Thomas E. Hamilton

Thyrotropin Levels in a Population with No Clinical, Autoantibody, or Ultrasonographic Evidence of Thyroid Disease: Implications for the Diagnosis of Subclinical Hypothyroidism

CONTEXT The current debate regarding whether to decrease the upper limit for the TSH reference range to 2.5 microIU/ml has considerable potential impact on the diagnosis and treatment of subclinical hypothyroidism worldwide. OBJECTIVE We report an analysis of TSH distribution in a population with no evidence of thyroid disease, including a normal thyroid ultrasound. DESIGN A subset of the Hanford Thyroid Disease Study cohort was used to examine the TSH distribution in a population having no evidence of thyroid disease, seronegative thyroid autoantibodies, no history of thyroid medications, and a normal thyroid ultrasound. The shape of the TSH distribution was compared with the Gaussian and lognormal distributions. SETTING This study was performed in the general community. PARTICIPANTS Of 1861 Hanford Thyroid Disease Study participants with TSH measured by ELISA who also had thyroid peroxidase antibody measurements, 766 comprised the normal reference group 3 (NRG-3) with no evidence of thyroid disease, including no positive antibodies and normal thyroid ultrasound. MAIN OUTCOME MEASURE TSH was measured. RESULTS The TSH distribution in the NRG (NRG-3) was right skewed and followed an approximate lognormal distribution. The best estimates of the 97.5th percentile, the percentage above 2.5 microIU/ml, and the percentage above 3.0 microIU/ml for TSH by 3rd generation immunochemiluminometric assay are 4.1 microIU/ml, 20% and 10.2%, respectively. CONCLUSION These results indicate that the TSH reference range should be narrowed and support a value of approximately 4.0 as the upper-reference limit.

The management of synchronous bilateral Wilms tumor: a report from the National Wilms Tumor Study Group.

Objective: To provide guidelines for future trials, we reviewed the outcomes of children with synchronous bilateral Wilms tumors (BWT) treated on National Wilms Tumor Study-4 (NWTS-4). Methods: NWTS-4 enrolled 3335 patients including 188 patients with BWT (5.6%). Treatment and outcome data were collected. Results: Among 188 BWT patients registered with NWTS-4, 195 kidneys in 123 patients had initial open biopsy, 44 kidneys in 31 patients had needle biopsies. Although pre-resection chemotherapy was recommended, 87 kidneys in 83 patients were managed with primary resection: Complete nephrectomy 48 in 48 patients, 31 partial/wedge nephrectomies in 27 patients, enucleations 8 in 8 patients. No initial surgery was performed in 45 kidneys in 43 patients, 5 kidneys in 3 patients not coded. Anaplasia was diagnosed after completion of the initial course of chemotherapy in 14 patients (initial surgical procedure: 9 open biopsies, 4 needle biopsies, 1 partial nephrectomy). The average number of days from the start of chemotherapy to diagnosis of anaplasia was 390 (range 44–1925 days). Relapse or progression of disease occurred in 54 children. End stage renal failure occurred in 23 children, 6 of whom had bilateral nephrectomies. The 8 year event free survival for BWT with favorable histology was 74%, and overall survival was 89%; whereas the event free survival for BWT with unfavorable histology was 40%, overall survival was 45%. Conclusion: The current analysis of patients with BWT treated on NWTS-4 shows that preservation of renal parenchyma is possible in many patients after initial preoperative chemotherapy. The incidence of end-stage renal disease remains significantly higher in children with BWT. Future studies are warranted to address the need for earlier biopsy in nonresponsive tumors and earlier definitive surgery to recognize unfavorable histology in these high-risk patients.

Congenital jejunal and ileal atresia: natural prenatal sonographic history and association with neonatal outcome.

Objective. The purpose of this study was to describe the prenatal sonographic features and natural course of congenital jejunal and ileal atresia and correlate the findings with neonatal outcomes. Methods. We identified all neonates with surgically confirmed jejunal or ileal atresia that had prenatal sonography and neonatal surgery in our center from January 1, 1995, to April 1, 2005. Sonography reports and images were reviewed, without knowledge of neonatal outcomes, for features of intestinal obstruction. Obstetric and neonatal outcomes were evaluated. Results. Fifteen (60%) of 25 offspring with atresias (10 jejunal, 4 ileal, and 1 jejunoileal) had sonography, of which 13 (86.6%) had features of atresia. Findings, number of affected fetuses, and gestational age at recognition included fetal echogenic bowel (n = 8), mean ± SD, 21.3 ± 3.8 weeks (range, 17.7–28.4 weeks); enlarged stomach (n = 5), 27.5 ± 5.0 weeks (range, 22.0–34.3 weeks); dilated bowel (n = 13), 27.8 ± 5.8 weeks (range, 18.3–35.9 weeks); and polyhydramnios (n = 6), 33.3 ± 1.7 weeks (range, 31.0–35.6 weeks). No fetus with ileal atresia had an enlarged stomach or polyhydramnios. Delivery occurred at a mean of 34.7 ± 3.6 weeks, with 9 (60%) cesarean deliveries. Neonatal outcomes of age at surgery, neonatal intensive care unit days, hospital days, total parenteral nutrition days, and death were similar whether or not fetal echogenic bowel, enlarged stomach, dilated bowel, or polyhydramnios was present. Likewise, these outcomes did not vary by type of atresia or time of diagnosis (prenatal or neonatal). Conclusions. Jejunal and ileal atresia have specific sonographic patterns allowing specific prenatal diagnoses in most affected fetuses. Prenatal sonographic findings and time of diagnosis did not affect neonatal outcome.

