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Reports of higher rates of medical errors in the month of July have generated concern regarding major surgery at academic institutions early in the yearly promotion cycle. This study was designed to evaluate perioperative outcomes in patients undergoing pancreaticoduodenectomy (PD) at different times of the year. Outcomes were retrospectively evaluated for patients treated in July versus the rest of the year and in the first quarter (July–September) versus the remaining quarters. The primary outcome was operative morbidity as measured by Clavien-Dindo grade, a classification system of surgical complications. Secondary outcomes included mortality, operative blood loss, pancreatic fistula formation, delayed gastric emptying, intraabdominal abscess, anastomotic leak, reoperation, and other variables of interest. From January 2003 to September 2015, 472 patients underwent PD by a single academic surgeon. Overall, 77.1% of PDs were performed for malignancy. The number of patients did not significantly vary by month or by quarter. The incidence of major morbidity (Clavien-Dindo grade ≥ III) in patients who had a PD was 12.2% in July and 17.5% in all other months (P = 0.79). The rate of pancreatic fistula, intraabdominal abscess, reoperation, readmission, and mortality did not differ significantly by month or by quarter (P > 0.05 for all). The current study does not find any correlation between time of year and operative morbidity or mortality, suggesting that PD can be safely performed irrespective of timing.

The incidence of pancreatic cystic neoplasms has grown because of increased detection. Among these lesions, serous cystadenoma was traditionally thought to be universally benign and indolent. However, there is an exceedingly rare malignant variant of serous cystadenoma known as serous cystadenocarcinoma (SCAC) that can exhibit local invasion into adjacent structures, hepatic implants, and metastatic spread to the abdominal viscera. Diagnosis of SCAC can be challenging as it is histologically identical to serous cystadenoma. To better understand this entity, a review of all published accounts of SCAC was performed in which tumor and patient factors were characterized. In addition, we present the case of a 49-year-old woman who was found to have a solitary hepatic metastasis due to SCAC, 11 years after a distal pancreatectomy for serous cystadenoma. She was successfully treated with percutaneous microwave ablation and has no evidence of recurrence 3 years later. This report details the first published account of percutaneous ablation in such a setting. Compared with hepatectomy, hepatic ablation may offer a less invasive but equally effective treatment option in well-selected patients.

It is unknown how many patients with localized melanoma undergo sentinel lymph node biopsy (SLNB) or if there is a therapeutic effect from performing nodal staging. We evaluated predictors for SLNB use and assessed if there was an association with improved survival in melanoma patients who had SLNB. The Surveillance, Epidemiology, and End Results database was queried for clinically node-negative melanoma cases ≥ 0.75 mm in thickness treated from 2010 to 2012. Clinicopathologic factors were correlated with SLNB use, overall survival (OS), and melanoma-specific survival (MSS). Overall, 13,703 cases were included. SLNB was performed in 1479 of 3439 thin cases (43.0%), 5810 of 8522 intermediate-thickness cases (68.2%), and 916 of 1742 thick cases (52.6%). On multivariable analysis, age ≥ 70 years, thickness 4 mm, head/neck or trunk tumor location, being unmarried, African American race, and residing in a county with a lower level of education were significantly associated with a lower likelihood of performing SLNB (p

Pancreatic neuroendocrine tumors (PNETs) are a heterogeneous group of islet cell-derived neoplasms with a propensity toward hormone production. Among PNETs, proinsulin-secreting tumors (proinsulinomas) are exceedingly rare. The objective of this study is to collect and summarize the existing literature to provide a comprehensive evaluation of this uncommon disease. A systematic review was performed to characterize the clinicopathologic features of proinsulinoma. Using the electronic biomedical databases PubMed, Ovid Medline, and Embase, 316 publications were screened for relevance of which 14 were selected. We also present two patients with proinsulinoma treated at Yale New Haven Hospital. Of the 16 patients included in the study, the mean age was 56.8 and there was a 2:1 female predominance. The majority of patients presented with symptomatic hypoglycemia with normal or low insulin levels. Median tumor diameter was 1.2 cm and 80% were located in the body and tail of the pancreas. Following resection, most patients had normalization of hormonal levels without recurrence (75%; 12/16). Proinsulinomas are rare pancreatic neuroendocrine tumors that have the potential to cause hypoglycemia. While insulinomas and proinsulin-secreting tumors have many physiologic parallels, these cases illustrate several key distinctions in their diagnosis and management.

