Three patients of a French family demonstrated an association of multiple endocrine neoplasia type 2A (MEN 2A) with a pruritic scapular skin lesion. The lesions are similar to those described as familial cutaneous lichen amyloidosis in unrelated MEN 2A and medullary thyroid carcinoma families, but histological, immunohistochemical, and ultrastructural analysis of skin biopsies from each patient in the French family did not show amyloid deposition. The topography of the lesion follows dermatomes C8-D3. The patients report not only pruritus but also paresthesia and hyperalgesia, and one showed touch hypoesthesia and pain hyperesthesia in the area of the lesion. Such an association of cutaneous and neurological features suggests notalgia paresthetica (NP), a neuropathy of the posterior dorsal rami nerves. We thus suggest that the cutaneous lesions associated with MEN 2A might be secondary to pathology in the neural crest-derived dorsal sensory nerves. The amyloid, when present, would be secondary to scratching. We propose that patients presenting with familial NP be suspect for MEN 2A.
Although the United States spends more on health care than any country in the world, access to that care is becoming increasingly difficult. The National Cancer Institute and other federal agencies are sponsoring innovative research for delivering effective medical services, particularly to underserved populations. Models of successful collaboration between private and public sectors concerned with health care can be adapted and implemented at the national, state, and local levels. However, other measures are needed to ensure access to adequate health care for all Americans. Minimal but effective regulations are needed to ensure quality control, reduce duplication of services, and minimize cost increases. Public and private sectors also need to consider ways to extend adequate health insurance coverage to all Americans and to provide compensation for preventive services.
The effect of the somatostatin analog octreotide on cAMP-mediated calcitonin (CT) secretion and cAMP accumulation in C-cells was investigated. Glucagon stimulated cAMP accumulation and CT secretion with a maximal effect at a concentration of 10(-6) M. The cAMP antagonist RpcAMPs blocked the glucagon-induced CT secretion down to control levels. Therefore, no other second messengers seem to be involved in glucagon-stimulated CT secretion. Octreotide in increasing doses (10(-9) to 10(-6) M) inhibited cAMP accumulation and CT secretion with a maximal effect at a concentration of 10(-7) (40% and 29% of control values, respectively). Pretreatment of the cells with 100 ng/mL pertussis toxin for 24 hours abolished the inhibitory effect of octreotide on cAMP accumulation and CT secretion (82% and 58% of control values, respectively). Similar results were obtained under the influence of the phosphodiesterase inhibitor IBMX. Therefore, we conclude that somatostatin modulates adenylate cyclase-coupled CT secretion in C-cells via a pertussis toxin-sensitive G-protein possibly in an autocrine/paracrine way.
We have analyzed DNA marker typing data contributed by six independent groups to estimate the pairwise genetic distances between these markers and the locus for multiple endocrine neoplasia type 2A (MEN 2A). We used LIPED to calculate these distances for female, male, and sex-average linkage maps and to determine the corresponding LOD scores. The preliminary analyses of this large data set (89 MEN 2A families and five non-MEN 2A references families, with 1,934 total individuals) are reported here. These refined estimates of the genetic map in this region will aid in the assignment of presymptomatic diagnoses. This study clearly points out the limitation of pairwise linkage analysis in further refining the position of MEN2A in this small region of chromosome 10. Further refinement of the genetic map position of MEN2A will be best accomplished by finding, verifying, and accurately mapping crossovers in specific families.
The search for the gene that causes the multiple endocrine neoplasia type 2A (MEN 2A) syndrome is entering a new phase. Genetic linkage studies have localized the gene to the pericentromeric region of chromosome 10. The statistical portion of mapping the gene for MEN 2A is nearly complete and now classical molecular biological/gene mapping techniques will be employed. We have used fluorescence in situ hybridization to estimate the size of the MEN2A region to be about 2 to 5 mb, using some liberal assumptions; at worst the region should contain no more than about 10 mb of non-alphoid DNA. Our mapping panels (meiotic recombinant and radiation reduced hybrid) give consistent orders of markers in this small region. We describe our initial attempts to clone the region using yeast artificial chromosomes.
