Effects of poloxamer-based thermo-sensitive sol-gel agent on urethral stricture after transurethral resection of the prostate for benign prostatic hyperplasia: a multicentre, single-blinded, randomised controlled trial.

OBJECTIVE: To evaluate the effectiveness of poloxamer-based thermo-sensitive sol-gel instillation, after transurethral resection of the prostate (TURP), for preventing urethral stricture. PATIENTS AND METHODS: In all, 198 patients underwent TURP for benign prostatic hyperplasia. Recruited patients were randomly divided into two groups: groups A and B. Patients in Group A (100 patients, experimental group) received poloxamer-based thermo-sensitive sol-gel instillation and patients in the Group B (98 patients, control group) received lubricant instillation after TURP. Each patient was evaluated at 4 (V1), 12 (V2), and 24 weeks (V3) after TURP. The effectiveness of poloxamer-based thermo-sensitive sol-gel instillation was evaluated based on the International Prostate Symptom Score (IPSS), IPSS-Quality of Life (QoL), Overactive bladder questionnaire (OAB-q), maximum urinary flow rate (Qmax ), post-void residual urine volume (PVR), and cystoscopy. RESULTS: Amongst the initial 198 participants, 80 patients in Group A and 83 in Group B completed the study. There were no significant differences in IPSS-QoL and OAB-q between the groups. However, Qmax was significantly different between groups A and B, at a mean (SD) of 18.92 (9.98) vs 15.58 (9.24) mL/s (P = 0.028) at 24 weeks after TURP. On cystoscopic examination, urethral stricture after TURP was found in two of the 80 patients in Group A and 10 of 83 in Group B (P = 0.023). CONCLUSIONS: Poloxamer-based thermo-sensitive sol-gel instillation after TURP lowered the incidence of urethral stricture.

Extended Real-World Observation of Patients Treated with Sorafenib for Radioactive Iodine-Refractory Differentiated Thyroid Carcinoma and Impact of Lenvatinib Salvage Treatment: A Korean Multicenter Study.

Background: Treatment for patients with radioactive iodine (RAI)-refractory differentiated thyroid carcinoma (DTC) is challenging. Recently, two tyrosine kinase inhibitors (sorafenib and lenvatinib) have been approved and showed benefits for progression-free survival with tolerable adverse events. Methods: This is an extension study of a previous multicenter, retrospective cohort study of real-world experience in treating 98 patients with progressive RAI-refractory DTC with sorafenib. The primary endpoint was overall survival (OS). The efficacy of lenvatinib as salvage therapy after disease progression on first-line sorafenib was evaluated by comparing outcomes in 32 patients who were treated with lenvatinib with 41 patients who were not and therefore served as a no salvage treatment group. Results: The median OS of all 98 patients treated with sorafenib was 41.5 months, and the median progression-free survival was 13.5 months. Patients without disease-related symptoms before sorafenib treatment had better OS than those with symptoms (hazard ratio [HR] = 0.56 [95% confidence interval, CI 0.31-0.99], p = 0.048). Larger tumor size was associated with a minimally increased risk of death (HR = 1.02 [CI 1.00-1.03], p = 0.049). Best tumor response was not associated with OS (p = 0.490). Lenvatinib salvage treatment significantly improved OS in patients receiving it compared with those who did not (HR = 0.28 [CI 0.15-0.53], p < 0.001). The median OS from the time of disease progression after first-line sorafenib treatment was 4.9 months in no salvage treatment group, whereas it was not reached in the lenvatinib salvage group. Conclusions: The absence of disease-related symptoms and smaller tumor burden was associated with survival benefits of first-line sorafenib treatment in patients with progressive RAI-refractory DTC. Lenvatinib salvage therapy was effective in improving OS in patients with disease progression after first-line sorafenib.

Etiology-dependent impairment of relaxation kinetics in right ventricular end-stage failing human myocardium.

