Early graft failure after infrainguinal arterial bypass.

INTRODUCTION: Early graft failure (EGF), defined as failure within 30 days of an index procedure, is a serious complication after infrainguinal arterial bypass. EGF has not been examined by the use of national data since the widespread adoption of percutaneous treatments for arterial occlusive disease. METHODS: We used data from the American College of Surgeons National Surgical Quality Improvement Program. Patients who underwent infrainguinal arterial bypass from 2005 to 2011 were selected from the American College of Surgeons National Surgical Quality Improvement Program database. The frequency of 30-day EGF was determined. Univariate and multivariate analyses evaluated risk factors for EGF. RESULTS: Of 23,468 patients who underwent open infrainguinal arterial bypass, 1,065 (4.5%) had EGF. Patients who had EGF were more likely to have a prolonged duration of stay (34.8% vs 12.0%, P < .001), greater rates of reoperation (82.1% vs 14.3%, P < .001) and increased 30-day mortality (5.1% vs 2.1%, P < .001). The rate of additional complications in patients who experienced EGF was 42.0%, compared with 25.4% in those who did not have EGF (P < .001). Patients who experienced complications in addition to EGF were more likely to have complications after graft failure (69.5% vs 31.3%). In multivariable analysis, EGF was associated with younger age, female sex, black race, obesity, thrombocytosis, increased international normalized ratio, femoral-to-tibial bypass, prosthetic graft, and emergent operation. CONCLUSION: The incidence of EGF after open lower extremity arterial bypass has not increased in an era of increased use of percutaneous techniques. Nevertheless, EGF occurs in almost 5% of patients and is strongly associated with additional complications and mortality. Identifying patients at risk for EGF may facilitate modification of contributing factors. Diminishing the incidence of graft occlusion will lead to decreased morbidity and mortality in this cohort of patients.

Readmission after abdominal aortic aneurysm repair: what does it mean?

Thirty-day readmission is common after AAA repair, an d postoperative events are strong predictors of readmission after adjusting for comorbidity. In addition, readmission is strongly associated with 1-year mortality. Considering the current evidence for readmission after AAA repair, improved coordination of care across the inpatient, transitional care, and outpatient settings, with active surveillance for procedure-specific (EVAR vs open) postoperative complications, may prevent some early readmissions. Given the pending financial implications and the striking association with 1-year mortality, developing interventions that target readmission after AAA repair is of paramount importance in the landscape of vascular surgery practice.

Preoperative factors predict mortality after major lower-extremity amputation.

BACKGROUND: The objective was to develop a preoperative mortality risk stratification tool for patients facing major amputation. METHODS: Patients who underwent above-knee (AKA) or below-knee amputation (BKA) from 2005 to 2010 were identified from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database. Univariate and multivariate analyses were performed to determine the association of preoperative factors with 30-day mortality. Multivariable models were used to create a computerized prediction tool. RESULTS: Of 9,368 patients, 4,032 underwent AKA and 5,336 BKA. The 30-day mortality rate after AKA was 12.8%, almost double that of BKA (6.5%, P < .001). The complication rate was statistically greater after AKA although numerically similar (28.5% vs 26.6%, P = .020), whereas the rate of reoperation was substantially greater after BKA (22.7% vs 11.7%, P < .001). Preoperative factors that predicted mortality after both procedures included older age, dependent functional status, dialysis, steroid use, preoperative sepsis, delirium, thrombocytopenia, increased international normalized ratio, and azotemia. Prediction tools were developed and validated, and their concordance indices were 0.75 for AKA and 0.81 for BKA, indicating good predictive accuracy. CONCLUSION: Preoperative factors predict mortality after major amputation, and the risk calculator that we have developed may facilitate informed decision-making and provide realistic expectations for surgeons and patients faced with limb-threatening disease.

Causes and implications of readmission after abdominal aortic aneurysm repair.

