Transcutaneous carbon dioxide suppresses skeletal muscle atrophy in a mouse model of oral squamous cell carcinoma.

Cancer cachexia causes skeletal muscle atrophy, impacting the treatment and prognosis of patients with advanced cancer, but no treatment has yet been established to control cancer cachexia. We demonstrated that transcutaneous application of carbon dioxide (CO2) could improve local blood flow and reduce skeletal muscle atrophy in a fracture model. However, the effects of transcutaneous application of CO2 in cancer-bearing conditions are not yet known. In this study, we calculated fat-free body mass (FFM), defined as the skeletal muscle mass, and evaluated the expression of muscle atrophy markers and uncoupling protein markers as well as the cross-sectional area (CSA) to investigate whether transcutaneous application of CO2 to skeletal muscle could suppress skeletal muscle atrophy in cancer-bearing mice. Human oral squamous cell carcinoma was transplanted subcutaneously into the upper dorsal region of nude mice, and 1 week later, CO2 gas was applied to the legs twice a week for 4 weeks and FFM was calculated by bioimpedance spectroscopy. After the experiment concluded, the quadriceps were extracted, and muscle atrophy markers (muscle atrophy F-box protein (MAFbx), muscle RING-finger protein 1 (MuRF-1)) and uncoupling protein markers (uncoupling protein 2 (UCP2) and uncoupling protein 3 (UCP3)) were evaluated by real-time polymerase chain reaction and immunohistochemical staining, and CSA by hematoxylin and eosin staining. The CO2-treated group exhibited significant mRNA and protein expression inhibition of the four markers. Furthermore, immunohistochemical staining showed decreased MAFbx, MuRF-1, UCP2, and UCP3 in the CO2-treated group. In fact, the CSA in hematoxylin and eosin staining and the FFM revealed significant suppression of skeletal muscle atrophy in the CO2-treated group. We suggest that transcutaneous application of CO2 to skeletal muscle suppresses skeletal muscle atrophy in a mouse model of oral squamous cell carcinoma.

Optimization of a mouse model of pancreatic cancer to simulate the human phenotypes of metastasis and cachexia.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) presents with a high mortality rate. Two important features of PDAC contribute to this poor outcome. The first is metastasis which occurs in ~ 80% of PDAC patients. The second is cachexia, which compromises treatment tolerance for patients and reduces their quality of life. Although various mouse models of PDAC exist, recapitulating both metastatic and cachectic features have been challenging. METHODS: Here, we optimize an orthotopic mouse model of PDAC by altering several conditions, including the subcloning of parental murine PDAC cells, implantation site, number of transplanted cells, and age of recipient mice. We perform spatial profiling to compare primary and metastatic immune microenvironments and RNA sequencing to gain insight into the mechanisms of muscle wasting in PDAC-induced cachexia, comparing non-metastatic to metastatic conditions. RESULTS: These modifications extend the time course of the disease and concurrently increase the rate of metastasis to approximately 70%. Furthermore, reliable cachexia endpoints are achieved in both PDAC mice with and without metastases, which is reminiscent of patients. We also find that cachectic muscles from PDAC mice with metastasis exhibit a similar transcriptional profile to muscles derived from mice and patients without metastasis. CONCLUSION: Together, this model is likely to be advantageous in both advancing our understanding of the mechanism of PDAC cachexia, as well as in the evaluation of novel therapeutics.

Gut Microbial Dysbiosis Differs in Two Distinct Cachectic Tumor-Bearing Models Consuming the Same Diet.