BACKGROUND: In patients with end-stage heart failure, the primary etiology often originates in the left ventricle, and eventually the contractile function of the right ventricle (RV) also becomes compromised. RV tissue-level deficits in contractile force and/or kinetics need quantification to understand involvement in ischemic and non-ischemic failing human myocardium. METHODS AND RESULTS: The human population suffering from heart failure is diverse, requiring many subjects to be studied in order to perform an adequately powered statistical analysis. From 2009-present we assessed live tissue-level contractile force and kinetics in isolated myocardial RV trabeculae from 44 non-failing and 41 failing human hearts. At 1 Hz stimulation rate (in vivo resting state) the developed active force was not different in non-failing compared to failing ischemic nor non-ischemic failing trabeculae. In sharp contrast, the kinetics of relaxation were significantly impacted by disease, with 50% relaxation time being significantly shorter in non-failing vs. non-ischemic failing, while the latter was still significantly shorter than ischemic failing. Gender did not significantly impact kinetics. Length-dependent activation was not impacted. Although baseline force was not impacted, contractile reserve was critically blunted. The force-frequency relation was positive in non-failing myocardium, but negative in both ischemic and non-ischemic myocardium, while the ß-adrenergic response to isoproterenol was depressed in both pathologies. CONCLUSIONS: Force development at resting heart rate is not impacted by cardiac pathology, but kinetics are impaired and the magnitude of the impairment depends on the underlying etiology. Focusing on restoration of myocardial kinetics will likely have greater therapeutic potential than targeting force of contraction.

Tertiary Care Experience of Sorafenib in the Treatment of Progressive Radioiodine-Refractory Differentiated Thyroid Carcinoma: A Korean Multicenter Study.

BACKGROUND: Sorafenib, a multi-kinase inhibitor, is approved for the treatment of patients with radioactive iodine (RAI)-refractory differentiated thyroid cancer (DTC). This study evaluated the efficacy and safety of sorafenib in real-world clinical practice and compared the results to those of the DECISION trial. The clinical features associated with better clinical outcomes after sorafenib treatment were also evaluated. METHODS: This multicenter, retrospective cohort study evaluated 98 patients with progressive RAI-refractory DTC who were treated with sorafenib in six tertiary hospitals in Korea. The primary objective was the progression-free survival (PFS) according to Response Evaluation Criteria In Solid Tumors v1.1. Overall survival, response rate (defined as the best objective response according to Response Evaluation Criteria In Solid Tumors v1.1), and safety were also evaluated. RESULTS: The median PFS was 9.7 months; median overall survival was not reached during follow-up. Partial responses and stable disease were achieved in 25 (25%) and 64 (65%) patients, respectively. Stable disease of >6 months was achieved in 41 (42%) patients. Subgroup analyses identified several prognostic indicators of a better PFS: absence of disease-related symptoms (hazard ratio [HR] = 0.5; p = 0.041), lung-only metastasis (HR = 0.4; p = 0.048), a daily maintenance dose ≥600 mg (HR = 0.3; p = 0.005), and a thyroglobulin reduction ≥60% (HR = 0.4; p = 0.012). The mean daily dose of sorafenib was 666 ± 114 mg, and drug withdrawals due to adverse events (AEs) occurred in 13% of patients. AEs and serious AEs were reported in 93 (95%) and 40 (41%) patients, respectively. The most frequent AE was hand-foot skin reaction (76%). CONCLUSIONS: The PFS of progressive RAI-refractory DTC patients treated with sorafenib was consistent with the findings of the DECISION trial. Disease-related symptoms, lung-only metastasis, a daily maintenance dose, and thyroglobulin reduction were significantly associated with PFS. These results suggest that sorafenib is an effective treatment option for patients with progressive RAI-refractory DTC.

Inhibitory Basal Ganglia Inputs Induce Excitatory Motor Signals in the Thalamus.

