Antonia E. Stephen

Accuracy of 4-dimensional computed tomography in poorly localized patients with primary hyperparathyroidism

BACKGROUND Four-dimensional computed tomography (4D-CT) utilizes multiplanar images and perfusion characteristics to identify abnormal parathyroid glands. We assessed the role of 4D-CT in patients with inconclusive preoperative ultrasound and sestamibi localization studies. METHODS Adult patients with primary hyperparathyroidism with negative or discordant standard imaging who underwent both localization with 4D-CT and operative intervention for curative intent were included. Patient characteristics, 4D-CT scan results compared with operative findings, and curative proportion were assessed. RESULTS Of the 60 patients, 4D-CT accurately lateralized 73% and localized 60% of abnormal glands found at operation. Single candidate lesions (46/60) were confirmed at operation in 70%. When multiple lesions were identified on 4D-CT (14/60), accuracy dropped to 29% (P = .03). The accuracy of 4D-CT was not different between primary and reoperative cases (P = .79). Of the 8 patients with multigland disease diagnosed perioperatively, 5 had multiple candidate lesions noted on 4D-CT. In 94% (48/51) of patients, a >50% drop in intraoperative parathormone (IOPTH) level was achieved after resection and 87% (48/55) had long-term cure with a median follow-up of 221 days. CONCLUSION 4D-CT identifies the more than half of abnormal parathyroids missed by traditional imaging and should be considered in cases with negative or discordant sestamibi and ultrasound. Bilateral exploration is warranted when multiple candidate lesions are reported on 4D-CT. Multigland disease remains a challenging entity.

Mullerian-inhibiting substance regulates NF–κB signaling in the prostate in vitro and in vivo

Mullerian-inhibiting substance (MIS) is a member of the transforming growth factor β superfamily, a class of molecules that regulates growth, differentiation, and apoptosis in many cells. MIS type II receptor in the Mullerian duct is temporally and spatially regulated during development and becomes restricted to the most caudal ends that fuse to form the prostatic utricle. In this article, we have demonstrated MIS type II receptor expression in the normal prostate, human prostate cancer cell lines, and tissue derived from patients with prostate adenocarcinomas. MIS induced NF–κB DNA binding activity and selectively up-regulated the immediate early gene IEX-1S in both androgen-dependent and independent human prostate cancer cells in vitro. Dominant negative IκBα expression ablated both MIS-induced increase of IEX-1S mRNA and inhibition of growth, indicating that activation of NF–κB signaling was required for these processes. Androgen also induced NF–κB DNA binding activity in prostate cancer cells but without induction of IEX-1S mRNA, suggesting that MIS-mediated increase in IEX-1S was independent of androgen-mediated signaling. Administration of MIS to male mice induced IEX-1S mRNA in the prostate in vivo, suggesting that MIS may function as an endogenous hormonal regulator of NF–κB signaling and growth in the prostate gland.

Clinical and Cytological Features Predictive of Malignancy in Thyroid Follicular Neoplasms

BACKGROUND The preoperative diagnosis of malignancy in nodules suspicious for a follicular neoplasm remains challenging. A number of clinical and cytological parameters have been previously studied; however, none have significantly impacted clinical practice. The aim of this study was to determine predictive characteristics of follicular neoplasms useful for clinical application. METHODS Four clinical (age, sex, nodule size, solitary nodule) and 17 cytological variables were retrospectively reviewed for 144 patients with a nodule suspicious for follicular neoplasm, diagnosed preoperatively by fine-needle aspiration (FNA), from a single institution over a 2-year period (January 2006 to December 2007). The FNAs were examined by a single, blinded pathologist and compared with final surgical pathology. Significance of clinical and cytological variables was determined by univariate analysis and backward stepwise logistic regression. Odds ratios (ORs) for malignancy, a receiver operating characteristic curve, and predicted probabilities of combined features were determined. RESULTS There was an 11% incidence of malignancy (16/144). On univariate analysis, nodule size >OR=4.0 cm nears significance (p = 0.054) and 9 of 17 cytological features examined were significantly associated with malignancy. Three variables stay in the final model after performing backward stepwise selection in logistic regression: nodule size (OR = 0.25, p = 0.05), presence of a transgressing vessel (OR = 23, p < 0.0001), and nuclear grooves (OR = 4.3, p = 0.03). The predicted probability of malignancy was 88.4% with the presence of all three variables on preoperative FNA. When the two papillary carcinomas were excluded from the analysis, the presence of nuclear grooves was no longer significant, and anisokaryosis (OR = 12.74, p = 0.005) and presence of nucleolus (OR = 0.11, p = 0.04) were significantly associated with malignancy. Excluding the two papillary thyroid carcinomas, a nodule size >or=4 cm, with a transgressing vessel and anisokaryosis and lacking a nucleolus, has a predicted probability of malignancy of 96.5%. CONCLUSIONS A combination of larger nodule size, transgressing vessels, and specific nuclear features are predictive of malignancy in patients with follicular neoplasms. These findings enhance our current limited predictive armamentarium and can be used to guide surgical decision making. Further study may result in the inclusion of these variables to the systematic evaluation of follicular neoplasms.

