Biomedical subjects

B Skogseid

Publications and source records attributed to B Skogseid.

At least 55 records · Page 3Linked to original sources

PubMed1996

Definition of the Minimal MEN1 Candidate Area Based on a 5-Mb Integrated Map of Proximal 11q13

Multiple endocrine neoplasia type 1 (MEN1) is an autosomal dominant disorder with a high penetrance characterized by tumors of the parathyroid glands, the endocrine pancreas, and the anterior pituitary. The MEN1 gene, a putative tumor suppressor gene, has been mapped to a 3- to 8-cM region in chromosome 11q13 but it remains elusive as yet. We have combined the efforts and resources from four laboratories to form the European Consortium on MEN1 with the aims of establishing the genetic and the physical maps of 11q13 and of further narrowing the MEN1 region. A 5-Mb integrated map of the region was established by fluorescence in situ hybridization on both metaphase chromosomes and DNA fibers, by hybridization to DNA from somatic cell hybrids containing various parts of human chromosome 11, by long-range restriction mapping, and by characterization of YACs and cosmids. Polymorphic markers were positioned and ordered by physical mapping and genetic linkage in 86 MEN1 families with 452 affected individuals. Two critical recombinants identified in two affected cases placed the MEN1 gene in an approximately 2-Mb region around PYGM, flanked by D11S1883 and D11S449.

Journal Article↗

PubMed1996

Surgery for asymptomatic pancreatic lesion in multiple endocrine neoplasia type I.

Patients with multiple endocrine neoplasia (MEN) type I underwent pancreatic surgery at presymptomatic (n = 8, mean age 33 years) or symptomatic (n = 12, mean age 51 years) stages of pancreatic endocrine involvement with the principal aim to evaluate postoperative morbidity, survival, and malignant potential of the pancreatic lesion. Radiologic signs of malignancy were not identified in any patient prior to exploration. All patients displayed multiple tumors with generally complex immunoreactivity. Normal postoperative pancreatic tumor markers were recorded in five of the asymptomatic patients, which became abnormal in three of them at a mean of 3 years after surgery. All patients remained without symptoms for a mean of 6 years after operation. In four symptomatic individuals (33%) metastases were identified at exploration, and two died with tumor; 83% of symptomatic patients displayed persistent or recurrent endocrine morbidity from the pancreatic lesion. Recognizing lead time bias, this limited and uncontrolled patient comparison suggests that exploration at the symptomatic stage of pancreatic involvement in MEN-I patients is unsatisfactory. Rather than to obtain biochemical cure, surgery in asymptomatic patients might be regarded as a means of cancer prevention. The malignancy of the pancreatic lesion may be preceded by several decades of biochemical abnormality. Extensive screening for this lesion allows diagnosis during adolescence and the timely application of primary exploration. Active management of individuals with repeated biochemical analyses followed by selective reintervention could enable satisfactorily maintained pancreatic functions and substantial duration of cancer prevention.

Adenoma↗

PubMed1996

Efficiency of percutaneous core biopsy in pancreatic tumor diagnosis.

BACKGROUND: Radiologic diagnosis of pancreatic tumors exhibits limited precision. The aim of this study was to investigate the outcome and complications of pancreatic core biopsy in patients with suspected pancreatic neoplasms. METHODS: One hundred patients underwent ultrasonography-guided core biopsy of 1.2 mm external diameter. Medical charts were examined for biochemical and clinical signs of complications. Final diagnosis was settled by operation, autopsy, and clinical signs of the disease including survival with at least 2.3 years of follow-up. RESULTS: Histopathologic biopsy evaluation showed correct discrimination between exocrine and endocrine tumors and nonneoplastic conditions in 89 patients. No false-positive cancer diagnosis was found, and guidance on nature of primary tumors was obtained for eight of eight metastases. The sensitivity was 91% for exocrine and 87% for endocrine pancreatic tumors, and negative predictive values of these diagnoses were 83% and 97%, respectively. No clinically significant complications were noted. CONCLUSIONS: Core biopsy is an attractive alternative to diagnostic laparotomy in unresectable pancreatic cancer and efficiently provides diagnosis of endocrine tumors and pancreatic metastases in conjunction with rare complications. Benign biopsy findings cannot be used to exclude presence of primary or metastatic pancreatic neoplasms.

Biopsy↗

PubMed1996

Intact adrenocorticotropic hormone secretion but impaired cortisol response in patients with active rheumatoid arthritis. Effect of glucocorticoids.

