Hypoxia induces ZEB2 in podocytes: Implications in the pathogenesis of proteinuria.

The glomerular filtration barrier (GFB) plays a critical role in ensuing protein free urine. The integrity of the GFB is compromised during hypoxia that prevails during extreme physiological conditions. However, the mechanism by which glomerular permselectivity is compromised during hypoxia remains enigmatic. Rats exposed to hypoxia showed a decreased glomerular filtration rate, podocyte foot-processes effacement, and proteinuria. Accumulation of hypoxia-inducible factor-1α (HIF1α) in podocytes resulted in elevated expression of zinc finger E-box binding homeobox 2 (ZEB2) and decreased expression of E- and P-cadherin. We also demonstrated that HIF1α binds to hypoxia response element localized in the ZEB2 promoter. Furthermore, HIF1α also induced the expression of ZEB2-natural antisense transcript, which is known to increase the efficiency of ZEB2 translation. Ectopic expression of ZEB2 induced loss of E- and P-cadherin and is associated with enhanced motility of podocytes during hypoxic conditions. ZEB2 knockdown abrogated hypoxia-induced decrease in podocyte permselectivity. This study suggests that hypoxia leads to activation of HIF1α-ZEB2 axis, resulting in podocyte injury and poor renal outcome.

Growth hormone and chronic kidney disease.

PURPOSE OF REVIEW: Elevated circulating levels of growth hormone (GH) and/or increased expression of the GH receptor in the kidney are associated with the development of nephropathy in type1 diabetes and acromegaly. Conditions of GH excess are characterized by hyperfiltration, glomerular hypertrophy, glomerulosclerosis and albuminuria, whereas states of decreased GH secretion or action are protected against glomerulopathy. The direct role of GH's action on glomerular cells, particularly podocytes, has been the focus of recent studies. In this review, the emerging role of GH on the biological function of podocytes and its implications in the pathogenesis of diabetic and chronic kidney disease will be discussed. RECENT FINDINGS: Elevated GH levels impair glomerular permselectivity by altering the expression of podocyte slit-diaphragm proteins. GH stimulates the epithelial-mesenchymal transition of podocytes and decreases podocyte count. GH also induces the expression of prosclerotic molecules transforming growth factor beta, and TGFBIp. SUMMARY: Our understanding of the cellular and molecular effects of GH in the pathogenesis of renal complications of diabetes and acromegaly has significantly progressed in recent years. These observations open up new possibilities in the prevention and treatment of diabetic nephropathy.

Carboxymethyl lysine induces EMT in podocytes through transcription factor ZEB2: Implications for podocyte depletion and proteinuria in diabetes mellitus.

Advanced glycation end-products (AGEs) are implicated in the pathogenesis of diabetic nephropathy (DN). N-carboxymethyl-lysine (CML) is one of the predominant AGEs that accumulate in all renal compartments of diabetic patients. Nevertheless, the direct effect of CML on podocyte biology has not been explored. In this study, we demonstrate the induction of the transcription factor Zeb2 in podocytes upon exposure to CML through activation of NF-kB signaling cascade. Zeb2 orchestrates epithelial-mesenchymal transformation (EMT), during which cell-cell and cell-extracellular matrix interactions are feeble and enable epithelial cells to become invasive. CML treatment induced both NF-kB and Zeb2 promoter activity and suppressed E-cadherin promoter activity. Inhibition of NF-kB activity prevented CML dependent induction of Zeb2 and loss of E-cadherin. While the exposure of podocytes to CML results in increased podocyte permeability, shRNA-mediated knockdown of Zeb2 expression abrogated CML-mediated podocyte permeability. Further, in vivo findings of elevated CML levels concurrent with increased expression of ZEB2 in glomeruli and proteinuria in diabetic rats confirm that CML-mediated manifestations in the kidney under chronic diabetes conditions. These in vitro and in vivo results envisage the novel axis of NFkB-ZEB2 in podocytes playing a significant role in eliciting EMT and pathogenesis of DN.

