Tryptophan metabolism and kynurenine metabolites in cancer: systemic nutritional and metabolic implications.

PURPOSE OF REVIEW: To describe the role of Tryptophan (Trp) metabolism and Kynurenine (Kyn) metabolites in nutritional and metabolic changes in cancer. RECENT FINDINGS: Trp is in part utilized for protein and neurotransmitters biosynthesis, but more than 95% is implicated in Kyn pathways. In this molecular cascade, metabolites are produced with distinct biological activities regulating the immune response and neurotransmission with potential implications in malnutrition/cachexia during cancer. Immune dysfunction is a phenomenon occurring during cancer and malnutrition. Kyn metabolites regulate lymphocytes activity and recent data in animals showed that the inhibition of indoleamine-2,3-dioxygenase (IDO) via 1-methyl-tryptophan determines partial amelioration of inflammation, but no positive effects on the preservation of muscularity were observed. Kynurenines seem to contribute to muscle catabolism via NAD+ biosynthesis and ROS generation. Trp metabolism via the serotonin biosynthesis is involved in appetite control in cancer. Moreover, kynurenines have a role in determining fatigue in conditions associated with inflammation. SUMMARY: Trp metabolism has implications in immune and energy balance in cancer. The modulation of Trp and kynurenines have impact on central nervous system mechanisms, including appetite, fatigue, and muscle wasting/cachexia. Research focusing on these clinical implications will open new scenario for therapeutic interventions aimed at counteracting nutritional derangements in cancer.

Metabolic and histomorphological changes of adipose tissue in cachexia.

PURPOSE OF REVIEW: To describe the role of the main changes occurring in adipose tissue during cachexia and how these affects patient's outcomes, with a specific focus on cancer. RECENT FINDINGS: In cachexia, the changes within the adipose tissue have been recently described as the presence of inflammatory infiltration (T-lymphocytes and macrophages), enhanced fibrosis, and the occurrence of beige adipocytes (i.e., browning). The latter one is a process driving cachexia enhancing thermogenesis, primarily via modulation of uncoupling protein 1. Also, increased lipolysis of white adipose tissue, especially in cancer, via higher expression of hormone sensible and adipose tissue triglyceride lipases, was detected in experimental models and in human adipose tissue. Other systemic metabolic alterations occur in association with changes in adiposity, including insulin resistance and increased inflammation, all conditions associated with a worse outcome. Moreover, these profound metabolic alterations were shown to be implicated in several consequences, including extreme and progressive unvoluntary body weight loss. SUMMARY: Alterations in adiposity occur early during cachexia. Adipose tissue atrophy, as well as metabolic changes of white adipose tissues were observed to be pivotal in cachexia, and to be implicated in several clinical complications and poor prognosis.Further research is necessary to clarify the mechanisms underlying the loss of adiposity and therefore to identify novel therapeutic options to counteract this phenomenon in cachexia.

Muscularity and adiposity are differently associated with inflammatory and nutritional biomarkers among patients on hemodialysis and peritoneal dialysis.

PURPOSE: Nutritional alterations are prevalent in patients undergoing hemodialysis (HD) and peritoneal dialysis (PD). We aimed at evaluating whether body composition parameters in HD vs PD are differently associated with nutritional and inflammatory biomarkers. METHODS: Body composition was assessed by bioimpedance analysis. Neutrophil to lymphocyte ratio (NLR), serum albumin and C-reactive protein were used as nutritional and inflammatory biomarkers. Multivariable linear regression analysis was used to determine association(s) of body composition parameters with biomarkers. RESULTS: We enrolled a total of 108 patients, 58 on HD and 50 on PD. Fat free mass percent was higher in HD patients than PD (p = 0.006) and higher extracellular water (ECW)/intracellular water (ICW) in HD compared to PD patients (p = 0.023), as well as fat mass index was greater in PD than HD (p = 0.004). In HD patients, albumin positively correlated with fat free mass (r = 0.42; p = 0.001) and ICW/h2 (r = 0.31; p = 0.02). In PD, NLR positively correlated with fat mass (r = 0.36; p = 0.01), fat mass index (r = 0.37; p = 0.01) and ECW (r = 0.41; p = 0.005), and negatively correlated with fat free mass percent (r = -0.30; p = 0.04) and ICW percent (r = -0.34; p = 0.02). By linear regression analysis, in HD fat free mass index was associated with albumin and the absence of diabetes. In PD, the association of fat free mass index was present with NLR. Regarding adiposity, in HD we found no association of ECW/ICW with NLR and CRP, whereas in PD the ECW/ICW was associated with NLR. CONCLUSION: Inflammation drives body composition changes with differences according to the type of dialysis, as expressed by the modulation of some circulating biomarkers.

