A Rare Case of Synchronous Intraductal Papillary Mucinous Neoplasm-Associated Pancreatic Adenocarcinoma and Signet Ring Cell Gastric Adenocarcinoma.

BACKGROUND Synchronous malignancies are primary cancers that are diagnosed in a single individual within a 2-month period. Synchronous malignancies are uncommon, involving only 2.4-8% of all cancer cases, with a very low number of cases of simultaneous gastric and pancreatic cancer. Although cases of synchronous malignancies do exist, synchronous pancreatic adenocarcinoma and signet ring cell (SRC) gastric adenocarcinoma have not been documented. CASE REPORT A 76-year-old woman with a previously diagnosed intraductal papillary mucinous neoplasm (IPMN) presented with left-sided abdominal pain. Initial workup, including computed tomography imaging and endoscopic ultrasound with biopsy, led to the diagnosis of pancreatic adenocarcinoma. Within 1 month of diagnosis, the patient underwent an extended Whipple procedure and was also found to have a primary SRC gastric adenocarcinoma on evaluation of the gastric tissue margins that were removed during the procedure. The patient was initiated on chemoradiation therapy with 5-fluorouracil. However, following a subsequent decline in performance status and multiple hospitalizations, she could not tolerate further cancer treatment and died soon afterwards. CONCLUSIONS Few cases of synchronous malignancies involving the stomach and pancreas have been reported. Because gastric cancer could easily be missed on screening endoscopy; physicians must have a high index of suspicion. In those patients with a prior history of cancer, biopsies should be performed to aid in early diagnosis. To our knowledge, only metachronous cases of SRC gastric and pancreatic adenocarcinoma have been documented. Therefore, this report represents the first case of synchronous SRC gastric adenocarcinoma and IPMN-associated pancreatic adenocarcinoma in the literature.

To treat or not to treat: the role of adjuvant radioiodine therapy in thyroid cancer patients.

Radioactive iodine (RAI) is used in treatment of patients with differentiated papillary and follicular thyroid cancer. It is typically used after thyroidectomy, both as a means of imaging to detect residual thyroid tissue or metastatic disease, as well as a means of treatment by ablation if such tissue is found. In this paper, we discuss the indications for and the mechanisms of RAI in the treatment of patients with thyroid cancer. We discuss the attendant risks and benefits that come with its use, as well as techniques used to optimize its effectiveness as an imaging tool and a therapeutic modality.

Esophageal stenting in the setting of malignancy.

Esophageal cancer is often diagnosed at an advanced stage, with many patients found to have locoregional or metastatic disease at time of diagnosis. Because of this, cure may be unlikely, leading treatment efforts to focus more on symptom palliation and improving patient quality of life. The majority of patients with advanced disease suffer from some degree of dysphagia. Palliative efforts are therefore directed at relieving dysphagia, allowing patients to manage their oropharyngeal secretions, reduce aspiration risk, and maintain caloric intake orally. A variety of endoscopic treatment modalities have been utilized with these objectives in mind, with options determined by the location and size of the tumor, as well as the patient's expected prognosis. In this article, we review the use of endoscopically-placed stents for palliation in patients with advanced esophageal cancer. We discuss the history of stent use in such cases, as well as more recent developments in stent technology. We give an overview of some of the more commonly used stents in practice, discuss the technique of insertion, and survey the short- and long-term outcomes of stent placement.

Multidisciplinary approach to esophageal and gastric cancer.

The incidence of esophageal and gastric malignancies has increased over the last decade. Historically, surgery has been considered the best treatment for these cancers. However, long-term survival after surgery is fair at best, because of the tendency of disease to recur locally and distantly. Presently, the management of these cancers involves surgery, chemotherapy, and radiation therapy. This article discusses various treatment strategies that employ these modalities either alone or in combination, in an attempt to improve survival rates for patients who have gastroesophageal malignancies.

Ovarian normal and tumor-associated fibroblasts retain in vivo stromal characteristics in a 3-D matrix-dependent manner.

