CT-based screening of sarcopenia and its role in cachexia syndrome in pancreatic cancer.

Since computed tomography (CT) is a part of standard diagnostic protocol in pancreatic ductal adenocarcinoma (PDAC), we have evaluated the value of CT for sarcopenia screening in patients with PDAC, intending to expand the diagnostic value of tomographic studies. In our study, we included 177 patients with available CT images. Two groups were formed: Group 1 consisted of 117 patients with PDAC in various locations and stages and Group 2, or the control group, consisted of 60 "nominally healthy" patients with other somatic non-oncological diseases. The body mass index (BMI) was defined as a ratio of patient's weight to the square of their height (kg/m2). CT-based body composition analysis was performed using commercially available software with evaluation of sarcopenia using skeletal muscle index (SMI, cm2/m2). Based on the SMI values, sarcopenia was found in 67.5% of patients (79 out of 117) in the first patient group. It was found more frequently in males (42 out of 56; 75%) than in females (37 out of 61; 60.6%). Additionally, we observed a decrease in muscle mass (hidden sarcopenia) in 79.7% in patients with a normal BMI. Even in overweight patients, sarcopenia was found in 50% (sarcopenic obesity). In patients with reduced BMI sarcopenia was found in all cases (100%). Statistically significant difference of SMI between two groups was revealed for both sexes (p = 0,0001), with no significant difference between groups in BMI. BMI is an inaccurate value for the assessment of body composition as it does not reflect in the details the human body structure. As SMI may correlate with the prognosis, decreased muscle mass- especially "hidden" sarcopenia or sarcopenic obesity- should be reported. The use of CT-based evaluation of sarcopenia and sarcopenic obesity will allow for a better treatment response assessment in patients with cancer cachexia.

Osteopenia is associated with wasting in pancreatic adenocarcinoma and predicts survival after surgery.

Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest of all common malignancies. Treatment is difficult and often complicated by the presence of cachexia. The clinical portrait of cachexia contributes to the poor prognosis experienced by PDAC patients and worsens therapeutic outcomes. We propose that low bone mineral density is a component of cachexia, which we explore herein through a retrospective review of all patients at our facility that underwent surgery for PDAC between 2011 and 2018 and compared to sex-, age- and comorbidity-matched control individuals. Data were abstracted from the medical record and pre-operative computed tomography scans. Muscle mass and quality were measured at the L3 level and bone mineral density was measured as the radiation attenuation of the lumbar vertebral bodies. Patients with PDAC displayed typical signs of cachexia such as weight loss and radiologically appreciable deterioration of skeletal muscle. Critically, PDAC patients had significantly lower bone mineral density than controls, with 61.2% of PDAC patients categorized as osteopenic compared to 36.8% of controls. PDAC patients classified as osteopenic had significantly reduced survival (1.01 years) compared to patients without osteopenia (2.77 years). The presence of osteopenia was the strongest clinical predictor of 1- and 2-year disease-specific mortality, increasing the risk of death by 107% and 80%, respectively. Osteopenia serves as a test of 2-year mortality with sensitivity of 76% and specificity of 58%. These data therefore identify impaired bone mineral density as a key component of cachexia and predictor of postoperative survival in patients with PDAC. The mechanisms that lead to bone wasting in tumor-bearing hosts deserve further study.

Subcutaneous, but not visceral, adipose tissue as a marker for prognosis in gastric cancer patients with cachexia.

