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Carcinoids of the stomach, duodenum, and pancreas are represented by a variety of tumors with variable histologic and clinical features. Multicentric gastric carcinoids and concomitant nonantral argyrophilic hyperplasia are common in... more
Carcinoids of the stomach, duodenum, and pancreas are represented by a variety of tumors with variable histologic and clinical features. Multicentric gastric carcinoids and concomitant nonantral argyrophilic hyperplasia are common in chronic atrophic gastritis, more rarely due to a multiple endocrine neoplasia (MEN)-related Zollinger-Ellison syndrome (ZES). These tumors are infrequently associated with metastases and may generally be dealt with by repeated endoscopic fulguration. Sporadic carcinoids tend to be larger, invasive, and more often metastatic, especially in the presence of atypical histology. Small tumors may be removed by endoscopy, but larger lesions need to be surgically excised. In association with metastases a histamine-related atypical carcinoid syndrome may evolve and require treatment with a somatostatin analog. Poorly differentiated neuroendocrine carcinomas of the stomach constitute markedly aggressive tumors that rarely are suitable for radical surgery. Gastrinomas are the most prevalent duodenal carcinoids and a common cause of ZES especially in MEN-I. Despite a marked tendency for regional lymph node dissemination, liver metastases occur late and duodenal gastrinomas are often excisable, thereby offering favorable odds for cure in ZES. Unusual somatostatin-rich carcinoids in the ampulla of Vater relate to von Recklinghausen's disease and may be the cause of obstructive jaundice; depending on their size, these tumors may be removed by local excision or pancreaticoduodenectomy. Gangliocytic paragangliomas are unusual, generally benign lesions of the duodenum. Rare pancreatic tumors with serotonin immunoreactivity may be classified as carcinoids and constitute an unusual cause of the carcinoid syndrome.
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Hypertension in primary hyperparathyroidism (HPT) was previously attributed to hypercalcemia per se or to impaired kidney function. Of 441 consecutive patients operated on for HPT over 24 years, 57% were hypertensive. Preoperative blood... more
Hypertension in primary hyperparathyroidism (HPT) was previously attributed to hypercalcemia per se or to impaired kidney function. Of 441 consecutive patients operated on for HPT over 24 years, 57% were hypertensive. Preoperative blood pressure remained fairly constant during the study period, despite otherwise markedly changing clinical picture with, latterly, more asymptomatic patients. The preoperative systolic blood pressure (SBP) was significantly correlated to both serum calcium (p less than 0.001) and serum creatinine (p less than 0.05), but not when the influence of age was taken into account in a multiple regression analysis. Other pathogenetic factors in hypertension were therefore probable. When the statistical analysis was adjusted for differences in age and serum calcium, blood pressure was lower in the HPT patients with parathyroid hyperplasia than in those with adenoma (153 +/- 31/90 +/- 14 vs. 163 +/- 29/91 +/- 14 mmHg, p less than 0.01 for SBP). The concept that parathyroid hyperplasia represents a mild (early) form of HPT that may precede adenoma formation is corroborated by our observations, which also indicate that there is no simple cause-and-effect relationship accounting for hypertension in primary HPT.
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Diarrhoea is an important feature of the carcinoid syndrome, and various agents which may be released from carcinoid tumours have been considered to contribute pathophysiologically. The aim of the present study was to determine luminal... more
Diarrhoea is an important feature of the carcinoid syndrome, and various agents which may be released from carcinoid tumours have been considered to contribute pathophysiologically. The aim of the present study was to determine luminal concentrations of possible chemical mediators in an uninvolved small intestinal segment using a two-balloon six-channel tube in nine patients with malignant midgut carcinoid disease. All patients were treated with interferon and/or octreotide to alleviate the most severe flush. Ion transport was measured during luminal perfusion and luminal perfusate concentrations of calcitonin gene-related peptide, neurotensin, prostaglandin E (PGE)2, neuropeptide Y, somatostatin, vasoactive intestinal polypeptide, substance P and other tachykinins (neurokinin A, neurokinin B, neuropeptide K, eledoisin) were determined by separate assays. Carcinoid patients showed decreased absorption of Cl-, Na+, K+ and water and increased luminal content of non-substance P tachyki...
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This contribution presents research progress concerning primary hyperparathyroidism (pHPT), and the background for recent notable changes in treatment policy. Research has clarified that most patients with pHPT require surgery due to risk... more
This contribution presents research progress concerning primary hyperparathyroidism (pHPT), and the background for recent notable changes in treatment policy. Research has clarified that most patients with pHPT require surgery due to risk for osteoporosis, renal stones, and possibly silent complications of renal impairment, cardiovascular disease, and common psychiatric disability. Genetic studies have advanced, but the cause of the disease remains unclear for most patients. Localization methods for parathyroid tumors have improved and increased the interest for less invasive operative methods with shorter hospital stays and reduced costs for the patient. It is important to delineate when this really will imply progress and to use the new diagnostic methods in discussions of appropriate treatment strategies. It has also become evident that older pHPT patients especially could benefit from medical treatment of bone mineral deficit, and they may also need vitamin D or vitamin D analog...
Vitamin D regulates parathyroid cell proliferation and secretion of PTH. Increased prevalence of the polymorphic vitamin D receptor (VDR) alleles b, a, and T has been reported in sporadic primary hyperparathyroidism (PHPT), suggesting... more
Vitamin D regulates parathyroid cell proliferation and secretion of PTH. Increased prevalence of the polymorphic vitamin D receptor (VDR) alleles b, a, and T has been reported in sporadic primary hyperparathyroidism (PHPT), suggesting that these genetic variants may predispose to the disease. Recently, another polymorphism in the VDR gene was related to bone mineral density, and this VDR-FokI polymorphism causes
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Genetic alteration of the RET proto-oncogene is associated with multiple endocrine neoplasia type 2A and 2B (MEN 2A and MEN 2B), familial medullary thyroid carcinoma (FMTC) and Hirschprung's disease. Oncogenically activated RET has... more
Genetic alteration of the RET proto-oncogene is associated with multiple endocrine neoplasia type 2A and 2B (MEN 2A and MEN 2B), familial medullary thyroid carcinoma (FMTC) and Hirschprung's disease. Oncogenically activated RET has also been demonstrated in sporadic medullary thyroid tumors, which in some cases show somatic missense mutations. We have recently described a complex 9 bp deletion in RET exon 11 in a single case of sporadic MTC. In order to determine the prevalence of this mutation among sporadic MTC tumors, we have now analysed 15 cases and five normal controls by PCR-based nonradioactive single-strand conformational polymorphism analysis (PCR-SSCP) and fragment size analysis of exon 11. DNA was extracted from microdissected tumor tissue or normal cells and subjected to nested PCR prior to analysis. A markedly divergent SSCP pattern and a PCR fragment 9 bp shorter than normal were demonstrated in 14 of the 15 MTC tumors. Sequencing revealed the deletion of nine bas...
