Faculty Bibliography

OBJECTIVES/HYPOTHESIS:Hashimoto's Thyroiditis (HT) is a common cause of hypothyroidism. Among adults with differentiated thyroid cancer (DTC), HT appears to be associated with less severe disease burden. In the absence of information regarding HT and disease burden among children with DTC, we assessed the relationship between pediatric DTC severity and HT. STUDY DESIGN:Retrospective cohort. METHODS:Charts from 90 pediatric patients who underwent surgical removal of DTC from 2002 to 2017 at tertiary-care children's hospital were reviewed. Demographic, clinical, surgical, pathology, and outcome details were compared between patients with and without HT. Consistency among diagnostic modalities of HT was also evaluated. RESULTS:Median age at presentation was 16.0 years (range 4.2-18.9 years). Twenty-two patients were male (24%). Forty-five patients (50%) had HT based on presence of thyroid autoantibodies and/or surgical pathology findings and 45 patients did not have HT. Patients with HT had increased odds of microcalcifications (odds ratio [OR]: 3.01, P = .031) and decreased odds of palpable nodules (OR: 0.212, P = .024) and T2 lesions (vs. T1) (OR: 0.261, P = .015) compared with non-HT. No significant differences in demographics and the incidence of multifocality, extrathyroidal extension, lymphovascular invasion, lymph node or pulmonary metastases, disease recurrence, or radioactive iodine treatment were found between the two groups. Thyroglobulin/thyroid peroxidase autoantibodies and surgical pathology indicative of HT were concordant in 82.4% (κ = 0.635, P < .001). CONCLUSION:HT was present in 50% of children with DTC. Patients with DTC and HT presented with smaller tumors compared to non-HT patients. No significant differences in other markers of disease aggressiveness were found between the two groups. LEVEL OF EVIDENCE:3 Laryngoscope, 132:1668-1674, 2022.

OBJECTIVES/UNASSIGNED:Data on the efficacy of including definitive local therapy to the primary site for head and neck squamous cell carcinoma (HNSCC) patients with synchronous distant metastasis are lacking. In multiple different solid tumor types, there has been benefit when using systemic therapy followed by local consolidative therapy (stereotactic ablative radiotherapy or surgery) directed at metastases. We proposed to retrospectively evaluate patients at our institution that received definitive treatment to the primary. METHODS/UNASSIGNED:Single institution retrospective study evaluating 40 patients with metastatic HNSCC treated with definitive surgery (55%) or chemoradiation (45%) to the primary site from 2000 to 2020. The major endpoints were overall survival (OS) and progression-free survival (PFS) for the total population and multiple sub-groups. Some variables were evaluated with multiple covariates Cox model. RESULTS/UNASSIGNED:The median PFS was 8.6 months (95% CI, 6.4-11.6), and OS was 14.2 months (95% CI, 10.9-27.5). In 28% of patients that received induction therapy, there was a twofold increase in median overall survival to 27.5 months. In the 33% of patients that received anti-PD-1 mAb as part of their treatment course, the median OS was significantly increased to 41.7 months (95% CI, 8.7-NR) versus 12.1 months (95% CI, 8.4-14.4) with a 5-year OS of 39%. Multivariate analysis for OS showed significance for age at diagnosis, use of IO, and number of metastatic sites. CONCLUSION/UNASSIGNED:We observed impressive survival outcomes in metastatic HNSCC patients treated with definitive local therapy to the primary site in addition to induction and/or immunotherapy. Further study is warranted.Level of Evidence: 3.

Surgical proctoring requires increasing resources in growing healthcare systems. In addition, travel has become less safe in the era of COVID-19. This study demonstrates surgeon satisfaction and safety with tele-proctoring in robotic gynecologic surgery. This pilot study assesses surgeon satisfaction and operative outcomes with a novel operative tele-proctoring system with a continuous two-way video-audio feed that allows the off-site surgeon to see the operating room, surgical field, and hands of the robotic surgeon. After thorough system testing, two experienced surgeons underwent tele-proctoring for hospital credentialing, completing 7 total cases. Each completed pre- and post-surveys developed from the Michigan Standard Simulation Experience Scale. Surgical characteristics were compared between tele-proctored cases and 59 historical cases proctored in-person over the last 8 years. Surgeons reported unanimous high satisfaction with tele-proctoring (5 ± 0). There were no major technologic issues. Five of the tele-proctored cases and 35 of controls were hysterectomies. Mean age was 48.2 ± 1.4 years, mean BMI was 29.6 ± 0.9 kg/m², and mean uterine weight was 152 ± 112.3 g. Two-thirds had prior abdominal surgery (P > 0.1). Tele-proctored hysterectomies were 58 ± 6.5 min shorter than controls (P = 0.001). There were no differences in EBL or complication rates (P > 0.1). Tele-proctoring resulted in high surgeon satisfaction rates with no difference in EBL or complications. Tele-mentoring is a natural extension of tele-proctoring that could provide advanced surgical expertise far beyond where we can physically reach.

