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L Delbridge

Publications and source records attributed to L Delbridge.

At least 19 recordsLinked to original sources
PubMed2002

Genetic analysis of lithium-associated parathyroid tumors.

OBJECTIVE: The aim of this study was to determine the primary genetic events that may underlie the formation of parathyroid tumors in patients with lithium-associated hyperparathyroidism (HPT). METHODS: Comparative genomic hybridization (CGH), loss of heterozygosity (LOH) and multiple endocrine neoplasia type 1 gene (MEN1) mutation analysis were used to analyze twelve parathyroid tumors from nine patients with lithium-associated HPT. For comparison, CGH was also carried out in a non-lithium-associated group of thirteen sporadic parathyroid tumors. RESULTS: A higher prevalence of multiglandular disease in the lithium-associated HPT patients compared with the idiopathic sporadic patients was observed (Fisher's exact test, P=0.02). CGH alterations were detected in four lithium-associated parathyroid tumors, involving loss at 1p, 11, 15q, 22q and gain of the X chromosome. In addition, one of these four cases exhibited LOH at 11q13 and was found to contain a novel somatic MEN1 mutation (c.1193insTAC). Although fewer lithium-associated parathyroid tumors were shown to contain genetic alterations compared with the sporadic parathyroid tumors, the changes detected were those frequently associated with both familial and sporadic parathyroid tumorigenesis. CONCLUSION: This is, to our knowledge, the first genetic analysis of parathyroid tumors in lithium-associated HPT patients. Our data indicated that the majority of lithium-associated parathyroid tumors do not contain gross chromosomal alterations and suggest that in most cases the tumorigenic pathway is independent of MEN1 and genes at 1p34.3-pter and 1q21-q32. It is possible that other discrete genetic alterations or epigenetic changes, not screened for in this study, could also be responsible for parathyroid tumorigenesis in lithium-associated HPT.

Adolescent↗
PubMed2001

Anaesthesia for amiodarone-induced thyrotoxicosis: a case review.

Amiodarone-induced thyrotoxicosis is a life-threatening problem that is very effectively managed by total thyroidectomy, although often many of these patients are considered "too unfit" for anaesthesia. The aim of this study was to review the safety of anaesthesia for total thyroidectomy in the acute management of amiodarone-induced thyrotoxicosis. Information was obtained retrospectively from a prospective endocrine surgical database and from hospital records. Data, including outcomes and morbidity, are presented from 12 patients who underwent anaesthesia for total thyroidectomy as an urgent procedure for amiodarone-induced thyrotoxicosis. Despite the fact that these patients had uncontrolled thyrotoxicosis and marked cardiac failure at the time of anaesthesia, no anaesthetic or surgical mortality was seen. We conclude that a challenging patient with amiodarone-induced thyrotoxicosis that has not responded to conservative measures may be considered for total thyroidectomy early in their management. Total thyroidectomy can be performed under general or local anaesthesia with apparent relative safety.

Adult↗
PubMed2000

Sporadic and familial pheochromocytomas are associated with loss of at least two discrete intervals on chromosome 1p.

