Management of thyroid nodules with atypical cytology on fine-needle aspiration biopsy.

BACKGROUND: Fine-needle aspiration biopsy (FNAB) of the thyroid categorized as atypia of undetermined significance/follicular lesion of undetermined significance (AUS/FLUS) is a newly defined category according to the recent Bethesda guidelines. We sought to assess the characteristics and treatment of patients with an AUS/FLUS FNAB at our institution. Additionally, we evaluated the utility of the recommended 3-month timing of repeat FNAB. METHODS: A retrospective study of all patients with an FNAB categorized as AUS/FLUS at an academic tertiary-care center. Clinical, cytological, and ultrasound variables were compared among management groups. Differences in patients receiving repeat FNAB before or after a 3-month interval were compared. RESULTS: A total of 203 patients of the 5,391 FNABs performed at our institution met the Bethesda criteria for AUS/FLUS; 62% were sent directly to surgery, 25% had a repeat FNAB, and 13% were observed. Younger (p=0.006) and male patients (p=0.04) were more likely to go directly to surgery. Microcalcifications, irregular margins, and marked hypoechogenicity on ultrasound did not appear to influence the decision to repeat the FNAB, observe the patient, or refer the patient for surgery. Timing of repeat FNAB (<3 months or ≥3 months) did not alter the diagnostic results of the second FNAB (p=0.73). The overall rate of malignancy in patients undergoing surgery was 15.7%. CONCLUSIONS: Gender and age, not ultrasound characteristics, appear to influence the decision for surgery in AUS/FLUS patients. Timing of repeat biopsy did not alter management, repeat FNAB diagnosis, or rate of malignancy in our cohort.

Targeting BRAFV600E with PLX4720 displays potent antimigratory and anti-invasive activity in preclinical models of human thyroid cancer.

PURPOSE: B-Raf(V600E) may play a role in the progression from papillary thyroid cancer to anaplastic thyroid cancer (ATC). We tested the effects of a highly selective B-Raf(V600E) inhibitor, PLX4720, on proliferation, migration, and invasion both in human thyroid cancer cell lines (8505c(B-RafV600E) and TPC-1(RET/PTC-1 and wild-type B-Raf)) and in primary human normal thyroid (NT) follicular cells engineered with or without B-Raf(V600E). EXPERIMENTAL DESIGN: Large-scale genotyping analysis by mass spectrometry was performed in order to analyze >900 gene mutations. Cell proliferation and migration/invasion were performed upon PLX4720 treatment in 8505c, TPC-1, and NT cells. Orthotopic implantation of either 8505c or TPC-1 cells into the thyroid of severe combined immunodeficient mice was performed. Gene validations were performed by quantitative polymerase chain reaction and immunohistochemistry. RESULTS: We found that PLX4720 reduced in vitro cell proliferation and migration and invasion of 8505c cells, causing early downregulation of genes involved in tumor progression. PLX4720-treated NT cells overexpressing B-Raf(V600E) (heterozygous wild-type B-Raf/B-Raf(V600E)) showed significantly lower cell proliferation, migration, and invasion. PLX4720 treatment did not block cell invasion in TPC-1 cells with wild-type B-Raf, which showed very low and delayed in vivo tumor growth. In vivo, PLX4720 treatment of 8505c orthotopic thyroid tumors inhibited tumor aggressiveness and significantly upregulated the thyroid differentiation markers thyroid transcription factor 1 and paired box gene 8. CONCLUSIONS: Here, we have shown that PLX4720 preferentially inhibits migration and invasion of B-Raf(V600E) thyroid cancer cells and tumor aggressiveness. Normal thyroid cells were generated to be heterozygous for wild-type B-Raf/B-Raf(V600E), mimicking the condition found in most human thyroid cancers. PLX4720 was effective in reducing cell proliferation, migration, and invasion in this heterozygous model. PLX4720 therapy should be tested and considered for a phase I study for the treatment of patients with B-Raf(V600E) ATC.

Effect of a novel financial incentive program on operating room efficiency.

