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• RxPONDER (SWOG S1007):
  • Changed adjuvant decision-making for patients with HR-positive, HER2-negative early breast cancer with 1 to 3 positive axillary nodes:
    • By showing that the value of chemotherapy depends heavily on menopausal status:
      • When the 21-gene recurrence score (Oncotype DX RS) is 0 to 25
  • The key practice-changing message is that postmenopausal women with RS 0 to 25:
    • Generally do not benefit from adjuvant chemotherapy:
      • Whereas premenopausal women with the same RS range do appear to benefit
• Trial design:
  • RxPONDER was a prospective randomized phase III trial enrolling more than 5,000 women with HR-positive, HER2-negative breast cancer, 1 to 3 positive lymph nodes, and an RS of 25 or lower
  • Patients were randomized to endocrine therapy alone or chemoendocrine therapy
  • The central goal was to determine whether recurrence score could identify node-positive patients who could safely avoid chemotherapy
• Main result:
  • In the overall study population, the effect of chemotherapy differed by menopausal status:
    • Among postmenopausal women:
      • Adding chemotherapy did not improve invasive disease–free survival
    • Among premenopausal women:
      • Chemotherapy did improve invasive disease–free survival and distant relapse–free survival:
        • This interaction is the most important clinical takeaway from the study
  • Postmenopausal patients:
    • For postmenopausal patients with 1 to 3 positive nodes and RS 0 to 25:
      • Chemotherapy can usually be omitted without compromising outcomes:
        • This is the group in which RxPONDER most clearly supports de-escalation
      • For the surgeon, this means that limited nodal positivity alone no longer automatically implies a chemotherapy recommendation in HR-positive / HER2-negative disease
  • Premenopausal patients:
    • For premenopausal patients with 1 to 3 positive nodes and RS 0 to 25:
      • Chemotherapy was associated with a statistically significant benefit
      • The trial did not prove whether that benefit came from cytotoxic therapy itself, chemotherapy-induced ovarian suppression, or both:
        • So multidisciplinary interpretation remains important
      • Current NCCN educational guidance reflects this nuance:
        • Noting that in premenopausal patients the assay may help frame discussion of alternatives such as ovarian function suppression, but chemotherapy and ovarian suppression are not yet proven interchangeable
• What it means for the surgical oncologist:
  • RxPONDER matters because it directly affects postoperative counseling after lumpectomy or mastectomy when final pathology shows 1 to 3 positive nodes
  • The surgeon should anticipate genomic testing in appropriate ER-positive / HER2-negative patients and should understand that:
    • Node-positive does not automatically mean chemotherapy
    • Menopausal status is central to interpretation:
      • In postmenopausal patients with RS 0 to 25:
        • Chemotherapy can often be avoided
      • In premenopausal patients with RS 0–25:
        • Chemotherapy is still generally recommended unless the medical oncology discussion supports a different endocrine-based strategy
• Practical surgical takeaway:
  • For a surgical oncologist:
    • RxPONDER shifts the conversation from “How many nodes are positive?” to “What is the biology, and is the patient premenopausal or postmenopausal?”
    • In modern breast practice, a patient with 1 to 3 positive nodes and favorable genomics may still avoid chemotherapy if she is postmenopausal:
      • But a similar premenopausal patient usually still merits strong consideration of chemotherapy
• Bottom line:
  • RxPONDER showed that for HR-positive, HER2-negative early breast cancer with 1 to 3 positive nodes and Oncotype DX RS 0 to 25, postmenopausal women do not derive meaningful chemotherapy benefit, while premenopausal women do:
    • That is the key message that should guide surgical counseling and multidisciplinary adjuvant planning
• Key references:
  • Kalinsky K, Barlow WE, Gralow JR, et al. 21-Gene Assay to Inform Chemotherapy Benefit in Node-Positive Breast Cancer. N Engl J Med. 2021;385:2336-2347. 
  • NCCN educational update on biomarkers in early-stage breast cancer, summarizing current use of the 21-gene assay in node-positive disease. 