The management of thyroid carcinoma invading the larynx or trachea.

To describe the controversies in the management of thyroid carcinoma invading the airway.

Tissue-engineered neomucosa: morphology, enterocyte dynamics, and SGLT1 expression topography.

Background. The standard therapy for short bowel syndrome is total parenteral nutrition, which is expensive and associated with significant morbidity and mortality. New therapeutic approaches for this disorder are needed. We have applied the techniques of tissue engineering to develop a prototype neointestine. We hypothesized that anastomosis of this neointestine to the native bowel would result in regeneration of mucosal morphology and enterocyte dynamics. Methods. Biodegradable polymers seeded with neonatal rat intestinal organoid units were implanted into the omenta of adult rats to form neointestinal cysts. Five weeks after implantation, side-to-side cyst-jejunal anastomoses were fashioned in one cohort of rats. Tissues were harvested from all rats at 5 months after implantation. Native jejunal (J) and non-anastomosed (N-N) and anastomosed (A-N) neointestinal tissues were assessed for morphology, epithelial cell proliferation (5-bromo-2-deoxyuridine immunohistochemistry), apoptotic rates (terminal deoxynucleotide transferase-mediated dUTP nick-end labeling assay), and SGLT1 in situ hybridization. Results. Mucosal morphology, rates and topography of enterocyte proliferation, and transporter expression in A-N neointestine recapitulated those of native jejunum. Each of these features was rudimentary in N-N neointestine. Conclusions. These results suggest that the tissue-engineered neomucosa can develop structural and dynamic features of the normal jejunum. Anastomosis to the native intestine is an essential step for neomucosal development. Tissue engineering offers promise as a novel approach to the treatment of patients suffering from short bowel syndrome.

Thyroid surgery in octogenarians is associated with higher complication rates

BACKGROUND The incidence of thyroid nodules increases with age and little information is available regarding the risks of thyroid surgery in elderly patients. The aim of this study was to determine whether thyroid surgery in patients > or =80 is associated with higher complication rates. METHODS Out of 3,568 patients undergoing thyroid surgery between July 2001 and October 2007 at a single institution, the records of 90 consecutive patients > or =80 years were reviewed retrospectively and compared with a cohort of 242 randomly selected patients aged 18-79, who underwent thyroid surgery during the same time period. Clinical variables included age, gender, pre-operative diagnosis, substernal component, previous surgery, final pathology, length of stay, comorbidities, American Society of Anesthesiologists (ASA) score, body mass index, postoperative complications, and mortality. RESULTS Preoperative indications for surgery included benign disease in 51% vs 39%, suspected malignancy in 19% vs 26%, and suspected follicular neoplasms in 30% vs 35% in the octogenarian patient group (> or =80 years old) vs the younger patient cohort (P = NS). Octogenarians had 20% significant malignancy on final pathology vs 27% in the younger cohort (P = NS). The overall complication rate in the octogenarian group was 24% vs 9% in the younger cohort (P < .001). Male gender and ASA > or =3 were found to be independent risk factors for perioperative complications after thyroid surgery, while age alone was not. CONCLUSION Age > or =80 is associated with higher morbidity after thyroid surgery, although not independently. Earlier operative intervention may be advised in those at high risk for disease progression, whereas follow-up strategies without operation may be advised for others.

Tissue-engineered cells producing complex recombinant proteins inhibit ovarian cancer in vivo

Techniques of tissue engineering and cell and molecular biology were used to create a biodegradable scaffold for transfected cells to produce complex proteins. Mullerian Inhibiting Substance (MIS) causes regression of Mullerian ducts in the mammalian embryo. MIS also causes regression in vitro of ovarian tumor cell lines and primary cells from ovarian carcinomas, which derive from Mullerian structures. In a strategy to circumvent the complicated purification protocols for MIS, Chinese hamster ovary cells transfected with the human MIS gene were seeded onto biodegradable polymers of polyglycolic acid fibers and secretion of MIS confirmed. The polymer-cell graft was implanted into the right ovarian pedicle of severe combined immunodeficient mice. Serum MIS in the mice rose to supraphysiologic levels over time. One week after implantation of the polymer-cell graft, IGROV-1 human tumors were implanted under the renal capsule of the left kidney. Growth of the IGROV-1 tumors was significantly inhibited in the animals with a polymer-cell graft of MIS-producing cells, compared with controls. This novel MIS delivery system could have broader applications for other inhibitory agents not amenable to efficient purification and provides in vivo evidence for a role of MIS in the treatment of ovarian cancer.