IMPORTANCE: Operating room (OR) turnaround times (TATs) and on-time first-case starts (FCSs) are commonly used measures of OR efficiency. Prolonged TATs and late FCSs occur frequently at academic medical centers. OBJECTIVE: To test the hypothesis that establishing a financial incentive program (FIP) for OR teams would improve efficiency, leading to decreased TATs and improved on-time FCSs. DESIGN, SETTING, AND PARTICIPANTS: Prospective study to evaluate the effect of an FIP on OR efficiency between March 1, 2013, and December 31, 2013, at a freestanding academic trauma hospital. Participants were all OR team members and included anesthesiologists, certified registered nurse anesthetists, nurses, and technicians. INTERVENTIONS: Operating room efficiency awareness education was conducted before FIP implementation beginning in February 2013. Each eligible OR team member achieving a TAT of 60 minutes or less or an on-time FCS was awarded 1 point. Reports listing individual performances were posted. Pay bonuses were awarded for achieving 1 of 3 progressive point totals in any month. MAIN OUTCOMES AND MEASURES: Outcomeswere TAT, whichwas defined as "wheels out" to "wheels in," and on-time FCS, which was defined as "wheels in" within 6 minutes of the scheduled start time. RESULTS: Before FIP implementation, the mean TAT varied between 77 and 83 minutes, with only 18%to 26%of TATs being 60 minutes or less; on-time FCSs averaged 29% to 34%. After FIP implementation, on-time FCSs improved from 31% to 64%(P < .001), and TATs of 60 minutes or less increased from 24%to 52%(P < .001). The cost of a 2-month FIP was $8340. We saved 13 minutes per TAT, for an estimated savings of $177 000.We estimate an additional savings of $33 000 for on-time FCSs, for a total hospital savings of $210 000. CONCLUSIONS AND RELEVANCE: A novel FIP improved OR efficiency. Given the small amount of money involved, it seems unlikely that financial incentives were solely responsible. Effectively communicating the importance of TATs and on-time FCSs and publishing individual results more likely increased staff awareness. Teamwork created by linking assignment of points to a team result likely contributed to success.

Late intervention with anti-BRAF(V600E) therapy induces tumor regression in an orthotopic mouse model of human anaplastic thyroid cancer.

Human anaplastic thyroid cancer (ATC) is a lethal disease with an advanced clinical presentation and median survival of 3 months. The BRAF(V600E) oncoprotein is a potent transforming factor that causes human thyroid cancer cell progression in vitro and in vivo; therefore, we sought to target this oncoprotein in a late intervention model of ATC in vivo. We used the human ATC cell line 8505c, which harbors the BRAF(V600E) and TP53(R248G) mutations. Immunocompromised mice were randomized to receive the selective anti-BRAF(V600E) inhibitor, PLX4720, or vehicle by oral gavage 28 d after tumor implantation, 1 wk before all animals typically die due to widespread metastatic lung disease and neck compressive symptoms in this model. Mice were euthanized weekly to evaluate tumor volume and metastases. Control mice showed progressive tumor growth and lung metastases by 35 d after tumor implantation. At that time, all control mice had large tumors, were cachectic, and were euthanized due to their tumor-related weight loss. PLX4720-treated mice, however, showed a significant decrease in tumor volume and lung metastases in addition to a reversal of tumor-related weight loss. Mouse survival was extended to 49 d in PLX4720-treated animals. PLX4720 treatment inhibited cell cycle progression from 28 d to 49 d in vivo. PLX4720 induces striking tumor regression and reversal of cachexia in an in vivo model of advanced thyroid cancer that harbors the BRAF(V600E) mutation.

Diagnostic yield of nondiagnostic thyroid nodules is not altered by timing of repeat biopsy.

BACKGROUND: Guidelines from the National Cancer Institute Thyroid Fine Needle Aspiration State of the Science Conference recommend a repeat fine-needle aspiration biopsy (FNAB) after 3 months for thyroid nodules with a nondiagnostic (ND) result. Our aims were to assess which factors influenced their clinical management and to determine if the timing of the repeat FNAB affects the diagnostic yield. METHODS: A retrospective institutional review of 298 patients from 1/2006 to 12/2007 with an ND FNAB was performed. The factors influencing the next step in management, including age, gender, history of radiation, presence of Hashimoto's thyroiditis, thyroid-stimulating hormone levels, and ultrasound characteristics, were evaluated. The effect of the time of the repeat FNABs on their diagnostic yield was assessed. RESULTS: Of the 298 patients in our cohort, 9% were referred directly for surgery, 76% had a repeat FNAB, and 15% were observed. Tumor size was the only independent variable correlated with treatment strategy after a ND FNAB. There was not a significant difference in diagnostic yields between repeat FNABs performed earlier than 3 months compared to those preformed later (p=0.58). CONCLUSION: The timing of repeat FNAB for an initial ND FNAB does not affect diagnostic yield of the repeat FNAB.

Overcoming obstacles to setting up office-based ultrasound for evaluation of thyroid and parathyroid diseases.

Ultrasound is an integral part of the preoperative workup for patients who are being evaluated for thyroid and parathyroid surgery. It helps improve the accuracy of a fine-needle aspiration biopsy and complements other imaging modalities used for planning the extent of surgery. It also allows imaging of vital structures in relation to the thyroid and parathyroid. The compact nature and portability of ultrasound machines in recent years has made it easier for motivated surgeons (head and neck, general, and endocrine surgeons) to incorporate them into their practice. However, successfully setting up such a service needs adequate planning and an understanding of the obstacles that are involved. We aim to discuss these obstacles in detail, with practical suggestions on how to overcome them. This review may serve as a resource when dealing with issues such as purchasing equipment, training, credentialing, billing, documentation, and collaboration. Although these are discussed with respect to surgeons with an interest in endocrine disease, with some modifications they may also apply to any surgeon who uses ultrasound frequently.