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• When resection is performed for patients with thyroid cancer ≤ 2 cm without gross extra-thyroidal extension (cT1) and without metastases (cN0M0):
  • The initial surgical procedure should be a thyroid lobectomy:
    • Unless there are bilateral cancers or other indications to remove the contralateral lobe:
      • Strong recommendation, Moderate certainty evidence
• For patients with low risk, unilateral thyroid cancer > 2 and ≤ 4 cm (cT2N0M0):
  • Thyroid lobectomy may be the preferred initial surgical treatment due to significantly lower risk and side effects:
    • However, the patient and treatment team may adopt total thyroidectomy to enable RAI administration and / or enhance follow-up based on disease features, suspicious contralateral nodularity, and / or patient preferences
  • When thyroid lobectomy is offered as initial treatment, counsel the patient about the possibility of conversion to total thyroidectomy or need for subsequent completion thyroidectomy if higher-risk factors emerge intraoperatively or postoper-
    atively:
    • Conditional recommendation, Low-moderate
      certainty evidence
• For patients with thyroid cancer > 4 cm (cT3a), cancer of any size with gross extra-thyroidal extension (cT3b or cT4), or clinically apparent metastatic disease to lymph nodes (cN1) or distant sites (cM1):
  • The initial surgical procedure should include a total thyroidectomy with gross removal of all primary tumor and node dissection unless there are contraindications to this procedure
    • Strong recommendation, Moderate
      certainty evidence

• Who was studied?
  • Population: 
    • Completely resected, intermediate-risk HNSCC of:
      • Oral cavity, oropharynx, or larynx:
        • Hypopharynx excluded
    • Intermediate-risk factors included any of: 
      • 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
    • Key baseline notes: 
      • Majority HPV-negative (~ 80%)
      • Oral cavity ~ 64%
      • EGFR high expression in ~ 85%(assayed for stratification, not a requirement) NRG Oncology+1
  • Study design and treatment:
    • Randomization (1:1): 
      • PORT alone vs PORT + cetuximab
    • PORT: 
      • IMRT 60 Gy in 30 fx (66 Gy allowed) ozarkscancerresearch.org
    • Cetuximab regimen: 
      • 400 mg/m² loading, then 250 mg/m² weekly x 6 during RT + 4 weekly doses post-RT (total 11) ozarkscancerresearch.org
    • Primary endpoint: 
      • Overall survival (OS) in all randomized / eligible
        • Pre-specified plan to test in HPV-negative subgroup
    • Secondary endpoints: 
      • Disease-free survival (DFS), toxicity, others PubMed
  • Results (median follow-up ~ 7.2 years):
    • Primary endpoint (OS): Negative:
      • 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
    • Secondary endpoint (DFS): Positive
      • 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
    • Toxicity:
      • 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
    • Quality of life: 
      • 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
• Interpretation (how to use this):
  • For HPV-negative, intermediate-risk patients who are not ideal candidates for high-dose cisplatin (remember cisplatin is reserved for high-risk ENE+ / positive-margin per RTOG 9501/EORTC 22931 era):
    • Adding cetuximab to PORT is a reasonable option to improve DFS without increasing late toxicity:
      • 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
  • Sites: 
    • Data are particularly representative for oral cavity primaries (largest stratum) Red Journal
• Practical selection checklist (tumor board quick hits):
  • Use PORT + cetuximab consideration when ALL are true:
    • HPV-negative HNSCC (oral cavity / oropharynx / larynx)
    • Intermediate-risk features as per protocol list above
    • No ENE or positive margins:
      • Those are high-risk → cisplatin-based CRT
    • Patient not a good candidate for cisplatin (comorbidities, renal / hearing issues)
    • Accepts higher acute toxicity risk and closer supportive care during RT ozarkscancerresearch.org+2PubMed+2
• Key trial specs (at a glance):
  • NCT00956007; Opened Nov 2009, closed Mar 2018; n=577 eligible. NRG Oncology+1
  • IMRT mandatory; p16 testing required for oropharynx; EGFR IHC collected (stratification/analysis). ozarkscancerresearch.org
• Citation anchors:
  • Machtay M, et al. JCO 2025;43(12):1474–1487. Epub Jan 22, 2025. (Primary publication.) PubMed
  • NRG Oncology press summary with HRs, 5-yr estimates, and toxicity breakdown. NRG Oncology
  • Protocol (2016) schema/eligibility for exact intermediate-risk feature definitions and cetuximab dosing. ozarkscancerresearch.org
  • Additional baseline composition (oral cavity %, EGFR high) from earlier abstract. Red Journal