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In patients with primary hyperparathyroidism, measurements were made of basal and stimulated levels of intact parathyroid hormone (PTH). The basal PTH values were elevated in all but six of 89 patients and provided clear separation... more
In patients with primary hyperparathyroidism, measurements were made of basal and stimulated levels of intact parathyroid hormone (PTH). The basal PTH values were elevated in all but six of 89 patients and provided clear separation towards normal individuals (n = 75) and patients with hypercalcemia of other origin (n = 34). The PTH value correlated with the serum calcium concentration in hyperparathyroidism and with the weight of excised parathyroid adenomas but not with that of chief cell hyperplasias. A constant ethylenediaminetetraacetic acid infusion during 60 minutes of induced essentially linear reductions of plasma-ionized calcium concentrations, averaging 0.02 mmol/L/10 minutes, which were associated with swift, curvilinear, elevations of PTH levels that reached a plateau after 10 to 20 minutes. The increment in serum PTH level correlated with the basal PTH value both in patients with hyperparathyroidism and controls. However, in proportion to the much greater glandular mass...
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Endothelins (ETs) are 21 amino acid peptides with vasoactive and mitogenic properties. The three isopeptides (ET-1, -2, and -3) and their receptors (E1A and ETB subtypes) display expression in numerous tissues and possibly mediate... more
Endothelins (ETs) are 21 amino acid peptides with vasoactive and mitogenic properties. The three isopeptides (ET-1, -2, and -3) and their receptors (E1A and ETB subtypes) display expression in numerous tissues and possibly mediate autocrine/paracrine actions. The present investigation shows that ET-1 triggers biphasic increases of the concentration of cytoplasmic Ca2+ ([Ca2+]i) in pathological human parathyroid cells. Both the peak and sustained [Ca2+]i increase, as well as the proportion of responding cells, are dose-dependent in the 10(-10)-10(-7) mol/L range of ET-1. In absence of external Ca2+, the ET-1-induced [Ca2+]i peak is attenuated. ET-3 has no effect on [Ca2+]i indicating functional dominance of the ETA receptor subtype. ET-1 (10 nmol/L) lowers parathyroid hormone secretion in 0.5 mmol/L but not in higher external Ca2+ concentrations, and parathyroid cell ET release is inhibited by increases of external Ca2+. Fibroblasts overgrowing the parathyroid chief cells during mono...
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Insulinomas are pancreatic islet tumors that inappropriately secrete insulin, producing hypoglycemia. Exome and targeted sequencing revealed that 14 of 43 insulinomas harbored the identical somatic mutation in the DNA-binding zinc finger... more
Insulinomas are pancreatic islet tumors that inappropriately secrete insulin, producing hypoglycemia. Exome and targeted sequencing revealed that 14 of 43 insulinomas harbored the identical somatic mutation in the DNA-binding zinc finger of the transcription factor Yin Yang 1 (YY1). Chromatin immunoprecipitation sequencing (ChIP-Seq) showed that this T372R substitution changes the DNA motif bound by YY1. Global analysis of gene expression demonstrated distinct clustering of tumors with and without YY1(T372R) mutations. Genes showing large increases in expression in YY1(T372R) tumors included ADCY1 (an adenylyl cyclase) and CACNA2D2 (a Ca(2+) channel); both are expressed at very low levels in normal β-cells and show mutation-specific YY1 binding sites. Both gene products are involved in key pathways regulating insulin secretion. Expression of these genes in rat INS-1 cells demonstrated markedly increased insulin secretion. These findings indicate that YY1(T372R) mutations are neomorp...
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One-fifth of all patients with small-intestinal neuroendocrine tumors (SI-NETs) present with or develop peritoneal carcinomatosis (PC). Our aim was to determine the prognosis and genetic profiles of tumors in patients with PC compared... more
One-fifth of all patients with small-intestinal neuroendocrine tumors (SI-NETs) present with or develop peritoneal carcinomatosis (PC). Our aim was to determine the prognosis and genetic profiles of tumors in patients with PC compared with tumors in patients without PC. We included SI-NET patients (cases with PC, n = 73, and controls without PC, n = 468) who underwent operation between 1985 and 2012. The Lyon prognostic index was used to correlate the amount of PC to survival. DNA samples from patients with (n = 8) and without (n = 7) PC were analyzed with a single-nucleotide polymorphism array (HumanOmni2.5 BeadChip, Illumina) to investigate genetic disparities between groups. Patients with PC had poorer survival (median 5.1 years) than controls (11.1 years). An advanced postoperative Lyon prognostic index was a negative prognostic marker for survival by multivariable analysis (P = .042). Patients with and without PC clustered differently based on loss of heterozygosity and copy nu...
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Pancreatico-duodenal tumors are the second most common endocrinopathy in multiple endocrine neoplasia syndrome type 1, and have a pronounced effect on life expectancy as the principal cause of disease-related death. Previous discussions... more
Pancreatico-duodenal tumors are the second most common endocrinopathy in multiple endocrine neoplasia syndrome type 1, and have a pronounced effect on life expectancy as the principal cause of disease-related death. Previous discussions about surgical management have focused mainly on syndromes of hormone excess and, in particular, the management of multiple endocrine neoplasia syndrome type 1-related Zollinger-Ellison syndrome. Since hormonal syndromes tend to occur late and indicate the presence of metastases, screening with biochemical markers and endoscopic ultrasound is recommended for early detection of pancreatico-duodenal tumors, and with early surgery before metastases have developed. Surgery is recommended in patients with or without hormonal syndromes in the absence of disseminated liver metastases. The suggested operation includes distal 80% subtotal pancreatic resection together with enucleation of tumors in the head of the pancreas, and in cases with Zollinger-Ellison ...
Research Interests: Humans and Lymph nodes
Parathyroid gland is the overall regulatory organ within the systemic calcium homeostasis. Through cell surface bound calcium-sensing receptors external calcium inversely regulates release of parathyroid hormone (PTH). This mechanism,... more
Parathyroid gland is the overall regulatory organ within the systemic calcium homeostasis. Through cell surface bound calcium-sensing receptors external calcium inversely regulates release of parathyroid hormone (PTH). This mechanism, which is voltage independent and most sensitive around physiologic calcium concentrations, is regulated through a 120 kDa calcium sensing receptor, CaR. Inherited inactivation of this receptor is the cause for familial hypocalciuric hypercalcemia (FHH). Parallel research identified the 550 kDa glycoprotein megalin, which also is expressed on the parathyroid cell surface, as another potential calcium sensing protein. Although this protein expresses numerous calcium binding sites on its external domain, its main function may be calcium sensitive binding and uptake of steroid hormones, such as 25-OH-vitamin D3 (bound to vitamin D binding protein) and retinol. In hyperparathyroidism (HPT), excessive PTH is secreted and the calcium sensitivity of the cells ...
