Biomedical subjects
Publications and source records attributed to Rebecca S Sippel.
Carcinoid tumors can present a difficult diagnostic and therapeutic dilemma. Despite their reputation as indolent tumors, they frequently metastasize and can cause significant symptomatology. The only curative therapy remains surgical resection. The prognosis and treatment of carcinoids vary based on location and histology, and therapy must be tailored to each patient.
BACKGROUND: Carcinoid heart disease occurs in over 65% of patients with the carcinoid syndrome and is characterized by fibrous thickening of cardiac valves, leading to heart failure. Whether serotonin is directly responsible for these cardiac abnormalities is unknown. Therefore, to further understand the etiology and pathophysiology of carcinoid heart disease, we developed an animal model of the carcinoid syndrome. MATERIALS AND METHODS: Seventeen nude mice underwent intrasplenic injection of human pancreatic carcinoid BON cells (10(7)) and then were euthanized 9 weeks later. Murine livers were analyzed by immunohistochemistry. Murine hearts were sectioned and the surface area of the right heart valves determined. Blood was also collected and analyzed for platelet serotonin by ELISA. RESULTS: Sixty-five percent of the mice developed gross carcinoid liver metastases demonstrated by chromogranin-A-staining lesions within the liver. Mice with carcinoid liver metastases had elevated platelet serotonin levels (1058 +/- 529 ng/ml versus 123 +/- 52 ng/ml, P = 0.002) when compared to the controls. Animals with carcinoid liver metastases also had a trend toward greater tricuspid valvular surface areas (242 +/- 24 versus 174 +/- 25 microm, P = 0.08). On histological examination, this increase in tricuspid surface area in mice with liver metastases appeared to be due to fibrosis of the valvular tissues, consistent with the pathologic findings of carcinoid heart disease. CONCLUSIONS: Using this novel animal model of carcinoid syndrome, the tricuspid valve thickening resembling carcinoid heart disease could be due to exposure to factors such as serotonin secreted by carcinoid tumor cells.
Gastrointestinal (GI) carcinoids are neuroendocrine tumors originating in multiple locations throughout the GI tract. The prognosis for patients with GI carcinoid tumors is diverse. To determine the factors that significantly affect prognosis, we reviewed our experience. Between 1992 and 2000 a total of 70 patients with GI carcinoid tumors underwent surgical resection at our institution. The patients were grouped into three categories based on the origin of the carcinoid tumor: foregut, midgut, hindgut. The mean age of the patients was 56 +/- 2 years. All patients with foregut carcinoids had symptoms upon presentation, whereas 61% of those with midgut carcinoids and only 37% of those with hindgut carcinoids had symptoms ( p < 0.001). The factors that most strongly affected survival on univariate analysis were a symptomatic presentation and the site of origin. Patients with foregut or midgut lesions had lower 5-year disease-free survivals than those with hindgut tumors. Moreover, the size of the primary tumor and the presence of liver metastases were not independent predictors of survival. Despite the larger tumor size and the higher incidence of liver metastases, patients with foregut carcinoids appear to have the same prognosis as those with midgut carcinoids. These data therefore suggest that the outcomes of patients with carcinoid tumors are highly dependent on the presence of symptoms and the site of origin.
Up to 20% of patients with adrenal incidentalomas have abnormal cortisol production, and can be classified as having subclinical Cushing's syndrome. Although these tumors do not secrete enough cortisol to lead to the development of overt Cushing's syndrome, they are likely playing a contributory role in the development of hypertension, diabetes, osteoporosis, and obesity. Studies suggest that many of these problems can be reversed with surgical treatment. Additionally, if this diagnosis is not sought out before pursuing an adrenalectomy for an incidentaloma, the patient can develop profound postoperative adrenal insufficiency.
BACKGROUND: Intravenous propofol (2,6-diisopropylphenol) infusion is used commonly for sedation/anesthesia during operations. Several authors have reported that propofol can interfere with intact parathyroid hormone (PTH) testing in vitro. Therefore, many surgeons avoid propofol during parathyroidectomy. METHODS: To determine whether propofol affects intraoperative PTH levels in vivo, we randomly assigned 34 patients (80% power; alpha < .05) with secondary hyperparathyroidism to undergo surgery for dialysis access. Patients were assigned randomly to local anesthesia with either propofol (n = 17 patients) or midazolam (n = 17 patients) sedation. PTH values were obtained before the procedure and at 10 minutes and 30 minutes after the start of the propofol or midazolam. RESULTS: Median preoperative serum PTH and calcium levels were 175 pg/mL (range, 27-2646 pg/mL) and 9.2 mg/dL (range, 8.1-10.8 mg/dL), respectively. There was no statistically significant difference between the PTH levels in the 2 groups at each of our time points. There was also no difference in the percentage of change from baseline in the PTH values between our 2 groups. No patient in either group had a sustained drop in their PTH level of greater than 50%. CONCLUSIONS: Intravenous propofol infusion does not alter PTH levels significantly during the operation. Therefore, we believe the intraoperative PTH assay can be used safely during propofol sedation when parathyroid surgical procedures are being performed.
