Many countries face an unprecedented challenge in aging demographics. This has led to an exponential growth in research on aging, which, coupled to a massive financial influx of funding in the private and public sectors, has resulted in seminal insights into the underpinnings of this biological process. However, critical validation in humans has been hampered by the limited translatability of results obtained in model organisms, additionally confined by the need for extremely time-consuming clinical studies in the ostensible absence of robust biomarkers that would allow monitoring in shorter time frames. In the future, molecular parameters might hold great promise in this regard. In contrast, biomarkers centered on function, resilience, and frailty are available at the present time, with proven predictive value for morbidity and mortality. In this review, the current knowledge of molecular and physiological aspects of human aging, potential antiaging strategies, and the basis, evidence, and potential application of physiological biomarkers in human aging are discussed.

Type 2 Diabetes Mellitus (T2DM) represents a major global health issue, with its incidence anticipated to increase markedly in the forthcoming decades. Efficient non-pharmacological therapies, especially dietary approaches, are essential for regulating glycemic control and facilitating weight reduction. Intermittent Fasting (IF) and Continuous Caloric Restriction (CCR) are two well researched methodologies, but their relative effectiveness and enduring advantages continue to be topics of active discussion. This review systematically assesses and contrasts the impacts of intermittent fasting (IF) and continuous calorie restriction (CCR) on glycemic regulation and weight reduction in persons with type 2 diabetes mellitus (T2DM), highlighting their short-term and long-term effects, safety profiles, and adherence rates. A thorough literature analysis was performed utilizing PubMed and Google Scholar, concentrating on papers published from 2000 to 2024. The review encompassed randomized controlled trials and observational studies that investigated the effects of intermittent fasting (IF) and continuous calorie restriction (CCR) on glycemic indicators (HbA1c, fasting glucose) and body weight. IF shown substantial short-term advantages, encompassing marked decreases in HbA1c levels, fasting glucose, and body weight. Mechanistic discoveries emphasized better insulin sensitivity, augmented fat metabolism, and autophagy as key aspects. In contrast, CCR was linked to enduring metabolic enhancements, including decreased visceral fat and improved insulin sensitivity. Nevertheless, both dietary approaches demonstrated constraints.

Research studies aimed at improving the outcomes of patients with pancreatic ductal adenocarcinoma (PDAC) have brought about limited progress, and in clinical practice, the optimized use of surgery, chemotherapy and supportive care have led to modest improvements in survival that have probably reached a plateau. As a result, PDAC is expected to be the second leading cause of cancer-related death in Western societies within a decade. The development of therapeutic advances in PDAC has been challenging owing to a lack of actionable molecular targets, a typically immunosuppressive microenvironment, and a disease course characterized by rapid progression and clinical deterioration. Yet, the progress in our understanding of PDAC and identification of novel therapeutic opportunities over the past few years is leading to a strong sense of optimism in the field. In this Perspective, we address the aforementioned challenges, including biological aspects of PDAC that make this malignancy particularly difficult to treat. We explore specific areas with potential for therapeutic advances, including targeting mutant KRAS, novel strategies to harness the antitumour immune response and approaches to early detection, and propose mechanisms to improve clinical trial design and to overcome various community and institutional barriers to progress.

Lung adenocarcinoma (LUAD) posed a significant threat to global human health. This study employed single-cell RNA sequencing (scRNA-seq) to analyze transcriptomic data from nine LUAD patients at different stages of tumor infiltration, aiming to elucidate the tumor microenvironment and key biological processes of LUAD.

In this study, we processed the scRNA-seq data using the Seurat package and sequentially applied principal component analysis followed by the Harmony package to effectively correct for batch effects, identifying 105,725 high-quality cells. Through cell clustering and gene expression profiling, we identified critical cell subpopulations and gene expression patterns in LUAD patients.

Our analysis revealed that the C4 MYH11+ Fibroblasts subtype was primarily involved in biological processes related to muscle function. Further investigations uncovered the MDK-SDC2 ligand-receptor pair as a critical regulator of tumor cell invasion, proliferation, and migration, driving LUAD progression. Additionally, we developed a gene-based prognostic model that effectively predicted patient survival, providing valuable clinical insights.

This study provided a comprehensive atlas of the LUAD tumor microenvironment, highlighted the role of the C4 MYH11+ Fibroblasts in tumor progression. It also proposed the MDK-SDC2 ligand-receptor pair as a novel mechanism, addressing a significant gap in this area of research. And presented a gene-based prognostic model as a novel perspective for research into immunotherapy and drug sensitivity in LUAD.

Pre-cancer onset of cachexia raises uncertainties regarding the optimal timing for early intervention in lung cancer patients. We aimed to examine changes in physical function, nutritional status, and cachexia incidence in patients with lung cancer from the initial visit to treatment initiation and determine the effect of these changes on lung cancer treatment.

This single-center retrospective cohort study enrolled patients suspected of having advanced lung cancer who visited Kansai Medical University Hospital between January and February 2023 and were definitely diagnosed with the disease. Patients were categorized into three groups based on their cachexia status: those with cachexia at initial diagnosis (group C), those who developed cachexia between the initial visit and treatment initiation (group OC), and those without cachexia (group NC).

Out of 61 patients, 21 had cachexia at their first outpatient visit (group C). The time between the first visit and treatment initiation was 42.5 days. The rate of cachexia in patients with stage IV lung cancer in group OC was significantly higher than that in patients with other stages (P = 0.008). Of the 33 patients with advanced lung cancer, 11 received supportive care only. The first-line treatment induction rate for the OC group was low. Half of the patients declined chemotherapy and received the best supportive care; their disease control rate (37.5%) was significantly worse than that of the other groups (P = 0.007).

Cachexia negatively impacts the effectiveness of initial cancer treatment, necessitating early anti-cachexia interventions at the first clinical visit.