OBJECTIVE: Due to a lack of experimental systems, little is known about ovarian stroma. Here, we introduce an in vivo-like 3-D system of mesenchymal stromal progression during ovarian tumorigenesis to support the study of stroma permissiveness in human ovarian neoplasias. METHODS: To sort 3-D cultures into 'normal,' 'primed' and 'activated' stromagenic stages, 29 fibroblastic cell lines from 5 ovarian tumor samples (tumor ovarian fibroblasts, TOFs) and 14 cell lines from normal prophylactic oophorectomy samples (normal ovarian fibroblasts, NOFs) were harvested and characterized for their morphological, biochemical and 3-D culture features. RESULTS: Under 2-D conditions, cells displayed three distinct morphologies: spread, spindle, and intermediate. We found that spread and spindle cells have similar levels of alpha-SMA, a desmoplastic marker, and consistent ratios of pFAKY(397)/totalFAK. In 3-D intermediate cultures, alpha-SMA levels were virtually undetectable while pFAKY(397)/totalFAK ratios were low. In addition, we used confocal microscopy to assess in vivo-like extracellular matrix topography, nuclei morphology and alpha-SMA features in the 3-D cultures. We found that all NOFs presented 'normal' characteristics, while TOFs presented both 'primed' and 'activated' features. Moreover, immunohistochemistry analyses confirmed that the 3-D matrix-dependent characteristics are reminiscent of those observed in in vivo stromal counterparts. CONCLUSIONS: We conclude that primary human ovarian fibroblasts maintain in vivo-like (staged) stromal characteristics in a 3-D matrix-dependent manner. Therefore, our stromal 3-D system offers a tool that can enhance the understanding of both stromal progression and stroma-induced ovarian tumorigenesis. In the future, this system could also be used to develop ovarian stroma-targeted therapies.

Surgical treatment of metastatic disease to the lung.

The presence of distant metastases usually implies disease not amenable to cure through surgical resection. In such cases, chemotherapy is the mainstay of treatment, with surgery or radiation reserved for palliative measures. However, metastases limited to the lung may be resected with resultant prolonged patient survival compared to unresectable, widely disseminated metastases. Isolated pulmonary metastases should therefore not be considered untreatable. In this review, we discuss the pathophysiology of pulmonary metastases. We outline prognostic factors associated with metastases, and propose criteria to help select patients for metastasectomy. Surgical approaches, including various open techniques and video-assisted thoracoscopy, are covered. Surgical issues, including the need for unilateral versus bilateral exploration, the extent of resection to achieve cure, the need for lymph node dissection, and the benefit of repeat operations, are discussed. Finally, we review some of the more common tumors that metastasize to the lungs, and the role of metastasectomy in their treatment. Resection of pulmonary metastases confers a survival benefit to a select group of patients so long as the primary tumor is controlled, metastases are limited to the lungs, the patient can tolerate the operation from a cardiopulmonary standpoint, and the metastases are completely resected.

Neoadjuvant therapy in pancreatic cancer.

Pancreatic cancer is the fourth leading cause of cancer deaths in the United States. Surgical resection offers the only hope of cure, though the addition of chemoradiation in the adjuvant setting has been shown to improve survival over surgery alone. Many patients are unable to receive adjuvant therapy due to prolonged postoperative recovery. For this reason, administration of chemoradiation preoperatively (neoadjuvant) has been proposed as an alternative to postoperative treatment. In patients with resectable disease, neoadjuvant therapy results in similar survivals compared to postoperative therapy, with a greater proportion of patients able to complete treatment. For selected patients with borderline or unresectable disease, neoadjuvant therapy offers the potential for tumor downstaging and increasing the likelihood of a margin-negative resection. This article reviews the use of neoadjuvant therapy in the treatment of pancreatic cancer.

In vivo and in vitro degradation of heparan sulfate (HS) proteoglycans by HPR1 in pancreatic adenocarcinomas. Loss of cell surface HS suppresses fibroblast growth factor 2-mediated cell signaling and proliferation.

