Clinical predictors of mortality and cause of death in lymphangioleiomyomatosis: a population-based registry.

PURPOSE: Lymphangioleiomyomatosis (LAM) is a rare, progressive, frequently lethal cystic lung disease that almost exclusively affects women. Prognostic information in LAM has been limited by small numbers and heterogeneous study methodology. Early retrospective cohorts cited 5- and 10-year mortality of 40 and 80 %, respectively. More recently, mortality at 10 years has been estimated to be approximately 10-20 % from the onset of symptoms and 30 % at 10 years from the time of lung biopsy but varies widely in individual patients. Given the heterogeneous disease course, it would be useful to establish which clinical characteristics are associated with survival to develop prediction models for disease outcome. METHODS: The LAM Foundation maintains a population-based registry of 1,149 registered self-identified LAM patients. Of these, 590 have completed a "General Information/Clinical History Questionnaire" with limited demographic and clinical data, 410 of whom were identified as U.S. residents and provided date of birth. Vital status was obtained on all 410 participants through December 31, 2007 by linking patient identifiers and the National Death Index. Survival time was calculated as the time since first lung-related symptom or physician diagnosis until censoring (still alive, received lung transplant, or died). Cox proportional hazard analysis evaluated the association of demographic and clinical features with survival. RESULTS: Among the 410 subjects, there were 50 deaths and 55 lung transplantations during a median of 10.4 years of observation time. The estimated median transplant-free survival time for LAM patients in the United States is 29 years from symptom onset and 23 years from diagnosis. The estimated 10-year survival transplant-free was 86 %. Age at disease onset, smoking status, race, presence of tuberous sclerosis, occurrence of pneumothorax, and pregnancy did not demonstrate an association with survival or transplant. Greater age at presentation and presence of angiomyolipoma were associated with less risk of mortality. Treatment with hormonal therapy was associated with an increased risk of death/transplant (hazard ratio (HR) 2.93; 95 % confidence interval (CI), 1.54-5.58; p = 0.001), particularly progesterone therapy (HR 2.17; 95 % CI 1.26-3.75, p = 0.005), and may represent confounding by indication. Patients who required oxygen therapy had a worse outcome (HR 4.53; 95 % CI 2.76-7.42; p < 0.001). CONCLUSIONS: Our population-based study showed that the median survival in patients with LAM from the onset of symptoms or diagnosis is much longer than previously described. This has important implications for life choices and treatment decisions regarding medication use and lung transplantation for patients with LAM.

Expression of endogenous xenotropic retrovirus by methylcholanthrene-induced squamous cell carcinoma of the mouse respiratory tract.

As a model for human lung cancer, squamous cell carcinomas were induced by 3-methylcholanthrene in mouse tracheas which had been explanted to a subcutaneous site. The tumors that developed were examined for both ecotropic and xenotropic infectious murine leukemia virus (MuLV). From all squamous carcinomas--six out of six--a xenotropic MuLV was isolated. From some of the fibrosarcomas that occurred incidentally in our induction system, ecotropic MuLV was isolated. However, in the fibrosarcomas, no xenotropic MuLV at all was found.

Purification and properties of a multifunctional calcium/calmodulin-dependent protein kinase from rat pancreas.

A calcium/calmodulin-dependent protein kinase (Ca/calmodulin protein kinase) was purified from rat pancreas using hydrophobic chromatography followed by gel filtration and affinity chromatography. Ca/calmodulin protein kinase from pancreas resembled previously described multifunctional Ca/calmodulin protein kinases from other tissues with respect to substrate specificity, autophosphorylation on serine and threonine residues, and catalytic and hydrodynamic properties. While Ca/calmodulin protein kinase from other tissues contains subunits of 53-60 kDa with variable proportions of a smaller 50-52 kDa subunit, pancreatic Ca/calmodulin protein kinase was found to contain a single component of 51 kDa. Experiments mixing brain Ca/calmodulin protein kinase with pancreatic homogenate suggest that the absence of a larger subunit in the pancreatic Ca/calmodulin protein kinase is not due to proteolytic degradation during enzyme preparation. Ca/calmodulin protein kinase binding to 125I-labeled calmodulin in solution was demonstrated using the photoaffinity cross-linker, N-hydroxysuccinimidyl-4-azidobenzoate. 125I-labeled calmodulin binding to Ca/calmodulin protein kinase was also demonstrated using filters containing Ca/calmodulin protein kinase transferred from polyacrylamide gels after two-dimensional gel electrophoresis. Finally, the ribosomal substrate for Ca/calmodulin protein kinase was identified as the ribosomal protein, S6. The purification procedure presented in this study promises to be useful in characterizing Ca/calmodulin protein kinase in other tissues and in clarifying the role of these enzymes in cellular function.

