import json, subprocess, base64, os
from io import BytesIO
from pptx import Presentation
from pptx.util import Inches, Pt, Emu
from pptx.dml.color import RGBColor
from pptx.enum.text import PP_ALIGN, MSO_ANCHOR
from pptx.util import Inches, Pt

# ── Colors ──────────────────────────────────────────────────────────────
DEEP_BLUE   = RGBColor(0x1A, 0x35, 0x6E)   # dark navy
MED_BLUE    = RGBColor(0x25, 0x5E, 0xAA)   # medium blue
ACCENT      = RGBColor(0xD9, 0x42, 0x2A)   # red accent
LIGHT_GRAY  = RGBColor(0xF2, 0xF4, 0xF7)
WHITE       = RGBColor(0xFF, 0xFF, 0xFF)
DARK_TEXT   = RGBColor(0x1C, 0x1C, 0x1C)
TEAL        = RGBColor(0x00, 0x7A, 0x87)
GOLD        = RGBColor(0xE8, 0x8A, 0x00)
LIGHT_BLUE  = RGBColor(0xE8, 0xF1, 0xFB)

# ── Image helper ─────────────────────────────────────────────────────────
def fetch_b64(url):
    try:
        result = json.loads(subprocess.check_output(
            ["python", "/tmp/skills/shared/scripts/fetch_images.py", url], timeout=30
        ))
        if result and result[0].get("base64"):
            return result[0]["base64"]
    except Exception as e:
        print(f"Fetch error for {url}: {e}")
    return None

def add_image_to_slide(slide, url, left, top, width, height):
    b64 = fetch_b64(url)
    if b64:
        raw = base64.b64decode(b64.split(",")[-1])
        slide.shapes.add_picture(BytesIO(raw), left, top, width, height)
        return True
    return False

# ── Drawing helpers ───────────────────────────────────────────────────────
def add_rect(slide, l, t, w, h, fill_rgb, line_rgb=None, line_width=None):
    from pptx.util import Pt
    from pptx.oxml.ns import qn
    shape = slide.shapes.add_shape(1, l, t, w, h)  # MSO_SHAPE_TYPE.RECTANGLE
    shape.fill.solid()
    shape.fill.fore_color.rgb = fill_rgb
    if line_rgb:
        shape.line.color.rgb = line_rgb
        if line_width:
            shape.line.width = line_width
    else:
        shape.line.fill.background()
    return shape

def add_text(slide, text, l, t, w, h, size, bold=False, color=WHITE,
             align=PP_ALIGN.LEFT, italic=False, wrap=True, font="Calibri"):
    tb = slide.shapes.add_textbox(l, t, w, h)
    tf = tb.text_frame
    tf.word_wrap = wrap
    tf.margin_left = 0; tf.margin_right = 0
    tf.margin_top = 0; tf.margin_bottom = 0
    p = tf.paragraphs[0]
    p.alignment = align
    run = p.add_run()
    run.text = text
    run.font.name = font
    run.font.size = Pt(size)
    run.font.bold = bold
    run.font.italic = italic
    run.font.color.rgb = color
    return tb

def add_multiline(slide, lines, l, t, w, h, size, color=DARK_TEXT,
                  bullet=True, bold_first=False, font="Calibri"):
    tb = slide.shapes.add_textbox(l, t, w, h)
    tf = tb.text_frame
    tf.word_wrap = True
    tf.margin_left = Pt(2); tf.margin_right = Pt(2)
    tf.margin_top = Pt(2); tf.margin_bottom = Pt(2)
    for i, line in enumerate(lines):
        if i == 0:
            p = tf.paragraphs[0]
        else:
            p = tf.add_paragraph()
        p.space_before = Pt(1)
        p.space_after = Pt(1)
        run = p.add_run()
        prefix = "• " if bullet else ""
        run.text = prefix + line
        run.font.name = font
        run.font.size = Pt(size)
        run.font.color.rgb = color
        if bold_first and i == 0:
            run.font.bold = True

# ═══════════════════════════════════════════════════════════════════════════
# SLIDE BUILDER
# ═══════════════════════════════════════════════════════════════════════════
prs = Presentation()
prs.slide_width  = Inches(13.333)
prs.slide_height = Inches(7.5)
blank = prs.slide_layouts[6]

W = prs.slide_width
H = prs.slide_height

# ─────────────────────────────────────────────────────────────────────────
# SLIDE 1 – TITLE SLIDE
# ─────────────────────────────────────────────────────────────────────────
def title_slide():
    slide = prs.slides.add_slide(blank)
    # Full background
    add_rect(slide, 0, 0, W, H, DEEP_BLUE)
    # Decorative diagonal stripe
    add_rect(slide, Inches(8.5), 0, Inches(5), H, MED_BLUE)
    # Red accent bar bottom
    add_rect(slide, 0, H - Inches(0.3), W, Inches(0.3), ACCENT)
    # Title
    add_text(slide, "Bone & Joint Pathology", Inches(0.6), Inches(1.2), Inches(7.8), Inches(1.5),
             44, bold=True, color=WHITE, align=PP_ALIGN.LEFT)
    add_text(slide, "Microscopic Pathology, Pathophysiology,\nGenetics, Causes & Complications",
             Inches(0.6), Inches(2.9), Inches(7.8), Inches(1.2),
             22, bold=False, color=RGBColor(0xCC, 0xDD, 0xFF), align=PP_ALIGN.LEFT)
    add_text(slide, "Lab Presentation", Inches(0.6), Inches(4.3), Inches(5), Inches(0.6),
             16, bold=True, color=GOLD, align=PP_ALIGN.LEFT)
    # Right panel content
    topics = [
        "BONES", "190 Bone-Renal Dystrophy", "191 Purulent Osteomyelitis",
        "41  Paget Disease of Bone", "17  Osteochondroma", "173 Fibrous Dysplasia",
        "193 Giant Cell Tumor", "254 Osteosarcoma", "92  Ewing's Tumor",
        "", "JOINTS & SOFT TISSUE", "13  Gout", "196 Rheumatoid Arthritis",
        "200 Osteoarthritis", "22  Skin Fibrosarcoma", "23  Rhabdomyosarcoma",
        "25  Liposarcoma", "101 Leiomyosarcoma"
    ]
    tb = slide.shapes.add_textbox(Inches(9.0), Inches(0.5), Inches(4.0), Inches(6.8))
    tf = tb.text_frame; tf.word_wrap = True
    for i, t in enumerate(topics):
        p = tf.paragraphs[0] if i == 0 else tf.add_paragraph()
        run = p.add_run(); run.text = t
        run.font.name = "Calibri"; run.font.size = Pt(11)
        if t in ("BONES", "JOINTS & SOFT TISSUE"):
            run.font.bold = True; run.font.color.rgb = GOLD
        else:
            run.font.color.rgb = WHITE
title_slide()

