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• LIBRETTO‑531:
  • Design & Patient Population:
    • Phase III, global, multicenter, open-label, randomized (2:1) trial (NCT04211337):
      • Comparing selpercatinib (160 mg BID) to physician’s choice of cabozantinib or vandetanib:
        • In MKI-naïve, progressive advanced /metastatic RET-mutant MTC patients 
      • Stratified by RET M918T mutation status and intended control arm MKI
      • Crossover permitted from MKI arm to selpercatinib upon progression
  • Efficacy Results (Interim, ~ 12-months follow-up):
    • Primary endpoint (PFS, RECIST v1.1):
      • Selpercatinib:
        • Median not reached
      • MKI arm:
        • 16.8 months (95% CI, 12.2–25.1); HR 0.28; P<0.001 
      • 12‑month PFS:
        • 86.8% vs 65.7%
    • Secondary endpoint (Treatment Failure-Free Survival – TFFS):
      • Not reached vs 13.9 months in MKI arm; HR 0.25
    • Overall Response Rate (ORR):
      • 69.4% in selpercatinib group vs 38.8% in MKI group 
    • Safety-driven dose modifications:
      • 38.9% with selpercatinib vs 77.3% with MKIs
    • Discontinuations 4.7% vs 26.8% 
• Safety & Patient-Reported Outcomes:
• Common ≥ 25% AEs:
  • Hypertension, edema, dry mouth, fatigue, diarrhea
• Grade 3/4 laboratory abnormalities:
  • Lymphopenia, elevated ALT / AST, electrolyte disturbances
• Patient-reported tolerability (FACT-GP5):
  • Demonstrated robust reliability (ICC 0.80–0.85); high side-effect burden correlated with decreased functioning
• Mechanism of Action:
  • Selpercatinib is a highly selective RET inhibitor, effective against both:
    • RET point mutations (e.g., M918T in MTC)
    • RET fusions (common in papillary thyroid carcinoma and NSCLC)
  • High selectivity translates to less off-target toxicity compared to multikinase inhibitors (vandetanib/cabozantinib), which inhibit VEGFR, MET, etc.
• Guideline Endorsements:
  • NCCN (2024) now includes selpercatinib as a Category 1 first-line option:
    • For RET-mutant, progressive/unresectable MTC, alongside cabozantinib and vandetanib
  • ATA Guidelines:
    • Similarly endorse selective RET inhibitors as preferred agents for RET-driven MTC
  • ESMO / European Consensus:
    • Align with use in RET-mutant MTC post-MKI therapy
• Regulatory Perspective:
  • FDA granted traditional approval on September 27, 2024 for adults and pediatrics ≥ 2 years with advanced / metastatic RET-mutant MTC requirement systemic therapy
  • Earlier accelerated approval received in 2020 for patients ≥ 12 years; expanded to ≥ 2 years with pediatric dosing in May 2024
• Clinical Implications for Head and Neck Oncology Teams:
  • First-line therapy improvement:
    • LIBRETTO‑531 is the first randomized trial demonstrating selpercatinib superiority over MKIs in efficacy and tolerability
    • Reduced surgical urgency:
      • Durable responses may defer or potentially downstage extra-thyroidal or metastatic disease, assisting in surgical planning
    • Multidisciplinary coordination:
      • Shared decision-making essential for selecting candidates, managing MTC lesion status, and monitoring biochemical markers (calcitonin, CEA)
    • Monitoring & sequencing:
      • Be vigilant for long-term tolerability needs, dose adjustments, and resistance (e.g., RET solvent-front mutations); TKIs sequencing should involve endocrine-oncology collaboration
• Recommended References for Further Reading:
  • Primary LIBRETTO‑531 publication: NEJM (PubMed PMID: 37870969) 
  • Preceding phase I/II evidence: Wirth et al., N Engl J Med 2020 (LIBRETTO‑001)
  • NCCN Thyroid Carcinoma Guidelines, v2.2024  .
    FDA approval details for selpercatinib
  • Patient-reported outcomes analysis: Regnault et al., J Patient Rep Outcomes 2024
• Summary for Surgical Experts:
  • Selpercatinib sets a new standard first-line systemic therapy in RET-mutant MTC, delivering superior tumor and nodal responses while maintaining patient quality-of-life
  • Surgeons should integrate molecular profiling early, allowing neoadjuvant-like benefit of targeted therapy before considering resection or resection of metastatic deposits
  • Long-term surgical planning may be increasingly influenced by TKI response and durability

