Paul G. Gauger

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.

Distinct Transcriptional Profiles of Adrenocortical Tumors Uncovered by DNA Microarray Analysis

Comprehensive expression profiling of tumors using DNA microarrays has been used recently for molecular classification and biomarker discovery, as well as a tool to identify and investigate genes involved in tumorigenesis. Application of this approach to a cohort of benign and malignant adrenocortical tissues would be potentially informative in all of these aspects. In this study, we generated transcriptional profiles of 11 adrenocortical carcinomas (ACCs), 4 adrenocortical adenomas (ACAs), 3 normal adrenal cortices (NCs), and 1 macronodular hyperplasia (MNH) using Affymetrix HG_U95Av2 oligonucleotide arrays representing approximately 10,500 unique genes. The expression data set was used for unsupervised hierarchical cluster analysis as well as principal component analysis to visually represent the expression data. An analysis of variance on the three classes (NC, ACA plus MNH, and ACC) revealed 91 genes that displayed at least threefold differential expression between the ACC cohort and both the NC and ACA cohorts at a significance level of P < 0.01. Included in these 91 genes were those known to be up-regulated in adrenocortical tumors, such as insulin-like growth factor (IGF2), as well as novel differentially expressed genes such as osteopontin (SPP) and serine threonine kinase 15 (STK15). Increased expression of IGF2 was identified in 10 of 11 ACCs (90.9%) and was verified by quantitative reverse transcriptase-polymerase chain reaction. Select proliferation-related genes (TOP2A and Ki-67) were validated at the protein level using immunohistochemistry and adrenocortical tissue microarrays. Our results demonstrated significant and consistent gene expression changes in ACCs compared to benign adrenocortical lesions. Moreover, we identified several genes that represent potential diagnostic markers and may play a role in the pathogenesis of ACC.

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.

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.

Surgeon's approach to the thyroid gland: surgical anatomy and the importance of technique.

The cornerstone of safe and effective thyroid surgery is thorough training in and understanding of thyroid anatomy and pathology. With appropriate techniques, total thyroid lobectomy and total thyroidectomy (which should be considered simply as a bilateral total thyroid lobectomy performed during the same operation) can be undertaken with minimal risk of damage to the recurrent laryngeal nerves, the external branches of the superior laryngeal nerves, and the parathyroid glands. Safe surgery requires a specific operative plan, progressing in a series of logical, orderly, anatomically based steps. Exposure of the thyroid gland is followed by careful dissection of the superior pole, utilizing the avascular plane between the superior pole and the cricothyroid muscle to identify and preserve the external branch of the superior laryngeal nerve. Medial retraction of the gland then allows dissection of the lateral aspect of the thyroid lobe. Protection of the recurrent laryngeal nerves and preservation of the blood supply to the parathyroid glands is best achieved by “capsular dissection,” ligating the tertiary branches of the inferior thyroid artery on the gland surface. If a parathyroid gland cannot be preserved or becomes ischemic after dissection of its vascular pedicle, it should be immediately minced and autotransplanted into the ipsilateral sternocleidomastoid muscle. The current evolution of outpatient or short-stay thyroidectomy emphasizes the need to avoid complications by utilizing meticulous surgical technique. Minimally invasive thyroidectomy utilizing endoscopic techniques may also affect the practice of thyroid surgery. Even so, understanding the surgical anatomy of the thyroid gland and its possible variations is paramount to safe and effective surgery.

Liquid ventilation in adults, children, and full-term neonates

We evaluated the safety and efficacy of partial liquid ventilation in a series of 19 adults, children, and neonates who were in respiratory failure and on extracorporeal life support. During partial liquid ventilation, the alveolar-arterial oxygen difference decreased from 590 (SE 25) to 471 (42) mm Hg (p = 0.0002) and static pulmonary compliance increased from 0.18 (0.04) to 0.29 (0.04) mL cm H2O-1 kg-1 (p = 0.0002). 11 patients (58%) survived. These preliminary data suggest that partial liquid ventilation can be safely used in patients with severe respiratory failure and may improve lung function.

