Using Ion Torrent sequencing to study genetic mutation profiles of fatal thyroid cancers.

BACKGROUND/PURPOSE: Surgery followed by radioiodine is a mainstay of treatment for thyroid cancers of follicular origins. However, about 5% of the thyroid cancers are non-operable and/or radioiodine-refractory diseases, which are either locally advanced or metastatic and result in a survival of less than 5 years. How to treat this population of thyroid cancer patients becomes a critical issue requiring further understanding of the tumor's genetic information. METHODS: We used formalin-fixed paraffin-embedded specimens of 22 fatal thyroid cancers and their corresponding non-tumor parts, if available, to yield genomic DNA, and applied the Ion Torrent™ Personal Genome Machine (IT-PGM) System (Life Technologies), a next generation sequencing technology, to interrogate 740 mutational hotspots in 46 oncogenes. We further validated the results by conventional direct sequencing. RESULTS: We confirmed 21 mutations of 11 oncogenes in the 22 fatal thyroid cancer samples. Among them, the MET p.N375S and MLH1 p.V384D mutations, each was detected in two cases, and has rarely been found to be involved in thyroid cancer pathogenesis before. We also identified homozygous PDGFRA p.V824V mutation in eight out of the 22 cases, while the non-tumor counterparts carried heterozygous PDGFRA p.V824V mutation. We noted that the Ion Torrent technique unfortunately showed high false positive rates for detecting EGFR mutations in thyroid cancers. CONCLUSION: The extensive genetic studies provide new insights to future targeted therapy in these patients. IT-PGM proved to be valuable for comprehensively searching genetic mutations in potentially fatal thyroid cancers.

Case detection and diagnosis of primary aldosteronism - The consensus of Taiwan Society of Aldosteronism.

BACKGROUND/PURPOSE: Even though the increasing clinical recognition of primary aldosteronism (PA) as a public health issue, its heightened risk profiles and the availability of targeted surgical/medical treatment being more understood, consensus in its diagnosis and management based on medical evidence, while recognizing the constraints of our real-world clinical practice in Taiwan, has not been reached. METHODS: The Taiwan Society of Aldosteronism (TSA) Task Force acknowledges the above-mentioned issues and reached this Taiwan PA consensus at its inaugural meeting, in order to provide updated information of internationally acceptable standards, and also to incorporate our local disease characteristics into the management of PA. RESULTS: When there is suspicion of PA, a plasma aldosterone to renin ratio (ARR) should be obtained initially. Patients with abnormal ARR will undergo confirmatory laboratory and image tests. Subtype classification with adrenal venous sampling (AVS) or NP-59 nuclear imaging, if AVS not available, to lateralize PA is recommended when patients are considered for adrenalectomy. The strengths and weaknesses of the currently available identification methods are discussed, focusing especially on result interpretation. CONCLUSION: With this consensus we hope to raise more awareness of PA among medical professionals and hypertensive patients in Taiwan, and to facilitate reconciliation of better detection, identification and treatment of patients with PA.

Blood-aqueous barrier function in a patient with choroideremia.

The purpose was to determine whether there was a breakdown of the blood-aqueous barrier in a patient with choroideremia. A 27-year-old man with typical choroideremia underwent standardized ophthalmo-logical evaluation, including quantitative measurement of aqueous flare intensity, by a laser flare-cell meter. The results showed areas of atrophy of the choriocapillaries and retinal pigment epithelium in the mid-periphery and posterior pole, although not in the macula. Fluorescein angiography showed areas of loss of the choriocapillaries and retinal pigment epithelium. The fovea was spared with a surrounding zone of hy-perfluorescence. Electroretinography showed a subnormal photopic amplitude and extinguished scotopic response. Electrooculography revealed that the light peak/dark trough ratio was reduced. Goldmann perimetry showed constricted peripheral fields. Laser photometry showed an increase in the aqueous flare intensity in both eyes, as compared with normal subjects. We conclude that the function of the blood-aqueous barrier might be affected in patients with choroideremia.

Genetic and environmental influences on adiponectin, leptin, and BMI among adolescents in Taiwan: a multivariate twin/sibling analysis.

