Search PubMed⌕ Search

Biomedical subjects

D L Fraker

Publications and source records attributed to D L Fraker.

At least 91 records · Page 5Linked to original sources
PubMed1994

Apparent lymph node primary gastrinoma.

BACKGROUND: The existence of lymph node (LN) primary gastrinoma as a cause of Zollinger-Ellison syndrome is controversial. We reviewed our experience with patients in whom gastrinomas were identified and excised only from LNs. METHODS: From 1982 to 1992, 110 patients with ZES underwent exploration for gastrinoma and 21 (19%) had disease limited to one or more LNs. Standardized exploration included intraoperative ultrasonography, intraoperative endoscopy with transillumination and exploratory duodenotomy in 86%, 67%, and 24% of patients, respectively. Each patient underwent yearly biochemical and radiologic follow-up. RESULTS: Thirteen patients (62%) with a median follow-up period of 5.8 years had an initial biochemical cure, whereas eight patients (38%) with a median follow-up period of 3.6 years had persistent disease. Of the 13 patients whose condition initially returned to normal, four have had biochemical recurrence, with a median time to recurrence of 4.2 years and a median follow-up period of 7.4 years. Nine patients (43%) remain biochemically cured, with a median follow-up period of 5.3 years. CONCLUSIONS: Resection of apparent LN primary gastrinoma is warranted, because 43% of those who underwent resection had no evidence of disease, with a median follow-up period of 5.3 years.

Adult↗
PubMed1994

Use of preoperative fine-needle aspiration in patients undergoing reoperation for primary hyperparathyroidism.

BACKGROUND: Neck reexploration for primary hyperparathyroidism has a lower success rate and greater morbidity than initial exploration because of scarring and distortion of tissue planes and the possibility of a parathyroid neoplasm located in an ectopic or unusual position. Although the use of standard noninvasive imaging studies for reoperative parathyroid surgical procedure is well accepted, the use of invasive studies to localize parathyroid neoplasms, particularly percutaneous aspiration of potential lesions, is controversial. In this report we analyze the results and morbidity in patients undergoing fine-needle aspiration before neck reexploration. METHODS: From 1982 to 1993, 255 patients underwent reexploration for persistent or recurrent hyperparathyroidism at the National Institutes of Health. Of these 255 patients 42 underwent 44 preoperative fine-needle aspirations by ultrasonography or computed tomography guidance in an attempt to localize a parathyroid neoplasm. The aspirated contents were then analyzed for parathyroid hormone content. RESULTS: Of the 44 aspirations 26 (59%) were true positives with no false positives. Of 18 negative fine-needle aspirations, 11 (25%) were false negatives, and seven (16%) were true negatives. The specificity and sensitivity of percutaneous fine-needle aspiration were 100% and 70%, respectively. CONCLUSIONS: Percutaneous fine-needle aspiration for parathyroid hormone is a safe, well-tolerated technique that is highly specific and allows a directed surgical resection avoiding further invasive workup when the aspirate is positive.

Adult↗
PubMed1994

Localization and operative management of undescended parathyroid adenomas in patients with persistent primary hyperparathyroidism.

BACKGROUND: Between 5% and 10% of patients who undergo cervical exploration for primary hyperparathyroidism will have persistent or recurrent hyperparathyroidism. Many of these patients have parathyroid tumors in unusual locations. One such site of ectopic parathyroid tissue is an undescended parathyroid adenoma at or superior to the carotid bifurcation. We describe our experience with the preoperative localization and surgical management of undescended parathyroid adenomas. METHODS: From 1982 to 1993 a consecutive series of 255 patients have undergone localization studies and surgical exploration for persistent or recurrent hyperparathyroidism at the Clinical Center of the National Institutes of Health. Operative strategy was determined by review of the patient's surgical history, disease reports, and data from localizing studies. Patients with an undescended parathyroid adenoma identified before the operation were examined with a direct approach high in the neck. Patients who did not have definitive preoperative localization were explored with the previous transverse cervical incision. RESULTS: Seventeen undescended parathyroid adenomas were identified in 255 patients. Thirteen (76%) of 17 patients had an undescended parathyroid adenoma precisely localized before the operation and were examined via a limited, oblique incision high in the neck anterior to the sternocleidomastoid muscle. In the 13 patients who had undergone accurate localization before the operation, the median operative time was 75 minutes compared with 235 minutes for four patients who did not have an undescended parathyroid adenoma identified before the operation and were examined via a previous transverse cervical incision. All patients were cured of their hyperparathyroidism. CONCLUSIONS: Undescended parathyroid adenomas were the cause of failed cervical exploration in 17 (7%) of 255 patients. Accurate preoperative localization of these lesions is possible in most cases with a combination of noninvasive and invasive modalities. Successful preoperative localization can convert a prolonged exploration of the neck and mediastinum into a brief, curative procedure with minimal morbidity.

