Extent of Surgery for Medullary Thyroid Cancer and Prevalence of Occult Contralateral Foci.

Importance: Standard treatment for patients with medullary thyroid cancer (MTC) consists of total thyroidectomy with central neck dissection, but the rationale for bilateral surgery in patients with unilateral disease on ultrasonography remains unclear. Objective: To determine the presence of occult contralateral disease (lesions not seen on preoperative ultrasonography) in patients with MTC as a rationale for total thyroidectomy. Design, Setting, and Participants: This multi-institutional, retrospective cohort study was conducted from September 1998 to April 2022 in academic medical centers and included patients with MTC who underwent thyroidectomy with preoperative imaging. Main Outcomes and Measures: The primary end point was the prevalence of sonographically occult foci of MTC in the contralateral lobe among patients with sporadic MTC. Results: The cohort comprised 176 patients with a median age at diagnosis of 55 years (range, 2-87 years), 69 (57.6%) of whom were female. Genetic testing was performed in 109 patients (61.9%), 48 (27.5%) of whom carried germline RET variants. Initial surgical management consisted of total thyroidectomy (161 [91.0%]), lobectomy followed by completion thyroidectomy (7 [4.0%]), and lobectomy alone (8 [4.5%]). Central and lateral neck dissections were performed as part of initial therapy for 146 patients (83.1%). In the entire cohort of 176 patients, 46 (26.0%) had contralateral foci disease and 9 (5.1%) had occult contralateral foci that were not identified on preoperative ultrasonography. Among 109 patients who underwent genetic testing, 38 (34.9%) had contralateral disease, 8 (7.3%) of whom had occult contralateral disease not seen on preoperative ultrasonography. Patients with sporadic MTC experienced a 95.7% reduction in the odds of having a focus of MTC in the contralateral lobe compared with patients with a germline RET variant (odds ratio, 0.043; 95% CI, 0.013-0.123). When adjusting for age, sex, tumor size, and lymph node involvement, the odds ratio of having contralateral MTC in patients with sporadic disease was 0.034 (95% CI, 0.007-0.116). Among patients who underwent lobectomy alone with postoperative calcitonin levels, 5 of 12 (41.7%) achieved undetectable calcitonin levels (<2.0 pg/mL; to convert to pmol/L, multiply by 0.292). Conclusions and Relevance: The results of this cohort study suggest that a staged approach involving initial thyroid lobectomy could be considered in patients with sporadic MTC and no contralateral ultrasonography findings, with no further surgery if calcitonin levels became undetectable. Further work using prospective randomized clinical trials to evaluate lobectomy as a biochemical cure in patients presenting with unilateral disease is warranted.

How Effective is the Use of Molecular Testing in Preoperative Decision Making for Management of Indeterminate Thyroid Nodules?

INTRODUCTION: We performed Thyroseq v2 molecular testing on indeterminate thyroid nodules and evaluated whether they underwent a management change from the standard of thyroid lobectomy. METHODS: We conducted a retrospective analysis of all indeterminate thyroid nodules that underwent Thyroseq v2 molecular testing from 2014 to 2019 at a large academic center. Pathology was reviewed by thyroid cytopathologists. Thyroseq results were reported benign (malignancy probability less than 10%) or suspicious (malignancy probability greater than 30%). The primary endpoint was a management change from a diagnostic lobectomy. RESULTS: A total of 142 nodules were included: 113 (80%) Bethesda III and 29 (20%) Bethesda IV. Seventy-three nodules underwent surgical management and 69 did not. We noted a change in management in 64% (91/142) of nodules. Patients who underwent a change in management to no surgery had a significantly higher rate of benign Thyroseq result than those without a change (75.8% vs. 49.0%, p = 0.001). On logistic regression analysis, a benign Thyroseq result was a positive independent predictor of a change to no surgery (OR 3.87, 95% CI 1.69-8.89). Nodule size, multiple nodules, compressive symptoms, and history of hypothyroidism were not significant. Of the 91 patients who underwent a management change, 71% (65/91) did not undergo surgery. On follow-up (average 985 ± 615 days), 12% (8/65) of those nodules were growing or developed suspicious features requiring surgery. CONCLUSIONS: Molecular testing helped avoid surgery in almost half our population with indeterminate thyroid nodules, and benign results may help avoid surgery in asymptomatic patients with indeterminate thyroid nodules.

