from reportlab.lib.pagesizes import A4
from reportlab.lib import colors
from reportlab.lib.units import cm, mm
from reportlab.lib.styles import getSampleStyleSheet, ParagraphStyle
from reportlab.lib.enums import TA_LEFT, TA_CENTER, TA_JUSTIFY
from reportlab.platypus import (SimpleDocTemplate, Paragraph, Spacer, Table,
                                 TableStyle, HRFlowable, PageBreak, KeepTogether)
from reportlab.platypus.tableofcontents import TableOfContents
from reportlab.pdfbase import pdfmetrics
from reportlab.pdfbase.ttfonts import TTFont
import os

OUTPUT = "/home/daytona/workspace/lymphoma-notes/Lymphoma_Harrison_NEET_SS_Notes.pdf"

# ─── Color palette ──────────────────────────────────────────────────────────
DARK_BLUE   = colors.HexColor("#1a2f5a")
MED_BLUE    = colors.HexColor("#2563a8")
LIGHT_BLUE  = colors.HexColor("#dbeafe")
ACCENT_TEAL = colors.HexColor("#0d9488")
ACCENT_PURPLE= colors.HexColor("#7c3aed")
HIGHLIGHT   = colors.HexColor("#fef9c3")
HIGHLIGHT2  = colors.HexColor("#fce7f3")
HIGHLIGHT3  = colors.HexColor("#dcfce7")
RED_ACCENT  = colors.HexColor("#dc2626")
ORANGE      = colors.HexColor("#ea580c")
GRAY_BG     = colors.HexColor("#f1f5f9")
GRAY_LINE   = colors.HexColor("#cbd5e1")
WHITE       = colors.white
BLACK       = colors.black

doc = SimpleDocTemplate(
    OUTPUT,
    pagesize=A4,
    rightMargin=1.8*cm, leftMargin=1.8*cm,
    topMargin=2*cm, bottomMargin=2*cm,
    title="Lymphoma – Harrison's 22E | NEET SS / PG Notes",
    author="Orris AI – Harrison's Principles of Internal Medicine 22E"
)

W, H = A4
CW = W - 3.6*cm  # content width

styles = getSampleStyleSheet()

# Custom styles
def ms(name, parent="Normal", **kw):
    return ParagraphStyle(name, parent=styles[parent], **kw)

cover_title  = ms("CoverTitle",  fontSize=28, textColor=WHITE, alignment=TA_CENTER, leading=36, fontName="Helvetica-Bold")
cover_sub    = ms("CoverSub",    fontSize=14, textColor=colors.HexColor("#bfdbfe"), alignment=TA_CENTER, leading=20)
cover_ref    = ms("CoverRef",    fontSize=10, textColor=colors.HexColor("#93c5fd"), alignment=TA_CENTER)

h1style = ms("H1", fontSize=16, textColor=WHITE, fontName="Helvetica-Bold",
             spaceAfter=4, spaceBefore=12, leading=20, leftIndent=0)
h2style = ms("H2", fontSize=13, textColor=DARK_BLUE, fontName="Helvetica-Bold",
             spaceAfter=4, spaceBefore=10, leading=17,
             borderPad=4, leftIndent=0)
h3style = ms("H3", fontSize=11, textColor=ACCENT_TEAL, fontName="Helvetica-Bold",
             spaceAfter=3, spaceBefore=6, leading=15)
h4style = ms("H4", fontSize=10, textColor=ACCENT_PURPLE, fontName="Helvetica-Bold",
             spaceAfter=2, spaceBefore=4, leading=13)

body = ms("Body", fontSize=9.5, leading=14, spaceAfter=4, alignment=TA_JUSTIFY)
bullet = ms("Bullet", fontSize=9.5, leading=13, spaceAfter=2,
            leftIndent=12, bulletIndent=0)
subbullet = ms("SubBullet", fontSize=9, leading=12, spaceAfter=2,
               leftIndent=24, bulletIndent=12)
highlight_box = ms("HLBox", fontSize=9.5, leading=13, spaceAfter=3,
                   backColor=HIGHLIGHT, leftIndent=6, rightIndent=6,
                   borderPad=5)
imp_box = ms("ImpBox", fontSize=9.5, leading=13, spaceAfter=3,
             backColor=HIGHLIGHT2, leftIndent=6, rightIndent=6, borderPad=5)
green_box = ms("GreenBox", fontSize=9.5, leading=13, spaceAfter=3,
               backColor=HIGHLIGHT3, leftIndent=6, rightIndent=6, borderPad=5)
small_italic = ms("SmItalic", fontSize=8.5, leading=11, textColor=colors.HexColor("#64748b"), fontName="Helvetica-Oblique")

def b(text): return f"<b>{text}</b>"
def i(text): return f"<i>{text}</i>"
def bi(text): return f"<b><i>{text}</i></b>"
def c(text, col): return f'<font color="{col}">{text}</font>'
def red(t): return c(t, "#dc2626")
def blue(t): return c(t, "#1d4ed8")
def teal(t): return c(t, "#0d9488")
def purple(t): return c(t, "#7c3aed")
def orange(t): return c(t, "#ea580c")

# ─── Helper builders ────────────────────────────────────────────────────────
def section_header(title, color=DARK_BLUE, bg=LIGHT_BLUE):
    data = [[Paragraph(f"<b>{title}</b>", ParagraphStyle("SH", fontSize=13, textColor=WHITE,
             fontName="Helvetica-Bold", leading=18, alignment=TA_LEFT))]]
    t = Table(data, colWidths=[CW])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), color),
        ("TOPPADDING", (0,0), (-1,-1), 7),
        ("BOTTOMPADDING", (0,0), (-1,-1), 7),
        ("LEFTPADDING", (0,0), (-1,-1), 12),
        ("ROUNDEDCORNERS", [6,6,6,6]),
    ]))
    return t

def subsection_header(title, color=ACCENT_TEAL):
    data = [[Paragraph(f"<b>{title}</b>", ParagraphStyle("SSH", fontSize=11.5, textColor=WHITE,
             fontName="Helvetica-Bold", leading=16))]]
    t = Table(data, colWidths=[CW])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), color),
        ("TOPPADDING", (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
        ("LEFTPADDING", (0,0), (-1,-1), 10),
    ]))
    return t

def info_table(rows, col_widths=None, header_bg=DARK_BLUE):
    if col_widths is None:
        col_widths = [CW/len(rows[0])]*len(rows[0])
    header = rows[0]
    data = []
    for i, row in enumerate(rows):
        data.append([Paragraph(str(cell), ParagraphStyle(f"TC{i}", fontSize=8.5, leading=12,
                     fontName="Helvetica-Bold" if i==0 else "Helvetica",
                     textColor=WHITE if i==0 else BLACK)) for cell in row])
    t = Table(data, colWidths=col_widths)
    style = [
        ("BACKGROUND", (0,0), (-1,0), header_bg),
        ("BACKGROUND", (0,1), (-1,-1), GRAY_BG),
        ("ROWBACKGROUNDS", (0,1), (-1,-1), [WHITE, GRAY_BG]),
        ("GRID", (0,0), (-1,-1), 0.4, GRAY_LINE),
        ("TOPPADDING", (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
        ("LEFTPADDING", (0,0), (-1,-1), 6),
        ("RIGHTPADDING", (0,0), (-1,-1), 6),
        ("VALIGN", (0,0), (-1,-1), "TOP"),
    ]
    t.setStyle(TableStyle(style))
    return t

def two_col(left_items, right_items, left_title="", right_title="",
            lbg=LIGHT_BLUE, rbg=HIGHLIGHT3):
    def build_cell(title, items, bg):
        paras = []
        if title:
            paras.append(Paragraph(f"<b>{title}</b>",
                ParagraphStyle("CT", fontSize=9.5, fontName="Helvetica-Bold",
                               textColor=DARK_BLUE, leading=14, spaceAfter=4)))
        for item in items:
            paras.append(Paragraph(f"• {item}",
                ParagraphStyle("CI", fontSize=9, leading=13, spaceAfter=2)))
        data = [[paras]]
        t = Table(data, colWidths=[(CW/2)-4])
        t.setStyle(TableStyle([
            ("BACKGROUND", (0,0), (-1,-1), bg),
            ("TOPPADDING", (0,0), (-1,-1), 7),
            ("BOTTOMPADDING", (0,0), (-1,-1), 7),
            ("LEFTPADDING", (0,0), (-1,-1), 8),
            ("RIGHTPADDING", (0,0), (-1,-1), 8),
            ("VALIGN", (0,0), (-1,-1), "TOP"),
        ]))
        return t
    outer = Table([[build_cell(left_title, left_items, lbg),
                    build_cell(right_title, right_items, rbg)]],
                  colWidths=[CW/2, CW/2], hAlign="LEFT")
    outer.setStyle(TableStyle([("LEFTPADDING",(0,0),(-1,-1),0),
                                ("RIGHTPADDING",(0,0),(-1,-1),0),
                                ("TOPPADDING",(0,0),(-1,-1),0),
                                ("BOTTOMPADDING",(0,0),(-1,-1),0)]))
    return outer

