Gregory D. Kennedy

Epstein-Barr virus provides a survival factor to Burkitt's lymphomas

Epstein-Barr virus (EBV) has been causally associated with at least five human malignancies. The exact contributions made by EBV to these cancers remain unknown. We demonstrate that one viral protein found in all EBV-associated malignancies, Epstein-Barr nuclear antigen 1 (EBNA-1), is required for survival of one of these cancers, EBV-positive Burkitts lymphoma. Inhibition of EBNA-1 decreases survival of these tumor cells by inducing apoptosis. Expression of EBNA-1 in uninfected cells also can inhibit apoptosis induced by expression of p53 in the absence of the EBV genome. Our findings demonstrate that EBNA-1 is critical for the continued survival of EBV-associated Burkitts lymphoma, and, by extension, for the other B cell tumors with which EBV is associated. Efficient inhibitors of EBNA-1s functions would likely prove useful in the therapy of EBV-associated malignancies.

Mortality by Stage for Right- Versus Left-Sided Colon Cancer: Analysis of Surveillance, Epidemiology, and End Results–Medicare Data

PURPOSE Recent studies have reported increased mortality for right-sided colon cancers but had limited adjustment for patient characteristics and conflicting results by stage. We examined the relationship between colon cancer location (right- v left-side) and 5-year mortality by stage. PATIENTS AND METHODS We identified Medicare beneficiaries from 1992 to 2005 with American Joint Commission on Cancer stages I to III primary adenocarcinoma of the colon who underwent surgery for curative intent through Surveillance, Epidemiology, and End Results (SEER) -Medicare data. Adjusted hazard ratios (HRs) and 95% CIs for predictors of all-cause 5-year mortality were obtained by using Cox proportional hazards regression. RESULTS Of 53,801 patients, 67% had right-sided colon cancer. Patients with right-sided cancer were more likely to be older, to be women, to be diagnosed with a more advanced stage, and to have more poorly differentiated tumors. Adjusted Cox regression showed no significant difference in mortality between right- and left-sided cancers for all stages combined (HR, 1.01; 95% CI, 0.98 to 1.04; P = .598) or for stage I cancers (HR, 0.95; 95% CI, 0.88 to 1.03; P = .211). Stage II right-sided cancers had lower mortality than left-sided cancers (HR, 0.92; 95% CI, 0.87 to 0.97; P = .001), and stage III right-sided cancers had higher mortality (HR, 1.12; 95% CI, 1.06 to 1.18; P < .001). CONCLUSION When analysis was adjusted for multiple patient, disease, comorbidity, and treatment variables, no overall difference in 5-year mortality was seen between right- and left-sided colon cancers. However, within stage II disease, right-sided cancers had lower mortality; within stage III, right-sided cancers had higher mortality.

Laparoscopy decreases postoperative complication rates after abdominal colectomy: results from the national surgical quality improvement program.

Objective:Compare outcomes of non-emergent laparoscopic to open colon surgery. Background:Laparoscopy has revolutionized much of gastrointestinal surgery. Colon and rectal surgery has seen drastic changes with many of the abdominal operations being performed laparoscopically. However, data comparing recovery and complications in patients undergoing laparoscopic and open colon surgery has shown only slight benefits for laparoscopy. Given the large benefits of laparoscopy in most gastrointestinal surgical procedures, this outcome is surprising. We, therefore, have set out to test the hypothesis that laparoscopic approaches decreases postoperative complications. Methods:We have undertaken a review of the database maintained by the American College of Surgeons National Surgical Quality Improvement Program. We have identified 8660 patients who met inclusion criteria for this study. Postoperative complication data were collected for patients undergoing laparoscopic or open colon surgery. Using a combination of univariate and multivariate analyses we evaluated for statistical significance. Results:We found that laparoscopy decreased overall complications as well as individual complications. We found a decreased length of stay as well as a decreased risk for postoperative complications in the elderly. We found that laparoscopy decreased complication rate independent of the probability of morbidity statistic. Conclusions:When controlled for probability of morbidity, laparoscopy decreases the rate of postoperative complications. Given the equivalent outcomes of laparoscopic approaches, we conclude that laparoscopy should be offered to all patients who lack an absolute contraindication for laparoscopic surgery.

EBNA-1, a Bifunctional Transcriptional Activator

ABSTRACT Transient-transfection assays have been used to identify transcription factors, and genetic analyses of these factors can allow a dissection of their mechanism of activation. Epstein-Barr nuclear antigen 1 (EBNA-1) has been shown to activate transcription from transfected templates, but its ability to activate transcription from nuclear templates has been controversial. We have established cells with integrated EBNA-1-responsive templates and have shown that EBNA-1 activates transcription from these chromatin-embedded templates dose dependently. A mutational analysis of EBNA-1 has identified a domain required for transcriptional activation of integrated templates, but not of transfected templates. The ability of EBNA-1 to activate transcription from both integrated and transfected templates can be inhibited by a derivative of EBNA-1 lacking the amino acids required for activation from integrated templates. EBNA-1s mode of activating transfected templates is therefore genetically distinct from that acting on integrated templates.

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.

