Parathyroid carcinoma is a rare, reported to be less than 1% of patients with primary hyperparathyroidism. Recently, cell cycle regulators such as the retinoblastoma gene and p53 have been implicated in the pathogenesis of parathyroid carcinoma. Yet definite diagnosis remains difficult not only clinically but also pathologically. However, the clinical presentation, biochemical and hormonal findings, and appearance at the operation may possibly raise suspicion regarding the diagnosis. A radical en bloc resection at the primary operation is most important. Even after a successful initial operation parathyroid carcinoma carries an increased risk of recurrence. There is wide diversity in the interval between the initial operation and the manifestation of metastasis. Histopathology and DNA ploidy are valuable predictors of the clinical outcome. Because the severe hypercalcemia it engenders has catastrophic consequences, proper management of the recurrent hypercalcemia is also mandatory. The lung is the most common site of distant metastasis. Selected patients with pulmonary metastasis of parathyroid carcinoma can obtain significant benefit from aggressive surgical resection even when they have multiple or recurrent lesions. When hypercalcemia is refractory to surgical resection, medical treatment with bisphosphonate has a beneficial effect.

Carcinoma↗

PubMedDate not supplied

Point mutations of ras genes in human adrenal cortical tumors: absence in adrenocortical hyperplasia.

Point mutations of ras genes (K-, H-, and N-ras) at codons 12, 13, and 61 and of the Gi2 alpha gene at codons 179 and 205, were studied in 56 primary adrenal cortical tumors and 6 adrenal cortical hyperplasias. Of 56 tumors, 24 were carcinomas and 32 were benign. The 24 carcinomas and 20 of the benign tumors were from American patients; the 12 remaining adenomas were from Japanese patients. Of the benign tumors 12 were cortisol-producing adenomas, 15 were aldosterone-producing adenomas, 3 were nonfunctioning adenomas, and 2 were adenomas that produced a virilizing syndrome. Tumor DNA obtained from archival formalin-fixed, paraffin-embedded tissue or fresh frozen tissue was amplified by polymerase chain reaction; and point mutations were detected by sequence-specific oligonucleotide hybridization. Activating ras mutations were found in 7 of 56 (12.5%) of all tumors: 3 of 24 (12.5%) carcinomas and 4 of 32 (12.5%) adenomas. Of adenomas from an American population, 4 of 20 (20%) exhibited positive ras mutations, whereas none was present in the Japanese tumors. All mutations detected were adenine to guanine transitions at the second position of N-ras codon 61, resulting in a conversion from glutamine to arginine. No mutations were found in K-ras or H-ras genes. Furthermore, no mutations of the Gi2 alpha gene were identified. These findings demonstrate that N-ras mutations at codon 61 may contribute to the genesis of both benign and malignant human adrenal cortical tumors. Finally, no mutations of the ras or Gi2 alpha genes were identified in hyperplastic adrenocortical tissues.

Adenoma↗

PubMedDate not supplied

Insulin-like growth factor I receptors and insulin-like growth factor-binding proteins in human parathyroid tumors.

Studies have demonstrated the presence of epidermal growth factor receptors in human parathyroid tumors. However, there is little information on the effect of other peptide growth factors on parathyroid cell growth. We therefore studied the interaction of insulin-like growth factor I (IGF-I) with human parathyroid tumor cells. Parathyroid tissues were obtained from 24 patients with primary or secondary hyperparathyroidism. There were 15 solitary adenomas, 5 carcinomas, and 4 hyperplastic tissues. First, the binding of [125I]IGF-I to the crude membrane fractions was studied by competitive inhibition with unlabeled IGF-I. Second, isolated parathyroid cells were cultured with IGF-I and examined for DNA synthesis. The IGF-binding protein (IGFBP) content of tissue homogenates was determined by ligand blot analysis. The binding of [125I]IGF-I to parathyroid membranes was dependent on time, temperature, and pH of the medium. Maximum binding was obtained after incubation for 18 hours at 4 degrees C. Specific binding to parathyroid cancer membranes (mean +/- SE, 10.75 +/- 10.55%/mg protein) was significantly (p < 0.05) greater than that in adenoma tissues (3.71 +/- 2.11%/mg). The value in hyperplastic tissues (4.78 +/- 2.97%/mg) was not different from that in adenomas. Affinity cross-linking and autoradiography demonstrated the type I IGF receptors. Cultured parathyroid cells responded to IGF-I with increased DNA synthesis. The parathyroid tumor tissues expressed IGFBPs. These results suggest that IGF-I and IGFBPs are involved in the growth regulation of parathyroid tumor cells.

Adenoma↗

PubMedDate not supplied

Hypoglycemia induced by excessive rebound secretion of insulin after removal of pheochromocytoma.