OBJECTIVE: To study the hypothalamic-pituitary-adrenal axis in rheumatoid arthritis (RA) and the influence of glucocorticoid treatment. METHODS: Consecutive untreated patients with RA with moderately high inflammatory activity were studied and compared with healthy subjects of similar age. Subjects were studied both at baseline and after multiple releasing hormone (MRH) stimulations. Patients were reexamined one week after starting prednisolone. RESULTS: The baseline cortisol/adrenocorticotropic hormone (ACTH) ratio was significantly lower in patients with RA. After corticotropin releasing hormone (CRH) stimulation, their serum cortisol response was reduced during the later test phases in spite of intact ACTH response. The baseline and stimulated levels of luteinizing hormone (LH), follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH) were normal. An impaired prolactin response was seen after MRH stimulation. After one week of prednisolone therapy the absolute response of serum cortisol to CRH was decreased and the stimulated prolactin response was normalized. CONCLUSION: Impaired cortisol secretion in patients with RA in the presence of intact ACTH secretion is consistent with relative adrenal glucocorticoid insufficiency. Adrenal impairment may be secondary to the inflammatory disease process.

Adolescent↗

PubMed1995

Islet amyloid polypeptide (IAPP) in patients with neuroendocrine tumours.

Although IAPP was first discovered and isolated from amyloid deposits in an endocrine pancreatic tumour (EPT), surprisingly few reports have investigated the potential use of IAPP as a marker for neuroendocrine tumour growth. In this study we present results from plasma measurements of IAPP in 102 patients with neuroendocrine tumours. Four of 35 patients (11%) with midgut carcinoid tumours, but none of the patients (4 and 5, respectively) with lung carcinoids or with rectal carcinoids displayed elevated plasma levels of IAPP. Five of 31 patients (16%) with sporadic EPT and 3 of 27 patients (11%) with EPT and multiple endocrine neoplasia type 1 syndrome disclosed elevated IAPP levels. Within the different syndromes, 1/11 individuals with insulinoma, 2/16 with gastrinoma, 0/2 with glucagonoma, 0/3 with VIPoma and 5/26 with non-functioning tumours showed elevated plasma levels of IAPP. In two patients, the plasma IAPP levels were extremely elevated. These patients also exhibited altered glucose homeostasis. In response to a standardised mixed meal test, IAPP increased in parallel to the insulin, pancreatic polypeptide, gastrin and glucose responses. In MEN1 patients with hypercalcaemia due to increased secretion of parathyroid hormone, the plasma levels of IAPP were significantly higher before than after surgical removal of the parathyroid adenomas. However in normocalcaemic patients, no correlation between the blood calcium and plasma IAPP levels was found. Immunocytochemical staining of tumour tissue showed that 9/13 (69%) of insulin producing tumours, 4/14 (29%) of non-functioning tumours and 1/9 (11%) of gastrin producing tumours were IAPP immunoreactive. Amyloid deposits were always IAPP immunoreactive. In conclusion, increased circulating levels of IAPP occurred in 12% of 102 patients with neuroendocrine tumours. In 2 patients with extremely elevated plasma levels of IAPP, effects on glucose homeostasis were recorded. Thus, IAPP may be useful as an additional marker for neuroendocrine tumour growth in selected cases.

Adult↗

PubMed1995

Adrenal lesion in multiple endocrine neoplasia type 1.

BACKGROUND: Multiple endocrine neoplasia (MEN) type 1 is accompanied by adrenal involvement, but characteristics and clinical handling of this lesion have been insufficiently explored. METHODS: Patients with MEN 1 (n = 43) were monitored (mean, 6.3 years) with annual biochemical and radiologic adrenal evaluation. Adrenal specimens were examined by in situ RNA-RNA hybridization for expression of the MEN1 candidate gene phospholipase C beta 3 (PLC beta 3) and immunostaining for insulin-like growth factor-1 receptor. RESULTS: Altogether 17 patients (40%) displayed adrenal enlargement, which was limited to the adrenal cortex and showed signs of progression, marked atypia, and cancer development in three of them. Only the carcinoma exhibited adrenocortical hormone excess. PLC beta 3 was expressed in the hyperplastic and adenomatous proliferation but not the carcinoma. Pancreatic endocrine tumors with insulin-proinsulin excess were overrepresented in the patients with adrenocortical involvement, but significant insulin-like growth factor-1 receptor immunoreactivity was restricted to the carcinoma. CONCLUSIONS: The prevalent adrenocortical lesion associated with MEN 1 requires regular attention because of malignant potential. It was unrelated to loss of constitution heterozygosity for the MEN1 locus (11q13) and PLC beta 3 expression, except for the cortical carcinoma exhibiting allelic losses involving also the Wiedemann-Beckwith gene at 11p15. Mechanisms for mitogenic relationships between the pancreatic and adrenal lesions of MEN 1 demand further clarification.