BACKGROUND & AIMS: Adipose tissue loss is one of the features in patients with cancer cachexia. However, whether subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT) contribute differently to the progress of cancer cachexia in gastric cancer patients with cachexia remains unclear. This study aim to investigate the effect of SAT and VAT in gastric cancer patients with cachexia. METHODS: Gastric cancer patients who underwent surgery were divided into cancer cachexia group and non-cachexia group. A new deep learning system was developed to segment SAT and VAT from the computed tomography images at the third lumbar vertebra. Indexes of SAT (SATI) and VAT (VATI) were compared between cachexia and non-cachexia groups. The prognostic values of SATI and VATI for patients with gastric cancer cachexia were analyzed by Kaplan-Meier method and Cox regression. RESULTS: A total of 1627 gastric cancer patients (411 cachexia and 1216 non-cachexia) were included in this study. A new V-Net-Based segmentation deep learning system was developed to quickly (0.02 s/image) and accurately segment SAT (dice scores = 0.96) and VAT (dice scores = 0.98). The SATI of gastric cancer patients with cachexia were significantly lower than non-cachexia patients (44.91 ± 0.90 vs. 50.92 ± 0.71 cm2/m2, P < 0.001), whereas no significant difference was detected in VATI (35.98 ± 0.84 VS. 37.90 ± 0.45 cm2/m2, P = 0.076). Cachexia patients with low SATI showed poor survival than those with high SATI (HR = 1.35; 95% CI = 1.06-1.74). In contrast, VATI did not show close correlation with survival in patients with cachexia (HR = 1.18; 95% CI = 0.92-1.51). CONCLUSION: SAT and VAT showed different effects on gastric cancer patients with cachexia. More attention should be paid to the loss of SAT during the progress of cancer cachexia.

Host autophagy mediates organ wasting and nutrient mobilization for tumor growth.

During tumor growth-when nutrient and anabolic demands are high-autophagy supports tumor metabolism and growth through lysosomal organelle turnover and nutrient recycling. Ras-driven tumors additionally invoke non-autonomous autophagy in the microenvironment to support tumor growth, in part through transfer of amino acids. Here we uncover a third critical role of autophagy in mediating systemic organ wasting and nutrient mobilization for tumor growth using a well-characterized malignant tumor model in Drosophila melanogaster. Micro-computed X-ray tomography and metabolic profiling reveal that RasV12 ; scrib-/- tumors grow 10-fold in volume, while systemic organ wasting unfolds with progressive muscle atrophy, loss of body mass, -motility, -feeding, and eventually death. Tissue wasting is found to be mediated by autophagy and results in host mobilization of amino acids and sugars into circulation. Natural abundance Carbon 13 tracing demonstrates that tumor biomass is increasingly derived from host tissues as a nutrient source as wasting progresses. We conclude that host autophagy mediates organ wasting and nutrient mobilization that is utilized for tumor growth.

Radiomics predicts risk of cachexia in advanced NSCLC patients treated with immune checkpoint inhibitors.

BACKGROUND: Approximately 50% of cancer patients eventually develop a syndrome of prolonged weight loss (cachexia), which may contribute to primary resistance to immune checkpoint inhibitors (ICI). This study utilised radiomics analysis of 18F-FDG-PET/CT images to predict risk of cachexia that can be subsequently associated with clinical outcomes among advanced non-small cell lung cancer (NSCLC) patients treated with ICI. METHODS: Baseline (pre-therapy) PET/CT images and clinical data were retrospectively curated from 210 ICI-treated NSCLC patients from two institutions. A radiomics signature was developed to predict the cachexia with PET/CT images, which was further used to predict durable clinical benefit (DCB), progression-free survival (PFS) and overall survival (OS) following ICI. RESULTS: The radiomics signature predicted risk of cachexia with areas under receiver operating characteristics curves (AUCs) ≥ 0.74 in the training, test, and external test cohorts. Further, the radiomics signature could identify patients with DCB from ICI with AUCs≥0.66 in these three cohorts. PFS and OS were significantly shorter among patients with higher radiomics-based cachexia probability in all three cohorts, especially among those potentially immunotherapy sensitive patients with PD-L1-positive status (p < 0.05). CONCLUSIONS: PET/CT radiomics analysis has the potential to predict the probability of developing cachexia before the start of ICI, triggering aggressive monitoring to improve potential to achieve more clinical benefit.

Association of Ultrasound-Derived Metrics of the Quadriceps Muscle with Protein Energy Wasting in Hemodialysis Patients: A Multicenter Cross-Sectional Study.

