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• Sweden, Denmark, Germany, Greece, Italy

• cN0, cT1 to cT3 tumors with 1 to 2 SLN macrometastases:
  • BCS or mastectomy allowed
• Extra capsular extension (ECE) and cT3 permitted
• SENOMAC did allow patients who had SLNB before neoadjuvant systemic therapy (NAST) to be enrolled if cN0 and with ≤ 2 SLN macrometastases:
  • Randomization was recommended before starting NAST

• Adjuvant therapy and radiation therapy (RT) per national guidelines

• N=2766 enrolled:
  • Per-protocol N=2540:
    • SLNB 1335
    • cALND 1205
  • Mastectomy ≈ 36% in each arm:
    • SLNB 490 / 1335
    • cALND 430 / 1205

• RT including nodal volumes given to ~ 90% in both arms:
  • SLNB 89.9%; cALND 88.4%
• Quality assessment (QA) check showed:
  • 99.3% concordance for breast / chest-wall fields and 96.6% for nodal targets

• Switched the primary endpoint to overall survival (OS):
  • To declare non-inferiority on OS, the trial needs 190 deaths:
    • At last analysis there weren’t enough events:
      • So OS is not yet formally tested

• ≈ 92.9% vs 92.0%

• HR 0.89 (95% CI 0.66–1.19) → non-inferior

• cALND upstaged more often (pN2 – 9.9%, pN3 – 3.0%) vs SLNB-only (pN2 – 0.5%):
  • Without outcome benefit
• Additional non-SLN metastasis on cALND in 34.5% overall:
  • If 1 SLN macrometatases:
    • 31.3% had more positive nodes
  • If 2 macrometastases:
    • 51.3% had more positive nodes

• SLNB-only patients reported less arm pain / symptoms and better function than cALND

• To prevent 1 iDFS event at 5 yrs via identifying ≥ pN2-pN3 with cALND:
  • ~ 104 cALNDs would be needed:
    • Causing severe / very severe arm dysfunction in ~ 9 / 104 at 1 year:
      • Discourages ALND purely to find pN2-pN3 for CDK4/6 indication

• Omitting cALND preserved control and survival and minimized arm morbidity:
  • Supports SLNB-only + RNI / PMRT for 1 to 2 SLN macrometastases after mastectomy

• ~ 90% received nodal RT

• Though granular nodal-level dose / field details were not yet available at reporting

• But event counts and narrow CIs yield precise estimates for NI

• Omitting cALND maintains disease control with less arm morbidity

• While acknowledging the need for longer follow-up and more granular RT-field reporting

• Is omitting axillary surgery non-inferior to sentinel lymph node biopsy (SLNB):
  • For 5-year distant disease-free survival (DDFS)? JAMA Network

• Showed no therapeutic benefit for ALND over less surgery (SLNB alone):
  • The next logical step tests whether staging itself (SLNB) can be omitted:
    • When it won’t change adjuvant plans:
      • Reducing morbidity without compromising oncologic safety JAMA Network

• 1:1 randomization to:
  • No axillary surgery vs SLNB

• 5-yr distant disease free survival (DDFS) (ITT)

• Disease free survival (DFS)
• Overal survival (OS)
• Cumulative incidence of distant and axillary recurrences, and adjuvant treatment recommendations JAMA Network

• Italy, Spain, Switzerland, and Chile

• Suspicious nodes required cytology to exclude metastasis

• Including partial breast and IORT

• SLNB 708
• Omit 697

• Negative AUS in the SOUND trial effectively ruled out heavy nodal burden:
  • SLNB arm had 13.7% any nodal metastasis but only 0.6% had ≥ 4 positive nodes
  • Axillary recurrence 0.4% at 5 years in both arms JAMA Network

• NI margin 2.5% for 5-year DDFS; HR with 90% CI and one-sided NI P-value
• Assumed 5-year DDFS ≈ 96.5%:
  • Observed outcomes were higher, increasing power to show NI if risks are truly similar JAMA Network

• 97.7% (SLNB) vs 98.0% (No surgery):
  • HR 0.84, 90% CI 0.45–1.54; P for non-inferiority = 0.02:
    • Two-arm difference not significant by log-rank (P=0.67) JAMA Network

• 94.7% (SLNB) vs 93.9% (No surgery), P=0.30.