• Takeaway: 
  • Concomitant chemotherapy + radiation therapy (RT):
    • Yields a statistically significant OS benefit vs RT alone:
      • HR ~ 0.83; ~ 6.5% 5-yr OS gain:
        • Driven by improved locoregional control
    • Induction alone or adjuvant alone did not improve OS
• Use: 
  • This underpins cisplatin-CRT as the default curative standard
• Refs: 
  • Lacas et al., MACH-NC (Radiother Oncol 2021; PMC)
• What it is individual-patient data meta-analysis updating the MACH-NC database:
  • To 107 RCTs / 19,805 patients:
    • Accrued 1965 to 2012
  • Updated median follow-up:
    • 6.6 years
  • Endpoints:
    • OS, EFS, 120-day mortality, loco-regional failure (LRF), distant failure (DF), cancer vs non-cancer deaths Groningen Research Portal+1
  • Results by timing of chemotherapy:
    • Concomitant chemoradiotherapy (CRT) vs loco-regional therapy alone:
      • 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
  • Induction chemotherapy (before RT / CRT):
    • OS and EFS: 
      • 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
  • Adjuvant chemotherapy (after loco-regional therapy):
    • OS and EFS: 
      • No benefit:
        • OS HR 1.02
        • EFS HR 0.98
    • Early mortality: 
      • 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
  • Direct head-to-head concomitant vs induction (same drugs):
    • Across eight comparisons (n=1,214), concomitant is superior: 
      • OS HR 0.84 (≈ + 6.2% absolute OS at 5 yr)
      • EFS HR 0.85
      • LRF HR 0.86
    • Indirect comparisons concur (interaction p<0.0001) Groningen Research Portal
  • Subgroups and modifiers:
    • Age: 
      • Benefit of concomitant chemotherapy decreases with increasing age:
        • Use added caution > 70 yr Groningen Research Portal
    • Performance status: 
      • Poorer PS attenuates benefit:
        • Noted in induction analyses:
          • Similar theme in concomitant Groningen Research Portal
    • HPV / smoking: 
      • Not evaluable here (most trials pre-HPV era)
      • Don’t expect HPV-specific signals from MACH-NC Groningen Research Portal
  • Practical takeaways:
    • For curative, non-metastatic HNSCC:
      • 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
    • Induction doesn’t improve OS vs loco-regional therapy alone (despite fewer distant mets)
    • Adjuvant chemo doesn’t improve OS and raises early mortality risk Groningen Research Portal+1
    • Within concomitant therapy:
      • Platinum-containing regimens carry the strongest signal:
        • This underpins cisplatin-based CRT as the benchmark Groningen Research Portal
• Limitations the paper notes:
  • Trials span 1965 to 2012:
    • Staging, RT techniques, supportive care evolved
    • Still, no interaction by accrual period and sensitivity analyses were consistent
    • HPV data were largely unavailable. Groningen Research Portal
• Citation (free full text): 
  • Lacas B, Carmel A, Landais C, et al. MACH-NC update—107 RCTs, 19,805 pts. Radiother Oncol. 2021;156:281-293. PMC8386522. Key effect sizes and table are in the PDF’s Table 1 and text (OS/EFS/120-day mortality/LRF/DF). 

