UCHL1 loss alters the cell-cycle in metastatic pancreatic neuroendocrine tumors.

Loss of ubiquitin carboxyl-terminal hydrolase L1 (UCHL1) expression by CpG promoter hypermethylation is associated with metastasis in gastroenteropancreatic neuroendocrine tumors; however, the mechanism of how UCHL1 loss contributes to metastatic potential remains unclear. In this study, we first confirmed that loss of UCHL1 expression on immunohistochemistry was significantly associated with metastatic tumors in a translational pancreatic neuroendocrine tumor (PNET) cohort, with a sensitivity and specificity of 78% and 89%, respectively. To study the mechanism driving this aggressive phenotype, BON and QGP-1 metastatic PNET cell lines, which do not produce UCHL1, were stably transfected to re-express UCHL1. In vitro assays, RNA-sequencing, and reverse-phase protein array (RPPA) analyses were performed comparing empty-vector negative controls and UCHL1-expressing cell lines. UCHL1 re-expression is associated with lower anchorage-independent colony growth in BON cells, lower colony formation in QGP cells, and a higher percentage of cells in the G0/G1 cell-cycle phase in BON and QGP cells. On RPPA proteomic analysis, there was an upregulation of cell-cycle regulatory proteins CHK2 (1.2 fold change, p=0.004) and P21 (1.2 fold change, p=0.023) in BON cells expressing UCHL1; western blot confirmed upregulation of phosphorylated CHK2 and P21. There were no transcriptomic differences detected on RNA-Sequencing between empty-vector negative controls and UCHL1-expressing cell lines. In conclusion, UCHL1 loss correlates with metastatic potential in PNETs and its re-expression induces a less aggressive phenotype in vitro, in part by inducing cell-cycle arrest through post-translational regulation of phosphorylated CHK2. UCHL1 re-expression should be considered as a functional biomarker in detecting PNETs capable of metastasis.

CHL1 expression differentiates Hürthle cell carcinoma from benign Hürthle cell nodules.

BACKGROUND AND OBJECTIVES: Hürthle cell carcinoma (HCC) is an unusual and relatively rare type of differentiated thyroid cancer. Currently, cytologic analysis of fine-needle aspiration biopsy is limited in distinguishing benign Hürthle cell neoplasms from malignant ones. The aim of this study was to determine whether differences in the expression of specific genes could differentiate HCC from benign Hürthle cell nodules by evaluating differential gene expression in Hürthle cell disease. METHODS: Eighteen benign Hürthle cell nodules and seven HCC samples were analyzed by whole-transcriptome sequencing. Bioinformatics analysis was carried out to identify candidate differentially expressed genes. Expression of these candidate genes was re-examined by quantitative real-time polymerase chain reaction (qRT-PCR). Protein expression was quantified by immunohistochemistry. RESULTS: Close homolog of L1 (CHL1) was identified as overexpressed in HCC. CHL1 was found to have greater than 15-fold higher expression in fragments per kilobase million in HCC compared with benign Hurthle cell tumors. This was confirmed by qRT-PCR. Moreover, the immunoreactivity score of the CHL1 protein was significantly higher in HCC compared with benign Hürthle cell nodules. CONCLUSIONS: CHL1 expression may represent a novel and useful prognostic biomarker to distinguish HCC from benign Hürthle cell disease.

STMN1 is Overexpressed in Adrenocortical Carcinoma and Promotes a More Aggressive Phenotype In Vitro.