• The oral cavity represents the entrance to the upper aerodigestive tract:
  • Which begins at the lips and ends at the anterior surface of the faucial arch
  • It is lined by:
    • Squamous epithelium with interspersed minor salivary glands
• The oral cavity also contains the:
  • Dentoalveolar structures:
    • With the upper and lower dentition
• The oral cavity is continuously exposed to inhaled and ingested carcinogens:
  • Thus it is the most common site for the origin of malignant epithelial neoplasms in the head and neck region
  • Known carcinogens for oral cavity carcinoma include:
    • Those present in tobacco, alcohol, and betel nuts
    • The association of human papilloma virus with oral cancer:
      • Is not as well established as in oropharyngeal cancers
• Primary tumors of the oral cavity may arise from the:
  • Surface epithelium
  • Minor salivary glands
  • Submucosal soft tissues
  • Lesions of dentoalveolar origin:
    • Representing a unique group of neoplasms and cysts
• The various anatomic sites within the oral cavity as described by the American Joint Committee on Cancer (AJCC) and International Union Against Cancer (UICC) staging system are shown below:

• More than 90% of malignant tumors in the oral cavity are:
  • Squamous cell carcinomas:
    • The remainder are:
      • Minor salivary gland carcinomas and other rare tumors
• Most patients with cancer in the oral cavity are men:
  • Although the incidence of tongue cancer in women in the United States has progressively increased over the past several decades
    • In the Western world:
      • The tongue (> 50% of cases) and floor of the mouth:
        • Are the most common sites of origin for primary squamous cell carcinomas in the oral cavity:
          • However, the retromolar trigone and buccal mucosa are the most frequently encountered primary sites in areas of the world where chewing of tobacco and / or betel nuts is common
• The site distribution of various primary cancers in the oral cavity in the United States is shown bowls:

#Arrangoiz #CancerSurgeon #HeadandNeckSurgeon #SurgicalOncologist #ThyroidSurgeon #ParathyroidSurgeon #MountSinaiMedicalCenter #MSMC #Miami #Mexico

• MINDACT:
  • Was the first large prospective randomized trial to test whether the 70-gene signature (MammaPrint):
    • Could help spare adjuvant chemotherapy in patients with early breast cancer:
      • Especially when clinical risk and genomic risk disagreed
  • Its key contribution was showing that some patients who appear high-risk by traditional clinicopathologic criteria:
    • Still have an excellent outcome without chemotherapy if they are genomically low-risk
• Trial design:
  • MINDACT enrolled 6,693 women with early-stage breast cancer
  • Patients were assigned both a clinical risk estimate and a genomic risk estimate:
    • Clinical risk was based on:
      • A modified Adjuvant! Online tool
    • Genomic risk was based on:
      • The 70-gene signature
  • Patients with concordant low risk generally avoided chemotherapy
  • Those with concordant high risk received it
  • Those with discordant risk:
    • Were randomized to treatment decisions based on either the clinical or genomic result:
      • The primary test population was the clinical high-risk / genomic low-risk group 
• Primary finding:
  • In patients with high clinical risk but low genomic risk:
    • Who did not receive chemotherapy:
      • The 5-year distant metastasis-free survival (DMFS) was 94.7% (95% CI 92.5–96.2):
        • Which met the study’s predefined benchmark for safety
      • This was the practice-changing result:
        • It supported omission of chemotherapy in selected patients despite unfavorable conventional features
• Longer-term follow-up:
  • With longer follow-up, the benefit of chemotherapy in the clinical high-risk / genomic low-risk group remained small overall
  • The 2021 update reported that the 8-year DMFS for this group was 92.0% with chemotherapy vs 89.4% without chemotherapy, an absolute difference of 2.6 percentage points
    • The authors concluded that the 70-gene signature continues to identify a group with excellent outcomes and only a limited average chemotherapy benefit
• Age-related nuance:
  • The most important nuance for multidisciplinary decision-making is age
  • In the updated analysis, the apparent chemotherapy benefit was not seen in women older than 50 years, while a potentially clinically relevant benefit appeared in women 50 years or younger
    • This raises the same question seen in other adjuvant trials:
      • How much of the effect reflects true cytotoxic benefit versus ovarian suppression / menopausal effect in younger patients
        • For the surgeon, this means a low-genomic-risk result should still be interpreted in the context of menopausal status and age
• Node-positive relevance:
  • A major practical strength of MINDACT is that it included not only node-negative disease but also patients with 1 to 3 positive nodes:
    • Making it more broadly relevant than node-negative-only genomic trials
  • For surgical oncologists, this is especially useful after lumpectomy or mastectomy when pathology shows limited nodal disease and the team is deciding whether anatomy alone should drive chemotherapy recommendations
• Ultralow-risk subgroup:
  • A later MINDACT analysis identified an ultralow-risk subgroup by the 70-gene assay
  • These patients had exceptionally favorable outcomes:
    • Including an 8-year distant metastasis-free interval of 97.0% and 8-year breast cancer-specific survival above 99%
  • This supports even more confidence in de-escalation discussions in carefully selected patients with highly favorable biology
• What this means for the surgical oncologist:
  • MINDACT matters because it reinforces that postoperative planning in early breast cancer is no longer based on tumor size, grade, and nodal status alone:
    • A patient with a large tumor or limited nodal involvement may still have a genomically low-risk cancer with only modest absolute chemotherapy benefit
  • In practical terms:
    • A surgeon should think about which ER-positive / HER2-negative patients may benefit from genomic testing as part of adjuvant planning
    • A clinical high-risk / genomic low-risk result can support a discussion about omitting chemotherapy, particularly in older than 50 patients
    • In younger / premenopausal patients, especially with higher tumor burden or limited node-positive disease:
      • The discussion remains more nuanced and should be individualized
• Bottom line:
  • MINDACT showed that biology can meaningfully refine risk beyond standard pathology
  • For the surgical oncologist, the main takeaway is that a patient who looks high-risk on anatomic grounds may still have a sufficiently favorable genomic profile to justify avoiding adjuvant chemotherapy:
    • Particularly if she is older than 50 years and has ER-positive / HER2-negative early breast cancer
• Key references:
  • Cardoso F, van’t Veer LJ, Bogaerts J, et al. 70-Gene Signature as an Aid to Treatment Decisions in Early-Stage Breast Cancer. N Engl J Med. 2016;375:717-729. 
  • Piccart M, van’t Veer LJ, Poncet C, et al. 70-gene signature as an aid for treatment decisions in early breast cancer: updated results of the phase 3 randomised MINDACT trial with an exploratory analysis by age. Lancet Oncol. 2021;22:476-488. 
  • Lopes Cardozo JMN, Drukker CA, Rutgers EJT, et al. Outcome of Patients With an Ultralow-Risk 70-Gene Signature in the MINDACT Trial. J Clin Oncol. 2022;40:1335-1345.