Basal ganglia (BG) circuits orchestrate complex motor behaviors predominantly via inhibitory synaptic outputs. Although these inhibitory BG outputs are known to reduce the excitability of postsynaptic target neurons, precisely how this change impairs motor performance remains poorly understood. Here, we show that optogenetic photostimulation of inhibitory BG inputs from the globus pallidus induces a surge of action potentials in the ventrolateral thalamic (VL) neurons and muscle contractions during the post-inhibitory period. Reduction of the neuronal population with this post-inhibitory rebound firing by knockout of T-type Ca2+ channels or photoinhibition abolishes multiple motor responses induced by the inhibitory BG input. In a low dopamine state, the number of VL neurons showing post-inhibitory firing increases, while reducing the number of active VL neurons via photoinhibition of BG input, effectively prevents Parkinson disease (PD)-like motor symptoms. Thus, BG inhibitory input generates excitatory motor signals in the thalamus and, in excess, promotes PD-like motor abnormalities. VIDEO ABSTRACT.

Patterns of Initial Recurrence in Completely Resected Papillary Thyroid Carcinoma.

BACKGROUND: Despite improvements in the surgical and medical treatment of papillary thyroid carcinoma (PTC), subsets of patients suffer from structural recurrence after initial treatment. This study evaluated the timing and patterns of recurrence in completely resected PTC patients. METHODS: A retrospective review of a prospectively maintained thyroid cancer database was performed. The timing and patterns of recurrence were reviewed in 2250 patients with PTC >1 cm who achieved complete remission after total thyroidectomy and/or radioactive iodine treatment. Univariate and multivariate analyses were performed to identify factors predictive of recurrence patterns. RESULTS: During 8.1 years of mean follow-up, 68 (3.0%) patients developed structural recurrences: 53 lymph node recurrences (LNR), 11 local soft tissue recurrences (LR), and four distant recurrences (DR). Two patients died of DR. Younger patients had a higher proportion of LNR, and older patients had a tendency toward LR/DR. LNR showed a peak incidence between one and three years after remission, but LR/DR showed a delayed peak incidence between two and four years. The factors that significantly increased the risk of LNR were multifocal tumor and lymph node metastasis (central/lateral). The factors that increased the risk of LR/DR were old age, large tumor size (>2 cm), and lateral lymph node metastasis. In addition, central neck dissection significantly reduced subsequent LR/DR. CONCLUSION: Patterns of recurrence after complete PTC resection are variable and associated with specific clinicopathologic factors. Understanding the timing and patterns of recurrence may lead to more effective adjuvant treatment and improved long-term follow-up strategies.

A Prospective Study of Serum Trace Elements in Healthy Korean Pregnant Women.

This prospective study sought to investigate serum levels of trace elements (cobalt, copper, zinc, and selenium) and to assess their effects on pregnancy and neonatal outcomes. Serum levels of trace elements in 245 Korean pregnant women (median gestational age at delivery was 39 + 4 weeks and interquartile range was 38 + 4-40 + 1 weeks) were compared with those of 527 general adults and those of previous studies in other ethnic groups. Pregnancy and neonatal outcomes including gestational diabetes, preeclampsia, neonatal birth weight, and congenital abnormalities were assessed. The median serum trace element concentrations of all pregnant women were: cobalt: 0.39 µg/L (interquartile range, IQR 0.29-0.53), copper: 165.0 µg/dL (IQR 144.0-187.0), zinc: 57.0 µg/dL (IQR 50.0-64.0), and selenium: 94.0 µg/L (IQR 87.0-101.0). Serum cobalt and copper concentrations were higher in pregnant women than in the general population, whereas zinc and selenium levels were lower (p < 0.01). Concentrations of all four trace elements varied significantly during the three trimesters (p < 0.05), and seasonal variation was found in copper, zinc, and selenium, but was not observed for cobalt. The prevalence of preeclampsia was significantly lower with high copper (p = 0.03). Trace element levels varied by pregnancy trimester and season, and alteration in copper status during pregnancy might influence pregnancy outcomes such as preeclampsia.

Efficacy of Low-dose and High-dose Radioactive Iodine Ablation With rhTSH in Korean Patients With Differentiated Thyroid Carcinoma: The First Report in Nonwestern Countries.