OBJECTIVE: To determine the frequency, causes, predictors, and consequences of 30-day readmission after abdominal aortic aneurysm (AAA) repair. BACKGROUND DATA: Centers for Medicare & Medicaid Services (CMS) will soon reduce total Medicare reimbursements for hospitals with higher-than-predicted 30-day readmission rates after vascular surgical procedures, including AAA repair. However, causes and factors leading to readmission in this population have never before been systematically analyzed. METHODS: We analyzed elective AAA repairs over a 2-year period from the CMS Chronic Conditions Warehouse, a 5% national sample of Medicare beneficiaries. RESULTS: A total of 2481 patients underwent AAA repair--1502 endovascular aneurysm repair (EVAR) and 979 open aneurysm repair. Thirty-day readmission rates were equivalent for EVAR (13.3%) and open repair (12.8%). Although wound complication was the most common reason for readmission after both procedures, the relative frequency of other causes differed-eg, bowel obstruction was common after open repair, and graft complication after EVAR. In multivariate analyses, preoperative comorbidities had a modest effect on readmission; however, postoperative factors, including serious complications leading to prolonged length of stay and discharge destination other than home, had a profound influence on the probability of readmission. The 1-year mortality in readmitted patients was 23.4% versus 4.5% in those not readmitted (P < 0.001). CONCLUSIONS: Early readmission is common after AAA repair. Adjusting for comorbidities, postoperative events predict readmission, suggesting that proactively preventing, detecting, and managing postoperative complications may provide an approach to decreasing readmissions, with the potential to reduce cost and possibly enhance long-term survival.

Adjuvant chemotherapy for stage II colon cancer with poor prognostic features.

PURPOSE: Adjuvant chemotherapy is typically considered for patients with stage II colon cancer characterized by poor prognostic features, including obstruction, perforation, emergent admission, T4 stage, resection of fewer than 12 lymph nodes, and poor histology. Despite frequent use, the survival advantage conferred on patients with stage II disease by chemotherapy is yet unproven. We sought to determine the overall survival benefit of chemotherapy among patients with stage II colon cancer having poor prognostic features. PATIENTS AND METHODS: A total of 43,032 Medicare beneficiaries who underwent colectomy for stage II and III primary colon adenocarcinoma diagnosed from 1992 to 2005 were identified from the Surveillance, Epidemiology, and End Results (SEER) -Medicare database. χ(2) and two-way analysis of variance were used to assess differences in patient- and disease-related characteristics. Five-year overall survival was examined using Kaplan-Meier survival analysis and Cox proportional hazards regression with propensity score weighting. RESULTS: Of the 24,847 patients with stage II cancer, 75% had one or more poor prognostic features. Adjuvant chemotherapy was received by 20% of patients with stage II disease and 57% of patients with stage III disease. After adjustment, 5-year survival benefit from chemotherapy was observed only for patients with stage III disease (hazard ratio[HR], 0.64; 95% CI, 0.60 to 0.67). No survival benefit was observed for patients with stage II cancer with no poor prognostic features (HR, 1.02; 95% CI, 0.84 to 1.25) or stage II cancer with any poor prognostic features (HR, 1.03; 95% CI, 0.94 to 1.13). CONCLUSION: Among Medicare patients identified with stage II colon cancer, either with or without poor prognostic features, adjuvant chemotherapy did not substantially improve overall survival. This lack of benefit must be considered in treatment decisions for similar older adults with colon cancer.

Predictors of surgical site infection after open lower extremity revascularization.

OBJECTIVES: Surgical site infection (SSI) after open surgery for lower extremity revascularization is a serious complication that may lead to graft infection, prolonged hospitalization, and increased cost. Rates of SSI after revascularization vary widely, with most studies reported from single institutions. The objective of this study was to describe the rate and predictors of SSI after surgery for arterial occlusive disease using national data, and to identify any association between SSI and length of hospital stay, reoperation, graft loss, and mortality. METHODS: Patients who underwent lower extremity arterial bypass or thromboendarterectomy from 2005-2008 were identified from the American College of Surgeons National Surgical Quality Improvement Program (ACS-NSQIP) participant use files. Multivariate logistic regression identified predictors of SSI. Odds ratios were adjusted for patient demographics, comorbidities, preoperative laboratory values, and operative factors. The association between SSI and other 30-day outcomes such as mortality and graft failure was determined. RESULTS: Of 12,330 patients who underwent revascularization, 1367 (11.1%) were diagnosed with an SSI within 30 days. Multivariate predictors of SSI included female gender (odds ratio [OR], 1.4; 95% confidence interval [CI], 1.3-1.6), obesity (OR, 2.1; 95% CI, 1.8-2.4), chronic obstructive pulmonary disease (OR, 1.2; 95% CI, 1.0-1.5), dialysis (OR, 1.5; 95% CI, 1.1-2.1), preoperative hyponatremia (OR, 1.2; 95% CI, 1.0-1.4), and length of operation >4 hours (OR, 1.4; 95% CI, 1.2-1.6). SSI was associated with prolonged (>10 days) hospital stay (OR, 1.8; 95% CI, 1.4-2.1) and higher rates of 30-day graft loss (OR, 2.3; 95% CI, 1.7-3.1) and reoperation (OR, 3.7; 95% CI, 3.1-4.6). SSI was not associated with increased 30-day mortality. CONCLUSION: SSI is a common complication after open revascularization and is associated with a more than twofold increased risk of early graft loss and reoperation. Several patient and operation-related risk factors that predict postoperative SSI were identified, suggesting that targeted improvements in perioperative care may decrease complications and improve outcomes in this patient population.