Changes in the proteome and its dysregulation have long been known to be a hallmark of aging. We derived a proteomic aging trait using data on 1459 plasma proteins from 44,435 UK Biobank individuals measured using an antibody-based assay. This metric is strongly associated with four age-related disease outcomes, even after adjusting for chronological age. Survival analysis showed that one-year older proteomic age, relative to chronological age, increases all-cause mortality hazard by 13 percent. We performed a genome-wide association analysis of proteomic age acceleration (proteomic aging trait minus chronological age) to identify its biological determinants. Proteomic age acceleration showed modest genetic correlations with four epigenetic clocks (Rg = 0.17 to 0.19) and telomere length (Rg = -0.2). Once we removed associations that were explained by a single pQTL, we were left with three signals mapping to BRCA1, POLR2A and TET2 with apparent widespread effects on plasma proteomic aging. Genetic variation at these three loci has been shown to affect other omics-related aging measures. Mendelian randomisation analyses showed causal effects of higher BMI and type 2 diabetes on faster proteomic age acceleration. This supports the idea that obesity and other features of metabolic syndrome have an adverse effect on the processes of human aging.

Inflammatory cytokines hijack a brain circuit to cause apathy in cancer.

The present study aims to investigate the prognostic impact of low physical performance in elderly patients undergoing radical gastrectomy for gastric cancer, and to explore the risk factors for low physical performance in these patients.

Clinical data of 840 elderly patients (≥ 65 years) who underwent radical gastrectomy for gastric cancer were prospectively collected. Physical performance was assessed by 6-m usual gait speed test. Muscle strength was measured by grip strength test and chair rise test. Body composition was analyzed by preoperative computed tomography (CT).

Low physical performance was associated with higher incidence of ileus and severe complications after surgery. Low physical performance was independently associated with worse overall survival and disease-free survival after adjusting for age, gender, tumor-node-metastasis (TNM) stage, and histological differentiation of tumor. Physical performance had a significant correlation with skeletal muscle index (SMI), skeletal muscle density (SMD), chair rise time, and grip strength, but not with fat mass. Females, nutritional risk, chair rise time ≥ 15 s, low grip strength, low SMD, and higher TNM stage of tumor were independent risk factors for low physical performance in elderly patients with gastric cancer.

Low physical performance was associated with worse postoperative outcomes in elderly patients undergoing radical gastrectomy for gastric cancer. Aging itself was not independently associated with low physical performance. Nutritional support, exercise strategies aiming to improve muscle strength and density, and anti-tumor treatments to reduce tumor burden could be beneficial to improve physical performance, which could further improve the prognosis in elderly patients with gastric cancer.

Endometrial cancer (EC) is one of the most common cancers in women, with a short overall survival and poor prognosis. Besides the biologically aggressive EC properties, Cancer-associated cachexia is the main factor. However, the detailed mechanism underlying EC-related cachexia and its harmful effects on EC progression and patient prognosis remains unclear.

For clinical specimen and the vitro experiment, we detected TRIM22 expression level, EC patients' survival time, EC cell functional change, and adipose thermogenic changes to identify the function of TRIM22 in EC progression, EC-associated cachexia, and their molecular mechanisms. Then, for the vivo experiment, we exploited the xenografts in mice to identify the function of TRIM22 again, and to screen the drug therapeutic schedule.

Herein, we demonstrated that TRIM22 inhibited EC cell growth, invasion, and migration. Interleukin (IL)-6 mediated brown adipose tissue activation and white adipose tissue browning which induced EC-related cachexia. TRIM22 suppressed the EC cells' secretion of IL-6, and IL-6 mediated EC-related cachexia. Mechanistically, TRIM22 inhibited EC progression by suppressing the nucleotide-binding oligomerization domain 2(NOD2)/nuclear factor-kappaB (NF-κB) signaling pathway, with the purpose of impeding the production of IL-6. Moreover, we revealed that TRIM22 inhibited EC-associated cachexia by suppressing the IL-6/IL-6 receptor (IL-6R) signaling pathway. Therapeutically, we demonstrated that combination treatment with a TRIM22 inducer (progesterone) and a thermogenic inhibitor (IL-6R antibody) synergistically augmented the antitumor efficacy of carbotaxol (carboplatin and paclitaxel), in vivo.

Our data reveals that TRIM22-EC-IL-6-cachexia cross-communication has important clinical relevance and that the use of combined therapy holds great promise for enhancing the efficacy of anti-ECs. (Fig. graphical abstract).

When treated with a macronutrient-balanced hypocaloric diet, do male individuals who have overweight and obesity lose relatively more dual-energy x-ray absorptiometry (DXA)-measured lean soft tissue (LST) mass than female individuals? Are there changes in bone mineral content (BMC), and if so, how do they impact relative reductions in LST compared to fat-free mass (FFM; LST plus BMC)? Are decrements in fat, LST, and FFM predictable from the magnitude of weight loss or baseline body composition?

To answer these questions, DXA studies were conducted before and after a 9- to 12-week calorie-restriction period in 43 male and 97 female individuals who lost a mean (SD) of 10.8% (2.2%) and 10.7% (1.6%) of their baseline weight, respectively.

The proportion of weight loss as LST was significantly (p < 0.001) larger in male (mean [SD], 0.33 [0.11] kg) than female individuals (0.25 [0.11] kg); BMC paradoxically increased, thereby leading to a significantly smaller reduction in FFM than LST in the male (-3.87 [1.73] kg vs. -3.92 [1.74] kg; p < 0.001) and female individuals (-2.22 [1.18] kg vs. -2.24 [1.18] kg; p < 0.001), and three different analyses showed that the composition of weight loss tracked as predicted a priori from weight change and baseline body composition.

These observations provide insights into and future guidance for analyzing the DXA-measured body composition changes associated with newer pharmacotherapies for weight loss.

