Biomedical subjects

Tobias Carling

Publications and source records attributed to Tobias Carling.

17 recordsLinked to original sources

PubMed2006

Minimally invasive parathyroidectomy using cervical block: reasons for conversion to general anesthesia.

HYPOTHESIS: We investigated the frequency and reasons for conversion from cervical block anesthesia to general anesthesia (GA) in patients undergoing minimally invasive parathyroidectomy for primary hyperparathyroidism. DESIGN: Prospective case series. SETTING: Tertiary university hospital. PATIENTS: A total of 441 consecutive patients with primary hyperparathyroidism undergoing minimally invasive parathyroidectomy under cervical block and monitored anesthesia care using midazolam and narcotics were included. Patients with known multiglandular, familial, or secondary hyperparathyroidism or noninformative preoperative localization or those electing minimally invasive parathyroidectomy under GA were excluded. INTERVENTION: All patients underwent cervical block anesthesia and focused exploration using minimally invasive techniques. MAIN OUTCOME MEASURE: Intraoperative need for conversion from cervical block anesthesia to general endotracheal anesthesia. RESULTS: Of the 441 patients, 47 (10.6%) required conversion to GA. In all instances, conversion was performed in a controlled fashion using neuromuscular blockade, endotracheal intubation, and maintenance of the original surgical field preparation. Sixteen procedures were converted to accomplish simultaneous thyroid resections. An additional 15 were converted because the intraoperative parathyroid hormone level failed to decrease by at least 50% from the baseline after resection of the incident parathyroid tumor and extensive exploration was required. Eight procedures were converted because of technical difficulties related to ensuring adequate protection of the recurrent laryngeal nerve. Five procedures were converted to optimize patient comfort, and 2 were converted because of the intraoperative recognition of parathyroid carcinoma. One patient experienced a toxic reaction to lidocaine, causing a seizure. CONCLUSIONS: The vast majority of minimally invasive parathyroidectomies can be performed using cervical block anesthesia. However, conversion to GA is appropriate when unexpected intraoperative findings are encountered or for patient comfort.

Anesthesia, General↗

PubMed2005

Follicular neoplasms of the thyroid: what to recommend.

Follicular neoplasms of the thyroid are usually diagnosed following fine-needle aspiration (FNA) biopsy of a dominant thyroid nodule. An FNA diagnosis of a follicular neoplasm represents a heterogeneous group of lesions including benign follicular hyperplasia, follicular adenomas, follicular carcinomas, and the follicular variant of papillary carcinoma. Hürthle cell neoplasms are also often included in this group. Because the criteria for malignancy in both follicular and Hürthle cell neoplasms requires vascular or capsular invasion seen on permanent histology, the majority of these patients undergo surgical resection. Intraoperative frozen section analysis of follicular neoplasms rarely renders informative information. Approximately 20% of these lesions prove to be malignant and for lesions greater than 1.0 cm in size, the majority of surgeons and endocrinologists recommend a total thyroidectomy. Postoperative treatment generally includes therapeutic doses of 131I for follicular carcinomas.

Adenocarcinoma, Follicular↗

PubMed2005

Multiple endocrine neoplasia syndrome: genetic basis for clinical management.

PURPOSE OF REVIEW: Multiple endocrine neoplasia (MEN) types 1 and 2 are rare hereditary cancer syndromes expressing a variety of mainly endocrine neoplasias. Improved understanding of the molecular and clinical genetics associated with these lesions will likely enhance the diagnosis and treatment of patients with these diseases. RECENT FINDINGS: The MEN1 gene causing MEN1 is a tumor suppressor gene and seems to act as a regulator of the transcriptional machinery. Novel genetic and diagnostic modalities tend to identify neoplastic lesions at an earlier stage, potentially improving outcome and quality of life. Improved understanding of genotype-phenotype correlations in MEN2, caused by a mutation in the RET oncogene, may enable a more individualized treatment for these patients. SUMMARY: Recent advances in molecular pathology, diagnosis, and management of patients with MEN1 and MEN2 are reviewed.

