Chronic Lymphocytic Thyroiditis May Limit the Utility of Molecular Testing in AUS/FLUS Thyroid Nodules.

INTRODUCTION: Chronic lymphocytic thyroiditis (CLT) may increase the likelihood of atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) results in thyroid nodules by fine needle aspiration (FNA). Gene expression classifier (GEC) and Thyroid Sequencing (ThyroSeq) may better stratify rate of malignancy (ROM) of AUS/FLUS thyroid nodules. This study compares the utility of molecular tests in determining malignancy in surgical patients with concomitant AUS/FLUS thyroid nodules and CLT. METHODS: A retrospective review of 1648 patients with index thyroid nodules who underwent FNA and thyroidectomy at a single institution was performed. Patients with concomitant AUS/FLUS thyroid nodules and CLT were subdivided into three diagnostic groups: FNA only, FNA with GEC, and FNA with ThyroSeq. Patients with AUS/FLUS thyroid nodules without CLT were subdivided into similar groups. Final histopathology of the cohorts was further stratified into benignity and malignancy and analyzed using Chi-squared statistics. RESULTS: Of 463 study patients, 86 had concomitant AUS/FLUS thyroid nodules and CLT with a 52% ROM, and the difference of ROM among FNA only (48%), suspicious GEC (50%), or positive ThyroSeq (69%) was not significant. In 377 patients with AUS/FLUS thyroid nodules without CL, ROM was 59%. ROM among these patients was significantly higher when molecular testing was used (FNA only 51%, suspicious GEC 65%, and positive ThyroSeq 68%; P < 0.05). CONCLUSIONS: Molecular tests may have limited value in predicting malignancy in surgical patients with concomitant AUS/FLUS thyroid nodules and CLT.

Depth of mediastinal extension can predict sternotomy need for substernal thyroid goiters.

BACKGROUND: Surgical excision of substernal thyroid goiters is usually achieved through a conventional transcervical approach, and transthoracic excision is rarely necessary. Currently, there are no clear guidelines for substernal thyroid goiters that may require a transthoracic approach. This study examined what preoperative factors were significantly associated with transthoracic surgical excision for substernal thyroid goiters. METHODS: A retrospective review of prospectively collected data of 109 patients with substernal thyroid goiters from a single institution was performed. The patients were stratified by transcervical and transthoracic approaches for substernal thyroid goiters. The factors possibly predictive of a transthoracic approach, including substernal extension beyond the thoracic inlet, patient-reported symptoms, tracheal deviation, and malignancy, were analyzed. Demographics including age, sex, and race, among others, were also studied. RESULTS: Of 1,080 patients who underwent surgical resection for multinodular goiter, there were 109 (10%) patients with substernal thyroid goiters. Of the substernal thyroid goiter group, 11 (10%) patients underwent partial sternotomy, whereas 6 (5.5%) underwent total sternotomy. On logistic regression, only substernal component of the thyroid goiter extending beyond the sternal notch into the mediastinum was statistically significant in predicting sternotomy (odds ratio 3.43, confidence interval 1.65-6.41, P < .001). Substernal thyroid goiters with mediastinal extension of ≥5 cm beyond the sternal notch showed a sensitivity of 94% and specificity of 86.5% to predict need of sternotomy. CONCLUSION: Patients with substernal thyroid goiters who exhibit progressive enlargement and/or compressive symptoms should undergo surgical excision. Although most are removed through the conventional transcervical approach, substernal thyroid goiters with a depth of mediastinal extension ≥5 cm have a high likelihood of requiring sternotomy.

Morbidity Associated With Surgical Removal of Substernal Thyroid Goiters.