def mnemonic_box(title, content, bg=colors.HexColor("#fffbeb")):
    paras = [Paragraph(f"<b>🔑 {title}</b>",
        ParagraphStyle("MT", fontSize=10, fontName="Helvetica-Bold",
                       textColor=colors.HexColor("#92400e"), leading=14, spaceAfter=4))]
    if isinstance(content, list):
        for c in content:
            paras.append(Paragraph(c, ParagraphStyle("MC", fontSize=9.5, leading=13)))
    else:
        paras.append(Paragraph(content, ParagraphStyle("MC", fontSize=9.5, leading=13)))
    data = [[paras]]
    t = Table(data, colWidths=[CW])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), bg),
        ("TOPPADDING", (0,0), (-1,-1), 8),
        ("BOTTOMPADDING", (0,0), (-1,-1), 8),
        ("LEFTPADDING", (0,0), (-1,-1), 12),
        ("RIGHTPADDING", (0,0), (-1,-1), 12),
        ("BOX", (0,0), (-1,-1), 1.5, colors.HexColor("#f59e0b")),
    ]))
    return t

def key_point(text):
    data = [[Paragraph(f"⭐ <b>{text}</b>",
        ParagraphStyle("KP", fontSize=9.5, leading=13,
                       textColor=colors.HexColor("#7c2d12")))]]
    t = Table(data, colWidths=[CW])
    t.setStyle(TableStyle([
        ("BACKGROUND", (0,0), (-1,-1), colors.HexColor("#fff7ed")),
        ("LEFTPADDING", (0,0), (-1,-1), 10),
        ("TOPPADDING", (0,0), (-1,-1), 5),
        ("BOTTOMPADDING", (0,0), (-1,-1), 5),
        ("LEFTBORDER", (0,0), (0,-1), 4),
        ("LINEABOVE", (0,0), (-1,0), 0.3, GRAY_LINE),
    ]))
    return t

# ═══════════════════════════════════════════════════════════════════════════
# BUILD DOCUMENT
# ═══════════════════════════════════════════════════════════════════════════
story = []
P = Paragraph
SP = Spacer
HR = HRFlowable

def sp(h=6): return SP(0, h)

# ─── COVER PAGE ─────────────────────────────────────────────────────────────
# Blue banner background via table
cover_data = [[P("", cover_title)]]
cover_tbl = Table([[
    P("LYMPHOMA", ParagraphStyle("CT1", fontSize=32, textColor=WHITE,
       fontName="Helvetica-Bold", alignment=TA_CENTER, leading=40)),
]], colWidths=[CW])
cover_tbl.setStyle(TableStyle([
    ("BACKGROUND", (0,0), (-1,-1), DARK_BLUE),
    ("TOPPADDING", (0,0), (-1,-1), 40),
    ("BOTTOMPADDING", (0,0), (-1,-1), 40),
    ("LEFTPADDING", (0,0), (-1,-1), 20),
    ("RIGHTPADDING", (0,0), (-1,-1), 20),
]))
story.append(sp(60))
story.append(cover_tbl)
story.append(sp(16))
story.append(P("Complete Notes for NEET SS / Medical Postgraduate Examinations",
    ParagraphStyle("CS1", fontSize=14, textColor=DARK_BLUE, alignment=TA_CENTER,
                   fontName="Helvetica-Bold", leading=20)))
story.append(sp(6))
story.append(P("Based on Harrison's Principles of Internal Medicine, 22nd Edition (2025)",
    ParagraphStyle("CS2", fontSize=11, textColor=colors.HexColor("#475569"),
                   alignment=TA_CENTER, leading=16)))
story.append(sp(6))
story.append(HR(width=CW*0.6, color=GRAY_LINE, thickness=1, hAlign="CENTER"))
story.append(sp(8))

topics = ["Non-Hodgkin's Lymphoma (NHL) | Hodgkin's Lymphoma (HL)",
          "WHO Classification | Epidemiology | Etiology",
          "Clinical Features | Staging | Prognostic Indices",
          "NHL Subtypes: FL, DLBCL, MCL, BL, MZL, T-cell",
          "HL Subtypes | Reed-Sternberg Cell | Immunophenotype",
          "Treatment Protocols: CHOP, ABVD, R-CHOP, BEACOPP",
          "High-Yield NEET SS Points | Mnemonics"]
for t in topics:
    story.append(P(f"• {t}",
        ParagraphStyle("CT3", fontSize=10, textColor=colors.HexColor("#334155"),
                       alignment=TA_CENTER, leading=16)))
story.append(sp(20))

info_row = [["Source", "Chapters", "Level", "Year"],
            ["Harrison's IM 22E", "113 (NHL), 114 (HL)", "NEET SS / PG", "2025"]]
story.append(info_table(info_row, [CW*0.25, CW*0.3, CW*0.25, CW*0.2]))
story.append(PageBreak())

# ═══════════════════════════════════════════════════════════════════════════
# SECTION 1 – OVERVIEW
# ═══════════════════════════════════════════════════════════════════════════
story.append(section_header("SECTION 1: OVERVIEW & CLASSIFICATION", DARK_BLUE))
story.append(sp(8))

story.append(P("""
Lymphomas are cancers of <b>mature lymphocytes</b> (B, T, or NK cells). They are broadly divided into:
<b>Non-Hodgkin's Lymphoma (NHL)</b> and <b>Hodgkin's Lymphoma (HL)</b>. The key differentiator
is the <b>Reed-Sternberg (RS) cell</b>, which is pathognomonic for HL.
""", body))
story.append(sp(6))

story.append(two_col(
    ["Cancers of mature B, T, NK cells",
     "~80,550 new cases/year (USA, 2023)",
     "7th most common cancer-related death",
     "Variable prognosis – depends on histology",
     "Majority have advanced-stage disease at diagnosis",
     "5-year survival: 74%"],
    ["Malignancy of mature B lymphocytes",
     "~8,830 new cases/year (USA, 2023)",
     "~10% of all lymphomas",
     "Cure rate >85% with modern therapy",
     "Bimodal age distribution (20s and 80s)",
     "Late toxicities now a major challenge"],
    "Non-Hodgkin's Lymphoma (NHL)", "Hodgkin's Lymphoma (HL)"
))
story.append(sp(10))

# WHO Classification Table
story.append(subsection_header("WHO-BIOM Classification of Lymphoid Malignancies (Table 113-1)", ACCENT_TEAL))
story.append(sp(6))
who_data = [
    ["B-CELL NEOPLASMS", "T-CELL / NK-CELL NEOPLASMS"],
    ["Lymphoplasmacytic lymphoma (Waldenström's macroglobulinemia)", "T-cell granular lymphocytic leukemia"],
    ["Hairy cell leukemia", "Adult T-cell leukemia/lymphoma (HTLV-1+)"],
    ["Splenic marginal zone B-cell lymphoma", "Extranodal NK/T-cell lymphoma, nasal type"],
    ["Extranodal marginal zone B-cell lymphoma (MALT type)", "Enteropathy-associated T-cell lymphoma"],
    ["Nodal marginal zone B-cell lymphoma", "Hepatosplenic T-cell lymphoma"],
    ["Follicular lymphoma (FL)", "Subcutaneous panniculitis-like T-cell lymphoma"],
    ["Mantle cell lymphoma (MCL)", "Mycosis fungoides / Sézary syndrome"],
    ["Diffuse large B-cell lymphoma (DLBCL)", "Peripheral T-cell lymphoma NOS"],
    ["High-grade B-cell lymphoma with MYC and BCL2 rearrangements (Double-hit)", "Angioimmunoblastic T-cell lymphoma"],
    ["Burkitt's lymphoma/Burkitt's cell leukemia", "Anaplastic large-cell lymphoma ALK+ / ALK-"],
    ["Primary mediastinal large B-cell lymphoma", ""],
    ["Primary effusion lymphoma (HHV-8+)", ""],
    ["Plasmablastic lymphoma", ""],
]
story.append(info_table(who_data,
    col_widths=[CW*0.52, CW*0.48],
    header_bg=DARK_BLUE))
story.append(sp(6))
story.append(P(i("Abbreviations: DLBCL – diffuse large B-cell lymphoma; HHV – human herpesvirus; HTLV – human T-cell lymphotropic virus; MALT – mucosa-associated lymphoid tissue; NK – natural killer; NOS – not otherwise specified"), small_italic))
story.append(sp(8))
story.append(mnemonic_box("NEET SS Tip: B vs T Frequency",
    ["• B-cell NHLs are far more common in Western countries (>85% of NHLs).",
     "• T-cell NHLs are more common in <b>Asia</b> than Western countries.",
     "• Follicular lymphoma (FL) is the most common indolent NHL in adults.",
     "• DLBCL is the most common aggressive NHL overall.",
     "• In children: DLBCL and Burkitt's lymphoma predominate."]))
story.append(PageBreak())