Diagnosis, Differential↗

PubMed2005

Deletions and altered expression of the RIZ1 tumour suppressor gene in 1p36 in pheochromocytomas and abdominal paragangliomas.

Pheochromocytomas and abdominal paragangliomas are rare catecholamine-producing tumours arising from neural crest-derived chromaffin cells. Frequent deletions of several distinct regions on the short arm of chromosome 1 suggest their involvement in the tumourigenesis process. The RIZ1 tumour suppressor encoded by the RIZ gene in 1p36.21 represents an attractive candidate target for the distal 1p deletions in these tumours. A panel of 18 pheochromocytomas (14 benign, and 4 malignant) and 11 abdominal paragangliomas (4 benign, and 7 malignant) were characterised for somatic deletions and mRNA expression status of RIZ1 using loss of heterozygosity (LOH) analysis and real-time quantitative PCR, respectively. Furthermore, we evaluated the methylation status of the RIZ1 promoter utilising methylation-specific PCR (MSP). Intragenic LOH at the RIZ locus was detected in 10 of 16 informative cases (62%), including 8 of 12 pheochromocytomas (67%) and 2 of 4 paragangliomas (50%). RIZ1 mRNA appeared to be significantly under-expressed in the tumour samples compared to normal adrenal controls (mean 0.6 vs. 1.0, p<0.001). This was not associated with RIZ1 promoter methylation in any of the samples, indicating that promoter hypermethylation is unlikely to be the underlying cause of the frequent expressional silencing. The recurrent inactivation of the tumour suppressor RIZ1 suggests that this event may be a significant contributing factor to tumour development in pheochromocytomas and abdominal paragangliomas.

Abdominal Neoplasms↗

PubMed2004

A histone methyltransferase is required for maximal response to female sex hormones.

RIZ1 is an estrogen receptor (ER) coactivator but is also a histone lysine methyltransferase that methylates lysine 9 of histone H3, an activity known to repress transcription. We show here that target organs of mice deficient in RIZ1 exhibit decreased response to female sex hormones. RIZ1 interacted with SRC1 and p300, suggesting that the coactivator function of RIZ1 may be mediated by its interaction with other transcriptional coactivators. In the presence of estrogen, RIZ1 binding to estrogen target genes became less direct and followed the binding of ER to DNA and RIZ1 methyltransferase activity on H3-Lys 9 was inhibited, indicating derepression may play a role in estrogen induction of gene transcription. Reducing RIZ1 level correlated with decreased induction of pS2 gene by estrogen in MCF7 cells. The data suggest that a histone methyltransferase is required for optimal estrogen response in female reproductive tissues and that estrogen-bound ER may turn a transcriptional repressor into a coactivator.

Animals↗

PubMed2003

Parathyroid tumors.

Parathyroid tumors causing primary hyperparathyroidism are common and often remain undiagnosed, despite that the diagnostic work-up is uncomplicated in most patients. The patients often do not receive the appropriate curative treatment, which is surgical. Recent studies show that surgery is beneficial in patients with mild asymptomatic disease, especially in the reversal of bone disease, neuropsychologic symptoms, and dyslipoproteinemia. All patients with the disease deserve a referral to an endocrine surgeon for discussions regarding surgical intervention. Minimally invasive techniques performed in the ambulatory setting have evolved rapidly and show an extraordinary high success rate, low-morbidity rate, and are likely to become the standard treatment for most patients with primary hyperparathyroidism.

Humans↗

PubMed2003

Intragenic allelic loss and promoter hypermethylation of the RIZ1 tumor suppressor gene in parathyroid tumors and pheochromocytomas.