Association between serum levels of GDF-15, suPAR, PIVKA-II, sdLDL and clinical outcomes in hospitalized COVID-19 patients.

To quantify the circulating levels of novel serum biomarkers including GDF-15, PIVKA-II, sdLDL, suPAR, and of CRP in hospitalized COVID-19 patients compared with healthy subjects, and to evaluate their association(s) with outcomes in COVID-19. We considered patients with confirmed COVID-19, hospitalized in an Internal Medicine ward. The clinical characteristics were collected, including the number and type of comorbidities. Serum levels of GDF-15, PIVKA-II, suPAR, sdLDL, as well as CRP were measured. As outcomes, we considered Intensive Care Unit (ICU) transfer or death, as well as the length of stay (days) and in-hospital complications. Data were statistically analyzed, as appropriate, and a p value < 0.05 was considered significant. Ninety-three patients and 20 healthy controls were enrolled. COVID-19 patients vs. controls showed higher median levels of GDF-15 (p < 0.0001), PIVKA-II (p < 0.0001) and sdLDL (p = 0.0002), whereas no difference was observed for suPAR. In COVID-19 patients, the most frequent comorbidities were arterial hypertension (62.4%) and cardiovascular disease (30.1%). GDF-15 levels positively correlated with age (r = 0.433, p < 0.0001), and this correlation was confirmed for suPAR (r = 0.308, p = 0.003) and CRP (Rho = 0.40 p < 0.0001), but not for PIVKA-II and sdLDL. Higher GDF-15 levels were associated with a higher number of comorbidities (p = 0.021). The median length of stay was 22 (15; 30) days. During hospitalization, 15 patients (16%) were ICU transferred, and 6 (6.45%) died. GDF-15 serum levels correlated with the length of stay (rho = 0.27 p = 0.010), and were associated with ICU transfer or death (p = 0.003), as well as PIVKA-II (p = 0.038) and CRP (p < 0.001). Moreover, higher GDF-15 and PIVKA-II serum levels were associated with infectious complications (p = 0.008 and p = 0.017, respectively). In this cohort of hospitalized COVID-19 patients, novel inflammatory biomarkers, including GDF-15, suPAR and PIVKA II were associated with some patient's clinical characteristics, complications, and poor outcomes.

Assessment of lipolysis biomarkers in adipose tissue of patients with gastrointestinal cancer.

BACKGROUND: Adipose tissue metabolism may be impaired in patients with cancer. In particular, increased lipolysis was described in cancer-promoting adipose tissue atrophy. For this reason, we assessed the expression of the lipolysis-associated genes and proteins in subcutaneous adipose tissue (SAT) of gastrointestinal (GI) cancer patients compared to controls to verify their involvement in cancer, among different types of GI cancers, and in cachexia. METHODS: We considered patients with GI cancer (gastric, pancreatic, and colorectal) at their first diagnosis, with/without cachexia, and controls with benign diseases. We collected SAT and total RNA was extracted and ATGL, HSL, PPARα, and MCP1 were analyzed by qRT-PCR. Western blot was performed to evaluate CGI-58, PLIN1 and PLIN5. RESULTS: We found higher expression of ATGL and HSL in GI cancer patients with respect to controls (p ≤ 0.008) and a trend of increase for PPARα (p = 0.055). We found an upregulation of ATGL in GI cancer patients with cachexia (p = 0.033) and without cachexia (p = 0.017) vs controls. HSL was higher in patients with cachexia (p = 0.020) and without cachexia (p = 0.021), compared to controls. ATGL was upregulated in gastric cancer vs controls (p = 0.014) and higher HSL was found in gastric (p = 0.008) and in pancreatic cancer (p = 0.033) vs controls. At the protein level, we found higher CGI-58 in cancer vs controls (p = 0.019) and in cachectic vs controls (p = 0.029), as well as in gastric cancer vs controls (p = 0.027). CONCLUSION: In our cohort of GI cancer patients, we found a modulation in the expression of genes and proteins involved in lipolysis, and differences were interestingly detected according to cancer type.

Evaluation of Anorexia in Cancer and Its Association with Autonomic Nervous System Activity Assessed by Heart Rate Variability.

