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Biomedical subjects

B McIver

Publications and source records attributed to B McIver.

At least 19 recordsLinked to original sources
PubMed2002

Percutaneous ethanol injection for treatment of cervical lymph node metastases in patients with papillary thyroid carcinoma.

OBJECTIVE: The objective of this study was to evaluate the technique, efficacy, and side effects of percutaneous ethanol injection in patients with limited cervical nodal metastases from papillary thyroid carcinoma. SUBJECTS AND METHODS: Fourteen patients who had undergone thyroidectomy for papillary thyroid carcinoma presented with limited nodal metastases (one to five involved nodes) in the neck between May 1993 and April 2000. All patients had received previous iodine-131 ablative therapy with a mean total dose per patient of 7,548 MBq. Ten of the patients either were considered poor surgical candidates or preferred not to have surgery, and all were unresponsive to iodine-131 therapy. Each metastatic lymph node was treated with percutaneous ethanol injection, and patients received both clinical and sonographic follow-up. RESULTS: Twenty-nine metastatic lymph nodes in our 14 patients were injected. Mean sonographic follow-up was 18 months (range, from 2 months to 6 years 5 months). All treated lymph nodes decreased in volume from a mean of 492 mm(3) before percutaneous ethanol injection to a mean volume of 76 mm(3) at 1 year and 20 mm(3) at 2 years after treatment. Six nodes were re-treated 2-12 months after initial percutaneous ethanol injection because of persistent flow on color Doppler sonography (n = 4), stable size (n = 1), or increased size (n = 1). Two patients developed four new metastatic nodes during the follow-up period that were amenable to percutaneous ethanol injection. Two patients developed innumerable metastatic nodes that precluded retreatment with percutaneous ethanol injection. No major complications occurred. All patients experienced long-term local control of metastatic lymph nodes treated by percutaneous ethanol injection. In 12 of 14 patients, percutaneous ethanol injection was successful in controlling all known metastatic adenopathy. CONCLUSION: Sonographically guided percutaneous ethanol injection is a valuable treatment option for patients with limited cervical nodal metastases from papillary thyroid cancer who are not amenable to further surgical or radioiodine therapy.

Adult↗
PubMed2001

Anaplastic thyroid carcinoma: a 50-year experience at a single institution.

BACKGROUND: Anaplastic thyroid carcinoma (ATC) is among the most aggressive of human malignancies. However, there have been few large studies of histologically well-defined ATC. We report the results of a 50-year experience of this lethal malignancy. METHODS: We reviewed all cases of ATC managed in this institution between 1949 and 1999. One pathologist (J.R.G.) reviewed all pathologic material. Clinical details were obtained from medical records, and current status of all patients was determined. RESULTS: There were 134 cases, with a female-to-male ratio of 1.5:1 and a mean age of 67 years. Benign thyroid disease was present in 27 cases (20%) and well-differentiated thyroid carcinoma in 31 (23%). Sixty-two patients (46%) had distant metastases at diagnosis, and 98% of the tumors were locally invasive. Primary treatment was surgical for 96 patients (72%). Complete resection was achieved in 29 cases (30%), with "minimal residual disease" in 25. Neither extent of operation nor completeness of resection affected survival (P > .4). Postoperative radiotherapy gave slightly longer median survival (5 vs 3 months), which was not significant (P < .08). Multimodal therapy, including operation, chemotherapy, and radiotherapy, did not improve survival. CONCLUSIONS: The outlook for patients with ATC remains grim. Novel treatments for ATC are desperately needed.

Adult↗
PubMed2000

Papillary thyroid cancer with pulmonary metastases in children: long-term prognosis.