The impact of cancer cachexia on the colonic microbiota is poorly characterized. This study assessed the effect of two cachectic-producing tumor types on the gut microbiota to determine if a similar dysbiosis could be found. In addition, it was determined if a diet containing an immunonutrient-rich food (walnuts) known to promote the growth of probiotic bacteria in the colon could alter the dysbiosis and slow cachexia. Male Fisher 344 rats were randomly assigned to a semi-purified diet with or without walnuts. Then, within each diet group, rats were further assigned randomly to a treatment group: tumor-bearing ad libitum fed (TB), non-tumor-bearing ad libitum fed (NTB-AL), and non-tumor-bearing group pair-fed to the TB (NTB-PF). The TB group was implanted either with the Ward colon carcinoma or MCA-induced sarcoma, both transplantable tumor lines. Fecal samples were collected after the development of cachexia, and bacteria species were identified using 16S rRNA gene analysis. Both TB groups developed cachexia but had a differently altered gut microbiome. Beta diversity was unaffected by treatment (NTB-AL, TB, and NTB-PF) regardless of tumor type but was affected by diet. Also, diet consistently changed the relative abundance of several bacteria taxa, while treatment and tumor type did not. The control diet increased the abundance of A. Anaeroplasma, while the walnut diet increased the genus Ruminococcus. There were no common fecal bacterial changes characteristic of cachexia found. Diet consistently changed the gut microbiota, but these changes were insufficient to slow the progression of cachexia, suggesting cancer cachexia is more complex than a few gut microbiota shifts.

Effects of cancer-induced cachexia and administration of L-glutathione on the intestinal mucosa in rat.

Walker-256 tumor is an experimental model known to promote cachexia syndrome, oxidative stress, and systemic inflammation. This study evaluated the duodenal mucosa of rats with Walker-256 tumor administered with 1% L-glutathione, intending to evaluate the damage caused by cancer-associated cachexia in the gastrointestinal tract and the effects of antioxidant administration on mucosal protection. Twenty-four 55-day-old male Wistar rats were distributed into four groups: control (C); control administered with 1% L-glutathione (C-GSH); Walker-256 tumor (W) and Walker-256 tumor administered with 1% L-glutathione (W-GSH). After 14 days of treatment, the duodenum was harvested for morphometric analysis of the mucosa, proliferation, apoptosis, immunostaining of varicosities immunoreactive (IR) to vasoactive intestinal peptide (VIP) and 5-HT-IR cells, and quantification of mast cells and goblet cells. Walker-256 tumor-bearing rats showed cachexia syndrome, mucosal atrophy, reduced cell proliferation, reduced 5-HT-IR cells, and increased goblet cells and VIPergic varicosities, which were not reversed by L-glutathione. On the other hand, L-glutathione caused a reduction of cells in apoptosis and mast cell recruitment, demonstrating a partial recovery of the damage detected in the intestinal mucosa.

Sex differences in cachexia and branched-chain amino acid metabolism following chemotherapy in mice.

Chemotherapy is a major contributor to cachexia, but studies often investigate male animals. Here, we investigated whether sex modifies the effects of chemotherapy on cachexia and BCAA metabolism. Ten-week-old CD2F1 male and female mice were treated with the chemotherapy drug cocktail folfiri (50 mg/kg 5-fluorouracil, 90 mg/kg leucovorin, and 24 mg/kg CPT11) (drug) or vehicle twice a week for 6 weeks. Insulin tolerance tests were conducted and BCAA levels and metabolism were measured in plasma and tissues. Drug treatment reduced body and skeletal muscle weights and anabolic signaling in both sexes, with females showing worsened outcomes (p < 0.05 for all). Drug treatment increased plasma BCAA only in males, but BCAA concentrations in the skeletal muscle of both sexes were decreased; this decrease was more profound in males (p = 0.0097). In addition, muscle expression of the BCAA transporter LAT1 was reduced; this reduction was more severe in females (p = 0.0264). In both sexes, the (inhibitory) phosphorylation of BCKD-E1αser293 was increased along with decreased BCKD activity. In the liver, drug treatment increased BCAA concentrations and LAT1 expression, but BCKD activity was suppressed in both sexes (p < 0.05 for all). Our results demonstrate that altered BCAA metabolism may contribute to chemotherapy-induced cachexia in a sex-dependent manner.

Effect of preoperative immunonutrition on postoperative short-term clinical outcomes in patients with gastric cancer cachexia: a prospective randomized controlled trial.