BACKGROUND: Adrenocortical carcinoma (ACC) is a rare endocrine malignancy with a poor prognosis and few therapeutic options. Stathmin1 (STMN1) is a cytosolic protein involved in microtubule dynamics through inhibition of tubulin polymerization and promotion of microtubule depolymerization, which has been implicated in carcinogenesis and aggressive behavior in multiple epithelial malignancies. We aimed to evaluate expression of STMN1 in ACC and to elucidate how this may contribute to its malignant phenotype. METHODS: STMN1 was identified by RNA sequencing as a highly differentially expressed gene in human ACC samples compared with benign adrenal tumors. Expression was confirmed by quantitative reverse transcription-polymerase chain reaction (qRT-PCR), Western blot, and immunohistochemical (IHC) staining of a tissue microarray (TMA) from two independent cohorts. The biologic relevance of STMN1 was investigated in NCI-H295R cells by lentivirus-mediated silencing. RESULTS: Differential gene expression demonstrated an eightfold increase in STMN1 messenger RNA (mRNA) in malignant compared with benign adrenal tissue. IHC showed significantly higher expression of STMN1 protein in ACC compared with normal and benign tissues. STMN1 knockdown in an ACC cell line resulted in decreased cell viability, cell-cycle arrest at G0/G1, and increased apoptosis in serum-starved conditions compared with scramble short hairpin RNA (shRNA) controls. STMN1 knockdown also decreased migration, invasion, and anchorage-independent growth compared with controls. CONCLUSIONS: STMN1 is overexpressed in human ACC samples, and knockdown of this target in vitro resulted in a less aggressive phenotype of ACC, particularly under serum-starved conditions. Further study is needed to investigate the feasibility of interfering with STMN1 as a potential therapeutic target.

Protein Expression of PTTG1 as a Diagnostic Biomarker in Adrenocortical Carcinoma.

BACKGROUND: Adrenocortical carcinoma (ACC) has a poor prognosis and there is an unmet clinical need for biomarkers to improve both diagnostic and prognostic assessment. Pituitary-tumor transforming gene (PTTG1) has been shown to modulate cancer invasiveness and response to therapy. The potential role of PTTG1 protein levels in ACC has not been previously addressed. We assessed whether increased nuclear protein expression of PTTG1 distinguished ACCs from adrenocortical adenomas (ACAs). METHODS: Patients with ACC or ACA were identified from prospective tissue banks at two independent institutions. Two tissue microarrays (TMAs) consisting of adrenal specimens from 131 patients were constructed and clinically annotated. Immunohistochemical analysis for PTTG1 and Ki-67 was performed on each TMA. RESULTS: TMA-1 (n = 80) contained 20 normal adrenals, 20 ACAs, and 40 ACCs, and the validation, TMA-2 (n = 51), consisted of 10 normal adrenals, 14 ACAs, and 27 ACCs. On TMA-1, nuclear staining of PTTG1 was detected in 12 (31%) ACC specimens, while all ACAs and normal adrenal glands were negative for PTTG1. On TMA-2, 20 (74%) of the ACC tumors demonstrated PTTG1 nuclear staining of PTTG1, and 13 (93%) ACA and 4 (44%) normal adrenal glands were negative for PTTG1. ACC tumors with increased PTTG1 protein staining had a significantly higher Ki-67 index (p < 0.001) than those with lower levels of PTTG1. CONCLUSIONS: Increased nuclear protein expression of PTTG1 was observed in malignant adrenal tumors. PTTG1 correlated with Ki-67 in two independent TMAs. PTTG1 is a promising biologic marker in the evaluation of adrenal tumors.

Well-Differentiated Thyroid Cancer Neovasculature Expresses Prostate-Specific Membrane Antigen-a Possible Novel Therapeutic Target.

Prostate-specific membrane antigen (PSMA), a type II transmembrane glycoprotein receptor, is highly expressed in prostate cancer and in the tumor neovasculature of colon, breast, and adrenocortical tumors. Here, we analyzed PSMA expression in the neovasculature of various thyroid cancer subtypes and assessed whether PSMA expression is correlated with aggressive behavior. From a prospectively maintained database, we evaluated 91 samples from 68 patients, including 37 primary differentiated thyroid cancers (DTCs) [11 classic papillary (cPTC), 9 follicular-variant (FvPTC), 11 follicular (FTC), 6 radioactive iodine-refractory (RAIR)], 5 anaplastic (ATC) carcinomas, 9 distant and 12 lymph node metastases, 21 benign thyroid nodules, and 7 normal thyroid specimens. Formalin-fixed paraffin-embedded tissue blocks were immunostained for vascular endothelial marker CD31 and PSMA with proper controls. PSMA expression was not detected in normal thyroid tissue. DTC tumors demonstrated a significantly higher PSMA expression, in regard to both intensity and percentage of vessels stained, than benign tumors (p < 0.001). Among the histologic subtypes, cPTC, FTC, and RAIR carcinomas demonstrated the highest percent of moderate to strong PSMA staining. PSMA expression was seen more frequently in specimens from distant metastases (100%) compared with specimens from only lymph node metastases (67%). PSMA is significantly overexpressed in the neovasculature of DTCs compared with normal and benign thyroid nodules specifically with increased expression in RAIR carcinomas and distant metastases. PSMA should be further explored as a novel therapeutic target for metastatic and RAIR carcinomas.

