Iatrogenic pheochromocytomatosis: a previously unreported result of laparoscopic adrenalectomy.

BACKGROUND: Laparoscopic adrenalectomy is now regarded as the procedure of choice for treatment of small or benign adrenal tumors, including pheochromocytoma. However, long-term outcomes have not been critically assessed. We report here 3 cases of pheochromocytomatosis recurring 3 to 4 years after laparoscopic adrenalectomy. We postulate laparoscopic-induced seeding of tumor as the mechanism of recurrence. METHODS: We retrospectively reviewed the cases of 3 patients with documented biochemical and radiolabeled metaiodobenzylguanidine evidence of recurrent pheochromocytoma after prior presumed curative laparoscopic adrenalectomy. RESULTS: Original pheochromocytomas were 5.5 to 6.5 cm in diameter. At the time of laparoscopic adrenalectomy, tumors were not believed to be malignant, based on clinical or histopathologic data. However, on 3- to 4-year follow-up, each patient developed symptoms, elevated urinary catecholamine levels, and metaiodobenzylguanidine imaging consistent with recurrence. At reoperation, multiple small tumor nodules were found in the adrenal bed near the site of the initial laparoscopic resection. The original operative notes suggested some possible method of local seeding: tumor fragmentation and spillage or excessive tumor manipulation. CONCLUSIONS: Pheochromocytoma recurrence may occur as a result of local spillage of tumor during laparoscopic adrenalectomy. The relative risk of recurrence between open and laparoscopic resection needs to be assessed. Long-term follow-up will continue to be important, regardless of operative approach.

Genetically modified foods--safety and regulatory issues.

Gene technology is a new form of biotechnology with much greater potential applications.

Normal female infants born of mothers with classic congenital adrenal hyperplasia due to 21-hydroxylase deficiency.

Women with congenital adrenal hyperplasia due to 21-hydroxylase deficiency, especially those patients with the salt-losing form, have decreased fertility rates. Pregnancy experience in this population is limited. We report the pregnancy outcomes and serial measurements of maternal serum steroid levels in four women with classic 21-hydroxylase deficiency, three of whom were female pseudohermaphrodites with the salt-losing form. These glucocorticoid-treated women gave birth to four healthy female newborns with normal female external genitalia, none of whom were affected with 21-hydroxylase deficiency. In three women, circulating androgen levels increased during gestation, but remained within the normal range for pregnancy during glucocorticoid therapy. In the fourth patient, androgen levels were strikingly elevated during gestation despite increasing the dose of oral prednisone from 5 to 15 mg/day (two divided doses). Notwithstanding the high maternal serum concentration of androgens, however, placental aromatase activity was sufficient to prevent masculinization of the external genitalia of the female fetus and quite likely the fetal brain, consistent with the idea that placental aromatization of androgens to estrogens is the principal mechanism that protects the female fetus from the masculinizing effects of maternal hyperandrogenism. These four patients highlight key issues in the management of pregnancy in women with 21-hydroxylase deficiency, particularly the use of endocrine monitoring to assess adrenal androgen suppression in the mother, especially when the fetus is female. Recommendations for the management of pregnancy and delivery in these patients are discussed.

Occult virilizing ovarian tumours in postmenopausal women: problems in evaluation with reference to a case.

A 53-year-old postmenopausal presented with hirsutism, acne, receding hairline, male-pattern baldness, and deepening of voice developing over the last five years. Her left ovary had been removed at the age of 38 years old for a benign cyst and vaginal hysterectomy was performed one year later for cervical carcinoma. She had taken premarin 0.625 mg daily since her surgeries. Initial hormonal studies revealed elevated serum concentrations of total testosterone 524 ng/dL (N: 6-86 ng/dL), free testosterone 20.9 pg/mL (N: 0.3-2.7 pg/mL), and 17-hydroxyprogesterone 270 ng/dL (N: < 70 ng/dL); but normal baseline concentrations of dehydroepiandrosterone-sulfate, androstenedione, and cortisol. Computed tomographic (CT) scans of the adrenals and ultrasonography of the pelvis were negative. Magnetic resonance imaging (MRI) of the abdomen and pelvis similarly were non-revealing. She was given glucocorticoids without effect. Subsequently, retrograde selective venous sampling showed a marked testosterone gradient in the right ovarian vein. A laparoscopic right oophorectomy was performed and a 11 mm Leydig cell tumour of hilus cell type was detected on histologic examination. Postoperative testosterone levels returned to normal and she had slow regression of hirsutism. Our case illustrates that a virilizing ovarian neoplasm can be small and elude imaging studies. We suggest bilateral oophorectomy for postmenopausal women with severe recent-onset virilization and without Cushing's syndrome and with normal adrenal imaging. This approach avoids unnecessary investigations and delays in definitive management.