Pheochromocytomas are tumors of the adrenal medulla originating in the chromaffin cells derived from the neural crest. Ten % of these tumors are associated with the familial cancer syndromes multiple endocrine neoplasia type 2, von Hippel-Lindau disease (VHL), and rarely, neurofibromatosis type 1, in which germ-line mutations have been identified in RET, VHL, and NF1, respectively. In both the sporadic and familial form of pheochromocytoma, allelic loss at 1p, 3p, 17p, and 22q has been reported, yet the molecular pathogenesis of these tumors is largely unknown. Allelic loss at chromosome 1p has also been reported in other endocrine tumors, such as medullary thyroid cancer and tumors of the parathyroid gland, as well as in tumors of neural crest origin including neuroblastoma and malignant melanoma. In this study, we performed fine structure mapping of deletions at chromosome 1p in familial and sporadic pheochromocytomas to identify discrete regions likely housing tumor suppressor genes involved in the development of these tumors. Ten microsatellite markers spanning a region of approximately 70 cM (1pter to 1p34.3) were used to screen 20 pheochromocytomas from 19 unrelated patients for loss of heterozygosity (LOH). LOH was detected at five or more loci in 8 of 13 (61%) sporadic samples and at five or more loci in four of five (80%) tumor samples from patients with multiple endocrine neoplasia type 2. No LOH at 1p was detected in pheochromocytomas from two VHL patients. Analysis of the combined sporadic and familial tumor data suggested three possible regions of common somatic loss, designated as PC1 (D1S243 to D1S244), PC2 (D1S228 to D1S507), and PC3 (D1S507 toward the centromere). We propose that chromosome 1p may be the site of at least three putative tumor suppressor loci involved in the tumorigenesis of pheochromocytomas. At least one of these loci, PC2 spanning an interval of <3.8 cM, is likely to have a broader role in the development of endocrine malignancies.

Adolescent↗
PubMed2000

Differential nuclear and cytoplasmic expression of PTEN in normal thyroid tissue, and benign and malignant epithelial thyroid tumors.

Germline mutations in PTEN (MMAC1/TEP1) are found in patients with Cowden syndrome, a familial cancer syndrome which is characterized by a high risk of breast and thyroid neoplasia. Although somatic intragenic PTEN mutations have rarely been found in benign and malignant sporadic thyroid tumors, loss of heterozygosity (LOH) has been reported in up to one fourth of follicular thyroid adenomas (FAs) and carcinomas. In this study, we examined PTEN expression in 139 sporadic nonmedullary thyroid tumors (55 FA, 27 follicular thyroid carcinomas, 35 papillary thyroid carcinomas, and 22 undifferentiated thyroid carcinomas) using immunohistochemistry and correlated this to the results of LOH studies. Normal follicular thyroid cells showed a strong to moderate nuclear or nuclear membrane signal although the cytoplasmic staining was less strong. In FAs the neoplastic nuclei had less intense PTEN staining, although the cytoplasmic PTEN-staining intensity did not differ significantly from that observed in normal follicular cells. In thyroid carcinomas as a group, nuclear PTEN immunostaining was mostly weak in comparison with normal thyroid follicular cells and FAs. The cytoplasmic staining was more intense than the nuclear staining in 35 to 49% of carcinomas, depending on the histological type. Among 81 informative tumors assessed for LOH, there seemed to be an associative trend between decreased nuclear and cytoplasmic staining and 10q23 LOH (P = 0.003, P = 0.008, respectively). These data support a role for PTEN in the pathogenesis of follicular thyroid tumors.

Cell Nucleus↗
PubMed2000

Authors' reply

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Journal Article↗
PubMed2000

Loss of heterozygosity in sporadic parathyroid tumours: involvement of chromosome 1 and the MEN1 gene locus in 11q13.