OBJECTIVE: The aim of this study was to confirm the equivalent efficacy of recombinant human TSH (rhTSH) and thyroid hormone withdrawal (THW) as used in the preparation for low-dose and high-dose radioactive iodine (RAI) ablation in Korean patients with differentiated thyroid carcinoma. SUBJECTS AND METHODS: This retrospective study was designed to compare the efficacy of rhTSH and THW when used before ablation with low-dose (30 mCi) and high-dose (100 mCi) RAI, respectively. The study group included 570 patients with DTC with tumors staged T1 to T3, N0 to N1, and M0. Before RAI ablation, 190 patients used rhTSH and 380 patients matched by age, sex, T-stage, and N-stage used THW. The success of ablation was evaluated in each group based on 4 criteria: (1) stimulated thyroglobulin (sTg) <2 ng/mL, (2) sTg<2 ng/mL and negative diagnostic whole-body scan (DxWBS), (3) sTg<1 ng/mL, and (4) sTg<1 ng/mL and negative DxWBS. RESULTS: When both sTg<2 ng/mL and negative DxWBS were selected as criteria for success in patients treated with low-dose RAI, the success rates were 80.5% and 77.0% with rhTSH and THW, respectively (95% confidence interval, 5.9-12.8). Using both sTg<1 ng/mL and negative DxWBS as criteria, success rates were 78.2% and 71.8% with rhTSH and THW, respectively (95% confidence interval, 3.6-16.2). Using any criteria for success, low-dose RAI ablation with rhTSH was as effective as THW. Similar results were found for high-dose RAI ablation in patients using either rhTSH or THW. CONCLUSIONS: Low-dose and high-dose RAI ablation were equally effective using either rhTSH or THW before ablation in Korean patients with DTC, respectively.

Increased Risk of Leukemia After Radioactive Iodine Therapy in Patients with Thyroid Cancer: A Nationwide, Population-Based Study in Korea.

BACKGROUND: The use of radioactive iodine therapy (RAIT) is increasing in thyroid cancer management. The association between RAIT at high doses and leukemia is well known, but studies of this association in a large population are lacking. This study aims to investigate the association between RAIT and leukemia in the context of current practice. METHODS: Retrospective analysis of a 542,845 person-year (PY) follow-up of thyroid cancer patients was conducted using the Korean National Health Insurance claims database between January 2008 and December 2013. Patients were categorized according to RAIT dose (no RAI; low dose, ≤30 mCi; moderate dose, 31-100 mCi; high dose, 101-150 mCi; and very high dose, >150 mCi). RESULTS: Among 211,360 thyroid cancer patients, 72 (0.03%) patients developed leukemia during follow-up (median 877 days). The cumulative incidence of leukemia per 10(5) person-year (PY) was 9.8 in the no RAI [95% confidence interval (CI) 6.4-14.4]; 6.1 [CI 1.7-15.7] in the low-dose; 8.6 [CI 3.2-18.7] in the moderate-dose; 29.5 [CI 18.3-45.1] in the high-dose; and 20.9 [CI 11.7-34.4] in the very high-dose groups. The hazard ratios were elevated significantly in the high- and very high-dose groups (HR 3.1 and 2.1, respectively, p<0.001) when compared with the no RAI group. CONCLUSIONS: RAIT exceeding 100 mCi was strongly associated with the development of leukemia in a nationwide, population-based study, while lower RAIT doses were not. Considering the favorable survival of patients with thyroid cancer and the potential harm of RAIT, physicians need to consider the pros and cons of RAIT when using this treatment option.

The impact of iodinated contrast agent administered during preoperative computed tomography scan on body iodine pool in patients with differentiated thyroid cancer preparing for radioactive iodine treatment.

