Predictors of recurrence in pheochromocytoma.

BACKGROUND: The recurrence rate of pheochromocytoma after adrenalectomy is 6.5-16.5%. This study aims to identify predictors of recurrence and optimal biochemical testing and imaging for detecting the recurrence of pheochromocytoma. METHODS: In this retrospective study we reviewed all patients who underwent adrenalectomy for pheochromocytoma during a 14-year period at a single institution. RESULTS: One hundred thirty-five patients had adrenalectomy for pheochromocytoma. Eight patients (6%) developed recurrent disease. The median time from initial operation to diagnosis of recurrence was 35 months. On multivariate analysis, tumor size >5 cm was an independent predictor of recurrence. One patient with recurrence died, 4 had stable disease, 2 had progression of disease, and 1 was cured. Recurrence was diagnosed by increases in plasma and/or urinary metanephrines and positive imaging in 6 patients (75%), and by positive imaging and normal biochemical levels in 2 patients (25%). CONCLUSION: Patients with large tumors (>5 cm) should be followed vigilantly for recurrence. Because 25% of patients with recurrence had normal biochemical levels, we recommend routine imaging and testing of plasma or urinary metanephrines for prompt diagnosis of recurrence.

A multi-institutional international study of risk factors for hematoma after thyroidectomy.

BACKGROUND: Cervical hematoma can be a potentially fatal complication after thyroidectomy, but its risk factors and timing remain poorly understood. METHODS: We conducted a retrospective, case-control study identifying 207 patients from 15 institutions in 3 countries who developed a hematoma requiring return to the operating room (OR) after thyroidectomy. RESULTS: Forty-seven percent of hematoma patients returned to the OR within 6 hours and 79% within 24 hours of their thyroidectomy. On univariate analysis, hematoma patients were older, more likely to be male, smokers, on active antiplatelet/anticoagulation medications, have Graves' disease, a bilateral thyroidectomy, a drain placed, a concurrent parathyroidectomy, and benign pathology. Hematoma patients also had more blood loss, larger thyroids, lower temperatures, and higher blood pressures postoperatively. On multivariate analysis, independent associations with hematoma were use of a drain (odds ratio, 2.79), Graves' disease (odds ratio, 2.43), benign pathology (odds ratio, 2.22), antiplatelet/anticoagulation medications (odds ratio, 2.12), use of a hemostatic agent (odds ratio, 1.97), and increased thyroid mass (odds ratio, 1.01). CONCLUSION: A significant number of patients with a postoperative hematoma present >6 hours after thyroidectomy. Hematoma is associated with patients who have a drain or hemostatic agent, have Graves' disease, are actively using antiplatelet/anticoagulation medications or have large thyroids. Surgeons should consider these factors when individualizing patient disposition after thyroidectomy.

The prevalence of undiagnosed and unrecognized primary hyperparathyroidism: a population-based analysis from the electronic medical record.

BACKGROUND: The electronic medical record (EMR) of a large, tertiary referral center was examined to study the prevalence of undiagnosed and unrecognized primary hyperparathyroidism (PHPT). METHODS: The EMR was queried for outpatient serum calcium >10.5 mg/dL over a 2-year period. RESULTS: Of 2.7 million patients, 54,198 (2%) had hypercalcemia (>10.5 mg/dL). In a 2-year sample of 7,269 patients, 1.3% (95 patients) had a recorded diagnosis of PHPT, and 0.3% (16 patients) had parathyroidectomy. Of the remaining patients, parathyroid hormone (PTH) values were recorded in 32% (2,337 patients). Of patients with PTH measured, 71% (1,662 patients) had PHPT (PTH > 30 pg/mL). Patients with calcium of 11.1­11.5 mg/dL were most likely to have PHPT (55%). Patients with calcium >12 mg/dL were most likely to have PTH measured (52%). Of hypercalcemic patients, 67% never had PTH obtained, 28% of whom were likely to have PHPT. It is estimated that 43% of hypercalcemic patients are likely to have PHPT. The estimated prevalence of PHPT in the general population is 0.86%. CONCLUSION: PHPT is a more common disorder than previously documented. It is crucial to evaluate even mild hypercalcemia, because 43% of these patients have PHPT. PHPT is underdiagnosed and undertreated.

The effect of vitamin D levels on postoperative calcium requirements, symptomatic hypocalcemia, and parathormone levels following parathyroidectomy for primary hyperparathyroidism.

BACKGROUND: Low vitamin D-25 is common in primary hyperparathyroidism but the effect of this deficiency on postparathyroidectomy calcium requirements is unclear. METHODS: A prospective study was conducted on 4 groups based on preoperative vitamin D-25 levels: very low (<20 ng/mL, n = 500); low (21 to 30 ng/mL, n = 500); normal (>30 ng/mL, n = 500); and supplemented (<25 ng/mL supplemented to >40 ng/mL, n = 285). Patients were placed on identical postoperative oral calcium regimens, and hypocalcemia symptoms were recorded. Total calcium requirements for 2 weeks postoperation were calculated and parathormone (PTH) levels were measured for 2-6 months. RESULTS: Mean vitamin D levels (ng/mL) for each group were: very low (14.2); low (24.4); normal (38.3); and supplemented (16.5 supplemented to 54.3). Postoperative oral calcium requirements (in grams) were identical for all groups (18.7, 18.2, and 18.6, and 19.0, respectively, all P = NS); the incidence and timing of hypocalcemia symptoms were nearly identical for all groups: 8.1%, 7.9%, and 7.8% (P = .8). Elevated postsurgical PTH was identical (below 8%) and was not influenced by vitamin D levels. CONCLUSION: The incidence of hypocalcemic symptoms and the postoperative calcium requirements are identical for patients with very low, low, normal, or supplemented (high) vitamin D. The incidence of persistently elevated PTH postoperatively is also unrelated to preoperative vitamin D levels. Vitamin D supplementation from very low to high levels has no clinical benefit.