OBJECTIVE: Hyperparathyroidism (HPT) is a common endocrine disorder. Several loci of genetic interest have been identified in parathyroid tumours, including the MEN1 gene locus at 11q13; the HPT-JT region at 1q21-q32; and a putative tumour suppressor gene on 1p. We analysed these intervals, which harbour known genes or putative loci associated with familial hyperparathyroidism, in order to clarify the involvement of the respective regions in parathyroid tumourigenesis. DESIGN: We performed loss of heterozygosity (LOH) studies on 33 sporadic parathyroid tumours using a PCR based technique. A total of 22 microsatellite markers were used to analyse loci at 11q13, 1q21-q32 and 1p. Ten markers located distal on 1p, eight markers encompassed the HPT-JT region at 1q21-q32 and four markers surrounded the MEN1 gene locus at 11q13. MEN1 mutations were screened for using Single Strand Conformation Polymorphism analysis (SSCP) and automated sequencing of SSCP variants. PATIENTS: Thirty-three parathyroid glands and the corresponding blood samples were obtained from 33 patients (26 females and seven males) who underwent parathyroidectomy for primary hyperparathyroidism. RESULTS: Loss of heterozygosity was detected in 13 of 33 (39%) cases at 11q13, 6 of 33 (18%) cases at 1p, and in three of 33 (9%) cases at 1q (in conjunction with 1p loss). Only one of the 18 tumours in which LOH was detected, showed LOH at both chromosome 1 and chromosome 11. Additionally, those tumours found to exhibit LOH at 11q13 were screened for MEN1 mutations using single strand conformation polymorphism analysis (SSCP) and automated sequencing. Nine novel somatic mutations were found on the remaining allele in 13 (69%) tumours. CONCLUSIONS: This study consolidates the role of multiple loci in the pathogenesis of sporadic parathyroid tumours. The results indicate that there are at least two genetic loci involved in sporadic parathyroid tumourigenesis on chromosome 1, one of which has been linked to the distinct familial parathyroid condition, hyperparathyroidism-jaw tumour (HPT-JT) syndrome. The high frequency of loss of heterozygosity at 1p suggests the presence of a tumour suppressor at this locus.

Adenoma↗
PubMed2000

Thyroid surgery and anaesthesia following head and neck irradiation for childhood malignancy.

BACKGROUND: Increasing numbers of adolescents and young adults are undergoing thyroid surgery because of the risk of malignancy following previous irradiation for childhood malignancy. Irradiation to the head and/or neck regions may induce changes in the soft tissues and larynx that are far from normal with respect to both size and mobility. The aim of the present study was to evaluate the possible impact of such changes on both surgical and anaesthetic technique during thyroidectomy. METHODS: This was a retrospective ease study. Thirty consecutive patients undergoing total thyroidectomy following previous irradiation for childhood malignancy formed the study group. RESULTS: There were no permanent surgical or anaesthetic complications in the group. In particular there were no cases of either permanent recurrent laryngeal nerve palsy or permanent hypoparathyroidism. Twenty-eight patients had an uneventful intubation and two were unable to be intubated directly, one requiring fibre-optic bronchoscopic intubation and the other having surgery performed with a laryngeal mask following failed bronchoscopy. Both of these patients had received high-dose direct irradiation to the larynx for solid tumours. CONCLUSIONS: Despite potential difficulties associated with the heavily irradiated larynx, thyroid surgery and anaesthesia can be performed safely with minimal complications in experienced hands.

Adolescent↗
PubMed2000

Cardiac hypertrophy depends upon sleep blood pressure: a study in rats.

OBJECTIVE: The objective of this study was to determine whether cardiac hypertrophy in hypertensive rats could be reduced and normalized by intermittent reduction of blood pressure, and to determine whether left ventricular hypertrophy was related to 24 h workload or peak blood pressure responses. METHODS: Hypertension was created by the application of a 0.20 mm clip to the left renal artery. Blood pressure response was monitored using a telemetry system (Data Science International). Blood pressure was reduced for varying periods of the day by giving different doses of captopril in the drinking water or by intra-peritoneal administration. Cardiac size was measured by weighing the ventricles and factoring by the body weight to obtain a cardiac index. RESULTS: Captopril 75 mg/kg per day and 25 mg/kg per day in the drinking water administered between 1800 and 2000 h lowered the 24 h blood pressure more than captopril 15 mg/kg per day or 5 mg/kg per day intra-peritoneally given at 0800 h. Captopril 75 mg/kg per day and captopril 15 mg/kg per day (intra-peritoneal) caused regression of cardiac hypertrophy whereas the other doses had no effect The best predictor of the cardiac hypertrophy response was the blood pressure between 0800 and 1200 h (i.e. the sleeping blood pressure). Twenty-four hour cardiac work did not correlate with the response. CONCLUSION: Cardiac hypertrophy can be reduced by intermittent treatment of elevated blood pressure. It is also caused by intermittent elevation of blood pressure. It appears that the crucial factor is when these alterations in blood pressure take place. An elevated blood pressure during the sleeping hours causes left ventricular hypertrophy, whereas a normal blood pressure during the sleeping hours allows reduction. It is suggested that acute wall stress is the signal to initiate the events that lead to cardiac hypertrophy but this only occurs if the hormonal milieu is appropriate.