PURPOSE: Preoperative Tc-99m sestamibi scanning can identify candidates for minimally invasive parathyroid surgery. However, a significant number of patients with single gland disease have negative scans and are not considered for the minimally invasive procedure. MATERIALS AND METHODS: To determine if T1-201/Tc-99m sodium pertechnetate subtraction scanning (TPSS) is a viable alternative imaging technique for patients with primary hyperparathyroidism (1 degrees HPTH), we reviewed our experience. The outcomes of 100 consecutive patients with 1 degrees HPTH who underwent preoperative TPSS and parathyroid exploration between 1995 and 2000 at our institution were retrospectively reviewed. RESULTS: The mean preoperative calcium and parathyroid hormone levels were 10.8 mg/dL and 220 pg/mL, respectively. The overall cure rate was 96%. Single gland disease was present in 88%. Of the 100 patients studied, 15 underwent both a Tc-99m sestamibi scan and TPSS, whereas the other 85 had only the TPSS. CONCLUSIONS: The sensitivity and positive predictive value of the TPSS were 73.3% and 90.4%, respectively. In the patients undergoing both TPSS and Tc-99m sestamibi scans, the results concurred in 60%. However, in 20% of the remaining patients, TPSS correctly localized the abnormal parathyroid(s) when Tc-99m sestamibi failed. TPSS has a comparable sensitivity and positive predictive value to Tc-99m sestamibi scanning. In patients with a negative Tc-99m sestamibi scan, TPSS can provide additional localizing information. As a result of the high positive predictive value of TPSS, a single parathyroid gland localized by TPSS alone can then be approached by minimally invasive parathyroidectomy.
BACKGROUND: Human achaete-scute homolog-1 (hASH1) is a transcription factor that is expressed highly in neuroendocrine tumors such as medullary thyroid cancer (MTC). Thyroid C-cells do not develop in hASH1 knockout mice, which suggests that hASH1 is essential for normal C-cell development. METHODS: To determine the effect of raf-1 induction on hASH1 and hormone production, we used an estrogen inducible raf-1 construct in MTC cell line (TT) cells (TT-raf cells). TT or TT-raf cells were treated with control or 1 microM estradiol. After 48 hours, the cells were analyzed for levels of hASH1 and chromogranin A by Western blotting and for calcitonin production by enzyme-linked immunosorbent assay. RESULTS: Activation of raf-1 in the TT-raf cells resulted in high levels of phosphorylated MEK and ERK1/2, a morphologic transdifferentiation, and a decrease in chromogranin A and calcitonin levels that are associated with a reduction in hASH1 production. Furthermore, using MEK inhibitors, we demonstrated that these raf-1-mediated changes are dependent on MEK but not ERK1/2 activation. CONCLUSION: hASH1 down-regulation by raf-1 in MTC cells is associated with a significant decrease in hormone production. Thus, hASH1 appears to be important in the endocrine phenotype of MTC tumors and may serve as a molecular target for the treatment of patients with MTC.
Gastrointestinal carcinoid cells secrete multiple neuroendocrine markers and hormones including 5-HT and chromogranin A. The intracellular signaling pathways that regulate production of bioactive molecules are not completely understood. Our aim was to determine whether activation of the raf-1/MEK/MAPK signal transduction pathway in carcinoid cells could modulate production of neuroendocrine markers and hormones. Human pancreatic carcinoid cells (BON) were stably transduced with an estrogen-inducible raf-1 construct creating BON-raf cells. Activation of raf-1 in BON-raf cells led to a marked induction of phosphorylated MEK and ERK1/2 within 48 h. Importantly, raf-1 activation resulted in morphological changes accompanied by a marked decrease in neuroendocrine secretory granules by electronmicroscopy. Moreover, induction of raf-1 in BON-raf cells led to significant reductions in 5-HT, chromogranin A, and synaptophysin levels. Furthermore, treatment of BON-raf cells with MEK inhibitors PD-98059 and U-0126 blocked raf-1-mediated morphological changes and hormone suppression but not ERK1/2 phosphorylation. These results show that raf-1 induction suppresses neuroendocrine marker and hormone production in human gastrointestinal carcinoid cells via a pathway dependent on MEK activation.