Adrenal Gland Diseases↗

PubMed1995

Candidate genes for multiple endocrine neoplasia type 1.

The aim of this study was to isolate and characterize candidates for the multiple endocrine neoplasia type 1 (MEN1) gene. The development of tumours related to MEN1 is associated with somatic deletions involving the MEN1 locus, suggesting inactivation of a tumour-suppressor gene in this region. We have isolated five cDNA candidates located within the 900 kb remaining for the MEN1 gene, determined their sequence, and characterized their expression in normal tissues and several endocrine tumours. One of the candidates, encoding for phospholipase C-beta 3, showed properties consistent with the idea of a tumour-suppressor gene.

Blotting, Northern↗

PubMed1995

Experience with multiple endocrine neoplasia type 1 screening.

Screening for multiple endocrine neoplasia type 1 (MEN1) may be conducted for a variety of reasons. The principal aims may be more or less scientific, such as early identification of the trait. Other reasons for screening comprise attempts to avoid endocrine morbidity and possibly forthcoming problems from malignant transformation, as well as attempts to identify and treat gene carriers with a clinically overt disease. Several reports have substantiated the diagnostic yield from screening efforts among MEN1 kindreds. Such increases in detection of the disease ideally should be accompanied by enhanced rates of survival in order to fully justify an unlimited search for the trait. However, studies are lacking a clearly verifying reduction of mortality from the detection of presymptomatic MEN1 individuals. While waiting for the results of survival studies in progress, the generally prevailing opinion favours widespread screening because of the evidently decreased morbidity resulting from early diagnosis of the MEN1 trait, which apparently persists even during decades of follow-up. This paper presents the clinical features of the disease and experience derived from a prospective screening programme for MEN1 detection.

Cell Transformation, Neoplastic↗

PubMed1995

Operative tumour yield obviates preoperative pancreatic tumour localization in multiple endocrine neoplasia type 1.

The efficiency of pancreatic tumour localization was prospectively evaluated in 12 consecutive patients with multiple endocrine neoplasia type 1 (MEN1), who were subjected to extirpation of 56 islet cell neoplasms of 0.2-4 cm in diameter (mean 0.8 cm) during pancreatic resection and enucleation. Computed tomography, angiography of the coeliac trunc and superior mesenteric artery, and percutaneous ultrasound correctly localized 7-12% of the tumours and 21-37% of the 19 lesions measuring at least one centimetre in diameter. Transhepatic portal vein sampling correctly located tumour sites in the proximal or distal portions of the pancreas in four out of six patients, but demonstrated unsatisfactory specificity. Intra-operative ultrasound and bidigital palpation of the pancreas had overall sensitivities of 86 and 45%, respectively, and eight lesions below 0.3 cm in diameter remained undetected with intraoperative ultrasound. It is concluded that diagnosis of endocrine pancreatic neoplasms is biochemical in MEN1 and that broad screening of tumour markers efficiently reveals pancreatic involvement decades before the development of a clinically overt disease. Intra-operative ultrasound is a requisite for pancreatic endocrine surgery in MEN1, and it obviates the need for conventional pancreatic imaging unless a pre-operative search for metastatic disease and anatomical aberrations is considered important.

Adult↗

PubMed1995

Assignment of the mouse homologue of a human MEN1 candidate gene, phospholipase C-beta 3 (Plcb3), to chromosome region 19B by FISH.

A recent study using comparative mapping analysis suggests that the proximal segment of mouse chromosome 19 contains the mouse homologs of the human multiple endocrine neoplasia type 1 (MEN1) flanking markers proximal to the locus. We have recently shown that phospholipase C-beta 3 (PLCB3) is a candidate gene for the MEN1 syndrome. In the present investigation we used fluorescence in situ hybridization with a genomic DNA clone for mouse Plcb3, and mapped the locus to chromosome region 19B. This is in agreement with the comparative mapping of the MEN1 flanking markers in mouse.

Animals↗

PubMed1994

Different splice variants of CD44 are expressed in gastrinomas but not in other subtypes of endocrine pancreatic tumors.