# ═══════════════════════════════════════════════════════════════════════════
# SECTION 2 – EPIDEMIOLOGY & ETIOLOGY
# ═══════════════════════════════════════════════════════════════════════════
story.append(section_header("SECTION 2: EPIDEMIOLOGY & ETIOLOGY", DARK_BLUE))
story.append(sp(8))

story.append(subsection_header("2A. Non-Hodgkin's Lymphoma – Epidemiology", ACCENT_TEAL))
story.append(sp(6))
story.append(P("• 80,550 new cases/year (USA 2023) – ~4% of all cancers.", bullet))
story.append(P("• Incidence is nearly <b>10× the incidence of HL</b>.", bullet))
story.append(P("• Incidence <b>doubled over the past 20-40 years</b>; rising 1.5-2%/year.", bullet))
story.append(P("• Slight male predominance; higher in Caucasians vs African Americans.", bullet))
story.append(P("• 5-year survival rate: 74% (higher in Caucasians).", bullet))
story.append(P("• Geographic variation: T-cell NHLs more common in Asia; FL more common in Western countries.", bullet))
story.append(sp(8))

story.append(subsection_header("2B. Infectious Agents Associated with NHL (Table 113-2)", ACCENT_PURPLE))
story.append(sp(6))
inf_data = [
    ["Infectious Agent", "Associated NHL Subtype", "Mechanism/Notes"],
    ["Epstein-Barr Virus (EBV)", "Burkitt's lymphoma (Central Africa); CNS lymphoma in immunosuppressed", "Oncogenic transformation"],
    ["EBV", "Extranodal NK/T-cell lymphoma (nasal type)", "Asia, South America"],
    ["HTLV-1", "Adult T-cell leukemia/lymphoma (ATL)", "Ingestion of breast milk; long latency >56 yrs to oncogenesis"],
    ["HIV", "Aggressive B-cell NHL (DLBCL, BL)", "Via IL-6 overexpression by infected macrophages"],
    ["Helicobacter pylori", "Gastric MALT lymphoma", "Chronic antigenic stimulation → neoplasia; antibiotic Rx causes regression"],
    ["Borrelia species", "MALT lymphoma of skin (Europe)", ""],
    ["Chlamydia psittaci", "MALT lymphoma of eyes", ""],
    ["Campylobacter jejuni", "MALT lymphoma of small intestine", ""],
    ["Hepatitis C virus (HCV)", "Lymphoplasmacytic lymphoma; Splenic MZL", "Chronic infection"],
    ["HHV-8", "Primary effusion lymphoma; Multicentric Castleman's disease", "HIV-infected persons"],
]
story.append(info_table(inf_data,
    col_widths=[CW*0.28, CW*0.42, CW*0.3],
    header_bg=ACCENT_PURPLE))
story.append(sp(8))

story.append(subsection_header("2C. Other Predisposing Conditions", ACCENT_TEAL))
story.append(sp(4))
story.append(two_col(
    ["Primary immunodeficiencies (inherited)",
     "HIV infection / AIDS",
     "Organ transplantation (iatrogenic immunosuppression)",
     "Autoimmune conditions (RA, Sjögren's, SLE)",
     "Agricultural chemical exposures",
     "Prior treatment for Hodgkin's lymphoma"],
    ["Helicobacter pylori (gastric MALT)",
     "Celiac disease → enteropathy-associated T-cell lymphoma",
     "Dermatitis herpetiformis",
     "HTLV-1 infection (ATL)",
     "Hepatitis C (splenic MZL, lymphoplasmacytic)",
     "Borrelia, Chlamydia, Campylobacter (site-specific MALT)"],
    "Immunodeficiency/Systemic", "Infectious/Specific Associations"
))
story.append(sp(8))

story.append(subsection_header("2D. Hodgkin's Lymphoma – Epidemiology", DARK_BLUE))
story.append(sp(6))
story.append(P("• ~8,830 new cases/year (USA 2023); ~10% of all lymphomas.", bullet))
story.append(P("• More common in <b>whites</b> than blacks; more common in <b>males</b> than females.", bullet))
story.append(P("• <b>Bimodal age distribution:</b> Peak 1 – patients in their 20s; Peak 2 – patients in their 80s.", bullet))
story.append(P("• <b>EBV association:</b> Monoclonal/oligoclonal EBV proliferation in 20-40% of HL cases.", bullet))
story.append(P("• In <b>HIV-associated HL</b>: EBV detected in nearly ALL cases (vs 1/3 non-HIV HL).", bullet))
story.append(P("• HIV infection is a <b>risk factor</b> for developing HL.", bullet))
story.append(sp(8))

story.append(mnemonic_box("NEET SS High-Yield: Infectious Associations",
    ["• <b>H. pylori → Gastric MALT</b> lymphoma (antibiotic Rx → regression)",
     "• <b>EBV → Burkitt's</b> (Africa, immunosuppressed) + <b>NK/T-cell</b> (Asia)",
     "• <b>HTLV-1 → ATL</b> (Japan, Caribbean; breast milk transmission; long latency)",
     "• <b>HIV → Aggressive B-cell NHL</b> (DLBCL, BL, primary effusion lymphoma)",
     "• <b>HHV-8 → Primary effusion lymphoma</b> (body cavity lymphoma)",
     "• <b>HCV → Lymphoplasmacytic + Splenic MZL</b>"]))
story.append(PageBreak())

# ═══════════════════════════════════════════════════════════════════════════
# SECTION 3 – STAGING
# ═══════════════════════════════════════════════════════════════════════════
story.append(section_header("SECTION 3: STAGING & PROGNOSTIC INDICES", DARK_BLUE))
story.append(sp(8))

story.append(subsection_header("3A. Ann Arbor Staging System (Table 113-6)", ACCENT_TEAL))
story.append(sp(6))
staging_data = [
    ["Stage", "Description"],
    ["I", "Involvement of a SINGLE lymph node region (I)\nor a single extranodal site (IE)"],
    ["II", "Involvement of TWO OR MORE lymph node regions on the SAME SIDE of the diaphragm (II)\nor with limited contiguous extralymphatic tissue (IIE)"],
    ["III", "Involvement of lymph node regions on BOTH SIDES of the diaphragm (III)\nMay include spleen (IIIS), extralymphatic tissue (IIIE), or both (IIIES)"],
    ["IV", "DIFFUSE or DISSEMINATED involvement of one or more extralymphatic organs\n(with or without lymphatic involvement)"],
]
story.append(info_table(staging_data, col_widths=[CW*0.12, CW*0.88]))
story.append(sp(6))
story.append(P("<b>B symptoms</b> (suffix B): Fevers, Night sweats, Weight loss >10% body weight over 6 months prior to diagnosis.", imp_box))
story.append(P("<b>A symptoms</b> (suffix A): Absence of the above B symptoms.", imp_box))
story.append(sp(6))
story.append(mnemonic_box("Staging Limitation in NHL",
    "The Ann Arbor staging system is <b>less useful in NHL</b> because NHL disseminates widely "
    "in a non-stepwise, non-contiguous fashion. Majority of NHL patients have advanced-stage "
    "disease at diagnosis. Histology and clinical parameters (IPI) are more prognostically important than stage."))
story.append(sp(8))

story.append(subsection_header("3B. International Prognostic Index (IPI) – for Aggressive NHL", ACCENT_PURPLE))
story.append(sp(6))
story.append(P("""The IPI was developed from >2000 patients with aggressive NHL treated with anthracycline-containing regimens.
Each factor scores 1 point (0-5 total).""", body))
story.append(sp(4))
ipi_data = [
    ["IPI Factor", "Adverse Value", "Favorable Value"],
    ["Age", "> 60 years", "≤ 60 years"],
    ["Serum LDH", "> Normal", "≤ Normal"],
    ["Performance Status (ECOG)", "2, 3, or 4", "0 or 1"],
    ["Stage (Ann Arbor)", "III or IV", "I or II"],
    ["Extranodal sites", "> 1 site", "0 or 1 site"],
]
story.append(info_table(ipi_data, col_widths=[CW*0.4, CW*0.3, CW*0.3], header_bg=ACCENT_PURPLE))
story.append(sp(6))
ipi_risk_data = [
    ["IPI Score", "Risk Group", "5-Year Overall Survival"],
    ["0 or 1", "Low", "73%"],
    ["2", "Low-Intermediate", "51%"],
    ["3", "High-Intermediate", "43%"],
    ["4 or 5", "High", "26%"],
]
story.append(info_table(ipi_risk_data, col_widths=[CW*0.2, CW*0.4, CW*0.4]))
story.append(sp(8))