# ─────────────────────────────────────────────────────────────────────────
# Helper: standard content slide with image
# ─────────────────────────────────────────────────────────────────────────
def content_slide(title, specimen_no, subtitle,
                  pathophysiology, gene_involvement, causes, complications,
                  microscopy_notes, image_urls, magnifications):
    """
    Two-column layout:
    Left (~7.5") – text content
    Right (~5.5") – image(s)
    """
    slide = prs.slides.add_slide(blank)
    # Header bar
    add_rect(slide, 0, 0, W, Inches(1.05), DEEP_BLUE)
    # Specimen badge
    add_rect(slide, Inches(0.15), Inches(0.12), Inches(0.9), Inches(0.8), ACCENT)
    add_text(slide, specimen_no, Inches(0.15), Inches(0.12), Inches(0.9), Inches(0.8),
             17, bold=True, color=WHITE, align=PP_ALIGN.CENTER)
    # Title
    add_text(slide, title, Inches(1.2), Inches(0.1), Inches(6.8), Inches(0.7),
             22, bold=True, color=WHITE)
    add_text(slide, subtitle, Inches(1.2), Inches(0.72), Inches(6.8), Inches(0.32),
             11, bold=False, color=RGBColor(0xCC, 0xDD, 0xFF))

    # Body background
    add_rect(slide, 0, Inches(1.05), W, H - Inches(1.05), LIGHT_GRAY)

    # Left column sections
    y = Inches(1.15)
    col_w = Inches(7.3)
    section_h = Inches(0.28)

    def section(label, items, color_bar=MED_BLUE):
        nonlocal y
        add_rect(slide, Inches(0.15), y, col_w, section_h, color_bar)
        add_text(slide, label, Inches(0.22), y + Pt(2), col_w - Inches(0.1), section_h - Pt(4),
                 10, bold=True, color=WHITE)
        y += section_h
        # content box
        lines = items if isinstance(items, list) else [items]
        item_h = Inches(0.22) * len(lines)
        bg = add_rect(slide, Inches(0.15), y, col_w, item_h, WHITE,
                      line_rgb=RGBColor(0xCC, 0xCC, 0xCC))
        add_multiline(slide, lines, Inches(0.25), y + Pt(2),
                      col_w - Inches(0.12), item_h - Pt(4), 9,
                      color=DARK_TEXT, bullet=True)
        y += item_h + Inches(0.06)

    section("PATHOPHYSIOLOGY", pathophysiology, MED_BLUE)
    section("GENE INVOLVEMENT", gene_involvement, TEAL)
    section("CAUSES / RISK FACTORS", causes, RGBColor(0x5A, 0x2D, 0x82))
    section("COMPLICATIONS", complications, ACCENT)

    # Microscopy notes (bottom of left col)
    section("MICROSCOPIC FEATURES", microscopy_notes, RGBColor(0x2E, 0x7D, 0x32))

    # Right column – images
    img_x = Inches(7.65)
    img_w = Inches(5.45)
    available_h = H - Inches(1.15) - Inches(0.15)
    n = len(image_urls)
    if n == 0:
        return
    slot_h = available_h / n - Inches(0.25)

    for idx, (url, mag) in enumerate(zip(image_urls, magnifications)):
        iy = Inches(1.15) + idx * (slot_h + Inches(0.25))
        # image frame
        add_rect(slide, img_x, iy, img_w, slot_h, WHITE,
                 line_rgb=RGBColor(0xAA, 0xAA, 0xAA))
        ok = add_image_to_slide(slide, url, img_x + Inches(0.05),
                                iy + Inches(0.05),
                                img_w - Inches(0.1),
                                slot_h - Inches(0.3))
        # magnification label
        add_rect(slide, img_x, iy + slot_h - Inches(0.28),
                 img_w, Inches(0.25), RGBColor(0x00, 0x00, 0x00))
        add_text(slide, mag,
                 img_x + Inches(0.1), iy + slot_h - Inches(0.27),
                 img_w - Inches(0.15), Inches(0.22),
                 9, color=WHITE, bold=True)

# ─────────────────────────────────────────────────────────────────────────
# SLIDE DATA – all 15 conditions
# ─────────────────────────────────────────────────────────────────────────
slides_data = [
    # ── 190 BONE-RENAL DYSTROPHY ─────────────────────────────────────────
    dict(
        title="Bone-Renal Dystrophy (Renal Osteodystrophy)",
        specimen_no="190",
        subtitle="Metabolic bone disease secondary to chronic kidney disease",
        pathophysiology=[
            "CKD → ↓ phosphate excretion → hyperphosphatemia",
            "↓ 1-alpha-hydroxylase → ↓ active vitamin D (calcitriol) → ↓ Ca²⁺ absorption",
            "Secondary hyperparathyroidism → PTH-driven osteoclastic resorption",
            "Mixed lesion: osteitis fibrosa cystica + osteomalacia + adynamic bone",
        ],
        gene_involvement=[
            "FGF23 gene – elevated FGF23 from kidneys suppresses vitamin D activation",
            "PHEX – mutations mimic phenotype (phosphate regulation)",
            "KL (Klotho) gene – co-receptor for FGF23 signaling",
        ],
        causes=[
            "Chronic glomerulonephritis, diabetic nephropathy",
            "Polycystic kidney disease, hypertensive nephrosclerosis",
            "Any cause of CKD (GFR < 60 mL/min sustained)",
        ],
        complications=[
            "Pathological fractures and bone pain",
            "Vascular and soft-tissue calcifications (calciphylaxis)",
            "Brown tumors (focal PTH-driven osteolysis)",
            "Growth retardation in children; Rugger-jersey spine on X-ray",
        ],
        microscopy_notes=[
            "LPO (4x): Widened osteoid seams around trabeculae (osteomalacia component)",
            "HPO (10x): Peritrabecular fibrosis – osteitis fibrosa cystica",
            "HPO (40x): Increased osteoclasts in Howship's lacunae; tunneling resorption",
            "Brown tumor: fibrous tissue + osteoclast-like giant cells + hemosiderin",
        ],
        image_urls=[
            "https://cdn.orris.care/cdss_images/c9a8e07ed5702308cede4b46044d25c3b841e1ecf811a730d98ddc619f8f8d28.png",
        ],
        magnifications=[
            "Paget/Bone texture: Mosaic cement lines (analogous HPO 10x) – Source: Robbins Basic Pathology"
        ]
    ),

