Willieford Moses

Clinical Features and Genetic Predisposition to Hereditary Nonmedullary Thyroid Cancer

BACKGROUND Approximately 5% of the nonmedullary thyroid cancers are hereditary. Hereditary nonmedullary thyroid cancer may occur as a minor component of familial cancer syndromes (familial adenomatous polyposis, Gardners syndrome, Cowdens disease, Carneys complex type 1, Werners syndrome, and papillary renal neoplasia) or as a primary feature (familial nonmedullary thyroid cancer [FNMTC]). The goal of this article was to review our current knowledge on the hereditary nonmedullary thyroid cancer. SUMMARY Epidemiologic and clinical kindred studies have demonstrated that FNMTC is a unique clinical entity. Most studies suggest that FNMTC is associated with more aggressive disease than sporadic cases, with higher rates of multicentric tumors, lymph node metastasis, extrathyroidal invasion, and shorter disease-free survival. A hereditary predisposition to nonmedullary thyroid cancer is well established, but the susceptibility genes for isolated FNMTC have not been identified. However, additional susceptibility loci for FNMTC have been recently identified in classic isolated cases of FNMTC (1q21, 6q22, 8p23.1-p22, and 8q24). CONCLUSIONS More studies are needed to validate chromosomal susceptibility loci and identify the susceptibility genes for FNMTC. The discovery of the predisposing genes may allow for screening and early diagnosis, which could lead to improved outcomes for patients and their families.

Prevalence, clinicopathologic features, and somatic genetic mutation profile in familial versus sporadic nonmedullary thyroid cancer.

BACKGROUND Although hereditary nonmedullary thyroid cancer is recognized as a distinct and isolated familial syndrome, the precise prevalence and genetic basis are poorly understood. Moreover, whether familial nonmedullary thyroid cancer (FNMTC) has a more aggressive clinical behavior is controversial. The objectives of this study were to determine the prevalence of FNMTC, and compare the extent of disease and tumor somatic genetic alteration in patients with familial and sporadic papillary thyroid cancer. METHODS The main study entry criterion was patients who had a thyroid nodule that required a clinical evaluation with fine-needle aspiration biopsy and or thyroidectomy. A family history questionnaire was used to determine the presence of familial and sporadic thyroid cancer. Thyroid nodule fine-needle aspiration biopsy samples and tumor tissue at the time of thyroidectomy were used to test for somatic genetic mutations (BRAF V600E, NRAS, KRAS, NTRK1, RET/PTC1, and RET/PTC3). RESULTS There were 402 patients with 509 thyroid nodules enrolled in the study. The prevalence of FNMTC was 8.8% in all patients with thyroid cancer and 9.4% in patients with only papillary thyroid cancer. None of the patients with FNMTC had another familial cancer syndrome. There was no significant difference in gender, tumor size, lymph node metastasis, and overall stage between sporadic and familial cases of thyroid cancer. Patients with FNMTC were younger at diagnosis than patients with sporadic papillary thyroid cancer (p < 0.002). Seventy-nine of the 504 thyroid nodules had somatic genetic mutations (29 BRAF V600E, 29 NRAS, 8 KRAS, 1 NTRK1, 4 RET/PTC1, and 8 RET/PTC3). There was no significant difference in the number or type of somatic mutations between sporadic and hereditary cases of papillary thyroid cancer. CONCLUSIONS We found a higher prevalence of FNMTC in patients with papillary thyroid cancer than previously reported. Patients with FNMTC present at a younger age. Somatic mutations and extent of disease are similar in sporadic and FNMTC cases.

Clinical and molecular features of papillary thyroid cancer in adolescents and young adults

Age disparities in thyroid cancer incidence and outcome among adolescents and young adults (AYAs) with thyroid cancer are under reported. In this study, the authors compared the molecular and clinical features of papillary thyroid cancer (PTC) in AYAs with the same features among patients in other age groups.