This study aimed to assess muscle wasting and risk of protein energy wasting (PEW) in hemodialysis (HD) patients using an ultrasound (US) imaging method. PEW was identified using the ISRNM criteria in 351 HD patients. Quadriceps muscle thickness of rectus femoris (RF) and vastus intermedius (VI) muscles and cross-sectional area (CSA) of the RF muscle (RFCSA) were measured using US and compared with other physical measures. Associations of US indices with PEW were determined by logistic regression. Irrespective of gender, PEW vs. non-PEW patients had smaller RF, VI muscles, and RFCSA (all p < 0.001). US muscle sites (all p < 0.001) discriminated PEW from non-PEW patients, but the RFCSA compared to bio-impedance spectroscopy had a greater area under the curve (AUC, 0.686 vs. 0.581), sensitivity (72.8% vs. 65.8%), and specificity (55.6% vs. 53.9%). AUC of the RFCSA was greatest for PEW risk in men (0.74, 95% CI: 0.66-0.82) and women (0.80, 95% CI: 0.70-0.90) (both p < 0.001). Gender-specific RFCSA values (men < 6.00 cm2; women < 4.47 cm2) indicated HD patients with smaller RFCSA were 8 times more likely to have PEW (AOR = 8.63, 95% CI: 4.80-15.50, p < 0.001). The US approach enabled discrimination of muscle wasting in HD patients with PEW. The RFCSA was identified as the best US site with gender-specific RFCSA values to associate with PEW risk, suggesting potential diagnostic criteria for muscle wasting.

Meeting Minimum ESPEN Energy Recommendations Is Not Enough to Maintain Muscle Mass in Head and Neck Cancer Patients.

The relationship between dietary intake and body composition changes during cancer treatment has not been well characterized. The aim of this study was to compare dietary intake at diagnosis and end of treatment in relation to changes in muscle mass and adiposity in head and neck cancer (HNC) patients. Dietary intakes (three-day food record) and body composition using computed tomography (CT) were assessed at diagnosis (baseline) and after treatment completion (post-treatment). Skeletal muscle (SM) loss was explored as a consequence of energy and protein intake in relation to the minimum and maximum European Society of Parenteral and Enteral Nutrition (ESPEN) guidelines. Higher energy intakes (kcal/kg/day) and increases in energy intake (%) from baseline to post-treatment were correlated with attenuated muscle loss (r = 0.62, p < 0.01; r = 0.47, p = 0.04, respectively). Post-treatment protein intake demonstrated a weak positive correlation (r = 0.44, p = 0.05) with muscle loss, which did not persist when controlling for covariates. Meeting minimum ESPEN energy guidelines (25 kcal/kg/day) did not attenuate SM loss, whereas intakes >30 kcal/kg/day resulted in fewer participants losing muscle. Greater baseline adiposity correlated with greater SM loss (p < 0.001). Energy intakes of 30 kcal/kg/day may be required to protect against SM loss during treatment in HNC patients. The influence of adiposity on SM loss requires further exploration.

Diffusely Decreased Liver Uptake on FDG PET and Cancer-Associated Cachexia With Reduced Survival.

OBJECTIVES: We investigated clinical characteristics of patients with extremely increased or decreased physiologic F-FDG uptake of the liver and their prognosis. METHODS: One thousand four hundred eighty-seven PET/CT scans of patients with known or suspected malignancy were retrospectively analyzed. A spherical volume of interest (3 cm in diameter) was set on the right lobe of the liver to calculate the SUVmean. Scans with extremely high (SUVmean >97.5th percentile) and low (SUVmean <2.5th percentile) FDG uptake in the liver were evaluated. Physical and laboratory data among a control group (n = 30), the extremely high liver uptake group (HG, n = 36), and the extremely low liver uptake group (LG, n = 36) were compared. Overall survival (OS) of the 3 groups was also compared. RESULTS: Body weight and body mass index in the HG (SUVmean ≥3.04) were significantly higher than those in the control group. The LG cases (SUVmean ≤1.78) had anemia, impaired liver function, and systemic inflammation. They were also in a poor nutritional state. The characteristics of LG cases had many things in common with those of cachectic patients. Indeed, 36.1% of LG cases met the diagnostic criteria for cachexia. Moreover, in LG cases with viable and/or recurrent malignant lesions on FDG PET, the proportion of cachexia increased by 52.6%. The OS of LG cases (median, 33 months) was significantly worse than that of controls and HG cases. CONCLUSIONS: Our data indicate that cancer patients with extremely decreased liver FDG uptake were likely to have cancer cachexia and a lower OS.

