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.

Pancreatic cancer is the fourth leading cause of cancer-related death among men and women in the United States. A major challenge in treatment remains patients’ advanced disease at diagnosis. The NCCN Guidelines for Pancreatic Adenocarcinoma provides recommendations for the diagnosis, evaluation, treatment, and follow-up for patients with pancreatic cancer. Although survival rates remain relatively unchanged, newer modalities of treatment, including targeted therapies, provide hope for improving patient outcomes. Sections of the manuscript have been updated to be concordant with the most recent update to the guidelines. This manuscript focuses on the available systemic therapy approaches, specifically the treatment options for locally advanced and metastatic disease.

Anaplastic thyroid carcinoma (ATC) is a frequently lethal malignancy that is often unresponsive to available therapeutic strategies. The tumorigenesis of ATC and its relationship to the widely prevalent well-differentiated thyroid carcinomas are unclear. We have analyzed 22 cases of ATC as well as 4 established ATC cell lines using whole-exome sequencing. A total of 2674 somatic mutations (121/sample) were detected. Ontology analysis revealed that the majority of variants aggregated in the MAPK, ErbB and RAS signaling pathways. Mutations in genes related to malignancy not previously associated with thyroid tumorigenesis were observed, including mTOR, NF1, NF2, MLH1, MLH3, MSH5, MSH6, ERBB2, EIF1AX and USH2A; some of which were recurrent and were investigated in 24 additional ATC cases and 8 ATC cell lines. Somatic mutations in established thyroid cancer genes were detected in 14 of 22 (64%) tumors and included recurrent mutations in BRAF, TP53 and RAS-family genes (6 cases each), as well as PIK3CA (2 cases) and single cases of CDKN1B, CDKN2C, CTNNB1 and RET mutations. BRAF V600E and RAS mutations were mutually exclusive; all ATC cell lines exhibited a combination of mutations in either BRAF and TP53 or NRAS and TP53. A hypermutator phenotype in two cases with >8 times higher mutational burden than the remaining mean was identified; both cases harbored unique somatic mutations in MLH mismatch-repair genes. This first comprehensive exome-wide analysis of the mutational landscape of ATC identifies novel genes potentially associated with ATC tumorigenesis, some of which may be targets for future therapeutic intervention.

Adrenal tumors autonomously producing cortisol cause Cushing syndrome1–4. Exome sequencing of 25 tumor-normal pairs revealed two groups. Eight tumors (including 3 carcinomas) had many somatic copy number variants (CNV+) with frequent deletion of CDC42 and CDKN2A, amplification of 5q31.2, and protein-altering mutations in TP53 and RB1. Seventeen (all adenomas) had no CNVs (CNV-), TP53 or RB1 mutations. Six of these had known gain of function mutations in CTNNB15,6 (beta-catenin) or GNAS7,8 (Gαs), Six others had somatic p.Leu206Arg mutations in PRKACA (protein kinase A (PKA) catalytic subunit). Further sequencing identified this mutation in 13 of 63 tumors (35% of adenomas with overt CS). PRKACA, GNAS and CTNNB1 mutations were mutually exclusive. Leu206 directly interacts with PKA’s regulatory subunit, PRKAR1A9,10. PRKACAL206R loses PRKAR1A binding, increasing phosphorylation of downstream targets. PKA activity induces cortisol production and cell proliferation11–15, providing a mechanism for tumor development. These findings define distinct mechanisms underlying adrenal cortisol-producing tumors.

Parathyroid localization is indicated in surgical candidates. Crucial considerations when selecting an imaging study include availability, cost, radiation exposure, local expertise, and accuracy. Additional factors include the patient's anticipated pathology and whether it is de novo or refractory disease. An approach to imaging for patients with primary hyperparathyroidism is presented.

These findings highlight the importance of Wnt pathway dysregulation in ACC and corroborate the finding of homozygous deletion of Wnt repressors ZNRF3 and KREMEN1. Overall, mutations in either TP53 or CTNNB1 as well as focal CNAs at the ZNRF3 or TERT loci denote mutually exclusive events, suggesting separate mechanisms underlying the development of these tumors.

Summary Aldosterone-producing adenomas (APAs) and bilateral adrenal hyperplasia are important causes of secondary hypertension. Somatic mutations in KCNJ5, CACNA1D, ATP1A1, ATP2B3 and CTNNB1 have been described in APAs. Objective To characterize clinical-pathological features in APAs and unilateral adrenal hyperplasia, and correlate them with genotypes. Design Retrospective study. Subjects and Measurements Clinical and pathological characteristics of 90 APAs and 7 diffusely or focally hyperplastic adrenal glands were reviewed, and samples were examined for mutations in known disease genes by Sanger or exome sequencing. Results Mutation frequencies were: KCNJ5, 37.1%; CACNA1D, 10.3%; ATP1A1, 8.2%; ATP2B3, 3.1%; CTNNB1, 2.1%. Previously unidentified mutations included I157K, F154C and 2 insertions (I150_G151insM and I144_E145insAI) in KCNJ5, all close to the selectivity filter, V426G_V427Q_A428_L433del in ATP2B3, and A39Efs*3 in CTNNB1. Mutations in KCNJ5 were associated with female, and other mutations with male gender (p=0.007). On computed tomography, KCNJ5-mutant tumors displayed significantly greater diameter (p=0.023), calculated area (p=0.002) and lower pre-contrast Hounsfield Units (p=0.0002) vs. tumors with mutations in other genes. Accordingly, KCNJ5-mutant tumors were predominantly comprised of lipid-rich fasciculata-like clear cells, whereas other tumors were heterogeneous (p=5×10−6 vs. non-KCNJ5 mutant and p=0.0003 vs. wild type tumors, respectively). CACNA1D mutations were present in two samples with hyperplasia without adenoma. Conclusions KCNJ5 mutant tumors appear to be associated with fasciculata-like clear cell predominant histology and tend to be larger with a characteristic imaging phenotype. Novel somatic KCNJ5 variants likely cause adenomas by loss of potassium selectivity, similar to previously described mutations.

The scenarios identified by the high-risk FRS zone represent challenging anastomoses associated with markedly elevated rates of fistula. Externalized stents and omission of prophylactic octreotide, in the setting of intraperitoneal drainage and pancreaticojejunostomy reconstruction, provides optimal outcomes.