• 98.2% (SLNB) vs 98.4% (No surgery), P=0.72 JAMA Network

• 5-year cumulative axillary recurrence = 0.4% in each arm (Gray P=0.91)

• 1.7% (SLNB) vs 1.6% (No surgery) JAMA Network

• SLNB: 
  • 13 distant metastases (1.8%), 21 deaths (3.0%).
• No surgery: 
  • 14 distant metastases (2.0%), 18 deaths (2.6%) JAMA Network

• No material differences in systemic therapy or RT use between arms:
  • Supporting that, in this AUS-negative group:
    • Pathologic nodal information didn’t drive adjuvant decisions JAMA Network
• Radiotherapy details:
  • All RT options allowed, including partial breast / IORT
  • Notably, 114 patients (16.3%) in the no-surgery arm received ELIOT (full-dose or boost)
  • Despite this heterogeneity:
    • Axillary failures stayed 0.4% at 5 years in both arms JAMA Network

• Skipping SLNB is non-inferior for 5-yearr DDFS:
  • With no increase in axillary failures and no detectable survival trade-off – and you avoid the morbidity of axillary surgery JAMA Network

• Authors estimate ~ 25% of all breast cancer (BC) cases may fit these criteria JAMA Network

• Short-to-mid-term risk low:
  • Longer follow-up always helpful JAMA Network

• Adjuvant-recommendation analysis was secondary JAMA Network

• Nonetheless axillary failure remained 0.4% in both arms JAMA Network

• Avoid extrapolating JAMA Network

• Nodal positivity can still influence chemo or endocrine therapy type / duration:
  • If nodal information truly changes systemic therapy:
    • SLNB may remain reasonable JAMA Network

• Cite SOUND + INSEMA JAMA Network+1]

• Younger HR+ / HER2-

• Median f/u 5.7 yrs. JAMA Network

• 97.7% vs 98.0% (HR 0.84; 90% CI 0.45–1.54; NI P=0.02) JAMA Network

• 94.7% vs 93.9% (P=0.30)

• 0.4% vs 0.4%

• 13.7%

• 0.6% JAMA Network

• 16.3% of omission arm received ELIOT (full-dose / boost) JAMA Network

• SOUND chose DDFS to reflect oncologic safety independent of local RT nuances JAMA Network

• If so, why are axillary failures identically rare in both arms? JAMA Network

• Invasive DFS primary outcome was non-inferior, with less arm morbidity in the omission group

• All favored cisplatin PubMed+1

• Discuss RT + cetuximab (Bonner) or altered-fractionation RT

• To cisplatin-eligible patients is incorrect New England Journal of Medicine
• Bonner:
  • 5-yr OS 45.6% with RT + cetuximab vs 36.4% RT alone:
    • Not a comparison to cisplatin

• Document shared decision-making when deviating

RTOG – 1016 (NI trial, Lancet 2019):

De-ESCALaTE HPV (Lancet 2019):

• To “de-intensify”

• RT + cetuximab vs RT + cisplatin 100 mg / m² × 2 in HPV⁺ OPSCC
• Primary endpoint OS:
  • Non-Inferiority (NI) margin HR 1.45

• 5-yr OS: 
  • 77.9% cetuximab vs 84.6% cisplatin:
    • HR 1.45 → non-inferior criterion failed:
      • Inferior with cetuximab
• PFS: 
  • HR 1.72:
    • Worse with cetuximab
• Locoregional failure: 
  • HR 2.05:
    • Higher with cetuximab
• Acute / late grade ≥ 3 toxicity: 
  • Overall similar rates (different profiles):
    • So efficacy — not toxicity — drives the choice PubMed+1

