Gerard M. Doherty

Revised American Thyroid Association Management Guidelines for Patients with Thyroid Nodules and Differentiated Thyroid Cancer

BACKGROUND Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the publication of the American Thyroid Associations guidelines for the management of these disorders was published in 2006, a large amount of new information has become available, prompting a revision of the guidelines. METHODS Relevant articles through December 2008 were reviewed by the task force and categorized by topic and level of evidence according to a modified schema used by the United States Preventative Services Task Force. RESULTS The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to optimal surgical management, radioiodine remnant ablation, and suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using ultrasound and serum thyroglobulin as well as those related to management of recurrent and metastatic disease. CONCLUSIONS We created evidence-based recommendations in response to our appointment as an independent task force by the American Thyroid Association to assist in the clinical management of patients with thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

2015 American Thyroid Association Management Guidelines for Adult Patients with Thyroid Nodules and Differentiated Thyroid Cancer: The American Thyroid Association Guidelines Task Force on Thyroid Nodules and Differentiated Thyroid Cancer

BACKGROUND Thyroid nodules are a common clinical problem, and differentiated thyroid cancer is becoming increasingly prevalent. Since the American Thyroid Associations (ATAs) guidelines for the management of these disorders were revised in 2009, significant scientific advances have occurred in the field. The aim of these guidelines is to inform clinicians, patients, researchers, and health policy makers on published evidence relating to the diagnosis and management of thyroid nodules and differentiated thyroid cancer. METHODS The specific clinical questions addressed in these guidelines were based on prior versions of the guidelines, stakeholder input, and input of task force members. Task force panel members were educated on knowledge synthesis methods, including electronic database searching, review and selection of relevant citations, and critical appraisal of selected studies. Published English language articles on adults were eligible for inclusion. The American College of Physicians Guideline Grading System was used for critical appraisal of evidence and grading strength of recommendations for therapeutic interventions. We developed a similarly formatted system to appraise the quality of such studies and resultant recommendations. The guideline panel had complete editorial independence from the ATA. Competing interests of guideline task force members were regularly updated, managed, and communicated to the ATA and task force members. RESULTS The revised guidelines for the management of thyroid nodules include recommendations regarding initial evaluation, clinical and ultrasound criteria for fine-needle aspiration biopsy, interpretation of fine-needle aspiration biopsy results, use of molecular markers, and management of benign thyroid nodules. Recommendations regarding the initial management of thyroid cancer include those relating to screening for thyroid cancer, staging and risk assessment, surgical management, radioiodine remnant ablation and therapy, and thyrotropin suppression therapy using levothyroxine. Recommendations related to long-term management of differentiated thyroid cancer include those related to surveillance for recurrent disease using imaging and serum thyroglobulin, thyroid hormone therapy, management of recurrent and metastatic disease, consideration for clinical trials and targeted therapy, as well as directions for future research. CONCLUSIONS We have developed evidence-based recommendations to inform clinical decision-making in the management of thyroid nodules and differentiated thyroid cancer. They represent, in our opinion, contemporary optimal care for patients with these disorders.

Prevalence of Regulatory T Cells Is Increased in Peripheral Blood and Tumor Microenvironment of Patients with Pancreas or Breast Adenocarcinoma

Regulatory T cells (Treg) that prevent autoimmune diseases by suppression of self-reactive T cells may also suppress the immune response against cancer. In mice, depletion of Treg by Ab therapy leads to more efficient tumor rejection. Treg-mediated suppression of antitumor immune responses may partly explain the poor clinical response to vaccine-based immunotherapy for human cancer. In this study, we measured the prevalence of Treg that coexpress CD4 and CD25 in the PBLs, tumor-infiltrating lymphocytes, and regional lymph node lymphocytes from 65 patients with either pancreas or breast cancer. In breast cancer patients (n = 35), pancreas cancer patients (n = 30), and normal donors (n = 35), the prevalence of Treg were 16.6% (SE 1.22), 13.2% (SE 1.13), and 8.6% (SE 0.71) of the total CD4+ cells, respectively. The prevalence of Treg were significantly higher in breast cancer patients (p < 0.01) and pancreas cancer patients (p < 0.01) when compared with normal donors. In tumor-infiltrating lymphocytes and lymph node lymphocytes, the Treg prevalence were 20.2% (SE 3.93) and 20.1% (SE 4.3), respectively. Treg constitutively coexpressed CTLA-4 and CD45RO markers, and secreted TGF-β and IL-10 but did not secrete IFN-γ. When cocultured with activated CD8+ cells or CD4+25− cells, Treg potently suppressed their proliferation and secretion of IFN-γ. We conclude that the prevalence of Treg is increased in the peripheral blood as well as in the tumor microenvironment of patients with invasive breast or pancreas cancers. These Treg may mitigate the immune response against cancer, and may partly explain the poor immune response against tumor Ags.