BACKGROUND: Loss of heterozygosity (LOH) at chromosome 1p is a common abnormality in both parathyroid tumors and pheochromocytomas. The recently characterized tumor suppressor gene RIZ1, located at 1p36, has emerged as a putative candidate to be involved in endocrine tumorigenesis. MATERIAL: Presence of allelic loss, promoter hypermethylation, and mutational aberrations of the RIZ1 gene were investigated using PCR-based techniques in 47 parathyroid tumors and 23 pheochromocytomas. Gene expression studies used the RNAse protection assay. RESULTS: RIZ1 mRNA is expressed in pathologic tissues of the parathyroid and adrenal medulla. Thirteen of 47 (28%) parathyroid tumors, and 9/23 (39%) pheochromocytomas displayed LOH within the RIZ1 gene locus. Promoter hypermethylation of RIZ1 was detected in 36% of the parathyroid tumors and was related to LOH at the RIZ1 locus (P=.01), and absence of somatic mutation of the MEN1 gene (P=.044). In the pheochromocytomas, none of the benign tumors, but 2/4 malignant specimens exhibited RIZ1 promoter hypermethylation. CONCLUSION: Alteration of the RIZ1 gene locus via intragenic allelic loss and promoter hypermethylation seem common in parathyroid tumors. Inactivation of the RIZ1 gene may cause parathyroid tumorigenesis via a mechanism in which genetic alteration of the MEN1 gene is redundant.

Adolescent↗

PubMed2002

Loss of heterozygosity on the short arm of chromosome 1 in pheochromocytoma and abdominal paraganglioma.

Pheochromocytomas and abdominal paragangliomas are catecholamine-producing tumors that arise from sympathetic paraganglia within and outside the adrenal medulla, respectively. Deletions of the short arm of chromosome 1 have been implicated as important genetic events in their tumorigenesis and suggest a common genetic etiology. The aim of this study was to define further the chromosomal regions on 1p that are involved in the development of these tumor types. We analyzed 46 pheochromocytomas (1 benign, 6 malignant, 9 hereditary) and 7 paragangliomas (3 benign, 4 malignant) from 50 patients for loss of heterozygosity (LOH) on 1p by genotyping 15 microsatellite markers spread over the chromosome arm. Overall, LOH was detected in 33 of 46 pheochromocytomas (72%) and in 6 of 7 (86%) paragangliomas. Three minimal regions of overlapping deletions were identified: one telomeric of D1S1612(1p36.2-pter), one centromeric of D1S429 (1cen-p13), and one in the 18 cM interval defined by D1S2134 andD1S1669 (1p32). The latter region harbors the leukocyte common antigen-related (LAR) gene, which shows altered expression in sporadic rat pheochromocytomas. In conclusion, chromosome 1p may be the site of at least three putative tumor-suppressor gene loci involved in the tumorigenesis of pheochromocytomas and abdominal paragangliomas. Further studies of these regions and of LARas a candidate gene would be valuable.

Adrenal Gland Neoplasms↗

PubMed2002

Alterations of the SDHD gene locus in midgut carcinoids, Merkel cell carcinomas, pheochromocytomas, and abdominal paragangliomas.

Several types of endocrine tumors show frequent somatic deletions of the distal part of chromosome arm 11q, where the tumor-suppressor gene SDHD (succinate-ubiquinone oxidoreductase subunit D), constitutionally mutated in paragangliomas of the head and neck, is located. In this study, we screened 18 midgut carcinoids, 7 Merkel cell carcinomas, 46 adrenal pheochromocytomas (37 sporadic and 9 familial), and 7 abdominal paragangliomas for loss of heterozygosity (LOH) and/or mutations at the SDHD gene locus. LOH was detected in 5 out of 8 (62%) informative midgut carcinoids, in 9 out of 30 (30%) sporadic pheochromocytomas, in none of the familial pheochromocytomas (0%), and in 1 out of 6 (17%) abdominal paragangliomas. No sequence variants were detected in the pheochromocytomas or paragangliomas. However, two constitutional putative missense mutations, H50R and G12S, were detected in two midgut carcinoids, which were both associated with LOH of the other allele. The same sequence variants were also detected in two Merkel cell carcinomas. In addition, the S68S polymorphism was found to coexist with the G12S sequence variant in both cases. In conclusion, we show that alterations of the SDHD gene seem to be involved in the tumorigenesis of both midgut carcinoids and Merkel cell carcinomas.

Abdominal Neoplasms↗

PubMed2002

Allelic loss in clinically and screening-detected primary hyperparathyroidism.