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 Hashimotos 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.

Diagnosis and management of pheochromocytoma

Tumors that that secrete excessive levels of catecholamines, commonly termed “pheochromocytomas,” can arise from the adrenal gland (pheochromocytomas [PCCs]) or from the sympathetic ganglia (paragangliomas [PGLs] or extra-adrenal PCCs). The adrenal glands, also known as the suprarenal glands, are located in the retroperitoneum, superomedial to the kidneys and high up under the costal margin adjacent to the diaphragm. Histologically, the adrenal glands consist of an outer cortex and inner medulla and secrete hormones essential for normal human physiologic function. Each of the adrenal glands, in their normal size and configuration, measure approximately 3-5 cm in length, 4-6 mm in thickness, and weigh approximately 4-5 g. They are closely approximated to the superomedial aspect of the kidneys and are surrounded by a fibrous capsule of connective tissue (Gerota fascia of the kidney) outside of which is loose connective tissue and abundant perinephric and retroperitoneal fat. The adrenal glands are clearly distinguished from the surrounding fat by their bright yellow color and more nodular and fibrous consistency. The bright yellow color is the adrenal cortical tissue. The inner medulla, only apparent with adrenal sectioning after removal, is gray-brown in color. Despite the distinct color and appearance of the adrenal cortex, the retroperitoneal location and covering of fat and connective tissue can obscure the gland. A significant amount of dissection in the retroperitoneal and perirenal fat is often required to locate the adrenal glands during surgery. The adrenal glands are composed of 2 discrete and separate anatomical, embryologic, and functional regions: the adrenal cortex and the adrenal medulla. The outer layer, or the adrenal cortex, arises from the mesoderm during embryologic development and accounts for the majority of the gland substance. The cortex has 3 separate layers or zones, and each secretes a different set of hormones. The outermost layer is the zona glomerulosa and secretes the mineralocorticoid known as aldosterone. The primary function of aldosterone is to increase renal sodium reabsorption and potassium excretion. Tumors from this adrenal cortical layer that overproduce aldosterone cause a clinical syndrome termed “Conn syndrome,” and patients frequently present with hypertension and hypokalemia. The middle layer and inner regions of the cortex, the zona fasciculata and the zona reticularis, secrete glucocorticoids (cortisol) and androgens, respectively. Hormonally active tumors from these regions can cause Cushing syndrome (excess cortisol) or a virilizing syndrome (excess androgens). The innermost region of the adrenal gland is the medulla, which is derived from the same neural crest cells that comprise the sympathetic ganglia. The adrenal medulla is innervated by preganglionic fibers of the

Preoperative basal calcitonin and tumor stage correlate with postoperative calcitonin normalization in patients undergoing initial surgical management of medullary thyroid carcinoma

BACKGROUND The optimal initial operative management of medullary thyroid cancer (MTC) and the use of biomarkers to guide the extent of operation remain controversial. We hypothesized that preoperative serum levels of calcitonin and carcinoembryonic antigen (CEA) correlate with extent of disease and postoperative levels reflect the extent of operation performed. METHODS We assessed retrospectively clinical and pathologic factors among patients with MTC undergoing at least total thyroidectomy; these factors were correlated with biomarkers using regression analyses. RESULTS Data were obtained from 104 patients, 28% with hereditary MTC. Preoperative calcitonin correlated with tumor size (P < .001) and postoperative serum calcitonin levels (P = .01) after multivariable adjustment for lymph node positivity, extent of operation, and hereditary MTC. No patient with a preoperative calcitonin level of <53 pg/mL (n = 20) had lymph node metastases. TNM stage (P = .001) and preoperative calcitonin levels (P = .04), but not extent of operation, independently correlated with the failure to normalize postoperative calcitonin. Postoperative CEA correlated with positive margins (adjusted P = 04). Neither preoperative nor postoperative CEA was correlated with lymph node positivity or extent of surgery. CONCLUSION Preoperative serum calcitonin and TMN stage, but not extent of operation, were independent predictors of postoperative normalization of serum calcitonin levels. Future studies should evaluate preoperative serum calcitonin levels as a determinate of the extent of initial operation.