    # ── 191 PURULENT OSTEOMYELITIS ───────────────────────────────────────
    dict(
        title="Purulent Osteomyelitis",
        specimen_no="191",
        subtitle="Suppurative bacterial infection of bone",
        pathophysiology=[
            "Hematogenous seeding OR contiguous spread OR direct inoculation",
            "Bacteria lodge in metaphyseal sinusoidal vessels (sluggish flow, no phagocytes)",
            "PMN infiltration → pus → raised intraosseous pressure → ischaemia",
            "Ischaemia → cortical necrosis → sequestrum formation",
            "Periosteum elevates → new bone (involucrum) surrounds dead bone",
        ],
        gene_involvement=[
            "IL-1β, TNF-α, IL-6 – cytokine storm drives bone destruction",
            "NOD2/CARD15 – polymorphisms increase susceptibility",
            "VDR gene – vitamin D receptor variants affect innate immunity",
        ],
        causes=[
            "Most common: Staph. aureus (all ages); MRSA increasingly common",
            "Neonates: Group B Strep, S. aureus, E. coli",
            "Sickle cell disease: Salmonella spp.",
            "Post-surgical / open fracture: Gram-negatives, Pseudomonas",
            "Risk factors: IV drug use, diabetes, immunosuppression",
        ],
        complications=[
            "Chronic osteomyelitis – sequestrum + involucrum + sinus tract",
            "Pathological fracture; septic arthritis (if subarticular)",
            "Brodie abscess (walled-off chronic abscess)",
            "Marjolin's ulcer (squamous carcinoma in chronic sinus tract)",
            "Amyloidosis (secondary AA); growth arrest in children",
        ],
        microscopy_notes=[
            "LPO (4x): Necrotic bone trabeculae – sequestrum (pink acellular bone)",
            "HPO (10x): Dense neutrophilic infiltrate, fibrous tissue, granulation tissue",
            "HPO (40x): Osteoclastic resorption + new woven bone (involucrum formation)",
            "Chronic phase: lymphocytes, plasma cells replace neutrophils",
        ],
        image_urls=[
            "https://cdn.orris.care/cdss_images/742403518580f55469d5430f44196b49e177c6aaba2ead57140504f2cebd10bb.png",
        ],
        magnifications=[
            "Osteoid trabeculae rimmed by osteoblasts (10x) – Source: Robbins Basic Pathology"
        ]
    ),

    # ── 41 PAGET DISEASE ─────────────────────────────────────────────────
    dict(
        title="Paget Disease of the Bone (Osteitis Deformans)",
        specimen_no="41",
        subtitle="Disordered bone remodeling with excessive osteoclastic activity",
        pathophysiology=[
            "Phase 1 – Lytic: Hyperactive osteoclasts with >100 nuclei; massive bone resorption",
            "Phase 2 – Mixed: Osteoclasts + osteoblasts active simultaneously",
            "Phase 3 – Sclerotic: Disorganized lamellar bone with mosaic cement lines",
            "Resulting bone is thick but architecturally weak → prone to fracture",
        ],
        gene_involvement=[
            "SQSTM1 (p62) – 50% familial, 10% sporadic; ↑ NF-κB → osteoclast activity",
            "RANK (TNFRSF11A) – activating mutations in juvenile Paget disease",
            "OPG (TNFRSF11B) – loss-of-function in juvenile Paget disease",
            "Possible environmental trigger: paramyxovirus (measles) viral inclusions in osteoclasts",
        ],
        causes=[
            "Unknown – multifactorial (genetic + environmental)",
            "Age >40 years; M > F; Northern European ancestry",
            "Possible measles/RSV viral infection of osteoclast precursors",
        ],
        complications=[
            "Pathological fractures (chalk-stick type in lower limbs)",
            "Deafness (temporal bone involvement → 8th nerve compression)",
            "High-output cardiac failure (AV shunting in hypervascular bone)",
            "Osteosarcoma (1% risk) – most feared complication",
            "Leontiasis ossea (facial bone overgrowth); nerve root compression",
        ],
        microscopy_notes=[
            "LPO (4x): Irregular thickening of trabeculae; mosaic pattern throughout",
            "HPO (10x): MOSAIC CEMENT LINES – jigsaw puzzle appearance (pathognomonic)",
            "HPO (40x): Basophilic cement lines separating lamellar bone units",
            "Phase-dependent: osteoclasts with >100 nuclei (active phase); sclerosis (late)",
        ],
        image_urls=[
            "https://cdn.orris.care/cdss_images/c9a8e07ed5702308cede4b46044d25c3b841e1ecf811a730d98ddc619f8f8d28.png",
        ],
        magnifications=[
            "Mosaic cement lines – pathognomonic of Paget disease (HPO 10x) – Source: Robbins Basic Pathology"
        ]
    ),

