Roderick M. Quiros

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.

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.

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 ≥ 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.

Intraoperative total serum calcium levels, unlike intraoperative intact PTH levels, do not correlate with cure of hyperparathyroidism.

BACKGROUND Intraoperative intact parathyroid hormone (iPTH) monitoring is useful in the operative management of hyperparathyroidism. Recent studies suggest that measurement of intraoperative total serum calcium (TSC) levels may be a more cost effective and readily available method of intraoperative guidance during neck dissection than iPTH levels, the gold standard. We compared the accuracy of intraoperative TSC to iPTH in predicting surgical cure during parathyroidectomy. PATIENTS AND METHODS From September 1, 2001 to October 31, 2002, 88 parathyroidectomies were performed. iPTH and TSC were measured at the start of the operation, and at 5 and 10 min after gland removal. Data were compared, and trends were analyzed with respect to removal of abnormal parathyroid tissue as confirmed by pathology. One-way analysis of variance was used to determine if decreases in TSC were significant. RESULTS The mean baseline iPTH level (418 +/- 610 pg/ml) dropped by 70% 5 min after removal of the abnormal glands (86 +/- 102 pg/ml) and by 85% at 10 min (39 +/- 39 pg/ml). The mean baseline TSC level (10.0 +/- 0.8 mg/dl) dropped by 4% at 5 min after removal of the abnormal glands (9.6 +/- 0.9 mg/dl) and remained at 4% at 10 min (9.6 +/- 0.8 mg/dl). iPTH dropped by > or =50% in 73 patients (83%) at 5 min and in 87 patients (99%) at 10 min after gland resection. TSC decreased below baseline at 5 min and remained below baseline at 10 min in only 47 patients (54%). In the remaining patients, intraoperative TSC changes were less predictable and did not respond consistently to resection of abnormal glands. CONCLUSIONS The decreases in TSC during parathyroidectomy, if present, are minimal. Unlike iPTH levels, TSC levels do not consistently decrease at 5 and 10 min after gland resection. While attractive in terms of cost and availability, intraoperative TSC levels are not clinically reliable in confirming removal of abnormal parathyroid tissue.