BACKGROUND: Although current guidelines(ESPEN guideline: Clinical nutrition in surgery and other guidelines) recommend preoperative immunonutrition for cachectic gastric cancer patients, the strength of the recommendation is weak, and the level of evidence is low. The benefits of preoperative immunonutrition still remain controversial. PATIENTS AND METHODS: 112 patients with gastric cancer cachexia were enrolled in the study and randomly assigned in a 1:1 ratio to receive either preoperative enteral immunonutrition support (IN, n = 56) or standard enteral nutrition support (SEN, n = 56). The primary endpoint was the incidence of infectious complications, and the secondary endpoints included the nutritional indicators, inflammatory markers, immune parameters, postoperative recovery and complications and gastrointestinal intolerance reactions. RESULTS: The incidence of postoperative infectious complications(P = 0.040) and overall complications (P = 0.049)was significantly lower in the IN group compared to the SEN group. In terms of laboratory inflammatory indexes, patients in the IN group demonstrated significantly lower levels of white blood cells (WBC), C-reactive protein (CRP), and interleukin-6 (IL-6), as well as higher levels of lymphocytes (LYMPH) and immunoglobulin A (IgA), compared to patients in the SEN group, with statistically significant differences. In terms of clinical outcomes, the IN group had a shorter duration of antibiotic use (P = 0.048), shorter hospital stay (P = 0.018), and lower total hospital costs (P = 0.034) compared to the SEN group. The IN group also experienced significantly less weight loss after surgery (P = 0.043). CONCLUSION: Preoperative administration of immunonutrition formula has a positive impact on the incidence of infectious complications in patients with gastric cancer cachexia after surgery. It improves patients' inflammatory and immune status, shortens hospital stays, and reduces healthcare costs. Preoperative use of immunonutrition may contribute to the improvement of prognosis in this high-risk population.

Comparison of the efficacy of enfortumab vedotin between patients with metastatic urothelial carcinoma who were treated with avelumab or pembrolizumab: real-world data from a multi-institutional study in Japan.

OBJECTIVES: Enfortumab vedotin (EV) is a novel antibody-drug conjugate approved for metastatic urothelial carcinoma (UC) refractory to prior treatment with immune checkpoint inhibitors (ICIs). However, the difference in efficacy of EV after each ICIs and prognostic factors are not well known. We aimed to compare the efficacy of EV in patients with metastatic UC who were treated with avelumab or pembrolizumab and to identify the prognostic factors. METHODS: The records of 100 patients with advanced metastatic UC who received EV after the administration of either avelumab or pembrolizumab were retrospectively collected from five academic hospitals in Japan. RESULTS: The median follow-up period was 6.7 months. The median overall survival (OS) and progression-free survival (PFS) in the EV after avelumab/pembrolizumab group were not reached/14.7 months (p = 0.17) and 10.4/5.2 months (p = 0.039), respectively. The objective response rates (ORR) were 66.6% and 46.8% in EV after avelumab and EV after pembrolizumab groups, respectively (p = 0.14). Multivariate analysis identified histological variants, liver metastasis, low serum albumin levels, and high serum CRP level as significant poor prognostic factors. The median OS and PFS of cachexia patients with both low serum albumin levels and high serum CRP levels were 6.0 months and 0.93 months, respectively. CONCLUSION: PFS was superior in patients treated with EV after avelumab to EV after pembrolizumab. However, OS showed no significant difference between the two groups. Because the prognosis of patients with cachexia is extremely poor, the initiation of EV should be discussed in these patients.

Metabolomic profiling of cancer-related fatigue involved in cachexia and chemotherapy.