story.append(subsection_header("3C. FLIPI – Follicular Lymphoma International Prognostic Index", ACCENT_TEAL))
story.append(sp(4))
flipi_data = [
    ["FLIPI Factor", "Adverse"],
    ["Age", "> 60 years"],
    ["Stage", "III or IV"],
    ["Hemoglobin", "< 12 g/dL"],
    ["Serum LDH", "> Normal"],
    ["Number of nodal sites", "> 4"],
]
story.append(info_table(flipi_data, col_widths=[CW*0.5, CW*0.5]))
story.append(sp(4))
story.append(P("• Low risk (0-1 factors): 10-yr OS ~71%  |  Intermediate (2): ~51%  |  High (≥3): ~36%", bullet))
story.append(sp(4))
story.append(P("<b>Prognostic Significance:</b> Patients with high-risk FLIPI AND no complete metabolic response by PET/CT to primary therapy AND relapse within 2 years of completion of first-line therapy → very poor prognosis.", imp_box))
story.append(sp(8))

story.append(subsection_header("3D. Staging Evaluation for NHL (Table 113-5)", DARK_BLUE))
story.append(sp(4))
story.append(two_col(
    ["Physical examination",
     "Documentation of B symptoms",
     "Complete blood counts (CBC)",
     "Liver function tests",
     "Serum uric acid",
     "Serum calcium",
     "Serum protein electrophoresis"],
    ["Serum β2-microglobulin",
     "Chest X-ray",
     "CT scan: chest, abdomen, pelvis",
     "Bone marrow biopsy",
     "PET/CT scan (large-cell, aggressive lymphomas)",
     "Lumbar puncture (lymphoblastic, Burkitt's, DLBCL with +ve marrow)"],
    "Clinical/Lab", "Imaging/Procedures"
))
story.append(PageBreak())

# ═══════════════════════════════════════════════════════════════════════════
# SECTION 4 – NHL SUBTYPES
# ═══════════════════════════════════════════════════════════════════════════
story.append(section_header("SECTION 4: NON-HODGKIN'S LYMPHOMA – SUBTYPES", DARK_BLUE))
story.append(sp(8))

# ── 4A: Follicular Lymphoma ──
story.append(subsection_header("4A. Follicular Lymphoma (FL) – Most Common Indolent NHL", ACCENT_TEAL))
story.append(sp(6))
fl_data = [
    ["Feature", "Details"],
    ["Prevalence", "2nd most common NHL; most common indolent B-cell NHL in adults"],
    ["Cell origin", "Germinal center B cells (centrocytes and centroblasts)"],
    ["Cytogenetics", "t(14;18) translocation → BCL2 overexpression (anti-apoptotic) – found in ~85%"],
    ["Immunophenotype", "CD19+, CD20+, CD10+, BCL2+, BCL6+; CD5-, CD23-"],
    ["Clinical features", "Painless lymphadenopathy; waxing & waning; usually advanced (stage III/IV) at Dx"],
    ["Bone marrow", "Positive in 85% at diagnosis"],
    ["Natural history", "Indolent but INCURABLE with standard therapy; median OS 15-20 years"],
    ["Transformation", "Histologic transformation to DLBCL (~30% over lifetime; associated with worse prognosis)"],
    ["1st line treatment", "Bendamustine + Rituximab (BR) – standard of care for medium/high-volume disease"],
    ["Alternative", "R-CHOP, R-CVP, Rituximab alone (low volume), Obinutuzumab + chemo, R-Lenalidomide"],
    ["Relapsed/Refractory", "CAR-T (axi-cel, tisa-cel) approved 3rd line+; Mosunetuzumab (CD20×CD3 bispecific)"],
    ["Maintenance", "Maintenance rituximab post-induction improves response duration"],
    ["HSCT", "Auto-HSCT: 40% long-term remission; Allo-HSCT: 60% (more toxicity)"],
]
story.append(info_table(fl_data, col_widths=[CW*0.32, CW*0.68]))
story.append(sp(8))

# ── 4B: DLBCL ──
story.append(subsection_header("4B. Diffuse Large B-Cell Lymphoma (DLBCL) – Most Common Aggressive NHL", ACCENT_PURPLE))
story.append(sp(6))
dlbcl_data = [
    ["Feature", "Details"],
    ["Prevalence", "Most common NHL overall (~30-35% of all NHLs)"],
    ["Cell origin", "Mature B cells (post-germinal center or germinal center)"],
    ["GC vs ABC", "Germinal Center (GC-type): better prognosis | Activated B-Cell (ABC-type): worse prognosis"],
    ["Immunophenotype", "CD19+, CD20+, CD22+, CD79a+; variable CD10, BCL6, MUM1"],
    ["Clinical features", "Rapidly growing nodal/extranodal mass; B symptoms common; elevated LDH"],
    ["Double-hit lymphoma", "MYC rearrangement + BCL2 or BCL6 rearrangement → extremely aggressive; treated with DA-EPOCH-R"],
    ["Standard treatment", "R-CHOP (Rituximab + Cyclophosphamide, Doxorubicin, Vincristine, Prednisone) × 6 cycles"],
    ["CNS prophylaxis", "High-risk: intrathecal MTX or systemic high-dose MTX (IPI ≥4, double-hit, kidney/adrenal involvement)"],
    ["Relapsed/Refractory", "Salvage chemo → Auto-HSCT (if chemo-sensitive); CAR-T (axi-cel, liso-cel, tisa-cel) as 3rd-line"],
    ["Cure rate", "~60-70% with R-CHOP; lower in high-IPI disease"],
    ["Primary CNS DLBCL", "High-dose MTX-based regimens; EBV-associated in immunosuppressed patients"],
]
story.append(info_table(dlbcl_data, col_widths=[CW*0.32, CW*0.68]))
story.append(sp(8))

# ── 4C: Mantle Cell Lymphoma ──
story.append(subsection_header("4C. Mantle Cell Lymphoma (MCL)", colors.HexColor("#b45309")))
story.append(sp(6))
mcl_data = [
    ["Feature", "Details"],
    ["Cytogenetics", "t(11;14) → Cyclin D1 (BCL1) overexpression – PATHOGNOMONIC"],
    ["Immunophenotype", "CD19+, CD20+, CD5+, CD23-, Cyclin D1+, SOX11+"],
    ["Differentials", "Unlike CLL/SLL: CD23-; Unlike FL: CD10-"],
    ["Clinical", "Typically advanced stage; often involves GI tract (lymphomatous polyposis), bone marrow, blood"],
    ["Behavior", "Considered aggressive despite appearing indolent; generally INCURABLE"],
    ["Treatment", "Rituximab-containing regimens (R-CHOP, R-HDAC, BR); HSCT for younger fit patients; BTK inhibitors (ibrutinib, acalabrutinib) for relapsed"],
]
story.append(info_table(mcl_data, col_widths=[CW*0.32, CW*0.68], header_bg=colors.HexColor("#b45309")))
story.append(sp(8))

# ── 4D: Burkitt's Lymphoma ──
story.append(subsection_header("4D. Burkitt's Lymphoma (BL)", RED_ACCENT))
story.append(sp(6))
bl_data = [
    ["Feature", "Details"],
    ["Cytogenetics", "t(8;14) (most common, 80%) → MYC overexpression | Also t(2;8), t(8;22)"],
    ["Immunophenotype", "CD19+, CD20+, CD10+, BCL6+; BCL2-, TdT-; Ki-67 ~100%"],
    ["Variants", "Endemic (African/EBV-associated, jaw/facial bones), Sporadic (abdomen), Immunodeficiency-related (HIV+)"],
    ["Starry sky pattern", "Classic histology: sheets of lymphocytes with interspersed tingible body macrophages"],
    ["Clinical", "Fastest growing human tumor; highly aggressive; jaw involvement in endemic form"],
    ["Treatment", "Short, intensive chemo: CODOX-M/IVAC, hyper-CVAD, or R-EPOCH; NOT standard R-CHOP"],
    ["Tumor lysis syndrome", "High risk – prophylaxis with hydration, allopurinol/rasburicase mandatory"],
    ["Cure rate", "~90% with intensive regimens in localized disease; lower in advanced"],
]
story.append(info_table(bl_data, col_widths=[CW*0.32, CW*0.68], header_bg=RED_ACCENT))
story.append(sp(6))
story.append(mnemonic_box("Burkitt's MYC Translocations",
    ["• t(8;<b>14</b>) – <b>IgH</b> locus (chr 14) – most common (80%)",
     "• t(<b>2</b>;8) – Igκ locus (chr 2)",
     "• t(8;<b>22</b>) – Igλ locus (chr 22)",
     "Mnemonic: <b>14-2-22 = 'One Four, Two, Two-Two'</b>"]))
story.append(PageBreak())