OBJECTIVE: Parathyroid adenomas frequently harbour deletions of genomic DNA at chromosome regions 1p, 6q and 11q. In this study we related clinical characteristics in 56 patients with primary hyperparathyroidism (pHPT) to loss of heterozygosity (LOH) in these chromosome regions. DESIGN: LOH analysis was performed on 56 sporadic parathyroid tumours using a total of 18 microsatellite markers for chromosome regions 1p, 6q and 11q. LOH was identified, for either radioactive or fluorescent labelled markers, as total absence or reduction of > or = 50% of the signal intensity of an allele in the tumour DNA vs. constitutional DNA. PATIENTS: Twenty-one of the patients were recruited by a population-based screening for pHPT and the remaining pHPT patients were gathered from routine clinical practice. RESULTS: In total, 27%, 23% and 23% of the tumours showed LOH at 1p, 6q and 11q, respectively. LOH at both 1p and 11q was more common in the screening-detected pHPT patients compared to those recruited from clinical practice (38% vs. 20%; P = 0.02 and 43% vs. 11%; P = 0.001, respectively), while allelic loss at 6q was more prevalent in the latter group (11% vs. 31%; P = 0.001). No apparent relationships between LOH at 1p, 6q, and 11q and clinical characteristics, such as glandular weight, serum levels of PTH or calcium, were demonstrated. Moreover, additional LOH analysis of chromosome 1p suggested a putative parathyroid tumour suppressor gene(s) in the region between markers DS214 and D1S503, spanning approximately 6 cM. CONCLUSION: A high frequency of LOH at 1p and 11q in tumours of screening-detected pHPT patients is intriguing, and may suggest that inactivation of known (the MEN1 gene) and putative tumour suppressor genes at these chromosomal regions is associated with a more benign disease.

Aged↗

PubMed2002

Parathyroidectomy in familial hypercalcemia with clinical characteristics of primary hyperparathyroidism and familial hypocalciuric hypercalcemia.

BACKGROUND: Familial primary hyperparathyroidism is associated with tumor-susceptibility syndromes, which are unrelated to mutations in the calcium receptor gene. This study describes parathyroidectomy in a kindred with hypercalcemia due to a heterozygous point mutation in the calcium receptor gene. METHODS: Seventeen family members were studied, and postoperative follow-up averaged 5.1 years. RESULTS: Radical parathyroid resection with total parathyroid remnants of 10 to 20 mg or total parathyroidectomy with autotransplantation normalized the serum calcium and parathyroid hormone values in 12 family members. Persistent hypercalcemia was noted in 3 of 5 patients subjected to less radical procedures. Diffuse to nodular hyperplasia and microscopic findings, interpreted incorrectly as a single adenoma, were found. Weight of the parathyroid tissue increased with the age of the patients (P <.05), and almost one third of them (29%) had 1 to 3 atypically located glands. There were no patients with recurrent hypercalcemia during follow-up. CONCLUSIONS: The heterozygous inactivating mutation of the calcium receptor gene of this family is accompanied by mild increases in parathyroid gland x weight and diffuse parathyroid hyperplasia with possibly secondary genetic events causing nodule formation. Radical parathyroid resection is advocated in this hypercalcemic disorder, which may represent an intermediary stage between primary hyperparathyroidism and familial hypocalciuric hypercalcemia.

Adult↗

PubMed2002

Multiple endocrine neoplasia type 1 polymorphism D418D is associated with sporadic primary hyperparathyroidism.