    # ── 17 OSTEOCHONDROMA ────────────────────────────────────────────────
    dict(
        title="Osteochondroma (Exostosis)",
        specimen_no="17",
        subtitle="Most common benign bone tumor – cartilage-capped bony exostosis",
        pathophysiology=[
            "Outgrowth from epiphyseal cartilage plate during enchondral ossification",
            "Abnormal heparan sulfate synthesis → disrupts Indian Hedgehog (Ihh) signaling",
            "Chondrocytes fail to differentiate normally → outward bony projection forms",
            "Cartilage cap undergoes endochondral ossification; medullary cavity continuous with host bone",
        ],
        gene_involvement=[
            "EXT1 (8q24) – encodes exostosin glycosyltransferase-1; tumor suppressor",
            "EXT2 (11p13) – heterodimeric partner; mutations → Multiple Hereditary Exostoses (MHE)",
            "Loss of both alleles (two-hit model) in chondrocytes of growth plate",
            "Reduced heparan sulfate glycosaminoglycan chains → ↓ Ihh diffusion gradient",
        ],
        causes=[
            "Sporadic (85%): somatic EXT1/EXT2 mutation",
            "Multiple Hereditary Exostoses: germline EXT1/EXT2 – autosomal dominant",
            "Radiation-induced osteochondroma (after childhood irradiation)",
        ],
        complications=[
            "Mechanical impingement on nerves, vessels, tendons",
            "Fracture of stalk (painful)",
            "Malignant transformation to secondary chondrosarcoma (<1% solitary; 5–25% MHE)",
            "Spinal cord compression (vertebral lesions)",
        ],
        microscopy_notes=[
            "LPO (4x): Hyaline cartilage cap overlying cancellous bone stalk",
            "HPO (10x): Chondrocytes in lacunae within hyaline matrix – recapitulates growth plate",
            "HPO (40x): Gradual endochondral ossification at base of cap → woven then lamellar bone",
            "Key: Continuity of stalk medullary cavity with host bone medullary cavity",
        ],
        image_urls=[
            "https://cdn.orris.care/cdss_images/cfcc1d74c2a0e8741804a8ce03cfe2ae6269ee00b5b076f8b99366ca3249a9f7.png",
        ],
        magnifications=[
            "Osteochondroma: X-ray + whole mount section showing cartilage cap (LPO) – Source: Robbins Basic Pathology"
        ]
    ),

    # ── 173 FIBROUS DYSPLASIA ────────────────────────────────────────────
    dict(
        title="Fibrous Dysplasia",
        specimen_no="173",
        subtitle="Benign developmental arrest – fibrous tissue replaces normal bone",
        pathophysiology=[
            "Somatic GNAS1 gain-of-function mutation → constitutively active Gs-alpha protein",
            "↑ cAMP → ↑ osteoblast proliferation + disrupted differentiation",
            "Fibrous stroma replaces normal marrow; woven bone trabeculae form without osteoblast rimming",
            "Bone weaker structurally → deformation, shepherd's crook deformity",
        ],
        gene_involvement=[
            "GNAS1 (20q13.2-q13.3) – encodes Gsα; somatic activating mutations",
            "Same gene mutated in McCune-Albright syndrome (polyostotic + endocrine abnormalities)",
            "Mazabraud syndrome: GNAS1 mutations + soft tissue myxomas",
            "Phenotype severity correlates with timing of mutation during embryogenesis",
        ],
        causes=[
            "Somatic GNAS1 mutation (not inherited) acquired during embryogenesis",
            "Monostotic (70%): isolated single-bone involvement",
            "Polyostotic (30%): multiple bones; may be part of McCune-Albright",
            "No familial transmission",
        ],
        complications=[
            "Pathological fractures and progressive deformity (shepherd's crook femur)",
            "Pain (most common symptom)",
            "Malignant transformation → osteosarcoma (rare, <1%; higher if prior radiation)",
            "McCune-Albright: precocious puberty, hyperthyroidism, Cushing's syndrome",
            "Vision/hearing loss (craniofacial involvement)",
        ],
        microscopy_notes=[
            "LPO (4x): Intramedullary fibrous tissue replacing marrow; lytic appearance",
            "HPO (10x): Curvilinear woven bone trabeculae (C/S-shapes) – 'Chinese letters' pattern",
            "HPO (40x): NO osteoblastic rimming of trabeculae (distinguishes from normal bone)",
            "Background: bland fibroblastic stroma; occasional foamy macrophages; cystic degeneration",
        ],
        image_urls=[
            "https://cdn.orris.care/cdss_images/5a21dfcdb6d8aff514799c2d933b147235b970d98aa8a6f218ef8296df2a7fdc.png",
        ],
        magnifications=[
            "Fibrous dysplasia: curvilinear woven bone trabeculae without osteoblastic rimming (HPO 10x) – Source: Robbins Basic Pathology"
        ]
    ),

    # ── 193 GIANT CELL TUMOR ─────────────────────────────────────────────
    dict(
        title="Giant Cell Tumor of Bone",
        specimen_no="193",
        subtitle="Locally aggressive epiphyseal tumor – osteoclast-type giant cells",
        pathophysiology=[
            "Neoplastic cells are primitive osteoblast precursors overexpressing RANKL",
            "RANKL → stimulates osteoclast precursor proliferation and differentiation",
            "Osteoclasts (multinucleate giant cells) destroy bone without feedback inhibition",
            "Result: soap-bubble lytic lesion in epiphysis → cortical destruction",
        ],
        gene_involvement=[
            "H3F3A – histone H3.3 mutations (G34W/L) in >90% of giant cell tumors",
            "RANKL (TNFSF11) overexpressed by neoplastic stromal cells",
            "Denosumab (anti-RANKL Ab) is therapeutic target",
            "Telomeric associations with chromosome 11, 14, 15, 19p",
        ],
        causes=[
            "Unknown etiology; 3rd–5th decade of life",
            "Women slightly more affected than men (1.5:1 F:M)",
            "Rare secondary GCT: post-Paget disease",
            "Prior radiation – may trigger malignant GCT",
        ],
        complications=[
            "40–60% local recurrence after curettage",
            "Pathological fracture (presents as first symptom in some cases)",
            "Lung metastases in ~4% (behave benignly – excisable)",
            "Malignant transformation (rare): prior radiation accelerates",
            "Joint destruction and secondary osteoarthritis",
        ],
        microscopy_notes=[
            "LPO (4x): Diffuse sheets of cells with scattered giant cells throughout",
            "HPO (10x): Multinucleate osteoclast-type giant cells (>100 nuclei) among mononuclear stromal cells",
            "HPO (40x): Giant cell nuclei identical to mononuclear stromal cell nuclei (key feature)",
            "Red-brown hemorrhagic gross appearance; cystic degeneration common",
        ],
        image_urls=[
            "https://cdn.orris.care/cdss_images/2bf6f33114d8a1646207191fb7625b3486e4b5003dc1532a29af40ebb9049321.png",
        ],
        magnifications=[
            "Giant cell tumor: abundant multinucleate giant cells + mononuclear stromal cells (HPO 10x) – Source: Robbins Basic Pathology"
        ]
    ),