• TAILORx (Trial Assigning Individualized Options for Treatment):
  • Was the landmark prospective trial that validated use of the 21-gene recurrence score (Oncotype DX):
    • To guide adjuvant chemotherapy decisions in women with:
      • HR-positive, HER2-negative, axillary node-negative early breast cancer
  • Its main practice-changing contribution was showing that:
    • Most women with an intermediate recurrence score:
      • Do not benefit from adjuvant chemotherapy:
        • Particularly those older than 50 years
• Study design:
  • The trial enrolled:
    • 9,719 women with HR-positive, HER2-negative, node-negative breast cancer
  • Patients with a recurrence score (RS) 0 to 10 received endocrine therapy alone; those with RS 26 to 100 received chemoendocrine therapy; and those with RS 11 to 25 were randomized to endocrine therapy alone versus chemoendocrine therapy
• Primary result:
  • Among women with RS 11 to 25:
    • Endocrine therapy alone was noninferior to chemoendocrine therapy for invasive disease–free survival:
    • At 9 years:
      • Invasive disease–free survival was 83.3% with endocrine therapy alone versus 84.3% with chemoendocrine therapy
    • Distant recurrence rates were also very similar:
      • This established that for the overall randomized group:
        • Adding chemotherapy did not provide a clinically meaningful benefit
  • Age-specific nuance:
    • The critical nuance from TAILORx is age
    • In women 50 years or younger:
      • There appeared to be some chemotherapy benefit in subsets with RS 16 to 25:
        • Especially at the upper end of that range
    • By contrast, women older than 50 with RS 11 to 25 generally did not benefit from chemotherapy
    • The NCI summary estimated that chemotherapy can be safely avoided in about 70% of women with this common breast cancer subtype, including:
      • Any age with RS 0 to 10
      • Age > 50 with RS 11 to 25
      • Age ≤ 50 with RS 11 to 15
• Low-score group (RS 0 to 10):
  • The earlier prospective TAILORx report showed that women with RS 0 to 10 treated with endocrine therapy alone had very low recurrence rates:
    • Supporting omission of chemotherapy in this low-risk group
  • High-score group (RS 26 to 100):
    • Patients with RS 26 to 100 were assigned to chemotherapy plus endocrine therapy
    • Follow-up analyses supported the standard recommendation to offer chemotherapy to this high-risk group:
      • NCI reported that women in this category had strong 5-year outcomes with chemoendocrine therapy:
        • Reinforcing that these patients should still be considered for systemic intensification rather than endocrine therapy alone
• Clinical risk analysis:
  • A secondary analysis integrating clinical risk (tumor size and grade) found that clinical risk adds prognostic information:
    • But was not clearly predictive of chemotherapy benefit in the overall population:
      • However, in women 50 years or younger, chemotherapy benefit was more apparent in those with RS 16 to 20 and high clinical risk, and in those with RS 21 to 25 regardless of clinical risk
• Practical takeaways for the surgical oncologist:
• TAILORx matters because it reframes postoperative discussions after definitive surgery in node-negative HR+ / HER2- disease:
  • Genomic testing is central to adjuvant planning after surgery in appropriate patients
  • TAILORx made the recurrence score part of standard decision-making:
    • Not just a prognostic adjunct
  • Chemotherapy can often be omitted in postmenopausal or older patients with RS 11 to 25:
    • Which is highly relevant when counseling patients after lumpectomy or mastectomy
  • In premenopausal or younger patients, especially ≤v50 years with RS 16 to 25:
    • The conversation is more nuanced:
      • These patients may derive benefit from chemotherapy:
        • Though some experts note that part of this benefit may reflect ovarian function suppression rather than direct cytotoxic effect alone
• TAILORx applies to node-negative disease
  • For 1 to 3 positive nodes:
    • The more relevant prospective trial is RxPONDER, not TAILORx
• Bottom line:
  • TAILORx changed practice by showing that adjuvant chemotherapy is unnecessary for most women with node-negative HR-positive / HER2-negative early breast cancer who have a midrange Oncotype DX recurrence score, particularly those older than 50
  • The major exception is the younger / premenopausal subgroup with RS 16 to 25:
    • Where chemotherapy may still offer benefit and multidisciplinary discussion remains essential
• Key references:
  • Sparano JA, Gray RJ, Makower DF, et al. Adjuvant Chemotherapy Guided by a 21-Gene Expression Assay in Breast Cancer. N Engl J Med. 2018;379:111-121. 
  • Sparano JA, Gray RJ, Ravdin PM, et al. Clinical and Genomic Risk to Guide the Use of Adjuvant Therapy for Breast Cancer. N Engl J Med. 2019;380:2395-2405. 
  • National Cancer Institute. TAILORx trial finds most women with early breast cancer do not benefit from chemotherapy. 2018. 
    National Cancer Institute PDQ. Breast Cancer Treatment (PDQ®), updated 2025. 