Both exercise and cancer can cause adipose tissue shrinkage. However, only cancer-associated weight loss, namely cachexia, is characterized by profound adipose inflammation and fibrosis. Here, we identified tumor-secreted macrophage migration inhibitory factor (MIF) as a major driver that skews the differentiation of adipose stem and progenitor cells (ASPCs) toward a pro-inflammatory and pro-fibrogenic direction, with reduced adipogenic capacity in cancer cachexia. By contrast, circulating MIF is moderately reduced after exercise. Mechanistically, atypical chemokine receptor 3 (ACKR3) in ASPCs serves as the predominant MIF receptor mediating its pathological effects. Inhibition of MIF by gene ablation in tumor cells or pharmacological blockade, as well as ASPC-specific Ackr3 deficiency, markedly alleviates tumor-induced cachexia. These findings unveil MIF-ACKR3 signaling as a critical link between tumors and cachectic manifestations, providing a promising therapeutic target for cancer cachexia.

Mobility disability is a common condition affecting older adults, making walking and the performance of activities of daily living difficult. Frailty, cachexia and sarcopenia are related conditions that occur with advancing age and are characterized by a decline in muscle mass, strength, and functionality that negatively impacts health. Chronic low-grade inflammation is a significant factor in the onset and progression of these conditions. The toll-like receptors (TLRs) and the NLRP3 inflammasome are the pathways of signaling that regulate inflammation. These pathways can potentially be targeted therapeutically for frailty, cachexia and sarcopenia as research has shown that dysregulation of the TLR/NLRP3 inflammasome signaling pathways is linked to these conditions. Activation of TLRs with pathogen-associated molecular patterns (PAMPs or DAMPs) results in chronic inflammation and tissue damage by releasing pro-inflammatory cytokines. Additionally, NLRP3 inflammasome activation enhances the inflammatory response by promoting the production and release of interleukins (ILs), thus exacerbating the underlying inflammatory mechanisms. These pathways are activated in the advancement of disease in frail and sarcopenic individuals. Targeting these pathways may offer therapeutic options to reduce frailty, improve musculoskeletal resilience and prevent or reverse cachexia-associated muscle wasting. Modulating TLR/NLRP3 inflammasome pathways may also hold promise in slowing down the progression of sarcopenia, preserving muscle mass and enhancing overall functional ability in elderly people. The aim of this review is to investigate the signaling pathways of the TLR/NLRP3 inflammasome as a main target in frailty, cachexia and sarcopenia.

Cachexia, a severe wasting syndrome characterized by tumour-induced metabolic dysregulation, is a leading cause of death in people with cancer, yet its underlying mechanisms remain poorly understood. Here we show that a longitudinal full-body single-nuclei-resolution transcriptome analysis in a Drosophila model of cancer cachexia captures interorgan dysregulations. Our study reveals that the tumour-secreted interleukin-like cytokine Upd3 induces fat-body expression of Pepck1 and Pdk, key regulators of gluconeogenesis, disrupting glucose metabolism and contributing to cachexia. Similarly, in mouse cancer cachexia models, we observe IL-6-JAK-STAT-signalling-mediated induction of Pck1 and Pdk3 expression in the liver. Increased expression of these genes in fly, mouse, and human correlates with poor prognosis, and hepatic expression of Pdk3 emerges as a previously unknown mechanism contributing to metabolic dysfunction in cancer cachexia. This study highlights the conserved nature of tumour-induced metabolic disruptions and identifies potential therapeutic targets to mitigate cachexia in people with cancer.

Cancer-associated weight loss occurs frequently in patients with advanced lung cancer. Many studies have demonstrated that tumor-derived exosomes could mediate the interplay between tumor cells and distal organs. In this study, we explored the interaction between lung cancer cell-derived exosomes (LCCDEs) and the niche of intestinal stem cells (ISCs).

Lewis lung carcinoma-1 (LLC1)-conditional medium (LLC1-CM), N,N'-Bis[5-(2,3-dihydro-1H-indol-1-yl)pentyl]-1,6-hexanediamine (GW4869)-conditional medium (GW4869-CM), LCCDEs and phosphate-buffered saline (PBS) were used to treat 6- to 8-week-old healthy male C57BL/6J mice (18-22 g) and B6.129P2-Lgr5tm1(cre/ERT2)Cle/J (Lgr5-EGFP-IRES-creERT2) mice (Lgr5-EGFP mice). Additionally, enteroids were treated with LLC1-CM, A549 human lung adenocarcinoma cells (A549)-CM, LCCDEs of LLC1 cells and A549 cells and PBS. LCCDEs were characterized by transmission electron microscopy, Western blot, and nanoparticle tracking analysis. The influence of LCCDEs on intestine and ISCs was explored by hematoxylin & eosin staining, proliferation, differentiation, enteroid culture, and quantitative polymerase chain reaction. PKH26-labeled LCCDEs were detected in intestinal epithelial cell line 6 (IEC-6) cells and Lgr5-EGFP mice. The changes of ISCs' niche caused by LCCDEs were examined by p-S6, pERK1/2 and p-STAT3 immunostaining.

LLC1-CM damaged the small intestines and small intestinal organoids. The inhibition of exosomes by GW4869 partially alleviated these effects. Purified LCCDEs altered the structure of the intestines, changed the proliferation and differentiation of ISCs and inhibited the growth of enteroids. In addition, PKH26-labeled LCCDEs entered the cytoplasm of IECs and Paneth cells and changed the messenger ribonucleic acid (mRNA) expression of many genes, including stem cell marker genes, growth factor genes, and epithelial marker genes. Mechanistically, LCCDEs decreased mTORC1 activity in Paneth cells and inhibited p-ERK1/2 signaling in ISCs.

We demonstrated that circulating exosomes derived from lung cancer could impair ISCs and alter their niche in mice, which further explained the interaction between lung cancer and the gastrointestinal tract. This study proposes a promising and novel therapy to overcome weight loss in patients by decreasing LCCDEs secretion and blocking their binding to the intestine, which might be a feasible therapeutic approach in future clinical practice.