Central lymph node dissection in differentiated thyroid cancer

BackgroundThere has been renewed interest in extensive lymph node dissection for papillary thyroid cancer (PTC), and a number of reports have been published concerning compartment-oriented dissection of regional lymph nodes in PTC. A comprehensive review of this body of literature using evidence-based methodology is pending.MethodsSystematic review of the literature using evidence-based criteria.ResultsIssue 1: Systematic compartment-oriented central lymph node dissection (CLND) may decrease recurrence of PTC (Levels IV and V data, no recommendation) and likely improves disease-specific survival (grade C recommendation). Limited level III data suggest survival benefit with the addition of prophylactic dissection to thyroidectomy (grade C recommendation). The addition of CLND to total thyroidectomy can significantly reduce levels of serum thyroglobulin and increase rates of athyroglobulinemia (level IV data, no recommendation). Issue 2: There may be a higher rate of permanent hypoparathyroidism and unintentional permanent nerve injury when CLND is performed with total thyroidectomy than for total thyroidectomy alone (grade C recommendation). Issue 3: Reoperation in the central neck compartment for recurrent PTC may increase the risk of hypoparathyroidism and unintentional nerve injury when compared with total thyroidectomy with or without CLND (grade C recommendation), supporting a more aggressive initial operation.ConclusionEvidence-based recommendations support CLND for PTC in patients under the care of experienced endocrine surgeons.

Molecular classification of papillary thyroid carcinoma: distinct BRAF , RAS , and RET/PTC mutation-specific gene expression profiles discovered by DNA microarray analysis

Thyroid cancer poses a significant clinical challenge, and our understanding of its pathogenesis is incomplete. To gain insight into the pathogenesis of papillary thyroid carcinoma, transcriptional profiles of four normal thyroids and 51 papillary carcinomas (PCs) were generated using DNA microarrays. The tumors were genotyped for their common activating mutations: BRAF V600E point mutation, RET/PTC1 and 3 rearrangement and point mutations of KRAS, HRAS and NRAS. Principal component analysis based on the entire expression data set separated the PCs into three groups that were found to reflect tumor morphology and mutational status. By combining expression profiles with mutational status, we defined distinct expression profiles for the BRAF, RET/PTC and RAS mutation groups. Using small numbers of genes, a simple classifier was able to classify correctly the mutational status of all 40 tumors with known mutations. One tumor without a detectable mutation was predicted by the classifier to have a RET/PTC rearrangement and was shown to contain one by fluorescence in situ hybridization analysis. Among the mutation-specific expression signatures were genes whose differential expression was a direct consequence of the mutation, as well as genes involved in a variety of biological processes including immune response and signal transduction. Expression of one mutation-specific differentially expressed gene, TPO, was validated at the protein level using immunohistochemistry and tissue arrays containing an independent set of tumors. The results demonstrate that mutational status is the primary determinant of gene expression variation within these tumors, a finding that may have clinical and diagnostic significance and predicts success for therapies designed to prevent the consequences of these mutations.