CD8+ T cells induce cachexia during chronic viral infection.

Cachexia represents a leading cause of morbidity and mortality in various cancers, chronic inflammation and infections. Understanding of the mechanisms that drive cachexia has remained limited, especially for infection-associated cachexia (IAC). In the present paper we describe a model of reversible cachexia in mice with chronic viral infection and identify an essential role for CD8+ T cells in IAC. Cytokines linked to cancer-associated cachexia did not contribute to IAC. Instead, virus-specific CD8+ T cells caused morphologic and molecular changes in the adipose tissue, which led to depletion of lipid stores. These changes occurred at a time point that preceded the peak of the CD8+ T cell response and required T cell-intrinsic type I interferon signaling and antigen-specific priming. Our results link systemic antiviral immune responses to adipose-tissue remodeling and reveal an underappreciated role of CD8+ T cells in IAC.

Cancer cachexia is defined by an ongoing loss of skeletal muscle mass.

Since 2007, a quantitative, specific and precise approach to the detection of muscle loss has become accessible with the advent of image-based assessments. Computed tomography images acquired as part of standard cancer care are the serendipitous substrate for these analyses. Three radiologically-determined abnormalities, sarcopenia (severe muscle depletion), catabolic loss of muscle over time, and reduced muscle radiation attenuation associate with progressive functional impairment, treatment-related complications, reduced quality of life, and mortality. Fundamental understanding of muscle wasting in cancer cachexia has been developed on a base of clinical and experimental studies, which have identified alterations in muscle protein synthesis, autophagy and ubiquitin-mediated proteolysis as key contributors to muscle loss. The etiology of cancer-associated muscle wasting is multifactorial. Tumor metabolism captures energy fuels and amino acids, and a suite of tumor-derived molecules elicits catabolic pathways at the tissue level in muscle. Endocrine, neural and inflammatory derangements add further catabolic drive. Antineoplastic agents make a substantial contribution to muscle wasting by directly action on muscle cells, as well as secondarily via their systemic side effects. Encouraging data is emerging as to the potential reversibility of muscle loss and/or reduced muscle radiation attenuation through modulation of specific mechanisms. In the first line, pain and symptom management is a key element of the prevention of catabolic loss of muscle. Intake of intake of high-quality proteins and ω-3 polyunsaturated fatty acids support retention or gain of muscle mass. While there is no approved drug therapy for the indication of cancer-associated muscle wasting, there is preliminary evidence for robust gain of skeletal muscle mass in research studies of new therapeutics including inhibitors of mitogen-activated protein kinase kinases and ghrelin receptor agonists.

What's next in using CT scans to better understand cachexia?

PURPOSE OF REVIEW: Cachexia (CAX), a protein metabolism disorder commonly associated with cancer, can be evaluated by computed tomography (CT) scan assessment of skeletal muscle mass (SMM), a parameter associated with patient outcome. This review analyzes current barriers for using CT scans of SMM in routine management for defining prognostic risk groups, and proposes new areas of research to reach a better understanding of CAX mechanisms. RECENT FINDINGS: Current research is focused on establishing a robust and relevant CAX staging system to reach a consensual definition. Previous biomarkers of CAX are poorly associated with outcome and do not exhibit clinical benefit. Systemic inflammatory marker, decrease in intake assessments, and/or nonnutritional criteria have been integrated to develop a multidimensional, highly complex CAX signature and CAX staging. SUMMARY: A standardized definition of sarcopenia is essential, and its value in clinical practice should be evaluated in prospective interventional studies using skeletal muscle assessment. SMM loss may be a key element in defining early protein disorders occurring before weight loss and could be used as a trigger for initiating early nutritional support. Changes in SMM and body composition during follow-up are useful tools for exploring CAX mechanisms in terms of intrinsic factors or tumor evolution.