    # ── 254 OSTEOSARCOMA ──────────────────────────────────────────────────
    dict(
        title="Osteogenic Sarcoma (Osteosarcoma)",
        specimen_no="254",
        subtitle="Most common primary malignant bone tumor; produces osteoid matrix",
        pathophysiology=[
            "Malignant osteoblastic cells produce disorganized osteoid / woven bone",
            "Arises in metaphysis of rapidly growing bones (↑ cell proliferation → mutation risk)",
            "Tumor invades cortex → periosteum elevation → Codman triangle (reactive bone)",
            "Aggressive angiogenesis; early hematogenous spread (lungs most common)",
        ],
        gene_involvement=[
            "RB1 (13q14) – retinoblastoma gene; loss of heterozygosity; hereditary Rb → 500× risk",
            "TP53 – mutations in ~50% sporadic cases; Li-Fraumeni syndrome",
            "MDM2 amplification – secondary osteosarcoma in older adults",
            "CDKN2A loss; DLX5/DLX6 dysregulation; RUNX2 overexpression",
        ],
        causes=[
            "Primary: adolescents 10–20 yr (rapid bone growth); M > F (1.6:1)",
            "Secondary: Paget disease, bone infarcts, prior radiation exposure",
            "Hereditary Rb, Li-Fraumeni syndrome, Rothmund-Thomson syndrome",
            "Location: metaphysis of distal femur > proximal tibia > proximal humerus",
        ],
        complications=[
            "Pulmonary metastases (most common, 15–20% at diagnosis)",
            "Pathological fracture (Codman triangle)",
            "Skip lesions in same bone (discontiguous tumor foci)",
            "Post-treatment: limb salvage complications; second sarcoma from chemo",
            "5-year survival: ~70% with chemotherapy + surgery",
        ],
        microscopy_notes=[
            "LPO (4x): Malignant spindle cells producing pink osteoid matrix in lace-like pattern",
            "HPO (10x): Pleomorphic osteoblast-like cells with hyperchromatic nuclei + pink osteoid",
            "HPO (40x): Marked nuclear atypia, atypical mitoses, tumor giant cells + osteoid production",
            "Key: Tumor osteoid (pink homogeneous matrix) = diagnostic hallmark",
        ],
        image_urls=[
            "https://cdn.orris.care/cdss_images/393983627f910dbe2890e4171c6754c66b496a5b5bb49f34427b6303fced4c9a.png",
        ],
        magnifications=[
            "Osteosarcoma distal femur: Codman triangle (arrow) on X-ray – Source: Robbins Basic Pathology"
        ]
    ),

    # ── 92 EWING'S TUMOR ─────────────────────────────────────────────────
    dict(
        title="Ewing's Sarcoma / Ewing Tumor",
        specimen_no="92",
        subtitle="Malignant small round blue cell tumor; EWSR1 gene translocation",
        pathophysiology=[
            "EWS-FLI1 fusion protein dysregulates transcription → uncontrolled proliferation",
            "Arises in diaphysis; invades cortex and periosteum",
            "Periosteal reaction → onion-skin layers of reactive bone (radiologic hallmark)",
            "No bone or cartilage production by tumor cells (unlike osteosarcoma)",
            "Rich glycogen in cytoplasm → PAS-positive clear cells",
        ],
        gene_involvement=[
            "t(11;22)(q24;q12) – EWSR1::FLI1 fusion in >85% of cases",
            "t(21;22)(q22;q12) – EWSR1::ERG fusion in ~10%",
            "EWS gene on chr 22 – encodes RNA-binding protein",
            "FLI1 – ETS family transcription factor; dysregulates growth genes",
            "STAG2, TP53, CDKN2A – secondary mutations in advanced cases",
        ],
        causes=[
            "Unknown; Caucasians >> African/Asian populations",
            "Age: 80% under 20 years; slight male predominance",
            "Diaphysis of long bones (femur, tibia) and flat bones (pelvis, ribs)",
            "No strong hereditary predisposition",
        ],
        complications=[
            "Metastases (lungs, other bones, bone marrow) – 25% at diagnosis",
            "Pathological fracture",
            "Fever and elevated ESR mimic infection (can delay diagnosis)",
            "Treatment-related: secondary leukemia from alkylating agents",
            "5-year survival: ~70% localized; 30% metastatic",
        ],
        microscopy_notes=[
            "LPO (4x): Sheets of small round blue cells; no matrix production",
            "HPO (10x): Uniform small cells slightly larger than lymphocytes; scant cytoplasm",
            "HPO (40x): Round nuclei, fine chromatin; clear cytoplasm (glycogen); Homer-Wright rosettes",
            "PAS stain: POSITIVE (cytoplasmic glycogen); CD99 (MIC2) strongly positive by IHC",
        ],
        image_urls=[
            "https://cdn.orris.care/cdss_images/30c8480a7f30bce53774d5e9ad4323fcd0eab819c9a6ca6421bec20de23f6393.png",
        ],
        magnifications=[
            "Ewing sarcoma: sheets of small round cells with minimal clear cytoplasm (HPO 10x) – Source: Robbins Basic Pathology"
        ]
    ),

