Pituitary Gland Tumors Research Articles

The role of genetics in the surgical management of familial endocrinopathy syndromes.

Our knowledge of genetics has increased dramatically in recent decades and this has led to important changes in the medical and surgical management of hereditary endocrine diseases. Genetic screening for disease-causing mutations can identify carriers at young ages, which has enabled earlier diagnosis and surgical intervention. For example prophylactic thyroidectomy is now routine in patients with multiple endocrine neoplasia type 2 (MEN2). Appropriately timed surgical intervention will minimize disease-specific morbidity and mortality, but the diagnosis and surgical treatment of disease in presymptomatic patients is much more complex than in symptomatic patients with measurable disease. Surgeons must remain conversant with the developments in genetic technology and the established role for genetic counselors in the multidisciplinary management of hereditary endocrine syndromes. In this article we briefly review the clinically relevant information and indications for genetic testing for the most common hereditary endocrine syndromes including multiple endocrine neoplasia type 1 (MEN1), MEN2, von Hippel-Lindau syndrome (VHL), and hereditary paraganglioma syndrome. We also use several case descriptions to illustrate the impact of genetic counseling on the management of familial cancer. Finally we provide several key genetic counseling resources available for the proper identification and expeditious referral of patients at risk for these familial endocrine syndromes. MULTIPLE ENDOCRINE NEOPLASIA TYPE 1 MEN1 is an autosomal dominant disease that demonstrates nearly complete penetrance in the form of various combinations of endocrine tumors involving the parathyroid glands, pancreatic islet cells and duodenum, and pituitary gland (Table 1). Hyperparathyroidism (HPT) is the most prevalent (90% to 97%) and is usually the first manifestation, typically appearing between the ages of 20 and 25 years but sometimes as late as the fifth decade of life. Anterior pituitary gland tumors in patients with MEN1 are less common (33%) and may be nonfunctioning or may secrete hormones such as prolactin. Tumors of the pancreatic islet cells and duodenum (pancreatic endocrine tumors, PETs) occur in as many as 30% to 80% of patients. Some PETs are nonfunctioning, but many secrete one or more pancreatic hormones. With earlier diagnosis and control of hormone-associated complications such as ZollingerEllison syndrome, metastatic neuroendocrine tumors of the pancreas are now the leading cause of disease-specific mortality in patients with MEN1. Because PETs in MEN1 patients are multifocal and distributed throughout the pancreas, their proper management remains poorly defined. This issue was summarized in a recent consensus statement in which it was concluded that surgical treatment for MEN1-related PETs is controversial except for patients with hypoglycemia secondary to insulinoma syndrome in whom pancreatic resection is indicated. There is currently no consensus on the timing and extent of surgical treatment for gastrinoma and nonfunctioning PETs in patients with MEN1. Less prevalent tumors associated with MEN1 include adrenocortical tumors, lipomas, and foregut carcinoid tumors. Foregut carcinoids are found in 2% to 8% of patients with MEN1, but bronchial carcinoids are more common in women and thymic carcinoids are more common in men. The malignant potential of carcinoids, particularly thymic carcinoids, has led to recent No competing interests declared.

Reproductive disturbances, pituitary lactotrope adenomas, and mammary gland tumors in transgenic female mice producing high levels of human chorionic gonadotropin.

To assess the consequences of prolonged exposure to elevated levels of LH/human chorionic gonadotropin (hCG) in the female, we developed a transgenic (TG) mouse model (hCGbeta+) that overexpresses the hCGbeta-subunit cDNA. Because of the promoter used, ubiquitin C, the transgene is expressed in multiple tissues, including the pituitary gland, in which coupling with the endogenous common alpha-subunit results in synthesis of high levels of bioactive hCG. The TG females presented with precocious puberty, infertility, enhanced ovarian steroidogenesis, and abnormal uterine structure. Pituitary enlargement was evident from the age of 2 months, which progressed to adenomas by the age of 10-12 months. Immunohistochemical studies and electron microscopy demonstrated lactotrope origin for the adenomas, associated with severe hyperprolactinemia. The mammary glands of TG females showed marked lobuloalveolar development followed by mammary tumors with characteristics of adenocarcinoma at the age of 9-12 months. More than 90% of penetrance and high frequency of metastasis (47%) was observed. Formation of the pituitary and mammary gland tumors was totally abolished by ovariectomy despite persistently elevated hCG levels. Taken together, these findings suggest that the hCG-induced aberrations of ovarian function are clearly responsible for the extragonadal tumors observed in these TG mice.