The Mount Sinai Clinical Pathway for the Diagnosis and Management of Hypercortisolism due to Ectopic ACTH Syndrome.

Neoplasms that secrete ectopic adrenocorticotropin (ACTH) may cause severe, life-threatening hypercortisolism. These tumors are often difficult to localize and treat, requiring a comprehensive and systematic management plan orchestrated by a multidisciplinary team. The Mount Sinai Adrenal Center hosted an interdisciplinary retreat of experts in adrenal disorders and neuroendocrine tumors (NETs) with the aim of developing a clinical pathway for the management of Cushing syndrome due to ectopic ACTH production. The result was institutional recommendations for the diagnosis, localization, surgical approaches to intrathoracic tumors and bilateral adrenalectomy, and perioperative and postoperative medical management of hypercortisolism and its sequelae. Specific recommendations were made regarding the timing and selection of therapies based on the considerations of our team as well as a review of the current literature. Our clinical pathway can be applied by other institutions directly or serve as a guide for institution-specific management.

The Role of Surgeon-Performed Office and Preincision Ultrasounds in Localization of Parathyroid Adenomas in Primary Hyperparathyroidism.

OBJECTIVE: We studied the use of surgeon-performed office ultrasound (OU) and preincision ultrasound (PIU) in preoperatively localizing parathyroid adenomas in primary hyperparathyroidism (PHPT). METHODS: A retrospective chart review was performed for patients with PHPT who underwent parathyroidectomy between 2013 and 2015. The results of OU and PIU were recorded and compared with the final surgical pathology. RESULTS: Of 348 patients with PHPT, 285 (81.9%) had single-lesion disease, 49 (14.1%) had double-lesion disease, and 14 (4.0%) had multigland disease with 3 or more lesions. For single-lesion disease, the overall sensitivity and specificity of OU to correctly lateralize the lesion were 64.2% and 91.2%, while those of PIU were 89.4% and 93.6%, respectively. The sensitivity and specificity of PIU were comparable to those of 4-dimensional computed tomography (87.1% and 90.7%, respectively) and 99mTc-sestamibi scintigraphy (70.4% and 95.9%, respectively). While the majority of PIU cases were preceded by other imaging studies, the accuracy in localizing lesions was not largely affected by the presence of prior computed tomography and/or 99mTc-sestamibi scintigraphy, as opposed to ultrasounds only. For detecting the presence of multigland disease, the sensitivity and specificity of OU were 26% and 92.2%, while those of PIU were 64.3% and 94.7%, respectively. CONCLUSION: Surgeon-performed OU and PIU are valuable tools in preoperatively localizing the parathyroid adenoma in single-lesion disease, while their utility may be limited for double-lesion or multigland disease. PIU in particular yields high accuracy in detecting parathyroid lesions in combination with other imaging modalities.

A novel approach for the detection and genetic analysis of live melanoma circulating tumor cells.

BACKGROUND: Circulating tumor cell (CTC) detection and genetic analysis may complement currently available disease assessments in patients with melanoma to improve risk stratification and monitoring. We therefore sought to establish the feasibility of a telomerase-based assay for detecting and isolating live melanoma CTCs. METHODS: The telomerase-based CTC assay utilizes an adenoviral vector that, in the presence of elevated human telomerase activity, drives the amplification of green fluorescent protein. Tumor cells are then identified via an image processing system. The protocol was tested on melanoma cells in culture or spiked into control blood, and on samples from patients with metastatic melanoma. Genetic analysis of the isolated melanoma CTCs was then performed for BRAF mutation status. RESULTS: The adenoviral vector was effective for all melanoma cell lines tested with sensitivity of 88.7% (95%CI 85.6-90.4%) and specificity of 99.9% (95%CI 99.8-99.9%). In a pilot trial of patients with metastatic disease, CTCs were identified in 9 of 10 patients, with a mean of 6.0 CTCs/mL. At a cutoff of 1.1 CTCs/mL, the telomerase-based assay exhibits test performance of 90.0% sensitivity and 91.7% specificity. BRAF mutation analysis of melanoma cells isolated from culture or spiked control blood, or from pilot patient samples was found to match the known BRAF mutation status of the cell lines and primary tumors. CONCLUSIONS: To our knowledge, this is the first report of a telomerase-based assay effective for detecting and isolating live melanoma CTCs. These promising findings support further studies, including towards integrating into the management of patients with melanoma receiving multimodality therapy.