The role of sodium-glucose co-transporter 2 inhibitor (SGLT2i) drugs in the management of diabetes and cardiovascular disease is well-established, but emerging evidence suggests potential effects on cancer outcomes, including gastrointestinal (GI) cancers. We conducted an extensive, sex-oriented, real-world data analysis to investigate whether SGLT2i can enhance GI cancer outcomes when used alongside standard therapies such as chemotherapy and radiotherapy.

The study applied a retrospective cohort design with data from the TriNetX research database ( https://trinetx.com ), examining GI cancer patients treated with chemotherapy and/or radiotherapy between 2013 and 2023. The intervention cohort consisted of Gl cancer patients who received SGLT2i, while the control cohort did not. A 5-year follow-up period was used, and baseline characteristics were balanced using a 1:1 propensity score matching technique. Cox proportional-hazards and logistic regression models assessed mortality and morbidity risks between the cohorts.

The study included 6,389 male and 3,457 female patients with GI cancer (ICD-10: C15-C25). The use of SGLT2i was significantly associated with improved survival for both male (HR 0.568; 95% CI 0.534-0.605) and female (HR 0.561; 95% CI 0.513-0.614) patients undergoing chemotherapy and/or radiotherapy. SGLT2i use also correlated significantly with lower hospitalisation rates both in male (OR 0.684; 95% CI 0.637-0.734) and female (OR, 0.590; 95% CI 0.536-0.650) patients. The analysis of GI cancer subtypes also demonstrated similar benefits, without significant adverse effects.

Repurposing SGLT2 inhibitors for cancer treatment could potentially improve outcomes for GI cancer patients without causing significant side effects. Further clinical trials are needed to confirm these findings and establish the optimal condition for its application in GI cancer treatment.

The sequence of events associated with cancer cachexia induction needs to be further characterized. Using the C26 mouse model, we found that prior to cachexia, cancer progression was associated with increased levels of IL-6 and growth differentiation factor 15 (GDF15), highly induced production of positive acute phase proteins (APPs) and reduced levels of most amino acids in the systemic circulation, while signal transducer and activator of transcription 3 (STAT3) signaling was induced (1) in the growing spleen, alongside activation of ribosomal protein S6 (rpS6) and alpha subunit of eukaryotic translation initiation factor-2 (eIF2α) signalings, and (2) in the liver, alongside increased positive-APP expression, decreased albumin expression, and upregulation of autophagy. At the onset of cachexia, rpS6 and eIF2α signalings were concomitantly activated in the liver, with increased expression of activating transcription factor 4 (ATF4) target genes involved in amino acid synthesis and transport, as well as autophagy. Data show that pre-cachectic (pre-Cx) alterations in protein/aa homeostasis are followed by activation of eIF2α signaling in the liver, an adaptive mechanism likely regulating protein/amino acid metabolism upon progression to cachexia.

Diet is believed to be an important mediator of oncogenesis and response to anti-cancer therapies, although no evidence-based dietary guidelines exist for patients with cancer. Limiting protein intake can suppress tumor growth by both inducing nutrient stress and enhancing anti-tumor immunity. However, little is known about the impact of reducing dietary protein on the efficacy of chemotherapy, the most widely used anti-cancer treatment. Here, we present evidence that reducing protein intake in mice by 50% stops the growth of established tumors, in parallel with inducing a stress response and DNA damage. Further, a reduced protein (RP) diet enhances tumor regression upon treatment with 5-fluorouracil (5-FU). This effect is accompanied by elevated apoptosis and suppressed mitosis of tumor cells. Proteomic analysis of tumors revealed marked differences between 5-FU treated mice fed control or RP diet including decreased abundance of proteins that mediate DNA repair and replication in mice consuming RP. In vitro studies mimicking amino acid changes found in tumors from RP-fed mice showed that cGAS/STING1 signaling, including transcription of Interferon beta 1, was maximally increased in 5-FU treated cells cultured in modified amino acid medium. These findings correlated with enhanced immune cell influx into tumors from mice treated with 5-FU while consuming a RP diet, an effect that was causally linked to improved response to chemotherapy. Collectively, these findings suggest that reducing dietary protein in cancer patients may enhance the efficacy of chemotherapy by promoting anti-tumor immunity.

Cachexia is a systemic response syndrome characterized by disabling wasting during disease progression. This study aimed to elucidate factors associated with cachexia in patients with cirrhosis and to examine the impact of cachexia on patient survival.

This multicenter retrospective cohort study included patients with cirrhosis admitted to two distinct institutes in Japan. Cachexia was diagnosed according to the criteria proposed by the Asian Working Group for Cachexia. Factors associated with cachexia and the prognostic impact of cachexia were assessed using logistic regression and Cox proportional hazards regression, respectively.

Of the 723 patients enrolled (median [interquartile range] age, 71 [64-77] years; 456 [63%] were male; and 390 [54%] had viral hepatitis), 200 (28%) met the criteria for cachexia diagnosis, with the prevalence increasing with Child-Pugh class from A (17%) to B (40%) and C (66%). Multivariable logistic regression analysis revealed that age and indices of liver function reserve, including Child-Pugh score, were associated with cachexia, whereas sex, etiology of cirrhosis, and complications with hepatocellular carcinoma (HCC) were not. During a median follow-up period of 3.2 years, 264 (37%) patients died. Multivariable Cox regression analyses showed that cachexia was independently associated with increased mortality (adjusted hazard ratio, 1.59; 95% confidence interval, 1.43-1.77), along with factors related to liver function, HCC, and alcohol-associated liver disease as the etiology.

Cachexia is associated with poor liver function in patients with cirrhosis and is an independent prognostic factor.

Sex-related differences in eating-related distress (ERD) experienced by cancer patients have not previously been clarified.