INTRODUCTION: Surgical excision of substernal thyroid goiters (STG) can be challenging while minimizing postoperative morbidity. Postoperative complication rates associated with transcervical and transthoracic approaches (i.e., partial or total sternotomy) for STG compared to multinodular goiters (MNG) limited to the neck (i.e., non-substernal) remains unclear. This study examines postoperative morbidity related to surgical approaches in the removal of STG and MNG. METHODS: A retrospective review of prospectively collected data of 988 patients with STG and non-substernal MNG from a single institution between 2010 and 2021 was performed. Patients were stratified by STG and conventional non-substernal MNG limited to the neck excised by transcervical and transthoracic approach. Postoperative complications including neck hematoma requiring return to the operating room, permanent recurrent laryngeal nerve injury and hypocalcemia, and transient or temporary recurrent laryngeal nerve injury and hypocalcemia were identified. Demographics including age, sex, and race, among others, were analyzed. RESULTS: Of the 988 cases, there were 887 (90%) MNG and 101 (10%) STG. Of the STG cohort, 11 (11%) required a partial sternotomy and 4 (4%) required a total sternotomy. Permanent complication rates for non-substernal MNG and STG patients were 1.5% and 0.9%, respectively. Only transient or temporary hypocalcemia rates were statistically different between the STG and MNG cohorts (9.9% versus 3.8%, P < 0.001). CONCLUSIONS: Regardless of transcervical or transthoracic approach, postoperative complications associated with the surgical removal of STG are low in the hands of experienced, high-volume thyroid surgeons.

Transient Hypocalcemia After Total Thyroidectomy: The Obesity Paradox at Work?

INTRODUCTION: With increasing rates of obesity worldwide, a correlation between high body mass index (BMI) and postoperative morbidity after thyroid surgery remains unclear. Postoperative transient hypocalcemia is common after total thyroidectomy due to interruption of parathyroid function. This study examines the relationship between BMI and hypocalcemia after total thyroidectomy. MATERIALS AND METHODS: A retrospective review of prospectively collected data for 1135 patients who underwent total thyroidectomy for cancer, multinodular goiter (MNG), or Graves' disease between June 2009 and November 2020 at a single institution was performed. BMI groups followed the World Health Organization classification. Hypocalcemia was defined as serum calcium ≤8 mg/dL. Calcium levels measured on postoperative day 0 and the following morning were compared between the BMI groups. RESULTS: Of 1135 total thyroidectomy patients, 85% were women. The mean age and standard deviation of patients was 49 (± 13) y, with most of Hispanic origin (64%). Overall, 41.5% of patients had cancer, 45% nontoxic MNG, 5.8% toxic MNG, and 12% Graves' disease. Stratified by BMI, 27% of patients were normal, 34% overweight, and 39% obese. Overall, overweight and obese patients experienced less transient hypocalcemia at both time points compared to normal patients postoperatively (P = 0.01 and P = 0.009). Furthermore, overweight and obese patients with Graves' disease experienced less transient hypocalcemia at both time points (P = 0.04 and P = 0.05). There was no statistical difference in other groups. CONCLUSIONS: A protective role of higher BMI or "obesity paradox" for postoperative hypocalcemia may exist in those obese patients after total thyroidectomy.

Small molecule profiling to define synergistic EGFR inhibitor combinations in head and neck squamous cell carcinoma.

BACKGROUND: Head and neck squamous cell carcinoma (HNSCC) is a debilitating disease with poor survival. Although epidermal growth factor receptor (EGFR)-targeting antibody cetuximab improves survival in some settings, responses are limited suggesting that alternative approaches are needed. METHODS: We performed a high throughput drug screen to identify EGFR inhibitor-based synergistic combinations of clinically advanced inhibitors in models resistant to EGFR inhibitor monotherapies, and then performed downstream validation experiments on prioritized synergistic combinations. RESULTS: From our screen, we re-discovered known synergistic EGFR inhibitor combinations with FGFR or IGF-1R inhibitors that were broadly effective and also discovered novel synergistic combinations with XIAP inhibitor and DNMT inhibitors that were effective in only a subset of models. CONCLUSIONS: Conceptually, our data identify novel synergistic combinations that warrant evaluation in future studies, and suggest that some combinations, although highly synergistic, will require parallel companion diagnostic development to be effectively advanced in patients.

Sex Differences in Papillary Thyroid Cancer.

