Thomas J. Fahey

Factors Affecting Recurrence following Incisional Herniorrhaphy

The purpose of this study was to determine the influence of chronic illness, obesity, and type of repair on the likelihood of recurrence following incisional herniorrhaphy. The medical records of 77 patients who underwent elective repair of a midline incisional hernia at the Dallas Veterans Affairs Medical Center between 1991 and 1995 were reviewed. Demographic data, presence of chronic illnesses, type of repair, and presence of recurrence were noted. Ninety-six percent of the patients were men, with an average age of 59 years. More than 50% of the patients had chronic lung or cardiac diseases and more than 40% weighed ≥120% of their ideal body weight and had a body mass index (BMI) ≥30. Sixty-two percent of the patients underwent primary reapproximation of the fascia (tissue repair), whereas 38% underwent repair with prosthetic material (prosthetic repair). The overall recurrence rate was 45%, with a median follow-up of 45 months (range 6–73). Seventy-four percent of the recurrences presented within 3 years of repair. The recurrence rate for those patients undergoing a tissue repair was 54%, whereas the recurrence rate following prosthetic repair was 29%. The incidence of recurrence for patients with pulmonary or cardiac disease or diabetes mellitus was similar to that of patients without these illnesses. The percent ideal body weight and BMI of patients who developed a recurrent hernia, particularly following a prosthetic repair, were significantly greater than those of patients whose repairs remained intact. These data strongly support the use of prosthetic repairs for incisional hernias, particularly in patients who are overweight.

Telomerase activity in benign and malignant thyroid diseases.

BACKGROUNDnTelomerase, an enzyme associated with cellular immortality, is expressed by most malignant cells and is inactive in most normal somatic cells, with the excitation of proliferative stem cells, male germ cells, and activated lymphocytes. The measurement of telomerase activity in clinically obtained tissue samples may provide useful information as both a diagnostic and prognostic marker. In this study, we sought to determine whether telomerase activity might prove helpful in the assessment of benign and malignant thyroid tumors.nnnMETHODSnA modified, semiquantitative polymerase chain reaction-based telomeric repeat amplification protocol assay was used for detection of telomerase activity in 59 samples obtained at thyroidectomy, including 15 thyroid cancers, 22 benign thyroid diseases, and 22 adjacent normal thyroid tissues.nnnRESULTSnFour of 13 differentiated thyroid carcinomas (30%) and 2 of 2 medullary carcinomas (100%) expressed telomerase activity. Unexpectedly, we also detected activity in 3 of 22 (14%) adjacent normal thyroid tissues and 6 of 22 (28%) benign thyroid diseases. Pathologic review of the telomerase-positive benign specimens revealed that many contained extensive lymphoid infiltrates with germinal centers (six of nine, 67%), as did two of four telomerase-positive papillary carcinomas.nnnCONCLUSIONSnIn contradistinction to other epithelial carcinomas, telomerase does not appear to be frequently reactivated in differentiated thyroid carcinomas.

Summary statement: Utility of molecular marker testing in thyroid cancer

The use of molecular markers for thyroid cancer diagnosis, prognosis, and surveillance have been an exciting area of study and change. Recent investigative focus on promising new markers will very likely lead to improvements in the diagnostic utility of fine needle aspiration biopsy (FNAB) in predicting malignancy, as well as provide more accurate prognostic information pre- and postoperatively. The 2010 Annual Meeting of the American Association for Endocrine Surgeons featured a symposium dedicated to molecular marker testing in thyroid cancer and its potential clinical applicability.

Large-volume liposuction complicated by retroperitoneal hemorrhage: management principles and implications for the quality improvement process.

Large-volume liposuction can be associated rarely with major medical complications and death. The case of exsanguinating retroperitoneal hemorrhage that led to cardiopulmonary arrest in an obese 47-year-old woman who underwent large-volume liposuction is described. Extensive liposuction is not a minor procedure. Performance in an ambulatory setting should be monitored carefully, if it is performed at all. Reporting of adverse events associated with outpatient procedures performed by plastic surgeons should be mandated. Hemodynamic instability in the early postoperative period in an otherwise healthy patient may be due to fluid overload, lidocaine toxicity, or to hemorrhagic shock and must be recognized and treated aggressively. Guidelines for the safe practice of large-volume liposuction need to be established.

Management of hypertension in primary aldosteronism

Hypertension causes significant morbidity and mortality worldwide, owing to its deleterious effects on the cardiovascular and renal systems. Primary hyperaldosteronism (PA) is the most common cause of reversible hypertension, affecting 5%-18% of adults with hypertension. PA is estimated to result from bilateral adrenal hyperplasia in two-thirds of patients, and from unilateral aldosterone-secreting adenoma in approximately one-third. Suspected cases are initially screened by measurement of the plasma aldosterone-renin-ratio, and may be confirmed by additional noninvasive tests. Localization of aldostosterone hypersecretion is then determined by computed tomography imaging, and in selective cases with adrenal vein sampling. Solitary adenomas are managed by laparoscopic or robotic resection, while bilateral hyperplasia is treated with mineralocorticoid antagonists. Biochemical cure following adrenalectomy occurs in 99% of patients, and hemodynamic improvement is seen in over 90%, prompting a reduction in quantity of anti-hypertensive medications in most patients. End-organ damage secondary to hypertension and excess aldosterone is significantly improved by both surgical and medical treatment, as manifested by decreased left ventricular hypertrophy, arterial stiffness, and proteinuria, highlighting the importance of proper diagnosis and treatment of primary hyperaldosteronism. Although numerous independent predictors of resolution of hypertension after adrenalectomy for unilateral adenomas have been described, the Aldosteronoma Resolution Score is a validated multifactorial model convenient for use in daily clinical practice.

