Cancer cachexia is a debilitating syndrome defined by involuntary weight loss due to loss of muscle mass, with or without loss of fat mass. Cachexia is particularly prevalent in pancreatic cancer, affecting up to 70% of patients at diagnosis, and is associated with reduced physical function, impaired treatment tolerance, and worsened survival. Skeletal muscle, including muscles involved in respiration and locomotion, exhibits extensive pathological remodeling in cachexia, including myofiber atrophy and transcriptional reprogramming. Whether muscles that are critical to chewing and swallowing respond similarly remains unknown. To address this gap, we collected masseter (chewing) and digastric (swallowing) muscles from cachectic mice bearing orthotopic KPC pancreatic tumors (n = 8) and cancer-free Sham controls (n = 8). Hematoxylin and eosin staining revealed increased mononuclear cell content, centralized nuclei, and expanded interstitial spaces in both muscles of KPC mice. Myofiber cross-sectional area was reduced by 42% in the masseter and 23% in the digastric. RNA sequencing revealed distinct transcriptional responses between these muscles. The masseter muscle showed enrichment of catabolic signaling pathways, including proteolytic and stress-response programs, alongside downregulation of extracellular matrix and growth-related programs. In contrast, the digastric muscle exhibited robust upregulation of immune and inflammatory pathways, including innate and adaptive immune signaling, with minimal overlap between muscles. Collectively, these findings demonstrate that pancreatic cancer drives pathological remodeling and atrophy in muscles central to chewing and swallowing while eliciting distinct, muscle-specific transcriptional responses, changes that could negatively affect food and nutrient intake and thereby contribute to cachexia progression.NEW & NOTEWORTHY To the best of our knowledge, this is the first study to examine how pancreatic cancer affects muscles involved in chewing and swallowing. Pancreatic cancer causes myofiber atrophy and pathological remodeling in the masseter and digastric muscles while driving distinct transcriptional programs, including catabolic signaling in the masseter and immune-inflammatory remodeling in the digastric. These findings identify feeding muscles as an underexplored component of cancer cachexia with potential relevance to nutritional decline in pancreatic cancer.

Lead toxicity in adults is uncommon and can present with progressive neurological manifestations that mimic neurodegenerative diseases. We describe the case of a 61-year-old man with a several-year history of worsening gait instability, cognitive decline, dysarthria, and involuntary movements in the setting of persistently elevated blood lead levels. The patient's symptoms began in late 2023 with balance difficulties and frequent falls, followed by progressive cognitive impairment, personality changes, and a 100 lb unintentional weight loss. His clinical course was further complicated by chronic non-healing wounds and imaging evidence of renal and hepatic scarring. Extensive neurological evaluation, including CT and MRI of the brain and genetic testing for Huntington's, was unrevealing. The patient was found to have repeatedly elevated blood lead levels, initially in the 30 μg/dL range and later peaking in the 60 μg/dL range, despite cessation of work at the chemical and metal processing facility he had been employed at. Evaluation of potential ongoing sources revealed multiple retained BB fragments in the hand and foot dating back to early adulthood. These were initially considered as possible contributors, but point-of-care testing of the fragments on removal was negative for lead. A fragment in the foot was embedded in the bone and not amenable to removal. Additionally, possible residential exposure was considered, as the patient resided in a mid-20th-century home. He required multiple hospitalizations for progressive neurologic decline and elevated lead levels, during which he received inpatient chelation therapy with succimer. Chelation was associated with partial improvement and modest cognitive stabilization, though his dysarthria and gait ataxia persisted. His outpatient course was complicated by financial barriers that limited sustained chelation therapy, resulting in recurrent elevations of blood lead levels. Ongoing management included serial monitoring of lead levels following chelation, with plans to pursue surgical removal of a retained abdominal wall wire if levels were to rise again, suggesting an endogenous source.

Cancer cachexia is a multifactorial syndrome characterized by involuntary loss of skeletal muscle and adipose tissue that is often resistant to nutritional support. The branched-chain amino acids (BCAAs: leucine, isoleucine, and valine) stimulate protein synthesis, yet BCAA-targeted therapies have yielded limited clinical benefit and inconsistent results. This might be related to the altered metabolism of BCAA in cachexia. In this study, a C26 tumor allograft mouse model was used to examine how tumor burden alters BCAA metabolism across tumor tissue, liver, kidney, adipose tissue, and skeletal muscle. Tumor tissue at 4 wk exhibited higher BCAA levels and elevated branched-chain α-keto acid dehydrogenase (BCKD) activity compared to samples collected at 2 wk. At 4 wk, skeletal muscles from tumor-bearing mice showed reduced BCAA concentrations relative to controls. In contrast, liver and adipose tissue did not demonstrate uniform reductions in BCAA content, indicating tissue-specific metabolic responses. Multiple peripheral tissues also displayed lower expression of the L-type amino acid transporter 1 (LAT1) and alterations in downstream mechanistic target of rapamycin complex 1 (mTORC1) signaling. Notably, the soleus muscle maintained elevated phosphorylated S6 (P-S6) levels despite reduced BCAA availability, suggesting muscle-specific adaptations. These findings demonstrate distinct tumor and peripheral tissue alterations in BCAA handling in C26 tumor-bearing mice. The observed changes in BCAA metabolism may underlie the limited success of BCAA-based interventions in cachexia and highlight the need for therapies that address both tumor and host metabolism.NEW & NOTEWORTHY This is the first study to profile branched-chain α-keto acid (BCKA) levels together with branched-chain amino acid (BCAA) metabolism across multiple tissues in a cancer cachexia model. Tumor progression was associated with higher BCAA levels. Some peripheral tissues showed BCAA depletion, and all peripheral sites exhibited reduced expression of the L-type amino acid transporter 1 (LAT1). These tissue-specific adaptations reveal systemic metabolic reprogramming and may explain the limited efficacy of BCAA-based therapies.