Endocrine pancreatic tumors are neuroendocrine neoplasms with malignant potential and give rise to varied clinical syndromes due to excessive secretion of multiple hormones. In this study 22 endocrine pancreatic tumors and 11 carcinoid tumors were examined for the expression of CD44 using a monoclonal antibody. CD44 gene activity of 11 endocrine pancreatic tumor tissues and five carcinoid tumor tissues was also studied by amplifying messenger RNA with the polymerase chain reaction followed by electrophoresis and blot hybridization. Strong immunoreactivity was detected on all gastrinomas examined (P < 0.001), and in two non-functioning endocrine pancreatic tumors. Such immunoreactivity was not observed in other subtypes of endocrine pancreatic tumors. In the normal human pancreas, the acinar portion and ductal epithelial cells stained strongly positive but pancreatic islet cells did not show any significant immunostaining. Furthermore, in endocrine pancreatic tumors with metastatic disease, CD44-positive tumors had a tendency to metastasize to lymph nodes (P = 0.005), as compared with CD44-negative tumors which were locally invasive or metastasized to the liver. Although, in this limited material and short follow-up, we were not able to show any statistical significance, patients with CD44-negative endocrine pancreatic tumors had prolonged survival time compared with patients with CD44-positive tumors (73% versus 59% at 5 years; P = 0.7). Of 10 carcinoid tumors examined, all three foregut carcinoids and one midgut carcinoid stained strongly positive, whereas all other midgut carcinoids were negative. Analysis of CD44 splice variants showed that in all five gastrinomas there was overproduction of alternatively spliced larger molecular variants as compared with other types of endocrine pancreatic tumors and carcinoid tumors. The band pattern from one case of carcinoid tumor with a fulminant clinical course was similar to that of gastrinomas, whereas other carcinoid tumors expressed the epithelial form of CD44. The earlier identified splice variants which confer metastatic behavior on a pancreatic tumor cell line were not expressed in neuroendocrine tumors. Our data indicate that CD44 expression in endocrine pancreatic tumors correlates with the ability to give rise to lymph node metastases and may play a vital role in determining the fate of metastasizing cells. Moreover, because gastrin is not detectable in the normal human pancreas, the pancreatic ductal cell positivity for CD44 strengthened the ductal origin concept of gastrinomas. The band pattern of CD44 splice variants suggests that the previously described splice variants conferring metastatic behavior do not accompany metastatic activity of neuroendocrine tumors.

Adult↗

PubMed1994

The phospholipase C beta 3 gene located in the MEN1 region shows loss of expression in endocrine tumours.

Oncogenesis of tumours related to multiple endocrine neoplasia type 1 (MEN1) is associated with somatic deletions involving the MEN1 locus, suggesting inactivation of a tumour suppressor gene in this region. Identification of meiotic cross-overs in MEN1 families has placed the MEN1 locus centromeric of D11S807. An extended deletion mapping was performed in 27 primary parathyroid tumours, and identified D11S427 as the closest centromeric flanking marker. Through physical mapping using newly isolated cDNA clones, we estimated the distance between the flanking markers D11S807 and D11S427 to be less than 900 kb. One of these cDNA clones showed expression of a 4.4 kb message in multiple tissues, including those affected in MEN1, while in five endocrine tumours no transcript was detected. Sequence characterization showed that this gene encodes for the phospholipase C beta 3, a key enzyme in signal transduction.

Blotting, Northern↗

PubMed1994

Multiple endocrine neoplasia type 1. Clinical features and screening.

The clinical and biochemical features of multiple endocrine neoplasia type 1 are presented with a focus on methods for the early detection of the parathyroid, pituitary, and endocrine pancreas. A rationale is provided for early detection of MEN 1-associated abnormalities including a discussion of improved quality of life and reduction of morbidity and mortality.

Genetic Testing↗

PubMed1993

Exclusion of FAU as the multiple endocrine neoplasia type 1 (MEN1) gene.

The FAU gene (FBR-MuSV associated ubiquitously expressed gene) encodes the ribosomal protein S30 fused with a Ubiquitin-like molecule. The FAU gene is expressed in a wide range of tissues, is evolutionarily conserved, and has putative tumour suppressor activity in vitro. The human FAU gene maps to the long arm of chromosome 11 band q13, close to the PYGM locus. This locus is tightly linked to the Multiple Endocrine Neoplasia type 1 (MEN1) locus. The FAU gene properties, together with its chromosomal localisation on 11q13, make it a candidate gene for MEN1. To test this hypothesis we screened 33 unrelated patients with MEN1 for constitutional genetic alterations in the FAU gene by Southern blot analysis, denaturing gradient gel electrophoresis (DGGE) and in two cases complemented by DNA sequencing to confirm the DGGE data. Furthermore, 10 parathyroid and pancreatic tumours from MEN1 patients and 15 each of sporadic parathyroid and pituitary tumours were similarly examined. In addition, we studied the expression of the FAU gene at the RNA level in 9 MEN1-associated tumours by Northern blot analysis. No FAU gene anomalies could be demonstrated by any of these techniques. We conclude that FAU is not likely to be the MEN1 tumour suppressor gene.