Lethality of Multiple Endocrine Neoplasia Type I

Abstract. The lethality of the endocrine tumors associated with multiple endocrine neoplasia type I (MEN-I), particularly the pancreatic islet cell tumors, has been controversial. We evaluated the cause and age of death in MEN-I kindreds. Our database contains 34 distinct kindreds with 1838 members. Reliable death data are available for 103 people (excluding accidents and age < 18 years). We compared survival curves of MEN-I patients who died from causes related to MEN-I with those from MEN-I carriers who died from a nonendocrine cause and unaffected kindred members. We also compared ages of death between affected and unaffected members of MEN-I kindreds. Of 59 MEN-I-affected patients, 27 died directly of MEN-I-specific illness and 32 of non-MEN-I causes. The MEN-I-specific deaths occurred at a younger age (median 47 years) than either MEN-I patients whose death was from some nonendocrine cause (median 60 years,p < 0.02) or than all kindred members who did not die of MEN-I disease (median 55 years,p < 0.05). The causes of death of the MEN-I patients included islet cell tumor (n= 12), ulcer disease (n= 6), hypercalcemia/uremia (n= 3), carcinoid tumor (n= 6), and nonendocrine malignancies (n= 9). There was no difference in survival between MEN-I carriers and unaffected kindred members. Of our MEN-I patients, 46% died from causes related to their endocrine tumors after a median age of 47 years, which was younger than family members who did not die from these tumors. Pancreatic islet cell tumors were the most common cause of death of MEN-I patients. Management of kindreds with MEN-I should include an aggressive screening program with early therapeutic intervention when a tumor is identified.

Molecular Classification and Prognostication of Adrenocortical Tumors by Transcriptome Profiling

Purpose: Our understanding of adrenocortical carcinoma (ACC) has improved considerably, yet many unanswered questions remain. For instance, can molecular subtypes of ACC be identified? If so, what is their underlying pathogenetic basis and do they possess clinical significance? Experimental Design: We did a whole genome gene expression study of a large cohort of adrenocortical tissues annotated with clinicopathologic data. Using Affymetrix Human Genome U133 Plus 2.0 oligonucleotide arrays, transcriptional profiles were generated for 10 normal adrenal cortices (NC), 22 adrenocortical adenomas (ACA), and 33 ACCs. Results: The overall classification of adrenocortical tumors was recapitulated using principal component analysis of the entire data set. The NC and ACA cohorts showed little intragroup variation, whereas the ACC cohort revealed much greater variation in gene expression. A robust list of 2,875 differentially expressed genes in ACC compared with both NC and ACA was generated and used in functional enrichment analysis to find pathways and attributes of biological significance. Cluster analysis of the ACCs revealed two subtypes that reflected tumor proliferation, as measured by mitotic counts and cell cycle genes. Kaplan-Meier analysis of these ACC clusters showed a significant difference in survival (P < 0.020). Multivariate Cox modeling using stage, mitotic rate, and gene expression data as measured by the first principal component for ACC samples showed that gene expression data contains significant independent prognostic information (P < 0.017). Conclusions: This study lays the foundation for the molecular classification and prognostication of adrenocortical tumors and also provides a rich source of potential diagnostic and prognostic markers.

Laparoscopic Skills Are Improved With LapMentor™ Training: Results of a Randomized, Double-Blinded Study

Objective:To determine if prior training on the LapMentor™ laparoscopic simulator leads to improved performance of basic laparoscopic skills in the animate operating room environment. Summary Background Data:Numerous influences have led to the development of computer-aided laparoscopic simulators: a need for greater efficiency in training, the unique and complex nature of laparoscopic surgery, and the increasing demand that surgeons demonstrate competence before proceeding to the operating room. The LapMentor™ simulator is expensive, however, and its use must be validated and justified prior to implementation into surgical training programs. Methods:Nineteen surgical interns were randomized to training on the LapMentor™ laparoscopic simulator (n = 10) or to a control group (no simulator training, n = 9). Subjects randomized to the LapMentor™ trained to expert criterion levels 2 consecutive times on 6 designated basic skills modules. All subjects then completed a series of laparoscopic exercises in a live porcine model, and performance was assessed independently by 2 blinded reviewers. Time, accuracy rates, and global assessments of performance were recorded with an interrater reliability between reviewers of 0.99. Results:LapMentor™ trained interns completed the 30° camera navigation exercise in significantly less time than control interns (166 ± 52 vs. 220 ± 39 seconds, P < 0.05); they also achieved higher accuracy rates in identifying the required objects with the laparoscope (96% ± 8% vs. 82% ± 15%, P < 0.05). Similarly, on the two-handed object transfer exercise, task completion time for LapMentor™ trained versus control interns was 130 ± 23 versus 184 ± 43 seconds (P < 0.01) with an accuracy rate of 98% ± 5% versus 80% ± 13% (P < 0.001). Additionally, LapMentor™ trained interns outperformed control subjects with regard to camera navigation skills, efficiency of motion, optimal instrument handling, perceptual ability, and performance of safe electrocautery. Conclusions:This study demonstrates that prior training on the LapMentor™ laparoscopic simulator leads to improved resident performance of basic skills in the animate operating room environment. This work marks the first prospective, randomized evaluation of the LapMentor™ simulator, and provides evidence that LapMentor™ training may lead to improved operating room performance.