• RT + cetuximab vs RT + cisplatin
• Primary end point:
  • Severe toxicity

• OS: 
  • 97.5% cisplatin vs 89.4% cetuximab:
    • HR ~ 5.0:
      • Significantly worse with cetuximab
• Recurrence: 
  • 6.0% cisplatin vs 16.1% cetuximab:
    • HR ~ 3.4
• Severe toxicity: 
  • Similar overall rates
  • More sever adverse effects (SAEs) with cisplatin:
    • But not enough to offset the clear efficacy loss with cetuximab The Lancet+2Taylor & Francis Online+2

• Concurrent cisplatin outperformed cetuximab with RT:
  • Mature results reiterate inferior outcomes with cetuximabPMC+1

• NCCN and contemporary reviews state that RT + cisplatin remains standard for eligible HPV⁺ OPSCC:
  • Cetuximab – RT is reserved for:
    • True cisplatin ineligibility:
      • CrCl < 50 mL / min, grade ≥ 2 SNHL / neuropathy) JNCCN

• q3-weekly 100 mg / m² × 2 to 3, or weekly in appropriate settings:
  • To achieve ≥ 200 mg/m² cumulative if feasible (De-escalation ≠ drug substitution) PubMed

• RT + cetuximab (or institutionally accepted alternatives) with explicit counseling that efficacy:
  • Is inferior to cisplatin in HPV⁺ disease:
    • Use only because platinum cannot be given JNCCN

• Cells need “molecular Velcro” that works under shear.

• E-selectin:
  • Induced by TNF-α / IL-1
• P-selectin:
  • Rapidly mobilized from Weibel–Palade bodies
  • Also on platelets

• PSGL-1 and other sialyl-Lewis^x (sLe^x):
  • Decorated glycoproteins
• L-selectin (CD62L) is on leukocytes:
  • Not endothelium:
    • It helps secondary capture / rolling:
      • Leukocyte–leukocyte interactions
        • Binds Peripheral Node Addressin on High Endothelial Venules (PNAd on HEVs)
• Mechanics: 
  • “Catch bonds” let cells roll, sampling endothelium for activating cues
• ✅ Fix to your line: 
  • Rolling is mainly:
    • E-selectin / P-selectin (endothelium) ↔ sLe^x/PSGL-1 (leukocyte)
  • L-selectin:
    • Is leukocyte-borne:
      • It augments rolling
  • P-selectin:
    • Is not on neutrophils

• For example:
  • CXCL8 /IL-8 (neutrophils), CCL2 / MCP-1(monocytes):
    • Bind GPCRs (CXCR1/2, CCR2…), engaging Gαi → Rap1 → talin / kindlin:
      • To flip integrins into high-affinity and clustered states

• β2 family: 
  • LFA-1 (αLβ2; CD11a/CD18)
  • Mac-1 (αMβ2; CD11b/CD18).
• β1 family: 
  • VLA-4 (α4β1):
    • Prominent in monocytes / lymphocytes

• Through junctions

• Through individual endothelial cells

• Mostly homophilic interactions at junctions

• Chemokines: 
  • CXCL8 (neutrophils), CCL2 (monocytes), CCL19/21 (lymphocyte homing)
• Lipid mediators: 
  • LTB4, PGE₂ (context-dependent)
• Complement & danger cues: 
  • C5a, fMLP from bacteria

• Strong recommendation, Moderate certainty evidence

• Oral cavity, oropharynx, or larynx:
  • Hypopharynx excluded

• Pernineural invasion (PNI)
• Lymphovascular ivasion (LVI)
• ≥ 2 lymph nodes (LNs) (all < 6 cm) or one LN > 3 cm (no extranodal extension (ENE))
• Close margin(s) < 5 mm or focally positive then re-resected negative
• pT3 to pT4a primary, or T2 oral cavity with DOI > 5 mm ozarkscancerresearch.org

• Majority HPV-negative (~ 80%)
• Oral cavity ~ 64%
• EGFR high expression in ~ 85%(assayed for stratification, not a requirement) NRG Oncology+1