Heparan sulfate proteoglycans (HSPGs) function as a co-receptor for heparin-binding growth factors, such as fibroblast growth factors (FGFs) and heparin-bound epidermal growth factor (HB-EGF). The HS side chain of HSPGs can be cleaved by HPR1 (heparanase-1), an endoglycosidase that is overexpressed in many types of malignancies. In the present study, we demonstrated that HPR1 expression in pancreatic adenocarcinomas inversely correlated with the presence of heparan sulfate (HS) in the basement membrane. In vitro cell culture study revealed that cell surface HS levels inversely correlated with HPR1 activity in five pancreatic cancer cell lysates and their conditioned media. Heparin and PI-88, two HPR1 inhibitors, were able to increase cell surface HS levels in PANC-1 cells in a dose-dependent manner. The ability of HPR1 to degrade cell surface HS was confirmed by showing that cell surface HS levels were increased in HT1080 cells stably transfected with the HPR1 antisense gene but was decreased in the cells overexpressing HPR1. Further studies showed that PI-88 and heparin were able to stimulate PANC-1 cell proliferation in the absence or presence of exogenous FGF2, whereas exogenous HPR1 was able to inhibit PANC-1 cell proliferation in a dose-dependent manner. Modulation of PANC-1 cell proliferation by HPR1 or HPR1 inhibitors corresponded with the inhibition or activation of the mitogen-activated protein kinase. Our results suggest that HPR1 expressed in pancreatic adenocarcinomas can suppress the proliferation of pancreatic tumor cells in response to the growth factors that require HSPGs as their co-receptors.

Elevated serum heparanase-1 levels in patients with pancreatic carcinoma are associated with poor survival.

BACKGROUND: It has previously been shown that heparanase-1 (HPR1), an endoglycosidase, is up-regulated in pancreatic carcinoma. The purpose of this study was to test whether serum HPR1 levels in pancreatic carcinoma patients are elevated, and whether higher serum HPR1 levels are associated with a shortened survival. METHODS: Serum HPR1 levels in 40 healthy donors, 31 pancreatic carcinoma patients, and 11 patients treated with gemcitabine were measured by a novel enzyme-linked immunoadsorbent assay. HPR1 expression in tumors was analyzed by immunohistochemical staining. Patient overall survival time was determined according to the Kaplan-Meier method, and their difference was evaluated by the log-rank test. A P value<0.05 was considered statistically significant. RESULTS: The mean serum HPR1 activity in pancreatic carcinoma patients was 439+/-14 units/mL, compared with 190+/-4 units/mL in the control serum samples from healthy donors. Serum HPR1 levels were significantly higher in patients with HPR1-positive tumors (660+/-62 units/mL) compared with those with HPR1-negative tumors (241+/-14 units/mL). The mean survival of 19 pancreatic carcinoma patients with serum HPR1 activity>300 units/mL was 7.9+/-0.2 months, whereas the mean survival of 12 patients with serum HPR1 activity<300 units/mL was 13.3+/-0.6 months. A Kaplan-Meier plot of the patient survival curve followed by log-rank test revealed that patients in the high serum HPR1 group had a significantly shorter survival compared with those in the low serum HPR1 group. Mean serum HPR1 activity decreased by 64% in 11 pancreatic carcinoma patients after 2 weeks of treatment with gemcitabine. CONCLUSIONS: Serum HPR1 activity in pancreatic carcinoma patients was found to be significantly elevated, in particular in those with HPR1-positive tumors. Increased serum HPR1 activity was associated with a shorter survival in patients with pancreatic carcinoma patients.

Participants' opinions of laparoscopic training devices after a basic laparoscopic training course.

BACKGROUND: Basic laparoscopic skills are initially best taught and practiced in an inanimate setting. Various devices are used to aid in this education of laparoscopic skills. These devices range from simple box trainers to sophisticated virtual reality trainers. This investigation tested the hypothesis that participants would prefer one trainer to another trainer. METHODS: Preclinical medical students volunteered for this study. All underwent a porcine laboratory. The students were then divided into 3 groups by method of training: group A--a virtual reality trainer (MIST-VR), group B--an inanimate box trainer (LTS 2000), and group C--both trainers. Each group participated in 10 laboratories with the assigned trainer(s). After completion of the laboratories, all students underwent a similar porcine laboratory. During this laboratory, opinions of each trainer and specific tasks were ascertained from each student. RESULTS: No statistical difference was seen between groups A and B when asked if their specific trainer helped their skills, was realistic, helped in the animal laboratory, and was interesting. When group C was asked the same questions about each trainer, no statistical difference was seen except that 47% thought the MIST-VR was not realistic as opposed to 0% who thought the LTS 2000 was not realistic (P <.003). The level of difficulty of each task correlated with how much the specific task helped in development of skills for both trainers (P <.0001). In group C, 89% of the participants thought the LTS 2000 helped more that the MIST-VR and 56% thought the LTS 2000 was more interesting than the MIST-VR. In addition, 83% of students in group C chose LTS 2000 when asked to pick only one trainer. CONCLUSIONS: While virtual reality trainers may have some advantages, most participants feel that inanimate box trainers help more, are more interesting, and should be chosen over virtual reality trainers if only one trainer is allowed. Further studies need to investigate if the opinions affect participants' utilization of these trainers.