Diabetes insipidus from sarcoidosis confined to the posterior pituitary.

A young white man with new-onset central diabetes insipidus was discovered to have a posterior pituitary mass on magnetic resonance imaging. No other radiological abnormalities were noted in the anterior pituitary, infundibulum or hypothalamus. No other endocrinopathies were present: laboratory investigations showed normal basal concentrations of anterior pituitary hormones, including prolactin. The patient was suspected to have sarcoidosis affecting the posterior pituitary, because of the discovery of pulmonary sarcoidosis during his diagnostic evaluation. His symptoms of polydipsia and polyuria responded promptly to intranasal administration of 1-desamino-8-D-arginine vasopressin (DDAVP). The patient demonstrated complete regression of the posterior pituitary mass after a course of corticosteroid therapy. However, his diabetes insipidus persisted and he continues to need DDAVP treatment, currently at 12 months of follow-up. The resolution of the neurohypophysial mass was compatible with the diagnosis of pituitary sarcoidosis and this precluded the need for a transsphenoidal biopsy or surgery.

The treatment of malignant pheochromocytoma with iodine-131 metaiodobenzylguanidine (131I-MIBG): a comprehensive review of 116 reported patients.

Iodine-131 metaiodobenzylguanidine (131I-MIBG), a radiopharmaceutical agent used for scintigraphic localization of pheochromocytomas, has been employed to treat malignant pheochromocytomas since 1983 in a few specialized centers around the world. We review our clinical experience together with the published experience of 23 other centers in 10 countries, regarding the use of 1311-MIBG for treating patients with malignant adrenal pheochromocytomas or extra-adrenal paragangliomas. There were a total of 116 evaluable patients: 3 were from our current report and another 113 were reported in the literature from 1983 to 1996. A majority of the patients were selected for treatment based upon positive tracer uptake studies. The cumulative dose of 131I-MIBG administered ranged from 96 to 2,322 mCi (3.6 to 85.9 GBq), with a mean (+/-SD) of 490+/-350 mCi (18.1+/-13.0 GBq). The subjects received a mean single therapy dose of 158 mCi (5.8 GBq) and the number of doses administered ranged from 1 to 11, with a mean of 3.3+/-2.2 doses. Initial symptomatic improvement was achieved in 76% of patients, tumor responses in 30%, and hormonal responses in 45%. Five patients had complete tumor and hormonal responses, ranging from 16 to 58 months, which were sustained at the time of reporting. Patients with metastases to soft tissue had more favorable responses to treatment than those with metastases to bone. No difference was noted in the age between the responders and non-responders. Adverse effects, recorded in 41% of the treated patients, were generally mild except for one fatality from bone marrow aplasia. Among 89 patients with follow-up data, 45% of the responders had relapsed with recurrent or progressive disease after a mean interval of 29.3+/-31.1 months (median 19 months). Of patients with an initial response to 1311-MIBG, death was reported in 33% after a mean of 23.2+/-8.1 months (median 22 months) following treatment. Of non-responders, death was reported in 45% after a mean of 14.3+/-8.3 months (median 13 months). In conclusion, this review suggests that 131I-MIBG therapy may be a useful palliative adjunct in selected patients with malignant pheochromocytoma or paraganglioma. Although controlled studies are lacking, our review raises the hope that this therapeutic modality may prolong survival with an occasional sustained complete remission or possible cure.

Two fetal hemoglobin variants affecting the same residue: Hb F-Emirates [G gamma 59(E3)Lys-->Glu] and Hb F-Sacromonte [G gamma 59(E3)Lys-->Gln].

Two fast-moving fetal hemoglobin variants were discovered in hematologically normal newborn babies; the first originated in the United Arab Emirates and the second in France. The structural study, carried out by miniaturized techniques of protein chemistry, showed that these two mutations affected the same residue of the G gamma chain, the lysine at position 59(E3) was replaced by glutamic acid in Hb F-Emirates, and by glutamine in Hb F-Sacromonte.

HB Al-Ain Abu Dhabi [alpha 18(A16)Gly----Asp]: a new hemoglobin variant discovered in an Emiratee family.

During a routine program of hemoglobin screening performed in the United Arab Emirates, we observed an electrophoretically fast-moving variant in a 9-month-old girl and in several members of her family. The structural determination, performed by reversed phase high performance liquid chromatography and amino acid sequencing, revealed a new variant that we named Hb Al-Ain Abu Dhabi [alpha 18(A16) Gly----Asp]. Its functional properties were normal.

Human pituitary tumors secrete chromogranin-A.