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Primary hyperparathyroidism is a common endocrine disease particularly prevalent among elderly women. A majority of these patients diagnosed today are mildly hypercalcaemic, and many seem to lack manifest symptoms or complications. In... more
Primary hyperparathyroidism is a common endocrine disease particularly prevalent among elderly women. A majority of these patients diagnosed today are mildly hypercalcaemic, and many seem to lack manifest symptoms or complications. In such cases, conservative follow-up rather than parathyroid surgery may be suggested. However, long-term follow-up may entail costly investigations and be difficult to accomplish. Moreover, conservative follow-up is associated with a risk of subsequent complications or even premature death due to cardiovascular disorders. A Scandinavian multicentre study has been initiated to assess survival, morbidity and quality of life in surgically vs. conservatively treated patients.
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Germ line point mutations in the RET proto-oncogene have been implicated in four inherited disorders: multiple endocrine neoplasia 2A (MEN 2A) and 2B (MEN 2B); familial medullary thyroid carcinoma (FMTC); and Hirschprung's disease, a... more
Germ line point mutations in the RET proto-oncogene have been implicated in four inherited disorders: multiple endocrine neoplasia 2A (MEN 2A) and 2B (MEN 2B); familial medullary thyroid carcinoma (FMTC); and Hirschprung's disease, a congenital lack of enteric plexus neurons. Oncogenically activated RET has also been demonstrated in some sporadic medullary thyroid tumors, which show somatic missense mutations in the same regions as those found in MEN 2B. Upon screening archival sporadic MTC tumor tissue by nonradioactive single-strand conformational polymorphism analysis (SSCP), a markedly divergent exon 11 pattern was found in an unusually aggressive neoplasm. Sequencing of PCR amplified DNA revealed the deletion of nine bases encompassing a key cysteine codon at position 1831-3, often altered in MEN 2A. Normal thyroid tissue from the same patient showed a normal SSCP pattern and sequence for this exon. This novel somatic mutation further implicates the RET proto-oncogene in th...
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Despite its tendency to metastasize and grow multifocally, papillary thyroid carcinoma (PTC), the most common endocrine malignancy, usually displays an indolent clinical course. Although this behavior probably reflects the inherent low... more
Despite its tendency to metastasize and grow multifocally, papillary thyroid carcinoma (PTC), the most common endocrine malignancy, usually displays an indolent clinical course. Although this behavior probably reflects the inherent low growth potential of PTC cells, it has been postulated that the striking inflammatory reaction often present in PTC represents the activation of a protective, tumor-induced immune response. In a recent immunohistochemical study, we reported that immunoglobulin (IgG) and complement (C3d, C4d and C5) are specifically deposited in PTC tumor tissue. Endeavors were then made to isolate and identify tumor-associated antigens. Immunoprecipitation employing the serum and tumor tissue of PTC patients produced two bands by SDS-PAGE, at approximately 34.5 and 35 kD, which were not present in normal thyroid tissue. Three tryptic peptides of the 35 kD band were sequenced, identifying it as a fragment of cytokeratin 1, a structural protein not normally expressed in ...
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ABSTRACT
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Normal and abnormal human parathyroid tissue express the T-lymphocyte protein CD4, and parathyroid and lymphocyte cells show similarities with respect to mechanisms of calcium permeability and regulation of the cytoplasmic calcium... more
Normal and abnormal human parathyroid tissue express the T-lymphocyte protein CD4, and parathyroid and lymphocyte cells show similarities with respect to mechanisms of calcium permeability and regulation of the cytoplasmic calcium concentration. Anti-Leu4, a monoclonal antibody recognizing the T-lymphocyte glycoprotein complex CD3, is used to immunohistochemically stain normal and abnormal human parathyroid cells and to explore influences on the parathyroid hormone (PTH) secretion of enzymatically dispersed parathyroid cells. Parathyroid glands of patients with different forms of hyperparathyroidism displayed variable expression of the anti-CD3 reactive complex. The stainings correlated both positively and inversely to immunoreactivity for a previously defined calcium sensor, the decreased expression of which may constitute a molecular basis for hyperparathyroidism. Incubation of parathyroid cells with the anti-Leu4 antibody inhibited PTH secretion and reduced its sensitivity to ext...
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Dispersed parathyroid cells from normal human and bovine glands and from 10 patients with primary (7 adenomas, 3 hyperplasias) and 4 patients with uraemic hyperparathyroidism (HPT) have been investigated with respect to density,... more
Dispersed parathyroid cells from normal human and bovine glands and from 10 patients with primary (7 adenomas, 3 hyperplasias) and 4 patients with uraemic hyperparathyroidism (HPT) have been investigated with respect to density, morphology and parathyroid hormone (PTH) release. Percoll density gradients enabled an efficient isolation of viable parathyroid cells which generally banded between 1.035-1.090 g/ml. The average density was significantly higher in cells from the normal than the abnormal glands. The pathological glands contained large chief cells, oxyphil and transitional oxyphil cells and, in one case, water-clear cells which were enriched in fractions with densities below 1.055 g/ml. Measurements of cell diameters revealed an increased proportion of enlarged cells in the preparation of abnormal glands. Nuclear diameters were similar in the normal human glands, adenomas and hyperplasias, but the variability was greater among the adenomas. In comparison to normal bovine para...
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Surgical and histopathologic findings and results of subtotal resection and total parathyroidectomy with autotransplantation were evaluated in 82 hypercalcemic patients with uremic hyperparathyroidism. The mean preoperative serum calcium... more
Surgical and histopathologic findings and results of subtotal resection and total parathyroidectomy with autotransplantation were evaluated in 82 hypercalcemic patients with uremic hyperparathyroidism. The mean preoperative serum calcium concentration was 2.89 mM, and the highest values were associated with more rapidly progressing hypercalcemia. Despite greatly increased total weight of the parathyroid tissue (mean 1,509 mg), 34 patients had one to five normal-sized parathyroid glands. The incidence of such glands decreased with total gland weight. Nodular hyperplasia was found in 74% of the patients, and was characterized by considerable intraindividual size difference, while diffuse hyperplasia was associated with more moderate and symmetric glandular enlargement. During follow-up averaging 4.5 years, the incidence of persistent or recurrent hypercalcemia was slightly higher after subtotal than after total parathyroidectomy (11 and 11%, vs. 9 and 7%). Biochemical and/or radiologi...