Characteristics of contralateral carcinomas in patients with differentiated thyroid cancer larger than 1 cm.

PURPOSE: Traditionally, total thyroidectomy has been advocated for patients with tumors larger than 1 cm. However, according to the ATA and NCCN guidelines (2015, USA), patients with tumors up to 4 cm are now eligible for lobectomy. A rationale for adhering to total thyroidectomy might be the presence of contralateral carcinomas. The purpose of this study was to describe the characteristics of contralateral carcinomas in patients with differentiated thyroid cancer (DTC) larger than 1 cm. METHODS: A retrospective study was performed including patients from 17 centers in 5 countries. Adults diagnosed with DTC stage T1b-T3 N0-1a M0 who all underwent a total thyroidectomy were included. The primary endpoint was the presence of a contralateral carcinoma. RESULTS: A total of 1313 patients were included, of whom 426 (32 %) had a contralateral carcinoma. The contralateral carcinomas consisted of 288 (67 %) papillary thyroid carcinomas (PTC), 124 (30 %) follicular variant of a papillary thyroid carcinoma (FvPTC), 5 (1 %) follicular thyroid carcinomas (FTC), and 3 (1 %) Hürthle cell carcinomas (HTC). Ipsilateral multifocality was strongly associated with the presence of contralateral carcinomas (OR 2.62). Of all contralateral carcinomas, 82 % were ≤10 mm and of those 99 % were PTC or FvPTC. Even if the primary tumor was a FTC or HTC, the contralateral carcinoma was (Fv)PTC in 92 % of cases. CONCLUSIONS: This international multicenter study performed on patients with DTC larger than 1 cm shows that contralateral carcinomas occur in one third of patients and, independently of primary tumor subtype, predominantly consist of microPTC.

Association of BRAF V600E Mutation and MicroRNA Expression with Central Lymph Node Metastases in Papillary Thyroid Cancer: A Prospective Study from Four Endocrine Surgery Centers.

BACKGROUND: Studies have demonstrated an association of the BRAF(V600E) mutation and microRNA (miR) expression with aggressive clinicopathologic features in papillary thyroid cancer (PTC). Analysis of BRAF(V600E) mutations with miR expression data may improve perioperative decision making for patients with PTC, specifically in identifying patients harboring central lymph node metastases (CLNM). METHODS: Between January 2012 and June 2013, 237 consecutive patients underwent total thyroidectomy and prophylactic central lymph node dissection (CLND) at four endocrine surgery centers. All tumors were tested for the presence of the BRAF(V600E) mutation and miR-21, miR-146b-3p, miR-146b-5p, miR-204, miR-221, miR-222, and miR-375 expression. Bivariate and multivariable analyses were performed to examine associations between molecular markers and aggressive clinicopathologic features of PTC. RESULTS: Multivariable logistic regression analysis of all clinicopathologic features found miR-146b-3p and miR-146b-5p to be independent predictors of CLNM, while the presence of BRAF(V600E) almost reached significance. Multivariable logistic regression analysis limited to only predictors available preoperatively (molecular markers, age, sex, and tumor size) found miR-146b-3p, miR-146b-5p, miR-222, and BRAF(V600E) mutation to predict CLNM independently. While BRAF(V600E) was found to be associated with CLNM (48% mutated in node-positive cases vs. 28% mutated in node-negative cases), its positive and negative predictive values (48% and 72%, respectively) limit its clinical utility as a stand-alone marker. In the subgroup analysis focusing on only classical variant of PTC cases (CVPTC), undergoing prophylactic lymph node dissection, multivariable logistic regression analysis found only miR-146b-5p and miR-222 to be independent predictors of CLNM, while BRAF(V600E) was not significantly associated with CLNM. CONCLUSION: In the patients undergoing prophylactic CLNDs, miR-146b-3p, miR-146b-5p, and miR-222 were found to be predictive of CLNM preoperatively. However, there was significant overlap in expression of these miRs in the two outcome groups. The BRAF(V600E) mutation, while being a marker of CLNM when considering only preoperative variables among all histological subtypes, is likely not a useful stand-alone marker clinically because the difference between node-positive and node-negative cases was small. Furthermore, it lost significance when examining only CVPTC. Overall, our results speak to the concept and interpretation of statistical significance versus actual applicability of molecular markers, raising questions about their clinical usefulness as individual prognostic markers.