Adrenocortical carcinoma is a rare neoplasm with a poor prognosis. Conversely, adrenocortical adenomas are common and benign. Despite their shared histologic origin, little evidence exists to suggest that adrenocortical adenoma arises from adrenocortical carcinoma. Recent genetic analyses of adrenocortical carcinoma have shown recurrent gene copy deletion of CYP4B1, a cytochrome P450 isozyme. This study investigates a potential role for CYP4B1 in modulating adrenocortical tumorigenesis and/or conferring chemoresistance to adrenocortical carcinomas.Using TaqMan, real-time quantitative polymerase chain reaction techniques, we investigated CYP4B1 expression in normal adrenal cortex (n = 10), histologically confirmed adrenocortical adenomas (n = 10), and adrenocortical carcinomas (n = 10). Adrenocortical carcinoma cell lines were enforced to express CYP4B1, and effects on cell death and enhanced mitotane and cisplatin sensitivity were tested.Gene expression analyses demonstrated suppression of CYP4B1 in 100% of both the adrenocortical adenomas (10/10) and adrenocortical carcinomas (10/10) tested. Average relative expression of CYP4B1 was decreased at 0.19 (0.01-0.50; P .01) in adrenocortical adenomas and nearly absent in adrenocortical carcinomas (0.01; 0.00-0.05; P .01). Protein expression correlated with mRNA expression. Ectopic expression of CYP4B1 promoted cytotoxicity and increased chemosensitivity in adrenocortical carcinoma cell lines.CYP4B1 is silenced in both benign and malignant adrenocortical tumors and may contribute to tumorigenesis and chemoresistance. Sensitization of adrenocortical carcinoma cells engineered to overexpress CYP4B1 further supports this notion.

Context Sporadic, solitary parathyroid adenoma is the most common cause of primary hyperparathyroidism (PHPT). Apart from germline variants in certain cyclin-dependent kinase inhibitor genes and occasionally in MEN1, CASR, or CDC73, little is known about possible genetic variants in the population that may confer increased risk for development of typical sporadic adenoma. Transcriptionally activating germline variants, especially within in the C-terminal conserved inhibitory domain (CCID) of glial cells missing 2 (GCM2), encoding a transcription factor required for parathyroid gland development, have recently been reported in association with familial and sporadic PHPT. Objective To evaluate the potential role of specific GCM2 activating variants in sporadic parathyroid adenoma. Design and patients Regions encoding hyperparathyroidism-associated, activating GCM2 variants were PCR amplified and sequenced in genomic DNA from 396, otherwise unselected, cases of sporadic parathyroid adenoma. Results Activating GCM2 CCID variants (p.V382M and p.Y394S) were identified in six of 396 adenomas (1.52%), and a hyperparathyroidism-associated GCM2 non-CCID activating variant (p.Y282D) was found in 20 adenomas (5.05%). The overall frequency of tested activating GCM2 variants in this study was 6.57%, approximately threefold greater than their frequency in the general population. Conclusions The examined, rare CCID variants in GCM2 were enriched in our cohort of patients and appear to confer a moderately increased risk of developing sporadic solitary parathyroid adenoma compared with the general population. However, penetrance of these variants is low, suggesting that the large majority of individuals with such variants will not develop a sporadic parathyroid adenoma.

Telomere maintenance, most commonly achieved by telomerase activation through induction of the telomerase reverse transcriptase (TERT) gene, is required for cell immortalization, a hallmark of cancer. Adrenocortical carcinoma (ACC) is an endocrine tumor for which TERT promoter mutations and telomerase activation have been reported. The present study assessed alterations of the TERT gene locus and telomere length in relation to clinical characteristics in ACC. In total, 38 cases of ACC with known TERT promoter mutational status were included. TERT promoter methylation densities were assessed by pyrosequencing, and TERT copy numbers and telomere length were determined by quantitative polymerase chain reaction analysis, followed by comparison of the mRNA expression of TERT and clinical parameters. The ACC tissue samples showed increased TERT copy numbers, compared with normal adrenal tissue (NAT) samples (P=0.001). Mutually exclusive TERT copy number gains or promoter mutation were present in 70% of the ACC samples. The ACC tissues exhibited higher levels of CpG promoter methylation of all eight CpG sites investigated within the ‑578 to ‑541 bp (Region A), compared with the NATs (P=0.001). High methylation density at this region was associated with metastatic disease and/or relapse, poor survival rates and higher European Network for the Study of Adrenal Tumor stage (P