Research Interests: Adolescent, Methods, Humans, Female, Male, and 6 moreFollow-up studies, Aged, Middle Aged, Adult, Hyperparathyroidism, and Hypercalcemia
All the 249 patients with medullary thyroid carcinoma (MTC) diagnosed during a 23-year period in Sweden were followed up completely for 4-27 years. The overall relative survival was 79.9% at 5 years after diagnosis and 68.6% at 10 years.... more
All the 249 patients with medullary thyroid carcinoma (MTC) diagnosed during a 23-year period in Sweden were followed up completely for 4-27 years. The overall relative survival was 79.9% at 5 years after diagnosis and 68.6% at 10 years. After 5 years of follow-up, the relative survival rate was 5 percentage points higher in females than in males; 30 percentage points higher in patients aged less than 40 than in those 60-69 years at diagnosis; 24 percentage points higher in patients with familial disease detected at screening than in those with sporadic MTC; 20, 26 and 48 percentage points lower in patients with stage II, III, and IV, respectively, than in those with stage I; and almost 30 percentage points lower in the group of patients with a large tumor (greater than 3 cm) than in the group with a small one (less than 1 cm). In multivariate proportional hazards analyses of all these important determinants of outcome, the prognostic information provided by age and stage was still ...
Research Interests: Adolescent, Sweden, Humans, Child, Female, and 9 moreMale, Aged, Middle Aged, Carcinoma, Adult, Sex Factors, Survival Rate, Prognosis, and Age Factors
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Operation and reoperation for hyperparathyroidism in multiple endocrine neoplasia type 1 (MEN 1) is controversial regarding surgical strategy, preoperative localization, and biochemical indexes of recurrence. Fifty patients with MEN 1... more
Operation and reoperation for hyperparathyroidism in multiple endocrine neoplasia type 1 (MEN 1) is controversial regarding surgical strategy, preoperative localization, and biochemical indexes of recurrence. Fifty patients with MEN 1 with hyperparathyroidism were followed up 2 to 27 years after subtotal (SPX; n = 35) or total parathyroidectomy with forearm autografiing (TPX; n = 15), including 24 who underwent 28 reoperations because of persistent or recurrent hyperparathyroidism. Persistent or recurrent hyperparathyroidism was seen in 66% and 20% of patients after SPX involving extirpation of at least 3 glands and TPX, respectively, and 100% after single-gland excision as a primary procedure. After reoperation, hypercalcemia was reversed in 33% of patients by SPX and 61% by intended TPX procedures. All patients received vitamin D substitution after TPX, but restricted thyroid function allowed withdrawal in all but 10 patients (36%). Intact serum parathyroid hormone levels in nongrafted and grafted arms rose with time, but only exceptional ratios localized graft recurrence. Localization of recurrent hyperparathyroidism was achieved with 11C-labeled methionine positron emission tomography. MEN 1 hyperparathyroidism has a high risk of recurrence, and operation may include primarily SPX of at least 3 glands or TPX, although the latter includes a higher risk of long-term hypoparathyroidism. Reoperation should involve TPX with recognition of the enhanced recurrence rate in individuals with postoperative hyperparathyroidism.
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Vitamin D and retinoids are important regulators of differentiation and proliferation in a number of tissues, and have been implicated as chemopreventive agents in several different tumors. While vitamin D is known to be important for... more
Vitamin D and retinoids are important regulators of differentiation and proliferation in a number of tissues, and have been implicated as chemopreventive agents in several different tumors. While vitamin D is known to be important for regulation of parathyroid function and proliferation, it has recently been established that parathyroid cells also are targets for retinoids. Hyperparathyroidism (HPT) is a common disorder, and evaluation of the disease has indicated high prevalence of subclinical disease, as well as clear benefits of offering treatment for the disease. This review summarizes the data so far gathered concerning parathyroid cells, vitamin D and retinoids, with clear implication on prospects of possible medical treatment of hyperparathyroidism.
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Insulin-like growth factor 1 (IGF-1) may influence cellular growth, differentiation and secretion. Cryosectioned normal human adrenal glands (n = 6), cortical adenoma (n = 21), and carcinoma (n = 17) were stained immunohistochemically for... more
Insulin-like growth factor 1 (IGF-1) may influence cellular growth, differentiation and secretion. Cryosectioned normal human adrenal glands (n = 6), cortical adenoma (n = 21), and carcinoma (n = 17) were stained immunohistochemically for IGF-1 and its receptor, and human adrenocortical cancer cells expressing the receptor were analysed for influences on proliferation. Normal cortical parenchyma generally displayed faint IGF-1 reactivity and intracellular receptor staining. Similar labelling encompassed the adenomas, but only 6 of them were receptor reactive. IGF-1 expression was conspicuous in 11 carcinomas, and 6 of them displayed cell surface receptor reactivity. All aldosterone producing lesions were receptor antibody unreactive. Recombinant IGF-1 dose-dependently stimulated the cell proliferation, and this effect was reversed by the receptor antibody. IGF-1 may interact with function and proliferation of the human adrenal cortex with particular reference to cortical carcinomas lacking discernible aldosterone excess.
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ABSTRACT The name “carcinoid” was first used by Oberndorfer in 1907 to describe uncommon ileal tumors with benign behavior in contrast to common bowel carcinomas. The term was subsequently used as an overall name for neuroendocrine... more
ABSTRACT The name “carcinoid” was first used by Oberndorfer in 1907 to describe uncommon ileal tumors with benign behavior in contrast to common bowel carcinomas. The term was subsequently used as an overall name for neuroendocrine cell-derived tumors. Based on their embryological origin these tumors have commonly been classified into foregut, midgut, and hindgut carcinoids. In recent classifications the carcinoids have been named neuroendocrine tumors of the respective organs, and classified into the categories: well-differentiated neuroendocrine tumors, well-differentiated endocrine carcinoma, poorly differentiated endocrine carcinomas, and mixed exocrine–endocrine tumors [1]. In this chapter we will cover the clinical presentation, diagnosis and surgical management of carcinoids, and for clarity have used a common older classification. Carcinoids are rare with an incidence of 1–2/100,000 population/year. About 70% occur in the gastrointestinal tract [2]. They typically stain positively for chromogranin A and/or synaptophysin. The majority are differentiated (with low mitotic activity and low Ki67 proliferation index, often <2%), while others are intermediate or poorly differentiated, with an increased mitotic rate and higher proliferation (Ki67 index 10–40%) [1]. Most carcinoids are clinically nonfunctional, but some have dominant secretion (serotonin, histamine, gastrin, somatostatin), sometimes causing severe symptoms. The most common is the carcinoid syndrome, associated with the “classical” midgut jejuno-ileal carcinoid. Rare foregut carcinoids can have ectopic adrenocorticotropic hormone (ACTH) or corticotropin-releasing factor (CRF) secretion, causing ectopic Cushing’s syndrome [1]. The well-differentiated tumors often have an extended clinical course and therefore have specific surgical requirements based on tumor type and localization.