• What to monitor (and when):
  • Before starting (≤ 7 days prior):
    • BMP / eGFR + electrolytes: 
      • Cr, BUN, Mg, K, Ca, Na, PO₄
    • Urinalysis if concern for renal injury
      • Why: 
        • Baseline renal reserve; cisplatin causes salt wasting (especially Mg) and AKI eviQ
    • CBC with differential:
      • Why:
        • Myelosuppression risk DailyMed+1
    • Audiology (baseline audiogram):
      • 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
    • Medication review and vitals / weight.:
      • Hold / avoid nephrotoxins:
        • NSAIDs, IV contrast, aminoglycosides
      • Assess fluid status eviQ
    • Antiemetic plan (cisplatin = high emetic risk):
      • Day 1: 
        • NK1RA + 5-HT3RA + dexamethasone + olanzapine
      • Continue dexamethasone ± olanzapine Days 2 to 4 American Society of Clinical Oncology+2Janet Abrahm, M.D.+2
  • Each cisplatin day (same day or within 24 to 48 hour before dose):
    • BMP / eGFR + Mg / K / Ca / Na / PO₄ and CBC
      • 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
    • Hydration status and urine output:
      • 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
    • Symptom screen: 
      • 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
  • Weekly during RT (even if cisplatin is q3-weekly):
    • BMP / eGFR + Mg / K / Ca (at least weekly), CBC weekly, weight, I/Os
      • Why:
        • Catch AKI and hypomagnesemia early
        • Track cytopenias and dehydration eviQ+1
    • Audiology: 
      • 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
• What to do with common issues?
  • Rising creatinine / suspected AKI:
    • Trigger: 
      • ≥ 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
    • Escalate care by stage Merck Manuals+1
  • Hypomagnesemia (very common):
    • Prevention / correction:
      • Include MgSO₄ in pre-hydration (e.g., 10 mmol in 1 L NS) and replete as needed:
        • Mg protects against cisplatin nephrotoxicity eviQ+1
  • Emesis despite prophylaxis
    • Action:
      • Optimize 4-drug regimen (ensure NK1RA)
      • Consider scheduled olanzapine days 2 oto 4
      • Add rescue (metoclopramide, prochlorperazine) American Society of Clinical Oncology+1
  • Ototoxicity symptoms (tinnitus, high-frequency loss):
    • Action: 
      • Prompt audiogram:
        • If confirmed / worsening:
          • Discuss dose holding or regimen change (risk rises with cumulative dose) American Academy of Audiology+1
• Hydration—practical template (adjust per institution):
  • Pre-hydration: 
    • 1 L NS over ~ 60 min with 10 mmol MgSO₄
  • Cisplatin infusion: 
    • 1 L NS over ~ 60 min (institutional)
  • Post-hydration: 
    • 1 L NS over ~ 60 min:
      • Encourage oral fluids (≥ 500 mL if tolerated)
  • Mannitol / diuretics:
    • Not routine; consider case-by-case (e.g., very high-dose)  eviQ
• One-look table (what/why/act);
  • BMP / eGFR + Mg / K / Ca / Na / PO₄ (baseline and weekly):
    • Nephrotoxicity / salt wasting → hydrate, replete Mg / K, hold if AKI eviQ
  • CBC weekly: 
    • Myelosuppression → delay / modify if grade ≥ 3, treat per protocol DailyMed
  • Audiogram baseline ± before each cycle / PRN: 
    • Ototoxicity → hold / switch if worsening American Academy of Audiology
  • Antiemetics each dose: 
    • Cisplatin = high emetic risk → 4-drug prophylaxis American Society of Clinical Oncology
• Bottom line: 
  • Weekly labs (BMP / eGFR, Mg / K / Ca) + CBC
  • Disciplined hydration with Mg supplementation
  • Symptom-triggered audiology are the pillars that prevent missed AKI, hypomagnesemia, cytopenias, and ototoxicity during CRT with cisplatin