Well-differentiated thyroid cancer accounts for the majority of endocrine malignancies and, in general, has an excellent prognosis. In contrast, the less common poorly differentiated thyroid carcinoma (PDTC) and anaplastic thyroid carcinoma (ATC) are two of the most aggressive human malignancies. Recently, there has been an increased focus on the epigenetic alterations underlying thyroid carcinogenesis, including those that drive PDTC and ATC. Dysregulated epigenetic candidates identified include the Aurora group, KMT2D, PTEN, RASSF1A, multiple non-coding RNAs (ncRNA), and the SWI/SNF chromatin-remodeling complex. A deeper understanding of the signaling pathways affected by epigenetic dysregulation may improve prognostic testing and support the advancement of thyroid-specific epigenetic therapies. This review outlines the current understanding of epigenetic alterations observed in PDTC and ATC and explores the potential for exploiting this understanding in developing novel therapeutic strategies.

Background Dysregulated WNT signaling dominates adrenocortical malignancies. This study investigates whether silencing of the WNT negative regulator DKK3 (Dickkopf-related protein 3), an implicated adrenocortical differentiation marker and an established tumor suppressor in multiple cancers, allows dedifferentiation of the adrenal cortex. Methods We analyzed the expression and regulation of DKK3 in human adrenocortical carcinoma (ACC) by qRT-PCR, immunofluorescence, promoter methylation assay, and copy number analysis. We also conducted functional studies on ACC cell lines, NCI-H295R and SW-13, using siRNAs and enforced DKK3 expression to test DKK3’s role in blocking dedifferentiation of adrenal cortex. Results While robust expression was observed in normal adrenal cortex, DKK3 was down-regulated in the majority (>75%) of adrenocortical carcinomas (ACC) tested. Both genetic (gene copy loss) and epigenetic (promoter methylation) events were found to play significant roles in DKK3 down-regulation in ACCs. While NCI-H295R cells harboring β-catenin activating mutations failed to respond to DKK3 silencing, SW-13 cells showed increased motility and reduced clonal growth. Conversely, exogenously added DKK3 also increased motility of SW-13 cells without influencing their growth. Enforced over-expression of DKK3 in SW-13 cells resulted in slower cell growth by an extension of G1 phase, promoted survival of microcolonies, and resulted in significant impairment of migratory and invasive behaviors, largely attributable to modified cell adhesions and adhesion kinetics. DKK3-over-expressing cells also showed increased expression of Forkhead Box Protein O1 (FOXO1) transcription factor, RNAi silencing of which partially restored the migratory proficiency of cells without interfering with their viability. Conclusions DKK3 suppression observed in ACCs and the effects of manipulation of DKK3 expression in ACC cell lines suggest a FOXO1-mediated differentiation-promoting role for DKK3 in the adrenal cortex, silencing of which may allow adrenocortical dedifferentiation and malignancy. Electronic supplementary material The online version of this article (doi:10.1186/s12885-017-3152-5) contains supplementary material, which is available to authorized users.

Cytochrome P450-mediated metabolism of chemotherapeutic agents contributes to chemotherapy resistance in multiple malignancies. Adrenocortical carcinoma is known to have a poor response to adjuvant therapies; however, the mechanism remains unknown. Recent comprehensive genetic analyses of adrenocortical carcinomas demonstrated recurrent copy number gains in multiple cytochrome P450 genes prompting investigation into whether cytochrome P450 overexpression potentiates adrenocortical carcinoma chemoresistance.We determined the expression patterns of 6 cytochrome P450 genes (CYP2A6, CYP2A7, CYP2A13, CYP2B6, CYP2S1, and CYP4F2) predicted to be amplified in adrenocortical carcinoma (n = 29) relative to normal adrenal cortex (n = 10). Gene copy numbers were determined with the TaqMan copy number assay. Gene silencing was performed via small interfering RNA (siRNA) in the adrenocortical carcinoma cell line NCI-H295R and treated with mitotane and cisplatin.Of the 6 cytochrome P450 genes tested, CYP2A6 was overexpressed with a 55-fold mean increase compared to normal adrenal samples (P .05). Immunohistochemical analysis confirmed protein overexpression. Copy gains of CYP2A6 were found in 26% (7/27) of adrenocortical carcinoma specimens. Silencing of CYP2A6 in NCI-H295R cells resulted in decreased cell viability and increased chemosensitivity (P .05).Frequent upregulation in adrenocortical carcinomas and the reversal of chemoresistance in adrenocortical carcinoma cells via enforced silencing suggest a role for CYP2A6 in adrenocortical malignancy.