    # ── 13 GOUT ──────────────────────────────────────────────────────────
    dict(
        title="Gout",
        specimen_no="13",
        subtitle="Crystal arthropathy from monosodium urate deposition",
        pathophysiology=[
            "Hyperuricemia → supersaturation → MSU crystal deposition in joints/soft tissue",
            "Crystals activate NLRP3 inflammasome → IL-1β, IL-18 release",
            "Massive neutrophil infiltration → acute inflammation, cartilage damage",
            "Chronic tophaceous gout: urate crystals surrounded by foreign-body giant cells",
            "MSU crystals: negatively birefringent, needle-shaped under polarized light",
        ],
        gene_involvement=[
            "ABCG2 (BCRP) – major uric acid transporter; variants ↑ serum urate",
            "SLC22A12 (URAT1) – urate reabsorption in renal tubule; loss-of-function = hypouricemia",
            "SLC2A9 (GLUT9) – fructose/urate transporter; SNPs strongly associated",
            "ALDH16A1, PDZK1 – GWAS-identified loci for hyperuricemia",
        ],
        causes=[
            "Primary: inborn errors – HPRT deficiency (Lesch-Nyhan), PRPP synthetase overactivity",
            "Secondary: myeloproliferative disorders, psoriasis (↑ cell turnover → ↑ purines)",
            "Drugs: thiazide diuretics, low-dose aspirin, cyclosporine → ↓ urate excretion",
            "Diet: purine-rich foods (red meat, organ meat, beer, shellfish)",
            "Renal insufficiency – impaired urate excretion",
        ],
        complications=[
            "Chronic tophaceous gout – joint deformity, functional impairment",
            "Urate nephropathy and nephrolithiasis (uric acid stones)",
            "Cardiovascular disease (hyperuricemia is independent risk factor)",
            "Secondary osteoarthritis from cartilage erosion",
        ],
        microscopy_notes=[
            "LPO (4x): Tophi – amorphous crystalline deposits (MSU) in fibrous tissue",
            "HPO (10x): Needle-shaped urate crystals (dissolved in formalin → ghost spaces)",
            "HPO (40x): Foreign-body giant cell granulomatous reaction around crystal spaces",
            "Polarized light: negatively birefringent needle crystals – diagnostic gold standard",
        ],
        image_urls=[
            "https://cdn.orris.care/cdss_images/9eca3095a6a7a10ade646ec1abc2b62ab291a9fab6b5512a70acbefb669354ec.png",
        ],
        magnifications=[
            "OA pathway diagram (analogous joint destruction mechanism) – Source: Robbins Basic Pathology"
        ]
    ),

    # ── 196 RHEUMATOID ARTHRITIS ─────────────────────────────────────────
    dict(
        title="Rheumatoid Arthritis (RA)",
        specimen_no="196",
        subtitle="Chronic systemic autoimmune joint destruction; symmetric polyarthritis",
        pathophysiology=[
            "Citrullinated peptides presented by HLA-DR4/DR1 → autoreactive T cell activation",
            "T cells activate B cells → ACPA (anti-CCP) + RF production",
            "Synovial hyperplasia → pannus formation – aggressive granulation tissue",
            "Pannus invades and erodes cartilage + subchondral bone (TNF, IL-1, IL-6, MMPs)",
            "End stage: fibrous or bony ankylosis (joint fusion)",
        ],
        gene_involvement=[
            "HLA-DRB1 (SE alleles) – 'Shared Epitope' at positions 70–74: strongest genetic risk",
            "PTPN22 – protein tyrosine phosphatase; LYP variant ↑ T cell activation",
            "CTLA4 variants – reduced T cell co-stimulatory control",
            "PADI4 – citrullination enzyme; SNPs increase ACPA production",
        ],
        causes=[
            "Autoimmune – exact trigger unknown; molecular mimicry suspected",
            "Smoking – strongest environmental risk; promotes citrullination",
            "HLA-DR4/DR1 haplotype (genetic predisposition)",
            "Women 3× more affected; peak onset 40–60 years",
        ],
        complications=[
            "Joint deformity: swan neck, boutonniere, ulnar deviation, Z-thumb",
            "Atlantoaxial subluxation → spinal cord compression",
            "Rheumatoid nodules (skin, lungs, heart valves)",
            "Vasculitis, Felty's syndrome (RA + splenomegaly + neutropenia)",
            "Secondary amyloidosis (AA); increased cardiovascular mortality",
            "Caplan syndrome (RA + pneumoconiosis nodules)",
        ],
        microscopy_notes=[
            "LPO (4x): Synovial villous hypertrophy; pannus extending over cartilage",
            "HPO (10x): Dense lymphoplasmacytic infiltrate in synovium; germinal centers",
            "HPO (40x): Pannus – fibrovascular granulation tissue at cartilage-pannus junction",
            "Rheumatoid nodule: central fibrinoid necrosis + palisading histiocytes",
        ],
        image_urls=[
            "https://cdn.orris.care/cdss_images/9eca3095a6a7a10ade646ec1abc2b62ab291a9fab6b5512a70acbefb669354ec.png",
        ],
        magnifications=[
            "Joint destruction diagram illustrating pannus/inflammatory cascade – Source: Robbins Basic Pathology"
        ]
    ),

    # ── 200 OSTEOARTHRITIS ────────────────────────────────────────────────
    dict(
        title="Osteoarthritis (OA) – Degenerative Joint Disease",
        specimen_no="200",
        subtitle="Most common joint disease; primary cartilage degeneration",
        pathophysiology=[
            "Biomechanical stress → chondrocyte injury → ↑ MMP-1, MMP-3, MMP-13 (collagen breakdown)",
            "↑ NO, PGE2, IL-1β, TNF → further matrix degradation",
            "Chondrocyte hypertrophy and apoptosis → loss of type II collagen + aggrecan",
            "Subchondral bone sclerosis; cyst formation; osteophyte (bone spur) formation at joint margins",
            "Cartilage fibrillation → eburnation (ivory-like polished bone)",
        ],
        gene_involvement=[
            "COL2A1 – type II collagen gene mutations in familial OA",
            "GDF5 – growth differentiation factor; joint development variants ↑ risk",
            "TGFB1, BMP2 – chondroprotective vs. pro-osteophyte roles",
            "ALDH1A2, LTBP3 – identified in GWAS for hip/knee OA",
            "Mitochondrial mtDNA haplogroups – modulate cartilage oxidative stress",
        ],
        causes=[
            "Primary: aging, obesity, female gender, genetic predisposition",
            "Secondary: previous joint trauma, meniscectomy, congenital dysplasia",
            "Joint hypermobility, inflammatory arthropathies, crystal deposition",
            "Weight-bearing joints: knees, hips, lumbar spine; hands (DIP joints)",
        ],
        complications=[
            "Progressive disability and loss of function",
            "Heberden's nodes (DIP) and Bouchard's nodes (PIP) in hands",
            "Secondary synovitis – mild inflammation from released cartilage debris",
            "Subchondral cyst rupture → loose bodies (joint mice)",
            "Genu varus/valgus deformity; hip arthroplasty required in advanced disease",
        ],
        microscopy_notes=[
            "LPO (4x): Cartilage fibrillation (surface irregularity) and full-thickness fissures",
            "HPO (10x): Chondrocyte loss ('empty lacunae'); tidemark duplication",
            "HPO (40x): Chondrocyte cloning (cluster formation) – attempted repair response",
            "Subchondral bone: sclerosis; reactive new bone; subchondral cysts lined by fibrous tissue",
        ],
        image_urls=[
            "https://cdn.orris.care/cdss_images/9eca3095a6a7a10ade646ec1abc2b62ab291a9fab6b5512a70acbefb669354ec.png",
        ],
        magnifications=[
            "OA schematic: injury → early → late OA with cellular changes labeled – Source: Robbins Basic Pathology"
        ]
    ),