During an 8-year-period from 1981, a total of 6 of 45 patients with pheochromocytoma developed severe hypoglycemia (plasma glucose, 12-50 mg/dl) 2-4 1/2 hours after removal of the tumor. In order to elucidate the pathogenesis of the hypoglycemic attack, the levels of plasma immunoreactive insulin (IRI) and glucose were sequentially measured at surgery in 10 patients with pheochromocytoma, from the beginning of the operation until usually 5 hours after tumor resection. The same examinations were carried out in 4 patients with primary aldosteronism and 1 patient with Cushing's syndrome as controls. The highest plasma IRI levels observed in the 2 patients with postexcisional hypoglycemia were 174 and 2,081 microU/ml and those in the 8 patients without hypoglycemia were 13-222 microU/ml (mean, 77), but they were only 14-33 microU/ml (mean, 22) in the 5 control patients. The mean of the highest plasma IRI/glucose ratios in the immediate postoperative phase was 1.37 +/- 0.87 in the 10 patients with pheochromocytoma but only 0.16 +/- 0.04 in the 5 control patients (p less than 0.01). Review of the clinical data in our series disclosed that patients with higher levels of preoperative urinary epinephrine excretion and those with either diabetes mellitus or impaired glucose tolerance tended to develop postoperative hypoglycemia. These observations suggest that endogenous insulin secretion is suppressed by increase plasma catecholamines, and that excessive rebound secretion of insulin after removal of a pheochromocytoma is a rather common phenomenon. Intravenous infusion of glucose is necessary and plasma glucose levels should be monitored after resection of a pheochromocytoma.

Adrenal Gland Neoplasms↗

PubMedDate not supplied

Clinical significance of associated nodular lesions of the adrenal in patients with aldosteronoma.

Thirty-seven patients with primary aldosteronism were treated by unilateral total adrenalectomy during a 7-year period (1981-1987). The 37 patients were classified into 3 groups on the basis of adrenal pathology: unilateral solitary adenoma, 23 cases (group 1); unilateral adenomas, 3 cases (group 2); and adenoma with multiple macro- or microscopic nodules, 11 cases (group 3). The preoperative conditions of the patients (age, duration of hypertension, plasma renin activity, plasma aldosterone concentration, and serum potassium concentration), postoperative sequential changes of hormone levels, and outcome of hypertension were compared among the groups in order to determine whether the differences of adrenal pathology would affect the postoperative course. The preoperative parameters excluding age at surgery did not differ significantly among the 3 groups. The mean age in group 3, however, was slightly higher than in groups 1 and 2 (47.8 versus 42.8 versus 42.7 years). Postoperative hormonal changes were also similar, particularly in groups 1 and 3, staying within the normal range throughout the follow-up period (mean, 31 months; range, 3-86 months). However, postoperative improvement of hypertension showed marked differences, being significantly retarded in patients with multinodular lesions (group 3), about half of whom remained hypertensive even after 1 year. Nodular lesions other than adenoma(s) were, therefore, thought not to contribute to hormonal excess but to result from intractable hypertension.

Adenoma↗

PubMedDate not supplied

Diagnosis and treatment of patients with parathyroid carcinoma: an update and review.

Parathyroid carcinoma is a rare cause of primary hyperparathyroidism. However, to our best knowledge, at least 163 cases of functioning parathyroid carcinoma appeared in the English literature from 1981 to 1989. We summarize the available information obtained from the reports of those patients and compare it with previous descriptions of the disease. The etiology of parathyroid carcinoma is usually obscure, but the possibility of a radiation-induced malignant change in the parathyroid gland became evident in a few patients. Clinical manifestations, including age, sex, symptoms, and biochemical findings in this review were comparable to those in previous reviews. Noninvasive localization studies such as ultrasonography may offer a diagnostic clue to parathyroid carcinoma. Measurement of DNA content is a useful adjunct for making the histologic diagnosis of parathyroid carcinoma and prediction of the clinical outcome. Since the initial operation offers the best chance for cure, pre-operative suspicion and intra-operative recognition of the parathyroid cancer are essential. The initial operation should be en bloc resection of the tumor, avoiding rupture of the tumor capsule and spillage of tumor cells. As parathyroid carcinoma is a slow-growing but tenacious malignancy, repeated resection of local recurrent tumors or even distant metastases is effective for palliation of recurrent hypercalcemia and occasional cure. When hypercalcemia is refractory to surgical therapy or no recurrent tumor can be identified, other modalities of therapy must be considered. New drugs to control hypercalcemia by inhibiting bone resorption may hold promise in patients with recurrent parathyroid carcinoma.

Humans↗

PubMedDate not supplied

Retrospective analysis of prognostic factors affecting the thyroid functional status after subtotal thyroidectomy for Graves' disease.