Evidence that one subset of anaplastic thyroid carcinomas are derived from papillary carcinomas due to BRAF and p53 mutations.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is the most lethal form of thyroid neoplasia and represents the end stage of thyroid tumor progression. In the current study, genetic alterations in a panel of ATC were profiled to determine the origins of ATC. METHODS: Eight ATC were analyzed for BRAF mutation at codon 599 by using mutant-allele-specific polymerase chain reaction (PCR) and DNA sequencing of the PCR-amplified exon 15. RAS mutation (HRAS, KRAS, and NRAS) at codons 12, 13, and 61 was analyzed by direct sequencing of PCR-amplified exons 1 and 2 of the RAS gene. RET/PTC rearrangements and p53 mutation were monitored by immunohistochemical (IHC) staining by anti-RET antibodies and an anti-p53 mAb, respectively. RESULTS: BRAF was mutated in 5 of the 8 ATCs tested. Histologic examination revealed that 4 of these 5 BRAF-mutated ATCs contained a PTC component, suggesting that they may be derived from BRAF-mutated PTC. Of the 3 ATCs with wild-type BRAF, 2 had spindle cell features; one had follicular neoplastic characteristics mixed with papillary structures. Analysis of RAS mutation revealed only an HRAS mutation at codon 11, due to the transversion of GCC to TCC in one ATC with wild-type BRAF. This leads to the substitution of valine to serine. IHC analysis of RET/PTC rearrangements revealed no positive staining of RET in any of 8 ATCs, suggesting that these ATCs are not derived from RET/PTC- rearranged PTC. In contrast, IHC analysis of p53 mutation revealed that p53 was detected in the nuclei of 5 of 5 BRAF-mutated ATCs and 2 of 3 ATCs with wild-type BRAF. p53 staining was present only in anaplastic thyroid tumor cells but not in neighboring papillary thyroid tumor cells. CONCLUSIONS: These results suggest that many ATCs with papillary components are derived from BRAF-mutated PTC, because of the addition of p53 mutation.

Intraoperative parathyroid hormone levels in thyroid surgery are predictive of postoperative hypoparathyroidism and need for vitamin D supplementation.

BACKGROUND: Intraoperative parathyroid hormone (ioPTH) levels are not monitored routinely in thyroid surgery, although they are used widely during parathyroidectomy as an indicator of parathyroid gland function. This prospective study evaluated the occurrence of hypoparathyroidism after thyroid surgery and the use of ioPTH levels to predict the need for postoperative vitamin D supplementation. METHODS: Seventy-two patients underwent thyroidectomy or neck dissection by 1 surgeon. Forty-five patients had a total thyroidectomy, 16 patients had a hemithyroidectomy, 9 patients had a completion thyroidectomy, and 2 patients had a neck dissection alone for recurrent thyroid cancer. ioPTH and serum calcium (SCa) levels were obtained during the course of surgery and 1 month after surgery. Levels from these time points were compared, and correlated with the need for vitamin D supplementation at the 1-month follow-up evaluation using the Fisher exact test. RESULTS: Of the 72 patients, 14 had an ioPTH level less than 10 pg/mL at closure. At the 1-month evaluation, 11 of these 14 patients required vitamin D supplementation because of persistent hypoparathyroidism or hypocalcemia (P <.001). The remaining 3 of the 14 patients with ioPTH levels less than 10 pg/mL at closure did not require vitamin D supplementation at the 1-month evaluation because they were asymptomatic and their PTH and SCa levels had normalized. None of the 58 patients with an ioPTH level greater than 10 pg/mL at closure needed vitamin D supplementation at the 1-month follow-up evaluation. CONCLUSIONS: An ioPTH level less than 10 pg/mL at closure is a strong predictor of hypoparathyroidism after thyroid surgery. Patients with ioPTH levels less than 10 pg/mL at closure should be placed on vitamin D supplementation after surgery to anticipate decreased parathyroid gland function and to avoid symptomatic hypocalcemia.