Animals↗
PubMed1999

Total thyroidectomy for bilateral benign multinodular goiter: effect of changing practice.

HYPOTHESIS: That changing practices in a single institution toward performing total thyroidectomy as the preferred option for the treatment of bilateral benign multinodular goiter (BMNG) can alter attitudes and practice within an entire region (Australia and New Zealand). DESIGN: (1) Single-institution study of patients with bilateral BMNG treated by thyroidectomy over a 40-year period, examining the changing pattern of use of bilateral subtotal thyroidectomy and total thyroidectomy in the initial surgical treatment of nodular goiter. (2) Mail survey of all endocrine surgeons (n = 75) in Australia and New Zealand, seeking information on their changing practice in the surgical treatment of BMNG. SETTING: Tertiary academic referral center. PATIENTS: A group of 3468 patients who underwent thyroidectomy for bilateral BMNG during the study period. Of these, 1838 had a subtotal thyroidectomy performed and 1251 had a total thyroidectomy as the primary surgical treatment. MAIN OUTCOME MEASURES: The changing incidence of each type of thyroid procedure each year over the study period. RESULTS: Within our unit, bilateral subtotal thyroidectomy was the principal procedure performed until 1984, when total thyroidectomy became the preferred procedure. Our unit now treats 94% of these patients with total thyroidectomy. Secondary thyroidectomy for recurrent goiter initially increased over the years (with a lag period of 13 years), reflecting the numbers of subtotal procedures previously performed, and is now declining. This pattern has been reflected throughout Australia and New Zealand; 60% of practicing endocrine surgeons now perform total thyroidectomy as the preferred treatment for bilateral BMNG. CONCLUSIONS: Total thyroidectomy is a safe and effective treatment for bilateral BMNG, and it is now the routine procedure throughout Australia and New Zealand. Its use has corresponded to a reduction in the need for secondary thyroidectomy for recurrent goiter.

Adult↗
PubMed1999

Fine-structure deletion mapping of 10q22-24 identifies regions of loss of heterozygosity and suggests that sporadic follicular thyroid adenomas and follicular thyroid carcinomas develop along distinct neoplastic pathways.

Previous studies have demonstrated frequent loss of heterozygosity (LOH) of markers on chromosome arm 10q in both follicular thyroid carcinomas (FTCs) and follicular thyroid adenomas (FAs). A novel tumor suppressor gene, PTEN, has been mapped to 10q23.3 and is the susceptibility gene for Cowden syndrome, an autosomal dominant disorder characterized by multiple hamartomas and a risk of benign and malignant tumors of the breast and thyroid. Studies examining the relationship of somatic PTEN status and follicular thyroid neoplasms have only demonstrated a variable subset of tumors that have somatic monoallelic deletions of PTEN, suggesting that other tumor suppressor genes may be present in this region. We therefore sought to conduct a detailed examination of LOH of 20 polymorphic markers in a 19-cM region spanning 10q22-24, including PTEN, in 44 FAs and 17 FTCs. Using this fine-structure somatic mapping approach, we defined at least two novel regions of LOH in follicular adenomas and follicular carcinomas, suggesting the presence of at least two distinct tumor suppressor genes that may play a role in thyroid neoplasia. Furthermore, the difference in patterns of LOH in adenomas versus carcinomas lends additional support to the hypothesis that adenomas and carcinomas can develop along two separate, nonserial pathways. Genes Chromosomes Cancer 26:322-328, 1999.

Adenocarcinoma, Follicular↗
PubMed1999

Pathology and outcome of surgical treatment for lithium-associated hyperparathyroidism.