• PORT alone vs PORT + cetuximab

• IMRT 60 Gy in 30 fx (66 Gy allowed) ozarkscancerresearch.org

• 400 mg/m² loading, then 250 mg/m² weekly x 6 during RT + 4 weekly doses post-RT (total 11) ozarkscancerresearch.org

• Overall survival (OS) in all randomized / eligible
  • Pre-specified plan to test in HPV-negative subgroup

• Disease-free survival (DFS), toxicity, others PubMed

• OS HR 0.81; one-sided p=0.075 (did not meet significance)
• 5-yr OS: 
  • 76.5% (PORT+cetuximab) vs 68.7% (PORT) NRG Oncology

• DFS HR 0.75; one-sided p=0.017
• 5-yr DFS: 
  • 71.7% (PORT+cetuximab) vs 63.6% (PORT)
    • Benefit limited to HPV-negative population NRG Oncology+1

• Acute grade 3 to 4: 
  • 70.3% (PORT+cetuximab) vs 39.7% (PORT); p<0.0001:
    • Largely more mucositis / dermatitis NRG Oncology
• Late grade 3 to 4: 
  • 33.2% vs 29.0%, p=0.31 (no significant increase)
• No grade-5 events NRG Oncology

• A dedicated RTOG-0920 QoL analysis was presented at ASCO 2025:
  • Aligns with the toxicity profile (no long-term penalty reported in the abstract listing). ASC Publications+1

• With trade-off of substantially higher acute toxicity
• OS was not improved PubMed+1
• HPV-positive:
  • No signal of benefit:
    • Do not extrapolate a DFS advantage here. PubMed

• Those are high-risk → cisplatin-based CRT

• HR ~ 0.83; ~ 6.5% 5-yr OS gain:
  • Driven by improved locoregional control

• Overall survival: 
  • HR 0.83 (95% CI 0.79–0.86):
    • Absolute OS gain + 6.5% at 5 yr and + 3.6% at 10 yr (≈ NNT ~ 15 at 5 yr)
• EFS:
  • HR 0.80 with + 5.8% at 5 yr
• No increase in 120-day mortality:
  • HR 1.07, p=0.37 Groningen Research Portal
• Patterns of failure: 
  • Marked LRF reduction (sub-HR 0.71)
  • No DF effect (HR 1.04)
  • Survival benefit driven by lower cancer mortality (HR 0.79; − 9.8% at 5 yr):
    • With no change in non-cancer deaths (HR 1.01) Groningen Research Portal
• Regimen effects: 
  • Greatest effect for platinum-containing polychemotherapy (EFS HR 0.74)
  • Smallest for non-platinum monochemotherapy (HR 0.86)
  • Benefit consistent across eras and RT modalities Groningen Research Portal

• No significant benefit:
  • OS HR 0.96
  • EFS HR 0.96
• DF decreases (HR 0.76):
  • But no LRF improvement (sub-HR 1.07)
• Benefit attenuates with worse performance status Groningen Research Portal

• No benefit:
  • OS HR 1.02
  • EFS HR 0.98

• Higher 120-day mortality (HR 1.89, p=0.0003)
• Some reduction in LRF (sub-HR 0.84) and DF(HR 0.77) without survival gain Groningen Research Portal

• OS HR 0.84 (≈ + 6.2% absolute OS at 5 yr)
• EFS HR 0.85
• LRF HR 0.86

• Benefit of concomitant chemotherapy decreases with increasing age:
  • Use added caution > 70 yr Groningen Research Portal

• Poorer PS attenuates benefit:
  • Noted in induction analyses:
    • Similar theme in concomitant Groningen Research Portal

• Not evaluable here (most trials pre-HPV era)
• Don’t expect HPV-specific signals from MACH-NC Groningen Research Portal

• The only timing with proven OS benefit is concomitant chemo with RT
• Expect ~ 6% to 7% absolute 5-yr OS gain:
  • Driven by better loco-regional control Groningen Research Portal