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ABSTRACT Pearls and PitfallsGastric CarcinoidsGastrin-dependent gastric carcinoids and gastric endocrine cell hyperplasia occur in 1% of patients with atrophic gastritis, and in MEN1 patients with Zollinger-Ellison syndrome, with... more
ABSTRACT Pearls and PitfallsGastric CarcinoidsGastrin-dependent gastric carcinoids and gastric endocrine cell hyperplasia occur in 1% of patients with atrophic gastritis, and in MEN1 patients with Zollinger-Ellison syndrome, with increased gastric acid, and without mucosal atrophy.Correct diagnosis requires multiple gastric mucosal biopsies:If biopsies show atrophic gastritis, the carcinoid is type 1; endoscopic excision and surveillance is adequate because risk for metastases is minimal.If there is no atrophic gastritis and the patient has MEN1, the carcinoid is type 2, and usually single, larger, invasive, and requires resection.In the absence of atrophic gastritis and MEN1, the lesion is type 3, sporadic gastric carcinoid prognosis is poorer, and aggressive resection is warranted.Midgut CarcinoidsThe small ileal tumor and large mesenteric metastases encircled by fibrosis should raise suspicion of a midgut carcinoid.Even with grossly radical excision, liver metastases may o ...
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Despite its predilection for multifocal growth and regional metastasis, papillary thyroid carcinoma (PTC) is a clinically indolent malignancy with an exceptionally favorable long-term prognosis. Together with the often striking... more
Despite its predilection for multifocal growth and regional metastasis, papillary thyroid carcinoma (PTC) is a clinically indolent malignancy with an exceptionally favorable long-term prognosis. Together with the often striking inflammatory reaction present in PTC, its quiescent behavior has been suggested to reflect the activation of a tumor-induced immune response. To examine this possibility, we have studied the deposition of immunoglobulins and complement in PTC tissue. Samples from 70 cases of neoplastic and autoimmune thyroid diseases, including PTC (n = 41), follicular, anaplastic, and medullary carcinomas (n = 12), follicular adenoma (n = 6), Graves' disease (n = 8), and Hashimoto's thyroiditis (n = 3) were analyzed immunohistochemically. Cellular deposits of immunoglobulin G (IgG), particularly subclasses IgG1 and IgG4, and complement factors C3d, C4d, and C5 were shown in up to 80% of the PTC cases, whereas the other thyroid diseases studied showed little or no cellular deposition. Nonneoplastic tissue of PTC-containing thyroid glands (n = 22) lacked staining for IgG in 50% of the cases, and 82% were devoid of complement. The results suggest a tumor-specific immune response in PTC with activation of the classical complement cascade.
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The optimal treatment of Graves disease (GD) is still controversial. Surgery is one treatment option along with radioactive iodine (RAI) and antithyroid medication. In this evidence-based review, we examine four issues: (1) Is surgery... more
The optimal treatment of Graves disease (GD) is still controversial. Surgery is one treatment option along with radioactive iodine (RAI) and antithyroid medication. In this evidence-based review, we examine four issues: (1) Is surgery better than RAI or long-term antithyroid medication? (2) What is the recommended surgical approach? (3) How does the presence of Graves' ophthalmopathy (GO) influence the role of surgery? (4) What is the role of surgery in children with GD? We conducted a systematic review of the literature using evidence-based criteria regarding these four issues. (1) There are no recommendations reaching any grade of evidence for which treatment to choose for adults with GD. (2) Total thyroidectomy has complication rates equal to those seen with lesser resections but it has higher cure rates and negligible recurrence rates (Level I-IV data leading to a grade A recommendation). (3) Data support surgery when severe GO is present, but RAI combined with glucocorticoids may be equally safe (Level II-IV data, grade B recommendation). The extent of thyroid resection does not influence the outcome of GO (Level II data, grade B recommendation). (4) Based on the available data, definitive treatment can be advocated for children (Level IV data, grade C recommendation) using either RAI or surgery. No recommendation can be given as to whether RAI or surgery is preferred owing to the lack of studies addressing this issue. Increased cancer risk with RAI in children below the age of 5 years supports surgery in this setting (Level I data, grade A recommendation). If surgery is considered for definitive management, evidence-based criteria support total thyroidectomy as the surgical technique of choice for GD. Available evidence also supports surgery in the presence of severe endocrine GO. Children with GD should be treated with an ablative strategy. Whether this is achieved by total thyroidectomy or RAI may still be debatable. Data on long-term cancer risk are missing or conflicting; and until RAI has proven harmless in children, we continue to recommend surgery in this group.
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Primary hyperparathyroidism (HPT) is a common disorder that mainly afflicts elderly women. It can be diagnosed in at least 1% of all postmenopausal females and autopsy studies indicate an even higher frequency. Although the widespread use... more
Primary hyperparathyroidism (HPT) is a common disorder that mainly afflicts elderly women. It can be diagnosed in at least 1% of all postmenopausal females and autopsy studies indicate an even higher frequency. Although the widespread use of automated serum calcium analyses has increased the awareness of HPT, only 10% of all cases seem to be identified. The diagnosis relies on the demonstration of an inappropriately elevated serum concentration of parathyroid hormone (PTH) relative to the serum calcium value, which need not be markedly raised. Measurements of intact PTH with immunometric methods have considerably improved the diagnostic precision but it is still difficult to evaluate patients with only marginal hypercalcemia. Few patients with diagnosed HPT are completely without symptoms. Symptoms commonly encountered are psychiatric and neuromuscular disturbances. Subclinical bone disease might be relevant but there is insufficient information about its importance in otherwise asymptomatic individuals. Various cardiovascular risk factors appear more commonly in patients with HPT and untreated disease is associated with an increased risk of premature death.
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Three monoclonal IgG 2a antibodies were produced after immunization of mice with dispersed cells from a human mid-gut carcinoid tumor. Acetone-fixed cryosections of 57 primary and metastatic mid-gut carcinoid tumors as well as 2 hind-gut... more
Three monoclonal IgG 2a antibodies were produced after immunization of mice with dispersed cells from a human mid-gut carcinoid tumor. Acetone-fixed cryosections of 57 primary and metastatic mid-gut carcinoid tumors as well as 2 hind-gut (rectal) carcinoids showed a conspicuous immunoreaction while a thymic carcinoid was essentially unstained with the antibodies. The 3 antibodies yielded a similar pattern of immunostaining. The immunoreaction comprised more than 95% of the carcinoid tumor cells, and it was more uniform and intense in primary tumors than in mesenteric, hepatic, and ovarian metastases of the mid-gut carcinoid tumors. Immunofluorescence studies on suspended carcinoid tumor cells showed that the antibodies bound to the surface membrane of the cells. The antibodies immunostained enterocytes of the small and large bowel, intestinal metaplasia of the stomach mucosa as well as colorectal adenocarcinomas. Endocrine pancreatic tumors producing vasoactive intestinal polypeptide, gastrin, somatostatin, and/or pancreatic polypeptide as well as the epithelium of pancreatic ducts were also stained with the antibodies, whereas a large number of other normal and abnormal human tissues, including benign and malignant insulinomas, were unreactive. The findings indicate that the antibodies recognize differentiation antigens on the carcinoid tumor cell surface preserved also on endocrine and nonendocrine cells of the normal bowel mucosa. The restricted tissue reactivity of the antibodies suggests that they may constitute useful tools in the histological characterization of carcinoid tumors. Further studies may reveal if they are applicable for immunolocalization and perhaps even immunotherapy of these neoplasms.