Adenoma↗
PubMed1994

The use of tumour necrosis factor (TNF) in isolated perfusion: results and side effects. The NCI results.

The Surgery Branch of the National Cancer Institute has initiated several clinical trials involving the use of high-dose TNF in isolated limb perfusions. A phase III trial compares the three drug combination of TNF, interferon-gamma (IFN-gamma) and melphalan with a standard melphalan-alone perfusion in a prospective randomized trial. Another protocol escalates the dose of TNF in the perfusate to define the maximally tolerated dose that can be administered in this regional manner. A third protocol adds systemic high-dose interleukin-2 postoperatively to a TNF, IFN, and melphalan limb perfusion for patients with stage IV melanoma with the bulk of the disease in the extremity. This brief review highlights the rationale and study design of these TNF limb perfusion protocols.

Antineoplastic Combined Chemotherapy Protocols↗
PubMed1993

Passive immunization of mice against D factor blocks lethality and cytokine release during endotoxemia.

D factor, also known as leukemia inhibitory factor, is a pleiotropic cytokine whose role during acute injury and inflammation is not known. Intraperitoneal administration of Escherichia coli endotoxin induced D factor gene expression in mice, and passive immunization against D factor protected them from the lethal effects of endotoxin and blocked endotoxin-induced increases in serum levels of interleukin 1 and 6. Peak levels of tumor necrosis factor and interferon gamma were not affected. These results indicate that D factor is an essential early mediator of the inflammatory cytokine response and therefore may be important in the pathogenesis of the many inflammatory conditions, such as sepsis, arthritis, allograft rejection, and cancer immunotherapy.

Animals↗
PubMed1993

IL-1 receptor antagonist (IL-1ra) augments IL-2-induced pulmonary vascular leak.

Interleukin-2 (IL-2) therapy is dose limited by a severe vascular leak with resulting systemic and pulmonary toxicity. Although recognized as a mediator of septic shock and vascular leak, the relative role of IL-1 in IL-2 toxicity is unclear. We evaluated the effect of IL-1 receptor antagonist (IL-1ra) on IL-2 lethality, pulmonary vascular leak, and treatment of pulmonary metastases in a murine model. In vivo induction of mRNA for IL-1 alpha was evaluated in liver by Northern blots after 0, 5, 8, and 11 doses of IL-2 in C3H/HEN mice. The expression index for the IL-1 alpha gene increased from 0.16 to 0.74 after 5 doses of IL-2, and further increased to 1.04 after 11 doses of IL-2. C3H/HEN mice (n = 56) were randomized to receive phosphate-buffered saline (PBS), IL-1ra high dose (HD), or IL-1ra low dose (LD) by continuous subcutaneous infusion via Alzet mini-pumps. The biologic effectiveness of the dose and administration of IL-1ra was determined by the ability to block IL-1-induced IL-6 production in vivo. Mean serum IL-6 levels 3 hr after intraperitoneal IL-1 alpha (10 micrograms/kg) were: PBS, 3730 +/- 526 (mean +/- SEM pg/ml); IL-1ra (LD), 1156 +/- 398; and IL-1ra (HD), 594 +/- 30 (P < 0.01, IL-1ra HD or LD vs PBS). Pulmonary vascular leak was measured by iv I125 albumin after 8 doses of IL-2 (100,000 U ip q 8 hr).(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1993

Flow cytometry and Zollinger-Ellison syndrome: relationship to clinical course.