We conducted a multicenter survey among advanced cancer patients referred to palliative care. Data on patient characteristics were collected from the electronic medical records, and data on measurement outcomes were obtained from a questionnaire. Patients were categorized into male and female groups. We measured ERD using the Questionnaire for Eating-Related Distress among Patients with advanced cancer (QERD-P). The QERD-P comprises 3 items in each of the 7 factors, for a total of 21 items, and each item is rated on a 7-point Likert scale. High scores indicate worse distress. Comparisons were calculated using the Mann-Whitney U test. To assess associations between sexes and ERD, multivariate logistic regression analysis was performed.

A total of 192 patients were enrolled and divided into the male (n = 92) and female (n = 100) groups. The total score of the QERD-P was significantly higher in the male group (p = 0.018). The subtotal scores of "reasons why I cannot eat," "insufficient information," and "arguments with my family" were significantly higher in the male group (p = 0.035, 0.032, and 0.003, respectively). The male group had significantly higher risks for ERD associated with "arguments with my family" and "time with my family" (odds ratio [OR] 2.69, 95% confidence interval [CI] 1.38-5.24; OR 2.28, 95% CI 1.15-4.53).

Males had significantly worse ERD and were at higher risk of ERD in family relationships than females.

A pragmatic trial and its secondary analyses have demonstrated that nutritional care not only reduces complications but also significantly improves survival in medical patients at risk of malnutrition. In contrast, for critically ill patients comparable evidence is scarce. Consequently, many propositions for refining the research agenda and study design in the field of critical care nutrition have already been made. The aim of this paper is to elucidate further critical problems in nutritional care.

Critical appraisal of the literature from the past 70 years.

We identified five key problems: 1. The immunologic background of catabolism 2. The energy goal during the acute phase 3. The quantification of endogenous substrate production 4. The incorporation of clinical and biological data into the study design, and 5. The energy goal and cardiopulmonary exercise testing during the recovery phase.

The solution of these problems should supplement the propositions made by other authors and is essential to improving nutrition during and after critical care.

Background: Sarcopenia has been associated with poor outcomes in pancreatic cancer (PC). However, published results are heterogeneous in terms of study design, oncological outcomes, and sarcopenia measurements. This meta-analysis aims to evaluate the impact of computed tomography (CT)-based sarcopenia on overall survival (OS) and progression-free survival (PFS) in patients with PC, considering potential confounders such as the CT-based method and thresholds used to define sarcopenia, as well as treatment intention. Methods: We systematically searched databases for observational studies reporting hazard ratios (HRs) for OS and PFS in PC patients stratified by CT-based sarcopenia status. Random-effects models were used to calculate pooled crude and adjusted HRs (cHRs and aHRs, respectively), with subgroup analyses based on sarcopenia measurement methods, cutoff values, sarcopenia prevalence, and treatment intention. Heterogeneity was assessed using the I2 and τ2 statistics, and publication bias was evaluated using funnel plots and Egger's test. Results: Data from 48 studies were included. Sarcopenia was significantly associated with worse OS (pooled cHR = 1.58, 95% CI: 1.38-1.82; pooled aHR = 1.39, 95% CI: 1.16-1.66) and worse PFS (pooled cHR = 1.55, 95% CI: 1.29-1.86; pooled aHR = 1.31, 95% CI: 1.11-1.55). Subgroup analyses revealed significantly different, stronger associations in studies using stricter sarcopenia cutoffs (<50 cm2/m2 for males) and in patients undergoing curative treatments. Heterogeneity was substantial across analyses (I2 > 67%), but with generally low τ2 values (0.01-0.25). Egger's test indicated potential publication bias for OS (p < 0.001), but no significant bias was observed for PFS (p = 0.576). Conclusions: Sarcopenia determined by CT is an independent predictor of poor OS and PFS in PC, but this association varies depending on the cutoff used for its definition as well as on the treatment intention. Therefore, its routine assessment in clinical practice could provide valuable prognostic information, but future research should focus on standardizing sarcopenia assessment methods.

Tumors can exert a far-reaching influence on the body, triggering systemic responses that contribute to debilitating conditions like cancer cachexia. To characterize the mechanisms underlying tumor-host interactions, we utilized a BioID-based proximity labeling method to identify proteins secreted by Ykiact adult Drosophila gut tumors into the bloodstream/hemolymph. Among the major proteins identified are coagulation and immune-responsive factors that contribute to the systemic wasting phenotypes associated with Ykiact tumors. The effect of innate immunity factors is mediated by NFκB transcription factors Relish, dorsal, and Dif, which in turn upregulate the expression of the cachectic factors Pvf1, Impl2, and Upd3. In addition, Ykiact tumors secrete Eiger, a TNF-alpha homolog, which activates the JNK signaling pathway in neighboring non-tumor cells, leading to cell death. The release of damage-associated molecular patterns (DAMPs) from these dying cells presumably amplifies the inflammatory response, exacerbating systemic wasting. Targeting the inflammatory response, the JNK pathway, or the production of cachectic factors could potentially alleviate the debilitating effects of cancer cachexia.

In the present study, we investigated the associations of cachexia (loss of muscle, weight and fat) and frailty (loss of weight and muscle) status with the risk of developing amyotrophic lateral sclerosis, because these specific terms are rarely used in this research area. In this prospective study, we extracted cachexia and frailty status from the UK Biobank cohort to study the associations of these conditions (as determined via international classification of disease-10 codes) with amyotrophic lateral sclerosis. There was a greater risk of developing amyotrophic lateral sclerosis among individuals with cachexia and frailty status after adjusting for age, sex, income (pounds), body mass index, UK Biobank centers and smoking status. Among individuals with frailty status: a grip strength of < 21 kg, a slow walking speed, and exhaustion (more than half the days or nearly every day) increase the risk of developing amyotrophic lateral sclerosis. We believe that studying cachexia and frailty status can be used to help define and treat amyotrophic lateral sclerosis.

