Validating the Modified McGill Thyroid Nodule Score for Assessment of Preoperative Risk of Pediatric Thyroid Malignancy.

OBJECTIVE: The McGill Thyroid Nodule Score (MTNS) is a preoperative tool used to predict the risk for well-differentiated thyroid cancer in adults. It was developed by a multidisciplinary team using established evidence-based risk factors for thyroid cancer. The modified McGill Thyroid Nodule Score (mMTNS) was developed to predict malignancy risk in children. A pilot study suggested the mMTNS was able to assess malignancy risk in children with indeterminate cytology on fine needle aspiration (FNA). This study seeks to validate these findings. METHODS: Retrospective chart review identified subjects who underwent FNA biopsy and subsequent resection. Each patient was assigned a score to compare to final pathology. Statistical analysis was performed with SPSS. All tests were 2-tailed and statistical significance defined p < 0.05. Logistic regression used to determine predictive values of scores. RESULTS: 46 patients ≤21 years of age underwent resection of a thyroid nodule. Female predominance of 85% (n = 39). 78% (n = 36) of patients had palpable nodule. 65% (n = 30) found to have benign pathology and 35% (n = 16) found to have malignancy. Malignant nodules associated with greater mean mMTNS compared to benign [13.63 vs 7.23]. An mMTNS greater >12 had sensitivity of 86.7%, specificity of 90.3%, positive predictive value of 81.3%, and negative predictive value of 93.3%. CONCLUSION: Our data suggests the mMTNS continues to be a useful adjunct in predicting malignancy risk of pediatric thyroid nodules. An mMTNS >12 has a high risk for malignancy, which can aid in counseling and clinical decision making, particularly when there is indeterminate cytology on FNA. LEVEL OF EVIDENCE: IV.

A Critical Appraisal of the July Effect: Evaluating Complications Following Pancreaticoduodenectomy.

BACKGROUND: 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. MATERIALS AND METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

Pediatric intussusception in Uganda: differences in management and outcomes with high-income countries.

PURPOSE: In high-income countries the presentation and treatment of intussusception is relatively rapid, and most cases are correctable with radiographically-guided reduction. In low-income countries, many delays affect outcomes and surgical intervention is required. This study characterizes the burden and outcome of pediatric intussusception in Uganda. METHODS: Prospective case series of intussusception cases from May 2015 to July 2016 at a tertiary referral hospital in Uganda. RESULTS: Forty patients were included in the study. Male to female ratio was 3:2. Average duration of symptoms before presentation was 4.5 days. Median duration of symptoms in referred patients was 4 days and 2 days in non-referred patients (P value 0.0009). All 40 patients underwent surgical treatment: 25% had resection and enterostomy, 15% had resection and primary anastomosis, 2.5% had resection, primary anastomosis and enterostomy and 57.5% underwent manual reduction. Mortality was 32% and febrile patients on admission were 20 times more likely to die (P value 0.040). CONCLUSION: Intussusception carries a high operative and mortality rate in Uganda. Referred patients presented later than non-referred patients to health facilities. Fever on examination at admission was positively associated with mortality. This disease remains a target for quality metrics in global pediatric surgery. TYPE OF STUDY: Diagnostic study. LEVEL OF EVIDENCE: III.

Whole-Exome Sequencing of Syndromic Adrenocortical Carcinoma Reveals Distinct Mutational Profile From Sporadic ACC.

Next-generation sequencing has provided genetic profiles of a large number of sporadic adrenocortical carcinomas (ACCs), but the applicability of these results to ACC cases associated with tumor predisposition syndromes is unclear. Although the germline features of these syndromes have been well described, the somatic mutational landscape of the tumors they give rise to is less clear. Our group obtained germline and tumor tissue from a pediatric patient who developed ACC during her first year of life, which was treated successfully. She was subsequently diagnosed with additional tumors later in childhood. Whole exome sequencing analysis was performed followed by in silico protein function prediction, revealing a probably deleterious germline TP53 L265P mutation. The somatic mutational burden was comparable between the index case and a previously published cohort of 40 sporadic cases, but the mutational spectrum was distinct in terms of raw base-change frequency as well as in a trinucleotide context-specific analysis. No canonical somatic genetic drivers of ACC were identified in the reported case, suggesting that syndromic adrenocortical tumors may represent a genetically distinct entity from sporadic tumors.