Targeted expression of a human pituitary tumor-derived isoform of FGF receptor-4 recapitulates pituitary tumorigenesis.

It is estimated that up to one in five individuals develop pituitary gland tumors. Despite the common occurrence of these tumors, the pathogenetic mechanisms underlying their development remain largely unknown. We report the identification of a novel pituitary tumor-derived, N-terminally truncated isoform of FGF receptor-4 (ptd-FGFR4). The corresponding mRNA results from alternative transcription initiation and encodes a polypeptide that lacks a signal peptide and the first two extracellular Ig-like domains. ptd-FGFR4 has a distinctive cytoplasmic residence, is constitutively phosphorylated, and is transforming in vitro and in vivo. Here we show that targeted expression of ptd-FGFR4, but not FGFR4, results in pituitary tumors that morphologically recapitulate the human disease.

Targeted expression of a human pituitary tumor–derived isoform of FGF receptor-4 recapitulates pituitary tumorigenesis

It is estimated that up to one in five individuals develop pituitary gland tumors. Despite the common occurrence of these tumors, the pathogenetic mechanisms underlying their development remain largely unknown. We report the identification of a novel pituitary tumor–derived, N-terminally truncated isoform of FGF receptor-4 (ptd-FGFR4). The corresponding mRNA results from alternative transcription initiation and encodes a polypeptide that lacks a signal peptide and the first two extracellular Ig-like domains. ptd-FGFR4 has a distinctive cytoplasmic residence, is constitutively phosphorylated, and is transforming in vitro and in vivo. Here we show that targeted expression of ptd-FGFR4, but not FGFR4, results in pituitary tumors that morphologically recapitulate the human disease.

The legacy of Harvey Cushing.

Dr Harvey Cushing. Illustration by Venita Jay, MD, FRCPC. I is a formidable task for any biographer to record all of the achievements of Harvey William Cushing, commonly known as the Father of American Neurosurgery. Regarded as the leading neurosurgeon of the 20th century, Cushing was a tireless investigator, dedicated teacher, prolific writer, gifted artist, and ardent bibliophile. His name is known to every medical student and is immortalized in the well-known Cushing syndrome, Cushing disease, Cushing reflex, and Cushing ulcer. Cushing also left a lasting legacy in pathology with his work on the pituitary gland and brain tumors. Cushing launched neurosurgery as a distinct discipline and firmly established it as a separate specialty. Every phase of Cushing’s career has been the subject of intense scrutiny, with extensive biographies detailing his college days at Yale, medical training at Harvard, surgical residency at Johns Hopkins, and the years at Peter Bent Brigham and Yale. There are also several well-known biographies of Cushing, including those written by John F. Fulton, Elizabeth H. Thomson, and Justin F. Denzel. Born on April 8, 1869, in Cleveland, Ohio, Cushing was the youngest of 10 children, 7 of whom survived to maturity. His great-grandfather, grandfather, father, and older brother Ned were physicians. Cushing attended Yale College in New Haven, Conn, and graduated from that institution in 1891. While at Yale, Russell Chittenden encouraged in Cushing an interest in physiological chemistry. Cushing greatly admired his father and his brother Ned. He followed in the family tradition and embarked on a medial career, joining Harvard Medical School in Boston, Mass. Cushing attended Harvard from 1891 to 1896 and received his medical degree in 1895. He completed his internship at Massachusetts General Hospital. During his medical school years, Cushing was a keen and observant student, who was able to recognize the importance of new developments. Ether anesthesia had come into vogue, and medical students were called upon to administer it. One patient anesthetized by Cushing died, which disturbed Cushing so much that he wanted to quit medicine. Brooding over the tragedy and hoping that such deaths could be prevented if vital signs were monitored, he embarked on a new venture with fellow student Ernest Amory Codman. Together, they developed a record of an-