Circulating levels of leptin and adiponectin are closely associated with obesity. However, it is not known whether there are common shared genes or environment exerting influences on the levels of leptin, adiponectin, and BMI. We aimed to assess the relative contribution of genes and environment to adiponectin, leptin, and BMI individually as well as simultaneously to the three measures. Our subjects included a total of 228 twin/sibling pairs aged 12 to 18 (130 monozygotic twins, 68 dizygotic twins and 30 sibling pairs) were recruited from the middle schools. Multivariate analyses were applied to twin/sibling data using structural equation modeling. The results showed that intraclass correlations for adiponectin, leptin and BMI were higher in the MZ twins than those in the DZ/SP group. The relative contribution of genes to adiponectin (39%) was comparable to those of shared environment (40%). In contrast, leptin and BMI were influenced mostly by genes (74% and 89%, respectively). The multivariate genetic analyses showed that a latent factor underlying the three measures was identified, with BMI being equivalent to this latent factor. The BMI-dependent genetic factor explains only 15% and 34% of variation of adiponectin and leptin, respectively. These data indicate a differential contribution of genetic factors for the variation of adiponectin, leptin and BMI. More importantly, only a small portion of the genetic influences on adiponectin and leptin was attributed to BMI. Our findings provided more insight into the complex regulation of adiponectin and leptin in obesity.

Gas tamponade and macular grid laser photocoagulation in the management of recurrent retinal detachment.

BACKGROUND AND OBJECTIVE: To evaluate the efficacy of intraocular gas tamponade and macular grid laser photocoagulation to manage recurrent macular hole retinal detachment after an initially successful reattachment by gas tamponade in highly myopic eyes. PATIENTS AND METHODS: Five patients with high myopia and macular hole retinal detachment were treated by gas tamponade at the initial operation. Gas tamponade and macular grid laser photocoagulation were performed to treat recurrent retinal detachment at the second surgery. Demographic information, anatomic reattachment of the retina, and final visual acuity were studied. RESULTS: Final successful retinal reattachment at the end of follow-up was obtained in all five eyes. Improvement of postoperative visual acuity with respect to preoperative visual acuity was observed in all patients. CONCLUSION: Intraocular gas tamponade and grid laser photocoagulation in the macula for the management of recurrent macular hole retinal detachment provides good long-term anatomic success and acceptable functional results.

Reticular dystrophy of the retinal pigment epithelium.

A laser flare-cell meter was used to examine blood-aqueous barrier function in a 57-year-old male patient who had typical reticular dystrophy of the retinal pigment epithelium with a bilateral hyperpigmented reticular pattern at the posterior pole in both eyes. Fluorescein angiography showed hypofluorescent reticular net resembling a fishing net with knots associated with a central diffuse hyperfluorescence. Dark adaptation test revealed that the final rod threshold was elevated. Laser photometry showed an increase in the aqueous flare intensity in both eyes, as compared to the results in normal subjects. Quantitative measurement of the aqueous flare intensity by a laser flare-cell meter might indicate abnormalities in the blood-aqueous barrier in patients with reticular dystrophy of the retinal pigment epithelium.

Retinal detachment in a patient with microphthalmos and choroidal coloboma.

We report a rare case of retinal detachment with microphthalmos and choroidal coloboma. A 28-year-old man who had suffered from poor vision since early childhood was examined because of progressive deterioration of vision in his right eye. Examination of the anterior segment showed microphthalmos with microcornea and coloboma of the iris. Fundus examination revealed an inferior choroidal coloboma extending to the optic disc. The patient also had total bullous retinal detachment. Pars plana vitrectomy with silicone oil tamponade was performed, and the retina was reattached. Although rare, retinal detachment may develop in patients with microphthalmos and choroidal coloboma. Pars plana vitrectomy with additional scleral encircling buckle may be performed to treat this condition.

Follicular thyroid carcinoma with NRAS Q61K and GNAS R201H mutations that had a good (131)I treatment response.