• Complement System:
  • The complement cascade is a system of immune proteins:
    • That activates in a cascade-like fashion:
      • To fight infection and promote tissue repair:
        • But also contributes to inflammation and disease when overactivated
  • It works via three pathways (classic, lectin, alternative):
    • That converge to create inflammatory fragments called:
      • Anaphylatoxins and form a membrane attack complex (MAC) that can kill pathogens
  • Beyond infection:
    • Complement plays roles in clearing cellular debris, facilitating tissue regeneration, and regulating neuronal function:
      • But inappropriate activation can cause:
        • Chronic pain, autoimmune disease, and organ damage
  • Pathways and Triggers:
    • Each pathway initiates the cascade through different triggers but ultimately leads to the same outcomes: 
      • 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 
    • Classical pathway (antibody-dependent):
      • 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
    • Lectin pathway (antibody-independent; same cascade as classical after C4):
      • 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)
    • Alternative pathway (antibody-independent; tickover on surfaces):
      • 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
    • The final, common pathway:
      • 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
    • C3 / C5 Convertases (know these cold):
      • 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
              
              

• Hepatic acute-phase response (APR) in trauma — what rises, what falls, and why it matters
  • What it is?
    • Within hours of significant injury:
      • IL-6 (with TNF-α / IL-1) shifts hepatocyte transcription toward acute-phase proteins (APPs):
        • Away from constitutive proteins
      • This fuels host defense:
        • Opsonization, complement, coagulation control, metal sequestration:
          • But distorts common labs

Protein	Kinetics after trauma	Key functions	Clinical pearls
CRP	↑ at 6–8 h; peak 48–72 h; t½ ≈ 19 h	Opsonin; complements classical/lectin pathways	Tracks inflammatory burden; falls promptly as inflammation resolves (good trend marker).
Serum amyloid A (SAA)	↑ within 4–6 h; very high amplitude	HDL remodeling; leukocyte recruitment	Rises earlier/higher than CRP; very sensitive to tissue injury.
Fibrinogen	↑ Day 2–3	Coagulation substrate; fibrin matrix for repair	Drives ESR; hyperfibrinogenemia promotes thrombosis risk.
Haptoglobin	↑ 24–48 h	Binds free Hb; antioxidant	Low in hemolysis despite APR (consumption).
Hepcidin	↑ within hours–24 h	Decreases ferroportin → hypoferremia	Mechanism of anemia of inflammation; ferritin may be high despite low iron.
Ferritin	↑ 24–48 h	Iron storage/sequestration	High ferritin doesn’t mean iron repletion in APR.
Complement (C3, C4), MBL	↑ 24–72 h	Opsonization, pathogen lysis	Low levels suggest consumption or hepatic failure.
α1-antitrypsin	↑ 24–48 h	Serine protease inhibition; tissue protection	Deficiency predisposes to unchecked proteolysis.
α1-acid glycoprotein (orosomucoid)	↑ 24–48 h	Modulates immune response; drug binding	Increases binding of basic drugs → lower free fraction.
Ceruloplasmin	↑ 24–48 h	Copper transport; oxidase activity	Oxidative defense; explains ↑ serum copper.
LPS-binding protein (LBP)	↑ 12–24 h	Presents LPS to CD14/TLR4	Often elevated after trauma even without infection.
PAI-1	↑ early	Inhibits fibrinolysis	Favors microthrombosis; part of trauma-induced coagulopathy spectrum.

• Procalcitonin (PCT):
  • Rises after major trauma but is not hepatic:
    • It’s produced systemically (notably in bacterial sepsis):
      • Helpful to distinguish sterile inflammation vs secondary infection (trajectory matters)

Protein	Why it falls	Practical read
Albumin	Reprioritized synthesis + capillary leak	Not a nutrition marker in acute illness; low from redistribution/APR.
Prealbumin (Transthyretin)	Short t½ (≈2 d) + reprioritization	Falls quickly; still APR-sensitive, not pure nutrition.
Transferrin	Iron sequestration program	Falls early; contributes to hypoferremia.
Retinol-binding protein	Reprioritization	Declines with inflammation.
Antithrombin, Protein C/S	Consumption + reduced synthesis	Pro-thrombotic tilt; watch in TIC/ICU patients.