Mouse models of cancer-induced cachexia: Hind limb muscle mass and evoked force as readouts.

The majority of patients with advanced cancer suffer from cachexia, a systemic wasting syndrome, which subsequently impacts the tolerance to anti-cancer treatments, response to therapy, quality of life, and eventually, survival. Despite a high unmet medical need, there is currently no specific remedy available for an effective treatment of cachexia and its sequelae. A key feature of cachexia is the inexorable loss of skeletal muscle mass, which constitutes a main contributor to body weight loss and progressive functional impairments. Therefore, it's crucial to identify early readouts to detect and monitor the loss of muscle mass and function to initiate appropriate treatments timely. Here, we describe experimental cancer models using mouse (syngeneic) or human (xenograft) cancer cell lines with a rapid onset of tumor growth and cachexia. These models are easier to establish, monitor and reproduce compared to the genetically engineered mouse models currently available. Moreover, we establish readouts such as hind limb muscle mass and volume, as well as evoked force and food intake measurements, to allow the evaluation of potential therapeutic agents for the early treatment of cachexia and associated impairments.

Magnetic Resonance Imaging of Adipose Tissue in Metabolic Dysfunction.

BACKGROUND: Adipose tissue has become an increasingly important tissue target in medicine. It plays a central role in the storage and release of energy throughout the human body and has recently gained interest for its endocrinologic function. Magnetic resonance imaging (MRI) is an established method for quantitative direct evaluation of adipose tissue distribution, and is used increasingly as the modality of choice for metabolic phenotyping. The purpose of this review was the identification and presentation of the currently available literature on MRI of adipose tissue in metabolic dysfunction. METHOD: A PubMed (http://www.ncbi.nlm.nih.gov/pubmed) keyword search up to August 2017 without starting date limitation was performed and reference lists of relevant articles were searched. RESULTS AND CONCLUSION: MRI provides excellent tools for the evaluation of adipose tissue distribution and further characterization of the tissue. Standard as well as newly developed MRI techniques allow a risk stratification for the development of metabolic dysfunction and enable monitoring without the use of ionizing radiation or contrast material. KEY POINTS: · Different types of adipose tissue play a crucial role in various types of metabolic dysfunction.. · Magnetic resonance imaging (MRI) is an excellent tool for noninvasive adipose tissue evaluation with respect to distribution, composition and metabolic activity.. · Both standard and newly developed MRI techniques can be used for risk stratification for the development of metabolic dysfunction and allow monitoring without the use of ionizing radiation or contrast material.. CITATION FORMAT: · Franz D, Syväri J, Weidlich D et al. Magnetic Resonance Imaging of Adipose Tissue in Metabolic Dysfunction. Fortschr Röntgenstr 2018; 190: 1121 - 1130.

Micro-computed tomography for non-invasive evaluation of muscle atrophy in mouse models of disease.