Chromogranin-A (CgA) has emerged as a serum and tissue marker for a number of endocrine tumors. We studied 15 patients with pituitary tumors to evaluate the clinical value of CgA as a serum and tissue marker for such tumors. One third of the patients had elevated serum CgA levels; 2 of these patients had nonsecreting pituitary tumors, and the other 3 had corticotroph adenomas. CgA-positive cells were detected in 9 of the 11 anterior pituitary tumors that were immunostained; in these 9 tumors at least half of the cells were CgA positive. We conclude that CgA production is common in pituitary tumors and that immunohistochemical studies for CgA may aid in their classification. In addition, serum CgA measurements may help to identify patients with pituitary tumors, especially those that do not secrete a known pituitary peptide.

Cushing's syndrome due to bilateral adrenal macronodular hyperplasia with undetectable ACTH: cell culture of adenoma cells on extracellular matrix.

A 59-year-old man developed Cushing's syndrome with massive bilateral adrenal macronodular hyperplasia. Plasma ACTH levels were undetectable both peripherally and in the inferior petrosal sinus. Computed tomography scans of his pituitary were normal. Hypercortisolism was not suppressed by high doses of dexamethasone. His adrenal cells were successfully isolated and grown on bovine corneal extracellular matrix. The cultured cells displayed strikingly rapid growth and hypersecretion of cortisol during incubation with control serum. Addition of the patient's serum to cultured fetal adrenal cells did not accelerate their growth. This was the first experience with our in vitro system in this rare clinical condition. The techniques described here may be used for future in vitro adrenal studies. These in vivo and in vitro data indicate that this patient's bilateral adrenal hyperfunction and growth were independent of ACTH.

Changes in milk carbohydrates during lactation in the eastern quoll, Dasyurus viverrinus (Marsupialia).

1. Milk samples were obtained at various stages of lactation from 16 captive eastern quolls. 2. The mean milk carbohydrate concentration was 7.4% (w/v; total hexose) at 8 weeks post partum, decreasing to 5.2% at 17 weeks and to less than 2% at the end of lactation. 3. The predominant monosaccharide constituent of the carbohydrates was galactose, followed by glucosamine, glucose and sialic acid. 4. Thin layer and gel chromatography showed that the milk carbohydrates consisted of lactose and a variety of higher oligosaccharides, some of which appeared to be identical to oligosaccharides of known structure previously isolated from milk of the tammar wallaby, Macropus eugenii. 5. In general, both the quantitative and qualitative changes observed in the milk carbohydrates of the eastern quoll were similar to those documented for macropodids.

Opportunistic infections in acquired immune deficiency syndrome result from synergistic defects of both the natural and adaptive components of cellular immunity.

We evaluated the cellular immunity of 408 clinically stratified subjects at risk for acquired immune deficiency syndrome (AIDS), to define the role of interferon-alpha production deficits in the pathogenesis of opportunistic infections (OI). We followed 115 prospectively for up to 45 mo. Onset of OI was associated with, and predicted by, deficiency both of interferon-alpha generation in vitro, and of circulating Leu-3a+ cells. Interferon-alpha production is an index of the function of certain non-T, non-B, large granular lymphocytes (LGL) that are independent of T cell help. Leu-3a+ cell counts are a marker of T cell function. OI did not usually develop until both of these mutually independent immune functions were simultaneously critically depressed, leading to a synergistic interaction. These data suggest that the AIDS virus affects a subset of LGL, and that cytokine production by these cells is an important component of the host defense against intracellular pathogens that becomes crucial in the presence of severe T cell immunodeficiency.

Natural killer cell function and interferon generation in patients with primary immunodeficiencies.

Patients with primary immunodeficiency disorders were evaluated for three aspects of natural defense: natural killer (NK) cells which lyse HSV-infected fibroblasts [NK(HSV-FS)], NK cells which lyse K562 tumor targets [NK(K562)], and interferon-alpha generation. In addition, capacity to make interferon upon challenge with other commonly used inducers was also evaluated. Most patients with severe combined immunodeficiency disease (SCID) and deficits of both T- and B-cell function demonstrated normal NK function with one or both targets. Six of eight SCID patients generated interferon-alpha at or below the lower limit of normal while only two made clearly normal levels. Six of 10 patients with Wiskott-Aldrich syndrome (WAS) had normal NK(K562) and five of 10 generated normal levels of interferon-alpha but all had severely deficient NK(HSV-FS). Patients with Bruton's agammaglobulinemia demonstrated normal NK and interferon generation, as did patients with common variable immunodeficiency, even when subdivided into patients with T-cell proliferative deficiencies and those with only hypogammaglobulinemia. Natural defense parameters may help categorize patients with SCID and WAS and help define these heterogeneous diseases.

Cerebral salt wasting after pituitary exploration and biopsy: case report.

We report a case of hyponatremia associated with volume depletion after pituitary exploration and biopsy. The presence of clinical dehydration precluded diagnosis of the syndrome of inappropriate secretion of antidiuretic hormone. The absence of a hypoadrenal state and the patient's response to volume reexpansion were consistent with a diagnosis of primary cerebral salt wasting.