Prediction of Postoperative Surgical Risk: A Needs Assessment for a Medical Student Curriculum.

OBJECTIVE: Medical students' abilities to predict postoperative complications and death are unknown. We hypothesize that medical students will lack confidence in determining surgical risk and will significantly overestimate surgical risk for post-operative morbidities and mortality. DESIGN: Participants were invited to participate in an electronic, anonymous survey to assess their ability to predict surgical risk. The survey presented 7 complex clinical scenarios representative of a diverse general surgery practice. Participants were asked to assess the likelihood of different morbidities and mortality on a 0-100% scale, and predictions were compared to the ACS NSQIP risk calculator. SETTING: Yale School of Medicine, New Haven, Connecticut; Tertiary medical center PARTICIPANTS: Third year medical students on their surgery clerkship as well as general surgery residents were invited to participate. RESULTS: Most students were not confident about predicting postoperative complications (83.3%) or mortality (70.8%). Most students did not feel that the surgery clerkship adequately prepared them to assess surgical risk (69.6%). When compared to surgical residents for most presented cases (57% of cases), students and residents similarly overestimated postoperative morbidities and mortality. Estimates varied significantly, with wide 95% confidence intervals. Only 17% of NSQIP predicted estimates fell within the 95% confidence intervals. CONCLUSIONS: Medical students overestimate morbidity and mortality following surgery in complex patients. Additionally, they lack confidence in their ability to predict surgical complications. A formal curriculum for risk prediction is needed for medical students.

Association of Lowering Default Pill Counts in Electronic Medical Record Systems With Postoperative Opioid Prescribing.

Importance: Reliance on prescription opioids for postprocedural analgesia has contributed to the opioid epidemic. With the implementation of electronic medical record (EMR) systems, there has been increasing use of computerized order entry systems for medication prescriptions, which is now more common than handwritten prescriptions. The EMR can autopopulate a default number of pills prescribed, and 1 potential method to alter prescriber behavior is to change the default number presented via the EMR system. Objective: To investigate the association of lowering the default number of pills presented when prescribing opioids in an EMR system with the amount of opioid prescribed after procedures. Design, Setting, and Participants: A prepost intervention study was conducted to compare postprocedural prescribing patterns during the 3 months before the default change (February 18 to May 17, 2017) with the 3 months after the default change (May 18 to August 18, 2017). The setting was a multihospital health care system that uses Epic EMR (Hyperspace 2015 IU2; Epic Systems Corporation). Participants were all patients in the study period undergoing 1 of the 10 most common operations and discharged by postoperative day 1. Intervention: The default number of opioid pills autopopulated in the EMR when prescribing discharge analgesia was lowered from 30 to 12. Main Outcomes and Measures: Linear regression estimating the change in the median number of opioid pills and the total dose of opioid prescribed was performed. Opioid doses were converted into morphine milligram equivalents (MME) for comparison. The frequency of patients requiring analgesic prescription refills was also evaluated. Results: There were 1447 procedures (mean [SD] age, 54.4 [17.3] years; 66.9% female) before the default change and 1463 procedures (mean [SD] age, 54.5 [16.4] years; 67.0% female) after the default change. After the default change, the median number of opioid pills prescribed decreased from 30 (interquartile range, 15-30) to 20 (interquartile range, 12-30) per prescription (P < .001). The percentage of prescriptions written for 30 pills decreased from 39.7% (554 of 1397) before the default change to 12.9% (183 of 1420) after the default change (P < .001), and the percentage of prescriptions written for 12 pills increased from 2.1% (29 of 1397) before the default change to 24.6% (349 of 1420) after the default change (P < .001). Regression analysis demonstrated a decrease of 5.22 (95% CI, -6.12 to -4.32) opioid pills per prescription after the default change, for a total decrease of 34.41 (95% CI, -41.36 to -27.47) MME per prescription. There was no statistical difference in opioid refill rates (3.0% [4 of 135] before the default change vs 1.5% [2 of 135] after the default change, P = .41). Conclusions and Relevance: Lowering the default number of opioid pills prescribed in an EMR system is a simple, effective, cheap, and potentially scalable intervention to change prescriber behavior and decrease the amount of opioid medication prescribed after procedures.