Tracking viable circulating tumor cells (CTCs) in the peripheral blood of non-small cell lung cancer (NSCLC) patients undergoing definitive radiation therapy: pilot study results.

BACKGROUND: Assays identifying circulating tumor cells (CTCs) allow noninvasive and sequential monitoring of the status of primary or metastatic tumors, potentially yielding clinically useful information. However, to the authors' knowledge, the effect of radiation therapy (RT) on CTCs in patients with non-small cell lung cancer (NSCLC) has not been previously explored. METHODS: This report describes results from a pilot study of 30 patients with NSCLC who received RT. Peripheral blood samples obtained from these patients were assayed for CTCs using an assay that identified live cells using an adenoviral probe that detected the elevated telomerase activity present in almost all cancer cells, but not in normal cells, and the validity of the assay was confirmed with secondary tumor-specific markers. Patients were assayed before initiation of RT (pre-RT), during the RT course, and/or after the completion of RT (post-RT). RESULTS: The assay successfully detected CTCs in the majority of patients, including 65% of patients before the start of RT, and in patients with both epidermal growth factor receptor wild-type and mutation-positive tumors. The median CTC counts in patients before RT was 9.1 CTCs per mL (range, undetectable to 571 CTCs per mL) and was significantly higher than the average post-RT count of 0.6 CTCs per mL (range, undetectable to 1.8 CTCs per mL; P<.001). Sequential CTC counts were available in a subset of patients and demonstrated decreases after RT, except for 1 patient who subsequently developed distant failure. CONCLUSIONS: The current pilot data suggest that CTC counts appear to reflect response to RT in patients with localized NSCLC. On the basis of these promising results, the authors have launched a more comprehensive and detailed clinical trial.

Application of a telomerase-based circulating tumor cell (CTC) assay in bladder cancer patients receiving postoperative radiation therapy: a case study.

BACKGROUND: Muscle invasive bladder carcinoma is an often lethal disease that requires aggressive treatment. Improved assays would contribute to better risk prediction and clinical management of this disease. A telomerase-based assay to detect circulating tumor cells (CTCs) may usefully fulfill this role. METHODS: Two patients (C1 and C2) were enrolled onto an IRB-approved bladder biomarker study before initiating post-operative radiation therapy (RT) for muscle invasive bladder carcinoma. Blood samples were taken at predefined intervals: before, during, and after RT and then retrospectively correlated with imaging studies and disease course. RESULTS: C1 began RT for positive resection margins on surgical pathology, at which time CTCs were undetectable and pelvic imaging demonstrated no evidence of disease. However, following the completion of treatment, the patient's CTC count was found to have increased to 202 CTCs/mL, and MRI demonstrated new abdominal and pelvic masses consistent with progressive disease. C1 ultimately died of disease with distant and local failure. Conversely, C2 was found to have 632 CTCs/mL before the initiation of RT for positive surgical margins, although imaging demonstrated no visible masses. At the conclusion of RT, repeat imaging showed changes that were indeterminate for either tumor recurrence or post-radiation effects. However, the patient's CTC count had dropped to 184 CTCs/mL. Furthermore, a second follow-up assay performed 6 months later revealed no detectable CTCs and repeat imaging showed complete resolution of worrisome imaging changes, thus excluding tumor progression. CONCLUSIONS: To our knowledge this is the first report of a telomerase-based assay to identify CTCs in bladder cancer patients. Further studies are required to fully determine the ultimate clinical utility of this assay. However, the two patient vignettes described here illustrate how serial CTC assays may track the disease course and inform the management of bladder cancer patients undergoing adjuvant RT and potentially chemotherapy.