Immunohistochemical detection of hormones in hypophyseal adenomas of the rat after fractionated irradiation

The aim of this study was to determine the hormones produced in pituitary gland tumours (TM) following fractionated external irradiation in rats. The TM arose in the course of studies on other questions of radiation effects. The left neck and skull base of sixty female Wistar rats, 3 to 4 months of age at the beginning of the external irradiation, were subjected to roentgen rays exposure, fractionated to 2 Grays daily, either up to 20, 40 or 60 Gy. The midline of the neck and skull was always inside the radiation field. The animals were sacrificed either 6 months or 12 months after completion of the randomly assigned irradiation protocol. Five non-irradiated rats served as controls. No TM developed in the non-irradiated animals. Out of 60 irradiated rats 9 developed a pituitary TM (15%). In remnants of the normal adenohypophysis we revealed immunohistochemical reactivity for growth hormone (GH), adrenocorticotropic hormone (ACTH), prolactin (PRL), thyroid stimulating hormone (TSH), and follicle stimulating hormone (FSH). In the radiation-induced adenomas, 4 TM were immuno-reactive for TSH, 4 for GH, 2 for PRL, and 2 for FSH. The TM did not react with anti-ACTH and anti-LH (luteinizing hormone) anti-sera. Obviously, irradiation accelerates the development of pituitary gland adenomas. In this series the TM were predominantly incidental findings at necropsies after pretermed follow-up intervals with a variety of hormone-producing cells. On the other hand, four of nine TM were null adenomas. Necropsies of the brain should be carried out routinely in irradiation studies of the skull.

Regulation of mucociliary motility by nitric oxide and expression of nitric oxide synthase in the human sinus epithelial cells.

This study was performed to investigate the changes in ciliary beat frequency (CBF) after treatment with Larginine in the human sinus mucosa and to determine the distribution of inducible nitric oxide synthase (iNOS) and endothelial nitric oxide synthase (eNOS) in the healthy sinus mucosa. CBF was measured in the sphenoid sinus mucosa of 12 patients who underwent trans-septal trans-sphenoidal hypophysectomy for the treatment of pituitary gland tumor. CBF was measured over 24 hours in Dulbecco's modified Eagle's medium (DMEM) after treatment with L-arginine, its inactive spatial isomer D-arginine, or an NOS inhibitor, N(G)-nitro-L-arginine methyl ester (L-NAME). DMEM without treatment with these materials was used as a control. Other pieces of the mucosa were exposed to L-NAME and its inactive spatial isomer D-NAME after preincubation with L-arginine. The specimens were immunohistochemically stained for iNOS and eNOS. CBF increased 24 hours after treatment with L-arginine as compared with control groups. CBF increased in proportion to the increasing concentrations of L-arginine. There was no significant change after treatment with D-arginine or L-NAME. CBF increased after treatment with L-arginine at 30 minutes and maintained for 24 hours. L-NAME inhibited the increase in CBF by L-arginine, but D-NAME showed no such effect. Immunoreactivity to both iNOS and eNOS was frequently observed in the ciliated epithelial cells and was stronger to eNOS than to iNOS. From the results of this study it is suggested that nitric oxide (NO) produced by iNOS and eNOS using L-arginine may increase CBF in the healthy sinus mucosa and that NO may have a regulatory function in ciliary motility in the human sinus mucosa.

Pituitary disease and anaesthesia

C outline the postoperative complications of transsphenoidal pituitary surgery. Patients with pituitary gland tumours comprise a significant proportion of the neurosurgical population, making transsphenoidal pituitary surgery a relatively common procedure. Such patients present anaesthetists with unique challenges resulting from hormone hypersecretion, pituitary hypofunction or tumour mass effect. To understand this pathophysiology requires a good working knowledge of normal pituitary anatomy and physiology. An appreciation of the respiratory and cardiovascular comorbidities associated with pituitary tumours is also essential to the anaesthetist. We aim to review the key principles involved in the preoperative assessment, intraoperative management and postoperative care of these patients.