Prostate-Specific Membrane Antigen Is a Potential Antiangiogenic Target in Adrenocortical Carcinoma.

CONTEXT: Adrenocortical carcinoma (ACC) is a rare tumor type with a poor prognosis and few therapeutic options. OBJECTIVE: Assess prostate-specific membrane antigen (PSMA) expression as a potential novel therapeutic target for ACC. DESIGN: Expression of PSMA was evaluated in benign and malignant adrenal tumors and 1 patient with metastatic ACC. SETTING: This study took place at a tertiary referral center. PATIENTS: Fifty adrenal samples were evaluated, including 16 normal adrenal glands, 16 adrenocortical adenomas, 15 primary ACC, and 3 ACC metastases. MAIN OUTCOME MEASURES: Demographics, PSMA expression levels via real-time quantitative polymerase chain reaction and immunohistochemistry and whole-body positron emission tomography-computed tomography standardized uptake values for 1 patient. RESULTS: qPCR demonstrated an elevated level of PSMA in ACC relative to all benign tissues (P < .05). Immunohistochemistry localized PSMA expression to the neovasculature of ACC and confirmed overexpression of PSMA in ACC relative to benign tissues both in intensity and percentage of vessels stained (78% of ACC, 0% of normal adrenal, and 3.27% of adenoma-associated neovasculature; P < .001). Those with more than 25% PSMA-positive vessels were 33 times more likely to be malignant than benign (odds ratio, P < .001). Whole-body positron emission tomography-computed tomography imaging showed targeting of anti-PSMA Zr89-J591 to 5/5 of the patient's multiple lung masses with an average measurement of 3.49 ± 1.86 cm and a standardized uptake value of 1.4 ± 0.65 relative to blood pool at 0.8 standardized uptake value. CONCLUSIONS: PSMA is significantly overexpressed in ACC neovasculature when compared with normal and benign adrenal tumors. PSMA expression can be used to image ACC metastases in vivo and may be considered as a potential diagnostic and therapeutic target in ACC.

Cost disparity between health care systems--it's not the surgeons: A cost analysis of thyroid cancer care between the United States and France.

BACKGROUND: The cost disparity between the United States and other advanced health care systems, including France, is expanding. In this report we identified the management of papillary thyroid cancer (PTC) that contribute to reimbursement disparity. METHODS: A tri-institutional, retrospective review included 200 patients with PTC (100 from the United States, 100 from France) treated by total thyroidectomy with/without central neck dissection. A cost model was generated incorporating perioperative management variables (within 1 year) and their reimbursement rates according to the 2014 US Medicare and French government fee-schedules. RESULTS: In the United States, total thyroidectomy with central neck dissection was more frequent (92% vs 35%, P < .001), median duration of stay was less (1 vs 3 days, P < .001), and use of radioactive iodine was less (66% vs 93%, P < .001), although Thyrogen stimulation was more prevalent (100% vs 43%, P < .001). Overall, the median cost per patient was greater in the United States ($14,069 vs $4,590, P < .001). Reimbursements to the hospital facility accounted for 70% of the disparity, despite lesser durations of stay. Nuclear medicine accounted for 19%, mostly from Thyrogen reimbursement despite less use of radioactive iodine. Surgeon fees accounted for 6%, followed by office visits, laboratory/imaging, anesthesia/pathology fees, and medications. CONCLUSION: The costs of management of PTC are substantially greater in the US compared with France. Efforts to decrease this disparity should focus on reimbursements for hospital facility and use of nuclear medicine imaging.

Minimal impact of calcimimetics on the management of hyperparathyroidism in chronic dialysis.