    # ── 22 SKIN FIBROSARCOMA ──────────────────────────────────────────────
    dict(
        title="Fibrosarcoma (Skin / Dermatofibrosarcoma Protuberans)",
        specimen_no="22",
        subtitle="Malignant fibroblastic tumor with herringbone (fascicular) pattern",
        pathophysiology=[
            "Malignant proliferation of fibroblasts producing abundant collagen",
            "DFSP variant: t(17;22) → COL1A1-PDGFB fusion → constitutive PDGF receptor activation",
            "Cells arranged in interlacing fascicles producing characteristic 'herringbone' pattern",
            "Local invasion along fascial planes; low metastatic potential (conventional DFSP)",
        ],
        gene_involvement=[
            "COL1A1-PDGFB fusion (t(17;22)) – in DFSP; PDGFR-beta constitutive activation",
            "TP53, RB1 – mutations in high-grade fibrosarcoma",
            "TERT promoter mutations – in aggressive variants",
            "NF1 – neurofibromatosis 1 patients have increased risk",
        ],
        causes=[
            "Sporadic; prior radiation exposure or scar tissue (rare trigger)",
            "DFSP: young to middle-aged adults; trunk and proximal extremities",
            "High-grade fibrosarcoma: may arise de novo or from dedifferentiated DFSP",
            "Trauma/burn scar (rare trigger for sarcoma transformation)",
        ],
        complications=[
            "Local recurrence after excision (>50% if inadequate margins)",
            "Distant metastases in high-grade lesions (lungs most common)",
            "Fibrosarcomatous transformation of DFSP → worse prognosis",
            "Imatinib effective in COL1A1-PDGFB fusion DFSP (targeted therapy)",
        ],
        microscopy_notes=[
            "LPO (4x): Highly cellular spindle cell neoplasm with fascicular growth",
            "HPO (10x): HERRINGBONE pattern – intersecting fascicles at acute angles",
            "HPO (40x): Elongated fibroblasts with tapered nuclei; variable mitoses; collagen between cells",
            "DFSP: storiform pattern; CD34 positive by IHC; factor XIIIa negative",
        ],
        image_urls=[
            "https://cdn.orris.care/cdss_images/83654b8c6e0775a6e6f779333ed07a555d473664e3e113269c5b9351f32b3cd7.png",
        ],
        magnifications=[
            "Spindle cell storiform pattern – fibrous cortical defect (analogous architecture, HPO 10x) – Source: Robbins Basic Pathology"
        ]
    ),

    # ── 23 RHABDOMYOSARCOMA ───────────────────────────────────────────────
    dict(
        title="Rhabdomyosarcoma",
        specimen_no="23",
        subtitle="Most common soft tissue sarcoma in children; skeletal muscle differentiation",
        pathophysiology=[
            "Malignant cells show skeletal muscle differentiation (desmin, myogenin, MyoD1 positive)",
            "Embryonal type: loss of heterozygosity at 11p15.5 → IGF2 overexpression",
            "Alveolar type: PAX3/7-FOXO1 fusion → transcriptional dysregulation",
            "Cells range from round (embryonal) to strap cells with cross-striations (rhabdomyoblasts)",
        ],
        gene_involvement=[
            "PAX3-FOXO1 t(2;13)(q36;q14) – alveolar RMS; ~55% cases; poor prognosis",
            "PAX7-FOXO1 t(1;13)(p36;q14) – alveolar RMS; ~22% cases; better prognosis",
            "IGF2 overexpression at 11p15.5 – embryonal RMS",
            "RAS mutations (NRAS, KRAS, HRAS) – embryonal RMS; NF1 association",
            "TP53 mutations in pleomorphic RMS (adults)",
        ],
        causes=[
            "Children 2–6 yr (embryonal) and 10–18 yr (alveolar)",
            "Head and neck (orbit), GU tract, extremities, retroperitoneum",
            "Li-Fraumeni syndrome (TP53), NF1, Costello syndrome (HRAS)",
            "No known environmental causes",
        ],
        complications=[
            "Local invasion of critical structures (orbit, CNS, airway)",
            "Regional lymph node and hematogenous metastases (lungs, bone marrow)",
            "5-year survival: ~70% localized; <30% metastatic",
            "Treatment: multimodal – surgery + radiation + vincristine/actinomycin/cyclophosphamide",
        ],
        microscopy_notes=[
            "LPO (4x): Cellular neoplasm with variable architecture (solid, alveolar, botryoid)",
            "HPO (10x): Small round to oval cells with hyperchromatic nuclei; variable stroma",
            "HPO (40x): RHABDOMYOBLASTS – strap cells with bright eosinophilic cytoplasm; cross-striations",
            "Alveolar: fibrous septa with discohesive cells clinging to borders (alveolar pattern)",
            "IHC: Desmin, MyoD1, Myogenin (nuclear) – gold standard for diagnosis",
        ],
        image_urls=[
            "https://cdn.orris.care/cdss_images/09901ef8609aabfcb9ead3c147af51ca5f50e4dc892ab4dc10640ab0fc93e25a.png",
        ],
        magnifications=[
            "Chondrosarcoma matrix (analogous cellular sarcoma – source image) – Source: Robbins Basic Pathology"
        ]
    ),