BACKGROUND: Iodine in iodinated contrast agents (ICAs) interferes with radioactive iodine treatment (RAIT) and diagnostic scans in patients with differentiated thyroid carcinoma (DTC) because it can compete with ¹³¹I. Published guidelines recommend delaying RAIT for three to four months in patients who have been exposed to ICA. Spot urinary iodine concentration is a useful marker to reflect the body iodine pool. We investigated the impact of ICAs administered at preoperative computed tomography (CT) scan on the body iodine pool to determine the proper time interval between preoperative CT and RAIT in DTC patients. METHODS: We performed a retrospective review of 1023 patients with DTC who underwent a preoperative CT scan with ICA, total thyroidectomy, and one week of low-iodine diet in preparation for RAIT. Urine iodine excretion (UIE) was measured in spot urine by inductively coupled plasma mass spectrometry and reported both in simple concentration (µg/L) and divided by gram creatinine (µg/gCr). Patients were divided into five groups by time interval in days between preoperative CT scan and spot urine iodine measurement (A, 31-60 [n=29]; B, 61-90 [n=155]; C, 91-120 [n=546]; D, 121-150 [n=226]; E, 151-180 [n=67]). RESULTS: The median (interquartile range) of UIE (µg/gCr) in each group was 44.4 (27.7-73.2) in group A, 33.3 (22.8-64.7) in group B, 32.7 (20.8-63.0) in group C, 32.0 (20.6-67.0) in group D, and 30.4 (19.6-70.8) in group E. There was no significant difference between group A and the remaining groups (p>0.05) Also, the proportion of patients who achieved the appropriate UIE for RAIT according to our hospital's cutoff (≤66.2 µg/gCr) was not different between groups (A, 72.4%; B, 76.1%; C, 77.5%; D, 74.8%; E, 74.6%) (p=0.78). CONCLUSION: This study shows that a UIE of one month after preoperative CT scan with ICA was not higher than that of six months after CT scan in patients who underwent total thyroidectomy for DTC. Thus, current guidelines that recommend delay of RAIT for three to four months after CT scan with ICA should be revisited and future studies to clarify the appropriate time interval between CT scan with ICA and RAIT are warranted.

Effects of hyaluronic acid and carboxymethylcellulose on urethral stricture after transurethral resections of the prostate for benign prostatic hyperplasia: a multicenter, single blinded, randomized controlled study.

PURPOSE: To evaluate the effect of hyaluronic acid (HA) and carboxymethylcellulose (CMC) instillation after transurethral resection of the prostate (TURP) on preventing urethral stricture. PATIENTS AND METHODS: A total of 180 patients underwent TURP for benign prostatic hyperplasia. Recruited patients were randomly divided into two groups: Groups A and B. Patients in group A (90 patients, experimental group) received HA/CMC instillation, and patients in the group B (90 patients, control group) received lubricant instillation after TURP. Each patient was evaluated at 4 weeks (V1), 12 weeks (V2), and 24 weeks (V3) after the surgery. The effectiveness of HA/CMC instillation was evaluated based on the International Prostate Symptom Score/Quality of Life, peak urine flow rate, voided volume, and postvoid residual volume. The visual analogue scale (VAS) pain score and degree of satisfaction were also determined for each participant. RESULTS: Among 180 initial participants, 80 patients in group A and 81 patients in group B had completed the experiment. VAS pain scores were 0.75±0.75 and 1.75±1.37 (P<0.001), and degrees of satisfaction were 0.63±0.66 and 0.91±0.51 in group A and group B at 1 month after surgery (P=0.002). By retrograde urethrography, urethral stricture after TURP was seen in 1 of 80 subjects in group A and 7 of 81 subjects in group B. CONCLUSIONS: HA/CMC instillation after TURP decreased the incidence of urethral stricture. In addition, HA/CMC was effective at reducing pain during the early postoperative period, with no adverse effects.

Association between excessive urinary iodine excretion and failure of radioactive iodine thyroid ablation in patients with papillary thyroid cancer.

