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Familial primary hyperparathyroidism (FPHPT) may occur due to an underlying germ-line mutation in the MEN1, CASR, or HRPT2/CDC73 genes. The disease may be undiagnosed in the absence of a history suggestive of FHPT. Young PHPT patients (≤45 years of age) are more likely to harbor occult FPHPT. A total of 1,161 (136 were ≤45 years of age) PHPT patients underwent parathyroidectomy from 2001 to 2009. Thirty-four patients declined participation. Sixteen patients were diagnosed in the clinical routine with FPHPT (11 MEN1, four MEN2A, and one HPT-JT) and were not included in the genetic analysis. Eighty-six young (≤45 years of age) patients with clinically non-syndromic PHPT underwent genetic analysis. Sanger sequencing of all coding regions of the MEN1, CASR, and the HRPT2/CDC73 genes was performed. Eight of 86 (9.3%) young patients with clinically non-familial PHPT displayed deleterious germ-line mutations in the susceptibility genes (4 MEN1, 3 CASR, and 1 HRPT2/CDC73). There was one insertion, one deletion, two nonsense, and four missense mutations, all predicted to be highly damaging to protein function and absent in 3,244 control chromosomes. Germ-line mutations in known susceptibility genes within young patients with PHPT, including those diagnosed in the clinical routine, was 24/102 (23.5%; 15 MEN1, four RET, three CASR, and two HRPT2/CDC73). We demonstrate that germ-line inactivating mutations in susceptibility genes are common in young patients with clinically non-familial PHPT. Thus, enhanced use of genetic analysis may be warranted in clinically non-familial young PHPT patients.

Primary hyperparathyroidism (pHPT) is a pathology associated with one or multiple hyperfunctioning parathyroid glands. The disease prevalence occurs in roughly 1-2% of the population primarily post-menopausal women. The molecular pathology of the disease is poorly understood. Elevated serum calcium levels in the setting of an inappropriately elevated parathyroid hormone level are indicative of the disease process. The ultimate treatment of the disease is to remove the hyperfunctioning gland.The aim of this thesis was to examine potential genetic and epigenetic aberrations that are potentially disease causing.The methylation signature of normal and pathological parathyroid tissue has yet to be investigated. DNA was bisulphite modified and analyzed using the Infinium HumanMethylation27 BeadChip. Distinct hierarchical clustering of genes with altered DNA methylation profiles in normal and pathologic parathyroid tissue was evident. DNA hypermethylation of CDKN2B, CDKN2A, WT1, SFRP1, SFRP2, and SFRP4 known to be important in the development of parathyroid tumors were associated with reduced gene expression in both benign and malignant parathyroid tumors.Familial primary hyperparathyroidism (FPHPT) may occur due to an underlying germ-line mutation in the MEN1, CASR, or HRPT2/CDC73 genes. Eighty-six young (≤45 years of age) patients with clinically non-syndromic PHPT underwent genetic analysis. Eight of 86 (9.3%) young patients with clinically non-familial PHPT displayed deleterious germ-line mutations in the susceptibility genes (4 MEN1, 3 CASR, and 1 HRPT2/ CDC73).Accumulation of non-phosphorylated active β -catenin has been reported to commonly occur in parathyroid adenomas from patients with primary hyperparathyroidism (pHPT). We assessed possible β-catenin stabilizing mutations in a large series of parathyroid adenomas. A total of one hundred and eighty sporadic parathyroid adenomas were examined for mutations in exon 3 of the CTNNB1gene. The mutation S33C (TCT >TGT) was detected by direct-DNA sequencing of PCR fragments in 1 out of 180 sporadic parathyroid adenomas (0.68 %).Eight matched tumor-constitutional DNA pairs from patients with sporadic parathyroid adenomas underwent whole-exome capture and high-throughput sequencing. Four of eight tumors displayed a frame shift deletion or nonsense mutations within the MEN1 gene, which was accompanied by loss of heterozygosity of the remaining wild-type allele. One tumor harbored a Y641N mutation of the histone methyltransferase EZH2 gene, previously linked to myeloid and lymphoid malignancy formation. Targeted sequencing in the additional 185 parathyroid adenomas revealed a high rate of MEN1 mutations (35%).

