Carmen C. Solorzano

Quick Intraoperative Parathyroid Hormone Assay: Surgical Adjunct to Allow Limited Parathyroidectomy, Improve Success Rate, and Predict Outcome

Intraoperative parathyroid hormone (PTH) assay (QPTH) has made possible less invasive operative approaches in the treatment of primary hyperparathyroidism with stated advantages. When compared to the traditional bilateral neck exploration (BNE), only the targeted, hypersecreting gland is excised, leaving in situ non-visualized but normally functioning parathyroids. The QPTH-guided limited parathyroidectomy (LPX) must be able to identify multiglandular disease (MGD), predict a successful outcome, and have a low recurrence rate. In our series, 421 patients who underwent LPX were compared to 340 undergoing BNE; all operative failures and patients followed for 6 months or longer were included. Operative failure occurred if serum calcium and PTH levels were elevated within 6 months of parathyroidectomy. Multiglandular disease was defined in the LPX group as more than one gland excision guided by QPTH or operative failure after removal of a single abnormal gland; in the BNE group it was defined as excision of more than one enlarged gland. Recurrence was defined as elevated calcium and PTH after 6 months of eucalcemia. Operative failure and MGD rates were compared using chi-squared analysis. The method of Kaplan-Meier and the log-rank test were used to compare recurrence rates. Operative success was seen in 97% of LPX patients and in 94% of the BNE group (p = 0.02). Multiglandular disease was identified in 3% of LPX patients and 10% of BNE patients (p < 0.001). There was no statistical difference in the overall recurrence rates (p = 0.23). The QPTH-guided parathyroidectomy identifies MGD and allows an improved success rate with the same low recurrence rate when compared to the results of BNE.

Effect of the vascular endothelial growth factor receptor-2 antibody DC101 plus gemcitabine on growth, metastasis and angiogenesis of human pancreatic cancer growing orthotopically in nude mice

Vascular endothelial growth factor (VEGF) is the major pro‐angiogenic factor for most tumors. VEGF expression has been shown to be associated with a poor prognosis in human pancreatic cancer. The purpose of our study was to determine the effect of blockade of VEGF receptor‐2 activity with or without gemcitabine on tumor growth and metastasis in an orthotopic model of human pancreatic cancer in nude mice. Therapy with gemcitabine or DC101, a VEGF receptor‐2 antibody, resulted in a significant reduction of primary pancreatic tumor growth compared to untreated controls. The combination of DC101 and gemcitabine inhibited primary pancreatic tumor growth and lymphatic metastasis to a greater degree than either agent alone. Treatment with DC101 decreased vessel counts and increased the area of hypoxic tumor tissue compared to controls. Immunofluorescent double staining for apoptotic endothelial cells demonstrated a significant increase in the number apoptotic endothelial cells 24 days after initiation of therapy with DC101 plus gemcitabine. DC101 plus gemcitabine also increased tumor cell death and decreased tumor cell proliferation in pancreatic tumors. These findings indicate that blockade of VEGF receptor activation interferes with the survival of tumor endothelial cells, resulting in a reduction of primary pancreatic tumor growth in nude mice. Furthermore, the data demonstrate that anti‐VEGF receptor‐2 therapy potentiates the tumoricidal effect of gemcitabine in this model. Anti‐VEGF receptor‐2 therapy in combination with gemcitabine may be a novel therapeutic approach for advanced pancreatic cancer.

Thyroid cancer: is the incidence still increasing?

Background: The objective of this study was to define the epidemiology of thyroid cancer in our regional population and compare results with Surveillance, Epidemiology, and End Results (SEER) Program cancer registry trends.Methods: Thyroid cancer cases diagnosed between 1990 and 2000 were identified in the Florida Cancer Data System (FCDS). Overall, gender-specific, age-specific, and stage-specific incidence rates were calculated. All rates are per 100,000 and age-adjusted to the 2000 U.S. standard population. Estimated Annual Percent Change (EAPC) was calculated with a linear least-squares model.Results: Patients with thyroid cancer (n = 8603) were identified in the FCDS registry. Age-adjusted incidence rates increased from 4.2 per 100,000 to 7 per 100,000 in 2000. The EAPC for this period was 5.5% (P < .001). The SEER incidence rates increased from 7.9 to 10.2 per 100,000, and the EAPC was 3.7% (P < .05). Analysis of gender-specific incidence rates showed increases from 6 and 2.2 per 100,000 in 1990 to 10.1 and 3.8 per 100,000 in 2000 among females and males, respectively, with EAPCs of 5.9% (females) and 4.5% (males) (P < .001). With stratification by age group, the highest incidence rates were 9 per 100,000 in the group aged 65 to 84 years and 8.4 per 100,000 in the group aged 45 to 64 years.Conclusions: Thyroid cancer incidence rates in Florida almost doubled over the 1990–2000 period and are concordant with SEER trends. Etiologic studies addressing temporal changes in reproductive factors, more intensive diagnostic activities, and changes in histological criteria are warranted.

Progress in the operative management of sporadic primary hyperparathyroidism over 34 years.