Alterations in the central nervous system in cancer patients are pivotal in determining appetite dysregulation and body weight loss (BWL). Autonomic nervous system activity was tested by measuring heart rate variability (HRV) in cancer patients presenting with anorexia. We considered inpatients with different types of cancer and investigated anorexia using their FAACT scores. HRV was evaluated by a three-channel Holter ECG. The domains of low frequencies (LF, sympathetic activity) and high frequencies (HF, parasympathetic activity) were calculated. Also, SDNN (autonomic activity) and RMSSD (parasympathetic activity) were assessed. We enrolled 56 patients with cancer and 23 controls. In cancer patients, RMSSD and SDNN were lower than in controls (p < 0.001 and p = 0.009). Sympathetic activity (LF nu) was lower in cancer patients than in controls (p = 0.023), including sympathovagal balance (LF/HF nu ratio) (p = 0.025). RMSSD was reduced in anorexic (p < 0.001) and non-anorexic (p = 0.003) cancer patients compared to controls. The SDNN was lower in anorexic cancer patients than in non-anorexic cancer patients (p = 0.025), and it was lower in anorexic cancer patients than in controls (p = 0.001). LF nu was lower in anorexic cancer patients than in controls (p = 0.015), as was LF/HF (p = 0.031). SDNN was negatively correlated with BWL in the cancer group (rho = -0.40; p = 0.007). Our data support the hypothesis that autonomic nervous system dysregulation exists in patients with cancer presenting with anorexia, with implications for its diagnosis and treatment.

Effects of oral immunonutrition on histological changes of inflammatory infiltration of the tumor microenvironment among patients with a new diagnosis of gastric cancer.

OBJECTIVES: We assessed the effects of oral immunonutrition (OI) on the inflammatory infiltration of the tumor microenvironment (TME) of patients undergoing surgery for gastric cancer. METHODS: We analyzed patients at the time of their first gastric cancer diagnosis. We collected surgical tissue specimens (stomach), and performed an immunohistochemical analysis to evaluate the inflammatory infiltration of the TME. Patients receiving OI were compared with patients receiving standard oral nutritional supplements and no nutritional support. RESULTS: We enrolled 12 patients with gastric cancer in the study. The median body weight loss was 5.6%. Four patients received OI, five patients received standard nutritional supplement, and three patients received no nutritional supplementation. No difference in age, body mass index (BMI), and body weight loss was observed between the three groups. The OI group showed a tendency of increased number of T-lymphocyte cluster of differentiation (CD) 8+ compared with the other groups, as well as the number of CD83+ and CD68+. The absence of F4/80+ cells was documented only in the TME of the OI group, where a linear positive correlation was present between lymphocytes CD4+ and CD8+ (R = 0.48), and between CD4+ and CD83+ (R = 0.89), although not statistically significant. In the OI group, we observed a positive correlation (not significant) between the number of lymphocytes CD8+ and macrophages CD68+ (R = 0.70; P = 0.30). A strong significant correlation was documented between CD68+ and CD40+ (R = 0.99; P = 0.01), but this correlation did not reach the significance among the patients of the other two groups (R = 0.60; P = 0.116). CONCLUSIONS: The administration of OI in patients with gastric cancer might determine changes in inflammatory patterns of the TME.

Changes of gene expression in peripheral blood mononuclear cells of lung cancer patients with or without anorexia.

BACKGROUND & AIMS: Anorexia is a disabling symptom in cancer and we aimed at investigating the role of changes in gene expression in lung cancer patients presenting with anorexia. METHODS: Genome-wide transcriptomic profiling was assessed in PBMCs RNA from newly diagnosed lung cancer patients and in a control group. RT-qPCR was used for selected genes. RESULTS: RNA-Seq analysis revealed among groups a large number of differentially expressed genes mainly implicated in immune system regulation, oxidative stress and cytokine-mediated inflammation signaling pathways. In particular, we identified a total of 983 DEGs (843 up-regulated; 140 down-regulated) in anorexic cancer compared to controls. A selected number of DEGs including ADAM8, SMAD4, CCR4 and CLU were differentially expressed within cancer group according to the presence/absence of anorexia. In terms of RT-qPCR, ADAM8 was less expressed in cancer patients than controls (p < 0.001), and in anorexic patients vs controls (p = 0.001). The expression of SMAD4 was lower in cancer vs controls (p = 0.005), and in anorexic patients vs controls (p = 0.009). We observed lower CCR4 expression in both anorexic and non-anorexic vs control (p = 0.004, p = 0.011, respectively) and a similar trend was present for CLU. CONCLUSIONS: Our data shed new light on the role of specific genes and their associated molecular pathways as potential key mechanisms for the development of anorexia and may represent a novel landmark for understanding the complex pathophysiology of impaired appetite in cancer.