The authors make the point that completion appendectomy in cases of stump appendicitis should be performed laparoscopically when possible guided by CT scan findings., Background: Stump appendicitis is defined by the recurrent inflammation of the residual appendix after the appendix has been only partially removed during an appendectomy for appendicitis. Forty-eight cases of stump appendicitis were identified in the English literature. Database: The institutional CPT codes were evaluated for multiple hits of the appendectomy code, yielding a total of 3 patients. After appropriate approval from an internal review board, a retrospective chart review was completed and all available data extracted. All 3 patients were diagnosed with stump appendicitis, ranging from 2 months to 20 years after the initial procedure. Two patients underwent a laparoscopic and the one an open completion appendectomy. All patients did well and were discharged home in good condition. Conclusion: Surgeons need a heightened awareness of the possibility of stump appendicitis. Correct identification and removal of the appendiceal base without leaving an appendiceal stump minimizes the risk of stump appendicitis. If a CT scan has been obtained, it enables exquisite delineation of the surrounding anatomy, including the length of the appendiceal remnant. Thus, we propose that unless there are other mitigating circumstances, the completion appendectomy in cases of stump appendicitis should also be performed laparoscopically guided by the CT findings.

During the past decade and a half, studies of genetic predisposition, parathyroid tumorigenesis, and molecular genetics of familial hyperparathyroid disorders have started to unveil the molecular basis of pHPT. Primary HPT is found in several distinct disorders with autosomal dominant inheritance such as in multiple endocrine neoplasia type 1 (MEN1), MEN2A, the HPT-jaw tumor syndrome (HPT-JT), familial isolated hyperparathyroidism (FIHPT), autosomal dominant mild hyperparathyroidism (ADMH), and neonatal severe HPT (NSHPT).

The overwhelming mode of traumatic injury to the IVCoccurs from penetrating trauma when compared to blunt trauma.Due to the high mortality rates of IVC injuries there is only aminimal amountofdataavailableregardinglongtermfollow-upofthese patients. Most of the long term follow-up data pertaining toIVC ligation stems from patients who underwent infra-renal IVCligation.

Endocrine tumors arise from endocrine glands. Most endocrine tumors are benign but malignant variants exist. Several endocrine neoplasms display loss of parts of chromosome 11 or 18, produce hormones and responds poorly to conventional chemotherapeutics. The multiple endocrine neoplasia syndromes are mainly confined to endocrine tumors. This opens the question if there exists a single or several endocrine tumor genes.The aim of the study was to describe genetic derangements in endocrine tumors.Paper I: Investigation of mutational status of SDHAF2 in parathyroid tumors. SDHAF2 is located in the proximity of 11q13, a region that frequently displays loss in parathyroid tumors. We established that mutations in SDHAF2 are infrequent in parathyroid tumors.Paper II: Study of SDHAF2 gene expression in a cohort of benign pheochromocytomas (PCC) (n=40) and malignant PCC (n=10). We discovered a subset of benign PCC (28/40) and all malignant PCC (10/10) with significantly lower SDHAF2 expression. Benign PCC with low SDHAF2 expression and malignant tumors consistently expressing low levels of SDHAF2 were methylated in the promoter region. SDHAF2 expression was restored in vitro after treatment with 5- aza-2-deoxycytidine.Paper III: HumanMethylation27 array (Illumina) covering 27578 CpG sites spanning over 14495 genes were analyzed in a discovery cohort of 10 primary small neuroendocrine tumors (SI-NETs) with matched metastases. 2697 genes showed different methylation pattern between the primary tumor and its metastasis. We identified several hypermethylated genes in key regions. Unsupervised clustering of the tumors identified three distinct clusters, one with a highly malignant behavior.Paper IV: Loss of chromosome 18 is the most frequent genetic aberration in SI-NETs. DNA from SI-NETs were subjected to whole exome capture sequencing and high resolution SNP array. Genomic profiling revealed loss of chromosome 18 in 5 out of 7 SI-NETs. No tumor-specific somatic mutation on chromosome 18 was identified which suggests involvement of other mechanisms than point mutations in SI-NET tumorigenesis.Paper V: The cost for diagnostic genetic screening of common susceptibility genes in PCC is expensive and labor intensive. Three PCC from three patients with no known family history were chosen for exome capture sequencing. We identified three variants in known candidate genes. We suggest that exome-capture sequencing is a quick and cost-effective tool.