Spontaneous neoplastic lesions in Harlan Sprague-Dawley rats

In a 24-months study, the spontaneous tumour spectrum of the Hsd:Sprague-Dawley stock was examined. Pituitary gland tumours were found in 20% of the males and 39% of the females. This relatively low incidence, compared to other SPRD stocks, had little effect on the survival of females (50%), due to the high incidence (76%) of mammary gland tumours (predominantly fibroadenomas) that resulted in unscheduled sacrifices of many females. Other common neoplasms in Hsd:Sprague-Dawley rats were benign medullary tumours (27% in males, 11% in females), C-cell adenomas (23% in males, 28% in females), and endometrial stromal polyps (22% in females).

Cobalt 60 irradiation of pituitary gland tumors in three cats with acromegaly

The most common cause of naturally developing acromegaly in cats is a growth hormone-secreting adenoma of the pituitary pars distalis somatotropic cells. Irradiation of pituitary gland tumors in cats with acromegaly may result in transient or long-term resolution of acromegaly and diabetes mellitus. Diabetic cats with acromegaly may have a history of weight loss instead of weight gain.

Spontaneous neoplasm incidences in Fischer 344 rats and B6C3F1 mice in two-year carcinogenicity studies: a National Toxicology Program update.

Spontaneous neoplasm rates were determined for control Fischer 344 (F344) rats and B6C3F1 mice from 2-yr rodent carcinogenicity studies carried out by the National Toxicology Program (NTP). The most frequently occurring neoplasms in untreated male F344 rats were testicular adenoma (89.1%), mononuclear cell leukemia (50.5%), adrenal gland pheochromocytoma (31.9%), and pituitary gland neoplasms (30.4%). For untreated female F344 rats, the most frequently occurring neoplasms were pituitary gland neoplasms (54.2%), mammary gland fibroadenoma (41.2%), and mononuclear cell leukemia (28.1%). The most frequently occurring neoplasms in untreated male B6C3F1 mice were liver adenoma/carcinoma (42.2%), lung adenoma/carcinoma (20.5%), and malignant lymphoma (8.3%). For untreated female B6C3F1 mice, the most frequently occurring neoplasms were liver adenoma/carcinoma (23.6%), malignant lymphoma (20.9%), and pituitary gland adenoma/carcinoma (14.8%). The tumor rates observed in feeding study (untreated) and inhalation study (chamber) control rats were generally similar. The major exceptions were pituitary gland tumors and testicular adenoma in male F344 rats. The overall incidence of testicular adenoma was much lower in chamber controls (69.4%) than in feeding study controls (89.1%), whereas pituitary gland neoplasm showed the opposite trend (60.7% vs 30.4%). The most likely explanation for this difference is related to the individual housing of chamber controls and the group housing of feeding study controls. Differences in diagnostic criteria may influence reported tumor rates. To ensure consistency and comparability of tumor diagnosis from study to study, the NTP uses rigorous histopathology quality assurance and peer review procedures. Biological factors such as body weight may also affect tumor incidence. For example, increased body weights are associated with increased incidences of certain site-specific neoplasms, especially pituitary gland and mammary gland neoplasms in rats and liver tumors in mice. The presence of Helicobacter hepaticus has been associated with an increased incidence of liver neoplasms in male B6C3F1 mice. Other factors that may produce differences in control tumor rates from study to study include diet, environmental factors, genetic drift, study duration, and survival differences. The NTP database provides historical control data that may be useful in the evaluation of possible chemically related changes in tumor incidence. However, it is essential that the study being evaluated be comparable to those in the NTP database with respect to those factors that are known to influence tumor occurrence.