Short-term outcomes after laparoscopic-assisted proctectomy for rectal cancer: results from the ACS NSQIP.

BACKGROUND: Although numerous studies have demonstrated improved short-term outcomes after laparoscopic resection of colon cancer, the benefits of laparoscopic-assisted proctectomy (LAP) for rectal cancer are less clear. The current report addresses the need for a large multi-institutional study on early outcomes after proctectomy for cancer. STUDY DESIGN: Patients who underwent elective LAP or open proctectomy for cancer during 2005 to 2009 were identified from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database. The frequency of postoperative complications and other early outcomes was determined. Multivariate logistic regression identified predictors of 30-day morbidity. Propensity scores, stratified by quintiles, were included in all multivariable models to partially adjust for nonrandom assignment of treatment. RESULTS: Of 5,420 patients who underwent surgery for rectal cancer, 4,380 underwent open proctectomy and 1,040 (19.2%) LAP. The LAP group had a lower frequency of blood transfusion (12.3% versus 4.3%; p < 0.0001) and a longer mean operative time (242 versus 219 minutes; p < 0.0001). Median length of stay was 5 days after LAP and 7 days after open resection (p < 0.0001). Although no difference in 30-day mortality was detected, the frequency of complications was less after LAP (20.5% versus 28.8%; p < 0.0001). Specifically, the frequencies of superficial surgical site infection, sepsis, respiratory complications, renal failure, and venous thromboembolism were each lower in the LAP group. After adjusting for potential confounders, the likelihood of 30-day morbidity was significantly greater in open versus laparoscopic proctectomy (odds ratio = 1.41; 95% CI, 1.19-1.68). CONCLUSIONS: Compared with open proctectomy, LAP is associated with decreased length of stay and 30-day morbidity. If ongoing randomized clinical trials confirm oncologic equivalency, LAP might eventually replace open resection as the standard of care for the treatment of patients with resectable rectal cancer.

Preoperative factors predict perioperative morbidity and mortality after pancreaticoduodenectomy.

BACKGROUND: Pancreaticoduodenectomy (PD) has long been associated with high rates of morbidity and mortality. The objective of this study was to identify preoperative risk factors for serious complications and mortality after PD and to construct a prediction tool to facilitate risk stratification prior to surgery. MATERIALS AND METHODS: Patients who underwent elective PD from 2005 to 2009 were identified from the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP) database. Multivariate logistic regression identified predictors of 30-day serious complications and mortality. A prediction tool was created and validated in a sample of 1254 patients. RESULTS: Of 4945 patients who underwent PD, 1342 (27.1%) suffered a serious complication and 127 (2.6%) died within 30 days. The most frequent complications were sepsis (15.3%), surgical site infection (13.1%), and respiratory complications (9.5%). After adjusting for potential confounders, the significant predictors of morbidity included older age, male gender, overweight and obesity, dependent functional status, chronic obstructive pulmonary disease (COPD), steroid use, bleeding disorder, leukocytosis, elevated serum creatinine, and hypoalbuminemia. Significant predictors of 30-day mortality included COPD, hypertension, neoadjuvant radiation therapy, elevated serum creatinine, and hypoalbuminemia. Multivariable models were used to construct a preoperative risk stratification tool. CONCLUSIONS: Preoperative factors are associated with perioperative outcomes after PD. The prediction tool estimates the probability of early morbidity and mortality for patients undergoing PD. The tool may be used to provide information for patient counseling during the informed consent process and to identify high-risk patients for the purpose of tailoring perioperative care.