In phase I development, CDX-3379, an anti-ErbB3 monoclonal antibody, showed promising molecular and antitumor activity in head and neck squamous cell carcinoma (HNSCC), alone or in combination with cetuximab. Preliminary biomarker data raised the hypothesis of enhanced response in tumors harboring FAT1 mutations. This phase II, multicenter trial used a Simon 2-stage design to investigate the efficacy of CDX-3379 and cetuximab in 30 patients with recurrent/metastatic, HPV-negative, cetuximab-resistant HNSCC. The primary endpoint was objective response rate (ORR). Secondary endpoints included ORR in patients with somatic FAT1 mutations, progression-free survival (PFS), overall survival (OS), and safety. Thirty patients were enrolled from March 2018 to September 2020. The ORR in genomically unselected patients was 2/30 (6.7%; 95% confidence interval [CI], 0.8-22.1). Median PFS and OS were 2.2 (95% CI: 1.3-3.6) and 6.6 months (95% CI: 2.7-7.5), respectively. Tissue was available in 27 patients including one of two responders. ORR was 1/10 (complete response; 10%; 95% CI 0.30-44.5) in the FAT1-mutated versus 0/17 (0%; 95% CI: 0-19.5) in the FAT1-wildtype cohorts. Sixteen patients (53%) experienced treatment-related adverse events (AEs) ≥ grade 3. The most common AEs were diarrhea (83%) and acneiform dermatitis (53%). Dose modification was required in 21 patients (70%). The modest ORR coupled with excessive, dose-limiting toxicity of this combination precludes further clinical development. Dual ErbB3-EGFR inhibition remains of scientific interest in HPV-negative HNSCC. Should more tolerable combinations be identified, development in an earlier line of therapy and prospective evaluation of the FAT1 hypothesis warrant consideration.

PURPOSE:Concurrent radiotherapy with cetuximab, an anti-EGFR mAb, is a standard treatment for locally advanced head and neck squamous carcinoma (HNSCC). Cytotoxic T lymphocyte antigen-4-positive (CTLA-4+) regulatory T cells (Treg) dampen cellular immunity and correlate negatively with clinical outcomes. This phase I study added ipilimumab, an anti-CTLA-4 mAb, to cetuximab-radiotherapy. PATIENTS AND METHODS:A (3 + 3) design was used to establish the recommended phase II dose (RP2D) of ipilimumab, added at week 5 for four, every-3-week doses to fixed, standard cetuximab-radiotherapy. Eligible subjects had stage III to IVb, high-risk [human papillomavirus-negative (HPV-)] or intermediate-risk HPV-positive (HPV+)] HNSCC. Dose-limiting toxicity (DLT) was defined as any grade 4 adverse event (AE) except in-field radiation dermatitis or immune-related (ir) AE requiring ≥2 weeks of systemic steroids. Baseline tumor and serial blood specimens were collected for immune correlatives. RESULTS:From July 2013 to May 2016, 18 patients enrolled. Two of 6 in cohort 1 (ipilimumab 3 mg/kg) experienced grade 3 dermatologic DLTs, triggering deescalation of ipilimumab to 1 mg/kg. Dose level -1 was expanded to N  =  12 without DLT. irAE included: grade 1, 2, and 3 dermatitis (2, 1, and 3 cases), grade 4 colitis (1), and grade 1 hyperthyroidism (1). Three-year disease-free survival (DFS) and overall survival were 72% [90% confidence interval (CI), 57-92] and 72% (90% CI, 56-92). High expression of coinhibitory receptors PD1/LAG3/CD39 on baseline tumor-infiltrating Treg was associated with worse DFS (HR = 5.6; 95% CI, 0.83-37.8; P = 0.08). CONCLUSIONS:The RP2D for ipilimumab plus standard cetuximab-radiotherapy is 1 mg/kg in weeks 5, 8, 11, and 14. The regimen is tolerable and yields acceptable survival without cytotoxic chemotherapy.

BACKGROUND:We ascertain the role of a low cervical paraspinal skeletal muscle index (CPSMI) as a biomarker for poor treatment tolerance in patients with operable mucosal head and neck squamous cell carcinoma (HNSCC). METHODS:A prospective cohort of patients with operable HNSCC requiring microvascular reconstruction was evaluated. Low CPSMI was calculated using preoperative CT neck imaging. Poor treatment tolerance, a composite measure of incomplete therapy or severe morbidity/mortality during treatment, was the primary outcome. RESULTS:One hundred and twenty-seven patients underwent extirpative surgery with a mean age was 60.5. Poor treatment tolerance occurred in 71 (56%) patients with 21 not completing recommended adjuvant therapy and 66 having severe treatment-related morbidity. A low CPSMI was independently associated with poor treatment tolerance (OR 2.49, 95%CI 1.10-5.93) and delay to adjuvant therapy (OR 4.48, 95%CI 1.07-27.6) after adjusting for multiple confounders. CONCLUSION:Low CPSMI was independently associated with poor treatment tolerance in patients with operable HNSCC.

OBJECTIVES:Increasing use of transoral robotic surgery (TORS) is likely to impact outcomes for HPV+ oropharyngeal squamous cell carcinomas (OPSCCs). We aimed to describe oncologic outcomes for a large HPV+ OPSCC cohort after TORS and develop a risk prediction model for recurrence under this treatment paradigm. MATERIALS AND METHODS:634 HPV+ OPSCC patients receiving TORS-based therapy at a single institution were reviewed retrospectively to describe survival across the entire cohort and for patients suffering recurrence. Risks for distant metastatic recurrence (DMR) and locoregional recurrence (LRR) were modeled using multivariate logistic regression analyses of case-control sub-cohorts. RESULTS:5-year overall and recurrence-free survival were 91.2% and 86.1%, respectively. 5-year overall survival was 52.5% following DMR and 83.3% after isolated LRR (P = .01). In case-control analyses, positive surgical margins were associated with DMR (adjusted OR 5.8, CI 2.1-16.0, P = .001), but not isolated LRR, and increased DMR risk 4.2 fold in patients with early clinical stage disease. By contrast, LRR was associated with not receiving recommended adjuvant therapy (OR 13.4, CI 6.3-28.5, P < .001). CONCLUSIONS:This study sets a benchmark for oncologic outcomes from HPV+ OPSCC after TORS-based therapy. Under this treatment paradigm, margins are relevant for assessing lethal recurrence risk during clinical trial design and post-treatment surveillance.