Cancer-associated fibroblasts (CAFs) are abundant components of the tumor microenvironment (TME) of most solid malignancies and have emerged as key regulators of cancer progression and therapy response. Although recent technological advances have uncovered substantial CAF molecular heterogeneity at the single-cell level, defining functional roles for most described CAF populations remains challenging. With the aim of bridging CAF molecular and functional heterogeneity, this review focuses on recently identified functional interactions of CAF subtypes with malignant cells, immune cells, and other stromal cells in primary tumors and metastases. Dissecting the heterogeneous functional crosstalk of specific CAF populations with other components is starting to uncover candidate combinatorial strategies for therapeutically targeting the TME and cancer progression.

Cachexia is a systemic wasting syndrome prevalent in patients with cancer that significantly affects quality of life, health care costs, and therapeutic outcomes. Despite its clinical importance, cachexia is rarely formally diagnosed. This deficiency presents a challenge for effective patient management and care, health care resource allocation, and the advancement of therapeutic approaches. Here, we highlight impedances to the diagnosis and coding of cachexia, including the absence of standardized therapy, a lack of incentives for accurate coding, and overlapping clinical features with other conditions. We differentiate cachexia from related conditions like unintentional weight loss, sarcopenia, frailty, and protein-calorie malnutrition, outlining their distinct clinical features and inter-relations. We propose an approach to enhance diagnostic accuracy and coding for cachexia. This effort will enable better prevalence data, translation of mechanism-based therapy development, patient identification and stratification, and ultimately advanced diagnostics and US Food and Drug Administration-approved treatments for cachexia.

Cachexia is a complex metabolic disorder characterized by negative energy balance due to increased consumption and lowered intake, leading to progressive tissue wasting and inefficient energy distribution. Once considered as passive bystander, metabolism is now acknowledged as a regulator of biological functions and disease progression. This shift in perspective mirrors the evolving understanding of cachexia itself, no longer viewed merely as a secondary consequence of cancer but as an active process. However, metabolic dysregulations in cachexia are currently studied in an organ-specific manner, failing to be fully integrated into a comprehensive framework that explains their functional roles in disease progression. Thus, in this review, we aim to provide a general overview of the various metabolic alterations with a potential systemic impact.

Sarcopenia is defined as a muscle-wasting syndrome that occurs with accelerated aging, while cachexia is a severe wasting syndrome associated with conditions such as cancer and immunodeficiency disorders, which cannot be fully addressed through conventional nutritional supplementation. Sarcopenia can be considered a component of cachexia, with the bidirectional interplay between adipose tissue and skeletal muscle potentially serving as a molecular mechanism for both conditions. However, the underlying mechanisms differ. Recognizing the interplay and distinctions between these disorders is essential for advancing both basic and translational research in this area, enhancing diagnostic accuracy and ultimately achieving effective therapeutic solutions for affected patients. This review discusses the muscle microenvironment's changes contributing to these conditions, recent therapeutic approaches like lifestyle modifications, small molecules, and nutritional interventions, and emerging strategies such as gene editing, stem cell therapy, and gut microbiome modulation. We also address the challenges and opportunities of multimodal interventions, aiming to provide insights into the pathogenesis and molecular mechanisms of sarcopenia and cachexia, ultimately aiding in innovative strategy development and improved treatments.

Serum C-reactive protein (CRP) levels are correlated with patient outcomes in cancer. This study aimed to determine associations between the CRP level and the dietary intake, symptoms, and eating-related distress (ERD).

We conducted a multicenter survey among advanced cancer patients. Information on patient characteristics was retrieved from the electronic medical records. Data on patient outcomes were obtained through the questionnaire. Patients were categorized into the low CRP group (<5 mg/dL) and the high CRP group (≥5 mg/dL). Comparisons were calculated using the Mann-Whitney U test or chi-squared test. To assess associations between CRP levels and ERD, multivariate logistic regression analysis was performed.

A total of 191 patients were enrolled and divided into the low CRP group (n = 117) and the high CRP group (n = 74). The high CRP group had a more reduced dietary intake (p = 0.002) and more severe appetite loss (p = 0.008). The total scores of the ERD questionnaire (both the long and short versions) were significantly higher in the high CRP group (p = 0.040 and 0.029). The high CRP group also had significantly higher risks for ERD, as assessed using the long and short versions of the questionnaire (odds ratio [OR] 2.13, 95% confidence interval [CI] 1.10-4.11; OR 2.06, 95% CI 1.05-4.05).

High CRP levels were significantly associated with reduced dietary intake, appetite loss, and ERD. A serum CRP value of 5 mg/dL may be a useful indicator for initiating cancer cachexia care.

Cancer has long been believed to be a genetic disease caused by the accumulation of mutations in key genes involved in cellular processes. However, recent advances in sequencing technology have demonstrated that cells with cancer driver mutations are also present in normal tissues in response to aging, environmental damage, and chronic inflammation, suggesting that not only intrinsic factors within cancer cells, but also environmental alterations are important key factors in cancer development and progression. Pancreatic cancer tissue is mostly comprised of stromal cells and immune cells. The desmoplasmic microenvironment characteristic of pancreatic cancer is hypoxic and hypotrophic. Pancreatic cancer cells may adapt to this environment by rewiring their metabolism through epigenomic changes, enhancing intrinsic plasticity, creating an acidic and immunosuppressive tumor microenvironment, and inducing noncancerous cells to become tumor-promoting. In addition, pancreatic cancer has often metastasized to local and distant sites by the time of diagnosis, suggesting that a similar mechanism is operating from the precancerous stage. Here, we review key recent findings on how pancreatic cancers acquire plasticity, undergo metabolic reprogramming, and promote immunosuppressive microenvironment formation during their evolution. Furthermore, we present the following two signaling pathways that we have identified: one based on the small G-protein ARF6 driven by KRAS/TP53 mutations, and the other based on the RNA-binding protein Arid5a mediated by inflammatory cytokines, which promote both metabolic reprogramming and immune evasion in pancreatic cancer. Finally, the striking diversity among pancreatic cancers in the relative importance of mutational burden and the tumor microenvironment, their clinical relevance, and the potential for novel therapeutic strategies will be discussed.