# ── 4E: Marginal Zone ──
story.append(subsection_header("4E. Marginal Zone Lymphomas (MZL)", ACCENT_TEAL))
story.append(sp(6))
mzl_data = [
    ["Type", "Site", "Association", "Key Features"],
    ["MALT (Extranodal MZL)", "Stomach (most common), lungs, thyroid, eyes, skin, salivary glands", "H. pylori (gastric), Borrelia (skin), C. psittaci (eyes), HCV", "Antibiotic treatment for H. pylori causes regression; t(11;18) predicts no response to antibiotics"],
    ["Splenic MZL", "Spleen, peripheral blood", "HCV, HBV", "Villous lymphocytes on blood smear; treat HCV if present"],
    ["Nodal MZL", "Lymph nodes", "—", "Rarest type; similar to FL but without t(14;18)"],
]
story.append(info_table(mzl_data, col_widths=[CW*0.22, CW*0.28, CW*0.25, CW*0.25]))
story.append(sp(8))

# ── 4F: T-cell Lymphomas ──
story.append(subsection_header("4F. Key T-Cell / NK-Cell Lymphomas", colors.HexColor("#be185d")))
story.append(sp(6))
tcl_data = [
    ["Subtype", "Key Features", "Treatment"],
    ["Peripheral T-cell lymphoma NOS (PTCL-NOS)", "Most common T-cell NHL; poor prognosis; CD4+ or CD8+", "CHOP-based ± etoposide (CHOEP); HSCT"],
    ["Angioimmunoblastic T-cell lymphoma (AITL)", "CD4+; hypergammaglobulinemia; B symptoms; skin rash; EBV-associated; constitutional symptoms", "CHOP-based; HSCT"],
    ["Anaplastic large-cell lymphoma (ALCL) ALK+", "CD30+, ALK+; younger patients; best prognosis of T-cell NHLs; bimodal age", "CHOP + brentuximab vedotin (BV); excellent response"],
    ["ALCL ALK-", "CD30+, ALK-; older patients; worse prognosis than ALK+", "BV + CHP (replace vincristine with BV)"],
    ["Adult T-cell leukemia/lymphoma (ATL)", "HTLV-1; Japan/Caribbean; hypercalcemia; skin lesions; lytic bone lesions; Flower cells", "Zidovudine + IFN-α; poor prognosis"],
    ["Extranodal NK/T-cell lymphoma, nasal type", "EBV+; Asia/Latin America; midline facial destruction; angioinvasive", "Non-anthracycline (SMILE/DDGP); radiation for localized"],
    ["Mycosis fungoides/Sézary syndrome", "Cutaneous T-cell lymphoma; Pautrier microabscesses (histology); Sézary cells (cerebriform nuclei)", "Skin-directed therapy; PUVA; systemic for advanced"],
    ["Hepatosplenic T-cell lymphoma", "Young males; γδ T-cell; isochromosome 7q; hepatosplenomegaly without lymphadenopathy; very poor prognosis", "Intensive chemo; HSCT"],
    ["Enteropathy-associated T-cell lymphoma (EATL)", "Associated with celiac disease; jejunum; poor prognosis", "Aggressive chemo; HSCT"],
]
story.append(info_table(tcl_data, col_widths=[CW*0.32, CW*0.42, CW*0.26], header_bg=colors.HexColor("#be185d")))
story.append(sp(8))

story.append(mnemonic_box("T-cell Lymphoma NEET Points",
    ["• <b>ALK+ ALCL</b> = Best prognosis T-cell NHL (young patients)",
     "• <b>ATL</b> = HTLV-1 + Hypercalcemia + Flower cells",
     "• <b>Nasal NK/T-cell</b> = EBV + Midline destruction + Asia (use non-anthracycline regimen)",
     "• <b>Hepatosplenic T-cell</b> = γδ T-cell + i(7q) + No lymphadenopathy + Very poor prognosis",
     "• <b>EATL</b> = Celiac disease association",
     "• <b>Mycosis fungoides</b> = Pautrier microabscesses + Sézary syndrome (leukemic phase)"]))
story.append(PageBreak())

# ═══════════════════════════════════════════════════════════════════════════
# SECTION 5 – HODGKIN'S LYMPHOMA
# ═══════════════════════════════════════════════════════════════════════════
story.append(section_header("SECTION 5: HODGKIN'S LYMPHOMA (HL)", DARK_BLUE))
story.append(sp(8))

story.append(P("""Hodgkin's lymphoma is a <b>malignancy of mature B lymphocytes</b>. It represents ~10% of all lymphomas.
The majority of HL is <b>classical HL (cHL)</b>. A minor subtype, <b>Nodular Lymphocyte-Predominant HL (NLPHL)</b>,
is now recognized as biologically distinct from cHL. Cure rates now exceed <b>85%</b> with modern therapy.""", body))
story.append(sp(8))

story.append(subsection_header("5A. Reed-Sternberg (HRS) Cell – Pathognomonic of cHL", RED_ACCENT))
story.append(sp(6))
rs_data = [
    ["Feature", "Details"],
    ["Cell origin", "Clonal B lymphocyte (germinal center B cell that has lost B-cell program)"],
    ["Morphology", "Large cells with abundant cytoplasm; BILOBED and/or MULTIPLE NUCLEI; prominent eosinophilic 'owl-eye' nucleoli"],
    ["CD15", "Positive in 85% of cases (Leu-M1)"],
    ["CD30", "Positive in 100% of cases (Ki-1) – MOST CONSISTENT MARKER"],
    ["PAX-5", "Positive (but dim/weak) – vestigial B-cell marker"],
    ["CD19, CD20", "Low to absent expression (despite B-cell origin)"],
    ["CD45 (LCA)", "NEGATIVE (key differentiator from NHL)"],
    ["Tumor cellularity", "HRS cells comprise <1% of tumor; rest is inflammatory infiltrate (polyclonal T cells, eosinophils, plasma cells, histiocytes)"],
    ["EBV (LMP-1)", "Positive in ~1/3 of non-HIV HL; nearly 100% of HIV-associated HL"],
]
story.append(info_table(rs_data, col_widths=[CW*0.3, CW*0.7], header_bg=RED_ACCENT))
story.append(sp(6))
story.append(mnemonic_box("RS Cell Immunophenotype Memory Aid",
    ["<b>Positive:</b> CD15, CD30, PAX-5 (weak)",
     "<b>Negative:</b> CD45, CD19, CD20 (weak/absent)",
     "Mnemonic: 'RS cells are <b>CD15+, CD30+</b> but CD45−'",
     "CD30 = 100% positive → target for <b>Brentuximab Vedotin</b> (anti-CD30 ADC)"]))
story.append(sp(8))

story.append(subsection_header("5B. cHL Subtypes (Table 114-1)", ACCENT_TEAL))
story.append(sp(6))
hl_sub_data = [
    ["Subtype", "Frequency", "RS Cells", "Background", "EBV", "Clinical"],
    ["Nodular Sclerosis (NS)", "~70% (most common in US)", "Lacunar cells", "Bands of collagen/fibrosis; nodular pattern", "~15-25%", "Young adults; mediastinal mass; Stage II"],
    ["Mixed Cellularity (MC)", "~20-25%", "Classic RS cells (abundant)", "Mixed inflammatory cells (eosinophils, plasma cells, lymphocytes)", "~70%", "Older patients, HIV+, developing countries; more advanced stage"],
    ["Lymphocyte-Rich (LR)", "~5%", "RS cells (rare)", "Predominantly lymphocytes; nodular or diffuse", "~15-25%", "Good prognosis; similar to NS"],
    ["Lymphocyte-Depleted (LD)", "~1-2% (rarest)", "Abundant RS + variants", "Few lymphocytes; fibrosis or diffuse RS", "~80-90%", "Elderly, HIV+, developing countries; advanced stage; worst prognosis"],
]
story.append(info_table(hl_sub_data, col_widths=[CW*0.22, CW*0.14, CW*0.17, CW*0.2, CW*0.1, CW*0.17]))
story.append(sp(6))
story.append(P("• Together, <b>Nodular Sclerosis + Mixed Cellularity</b> account for nearly <b>95%</b> of cHL cases.", key_point("").getFlowableToWrap if hasattr(key_point(""), "getFlowableToWrap") else bullet))
story.append(P("⭐ <b>Nodular sclerosis</b> = young adults + mediastinum = most common HL subtype in USA/Western countries", imp_box))
story.append(P("⭐ <b>Mixed cellularity / Lymphocyte-depleted</b> = elderly + HIV+ + developing countries", imp_box))
story.append(sp(8))