• Clinical Implications for Surgeons and Oncologists:
  • Preoperative:
    • Patients with borderline resectable MTC may benefit from downstaging with selpercatinib
    • Early molecular testing for RET mutations is essential
  • Postoperative:
    • Patients with biochemical persistence (calcitonin / CEA) or structural recurrence can receive selpercatinib earlier
    • More favorable AE profile allows longer-term outpatient management
• References:
  • Wirth LJ, et al. Selpercatinib vs Standard Therapy in RET-Mutant MTC. N Engl J Med. 2023;389(15):1344-1356. PMID: 37870969
    NCCN Guidelines: Thyroid Carcinoma v2.2024. https://www.nccn.org
  • ATA Guidelines Update (Thyroid, 2022): Use of targeted therapy in RET-mutant disease
    FDA Approval Summary: https://www.fda.gov/drugs
  • Drilon A, et al. Targeting RET-driven cancers with selpercatinib. Cancer Discov. 2020. PMID: 3221355

• The Delphi criteria for advanced disease in thyroid cancer:
  • Refer to a consensus-based set of clinical, pathological, and radiological features:
    • Developed by expert panels (often using the Delphi method):
      • To define what constitutes advanced thyroid cancer
  • These criteria help guide decision-making:
    • In terms of treatment strategies, referral to tertiary centers, and inclusion in clinical trials
• While there is no universal single set of “Delphi criteria” adopted globally for thyroid cancer:
  • Multiple Delphi panels have been convened in recent years to create consensus on what features define advanced or aggressive disease
• Below is a synthesis of key features commonly included in such panels and used in high-level consensus guidelines:
  • ATA, NCCN, and expert Delphi studies
• Delphi-Based Criteria for Advanced Thyroid Cancer:
  • Clinical Features:
    • Age > 55 years:
      • For differentiated thyroid cancer (DTC)
    • Rapid tumor growth
    • Hoarseness or vocal cord paralysis
    • Dysphagia or airway compression
    • Distant metastases:
      • Lung, bone, brain
    • Recurrent or persistent disease after initial therapy
  • Pathological Features:
    • High-risk histologies:
      • Poorly differentiated thyroid carcinoma
      • Anaplastic thyroid carcinoma
      • Hürthle cell carcinoma with widely invasive features
      • Tall cell, hobnail, or columnar variants of PTC
      • Extensive vascular invasion
      • Extrathyroidal extension:
        • Especially gross
      • Incomplete resection margins:
        • R2 or R1
  • Radiological Features:
    • Evidence of invasion into adjacent structures::
      • Trachea, esophagus, larynx, recurrent laryngeal nerve, carotid artery
    • Radiographic evidence of unresectability
    • Distant metastases confirmed via CT, MRI, or PET / CT
  • Molecular/Functional Criteria:
    • RAI-refractory disease:
      • Based on functional imaging and response
    • Presence of high-risk mutations:
      • TERT promoter
      • TP53
      • BRAF + TERT
    • High FDG-avidity on PET scan:
      • Often correlates with aggressiveness
  • Biochemical Markers:
    • Rapidly rising thyroglobulin levels post-thyroidectomy and RAI
    • Elevated Tg levels with negative RAI uptake:
      • Suggesting RAI-refractory disease
• Notable Delphi Studies / Consensus Papers:
  • Tuttle RM et al., Memorial Sloan Kettering Cancer Center: Clinical criteria for RAI-refractory DTC
  • American Thyroid Association (ATA) 2015 Guidelines: Use a similar risk stratification model that incorporates many of these features
  • NCCN Guidelines (latest version): Lists features of unresectable, progressive, or symptomatic disease requiring systemic therapy
  • Molecular Oncology Tumor Boards have also developed decision-making algorithms based on Delphi consensus

• After initial parathyroidectomy, reported rates of moderate postoperative hypocalcemia range from 5% to 47%:
  • However, permanent hypoparathyroidism and severe hypocalcemia due to hungry bone syndrome are rare