From their early genesis, tumour cells integrate with the surrounding normal cells to form an abnormal structure that is tightly integrated with the host organism via blood and lymphatic vessels and even neural associations. Using these connections, emerging cancers send a plethora of mediators that efficiently perturb the entire organism and induce changes in distant tissues. These perturbations serendipitously favour early metastatic establishment by promoting a more favourable tissue environment (niche) that supports the persistence of disseminated tumour cells within a foreign tissue. Because the establishment of early metastatic niches represents a key limiting step for metastasis, the creation of a more suitable pre-conditioned tissue strongly enhances metastatic success. In this Review, we provide an updated view of the mechanisms and mediators of primary tumours described so far that induce a pro-metastatic conditioning of distant organs, which favours early metastatic niche formation. We reflect on the nature of cancer-induced systemic conditioning, considering that non-cancer-dependent perturbations of tissue homeostasis are also able to trigger pro-metastatic conditioning. We argue that a more holistic view of the processes catalysing metastatic progression is needed to identify preventive or therapeutic opportunities.

Cancer cachexia can impact prognosis, cause resistance to anticancer treatments and affect the tolerability of treatments. This study aims to identify hepatocellular carcinoma (HCC) with cachexia by characterizing longitudinal body composition (BC) trajectories.

This longitudinal, multicentre cohort study included unresectable HCC patients treated with first-line programmed death-(ligand)1 inhibitors plus anti-vascular endothelial growth factor antibody/tyrosine kinase inhibitors between 01/2018-12/2022. BC measurements including skeletal muscle mass (SMM) and total adipose tissue area (TATA) were evaluated by computed tomography at the third lumbar vertebra at baseline and follow-up imaging. Unsupervised latent class growth mixed models were applied to distinguish potential longitudinal SMM and TATA trajectories for identifying cachexia. The primary study endpoint was overall survival (OS), with secondary endpoints including progression-free survival (PFS), objective response rate (ORR) and safety. Multiple Cox proportional hazards models were used to calculate adjusted hazard ratios (HRs) for survival.

A total of 411 patients with 2138 time-point measurements were included. The median age was 56 years, and 50 (12.2%) patients were female. Two distinct trajectories were identified for SMM and TATA: sharp-falling and stable. SMM sharply declined in 58 patients (14.1%) and TATA in 71 of 406 patients (17.5%) with significant worse OS (for SMM, 17.0 vs. 24.9 months; p < 0.001; HR = 0.59; for TATA, 15.3 vs. 25.1 months; p < 0.001; HR = 0.44). Patients were categorized into three phases based on trajectories: pre-cachexia (SMM and TATA stable, n = 299, 73.6%), cachexia (SMM or TATA sharp-falling, n = 86, 21.2%) and refractory cachexia (SMM and TATA sharp-falling, n = 21, 5.2%). Patients with refractory cachexia exhibited the worst OS, PFS and ORR, followed by those with cachexia. The median OS was 11.5 months for refractory cachexia, 17.7 for cachexia and 26.0 for pre-cachexia; median PFS was 6.0, 7.9 and 10.9 months, respectively, with ORR of 4.8%, 39.5% and 54.2%, respectively (all ps < 0.001). Multivariable Cox analysis identified refractory cachexia as an independent risk factor for both OS (HR = 3.31; p < 0.001) and PFS (HR = 2.94; p < 0.001), with cachexia also showing significant impacts. Grade 3-4 adverse events were higher in patients with refractory cachexia (23.8%) and cachexia (8.1%) compared with pre-cachexia (6.0%; p = 0.010).

HCC patients with cachexia and refractory cachexia were identified by longitudinal BC trajectories. Falling trajectories of BC identified refractory cachexia patients with worst response, survival and poor tolerability from systemic therapy combinations.

ClinicalTrials.gov identifier: NCT05278195.

The prognosis of pancreatic ductal adenocarcinomas (PDAC) remains very poor, emphasizing the critical importance of early detection, where biomarkers offer unique potential. Although growth differentiation factor 15 (GDF15) and Lipocalin 2 (LCN2) have been linked to PDAC, their precise roles as biomarkers are uncertain.

Circulating levels of GDF15 and LCN2 were examined in human PDAC patients, heathy controls, and individuals with benign pancreatic diseases. Circulating levels of IL-6, CA19-9, and neutrophil-to-lymphocyte ratio (NLR) were measured for comparisons. Correlations between PDAC progression and overall survival were assessed. A mouse PDAC model was employed for comprehensive analyses, complementing the human studies by exploring associations with various metabolic and inflammatory parameters. Sensitivity and specificity of the biomarkers were evaluated.

Our results demonstrated elevated levels of circulating GDF15 and LCN2 in PDAC patients compared to both healthy controls and individuals with benign pancreatic diseases, with higher GDF15 levels associated with disease progression and increased mortality. In PDAC mice, circulating GDF15 and LCN2 progressively increased, correlating with tumor growth, behavioral manifestations, tissue and molecular pathology, and cachexia development. GDF15 exhibited highly sensitive and specific for PDAC patients compared to CA19-9, IL-6, or NLR, while LCN2 showed even greater sensitivity and specificity in PDAC mice. Combining GDF15 and LCN2, or GDF15 and CA19-9, enhanced sensitivity and specificity.

Our findings indicate that GDF15 holds promise as a biomarker for early detection and prognosis of PDAC, while LCN2 could strengthen diagnostic panels.