Detection of thyroglobulin, thyroid peroxidase, and RET/PTC1 mRNA transcripts in the peripheral blood of patients with thyroid disease.

PURPOSE: Detection of mRNA transcripts for thyroglobulin (TG), thyroid peroxidase (TPO) and RET/PTC1 in the peripheral blood of patients with thyroid disease. PATIENTS AND METHODS: TG, TPO, and RET/PTC1 mRNA were analyzed in 52 peripheral-blood samples from 44 patients diagnosed with thyroid carcinoma (24 patients), adenoma (five patients), and nodular hyperplasia (15 patients) by reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: TG and TPO were identified in 13 patients (54.2%) with thyroid carcinoma, which includes five of eight patients with no clinical evidence of disease at the time of blood collection. Four of 5 patients had cervical lymph node metastases and/or extrathyroid extension at the time of the initial surgery. RET/PTC1 mRNA was detected in the peripheral blood of only one patient with papillary thyroid carcinoma. This sample was also positive for TG and TPO. TG and TPO were detected in two patients (10%) with benign thyroid nodules. All positive samples from patients with benign thyroid lesions were collected before surgery, whereas all samples collected after surgery were negative. RET/PTC1 mRNA was not detected in any of the patients with benign thyroid nodules. RT-PCR positivity for TG and TPO mRNA was higher in patients with carcinoma than in patients with benign lesions (P = .002). CONCLUSION: TG, TPO, and RET/PTC1 mRNA are detectable in the peripheral blood of patients with thyroid disease, which correlates with a diagnosis of carcinoma.

Expression of messenger ribonucleic acids encoding a parathyroid hormone-like peptide in normal human and animal tissues with abnormal expression in human parathyroid adenomas.

A novel PTH-like peptide has recently been purified and cloned from human tumors associated with the syndrome of humoral hypercalcemia of malignancy. We surveyed the expression of mRNAs encoding this peptide in normal tissues by Northern analysis. One or more low abundance hybridizing transcripts was identified in poly(A)+ RNA prepared from human keratinocytes, thyroid, bone marrow, and fibroblasts, from bovine hypothalamus, pituitary, parathyroid, adrenal cortex, and adrenal medulla, and from rat brain, stomach mucosa, and fetal but not adult liver. One or more hybridizing transcripts was also identified in poly(A)+ RNA prepared from a number of established lines, including rat pituitary (GH4), rat pheochromocytoma (PC 12), human osteosarcoma (TE-85), and human medullary carcinoma (TT) cells. Northern analysis of mRNAs from abnormal human parathyroid tissue revealed an overexpression of transcripts for the PTH-like peptide which appeared to be specific for adenomatous or autonomous glands. These findings suggest that the PTH-like peptide is expressed in a number of endocrine and nonendocrine tissues, that it is developmentally expressed in at least one tissue (fetal liver), and that the regulation of its expression is abnormal in human parathyroid adenomas.

Transplantation of thymic tissue into patients with AIDS. An attempt to reconstitute the immune system.