• Platinum-containing regimens carry the strongest signal:
  • This underpins cisplatin-based CRT as the benchmark Groningen Research Portal

• Cr, BUN, Mg, K, Ca, Na, PO₄

• Why: 
  • Baseline renal reserve; cisplatin causes salt wasting (especially Mg) and AKI eviQ

• Why:
  • Myelosuppression risk DailyMed+1

• Why:
  • Ototoxicity risk:
    • Establish baseline threshold:
      • Audiology societies and monographs recommend baseline and interval monitoring American Academy of Audiology+2audiology-web.s3.amazonaws.com+2

• Hold / avoid nephrotoxins:
  • NSAIDs, IV contrast, aminoglycosides
• Assess fluid status eviQ

• Day 1: 
  • NK1RA + 5-HT3RA + dexamethasone + olanzapine
• Continue dexamethasone ± olanzapine Days 2 to 4 American Society of Clinical Oncology+2Janet Abrahm, M.D.+2

• Act: 
  • Replete Mg (often 10 mmol MgSO₄ pre-hydration) and correct K / Ca before dosing
  • If eGFR ↓ or SCr ↑:
    • Evaluate per KDIGO, hydrate, and hold / modify eviQ

• Act: 
  • Use isotonic saline pre / post hydration:
    • Typical total 2.5 to 3.0 L around infusion
  • Routine mannitol not required:
    • Consider only for very high-dose eviQ

• Tinnitus, hearing change, paresthesias, nausea / vomiting, cramps (hypo-Mg), mucositis, dysphagia
• Act:
  • Audiogram if otologic symptoms
  • Neuro exam each visit American Academy of Audiology+1

• Why:
  • Catch AKI and hypomagnesemia early
  • Track cytopenias and dehydration eviQ+1

• Repeat before each cycle (q3-weekly) or sooner if symptoms; for weekly cisplatin, obtain symptom-triggered or mid-course checks per local protocol American Academy of Audiology+1

• ≥ 0.3 mg/dL increase or ≥ 1.5 × baseline (KDIGO stage 1+):
  • Hold cisplatin, hydrate (NS), replete Mg / K, stop nephrotoxins, reassess in 24 to 72 hours

• Include MgSO₄ in pre-hydration (e.g., 10 mmol in 1 L NS) and replete as needed:
  • Mg protects against cisplatin nephrotoxicity eviQ+1

• Optimize 4-drug regimen (ensure NK1RA)
• Consider scheduled olanzapine days 2 oto 4
• Add rescue (metoclopramide, prochlorperazine) American Society of Clinical Oncology+1

• Prompt audiogram:
  • If confirmed / worsening:
    • Discuss dose holding or regimen change (risk rises with cumulative dose) American Academy of Audiology+1

• Encourage oral fluids (≥ 500 mL if tolerated)

• To fight infection and promote tissue repair:
  • But also contributes to inflammation and disease when overactivated

• Anaphylatoxins and form a membrane attack complex (MAC) that can kill pathogens

• But inappropriate activation can cause:
  • Chronic pain, autoimmune disease, and organ damage

• Classical Pathway: 
  • Activated by the binding of antibodies (like IgG and IgM) to antigens:
    • On the surface of a pathogen
• Lectin Pathway: 
  • Initiated when mannose-binding lectin (MBL):
    • Binds to carbohydrate structures on bacterial cell walls 
• Alternative Pathway: 
  • Triggered by the direct binding of complement components to foreign surfaces, such as pathogens, without the need for antibodies 

• Trigger: 
  • C1q, a component of the C1 protein complex:
    • Binds to an antibody-antigen complex:
      • On a pathogen surface
    • The C1 complex is composed of:
      • C1q, C1r, and C1s
• Cascade:
  • C1r and C1s are activated:
    • Which then cleave complement proteins C4 and C2
    • The larger fragments, C4b and C2b (also called C2a):
      • Bind together to form the classical pathway’s C3 convertase (C4b2b) 
• Antigen – antibody complexes:
  • Best: 
    • IgM:
      • Then IgG1 / IgG3
• Early components unique to this pathway: 
  • C1 (C1q, C1r, C1s), C2, C4
• C1 protein complex:
  • Needs Ca²⁺:
    • To stay assembled