Muscle wasting occurs during various chronic diseases and precedes death in humans as in mice. The evaluation of the degree of muscle atrophy in diseased mouse models is often overlooked since it requires the sacrifice of the animals for muscle examination or expensive instrumentation and highly qualified personnel, such as Magnetic Resonance Imaging (MRI). Very often behavioral tests for muscle strength evaluation are used as an outcome measurement in preclinical therapeutic trials. However, these tests are easy to perform serially, but not enough sensitive to detect early muscle changes during disease progression. Monitoring muscle loss in living animals could allow to perform more informative preclinical trials with a better evaluation of therapeutic benefit with respect to muscle wasting. We developed a non-invasive procedure based on micro-computed tomography (micro-CT) without contrast agents to monitor hind limb muscle wasting in mouse models of amyotrophic lateral sclerosis (ALS) and cancer cachexia: the transgenic SOD1G93A mouse and the colon adenocarcinoma C26-bearing mouse, respectively. We established the scanning procedure and the parameters to consider in the reconstructed images to calculate the Index of Muscle Mass (IMM). The coefficient of variance for the whole procedure was 2.2%. We performed longitudinally micro-CT scan of hind limbs in SOD1G93A mice at presymptomatic and symptomatic stages of the disease and calculated the IMM. We found that IMM in SOD1G93A mice was lower than age-matched controls even before symptom onset. We also detected a further decrease in IMM as disease progresses, most markedly just before disease onset. We performed the same analyses in the C26-based mouse model losing quickly body and muscle mass because of cancer cachexia. Overall, we found that the reduced muscle content detected by micro-CT mirrored the reduced muscle weight in both disease models. We developed a fast, precise and easy-to-conduct imaging procedure to monitor hind limb muscle mass, useful in therapeutic preclinical trials but also in proof-of-principle studies to identify the onset of muscle wasting. This method could be widely applied to other disease models characterized by muscle wasting, to assist drug development and search for early biomarkers of muscle atrophy. Moreover, reducing the number of mice needed for the experiments and being less distressing are in line with the 3R principle embodied in national and international directives for animal research.

Prognostic significance of cachexia score assessed by CT in male patients with small cell lung cancer.

To determine the prognostic significance of CT-determined cachexia scores (CSs) in 127 consecutive male small cell lung cancer (SCLC) patients, cross-sectional areas of muscle and fat tissues at the third lumbar vertebra (L3) were retrospectively measured on baseline CT images. CSs were determined based on the presence of sarcopenia and/or adipopenia. According to the presence of sarcopenia (L3 muscle index <55 cm2 /m2 , 86.8%) and adipopenia (L3 fat index <22 cm2 /m2 , 11.8%), CSs were defined as follows: CS2 (sarcopenia and adipopenia, 11.8%), CS1 (sarcopenia only, 74.8%) and CS0 (13.4%). CS2 was significantly related to lower body mass index (p < .001) and poor performance status (p = .002), and patients with CS2 had shorter OS than patients with CS1 or CS0 (median OS, 5.0 months vs. 8.9 months vs. 18.3 months; p = .007). Multivariable analysis revealed that CS was an independent prognostic factor of poor survival (HR, 1.99 for CS1 and 2.59 for CS2, p = .036 and .023, CS0 as a reference), along with extensive stage (p < .001), supportive care only (p < .001) and an elevated lactate dehydrogenase (p = .005). CT-determined CSs, based on the presence of sarcopenia and/or adipopenia, could be used to predict prognosis in male SCLC.

Computed tomography diagnosed cachexia and sarcopenia in 725 oncology patients: is nutritional screening capturing hidden malnutrition?