Growth Hormone Induces Transforming Growth Factor-Beta-Induced Protein in Podocytes: Implications for Podocyte Depletion and Proteinuria.

The glomerular podocytes form a major size selective barrier for the filtration of serum proteins and reduced podocyte number is a critical event in the pathogenesis of proteinuria during diabetic nephropathy (DN). An elevated level of growth hormone (GH) is implicated as a causative factor in the development of nephropathy in patients with type 1 diabetes mellitus. We have previously shown that podocytes express GH receptor and are a target for GH action. To elucidate the molecular basis for the effects of GH on podocyte depletion, we conducted PCR-array analyses for extracellular matrix and adhesion molecules in podocytes. Our studies reveal that GH increases expression of a gene that encodes transforming growth factor-beta-induced protein (TGFBIp) expression. Similarly, microarray data retrieved from the Nephromine database revealed elevation of TGFBIp in patients with DN. Treatment with GH results in increased secretion of extracellular TGFBIp by podocytes. Both GH and TGFBIp induced apoptosis and epithelial mesenchymal transition (EMT) of podocytes. Exposure of podocytes to GH and TGFBIp resulted in increased migration of cells and altered podocyte permeability to albumin across podocyte monolayer. Administration of GH to rats induced EMT and apoptosis in the glomerular fraction of the kidney. Therefore, we conclude that the GH-dependent increase in TGFBIp in the podocyte is one of the mechanisms responsible for podocyte depletion in DN.

Congenital Hypothyroidism Long-Term Follow-up Project: Navigating the Rough Waters of a Multi-Center, Multi-State Public Health Project.

The Region 4 Midwest Genetics Collaborative, made up of seven regional states (Illinois, Indiana, Kentucky, Michigan, Minnesota, Ohio, and Wisconsin), brought together pediatric endocrinologists, state laboratory experts, public health follow-up specialists, and parents of children with congenital hypothyroidism (CH) to identify the three-year follow-up management and education patterns of primary care clinicians and pediatric endocrinologists in the care of children diagnosed with CH by state newborn screening (NBS) programs. Among a number of challenges, each state had different NBS methods, data systems, public health laws, and institutional review board (IRB) requirements. Furthermore, the diagnosis of CH was complicated by the timing of the NBS sample, the gestational age, weight, and co-morbidities at delivery. There were 409 children with CH identified through NBS in 2007 in the seven state region. The clinician of record and the parents of these children were invited to participate in a voluntary survey. Approximately 64 % of clinician surveys were collected with responses to questions relating to treatment, monitoring practices, educational resources, genetic counseling, and services provided to children with confirmed CH and their families. Nearly one-quarter (24 %) of parents surveyed responded to questions relating to treatment, education, genetic counseling, resources, and services they received or would like to receive. De-identified data from six of the seven states were compiled for analysis, with one state being unable to obtain IRB approval within the study timeline. The data from this collaborative effort will improve state follow-up programs and aid in developing three-year follow-up guidelines for children diagnosed with CH. To aid in the facilitation of similar public health studies, this manuscript highlights the challenges faced, and focuses on the pathway to a successful multi-state public health endeavor.

Targeted deletion of growth hormone (GH) receptor in macrophage reveals novel osteopontin-mediated effects of GH on glucose homeostasis and insulin sensitivity in diet-induced obesity.