To determine the factors causing thyroid dysfunction after surgery for Graves' disease, we studied 321 patients who underwent subtotal thyroidectomy during the 7-year period from 1981 to 1987. Thyroid functional status was evaluated biochemically and the patients were divided into four categories: recurrent hyperthyroidism, euthyroidism, latent hypothyroidism, and hypothyroidism. The following factors were analyzed: sex, age at onset of the disease, indication for surgery, serum titer of antimicrosomal hemagglutination antibody (MCHA), weight of resected thyroid tissue, size of remnant thyroid relative to body surface area, pathological findings of lymphoid follicles, and lymphocytic infiltration in the thyroid tissue. Probabilities of failure (recurrent hyperthyroidism and hypothyroidism) were estimated by the Kaplan-Meier method. Prognostic factors for failure were identified by using Cox's proportional hazards model. The incidence of hyperthyroidism and hypothyroidism 5 years after subtotal thyroidectomy was 16.2% and 9.6%, respectively. Significant factors for hyperthyroidism were relatively large thyroid remnant, high serum titer of MCHA (greater than or equal to 1:3200), and age at onset of the disease less than 20 years. The significant factor for hypothyroidism was severe lymphocytic infiltration. The level of postoperative thyroid stimulating hormone (TSH)-binding inhibition immunoglobulins (TBII) in patients with recurrence was significantly higher than in patients in remission. It is reasonable to determine the amount of remnant thyroid tissue in relation to patient body surface area. Although subtotal thyroidectomy can induce immunological remission by reduction of antigen, if the remission disappears, that is if TBII increases, recurrence of hyperthyroidism may develop even in patients without the unfavorable factors.

Adolescent↗

PubMedDate not supplied

The role of epinephrine, norepinephrine, and dopamine in blood pressure disturbances in patients with pheochromocytoma.

Fifty-six patients with pheochromocytoma underwent surgery during the 9-year period from 1981 to 1990. These patients were divided into two groups according to whether the dominant plasma concentration was of epinephrine or norepinephrine. Plasma levels of the catecholamines were stratified into three grades at 5 and 10 times the normal upper limit. Pre-operative disturbances of blood pressure, sustained or paroxysmal, and normal blood pressure were highly correlated with the dominantly secreted catecholamine and its plasma concentration. Thirteen patients with high plasma norepinephrine levels (greater than or equal to 10 times normal) had sustained hypertension while 18 patients with moderate to high plasma epinephrine levels (greater than or equal to 5 times normal) had paroxysmal hypertension. In the majority of normotensive patients (12 of 14), plasma catecholamine levels were less than 10 times the upper normal limit. Urinary excretion of dopamine and size of the tumor were analyzed according to these patient groups. In the norepinephrine dominant group, urinary dopamine excretion tended to be proportional to the plasma epinephrine levels and when the patients were normotensive, urinary dopamine excretion decreased. In norepinephrine-secreting patients, urinary dopamine tended to be inversely correlated with the plasma norepinephrine level; however dopamine did not prevent the hypertensive action of norepinephrine. Tumor size showed no correlation with the plasma levels of catecholamine in the moderate to high plasma catecholamine groups. We conclude that the plasma catecholamine type and its level are the most important factors in determining the patterns of blood pressure disturbances of patients with pheochromocytoma.

Adrenal Gland Neoplasms↗

PubMedDate not supplied

Electrophysiological studies on the cultured cells obtained from transplantable pancreatic carcinoma in Syrian golden hamsters.

A pancreatic ductal carcinoma was established as a transplantable tumor line in an inbred strain of Syrian golden hamsters. Intracellular recordings of membrane potentials and input resistance were made from cultured cells obtained from the transplanted tumors using indwelling glass microelectrode. The mean value of the resting membrane potential was -46.5 +/- 1.8 mV (S.E.) (n = 13), while the mean resting input resistance was 21.2 +/- 4.3 M omega (S.E.) (N = 13). Dibutyryl cyclic AMP (2 X 10(-3)M) caused a marked hyperpolarization of about 30 mV accompanied by a reduction of input resistance. The transplantable tumor and its cultured cell line developed in this study have demonstrated their effectiveness as a reliable experimental model for use in pancreatic cancer research.

Animals↗

PubMedDate not supplied

Long-term follow-up of hepatitis using computed tomography.

Computed tomography of the liver was performed on two patients with subacute hepatitis. The CT findings included the presence of multiple regenerative nodules in the atrophied liver, shown by decreased CT attenuation. Complications due to hepatitis, such as massive ascites and splenomegaly, were also observed. The CT observations during the course of the disease suggested that the hepatic necrosis had been repaired by hypertrophy of regenerating nodules, not by an increase in the number of nodules, which ultimately gave rise to postnecrotic cirrhosis. Scintigraphy confirmed atrophy and repair of the liver. Thus, CT and scintigraphy were considered to be useful for the diagnosis of extensive hepatic necrosis and for evaluating the process of liver repair.