Fatigue in Patients on Chronic Hemodialysis: The Role of Indoleamine 2,3-Dioxygenase (IDO) Activity, Interleukin-6, and Muscularity.

Fatigue is a frequent symptom in hemodialysis (HD), and the indolamine-2,3-dioxygenase (IDO) metabolic trap has been hypothesized in the pathogenesis of fatigue. The association between IDO activity according to fatigue and its relationship with muscle mass and function in HD patients was verified. Chronic HD patients were considered, and fatigue was assessed. The plasma kynurenines and tryptophan ratio (Kyn/Trp), as surrogate of IDO activity, and interleukin (IL)-6 were measured. Muscularity was assessed by BIA and muscle strength by hand-grip dynamometer. 50 HD patients were enrolled, and fatigue was present in 24% of the cohort. Patients with fatigue showed higher Kyn/Trp (p = 0.005), were older (p = 0.007), and IL-6 levels resulted higher than in non-fatigue patients (p < 0.001). HD patients with fatigue showed lower intracellular water (surrogate of muscle mass) (p < 0.001), as well as lower hand grip strength (p = 0.02). The Kyn/Trp ratio positively correlated with IL-6 and ECW/ICW (p = 0.004 and p = 0.014). By logistic regression analysis, higher ICW/h2 was associated with lower odds of fatigue (OR, 0.10; 95% CI, 0.01 to 0.73). In conclusion, our cohort fatigue was associated with a higher Kyn/Trp ratio, indicating a modulation of IDO activity. The Kyn/Trp ratio correlated with IL-6, suggesting a potential role of IDO and inflammation in inducing fatigue and changes in muscularity.

CHA2DS2-VASc score as a predictor of clinical outcomes in hospitalized patients with and without chronic kidney disease.

BACKGROUND: High CHA2DS2-VASc score (Congestive heart failure, Hypertension, Age > 75 years, Diabetes mellitus, prior Stroke or transient ischemic attack or thromboembolism, Vascular disease, Age 65-74 and Sex category) was associated with adverse clinical outcomes in different settings. The aim of the present study was to evaluate the association between CHA2DS2-VASc score and R2CHA2DS2-VASc score (which includes renal impairment) with in-hospital mortality and length of hospital stay in patients hospitalized in an internal medicine ward. METHODS: We enrolled 983 consecutive patients admitted during 3 years in an internal medicine ward. R2CHA2DS2-VASc score was calculated by adding 2 points to CHA2DS2-VASc for the presence of chronic kidney disease (CKD), defined according to K-DOQI. The primary outcome was a composite of all-cause mortality and length of hospital stay > 10 days. RESULTS: Patients with CKD stages 3-5 presented with increased CHA2DS2-VASc vs stages 1-2 (p < 0.001). The composite outcome occurred in 47.3% of inpatients. Multivariable linear logistic regression analyses adjusted for presence of infectious diseases and cancer, with the occurrence of composite outcome showed an adjusted OR of 1.349 (95% CI 1.248-1.462) and 1.254 (95% CI 1.179-1.336) for CHA2DS2-VASc and R2CHA2DS2-VASc scores, respectively. No differences were found in the association between CHA2DS2-VASc and R2CHA2DS2-VASc scores with the composite outcome (AUC 0.631 vs 0.630), and furthermore, adding the presence/absence of infectious diseases during hospitalization and positive cancer history to the models increased the AUC (0.667 and 0.663). CONCLUSIONS: Incrementally higher CHA2DS2-VASc score is associated with increased length of hospital stay and mortality in patients hospitalized in an internal medicine ward, regardless of the presence of CKD.

Disease-related malnutrition with inflammation and cachexia.

In 2010, the definition of cachexia was jointly developed by the European Society for Clinical Nutrition and Metabolism (ESPEN) Special Interest Groups (SIG) "Cachexia-anorexia in chronic wasting diseases" and "Nutrition in geriatrics". Cachexia was considered as a synonym of disease-related malnutrition (DRM) with inflammation by the ESPEN guidelines on definitions and terminology of clinical nutrition. Starting from these concepts and taking into account the available evidence the SIG "Cachexia-anorexia in chronic wasting diseases" conducted several meetings throughout 2020-2022 to discuss the similarities and differences between cachexia and DRM, the role of inflammation in DRM, and how it can be assessed. Moreover, in line with the Global Leadership Initiative on Malnutrition (GLIM) framework, in the future the SIG proposes to develop a prediction score to quantify the individual and combined effect(s) of multiple muscle and fat catabolic mechanisms, reduced food intake or assimilation and inflammation, which variably contribute to the cachectic/malnourished phenotype. This DRM/cachexia risk prediction score could consider the factors related to the direct mechanisms of muscle catabolism separately from those related to the reduction of nutrient intake and assimilation. Novel perspectives in the field of DRM with inflammation and cachexia were identified and described in the report.