BACKGROUND: The calcimimetic drug cinacalcet has changed the prescription patterns in patients with secondary hyperparathyroidism, despite the lack of randomized studies that compare cinacalcet with conventional treatment, including parathyroidectomy. The aim of this study was to evaluate current management of patients on chronic dialysis with incidental and parathyroid hormone (PTH) levels ≥ 500 ng/L. METHODS: Prospective pharmacoepidemiologic study of chronic dialysis patients with PTH level ≥ 500 ng/L. RESULTS: We studied 269 patients. Among the 186 patients who had 2-year follow-up, 125 (67%) were managed using cinacalcet. At 2 years, when comparing the cinacalet with the noncinacalet groups, we found that mean PTH values were 400 ± 318 versus 388 ± 251 ng/L (P = ns) and the percentage of patients following 2009 PTH Kidney Disease Improving Global Outcomes (KDIGO) guidelines were 79 versus 85% (P = ns). Eight patients (4%) underwent parathyroidectomy. On multivariate analysis, the use of cinacalcet was not a predictor for PTH within KDIGO guidelines at 2-year follow-up. CONCLUSION: Cinacalcet was used in the majority (67%) of patients on chronic dialysis with secondary hyperparathyroidism, but the use of cinacalcet did not affect mean PTH values nor the proportion of patients following KDIGO guidelines compared with patients not using calcimimetics.

BRAVO esophageal pH monitoring: more cost-effective than empiric medical therapy for suspected gastroesophageal reflux.

INTRODUCTION: Early referral for catheter-based esophageal pH monitoring is more cost-effective than empiric proton-pump inhibitor (PPI) therapy to diagnose gastroesophageal reflux disease (GERD). We hypothesize that BRAVO wireless pH monitoring will also demonstrate substantial cost-savings compared to empiric PPI therapy, given its superior sensitivity and comfort. METHODS: We reviewed 100 consecutive patients who underwent wireless pH monitoring for suspected GERD at our institution. A cost model and a cost equivalence calculation were generated. Cost-saving analyses were performed for both esophageal and extraesophageal symptoms. RESULTS: Eighty-seven patients were available for analysis. Median PPI use prior to referral was 215 weeks (range 0-520). Forty-three patients (49 %) had BRAVO results diagnosing GERD; 98 % of these had esophageal symptoms. Patients with negative BRAVO studies had a median of 113 (0-520) weeks of unnecessary PPI therapy. Cost-savings ranged from $1048 to $15,853 per patient, depending on sensitivity (75-95 %), PPI dosage, and brand. Maximum cost-savings occurred in patients with extraesophageal symptoms ($2948-$31,389 per patient). The PPI cost equivalence of BRAVO placement was 36 and 6 weeks for low- and high-dose therapy, respectively. CONCLUSIONS: BRAVO wireless pH testing is more cost-effective than prolonged empiric medical management for GERD and should be incorporated early in the treatment algorithm.

General surgery training and robotics: Are residents improving their skills?

BACKGROUND: While robotic-assisted operations have become more prevalent, many general surgery residencies do not have a formal robotic training curriculum. We sought to ascertain how well current general surgery training permits acquisition of robotic skills by comparing robotic simulation performance across various training levels. STUDY DESIGN: Thirty-six participants were categorized by level of surgical training: eight medical students (MS), ten junior residents (JR), ten mid-level residents (MLR), and eight senior residents (SR). Participants performed three simulation tasks on the da Vinci (®) Skills Simulator (MatchBoard, EnergyDissection, SutureSponge). Each task's scores (0-100) and cumulative scores (0-300) were compared between groups. RESULTS: There were no differences in sex, hand dominance, video gaming history, or prior robotic experience between groups; however, SR was the oldest (p < 0.001). The median overall scores did not differ: 188 (84-201) for MS, 183 (91-234) for JR, 197 (153-218) for MLR, and 205 (169-229) for SR (p = 0.14). The median SutureSponge score was highest for SR (61, range 39-81) compared to MS (43, range 26-61), JR (43, range 11-72), and MLR (55, range 36-68) (p = 0.039). However, there were no significant differences in MatchBoard (p = 0.27) or EnergyDissection (p = 0.99) scores between groups. There was a positive correlation between SutureSponge score and number of laparoscopic cases logged (p = 0.005, r(2) = 0.21), but this correlation did not exist for the MatchBoard or EnergyDissection tasks. Lastly, there was no correlation between total lifetime hours of video gaming and overall score (p = 0.89, R(2) = 0.0006). CONCLUSIONS: Robotic skillsets acquired during general surgery residency show minimal improvement during the course of training, although laparoscopic experience is correlated with advanced robotic task performance. Changes in residency curricula or pursuit of fellowship training may be warranted for surgeons seeking proficiency.