Risk stratification for distal pancreatectomy utilizing ACS-NSQIP: preoperative factors predict morbidity and mortality.

BACKGROUND: Evaluation of risk factors for adverse outcomes following distal pancreatectomy (DP) has been limited to data collected from retrospective, primarily single-institution studies. Using a large, multi-institutional prospectively collected dataset, we sought to define the incidence of complications after DP, identify the preoperative and operative risk factors for the development of complications, and develop a risk score that can be utilized preoperatively. METHODS: The American College of Surgeons National Surgical Quality Improvement Program participant use file was utilized to identify patients who underwent DP from 2005 to 2008 by Current Procedural Terminology codes. Multivariate logistic regression analysis was performed to identify variables associated with 30-day morbidity and mortality. A scoring system was developed to allow for preoperative risk stratification. RESULTS: In 2,322 patients who underwent DP, overall 30-day complication and mortality were 28.1% and 1.2%, respectively. Serious complication occurred in 22.2%, and the most common complications included sepsis (8.7%), surgical site infection (5.9%), and pneumonia (4.7%). On multivariate analysis, preoperative variables associated with morbidity included male gender, high BMI, smoking, steroid use, neurologic disease, preoperative SIRS/sepsis, hypoalbuminemia, elevated creatinine, and abnormal platelet count. Preoperative variables associated with 30-day mortality included esophageal varices, neurologic disease, dependent functional status, recent weight loss, elevated alkaline phosphatase, and elevated blood urea nitrogen. Operative variables associated with both morbidity and mortality included high intraoperative transfusion requirement (≥3 U) and prolonged operation time (>360 min). Weighted risk scores were created based on the preoperatively determined factors that predicted both morbidity (p < 0.001) and mortality (p < 0.001) after DP. DISCUSSION: The rate of serious complication after DP is 22%. The DP-specific preoperative risk scoring system described in this paper may be utilized for patient counseling and informed consent discussions, identifying high-risk patients who would benefit from disease optimization, and risk adjustment when comparing outcomes between institutions.

Lithium inhibits carcinoid cell growth in vitro.

Carcinoids are slow growing neuroendocrine tumors that often cause debilitating symptoms due to excessive secretion of hormones such as serotonin. Surgery is the only potentially curative treatment, but many patients have unresectable metastatic disease. Lithium is a non- competitive inhibitor of GSK-3 with an established safety profile. The objective of this study was to investigate the effects of lithium on carcinoid cell growth in vitro. Lithium treatment caused a dose-dependent reduction in carcinoid cancer cell (BON and H727) growth. Western blot analysis revealed increased expression of cleaved poly (ADP-ribose) polymerase (PARP), indicating the induction of apoptosis. Lithium treatment also suppressed cellular levels of serotonin and chromogranin A. In summary, lithium inactivates GSK-3, induces apoptosis, and suppresses carcinoid cancer cell growth in vitro. The drug has been used clinically since the 19(th) century to treat a variety of diseases including bipolar disorder, and its safety profile is well documented. Therefore, based on these findings, we have undertaken a clinical trial of lithium chloride in the treatment of patients with unresectable carcinoid cancer.

Readmission after colectomy for cancer predicts one-year mortality.

OBJECTIVES: Early hospital readmission is a common and costly problem in the Medicare population. In 2009, the Centers for Medicaid and Medicare Services began mandating hospital reporting of disease-specific readmission rates. We sought to determine the rate and predictors of readmission after colectomy for cancer, as well as the association between readmission and mortality. METHODS: Medicare beneficiaries who underwent colectomy for stage I to III colon adenocarcinoma from 1992 to 2002 were identified from the Surveillance, Epidemiology, and End Results-Medicare database. Multivariate logistic regression identified predictors of early readmission and 1-year mortality. Odds ratios were adjusted for multiple factors, including measures of comorbidity, socioeconomic status, and disease severity. RESULTS: Of 42,348 patients who were discharged, 4662 (11.0%) were readmitted within 30 days. The most common causes of rehospitalization were ileus/obstruction and infection. Significant predictors of readmission included male gender, comorbidity, emergent admission, prolonged hospital stay, blood transfusion, ostomy, and discharge to nursing home. Readmission was inversely associated with hospital procedure volume, but not surgeon volume. After adjusting for potential confounding variables, the predicted probability of 1-year mortality was 16% for readmitted patients, compared with 7% for those not readmitted. This difference in mortality was significant for all stages of cancer. CONCLUSIONS: Early readmission after colectomy for cancer is common and due in part to modifiable factors. There is a remarkable association between readmission and 1-year mortality. Early readmission is therefore an important quality-of-care indicator for colon cancer surgery. These findings may facilitate the development of targeted interventions that will decrease readmissions and improve patient outcomes.