Small non-coding RNA profiling in patients with gastrointestinal cancer.

BACKGROUND: Small non-coding (snc)RNAs, including microRNAs and P-element induced wimpy testis (PIWI)-interacting-RNAs (piRNAs), crucially regulate gene expression in both physiological and pathological conditions. In particular, some muscle-specific microRNAs (myomiRs) have been involved in the pathogenesis of cancer-induced muscle wasting. The aims of the present study were (i) to profile sncRNAs in both skeletal muscle and plasma of gastrointestinal cancer patients and (ii) to investigate the association among differentially expressed sncRNAs and the level of muscularity at body composition analysis. METHODS: Surgical patients with gastrointestinal cancer or benign disease were recruited. Blood samples and muscle biopsies (rectus abdominis) were collected during surgery. Low muscularity patients were those at the lowest tertile of skeletal muscle index (SMI; CT-scan), whereas moderate/high muscularity patients were in the middle and highest SMI tertiles. SncRNAs in the muscle were assessed by RNAseq, circulating microRNAs were evaluated by qPCR. RESULTS: Cancer patients (n = 25; 13 females, 52%) showed a mean age of 71.6 ± 11.2 years, a median body weight loss of 4.2% and a mean BMI of 27.0 ± 3.2 kg/m2 . Control group (n = 15; 9 females, 60%) showed a mean age 58.1 ± 13.9 years and a mean BMI of 28.0 ± 4.3 kg/m2 . In cancer patients, the median L3-SMI (cm2 /m2 ) was 42.52 (34.42; 49.07). Males showed a median L3-SMI of 46.08 (41.17-51.79) and females a median L3-SMI of 40.77 (33.73-42.87). Moderate-high and low muscularity groups included 17 and 8 patients, respectively. As for circulating microRNAs, miR-21-5p and miR-133a-3p were up-regulated in patients compared with controls, whereas miR-15b-5p resulted down-regulated in the same comparison (about 30% of control values). Sample clustering by muscularity and sex revealed increased miR-133a-3p and miR-206 only in moderate-high muscularity males. SncRNA profiling in the muscle identified 373 microRNAs and 190 piRNAs (72.5% and 18.7% of raw reads, respectively). As for microRNAs, 10 were up-regulated, and 56 were down-regulated in cancer patients versus controls. Among the 24 dysregulated piRNAs, the majority were down-regulated, including the top two most expressed piRNAs in the muscle (piR-12790 and piR-2106). Network analysis on validated mRNA targets of down-regulated microRNAs revealed miR-15b-5p, miR-106a-5p and miR-106b-5p as main interactors of genes related to ubiquitin ligase/transferase activities. CONCLUSIONS: These results show dysregulation of both muscle microRNAs and piRNAs in cancer patients compared with controls, the former following a sex-specific pattern. Changes in circulating microRNAs are associated with the degree of muscularity rather than body weight loss.

Current Screening Methods for the Risk or Presence of Malnutrition in Cancer Patients.

Malnutrition is highly common among cancer patients and is associated with a poor quality of life, increased treatment toxicities and decreased survival. The screening of malnutrition should be performed in an early stage of cancer disease and should be rapid, not expensive and highly sensitive to identify the risk of developing malnutrition. Importantly, international clinical guidelines suggest to perform screening for malnutrition in all cancer patients and if the risk is present, they recommend to perform a full nutritional assessment. During the screening phase, different nutritional parameters are considered including the loss of appetite, low food intake, body weight loss and burden of the disease. These items are present in several screening tools, such as the Nutrition Risk Screening (NRS)-2002, the Malnutrition Universal Screening Tool (MUST) and the Mini Nutritional Assessment (MNA) which represent the most widely used tools to screen for an altered nutritional status in cancer patients. Recently, the Global Leadership Initiative on Malnutrition (GLIM) developed an assessment tool for the diagnosis of malnutrition taking into account the presence of i) involuntary body weight loss, ii) body mass index, iii) low muscle mass, iv) low food intake and disease burden/inflammation; in particular, body weight loss, decreased body mass index (BMI), and low muscle mass are considered as phenotypic criteria, whereas reduced food intake, disease burden and inflammation are defined as etiologic criteria. To perform the diagnosis of malnutrition, GLIM consensus considered the presence of at least one phenotypic and one etiologic criterion. The above-mentioned screening tools were validated in different clinical settings and suggesting the use of one tool vs another is challenging considering, among others, different factors including the type and stage of cancer and the setting (i.e., inpatient or outpatient care). Recent data obtained among large cohorts of cancer patients indicate that personalized nutritional therapy reduced mortality risk and ameliorated quality of life and functionality among cancer patients with high nutritional risk, supporting the urgent need for implementing screening and diagnosis of malnutrition in this context.