More art than science: impedance analysis prone to interpretation error.

BACKGROUND: Impedance monitoring for reflux evaluation does not have standardized scoring, which can confound interpretation between observers. We investigated the variability of impedance testing interpretation between physicians and computer software. METHODS: Raw impedance data from 38 patients that underwent impedance monitoring at a tertiary referral center between 2008 and 2013 were collected. Two physicians and computer software each analyzed the same impedance dataset for reflux activity and symptom-reflux correlation. RESULTS: Normalized reflux activity interpretations did not differ between physicians and the computer for acid or non-acid reflux. However, for weakly acidic reflux, there was significant difference between physicians (p < 0.01) and between physician and computer (p < 0.01). In analyzing all reflux, significant variability existed between physicians (p < 0.01) but not between physician and computer. Variability in interpretation altered diagnosis in 24 % of patients when comparing between physicians, 18 % of patients when comparing both physicians to the computer, and an additional 24 % of cases when comparing a single physician to the computer. Symptom-reflux correlation differed in 7 % of physician-physician comparisons versus 8 % of computer-physician comparisons. CONCLUSION: Impedance testing analysis is subject to marked variability between physicians and computer software, making impedance prone to interpretation error that can lead to differences in diagnosis and management.

Navigating the management of follicular variant papillary thyroid carcinoma subtypes: a classic PTC comparison.

BACKGROUND: There are three subtypes of follicular variant papillary thyroid carcinoma (fvPTC): completely encapsulated, well circumscribed, and infiltrative. While infiltrative tumors are more aggressive than completely encapsulated, controversy exists regarding management of fvPTC subtypes. We compared the clinicopathologic features of fvPTC subtypes to those of classic PTC (cPTC) to help guide fvPTC management, using cPTC as a reference. METHODS: A retrospective review was performed on 316 patients with PTC treated at a single institution from 2004 to 2011. There were 197 cPTC and 119 fvPTC tumors, including completely encapsulated (n = 46), well circumscribed (n = 46), and infiltrative (n = 27). Clinicopathologic data were compared between groups. RESULTS: fvPTC patients had larger tumors than cPTC patients (1.6 cm vs. 1.2 cm, p = 0.001), but age, sex, and family history did not differ. Thirty-one percent of cPTC tumors had extrathyroidal extension compared to 0 % of completely encapsulated, 0 % of well-circumscribed, and 52 % of infiltrative fvPTC tumors (p < 0.05). Central lymph node metastasis occurred in 50 % of cPTC compared to 0 % in completely encapsulated, 20 % in well-circumscribed, and 72 % in infiltrative fvPTC tumors (p < 0.05). Notably, lymph node metastasis was significantly lower in completely encapsulated than in well-circumscribed tumors, without a difference in the median number of nodes sampled. There were no differences in lymphovascular invasion or extranodal extension. CONCLUSIONS: Like cPTC tumors, infiltrative fvPTC tumors have aggressive clinicopathologic features and thus should be treated similarly. Conversely, completely encapsulated and well-circumscribed tumors have less aggressive features compared to cPTC and are more self-limiting; however, well-circumscribed tumors still have a notable incidence of lymph node metastasis. Clinicians should consider this variability in their management algorithm for fvPTC.

Genomic medicine for cancer diagnosis.

Genomic diagnostics in cancer has evolved since the completion of the Human Genome Project and the advancements made in diagnosis and therapy in chronic myelogenous leukemia. Among the diseases to achieve limited success or potentially benefit from diagnostic genetic testing are thyroid cancer, Burkitt's lymphoma, gastrointestinal stromal tumors, adrenocortical carcinoma, and colorectal cancer. With increased understanding of genomics, genetic tests should improve diagnosis and help guide medical and surgical management.

Aldosteronoma resolution score predicts long-term resolution of hypertension.