A prospective study evaluating the accuracy of using combined clinical factors and candidate diagnostic markers to refine the accuracy of thyroid fine needle aspiration biopsy

BACKGROUND Approximately 30% of fine needle aspiration biopsies of the thyroid have inconclusive results. We conducted a prospective trial to determine whether clinical and molecular markers could be used in combination to improve the accuracy of thyroid fine needle aspiration biopsy. METHODS Clinical, tumor genotyping for common somatic mutations (BRAF V600E, NRAS, KRAS, RET/PTC1, RET/PTC3, and NTRK1), and the gene expression levels of 6 candidate diagnostic markers were analyzed by univariate and multivariate methods in 341 patients to determine whether they could distinguish reliably benign from malignant thyroid neoplasms, and a scoring model was derived. RESULTS By a multivariate analysis, fine needle aspiration biopsy cytology classification, the presence of a NRAS mutation, and the tissue inhibitor of metalloproteinase 1 expression level were associated jointly with malignancy. The overall accuracy of the scoring model, including these 3 variables, to distinguish benign from malignant thyroid tumors was 91%, including 67% for the indeterminate and 77% for the suspicious FNA subgroups. CONCLUSION Fine needle aspiration biopsy cytology classification, the presence of NRAS mutation, and tissue inhibitor of metalloproteinase 1 messenger RNA expression levels in combination provide a greater diagnostic accuracy than fine needle aspiration biopsy cytology alone to allow selection of more definitive initial operative treatment. The sensitivity of the scoring model, however, was too low to avoid the need for diagnostic thyroidectomies for indeterminate fine needle aspiration biopsy findings.

Multiple Genetic Alterations in Papillary Thyroid Cancer are Associated with Younger Age at Presentation

BACKGROUND There is a significant gender and age disparity in thyroid cancer incidence and outcome. The molecular basis for these divergent clinical presentations and outcome are essentially unknown. METHODS The primary tumor genotype in 217 patients with papillary thyroid cancer was determined for six common somatic genetic alterations (RET/PTC1, RET/PTC3, and NTRK1 rearrangements, and BRAF V600E, KRAS, and NRAS hotspot mutations) by PCR and direct sequencing, and nested PCR. Univariate and multivariate analyses were performed to determine the association of genetic changes and age, gender, and other clinicopathologic factors. RESULTS One hundred twenty-one of the 190 conventional papillary thyroid carcinoma samples (63.7%) had at least one genetic alteration, and 27 of the samples (14.2%) had more than one alteration. In the follicular variant of papillary thyroid carcinomas, 13 of the 27 samples (48.1%) had at least one genetic alteration and three of the 27 samples (11.1%) had more than one. The presence of multiple genetic alterations was associated with younger age at diagnosis (P=0.034), mean difference of 8 y earlier. We found no significant association with the number or type of genetic alterations present by gender, tumor size, extent of tumor differentiation, multicentricity, lymph node metastasis, distant metastases, TNM stage, and the AMES risk group. The association of multiple genetic alterations and younger age were independent of tumor size, lymph node or distant metastasis, TNM stage, or AMES risk group. CONCLUSIONS Multiple genetic alterations are more common in younger patients with papillary thyroid cancer, but there is no difference in the type or number of genetic alterations by gender. Our findings suggest that multiple genetic alterations in thyroid cancer may be associated with earlier disease initiation and or progression.

Diffusive Silicon Nanopore Membranes for Hemodialysis Applications

Hemodialysis using hollow-fiber membranes provides life-sustaining treatment for nearly 2 million patients worldwide with end stage renal disease (ESRD). However, patients on hemodialysis have worse long-term outcomes compared to kidney transplant or other chronic illnesses. Additionally, the underlying membrane technology of polymer hollow-fiber membranes has not fundamentally changed in over four decades. Therefore, we have proposed a fundamentally different approach using microelectromechanical systems (MEMS) fabrication techniques to create thin-flat sheets of silicon-based membranes for implantable or portable hemodialysis applications. The silicon nanopore membranes (SNM) have biomimetic slit-pore geometry and uniform pores size distribution that allow for exceptional permeability and selectivity. A quantitative diffusion model identified structural limits to diffusive solute transport and motivated a new microfabrication technique to create SNM with enhanced diffusive transport. We performed in vitro testing and extracorporeal testing in pigs on prototype membranes with an effective surface area of 2.52 cm2 and 2.02 cm2, respectively. The diffusive clearance was a two-fold improvement in with the new microfabrication technique and was consistent with our mathematical model. These results establish the feasibility of using SNM for hemodialysis applications with additional scale-up.