Evaluation of Browning Markers in Subcutaneous Adipose Tissue of Newly Diagnosed Gastrointestinal Cancer Patients with and without Cachexia.

We assessed the molecular phenotype of the browning of white adipose tissue in newly diagnosed cancer patients and controls undergoing surgery for gastrointestinal tumors and for non-malignant diseases, respectively. We collected subcutaneous adipose tissue (SAT) samples and using RT-PCR, we analyzed the expression of markers of browning and using Western blot the protein levels of UCP1 and PGC1α. The Ucp1 mRNA levels were lower in cancer patients vs. controls (p = 0.01), whereas Cidea and Tmem26 mRNA levels were higher in cancer patients. We found higher PGC1α protein levels in patients vs. controls, while no differences were seen for UCP1. The Ucp1 expression was lower in cachectic and non-cachectic patients vs. controls, whereas Cidea expression was higher in cachectic and non-cachectic patients vs. controls. Pgc1α mRNA levels were higher in cachectic vs. non-cachectic patients (p = 0.03) vs. controls (p = 0.016). According to type of tumors, we did not observe differences in Cidea expression, whereas Pgc1α was higher in pancreatic cancer vs. colorectal and vs. controls. We observed the lower expression of Ucp1 in pancreatic and colorectal cancer vs. controls. We documented higher UCP1 protein levels in pancreatic cancer patients vs. colorectal (p = 0.002) and vs. controls (p = 0.031). PGC1α protein levels were higher in pancreatic cancer patients vs. controls. Different markers of the browning of SAT are modulated, and pancreatic cancer showed changes in UCP1 and PGC1α; PGC1α was highly expressed in cachectic patients, with clinical implications that should be further clarified.

Histomorphological and inflammatory changes of white adipose tissue in gastrointestinal cancer patients with and without cachexia.

BACKGROUND: During cancer cachexia, several alterations occur in peripheral tissues, and the adipose tissue may be involved during the catabolic state. We aimed at investigating histological rearrangement and infiltration of inflammatory cells in subcutaneous adipose tissue (SAT) of patients with cancer undergoing surgery, according to the presence/absence of cachexia. METHODS: We considered gastrointestinal cancer patients and controls with non-malignant diseases undergoing surgery. We collected SAT samples and performed histomorphological analyses [cross-sectional area (CSA) and per cent of fibrosis] and immunohistochemistry to characterize the inflammatory cells. By computed tomography (CT) scan, we calculated SAT and visceral adipose tissue (VAT). RESULTS: We enrolled 51 participants (31 gastrointestinal cancer patients and 20 controls). In cancer patients, cachexia was present in 13/31 (42%). The CSA (µm2 ) of the adipocytes from SAT was reduced in cancer patients vs. controls (3148, inter-quartile range 2574-3755 vs. 4474, inter-quartile range 3654-5183) (P < 0.001), in particular in cachectic patients vs. non-cachectic (median 2518 vs. median 3470) (P = 0.03) and in cachectic vs. controls (P < 0.001), as well as in non-cachectic vs. controls (P = 0.04). The median per cent of fibrosis was higher in cancer patients vs. controls (9 vs. 3) (P = 0.0001), in particular in cachectic vs. non-cachectic (13.35 vs. 7.13) (P = 0.03). We observed a higher number of macrophages (CD68) (P = 0.0001) and T lymphocytes (CD3) (P = 0.002) in SAT of cancer patients vs. controls, and the number of T lymphocytes was higher in cachectic vs. non-cachectic patients (P = 0.025). Anorexic cancer patients showed in SAT a higher number of macrophages and T lymphocytes with respect to controls (P < 0.0001), whereas no difference was present between anorexic and non-anorexic patients. At CT scan, cachectic patients showed lower VAT and SAT vs. non-cachectic (VAT: 97.64 ± 40.79 vs. 212.53 ± 79.24, P = 0.0002; SAT: 126.27 ± 87.92 vs. 206.27 ± 61.93, P = 0.01, respectively). Cancer patients with low CSA, high degree of fibrosis, and high number of T lymphocytes presented with lower body mass index and lower SAT and VAT at CT scan (P ≤ 0.01). CONCLUSIONS: We found histological alterations of SAT among gastrointestinal cancer patients and in particular significant changes in CSA, fibrosis, and inflammation when cachexia was present; the changes in histomorphological parameters of the adipocytes reflected alterations in adiposity at body composition analysis.