BACKGROUND: The Aldosteronoma Resolution Score (ARS) takes into consideration four, readily available, preoperative clinical parameters in predicting the likelihood of resolution of hypertension in patients 6 months after undergoing unilateral adrenalectomy for aldosterone-producing adenoma (APA). We sought to determine the durability of this predictive model after 1 year. METHODS: Sixty patients who underwent unilateral adrenalectomy for APA at a single institution between 2004 and 2013 were reviewed retrospectively. Patients who were normotensive without any antihypertensive medication requirement at greater than 1-year follow-up were considered to have complete resolution of hypertension. RESULTS: Forty-seven patients had data available for analysis. Median follow-up was 1,135 days (371-3,202). Forty-five percent of patients had complete resolution, 45% had improvement, and 10% had no improvement in hypertension. Applying the ARS, we found there was complete resolution of hypertension in 73% of patients with ARS 4-5, 53% of patients with ARS 2-3, and 24% of patients with ARS 0-1 compared with 75% (P = .9), 46% (P = .66), and 28% (P = .76), respectively, in the original cohort used to create the ARS. CONCLUSION: Most patients (90%) have long-term improvement or complete resolution of hypertension after unilateral adrenalectomy for APA. The ARS predicts accurately a patient's likelihood of complete resolution of hypertension beyond 1 year.

Management of hypertension in primary aldosteronism.

Hypertension causes significant morbidity and mortality worldwide, owing to its deleterious effects on the cardiovascular and renal systems. Primary hyperaldosteronism (PA) is the most common cause of reversible hypertension, affecting 5%-18% of adults with hypertension. PA is estimated to result from bilateral adrenal hyperplasia in two-thirds of patients, and from unilateral aldosterone-secreting adenoma in approximately one-third. Suspected cases are initially screened by measurement of the plasma aldosterone-renin-ratio, and may be confirmed by additional noninvasive tests. Localization of aldostosterone hypersecretion is then determined by computed tomography imaging, and in selective cases with adrenal vein sampling. Solitary adenomas are managed by laparoscopic or robotic resection, while bilateral hyperplasia is treated with mineralocorticoid antagonists. Biochemical cure following adrenalectomy occurs in 99% of patients, and hemodynamic improvement is seen in over 90%, prompting a reduction in quantity of anti-hypertensive medications in most patients. End-organ damage secondary to hypertension and excess aldosterone is significantly improved by both surgical and medical treatment, as manifested by decreased left ventricular hypertrophy, arterial stiffness, and proteinuria, highlighting the importance of proper diagnosis and treatment of primary hyperaldosteronism. Although numerous independent predictors of resolution of hypertension after adrenalectomy for unilateral adenomas have been described, the Aldosteronoma Resolution Score is a validated multifactorial model convenient for use in daily clinical practice.

Use of hybrid vascular grafts in failing access for hemodialysis: report of two cases.

Purpose: Vascular access morbidity represents one of the most common indications for readmission in patients with end-stage renal disease (ESRD). We report the use of hybrid grafts in two patients for revision of failed vascular access for hemodialysis (HD). Case Presentations: The first patient was a 45-year-old woman with ESRD who presented with an arteriovenous graft (AVG) that had required multiple interventions for maintenance in whom much of the graft was lined with covered stents. The patient presented with erosion of a stent in the AVG through the skin to the emergency department. The second patient was a 41-year-old man with ESRD who also had an AVG that had required multiple interventions for maintenance. He presented to clinic with chronic bleeding from the AVG after HD sessions. Both patients were taken to the operating room for salvage of part of the AVG through the use of hybrid vascular access grafts. The patients have passed six and three months from the procedure, respectively, without needing additional interventions. Conclusions: This technique demonstrates successful use of hybrid vascular access grafts, specifically inside existing grafts in locations that contain stents utilizing the existing venous resources in that arm to carry out the surgical repair, thereby preserving venous capital.

Early postoperative intraperitoneal chemotherapy following cytoreductive surgery for appendiceal mucinous neoplasms with isolated peritoneal metastasis.