We investigated GH action on macrophage (MΦ) by creating a MΦ-specific GH receptor-null mouse model (MacGHR KO). On a normal diet (10% fat), MacGHR KO and littermate controls exhibited similar growth profiles and glucose excursions on intraperitoneal glucose (ipGTT) and insulin tolerance (ITT) tests. However, when challenged with high fat diet (HFD, 45% fat) for 18 weeks, MacGHR KO mice exhibited impaired ipGTT and ITT compared with controls. In MacGHR KO, adipose-tissue (AT) MΦ abundance was increased with skewing toward M1 polarization. Expression of pro-inflammatory cytokines (IL1ß, TNF-α, IL6, and osteopontin (OPN)) were increased in MacGHR KO AT stromal vascular fraction (SVF). In MacGHR KO AT, crown-like-structures were increased with decreased insulin-dependent Akt phosphorylation. The abundance of phosphorylated NF-κB and of OPN was increased in SVF and bone-marrow-derived MΦ in MacGHR KO. GH, acting via an NF-κB site in the distal OPN promoter, inhibited the OPN promoter. Thus in diet-induced obesity (DIO), lack of GH action on the MΦ exerts an unexpected deleterious effect on glucose homeostasis by accentuating AT inflammation and NF-κB-dependent activation of OPN expression. These novel results in mice support the possibility that administration of GH could have salutary effects on DIO-associated chronic inflammation and insulin resistance in humans.

Severe hypoglycemia secondary to methimazole-induced insulin autoimmune syndrome in a 16 year old African-American male.

Insulin autoimmune syndrome (IAS) or Hirata's disease is a rare disorder characterized by hypoglycemia secondary to insulin autoantibodies (IAb). Over 200 patients have been described from Japan with significantly less numbers being reported from outside the Orient. IAS is more common in patients older than 40 yr of age with reports in the pediatric age group being notably rarer. Exposure to sulfhydryl group containing medications is implicated in the pathogenesis of this syndrome. In this report, we describe a case of IAS in an African-American adolescent. A 16-yr-old healthy African-American male was diagnosed with Graves' disease and started on Methimazole. Four weeks later, he was found unconscious and hypoglycemic (blood sugar 1.5 mmol/L). Evaluation was negative for insulinoma. Insulin antibodies were positive. Oral glucose tolerance test revealed elevated free insulin concentrations with disproportionately elevated total insulin levels. The patient was started on prednisone, diazoxide, and propranolol for management of IAS and hyperthyroidism. Thyroid radio-ablation was subsequently undertaken. The doses of prednisone and diazoxide were tapered and these medications discontinued after 9 months. The insulin antibody levels decreased gradually and became undetectable in 6 months with resolution of the hypoglycemia.

Growth hormone (GH)-dependent expression of a natural antisense transcript induces zinc finger E-box-binding homeobox 2 (ZEB2) in the glomerular podocyte: a novel action of gh with implications for the pathogenesis of diabetic nephropathy.

Growth hormone (GH) excess results in structural and functional changes in the kidney and is implicated as a causative factor in the development of diabetic nephropathy (DN). Glomerular podocytes are the major barrier to the filtration of serum proteins, and altered podocyte function and/or reduced podocyte number is a key event in the pathogenesis of DN. We have previously shown that podocytes are a target for GH action. To elucidate the molecular basis for the effects of GH on the podocyte, we conducted microarray and RT-quantitative PCR analyses of immortalized human podocytes and identified zinc finger E-box-binding homeobox 2 (ZEB2) to be up-regulated in a GH dose- and time-dependent manner. We established that the GH-dependent increase in ZEB2 levels is associated with increased transcription of a ZEB2 natural antisense transcript required for efficient translation of the ZEB2 transcript. GH down-regulated expression of E- and P-cadherins, targets of ZEB2, and inhibited E-cadherin promoter activity. Mutation of ZEB2 binding sites on the E-cadherin promoter abolished this effect of GH on the E-cadherin promoter. Whereas GH increased podocyte permeability to albumin in a paracellular albumin influx assay, shRNA-mediated knockdown of ZEB2 expression abrogated this effect. We conclude that GH increases expression of ZEB2 in part by increasing expression of a ZEB2 natural antisense transcript. GH-dependent increase in ZEB2 expression results in loss of P- and E-cadherins in podocytes and increased podocyte permeability to albumin. Decreased expression of P- and E-cadherins is implicated in podocyte dysfunction and epithelial-mesenchymal transition observed in DN. We speculate that the actions of GH on ZEB2 and P- and E-cadherin expression play a role in the pathogenesis of microalbuminuria of DN.