BACKGROUND: Papillary thyroid cancer (PTC) in young patients may rarely be encountered with pulmonary metastases. Previous studies have suggested that, in the pediatric population, this may not portend a lethal outcome. Our present study, children with pulmonary metastases, was designed to clarify this issue. METHODS: Fourteen children and young adolescents (mean age, 13.5 years; range, 9.8-17 years) with PTC and pulmonary metastases were treated at our institution between 1937 and 1998. Surgical treatment consisted of total thyroidectomy (n = 10 patients), subtotal thyroidectomy (n = 3 patients), and a biopsy only procedure (n = 1 patient). All patients who underwent thyroidectomy also underwent a variety of cervical lymph node dissections, and all patients proved to have regional nodal disease. After the operation, 12 patients were treated with ablative doses of (131)I, 1 patient was treated with external beam irradiation, and all patients were placed on suppressive thyroid hormone therapy. The mean length of follow-up was 19.3 years (range, 1-45 years). RESULTS: Regional recurrent disease developed in 2 patients (15%). No patient experienced the development of worsening pulmonary disease or extra-pulmonary metastases. All patients with recurrent disease underwent selective nodal resections. No patient died of metastatic PTC. Seven patients (50%) remain completely free of disease and are probably cured; 7 patients (50%) are asymptomatic with residual pulmonary disease. CONCLUSIONS: A stepwise treatment approach allows long-term survival and frequent cure for young patients with PTC and concomitant pulmonary metastases.

Adolescent↗
PubMed2000

FHIT and TSG101 in thyroid tumours: aberrant transcripts reflect rare abnormal RNA processing events of uncertain pathogenetic or clinical significance.

OBJECTIVE: The chromosomal regions containing the two putative tumour suppressors, fragile histidine triad gene (FHIT) and tumour suppressor gene 101 (TSG101), are deleted frequently in thyroid tumours. We therefore analysed FHIT and TSG101 transcripts in a group of advanced thyroid tumours to establish their role in thyroid tumorigenesis. DESIGN: Retrospective analysis of FHIT and TSG101 mRNA transcripts and genomic DNA from cryo-preserved thyroid tumours. TP53, previously shown at the genomic level not to be mutated in this cohort of tumours, served as a control. PATIENTS: We analysed nine follicular thyroid carcinomas (FTC), six papillary thyroid carcinomas and six follicular adenomas (FA) and histologically normal thyroid tissue from four of the FA patients. MEASUREMENTS: Single stage and nested reverse transcription polymerase chain reaction (RT-PCR) products of FHIT, TSG101, and TP53 were analysed by agarose or polyacrylamide gel electrophoresis and sequenced. Genomic DNA was also analysed by polymerase chain reaction and sequencing (FHIT) or by Southern blotting (TSG101). Clinical data were correlated with the results of the mutation analysis. RESULTS: Truncated FHIT transcripts were observed frequently alongside full length transcripts with nested RT-PCR, most often in FTC, while single stage RT-PCR revealed only normal length transcripts in all tumours. Similar results were obtained for TP53, while abnormal TSG101 transcripts were detectable by single stage RT-PCR. Sequence analysis of the truncated FHIT and TSG101 transcripts revealed mainly exon skipping and alternate RNA processing events. Only a single point mutation (of TSG101) was found. Southern blotting for the TSG101 gene, and PCR amplification and sequencing of the FHIT gene showed no evidence of genomic abnormalities in either case, and there was no evidence of splice site mutations in the FHIT gene, suggesting that the truncated transcripts result from altered RNA processing. There was no relationship between tumour stage, grade or survival and the presence of FHIT or TSG101 abnormalities. CONCLUSIONS: Truncated FHIT and TSG101 transcripts in thyroid tumours reflect alternate mRNA splicing events, rather than genomic deletions. Such abnormal RNA processing seems to be common and widespread in thyroid neoplasms, as similar results were obtained by analysis of transcripts of TP53, which we had previously shown not to be mutated in these specimens. Although a pathogenetic role for these aberrant transcripts remains possible, no correlation was found with stage, histological grade or outcome in this small group of advanced thyroid malignancies. Relaxation of mRNA splice control appears to be a feature of follicular cell-derived thyroid neoplasms.

Acid Anhydride Hydrolases↗
PubMed1999

Cloning of a human ortholog (RPH3AL) of (RNO)Rph3al from a candidate 17p13.3 medulloblastoma tumor suppressor locus.