Background:Progress in the diagnosis, localization of abnormal parathyroids, and intraoperative management of primary hyperparathyroidism has been observed over the past 34 years. The goal of this study is to report the outcome of patients undergoing 2 different operative approaches in a single institution, showing the evolution of surgical management of sporadic primary hyperparathyroidism (SPHPT). Methods:Parathyroidectomy was performed in 890 (827 initial, 63 reoperative) patients with SPHPT using 2 different approaches: traditional bilateral neck exploration (BNE, n = 396) or limited parathyroidectomy guided by parathormone dynamics (LPX, n = 494). Seven hundred eighteen patients (335 BNE, 383 LPX) followed ≥ 6 months or identified as operative failures were studied. Operative failure is defined as hypercalcemia and high intact (1–84) parathyroid hormone molecule (iPTH) within 6 months after operation. Successful parathyroidectomy is normocalcemia for 6 months; hypercalcemia and elevated iPTH after this time is recurrent hyperparathyroidism. Results:There were 20 (6%) of 335 operative failures in the BNE group and 11 (3%) of 383 failures in the LPX group (P = 0.04). The incidence of multiglandular disease (MGD) determined by gland size (10%) versus hormone hypersecretion (3%) was statistically different (P < 0.001). Since most of the recurrences occurred later than 30 months, the incidence of recurrent hyperparathyroidism in patients followed for longer than 2.5 years was 4% (11/287) in the BNE group (average, 11.5 years) and 3% (5/183) in the LPX group (average, 4.2 years). Conclusion:LPX, with its reported advantages of minimal dissection, shorter operative time, and use in ambulatory settings, compares favorably with the traditional BNE. Parathyroidectomy guided by parathormone dynamics has an improved success rate and should be considered as a standard operative approach in SPHPT.

Inhibition of growth and metastasis of human pancreatic cancer growing in nude mice by PTK 787/ZK222584, an inhibitor of the vascular endothelial growth factor receptor tyrosine kinases.

Since vascular endothelial growth factor (VEGF) plays a major role in tumor angiogenesis, we determined whether blockage of VEGF receptor signaling using a novel tyrosine kinase inhibitor (PTK 787) decreases the growth and metastasis of human pancreatic carcinoma growing orthotopically in nude mice. Human pancreatic L3.6pl cells were injected into the pancreas of nude mice. Seven days later, groups of mice were given daily oral administrations of PTK 787 alone, twice weekly i.p. injections of gemcitabine, or combination therapy. The mice were necropsied when control mice became moribund (day 35). Therapy with PTK 787 alone, gemcitabine alone, or the combination of both agents produced respectively 60%, 70%, and 81% inhibition in the volume of pancreatic cancers. The combination therapy significantly decreased the incidence of lymph node and liver metastasis, leading to a significant increase in survival. Microvessel density (MVD) was significantly decreased in tumors treated with either PTK 787 alone or PTK 787 plus gemcitabine. MVD directly correlated with tumor cell proliferation and inversely correlated with apoptosis of tumor cells and associated endothelial cells. Collectively, our results demonstrate that blockade of VEGF-R signaling may provide an additional approach to the therapy of pancreatic cancer.

Long-term survival after surgical management of neuroendocrine hepatic metastases

BACKGROUND Surgical cytoreduction and endocrine blockade are important options for care for neuroendocrine liver metastases. We investigated the long-term survival of patients surgically treated for hepatic neuroendocrine metastases. METHODS Patients (n= 172) undergoing operations for neuroendocrine liver metastases from any primary were identified from a prospective liver database. Recorded data and medical record review were used to analyse the type of procedure, length of hospital stay, peri-operative morbidity, tumour recurrence, progression,and survival. RESULTS The median age was 56.8 years (range 11.5-80.7 years). 48.3% of patients were female. Median overall survival was 9.6 years (range 89 days to 22 years). On multivariate analysis, lung/thymic primaries were associated with worse survival [hazard ratio (HR): 15.6, confidence interval (CI): 4.3-56.8, P= 0.002]. Severe post-operative complications were also associated with worse long-term survival (P < 0.001). A positive resection margin status (R1) was not associated with a worse overall survival probability (P approximately 0.8). DISCUSSION Early and aggressive surgical management of hepatic metastases from neuroendocrine tumours is associated with significant long-term survival rates. Radiofrequency ablation is a reasonable option if a lesion is unresectable. R1 resections, unlike many other cancers, are not associated with a worse overall survival.