How this maps onto trauma phases

• Ebb (0 to 24 hours): 
  • Catecholamines / cortisol surge
  • TNF-α / IL-1 spark response
  • IL-6 begins hepatic switch
• Flow – catabolic (days 1–7): 
  • CRP / SAA peak
  • Fibrinogen, complement, haptoglobin, hepcidin rise
  • Albumin / transferrin / prealbumin fall
  • Plasminogen Activator Inhibitor-1 (PAI-1):
    • Favors impaired fibrinolysis
• Flow – anabolic (weeks): 
  • APR tapers
  • APPs normalize as repair predominates:
    • IL-10 / TGF-β tone higher

---

High-yield clinical pearls for surgery/ICU

• CRP trend > single value:
  • Expect a 48 to 72 hour peak post-op:
    • A secondary rise suggests infection / collection
• Hepcidin / ferritin pattern:
  • Low iron, low transferrin, high ferritin = anemia of inflammation:
    • Avoid reflex iron unless functional deficiency is proven
• Coagulation:
  • ↑ fibrinogen and PAI-1 tilt toward thrombosis:
    • Combine with VTE prophylaxis early unless contraindicated
• Drug dosing:
  • ↓ albumin raises free acidic drugs (e.g., phenytoin)
  • ↑ α-1-acid glycoprotein (AGP) / orosomucoid lowers free basic drugs (e.g., lidocaine)
  • Monitor levels / clinical effect
• Nutrition metrics:
  • Albumin / prealbumin reflect inflammation, not intake:
    • Use calorie / protein delivery, nitrogen balance, indirect calorimetry or functional metrics instead

---

Selected references

• Gabay C, Kushner I. Acute-phase proteins and systemic response to inflammation. N Engl J Med. 1999.
• Pepys MB, Hirschfield GM. C-reactive protein: a critical update. J Clin Invest. 2003.
• Heinrich PC, et al. Interleukin-6-type cytokine signaling in hepatocytes. Biochem J. 2003.
• Castell JV, Andus T. IL-6 and the acute-phase response. Biochem J. 1991/1992.
• Ganz T, Nemeth E. Hepcidin and iron homeostasis in inflammation. Nat Rev Immunol. 2015.
• Marnell L, Mold C, Du Clos TW. CRP and host defense. Immunol Res. 2005.
• Meisner M. Procalcitonin—biochemistry and clinical diagnosis. 2010 (monograph).

• Ebb phase:
  • First 6 to 24 hours to 48 hours:
    • “Shock, conserve”
  • Characterize by:
    • Hypometabolism
    • ↓O₂ consumption
    • Relative hypothermia
    • Neuroendocrine surge:
      • Catecholamines
      • Cortisol
      • Glucagon
    • The innate immune system is triggered:
      • Early TNF-α / IL-1 release:
        • Begins the inflammatory cascade / response PMC+1
• Flow phase:
  • Catabolic sub-phase:
    • From days ~ 1 to 7:
      • “Hypermetabolism, mobilize”
  • Characterize by:
    • ↑O₂ consumption
    • Hyperglycemia
    • Insulin resistance
    • Proteolysis
    • TNF-α and IL-1 drive the early wave:
      • Rapidly followed by IL-6:
        • Acute-phase switch
      • IL-8:
        • Neutrophil recruitment (PMN chemotaxis)
        • Angiogenesis
      • Counter-regulators like IL-10:
        • To prevent runaway inflammation
    • Clinically corresponds to SIRS:
      • An anti-inflammatory counter-swing (CARS):
        • Follows and may blend into MARS in severe injury PubMed+1
• Flow phase:
  • Anabolic / Recovery sub-phase:
    • Last weeks
  • Characterize by:
    • Gradual resolution of catabolism:
      • As inflammation recedes and tissue repair predominates
    • Cytokine tone shifts toward regulation and remodeling:
      • Persistent but lower IL-6:
        • More IL-10 / TGF-β signals ScienceDirect