Assessing Interest and Barriers for Resident and Faculty Involvement in Global Surgery.

BACKGROUND: Multiple institutions have developed international electives and sustainable global surgery initiatives to facilitate clinical, research, and outreach opportunities with hospitals in resource-poor areas. Despite increasing interest among programs, many institutions have not successfully reached potential involvement. OBJECTIVE: This study evaluates the experiences of Yale residents and faculty, measures interest in the development of an international surgical elective, and enumerates barriers to developing or participating in these opportunities. This was performed to develop a formalized elective and assess interest and capacity for surgical global health initiatives, as a seemingly increasing number of trainee applicants and residents were expressing interest in working in resource-poor settings. METHODS: Electronic survey of Yale Surgery residents and faculty analyzed using SPSS and Graphpad Prism. RESULTS: Among residents, previous global experience correlates with current interest in international opportunities, with 100% remaining interested, and 78% of those without prior experience also expressing interest (p = 0.018). Barriers to pursuing these activities included the use of vacation time, funding, scheduling, family obligations, and concern for personal safety. Among faculty, 28% of respondents have been involved internationally, and most (86%) expressed interest in additional opportunities and all were willing to take residents. Barriers to faculty participation included funding, relative value unit target reduction, protected time, and the desire for institutional support for such activities. CONCLUSIONS: A substantial proportion of residents and faculty have experience in global health and motivation to pursue additional opportunities. The main barriers to participation are not a lack of interest, but rather needs for funding support, protected time, and institutional recognition of academic contributions. These findings are being used to develop a global surgery elective and establish long-term partnerships with international colleagues.

Trainees as Agents of Change in the Opioid Epidemic: Optimizing the Opioid Prescription Practices of Surgical Residents.

OBJECTIVE: Opioid abuse has become an epidemic in the United States, causing nearly 50,000 deaths a year. Postoperative pain is an unavoidable consequence of most surgery, and surgeons must balance the need for sufficient analgesia with the risks of overprescribing. Prescribing narcotics is often the responsibility of surgical residents, yet little is known about their opioid-prescribing habits, influences, and training experience. DESIGN: Anonymous online survey that assessed the amounts of postoperative opioid prescribed by residents, including type of analgesia, dosage, and number of pills, for a series of common general surgery procedures. Additional questions investigated influences on opioid prescription, use of nonnarcotic analgesia, degree of engagement in patient education on opioids, and degree of training received on analgesia and opioid prescription. SETTING: Accreditation Council for Graduate Medical Education accredited general surgery program at a university-based tertiary hospital. PARTICIPANTS: Categorical and preliminary general surgery residents of all postgraduate years. RESULTS: The percentage of residents prescribing opioids postprocedure ranged from 75.5% for incision and drainage to 100% for open hernia repair. Residents report prescribing 166.3 morphine milligram equivalents of opioid for a laparoscopic cholecystectomy, yet believe patients will only need an average of 113.9 morphine milligram equivalents. The most commonly reported influences on opioid-prescribing habits include attending preference (95.2%), concern for patient satisfaction (59.5%), and fear of potential opioid abuse (59.5%). Only 35.8% of residents routinely perform a narcotic risk assessment before prescribing and 6.2% instruct patients how to properly dispose of excess opioids. More than 90% of residents have not had formal training in best practices of pain management or opioid prescription. CONCLUSION AND RELEVANCE: Surgical trainees are relying almost exclusively on opioids for postoperative analgesia, often in excessive amounts. Residents are heavily influenced by their superiors, but are not receiving formal opioid-prescribing education, pointing to a great need for increased resident education on postoperative pain and opioid management to help change prescribing habits.