Adult↗

PubMedDate not supplied

Urokinase-type plasminogen activator and plasminogen activator inhibitor-1 as a prognostic factor in human colorectal carcinomas.

BACKGROUND/AIMS: The urokinase pathway of plasminogen activation is known to be involved in proteolytic degradation of the extracellular matrix during carcinoma invasion. METHODOLOGY: We immunohistochemically examined 97 colorectal carcinomas for the expression of urokinase-type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) to investigate whether uPA and PAI-1 expressions could serve as prognostic parameters; the gene expression of uPA and PAI-1 in human colon cancer tissues was also analyzed using reverse transcription-polymerase chain reaction (RT-PCR). RESULTS: The relative expression levels of uPA and PAI-1 mRNAs were well correlated with immunoreactivities of uPA and PAI-1, respectively (p < 0.05). In immunohistochemical staining, diffuse specific staining was observed in the cytoplasm of carcinoma cells. uPA expression was detected in 57 carcinoma specimens (58.8%) and PAI-1 expression was detected in 36 specimens (37.1%). With regard to 5-year overall survival rate, patients whose tumors had positive uPA and negative PAI-1 immunoreactivities had a significantly poorer prognosis (p < 0.05). In multivariate analysis, the combined variable of uPA and PAI-1 was shown to be an independent prognostic indicator. CONCLUSIONS: Our results suggest that immunohistochemical combined analysis of uPA and PAI-1 may be a useful prognostic factor in colorectal carcinoma patients.

Adult↗

PubMedDate not supplied

Epithelial hyperplasia of the gallbladder in children with anomalous pancreaticobiliary ductal union.

BACKGROUND/AIMS: Few data are available on the fate and incidence of epithelial hyperplasia throughout the life of anomalous pancreaticobiliary ductal union (APBD) patients. The pathological study in pediatric APBD patients is less recognized. METHODOLOGY: Ten resected gallbladders obtained from children with APBD and control patients without APBD were examined histologically, and immunohistochemically for the detection of Ki-67 (as a proliferative marker) and p53. K-ras mutations in codon 12 were also examined. Epithelial hyperplasia was classified into high-grade and low-grade hyperplasia. RESULTS: Six (60%) of 10 patients with APBD had epithelial hyperplasia of the gallbladder, whereas no patients without APBD exhibited this lesion. Diffuse epithelial hyperplasia was observed in 1 (50%) of 2 undilated-type APBD and 5 (63%) of 8 dilated-type. Two (33%) of 6 patients with epithelial hyperplasia exhibited high-grade hyperplasia. Ki-67 labeling index (LI) was significantly higher in hyperplastic mucosa than in control gallbladder mucosa. K-ras mutations and p53 overexpression were not detected in hyperplastic and normal mucosa. CONCLUSIONS: Epithelial hyperplasia of the gallbladder accompanied by increased proliferative activity exists at birth or is acquired in childhood with APBD patients and may be an important factor predisposing to the development of gallbladder carcinoma.

Cell Division↗

PubMedDate not supplied

Estimation of time parameter of LQ-model in fractionated radiotherapy of medulloblastoma.

PURPOSE: To estimate the dose required to counteract accelerated proliferation, gamma/alpha, of medulloblastoma (MB) cells during fractionated radiotherapy. MATERIALS AND METHODS: Sixty-five patients with MB (local control rate at 5 years: 73%) treated between 1980 and 1990 at our university hospitals were analyzed. The gamma/alpha was estimated by applying the profile likelihood method to Cox's proportional hazards model including the maximum value of time-incorporated biologically effective dose, tBEDmax. The tBEDmax was conditionally calculated with various settings of alpha/beta, time to kick off accelerated proliferation, Tk, and gamma/alpha. Pretreatment T-stage, log(age+1), extent of removal, and use of chemotherapy and immunotherapy were also included in the multivariate model. RESULTS: When alpha/beta was taken to be 10 Gy, the estimate of gamma/alpha was 0.52 Gy/day (95% confidence limits: 0.29-0.75) for 0 day of Tk and was 0.55 Gy/day (0.30-0.80) for 21 days of Tk. The gamma/alpha values tended to be larger in the T3 subgroup and in the non-total removal subgroup than in all patients, by about 0.05 Gy/day and 0.1 Gy/day, respectively. When alpha/beta was taken to be 25 Gy, the estimated values were about 0.05 Gy/day smaller than these values. CONCLUSION: The estimated gamma/alpha values were considerably large. Therefore, it is preferable to take this consumed dose per day into consideration in planning and conducting treatments for MB.

Cerebellar Neoplasms↗