An overnight high-dose dexamethasone suppression test for rapid differential diagnosis of Cushing's syndrome.

We have developed a high-dose dexamethasone suppression test that can be administered overnight with a single 8-mg dose and used the new procedure in the differential diagnosis of 83 patients with Cushing's syndrome. In 76 patients with surgically or pathologically proven cause--60 with Cushing's disease, 7 with the ectopic adrenocorticotrophic hormone syndrome, and 9 with adrenal tumors--suppression of plasma cortisol levels to less than 50% of baseline indicated a diagnosis of Cushing's disease. The test had a sensitivity of 92%, a specificity of 100%, and a diagnostic accuracy of 93%. These values equal or exceed those of the standard 2-day test whether based on suppression of urinary 17-hydroxycorticosteroids or plasma cortisol. We conclude that this overnight, high-dose dexamethasone suppression test is practical and reliable in the differential diagnosis of Cushing's syndrome.

Human natural killer cells limit replication of herpes simplex virus type 1 in vitro.

Studies were undertaken to determine whether natural killer (NK) cells could inhibit the replication of herpes simplex virus type 1 (HSV-1) in culture. In the absence of effector cells, HSV-1 was found to replicate in fibroblasts with up to a 100-fold increase in virus titer from 4 to 16 hr after incubation at 37 degrees C. Human peripheral blood mononuclear cells were found to limit virus replication in a dose-dependent manner, with the greatest inhibition being observed at the highest concentration evaluated: i.e., an effector:target ratio of 800:1. The antiviral effect was not observed when nonactivated or virus-activated mononuclear cells were added to the virus preparations at the end (instead of the beginning) of the assay period, indicating that the observed effect was not due to a nonspecific toxicity of soluble factors released from freeze-thawed effectors. Neither was inhibition of HSV-1 replication due to the generation of interferon (IFN) during the NK assay, because the addition of anti-IFN did not abrogate the antiviral effect. Thus, the inhibition of viral replication was most likely due to a cytotoxic effector rather than to release of soluble factors. The effector cells responsible for limiting HSV-1 replication were shown to be NK cells by a number of criteria. Mononuclear cells from both HSV-1 seropositive and seronegative donors limited virus replication; their activity could be boosted by pretreatment of effector cells with IFN; the effector cells which limited virus replication were found in Percoll gradient fractions enriched for large granular lymphocytes; and the effector cells shared the cell surface phenotype of NK cells--they were enriched in populations depleted of T cells by panning with Leu-4 and were depleted of activity by treatment with the anti-NK antibody Leu-11b plus complement. We conclude that human NK cells are capable of recognizing and lysing HSV-1-infected target cells before infectious virus progeny are generated. These results suggest that NK cells, acting early in the course of an infection, might serve to limit HSV-1 replication and therefore reduce the virus load in the host before the development of the adaptive immune response and clearance of the infection.

Deficiency of interferon-alpha generating capacity is associated with susceptibility to opportunistic infections in patients with AIDS.

Acquired immune deficiency syndrome (AIDS) is a newly described syndrome in which patients are susceptible to certain malignancies and opportunistic infections (OI) usually found only in immunosuppressed individuals. Patients with AIDS have been found to have deficiencies of virtually all of their host defense systems. In this report, the natural resistance systems have been discussed. Although a deficiency of NK-cell function has been found in many patients with AIDS, this deficiency failed to distinguish patients susceptible to OI or malignancy from male homosexual controls. A deficiency of interferon-alpha generation by mononuclear cells upon exposure to HSV-1 infected fibroblasts was the best correlate with susceptibility to OI in AIDS patients. This deficiency failed to correlate with serum levels of acid-labile interferon-alpha in these patients. Although the interferon generating deficiency may be caused by the infections in these patients, it is more likely that the deficiency lays the groundwork for the establishment of the opportunistic infections.

Severe acquired immune deficiency syndrome in male homosexuals: diminished capacity to make interferon-alpha in vitro associated with severe opportunistic infections.

Natural killer cell function, directed against either K562 tumor targets or herpes simplex virus type 1-infected fibroblasts, was often low in patients with acquired immune deficiency syndrome (AIDS) but failed to distinguish these patients from either male homosexual controls or patients with lymphadenopathy. Mononuclear cells from patients with AIDS and opportunistic infections generated diminished levels of interferon-alpha in response to herpes simplex virus type 1-infected fibroblasts. This deficiency discriminated patients with severe opportunistic infections from most individuals with either generalized lymphadenopathy or Kaposi's sarcoma only and from male homosexual control subjects. The deficiency in interferon-alpha generation may be the consequence of the opportunistic infections that these individuals have contracted or may be a direct manifestation of AIDS itself.