– Borderline resectable oral cavity cancer is a surgical dilemma
Can chemo-immunotherapy increase operability?

A new Phase II trial suggests yes

🧪 NeoLOCUS trial (Lancet Regional Health SE Asia)

Regimen:
Carboplatin + nab-paclitaxel + low-dose nivolumab
•oral metronomic therapy (methotrexate + celecoxib + erlotinib)

🎯 Population
Borderline resectable OSCC
n = 34

📊 Key results

• ORR: 66.6%
• R0 resection after 2 cycles: 75.7%
• Overall surgical conversion: 90.3%
• Major pathological response: 41%
• pCR: 13.8%

🧬 Interesting biology
Good responders showed reduction in FOXP3+ Tregs, suggesting immune-microenvironment modulation.

⚠️ Safety
Grade ≥3 toxicity: 14.7%
No treatment-related deaths.

💡 Why this matters

Borderline OSCC often fails surgery after standard NACT.
This low-dose IO + metronomic + chemo strategy may offer an affordable outpatient approach in LMIC settings.

But this is single-arm Phase II → randomized validation needed.

Abstract

Context: Patients with elevated parathyroid hormone (PTH) and consistently normal serum calcium levels, in whom secondary causes of hyperparathyroidism have been excluded, may represent the earliest presentation of primary hyperparathyroidism (PHPT).

Objective: The objective of the study was to characterize patients with normocalcemic PHPT referred to a bone disease unit.

Design: This was a longitudinal cohort study.

Setting: Ambulatory patients were referred to the metabolic bone disease unit.

Patients: The study population included 37 patients [aged 58 yr, range 32–78; 95% female; serum calcium, 9.4 ± 0.1 (SEM) mg/dl (2.3 ± 0.02 mmol/liter), reference range, 8.5–10.4 (2.1–2.6 mmol/liter); PTH, 93 ± 5 pg/ml].