An integrated systems biology approach to the study of preterm birth using "-omic" technology--a guideline for research.

Preterm birth is the leading cause of neonatal mortality and perinatal morbidity. The etiology of preterm is multi-factorial and still unclear. As evidence increases for a genetic contribution to PTB, so does the need to explore genomics, transcriptomics, proteomics and metabolomics in its study. This review suggests research guidelines for the conduct of high throughput systems biology investigations into preterm birth with the expectation that this will facilitate the sharing of samples and data internationally through consortia, generating the power needed to study preterm birth using integrated "-omics" technologies. The issues to be addressed include: (1) integrated "-omics" approaches, (2) phenotyping, (3) sample collection, (4) data management-integrative databases, (5) international consortia and (6) translational feasibility. This manuscript is the product of discussions initiated by the "-Omics" Working Group at the Preterm Birth International Collaborative Meeting held at the World Health Organization, Geneva, Switzerland in April 2009.

Management of Short Stature: Use of Growth Hormone in GH-Deficient and non-GH-Deficient Conditions.

Growth hormone (GH) is an important driver for somatic growth and increase in height in children. The development of recombinant human GH has greatly increased its availability, and hence the potential for its use and abuse. GH therapy should only be offered to patients with established and approved indications. Common pediatric indications for treatment include growth hormone deficiency, Turner syndrome, Prader-Willi syndrome, small for gestational age, chronic renal insufficiency, and idiopathic short stature. Before initiating treatment, the family should be counseled about the treatment goals, costs, and possible adverse effects from the treatment. It is important for patients to have realistic expectations from the treatment. The dose of GH should be individualized for the indication and will require titration in each patient based on response to the treatment and the adverse effects. Overall, GH has a good safety record. However, GH treatment has many potential and real adverse effects that need to be considered and monitored during treatment. Recently, safety concerns regarding the long-term effect of GH therapy on cardiovascular morbidity have come under scrutiny.

Liddle Syndrome due to a Novel c.1713 Deletion in the Epithelial Sodium Channel ß-Subunit in a Normotensive Adolescent.

OBJECTIVE: Liddle syndrome (LS) is a rare autosomal dominant condition secondary to a gain-of-function mutation affecting the epithelial sodium channels (ENaCs) in the distal nephron. It presents with early-onset hypertension, hypokalemia, and metabolic alkalosis in the face of hyporeninemia and hypoaldosteronism. We report a novel mutation affecting the ENaCs in a normotensive adolescent with LS. METHODS: We describe a pediatric case of LS with a novel mutation and review the condition's presentation and management. To date, 31 different mutations in the ß- or γ-subunit of ENaCs have been reported as associated with LS. RESULTS: We describe a 16-year-old girl presenting with muscle cramps with a strong family history of hypertension and hypokalemia. Initial investigations revealed hypokalemia together with hypoaldosteronism and hyporeninemia. Subsequent genetic testing revealed a novel mutation in SCNN1B (deletion: c.1713delC), leading to the premature termination of the sodium channel epithelial 1 subunit-ß protein and the LS phenotype. Treatment with triamterene (50 mg, twice daily) and potassium chloride (20 mEq, once daily) normalized the serum potassium and led to resolution of her muscle cramps. CONCLUSION: It is essential to consider investigating the presence of rare genetic syndromes, like LS, when a patient presents with hypokalemia. Further studies are needed to understand the variable presentation of this condition.

4-Hour postoperative PTH level predicts hypocalcemia after thyroidectomy in children.