Thyroid resection improves perception of swallowing function in patients with thyroid disease.

BACKGROUND: Patients with thyroid disease frequently complain of dysphagia. To date, there have been no prospective studies evaluating swallowing function before and after thyroid surgery. We used the swallowing quality of life (SWAL-QOL) validated outcomes assessment tool to measure changes in swallowing-related QOL in patients undergoing thyroid surgery. METHODS: Patients undergoing thyroid surgery from May 2002 to December 2004 completed the SWAL-QOL questionnaire before and one year after surgery. Data were collected on demographic and clinicopathologic variables, and comparisons were made to determine the effect of surgery on patients' perceptions of swallowing function. RESULTS: Of 146 eligible patients, 116 (79%) completed the study. The mean patient age was 49 years, and 81% were female. Sixty-four patients (55%) underwent total thyroidectomy and the remainder received thyroid lobectomy. Thirty patients (26%) had thyroid cancer. The most frequent benign thyroid conditions were multinodular goiter (28%) and Hashimoto's thyroiditis (27%). Mean preoperative SWAL-QOL scores were below 90 for nine of the eleven domains, indicating the perception of impaired swallowing and imperfect QOL. After surgery, significant improvements were seen in eight SWAL-QOL domains. Recurrent laryngeal nerve injury was associated with dramatic score decreases in multiple domains. CONCLUSIONS: In patients with thyroid disease, uncomplicated thyroidectomy leads to significant improvements in many aspects of patient-reported swallowing-related QOL measured by the SWAL-QOL instrument.

Older age and larger tumor size predict malignancy in hürthle cell neoplasms of the thyroid.

BACKGROUND: Hürthle cell neoplasms (HCNs) are rare tumors of the thyroid gland. The definitive treatment for Hürthle cell carcinoma (HCC) is total thyroidectomy, while thyroid lobectomy is adequate for Hürthle cell adenoma (HCA). However, differentiating HCC from HCA either before or during surgery is a challenge. The purpose of this study was to identify factors that predict malignancy in patients with HCN. METHODS: Between May 1994 and January 2007, 1,199 patients underwent thyroid surgery at an academic medical center. Medical records of 55 consecutive patients who underwent thyroid resections for the preoperative diagnosis of HCN were reviewed. RESULTS: Of the 55 patients with HCN, 46 (84%) had adenomas and 9 (16%) had carcinomas. Patients with HCC were significantly older than those with HCA (66 +/- 6 years versus 53 +/- 2 years, P = 0.01). Patients with carcinoma also had significantly larger thyroid nodules (4.5 +/- 0.7 cm versus 2.5 +/- 0.2 cm, P < 0.001). All HCNs less than 2 cm in diameter were benign. The malignancy rate increased with nodule size: 18% of nodules measuring 2-4 cm, and 44% of those larger than 4 cm were HCC. One patient with HCC had recurrence of the disease, but there were no disease-related deaths. CONCLUSION: Advanced patient age and larger nodule size are two important factors that predict malignancy in patients with HCN. In patients with these and other known risk factors for HCC, total thyroidectomy should be considered.

Valproic acid activates Notch1 signaling and induces apoptosis in medullary thyroid cancer cells.