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• Trial Overview – ESTIMABL2 (NCT01837745):
  • Is a French, multicenter, phase III randomized trial investigating the necessity of post-thyroidectomy radioactive iodine (RAI) in patients with low-risk DTC:
    • Defined as intrathyroidal papillary carcinomas ≤ 1 cm (pT1a-m) or 1 to 2 cm (pT1b), with no suspicious lymph nodes on preoperative neck ultrasound (N0 / Nx)
  • All underwent total thyroidectomy (with or without prophylactic central neck dissection) and were randomized at 2 to 5 months post-op to:
    • RAI group:
      • 1.1 GBq (30 mCi) after rhTSH preparation
    • No‑RAI group:
      • Surveillance only 
  • Follow-up Protocol:
    • 3-year endpoint:
      • Thyroglobulin (Tg) and anti-Tg antibodies annually, neck ultrasound in alternating years
  • Event definition:
    • Need for further radioactive iodine or surgery:
      • Due to abnormal uptake, ultrasound changes, Tg rise, or antibody surge
    • Non-inferiority margin:
      • 5% difference in event-free survival 
  • Primary (3-Year) Results:
    • Evaluable patients:
      • 729 (FU: 367; RAI: 362)
      • Events:
        • 18 (4.9%) in surveillance vs 15 (4.1%) in RAI
      • Event-free survival:
        • 95.1% (no RAI) vs 95.9% (RAI)
        • Difference 0.8% (95% CI –3.3% to 1.8%) → non-inferiority confirmed 
  • Secondary interventions (surgery / RAI):
    • 6 (1.6%) vs 9 (2.5%)
• 5-Year Long-Term Outcomes:
  • Evaluable at 5 years:
    • 698 patients
  • Event-free survival:
    • No RAI: 93.2%
    • RAI: 94.8%
      • Difference: 1.6% (90% CI –4.5 to 1.4%)
        • Remains within non-inferiority bounds 
• Quality of response:
  • Surveillance group had higher rates of “excellent response” (83.3% vs 75.6%) and fewer indeterminate results 
• Clinical Implications for Surgeons:
  • Omission of adjuvant RAI in strictly defined ATA low-risk patients (pT1, cN0, complete surgery, normal Tg and US) is safe and effective, even at 5 years
  • Non-inferiority margin of 5% comfortably met at both 3 and 5 years, a robust outcome
  • Superior biochemical and imaging outcomes in the surveillance arm suggest less overdiagnosis and overtreatment
  • Reduces patient burden:
    • Avoids radiation, isolation, and enhances convenience
  • Supports tailored management:
    • RAI can be reserved for cases with unfavorable histology, remnant tissue on US, or rising Tg / antibodies
• Recommendations for Practice:
  • Strict selection is essential:
    • Only patients with pT1 N0 / Nx, complete surgery, and negative post-op US are eligible for RAI omission
  • Omit RAI in these low-risk patients, with follow-up consisting of Tg, TgAb, and periodic neck ultrasound
  • Reserve RAI for patients with adverse features:
    • Aggressive histology
    • Tg rise
    • Suspicious imaging
  • Discuss care pathway in MDT rounds, highlighting QoL gains and similar oncologic outcomes
  • Educate patients:
    • Provide clear rationale and plan for surveillance to avoid anxiety over omitted therapy
• Final Takeaways:
  • The ESTIMABL2 trial delivers strong evidence that surveillance alone post-thyroidectomy is a safe, effective, and patient-centric strategy in carefully selected ATA low-risk DTC patient:
    • Offering similar long-term outcomes to standard RAI treatment, with additional QoL and diagnostic benefits

👉Elevated serum calcium levels have been associated with thiazide diuretic use and need to be differentiated from primary hyperparthyroidism – Dr. Rodrigo Arrangoiz

👉The overall annual age- and sex-adjusted (to 2000 U.S. whites) incidence of hypercalcemia due to thiazide diuretic use was 7.7 (95% CI, 5.9 to 9.5) per 100,000 individuals.

👉The average 24-hour plasma calcium concentrations are increased with thiazide diuretic use, but the mean 24-hour PTH levels remain unchanged in subjects with normal baseline PTH levels and no evidence of hypercalciuria.

👉Thiazides diuretics have several metabolic effects that may contribute to increased calcium levels:

• A decrease in urine calcium excretion is the most likely cause.
• In some cases of diuretic use metabolic alkalosis can occur that could cause an increase in total serum calcium levels through a pH-dependent increase in protein-bound calcium.
• Although plasma 1,25 (OH) vitamin D levels are unchanged, increased intestinal calcium absorption in response to thiazide diurectic use has been noted and could also contribute to an increase in serum calcium.
• One last possible explanation for the elevated serum calcium levels associated with thiazide diuretic use is hemoconcentration associated with diuresis.

👉CheckYourCalcium (realízate un calcio total en sangre).