BACKGROUND: Nutrition screening on admission to hospital is mandated in many countries, but to date, there is no consensus on which tool is optimal in the oncology setting. Wasting conditions such as cancer cachexia (CC) and sarcopenia are common in cancer patients and negatively impact on outcomes; however, they are often masked by excessive adiposity. This study aimed to inform the application of screening in cancer populations by investigating whether commonly used nutritional screening tools are adequately capturing nutritionally vulnerable patients, including those with abnormal body composition phenotypes (CC, sarcopenia, and myosteatosis). METHODS: A prospective study of ambulatory oncology outpatients presenting for chemotherapy was performed. A detailed survey incorporating clinical, nutritional, biochemical, and quality of life data was administered. Participants were screened for malnutrition using the Malnutrition Universal Screening Tool (MUST), Malnutrition Screening Tool (MST), and the Nutritional Risk Index (NRI). Computed tomography (CT) assessment of body composition was performed to diagnose CC, sarcopenia, and myosteatosis according to consensus criteria. RESULTS: A total of 725 patients (60% male, median age 64 years) with solid tumours participated (45% metastatic disease). The majority were overweight/obese (57%). However, 67% were losing weight, and CT analysis revealed CC in 42%, sarcopenia in 41%, and myosteatosis in 46%. Among patients with CT-identified CC, the MUST, MST, and NRI tools categorized 27%, 35%, and 7% of them as 'low nutritional risk', respectively. The percentage of patients with CT-identified sarcopenia and myosteatosis that were categorised as 'low nutritional risk' by MUST, MST and NRI were 55%, 61%, and 14% and 52%, 50%, and 11%, respectively. Among these tools, the NRI was most sensitive, with scores <97.5 detecting 85.8%, 88.6%, and 92.9% of sarcopenia, myosteatosis, and CC cases, respectively. Using multivariate Cox proportional hazards models, NRI score < 97.5 predicted greater mortality risk (hazard ratio 1.8, confidence interval: 1.2-2.8, P = 0.007). CONCLUSIONS: High numbers of nutritionally vulnerable patients, with demonstrated abnormal body composition phenotypes on CT analysis, were misclassified by MUST and MST. Caution should be exercised when categorizing the nutritional risk of oncology patients using these tools. NRI detected the majority of abnormal body composition phenotypes and independently predicted survival. Of the tools examined, the NRI yielded the most valuable information from screening and demonstrated usefulness as an initial nutritional risk grading system in ambulatory oncology patients.

[A rare case of diencephalic cachexia in an adult female with cranio-pharyngioma]. / Redkii sluchai razvitiia diéntsefal'noi kakheksii u vzrosloi zhenshchiny s kraniofaringiomoi.

Diencephalic cachexia (DС) is progressive weight loss despite a normal caloric intake and a satisfactory state of health, which is caused by hypothalamic lesions. This is a rare (about 100 cases were reported) and potentially fatal disorder of unknown pathogenesis. At present, there is no effective pharmacological therapy for the disorder. Cachexia may regress only if the tumor reduces in size, therefore the timely diagnosis and treatment are of vital importance for the patient. DС is typical of early childhood, and only a few cases have been reported in adults. We present a rare case of DС in a 24-year-old female with papillary craniopharyngioma.

Establishment and characterization of a novel murine model of pancreatic cancer cachexia.

BACKGROUND: Cachexia is a complex metabolic and behavioural syndrome lacking effective therapies. Pancreatic ductal adenocarcinoma (PDAC) is one of the most important conditions associated with cachexia, with >80% of PDAC patients suffering from the condition. To establish the cardinal features of a murine model of PDAC-associated cachexia, we characterized the effects of implanting a pancreatic tumour cell line from a syngeneic C57BL/6 KRASG12D P53R172H Pdx-Cre+/+ (KPC) mouse. METHODS: Male and female C57BL/6 mice were inoculated subcutaneously, intraperitoneally, or orthotopically with KPC tumour cells. We performed rigorous phenotypic, metabolic, and behavioural analysis of animals over the course of tumour development. RESULTS: All routes of administration produced rapidly growing tumours histologically consistent with moderate to poorly differentiated PDAC. The phenotype of this model was dependent on route of administration, with orthotopic and intraperitoneal implantation inducing more severe cachexia than subcutaneous implantation. KPC tumour growth decreased food intake, decreased adiposity and lean body mass, and decreased locomotor activity. Muscle catabolism was observed in both skeletal and cardiac muscles, but the dominant catabolic pathway differed between these tissues. The wasting syndrome in this model was accompanied by hypothalamic inflammation, progressively decreasing brown and white adipose tissue uncoupling protein 1 (Ucp1) expression, and increased peripheral inflammation. Haematological and endocrine abnormalities included neutrophil-dominant leukocytosis and anaemia, and decreased serum testosterone. CONCLUSIONS: Syngeneic KPC allografts are a robust model for studying cachexia, which recapitulate key features of the PDAC disease process and induce a wide array of cachexia manifestations. This model is therefore ideally suited for future studies exploring the physiological systems involved in cachexia and for preclinical studies of novel therapies.