Neuroendocrine features and cytogenetic abnormalities of one continuous cell line (MTC-SK) and two long-term cultures (GER, STAH) derived from three sporadic cases of human medullary thyroid carcinomas (MTCs) were studied. Specific neuroendocrine markers (NSE, chromogranins, calcitonin, calcitonin gene-related peptide) were identified by electron microscopy and immunocytochemistry. In situ hybridochemistry and Northern blot analysis confirmed endocrine activity. Cytogenetic studies of the cell line MTC-SK revealed three consistent marker chromosomes, t(3;10), 11p+, and 22p+. Cells of long-term cultures GER and STAH exhibited a consistent translocation t(2;18), a trisomy 7, and two consistent marker chromosomes der3 and 5p+, respectively. Recently, we have isolated 12 stable clones of this MTC-SK cell line, which showed two different growth patterns. Quantitative measurement of mitotic activity flow cytometry and semiquantitative analysis of AgNOR-, Ki67-, and Cyclin/PCNA-(immuno)reactivity showed different DNA composition and duplication rates, indicating at least two subpopulations. Some of our clones developed a new consistent marker (i.e., an unbalanced translocation between mar11p+ and 1q). However, no correlations between chromosome findings, growth rate, and neuroendocrine markers were observed.
Multiple endocrine neoplasia type 1 (MEN 1) is an autosomal dominant predisposition to neoplastic lesions of the parathyroid glands, the neuroendocrine pancreas, and the anterior pituitary gland. The predisposing genetic defect was localized to the long arm of chromosome 11 by genetic linkage analysis in three affected families. By analyzing six MEN 1 families with 14 DNA marker systems located close to the MEN 1 gene, we have developed a method to identify carriers of the MEN 1 predisposition. We describe practical aspects of such DNA-based diagnostic procedures.
Seven members with multiple endocrine neoplasia type 2B from a 15-member family have been followed for 18 years. All affected had the neuroma phenotype in a distribution compatible with autosomal dominant inheritance. The phenotype features have allowed 100% initial and continuing prediction of affected versus nonaffected status in as early as 1.5 years. Among the affected: immunoreactive plasma calcitonin (iCT) concentration was high in 100%; thyroid palpation was false-negative in 71%; and thyroid scintiscan was false-negative in 83%. All had total thyroidectomy, plus lymphadenectomy in three, for bilateral medullary thyroid carcinoma (MTC) or C-cell hyperplasia (in the youngest). None has died directly from MTC. The index case died at age 68 and his son at age 32 years from complications of the syndrome. All but the youngest have continuing high iCT concentrations. No patient has had parathyroid disease. During preoperative calcium infusion, immunoreactive serum parathyroid hormone concentration declined by 35% to 84% of basal. At operation, macroscopically and microscopically normal parathyroid glands were found in all. No patient has had chemical suggestion of pheochromocytomas: at postmortem the index case had no adrenal medullary disease; his son had bilateral nodular adrenal hyperplasia; his daughter has had adrenal medullary hyperplasia and a renin-secreting juxtaglomerular tumor. Initially nonaffected members remain so.
We studied the expression of the ret proto-oncogene (proto-ret) in human medullary thyroid carcinomas (MTCs) and pheochromocytomas of multiple endocrine neoplasia type 2A (MEN 2A) by Northern blot analysis. Expression of the normal-sized transcripts was detected in all 12 MTCs and in 6 of 8 pheochromocytomas. In situ localization of proto-ret mRNA revealed that the signal was confined to the cytoplasm of MTC cells. By Southern blot analysis neither amplification nor gross genetic changes of proto-ret were found in the tumors. Although no transcripts were detected in the normal portion of the thyroid from one MEN 2A patient, faint signals were detected in normal adrenal glands by Northern blot analysis, probably due to minor populations of C-cells and chromaffin cells in specimens from which MTC and pheochromocytoma might later develop. Proto-ret may play an important role in differentiation of a specific cell lineage from neuroectoderm, and it may be involved in development of MEN 2A tumors.