Expression of cyclooxygenase-2 in the periprosthetic capsule surrounding a silicone shell implant in the rat.

Prosthetic breast implants are used frequently for both aesthetic and reconstructive purposes. Histologically, the normal tissue response to silicone implants typically involves an inflammatory infiltrate that consists initially of macrophages, and later consists of fibroblasts, myofibroblasts, and lymphocytes. To characterize further the nature of the inflammatory response to silicone breast implants, the authors evaluated the expression of the enzyme cyclooxygenase-2 (COX-2) by the tissues and cells of the breast capsule after silicone augmentation in an animal model. COX-2 is an inducible enzyme that is expressed primarily in response to inflammatory stimuli and mediates the production of prostaglandins that support the inflammatory process. Fifty-nine animals at five time points were evaluated. Specifically, on days 4, 7, 14, 28, and 80 the authors identified cytoplasmic COX-2 expression in each of the three cell types of interest, including endothelial cells, macrophages, and fibroblasts. Selective COX-2 inhibiting agents may be an appropriate pharmacological intervention for modulating the formation of periprosthetic capsules.McLean AL, Talmor M, Harper A, Fahey TJ, Gayle LB, Hoffman LA. Expression of cyclooxygenase-2 in the periprosthetic capsule surrounding a silicone shell implant in the rat.

201 Early Referral for 24-Hour Esophageal pH Monitoring Is More Cost-Effective Than Prolonged Use of Proton Pump Inhibitors in Patients With Suspected Gastroesophageal Reflux Disease

Introduction: Type VI collagen (COL6) forms a microfibrillar network associated with type I collagen fibrils and constitutes a major component of the prominent desmoplastic reaction in pancreatic ductal adenocarcinoma (PDA). We have demonstrated recently that a subunit of COL6, COL6A3, is expressed in high levels in PDA tissue. We also showed that COL6A3 gene undergoes tumor-specific alternative splicing to produce 3 isoforms E3, E4 and E6 that are tumor tissue-specific. The aim of this study is to investigate the diagnostic value and clinical significance of circulating COL6A3 isoforms mRNA in PDA. Methods: Serum samples were obtained frompatients that underwent pancreatic resection at a single institution between 2006 and 2009. COL6A3 levels in the sera from patients with pathologically confirmed PDA (n=40), intraductal papillary mucinous neoplasms (IPMN) (n=20), and chronic pancreatitis (n=10) were analyzed by real time PCR using isoform-specific primers for E3, E4 and E6 . In addition, sera from age-matched healthy volunteers were analyzed (n=30). The prediction levels for malignancy were determined by the area under the receiver operating characteristic curve (AUC). In vitro, wound healing, cell proliferation and softagar colony formation assays evaluated the functional impact of each isoform in PDA cells (MIAPACA-2 and ASP-C-1) transfectedwith isoform-specific siRNA. A panel of inflammationand invasion/angiogenesis-related genes was also evaluated. Results: Circulating E6 mRNA levels were significantly (p=0.006) elevated in PDA patients when compared to all benign lesions. E3 and E4 were expressed at extremely low levels in all patients. Compared to IPMN alone, E6 levels were significantly higher in PDA (p=0.0036). There were no significant differences between E6 levels in IPMN and Normal sera (p= 0.59). Using a logistic regression model, we found that for each increasing unit of log E6 COL6A3, patients are 9.5 times more likely to harbor a cancer rather than a benign lesion, 95% CI (2.4, 38.1), p=0.002. The area under the ROC curve, AUC, was 0.72. Knocking down E3 or E4 or E6 with isoform-specific siRNA resulted in reduced PDA cell migration and invasion and concomitant reduction of the expression of several inflammation and angiogenesis-related genes, such as MMP-9, OPN, MCP-1 and VEGF. Interestingly, knocking down any of the 3 isoforms resulted in increased expression of TNF-alpha. Conclusions: Our data show for the first time the potential clinical significance of circulating E6 COL6A3 levels in the diagnosis of pancreatic malignancy. Our in vitro data suggests a role for COL6A3 isoforms in PDA progression and metastatic potential.