BACKGROUND: With successful means of controlling gastric acid secretion in patients with Zollinger-Ellison syndrome, the gastrinoma itself is becoming the major determinant of long-term survival. No methods have yet been described to predict which tumors will have more malignant courses thereby indicating which patients should undergo aggressive surgery or antitumor therapy. Because DNA analysis, using flow cytometry, has proved helpful in this regard in other tumors, the current study was designed to evaluate its utility in gastrinoma patients. METHODS: Flow cytometry was performed on 81 paraffin-embedded gastrinoma specimens from 59 patients. Results were compared with preoperative patient characteristics, findings at surgery, and postoperative follow up. RESULTS: Tumors were diploid in 54% of patients, near diploid in 15%, pure tetraploid in 0%, nontetraploid aneuploid in 25%, and multiple stem line aneuploid in 5%. All patients with multiple stem line aneuploid tumors had wide-spread metastases whereas all patients with nontetraploid aneuploid tumors had localized or regional disease. Median S phase percentage was 3.6. S phase percentages were higher in patients with widespread metastatic disease than in patients with localized or regional disease. Disease extent also correlated closely with fasting serum gastrin level. After removing this variable with logistic regression analysis, the significant correlation between disease extent and DNA analysis persisted. CONCLUSIONS: DNA analysis of gastrinoma tissue specimens correlates independently with the extent of disease and may be useful in planning therapeutic strategies for patients with Zollinger-Ellison syndrome.

Adult↗
PubMed1993

An evaluation of human recombinant alpha interferon in patients with metastatic gastrinoma.

BACKGROUND: Metastatic gastrinoma is becoming increasingly recognized in patients with Zollinger-Ellison Syndrome. The mean 5-year survival of these patients is < 20%. Chemotherapeutic regimens are of limited benefit. The aim of this study was to evaluate the use of interferon in these patients because a preliminary report suggested it might be effective. METHODS: The efficacy and toxicity of interferon was assessed in 13 consecutive Zollinger-Ellison syndrome patients with liver metastases. Patients were treated with human recombinant alpha interferon (5 million IU, subcutaneously [SC]) daily and followed up at 3-month intervals with multiple imaging studies. At each follow-up, toxicity of therapy was assessed and fasting serum gastrin concentrations were obtained. RESULTS: No patient showed a reduction in tumor size at any follow-up. One patient died after 2 months. At 6 months, six patients (46%) had stable tumor size in the liver, although new bone metastases developed in one patient. Three patients showed stable disease for up to 21 months. Changes in serum gastrin correlated with tumor response at 6 months. All patients developed some side effects of therapy. Thirty-one percent required dose reduction, and one patient (8%) had to have interferon therapy interrupted briefly. CONCLUSIONS: These results fail to define a therapeutic role for interferon in the treatment of metastatic gastrinoma.

Adult↗
PubMed1993

A prospective study of intraoperative methods to diagnose and resect duodenal gastrinomas.

OBJECTIVE: This study determined, prospectively, whether duodenotomy (DX) should be routinely performed in explorations for patients with Zollinger-Ellison syndrome (ZES). SUMMARY BACKGROUND DATA: Duodenal gastrinomas are now being found with increasing frequency in patients with Zollinger-Ellison syndrome. The surgical approach used to detect these tumors is controversial. Some recommend intraoperative endoscopy with transillumination (IOE) at surgery, while others recommend routine DX. METHODS: Beginning in 1989, the authors prospectively compared the ability of palpation, intraoperative ultrasound (IOUS), IOE, and DX (in that sequence) to detect gastrinomas in 35 consecutive patients with ZES. Each patient also underwent preoperative localization studies. RESULTS: Thirty-three of 35 patients (94%) had tumor detected and excised; duodenal gastrinomas were excised in 27 patients (77%). The average size of the duodenal tumors was 0.8 cm, significantly smaller (p < 0.005) than the pancreatic and lymph node tumors in this series. Standard palpation after a Kocher maneuver identified 19 of the 31 duodenal tumors (61%) in the 27 patients. IOUS revealed only eight duodenal tumors (26%) and no new lesions. IOE identified 20 duodenal gastrinomas (64%) and 6 new lesions. DX identified 31 duodenal tumors (100%) and 5 additional tumors. The morbidity rate was 17%. One patient had a duodenal fistula after operation (2.8%) and subsequently recovered. No patient died. CONCLUSIONS: These results demonstrate that the duodenum is the most common location for gastrinoma in patients with ZES (77%) and that DX to detect and remove duodenal gastrinomas should be routinely performed in all explorations for patients with ZES.