Allelic loss of 17p13.3 is observed in approximately 40% of medulloblastomas, suggesting the presence of a tumor suppressor gene in this region. Deletion mapping has defined a region of common loss flanking the telomeric marker D17S34, and a recent report delineated a 9-kb homozygous deletion within the D17S34 locus in one such tumor. Using cDNA selection, we have identified a transcript spanning this deletion, designated (HSA)RPH3AL (rabphillin-3A-like), based on its 77% overall amino acid identity with a recently cloned rat gene, (RNO)Rph3al (originally termed Noc2), a gene putatively involved in regulated endocrine exocytosis through its interactions with the cytoskeleton. We determined the exon-intron boundaries of RPH3AL and screened the coding region for mutations by direct sequencing in DNA extracted from 33 tumor samples with allelic loss of 17p13, including 10 medulloblastoma, 14 follicular thyroid cancer (FTC), and 9 ovarian cancer specimens. No mutations were identified. Thus, despite its location in a homozygously deleted 17p13.3 locus, it is unlikely that RPH3AL is a gene involved in the oncogenesis of medulloblastoma, FTC, or ovarian cancer.

Adaptor Proteins, Signal Transducing↗
PubMed1999

Prostate-specific antigen (PSA) promoter-driven androgen-inducible expression of sodium iodide symporter in prostate cancer cell lines.

Currently, no curative therapy for metastatic prostate cancer exists. Causing prostate cancer cells to express functionally active sodium iodide symporter (NIS) would enable those cells to concentrate iodide from plasma and might offer the ability to treat prostate cancer with radioiodine. Therefore, the aim of our study was to achieve tissue-specific expression of full-length human NIS (hNIS) cDNA in the androgen-sensitive human prostatic adenocarcinoma cell line LNCaP and in subcell lines C4, C4-2, and C4-2b in vitro. For this purpose, an expression vector was generated in which full-length hNIS cDNA coupled to the prostate-specific antigen (PSA) promoter has been ligated into the pEGFP-1 vector (NIS/PSA-pEGFP-1). The PSA promoter is responsible for androgen-dependent expression of PSA in benign and malignant prostate cells and was therefore used to mediate androgen-dependent prostate-specific expression of NIS. In addition, two control vectors were designed, which consist of the pEGFP-1 vector containing the PSA promoter without NIS cDNA (PSA-pEGFP-1) and NIS cDNA without the PSA promoter (NIS-pEGFP-1). Prostate cancer cells were transiently transfected with each of the above-described expression vectors, incubated with or without androgen (mibolerone) for 48 h, and monitored for iodide uptake activity. In addition, stably transfected LNCaP cell lines were established for each vector. Prostate cells transfected with NIS/PSA-pEGFP-1 showed perchlorate-sensitive, androgen-dependent iodide uptake in a range comparable to that observed in control cell lines transfected with hNIS cDNA. Perchlorate-sensitive iodide uptake was not observed in cells transfected with NIS/PSA-pEGFP-1 and treated without androgen or in cells transfected with the control vectors. In addition, prostate cancer cell lines without PSA expression (PC-3 and DU-145) did not show iodide uptake activity when transfected with NIS/PSA-pEGFP-1. Western blotting of LNCaP and C4-2b cell membranes transfected with NIS/PSA-pEGFP-1 using a monoclonal antibody that recognizes the COOH-terminus of hNIS revealed a band with a molecular weight of 90,000 that was not detected in androgen-deprived cells or in cells transfected with the control vectors, as well as a minor band at Mr 150,000 in transiently transfected LNCaP cell membranes. In conclusion, tissue-specific androgen-dependent iodide uptake activity has been induced in prostate cancer cells by PSA promoter-directed NIS expression. This study represents an initial step toward therapy of prostate cancer with radioiodine.

Adenocarcinoma↗
PubMed1999

Impact of primary surgery on outcome in 300 patients with pathologic tumor-node-metastasis stage III papillary thyroid carcinoma treated at one institution from 1940 through 1989.

BACKGROUND: The pathologic tumor-node-metastasis (pTNM) system is universally used to define the extent of disease in human malignancies. This study evaluated the impact of initial therapy on cause-specific mortality (CSM) rates and recurrence rates in pTNM stage III papillary thyroid carcinoma. METHODS: Three hundred patients (median age, 58 years) were followed on average for 14 postoperative years. Of these, 246 patients (82%) had complete primary tumor resection; 208 patients (69%) had nodal metastases; 161 (54%) had locally invasive primary tumors; 45 patients (15%) underwent initial unilateral lobectomy (UL). Bilateral lobar resection (BLR) accounted for 242 patients (near-total, 54%; total thyroidectomy, 23%). RESULTS: The 30-year rates for CSM, distant metastases, nodal metastases, and local recurrence (LR) were 29%, 22%, 19%, and 16%, respectively. The 20-year rates for CSM were significantly higher (50% vs 14%) when primary tumor was incompletely resected (P = .0001). After complete resection, 20-year rates for CSM and LR after BLR were 12% and 10%, respectively, which were significantly lower (P < .05) than the 23% and 26% rates seen after UL. There were no significant differences in nodal metastases or distant metastases rates between UL and BLR (P > .4). The 20-year LR rate after total thyroidectomy (13%) was not different (P = .5) from the 11% seen after near-total thyroidectomy. CONCLUSIONS: In this nonrandomized evaluation of patients with pTNM stage III papillary thyroid carcinoma, the extent of primary thyroid resection appeared to significantly impact CSM and LR but did not apparently influence regional or distant metastasis.