story.append(subsection_header("5C. Nodular Lymphocyte-Predominant HL (NLPHL)", ACCENT_PURPLE))
story.append(sp(6))
nlphl_data = [
    ["Feature", "NLPHL", "cHL"],
    ["Frequency", "<5% of all HL", ">95% of all HL"],
    ["Malignant cell", "L&H ('Popcorn') cell = Lymphocyte & Histiocyte cell", "Reed-Sternberg (HRS) cell"],
    ["CD20", "POSITIVE (strong)", "Absent/low"],
    ["CD19, CD79a, BCL2, CD45", "POSITIVE", "Negative"],
    ["CD30", "NEGATIVE", "Positive (100%)"],
    ["CD15", "NEGATIVE", "Positive (85%)"],
    ["EBV", "Negative", "Positive in 20-40%"],
    ["Sex", "75% male", "Slight male predominance"],
    ["Natural history", "Chronic relapsing; can transform to DLBCL (specifically T-cell/histiocyte-rich B-cell lymphoma)", "Curable in >85%"],
    ["Early stage treatment", "Definitive radiotherapy (15-year non-relapse survival ~82%)", "ABVD ± radiation"],
    ["Advanced treatment", "R-CHOP (100% response in small series; may be curative) OR watchful waiting", "ABVD or BEACOPP"],
]
story.append(info_table(nlphl_data, col_widths=[CW*0.3, CW*0.35, CW*0.35]))
story.append(PageBreak())

# ═══════════════════════════════════════════════════════════════════════════
# SECTION 6 – HL TREATMENT
# ═══════════════════════════════════════════════════════════════════════════
story.append(section_header("SECTION 6: TREATMENT OF HODGKIN'S LYMPHOMA", DARK_BLUE))
story.append(sp(8))

story.append(subsection_header("6A. Early-Stage cHL Treatment", ACCENT_TEAL))
story.append(sp(6))
story.append(P("""<b>Standard regimen: ABVD</b> (Adriamycin/Doxorubicin, Bleomycin, Vinblastine, Dacarbazine)
– given every other week (2 treatments per cycle).""", body))
story.append(sp(4))
es_data = [
    ["Disease Group", "Regimen", "Outcomes"],
    ["Favorable/Low-risk early stage", "4-6 cycles ABVD alone (without RT)", "PFS 88-92%; OS 97-100% at 5-7 years"],
    ["Favorable + very good risk (≤2 nodal areas)", "ABVD × 2 cycles + low-dose RT (20 Gy) [German study]", "Equivalent to ABVD × 4 + 30 Gy RT"],
    ["Unfavorable/High-risk early stage", "ABVD × 4 cycles + involved-field RT\n OR ABVD × 6 cycles alone", "Combined modality for bulky disease; chemo alone if RT contraindicated"],
    ["Bulky disease + negative interim PET/CT", "May omit radiation therapy after chemotherapy", "PET-adapted approach"],
    ["Alternative regimens", "Stanford V; escalated BEACOPP", "NOT superior to ABVD in early-stage"],
]
story.append(info_table(es_data, col_widths=[CW*0.28, CW*0.42, CW*0.3]))
story.append(sp(6))
story.append(P("⭐ <b>Role of interim PET/CT:</b> Negative PET/CT after 2-3 cycles of ABVD → excellent outcomes; may allow de-escalation or omission of RT.", imp_box))
story.append(sp(8))

story.append(subsection_header("6B. Advanced-Stage cHL Treatment", ACCENT_PURPLE))
story.append(sp(6))
story.append(P("Advanced-stage disease: <b>NO benefit from adding radiation therapy</b> after complete response to chemotherapy.", body))
story.append(sp(4))
as_data = [
    ["Regimen", "Details", "Notes"],
    ["ABVD (standard)", "Adriamycin + Bleomycin + Vinblastine + Dacarbazine\n× 6 cycles", "Most widely used; OS ~80% at 5-yrs; pulmonary toxicity with bleomycin"],
    ["BV-AVD (preferred if fit)", "Brentuximab vedotin + Doxorubicin + Vinblastine + Dacarbazine\n(replace bleomycin with BV)", "Improved OS vs ABVD in ECHELON-1 trial; now preferred in many centers"],
    ["Escalated BEACOPP", "Bleomycin, Etoposide, Adriamycin, Cyclophosphamide, Vincristine, Procarbazine, Prednisone", "Higher PFS but similar OS vs ABVD; more toxicity (myelosuppression, infertility)"],
    ["N-AVD (nivolumab-based)", "Nivolumab (PD-1 inhibitor) + AVD", "SWOG trial; potential for PD-1-based frontline therapy"],
]
story.append(info_table(as_data, col_widths=[CW*0.22, CW*0.42, CW*0.36]))
story.append(sp(8))

story.append(subsection_header("6C. ABVD Components – NEET Favorite", RED_ACCENT))
story.append(sp(4))
abvd_data = [
    ["Letter", "Drug", "Class", "Key Toxicity"],
    ["A", "Adriamycin (Doxorubicin)", "Anthracycline", "Cardiotoxicity (dilated cardiomyopathy)"],
    ["B", "Bleomycin", "Antitumor antibiotic", "Pulmonary fibrosis (dose-limiting); Raynaud's phenomenon"],
    ["V", "Vinblastine", "Vinca alkaloid", "Myelosuppression (marrow toxicity)"],
    ["D", "Dacarbazine (DTIC)", "Alkylating agent", "Nausea/vomiting; myelosuppression"],
]
story.append(info_table(abvd_data, col_widths=[CW*0.08, CW*0.28, CW*0.27, CW*0.37], header_bg=RED_ACCENT))
story.append(sp(4))
story.append(P("⭐ <b>ABVD advantage over MOPP:</b> Preserves fertility (very low infertility risk); less leukemogenic.", imp_box))
story.append(sp(8))

story.append(subsection_header("6D. BEACOPP Components", ACCENT_TEAL))
story.append(sp(4))
beacopp_data = [
    ["Letter", "Drug"],
    ["B", "Bleomycin"],
    ["E", "Etoposide"],
    ["A", "Adriamycin (Doxorubicin)"],
    ["C", "Cyclophosphamide"],
    ["O", "Oncovin (Vincristine)"],
    ["P", "Procarbazine"],
    ["P", "Prednisone"],
]
story.append(info_table(beacopp_data, col_widths=[CW*0.1, CW*0.9]))
story.append(sp(8))

story.append(subsection_header("6E. Relapsed/Refractory HL", DARK_BLUE))
story.append(sp(4))
rr_data = [
    ["Approach", "Details"],
    ["Salvage chemotherapy", "ICE (Ifosfamide, Carboplatin, Etoposide); ESHAP; GVD (Gemcitabine, Vinorelbine, Doxil)"],
    ["Brentuximab vedotin (BV)", "Anti-CD30 antibody-drug conjugate (ADC); highly active in relapsed cHL; used as bridge to HSCT or as maintenance post-HSCT"],
    ["PD-1 inhibitors", "Nivolumab (Opdivo) and Pembrolizumab (Keytruda) – approved for relapsed/refractory cHL after HSCT failure; ~70% response rate"],
    ["Autologous HSCT", "Standard of care for chemosensitive relapsed HL; long-term remission ~50%"],
    ["Allogeneic HSCT", "For multiply relapsed disease; graft-vs-lymphoma effect; higher TRM"],
]
story.append(info_table(rr_data, col_widths=[CW*0.3, CW*0.7]))
story.append(sp(8))

story.append(subsection_header("6F. Late Toxicities of HL Treatment", ORANGE))
story.append(sp(4))
story.append(P("The <b>new challenge</b> in HL treatment is late therapy-related toxicity (given the high cure rate):", body))
story.append(sp(4))
late_tox = [
    ["Late Toxicity", "Cause", "Notes"],
    ["Secondary malignancies", "Radiation + chemotherapy", "Breast cancer, lung cancer, thyroid cancer (most common after mediastinal RT)"],
    ["Cardiovascular disease", "Radiation (mediastinal/thoracic)", "Premature coronary artery disease, pericardial disease, valvular disease"],
    ["Stroke", "Radiation to neck/chest", "Carotid atherosclerosis"],
    ["Hypothyroidism", "Thoracic radiation", "Very common; monitor TSH regularly; can occur years later"],
    ["Lhermitte's syndrome", "Thoracic radiation", "~15% of patients; 'electric shock' sensation to lower limbs on neck flexion; self-limited"],
    ["Infertility (men)", "Alkylating agents (MOPP, BEACOPP)", "Nearly 100% permanent with alkylating agent chemo; VERY RARE with ABVD"],
    ["Infertility (women)", "Alkylating agents", "Age-dependent; younger women more likely to recover"],
    ["Pulmonary fibrosis", "Bleomycin (in ABVD)", "Monitor with PFTs; hold bleomycin if deterioration"],
]
story.append(info_table(late_tox, col_widths=[CW*0.27, CW*0.28, CW*0.45], header_bg=ORANGE))
story.append(PageBreak())