Initial experience with partial liquid ventilation in pediatric patients with the acute respiratory distress syndrome

OBJECTIVE Liquid ventilation with perfluorocarbon previously has not been reported in pediatric patients with respiratory failure beyond the neonatal period. We evaluated the technique of partial liquid ventilation in six pediatric patients with the acute respiratory distress syndrome of sufficient severity to require extracorporeal life support (ECLS). DESIGN This study was a noncontrolled, phase I/II experimental study with a single group pretest/posttest design. SETTING All studies were performed at a tertiary, pediatric referral hospital at the University of Michigan Medical School. PATIENTS Six pediatric patients, from 8 wks to 5 1/2 yrs of age, with severe respiratory failure requiring ECLS to support gas exchange. INTERVENTIONS After 2 to 9 days on ECLS, perfluorocarbon was administered into the trachea until the dependent zone of each lung was filled. The initial administered was 12.9 +/- 2.3 mL/kg (range 5 to 20). Gas ventilation of the perfluorocarbon-filled lungs (partial liquid ventilation) was then performed. The perfluorocarbon dose was repeated daily for a total of 3 to 7 days, with a cumulative dose of 45.2 +/- 6.1 mL/kg (range 30 to 72.5). MEASUREMENTS AND MAIN RESULTS All measurements of native gas exchange were made during brief periods of discontinuation of ECLS and include PaO2 and the alveolar-arterial oxygen gradient, P(A-a)O2. Static pulmonary compliance, corrected for weight, was also measured directly. The mean PaO2 increased from 39 +/- 6 to 92 +/- 29 torr (5.2 +/- 0.8 to 12.2 +/- 3.9 kPa) over the 96 hrs after the initial dose (p = .021 by repeated-measures analysis of variance). The average P(A-a)O2 decreased from 635 +/- 10 to 499 +/- 77 torr (84.7 +/- 1.3 to 66.5 +/- 10.3 kPa) over the same time period (p = .059), while the mean static pulmonary compliance (normalized for patient weight) increased from 0.12 +/- 0.02 to 0.28 +/- 0.08 mL/cm H2O/kg (p = .01). All six patients survived. Complications potentially associated with partial liquid ventilation were limited to pneumothoraces in two of six patients. CONCLUSIONS Perfluorocarbon may be safely administered into the lungs of pediatric patients with severe respiratory failure on ECLS and may be associated with improvement in gas exchange and pulmonary compliance.

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.

The most commonly occurring papillary thyroid cancer in the United States is now a microcarcinoma in a patient older than 45 years.

BACKGROUND The incidence of papillary thyroid cancer (PTC) is growing at a faster rate than any other malignancy. However, it is unknown what effect age is having on the changing PTC incidence rates. With the goal of understanding the role of age in thyroid cancer incidence, this study analyzes the changing demographics of patients with PTC over the past three decades. METHODS This was a retrospective evaluation of the incidence rates of PTC from 1973 to 2006 reported by the National Cancer Institutes Surveillance, Epidemiology, and End Results database. RESULTS From 1973-2006 the age group most commonly found to have PTC has shifted from patients in their 30s to patients in the 40-50-year-old age group. In 1973 60% of PTC cases were found in patients younger than 45, and the majority of cases continued to occur in younger patients until 1999. After 1999 PTC became more common in patients older than 45 years, and in 2006, 61% of PTC cases were in patients older than 45 years. From 1988 to 2003 there has been an increasing incidence of all sizes of PTC in all age groups with the largest increase in tumors <1 cm in patients older than 45. Forty-three percent of tumors in patients older than 45 are now <1 cm, whereas only 34% are <1 cm in patients younger than 45. Of the nearly 20,000 thyroid cancer cases in 2003, 24% were microcarcinomas in patients over the age of 45. CONCLUSIONS The incidence of PTC is increasing disproportionally in patients older than 45 years. The number of PTC tumors smaller than 1 cm is increasing in all age groups, and now the most commonly found PTC tumor in the United States is a microcarcinoma in a patient older than 45 years. These changing patterns relating age and incidence have important prognostic and treatment implications for patients with PTC.