Treatment and outcome of patients with intracystic papillary carcinoma of the breast

BACKGROUND Intracystic papillary carcinoma (IPC) of the breast is a rare form of noninvasive breast cancer. An appreciation of associated pathology with IPC may be critical in surgical decision-making. METHODS The medical records of all patients with IPC treated between 1985 and 2001 were retrospectively reviewed. Three patient groups were identified according to the pathologic features of the primary tumor: IPC alone, IPC with associated ductal carcinoma in situ (DCIS), and IPC with associated invasion with or without DCIS. Types of treatment and outcomes were compared between groups. RESULTS Forty patients were treated for IPC during the study period. Fourteen had pure IPC, 13 had IPC with DCIS, and 13 had IPC with invasion. The incidence of recurrence and the likelihood of dying of IPC did not differ between the three groups regardless of the type of surgery (mastectomy or segmental mastectomy) performed and whether radiation therapy was administered. The disease-specific survival rate was 100%. CONCLUSIONS When IPC is identified, it is frequently associated with DCIS and or invasion. Standard therapy should be based on associated pathology. The role of radiation therapy in pure IPC remains to be determined.

The American Association of Endocrine Surgeons Guidelines for Definitive Management of Primary Hyperparathyroidism

Importance Primary hyperparathyroidism (pHPT) is a common clinical problem for which the only definitive management is surgery. Surgical management has evolved considerably during the last several decades. Objective To develop evidence-based guidelines to enhance the appropriate, safe, and effective practice of parathyroidectomy. Evidence Review A multidisciplinary panel used PubMed to review the medical literature from January 1, 1985, to July 1, 2015. Levels of evidence were determined using the American College of Physicians grading system, and recommendations were discussed until consensus. Findings Initial evaluation should include 25-hydroxyvitamin D measurement, 24-hour urine calcium measurement, dual-energy x-ray absorptiometry, and supplementation for vitamin D deficiency. Parathyroidectomy is indicated for all symptomatic patients, should be considered for most asymptomatic patients, and is more cost-effective than observation or pharmacologic therapy. Cervical ultrasonography or other high-resolution imaging is recommended for operative planning. Patients with nonlocalizing imaging remain surgical candidates. Preoperative parathyroid biopsy should be avoided. Surgeons who perform a high volume of operations have better outcomes. The possibility of multigland disease should be routinely considered. Both focused, image-guided surgery (minimally invasive parathyroidectomy) and bilateral exploration are appropriate operations that achieve high cure rates. For minimally invasive parathyroidectomy, intraoperative parathyroid hormone monitoring via a reliable protocol is recommended. Minimally invasive parathyroidectomy is not routinely recommended for known or suspected multigland disease. Ex vivo aspiration of resected parathyroid tissue may be used to confirm parathyroid tissue intraoperatively. Clinically relevant thyroid disease should be assessed preoperatively and managed during parathyroidectomy. Devascularized normal parathyroid tissue should be autotransplanted. Patients should be observed postoperatively for hematoma, evaluated for hypocalcemia and symptoms of hypocalcemia, and followed up to assess for cure defined as eucalcemia at more than 6 months. Calcium supplementation may be indicated postoperatively. Familial pHPT, reoperative parathyroidectomy, and parathyroid carcinoma are challenging entities that require special consideration and expertise. Conclusions and Relevance Evidence-based recommendations were created to assist clinicians in the optimal treatment of patients with pHPT.

A matrix metalloproteinase inhibitor prevents processing of tumor necrosis factor α (TNFα) and abrogates endotoxin-induced lethality

Excessive tumor necrosis factor α (TNFα) production in response to Gram-negative bacteremia or endotoxemia can often lead to hypotension, shock, and increased mortality. Current approaches used to block the deleterious effects of exaggerated TNFα production rely on monoclonal antibodies or immunoadhesins that bind TNFα and thus prevent the interaction with its cellular receptors. This report examines whether a previously described inhibitor of matrix metalloproteinases, GM-6001, can inhibit TNFα processing and release and attenuate endotoxin-induced mortality. In human peripheral blood mononuclear cells stimulated in vitro with 1 μg/mL endotoxin, GM-6001 at concentrations <5 μg/mL blocked release of TNFα, but did not affect the release of either IL-1β or IL-6. GM-6001 also inhibited the release of soluble TNF receptor (p75) from peripheral blood mononuclear cells stimulated with endotoxin and/or TNFα. To confirm the role of secreted TNFα in endotoxic shock-induced mortality, C57BL/6 mice were challenged with either endotoxin alone (500 μg/mouse) or endotoxin (100 ng/mouse) plus D-galactosamine (8 mg/mouse). GM-6001 pretreatment (100 mg/kg) significantly attenuated the 90-minute plasma TNFα response in both models and improved survival in mice treated with low-dose endotoxin plus D-galactosamine. However, plasma IL-1β and IL-6 concentrations at 90 min after endotoxin treatment were unaffected by GM-6001 following lethal endotoxin challenge, confirming the in vivo specificity of this matrix metalloproteinase inhibitor for TNFα processing. These findings demonstrate that a novel inhibitor of matrix metalloproteinases can prevent the release of TNFα both in vitro and in vivo, and can abrogate the harmful sequelae of endotoxemic shock.

Surgical management of primary hyperparathyroidism: state of the art.

This article reviews the current state of the art regarding therapy for primary hyperparathyroidism. Clinical evaluation and indications for parathyroidectomy are described, followed by a review of surgical techniques currently being practiced and possible outcomes involved. Focused parathyroidectomy has become a successful alternative to conventional bilateral cervical exploration.