Estimation of thyroid radiation doses for the hanford thyroid disease study: results and implications for statistical power of the epidemiological analyses.

Residents of eastern Washington, northeastern Oregon, and western Idaho were exposed to 131I released into the atmosphere from operations at the Hanford Nuclear Site from 1944 through 1972, especially in the late 1940’s and early 1950’s. This paper describes the estimated doses to the thyroid glands of the 3,440 evaluable participants in the Hanford Thyroid Disease Study, which investigated whether thyroid morbidity was increased in people exposed to radioactive iodine from Hanford during 1944–1957. The participants were born during 1940–1946 to mothers living in Benton, Franklin, Walla Walla, Adams, Okanogan, Ferry, or Stevens Counties in Washington State. Whenever possible someone with direct knowledge of the participant’s early life (preferably the participant’s mother) was interviewed about the participant’s individual dose-determining characteristics (residence history, sources and quantities of food, milk, and milk products consumed, production and processing techniques for home-grown food and milk products). Default information was used if no interview respondent was available. Thyroid doses were estimated using the computer program Calculation of Individual Doses from Environmental Radionuclides (CIDER) developed by the Hanford Environmental Dose Reconstruction Project. CIDER provided 100 sets of doses to represent uncertainty of the estimates. These sets were not generated independently for each participant, but reflected the effects of uncertainties in characteristics shared by participants. Estimated doses (medians of each participant’s 100 realizations) ranged from 0.0029 mGy to 2823 mGy, with mean and median of 174 and 97 mGy, respectively. The distribution of estimated doses provided the Hanford Thyroid Disease Study with sufficient statistical power to test for dose-response relationships between thyroid outcomes and exposure to Hanford’s 131I.

Improving organ transplantation in the United States--a regulatory perspective.

During the next 3 years, survey teams under Centers for Medicare and Medicaid Services (CMS) guidance will visit each hospital transplant center in the United States for an on-site review to assess the extent to which the transplant center fulfills key expectations set forth in regulation. The regulation itself was recently promulgated through a 3year public process. As the surveys are underway now, it is appropriate to step back and seek perspective on both the challenges and opportunities inherent in these developments.

Effect of adenoviral early genes and the host immune system on in vivo pancreatic gene transfer in the mouse.

Gene transfer technology may provide a novel approach to treatment for pancreatic diseases. Recombinant adenovirus achieves efficient gene transfer in vivo. In this study, a murine model of adenoviral-mediated pancreatic gene transfer was developed, and the factors responsible for adenoviral elimination were investigated. Three days after direct pancreatic injection of a replication-defective adenovirus containing the lacZ transgene, a high proportion (76.8 ± 6.7%) of pancreatic cells expressed β-galactosidase, the gene product. Gene expression was absent by 28 days posttransduction. In immunodeficient mice, β-galactosidase expression persisted with 20.0 ± 6.0% of pancreatic cells staining positive 60 days after viral transduction. To test whether early viral proteins are the antigenic components responsible for the potent antiviral immune response, normal mice were injected with different adenoviral vectors containing early gene deletions. Vectors containing deletions in early region 2 or 4 expressed β-galactosidase at 28 days. Presently available adenoviral vectors engineered to avoid this response offer minimal improvements in transgene duration. Further vector modifications or alternative strategies are needed to achieve stable pancreatic adenoviral transgene expression.