Cancer cachexia is characterized by involuntary weight loss and wasting of fat and muscle, with diminished food intake commonly cited as a cause. However, the extent to which reduced food intake drives these symptoms, and other phenotypes such as physical weakness, remains unclear. Using the colon carcinoma 26 (C26) mouse model, we assessed the role of food intake in key cachexia phenotypes. We found that reduced food intake was the predominant driver of body weight loss and tissue wasting, suggesting no additional causal mechanisms. In contrast, food intake reduction did not affect physical performance, indicating food intake-independent factors in causing weakness. Thus, depending on the model or patient group, reduced food intake may primarily drive some cachectic phenotypes while having no role in others. Discriminating between food intake-mediated effects and those independent of it is critical for guiding research focus and unraveling the causal pathways of cancer cachexia.

Purpose: Cachexia, characterized by involuntary weight loss, muscle wasting, and metabolic dysfunction, is prevalent in advanced cancer and chronic illnesses. Despite its impact, outpatient treatment models in the U.S. remain limited and unstandardized. Here, we aim to describe the structure, implementation, patient characteristics, and real-world clinical trajectories of a multidisciplinary clinic for cancer cache as well as other forms of unintentional weight loss clinic within an academic endocrinology practice. Methods: We conducted a retrospective observational cohort study of 103 patients referred to a single-center unintentional weight loss clinic over five years. Patients received comprehensive assessments (weight trajectory, nutrition status, 5× sit-to-stand test, handgrip strength) and personalized interventions including nutrition counseling, resistance training, and pharmacologic therapies. Results: Among 103 patients (median age 69.7 years; 53% male), 64% had cancer, while 36% were referred for non-malignant causes of weight loss or cachexia. Reduced appetite or food intake was reported in 43%, and functional impairment was common, with low handgrip strength in 47% and impaired 5× sit-to-stand performance in 79% of assessed patients. Systemic abnormalities were frequent, including elevated hs-CRP (57%), elevated neutrophil-to-lymphocyte ratio (43%), and hypoalbuminemia (26%). Among patients with available paired follow-up data, the median rate of weight change shifted from -0.5 kg/month prior to enrollment to 0.0 kg/month three months after the initial visit (p < 0.0001). Five-times sit-to-stand performance improved modestly at three months (p = 0.042), while handgrip strength was unchanged. Half of patients that engaged with the clinic returned for at least follow-up, but there was no identifiable difference between the population of patients that returned versus those that did not. Conclusions: A structured, multidisciplinary unintentional weight loss clinic in an endocrinology setting was associated with stabilization of weight and modest changes in physical function in this single-center cohort among patients who engaged in follow-up. These findings highlight the successful implementation of integrated outpatient care models and provide practice-based context for future interventions and therapeutic evaluations.

Tuberculous pericarditis is a rare but important cause of constrictive pericarditis in developed countries, while remaining a significant public health concern in endemic regions. Myocardial involvement is uncommon and often underrecognized. A previously healthy 47-year-old man presented with a five-year history of progressive bilateral lower-limb edema and exertional dyspnea, with marked deterioration over the last five months, including severe fatigue and involuntary weight loss of 8 kg. On admission, imaging revealed biventricular systolic dysfunction, pericardial thickening with calcifications, and bilateral pleural effusions. Pleural fluid analysis demonstrated an exudative effusion with markedly elevated adenosine deaminase (ADA) levels (130 U/L), consistent with tuberculous pleuritis. Cardiac magnetic resonance imaging confirmed myopericarditis with diffuse pericardial thickening (up to 6 mm) and late gadolinium enhancement. Right heart catheterization demonstrated findings consistent with constrictive physiology. Given the presence of severe ventricular dysfunction, atrial fibrillation, and active extrapulmonary tuberculosis, pericardiectomy was deferred. Antituberculous therapy and guideline-directed medical treatment for heart failure were initiated. At three-month follow-up, the patient demonstrated mild functional improvement and continued on a standard six-month antituberculous regimen, which was ongoing at the time of reporting. In endemic areas, tuberculosis should be considered an important cause of constrictive pericarditis in patients with unexplained pericardial disease. Multimodality imaging is essential for accurate diagnosis and for guiding management, especially in complex presentations involving both the pericardium and myocardium. This case illustrates the diagnostic value of a multimodality approach and the management strategy in a high-risk surgical candidate.

Cancer cachexia (CC) is characterized by organ wasting and ensuing involuntary weight loss. Despite advances, underlying mechanisms initiating CC remain unclear, including early symptoms like anorexia. Here, we use a fly gut-tumor model with a precise time-window before organ wasting starts. We show that tumor-induced factors involved in inflammation (unpaired 3/ Interleukin-6-like) and reduced insulin signaling (ImpL2/ Insulin Growth Factor Binding Protein) decrease NPF (Neuropeptide F/ Neuropeptide Y) in the brain prior to organ wasting. This early NPF decrease triggers low protein-specific food appetite and anorexia. We find that ImpL2 reduces NPF signaling while upd3 helps by concurrently affecting the blood brain barrier. Tumor-induced NPF decrease, and early reduction of protein appetite drive the onset of weight loss and exacerbate the risk of death during organ wasting. Altogether, we provide evidence for an early orexigenic brain imbalance causing low protein appetite that regulates the onset and outcome of organ wasting.