BACKGROUND: Papillary thyroid cancer (PTC) is three times more common in women than men. However, PTC in men appears to be associated with poorer outcomes than in women. This study compares the clinical presentation and pathologic features of men and women with PTC. MATERIALS AND METHODS: A retrospective review of prospectively collected data for patients with PTC who underwent fine needle aspiration (FNA) of a solitary thyroid nodule and thyroidectomy at a single institution was performed. Factors including age, ultrasound features, FNA results, extent of surgical operation and final histopathology were compared between male and female patients. Descriptive statistics using chi-square and t-test statistics compared outcomes by sex. RESULTS: Of the 851 patients with PTC, 158 (19%) were men and 693 (81%) were women. Mean age and standard deviation (SD) of patients was 48 (± 14) years, and most were of Hispanic origin (69%). Men had a significantly higher rate of radiation exposure relative to women, respectively (8% vs. 2%, P<0.01). There were no ultrasonographic or FNA cytologic differences among sexes. Men had more aggressive pathologic features including lymphovascular invasion (LVI) (47% vs. 34%, P<0.01) and positive lymph nodes (LN) (36% vs. 27%, P<0.05) compared to women. Thyroid lobectomy with isthmusectomy was more commonly performed among men compared to women (24% vs. 13%, P<0.01). CONCLUSION: Men with PTC have higher rates of radiation exposure associated with more aggressive disease with LVI and LN involvement on final histopathology compared to women. Total thyroidectomy with possible central neck dissection should further be considered when counseling men with PTC.

One-year outcomes of congenital diaphragmatic hernia repair: Factors associated with recurrence and complications.

PURPOSE: Congenital diaphragmatic hernia (CDH) is a congenital anomaly associated with lifelong multisystem morbidity. This study sought to identify factors contributing to hospital readmission after CDH repair. METHODS: The Nationwide Readmissions Database from 2010 to 2014 was used to identify patients with CDH who underwent surgical repair. Primary outcomes included all cause readmission at 30-days and 1 year and readmission for hernia recurrence. Patient and hospital factors were compared using chi-squared analysis. RESULTS: Five hundred eleven patients were identified with neonatal CDH. All repairs were performed at teaching hospitals via laparotomy in 59% (n = 303), thoracotomy in 36% (n = 183), and minimally invasive (MIS) repair in 5% (n = 25). The readmission rate within 30-days was 32% (n = 163), and 97% (n = 495) within 1 year. The most common conditions surrounding readmission were for gastroesophageal reflux (20%), CDH recurrence (17%), and surgery for gastrostomy tube and/or fundoplication (16%). Recurrence was significantly higher after MIS repair (48%) compared to those with open repair via either approach (16%), p < 0.001. CONCLUSIONS: This is the first study to evaluate nationwide readmissions in newborns with CDH. Readmission is commonly due to CDH recurrence and reflux-associated complications. The recurrence rate is higher than previously reported and is more common after MIS and repair via thoracotomy. LEVEL OF EVIDENCE: Level III treatment study.

Mutant cartilage oligomeric matrix protein (COMP) compromises bone integrity, joint function and the balance between adipogenesis and osteogenesis.

Mutations in COMP (cartilage oligomeric matrix protein) cause severe long bone shortening in mice and humans. Previously, we showed that massive accumulation of misfolded COMP in the ER of growth plate chondrocytes in our MT-COMP mouse model of pseudoachondroplasia (PSACH) causes premature chondrocyte death and loss of linear growth. Premature chondrocyte death results from activation of oxidative stress and inflammation through the CHOP-ER pathway and is reduced by removing CHOP or by anti-inflammatory or antioxidant therapies. Although the mutant COMP chondrocyte pathologic mechanism is now recognized, the effect of mutant COMP on bone quality and joint health (laxity) is largely unknown. Applying multiple analytic approaches, we describe a novel mechanism by which the deleterious consequences of mutant COMP retention results in upregulation of miR-223 disturbing the adipogenesis - osteogenesis balance. This results in reduction in bone mineral density, bone quality, mechanical strength and subchondral bone thickness. These, in addition to abnormal patterns of ossification at the ends of the femoral bones likely contribute to precocious osteoarthritis (OA) of the hips and knees in the MT-COMP mouse and PSACH. Moreover, joint laxity is compromised by abnormally thin ligaments. Altogether, these novel findings align with the PSACH phenotype of delayed ossification and bone age, extreme joint laxity and joint erosion, and extend our understanding of the underlying processes that affect bone in PSACH. These results introduce a novel finding that miR-223 is involved in the ossification defect in MT-COMP mice making it a therapeutic target.