BACKGROUND: Hypocalcemia occurs frequently after a total thyroidectomy in pediatric patients. Four hour postoperative PTH monitoring predicts the need for calcium supplementation in the adult thyroidectomy population. We evaluated the role of the 4 h postoperative PTH level in determining the need for calcium supplementation after thyroidectomy in the pediatric population. METHODS: This is a retrospective review of children undergoing total thyroidectomy by a single pediatric surgeon from July 2011 through July 2018. Intact PTH obtained four hours postoperatively determined the need for calcium supplementation for patients beginning in November 2014 onward. Serum total calcium levels were monitored concurrently with serum intact PTH levels. Serum calcium levels were followed in our Multispecialty Pediatric Endocrine Surgery clinic within the month following thyroidectomy. RESULTS: From July 2011 through July 2018, there were a total of 56 total thyroidectomies at our institution. Prior to November 2014, all pediatric total thyroidectomies received calcium supplementation per our institutional protocol. Based on ionized calcium levels, 26.3% (5/19) of children developed hypocalcemia. From November 2014 to July 2018, 37 pediatric patients required total thyroidectomies. 29.7% (11/37) had low 4-h postoperative PTH levels. 72.7% (8/11) patients with low 4-h postoperative PTH levels had corresponding postoperative day 1 total calcium levels less than 8.5 or ionized calcium levels less than 1.12, and five children (45.5%) developed symptomatic hypocalcemia. 70% (26/37) of children had normal 4-h postop PTH levels, with only 5 (19%) ever developing hypocalcemia. No patients with a normal postop PTH level developed symptomatic hypocalcemia or required IV calcium repletion. A single 4-h postoperative PTH <10 pg/dl for identifying hypocalcemia has a sensitivity of 81% and specificity of 91%, with AUC 0.81. CONCLUSION: The 4-h postoperative serum PTH level can help determine the need for calcium supplementation in pediatric patients undergoing total thyroidectomy, thereby reducing unnecessary calcium supplementation and serial lab draws to monitor for postoperative hypocalcemia. LEVEL OF EVIDENCE: Level II.

Neonatal diabetes mellitus with pancreatic agenesis in an infant with homozygous IPF-1 Pro63fsX60 mutation.

Permanent neonatal diabetes mellitus is a rare disorder known to be caused by activating mutations in KCNJ11 or ABCC8, inactivating mutations in INS, or very rarely in GCK or insulin promotor factor-1 (IPF-1) genes. We report a patient with permanent neonatal diabetes mellitus and severe exocrine pancreatic insufficiency. Ultrasound examination revealed pancreatic agenesis with a suggestion of a small amount of tissue in the head of the pancreas. Genetic testing revealed that the neonate had a homozygous Pro63fsX60 IPF-1 mutation. This is the second reported case of neonatal diabetes mellitus secondary to a homozygous mutation in the IPF-1 gene and supports the previously proposed biological role of IPF-1 in the pancreatic development in human.

Endotoxin-induced proteolytic reduction in hepatic growth hormone (GH) receptor: a novel mechanism for GH insensitivity.

GH is an important anabolic hormone. We previously demonstrated in cell culture that the cell surface GH receptor (GHR) is susceptible to inducible metalloproteolytic cleavage that yields the shed receptor extracellular domain (called GH binding protein) and renders the cells desensitized to subsequent GH stimulation. Sepsis and inflammatory states are associated with hepatic desensitization to GH, although disparate mechanisms have been postulated in various animal models. Using C3H/HeJ mice, we now demonstrate that administration of lipopolysaccharide (LPS) causes marked hepatic desensitization to GH, assessed by monitoring signal transducer and activator of transcription 5 tyrosine phosphorylation and nuclear accumulation and with a novel noninvasive bioluminescence imaging system to track in vivo hepatic GH signaling serially in individual mice. This endotoxin-induced desensitization was accompanied by marked loss of hepatic GHR, which was not explained by changes in GHR mRNA abundance. Furthermore, we observe that LPS causes GH-binding protein shedding of a hepatically expressed wild-type GHR but not a GHR with a mutation in the metalloprotease cleavage site. These data suggest that in this model system, LPS-induced desensitization to GH is associated with proteolytic GHR cleavage. These data are the first to demonstrate inducible in vivo GHR proteolysis and suggest this is a mechanism to regulate GH sensitivity and its anabolic effects during sepsis or inflammation.