Aged↗
PubMed1999

Development of monoclonal antibodies against the human sodium iodide symporter: immunohistochemical characterization of this protein in thyroid cells.

The thyroid sodium-iodide symporter (NIS) is responsible for iodide concentrating ability within thyroid follicular cells. We sought to develop monoclonal antibodies against human NIS (hNIS) for use as reagents in structure-function studies of the protein, as well as potential tools in the assessment of NIS expression in benign and malignant thyroid tissues. Synthetic peptides corresponding to the second ExMD and to the carboxy-terminal ExMD of hNIS were produced and utilized as antigens to develop monoclonal antibodies, which were tested by Western blotting using membranes prepared from COS-7 cells transiently transfected with a pcDNA3 plasmid containing the gene for the full-length hNIS, or a control vector. Western blotting showed a major band with molecular weight (MW) of approximately 97 kDa and several minor bands with MW of approximately 160 kDa, 68 kDa, 30 kDa, and 15 kDa, all specific for hNIS-transfected cells. Immunohistochemistry was performed in various types of thyroid tissues and nonthyroidal tissues, using the monoclonal antibodies. Strong immunostaining was observed in Graves' tissue, intermediate staining in papillary and follicular thyroid cancer, and no staining in Hürthle cell cancer or in nonthyroidal tissue. The staining was specific for the follicular epithelium in each of the tissues and was most intense in the basolateral portion of the cell membrane. Overall, our observations indicate that the monoclonal antibodies are specific for hNIS and will be invaluable reagents for investigating the role of NIS in thyroid disease.

Amino Acid Sequence↗
PubMed1998

Differential loss of heterozygosity at 7q31.2 in follicular and papillary thyroid tumors.

We analysed 42 differentiated thyroid tumors including 15 follicular adenomas (FA), 13 papillary thyroid cancers (PTC) and 14 follicular thyroid carcinomas (FTC) with 13 microsatellite markers specific for the long arm of human chromosome 7 within 7q31; this region is deleted frequently in several other tumor types. Overall, 20 of the 42 samples analysed (48%) displayed LOH with one or more of the markers tested. LOH was detected most frequently (78%) in FTC, the most malignant of the thyroid tumors. A smallest common deleted region (SCDR) was defined in this tumor type flanked by markers D7S480 and D7S490. This SCDR is distinct from D7S522, the most commonly deleted locus in many other tumors, which was deleted in only one FTC. D7S522 did show LOH in two of six informative PTCs. None of the PTC and only two of the FAs showed LOH in the FTC SCDR. Since FA is considered a premalignant stage of FTC, our results suggest that inactivation of a putative tumor suppressor at 7q31.2 may be acquired during adenoma to carcinoma progression. The absence of LOH at this locus amongst PTC suggests that inactivation of this tumor suppressor is specific for FTC. In conclusion, LOH at 7q31 is a frequent event in differentiated thyroid cancer, and we have defined a 2 cM SCDR specific for FTC.

Adenoma↗
PubMed1998

The pathogenesis of Graves' disease.

Graves' disease, one of the autoimmune thyroid diseases, is caused by the production of IgG autoantibodies directed against the thyrotropin receptor. These antibodies bind to and activate the receptor, causing the autonomous production of thyroid hormones. Despite recent improvements in our understanding of the cellular and molecular basis of autoimmunity, our currently available treatments for Graves' disease have remained largely unchanged over the last 50 years. Nevertheless, new concepts in immune system regulation hold out the prospect in the future for intervention designed to modify, and possibly cure, the underlying disease process.