Adult↗
PubMed1993

Prospective evaluation of selective venous sampling for parathyroid hormone concentration in patients undergoing reoperations for primary hyperparathyroidism.

BACKGROUND: The utility of standard radiologic imaging studies in guiding reoperative parathyroid surgery for primary hyperparathyroidism is widely known and accepted. The additional information gained by selective venous sampling in that patient population has not been well defined. We report the results of our experience with this method. METHODS: Between 1982 and 1992, 223 consecutive patients underwent reoperations for persistent or recurrent primary hyperparathyroidism after a prospectively determined series of imaging studies. Patients underwent noninvasive testing consisting of ultrasonography, computed tomography, technetium thallium scanning, and magnetic resonance imaging. Patients with negative, equivocal, or discordant results on the noninvasive studies proceeded to angiography. If angiography was negative, selective venous sampling was performed. RESULTS: Eighty-six patients (39%) with negative or equivocal noninvasive test and angiogram results underwent selective venous sampling. Seventy-six patients (88%) had a significant gradient in levels of parathyroid hormone from veins draining the left side of the neck (n = 25), the right side of the neck (n = 33), both sides of the neck (n = 7), and the thymus (n = 11). Correlation of these findings with operative findings revealed a sensitivity of 88% and a specificity of 86%. In the subgroup of patients who underwent venous sampling and had completely negative results of standard radiologic studies (35 of 86; 40%), 28 patients (80%) had venous gradients and seven patients (20%) had no gradient. Of those 28 patients in whom the venous sampling gradients were the only positive localization study, the venous samplings were helpful in 23 patients (true positive gradients), and the operative success rate was 93%. In the seven patients with no positive preoperative localizing studies including venous sampling, there were two operative failures (operative success, 71%). CONCLUSIONS: Our results show that selective venous sampling is a highly sensitive and specific method to regionally localize abnormal parathyroid glands not imaged by standard noninvasive and invasive radiologic techniques. Venous sampling is the study of choice in guiding reoperative procedures for occult abnormal parathyroid glands that are undetected despite the use of all available imaging studies.

Diagnostic Imaging↗
PubMed1993

Effective reversibility of the signs and symptoms of hypercortisolism by bilateral adrenalectomy.

BACKGROUND: The long-term outcome of bilateral adrenalectomy in the management of patients with Cushing's syndrome has not been previously well studied. METHODS: We reviewed our long-term results in 34 patients treated with bilateral adrenalectomy between 1983 and the present. Fourteen presented with occult or metastatic ectopic adrenocorticotropic hormone (ACTH) syndrome, 10 with failed treatment of Cushing's disease, five with primary micronodular and four with massive macronodular adrenocortical disease and one with indeterminate cause of Cushing's syndrome. RESULTS: All patients underwent bilateral adrenalectomy. Of 19 patients who required antihypertensive medications before operation, 15 (79%) had significant improvement and were either off all antihypertensive medication or required less medication after operation. Of 7 patients who required medications for diabetes mellitus, after operation 6 (86%) required no medication or changed from injections to oral hypoglycemic agents. Of 9 patients with mood changes or depression, the symptoms of 8 (88%) resolved. Of 29 patients with documented weight gain, 23 (79%) showed marked weight loss. Of 13 hirsute patients, 10 (77%) had resolutions of symptoms. Of 21 patients with complaints of fatigue, the symptoms of 16 (76%) resolved. Of 8 women with amenorrhea, 6 (75%) had resolution of symptoms. Each patient in the primary adrenocortical disease group, except one with residual fatigue, had complete resolution of his or her symptoms. There was no difference in resolution of symptoms between the ectopic ACTH and Cushing's disease groups. Six patients died: in the ectopic ACTH group one died of suicide at 1 month, and four of metastatic tumor at 9, 24, 25, and 48 months, and the patient with macronodular adrenocortical hyperplasia died of a myocardial infarction at 30 months. The remainder of the patients have been followed for a mean of 32 months (3 to 67 months). None of the patients had any evidence of recurrent hypercortisolism. CONCLUSIONS: We conclude that bilateral adrenalectomy is a safe, effective, and long-lasting method to ameliorate the devastating signs and symptoms of hypercortisolism in patients with Cushing's syndrome.