Adrenal aldosterone-producing adenomas (APAs) constitutively produce the salt-retaining hormone aldosterone and are a common cause of severe hypertension. Recurrent mutations in the potassium channel KCNJ5 that result in cell depolarization and Ca2+ influx cause ~40% of these tumors1. We found five somatic mutations (four altering glycine 403, one altering isoleucine 770) in CACNA1D, encoding a voltage-gated calcium channel, among 43 non-KCNJ5-mutant APAs. These mutations lie in S6 segments that line the channel pore. Both result in channel activation at less depolarized potentials, and glycine 403 mutations also impair channel inactivation. These effects are inferred to cause increased Ca2+ influx, the sufficient stimulus for aldosterone production and cell proliferation in adrenal glomerulosa2. Remarkably, we identified de novo mutations at the identical positions in two children with a previously undescribed syndrome featuring primary aldosteronism and neuromuscular abnormalities. These findings implicate gain of function Ca2+ channel mutations in aldosterone-producing adenomas and primary aldosteronism.

Background: Aldosterone producing lesions are a common cause of hypertension, but genetic alterations for tumorigenesis have been unclear. Recently, either of two recurrent somatic missense mutations (G151R or L168R) was found in the potassium channel KCNJ5 gene in aldosterone producing adenomas. These mutations alter the channel selectivity filter and result in Na+ conductance and cell depolarization, stimulating aldosterone production and cell proliferation. Because a similar mutation occurs in a Mendelian form of primary aldosteronism, these mutations appear to be sufficient for cell proliferation and aldosterone production. The prevalence and spectrum of KCNJ5 mutations in different entities of adrenocortical lesions remain to be defined. Materials and Methods: The coding region and flanking intronic segments of KCNJ5 were subjected to Sanger DNA sequencing in 351 aldosterone producing lesions, from patients with primary aldosteronism and 130 other adrenocortical lesions. The specimens had been collected from 10 different worldwide referral centers. Results: G151R or L168R somatic mutations were identified in 47% of aldosterone producing adenomas, each with similar frequency. A previously unreported somatic mutation near the selectivity filter, E145Q, was observed twice. Somatic G151R or L168R mutations were also found in 40% of aldosterone producing adenomas associated with marked hyperplasia, but not in specimens with merely unilateral hyperplasia. Mutations were absent in 130 non-aldosterone secreting lesions. KCNJ5 mutations were overrepresented in aldosterone producing adenomas from female compared to male patients (63 vs. 24%). Males with KCNJ5 mutations were significantly younger than those without (45 vs. 54, respectively; p

Papillary thyroid carcinoma (PTC) accounts for over 80% of all thyroid malignancies. The molecular pathogenesis remains incompletely clarified although activation of the RET fusion oncogenes, and RAS and BRAF oncogenes, has been well characterized. Novel technologies using genome-wide approaches to study tumor genomes and epigenomes have provided great insights into tumor development. Growing evidence shows that acquired epigenetic abnormalities participate with genetic alterations to cause altered patterns of gene expression/function. It has been established beyond doubt that promoter cytosine methylation in CpG islands, and the subsequent gene silencing, is intimately involved in cancer development. These epigenetic events very likely contribute to significant variation in gene expression profiling, phenotypic features, and biologic characteristics seen in PTC. Hypermethylation of promoter regions has also been analyzed in PTC, and most studies have focused on individual genes or a small cohort of genes implicated in tumorigenesis.

Minimally invasive parathyroidectomy (MIP) is an operative approach for the treatment of primary hyperparathyroidism (pHPT). Currently, routine use of improved preoperative localization studies, cervical block anesthesia in the conscious patient, and intraoperative parathyroid hormone analyses aid in guiding surgical therapy. MIP requires less surgical dissection causing decreased trauma to tissues, can be performed safely in the ambulatory setting, and is at least as effective as standard cervical exploration. This paper reviews advances in preoperative localization, anesthetic techniques, and intraoperative management of patients undergoing MIP for the treatment of pHPT.

Colon carcinoma metastases to the thyroid are a rare phenomena. Here we report a case of multiple malignant neoplasms where an incidental diagnosis of colon cancer was made after pathologic evaluation of the thyroid specimen.