BACKGROUND: Sporadic primary hyperparathyroidism (pHPT) occurs separately and in several hereditary disorders including multiple endocrine neoplasia type 1. Irradiation to the neck, female gender, and age are well-identified risk factors that predispose to pHPT. The multiple endocrine neoplasia type 1 gene is the most commonly deranged gene in parathyroid adenomas and contains several polymorphisms including D418D with a prevalence of roughly 50%. METHODS: We genotyped 162 pHPT patients and control participants to evaluate if the D418D polymorphism is related to development of pHPT. One hundred fourteen of the pHPT patients and control participants were recruited from a health screening and were subjected to measurement of bone mineral density (BMD) at the lumbar spine, femoral neck, and total body. RESULTS: The prevalence of each genotype (ie, MM, Mm, and mm) was for all pHPT patients: 62%, 29%, and 9%; and for all control participants: 32%, 43%, and 25% (P <.0004). For the screening-detected pHPT patients and control participants, the genotype distribution for MM, Mm, and mm was 60%, 30%, and 10%; and 31%, 44%, and 25%, respectively (P =.009). In the screening-recruited control participants, but not in pHPT patients, the MM genotype was also associated with higher total body BMD (P =.01) and BMD at the femoral neck (P =.02), whereas it failed to be significant for BMD at the lumbar spine (P =.08). CONCLUSIONS: We report that the MM genotype was overrepresented in pHPT patients compared with control participants, suggesting a novel marker for pHPT. Furthermore, the MM genotype was associated with higher BMD at the femoral neck and in the total body in the screening-recruited control participants.

Aged↗

PubMed2002

25-hydroxyvitamin D(3)-1alpha-hydroxylase expression in normal and pathological parathyroid glands.

Active vitamin D, 1,25-dihydroxyvitamin D(3) [1,25(OH)(2)D(3)], plays a pivotal role in calcium homeostasis and bone metabolism. Circulating levels of 1,25(OH)(2)D(3) are thought to be dependent mainly on the activity of the renal cytochrome P450 enzyme 25-hydroxyvitamin D(3)-1alpha-hydroxylase (1alpha-hydroxylase), which is potently induced by PTH. However, 1alpha-hydroxylase activity or expression has also been reported at several extrarenal sites, at which local synthesis of 1,25(OH)(2)D(3) appears to fulfill autocrine or paracrine functions. This includes tissues such as placenta and brain that also express LRP-2/megalin, an endocytic receptor for multiple ligands, which is involved in the renal uptake of the substrate for 1alpha -hydroxylase, 25-hydroxyvitamin D(3). We have previously demonstrated LRP-2/megalin in parathyroid cells, and here we present results from RT-PCR and immunohistochemical analyses showing coincident expression of 1alpha-hydroxylase in normal and pathological parathyroid tissue. With real-time quantitative RT-PCR analysis, the expression of 1alpha-hydroxylase mRNA was higher in the majority of parathyroid adenomas and secondary hyperplastic glands but lower in parathyroid carcinomas, compared with normal parathyroid tissue. The findings imply that in addition to feedback control by circulating 1,25(OH)(2)D(3) levels, parathyroid cells may also be influenced by local 1alpha -hydroxylase activity with possible growth regulatory and differentiating effects.

25-Hydroxyvitamin D3 1-alpha-Hydroxylase↗

PubMed2002

Loss of heterozygosity in parathyroid glands of familial hypercalcemia with hypercalciuria and point mutation in calcium receptor.

Development of sporadic parathyroid tumors is accompanied by loss of heterozygosity (LOH) on several chromosomes like 1p, 1q, 6q, 11q, and 15q. Here, we investigate a unique variant of familial hypercalcemia, unrelated to multiple endocrine neoplasia and hyperparathyroidism-jaw tumor syndromes, with hypercalcemia due to a point mutation in the intracellular part of the calcium receptor (CaR) gene. The hypercalcemia and hypercalciuria of the family is accompanied by age-related growth of the parathyroid glands and transition from diffuse to nodular parathyroid hyperplasia. Genome-wide screening for allelic loss was performed on nine enlarged parathyroid glands (weighing 40-680 mg) from eight parathyroidectomized members of the family (aged 22-66 yr). Using 139 fluorescent- or (32)P-labeled microsatellite markers, informative results were obtained on all examined chromosome arms and 1p, 1q, 6q, 11q, and 15q were investigated more closely. All parathyroid glands displayed allelic loss on at least one chromosomal arm (range 1-7). Most of the common loci for allelic loss corresponded to findings in sporadic parathyroid tumors, but the unique variant of familial hypercalcemia also exhibited frequent LOH on 12q (67%) and 7q (44%). LOH could not be detected at 3q, where the CaR gene is located, and additional somatic mutations in exons 2-7 of the CaR gene was not found by sequencing. The point mutation resulting in alteration of the intracellular portion of CaR seems to cause sensitivity to secondary genetic hits, with increased frequency of allelic loss (P < 0.01, r(2) = 0.66) and weight of parathyroid tumors with age in this family.