Base Sequence↗

PubMed1992

Clinical and genetic features of adrenocortical lesions in multiple endocrine neoplasia type 1.

In multiple endocrine neoplasia type 1 (MEN-1), benign enlargement of the adrenal cortex has been found in about one third of necropsy cases. To elucidate the clinical and genetic characteristics of the MEN-1 adrenal lesion, we have investigated 33 MEN-1 patients. Twelve individuals (37%) demonstrated adrenal enlargement, which was bilateral in 7 of them. Histopathology revealed diffuse and nodular cortical hyperplasia, adenomas, and a single case of adrenocortical carcinoma. The apparently benign adrenal enlargements were not associated with presently ascertainable biochemical disturbances in the hypothalamic-pituitary-adrenocortical axis, and they were without radiological signs of progression during follow-up. The individual developing unilateral adrenocortical carcinoma showed rapid adrenal expansion, feminization, and an abnormal urinary steroid profile after 4 yr of observation for bilateral minor adrenal enlargements. Pancreatic endocrine tumors were significantly overrepresented and present in all MEN-1 individuals with adrenal involvement. In agreement with findings in sporadic cases, the MEN-1 adrenocortical carcinoma genome showed loss of constitutional heterozygosity for alleles at 17p, 13q, 11p, and 11q. The benign adrenal lesions retained heterozygosity for the MEN-1 locus at chromosome 11 q 13. Despite its prevalence and malignant potential, the pituitary-independent adrenocortical proliferation does not appear to be a primary lesion in MEN-1, but might represent a secondary phenomenon, perhaps related to the pancreatic endocrine tumor.

Adrenal Cortex↗

PubMed1992

Prospective screening in multiple endocrine neoplasia type 1.

To assess the age of clinically detectable onset of multiple endocrine neoplasia type 1 (MEN 1), 88 members of four families were invited to participate in a ten-year biochemical screening program. Evidence for clinically detectable MEN 1 was found in adolescence. Pancreatic endocrine dysfunction constituted the presenting lesion in a majority of these individuals. The age at diagnosis of pancreatic endocrine tumors averaged 25 years and was lowered by almost two decades by prospective investigation. Furthermore, the penetrance of the pancreatic endocrine and parathyroid lesions equaled the penetrance found in autopsy studies. The use of a standardized meal stimulation test with the measurement of serum pancreatic polypeptide (PP) and gastrin responses resulted in diagnostic sensitivities of 75% and 100%, respectively. In addition to basal serum PP and insulin values, the proinsulin level was predictive for early pancreatic involvement in MEN 1. Serum gastrin was another useful tumor marker but only in the patients with pancreatic tumors diagnosed outside the prospective investigation. Two of the four MEN 1 kindreds selected for the screening investigation displayed homogeneity within families with respect to the profile of peptide excess and malignant potential of the pancreatic endocrine lesion, while the remaining kindreds demonstrated variable MEN 1 traits.

Adolescent↗

PubMed1992

Practical guidelines for DNA-based testing in multiple endocrine neoplasia type 1.

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.

Blotting, Southern↗

PubMed1991

Multiple endocrine neoplasia type 1: a 10-year prospective screening study in four kindreds.

A total of 80 individuals in 4 kindreds with multiple endocrine neoplasia type 1 (MEN 1) have been subjected to repeated biochemical screening during a 10-yr period with the principal aim being to analyze characteristics of the developing pancreatic lesion. Age at presentation of the MEN 1 trait averaged 18 yr in 7 previously unaffected individuals, and this effect of the screening procedure represented a lowering by almost 2 decades. Pancreatic endocrine involvement was recognized at a mean age of 25 yr and constituted the presenting lesion in a majority of the patients. A standardized meal test and basal values of serum pancreatic polypeptide, insulin, proinsulin, and gastrin were the most efficient markers for the pancreatic lesion and preceded signs of pancreatic tumors upon radiological examinations by a mean of 3.5 yr. A 75% penetrance of the islet cell disease and 90% for primary hyperparathyroidism within the affected individuals equalled the prevalences reported in autopsy studies. Two of the kindreds showed signs of intrafamilial homogeneity with respect to the profile of peptide excess (P less than 0.05) and considerable discrepancy in the malignant potential of the pancreatic lesions. The results of early detection and surgical intervention of the pancreatic tumors in MEN 1 suggested an impact on morbidity, while any effect on the mortality of these individuals remains to be clarified.

Adult↗