• Conceptual arc: 
  • TNF-α / IL-1 ignite the response → IL-6 flips on the acute-phase program → IL-8 pulls in neutrophils (and supports angiogenesis) → IL-10 tempers the fire
  • In severe trauma, this oscillates between SIRS → CARS (sometimes MARS), tracking clinical risk for infection or organ failurePubMed+1
• Practical pearls you can teach on rounds:
  • CRP is an IL-6 barometer:
    • Rising CRP tracks the IL-6–driven hepatic response more than bacterial growth per se PubMed
  • Fever mechanics: 
    • IL-1 / TNF → PGE₂ in the hypothalamus:
      • Antipyretics reduce PGE₂ synthesis (COX inhibition) PMC
  • Atelectasis ≠ fever:
    • The long-taught notion that postoperative atelectasis causes fever isn’t supported by clinical data:
      • Early fevers are cytokine-mediated inflammation from surgical injury unless another source is found PubMed+1
• Summary (link cytokines to phases):
  • Ebb (0 to 24 hours ): 
    • Catecholamines / cortisol ↑
    • TNF-α / IL-1 spark local and systemic inflammation PMC
  • Flow:
    • Catabolic (days 1 to 7): 
      • IL-6 → CRP / SAA
      • IL-8 → neutrophil recruitment / angiogenesis
      • Persistent SIRS risks early MOF
      • Rising IL-10 signals CARS BioMed Central+1
    • Flow:
      • Anabolic (weeks): 
        • Inflammation resolves
        • IL-10 / TGF-β tone dominates
        • Net protein balance turns positive with rehab / nutrition ScienceDirect
• References:
  • Ebb/flow framework: Cuthbertson/Wilmore lineage and modern updates. PMC+1
  • TNF-α endothelial activation/adhesion: Parameswaran & Patial. PMC
  • IL-1 → PGE₂ fever (EP3 in POA): Blomqvist et al. PMC
  • IL-6 drives CRP/SAA (human hepatocytes): Castell et al.; Sack et al. PubMed+1
  • IL-8 neutrophil chemotaxis/angiogenesis: Cambier et al.; Koch et al. Nature+1
  • IL-10 anti-inflammatory: Schulte et al. PMC
  • SIRS → CARS model after trauma: Lenz et al.; Bone RC. PubMed+1
  • Atelectasis–fever myth: Mavros et al.; Stein et al. 