Beyond 250: A Comprehensive Strategy to Maximize the Operative Experience for Junior Residents.

OBJECTIVES: Among surgical educators, duty-hour restrictions led to concern regarding the adequacy of operative experience during residency, especially for junior residents. The American Board of Surgery recently instituted guidelines mandating "a minimum of 250 operations by the end of the PGY-2 year". A series of programmatic and institutional changes were implemented at our institution to augment the junior resident operative experience and to exceed compliance with this mandate. METHODS: Operative data from Accreditation Council for Graduate Medical Education case logs for categorical and nondesignated preliminary interns from our large academic surgical residency were identified for 5 consecutive academic years, 2011 until 2016. American Board of Surgery In-Training Examination (ABSITE) scores were collected anonymously. The program systematically instituted the following changes: night float minimization, identification of new surgical opportunities, augmenting use of midlevel care providers, identification of rotations with suboptimal operative experiences, maximizing rotations with involvement of junior residents in the operating room, and systematic review of junior case logs. RESULTS: After implementation, average total cases for residents completing postgraduate year (PGY)-2 increased from 176 to 330 (p < 0.001). Specifically, there was an 18% increase for interns (p = 0.059) and a 118% increase for PGY-2 residents (p < 0.001). There were statistically significant increases in skin and soft tissue cases, vascular cases, endoscopy, and complex laparoscopic cases. Average case volumes for senior residents did not change. Night float time was significantly decreased (5.7 vs 3.4 wk; p = 0.04). ABSITE scores were not significantly changed during this time. CONCLUSIONS: Before implementation of these interventions, our program would have had 0% compliance with the 250 junior resident case rule. Within 12 months of implementation, total case volumes for residents completing PGY-2 increased by 88%-exceeding minimum standards. Overall, 100% programmatic compliance was achieved. Our program's experience exemplifies how mandates from the American Board of Surgery can lead to programmatic changes that improve the experience of surgical house officers.

A novel FOXO1-mediated dedifferentiation blocking role for DKK3 in adrenocortical carcinogenesis.

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 ß-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.

Pancreaticoduodenectomy Can Be Performed Safely with Rare Employment of Surgical Drains.

Use of drain remains frequent following pancreaticoduodenectomy (PD) due to concern for postoperative pancreatic fistula (POPF) and anastomotic leak development. Despite controversy, a recent randomized trial suggested omitting drainage would result in a large increase in operative mortality. This study sought to comprehensively examine the effects of forgoing drainage in the large cohort of patients undergoing PD. A prospective cohort study of two consecutive groups undergoing PD was constructed. The initial group had operative drains placed in cases subjectively concerning for POPF development; the second cohort did not undergo operative drainage. Outcomes including POPF incidence, need for reintervention, and overall morbidity were examined. A total of 106 patients were evaluated in two consecutive cohorts of 53; in the first group, 30 per cent had operative drains placed; 22.6 per cent developed POPF versus 7.5 per cent of patients in the no drainage group (P = 0.06). Despite this, no significant difference in major morbidity (Clavien ≥3, 20.8% versus 17.0%) or need for procedural reintervention (18.9% versus 15.1%) was observed. A subsequent validation cohort of 237 additional patients where drains were used only in exceptional circumstances was examined. Operative drains were placed in only 3 per cent of patients (n = 7) and 90-day mortality was 1.3 per cent (n = 3). Incidence of POPF was 8.0 per cent and the overall major complication rate was 14.8 per cent. Given such findings, it appears that drainage after PD can be avoided resulting in acceptable operative morbidity and mortality in most cases.

Pediatric incidental appendectomy: a systematic review.