Adult↗

PubMed2002

Involvement of the MEN1 gene locus in familial isolated hyperparathyroidism.

BACKGROUND: Familial isolated hyperparathyroidism (FIHP) is a hereditary disorder characterised by uni- or multiglandular parathyroid disease. A subset of families are likely to be genetic variants of other familial tumour syndromes in which PHPT is the main feature, for example multiple endocrine neoplasia type 1 (MEN 1) and the hyperparathyroidism-jaw tumour syndrome (HPT-JT). OBJECTIVE: To investigate seven families diagnosed with FIHP, each with two to eight affected family members, to clarify the underlying genetic mechanism. METHODS: The entire MEN1 gene was sequenced for germline mutations and, in addition, tumour specimens were analysed in comparative genomic hybridisation and loss of heterozygosity studies. RESULTS: Two families exhibited MEN1 mutations, L112V and 1658delG, which were associated with loss of the wild-type 11q13 alleles in all tumours analysed. In the remaining five families, no MEN1 mutation was identified. CONCLUSION: These results support the involvement of the MEN1 tumour suppressor gene in the pathogenesis of some of the FIHP kindreds. However, loss on chromosome 11 was seen in all tumours exhibiting somatic deletions, although in two families the tumour deletions involved 11q distal to MEN1. We conclude that the altered MEN1 gene function is of importance in the development of FIHP.

Adult↗

PubMedDate not supplied

The tumor suppressor gene RIZ in cancer gene therapy (review).

In recent years, significant progress has been made in understanding the nature of the human genome and the role that genes and their related proteins play in both normal and diseased cells. It has been proven that many cancers are caused by the mutation of certain genes or lack of gene function. The introduction of those genes into cancer cells where gene function is compromised, can work to restore gene function and stop tumor progression. There have been numerous clinical trials, which have shown that gene therapy products are efficacious in humans. The RIZ1 gene is a member of a superfamily of histone/protein methyltransferases. The gene is commonly inactivated in human cancers. Gene knock-out study has established RIZ1 as a tumor susceptibility gene in mice. The gene has potent tumor suppressive activities in causing apoptosis, G2/M arrest, or both. Preclinical animal studies have shown that a recombinant adenovirus expressing the gene, AdRIZ1, can suppress the growth of colon cancer xenografts. Therefore, AdRIZ1 shows promise as a new generation of gene therapy products to enter the clinic.

DNA-Binding Proteins↗

PubMedDate not supplied

In situ RNA-RNA hybridisation of phospholipase C beta 3 shows lack of expression in neuroendocrine tumours.

BACKGROUND: Phospholipase C beta 3 (PLCB3) plays an important role in the signal transduction of the seven transmembrane receptors. The gene is located in the vicinity of the Multiple Endocrine Neoplasia type 1 (MEN1) gene on chromosome 11q13. Transfection of PLCB3 to neuroendocrine cell lines lacking expression suppresses the neoplastic phenotype and affects the gene expression of S100A3 and human mismatch repair protein, suggesting a role for PLCB3 in neuroendocrine tumorigenesis. MATERIALS AND METHODS: We used RNA-RNA in situ hybridisation for PLCB3 on a total of 82 samples including 34 from MEN1 patients. RESULTS: We show that the PLCB3 transcript is missing in 8 out of 14 MEN1-associated neoplasias as well as in 4 out of 10 bronchial carcinoids, 2 out of 10 exocrine pancreatic cancers and one sporadic adrenocortical carcinoma. CONCLUSION: Low or lack of PLCB3 expression in a subset of endocrine tumours, together with earlier published in vitro data on suppressor characteristics upon transfection, indicate that PLCB3 could be involved in the tumorigenesis in a subset of endocrine tumours.

Animals↗