Thymic epithelial fragments were transplanted into 15 patients in an advanced stage of the acquired immunodeficiency syndrome (AIDS). One patient was given interleukin 2 in addition to thymic tissue. We demonstrated the following: Thymic epithelial fragments cultured before transplantation to remove T cells survived for months after transplantation in eight of 15 patients and seemed to be responsible for a partial, selective, but transient repopulation of the circulating T-cell pool. The absolute number of T8 cells, but not T4 cells, increased three to four weeks after the procedure in eight of the 15 subjects. This increase in T8 cells was associated with clinical improvement in some cases and increased T-cell responsiveness in vitro. Thymic tissue transplantation as a single therapeutic maneuver is unlikely to reconstitute the immune system of patients with AIDS, but the potential of the approach, used in combination with agents that block replication of human T-cell lymphotropic virus type III, deserves further study.

Antibodies to an epitope on synapsin I detect a protein associated with the endocytic compartment in non-neuronal cells.

To detect potential substrate proteins for Ca2+/calmodulin-dependent protein kinase II outside the central nervous system, antibodies were made to a synthetic peptide corresponding to a sequence within synapsin I which is phosphorylated by this enzyme. In neural tissues, this antibody (212) identified an 86/80 kDa doublet corresponding to synapsin I. In rat liver, intestinal enterocytes and the clone 9 cell line this antibody identified two proteins of 170 and 85 kDa. These proteins were present in the particulate fraction of liver postnuclear supernatant, and were released into the soluble fraction when extracted with 100 mM NaCl. In liver, enterocytes, and clone 9 cells, these antigens were localized by immunocytochemical techniques to small intracellular vesicles. The endocytic compartment of clone 9 cells was labeled by continuous uptake of horseradish peroxidase; antibody 212-labeled vesicles exhibited overlap with the compartment. To confirm the identity of this compartment as endosomal, rat liver endosomes were labeled in vivo by intravenous injection of horseradish peroxidase. Horseradish peroxidase-containing endosomes of approximately 80 nm were recognized by antibody 212. Occasionally, larger endosomes (approximately 300-500 nm) were also labeled. In clone 9 cells, partial overlap was observed between the 212 antigen and a transferrin receptor-positive, brefeldin A-sensitive compartment. In clone 9 cells double-labeled with anti-tubulin and antibody 212, then imaged using confocal microscopy, these vesicles appeared to be associated with microtubules. This antigen has properties similar to that of CLIP-170, a membrane-associated endosomal phosphoprotein. These findings demonstrate that a 170/85 kDa antigen containing an epitope for the Ca2+/calmodulin-dependent protein kinase II phosphorylation sequence is associated with an endocytic compartment.

Calcium-calmodulin-dependent protein kinase in hyperplastic human parathyroid glands.

The function of the parathyroid gland is closely linked to intracellular and extracellular Ca2+ concentrations. As a step toward understanding the mechanism of action of Ca2+ on the parathyroid, we examined hyperplastic human parathyroid tissue for Ca2+ and calmodulin-dependent protein kinase activity. In parathyroid homogenates, Ca2+ stimulates the phosphorylation of substrate protein in the presence of calmodulin or phospholipid. The calmodulin (CaM)-stimulated activity is present in a soluble fraction of parathyroid and can be separated from other protein kinase activities by gel filtration chromatography. The concentration dependence of CaM kinase on Ca2+ and CaM was determined using the gel filtration. The Ka values for CaM and calcium were 100 nM and 5 microM, respectively. The fraction containing the CaM kinase activity had a calculated mol wt of 5.5 X 10(5). It contained a protein with a mol wt of 4.9 X 10(4) whose phosphorylation was Ca2+ CaM dependent and a CaM-binding protein of mol wt 4.9 X 10(4) which we suggest may be the catalytic subunit of a type II Ca2+-CaM dependent protein kinase. Hyperplastic human parathyroid tissue contains a type II Ca2+-CaM dependent protein kinase which may serve an important function in Ca2+-directed metabolism.

Reconstitution of calcium-regulated parathyroid hormone secretion from streptolysin-O-permeabilized parathyroid cells by guanosine 5'-O-(thio)triphosphate.