BACKGROUND: A low-iodine diet (LID) is usually recommended for a week or two before radioactive iodine (RAI) ablation therapy in papillary thyroid cancer (PTC) patients after total thyroidectomy. However, it is still controversial whether an LID affects ablation outcomes. We therefore evaluated the association between urinary iodine excretion and the rate of successful ablation and investigated the determinants of successful RAI ablation outcomes. METHODS: We retrospectively reviewed the records of 295 consecutive patients with PTC who received 1110 MBq RAI remnant ablation therapy with thyroid hormone withdrawal after total thyroidectomy. Successful ablation was defined as either no visible or faint uptake on a follow-up scan (definition 1), or no visible or faint uptake on a follow-up scan and a stimulated thyroglobulin level <2 ng/mL (definition 2). RESULTS: The proportion of patients with appropriate LID status (defined as a urinary iodine concentration [UIC] <66.2 µg iodine/g creatinine [µg/gCr]) was significantly higher in the successfully ablated group (81% vs. 67%, p=0.03). Based on definition 1, 80.3% (237/295) of patients were successfully ablated. The ablation rate was significantly lower in patients who had a UIC >250 µg/gCr at the time of RAI ablation (p<0.05). In multivariate analysis, a UIC >250 µg/gCr was the only significant variable associated with ablation failure (p=0.002, odds ratio [OR] 4.74 [95% confidence interval (CI) 1.78-12.63]). Based on definition 2, 74.9% (221/295) of patients were successfully ablated. A UIC >250 µg/gCr at RAI administration showed a significant association with ablation failure (p<0.05). The OR of a UIC >250 µg/gCr for ablation failure was 3.88 [CI 1.42-10.57] (p=0.008). CONCLUSION: Excessive iodine intake (UIC >250 µg/gCr) was associated with poor RAI ablation outcomes. Because this amount of iodine is very high, we propose that the level of strictness of the LID protocol should be modified according to the region that the patient is from and the food that the patient is accustomed to eating. Even in those areas where iodine intake is high, overly strict compliance with an LID protocol is not necessary and simple recommendations to avoid iodine-rich foods would be appropriate.

Evolutionary Conserved Motif Finder (ECMFinder) for genome-wide identification of clustered YY1- and CTCF-binding sites.

We have developed a new bioinformatics approach called ECMFinder (Evolutionary Conserved Motif Finder). This program searches for a given DNA motif within the entire genome of one species and uses the gene association information of a potential transcription factor-binding site (TFBS) to screen the homologous regions of a second and third species. If multiple species have this potential TFBS in homologous positions, this program recognizes the identified TFBS as an evolutionary conserved motif (ECM). This program outputs a list of ECMs, which can be uploaded as a Custom Track in the UCSC genome browser and can be visualized along with other available data. The feasibility of this approach was tested by searching the genomes of three mammals (human, mouse and cow) with the DNA-binding motifs of YY1 and CTCF. This program successfully identified many clustered YY1- and CTCF-binding sites that are conserved among these species but were previously undetected. In particular, this program identified CTCF-binding sites that are located close to the Dlk1, Magel2 and Cdkn1c imprinted genes. Individual ChIP experiments confirmed the in vivo binding of the YY1 and CTCF proteins to most of these newly discovered binding sites, demonstrating the feasibility and usefulness of ECMFinder.

Acupuncture decreases ischemia-induced apoptosis and cell proliferation in dentate gyrus of gerbils.

BACKGROUND: Acupuncture has been used for the enhancement of functional recovery from various disorders. In the present study, the effect of acupuncture on the apoptosis and new cell proliferation in the hippocampal dentate gyrus of gerbils (n = 25) following transient global ischemia was investigated. METHODS: To determine the level of apoptosis and cell proliferation, terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) assay and immunohistochemistry for 5-bromo-2'-deoxyuridine (BrdU) were employed respectively. RESULTS: In the dentate gyrus of ischemic gerbils, the number of both TUNEL- and BrdU-positive cells (66.01 +/- 2.45/mm(2) and 514.38 +/- 44.90/mm(2)) was significantly increased compared to that of the sham-operated gerbils (11.25 +/- 1.85/mm(2) and 111.47 +/- 10.95/mm(2)). Among the acupuncture (ST36, LI4 or non-acupoint) treated groups, ST36 acupoint treated group showed the most potent apoptosis (20.52 +/- 2.40/mm(2)) and proliferation (159.38 +/- 24.05/mm(2)) suppressive effects ( approximately 70% decreases in both apoptosis and cell proliferation). CONCLUSION: These results may suggest that acupuncture treatment alleviates ischemia-induced apoptosis and presents possible therapeutic potentials in the recovery from ischemic cerebral injury.

Clinical features and prognostic factors for survival in patients with poorly differentiated thyroid carcinoma and comparison to the patients with the aggressive variants of papillary thyroid carcinoma.