Patients with advanced cancer are frequently burdened with a severe sensation of fatigue called cancer-related fatigue (CRF). CRF is induced at various stages and treatments, such as cachexia and chemotherapy, and reduces the overall survival of patients. Objective and quantitative assessment of CRF could contribute to the diagnosis and prediction of treatment efficacy. However, such studies have not been intensively performed, particularly regarding metabolic profiles. Here, we conducted plasma metabolomics of 15 patients with urological cancer. The patients with and without fatigue, including those with cachexia or chemotherapy-induced fatigue, were compared. Significantly lower concentrations of valine and tryptophan were observed in fatigued patients than in non-fatigued patients. In addition, significantly higher concentrations of polyamine pathway metabolites were observed in patients with fatigue and cachexia than in those without cachexia. Patients with exacerbated fatigue due to chemotherapy showed significantly decreased cysteine and methionine metabolism before chemotherapy compared with those without fatigue exacerbation. These findings suggest that plasma metabolic profiles could help improve the diagnosis and monitoring of CRF.

[Pathological profile of S.P. Botkin infectious hospital during the siege of Leningrad (1941-1944)]. / Patologo-anatomicheskii profil' infektsionnoi bol'nitsy im. S.P. Botkina v gody blokady Leningrada (1941­1944 gg.).

The results of autopsies performed in the pathological department of the Infectious Diseases Hospital named after. S.P. Botkin during the siege of Leningrad (from September 8, 1941 to January 27, 1944). The structure of diseases of the deceased varied during different periods of the siege of Leningrad. In the first period (September-December 1941), diphtheria, dysentery, measles, typhoid fever, and scarlet fever prevailed among the diseases. The most common causes of death in the second period (April-December 1942) were typhus, dysentery, tuberculosis, lobar pneumonia, and typhoid fever. Nosological structure in the third period of the blockade (January 1943 - January 1944): tuberculosis, dysentery, cachexia, lobar pneumonia, infectious jaundice. The discrepancy between clinical and morphological diagnoses is most often noted for the following nosology: pulmonary tuberculosis, typhoid fever, pneumonia, stomach and hepatopancreatobiliary cancer, measles, influenza. The first period of the blockade was distinguished by a high specific proportion of examination of children's bodies - 51.2% of all autopsies; in subsequent periods, the specific share of autopsies of deceased adults (20-59 years) increased to 76.2%. The difference in the nosological structure and age groups of those who died during different periods of the siege of Leningrad was determined by the epidemiological situation in the city, social and living conditions and medical and organizational factors. Conducted in the pathological-anatomical department of the hospital named after. S.P. Botkin during the siege of Leningrad, pathological studies made it possible to timely establish the causes of deaths and identify the peculiarities of the course of infectious diseases against the background of cachexia. Regularly held clinical and anatomical conferences contributed to the reduction of defects in the diagnosis and treatment of infectious diseases.

Cachexia index for prognostication in surgical patients with locally advanced oesophageal or gastric cancer: multicentre cohort study.

BACKGROUND: Features of cancer cachexia adversely influence patient outcomes, yet few currently inform clinical decision-making. This study assessed the value of the cachexia index (CXI), a novel prognostic marker, in patients for whom neoadjuvant chemotherapy and surgery for oesophagogastric cancer is planned. METHODS: Consecutive patients newly diagnosed with locally advanced (T3-4 or at least N1) oesophagogastric cancer between 1 January 2010 and 31 December 2015 were identified through the West of Scotland and South-East Scotland Cancer Networks. CXI was calculated as (L3 skeletal muscle index) × (serum albumin)/(neutrophil lymphocyte ratio). Sex-stratified cut-off values were determined based on the area under the curve (AUC), and patients were divided into groups with low or normal CXI. Primary outcomes were disease progression during neoadjuvant chemotherapy and overall survival (at least 5 years of follow-up). RESULTS: Overall, 385 patients (72% men, median age 66 years) were treated with neoadjuvant chemotherapy for oesophageal (274) or gastric (111) cancer across the study interval. Although patients with a low CXI (men: CXI below 52 (AUC 0.707); women: CXI below 41 (AUC 0.759)) were older with more co-morbidity, disease characteristics were comparable to those in patients with a normal CXI. Rates of disease progression during neoadjuvant chemotherapy, leading to inoperability, were higher in patients with a low CXI (28 versus 12%; adjusted OR 3.07, 95% c.i. 1.67 to 5.64; P < 0.001). Low CXI was associated with worsened postoperative mortality (P = 0.019) and decreased overall survival (median 14.9 versus 56.9 months; adjusted HR 1.85, 1.42 to 2.42; P < 0.001). CONCLUSION: CXI is associated with disease progression, worse postoperative mortality, and overall survival, and could improve prognostication and decision-making in patients with locally advanced oesophagogastric cancer.