UNLABELLED: We report a case of follicular thyroid carcinoma with concomitant NRAS p.Q61K and GNAS p.R201H mutations, which manifested as a 13.5 cm thyroid mass with lung, humerus and T9 spine metastases, and exhibited good response to radioactive iodine treatment. LEARNING POINTS: GNAS p.R201H somatic mutation is an activating or gain-of-function mutation resulting in constitutively activated Gs-alpha protein and downstream cAMP cascade, independent of TSH signaling, causing autonomously functioning thyroid nodules. NRAS p.Q61K mutations with GNAS p.R201H mutations are known for a good radioactive iodine treatment response.Further exploration of the GNAS-activating pathway may provide therapeutic insights into the treatment of metastatic follicular carcinoma.

Unusual presentation of thyrotoxicosis as bradycardia, acute renal failure and hyperuricemia in an elderly patient.

Bradycardia with renal system involvement in patients with thyrotoxicosis has rarely been reported. We report a 72-year-old woman with unusual presentations of sinus bradycardia and normothermia accompanied by acute renal failure and hyperuricemia in thyrotoxicosis. The electrocardiogram changes in this patient included sinus bradycardia (50 beats per minute), followed by atrial fibrillation (84 beats per minute), and finally sinus rhythm with T wave inversion (80 beats per minute). Her renal function and hyperuricemia completely recovered after appropriate antithyroid therapy. A high index of suspicion is needed for early diagnosis and antithyroid treatment in patients with unusual manifestations of thyrotoxicosis in general clinical practice.

Post-traumatic anterior and posterior pituitary dysfunction.

BACKGROUND AND PURPOSE: The recognition of hypopituitarism after head trauma is important because related neurobehavioral problems can be alleviated by hormone replacement. This study investigated the clinical presentations and imaging findings of patients with hypopituitarism developing after head trauma. METHODS: We retrospectively reviewed the medical records of patients with hypopituitarism from 1982 through 2002. Data on disease history and hormone deficiencies of patients with hypopituitarism which developed after head trauma were analyzed. RESULTS: Eighteen patients with hypopituitarism or diabetes insipidus (DI) due to head trauma, including 11 men and 7 women, were identified. Head trauma thus accounted for the etiology in 2.8% of all 635 patients with a diagnosis of hypopituitarism during the study period. The major cause of head trauma was road accident (n = 11, 61%). Ten of the patients (56%) had lost consciousness after the head injury. The duration from head trauma to the onset of symptoms of hypopituitarism ranged from < 1 month to 15 years. Sex hormone (61%) and growth hormone (56%) were the most common hormone deficiencies, followed by corticotropin deficiency (39%) and thyrotropin deficiency (22.2%). DI developed in 9 patients (50%) and 5 of these patients had only DI without anterior hypopituitarism. Routine skull radiograph did not show abnormal signs. Among the 10 patients with magnetic resonance imaging of the pituitary gland, a small or atrophic anterior lobe was seen in patients with anterior hypopituitarism. Loss of bright signal intensity from the pituitary posterior lobe on T1-weighted magnetic resonance imaging was seen in all 3 patients with DI. An ectopic posterior lobe could be seen in 2 patients with hypopituitarism without DI. CONCLUSIONS: Identification of head trauma as the etiology of hypopituitarism may be overlooked if there is a long delay in onset after trauma. DI is a common early complication. Since anterior hypopituitarism can develop decades after the episode of head trauma, monitoring for endocrine dysfunction during follow-up of these patients is important.

Blood-aqueous barrier function in a patient with combined hamartomas of the retina and retinal pigment epithelium.

Clinical data showing breakdown in the blood-aqueous barrier in patients with combined hamartomas of the retina and retinal pigment epithelium are very limited. We used a laser flare-cell meter to examine blood-aqueous barrier function in a 35-year-old male patient who had typical combined hamartomas of the retina and retinal pigment epithelium characterized by an ill-defined, slightly elevated, grey-white epipapillary lesion with overlying glial proliferation and surrounding vascular tortuosity. Fluorescein angiography showed early hypofluorescence corresponding to the pigmented area with speckled hyperfluorescence in the lesion. Prominent retinal vascular tortuosity and late dye leakage were noted in the late phase. Visual evoked potential demonstrated poor waveform. Laser photometry showed an increase in the aqueous flare intensity in the affected eye, as compared to the results in the unaffected eye and to data from normal subjects. The increase in the aqueous flare intensity in this patient suggests that the function of the blood-aqueous barrier may be affected in combined hamartomas of the retina and retinal pigment epithelium.