Identification of five mouse mu-opioid receptor (MOR) gene (Oprm1) splice variants containing a newly identified alternatively spliced exon.

The mouse mu-opioid receptor gene, Oprm1, currently contains 18 recognized alternatively spliced exons [Doyle, G.A., Sheng, X.R., Lin, S.S.J., Press, D.M., Grice, D.E., Buono, R.J., Ferraro, T.N., Berrettini, W.H., 2007. Identification of three mouse mu-opioid receptor (MOR) gene (Oprm1) splice variants containing a newly identified alternatively spliced exon. Gene 388 (1-2) 135-147, in press (doi:10.1016/j.gene.2006.10.017). Electronic publication 2006 November 1] that generate 27 splice variants encoding at least 11 morphine-binding isoforms of the receptor. Here, we identify five MOR variants that contain an as yet undescribed exon (exon 19) of the gene, and we provide evidence that these MOR splice variants are expressed in the C57BL/6 and DBA/2 mouse strains. Three splice variants, MOR-1Eii, MOR-1Eiii and MOR-1Eiv, encode the MOR-1E isoform and contain the newly identified exon 19 in their 3' untranslated regions. The fourth splice variant encodes a novel mu-opioid receptor isoform, MOR-1U, and contains exon 19 in its coding region. The cytoplasmic tail of the putative MOR-1U isoform contains a putative nuclear localization signal encoded by the sequence of exon 19. Exon 19 appears to be conserved in the rat, but not in humans. In mouse and rat Oprm1, exon 19 is located between described exons 7 and 8. We also report the cloning of the "full-length" MOR-1T splice variant [Kvam, T.-M., Baar, C., Rakvag, T.T., Kaasa, S., Krokan, H.E., Skorpen, F., 2004. Genetic analysis of the murine mu-opioid receptor: increased complexity of Oprm1 gene splicing, J. Mol. Med. 82 (4) 250-255] that encodes MOR-1 and contains the newly identified exon in its 3' UTR. RT-PCR analysis suggests that splice variants MOR-1Eii, MOR-1Eiii, MOR-1Eiv, MOR-1T and MOR-1U are expressed in all brain regions analyzed (cortex, cerebellum, hypothalamus, thalamus and striatum). These exon 19-containing splice variants add to the growing complexity of the mouse Oprm1 gene.

Identification of three mouse mu-opioid receptor (MOR) gene (Oprm1) splice variants containing a newly identified alternatively spliced exon.

The mouse mu-opioid receptor gene, Oprm1, is recognized currently to contain 17 alternatively spliced exons that generate 24 splice variants encoding at least 11 morphine-binding isoforms of the receptor. Here, we identify three new MOR splice variants that contain a previously undescribed exon, exon 18, and provide evidence that they are expressed in two mouse strains. The transcripts containing the newly identified exon 18 encode two new putative mu-opioid receptor isoforms, MOR-1V and MOR-1W. In mouse Oprm1, exon 18 is located between the described exons 10 and 6. Exon 18 appears to be conserved in the rat genome between exons 4 and 7. A BLAST search of the non-redundant GenBank database suggests that human OPRM1 may also contain exon 18. Analysis of mouse brain mRNA by RT-PCR suggests that MOR-1Vii transcripts are expressed in all areas of the brain analyzed, whereas expression of MOR-1Vi transcripts was restricted to thalamus and striatum. MOR-1W transcripts are expressed most highly in the hypothalamus, thalamus and striatum. In summary, we have identified three brain expressed, alternatively spliced mouse MOR splice variants containing a novel exon and encoding new putative MOR isoforms, MOR-1V and MOR-1W.

Fine mapping of a seizure susceptibility locus on mouse Chromosome 1: nomination of Kcnj10 as a causative gene.

Previous quantitative trait loci (QTL) mapping studies document that the distal region of mouse Chromosome (Chr) 1 contains a gene(s) that is in large part responsible for the difference in seizure susceptibility between C57BL/6 (B6) (relatively seizure-resistant) and DBA/2 (D2) (relatively seizure-sensitive) mice. We now confirm this seizure-related QTL ( Szs1) using reciprocal, interval-specific congenic strains and map it to a 6.6-Mb segment between Pbx1 and D1Mit150. Haplotype conservation between strains within this segment suggests that Szs1 may be localized more precisely to a 4.1-Mb critical interval between Fcgr3 and D1Mit150. We compared the coding region sequences of candidate genes between B6 and D2 mice using RT-PCR, amplification from genomic DNA, and database searching and discovered 12 brain-expressed genes with SNPs that predict a protein amino acid variation. Of these, the most compelling seizure susceptibility candidate is Kcnj10. A survey of the Kcnj10 SNP among other inbred mouse strains revealed a significant effect on seizure sensitivity such that most strains possessing a haplotype containing the B6 variant of Kcnj10 have higher seizure thresholds than those strains possessing the D2 variant. The unique role of inward-rectifying potassium ion channels in membrane physiology coupled with previous strong association between ion channel gene mutations and seizure phenotypes puts even greater focus on Kcnj10 in the present model. In summary, we confirmed a seizure-related QTL of large effect on mouse Chr 1 and mapped it to a finely delimited region. The critical interval contains several candidate genes, one of which, Kcnj10, exhibits a potentially important polymorphism with regard to fundamental aspects of seizure susceptibility.