Burden of undernutrition among under-five Bengali children and its determinants: Findings from Demographic and Health Surveys of Bangladesh and India.

BACKGROUND: Globally, undernutrition is the leading cause of mortality among under-five children. Bangladesh and India were in the top ten countries in the world for under-five mortality. The aim of the study was to investigate the nutritional status of Bengali under-five children. METHODS: Data on 25938 under-five children were retrieved from the Bangladesh Demographic and Health Survey 2017-18 (BDHS) and the National Family Health Survey of India 2015-16 (NFHS-4). Stunting, wasting, underweight and thinness were considered to understand the nutritional status of under-five children. Binary logistic regression was used to identify associated factors of undernutrition among children. RESULTS: Over one-quarter of Bengali under-five children were found to be suffering from the problem of stunting (31.9%) and underweight (28.1%), while other nutritional indicators raised serious concern and revealed inter-country disparities. In the cases of wasting, underweight and thinness, the mean z-scores and frequency differences between Bangladesh and India were significant. The nutritional status of Bengali under-five children appeared to have improved in Bangladesh compared to India. Child undernutrition had significant relations with maternal undernutrition in both countries. Girls in Bangladesh had slightly better nutritional status than boys. In Bangladesh, lack of formal education among mothers was a leading cause of child undernutrition. Stunting and underweight coexist with low household wealth index in both counties. CONCLUSIONS: The research revealed that various factors were associated with child undernutrition in Bengalis. It has been proposed that programmes promoting maternal education and nutrition, along with household wealth index be prioritised. The study recommends that the Governments of Bangladesh and India should increase the budget for health of children so as to reach the sustainable development goals.

Improving the Nutritional Status of Socially Vulnerable Children in Manaus, Brazilian Amazon, through a Food Supplementation Programme.

Information on the effects of government nutrition programmes provided to socially vulnerable children to improve their nutritional status is scarce. We analysed the effectiveness of a nutritional programme, including food supplementation with infant formula, on the evolution of the weight and height of socially vulnerable children from Manaus in the Brazilian Amazon. This study included 7752 children aged 12-24 months admitted to the programme between 2017 and 2020. Weight and height measurements at admission and every three months thereafter were extracted from the programme database. Weight-for-age, weight-for-height, body mass index-for-age (BMI/A), and height-for-age z-scores were analysed using a multilevel linear regression model, which showed a statistically significant decrease in nutritional deficits toward nutritional recovery at follow-up. The programme's effectiveness was evaluated in 1617 children using a paired analysis comparing data from between 12 and 15 months of age at admission and follow-up after 6-9 months. Children admitted with wasting presented an increase in the BMI/A z-score, whereas children admitted with a risk of being overweight and obese had a statistically significant decrease in the BMI/A z-score. Children admitted with stunted growth also showed increased height-for-age z-scores. The nutrition programme was effective for children experiencing wasting and reducing excess weight.

Comprehensive evaluation of serum hepatic proteins in predicting prognosis among cancer patients with cachexia: an observational cohort study.