OBJECTIVE: To examine the effects of valproic acid (VPA) on Notch1 expression and cancer cell proliferation in medullary thyroid cancer (MTC) cells. BACKGROUND: Other than surgery, there are no effective treatments for MTC, a neuroendocrine malignancy that frequently metastasizes. We have previously shown that over-expression of Notch1 in MTC cells inhibits cell growth and hormone production. VPA, a drug long used for the treatment of epilepsy, has recently been identified as a potential Notch1 activator. We hypothesized that VPA might activate Notch1 signaling in MTC cells, with antiproliferative effects. METHODS: Human MTC cells were treated with VPA (0-5 mM) and Western blotting was performed to measure levels of Notch1 pathway proteins and neuroendocrine tumor markers. After confirming that VPA is a Notch1 activator in MTC cells, we performed cell proliferation assay. Finally, to determine the mechanism of growth inhibition, we measured protein levels of various markers of apoptosis. RESULTS: Notch1 was absent in MTC cells at baseline. VPA treatment resulted in an increase in both full-length and active Notch1 protein. Notch1 activation with VPA suppressed 2 neuroendocrine tumor markers, ASCL1 and chromogranin A. Importantly, VPA inhibited the growth of MTC cells in a dose-dependent manner. Immunoblot analysis demonstrated caspase activation and poly(ADP-ribose) polymerase cleavage, indicating the induction of apoptosis. CONCLUSIONS: VPA activates Notch1 signaling in MTC cells and inhibits their growth by inducing apoptosis. As the safety of VPA in human beings is well established, a clinical trial using this drug to treat patients with advanced MTC could be initiated in the near future.

Valproic acid induces Notch1 signaling in small cell lung cancer cells.

BACKGROUND: Small cell lung cancer (SCLC) is an aggressive malignancy. Current treatments yield dismal survival rates. We have previously demonstrated that histone deacetylase (HDAC) inhibitors can inhibit neuroendocrine tumor growth. Activation of the Notch1 signaling pathway also impairs SCLC cell viability. In this study, we investigated the ability of the HDAC inhibitor valproic acid (VPA) to activate Notch1 signaling and inhibit proliferation in SCLC cells. MATERIALS AND METHODS: DMS53 human SCLC cells were treated with VPA (0-10 mM) for 2 d. Light microscopy was used to examine changes in cell morphology. Western analysis was performed using antibodies against various Notch1 pathway proteins to assess Notch1 activation. Additionally, immunoblotting was performed for two neuroendocrine tumor markers, chromogranin A and achaete-scute complex-like 1. Finally, a cell proliferation assay was used to measure the effects of VPA on SCLC growth over 8 d. RESULTS: After treatment with VPA, DMS53 cells underwent dramatic changes in morphology. VPA induced expression of the full-length and active forms of Notch1 protein. Furthermore, VPA suppressed levels of neuroendocrine tumor markers chromogranin A and ASLC-1. Importantly, VPA treatment led to dose-dependent inhibition of SCLC cell proliferation. CONCLUSIONS: The HDAC inhibitor VPA activates Notch1 signaling in SCLC cells. VPA induces changes in cell morphology and suppresses neuroendocrine tumor markers, indicating a change in phenotype. Additionally, VPA profoundly inhibits SCLC cell growth. These results suggest that VPA has potential as a novel therapeutic agent for SCLC.

The role of intraoperative frozen section if suspicious for papillary thyroid cancer.

BACKGROUND: Optimal surgical intervention is straightforward when a fine-needle aspiration (FNA) is diagnostic for papillary thyroid cancer (PTC). However, if there are characteristics of an aspirate suspicious for PTC but not meeting criteria for diagnosis of PTC, the management is less clear. METHODS: Of the 1,051 patients who underwent thyroid surgery at the University of Wisconsin between May 24, 1994, and October 21, 2004, 102 had preoperative FNA cytology that was diagnostic or suspicious for PTC. Within the subgroups of diagnostic for PTC and suspicious for PTC, we evaluated the accuracy of FNA, the utility of frozen section (FS), and the predictive value of demographic and pathologic variables. RESULTS: When diagnostic for PTC, FNA was 97% accurate and FS did not alter management. However, if an FNA was interpreted as suspicious for PTC, there was a 57% (17/30) likelihood of PTC on permanent histology. In this subgroup, FS led to the optimal operative procedure in 96% (25/26) of cases. With the exception of size greater than 4 cm, demographic and pathologic variables did not predict malignancy or increase the likelihood of an FNA being diagnostic for PTC. CONCLUSION: Intraoperative FS is a useful diagnostic tool when an FNA is suspicious for PTC.

Suberoyl bis-hydroxamic acid activates Notch-1 signaling and induces apoptosis in medullary thyroid carcinoma cells.