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Coincident with medical antitumor treatment of 138 patients suffering from mid-gut carcinoid tumors, 51 patients were subjected to surgery with the principal aims of removing primary tumors and debulking mesenteric or liver metastases.... more
Coincident with medical antitumor treatment of 138 patients suffering from mid-gut carcinoid tumors, 51 patients were subjected to surgery with the principal aims of removing primary tumors and debulking mesenteric or liver metastases. Sixteen patients had previously been operated with intestinal resection or, when the tumors had been considered inexcisable, with intestinal bypass or laparotomy alone. Apart from exhibiting symptoms related to the carcinoid syndrome, the majority (approximately 60%) of the 51 patients had generally intermittent, subileus-like abdominal pain and weight loss. In 18 patients, these symptoms were pronounced and associated with intestinal obstruction or severe malnutrition. Computed tomography and arteriography efficiently demonstrated mesenteric and liver metastases. At laparotomy, the primary intestinal tumors were small, mainly less than 1 cm in diameter, and they were multiple in 39% of the patients. Mesenteric metastases measuring up to 12 cm in diameter were present in 86% of the patients. These metastases were frequently associated with a pronounced mesenteric and retroperitoneal fibrosis causing fixation, angulation, and obstruction of the bowel as well as incipient intestinal gangrene in 8 patients. In all but 6 patients, the primary tumors could be removed by comparatively limited intestinal resections although bulky mesenteric metastases were often dissected from the mesenteric vessels. Liver metastases, found in 49% of the patients, were generally bilateral and multiple, and major hepatic metastases were resected in 6 patients. The results support a role for surgery also in the more compromised patients with mid-gut carcinoid tumors and that such intervention may be associated with considerable symptomatic relief and substantial periods of survival.
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A majority of patients with small intestinal neuroendocrine tumors (SI-NETs) present with or develop liver metastases (LM). A number of treatments for LM are used clinically, including liver transplantation (LTx). Indications for LTx are... more
A majority of patients with small intestinal neuroendocrine tumors (SI-NETs) present with or develop liver metastases (LM). A number of treatments for LM are used clinically, including liver transplantation (LTx). Indications for LTx are under debate; young age(<65 years), absence of extrahepatic disease, resected primary tumor and limited extent of LM have been suggested as inclusion criteria for LTx with the aim to optimize outcome. From our series of 672 patients with SI-NET treated at the University Hospital in Uppsala between 1985 and 2012, we identified 78 patients according to the following criteria: <65 years of age, locoregional surgery (LRS) of the primary tumor and mesenteric metastases successfully performed, LM present but no extrahepatic disease. Baseline was chosen as the first date the following points were met: First visit to our center,LRS performed, LM present. The patients underwent treatment according to the standard clinical protocols at our center, and during this time period we did not perform or refer any SI-NET patients for LTx. Kaplan-Meier survival analyses were performed in three different groups based on hypothetical criteria for LTx. Five-year overall survival rates for patients <65 years (n = 78) and <55 years (n = 36) of age were 84 ± 8 and 92 ± 9 %, respectively. For patients fulfilling the Milan criteria (n = 33) the 5-year survival was 97 ± 6 %. Most young patients (<65 years) with SINET and LM have a favorable survival with standardized multimodality treatment. Indeed, most survival figures reported after LTx of NET do not surpass these figures.
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Thirty-nine patients with hyperparathyroidism (HPT) in association with the multiple endocrine neoplasia type I (MEN-I) syndrome underwent parathyroid surgery from 1961 to 1985. Twenty-one patients underwent resection of 1–21/2 glands, 6... more
Thirty-nine patients with hyperparathyroidism (HPT) in association with the multiple endocrine neoplasia type I (MEN-I) syndrome underwent parathyroid surgery from 1961 to 1985. Twenty-one patients underwent resection of 1–21/2 glands, 6 had 3–31/2 glands removed, and 18 (9 of whom had previously been subjected to parathyroid surgery) underwent total parathyroidectomy with autotransplantation to the forearm. Resection of 1–21/2 glands resulted
Research Interests: Methods, Humans, World, Female, Male, and 5 moreHyperplasia, Clinical Sciences, Middle Aged, Adult, and Hyperparathyroidism
Primary hyperparathyroidism (HPT) is often caused by a benign parathyroid tumor, adenoma; less commonly by multiglandular parathyroid disease/hyperplasia; and rarely by parathyroid carcinoma. Patients with multiple tumors require wider... more
Primary hyperparathyroidism (HPT) is often caused by a benign parathyroid tumor, adenoma; less commonly by multiglandular parathyroid disease/hyperplasia; and rarely by parathyroid carcinoma. Patients with multiple tumors require wider exploration to avoid recurrence and have increased risk for hereditary disease. Secondary HPT is a common complication of renal failure. Improved knowledge of the molecular background of parathyroid tumor development may help select patients for appropriate surgical treatment and can eventually provide new means of treatment. The present contribution summarizes more recent knowledge of parathyroid molecular genetics. A literature search and review was made to evaluate the level of evidence concerning molecular biology and genetics of primary, secondary, and familial HPT according to criteria proposed by Sackett, with recommendation grading by Heinrich et al. Most parathyroid adenomas and hyperplastic glands are monoclonal lesions. Cyclin D1 gene (CCND1) translocation and oncogene action occur in 8% of adenomas; cyclin D1 overexpression is seen in 20% to 40% of parathyroid adenomas and in 31% of secondary hyperplastic glands. Somatic loss of one MEN1 allele is seen in 25% to 40% of sporadic parathyroid adenomas, half of which have inactivating mutation of the remaining allele. Inactivating somatic HRPT2 mutations are common in parathyroid carcinoma, often causing decreased expression of the protein parafibromin involved in cyclin D1 regulation. Aberrant regulation of Wnt/beta-catenin signaling may be important for parathyroid tumor development. Molecular genetic studies of parathyroid tumors are well designed basic experimental studies providing strong level III evidence, with data frequently confirmed by subsequent studies.