• Trigger: 
  • The pattern recognition molecule:
    • Mannose-binding lectin (MBL) or ficolins:
      • Bind to specific carbohydrate patterns (like mannose) on the surface of pathogens
• Cascade:
  • This binding activates MBL-associated serine proteases (MASPs):
    • Which are functionally similar to C1r and C1s
  • The MASPs cleave C4 and C2:
    • Forming the same C3 convertase (C4b2b) used by the classical pathway 
• Mannose-binding lectin (MBL) or ficolins binding microbial sugars:
  • Enzymes: 
    • MASP-1 / MASP-2 cleave C4 and C2:
      • Merges with classic pathway a:
        • C3 convertase (C4b2a)

• Trigger: 
  • This pathway is always active at a low level through a “tickover” mechanism:
    • Where C3 is spontaneously hydrolyzed
  • It is further activated when C3b, a fragment of C3:
    • Binds directly to the surface of a pathogen or foreign material
• Cascade:
  • Factor B binds to the surface-bound C3b and is then cleaved by Factor D to form C3bBb:
    • The alternative pathway’s C3 convertase
  • The protein properdin stabilizes this complex:
    • Amplifying the cascade
  • This pathway also acts as an amplification loop for the classical and lectin pathways
• Spontaneous C3 hydrolysis on microbial / endotoxin surfaces:
  • Amplified by Factor B, Factor D, Properdin (P)
  • Note: 
    • Mg²⁺ is required for Factor B binding to C3b
    • Properdin stabilizes the convertase
• Common note: 
  • C3:
    • Common to and is the convergence point for the three pathways

• All three initiation pathways converge to form a C3 convertase:
  • Which ultimately leads to the creation of the:
    • Membrane attack complex (MAC) 
• C3 cleavage:
  • A C3 convertase cleaves C3 into two pieces:
    • C3a:
      • A small fragment that acts as a potent:
        • Anaphylatoxin, triggering inflammation
    • C3b:
      • A larger fragment that acts as an opsonin, or “tag,” marking the pathogen for destruction
      • It also attaches to the C3 convertase to create a C5 convertase
• C5 cleavage:
  • The C5 convertase cleaves C5 into C5a (a potent anaphylatoxin and chemoattractant) and C5b
• Membrane Attack Complex (MAC):
  • The C5b fragment recruits and assembles the remaining complement proteins (C6, C7, C8, and multiple C9 molecules):
    • To form a cylindrical pore in the pathogen’s membrane:
      • This pore disrupts the cell’s osmotic balance:
        • Causing it to lyse and die