Early impairment of food intake in patients newly diagnosed with cancer.

Background: Patients with gastrointestinal or lung cancer often suffer from a loss of appetite (anorexia), resulting in reduced food intake (hypophagia) and body weight loss. This study evaluated the prevalence of anorexia, hypophagia, pre-cachexia and cachexia in patients with cancer at time of diagnosis. Patients and methods: Patients with newly diagnosed gastrointestinal or lung cancers were included. Body mass index (BMI) and weight loss over the prior 6 months were recorded. Patients were assessed for (pre-)cachexia and for anorexia using the Functional Assessment of Anorexia/Cachexia Therapy (FAACT) and a specific anorexia questionnaire (AQ). Energy and protein intake were calculated through food diaries. Patients were considered hypophagic if intake was ≤70% of guideline-recommended levels. Results: Overall, 102 patients [53 male; median age: 67 (range, 21-88) years] were enrolled. Mean BMI (± standard deviation) was 23.1 ± 3.4 kg/m2; average percentage of weight loss was 10.1 ± 7.8%. At diagnosis, 68% (69/102) of patients had cachexia, and 11% (11/102) pre-cachexia. Prevalence of anorexia was 57% (58/102) and 75% (76/102) according to FAACT and AQ, respectively. Forty-eight percent (49/102) of patients had hypophagia. Patients with anorexia had lower daily energy (p = 0.002) and protein intake (p = 0.0257), and greater percentage of weight loss (p = 0.0005). In patients with hypophagia, negative correlations were observed between percentage of weight loss and total daily calorie (r = -0.40; p = 0.01) and protein intake (r = -0.340; p = 0.018). Conclusion: Anorexia, inadequate nutritional intake and cachexia are highly prevalent in patients with gastrointestinal or lung cancer at diagnosis. Negative protein and energy balance may play an important role in the pathogenesis of cachexia. Early multimodal strategies to improve food intake are urgently needed.

Cancer-associated anorexia: Validity and performance overtime of different appetite tools among patients at their first cancer diagnosis.

BACKGROUND & AIMS: Anorexia is a frequent symptom in cancer and we aimed to assess its prevalence among patients at their first cancer diagnosis by different appetite tools and the relationship between each tool with self-reports of food intake. We also tested whether cancer anorexia influences outcomes independently of reduced food intake or body weight loss (BWL) overtime and whether BWL was associated with complications during anticancer-therapy. METHODS: Functional Assessment of Anorexia/Cachexia Therapy (FAACT) score, self-assessment of appetite, Anorexia Questionnaire (AQ) and Visual Analog Scale (VAS) were administered. Percent of food intake was used as a criterion measure of anorexia. We registered BWL and anticancer-therapy complications over 3-month-follow-up. RESULTS: 438 cancer patients from 7 cancer-centers worldwide were included. The prevalence of anorexia was 39.9% by FAACT score, 40.2% by VAS, 40.6% by the self-assessment of appetite and 65.4% by AQ. Low food intake (≤50%) was reported in 28% of patients. All appetite tools correlated with food intake percent (P < 0.0001). We documented a correlation between self-assessment of appetite, FAACT score, VAS and BWL overtime (P < 0.04). The self-assessment of appetite (P = 0.0152) and the FAACT score (P = 0.043) were associated with BWL independently of anticancer therapies. Among patients with BWL, the risk to develop complications was greater with respect to those who maintained a stable or gained body weight (P = 0.03). CONCLUSIONS: In our sample of cancer patients, FAACT score and self-assessment of appetite performed well when low food intake was used as a criterion measure, and revealed an association of anorexia with BWL, which was, in turn, related to the development of anticancer-therapy complications.

Effects of Inositol Hexaphosphate and Myo-Inositol Administration in Breast Cancer Patients during Adjuvant Chemotherapy.