Sex-related differences between adiponectin and insulin resistance in schoolchildren.

OBJECTIVE: To study the effect of body composition and adiponectin on insulin resistance and beta-cell function in schoolchildren during puberty. RESEARCH DESIGN AND METHODS: Plasma adiponectin level and its relationships with insulin sensitivity and beta-cell function were analyzed in 500 randomly recruited nondiabetic Taiwanese schoolchildren (245 boys and 255 girls) aged 6-18 years in a national survey program for diabetes in 1999. Insulin resistance and beta-cell function were evaluated by homeostasis model assessment (HOMA). Plasma adiponectin concentrations were determined with radioimmunoassay. RESULTS: Plasma glucose levels remained stable, whereas insulin resistance increased with a compensatory rise in beta-cell function during this period. A transient drop of adiponectin level with a trough at 10-12 years was found in boys but not in girls. This pubertal drop of adiponectin levels in boys coincides with the sharp rise in testosterone concentration. A negative correlation between testosterone levels and adiponectin concentration was also noted in boys (r = -0.142, P = 0.032). Plasma adiponectin levels correlated inversely with relative body weight, fasting insulin concentrations, and insulin resistance index by HOMA in boys aged 15-18 years and in girls aged 11-14 years. No association was observed between adiponectin levels and beta-cell function by HOMA. CONCLUSIONS: There is a transient drop in the level of adiponectin during male puberty, correlated with the increase in testosterone level in boys. Plasma adiponectin levels were inversely correlated with obesity and insulin resistance in boys and girls during the pubertal period.

Genetic determinants of antithyroid drug-induced agranulocytosis by human leukocyte antigen genotyping and genome-wide association study.

Graves' disease is the leading cause of hyperthyroidism affecting 1.0-1.6% of the population. Antithyroid drugs are the treatment cornerstone, but may cause life-threatening agranulocytosis. Here we conduct a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves' disease controls), using direct human leukocyte antigen genotyping and SNP-based genome-wide association study. We demonstrate HLA-B*38:02 (Armitage trend Pcombined=6.75 × 10(-32)) and HLA-DRB1*08:03 (Pcombined=1.83 × 10(-9)) as independent susceptibility loci. The genome-wide association study identifies the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval=11.13-41.48) and 6.13 (95% confidence interval=3.28-11.46), respectively. Carrying both HLA-B*38:02 and HLA-DRB1*08:03 increases odds ratio to 48.41 (Pcombined=3.32 × 10(-21), 95% confidence interval=21.66-108.22). Our results could be useful for antithyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals.

Primary adrenal insufficiency in patients with acquired immunodeficiency syndrome: report of four cases.

Adrenal insufficiency, though rare, is a well-known complication of acquired immunodeficiency syndrome (AIDS). Over the past 9 years at the National Taiwan University Hospital, 4 patients were diagnosed with primary adrenal insufficiency among 854 non-hemophiliac patients with human immunodeficiency virus infection, with an incidence of 0.19 per 100 patient-years (95% confidence interval, 0.17-0.21 per 100 patient-years). All of the 4 patients were severely immunosuppressed and had been diagnosed with at least 1 AIDS-defining opportunistic illness ever reported to produce adrenal insufficiency in AIDS patients. In 1 of the patients, fluconazole was considered contributory to the development of adrenal insufficiency after treatment at a daily dose of 800 mg for 68 days.

Adrenal lymphoma and Addison's disease: report of a case.