BACKGROUND: Hyperparathyroidism associated with long-term lithium therapy is well described. However, few studies have clearly defined the pathological findings or looked at the outcome of surgical treatment. METHODS: The study was a retrospective review of 11 patients with bipolar affective disorder who had surgery for lithium-associated hyperparathyroidism. RESULTS: Twelve patients were identified who had received lithium therapy, of whom 11 (nine women and two men, aged 46-84 (mean 65) years) had prolonged treatment from 2 to 30 (mean 15.3) years. At operation a single adenoma was identified in six patients, whereas multigland disease was seen in five patients. All patients resumed lithium treatment after operation. One patient had recurrent hyperparathyroidism at 3 years, while another had an increased serum level of parathyroid hormone in the presence of a normal serum calcium level after 1 year. CONCLUSION: Hyperparathyroidism associated with lithium may be due to either parathyroid hyperplasia or adenoma. Observations in the present study supported a true cause and effect relationship. Routine bilateral neck exploration should be performed because of a relatively high frequency of multigland involvement. However, parathyroid resection should be limited to evident disease.

Aged↗
PubMed1999

Multinodular goitre presenting as a clinical single nodule: how effective is hemithyroidectomy?

BACKGROUND: Patients who present with a single thyroid nodule that requires surgery will generally undergo hemithyroidectomy. If, however, the subsequent histological examination shows unsuspected multinodular change, there is a risk of recurrence in the remain ing lobe. The aim of this study was to determine the clinical outcome in patients who have had a hemithyroidectomy for a single thyroid nodule that was shown on subsequent histopathological examination to be part of a multinodular goitre. METHODS: A survey was undertaken of patients who were identified from a thyroid surgery database with the following criteria: (i) hemithyroidectomy for clinical single nodule; and (ii) multinodular change on histopathology. Main outcome measures were clinical recurrence rate, the frequency of further thyroid surgery, and the efficacy of thyroxine treatment on recurrence. RESULTS: In the 229 patients studied, the clinical recurrence rate was 12%. Fourteen of the 28 patients with recurrence required further surgery. Thyroxine therapy did not influence the recurrence rate. CONCLUSION: When surgery for a clinically benign single thyroid nodule is indicated, hemithyroidectomy is an adequate surgical procedure in cases where the single nodule is subsequently found to be part of a multinodular goitre. Such patients can be reassured that the chance of clinical recurrence is low. Thyroxine replacement therapy appears not to prevent recurrence.

Adolescent↗
PubMed1999

Routine autotransplantation of at least one parathyroid gland during total thyroidectomy may reduce permanent hypoparathyroidism to zero.

BACKGROUND: Permanent hypoparathyroidism, although a recognized complication of total thyroidectomy, is an outcome that all endocrine surgeons try to avoid. METHODS: To minimize the risk of postoperative hypoparathyroidism a strategy was developed of routine autotransplantation of at least one parathyroid gland into the ipsilateral sternomastoid muscle during every total thyroidectomy. One hundred consecutive patients undergoing total thyroidectomy were included in the study. Serum calcium and albumin levels were measured pre-operatively, on the first 2 postoperative days, and after 2 weeks, or until return to normal serum calcium levels without calcium supplementation. If patients developed biochemical evidence or symptoms of hypocalcaemia postoperatively, a calcium replacement was administered according to defined protocol. RESULTS: In 74 cases one parathyroid gland was autotransplanted: 44 for inadvertent removal or anatomical reasons, 19 because of devascularization (assessed by a cut through the gland's capsule and evaluation of the capillary bleeding pattern), and 11 by protocol. In 25 cases, two or more glands were autotransplanted. Fourteen patients developed symptoms of hypocalcaemia and received calcium supplementation, as did another 13 asymptomatic patients with only biochemical evidence of hypocalcaemia. At follow-up 3 months postoperatively the incidence of permanent hypoparathyroidism was zero, with all patients being normocalcaemic without calcium supplementation. CONCLUSIONS: This strategy, easily adopted by any experienced surgeon, has the potential to eliminate permanent hypoparathyroidism following total thyroidectomy.