Intracellular Ca2+ levels determine the amount of PTH secretion from parathyroid cells. Dissociated calf parathyroid cells were permeabilized with streptolysin-O (SLO) to provide an in vitro model system to examine Ca(2+)-dependent regulation of hormone secretion. PTH release from these cells was energy dependent and increased by cytosolic cofactors. Guanosine 5'-O-(thio)triphosphate (GTP gamma S) increased PTH secretion from SLO-permeabilized cells in a dose-dependent manner from 0.1-100 microM. In the absence of GTP gamma S there was no relationship between the ambient Ca2+ concentration and the rate of PTH secretion. However, in the presence of GTP gamma S, intracellular Ca2+ inhibited PTH secretion with an EC50 of approximately 0.1 microM, corresponding to physiological intracellular Ca2+ levels. Thus, the addition of GTP gamma S to SLO-permeabilized parathyroid cells reconstituted the inverse relationship between extracellular Ca2+ and PTH secretion that is observed in vivo and in intact cells. The data indicate that this effect is mediated at least in part by heterotrimeric guanosine triphosphatases. In addition, calcium/calmodulin-dependent protein kinase II appears to mediate low Ca(2+)-dependent PTH secretion from these cells.

Expression of transcripts encoding a parathyroid hormone-related peptide in abnormal human parathyroid tissues.

A PTH-related peptide (PTHRP) has been identified and its cDNA cloned from human tumors associated with the syndrome of humoral hypercalcemia of malignancy. The human PTHRP gene has been recently isolated and found to be a complex transcriptional unit using multiple promoters and containing alternatively spliced 3' exons which result in three mRNA classes, each class encoding a PTHRP with a unique carboxy-terminus. The PTHRP gene appears to be expressed in a number of normal tissues, and PTHRP transcripts have been previously reported to be overexpressed in a small sample of human parathyroid adenomas. In the present study we surveyed RNA prepared from a total of 60 abnormal human parathyroid glands for PTHRP gene expression using a combination of Northern blotting and RNase protection techniques. Apparent overexpression of PTHRP mRNA was observed in two thirds of parathyroid adenomas, whereas no overexpression was found in 7 examples of sporadic primary hyperplasia, 5 examples of secondary hyperplasia, and 3 examples of parathyroid carcinoma. Apparent overexpression was also observed in 1 of 4 cases of multiple endocrine neoplasia type 1, 1 of 2 examples of multiple endocrine neoplasia type 2, and 1 gland considered to represent tertiary hyperparathyroidism. Northern analysis of poly(A)+ RNA prepared from three representative adenomas using region-specific probes indicated that two putative promoters are used and revealed a pattern of preferential splicing of transcripts to include the most distal 3' exon. These findings suggest that the PTHRP gene is commonly overexpressed in adenomatous parathyroid glands, but not in sporadic primary hyperplasia, that this overexpression does not seem to be dependent on the use of a single specific promoter, and that adenomatous parathyroid cells appear to preferentially use one of several alternative splicing pathways. It is presently not known whether PTHRP is secreted by abnormal parathyroid tissues and, if so, in what form.

DARPP-32 (dopamine and cAMP-regulated phosphoprotein, M(r) 32,000) is a membrane protein in the bovine parathyroid.

A distinct form of DARPP-32, a protein phosphatase-1 inhibitor, has been identified in bovine calf parathyroid glands. Immunoblot analysis of parathyroid tissue revealed a 32 kDa protein present predominantly in a particulate fraction; it remained particulate after treatment with 1.0 M NaCl or 0.1 M Na2CO3. Metabolic labeling of parathyroid cells with mevalonolactone demonstrated that DARPP-32 is isoprenylated. Immunocytochemical localization studies demonstrated that DARPP-32 is present in vesicles throughout the cytoplasm of parathyroid cells, and that protein phosphatase-1 gamma is concentrated in the region of the plasma membrane. Thus, in contrast to the predominately soluble form of DARPP-32 that has been characterized in selected areas of the central nervous system, the parathyroid form is tightly associated with intracellular membranes.

Corticotroph cell pituitary adenoma within an ovarian teratoma. A new cause of Cushing's syndrome.