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Double parathyroid adenoma (DA) has been suggested to be a clinically distinct entity of primary hyperparathyroidism (HPT). Altogether 659 patients with sporadic primary HPT were analyzed retrospectively by evaluating consecutive primary... more
Double parathyroid adenoma (DA) has been suggested to be a clinically distinct entity of primary hyperparathyroidism (HPT). Altogether 659 patients with sporadic primary HPT were analyzed retrospectively by evaluating consecutive primary operations for more than three decades. Patients with postoperatively persistent HPT and those with incomplete medical, operative, or histologic records were disregarded. The mean age (+/- SD) at surgery was 60.9 +/- 12.7 years; 78% of the patients were female; and the duration of postoperative follow-up averaged 7.8 +/- 7.2 years. DA, defined as two enlarged parathyroid glands, was found in 77 patients (12%). Enlargement of a single gland (SA) or three or more glands (MA) occurred in 80% and 8%, respectively. DAs were bilateral in 72% of patients, and the weight of the two glands differed by 317 +/- 407 mg. The three histologic subgroups of patients exhibited no significant discrepancy with respect to age, classic symptoms of HPT, proportion of overtly asymptomatic individuals, or parathyroid tissue weight. A lower female predominance and extent of hypercalcemia and higher preoperative serum creatinine level occurred with DA and MA compared to SA. SA and DA differed from MA with respect to variably strong trends to lower postoperative incidences of recurrent HPT and hypoparathyroidism. DA seems to comprise an underrated histologic cause of HPT, which is eligible for a conservative operative approach. Clinical characteristics consistent with a distinct entity of sporadic primary HPT were not seen.
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Calcitriol, via its receptor (VDR), inhibits parathyroid hormone (PTH) secretion and cell proliferation. Physically linked polymorphic VDR alleles denoted b,a, and T, comprise a novel risk factor for postmenopausal primary... more
Calcitriol, via its receptor (VDR), inhibits parathyroid hormone (PTH) secretion and cell proliferation. Physically linked polymorphic VDR alleles denoted b,a, and T, comprise a novel risk factor for postmenopausal primary hyperparathyroidism (pHPT) by their presumed coupling to reduced VDR expression. This study examines VDR gene polymorphisms, parathyroid calcium-regulated cytoplasmic calcium concentrations ([Ca2+]i) and parathyroid expression of a calcium sensor protein (CAS/gp330). Genomic DNA was obtained from 66 postmenopausal women with pHPT and 66 age-matched female controls. Polymorphic VDR alleles were detected after polymerase chain reaction (PCR) and restriction digestion. Cryosections of pathologic parathyroid glands from 41 of the patients were immunostained with a monoclonal anti-CAS/gp330 antibody. Homozygosity for the VDR alleles b, a, and T was overrepresented in pHPT (p < 0.01-0.05) but did not couple to ED50 for calcium-regulated [Ca2+]i. The enlarged parathyroid glands possessed heterogeneous down-regulation of CAS/gp330. This down-regulation was the least conspicuous in the BBgenotype, and these few patients generally had larger parathyroid lesions (p < 0. 05). The VDR haplotype baTis a risk factor for pHPT possibly by hampering the regulatory actions of calcitriol. In contrast the BAt haplotype seems to be underrepresented in pHPT and to couple to larger parathyroid lesions as well as less deranged CAS/gp330 expression and parathyroid cell function. HPT in these individuals may relate to genetic events principally altering the regulation of cell proliferation, rather than calcium sensing of the parathyroid cells.
Research Interests: Genetics, Polymorphism, Calcium, Immunohistochemistry, Postmenopausal Women, and 16 moreHumans, Vitamin D receptor, World, Female, Polymerase Chain Reaction, Risk factors, Parathyroid Hormone, Clinical Sciences, Aged, Middle Aged, Gene Polymorphism, Genomic DNA, Risk Factors, Cell Proliferation, Hyperparathyroidism, and Primary hyperparathyroidism
Radiologically demonstrable pancreatic endocrine tumors are a frequent requirement for exploration in patients with multiple endocrine neoplasia type I (MEN-I). Such delayed intervention is accompanied by a 30% to 50% incidence of... more
Radiologically demonstrable pancreatic endocrine tumors are a frequent requirement for exploration in patients with multiple endocrine neoplasia type I (MEN-I). Such delayed intervention is accompanied by a 30% to 50% incidence of pancreatic endocrine metastases. This study explores biochemical tumor markers and operative findings in relation to preoperative pancreatic radiology in 25 MEN-I patients. They underwent pancreatic surgery with (n = 19) or without (n = 6) radiologic signs of primary tumor and absence of metastases upon conventional examination, including OctreoScan testing (n = 10). Biochemical diagnosis required an increasing elevation of at least two independent pancreatic tumor markers. Tumor diameters averaged 1.1 cm (0-5 cm) and 0.9 cm (0.2-1.5 cm) in the patients with and without positive preoperative radiology, respectively. These investigations never displayed more than one of the consistently multiple tumors, and the results were falsely positive in 26%. Preoperatively unidentified regional or hepatic metastases were found at surgical exploration in 26% of patients with radiologic localization and in none of the others. Limited pancreatic tumor involvement necessitated intraoperative absence of metastases and pancreatic lesions </= 1 cm in diameter on palpation, intraoperative ultrasonography, and microscopy. It occurred in 37% and 50% of the patients with and without radiologic tumor localization, respectively. The number of positive tumor markers was similar for patients with limited and major disease (2.3 vs. 2.7), whereas four or more such markers were found in all those with malignancies. The mean marker level was higher in patients with radiologically demonstrable tumors and lower in those with limited disease, but with a substantial overlap. OctreoScan testing was negative in all cases with limited disease and was the single most sensitive method (75%) in the others. Limited pancreatic disease could not be identified preoperatively, and the present means of biochemical pancreatic tumor identification invariably involved the presence of at least one lesion >/= 7 mm in diameter. Conventional pancreatic imaging is insensitive and nonspecific for recognizing even substantial pancreatic tumors associated with MEN-I.
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Patients with midgut carcinoid (MGC) tumors are commonly treated with somatostatin analogs. Adverse effects of these drugs include impairment of gallbladder function, formation of gallstones, and cholecystitis. Prophylactic... more
Patients with midgut carcinoid (MGC) tumors are commonly treated with somatostatin analogs. Adverse effects of these drugs include impairment of gallbladder function, formation of gallstones, and cholecystitis. Prophylactic cholecystectomy has been advocated, but data to support this recommendation are sparse. We have analyzed a cohort of 235 patients with MGC focusing on the risk for gallstone formation and complications thereof. Forty-eight of the 235 patients had been cholecystectomized before surgery for MGC. Of the remaining 187 patients, 144 were treated with somatostatin analogs. Eighteen of the 187 patients had their gall bladder removed during the primary carcinoid surgery. Twenty-two of the 144 somatostatin-analog-treated patients developed complications, such as gallbladder empyema (n = 1), cholangitis (n = 2), acute cholecystitis (n = 6), acute pancreatitis (n = 1) or acute pancreatitis and cholecystitis (n = 1), or biliary colic (n = 11). Ninety-two of the 144 were examined during surgery, by computed tomography, or by ultrasound, most for reasons other than gallbladder-related indications, and 63% (58/92) of these examinations revealed gallstones. Of the 43 patients not treated with somatostatin analogs, only 3 patients suffered from biliary colic and underwent cholecystectomy. In our study the incidence of gallstone-related complications seems to be higher than in the general population. We recommend that prophylactic cholecystectomy is liberally performed during laparotomy for MGC if patients are planned to undergo treatment with somatostatin analogs.
