(a) Define 'metastasis'. Enumerate the steps involved in metastasis. Write briefly about the role of stromal elements in…

(a) Metastasis Metastasis is the spread of malignant cells from the primary tumour to a distant organ, where they survive and form a secondary tumour. It is the main cause of cancer death. The steps are: (1) local invasion, in which cancer cells detach, undergo epithelial-mesenchymal transition, degrade basement membrane and extracellular matrix, and invade surrounding tissue; (2) intravasation, in which they enter lymphatic or blood vessels; (3) survival in circulation, resisting shear stress and anoikis; (4) extravasation, in which they exit vessels at a distant site; and (5) colonization and outgrowth, in which they adapt to the new microenvironment and form a macroscopic tumour. Stromal elements are essential. Cancer-associated fibroblasts activate tumour cells, remodel the extracellular matrix, and secrete growth factors. Matrix metalloproteinases and collagen remodelling create tracks for invasion. Tumour cells induce angiogenesis through VEGF, providing oxygen and nutrients. Hypoxia, HIF-1α, cytokines and exosomes prepare a pre-metastatic niche in distant organs, especially bone marrow and liver, allowing circulating tumour cells to arrest, survive and grow. Endothelial cells and bone-marrow stroma provide adhesion molecules and growth factors.

(b)(i) Immunoglobulins and T-cell subsets Immunoglobulins are glycoproteins that mediate humoral immunity. IgG is the major serum antibody, crosses the placenta, and is important in secondary responses, opsonization, neutralization and complement activation. IgM is the first antibody in primary responses, exists mainly as a pentamer, fixes complement strongly, and is present on B-cell surfaces. IgA is the main mucosal antibody, occurs as a dimer with secretory component, and prevents attachment of microbes to mucosae. IgE binds mast cells and basophils and mediates immediate hypersensitivity and defence against helminths. IgD is mainly a B-cell receptor and helps B-cell maturation. T-lymphocytes are divided into CD4+ helper cells and CD8+ cytotoxic cells. CD4+ subsets include Th1 cells, which secrete IFN-γ and activate macrophages; Th2 cells, which secrete IL-4, IL-5 and IL-13 and support IgE and eosinophil responses; Th17 cells, which secrete IL-17 and IL-22 and recruit neutrophils at mucosal barriers; and Treg cells, which secrete IL-10 and TGF-β and maintain tolerance. CD8+ cytotoxic T lymphocytes kill infected or malignant cells by perforin, granzyme and Fas-FasL pathways.

(b)(ii) Amoebiasis Amoebiasis, caused mainly by Entamoeba histolytica, has intestinal and extraintestinal forms. Intestinal manifestations include asymptomatic carriage, amoebic dysentery with blood and mucus, flask-shaped ulcers in the caecum and colon, amoeboma, toxic megacolon, perforation and peritonitis. Extraintestinal manifestations occur after trophozoites spread through the portal circulation. The liver abscess is the most common and presents with fever, right upper abdominal pain and tender hepatomegaly. Other sites include lung, brain, peritoneum, cutaneous tissue, parotid and other rare organs.

(c) Insulin analogues Longer-acting insulin analogues are modified insulins designed to provide basal insulin over a prolonged period. The main agents are insulin glargine, insulin detemir and insulin degludec. They differ from conventional human insulin preparations because amino acid substitutions or structural modifications alter solubility, hexamer formation and binding to albumin. Glargine forms soluble hexamers at acidic pH and slowly precipitates at neutral pH; detemir binds albumin after fatty-acid modification; degludec forms multi-needle structures and has an ultralong duration. Compared with NPH or regular human insulin, they have a flatter, more predictable profile, less peak effect, and reduced nocturnal hypoglycaemia. Glargine and detemir provide about 24-hour basal cover, while degludec is ultralong and may be given at flexible times. They are used as basal insulin in type 1 diabetes, type 2 diabetes when oral agents are insufficient, and gestational diabetes. Adverse effects include hypoglycaemia, weight gain, lipohypertrophy or lipoatrophy at injection sites, local reactions, rare allergy, and, with insulin therapy generally, fluid retention.

(d) Chronic inflammation Chronic inflammation is a prolonged inflammatory response, usually lasting weeks to years, characterized by infiltration with mononuclear cells, tissue destruction, and attempts at repair by fibrosis and angiogenesis. Causes include persistent infections such as tuberculosis, leprosy, syphilis, fungal and viral infections; autoimmune diseases such as rheumatoid arthritis, systemic lupus erythematosus and inflammatory bowel disease; foreign bodies such as sutures, talc, asbestos and silica; chronic exposure to toxic agents; and idiopathic conditions such as sarcoidosis. Macrophages are the central cells. They phagocytose debris and microbes, present antigen to T cells, secrete IL-1, TNF-α, IL-6, IL-12 and chemokines, recruit other leukocytes, release reactive oxygen and nitrogen species, stimulate fibroblasts, and produce growth factors that cause tissue remodelling and fibrosis. In granulomatous inflammation, macrophages fuse into multinucleated giant cells and form epithelioid granulomas.

(e) Data of identification and fingerprinting Data of identification are objective features used to establish identity. They include anthropometric measurements (Bertillon system), dactylography or fingerprints, DNA profiling, odontology, iris recognition, voice analysis, handwriting, photographs, scars, tattoos, moles, personal effects and circumstantial evidence. Fingerprinting is the study of friction-skin ridges on fingers and palms. The main ridge patterns are arch, loop and whorl. Identification depends on minutiae, also called Galton details, such as ridge endings, bifurcations, dots, short ridges, lakes, islands and enclosures. Modern systems use AFIS to compare digital impressions, and poroscopy examines the pore pattern for individualization. In India, FSL and state forensic laboratories use AFIS in criminal investigations. Fingerprinting is valuable because it is rapid, inexpensive, durable, and can identify a person even when other features are damaged. In Indian forensic practice, fingerprints are collected under the Fingerprint Act, 1898 and Section 53A of the Code of Criminal Procedure, and are admitted as expert opinion under Section 45 of the Indian Evidence Act. The Indian Evidence Act does not prescribe a fixed number of matching minutiae; the court considers the number, quality and clarity of points, absence of unexplained discrepancies, and the opinion of a forensic expert. Thus, identification in forensic medicine rests on cumulative objective data, and fingerprinting remains a rapid, durable and legally admissible method in Indian criminal procedure.