Interventions: Interventions included yearly (median 3 yr; range 1–8 yr) physical examination, biochemical indices, and bone mineral density (BMD).

Main Outcome Measures: We measured the development of features of PHPT.

Results: Evaluation for classical features of PHPT revealed a history of kidney stones in five (14%), fragility fractures in four (11%), and osteoporosis in 57% [spine (34%), hip (38%), and/or distal one third radius (28%)]. BMD did not show preferential bone loss at the distal one third radius (T scores: spine, −2.00 ± 0.25; hip, −1.84 ± 0.18; one third radius, −1.74 ± 0.22). Further signs of PHPT developed in 40% (seven hypercalcemia; one kidney stone; one fracture; two marked hypercalciuria; six had >10% BMD loss at one or more site(s) including four patients developing World Health Organization criteria for osteoporosis). Seven patients (three hypercalcemic, four persistently normocalcemic) underwent successful parathyroidectomy.

Conclusions: Patients seen in a referral center with normocalcemic hyperparathyroidism have more substantial skeletal involvement than is typical in PHPT and develop more features and complications over time. These patients may represent the earliest form of symptomatic, rather than asymptomatic, PHPT.

Lowe, Hyesoo et al. “Normocalcemic primary hyperparathyroidism: further characterization of a new clinical phenotype.” The Journal of clinical endocrinology and metabolism 92 8 (2007): 3001-5 .

#Arrangoiz #ParathyroidSurgeon #ParathyroidExpert #Hyperparathyroidism #PrimaryHyperparathyroidism #CancerSurgeon #EndocrineSurgery #Teacher #Surgeon #HeadandNeckSurgeon #SurgicalOncologist #ParathyroidAdenoma #Hypercalcemia #ElevatedCalciumLevels #Miami #MountSinaiMedicalCenter #MSMC #Mexico #Hialeah

• Type A:
  • Adherent to the posterior thyroid parenchyma:
    • Posterior to the upper pole of the thyroid:
      • But not intrathyroidal
  • Type A glands are in the accepted, expected location of a normal parathyroid gland
• Type B:
  • Behind the thyroid parenchyma
  • Type B glands are exophytic to the thyroid parenchyma and lie in the tracheoesophageal groove:
    • This category includes adenomas in:
      • Retroesophageal, retropharyngeal, high lateral pharyngeal, and carotid sheath locations
  • A ‘‘B+’’ subcategory can be used to document the location of adenomas above the level of the hyoid bone:
    • The ‘‘+’’ is meant to reflect cranial elevation
• Type C:
  • Caudal to the thyroid parenchyma:
    • In the tracheoesophageal groove
  • A type C gland is more inferior than a type B gland on lateral images:
    • Located inferior to the inferior pole of the thyroid (closer to the clavicle)
• Type D:
  • Directly over the recurrent laryngeal nerve:
    • At the level of the inferior thyroid vessels
  • The dissection may be difficult:
    • Because a type D gland is dangerously close to the recurrent laryngeal nerve
• Type E:
  • Located in the external aspect of the inferior pole of the thyroid
  • A type E gland is in a location that is:
    • More superficial in an anterior–posterior plane than the recurrent laryngeal nerve:
      • It is the easiest to resect
• Type F:
  • ‘‘Fallen’’ into the thyrothymic ligament:
    • Below the inferior pole of the thyroid in a pretracheal plane
  • A type F gland is frequently referred to as an ectopic gland:
    • Its resection usually involves:
      • Transcervical delivery of the thyrothymic ligament or superior portion of the thymus
• Type G:
  • A gauge, true intrathyroidal gland location

• This nomenclature system has been designed that takes into account the pathologic position of the parathyroid glands (Figure):
  • Superior and inferior glands:
    • Are defined by the location of the gland’s pedicle and its relationship to the RLN:
      • Superior parathyroid glands:
        • Anatomically have a vascular pedicle superior and lateral to the RLN (type A through D glands)
      • Inferior parathyroid glands:
        • Anatomically have a vascular pedicle inferior and medial to the RLN (type D through F glands)
    • Type G glands:
      • Represent intrathyroidal parathyroid lesions
  • This information not only helps radiologists communicate potential parathyroid lesions of interest to surgeons:
    • But also helps surgeons direct their dissection in relation to the RLN