#CheckYourCalcium #Arrangoiz #ParathyroidExpert #ParathyroidSurgeon #Hiperparatiroidism #Hipercalcemia #CheckYourCalcium #HeadandNeckSurgeon #MountSinaiMedicalCenter #MSMC #Miami #Mexico #Hyperparathyroidism

👉 Para obtener más información sobre el hiperparatiroidismo:

https://s3.amazonaws.com/academia.edu.documents/48239291/Current_Thinking_in_Hyperparathyroidism.pdf?response-content-disposition=attachment%3B%20filename%3DCurrent_Thinking_in_Hyperparathyroidism.pdf&X-Amz-Algorithm=AWS4-HMAC-SHA256&X-Amz-Credential=AKIAIWOWYYGZ2Y53UL3A%2F20190724%2Fus-east-1%2Fs3%2Faws4_request&X-Amz-Date=20190724T015127Z&X-Amz-Expires=3600&X-Amz-SignedHeaders=host&X-Amz-Signature=9633131723dc3e5fa1671838123524ae980c0bfb31e4a92be406b43a103bc355

• Title:
  • Outcome after ablation in patients with low‑risk thyroid cancer (ESTIMABL1)
• Design:
  • A multicenter, randomized, open-label, phase III equivalence trial:
    • Across 24 centers in France (2007 to 2010)
• Population:
  • 752 adults with low-risk papillary or follicular differentiated thyroid cancer (DTC) post-total thyroidectomy
• Randomization (1:1:1:1) into four groups:
  • RAI dose:
    • Low (1.1 GBq / ~30 mCi) vs High (3.7 GBq / ~100 mCi)
  • TSH stimulation:
    • rhTSH injections vs thyroid hormone withdrawal
• Primary Endpoint:
  • Successful remnant ablation at 6 to 10 months:
    • Defined as stimulated thyroglobulin ≤ 1 ng/mL and no residual tissue on ultrasound
• Initial and Long-Term Efficacy:
  • 6 to 10 Month Ablation Success:
    • ~ 92% across all groups:
      • With equivalence between:
        • Low and high dose
        • rhTSH vs withdrawal
  • 5.4-Year Median Follow-Up (n = 726):
    • 98% had no evidence of disease (715 / 726)
    • 11 patients had evidence of persistent or recurrent disease (structural or biochemical)
      • Recurrence was evenly distributed across RAI dose and stimulation method:
        • Indicating no impact of strategy on long-term outcomes
• Prognostic Predictors:
  • Stimulated thyroglobulin at ablation:
    • Was predictive of eventual disease status and ablation success:
      • Patients with higher thyroglobulin were more likely to have persistent disease regardless of group
  • No lymph node stratification influence or stimulation method effect was observed
• Clinical Implications:
  • Low-dose RAI (1.1 GBq) with rhTSH is validated as standard of care:
    • Equivalent efficacy with better patient experience
  • ATA 2015 guidelines endorse this strategy for low-risk DTC:
    • Simplified staging and reduced toxicity
  • No impact on long-term disease-free survival:
    • Supports tailored management based on disease biology rather than RAI intensity
• Evidence Synthesis:
  • Meta-analysis of RCTs (> 1,500 patients, 4 to 10 years follow-up):
    • Confirms no difference in long-term recurrence between 1.1 GBq and 3.7 GBq (OR 0.93, 95% CI 0.53–1.63)
  • Similar equivalence was seen between rhTSH vs hormone withdrawal and across centers (France & UK)
  • HiLo trial results align, confirming comparable recurrence rates with low-dose RAI and rhTSH
• Surgical Take-Home Points:
  • Remnant ablation using low-dose RAI + rhTSH is effective and minimizes side effects compared to high-dose or withdrawal strategies
  • Stimulated thyroglobulin at post-op ablation is a stronger predictor of recurrence than RAI dose or preparation method
  • No difference in long-term disease-free survival across dose or stimulation arms supports risk-adapted RAI use
  • Multidisciplinary protocols should adopt low-dose rhTSH-based ablation for ATA low-risk patients, reserving higher dose only for select cases (e.g., unresected tissue, aggressive pathology)
  • Surveillance strategies:
    • Regular ultrasound + Tg on levothyroxine; use stimulated Tg selectively for indeterminate findings

👉Negative preoperative imaging does not exclude patients from surgery for hyperparathyroidism.

👉Experienced parathyroid surgeons have high cure rate (95%) with or without preoperative localization.