One of the surgical options for symptomatic secondary hyperparathyroidism is a total parathyroidectomy with forearm implantation. Recurrence can occur and is most likely caused by hyperplasia of the small fragments of parathyroid tissue implanted in the forearm muscle. Forearm graft hyperplasia can be detected using Tc-99m sestamibi scanning of the forearm, which can show abnormal enhancement at the former graft site. In this report, we present the case of a 49-year-old gentleman with recurrent hyperparathyroidism caused by hyperplasia of forearm graft fragments. Unfortunately, no sutures or clips were placed at his initial surgery to identify the location of the parathyroid tissue in the forearm. Thus, we describe the first reported use of radioguided techniques using Tc-99m sestamibi injection and intraoperative gamma probe to localize parathyroid fragments in the forearm muscle. During our initial exploration, we found that injection of the tracer in the operative arm leads to prohibitively high levels of background activity. During a second exploration, the tracer was injected in the lower extremity, minimizing the background in the forearm and allowing the gamma probe to clearly identify two areas of abnormal parathyroid tissue. The intraoperative radioprobe allowed quick identification and removal of the abnormal parathyroid tissue in a case that was made particularly challenging by the absence of marking sutures.
BACKGROUND: Current treatment of malignant lymphoma of the thyroid consists of chemotherapy and external beam radiation. The diagnosis can routinely be made by fine-needle aspiration, obviating the need for surgery. However, a significant number of patients present with symptoms of obstruction, necessitating thyroidectomy for palliation. METHODS: To determine the outcomes of patients with malignant thyroid lymphoma after palliative thyroidectomy, we reviewed our experience. Between 1980 and 2001, 27 patients with thyroid lymphoma and symptoms or signs of airway and/or esophageal obstruction were evaluated at 1 of 3 academic institutions. RESULTS: The mean age of the patients was 66 +/- 3 years, and the majority was female. Patients presented with symptoms of dyspnea/stridor (30%), dysphagia/pain (30%), or impending airway obstruction (40%). All underwent palliative surgery. In addition to surgery, 10 patients had combined chemo- and radiotherapy, 10 had radiotherapy alone, and 4 had only chemotherapy. Symptom-free survival after palliative surgery was determined by Kaplan-Meier analysis. The mean actuarial symptom-free survival of patients with symptomatic, malignant thyroid lymphoma was 10 years (95% confidence interval, 7.67 to 12.33 years). CONCLUSIONS: Patients with malignant lymphoma of the thyroid can present with obstructive symptoms requiring palliative intervention. In this group of patients, thyroidectomy can be associated with good long-term palliation and low morbidity.
BACKGROUND: Recent studies of neuroendocrine tumor cell lines suggest that ras/raf-1 activation could be detrimental to tumorigenesis. The mechanism by which it alters neuroendocrine tumor cells is unclear. We hypothesize that activation of the ras/raf signal transduction pathway may alter gastrointestinal carcinoid cells by inducing morphologic transdifferentiation. METHODS: Pancreatic carcinoid (BON) cells were transduced in a stable manner with an estrogen inducible raf-1 fusion protein (creating "BON-raf cells"). BON and BON-raf cells were then treated with either control or 1 micromol/L estradiol (E2). Western blots were used to confirm the phosphorylation of extracellular signal-regulated kinase 1/2. Morphologic changes were evaluated using light and electron microscopy. RESULTS: Western blots using antibodies against phosphorylated and unphosphorylated extracellular signal-regulated kinase 1/2. confirmed that phosphorylation was only present in the BON-raf E2 cells. BON cells treated with control and E2 and BON-raf cells treated with control all looked identical in culture. After treatment with E2 to induce raf-1, the BON-raf cells underwent dramatic morphologic changes. Under light and electron microscopy the cells became flatter and developed much sharper cellular borders mimicking cellular differentiation. CONCLUSIONS: Activation of the ras/raf-1 signal transduction pathway leads to prominent phenotypic changes that resemble differentiation of gastrointestinal carcinoid cells in vitro.