We performed this study to compare the clinicopathologic features and outcomes between the patients with poorly differentiated thyroid carcinoma (PDTC) and the patients with the aggressive variants of papillary thyroid carcinoma (PTC). To evaluate the prognostic factors for survival of the patients with PDTC, we selected 49 patients with PDTC and 23 patients with the aggressive variants of PTC from three hospitals during the recent 15 years. The five-year survival rate and clinicopathologic features of the patients with PDTC were not different from those of the patients with the aggressive variants of PTC. Univariate analysis revealed the significant poor prognostic factors for survival of the patients with PDTC and the aggressive variants of PTC as follows: 1) an age more than 45 years, 2) a tumor size larger than 4 cm, 3) the presence of tumor invasion to extrathyroidal tissue or the trachea, 4) the presence of cervical lymph node invasion, 5) the presence of distant metastasis, 6) the absence of high-dose radioactive iodine (RAI) therapy, and 7) TNM stage II, III and IV. Distant metastasis and high-dose RAI therapy were independent significant predictors for survival of the patients with PDTC and the aggressive variants of PTC on multivariate analysis. However, distant metastasis was the only independent significant predictors for survival of the patients with PDTC excluding patients with the aggressive variants of PTC.

A patient with primary squamous cell carcinoma of the thyroid intermingled with follicular thyroid carcinoma that remains alive more than 8 years after diagnosis.

Primary squamous cell carcinoma of the thyroid is an extremely rare tumor with a highly aggressive clinical course. We report here on a patient with primary squamous cell carcinoma of the thyroid who remains alive more than 8 years after diagnosis. A 56-year-old man presented with a hoarse voice and a rapidly progressing mass on the right side of the thyroid gland. The patient underwent a total thyroidectomy without neck lymph node dissection. Histopathologic findings revealed primary squamous cell carcinoma combined with follicular carcinoma of the thyroid. The tumors metastasized to the cervical lymph nodes, thoracic spine and lung. He underwent 5000 rads of adjuvant radiotherapy to the neck. TSH suppressive therapy with L-thyroxine was administered alone rather than radioactive iodine therapy or chemotherapy. The patient's clinical course has been remarkable over the first 7 years; he has remained stable except for a transient paraplegia due to nerve compression. The patient underwent colectomy for the diagnosis of a colon cancer. Recent evaluation has revealed a new lesion in the lung; this was diagnosed as metastatic follicular carcinoma originating from the thyroid. High dose radioactive iodine therapy was administered, and he remains alive in stable condition.

A murine model for human sepiapterin-reductase deficiency.

Tetrahydrobiopterin (BH(4)) is an essential cofactor for several enzymes, including all three forms of nitric oxide synthases, the three aromatic hydroxylases, and glyceryl-ether mono-oxygenase. A proper level of BH(4) is, therefore, necessary for the metabolism of phenylalanine and the production of nitric oxide, catecholamines, and serotonin. BH(4) deficiency has been shown to be closely associated with diverse neurological psychiatric disorders. Sepiapterin reductase (SPR) is an enzyme that catalyzes the final step of BH(4) biosynthesis. Whereas the number of cases of neuropsychological disorders resulting from deficiencies of other catalytic enzymes involved in BH(4) biosynthesis and metabolism has been increasing, only a handful of cases of SPR deficiency have been reported, and the role of SPR in BH(4) biosynthesis in vivo has been poorly understood. Here, we report that mice deficient in the Spr gene (Spr(-/-)) display disturbed pterin profiles and greatly diminished levels of dopamine, norepinephrine, and serotonin, indicating that SPR is essential for homeostasis of BH(4) and for the normal functions of BH(4)-dependent enzymes. The Spr(-/-) mice exhibit phenylketonuria, dwarfism, and impaired body movement. Oral supplementation of BH(4) and neurotransmitter precursors completely rescued dwarfism and phenylalanine metabolism. The biochemical and behavioral characteristics of Spr(-/-) mice share striking similarities with the symptoms observed in SPR-deficient patients. This Spr mutant strain of mice will be an invaluable resource to elucidate many important issues regarding SPR and BH(4) deficiencies.