BACKGROUND: Hepatic proteins, including albumin, prealbumin, and transferrin have been confirmed to be prognostic predictors in various cancers. This study aimed to comprehensively assess the prognostic value of these three serum markers in patients with cancer cachexia. METHODS: This multicenter prospective cohort study included 1303 cancer cachexia patients, among whom 592 deaths occurred during a median follow-up of 20.23 months. The definition of cachexia was based on the 2011 international consensus. Concordance index (C-index) and receiver operating characteristic (ROC) curves were applied to compare the prognostic performance. The primary outcome was overall survival, which was calculated using the Kaplan-Meier method generated by log-rank test. A Cox proportional hazard regression model was used to identify independent predictors associated with survival. The secondary outcomes included 90-days mortality and quality of life (QoL). RESULTS: C-index and ROC curves showed that albumin had the most accurate predictive capacity for survival, followed by transferrin and prealbumin. Multivariate Cox analysis confirmed that low albumin (hazard ratio [HR] = 1.51, 95% confidence interval [95%CI] = 1.28-1.80, P < 0.001), prealbumin (HR = 1.42, 95%CI = 1.19-1.69, P < 0.001), and transferrin (HR = 1.50, 95%CI = 1.25-1.80, P < 0.001) were independent risk factors for long-term survival in cancer patients with cachexia. In subgroup analysis, the prognostic value of low albumin was significant in patients with upper gastrointestinal, hepatobiliary and pancreatic, and colorectal cancers; low prealbumin was significant in colorectal cancer; and low transferrin was significant in patients with upper gastrointestinal and colorectal cancer. All three hepatic proteins were valuable as prognostic predictors for patients with advanced (Stage III and IV) cancer with cachexia. The risks of 90-days mortality and impaired QoL were higher in cachexia patients with low albumin, prealbumin, and transferrin levels. CONCLUSION: Low albumin, prealbumin, and transferrin levels were all independent prognostic factors affecting patients with cancer cachexia, especially in patients in the advanced stages. These results highlight the value of routinely checking serum hepatic proteins in clinical practice to predict the prognosis of patients with cancer cachexia.

Association between BMI z-score and body composition indexes with blood pressure and grip strength in school-age children: a cross-sectional study.

Childhood obesity is linked to diverse health outcomes, including elevated blood pressure (EBP). Emerging evidence showed that excess fat mass (FM) may have a deleterious impact on blood pressure even in normal-weight children. The primary objective of this study was to assess the association between body weight status by BMI z-score and body composition parameters by conventional bioelectrical impedance analysis (BIA) and bioelectrical impedance vector analysis (BIVA). Also, we aimed to explore the performance of BMI z-score, %FM, and FM index (FMI) in discriminating EBP in a sample of school-age Mexican children. Children were classified as having normal weight, overweight or obesity according to WHO criteria for BMI z-score. FMI was considered high when above 75th percentile, and fat free mass index (FFMI) was considered low when below 25th percentile of the reference population. Body composition was also classified according to the BIVA method and EBP was determined when systolic and/or diastolic blood pressure ≥ 90th percentile. BMI z-score groups were compared by Student´s t-test or the Mann-Whitney U test, or by the chi-square test or Fisher exact test. Receiving operating characteristic (ROC) analysis was performed. 61 children were included (52.5% boys, median age 9.8 (25th, 75th percentiles: 8.5, 11.0)) years. High FMI was observed in 32.3% of children with normal weight. Low FFMI was present in 93.5% of children with normal weight and 53.3% of those with overweight/obesity. According to BIVA, 58.1% and 43.3% of children with normal weight and overweight/obesity were classified as having cachexia. All the three adiposity indicators showed significant areas under the ROC curve (AURC) greater than 0.775 for EBP, with the largest one displayed for FM% (0.794). Hight FMI and low FFMI are common in children with normal weight. Identifying deficiency of FFM might be limited by using solely BMI indicators. Cachexia by BIVA was present in a high proportion of children with either normal weight or overweight/obesity. Both BMI z-score and FM (% and FMI) performed well at discriminating EBP, with a numerically greater AURC observed for FM%. Body composition in pediatric population is relevant for identifying body composition abnormalities at early age.

[The Second Web Questionnaire Survey on Cancer Cachexia Japanese Evidence for Patients Of Cancer Cachexiaâ ¡ (J-EPOCCâ ¡)-Challenges in Early Detection and Early Intervention for Appetite Loss and Weight Loss During Cancer Treatment].