Lower Gastrointestinal Bleeding & Intussusception

Relatively uncommon compared with the adult population, lower gastrointestinal bleeding in children requires expeditious evaluation and management because of the variety of causes ranging from benign to life-threatening conditions. The causes of lower gastrointestinal bleeding (LGIB) vary with patient age. This review focuses on the differential diagnosis and management of LGIB in children. Because intussusception is one of the most common sources of LGIB, particular attention will be given to its diagnosis and management.

Silicon Micropore‐Based Parallel Plate Membrane Oxygenator

Extracorporeal membrane oxygenation (ECMO) is a life support system that circulates the blood through an oxygenating system to temporarily (days to months) support heart or lung function during cardiopulmonary failure until organ recovery or replacement. Currently, the need for high levels of systemic anticoagulation and the risk for bleeding are main drawbacks of ECMO that can be addressed with a redesigned ECMO system. Our lab has developed an approach using microelectromechanical systems (MEMS) fabrication techniques to create novel gas exchange membranes consisting of a rigid silicon micropore membrane (SμM) support structure bonded to a thin film of gas-permeable polydimethylsiloxane (PDMS). This study details the fabrication process to create silicon membranes with highly uniform micropores that have a high level of pattern fidelity. The oxygen transport across these membranes was tested in a simple water-based bench-top set-up as well in a porcine in vivo model. It was determined that the mass transfer coefficient for the system using SµM-PDMS membranes was 3.03 ± 0.42 mL O2 min-1 m-2 cm Hg-1 with pure water and 1.71 ± 1.03 mL O2 min-1 m-2 cm Hg-1 with blood. An analytic model to predict gas transport was developed using data from the bench-top experiments and validated with in vivo testing. This was a proof of concept study showing adequate oxygen transport across a parallel plate SµM-PDMS membrane when used as a membrane oxygenator. This work establishes the tools and the equipoise to develop future generations of silicon micropore membrane oxygenators.

Sterilization effects on ultrathin film polymer coatings for silicon-based implantable medical devices

Novel biomaterials for medical device applications must be stable throughout all stages of preparation for surgery, including sterilization. There is a paucity of information on the effects of sterilization on sub-10 nm-thick polymeric surface coatings suitable for silicon-based bioartificial organs. This study explores the effect of five standard sterilization methods on three surface coatings applied to silicon: polyethylene glycol (PEG), poly(sulfobetaine methacrylate) (pSBMA), and poly (2-methacryloyloxyethyl phosphorylcholine) (pMPC). Autoclave, dry heat, hydrogen peroxide (H2 O2 ) plasma, ethylene oxide gas (EtO), and electron beam (E-beam) treated coatings were analyzed to determine possible polymer degradation with sterilization. Poststerilization, there were significant alterations in contact angle, maximum change resulting from H2 O2 (Δ - 14°), autoclave (Δ + 15°), and dry heat (Δ + 23°) treatments for PEG, pSBMA, and pMPC, respectively. Less than 5% coating thickness change was found with autoclave and EtO on PEG-silicon, E-beam on pSBMA-silicon and EtO treatment on pMPC-silicon. H2 O2 treatment resulted in at least 30% decrease in thickness for all coatings. Enzyme-linked immunosorbent assays showed significant protein adsorption increase for pMPC-silicon following all sterilization methods. E-beam on PEG-silicon and dry-heat treatment on pSBMA-silicon exhibited maximum protein adsorption in each coating subset. Overall, the data suggest autoclave and EtO treatments are well-suited for PEG-silicon, while E-beam is best suited for pSBMA-silicon. pMPC-silicon was least impacted by EtO treatment. H2 O2 treatment had a negative effect on all three coatings. These results can be used to determine which surface modifications and sterilization processes to utilize for devices in vivo.

Radiologic assessment of fetal tracheal balloon occlusion

Fetal endoscopic tracheal occlusion (FETO) is a novel technique to treat cases of isolated severe congenital diaphragmatic hernia (CDH). Although there are benefits of MRI over ultrasound in assessing lung volumes, it is unknown whether there are benefits of MRI for localizing the tracheal balloon. This is a retrospective study reviewing the imaging characteristics of FETO in patients who underwent both MRI and ultrasound exams done to localize tracheal balloons.