BACKGROUND: Treatment of breast cancer (BC) includes locoregional and systemic therapies depending on tumor and patient's characteristics. Inositol hexaphosphate (IP6) is known as a strong antioxidant agent, able to improve local (i.e., breast region) side effects, functional status and quality-of-life. We investigated some potential beneficial effects, including hematological and local, of the combined therapy with oral myo-inositol administration and topical IP6 application in patients undergoing surgery for BC and eligible to adjuvant chemotherapy. METHODS: We considered BC patients randomly assigned to the Inositol Group (oral myo-inositol + IP6 local application for the entire neoadjuvant treatment period) and to the Control Group (standard of care). The EORTC QLQ-BR23 and QLQ-C30 questionnaires were administered to both groups and blood parameters were assessed as per clinical routine practice at baseline (before starting adjuvant chemotherapy), T1 (after the first two doses of epirubicin-cyclophosphamide regimen), T2 (at the end of epirubicin-cyclophosphamide regimen), T3 (after the first six doses of paclitaxel regimen), and T4 (at the end of the paclitaxel treatment). RESULTS: A total of 36 BC patients were considered, 18 in the Inositol Group and 18 in the Control Group. The Inositol Group showed a lower decrease in red blood cells, hemoglobin levels and white blood cells with respect to controls (p ≤ 0.02), as well as amelioration in scores related to breast and arm local symptoms (p ≤ 0.02), body image (p = 0.04) and quality-of-life related symptoms (p ≤ 0.04). CONCLUSIONS: In our cohort of BC patients, a combined treatment with oral myo-inositol + IP6 local application was able to improve local symptoms and quality-of-life related symptoms which represent clinically relevant aspects associated with patient's prognosis.

Plasma enterobacterial ClpB levels and ClpB- and α-MSH-reactive immunoglobulins in lung cancer patients with and without anorexia.

OBJECTIVES: Anorexia represents a common and debilitating clinical problem in patients with several forms of cancer, in particular lung cancer, but its mechanisms are not completely understood. Recently, the caseinolytic-protease-B (ClpB) homologue protein, produced by common gut bacteria, such as Escherichia coli, was identified as an antigen-mimetic of α-melanocyte-stimulating hormone (α-MSH), an anorexigenic neuropeptide. ClpB was previously detected in human plasma and displayed satietogenic properties; however, its possible relevance to cancer anorexia has not yet been investigated. METHODS: To address this question, we analyzed plasma ClpB concentrations as well as levels and affinities of anti-ClpB and α-MSH-reactive antibodies in patients with lung cancer with and without anorexia as compared with body mass index-matched healthy controls with normal appetite. RESULTS: We found that plasma ClpB concentrations were significantly lower in non-anorexic patients with cancer than those of the control group (P = 0.028). In contrast, patients with cancer and anorexia had lower levels of anti-ClpB immunoglobulins (Ig)M (P < 0.0001) and of both α-MSH IgM and IgG (P < 0.05) with respect to controls. Moreover, in patients with cancer and anorexia, anti-ClpB IgG showed a trend of lower affinities compared with non-anorexic patients (P = 0.05). CONCLUSIONS: Taken together, the results revealed a reduced humoral immune response to ClpB in patients with cancer and anorexia, which may lead to an enhanced satietogenic effect of this enterobacterial protein contributing to the mechanisms of reduced appetite.

Locoregional Surgery in Metastatic Breast Cancer: Do Concomitant Metabolic Aspects Have a Role on the Management and Prognosis in this Setting?

Although they cannot be considered curative, the new therapeutic integrated advances in metastatic breast cancer (MBC) have substantially improved patient outcomes. Traditionally, surgery was confined to palliation of symptomatic or ulcerating lumps. Data suggest, in some cases, a possible additive role for more aggressive locoregional surgical therapy in combination with systemic treatments in the metastatic setting, although a low level of evidence has been shown in terms of improvement in overall survival in MBC patients treated with surgery and medical treatment compared to medical treatment alone. In this light, tumor heterogeneity remains a challenge. To effectively reshape the therapeutic approach to MBC, careful consideration of who is a good candidate for locoregional resection is paramount. The patient's global health condition, impacting on cancer progression and morbidity and their associated molecular targets, have to be considered in treatment decision-making. In particular, more recently, research has been focused on the role of metabolic derangements, including the presence of metabolic syndrome, which represent well-known conditions related to breast cancer recurrence and distant metastasis and are, therefore, involved in the prognosis. In the present article, we focus on locoregional surgical strategies in MBC and whether concomitant metabolic derangements may have a role in prognosis.