Twenty‐four‐month oral carcinogenicity study of ebrotidine in rats

Three groups of Sprague-Dawley CD rats (males and females) were initially administered p.o. with ebrotidine, a novel H2-receptor antagonist, mixed with the diet, at 50, 200, and 500 mg/kg/d, respectively. Two concurrent control groups of animals were used. After 13 months, initial 200 mg/kg was lowered to 150 mg/kg, and a new group was administered with 300 mg/kg, due to the body weight reduction observed in the top dose group. After 24 months, survivors were killed and necropsied, and a histopathological study was performed. The frequencies of the different tumour types that were found were not raised due to the treatment. Lower frequencies of some types of pituitary and mammary gland tumours, in the groups treated with the higher doses, were the only statistically significant changes. Among the non-neoplastic effects, a lower body weight increment and food consumption (500 and 300 mg/kg, both sexes), lower survival (500 mg/kg, males), presence of lipoid pneumonia (500 mg/kg, only in males, and 300 mg/kg, both sexes), and lithiasis in urinary system (500 mg/kg) were observed. No changes in gastric mucosa (the main target organ) were attributable to ebrotidine. Regarding the non-neoplastic effects, 150 mg/kg was the no observed adverse effect level. According to the previous results of the carcinogenicity study in mice, conjointly with those of the study in rats reported here, there is no evidence of carcinogenic risk either in males or in females in these species. Teratogenesis Carcinog. Mutagen. 18:263–277, 1998. © 1998 Wiley-Liss, Inc.

Twenty-four-month oral carcinogenicity study of ebrotidine in rats

Three groups of Sprague-Dawley CD rats (males and females) were initially administered p.o. with ebrotidine, a novel H2-receptor antagonist, mixed with the diet, at 50, 200, and 500 mg/kg/d, respectively. Two concurrent control groups of animals were used. After 13 months, initial 200 mg/kg was lowered to 150 mg/kg, and a new group was administered with 300 mg/kg, due to the body weight reduction observed in the top dose group. After 24 months, survivors were killed and necropsied, and a histopathological study was performed. The frequencies of the different tumour types that were found were not raised due to the treatment. Lower frequencies of some types of pituitary and mammary gland tumours, in the groups treated with the higher doses, were the only statistically significant changes. Among the non-neoplastic effects, a lower body weight increment and food consumption (500 and 300 mg/kg, both sexes), lower survival (500 mg/kg, males), presence of lipoid pneumonia (500 mg/kg, only in males, and 300 mg/kg, both sexes), and lithiasis in urinary system (500 mg/kg) were observed. No changes in gastric mucosa (the main target organ) were attributable to ebrotidine. Regarding the non-neoplastic effects, 150 mg/kg was the no observed adverse effect level. According to the previous results of the carcinogenicity study in mice, conjointly with those of the study in rats reported here, there is no evidence of carcinogenic risk either in males or in females in these species.

The German Study Group, “Pituitary Gland and Pituitary Tumors”—A Portrait

The German Study Group, “Pituitary Gland and Pituitary Tumors”—A Portrait

Body weight-tumor incidence correlations in long-term rodent carcinogenicity studies.

Associations between body weight and tumor incidence and among the incidences of selected site-specific tumors were examined for more than 4,000 male and female Fischer-344 rats and B6C3F1 mice in the National Toxicology Program historical control database. Incidences of certain site-specific tumors, most notably mammary gland and pituitary gland tumors in rats and liver tumors in mice, were shown to have a strong positive correlation with 52-wk body weight. Using individual animal data, logistic regression models were derived for predicting site-specific tumor incidence as a function of 52-wk body weight, age, and other factors. This association between body weight and tumor incidence can explain many of the decreased tumor incidences observed in National Toxicology Program carcinogenicity studies. Body weight differences between dosed and control groups can also mask carcinogenic effects for those sites sensitive to body weight changes. Thus, when designing long-term rodent carcinogenicity studies, measures should be taken to minimize potential body weight differences between dosed and control groups. There were a number of small but significant negative correlations among tumor incidences, reflecting primarily the lethality of the tumors in question. None of these correlations (nor the 2 small positive correlations found) are likely to have any impact on the interpretation of experimental results. However, the high negative correlation between pituitary gland and testis tumors in male Fischer-344 rats cannot be dismissed so easily, does not reflect tumor lethality, and is currently being studied further.