In 2019, the Cancer Cachexia Web Questionnaire Survey(J-EPOCC), conducted among cancer patients, their families and healthcare professionals in Japan showed that nearly half of patients who had experienced appetite loss or weight loss during cancer treatment had not consulted with healthcare professionals about their symptoms, and it meant that patients missed the opportunity to receive medical intervention. Since anamorelin was approved in 2021 fo"r Cancer cachexia in non- small cell lung cancer, gastric cancer, pancreatic cancer and colorectal cancer", the treatment environment for cancer cachexia has greatly changed. Thus, the second Web Questionnaire Survey(J-EPOCCⅡ)was conducted in June 2022 to investigate changes in the problem awareness of cancer cachexia, especially appetite loss and weight loss, among patients and their family and healthcare professionals. The results showed that there was no apparent change in awareness of appetite loss and weight loss, suggesting many patients may miss treatment opportunities. Further disease awareness is required among patients and their families to enhance the understanding of the significance of therapeutic interventions for appetite loss or weight loss, and to call their attention for early detection and treatment.

GFRAL Is Widely Distributed in the Brain and Peripheral Tissues of Mice.

In 2017, four independent publications described the glial cell-derived neurotrophic factor (GDNF) receptor alpha-like (GFRAL) as receptor for the growth differentiation factor 15 (GDF15, also MIC-1, NAG-1) with an expression exclusively in the mice brainstem area postrema (AP) and nucleus tractus solitarii (NTS) where it mediates effects of GDF15 on reduction of food intake and body weight. GDF15 is a cell stress cytokine with a widespread expression and pleiotropic effects, which both seem to be in contrast to the reported highly specialized localization of its receptor. This discrepancy prompts us to re-evaluate the expression pattern of GFRAL in the brain and peripheral tissues of mice. In this detailed immunohistochemical study, we provide evidence for a more widespread distribution of this receptor. Apart from the AP/NTS region, GFRAL-immunoreactivity was found in the prefrontal cortex, hippocampus, nucleus arcuatus and peripheral tissues including liver, small intestine, fat, kidney and muscle tissues. This widespread receptor expression, not taken into consideration so far, may explain the multiple effects of GDF-15 that are not yet assigned to GFRAL. Furthermore, our results could be relevant for the development of novel pharmacological therapies for physical and mental disorders related to body image and food intake, such as eating disorders, cachexia and obesity.

Prevalence and prognosis of cachexia according to the Asian Working Group for Cachexia criteria in sarcopenic dysphagia: A retrospective cohort study.

OBJECTIVE: The aim to examine the prevalence and prognosis of cachexia according to the Asian Working Group for Cachexia (AWGC) criteria in patients with sarcopenic dysphagia. METHODS: A retrospective cohort study was conducted with 271 patients diagnosed with sarcopenic dysphagia out of 467 patients enrolled in the Japanese sarcopenic dysphagia database. Cachexia was diagnosed by the AWGC criteria. The AWGC criteria includes chronic diseases, either or both weight loss (2% or more over 3-6 mo) or low BMI (<21 kg/m2), and at least one of the following: anorexia, decreased grip strength (<28 kg in men and <18 kg in women), or elevated C-reactive protein levels (>0.5 mg/dL). Outcomes were death, swallowing function as assessed by the Food Intake LEVEL Scale (FILS), and activities of daily living as assessed by the Barthel Index (BI) at follow-up. RESULTS: The mean age was 84 (±8) y; 152 (56%) were female, and 97 (36%) had cachexia. In univariate analysis, death was significantly more common in the cachexia group (15% versus 2%, P ≤ 0.001). Logistic regression analysis showed that cachexia was independently associated with death (odds ratio: 3.557, 95% confidence interval: 1.010, 12.529). No significant differences were found in the presence or absence of cachexia in the FILS (7 versus 8, P = 0.849) and BI (55 versus 52.5, P = 0.892). CONCLUSIONS: Cachexia was found in 36% of patients with sarcopenic dysphagia, and death was significantly higher in cachexia.

Integrated neutrophil-to-lymphocyte ratio and handgrip strength better predict survival in patients with cancer cachexia.

