David Yu Greenblatt

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.

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.

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.

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.

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.

Fine-needle aspiration optimizes surgical management in patients with thyroid cancer

BackgroundFine-needle aspiration (FNA) is accurate in diagnosing papillary, medullary, and anaplastic thyroid cancer, as well as lymphoma. Although many surgeons routinely perform FNA before surgery, some question whether FNA influences operative management. Therefore, to determine whether FNA affects surgical management in patients with thyroid cancer, we reviewed our experience.MethodsA total of 442 consecutive patients underwent thyroid surgery at 1 academic center. Of these, 411 had surgery for an index nodule in the absence of previous radiation or familial thyroid cancer. FNA, operative, and permanent histology findings were reviewed.ResultsThe average patient age was 46 years, and 79% were female. A total of 211 patients (51%) had a preoperative FNA, and 71 (17%) had a final diagnosis of cancer. The sensitivity and specificity of FNA for thyroid cancer were 89% and 92%, respectively. In the FNA group, 1 (2.4%) of 41 patients with papillary thyroid cancer required completion thyroidectomy. In contrast, in the no-FNA group, 4 (40%) of 10 patients with papillary thyroid cancer required a second operation. No patient in the FNA group received thyroid resection for lymphoma, whereas three (100%) of three patients with lymphoma in the no-FNA group were treated surgically. A total of 98% of the FNA group, compared with 54% of the no-FNA group, received optimal surgical treatment for thyroid cancer.ConclusionsFNA is a sensitive and specific test for the diagnosis of thyroid cancer, allowing definitive initial surgery and avoiding unnecessary procedures. Therefore, we recommend routine use of preoperative thyroid FNA, even in those patients in whom a resection is already planned.

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 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.

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.

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.