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Midgut carcinoid (MGC) tumors generally develop in the small intestine and in >50% of cases also present with lymph node metastases in the mesentery. The majority of these tumors are surgically resectable,... more
Midgut carcinoid (MGC) tumors generally develop in the small intestine and in >50% of cases also present with lymph node metastases in the mesentery. The majority of these tumors are surgically resectable, but a fraction are inoperable and may cause obstruction of the superior mesenteric vein (SMV), often associated with stasis of the intestinal wall and severe symptoms. These symptoms include severe abdominal pain, attacks of diarrhea, and malnutrition. Seven patients with severe MGC including a large fibrotic inoperable mesenteric mass and severe symptoms were studied. After an obstructed SMV and signs of venous stasis in the small intestine were demonstrated, an expandable stent was inserted after puncturing an intrahepatic portal venous branch. The associated venography, patient symptoms, and radiological signs on computed tomography (CT) scans were evaluated. Four patients demonstrated resolution of their symptoms. In one patient who had intra-abdominal lymph leakage/chyloperitoneum, a complete normalization of the circulation followed and the intra-abdominal lymph leakage stalled. The venographies demonstrated normalization of the venous blood flow through the SMV, and CT scans demonstrated reduction in the thickness of the intestinal wall. In two cases there were no changes in the symptoms, and in one case a slight worsening of the symptoms ensued. In general, reductions of symptoms were associated with the degree of normalization of venous blood flow. We conclude that in selected patients with MGC stenting of the SMV may improve symptoms.
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Forty-two patients with primary hyperparathyroidism (HPT) of multiple endocrine neoplasia type 1 (MEN-1) were evaluated a mean of 8.9 years after subtotal parathyroid resection (SPX, n = 34) or total parathyroidectomy with... more
Forty-two patients with primary hyperparathyroidism (HPT) of multiple endocrine neoplasia type 1 (MEN-1) were evaluated a mean of 8.9 years after subtotal parathyroid resection (SPX, n = 34) or total parathyroidectomy with autotransplantation to the forearm (TPX, n = 23). TPX as the primary operation revealed asymmetric and mainly nodular enlargement of the parathyroid glands with the presence of at least one normal-size gland in half of the individuals. TPX and SPX were accompanied by resolution of the hypercalcemia in 78% and 38% of the patients. Persistent and recurrent HPT occurred in 22% and 61% of the patients, while hypoparathyroidism requiring oral supplements occurred in 30% and 12% of the patients, respectively. Intact serum parathyroid hormone (PTH) in the arm of parathyroid autograft was high in the normocalcemic patients, somewhat lower in the patients with recurrent HPT, and normal to very low in the hypoparathyroid patients. Ratios of intact PTH between the grafted and non-grafted arms varied from 1 to 56.3, with average of 28.1 in the normocalcemic individuals, 8.2 in the patients with recurrent HPT, and 3.3 in those requiring supplements to maintain normocalcemia. These findings substantiate an 80% to 92% reversal of hypercalcemia during long-term follow-up of MEN-1 patients undergoing total parathyroidectomy or subtotal resection of 3-4 parathyroid glands as primary operative procedures and demonstrate the usefulness of intact serum PTH for functional evaluation of parathyroid autografts.
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Hypercalcemia was corrected in 62 (90%) of 69 patients after re-operation for primary hyperparathyroidism during a mean follow-up of 6.3 years. Failed primary exploration was mainly due to inadequate visualization of the pathological... more
Hypercalcemia was corrected in 62 (90%) of 69 patients after re-operation for primary hyperparathyroidism during a mean follow-up of 6.3 years. Failed primary exploration was mainly due to inadequate visualization of the pathological parathyroid glands, often in association with misleading or absent peroperative histology. Other causes included seeding of parathyroid adenoma tissue, truly recurrent adenomas, and recurrent hyperplasia, especially in patients with multiple endocrine neoplasia type 1. A considerable number of parathyroid glands missed at the primary operations were subsequently found in essentially normal positions. Ectopic superior glands were most frequently positioned para-esophageally or retro-esophageally, while abnormally placed inferior glands were generally situated within or close to the thymus. Glands in 3 patients were dissected from around the large vessels in the mediastinum. Concomitant thyroid procedures during the primary operation yielded few abnormal parathyroids and made the re-exploration considerably more difficult. We suggest a semilateral approach and caudal identification of the recurrent laryngeal nerve to reduce the hazards of difficult parathyroid re-operations. Mediastinal exploration may require total removal of the thymus and careful dissection of the middle mediastinum.
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A total of 121 consecutive patients with midgut carcinoid tumors underwent regular clinical control and 158 laparotomies for abdominal symptoms with 1 to 11 years (mean 5.2 years) of follow-up. Metastases were present in 93% of the... more
A total of 121 consecutive patients with midgut carcinoid tumors underwent regular clinical control and 158 laparotomies for abdominal symptoms with 1 to 11 years (mean 5.2 years) of follow-up. Metastases were present in 93% of the patients at study inclusion and developed at initially uninvolved sites with an overall probability of 0.38. Patients without initial tumor spread developed mesenteric or liver metastases with the probability of 0.25 (mean delay 12 years), whereas those with mesenteric metastases exhibited a probability 0.56 to develop liver metastases (mean delay 6.1 years). Spread to extraabdominal sites in patients with mesenteric and liver metastases exhibited a probability of 0.22 (mean delay 4.3 years), and this spread was especially frequent (probability 0.60) in patients with only liver metastases at inclusion. Patients without the carcinoid syndrome (52%) mainly suffered from more or less episodic abdominal pain, nausea, and diarrhea. Marked mesenteric fibrosis detected at surgery (n = 59) generally was accompanied by symptoms of abdominal pain and weight loss, and it often required urgent intervention due to intestinal obstruction or ischemia. Complete or partial symptom alleviation was accomplished in 82% of the operated patients, and generally was most auspicious after primary acute or subacute procedures (n = 54). The complete or partial symptom improvements after surgery lasted for mean 5.3 years and tended to be longer after elective (n = 50) than acute operations. The findings substantiate encouraging results of laparotomy in a compromised cohort of patients with midgut carcinoid tumors. Because the patients also displayed a generally slow progression of metastases, liberal indications for laparotomy should prevail in symptomatic and possibly also asymptomatic individuals with midgut carcinoid tumors.