ACTH Syndrome, Ectopic↗
PubMed1993

Neoadjuvant chemotherapy for locally advanced gastric adenocarcinoma.

Gastric adenocarcinoma is typically diagnosed at an advanced stage, and even with "curative" gastrectomy, most patients die of recurrent disease. Neoadjuvant chemotherapy for locally advanced gastric cancer is an experimental treatment strategy that may increase resectability and improve survival for patients afflicted with an almost uniformly fatal neoplasm. At our institution, we are evaluating the efficacy of fluorouracil, leucovorin, and interferon alfa-2A administered for three cycles, followed by surgery and consolidation therapy for patients with T3-4, N1-2, M0 gastric adenocarcinoma. The rationale for the use of neoadjuvant therapy combined with radical extirpative surgery in this setting and related issues are discussed.

Adenocarcinoma↗
PubMed1992

Differentiation factor/leukemia inhibitory factor protection against lethal endotoxemia in mice: synergistic effect with interleukin 1 and tumor necrosis factor.

Differentiation factor (D factor), also called leukemia inhibitory factor (LIF), is a glycoprotein that has been increasingly recognized to possess a wide range of physiological activities. We examined the possibility that the administration of D factor may confer beneficial effects and enhance host resistance against lethal endotoxemia. A single intravenous dose of recombinant human D factor completely protected C57/Bl6 mice from the lethal effect of Escherichia coli endotoxin (lipopolysaccharide [LPS]). The protective effects were dose dependent and observed when administered 2-24 h before LPS. Previous work has shown that interleukin 1 (IL-1) and tumor necrosis factor (TNF) also protect against a subsequent LPS challenge in a dose-dependent manner. When human D factor was combined with sub-protective doses of IL-1 beta or TNF-alpha, there was dramatic synergistic protection against a subsequent lethal LPS challenge.

Animals↗
PubMed1992

Tumour necrosis factor mediates the survival benefit of interleukin 2 in a murine pulmonary metastases model.

Antibody to tumour necrosis factor (TNF Ab) markedly decreases the toxicity of systemic interleukin-2 (IL-2) in mice but does not completely abrogate the anti-tumour response in terms of number of pulmonary metastases. Experiments were performed with a murine model of pulmonary metastases treated with high-dose IL-2 and concomitant TNF Ab or control antibody (CON Ab) to determine the effects of TNF Ab on survival. Mice were given either equal doses of IL-2 and TNF Ab or CON Ab or equitoxic doses of IL-2. In four consecutive experiments mice given TNF Ab tolerated 5 to 6 additional IL-2 doses (a 40-60% increase in total doses) in the equitoxic IL-2 dose group compared to the maximally tolerated dose with CON Ab. In all four experiments TNF Ab-treated mice had decreased survival compared to the CON Ab group given equal doses of IL-2 and in two of four experiments this difference was statistically significant (P2 < 0.01). Mice given 40-60% additional doses of IL-2 with TNF Ab had no improvement in survival compared with equitoxic doses of IL-2 with CON Ab in three of four experiments (P2 = 0.32, P2 = 0.67, P2 = 0.69). The TNF Ab preparation had no direct inhibition of IL-2 activity in an in vitro IL-2 proliferation bioassay. TNF Ab consistently blocks IL-2 toxicity and it also abrogates IL-2 therapeutic efficacy such that survival parallels treatment toxicity in this experimental model.

Animals↗
PubMed1992

Effective regional therapy of experimental cancer with paralesional administration of tumour necrosis factor-alpha + interferon-gamma.