BACKGROUND: Although cytoreductive surgery and intraperitoneal chemotherapy have been advocated as standard treatment for appendiceal neoplasms with isolated peritoneal metastasis, the optimal method of chemotherapy administration has not been established. At our institution, patients undergoing complete cytoreduction in this setting typically receive multiple cycles of early postoperative intraperitoneal chemotherapy. OBJECTIVES: The aim of this study was to describe patients with appendiceal neoplasms and peritoneal dissemination treated with complete cytoreductive surgery and early postoperative intraperitoneal chemotherapy and to document associated time to progression and morbidity. DESIGN: This is a retrospective study at a single specialty institution. Hospital and departmental databases were searched for patients presenting with primary appendiceal neoplasms undergoing cytoreductive surgery, placement of intraperitoneal port, and subsequent intraperitoneal chemotherapy from June 1995 to September 2009. SETTINGS: This study was conducted at Memorial Sloan-Kettering Cancer Center. PATIENTS: We identified 50 patients (30 female), median age 48 (range, 26-66) who met the criteria. INTERVENTIONS: Cytoreductive surgery, placement intraperitoneal port, and intraperitoneal chemotherapy were performed. RESULTS: All patients underwent intraperitoneal catheter placement after complete cytoreductive surgery, followed by a median of 4 cycles (range, 1-9) intraperitoneal 5-fluoro-2'-deoxyuridine (1000 mg/m daily for 3 days) plus leucovorin (240 mg/m). The median hospital length of stay was 9 days (maximum, 29). Thirty-four percent of the patients experienced complications; 12% experienced major complications (3 abdominal abscesses, 1 deep vein thrombosis, 1 abdominal hemorrhage, and 1 intraperitoneal port malfunction). There were no 30-day mortalities. Five-year recurrence-free interval was observed in 43%. Among 23 patients with recurrence, 18 had a recurrence only within the peritoneum. The median overall survival was 9.8 years. LIMITATIONS: This is a retrospective study. Many patients had surgery first at other institutions; therefore, pathologic examination of resected material was not possible in every case. Other factors possibly impacting time to recurrence (ie, preoperative chemotherapy, duration between onset of disease and presentation to our institution) varied among patients and were not controlled for. In the absence of a control arm undergoing complete cytoreduction without early postoperative intraperitoneal chemotherapy, we did not ascertain whether intraperitoneal chemotherapy confers additional benefit. CONCLUSIONS: Cytoreductive surgery plus multiple cycles of early postoperative intraperitoneal chemotherapy is safe, achieving survival results similar to published outcomes of other protocols (including hyperthermic intraperitoneal chemotherapy). Prospective trials are warranted to compare various methods of intraperitoneal chemotherapy in this setting.

Contemporary predictors of conversion from laparoscopic to open appendectomy.

BACKGROUND: We defined the contemporary conversion rate from laparoscopic appendectomy (LA) to open appendectomy and identified pre-operative factors associated with conversion. METHODS: Retrospective review of 941 consecutive LAs performed for suspected acute appendicitis in a single urban university hospital between 2000 and 2007. Patient characteristics, clinical features, physical examination findings, laboratory values, computed tomography (CT) findings, surgeon identity, operative findings, and pathologic results were assessed. Categorical variables were compared in patients undergoing LA and those in whom conversion was necessary using the Fisher exact test; the Student t-test was used to compare continuous variables. Multivariable analysis was performed with binomial logistic regression. Statistical significance was established at α = 0.05. RESULTS: The overall conversion rate was 4.1% and did not change significantly over the course of the study. By univariable analysis, conversion was significantly associated with older age, male gender, American Society of Anesthesiologists (ASA) score >2 points, longer duration of symptoms, rigidity on physical examination, increased percentage of neutrophils on admission white blood cell differential count, extraluminal air on CT, inexperience of the attending surgeon with LA, retrocecal location of the appendix, gross necrosis or perforation, murky or purulent ascites, and microscopic evidence of perforation. By multivariable analysis, advanced age (hazard ratio [HR] 1.02 per year; 95% confidence interval [CI] 1.01-1.04, p = 0.02), ASA score >2 points (HR 11.2; 95% CI 5.6-24.4; p < 0.001), CT inflammation grade ≥ 4 (HR 4.8; 95% CI 1.9-12.3; p = 0.001), and attending surgeon inexperience (HR 7.4; 95% CI 2.6-20.8; p < 0.001) were independent predictors of conversion. CONCLUSION: The conversion rate during laparoscopic appendectomy has not changed significantly over the past seven years and remains ~4%. Independent pre-operative predictors of conversion are advanced age, ASA score >2 points, attending surgeon inexperience, and extensive inflammation observed on pre-operative CT scan. Proceeding directly with open appendectomy under these circumstances may reduce operative time, expense, and morbidity.