The Effects of Diet, Overfeeding and Moderate Dietary Restriction on Sprague-Dawley Rat Survival, Disease and Toxicology

Overfeeding by ad libitum (AL) food consumption is the most significant, uncontrolled variable affecting the outcome of the current rodent bioassay. The correlation of food consumption, the resultant adult body weight and the 2-y survival in Sprague-Dawley rats is highly significant. Feeding natural ingredient diets that varied in protein, fiber and metabolizable energy content did not improve low 2-y survival if Sprague-Dawley rats were allowed AL food consumption. Moderate dietary restriction (DR) of all diets tested significantly improved survival and delayed the onset of spontaneous degenerative disease (i.e., nephropathy and cardiomyopathy) and diet-related tumors. By 2 y, moderate DR resulted in an incidence of spontaneous tumors similar to that seen with AL consumption; however, the tumors were more likely to be incidental and did not result in early mortality. There was a decreased age-adjusted incidence in pituitary and mammary gland tumors, but tumor volume and growth time were similar in the AL and DR groups, indicating a similar tumor progression with a delay in tumor onset. Moderate DR did not significantly alter drug-metabolizing enzyme activities or the toxicologic response to five pharmaceuticals tested at maximum tolerated doses (MTD). However, moderate DR did require higher doses of compounds to be given before classical MTD were produced with four pharmaceutical drug candidates. Toxicokinetic studies of two of these compounds demonstrated steady-state systemic exposures that were equal or higher in moderate DR-fed rats. These and other data indicate that moderate DR is the most appropriate method of dietary control for rodent bioassays used to assess human safety of candidate pharmaceuticals.

Dosimetry and pathology of 237Np in female rats

Female Sprague-Dawley rats, 10-12-week old and weighing about 240 g, were injected intravenously with 237Np-nitrate. In the toxicological study 77 rats served as controls and 28 rats per group received single doses of 5.2 and 26 kBq, respectively, per kg body weight. In addition, 12 rats of each injection level, sacrificed at defined points in time, were used for dosimetric studies. During the whole life-span the body weight and 237Np whole body-content of each animal were recorded. After death a detailed pathological examination was made of each animal in the cronical study. One day after injection 48% of the injected activity was in the skeleton, 9.3% in the liver, 3% in the kidneys and 4.4% in the rest of the organs. Whereas in all organs the activity decreased very fast, the half-life in the skeleton was about 1400 days. The bodyweights were comparable in the three groups, but the life span decreased from 800 days (control group) to 644 days after injection (26 kBq kg-1 body weight group). The main lesions in the female rats were mammary tumors (73%) and pituitary gland tumors (52%). With increasing activity the incidence of pituary gland tumors decreased and that of osteosarcomas increased from 1.3% (control group) to 32% (26 kBq kg-1 body weight group), whereas the remaining lesions showed no influence on the activity.

The effects of diet, ad libitum overfeeding, and moderate dietary restriction on the rodent bioassay: the uncontrolled variable in safety assessment.