Incidental appendectomy is the removal of the vermiform appendix accompanying another operation, without evidence of acute appendicitis. It is generally performed to eliminate the risk of future appendicitis. The risks and benefits of incidental appendectomy during various operations in children have been debated for over a century, but need to be revisited in light of innovations in medical practice, including minimally invasive surgery, improved imaging techniques, and use of the appendix as a tubular conduit for reconstruction. A detailed review was undertaken of the techniques, pathology, risks of appendectomy, utility of the appendix, and incidental appendectomy in the treatment of specific pediatric medical conditions. A comprehensive literature search was performed, and retrieved results were reviewed for relevance to the topic. The decision to perform a pediatric incidental appendectomy relies on informed consideration of the individual patient's co-morbid conditions, the indication for the initial operation, the future utility of the appendix, and the risk of future appendiceal pathology. The discussion includes a variety of situations and comorbid conditions that may influence a surgeon's decision to perform incidental appendectomy.

DNA copy amplification and overexpression of SLC12A7 in adrenocortical carcinoma.

BACKGROUND: Overexpression of Solute carrier family 12 member 7 (SLC12A7) promotes tumor aggressiveness in various cancers. Previous studies have identified the 5p15.33 region, containing the SLC12A7 locus, as being amplified frequently in adrenocortical carcinoma (ACC). Copy number amplifications (CNAs) may alter gene expression levels and occur frequently in ACC; however, SLC12A7 gene amplifications or expression levels have not been studied in ACC. METHODS: Fifty-five cases of clinically well-characterized ACCs were recruited for this study. Whole-exome sequencing was used to predict CNAs in 19 samples. CNA analysis was performed on an expanded cohort of 26 samples with the use of TaqMan Copy Number Assays. SLC12A7 mRNA expression was analyzed in 32 samples with real-time quantitative polymerase chain reaction and protein expression was assessed by immunohistochemistry. SLC12A7 CNAs and expression patterns were evaluated for correlation with patient and tumor characteristics. RESULTS: Whole-exome sequencing and TaqMan Copy Number Assays demonstrated SLC12A7 amplifications in 68.4% and 65.4% of ACCs tested, respectively. Furthermore, SLC12A7 copy gains were associated with increased gene expression (P < .05) and non-functional tumors (P < .05). SLC12A7 gene expression levels were increased in ACCs compared with normal adrenal tissue (P < .05). CONCLUSION: SLC12A7 gene amplification and overexpression occurs frequently in ACCs and may represent a novel molecular event associated with ACC.

Novel somatic mutations in primary hyperaldosteronism are related to the clinical, radiological and pathological phenotype.

UNLABELLED: 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 seven 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 as follows: KCNJ5, 37·1%; CACNA1D, 10·3%; ATP1A1, 8·2%; ATP2B3, 3·1%; and CTNNB1, 2·1%. Previously unidentified mutations included I157K, F154C and two 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 tumours displayed significantly greater diameter (P = 0·023), calculated area (P = 0·002) and lower precontrast Hounsfield units (P = 0·0002) vs tumours with mutations in other genes. Accordingly, KCNJ5-mutant tumours were predominantly comprised of lipid-rich fasciculata-like clear cells, whereas other tumours were heterogeneous (P = 5 × 10(-6) vs non-KCNJ5 mutant and P = 0·0003 vs wild-type tumours, respectively). CACNA1D mutations were present in two samples with hyperplasia without adenoma. CONCLUSIONS: KCNJ5-mutant tumours 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.

Proposal and critical appraisal of exclusion criteria to the international study group for pancreatic surgery definition of delayed gastric emptying.