Autoantigens↗
PubMed1997

Euthyroid sick syndrome: an overview.

Abnormalities of thyroid hormone concentrations are seen commonly in a wide variety of nonthyroidal illnesses, resulting in low triiodothyronine, total thyroxine, and thyroid stimulating hormone concentrations. These thyroid hormone changes may be mediated in part by cytokines or other inflammatory mediators, acting at the level of the hypothalamus and pituitary, the thyroid gland, and the hepatic deiodinase system, as well as on binding of thyroxine to thyroid binding globulin. The degree of thyroid function disturbance correlates with disease severity and low levels of thyroid hormones predict a poor prognosis in several illnesses. It remains unresolved whether the hormone responses in the euthyroid sick syndrome represent part of an adaptive response, which lowers tissue energy requirements in the face of systemic illness, or a maladaptive response, which induces damaging tissue hypothyroidism. Consequently, the use of thyroid hormone therapy in the euthyroid sick syndrome is controversial. The small number of controlled trials performed to date have shown conflicting results on the cardiovascular effects of triiodothyronine, and none has had the statistical power to address the question of altered mortality. Future trials of therapy should concentrate on patients with severe nonthyroidal illness and a high mortality rate. Meanwhile, better understanding is needed of the impact of the altered thyroid hormone status on tissue function.

Euthyroid Sick Syndromes↗
PubMed1997

Frequent loss of heterozygosity on chromosomes 3p and 17p without VHL or p53 mutations suggests involvement of unidentified tumor suppressor genes in follicular thyroid carcinoma.

Follicular thyroid carcinoma (FTC) exhibits frequent loss of heterozygosity (LOH) on chromosomes 10q and 3p, suggesting involvement of tumor suppressor genes. We screened 14 FTC (10 Hurthle cell carcinomas and 4 nonoxyphilic FTC), 14 papillary thyroid carcinomas, and 7 follicular adenomas for LOH on chromosome arms 1p, 3p, 3q, 10p, 10q, 11p, 11q, 13q, 17p, and 17q. LOH was more frequent in FTC than in follicular adenoma or papillary thyroid carcinoma. In FTC, rates of LOH on 3p (86%), 17p (72%), and 10q (57%) were higher than the average rate of LOH (33%; P < 0.05). Most frequently involved were 3p21-25 and 17p13.1-13.3, the sites for the VHL (3p25-26) and p53 (17p13.1) tumor suppressors. We, therefore, characterized these genes by dideoxy fingerprinting and DNA sequencing. Two FTC had mutations in p53, but only 1 of these exhibited LOH at 17p. No VHL gene mutations were found. Thus, neither p53 nor VHL genes play a significant role in the pathogenesis of differentiated thyroid cancer. LOH on 17p, but not on 3p or 10q, was correlated with mortality. Accordingly, 3p and 10q LOH may represent early, and 17p LOH late, events in FTC development. The data suggest the presence of novel tumor suppressor genes on chromosomes 3p and 17p that may be important in the pathogenesis of FTC.

Adenocarcinoma, Follicular↗
PubMed1997

Evaluation and management of amenorrhea.

All women who enter menopause experience amenorrhea unless they receive hormone replacement therapy. In younger women, amenorrhea unrelated to pregnancy and lactation can be a distressing symptom. In addition to its psychologic morbidity, amenorrhea may be the manifesting feature of a wide array of anatomic and endocrine abnormalities. Amenorrhea results in impaired fertility. When estrogen levels are low, changes in mineral, glucose, and fat metabolism accompany amenorrhea. These metabolic changes affect bone and cardiovascular health, increasing the risk of osteoporosis and coronary heart disease in later life. Amenorrhea with hyperandrogenism, most commonly caused by the polycystic ovarian syndrome, may cause endometrial hyperplasia and increases the risk of endometrial adenocarcinoma. Because of the broad differential diagnosis of amenorrhea, establishing an accurate diagnosis can prove challenging. In this article, we outline one approach to the assessment of patients with amenorrhea and to the management of its common causes and consequences.

Amenorrhea↗
PubMed1996

Lack of effect of thyroxine in patients with Graves' hyperthyroidism who are treated with an antithyroid drug.