The Pros and Cons of Prophylactic Central Compartment Lymph Node Dissection for Papillary Thyroid Carcinoma

A well-established feature of papillary thyroid carcinoma (PTC) is it propensity to metastasize to cervical lymph nodes in the central and lateral compartments. Currently, there is no nonor minimally invasive method that is completely reliable for detecting all of the metastases that are present. Therefore, some have advocated prophylactic cervical lymph node dissection as part of the operative procedure for PTC. There is no unanimity, however, on the efficacy and safety of prophylactic cervical lymph node dissection for this tumor. At the recent National Thyroid Cancer Workshop II,* two distinguished surgeons, Dr. Gerard M. Doherty from the University of Michigan and Dr. David L. Steward at the University of Cincinnati, were invited to debate the pros and cons of prophylactic cervical lymph node dissection. More specifically, Dr. Doherty was asked to take the positive view and Dr. Steward the contrary view concerning prophylactic central compartment (Level VI) dissection (CLND). By definition, this is a total compartment dissection that is performed when there is no preoperative or intraoperative evidence of cervical lymph-node metastases. Each participant was asked to marshal the case for one side and not necessarily reflect their personal views. To help them prepare, they were given the following hypothetical case to consider. A 22-year-old woman is referred by her endocrinologist for surgical management of an asymptomatic 2-cm PTC diagnosed 1 week before. There is no family history of thyroid cancer, and she has had no exposure to radiation. Her thyroidstimulating hormone (TSH) level is 1.7 (IU=mL. Repeat neck ultrasonography reveals a single 2-cm right lobe thyroid nodule with a hazy border and no lateral or central neck lymph-node abnormalities. The question posed to the debaters is: What are the pros and cons of prophylactic level VI lymph-node dissection for this patient? After the workshop, these surgeons, who are recognized authorities on the surgical management of thyroid cancer, were asked to prepare written commentary based on their presentations. What follows are two concise, carefully articulated, literature-based reviews that support each side of the debate.

Influence of prophylactic central lymph node dissection on postoperative thyroglobulin levels and radioiodine treatment in papillary thyroid cancer

BACKGROUND Prophylactic central lymph node dissection with total thyroidectomy (TT) for the treatment of papillary thyroid cancer (PTC) is controversial because of the possibility of increased morbidity with uncertain benefit. The purpose of this study is to determine whether prophylactic central neck dissection provides any advantages over TT alone. METHODS Retrospective cohort study of patients with PTC without preoperative evidence of lymph node involvement undergoing either TT or TT with bilateral central lymph node dissection (TT + BCLND). RESULTS From 2002 to 2009, 143 patients with clinically node-negative PTC underwent either TT (n = 65) or TT + BCLND (n = 78). The groups were similar in age, gender, tumor size, multifocality, angioinvasion, and metastasis/age/completeness-of-resection/invasion/size score. The presence of involved central neck lymph nodes upstaged 28.6% of patients in the TT + BCLND group to stage III disease, which resulted in higher radioactive iodine ablation doses. Stimulated serum thyroglobulin levels and the number of patients with undetectable stimulated thyroglobulin levels before and 1 year after radioactive iodine ablation were equivalent. CONCLUSION The addition of routine central lymph node dissection to TT for the treatment of PTC upstages nearly one third of patients over the age of 45 thereby changing the dose of radioactive iodine ablative therapy, but does not change postoperative thyroglobulin levels after completion of radioiodine treatment.