Addison's disease due to adrenal lymphoma usually manifests as bilateral adrenal enlargement. We report a patient with Addsion's disease in whom the initial overt primary adrenal insufficiency was accompanied by an only slightly enlarged right adrenal gland. The 80-year-old man presented with nausea, anorexia, weight loss, and hyperpigmentation of the skin and buccal mucosa. Addison's disease was diagnosed based on this clinical presentation and laboratory findings of low cortisol and high adrenocorticotropin levels. Computerized tomography (CT) of the adrenal glands revealed a small right adrenal tumor. His family refused to allow percutaneous or surgical biopsy to determine the nature of the tumor. His general condition improved after steroid supplementation. However, about 1 year later, dizziness, fever, night sweats, and edema of the lower legs developed, and adrenal CT scanning revealed that the left adrenal gland had enlarged and now exceeded the size of the right one. Left adrenalectomy was performed and pathology showed a diffuse large B-cell lymphoma. Staging work-up using whole-body CT scanning suggested a stage IIIb lymphoma. Chemotherapy was given, but the disease still progressed and the patient died 4 months after diagnosis. Primary adrenal lymphoma should be considered in the differential diagnosis of Addison's disease, even if only slight enlargement of the adrenal glands is found initially.

Application of a laser flare-cell meter to examine blood-aqueous barrier function in a patient with retinitis punctata albescens.

A laser flare-cell meter was used to examine blood-aqueous barrier function in a 21-year-old male patient who had typical retinitis punctata albescens with white dots scattered throughout large areas of the fundus in both eyes. Fluorescein angiography showed multiple areas of hyperfluorescence over dot lesions and window defects. Electroretinogram demonstrated subnormal amplitude and electrooculogram showed a reduced light-peak/dark-trough ratio. Goldmann perimetry revealed constricted peripheral fields. Laser photometry showed an increased aqueous flare intensity in both eyes compared to results in 10 normal subjects. Quantitative measurement of the aqueous flare intensity by a laser flare-cell meter might indicate abnormalities in the blood-aqueous barrier in patients with retinitis punctata albescens.

Factors affecting long-term survival of Taiwanese patients with medullary thyroid carcinoma.

BACKGROUND AND PURPOSE: Long-term survival of patients with postoperative recurrence of medullary thyroid carcinoma (MTC) is not uncommon. This study assessed whether local or distant recurrence after operation is a significant factor affecting long-term survival in Taiwanese patients with MTC. The benefit of family screening for MTC patients on survival was also evaluated. METHODS: A total of 54 patients with a diagnosis of MTC by pathology or cytology during the period from 1977 to 2000 were included in the study. Survival curves were compared between different groups according to age, gender, tumor size, metastasis, recurrence after surgical intervention, or diagnosis before and after the performance of family screening for MTC patients. RESULTS: The 5-year survival rate using the Kaplan-Meier method was 84.1% (95% confidence interval, 73.9% to 94.2%), and the 10-year survival rate was 77.6% (95% confidence interval, 64.9% to 90.3%). Patients with lymph node metastasis and distant metastasis before operation had significantly shorter survival. Surprisingly, recurrence was not associated with shorter survival. Patients diagnosed after the start of family screening in 1991 had fewer lymph node metastases before operation, and lived longer. CONCLUSIONS: Patients with lymph node or distant metastasis before operation had poor prognosis. However, local or distant recurrence after operation did not influence survival. Efforts to obtain early diagnosis and surgical intervention before tumor metastasis, such as family screening, resulted in improved survival.

Characteristics of Cushing's syndrome in Taiwanese.