Adolescent↗
PubMed1999

Age is no contraindication to thyroid surgery.

BACKGROUND: There is increased risk of surgical treatment in elderly patients, but little has been written on the safety and efficacy of thyroid surgery in this group. OBJECTIVE: To determine if there is an increased risk of morbidity and mortality of thyroid surgery in patients over 75 years old. PATIENTS AND METHODS: During the period 1986-96, 1631 patients aged 50 and over underwent 1673 procedures by two surgeons in our unit. We retrospectively compared indications for surgery, procedures, pathology complications and mortality in three groups: 50-60-year-olds (725 patients), 61-74-year-olds (685 patients) and those aged 75 years and over (221 patients) RESULTS: The main indication for surgery in all three groups was compression or risk of malignancy. Total thyroidectomy was the main procedure performed. Although benign multinodular goitre was the commonest diagnosis, the over-75-year-olds had fewer benign multinodular goitres than the 61-74 group and more malignancy than the other two groups. There was no significant difference in mortality between the three groups. CONCLUSIONS: Surgery in patients over 75 is as safe as in younger patients with no increase in morbidity and mortality. Benign multinodular goitre is the most common indication for surgery.

Age Factors↗
PubMed1998

Genetic and biochemical screening for endocrine disease: III. Costs and logistics.

The cost of screening tests in endocrine disease can be determined in a number of ways, including the charge or billed cost, the production cost, or most appropriately the cost to achieve the intended aim of the test (cost-effectiveness). Cost-effectiveness analysis allows clinicians to determine whether an added benefit of a test comes at an acceptable cost. For example, analysis of the cost-effectiveness of routine thyroid function tests prior to surgery in elderly patients with nodular thyroid disease shows that the cost per life saved is only US $405, making the tests clearly cost-effective. Cost-effectiveness does not always equate with affordability, however, especially in developing countries. Thyroid function testing prior to surgery represents only 0.8% of the average household income in Australia and is therefore both cost-effective and affordable, whereas in Sri Lanka the same screening test represents up to 50% of the average monthly income. A survey of membership of the International Association of Endocrine Surgeons worldwide showed that molecular genetic screening for endocrine disease is readily available in 67% of institutions, with all of those having facilities for the rearrangement during transfection (RET) proto-oncogene testing, and lesser numbers having access to the Menin gene, the von Hippel-Lindau syndrome (VHL) gene, or linkage analysis for familial pheochromocytoma. The median cost of screening for the RET proto-oncogene was $290 (range $100-3000). Cost-effectiveness analysis of molecular genetic screening for MEN-II syndrome demonstrates that the cost per life saved is only $5175. This compares favorably with reliance on screening based on annual pentagastrin testing, where the cost per life saved is as high as $76,315. Molecular genetic screening for endocrine disease (e.g., the MEN-II syndrome) is not only cost-effective but the therapy required (total thyroidectomy) is both acceptable and well tolerated.

Cost-Benefit Analysis↗
PubMed1998

A rapid method for DNA extraction from fine-needle aspiration biopsies of thyroid tumors, and subsequent RET mutation analysis.

The presence of germline and somatic mutations in the RET proto-oncogene (RET) in patients with hereditary and sporadic medullary thyroid carcinoma (MTC) may have important ramifications for patient management. It has been suggested that the presence of the mutation ATG-->ACG at codon 918 in sporadic MTC is associated with a worse prognosis, and hence the need for more aggressive surgical, or other, treatment. Since fine-needle aspiration biopsy (FNAB) is an important component of the preoperative management of patients with thyroid tumors, we developed a rapid (20-min) method that enables extraction of DNA from FNABs for RET mutation analysis. The method allows preoperative genetic analysis to aid in management of patients with MTC, and may be applied to other tumor types where a preoperative mutation analysis based on polymerase chain reaction amplification is desired.

Biopsy, Needle↗