Epigenetics of gastroenteropancreatic neuroendocrine tumors: A clinicopathologic perspective

Gastroenteropancreatic neuroendocrine tumors (GEP-NETs) are a heterogeneous group of rare tumors whose site-specific tumor incidence and clinical behavior vary widely. Genetic alterations associated with familial inherited syndromes have been well defined; however, the genetic profile of sporadic tumors is less clear as their tumorigenesis does not appear to be controlled by classic oncogenes such as P53, RB, or KRAS. Even within GEP-NETs, there are no common oncogenic drivers; for example, DAXX/ATRX mutations are strongly implicated in the tumorigenesis of pancreatic but not small bowel NETs. Accordingly, the dysregulation of epigenetic mechanisms has been hypothesized as a potential regulator of GEP-NET tumorigenesis and has become a major focus of recent studies. Despite the heterogeneity of tumor cohorts evaluated in these studies, it is obvious that there are methylation patterns, chromatin remodeling alterations, and microRNA and long non-coding RNA (lncRNA) differential expression profiles that are distinctive of GEP-NETs, some of which are correlated with significant differences in clinical outcomes. Several translational studies have provided convincing data identifying potential prognostic biomarkers, and some of these have demonstrated preliminary success as serum biomarkers that can be used clinically. Nevertheless, there are many opportunities to further define the mechanisms by which these epigenetic modifications influence tumorigenesis, and this will provide better insight into their prognostic and therapeutic utility. Furthermore, these findings form the foundation for future studies evaluating the clinical efficacy of epigenetic modifications as prognostic biomarkers, as well as potential therapeutic targets.

Reply to Preoperative BRAF(V600E) mutation screening is unlikely to alter initial surgical treatment of patients with indeterminate thyroid nodules: A prospective case series of 960 patients: Reply to Correspondence

We greatly appreciate the thoughtful comments provided by our colleagues from University Medical Center Utrecht regarding our article. The authors made a valid point that the implications of our study are largely dependent on institutional practice patterns. As noted, it is the practice at our institution to recommend a total thyroidectomy as the initial surgical procedure for patients with Bethesda category V nodules and Bethesda category III nodules with particularly worrisome atypical features. However, this is not the case at all centers worldwide, and there is even discrepancy among centers within the United States. Therefore, any surgeon who always recommends a hemithyroidectomy for any nodule that is not determined to be clearly malignant on preoperative fine-needle aspiration may come to an opposite conclusion to the one that we have proposed. We generally agree with Lodewijik et al that if preoperative BRAF(V600E) screening is to be offered, it is likely to be most beneficial to patients with Bethesda category V nodules as opposed to those with Bethesda III and IV nodules. As reported in our study, the sensitivity of BRAF screening for detecting malignancy among patients with Bethesda III and IV nodules was only 3% compared with 42% among patients with Bethesda V nodules. To follow on the argument proposed by Lodewijik et al, 272 Bethesda III or IV nodules had to be tested to detect 2 BRAF(V600E) mutations. Although we have not formally performed the calculations, we doubt that most centers would find this to be a cost-effective strategy given such a low pretest probability of identifying a mutation. Ultimately, we believe that the most effective use of preoperative BRAF(V600E) screening is for patients who have worrisome thyroid nodules and are resistant to commit to a total thyroidectomy because of the 20% to 30% chance that the nodule is benign, meaning that they have unnecessarily committed to lifelong thyroid hormone replacement therapy. Selectively offering those patients preoperative BRAF(V600E) screening may result in preoperative confirmation of malignancy and thereby avoid a 2-stage procedure. Although the management of Bethesda category V nodules may differ between centers, the management of Bethesda III and IV nodules is less variable. Therefore, the main conclusion of our study that preoperative BRAF(V600E) should not routinely be performed on all patients with Bethesda category III and IV nodules due to the very low likelihood of identifying a mutation among this subgroup is likely to apply to most centers within the United States and abroad.

High-dose radioactive iodine therapy is associated with decreased risk of recurrence in high-risk papillary thyroid cancer

Objectives: We aimed to determine the effect of adjuvant radioactive iodine dose on recurrence rate in high‐risk papillary thyroid cancer. Methods: More than 1,500 patients treated for papillary thyroid cancer at high‐volume centers in France and the United States from 2004–2014 were reviewed. Patients considered at high risk for recurrence per the 2015 American Thyroid Association guidelines were analyzed and grouped by initial radioactive iodine dose: intermediate (median 100 mCi) or high dose (median 150 mCi). Propensity score matching was performed to control for baseline characteristics. Results: In a propensity‐matched cohort of 66 patient pairs, there were equivalent rates of gross extrathyroidal extension (71% vs 71%, P = 1.00), positive margins (55% vs 55%, P = 1.00), lymph node metastases ≥ 3 cm (9% vs 9%, P = 1.00), extranodal extension (32% vs 33%, P = .85), and distant metastases (2% vs 5%, P = .31). Over a median follow‐up of 4.5 years (interquartile ratio 2.0–7.5 years), the intermediate‐dose radioactive iodine group had a significantly higher rate of recurrence than patients in the high‐dose radioactive iodine group: 24 out of 66 (36%) vs 13 out of 66 (20%), P = .03. Conclusion: High‐dose radioactive iodine is associated with lower recurrence rate compared with intermediate‐dose radioactive iodine for patients with American Thyroid Association high‐risk papillary thyroid cancer.