• Leukotrienes:
  • Are a family of potent inflammatory lipid mediators:
    • Derived from arachidonic acid in white blood cells (leukocytes) and other immune cells
  • Produced rapidly in response to injury, infection, or allergens
  • Leukotrienes:
    • Act as local hormones:
      • That help regulate immune and inflammatory responses 
• Biosynthesis pathway:
  • Leukotrienes are produced through the 5-lipoxygenase (5-LO) pathway 
  • An increase in intracellular calcium:
    • Activates the enzyme phospholipase A2 (cPLA2):
      • Which releases arachidonic acid (AA) from cell membrane phospholipids
  • AA is converted into an unstable epoxide intermediate:
    • Leukotriene A4 (LTA4):
      • Through a two-step process catalyzed by the 5-lipoxygenase enzyme.
    • LTA4 then branches into two main pathways:
      • Leading to the formation of two distinct classes of leukotrienes:
        • LTB4:
          • An LTA4 hydrolase enzyme converts LTA4 into leukotriene B4 (LTB4):
            • LTB4 is primarily involved in recruiting neutrophils and other leukocytes to inflammatory sites
        • Cysteinyl leukotrienes:
          • A separate enzyme, LTC4 synthase, conjugates LTA4 with glutathione to create:
            • Leukotriene C4 (LTC4):
              • LTC4 is subsequently metabolized into leukotriene D4 (LTD4) and leukotriene E4 (LTE4) by other enzymes
• Functions of leukotrienes :
  • Leukotrienes exert their effects by binding to G-protein-coupled receptors (GPCRs) on the surface of target cells 
  • LTB4:
    • Acts as a potent chemoattractant:
      • Recruiting immune cells like neutrophils, eosinophils, and T-cells to inflamed tissues
      • It is also involved in the initial sensitization phase of allergic responses
  • Cysteinyl Leukotrienes (CysLTs): The CysLTs (LTC4, LTD4, and LTE4) cause:
    • Bronchoconstriction
    • Increased vascular permeability:
      • Leading to swelling (edema) and the leakage of plasma and immune cells into tissues
    • Mucus production:
      • Stimulating the release of excess mucus, particularly in the airways
• Role in inflammatory diseases:
  • Because of their role in promoting inflammation:
    • Leukotrienes are implicated in a number of chronic inflammatory and allergic diseases
  • Asthma:
    • Overproduction of CysLTs is a major cause of the airway inflammation and bronchoconstriction seen in asthma, particularly exercise-induced asthma and aspirin-sensitive asthma
  • Allergic rhinitis:
    • CysLTs contribute to nasal congestion, mucus production, and other symptoms associated with hay fever
  • Rheumatoid arthritis and inflammatory bowel disease:
    • The pro-inflammatory effects of leukotrienes have been linked to these and other conditions
  • Cardiovascular disease:
    • Recent research suggests leukotrienes also play a role in cardiovascular diseases like atherosclerosis
• Clinical applications:
  • The central role of leukotrienes in inflammation makes them a target for medications called leukotriene modifiers
  • 5-Lipoxygenase inhibitors:
    • Drugs like zileuton block the 5-LO enzyme, preventing the synthesis of all leukotrienes (LTB4 and CysLTs)
  • Leukotriene receptor antagonists (LTRAs):
    • Drugs like montelukast (Singulair) and zafirlukast (Accolate) block CysLTs from binding to their receptors
    • These are primarily used to manage asthma and allergic rhinitis. 
  • By interfering with the leukotriene pathway:
    • These drugs can help manage symptoms associated with inflammatory and allergic conditions

• Post-op intermediate-risk pathology:
  • Perineural Invasion (PNI)
  • Lymphovascular Invasion (LVI)
  • pT3
  • ENE-negative
  • Negative margins
• Standard adjuvant plan: 
  • Postoperative radiation therapy (RT) alone (no concurrent cisplatin)
• Why?:
  • Two landmark randomized trials established who benefits from adding cisplatin to adjuvant RT:
    • EORTC 22931 (Bernier, NEJM 2004):
      • Showed CRT > RT overall in a broad high-risk cohort:
        • Improving PFS / OS:
          • Its Kaplan–Meier curves separate for combined therapy New England Journal of Medicine+2PubMed+2
    • RTOG 9501 (Cooper, NEJM 2004; 10-yr update 2012):
      • In the entire randomized population:
        • CRT did not significantly improve OS / DFS vs RT alone:
          • The KM benefit emerges only in the pre-specified subgroup with:
            • Positive margins and / or extranodal extension (ENE+):
              • Better LRC and DFS; OS trend
          • Outside that subgroup:
            • Curves do not show a clear advantage for adding cisplatin New England Journal of Medicine+2PubMed+2
    • Comparative analysis of EORTC 22931 and RTOG 9501 (Bernier et al., Head & Neck 2005):
      • Concluded the most consistent benefit from adjuvant CRT is confined to:
        • ENE+ and / or positive margins
      • Features such as pT3, PNI, LVI, or multiple nodes without ENE:
        • Did not reproducibly show survival benefit from adding cisplatin PubMed+1
• Guideline take-home:
  • Contemporary guidelines reflect these data:
    • For intermediate-risk pathology (PNI / LVI, pT3, multiple nodes without ENE, clear margins):
      • RT alone is recommended:;
        • Concurrent cisplatin is reserved for ENE+ and / or positive (or non-re-resectable “close”) margins JNCCN
  • Site-specific guidance (ASTRO 2024 HPV+ OPSCC):
    • Likewise recommends post-op RT alone for intermediate-risk categories:
      • Reserving systemic therapy for ENE+ or positive margins ScienceDirect+2ASTRO+2
• Practical pearls:
  • Don’t over-treat intermediate-risk patients with cisplatin unless risk escalators exist (e.g., ENE+, positive / non-re-resectable close margin):
    • This avoids unnecessary nephrotoxicity / ototoxicity / neurotoxicity without proven survival gain:
      • KM patterns from RTOG 9501:
        • Show separation only in ENE + / R + PubMed
  • RT planning: 
    • Typical adjuvant doses 60 to 66 Gy to the primary bed / high-risk nodal regions with elective coverage as indicated by subsite and pathologic mapping (per institutional / NCCN frameworks) JNCCN
  • Clinical trials:
    • If available, consider enrollment for intermediate-risk biology:
      • Biomarkers, de-intensification / intensification questions
      • Observational work underscores prognostic value of PNI / LVI but does not establish a chemotherapy benefit post-operatively PMC+1
• Bottom line: 
  • For PNI / LVI / pT3 (ENE-negative, margins clear):
    • Post-operative RT alone is the guideline-concordant standard.
  • Reserve cisplatin-RT for:
    • ENE+ and / or positive / irremediably close margins:
      • Which is where randomized trials (and their Kaplan–Meier curves):
        • Show the benefit of adding chemotherapy