    # ── 25 LIPOSARCOMA ────────────────────────────────────────────────────
    dict(
        title="Liposarcoma",
        specimen_no="25",
        subtitle="Most common soft tissue sarcoma in adults; lipoblast differentiation",
        pathophysiology=[
            "Malignant cells recapitulate different stages of adipocyte differentiation",
            "Well-differentiated (WD-LPS): MDM2/CDK4 amplification → p53 suppression",
            "Myxoid/round cell: FUS-DDIT3 fusion → disrupted adipogenesis",
            "Dedifferentiated: progression from WD-LPS with additional genomic instability",
            "Lipoblasts (diagnostic hallmark): scalloped nucleus, multi-vacuolated cytoplasm",
        ],
        gene_involvement=[
            "MDM2 amplification (12q15) – WD/dedifferentiated LPS; diagnostic by FISH",
            "CDK4 amplification – co-amplified with MDM2; inhibits Rb pathway",
            "FUS-DDIT3 (TLS-CHOP) fusion – myxoid LPS t(12;16)(q13;p11)",
            "EWSR1-DDIT3 – alternative fusion in myxoid LPS",
            "RB1, TP53 – loss in high-grade/dedifferentiated LPS",
        ],
        causes=[
            "Adults 40–70 years; retroperitoneum and deep soft tissue of extremities",
            "No clear environmental etiology; rare radiation-associated cases",
            "No specific hereditary syndrome strongly associated",
            "Retroperitoneal: often WD or dedifferentiated; extremity: myxoid most common",
        ],
        complications=[
            "Local recurrence (retroperitoneal LPS nearly universally recurs)",
            "Dedifferentiated/round cell/pleomorphic: distant metastases (lungs)",
            "Large retroperitoneal masses compress adjacent structures (kidney, bowel)",
            "WD-LPS: excellent prognosis; dedifferentiated: 5-yr survival 25–30%",
        ],
        microscopy_notes=[
            "LPO (4x): WD-LPS – mature adipocytes with scattered lipoblasts and fibrous septa",
            "HPO (10x): LIPOBLAST – cell with indented/scalloped nucleus pushed to periphery by fat vacuoles",
            "Myxoid LPS (10x): Uniform round to oval cells in myxoid stroma + plexiform capillary network",
            "HPO (40x): Lipoblast diagnostic detail: multivacuolated, scalloped nucleus",
            "Dedifferentiated: high-grade spindle cell component adjacent to WD area",
        ],
        image_urls=[
            "https://cdn.orris.care/cdss_images/960402e8e961c8538b23d35d588ab9fe3d2eae931dd42cdbebbb489973f4a602.png",
        ],
        magnifications=[
            "Enchondroma hand X-ray (source image) – Liposarcoma IHC: S100+, MDM2 FISH in WD-LPS – Source: Robbins Basic Pathology"
        ]
    ),

    # ── 101 LEIOMYOSARCOMA ────────────────────────────────────────────────
    dict(
        title="Leiomyosarcoma",
        specimen_no="101",
        subtitle="Malignant smooth muscle tumor; retroperitoneum and large vessels",
        pathophysiology=[
            "Malignant proliferation of smooth muscle cells showing actin + desmin expression",
            "High genomic complexity (unlike RMS); multiple chromosomal losses and gains",
            "RB1/p53 pathway inactivation central to pathogenesis",
            "Spindle cells with cigar-shaped (blunt-ended) nuclei; fascicular growth",
            "Vascular smooth muscle origin in some (IVC, uterine vessels)",
        ],
        gene_involvement=[
            "RB1 deletion/mutation – present in ~50% of LMS",
            "TP53 mutations and 17p loss – common in high-grade LMS",
            "ATRX mutations – chromatin remodeling; correlate with ALT telomere maintenance",
            "PTEN loss; complex karyotype (not a defining translocation like other sarcomas)",
            "MED12 mutations – in uterine LMS",
        ],
        causes=[
            "Adults, 50–70 years; slight female predominance",
            "Sites: retroperitoneum, uterus, IVC, GI tract, skin",
            "Rare: prior radiation exposure; EBV-associated in immunocompromised",
            "Sporadic – no hereditary syndrome typical",
        ],
        complications=[
            "Local recurrence after resection (retroperitoneal >50%)",
            "Hematogenous metastases – lungs and liver most common",
            "Retroperitoneal LMS: often large at presentation; difficult complete resection",
            "Uterine LMS: may be misdiagnosed as leiomyoma (fibroid) pre-op",
            "5-year survival: 15–60% depending on grade and site",
        ],
        microscopy_notes=[
            "LPO (4x): Interlacing fascicles of spindle cells in perpendicular arrangement",
            "HPO (10x): Eosinophilic spindle cells; blunt-ended (cigar-shaped) nuclei; fascicular pattern",
            "HPO (40x): Nuclear pleomorphism + atypical mitoses; perinuclear vacuoles",
            "IHC: SMA, desmin, h-caldesmon positive; S100 and CD34 negative",
            "Masson trichrome: red cytoplasmic filaments (myofibrils)",
        ],
        image_urls=[
            "https://cdn.orris.care/cdss_images/83654b8c6e0775a6e6f779333ed07a555d473664e3e113269c5b9351f32b3cd7.png",
        ],
        magnifications=[
            "Spindle cell fascicular pattern (analogous architecture – LPO/HPO) – Source: Robbins Basic Pathology"
        ]
    ),
]

# Build all slides
for d in slides_data:
    content_slide(**d)

# Save
out = "/tmp/workspace/bone-pathology-ppt/Bone_Joint_Pathology_Lab.pptx"
prs.save(out)
print(f"SAVED: {out}  ({len(prs.slides)} slides)")

Successfully replaced 1 instance(s) of the string in '/tmp/workspace/bone-pathology-ppt/build_ppt.py'