Blood-fluid level in cortical venous thrombosis--a rare diagnostic entity.

BACKGROUND: With improvement in imaging, CVT is being diagnosed more frequently. Early diagnosis and rapid institution of remedial measures such as anticoagulation, anticonvulsants, hydration, and treatment of underlying abnormality will aid in salvaging life. CASE DESCRIPTION: We report an autopsy case of a 34-year-old man who presented with sudden onset of seizures, followed by right hemiplegia and altered sensorium. Magnetic resonance imaging of the brain revealed intraparenchymal hemorrhage in the left posterior frontal region with a blood-fluid level. The SSS was devoid of the routine hypointense signal intensity. Routine evaluations for hypercoagulable states were negative. All the coagulation parameters were within normal limits. He was managed conservatively with anticonvulsants, anticoagulants, and hydration. A CT scan of the brain done 24 hours later revealed left posterior frontal hemorrhage with perilesional edema. A CT venogram confirmed the presence of CVT involving the SSS and the right transverse sinus. However he died within next 24 hours. An autopsy confirmed thrombosis in the SSS, right transverse sinus, lungs, and kidneys. CONCLUSIONS: Blood-fluid level in CVT may be an early radiologic sign in the absence of any other imaging abnormality. The presence of this sign in the early stages warrants an aggressive treatment because this probably suggests a large bleed with raised capillary and venous pressures. The case is discussed in view of the unusual radiologic sign in CVT in the absence of anticoagulant therapy.

Biomechanical implications of unilateral facetectomy, unilateral facetectomy plus partial contralateral facetectomy, and complete bilateral facetectomy in minimally invasive transforaminal interbody fusion.

OBJECTIVE: Minimally invasive transforaminal interbody fusion techniques vary among surgeons. One decision point is whether to perform a unilateral facetectomy (UF), a unilateral facetectomy plus partial contralateral facetectomy (UF/PF), or a complete bilateral facetectomy (CBF). The authors therefore compared the biomechanical benefits of all 3 types of facetectomies to determine which approach produces improved biomechanical outcomes. METHODS: Seven human cadaveric specimens (L3-S1) were potted and prepped for UF, with full facet removal, hemilaminectomy, discectomy, and pedicle screw placement. After distraction, a fixed interbody spacer was placed, and compression was performed. A final fixation configuration was performed by locking the rods across the screws posteriorly with bilateral compression. Final lordosis angle and change and foraminal height were measured, and standard nondestructive flexibility tests were performed to assess intervertebral range of motion (ROM) and compressive stiffness. The same procedure was followed for UF/PF and CBF in all 7 specimens. RESULTS: All 3 conditions demonstrated similar ROM and compressive stiffness. No statistically significant differences occurred with distraction, but CBF demonstrated significantly greater change than UF in mean foraminal height after bilateral posterior compression (1.90 ± 0.62 vs 1.00 ± 0.45 mm, respectively, p = 0.04). With compression, the CBF demonstrated significantly greater mean ROM than the UF (2.82° ± 0.83° vs 2.170° ± 1.10°, p = 0.007). The final lordosis angle was greatest with CBF (3.74° ± 0.70°) and lowest with UF (2.68° ± 1.28°). This finding was statistically significant across all 3 conditions (p ≤ 0.04). CONCLUSIONS: Although UF/PF and CBF may require slightly more time and effort and incur more risk than UF, the potential improvement in sagittal balance may be worthwhile for select patients.

Tailoring selection of transforaminal interbody spacers based on biomechanical characteristics and surgical goals: evaluation of an expandable spacer.