• Classical / Lectin pathway:
  • C3 convertase: 
    • C4b2a
  • C5 convertase: 
    • C4b2a3b
• Alternative pathway:
  • C3 convertase: 
    • C3bBb:
      • Stabilized by Properdin / P
  • C5 convertase: 
    • C3bBb3b
• Effector Functions (the “what does each piece do?”):
  • Anaphylatoxins: 
    • C3a, C4a, C5a:
      • ↑ vascular permeability
      • Vasodilation
      • Bronchoconstriction
      • Mast cell / basophil degranulation
    • Potency: 
      • C5a > C3a >> C4a (C4a is weak)
  • Chemotaxis (especially neutrophils): 
    • C5a is the major chemoattractant:
      • C3a contributes mainly as anaphylatoxin
    • C5a drives:
      • Leukocyte recruitment
      • Adhesion up-regulation
      • Oxidative burst
  • Opsonization: 
    • C3b (and iC3b), C4b
    • Coat pathogens (marks them for destruction):
      • CR1 / CR3 on phagocytes bind → enhanced phagocytosis
  • Membrane Attack Complex (MAC): 
    • C5b to C9
    • C5b:
      • Nucleates assembly with C6, C7, C8, C9 (polymerizes) → pore → osmotic lysis (classically Neisseria)
• Ion Requirements (exam-friendly correction):
  • Classical and Lectin Pathway: 
    • Ca²⁺ required for C1qrs (classical) and MBL – MASP (lectin) complexes:
      • Mg²⁺ also involved downstream
  • Alternative pathway: 
    • Mg²⁺ essential for Factor B – C3b interaction and convertase formation:
      • So: not “Mg for both pathways”:
        • Only – Classical / Lectin need Ca²⁺
        • Alternative needs Mg²⁺ (and Properdin)
• Regulation (why we don’t self-destruct):
  • C1 inhibitor (C1-INH): 
    • Blocks C1r / C1s and MASPs 1/2 (MASP-1 / MASP-2 cleave C4 and C2):
      • Turns off classic / lectin pathways early
  • Factor H and Factor I: 
    • Inactivate C3b (→ iC3b) on host cells:
      • Factor H prefers sialic acid – rich self surfaces
  • DAF / CD55: 
    • Disrupts C3 / C5 convertases on host cells
  • CD59 (Protectin): 
    • Blocks C9 polymerization:
      • Prevents MAC on self cells
  • Clinical Correlates (high-yield):
    • C1-INH deficiency → Hereditary angioedema:
      • Bradykinin-mediated edema:
        • ACE inhibitors worsen
      • Treat with C1-INH concentrate, bradykinin pathway blockers
    • C2 deficiency (most common classic pathway deficiency):
      • SLE-like disease, recurrent sinopulmonary infections
    • C3 deficiency:
      • Recurrent severe pyogenic infections:
        • Especially encapsulated bacteria; immune complex disease.
    • Terminal complement (C5 to C9) deficiency:
      • Recurrent Neisseria (meningitidis, gonorrhoeae)
    • DAF / CD55 or CD59 deficiency (e.g., PNH via PIGA mutation):
      • Intravascular hemolysis, hemoglobinuria, thrombosis
      • Treat with C5 inhibitors:
        • Eculizumab / ravulizumab
    • Factor H / I abnormalities:
      • Atypical HUS, C3 glomerulopathy
  • Laboratory Assessment:
    • CH50:
      • Total classic pathway function:
        • Low in classic component defects or terminal pathway defects
    • AH50:
      • Total alternative pathway function
    • Heat-labile:
      • Complement activity falls if serum is mishandled / warmed
• Quick “Apply It” Pearls:
  • Suspected meningococcemia with recurrence:
    • Check terminal complement (C5 to C9)
  • Recurrent pyogenic infections with low C3:
    • Evaluate classic / alternative convertase regulation
  • Episodic angioedema without urticaria:
    • Think C1-INH deficiency
  • Autoimmunity in a young patient + low early classic components (C1q/C2/C4) → screen for complement deficiencies
• One-Page Memory Map:
  • Triggers:
    • Classic pathway: 
      • IgM / IgG immune complexes → C1qrs (Ca²⁺)
    • Lectin pathway: 
      • MBL / ficolin (MASPs) → C4, C2
    • Alternative pathway: 
      • C3 tackover + B, D, Properdin (Mg²⁺)
    • Convertases:
      • Classic / Lectin: 
        • C4b2a (C3), C4b2a3b (C5)
      • Alternative:
        • C3bBb (C3), C3bBb3b (C5)
    • Effectors:
      • Opsonins: 
        • C3b/iC3b (± C4b)
      • Anaphylatoxins: 
        • C5a > C3a >> C4a
      • Chemotaxis: 
        • C5a
      • MAC: C5b to C9
    • Regulators: 
      • C1-INH, Factor H / I, DAF (CD55), CD59
    • Deficiencies (buzzwords): 
      • C1-INH—HAE
      • C2—SLE-like
      • C3—pyogenic infections
      • C5–C9—Neisseria
      • DAF/CD59—PNH
      • Factor H/I—aHUS