BACKGROUND: The International Study Group for Pancreatic Surgery (ISGPS) defined criteria to objectively standardize delayed gastric emptying (DGE) after pancreaticoduodenectomy (PD). These criteria are inclusive by design, and may overestimate actual DGE incidence. This study critically examined individual DGE cases after PD to determine which patients are misclassified by these criteria, and for what reasons. Exclusion criteria designed to optimize the accepted DGE definition are proposed and evaluated. STUDY DESIGN: We performed a retrospective review of prospectively collected data. We reviewed 357 consecutive patients undergoing PD by a single surgeon; included were 52 cases of ISGPS-defined DGE (14.6%). A detailed evaluation was conducted of cases using accepted and novel diagnostic criteria. RESULTS: Of 52 ISGPS-defined DGE cases, 12 (23%) appeared not to represent genuine DGE on clinical review. Six required nasogastric tube placement for reoperation or management of emesis secondary to non-DGE conditions, 4 for reintubation without other evidence of DGE, and 2 remained NPO to treat non-DGE conditions. The proposed exclusion criteria use absence of gastric distention, passage of oral contrast, and presence of documented non-DGE conditions to determine genuine DGE. The incidence of true DGE was 11.2% in this cohort. The overall positive predictive value of the ISGPS criteria was 76.9%. Preoperative variables, DGE class, and incidence of disease-specific outcomes were similar with both definitions. CONCLUSIONS: The ISGPS consensus guidelines promote a standardized, sensitive, and easily applicable definition of DGE, but may falsely classify DGE in approximately 23.1%. Introduction of the proposed exclusion criteria, which establish objective radiologic data as a component of the definition, could substantially limit this overestimation.

Characterization of the mutational landscape of anaplastic thyroid cancer via whole-exome sequencing.

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.

Effects of preoperative long-term glycemic control on operative outcomes following pancreaticoduodenectomy.

BACKGROUND: Diabetes mellitus is postulated to be both a risk factor and manifestation of pancreatic adenocarcinoma. This study evaluated the effects of preoperative glycemic control as determined by hemoglobin A1c (HbA1c) on outcomes following pancreaticoduodenectomy (PD). METHODS: A prospective cohort study whereby HbA1c was assessed preoperatively in 243 patients undergoing PD was performed. The primary outcome measure was operative morbidity. Secondary outcomes included individual adverse events, time to dietary resumption, and length of stay. RESULTS: Preoperative HbA1c ranged from 4.0% to 13.5%. Overall morbidity and incidence of specific adverse events were similar regardless of preoperative HbA1c. No correlation between HbA1c and length of stay, dietary resumption, or readmission was observed. Pancreatic fistula formation had a decreased incidence in patients with elevated versus normal HbA1c (2.2% vs. 9.6%, P = .083). CONCLUSIONS: PD can be safely performed in patients with HbA1c levels suggestive of poor long-term preoperative glycemic control. Medical efforts to optimize HbA1c should not delay resection.

Whole-exome sequencing characterizes the landscape of somatic mutations and copy number alterations in adrenocortical carcinoma.

CONTEXT: Adrenocortical carcinoma (ACC) is a rare and lethal malignancy with a poorly defined etiology, and the molecular genetics of ACC are incompletely understood. OBJECTIVE: To utilize whole-exome sequencing for genetic characterization of the underlying somatic mutations and copy number alterations present in ACC. DESIGN: Screening for somatic mutation events and copy number alterations (CNAs) was performed by comparative analysis of tumors and matched normal samples from 41 patients with ACC. RESULTS: In total, 966 nonsynonymous somatic mutations were detected, including 40 tumors with a mean of 16 mutations per sample and one tumor with 314 mutations. Somatic mutations in ACC-associated genes included TP53 (8/41 tumors, 19.5%) and CTNNB1 (4/41, 9.8%). Genes with potential disease-causing mutations included GNAS, NF2, and RB1, and recurrently mutated genes with unknown roles in tumorigenesis comprised CDC27, SCN7A, and SDK1. Recurrent CNAs included amplification at 5p15.33 including TERT (6/41, 14.6%) and homozygous deletion at 22q12.1 including the Wnt repressors ZNRF3 and KREMEN1 (4/41 9.8% and 3/41, 7.3%, respectively). Somatic mutations in ACC-established genes and recurrent ZNRF3 and TERT loci CNAs were mutually exclusive in the majority of cases. Moreover, gene ontology identified Wnt signaling as the most frequently mutated pathway in ACCs. CONCLUSIONS: 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.