Clinical Effects of Neoplasia PDF

Clinical E ffects of N eoplasia B e t h a n D a v i e s -J o n e s b .w. d a v i e s -j o n e s @ b a n g o r. a c . u k Learning Outcomes • Describe the local effect of neoplasia, including mass effect, ulceration and bleeding, pain and nerve compression, infection and tissue necrosis. • U...

Clinical E ffects of N eoplasia B e t h a n D a v i e s -J o n e s b .w. d a v i e s -j o n e s @ b a n g o r. a c . u k Learning Outcomes • Describe the local effect of neoplasia, including mass effect, ulceration and bleeding, pain and nerve compression, infection and tissue necrosis. • Understand the metabolic effects of neoplasia, such as cachexia and hypercalcemia. • Discuss the aetiologies and pathogenesis of paraneoplastic syndromes . Mass effect (compression) Growing tumours displacing and compressing adjacent structures Complications: • Vascular compression: ischemia, thrombosis, and oedema • Lymphatic obstruction: lymphedema and impaired immune function • Nerve compression: neuropathic pain, sensory deficits, and motor dysfunction • Organ compression: reduced organ function, organ failure, and obstructive symptoms Ulceration and bleeding • Tumour invasion of blood vessels and mucosal surfaces • Erosion and rupture of blood vessels • Bleeding: local, occult, or massive haemorrhage • Anaemia and hypovolemia as potential consequences • Disruption of mucosal surfaces • Ulceration: formation of open sores or lesions • Infections and impaired healing • Potential impact on quality of life and nutrition Pain and nerve compression Tumour infiltration of nerve structures • Direct invasion of nerves or nerve roots • Examples: Pancoast tumour (lung cancer), spinal cord compression by metastatic cancer Release of pain mediators • Inflammatory mediators: prostaglandins, bradykinin, and substance P • Tumour -derived factors: growth factors, cytokines, and chemokines Neuropathic pain and consequences • Chronic pain, paraesthesia, allodynia, and hyperalgesia • Impact on quality of life, sleep, and mental health Infection and tissue necrosis Compromised blood supply • Tumour -induced ischemia and hypoxia • Impaired delivery of nutrients, oxygen, and immune cells Impaired immune response • Local immunosuppression due to tumour -derived factors • Systemic immunosuppression from cancer treatments Tissue necrosis • Consequence of ischemia, hypoxia, and inflammation • Formation of necrotic tissue and potential for infection Infection risk factors • Ulceration, invasive procedures, and immunosuppression • Examples: wound infections, abscesses, and sepsis Systemic effects on metabolism Cachexia : Progressive weight loss and muscle wasting Paraneoplastic syndromes • Symptoms unrelated to tumour mass or metastasis • Ectopic hormone production or autoimmunity Hypercalcemia: Elevated calcium levels Cachexia • Multifactorial syndrome causing severe weight loss, muscle wasting, and reduced appetite • Affects 50 % of cancer patients (80% of advanced stages) • Interplay of tumour -derived factors, inflammatory cytokines, and metabolic alterations • Increased catabolism and decreased anabolism • Impaired immune function and reduced response to treatment Altered nutrient partitioning TUMOURS CONSUME A LARGE PORTION OF AVAILABLE NUTRIENTS, RESULTIN G IN INCREASED COMPETITION BETWEEN TUMOUR AND HOST TISSUES FOR ESSENTIAL NUTRIE NTS. a) Glucose Metabolism 1. Enhanced glucose uptake by tumours 2. Impaired glucose utilization in host tissues b ) Amino Acid Metabolism 1. Increased amino acid uptake by tumours 2. Muscle protein breakdown for energy production c) Lipid Metabolism 1. Enhanced lipolysis to support tumour growth 2. Depletion of host adipose tissue 3. The fat malabsorption seen in patients hints toward lower bile acid levels Consequences 1. Malnutrition, muscle wasting, and metabolic dysfunction 2. Exacerbation of cachectic state Key tumour - derived factors MOLECULES PRODUCED BY TUMOURS THAT IMPACT HOST METABOLISM a) P roteolysis -Inducing Factor (PIF) 1. Stimulates muscle proteolysis 2. Contribute to muscle wasting b ) Lipid -Mobilizing Factor (LMF) 1. Induces adipose tissue lipolysis 2. Promotes fat depletion c) Tumour -Derived Cytokines 1. TNF -α, IL -1, IL -6 2. Promote inflammation and catabolism Implications 1. Disruption of host metabolic homeostasis 2. Exacerbation of cachectic state 3. Compromised immune syste m Key aspects of host response THE HOST'S RESPONSE TO TUMOUR GROWTH AFFECTS METABOLISM AND ENER GY HOMEOSTASIS, LEADING TO SIGNIFICANT BIOLOGICAL CHANGES AND CONSEQUENCES. a) Hypermetabolic State 1. Increased resting energy expenditure 2. Elevated metabolic rate b ) Insulin Resistance 1. Impaired glucose metabolism and utilization 2. Compromised cellular energy production c) Elevated Gluconeogenesis 1. Breakdown of muscle protein and adipose tissue triglycerides 2. Provides alternative energy sources for host and tumour Consequences 1. Malnutrition, muscle wasting, and metabolic dysfunction 2. Exacerbation of cachectic state Key anabolic pathways suppressed by tumours TUMOURS PLAY A ROLE IN INHIBITING HOST ANABOLIC PATHWAYS, WHICH CONTRIBUTE TO THE DEVELOPMENT OF CANCER CACHEXIA. a) Growth Hormone (GH) and Insulin -like Growth Factor -1 (IGF -1) 1. Key regulators of protein synthesis 2. Inhibited by tumours b) PI3K/Akt/mTOR Pathway 1. Responsible for protein synthesis 2. Inhibited by tumour -derived factors c) Myostatin 1. Negative regulator of muscle growth 2. Upregulated by tumours Consequences 1. Reduced protein synthesis and muscle growth 2. Increased muscle wasting and atrophy 3. Exacerbation of cachectic state Key factors affecting appetite regulation a) Tumour -Derived Factors 1. Disrupt appetite -controlling hormones (leptin and ghrelin) 2. Affect hypothalamic appetite regulation b) Inflammation 1. Exacerbates cachexia -related anorexia 2. Increases metabolic rate Consequences 1. Anorexia, reduced food intake, and malnutrition 2. Exacerbation of cachectic state 3. Compromised immune function Mechanical limitations (e.g. difficulties in swallowing, feelings of saturation, nausea) restrict energy uptake and recovery in patients with gastrointestinal cancer. Chemotherapies are likely to contribute to the development of intestinal absorptive dysfunction. Mechanisms BAT = Brown adipose tissue WAT = White adipose tissue Gut barrier dysfunction and endotoxemia Breakdown of the intestinal barrier and the release of bacterial toxins into the bloodstream. Caused by: • Inflammation and oxidative stress caused by cancer and/or cancer treatment • Chemotherapy and radiation -induced mucositis • Altered gut microbiota and dysbiosis Consequences • Systemic inflammation • Increased lipopolysaccharides (LPS) in the bloodstream • Skeletal muscle wasting Clinical implications • Early identification and intervention are essential • Multimodal approach for optimal management • Ongoing research: • Understanding the underlying mechanisms • Developing novel therapeutic targets • Aim for improved patient outcomes and quality of life Paraneoplastic syndromes • A diverse group of symptoms and disorders that occur as a result of immune system reactions to underlying malignancies, yet not directly caused by the primary tumour or its metastases. • Often present before the diagnosis of cancer, making them valuable diagnostic clues for early cancer detection. • Can affect multiple organ systems, including: • Endocrine system (e.g., Cushing's syndrome, SIADH) • Neurological system (e.g., limbic encephalitis, Lambert -Eaton myasthenic syndrome) • Haematologic system (e.g., Trousseau's syndrome, anaemia) • Dermatologic system (e.g., acanthosis nigricans, paraneoplastic pemphigus) Aetiology Syndrome Tumour type Ectopic ACTH secretion (Cushing’s syndrome); SIADH (syndrome of inappropriate antidiuretic hormone secretion ); Lambert -Eaton myasthenic syndrome; Encephalomyelitis Lung (small -cell) Paraneoplastic hypercalcemia and ectopic gonadotropin production Ovarian cancer Paraneoplastic sensory neuronopathy; Stiff -person syndrome, Dermatomyositis Breast cancer Hypercalcaemia; P araneoplastic pemphigus; A utoimmune haemolytic anaemia and thrombocytopenia Lymphoma Pathophysiological mechanisms • Ectopic hormone production • Hormonal imbalances result in associated symptoms • e.g., small cell lung cancer can produce ACTH which results in Cushing's syndrome, ovarian cancer can produce PTHrP causing hypercalcemia. • Cross -reactivity between tumour antigens and host tissues • Leads to autoimmune -like symptoms • e.g., Anti -Hu antibodies in small cell lung cancer - Limbic encephalitis, Anti -Yo antibodies in ovarian cancer - Paraneoplastic cerebellar degeneration • Inflammatory cytokine release • Systemic effects cause a variety of symptoms • e.g., IL -6 production in Hodgkin's lymphoma - Anaemia of chronic disease, TNF -α production in various malignancies - Cancer -associated cachexia Factors influencing development • Genetic Predisposition • Genetic mutations or polymorphisms • Family history of malignancy or autoimmune disease • Tumour Type and Location • Specific cancer types more commonly associated with paraneoplastic syndromes • Tumour location may influence the organ system affected • Immune System Status • Strength of the immune response to tumour antigens • Presence of other immune -related conditions • Environmental Factors • Exposure to carcinogens or other risk factors • Lifestyle factors (e.g., smoking, diet, physical activity) Importance of understanding aetiology • Early cancer detection • Paraneoplastic syndromes can be initial manifestations of malignancy • P rompt recognition aids in early diagnosis and intervention • Identification of specific cancer types • Understanding aetiology helps guide diagnostic workup • Targeted investigations for efficient and accurate diagnosis • Improved patient outcomes • Timely intervention can slow disease progression and improve prognosis • Appropriate management of paraneoplastic manifestations enhances quality of life • Advancement of research and treatment • Aetiology understanding fosters development of targeted therapies • Potential for personalized medicine and tailored interventions Hypercalcaemia • High calcium (Ca2+) level in the blood serum. • The normal range is 8.5 to 10.2 mg/dL (2.13 to 2.55 millimole/ L). • Occurs in up to 30% of cancer patients • Ectopic parathyroid hormone releasing peptide (PTHrP) secretion by malignant cells accounts for 80% of cancer cases. • PTHrP is a cytokine -like protein that is structurally similar to parathyroid hormone (PTH). • PTHrP, can activate multiple signalling pathways that lead to increased bone resorption, decreased bone formation, and altered calcium homeostasis. • PTHrP can also increase calcium absorption from the intestines and decrease calcium excretion from the kidneys, further exacerbating hypercalcemia. Molecular mechanisms Wnt signalling pathway: • Involved in bone remodelling and can be activated by PTHrP. • Activation leads to increased osteoclast activity and decreased osteoblast activity, leading to bone resorption. Receptor activator of nuclear factor kappa -B ligand (RANKL): • A molecule involved in the regulation of osteoclast activity. • PTHrP can increase the expression of RANKL, leading to increased osteoclast activity and bone resorption . Interleukin -6 (IL -6): • Can be produced by cancer cells. • IL -6 can activate the RANKL pathway and increase osteoclast activity and bone resorption. Calcium -sensing receptor (CaSR): • A receptor that involved in the regulation of calcium homeostasis. • Expression and activity can be altered, leading to dysregulation of calcium homeostasis and hypercalcemia. Effects of hypercalcemia • Hypercalcemia can affect multiple organ systems, including the bones, kidneys, gastrointestinal tract, and nervous system • It can cause osteoporosis and bone pain, kidney stones, nausea and vomiting, constipation, and confusion or lethargy • It can also lead to increased thirst and urination, dehydration, and electrolyte imbalances, such as hypokalaemia and metabolic alkalosis Management • Treat the underlying malignancy • Adequate hydration through intravenous fluids • Medications like bisphosphonates, calcitonin, and denosumab can be used to inhibit bone resorption • Glucocorticoids can be used to inhibit the production of PTHrP • Dialysis may be necessary in severe cases to remove excess calcium from the bloodstream. Peer Guide Recruitment Anyone who is committed to helping new students settle in at Bangor can be a Peer Guide. We are always eager to recruit. 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