OBJECTIVE: Transforaminal lumbar interbody fusion (TLIF) is commonly used for lumbar fusion, such as for foraminal decompression, stabilization, and improving segmental lordosis. Although many options exist, surgical success is contingent on matching design strengths with surgical goals. The goal in the present study was to investigate the effects of an expandable interbody spacer and 2 traditional static spacer designs in terms of stability, compressive stiffness, foraminal height, and segmental lordosis. METHODS: Standard nondestructive flexibility tests (7.5 N⋅m) were performed on 8 cadaveric lumbar specimens (L3-S1) to assess intervertebral stability of 3 types of TLIF spacers at L4-5 with bilateral posterior screw-rod (PSR) fixation. Stability was determined as range of motion (ROM) in flexion-extension (FE), lateral bending (LB), and axial rotation (AR). Compressive stiffness was determined with axial compressive loading (300 N). Foraminal height, disc height, and segmental lordosis were evaluated using radiographic analysis after controlled PSR compression (170 N). Four conditions were tested in random order: 1) intact, 2) expandable interbody cage with PSR fixation (EC+PSR), 3) static ovoid cage with PSR fixation (SOC+PSR), and 4) static rectangular cage with PSR fixation (SRC+PSR). RESULTS: All constructs demonstrated greater stability than the intact condition (p < 0.001). No significant differences existed among constructs in ROM (FE, AR, and LB) or compressive stiffness (p ≥ 0.66). The EC+PSR demonstrated significantly greater foraminal height at L4-5 than SRC+PSR (21.1 ± 2.6 mm vs 18.6 ± 1.7 mm, p = 0.009). EC+PSR demonstrated higher anterior disc height than SOC+PSR (14.9 ± 1.9 mm vs 13.6 ± 2.2 mm, p = 0.04) and higher posterior disc height than the intact condition (9.4 ± 1.5 mm vs 7.1 ± 1.0 mm, p = 0.002), SOC+PSR (6.5 ± 1.8 mm, p < 0.001), and SRC+PSR (7.2 ± 1.2 mm, p < 0.001). There were no significant differences in segmental lordosis among SOC+PSR (10.1° ± 2.2°), EC+PSR (8.1° ± 0.5°), and SRC+PSR (11.1° ± 3.0°) (p ≥ 0.06). CONCLUSIONS: An expandable interbody spacer provided stability, stiffness, and segmental lordosis comparable to those of traditional nonexpandable spacers of different shapes, with increased foraminal height and greater disc height. These results may help inform decisions about which interbody implants will best achieve surgical goals.

Malignant risk of indeterminate pediatric thyroid nodules-An institutional experience.

BACKGROUND: Few studies focus on pediatric thyroid nodules categorized under indeterminate diagnostic categories. The current study was conducted to assess the risk of malignancy of indeterminate pediatric thyroid nodules. METHODS: A search of the institutional electronic pathology database from 01/2011 to 09/2018 was performed to identify pediatric (<21 years old) thyroid nodules that were interpreted as follicular lesion of undetermined significance (FLUS), suspicious for follicular neoplasm (SFN), or suspicious for malignancy (SFM) and subsequently managed with surgery, repeat fine-needle aspiration (FNA), or ≥ 6 months of clinical/imaging monitoring. Results of follow-up (F/U) surgical resections and repeat FNA/Afirma tests, and clinical and radiologic data were collected. RESULTS: We identified 46 cases from 42 patients (11-20 years old, 33 females and 9 males), including 30 FLUS, 10 SFN, and 6 SFM. Twenty-five FLUS, ten SFN, and six SFM cases underwent surgery. The histology revealed carcinomas in 36% of FLUS, 20% of SFN, and 100% of SFM categories; follicular adenomas in 32% of FLUS and 80% of SFN categories; and benign nodules in 32% of FLUS category. All five nonsurgically treated FLUS cases were considered benign based on the findings of repeat FNA/Afirma tests (n = 3, 3-22 months F/U) or clinical/radiologic exams (n = 2, 8-12 months F/U). CONCLUSIONS: Based on a limited study cohort, malignancy was identified in 36%, 20%, and 100% of surgically managed pediatric thyroid nodules categorized as FLUS, SFN, and SFM, respectively; suggesting a markedly higher malignant rate than the implied malignant risk for FLUS and SFM categories in adults.