• Design:
  • Phase III, randomized, non-inferiority trial: 
    • Micrometastatic (≤ 2 mm) SLN, tumor ≤ 5 cm, clinically node-negative (cN0); no extracapsular extension
  • Randomized:
    • ALND vs no ALND
  • Primary endpoint: 
    • DFS:
    • NI margin HR 1.25
  • Population:
    • N = 934 randomized:
      • ALND 465
      • No-ALND 469
    • Median age ≈ 55
    • Most patietns had:
      • Breast-conserving surgery (~ 91%)
      • Tumors < 3 cm (~ 92%)
      • Received adjuvant systemic therapy (~ 96%)
      • Mastectomy (~ 9%)
  • 5-year results (primary publication, Lancet Oncology 2013):
    • 5-yr DFS: 
      • 87.8% (No-ALND) vs 84.4% (ALND):
        • HR 0.78 (95% CI 0.55–1.11):
          • Non-inferior (p for NI = 0.0042)
    • Axillary / regional recurrences (early report): 
      • Very low and similar:
        • Reported counts: 
          • 1 ALND vs 5 No-ALND over early follow-up -absolute numbers small
    • Toxicity: 
      • Grade 3 to 4 surgical morbidities (neuropathy / lymphedema) occurred almost exclusively in the ALND arm
    • Conclusion: 
      • In SLN micro metastases:
        • Omitting ALND did not compromise DFS and reduced morbidity
  • 10-year update (Lancet Oncology 2018):
    • Median follow-up 9.7 y (IQR 7.8–12.7).
    • 10-yr DFS: 
      • 76.8% (No-ALND) vs 74.9% (ALND):
        • HR 0.85 (95% CI 0.65–1.11); log-rank p = 0.24:
          • Non-inferiority maintained (p for NI = 0.0024)
    • Long-term morbidity: 
      • Lymphedema (any grade):
        • 4% No-ALND vs 13% ALND
      • Sensory neuropathy 
        • 13% No-ALND vs 19% ALND
      • Motor neuropathy:
        • 3% No-ALND vs 9% ALND
  • Interpretation: 
    • 10-year outcomes corroborate 5-year findings and align with Z0011:
      • ALND can be omitted when SLN tumor burden is minimal
  • Practice take-home:
    • In cT1 to cT2, cN0 patients with SLN micrometastases ≤ 2 mm, skip ALND: 
      • Non-inferior DFS to 10 years and meaningfully less arm morbidity
    • Fits the broader de-escalation arc alongside ACOSOG Z0011 (1 to 2 macrometastases-positive SLNs in BCT + WBRT → omit ALND) and AMAROS (if nodal control needed, axillary RT ≈ ALND with less lymphedema)