Cancer cachexia significantly contributes to morbidity and mortality in patients with non-small-cell lung cancer (NSCLC). Inflammatory pathways mediated by interleukin-6 (IL-6) play a crucial role in the development of cancer cachexia. This study aimed to investigate the use of tocilizumab in the management of NSCLC with coexisting IL-6-elevated cachexia.

In this retrospective study, data were collected from patients with NSCLC and concurrent IL-6-elevated cachexia who received either tocilizumab plus antitumour therapy or antitumour therapy alone. The primary endpoints were overall survival (OS) and improved modified Glasgow Prognostic Score (mGPS) at Week 12. The secondary endpoints included changes from baseline over 12 weeks in body weight, albumin, C-reactive protein (CRP) and mGPS. Qualitative improvements in patient self-rated appetite and fatigue were reported as exploratory analysis.

The study included 49 patients diagnosed with NSCLC and IL-6-elevated cachexia, Eastern Cooperative Oncology Group performance status of 2-4. Of these, 26 received tocilizumab in combination with antitumour therapy, and 23 received antitumour therapy alone. The majority of these patients were male (87.8%). Baseline characteristics were almost identical between the two groups. The tocilizumab group demonstrated a significantly longer median OS compared to the control group (15.1 vs. 3.2 months; hazard ratio 0.18, 95% confidence interval 0.08-0.38; p < 0.001). The rate of patients surviving with mGPS improvement at Week 12 was significantly higher in the tocilizumab group than in the control group (risk difference 0.88, 95% confidence interval 0.75-1.00; p < 0.001). Over the 12-week period, significant improvements were observed in body weight, albumin, CRP and mGPS in the tocilizumab group compared to the control group (body weight: 5.15 ± 0.53 kg vs. -5.69 ± 0.76 kg, p = 0.041; albumin: 5.89 ± 0.70 g/L vs. -2.97 ± 0.71 g/L, p < 0.001; CRP: -91.50 ± 7.15 mg/L vs. 9.47 ± 13.69 mg/L, p < 0.001; mGPS: -1.61 ± 0.15 vs. 0.03 ± 0.08, p < 0.001). The tocilizumab group also displayed significantly higher rates of improvement in appetite and fatigue (both p < 0.001). The incidence of Grade 3 or higher adverse events was 34.6% in the tocilizumab group compared to 78.3% in the control group. Tocilizumab-related adverse events were observed in three patients (11.5%), including two cases of neutropenia and one case of skin and subcutaneous tissue infection.

Tocilizumab demonstrated significant benefits in survival and various clinical parameters, including body weight, albumin, CRP, mGPS and symptom burden in patients with NSCLC and concurrent IL-6-elevated cachexia. Given the existing unmet medical need for effective interventions for cancer cachexia, tocilizumab may be considered as a potential treatment option.

Cancer cachexia (CC), a syndrome of skeletal muscle and adipose tissue wasting, reduces responsiveness to therapies and increases mortality. There are no approved treatments for CC, which may relate to discordance between pre-clinical models and human CC. To address the need for clinically relevant models, we generated tamoxifen-inducible, epithelial cell specific Kras G12D/+ ( G12D ) mice. G12D mice develop CC over a protracted time course and phenocopy tissue, cellular, mutational, transcriptomic, and metabolic characteristics of human lung CC. CC in G12D mice is characterized by early loss of adipose tissue, a phenotype confirmed in a large cohort of patients with lung cancer. Tumor-released factors promote adipocyte lipolysis, a driver of adipose wasting in human CC, and adipose tissue wasting was inversely related to tumor burden. Thus, G12D mice model key features of human lung CC and suggest a novel role for early adipose tissue wasting in CC.

Cancer cachexia is a debilitating syndrome characterized by progressive weight loss, muscle wasting, and systemic inflammation. Despite the prevalence and severe consequences of cancer cachexia, effective treatments for this syndrome remain elusive. Therefore, there is a greater need for well-characterized animal models to identify novel therapeutic targets. Certain manifestations of cachexia, such as pain and depression, have been extensively studied using animal models of cancer-induced bone pain (CIBP). In contrast, other aspects of cachexia have received less attention in these models. To address this issue, we established the CIBP model by injecting Lewis lung carcinoma into the intramedullary cavity of the femur, observed cachexia-related symptoms, and demonstrated the utility of this model as a preclinical platform to study cancer cachexia. This model accurately recapitulates key features of cancer cachexia, including weight loss, muscle atrophy, adipose tissue depletion, CIBP, and anxiety. These findings suggest that psychological factors, in addition to physiological and metabolic factors, play significant roles in cancer cachexia development. Our model offers a valuable resource for investigating the underlying mechanisms of cancer cachexia and for developing innovative therapeutic strategies that target physical and psychological components.

In this editorial, we comment on the in-press article in the World Journal of Gastrointestinal Endoscopy concerning the treatment of malignant gastric outlet obstruction (mGOO). The original theory of treatment involves bypassing the obstruction or reenabling the patency of the passage. Conventional surgical gastroenterostomy provides long-term relief of symptoms in selected patients, with substantial morbidity and a considerable rate of delayed gastric emptying. Endoscopic stenting was introduced as an alternative minimally invasive procedure with less procedural morbidity and rapid clinical improvement; however, it presented a high rate of long-term recurrence. Therefore, challenges remain in the treatment of mGOO patients to improve clinical outcomes. Endoscopic ultrasound-guided gastroenterostomy has recently emerged as a promising method because of the combined effects of surgery and endoscopy, whereas stomach-partitioning gastrojejunostomy has been reported as a modified surgical procedure to reduce the rate of delayed gastric emptying. In decision-making regarding the treatment of choice, it should be taken into account that mGOO might be accompanied by a variety of pathological conditions, including cancer cachexia, anorexia, malabsorption, and etc., all of which can also lead to the characteristic symptoms and poor nutritional status of mGOO. The treatment plan should consider comprehensive aspects of patients to achieve practical improvements in prognosis and the quality of life.