# ═══════════════════════════════════════════════════════════════════════════
# SECTION 7 – NHL TREATMENT
# ═══════════════════════════════════════════════════════════════════════════
story.append(section_header("SECTION 7: TREATMENT OF NON-HODGKIN'S LYMPHOMA", DARK_BLUE))
story.append(sp(8))

story.append(subsection_header("7A. R-CHOP – Backbone of Aggressive B-cell NHL", ACCENT_TEAL))
story.append(sp(6))
rchop_data = [
    ["Drug", "Class", "Route", "Key Toxicity"],
    ["Rituximab (R)", "Anti-CD20 monoclonal antibody", "IV", "Infusion reactions; HBV reactivation; PML (rare)"],
    ["Cyclophosphamide (C)", "Alkylating agent", "IV/PO", "Hemorrhagic cystitis (prevent with mesna); myelosuppression"],
    ["Doxorubicin/Hydroxydaunorubicin (H)", "Anthracycline", "IV", "Cardiotoxicity (dilated CMP); cumulative dose-dependent"],
    ["Oncovin/Vincristine (O)", "Vinca alkaloid", "IV", "Peripheral neuropathy; constipation/ileus; SIADH"],
    ["Prednisone (P)", "Corticosteroid", "PO", "Hyperglycemia; mood changes; fluid retention; infection"],
]
story.append(info_table(rchop_data, col_widths=[CW*0.28, CW*0.25, CW*0.1, CW*0.37]))
story.append(sp(6))
story.append(P("• R-CHOP × 6 cycles is <b>standard of care for DLBCL</b> and R-CHOP or BR for FL requiring treatment.", bullet))
story.append(P("• Addition of <b>Rituximab</b> to CHOP improved CR rate and OS in B-cell NHL dramatically.", bullet))
story.append(sp(8))

story.append(subsection_header("7B. Novel Agents & Targeted Therapies in NHL", ACCENT_PURPLE))
story.append(sp(6))
novel_data = [
    ["Agent", "Class/Target", "Indication"],
    ["Rituximab", "Anti-CD20 mAb (chimeric)", "All CD20+ B-cell NHLs (FL, DLBCL, MCL, MZL)"],
    ["Obinutuzumab", "Anti-CD20 mAb (humanized, type II)", "FL (GALLIUM trial: superior PFS vs rituximab + chemo)"],
    ["Brentuximab Vedotin (BV)", "Anti-CD30 ADC (MMAE payload)", "ALK+ / ALK- ALCL; cHL (relapsed); BV-AVD frontline HL"],
    ["Ibrutinib / Acalabrutinib", "BTK inhibitor", "MCL (1st/2nd line); CLL; Waldenström's"],
    ["Lenalidomide", "Immunomodulatory (IMiD)", "Relapsed FL, MCL; R2 (rituximab + lenalidomide) for FL"],
    ["Tazemetostat", "EZH2 inhibitor", "Relapsed FL (EZH2 mutated or wild-type)"],
    ["Idelalisib / Copanlisib", "PI3K-delta / PI3K-alpha inhibitor", "Relapsed FL (limited use due to toxicity/lack of confirmatory RCT)"],
    ["Nivolumab / Pembrolizumab", "PD-1 checkpoint inhibitor", "Relapsed/refractory cHL after ASCT; CNS lymphoma"],
    ["CAR-T (Axi-cel, Tisa-cel)", "Anti-CD19 CAR-T cells", "Relapsed/refractory DLBCL (2nd line+ ); relapsed FL (3rd line+)"],
    ["Liso-cel", "Anti-CD19 CAR-T (4-1BB)", "Relapsed/refractory DLBCL"],
    ["Mosunetuzumab", "CD20×CD3 bispecific antibody", "Relapsed FL (3rd line+); off-the-shelf option vs CAR-T"],
    ["Polatuzumab vedotin", "Anti-CD79b ADC", "Relapsed DLBCL (Pola-BR regimen)"],
    ["Zanubrutinib", "BTK inhibitor (next-gen)", "MCL, WM, MZL"],
]
story.append(info_table(novel_data, col_widths=[CW*0.28, CW*0.35, CW*0.37]))
story.append(PageBreak())

# ═══════════════════════════════════════════════════════════════════════════
# SECTION 8 – HIGH-YIELD NEET SS TABLES
# ═══════════════════════════════════════════════════════════════════════════
story.append(section_header("SECTION 8: HIGH-YIELD COMPARISON TABLES", DARK_BLUE))
story.append(sp(8))

story.append(subsection_header("8A. Immunophenotype Quick Reference", ACCENT_TEAL))
story.append(sp(6))
immuno_data = [
    ["Lymphoma", "CD20", "CD10", "CD5", "CD23", "BCL2", "CD30", "CD15", "CD45", "Other"],
    ["Follicular (FL)", "+", "+", "-", "-/+", "+", "-", "-", "+", "BCL6+; t(14;18)"],
    ["DLBCL", "+", "+/-", "-", "-", "+/-", "-", "-", "+", "MUM1 in ABC type"],
    ["Mantle Cell (MCL)", "+", "-", "+", "-", "+", "-", "-", "+", "Cyclin D1+; SOX11+; t(11;14)"],
    ["Burkitt's (BL)", "+", "+", "-", "-", "-", "-", "-", "+", "Ki67~100%; t(8;14)"],
    ["Marginal Zone (MZL)", "+", "-", "-", "-", "+/-", "-", "-", "+", "CD43+/-"],
    ["CLL/SLL", "+", "-", "+", "+", "+", "-", "-", "+", "ZAP70+; CD38+"],
    ["Lymphoplasmacytic", "+", "-", "-", "-", "+", "-", "-", "+", "MYD88 L265P; IgM paraprotein"],
    ["Classical HL (HRS)", "- (weak)", "-", "-", "-", "-", "+", "+", "-", "PAX5+ (weak); EBV LMP1"],
    ["NLPHL (L&H cell)", "+", "+", "-", "-", "+", "-", "-", "+", "OCT2+; BOB1+"],
    ["ALCL ALK+", "-", "-", "-", "-", "-", "+", "-", "+/-", "ALK1+; EMA+"],
    ["ATL", "-", "-", "+", "-", "-", "+/-", "-", "+", "HTLV-1+; CD4+; CD25+"],
]
story.append(info_table(immuno_data,
    col_widths=[CW*0.2, CW*0.065, CW*0.065, CW*0.065, CW*0.065, CW*0.065, CW*0.065, CW*0.065, CW*0.065, CW*0.24],
    header_bg=DARK_BLUE))
story.append(sp(8))

story.append(subsection_header("8B. Cytogenetics / Molecular Markers – NEET Favorites", ACCENT_PURPLE))
story.append(sp(6))
cyto_data = [
    ["Translocation / Marker", "Gene Effect", "Lymphoma"],
    ["t(14;18)(q32;q21)", "BCL2 overexpression (anti-apoptotic)", "Follicular lymphoma (FL) – ~85%"],
    ["t(11;14)(q13;q32)", "Cyclin D1 (BCL1) overexpression", "Mantle cell lymphoma (MCL) – pathognomonic"],
    ["t(8;14)(q24;q32)", "MYC overexpression via IgH enhancer", "Burkitt's lymphoma (most common, 80%)"],
    ["t(2;8)(p12;q24)", "MYC + Igκ", "Burkitt's (10%)"],
    ["t(8;22)(q24;q11)", "MYC + Igλ", "Burkitt's (10%)"],
    ["t(11;18)(q21;q21)", "API2-MALT1 fusion", "Gastric MALT lymphoma (predicts no response to antibiotics)"],
    ["t(2;5)(p23;q35)", "NPM-ALK fusion protein", "ALCL ALK+ (pathognomonic)"],
    ["MYD88 L265P mutation", "NF-κB activation", "Lymphoplasmacytic lymphoma / Waldenström's (~90%)"],
    ["BCL6 rearrangements", "Germinal center transcription factor", "DLBCL, FL"],
    ["MYC + BCL2 rearrangements", "'Double-hit' – extremely aggressive", "High-grade B-cell lymphoma (Double-hit)"],
    ["MYC + BCL2 + BCL6", "'Triple-hit' – extremely aggressive", "High-grade B-cell lymphoma (Triple-hit)"],
    ["Isochromosome 7q [i(7q)]", "Chromosomal aberration", "Hepatosplenic T-cell lymphoma"],
    ["11q aberrations (no MYC)", "Burkitt's-like behavior", "High-grade B-cell lymphoma with 11q aberration"],
]
story.append(info_table(cyto_data, col_widths=[CW*0.32, CW*0.33, CW*0.35]))
story.append(PageBreak())

