cancer Center held an inaugural retreat on CAC that aimed to review the state of the science, identify knowledge gaps and research priorities, and foster transdisciplinary collaborative research projects. This review summarizes research priorities that emerged from the retreat, examples of ongoing collaborations, and opportunities to move science forward. The highest priorities identified include the need to (1) evaluate patient-reported outcome (PRO) measures obtained in clinical practice and assess their use in improving CAC-related outcomes; (2) identify biomarkers (imaging, molecular, and/or behavioral) and novel analytic approaches to accurately predict the early onset of CAC and its progression; and (3) develop and test interventions (pharmacologic, nutritional, exercise-based, and through mathematical modeling) to prevent CAC progression and improve associated symptoms and outcomes.

In Vitro Models for Cancer-Associated Cachexia: The Complex Modelling of a Multiorgan Syndrome

Cancer-associated cachexia is a multifactorial syndrome characterised by systemic inflammation and hypermetabolism that affects different tissues and organs. Is characterised by progressive and irreversible weight loss, mainly due to skeletal muscle wasting and often accompanied by loss of fat mass. Due to its complexity, and lack of effective treatment, this syndrome is a sign of poor prognosis in cancer patients. Cellular models constitute a valuable and powerful tool offering insights into the molecular pathways and cellular responses associated with cancer cachexia. Currently, there are robust and widely used cell lines used to establish models to study the pathophysiology of muscle wasting and adipose tissue loss. Various methods can be used to induce the cachectic phenotype in the cells, utilising genetic engineering or different inducing agents such as hormones, inflammatory factors and chemotherapeutic drugs. The available experimental data on their metabolic properties and transcriptional and proteomic profiles allows the selection of the most suitable research model to replicate the relevant aspects of cachexia. In this review, we make an overview of the in vitro models used to study biological aspects of cancer-associated cachexia and analyse their strengths and limitations in replicating the complex physiological environment and pathological processes of the syndrome. Herein, we also briefly approach the difficulty of modelling the contribution of different organs and crosstalk between different tissues.

Association of lung cancer-associated cachexia with the metastatic spread to pleura.

12095 Background: Cancer-associated cachexia (CAC), a major contributor to mortality in patients with non-small cell lung cancer (NSCLC), is characterized by alterations in body composition. Here, we explore the associations between body composition changes and the pattern of lung cancer metastatic spread. Methods: Computer tomography (CT) images from cancer diagnosis and recurrence were used to quantify subcutaneous and visceral adipose tissue (SAT, VAT) and skeletal muscle (SKM) tissue areas at the 3rd lumbar vertebrae level, using an DAFS AI-based software, Voronoi Analytics, in 101 NSCLC pts, who relapsed after surgical treatment of the primary tumor at the Medical University of Gdansk Hospital. The decrease in SKM, SAT and VAT of more than 5% or 10% at cancer relapse was compared with the pattern of cancer recurrence. Results: The median time to recurrence after primary tumor resection was 1.6 years (0.4–6.4 years). There were 38% local or regional recurrences, 59% distant recurrences, and 13% second primary lung cancers. Among the cases with distant recurrence, there were 19% brain recurrences, 22% pleural metastases, 34% lung metastases, 17% bone metastases, and 11% cases of liver relapse. More than one site of distant recurrence occurred in 51 (50%) of patients. Loss of &gt; 5% of SKM, SAT and VAT occurred in 61%, 33% and 41% respectively. Loss of &gt;5% or &gt;10% of SKM was associated with the pleural metastases at the time of cancer recurrence, ( P &lt; 0.001). Median muscle loss was –11.6% for patients with pleural relapse and –5.3 % for patients with other metastatic locations ( P &lt; 0.001). There were no significant associations between other body composition changes and the pattern of recurrences, tumor histology or age. Conclusions: NSCLC relapse to the pleura after surgical treatment of the primary tumor, appears to be associated with a decrease in the skeletal muscle compartment. This finding may inform the design of the future studies aiming to investigate molecular correlates of sarcopenia and cancer-associated cachexia.

Restoring adiponectin via rosiglitazone ameliorates tissue wasting in mice with lung cancer.

To investigate systemic regulators of the cancer-associated cachexia syndrome (CACS) in a pre-clinical model for lung cancer with the goal to identify therapeutic targets for tissue wasting. Using the Kras/Lkb1 (KL) mouse model, we found that CACS is associated with white adipose tissue (WAT) dysfunction that directly affects skeletal muscle homeostasis. WAT transcriptomes showed evidence of reduced adipogenesis, and, in agreement, we found low levels of circulating adiponectin. To preserve adipogenesis and restore adiponectin levels, we treated mice with the PPAR-γ agonist, rosiglitazone. Rosiglitazone treatment increased serum adiponectin levels, delayed weight loss, and preserved skeletal muscle and adipose tissue mass, as compared to vehicle-treated mice. The preservation of muscle mass with rosiglitazone was associated with increases in AMPK and AKT activity. Similarly, activation of the adiponectin receptors in muscle cells increased AMPK activity, anabolic signaling, and protein synthesis. Our data suggest that PPAR-γ agonists may be a useful adjuvant therapy to preserve tissue mass in lung cancer.

Testosterone replacement therapy in patients with cachexia: a contemporary review of the literature.

Patients with long-term chronic illnesses frequently present with hypogonadism, which is primarily managed through exogenous testosterone. These same patients also experience a high degree of cachexia, a loss of skeletal muscle and adipose tissue. To perform a contemporary review of the literature to assess the effectiveness of testosterone replacement therapy (TRT) for managing chronic disease-associated cachexia. We performed a PubMed literature search using MeSH terms to identify studies from 2000 to 2022 on TRT and the following cachexia-related chronic medical diseases: cancer, COPD, HIV/AIDS, and liver cirrhosis. From the literature, 11 primary studies and 1 meta-analysis were selected. Among these studies, 3 evaluated TRT on cancer-associated cachexia, 3 on chronic obstructive pulmonary disease, 4 on HIV and AIDS, and 2 on liver cirrhosis. TRT showed mixed results favoring clinical improvement on each disease. Cachexia is commonly observed in chronic disease states. Its occurrence with hypogonadism, alongside the shared symptoms of these 2 conditions, points toward the management of cachexia through the administration of exogenous testosterone. Robust data in the literature support the use of testosterone in increasing lean body mass, improving energy levels, and enhancing the quality of life for patients with chronic disease. However, the data are variable, and further studies are warranted on the long-term efficacy of TRT in patients with cachexia.