👉https://doi.org/10.1210/jc.2002-021095

#CheckYourCalcium #Arrangoiz #ParathyroidSurgeon #PararhyroidExpert MountSinaiMedicalCenter #MSMC #Miami #Mexico #HeadandNeckSurgeon #Hyperparathyroidism

• American Thyroid Association (ATA) Low-Risk of Recurrence Overview:
  • Patients considered low-risk (pre- or post-operative):
    • Intrathyroidal papillary thyroid cancer ≤ 4 cm:
      • T1 to T2
    • No clinical nodal involvement:
      • N0 or minimal N1a
    • No distant metastasis (M0)
    • No aggressive histologic variants
    • No gross extrathyroidal extension
• Core Randomized Trials:
  • ESTIMABL1 (2012, France):
    • Design:
      • 2 × 2 factorial randomized control trial (RCT):
        • Comparing low-dose (1.1 GBq) vs high-dose (3.7 GBq) radioactive iodine (RAI), and rhTSH stimulation vs thyroid hormone withdrawal for remnant ablation
    • Primary Outcome:
      • Remnant ablation success at 6 to 10 months:
        • ~92% to 95%
      • 5‑Year Follow-Up (2018):
        • 98% no evidence of disease
        • No differences between RAI dose or preparation method 
    • Clinical Meaning:
      • Low-dose RAI + rhTSH is as effective as high-dose with withdrawal
      • Lower toxicity, better patient convenience:
        • Incorporated in ATA 2015 guidelines (New Guidelines Coming Out Fall 2025)
  • HiLo (UK, Mallick et al., 2012):
    • Design:
      • Similar to ESTIMABL1:
        • Compared low- vs high-dose plus rhTSH vs withdrawal
    • Outcome:
      • Comparable ablation success and low recurrence rates 
  • ESTIMABL2 (France, 2022):
    • Design:
      • RCT of low-dose RAI (1.1 GBq) vs no RAI, post-total thyroidectomy in low-risk DTC
    • 3-Year Results:
      • Recurrence:
        • 2.7% (no RAI) vs 1.9% (RAI); non-inferior 
    • Commentary:
      • Non-inferiority holds even at lowest end of risk spectrum:
        • Upholds omission in select patients
  • IoN (“Iodine or Not”) Trial (UK, Lancet June 2025):
    • Design:
      • Phase II / III RCT randomizing 504 low-risk DTC patients to RAI vs no RAI
    • 5-Year Data:
      • 98% disease-free without RAI vs 96% with RAI
      • Omitting RAI improved quality of life and reduced isolation burden 
    • Significance:
      • Largest definitive trial confirming RAI omission is safe in ATA low-risk patients
  • Additional Evidence and Observational Data:
    • Long-term observational studies (> 8 years):
      • Show high remission and low recurrence with low-dose RAI 
    • Meta-analyses and reviews echo findings:
      • Low-dose or no RAI yields excellent oncologic outcomes in strictly low-risk DTC
• Clinical Take‑Home Points for Surgeons:
  • Low-dose (1.1 GBq) RAI is sufficient for remnant ablation when RAI is used
  • rhTSH is preferred for patient comfort
  • RAI omission is safe in ATA low-risk cases:
    • Per ESTIMABL2 and IoN with:
      • ~ 98% disease-free survival at 5 years
    • QoL benefit and reduced isolation burden when RAI is not used:
      • Especially relevant for younger, family-centered patients
  • ATA 2015 guidelines:
    • Support selective RAI omission, reinforced by current trials
  • Surgical completeness matters:
    • Trials include total thyroidectomy with low /absent nodal burden
    • Partial thyroidectomy or residual disease was excluded
  • Follow-up protocol:
    • Stringent ultrasound and thyroglobulin monitoring essential when omitting RAI
• Practical ATA-Based Approach:
  • Very Low / Low Risk ATA:
    • Intrathyroidal ≤ 4 cm
    • N0 to N1a
    • No vascular invasion:
      • Omit RAI:
        • Active surveillance with US + Tg (with / without rhTSH)
    • If ablation desired (e.g., Tg monitoring ease):
      • Use 1.1 GBq + rhTSH
  • Intermediate Risk:
    • Minimal extrathyroidal extension
    • > 5 involved nodes:
      • Consider selective RAI at low dose:
        • Decision individualized based on risk tolerance
• Summary:
  • In ATA-defined low-risk DTC:
    • Low-dose RAI + rhTSH is as effective as high-dose or withdrawal methods
  • Importantly, omission of RAI does not compromise outcomes and offers QoL and cost benefits
  • Surveillance replaces ablation, with triggers reserved for structural or biochemical recurrence

👉Did you know that the only cure for primary hyperparathyroidism is surgery?

👉Dr. Rodrigo Arrangoiz is Pioneer in Mexico in radio-guided minimally invasive parathyroidectomy.

https://m.youtube.com/watch feature=youtu.be&v=AgvQmtz1gnA

👉Find more info at http://www.hiperparatiroidismo.info

#Arrangoiz

#ParathyroidExpert #ParathyroidSurgeon #Hiperparatiroidismo #Hipercalcemia #CheckYourCalcium #HeadandNeckSurgeon #EndocrineSurgeon

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