A 24-year-old woman with severe Cushing's syndrome was found to have corticotroph cell pituitary adenoma arising within a benign cystic ovarian teratoma. The patient manifested sustained hypercortisolemia and lack of suppression of either adrenocorticotropin (ACTH) or cortisol production. There was no evidence of a pituitary mass or secretion of other hormones. After careful clinical evaluation, no other tumor masses were found. Resection of the ovarian tumor led to normalization of ACTH and cortisol levels. Densely granulated corticotroph tumor cells with prominent Type I microfilaments and intracytoplasmic ACTH immunoreactivity characterized the neoplasm as a pituitary corticotroph cell adenoma. This is, to our knowledge, the first case reported of a functioning pituitary adenoma arising within a benign cystic teratoma.

The H+, K(+)-ATPase inhibitor pantoprazole (BY1023/SK&F96022) interacts less with cytochrome P450 than omeprazole and lansoprazole.

The gastric acid antisecretory compound omeprazole (5-methoxy-2-((4-methoxy- 3,5-dimethyl-2-pyridinylmethyl)-sulphinyl)-1H-benzimidazole), a member of the new class of H+, K(+)-ATPase inhibitors, is known to interact with the metabolism of other drugs in vitro and in vivo. In this study, two other substituted benzimidazoles, pantoprazole (5-difluoromethoxy-2-((3,4-di-methoxy-2-pyridinylmethyl)-s ulp hinyl)-1H- benzimidazole) and lansoprazole (2-((3-methyl-4-(2,2,2-trifluoroethoxy)-2-pyridinylmethyl)- sulphinyl)-1H-benzimidazole) are compared for their ability to inhibit cytochrome P450 dependent biotransformation in vitro with regard to three representative reactions: O-dealkylation of 7-ethoxycoumarin (EC), N-demethylation of ethylmorphine (EM) and hydroxylation of lonazolac (Lona). These reactions can be seen in microsomes from phenobarbital pretreated rats representing the cytochrome P450IIB1 subfamily. As shown in presence of known inhibitors of cytochrome P450, e.g. SK&F 525A, metyrapone, chlorpromazine and nitrendipine, different enzymes seem to be responsible for these three indicator reactions of the cytochrome P450IIB1 complex. These reactions are inhibited to a different extent by the three H+, K(+)-ATPase inhibitors. Pantoprazole shows the lowest inhibitory activity versus the three reactions (Ki, mumol/L): EC, 138; EM, 104; Lona, 128. A greater effect is observed with omeprazole: EC, 38; EM, 68; Lona, 20. Lansoprazole exceeds omeprazole in inhibiting the three cytochrome P450 dependent enzymes: EC, 17; EM, 34; Lona, 8. In microsomes from untreated rats with the predominant cytochrome P450IIA1 subfamily as well as in microsomes from isopropanol treated rats (induction of cytochrome P450IIE1) which catalyse only lonazolac hydroxylation to a detectable amount, the latter reaction was inhibited by pantoprazole with a somewhat lower Ki of 77 whereas the values for omeprazole and lansoprazole remained unchanged in comparison to those found in microsomes from phenobarbital pretreated rats. The biotransformation rate of the substituted benzimidazoles themselves in microsomes from control and induced rats is lowest for pantoprazole followed by lansoprazole and omeprazole.

Inhibition of protein phosphatase 1 decreases PTH secretion from isolated dispersed parathyroid cells.

To investigate the regulation of parathyroid hormone secretion by phosphatases we examined the effect of okadaic acid, a selective inhibitor of protein phosphatases (PP)-1 and -2A, on isolated, dispersed parathyroid cells. Okadaic acid inhibited secretion from intact bovine, intact human and streptolysin-O permeabilized bovine cells. Approximately 10(-6) M okadaic acid resulted in a 50% decrease in parathyroid hormone (PTH) secretion from both intact and permeabilized cells, consistent with PP-1 being the target of inhibition. Upon subcellular fractionation, PP-1 overlapped but was not identical to either PTH, a marker of the secretory granule, or Na+/K+-ATPase, a plasma membrane marker. In summary, PP-1 activity is involved in Ca2+-dependent but not basal PTH secretion.