Surgical approaches to aortopexy for severe tracheomalacia

PURPOSE The purpose of this study was to determine the outcomes among three different surgical approaches for performing an aortopexy to treat severe tracheomalacia (STM). METHODS A retrospective review was performed for all patients who underwent an aortopexy by pediatric surgeons at a single institution during 1997-2012. Data collected included details of the operative approaches and clinical results. The data were analyzed using Chi-square and Fisher exact test. RESULTS Forty-one patients underwent an aortopexy. The operation was chosen by the surgeon and not randomized. Exposure was by partial sternotomy (PS) (20), open thoracotomy (12), or thoracoscopic approach (7). Only the PS approach was done by a single team. All groups showed improvement in work of breathing, prevention of severe respiratory distress, and acute life threatening events. These effects were more dramatic for the PS group, especially regarding oxygen and/or ventilator dependence and the ability to undergo tracheostomy decannulation. Among the sixteen patients with failure-to-thrive before successful aortopexy by any technique, ten demonstrated significant improvement in their growth (p=0.025). The recurrence rate for the thoracoscopic approach was 38%, and there were no recurrences in the partial sternotomy and the thoracotomy groups, 38% vs 0% vs 0%, p=0.005. Simultaneous bronchoscopy was utilized more commonly in the PS group compared to the thoracotomy and thoracoscopic group, 95% vs 62% vs 38%. CONCLUSIONS In this series, the partial sternotomy technique had the most reliable resolution of symptoms and no recurrence requiring reoperation. The PS approach to STM has the technical advantages of an improved exposure with equal access to the vessels over the right and left mainstem bronchi, as well as the trachea and a more specific elevation of the arteries, including suspension of the pulmonary arteries and trachea itself when desirable. Simultaneous bronchoscopy during aortopexy and an experienced team also likely contribute to improved outcomes. The variations in populations, follow-up, and use of continuous intraoperative bronchoscopy, however, make firm conclusions difficult.

Wilms tumor: recent advances in clinical care and biology.

Wilms tumor is the most common renal malignancy that occurs in childhood. The remarkable evolution of treatment for this malignancy has served as a paradigm for multimodal cancer treatment. A rich database has accrued over time from well-controlled clinical trials. Translational research has directly affected patient care by allowing risk-based therapy. This article will summarize advances in our knowledge of the biology of Wilms tumor and describe the impact on clinical treatment of Wilms tumor.

Accountability in Health Care—Transplant Community Offers Leadership

Two concerns expressed by the American Society of Transplant Surgeons (ASTS) are that (1) the new Medicare regulations for transplant hospitals take a ‘punitive’ approach and that (2) the outcome requirement may thwart innovation by not including certain risk factors into the risk adjustment used to calculate expected outcomes. This article explains efforts by the Centers for Medicare & Medicaid Services (CMS) to encourage quality improvement. CMS limits outcomes‐related enforcement to situations where failure rates exceed certain substantial ‘tolerance limits’, ensuring opportunity for quality improvement to be effective prior to enforcement. Transplantations involving a disproportionate share of risk factors not incorporated into the risk‐adjustment methodology can also be raised through CMS’‘mitigating factors’ process. Of the 22 mitigating factor requests completed through March 10, 2009, 7 raised issues of risk adjustment (none involved experimental protocols). Four of the seven requests were approved for other reasons (evidence of effective program changes and improved outcomes). CMS concluded that none of the seven made a persuasive case based on risk factors. The early data indicate that program deficiencies may outweigh risk adjustment issues. CMS agrees to consider the ASTS suggestions for future action and continues to monitor the situation in case a different pattern emerges.

Direct tracheobronchopexy to correct airway collapse due to severe tracheobronchomalacia: Short-term outcomes in a series of 20 patients

PURPOSE Tracheobronchomalacia (TBM) is associated with esophageal atresia, tracheoesophageal fistulas, and congenital heart disease. TBM results in chronic cough, poor mucous clearance, and recurrent pneumonias. Apparent life-threatening events or recurrent pneumonias may require surgery. TBM is commonly treated with an aortopexy, which indirectly elevates tracheas anterior wall. However, malformed tracheal cartilage and posterior tracheal membrane intrusion may limit its effectiveness. This study describes patient outcomes undergoing direct tracheobronchopexy for TBM. METHODS The records of patients that underwent direct tracheobronchopexy at our institution from January 2011 to April 2014 were retrospectively reviewed. Primary outcomes included TBM recurrence and resolution of the primary symptoms. Data were analyzed by McNemars test for matched binary pairs and logistic regression modeling to account for the endoscopic presence of luminal narrowing over multiple time points per patient. RESULTS Twenty patients were identified. Preoperative evaluation guided the type of tracheobronchopexy. 30% had isolated anterior and 50% isolated posterior tracheobronchopexies, while 20% had both. Follow-up was 5 months (range, 0.5-38). No patients had postoperative ALTEs, and pneumonias were significantly decreased (p=0.0005). Fewer patients had tracheobronchial collapse at postoperative endoscopic exam in these anatomical regions: middle trachea (p=0.01), lower trachea (p<0.001), and right bronchus (p=0.04). CONCLUSION The use of direct tracheobronchopexy resulted in ALTE resolution and reduction of recurrent pneumonias in our patients. TBM was also reduced in the middle and lower trachea and right mainstem bronchus. Given the heterogeneity of our population, further studies are needed to ascertain longer-term outcomes and a grading scale for TBM severity.