UNLABELLED:Two serum calcitonin assays with sensitivities < or = 10 pg/mL were compared to our standard radioimmunoassay (sensitivity 100 pg/mL) in multiple endocrine neoplasia type 2A (MEN 2A) screening. Values from the Nichols displacement radioimmunoassay averaged 38% higher than values from the CIS immunoradiometric assay; values from both were highly correlated, r = 0.845. In three individuals, both of the newer assays revealed abnormalities in pentagastrin tests three to four years before abnormalities were detected by the standard assay. Pentagastrin tests after total thyroidectomy were assayed by the newer methods in patients with medullary thyroid carcinoma (MTC) diagnosed at initial testing (group I); in patients with early MTC diagnosed by prospective screening (group II); and in patients with pure C-cell hyperplasia detected by prospective screening (group III). At least 64% of group I, at least 25% of group II, but none of group III had detectable postoperative C-cell function.CONCLUSIONS:1) The previous estimate of 12 years as median age of onset of C-cell disease in MEN 2A is probably three to four years too old. 2) Patients diagnosed with early MTC by screening had not necessarily skipped a preneoplastic phase of C-cell hyperplasias. At least some early disease was not detected by the standard assay. Higher sensitivity assay should improve screening for C-cell disease by earlier disease detection. 3) Biochemical cure by thyroidectomy after the development of MTC is not as frequent as previously thought, but the apparent cure rate of pure C-cell hyperplasia remains 100%.
In persistent, clinically inapparent medullary thyroid carcinoma, microsurgical dissection of all lymph node compartments of the neck was performed. Between August 1988 and September 1991, 28 cases (mean age 43.3 years) were treated with 38 surgical interventions. Twenty patients had the sporadic form and eight patients the familial form. Unilateral neck dissection resulted in normalization of serum calcitonin (CT) levels even after pentagastrin stimulation in two patients whereas 16 patients exhibited abnormal CT stimulation tests. Eight of ten patients who had bilateral neck dissections had positive pentagastrin test results after surgery. The main postoperative complications included loss of local cutaneous sensation, generally temporary, and unilateral recurrent laryngeal nerve paralysis.
The malignant C-cell releases several markers of potential clinical significance into the circulation. To determine the usefulness of these markers for management of medullary thyroid carcinoma (MTC), it is necessary to compare the usefulness of these markers with calcitonin (CT), the classical tumor marker for MTC. Measurement of serum concentrations of the peptide PDN-21 (katacalcin), a carboxyterminal cleavage product of procalcitonin, showed a high correlation with serum CT levels (r = 0.99, P < 0.01, n = 65 patients with MTC). The presence of equimolar concentrations of CT and PDN-21 (CT/PDN-21 molar ratio = 0.95 +/- 0.33) indicates the peptide is cosecreted with CT. Stimulation of CT release by intravenous pentagastrin was associated with a parallel increase of PDN-21, providing further evidence of cosecretion of these two peptides. Finally, measurement of either PDN-21 or CT in selective venous catheterization specimens was useful for localization of MTC. Chromogranin A (CgA) levels were also measured in patients with MTC. Circulating levels were elevated in most patients with advanced disease. There was a moderate correlation between CgA and CT serum levels (r = 0.87, P < 0.01, n = 61 patients with MTC). Pentagastrin did not stimulate CgA, and the long half-life of CgA in the circulation did not make it possible to use this peptide for tumor localization by selective venous catheterization. We conclude that measurement of PDN-21 provides an independent assay system for diagnosis, localization, and postoperative management of MTC, whereas CgA measurement is not useful in early diagnosis of MTC and is of limited value for localization or management of progressive disease.