BACKGROUND: Antithyroid drugs are effective in patients with hyperthyroidism due to Graves' disease, but the rate of recurrence after treatment is high. In a recent Japanese study, adjunctive treatment with thyroxine (T4) was associated with a recurrence rate 20 times lower than that among patients who received only an antithyroid drug. If these results are confirmed, combined therapy with an antithyroid drug and T4 might become the treatment of choice for all patients with Graves' hyperthyroidism. METHODS: We treated 111 patients (89 women and 22 men) who had Graves' hyperthyroidism. All patients initially received 40 mg of carbimazole daily for one month. Then one group received carbimazole alone for 17 months (52 patients), and the other group received carbimazole plus T4 for 17 months and T4 alone for 18 months (59 patients). In the carbimazole group, the dose was adjusted after one month to maintain a normal serum thyrotropin concentration. In the carbimazole-T4 group, the dose of carbimazole was not changed, but 100 micrograms of T4 per day was added to the regimen and the dose was adjusted to maintain an undetectable serum thyrotropin concentration (< 0.04 microU per milliliter). RESULTS: At the time of our analysis, 53 of the 111 patients had completed at least 3 months of follow-up (median, 12 months) after carbimazole was withdrawn. Hyperthyroidism recurred in eight patients in each group after a mean (+/- SD) of 6 +/- 4 months in the carbimazole group and 7 +/- 4 months in the carbimazole-T4 group. There was no difference between the recurrence rates in the two groups, despite the fact that serum thyrotropin concentrations were undetectable in 73 percent of patients in the carbimazole-T4 group on at least 75 percent of their visits. CONCLUSIONS: The administration of T4 to patients with Graves' disease during carbimazole treatment and after its withdrawal neither delays nor prevents the recurrence of hyperthyroidism.

Adult↗
PubMed1994

The use of chlorpromazine for symptom control in dying cancer patients.

Terminal restlessness is a significant problem in deaths from advanced cancer, it is difficult not only for patients, but for family and health-care providers also. Chlorpromazine is an antipsychotic phenothiazine, safe at high doses and by many routes. It has also been used as an adjunct to morphine in advanced cancer. We have conducted a study using chlorpromazine in 20 patients, in which the drug was administered intravenously (i.v.) or rectally (PR) in inpatients and outpatients for terminal restlessness and dyspnea. The median PR dose was 25 mg every 4-12 hr. The median IV dose was 12.5 mg every 4-12 hr. Eighteen patients had complete relief and two had partial relief before death. We find chlorpromazine safe and effective for the relief of terminal restlessness and dyspnea in advanced cancer.

Chlorpromazine↗
PubMed1993

Coagulation and fibrinolytic systems in type I diabetes: effects of venous occlusion and insulin-induced hypoglycaemia.

1. The effects of venous occlusion on the coagulation and fibrinolytic systems were investigated in six patients with type 1 (insulin-dependent) diabetes and 11 age- and sex-matched non-diabetic control subjects. The coagulation parameters (fibrinogen, prothrombin time, partial thromboplastin time with kaolin, von Willebrand factor antigen) did not differ between patients and control subjects either before or after 20 min of venous occlusion. No rise was observed in von Willebrand factor antigen after venous occlusion in either group. 2. In the diabetic patients, chronic activation of the fibrinolytic system was found at baseline, which was indicated by a shortened euglobulin lysis time (P < 0.01), increased tissue plasminogen activator activity (P < 0.05) and decreased plasminogen activator inhibitor type 1 antigen level (P < 0.05), when compared with control subjects. In both groups venous occlusion resulted in significant increments in all measurements, except plasminogen activator inhibitor type 1 antigen level. The post-occlusion values did not differ between the two groups, except the plasminogen activator inhibitor type 1 antigen level, which remained significantly lower in the diabetic patients. The mean increments in each parameter did not differ between the two groups. 3. Coagulation and fibrinolysis were assessed in response to acute insulin-induced hypoglycaemia. Von Willebrand factor antigen levels increased significantly in both groups, with no difference in maximal increments. Significant activation of the fibrinolytic system occurred in response to hypoglycaemia, demonstrated by shortened euglobulin lysis time and increased fibrin plate lysis, tissue plasminogen activator antigen level and tissue plasminogen activator activity.(ABSTRACT TRUNCATED AT 250 WORDS)

Acute Disease↗