story.append(subsection_header("8C. Indolent vs Aggressive NHL – Key Differences", ACCENT_TEAL))
story.append(sp(6))
ind_agg_data = [
    ["Feature", "Indolent NHL", "Aggressive NHL"],
    ["Examples", "FL, MALT, SLL/CLL, Splenic MZL, Lymphoplasmacytic", "DLBCL, MCL, BL, PTCL, ATL, ALCL"],
    ["Growth rate", "Slow (months to years)", "Rapid (days to weeks)"],
    ["Presentation", "Painless LAD; waxing-waning; asymptomatic often", "Rapidly enlarging mass; B symptoms common"],
    ["Stage at Dx", "Usually advanced (III/IV)", "Variable; localized or advanced"],
    ["Bone marrow +ve", "Common (esp. FL ~85%)", "Less frequent"],
    ["LDH", "Normal or mildly elevated", "Often markedly elevated"],
    ["Curability", "Generally INCURABLE with standard chemo (but long OS ~15-20 yrs for FL)", "POTENTIALLY CURABLE with aggressive chemo (60-80%)"],
    ["Watchful waiting", "Applicable for asymptomatic indolent disease", "NOT applicable – requires immediate treatment"],
    ["Transformation", "Can transform to aggressive NHL (histologic transformation)", "Does not transform"],
    ["Main prognostic index", "FLIPI (for FL)", "IPI (for aggressive NHL)"],
]
story.append(info_table(ind_agg_data, col_widths=[CW*0.22, CW*0.39, CW*0.39]))
story.append(sp(8))

story.append(subsection_header("8D. Primary CNS Lymphoma (PCNSL)", DARK_BLUE))
story.append(sp(6))
pcnsl_data = [
    ["Feature", "Details"],
    ["Histology", "DLBCL (most common type of CNS lymphoma)"],
    ["EBV association", "Majority of PCNSL in immunosuppressed patients are EBV-positive"],
    ["Imaging", "MRI: ring-enhancing or homogeneously enhancing periventricular lesion (frontal lobes, basal ganglia)"],
    ["Diagnosis", "Brain biopsy; vitreoretinal biopsy if ocular involvement; CSF cytology"],
    ["Treatment", "High-dose Methotrexate (HD-MTX) ± whole brain radiation (WBRT)"],
    ["Steroids", "Avoid steroids before biopsy – cause rapid regression (diagnostic difficulty); 'ghost tumor'"],
    ["Prognosis", "Poor; median OS ~12-18 months without treatment; better with HD-MTX in immunocompetent"],
]
story.append(info_table(pcnsl_data, col_widths=[CW*0.3, CW*0.7]))
story.append(sp(8))

# ─── Section 9: Mnemonics ────────────────────────────────────────────────────
story.append(PageBreak())
story.append(section_header("SECTION 9: MNEMONICS & EXAM PEARLS", DARK_BLUE))
story.append(sp(8))

mnemonics = [
    ("ABVD = A Beautiful Vinblastin Death", "A=Adriamycin(Doxorubicin) | B=Bleomycin | V=Vinblastine | D=Dacarbazine"),
    ("BEACOPP = BE A COP Please", "B=Bleomycin | E=Etoposide | A=Adriamycin | C=Cyclo | O=Oncovin | P=Procarbazine | P=Prednisone"),
    ("R-CHOP = Really CHOPping B cells", "R=Rituximab | C=Cyclophosphamide | H=Hydroxydaunorubicin (Doxorubicin) | O=Oncovin (Vincristine) | P=Prednisone"),
    ("RS Cell = CD15 & CD30 positive; CD45 NEGATIVE", "Remember: RS cells are CD15+, CD30+ but CD45− (key to differentiate from NHL)"),
    ("IPI = APLES", "A=Age>60 | P=Performance status≥2 | L=LDH>Normal | E=Extranodal sites>1 | S=Stage III/IV"),
    ("FLIPI = ASHLN", "A=Age>60 | S=Stage III/IV | H=Hemoglobin<12 | L=LDH>normal | N=Nodal sites>4"),
    ("Burkitt's t(8;14) Rule: 8 breaks and joins 14, 2, or 22", "t(8;14) = IgH (chr 14) = most common | t(2;8) = Igκ | t(8;22) = Igλ"),
    ("MCL = 'Mantle Cyclin D1': t(11;14) → Cyclin D1", "CD5+, CD23−, Cyclin D1+, SOX11+; t(11;14)"),
    ("FL = 'Follows BCL2': t(14;18) → BCL2", "Most common indolent NHL; follicular pattern; CD10+, BCL2+"),
    ("NLPHL 'Popcorn cells' = L&H cells", "CD20+, CD45+, CD30−, CD15−; <5% HL; chronic relapsing; R-CHOP curative intent"),
    ("ATL = HTLV-1 + Flower cells + HyperCalcemia", "Japan/Caribbean; breast milk transmission; CD4+, CD25+; treat with Zidovudine + IFN-α"),
    ("NK/T-cell nasal = EBV + Asia + Midline destruction", "Non-anthracycline regimen (SMILE); do NOT use CHOP"),
]

for title, content in mnemonics:
    story.append(mnemonic_box(title, content))
    story.append(sp(6))

story.append(PageBreak())
story.append(section_header("SECTION 10: SUMMARY QUICK-REFERENCE TABLE", DARK_BLUE))
story.append(sp(8))
summary_data = [
    ["Lymphoma Type", "Key Marker/Cytogenetics", "1st-Line Treatment", "Prognosis"],
    ["Follicular (FL)", "t(14;18); BCL2+; CD10+", "BR or R-CHOP (if treatment needed); watchful waiting if asymptomatic", "Indolent; OS 15-20 yrs; incurable but long survival"],
    ["DLBCL", "Variable; GCB vs ABC; double-hit (MYC+BCL2)", "R-CHOP × 6 cycles", "Curable ~60-70%; poor if double-hit"],
    ["Mantle Cell (MCL)", "t(11;14); Cyclin D1+; CD5+", "R-CHOP or BR + HSCT in fit young patients; BTK inhibitors (relapsed)", "Aggressive-indolent; generally incurable"],
    ["Burkitt's (BL)", "t(8;14); MYC; Ki67~100%", "CODOX-M/IVAC or hyper-CVAD + R; tumor lysis prophylaxis", "~90% cure in localized; worse in advanced"],
    ["Gastric MALT", "t(11;18); H. pylori", "H. pylori eradication antibiotics; RT for refractory", "Excellent if early stage"],
    ["Classical HL", "CD15+, CD30+; RS cells", "ABVD (early: ±RT; advanced: alone) or BV-AVD", "Cure >85%; late toxicities main challenge"],
    ["NLPHL", "CD20+, CD45+; L&H/popcorn cell", "RT (early); R-CHOP (advanced)", "Good; chronic relapsing; rare transformation to DLBCL"],
    ["ATL", "HTLV-1+; CD4+, CD25+", "Zidovudine + IFN-α; CHOP-based", "Very poor; median OS <1 year"],
    ["NK/T-cell nasal", "EBV+; CD56+", "SMILE or DDGP; RT for localized", "Poor in advanced; better if localized"],
    ["ALCL ALK+", "t(2;5); NPM-ALK; CD30+", "BV+CHP (A+AVD replacement) or CHOP", "Best prognosis T-cell lymphoma"],
    ["PCNSL (CNS DLBCL)", "EBV in immunosupp.; ring enhancement on MRI", "HD-MTX ± WBRT; NO steroids before biopsy", "Poor; OS ~12-18 months without treatment"],
]
story.append(info_table(summary_data, col_widths=[CW*0.2, CW*0.28, CW*0.32, CW*0.2]))
story.append(sp(10))

story.append(P("<b>Source:</b> Harrison's Principles of Internal Medicine, 22nd Edition (2025, McGraw-Hill Medical), Chapters 113 (Non-Hodgkin's Lymphoma) and 114 (Hodgkin's Lymphoma). Authors: Caron A. Jacobson, Dan L. Longo.", small_italic))
story.append(sp(4))
story.append(HR(width=CW, color=GRAY_LINE, thickness=0.5))
story.append(sp(4))
story.append(P("These notes are prepared for NEET SS / Medical Postgraduate examination preparation based on Harrison's 22E. For clinical decisions, always refer to current institutional guidelines.", small_italic))

# ─── Build ──────────────────────────────────────────────────────────────────
doc.build(story)
print(f"PDF created: {OUTPUT}")