Survival in Stage III Colon Cancer Is Independent of the Total Number of Lymph Nodes Retrieved

BACKGROUND Retrieval of >/= 12 lymph nodes has been set as a marker of quality for surgical resection for colon cancer. The aim of our study was to determine if increasing the number of lymph nodes recovered in stage III colon cancer results in improved survival and if it does represent a reasonable quality metric. STUDY DESIGN Data from patients with stage III colon cancer from 1996 to 2001 were analyzed. Outcomes after operation (cancer-specific survival, disease-free survival, and overall survival) with or without adjuvant therapy were evaluated in 3 categories: the entire cohort, patients with N1, and patients with N2 disease. These categories were then classified into subgroups by the number of nodes (</= 12 versus >12) retrieved per specimen and whether they had 5-FU-based chemotherapy or not. RESULTS Three hundred twenty-nine patients, with a median followup of 5 years with stage III colon cancer, were identified. Five-year cancer-specific and disease-free survival was 67.2% and 59.7%, respectively. A positive correlation between number of positive lymph nodes and overall survival was found (p < 0.05). No significant association was observed between the total number (> 12 versus </= 12) of lymph nodes removed either in the entire cohort or in patients with N1 (249 patients) and N2 (80 patients) disease. CONCLUSION Accurate staging requires an appropriate operation and a concerted pathologic effort to identify lymph nodes in the colon specimen. The total number of lymph nodes analyzed for stage III colon cancer is not a prognostic indicator of cancer-specific and disease-free survival.

MicroRNA-21 as a potential colon and rectal cancer biomarker

Colorectal cancer (CRC) is one of the most common malignant diseases worldwide and the prognosis is still poor although much progress has been achieved in recent years. In order to reduce CRC-related deaths, many studies are aimed at identifying novel screening- and prognosis-related biomarkers. MicroRNAs (miRNAs) are a class of 18-27-nucleotide single-stranded RNA molecules that regulate gene expression at the post-transcriptional level. It has been demonstrated that miRNAs regulate a variety of physiological functions, including development, cell differentiation, proliferation, and apoptosis. They play important roles in various physiologic and developmental processes and in the initiation and progression of various human cancers. It has been shown that miRNAs can critically regulate tumor cell gene expression, and evidence suggests that they may function as both oncogenes and tumor suppressor genes. In CRC, miRNAs-21 is one of the most important miRNAs and is rapidly emerging as a novel biomarker in CRC, with good potential as a diagnostic and therapeutic target. In this review, we summarize the latest research findings of the clinicopathological relevance of miRNAs-21 in CRC initiation, development, and progress, highlighting its potential diagnostic, prognostic, and therapeutic application, as well as discussing future prospects.

Postoperative complications in patients with rectal cancer are associated with delays in chemotherapy that lead to worse disease-free and overall survival.

OBJECTIVE: The objective of this study was to identify the risk factors for delays in chemotherapy after rectal cancer surgery and evaluate the effects of delayed therapy on long-term outcomes. We also sought to clarify what time frame should be used to define delayed adjuvant chemotherapy. BACKGROUND: Postoperative complications have been found to influence the timing of chemotherapy in patients with colon cancer. Delays in chemotherapy have been shown to be associated with worse overall and disease-free survival in patients with colorectal cancer, although the timing of delay has not been agreed upon in the literature. STUDY DESIGN: We performed a retrospective review of a prospectively maintained rectal cancer database. Univariate analysis was used to identify risk factors for delayed chemotherapy. Kaplan-Meier curves were generated to compare overall and disease-free survival in patients based on complications and timing of chemotherapy. SETTINGS: This study was performed at the University of Wisconsin Hospital, Madison, Wisconsin, between 1995 and 2012. PATIENTS: Patients with rectal cancer who underwent proctectomy with curative intent were included in this study. OUTCOME MEASURES: Timing of chemotherapy, 30-day complications, and 30-day readmissions were the main outcome measures. RESULTS: Postoperative complications and 30-day readmissions were associated with delays in chemotherapy ≥8 weeks after surgery. Patients who received chemotherapy ≥8 weeks postoperatively were found to have worse local and distant recurrence rates and worse overall survival in comparison with patients who received chemotherapy within 8 weeks of surgery. LIMITATIONS: The limitations of this study include its retrospective nature and that it was performed at a single institution. CONCLUSIONS: We found complications and readmissions to be risk factors for delayed chemotherapy. Patients who received therapy ≥8 weeks postoperatively had worse disease-free and overall survival.

Visceral obesity is associated with outcomes of total mesorectal excision for rectal adenocarcinoma

General obesity, measured by the body mass index (BMI), increases the technical difficulty of total mesorectal excision (TME) but does not affect oncologic outcomes. The purpose of this study is to compare visceral and general obesity as predictors of outcomes of TME for rectal adenocarcinoma.

Optimizing Surgical Care of Colon Cancer in the Older Adult Population

Objective:We have undertaken the current study to evaluate factors that correlate with postoperative complications in older patients undergoing surgery for colon cancer. Patients and Methods:The database of the American College of Surgeons (ACS) National Surgical Quality Improvement Program (NSQIP) from years 2005 to 2008 was accessed. Patients age 65 and older were included according to Current Procedural Terminology and International Classification of Disease-9 codes. Preoperative and operative variables were examined and postoperative complications assessed using a combination of univariate and multivariate statistical models. Propensity score matching was used to control for nonrandomization of the database. Results:We found that patients undergoing laparoscopic (n = 2113) and open (n = 3801) surgery for the diagnosis of colon cancer were similar in age and gender. However, patients undergoing laparoscopic surgery were generally at lower risk for developing postoperative complications (16.1% vs. 25.4%, P < 0.005). Statistical models controlling for preoperative and operative variables demonstrated patients with elevated body mass index (odds ratio [OR] = 1.26), a history of chronic obstructive pulmonary disease (OR = 1.63), over age 85 (OR = 1.35), a surgery lasting longer than 4 hours (OR = 1.48), or having undergone an open operation (OR = 1.53) to have increased risk for developing postoperative complications. Propensity score match analysis confirmed these results. Conclusions:Identification of preoperative factors that predispose patients to postoperative complications could allow for the institution of protocols that may decrease these events. Furthermore, expanding the role of laparoscopy in the treatment of older patients with colon cancer may decrease rates of postoperative complications.