Systemically administered tumour necrosis factor (TNF) has anti-tumour effects in animal tumour models but its clinical application is limited by severe toxicity. Interferon-gamma(IFN-gamma) has been shown to augment the anti-tumour effect of TNF. We evaluated the effect of paralesional (p.I.) injections of TNF plus IFN-gamma in a murine tumour model and compared the toxicity and anti-tumour effect with that seen with systemic administration. C57BL6 mice with 10-day subcutaneous MCA sarcomas were treated with daily p.I. injections of recombinant huTNF +/- IFN-gamma for 5 days. Optimal mean survival and 30-day cure rate was seen with doses of 5 micrograms TNF-alpha + 5000 U IFN-gamma (P < 0.05 vs. control or IFN-gamma alone). Tumour response after a single i.v. injection of 0-15 micrograms TNF + 5000 U IFN-gamma was then compared with five daily p.I. injections of the same dose of TNF-alpha and IFN-gamma. All animals with p.I. injections of > 5 micrograms TNF had initial complete necrosis of tumour with a variable degree of surrounding tissue necrosis, with rapid regrowth of tumour seen in some animals. Although treatment-related mortality was similar between i.v. and p.I. therapy, there was a higher percentage of animals cured with p.I. injections with overall cure rates in treated animals at 30 days of 17% vs. 72% (i.v. vs. p.I., P < 0.01) and 13% vs. 67% (P < 0.04) in a repeat study. 2+ clinical applications.

Animals↗
PubMed1992

Recombinant interleukin-1 receptor antagonist (IL-1ra): effective therapy against gram-negative sepsis in rats.

BACKGROUND: Morbidity and mortality from bacterial sepsis remain high despite aggressive diagnostic and therapeutic intervention. Interleukin-1 has been implicated as mediator of the lethal effects of endotoxemia or bacterial sepsis. The current experiments were designed to evaluate the therapeutic efficacy of a human recombinant interleukin-1 receptor antagonist (IL-1ra) against polymicrobial gram-negative septicemia in rats. METHODS: Male rats underwent placement of indwelling carotid arterial and superior vena caval catheters followed by cecal ligation and puncture (CLP). After 3 hours rats received either IL-1ra (10 mg/kg intravenous bolus followed by 5 mg/kg/hr) or an equal volume of vehicle intravenously for 24 hours. Heart rate, respirations, mean arterial blood pressure, and temperature were recorded at frequent intervals, and survival was assessed for 30 hours after CLP. RESULTS: There were no differences in vital signs between groups at baseline or before treatment, and all animals appeared ill with huddled posture, piloerection, and hyperventilation. Twenty-four hours after CLP, IL-1ra significantly ameliorated bradycardia (p = 0.01), hypothermia (p = 0.001), and hypotension (p = 0.05), and 30-hour survival was significantly improved (71% vs 20%, p less than 0.05). CONCLUSIONS: IL-1ra lessens the acute hemodynamic, hypothermic, and mortal effects of gram-negative sepsis induced by CLP in rats. These data suggest that IL-1 receptor blockade may be an important new treatment strategy against overwhelming bacterial sepsis.

Animals↗
PubMed1991

The roles of gamma-interferon and tumor necrosis factor alpha in an experimental rat model of cancer cachexia.

Administration of repetitive sublethal doses of either recombinant human tumor necrosis factor (TNF) or recombinant murine gamma-interferon (IFN) to non-tumor-bearing (NTB) rats caused a significant decline in food intake and body weight. After 3 days rats became resistant to the anorectic and weight loss effects of TNF but maintained persistent diminished food intake and diminished body weight gain while receiving recombinant murine IFN. Passive immunization against recombinant rat gamma-interferon allowed cachectic tumor-bearing (TB) rats to eat more food, have a lesser decline in body weight, live longer, and tolerate larger tumors than similar TB rats given nonspecific control antibody. TB rats treated with an antisera to recombinant murine TNF, which was 100% protective when given to NTB rats 6 h before a lethal endotoxin challenge, did not differ significantly from TB rats treated with control antibody with respect to food intake, body weight, survival, or tumor size. Serum levels of TNF or IFN were not detectable in cachectic tumor-bearing rats. The data indicate that the administration of exogenous IFN can simulate cachexia in NTB rats and that passive immunization against it can partially reverse the cachectic changes associated with cancer and prolong survival. These findings suggest that gamma-interferon may be an important mediator of cachexia in this rat tumor model.

Animals↗