Do intraoperative total serum and ionized calcium levels, like intraoperative intact PTH levels, correlate with cure of hyperparathyroidism?

Intraoperative parathyroid hormone (ioPTH) monitoring is useful in the operative management of hyperparathyroidism. Measurement of intraoperative total serum calcium (TSC) and ionized calcium (ICa) levels may be less expensive and more readily available methods of intraoperative guidance during neck dissection than ioPTH levels, the gold standard. We compared the accuracy of monitoring intraoperative TSC and ICa to that of ioPTH for predicting surgical cure during parathyroidectomy. Over a 10-month period, 47 parathyroidectomies were performed, during which ioPTH, TSC, and ICa were measured. Samples were obtained at the start of the operation and 5 and 10 minutes after gland removal. Data were compared and trends analyzed with respect to removal of abnormal parathyroid tissue as confirmed by pathology. The Wilcoxon signed rank test was used to determine if decreases in TSC and ICa were significant. The mean baseline ioPTH level (253 +/- 247 pg/ml) dropped by 70% at 5 minutes after removal of the abnormal glands (68 +/- 85 pg/ml) and by 83% at 10 minutes (32 +/- 25 pg/ml). The mean baseline TSC level (10.1 +/- 0.9 mg/dl) dropped by 4% at 5 minutes after removal of the abnormal glands (9.7 +/- 0.8 mg/dl) and remained at 4% at 10 minutes (9.6 +/- 0.7 mg/dl). The mean baseline ICa level (1.4 +/- 0.1 mmol/dl) also dropped by 4% at 5 minutes after removal of the abnormal glands (1.3 +/- 0.1 mmol/dl) and remained at 4% at 10 minutes (1.3 +/- 0.1 mg/dl). ioPTH dropped by > or = 50% in 39 patients (83%) at 5 minutes and in 46 patients (98%) at 10 minutes after gland resection. TSC decreased below baseline at 5 minutes and remained below baseline at 10 minutes in only 37 patients (79%). In the remaining 21% of patients, TSC decreased inconsistently, if at all, with respect to baseline at both the 5- and 10-minute time points. ICa decreased below baseline at 5 minutes and remained below baseline at 10 minutes in only 35 patients (77%). In the remaining 23% of patients, ICa, like TSC, changed inconsistently at 5 and 10 minutes after parathyroidectomy with respect to baseline levels. Decreases in TSC and ICa during parathyroidectomy, if present, are thus minimal. Unlike ioPTH levels, TSC and ICa levels do not consistently decrease at 5 and 10 minutes after gland resection. Although inexpensive and readily available, monitoring the intraoperative TSC and ICa is not clinically reliable for confirming removal of hyperfunctioning parathyroid glands.

Excision of a mediastinal parathyroid gland with use of video-assisted thoracoscopy, intraoperative 99mTc-sestamibi scanning, and intraoperative monitoring of intact parathyroid hormone.

OBJECTIVE: To report the complementary use of video-assisted thoracoscopic surgery (VATS) and intraoperative 99mTc-sestamibi scanning for persistent secondary hyperparathyroidism due to a mediastinal supernumerary parathyroid gland. METHODS: We describe a patient with recurrent secondary hyperparathyroidism attributable to a mediastinal parathyroid gland who underwent parathyroidectomy with use of VATS, intraoperative 99mTc-sestamibi scanning (gamma probe), and intraoperative monitoring of intact parathyroid hormone (iPTH). RESULTS: A 32-year-old man with chronic renal failure who had undergone a 4-gland parathyroidectomy with autotransplantation 14 years previously presented with symptomatic hypercalcemia. A preoperative single-photon emission computed tomographic (SPECT) sestamibi scan revealed a focus of mediastinal uptake, suggestive of an intrathymic gland. The patient underwent a cervical exploration, and the previously reimplanted parathyroid gland and the thymus were resected. iPTH levels failed to normalize, and the operation was terminated. A repeated SPECT scan again revealed an area of mediastinal uptake. Computed tomographic scan of the chest showed a mediastinal gland adjacent to the aortic arch. VATS and intra-operative sestamibi scanning aided in localization of the ectopic parathyroid gland. After removal of the hyperplastic gland, iPTH levels decreased appropriately. CONCLUSION: In reoperative parathyroidectomy involving mediastinal glands, VATS, complemented by gamma probe localization and iPTH monitoring, may be used to minimize the operative dissection needed to cure hyperparathyroidism.