BACKGROUND AND PURPOSE: Diagnosis and management of Cushing's syndrome is a challenge to the endocrinologist. This retrospective study investigated the etiology, clinical presentation, treatment and prognosis of endogenous Cushing's syndrome and compared the differences of prognostic factors between Cushing's disease patients with macroadenoma and microadenoma. METHODS: Data on disease history, physical examination, and biochemistry of Cushing's syndrome and factors related to the prognosis of Cushing's disease were analyzed. RESULTS: A total of 61 consecutive patients (52 women and 9 men) with endogenous Cushing's syndrome treated from January 1992 to July 2002 were included in this study. They comprised 31 cases of adrenal adenoma, 19 cases of Cushing's disease, 6 cases of ectopic adrenocorticotropin (ACTH) syndrome, 3 cases of adrenal carcinoma, 1 case of macronodular hyperplasia, and 1 case of micronodular hyperplasia. ACTH-independent Cushing's syndrome was the most frequent etiology in this series. The most common symptoms and signs were moon face (89%), weight gain (74%), buffalo hump (74%), and truncal obesity (72%). Hypercholesterolemia was noted in 27 of 45 patients (60.0%) checked for total serum cholesterol level. Elevation of serum lactate dehydrogenase was found in 29 (74.3%) of 39 patients assessed. Patients with adrenal adenoma had the highest cure rate. High residual (2/17, 11.8%) and recurrent rates (5/17, 29.4%) were found in patients with Cushing's disease. There were no significant differences in prognostic factors between Cushing's disease patients with macroadenoma and microadenoma. CONCLUSIONS: ACTH-independent Cushing's syndrome was the most frequent type of Cushing's syndrome in this series. The dyslipidemia and elevation of lactate dehydrogenase activity in this series indicated the need for routine laboratory testing in Cushing's syndrome patients. This study found no significant differences in prognostic factors between Cushing's disease patients with macroadenoma and microadenoma.

Role of vascular endothelial growth factor in the breakdown of the blood-aqueous barrier after retinal laser photocoagulation in pigmented rabbits.

PURPOSE: Retinal laser photocoagulation is used to treat a variety of retinal diseases. Breakdown of the blood-aqueous barrier has been noted after retinal laser photocoagulation. The effect of vascular endothelial growth factor (VEGF) on the function of the blood-aqueous barrier after retinal laser photocoagulation remains undetermined. The current study was designed to evaluate the relationship between intraocular levels of VEGF and breakdown of the blood-aqueous barrier after retinal laser photocoagulation in rabbits. METHODS: Pigmented rabbits were treated with retinal laser photocoagulation in one eye; the other served as control. Laser flare photometry was carried out on post-treatment days 1, 3, 7, and 14. Animals were sacrificed at the time period just mentioned postlaser, the eyes were removed, and samples of vitreous and aqueous humor were collected. Intraocular VEGF levels were measured by using an immunoassay. An intravitreal injection of VEGF was administered, and the aqueous flare intensity and VEGF levels in the aqueous and vitreous humor were measured at the time periods just mentioned. RESULTS: A significant increase in the aqueous flare intensity after retinal laser photocoagulation was noticed on postoperative day 1, with the values returning to baseline levels on day 14. The VEGF levels in the vitreous of the lasered eyes were significantly increased on day 1 compared with the nonlasered control eyes. The VEGF levels in the aqueous humor of the lasered eyes were also significantly increased on day 1 compared with the control eyes. An intravitreal injection of VEGF induced a significant increase in the aqueous flare intensity and VEGF levels in the aqueous and vitreous humor. CONCLUSIONS: The current results suggested that retinal laser photocoagulation can produce a breakdown of the blood-aqueous barrier. VEGF may play a role in the blood-aqueous barrier dysfunction after retinal laser photocoagulation.

Abnormal enlargement of pituitary gland during pregnancy remitted spontaneously after delivery.

Ovulation induction is seldom reported to cause pituitary abnormality and the physiological enlargement of the pituitary gland during pregnancy is asymptomatic. We report a woman who became pregnant after ovulation induction. She had symptomatic pituitary enlargement with a pituitary height of 2 cm on cranial magnetic resonance imaging (MRI) in the second trimester. Her symptoms (headache and blurred vision) improved greatly after delivery but she had absence of lactation. The height of the pituitary gland decreased to 1 cm on the second cranial MRI 40 days after delivery and her third cranial MRI only revealed a mild central bulge in the pituitary gland eight months after delivery. This article shows that the abnormal enlargement of the pituitary gland during pregnancy might remit spontaneously after delivery and these patients might have higher risk of postpartum hypopituitarism. Neurological symptoms and signs should be closely monitored during pregnancy and neurosurgery may not be necessary. Endocrine surveys should be performed regularly after delivery to detect hypopituitarism as early as possible.