OBJECTIVES: Systemic inflammation and skeletal muscle strength play crucial roles in the development and progression of cancer cachexia. In this study we aimed to evaluate the combined prognostic value of neutrophil-to-lymphocyte ratio (NLR) and handgrip strength (HGS) for survival in patients with cancer cachexia. METHODS: This multicenter cohort study involved 1826 patients with cancer cachexia. The NLR-HGS (NH) index was defined as the ratio of neutrophil-to-lymphocyte ratio to handgrip strength. Harrell's C index and receiver operating characteristic (ROC) curve analysis were used to assess the prognosis of NH. Kaplan-Meier analysis and Cox regression models were used to evaluate the association of NH with all-cause mortality. RESULTS: Based on the optimal stratification, 380 women (NH > 0.14) and 249 men (NH > 0.19) were classified as having high NH. NH has shown greater predictive value compared to other indicators in predicting the survival of patients with cancer cachexia according to the 1-, 3-, and 5-y ROC analysis and Harrell's C index calculation. Multivariate survival analysis showed that higher NH was independently associated with an increased risk of death (hazard ratio = 1.654, 95% confidence interval = 1.389-1.969). CONCLUSION: This study demonstrates that the NH index, in combination with NLR and HGS, is an effective predictor of the prognosis of patients with cancer cachexia. It can offer effective prognosis stratification and guidance for their treatment.

Circulating factors in cancer cachexia: recent opportunities for translational research.

PURPOSE OF REVIEW: To discuss the recent discoveries and limitations of the available literature on emerging circulating biomarkers of cancer cachexia. RECENT FINDINGS: Studies on circulating factors in cancer cachexia show promising alternatives for diagnosing the syndrome in a minimally invasive manner in the clinic setting, as well as potential targets for cancer cachexia treatment. Factors secreted by the tumor and the adipose tissue, such as extracellular vesicles and soluble proteins, respectively, have been shown to either directly induce wasting in vitro and in vivo or to be altered in the cachectic phenotype. The detection and characterization of circulating cells allows detection of the precachectic stage and the levels of the soluble immune checkpoint protein programmed death ligand-1 (PD-L1) are correlated with the presence of the hallmarks of cancer cachexia. SUMMARY: Structural, molecular, and metabolic alterations have been observed in various tissues, revealing the occurrence of sustained inter-compartment crosstalk in cachectic patients. Early diagnosis of cancer cachexia becomes crucial to avoid the establishment of refractory cachexia through the implementation of interventions that may attenuate systemic inflammation and muscle loss. More studies on human cancer cachexia are required in order to address the recently discovered cachexia-associated circulating factors' value as biomarkers of the syndrome.

Bridging gaps in cancer cachexia Care: Current insights and future perspectives.

Cachexia is characterized by severe weight loss and skeletal muscle depletion, and is a threat to cancer patients by worsening their prognosis. International guidelines set indications for the screening and diagnosis of cancer cachexia and suggest interventions (nutritional support, physical exercise, and pharmacological treatments). Nevertheless, real-life experience not always aligns with such indications. We aimed to review the current state of the field and the main advancements, with a focus on real-life clinical practice from the perspectives of oncologists, nutrition professionals, and radiologists. Pragmatic solutions are proposed to improve the current management of the disease, emphasizing the importance of increasing awareness of clinical nutrition's benefits, fostering multidisciplinary collaboration, promoting early identification of at-risk patients, and leveraging available resources. Given the distinct needs of patients who are receiving oncologic anti-cancer treatments and those in the follow-up phase, the use of tailored approaches is encouraged. The pivotal role of healthcare professionals in managing patients in active treatment is highlighted, while patient and caregiver empowerment should be strengthened in the follow-up phase. Telemedicine and web-based applications represent valuable tools for continuous monitoring of patients, facilitating timely and personalized intervention through effective communication between patients and healthcare providers. These actions can potentially improve the outcomes, well-being, and survival of cancer patients with cachexia.