Anorectal anatomy and embryology.

The anal canal is complex in its anatomy and its embryologic origin. The intricate and changing histology of the anal canal explains the different types of anal cancer. In addition, an understanding of the venous and the lymphatic drainage of the anal canal helps to explain its methods of dissemination. Finally, the basis for the treatment of anal cancer is derived from the cancer's anatomic origins.

An algorithm to maximize use of minimally invasive parathyroidectomy.

HYPOTHESIS: Minimally invasive parathyroidectomy (MIP) depends on accurate preoperative localization of abnormal parathyroid glands. If the findings of a technetium Tc 99m sestamibi-labeled single-photon emission computed tomography (SPECT) (hereafter referred to as sestamibi SPECT or scan) are negative or ambiguous, cervical ultrasonography (CUS) may increase the success of preoperative gland localization and MIP, avoiding bilateral neck exploration. DESIGN: We collected data regarding preoperative sestamibi SPECT and CUS for parathyroid gland localization and intraoperative findings. SETTING: Tertiary care university hospital. PATIENTS: From August 1, 2000, through January 31, 2003, 71 patients (12 men and 59 women; mean age, 59 years) with primary hyperparathyroidism underwent preoperative sestamibi SPECT and CUS. Patients with prior or concurrent thyroid surgery, reoperative parathyroid disease, secondary/tertiary hyperparathyroidism, or studies performed at outside hospitals, were excluded. The MIP was performed by 1 surgeon with a 2- to 3-cm incision made on the side of the neck where the abnormal gland was preoperatively located. MAIN OUTCOME MEASUREMENTS: Operative findings were compared with results of preoperative studies to determine the accuracy of sestamibi SPECT and CUS for successful MIP. RESULTS: All 71 patients underwent preoperative sestamibi SPECT and CUS. Sestamibi scanning was accurate in 53 (75%) of 71 patients, whereas CUS was accurate in 40 (56%) in determining the side where the glands were located. Sestamibi scan and CUS findings were negative in 5 patients. These patients underwent planned bilateral neck exploration. Of the remaining 66 patients, MIP was successfully performed in 60 (91%). The CUS was complementary to sestamibi scanning in 9 (15%) of these 60 patients, allowing them to avoid bilateral neck exploration. CONCLUSIONS: A positive sestamibi scan finding is the only preoperative requirement for most patients with primary hyperparathyroidism for MIP. If the sestamibi scan findings are negative or ambiguous, preoperative CUS can localize an additional 14% of enlarged parathyroid glands, further facilitating an MIP in these patients.

Outcome of laparoscopic adrenalectomy for pheochromocytomas vs aldosteronomas.

HYPOTHESIS: Laparoscopic adrenalectomy (LA) is most commonly performed for pheochromocytomas (PHEs) and aldosteronomas (ALDs). We hypothesize that LA for these differing tumor types is associated with different operative courses and outcomes. DESIGN: Retrospective study of a 10-year experience with LA. SETTING: University teaching hospital. PATIENTS: Laparoscopic adrenalectomy was performed on 149 patients. During data analysis, the initial 35 LAs performed for various adrenal lesions were excluded to account for the learning curve. Twenty-six of 30 PHEs and 34 of 45 ALDs were included. MAIN OUTCOME MEASURES: Analysis of variance was used to compare operative time, tumor size, estimated blood loss, and postoperative length of hospital stay between the PHE and ALD groups and subsets of these groups. chi(2) Analysis was used to compare tumor location, transfusion requirements, conversion to open procedures, and incidence of major complications. RESULTS: Right-sided lesions occurred in 19 of 26 PHEs, and left-sided lesions occurred in 28 of 34 ALDs (P <.001). Mean +/- SD tumor size of PHEs (4.9 +/- 1.8 cm) was larger than that of ALDs (2.7 +/- 1.7 cm) (P <.001). Mean +/- SD operative time for PHEs vs ALDs was 191 +/- 49 vs 162 +/- 48 minutes (P =.02). Mean +/- SD estimated blood loss was greater for PHEs (276 +/- 298 mL) than for ALDs (196 +/- 324 mL) (P =.33). Subset analysis revealed that the mean +/- SD size of right-sided PHEs (5.3 +/- 1.8 cm) was significantly larger than that of right-sided ALDs (3.0 +/- 1.5 cm) (P=.001). Mean +/- SD operative time for right-sided PHEs (198 +/- 44 minutes) was longer than that for right-sided ALDs (145 +/- 37 minutes) (P=.005). Six PHE patients required blood transfusions vs 2 ALD patients (P =.05). Two LAs, 1 PHE and ALD, were converted to open procedures. Mean +/- SD length of hospital stay was longer for PHE patients vs ALD patients (4 +/- 4 vs 2 +/- 3 days; P =.08). Six PHE patients had complications vs 3 ALD patients (P =.13). CONCLUSIONS: For PHEs, LA was associated with the removal of more right-sided lesions, larger tumors, longer operative times, and more complications. Trends toward greater estimated blood losses and longer hospital stays were observed for PHEs vs ALDs. Despite the advanced skills of an experienced surgeon, LA for PHEs is associated with a more complex course than for ALDs. Surgeons should begin performing LA for ALD early in their experience to avoid the potential pitfalls associated with PHEs.