Medullary thyroid carcinoma (MTC) is a neuroendocrine (NE) malignancy that frequently metastasizes and has limited treatments. We recently reported that ectopic expression of Notch-1 in human MTC cells suppresses growth. The objective of this study was to evaluate the ability of suberoyl bis-hydroxamic acid (SBHA) to modulate Notch-1 signaling in MTC cells. At baseline, no active Notch-1 protein was present in MTC cells. Treatment with SBHA resulted in a dose-dependent induction of the Notch-1 intracellular domain, the active form of the protein. Furthermore, with Notch-1 activation there was a concomitant decrease in achaete-scute complex-like 1 (ASCL-1), a downstream target of Notch-1 signaling, as well as the NE tumor marker chromogranin A (CgA). Transfection of Notch-1 small-interfering RNA into MTC cells blocked the effects of SBHA on Notch-1 activation, ASCL-1, and CgA. Importantly, SBHA treatment resulted in a dose-dependent decrease in cell viability. Treated cells had an increase in protein levels of cleaved caspase-3 and poly ADP-ribose polymerase, and changes in the expression of apoptotic mediators including Bcl-X(L) and Bad, indicating that the growth inhibition was a result of apoptosis. These results demonstrate that SBHA activates Notch-1 signaling, which is associated with the antiproliferative and apoptotic effects in MTC cells. Therefore, Notch-1 activation with SBHA is an attractive new strategy for the treatment of patients with MTC.

The utility of metaiodobenzylguanidine (MIBG) scintigraphy in patients with pheochromocytoma.

BACKGROUND: Radiolabeled metaiodobenzylguanidine scintigraphy (MIBG) can be used to image pheochromocytomas. While cross-sectional imaging techniques such as computed tomography (CT) or magnetic resonance imaging (MRI) usually localize the tumor, MIBG is often obtained to rule out multifocal and metastatic disease, and to corroborate anatomic imaging with functional data. We questioned the utility of MIBG in the diagnosis and management of pheochromocytoma. METHODS: All patients who received MIBG at one academic center from 1999 to 2004 were identified. For the subset of patients who received MIBG in the work-up of possible pheochromocytoma, the following data were reviewed: demographics, symptoms, results of biochemical and imaging studies, histopathological diagnosis, and management. RESULTS: A total of 60 patients received MIBG, including 27 patients for the evaluation of a possible pheochromocytoma. Biochemical testing was performed in all patients. Fourteen patients received MIBG despite normal biochemistry and an absence of risk factors such as a hereditary syndrome or prior history of pheochromocytoma. None of these 14 low-risk patients with negative biochemistry had a final diagnosis of pheochromocytoma. In the ten patients with pheochromocytoma, all tumors were localized by CT and/or MRI. Importantly, MIBG did not identify any foci of disease not seen on cross sectional imaging, and MIBG did not alter the surgical management of any patient in this series. CONCLUSIONS: In patients with clinical findings suggestive of pheochromocytoma, biochemical testing should be used to confirm the diagnosis, and cross-sectional imaging is sufficient for tumor localization. In the absence of hereditary disease or a past history of pheochromocytoma, MIBG does not alter the treatment plan and therefore should not be routinely performed. Instead, MIBG should be used selectively, such as for the rare patient with a biochemical diagnosis of pheochromocytoma and no tumor seen on exhaustive anatomical imaging.

Suberoyl bishydroxamic acid inhibits cellular proliferation by inducing cell cycle arrest in carcinoid cancer cells.

Carcinoid cancers arise from the neuroendocrine cell system of the gastrointestinal tract, lungs, and other organs. Hepatic metastases are common, and patients often suffer from endocrinopathies secondary to tumor secretion of various hormones and peptides. As complete surgical resection is often not possible because of widespread disease, new therapeutic and palliative treatments are needed. In this study, we characterized the effects of suberoyl bishydroxamic acid (SBHA), a histone deacetylase inhibitor, on the growth and neuroendocrine phenotype of carcinoid cancer cells. SBHA treatment of human gastrointestinal and pulmonary carcinoid cancer cells resulted in a dose-dependent inhibition of cell proliferation. Western blot analysis showed a decrease in cyclin D1 and an increase in p21 and p27, indicating that the mechanism of this growth inhibition is cell cycle arrest. Furthermore, SBHA treatment suppressed two neuroendocrine tumor markers, chromogranin A and achaete-scute complex-like 1. These changes in the growth and neuroendocrine phenotype of carcinoid cells were associated with activation of the Notch1 signaling cascade. We conclude that SBHA shows promise as a potential anticancer agent for the treatment of patients with advanced carcinoid tumor disease.