Hyperparathyroidism is a central component of multiple endocrine neoplasia type 1 (MEN 1), and both sporadic and familial forms of parathyroid disease may share certain pathogenetic features. We recently identified a gene that is clonally rearranged with the PTH locus in a subset of sporadic parathyroid adenomas. This candidate oncogene, PRAD1 (previously D11S287), appears to contribute to parathyroid tumorigenesis in a fashion analogous to activation of C-MYC or BCL-2 by rearrangement with tissue-specific enhancers of the immunoglobulin genes in B-lymphoid neoplasia. The PRAD1 gene maps to 11q13 and has been linked to the BCL-1 breakpoint locus, although not to the most tightly linked MEN 1 markers, by pulsed field gel electrophoresis. PRAD1 may, in fact, be the long-sought BCL-1 lymphoma oncogene. PRAD1 encodes a novel type of cyclin protein and thus may normally function in controlling the cell cycle, perhaps through direct interaction with cdc2 or a related kinase. PRAD1's possible primary, or more likely secondary, involvement in the pathogenesis of MEN 1-related tumors is unknown and under investigation.
To investigate the role of primary and/or secondary modified radical neck dissection (MRND) in patients with medullary thyroid carcinoma (MTC), follow-up data on 43 patients operated on between 1972 and 1983 were analyzed retrospectively; patients included 16 with sporadic MTC (group 1) and 27 with multiple endocrine neoplasia type 2 (group 2). Primary surgical therapy consisted of (near-) total thyroidectomy and limited lymph node dissection; one patient in group 1 and two in group 2 underwent primary MRND. Positive nodes were found in nine patients of group 1 and in 12 of group 2. Calcitonin (CT) was raised postoperatively in 11 group 1 patients, who all died (four after additional MRND). Postoperative CT was normal in the four survivors of group 1. In group 2, post-operative CT was raised in 15 patients, including those who had MRND and in four apparently node-negative patients. Three of them underwent additional MRND, which was successful in one case. One patient in this group died of the disease; two patients developed elevated CT levels during follow-up, whereas in one, CT normalized spontaneously. In conclusion, the role of extensive lymph node surgery in patients with more than limited lymph node involvement or elevated postoperative CT levels remains to be established.
Since the TT human medullary thyroid carcinoma cell line required fewer exogenous growth factors (serum), we investigated whether this line has an autocrine mechanism by examining the effects of antibodies directed toward insulin-like growth factor I (IGF-I) and its receptor on TT cell growth in serum-free conditions. Treating cells with anti-IGF-I antibody for four days reduced the cell number by more than 50% compared with a nonimmune IgG control. Furthermore, a monoclonal antibody to the IGF-I receptor suppressed DNA synthesis when determined by a [3H]thymidine incorporation assay. Exogenous IGF-I (20 ng/mL) stimulated [3H]thymidine incorporation in serum-free medium; approximately 70% of the IGF-I-induced stimulation was blocked by the presence of the receptor antibody. Treating TT cells with IGF-I for 48 hours increased the cell population in the S phase by 62% when analyzed by flow cytometry. These data suggest that TT cells might respond to endogenously produced IGF-I and therefore provide an in vitro model for autocrine regulation of human tumor cell growth by IGF-I.
GH and FA are useful monitors in the care of diabetic patients. For most situations, GH is the preferred test and should be routinely monitored. FA should be reserved for exceptional situations in which blood glucose control over one to two weeks must be assessed or in patients with a hemoglobinopathy. Patients with diabetes should be advised of their present GH level and the preferred goal.
Impotence commonly occurs as a result of treatment of carcinoma of the prostate. We review the etiology, evaluation, and treatment options available for these patients as well as our experience with fifty prostate cancer patients who underwent placement of penile prostheses. Several excellent alternatives are available for patients with impotence resulting from treatment of carcinoma of the prostate.