Ad libitum (AL) overfeeding is the most significant, uncontrolled variable affecting the outcome of the current rodent bioassay. There is a highly significant correlation between AL food consumption, the resultant obesity and body weight, and low 2-yr survival in rodents. AL feeding of diets with lowered protein, metabolizable energy (ME), and increased fiber does not improve survival. Only dietary restriction (DR) of all diets tested significantly improves survival and delays the onset of spontaneous degenerative disease (i.e., nephropathy and cardiomyopathy) and diet-related tumors. Moderate DR results in an incidence of spontaneous tumors similar to AL-fed rats, but the tumors are found incidentally and do not cause early mortality. There is a decreased age-adjusted incidence of pituitary and mammary gland tumors in moderate DR-fed rats, but tumor growth time is similar between AL and DR rats with only a delay in tumor onset time seen in DR-fed groups. Moderate DR does not significantly alter drug-metabolizing enzyme activities nor the toxicologic response to 5 pharmaceuticals tested at maximum tolerated doses (MTDs). However, moderate DR-fed rats did require much higher doses of 4 additional pharmaceutical compounds before classical MTDs were produced. Toxicokinetic studies of 2 of these compounds demonstrated equal or higher steady-state systemic exposures to parent drug and metabolites in moderate DR-fed rats. Markers of oxidative stress (lipid peroxidation, protein oxidation) are decreased and cytoprotective anti-oxidant markers are preserved in moderate DR-fed rats. But moderate DR does not delay reproductive senescence in female rats. Only marked DR delays reproductive senescence compared to AL and moderate DR-fed female rats. These and other data indicate that moderate DR is the most appropriate method of dietary control for the rodent bioassay when used to assess pharmaceuticals for human safety and compounds for risk assessment.

Posterior retroperitoneoscopy as a new minimally invasive approach for adrenalectomy: results of 30 adrenalectomies in 27 patients.

Posterior retroperitoneoscopic adrenalectomy is a new minimally invasive method. It represents an alternative to conventional open procedures and laparoscopic techniques. Between July 1994 and November 1995 a total of 30 retroperitoneoscopic adrenalectomies were performed on 27 patients. In 24 patients, unilateral tumors were seen (size 1-7 cm): seven Cushing adenomas, five Conn adenomas, seven pheochromocytomas, four hormonally inactive tumors, one cyst. Three patients suffered from Cushing syndrome with bilateral adrenal gland hyperplasias (two inoperable pituitary gland tumors, one bronchial carcinoid with ACTH secretion). The operations were carried out in prone position. After balloon dilatation of the retroperitoneum and creation of a pneumoperitoneum the preparation of the adrenal gland was performed via three trocar sites positioned below the 12th rib. Twenty-five adrenalectomies were completed endoscopically, and five times (among four patients) conversion to the conventional posterior technique was necessary. The average operating time of complete endoscopic adrenalectomies was 124 minutes (45-225 minutes); blood loss was 10 to 120 ml. With minimal need for postoperative analgesia (average dosage 7.9 mg of piritramide), mobilization and adequate food uptake were possible on the day of operation. The posterior retroperitoneoscopic adrenalectomy is a relatively fast, safe method, with the advantages of the posterior open approach and minimally invasive surgery. It therefore represents an important addition to adrenal gland surgery.

Analysis of National Toxicology Program rodent bioassay data for anticarcinogenic effects

We reanalyzed data from 218 two-year rodent carcinogenicity studies carried out by the National Toxicology Program (NTP). These data were originally collected for the purpose of identifying potential human carcinogens. However, the objective of our analysis was to investigate the frequency of possible anticarcinogenic effects in these data, since recurring cases of chemical-associated tumor reductions have been noted in the course of these studies over time. Our analysis reveals that most (> 90%) NTP-tested chemicals show at least one statistically significant ( p < 0.05) decrease in site-specific tumor incidence. Because of the large number of statistical comparisons made in a long-term bioassay, random variability can account for many of these tumor decreases. However, we found that certain tumors (predominantly those with a high spontaneous incidence) show chemically related decreases far more frequently than chance expectation. Many of these decreases, particularly those for pituitary and mammary gland tumors, adrenal pheochromocytoma and uterine polyps in rats and liver and lung tumors in mice, are associated with the reduced body weights frequently observed in the dosed groups. The chemically related decreased incidences of leukemia in rats appear to be related to spleen damage, i.e., chemically related splenic toxicity is evident for most chemicals showing decreased incidences of leukemia. While random variability, associations with body weight and splenic toxicity can account for most of the decreased tumor incidences observed in NTP studies, there are other tumor decreases that could not be totally explained by these factors. Further investigations of possible mechanisms of action are underway. These data are relevant to the concept of chemoprevention as well as to the task of using long-term laboratory animal studies to predict enhanced human environmental-cancer risk for regulatory purposes.