Management of ectopic thyroid nodules.

BACKGROUND: Surgical dictum states that the so-called lateral aberrant thyroid represents metastatic thyroid cancer. METHODS AND RESULTS: We present sixteen cases of patients with benign ectopic thyroid tissue. Seven cases were discovered during evaluation and treatment of hyperparathyroidism. The remaining nine cases were discovered during the evaluation and treatment of thyroid disorders or cervical nodules. In fifteen cases there is benign histology on the nodules. One case has been followed for 4 years with scans revealing a normal thyroid gland with an unchanging ectopic thyroid nodule in the superior mediastinum. In eight of our cases there have been thyroid resections searching for occult carcinomas. Histologic examination on these eight thyroid glands revealed either normal thyroid or benign nodules. CONCLUSIONS: Not all lateral aberrant thyroid tissue is malignant. The histologic condition of the nodule combined with intraoperative examination of the ipsilateral thyroid lobe can reliably guide therapy. The old dictum concerning lateral aberrant thyroid representing metastatic cancer should be removed from or modified in review texts and surgical examinations.

P-glycoprotein expression and multidrug resistance in adrenocortical carcinoma.

BACKGROUND: The response of adrenocortical carcinoma (ACC) to adjuvant chemotherapy has been disappointing with no significant impact on survival. The normal adrenal cortex has very high levels of P-glycoprotein, an energy-dependent efflux pump of a variety of structurally unrelated chemotherapeutic agents. P-glycoprotein has been implicated as a cause of multidrug resistance in a variety of neoplasms. The purpose of this study was to evaluate P-glycoprotein expression in ACC. METHODS: Eleven patients with ACC had paraffin-embedded tumor evaluated for P-glycoprotein expression. These were analyzed by immunohistochemistry assay with a battery of four anti-P-glycoprotein antibodies (MRK-16, JSB-1, UIC-2, MDR). RESULTS: All eleven cases showed intense, predominantly membrane immunoreactivity for P-glycoprotein. In 10 of the cases, most tumor cells were immunoreactive with at least three antibodies, and six of 11 cases were positive for all four antibodies. In this small series no correlation existed between P-glycoprotein expression and tumor grade, stage of disease, or survival. CONCLUSIONS: All 11 cases of ACC studied showed P-glycoprotein expression, which was similar to the normal adrenal cortex. This possible mechanism of multidrug resistance may help explain the significant chemoresistance seen in ACC.

Parathyroid carcinoma: the relationship of nuclear DNA content to clinical outcome.

This article reports the use of flow cytometry to determine tumor nuclear DNA content and its correlations with clinical outcome in a series of patients with parathyroid carcinoma. Information concerning nine patients with parathyroid cancer (aged 25 to 88 years) was reviewed. Paraffin-embedded, formalin-fixed archival tissue was used to determine tumor DNA content flow cytometrically. Twenty-five operative procedures were performed in nine patients, including 11 parathyroidectomies, two wide local excisions, six central neck dissections, and four median sternotomies for resection of metastases. With flow cytometry used to determine a tumor DNA index, five patients had evidence of tumor aneuploidy; in two patients two aneuploid peaks were evident. The DNA index ranged from 0.7 (hypodiploid) to 1.92 (mean, 1.31). Follow-up ranged from 1 to 18 years. Four patients died. Five were alive 1 to 13 years after diagnosis of parathyroid disease. Four of the five patients with evidence of tumor aneuploidy had metastatic disease and died, and the fifth has had three local recurrences. The four patients with diploid tumors were alive and free of disease 1, 3, 4, and 8 years after the initial operation. It is concluded that in patients with clinically or pathologically demonstrated parathyroid cancer, flow cytometry may help differentiate those whose cancers are likely to behave indolently (diploid tumors) from those with tumors (aneuploid) more likely to behave aggressively by recurring locally or metastasizing.