Inverse correlation between heparan sulfate composition and heparanase-1 gene expression in thyroid papillary carcinomas: a potential role in tumor metastasis.

PURPOSE: Heparanase-1 (HPR1) is an endoglycosidase that degrades the side chains of heparan sulfate proteoglycan (HSPG), a key component in cell surfaces, the extracellular matrix (ECM), and the basement membrane (BM). The purpose of this study was to evaluate HPR1 expression in thyroid neoplasms and its effect in degrading the HSPG substrates in the ECM and BM and to determine its role in thyroid tumor metastasis. EXPERIMENTAL DESIGN: HPR1 mRNA expression was analyzed by using in situ hybridization with a digoxigenin-labeled antisense RNA probe on paraffin-embedded tumor sections and reverse transcription-PCR (RT-PCR) in fresh tumor tissues. HPR1 protein expression was analyzed by using immunohistochemical staining with an anti-HPR1 rabbit antiserum and immunofluorescence (IF) with an anti-HPR1 monoclonal antibody. The effect of HPR1 expression in thyroid neoplasms was analyzed by examining the presence and integrity of the HSPG substrates in the ECM and BM using IF staining with a specific monoclonal antibody against heparan sulfate. The relationship of HPR1 expression in papillary thyroid carcinomas (PTCs) with various clinicopathological parameters was analyzed statistically. The role of HPR1 in thyroid tumor metastasis was further examined by comparing HPR1 levels in 10 thyroid tumor cell lines to their invasive and metastatic potential. RESULTS: In situ hybridization analysis of 81 tumor samples (62 papillary carcinomas and 19 follicular adenomas) revealed that HPR1 was expressed at a much higher frequency in PTCs than in follicular adenomas (P<0.05). RT-PCR analyses of fresh tumor tissues revealed that HPR1 mRNA could be detected in primary and metastatic thyroid papillary carcinomas. HPR1 expression was confirmed at the protein level by immunohistochemical staining and IF stainings. IF analysis of HSPG revealed that HS was deposited abundantly in the BM of normal thyroid follicles and benign follicular adenomas but was absent in most thyroid papillary carcinomas. A lack of heparan sulfate in PTCs inversely correlated with HPR1 expression. Clinicopathological data analyses revealed that PTCs with local and distant metastases scored HPR1 positive at a significantly higher frequency than nonmetastatic thyroid cancers (P=0.02). To further explore the role of HPR1 in tumor metastases, we characterized HPR1 expression in 10 thyroid tumor cell lines using RT-PCR and Western blot and measured HPR1 enzymatic activity using a novel ELISA. HPR1 was differentially expressed in different types of cell lines; overexpression of HPR1 in two tumor cell lines led to a dramatic increase of their invasive potential in vitro in an artificial BM. CONCLUSIONS: Our study suggests that HPR1 expressed in papillary carcinomas is functional and that HPR1 expression is associated with thyroid tumor malignancy and may significantly contribute to thyroid tumor metastases.