Poorly differentiated ("insular") carcinoma of the thyroid gland: an aggressive subset of differentiated thyroid neoplasms.

Four patients with a histologically distinctive thyroid carcinoma--which recently has been referred to as poorly differentiated ("insular") carcinoma--are reported. This study confirms the previous conclusions that patients with this neoplasm often experience an aggressive clinical course, with focal recurrences and distant metastases common, which results in death in the majority of patients. Such aggressive behavior may occur even when the insular component accounts for only a small percentage of an otherwise well-differentiated carcinoma, as seen in one of our patients. After subtotal or total thyroidectomy, three of the four patients have experienced local recurrence (1) and metastases to lung (3), mediastinum (1), and bone (1). All three of these patients died within 2 years of the diagnosis of insular carcinoma. The remaining patient is alive without evidence of disease 1 year after total thyroidectomy. Histologically, this neoplasm is characterized by well-defined nests (insulae) that are composed of relatively small, uniform cells and sometimes associated with small, thyroglobulin-containing follicles. Tumor necrosis is often present. Insular carcinoma may comprise the entire neoplasm (2 patients) or be associated with well-differentiated follicular (1 patient) or papillary (1 patient) carcinoma. The rapid and often fatal course associated with insular carcinoma warrants aggressive treatment at the time of initial diagnosis, including total thyroidectomy and node dissection (if involved), as well as possible iodine-131, external beam irradiation and chemotherapy.

Mechanism of technetium 99m sestamibi parathyroid imaging and the possible role of p-glycoprotein.

BACKGROUND: Localization of parathyroid glands is critical in the treatment of recurrent or persistent hyperparathyroidism. Technetium sestamibi imaging may improve localization; however, the mechanism of visualization of parathyroid tissue remains unclear. On the basis of the chemical structure of sestamibi it has been suggested that p-glycoprotein is involved in the transport of sestamibi across cell membranes. This study was designed to examine sestamibi uptake and retention and p-glycoprotein expression in normal and abnormal parathyroid tissue. METHODS: Thirty-two consecutive patients underwent 2-methoxy-isobutyl-isonitrile imaging immediately before parathyroid exploration. Tissue was obtained from normal and abnormal parathyroids and from the thyroid gland. Touch preparations gave rapid confirmation of tissue origin. Specimens were trimmed and weighed, and gamma-emission was counted. Percentage injected dose per gram of tissue was calculated. Immunohistochemistry was obtained with a battery of monoclonal antibodies to identify p-glycoprotein in parathyroid tissue submitted for permanent histologic examination. Slides were graded by a pathologist familiar with immunohistochemistry. RESULTS: Abnormal parathyroid tissue had a higher mean retention of injected dose per gram than did normal thyroid and parathyroid tissue. Immunohistochemistry revealed that abnormal parathyroid tissue expresses less p-glycoprotein. CONCLUSIONS: These results suggest that size is not the single determinant of parathyroid visualization and that p-glycoprotein expression may be involved in the mechanism of parathyroid imaging.

Advances in the diagnosis and treatment of pheochromocytoma.

Diagnosis and management of pheochromocytoma, once dangerous and uncertain, have been dramatically altered in recent years by advances in imaging, assays, and pharmaceuticals. During the past ten years we have treated 18 patients who had pheochromocytoma. Biochemical diagnosis was made in all patients by measurement of 24-hour urinary total catecholamine excretion or by epinephrine-norepinephrine fractionation. Determination of epinephrine-norepinephrine ratios was instrumental in making the diagnosis of pheochromocytoma in two patients in whom total catecholamine levels were normal. Localization of the pheochromocytoma in the most recently treated cases was accomplished by ultrasound, computed tomography, or iodine I 131 iobenguane (iodine I 131 metaiodobenzylguanidine) scanning. Nine patients in the series were prepared for surgery with phenoxybenzamine hydrochloride and six with prazosin hydrochloride. Preoperative total alpha-adrenergic blockade with phenoxybenzamine offered no advantage over selective blockade with prazosin in terms of perioperative fluid requirements or intraoperative hemodynamic stability.