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Purpose: Pancreatic ductal adenocarcinoma (PDA) cells are known to produce excessive amounts of reactive oxygen species (ROS), particularly superoxide, which may contribute to the aggressive and refractory nature of this disease. Extracellular superoxide dismutase (EcSOD) is an antioxidant enzyme that catalyzes the dismutation of superoxide in the extracellular environment. This study tests the hypothesis that EcSOD modulates PDA growth and invasion by modifying the redox balance in PDA.Experimental Design: We evaluated the prognostic significance of EcSOD in a human tissue microarray (TMA) of patients with PDA. EcSOD overexpression was performed in PDA cell lines and animal models of disease. The impact of EcSOD on PDA cell lines was evaluated with Matrigel invasion in combination with a superoxide-specific SOD mimic and a nitric oxide synthase (NOS) inhibitor to determine the mechanism of action of EcSOD in PDA.Results: Loss of EcSOD expression is a common event in PDA, which correlated with worse disease biology. Overexpression of EcSOD in PDA cell lines resulted in decreased invasiveness that appeared to be related to reactions of superoxide with nitric oxide. Pancreatic cancer xenografts overexpressing EcSOD also demonstrated slower growth and peritoneal metastasis. Overexpression of EcSOD or treatment with a superoxide-specific SOD mimic caused significant decreases in PDA cell invasive capacity.Conclusions: These results support the hypothesis that loss of EcSOD leads to increased reactions of superoxide with nitric oxide, which contributes to the invasive phenotype. These results allow for the speculation that superoxide dismutase mimetics might inhibit PDA progression in human clinical disease. Clin Cancer Res; 21(7); 1741–51. ©2015 AACR.

Supplementary Figures 1-3. S1: Creation and characterization of EcSOD stably expressing PDA cell lines.; S2: Activity of EcSOD activity from stably expression PDA cell lines; S3: L-NNA decreases NOS activity in PDA cells.

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Supplementary Table 2S from Progression of Barrett's Metaplasia to Adenocarcinoma Is Associated with the Suppression of the Transcriptional Programs of Epidermal Differentiation

We did expressional profiling on 24 paired samples of normal esophageal epithelium, Barrett's metaplasia, and esophageal adenocarcinomas. Matching tissue samples representing the three different histologic types were obtained from each patient undergoing esophagectomy for adenocarcinoma. Our analysis compared the molecular changes accompanying the transformation of normal squamous epithelium with Barrett's esophagus and adenocarcinoma in individual patients rather than in a random cohort. We tested the hypothesis that expressional profiling may reveal gene sets that can be used as molecular markers of progression from normal esophageal epithelium to Barrett's esophagus and adenocarcinoma. Expressional profiling was done using U133A GeneChip (Affymetrix), which represent approximately two thirds of the human genome. The final selection of 214 genes permitted the discrimination of differential gene expression of normal esophageal squamous epithelium, Barrett's esophagus, and adenocarcinoma using two-dimensional hierarchical clustering of selected genes. These data indicate that transformation of Barrett's esophagus to adenocarcinoma is associated with suppression of the genes involved in epidermal differentiation, including genes in 1q21 loci and corresponding to the epidermal differentiation complex. Correlation analysis of genes concordantly expressed in Barrett's esophagus and adenocarcinoma revealed 21 genes that represent potential genetic markers of disease progression and pharmacologic targets for treatment intervention. PCR analysis of genes selected based on DNA array experiments revealed that estimation of the ratios of GATA6 to SPRR3 allows discrimination among normal esophageal epithelium, Barrett's dysplasia, and adenocarcinoma.

BackgroundNicotinamide phosphoribosyltransferase (NAMPT) plays a key role in the biosynthesis of nicotinamide adenine dinucleotide (NAD+), which is a vital cofactor in redox reactions and a substrate for NAD+ consuming enzymes including CD38, PARPs and sirtuins. NAMPT over-expression has been shown in various cancers and its inhibition decreases cancer cell growth, making it an attractive therapeutic target. Here we examine the NAMPT expression in a large cohort of resected stage I/II pancreatic ductal adenocarcinomas (PDAs) and correlate its expression with clinical outcomes and pathologic features.MethodsA retrospective review of patients with PDAs was conducted at a single institution. Tissue microarrays (TMAs) containing primary PDAs and their metastatic lymph nodes (mLNs) were constructed and stained for NAMPT expression. Each TMA core was evaluated for staining intensity of cancer cells (0 = no staining, 1+ = weak, 2+ = moderate, 3+ = strong) and a mean score was calculated for each case with at least two evaluable cores. NAMPT expression was correlated with clinicopathological variables using chi-squared or Fisher's exact test, and t-tests for categorical and continuous variables, respectively. Survival probabilities were estimated and plotted using the Kaplan-Meier method. Cox proportional hazards regression was used to assess the effects of NAMPT staining values on recurrence-free survival (RFS) and overall survival (OS). This study was conducted under an approved IRB protocol.Results173 primary PDAs had at least 2 TMA cores with identifiable cancer cells. The mean IHC score was 0.55 (range: 0 to 2.33). The mean IHC score of mLNs was 0.39 (range: 0-2), which was not significantly different from their primary tumors (mean IHC score = 0.47, P = 0.38). Sixty-four percent (111/173) of PDAs were positive for NAMPT staining. Stage II tumors were more likely to be positive (68% of 151 vs 41% of 22; P = 0.01). Non-obese non-diabetic patients were more likely to have NAMPT+ tumors (43.7% vs. 27.9%, P = 0.04). While RFS and OS were not statistically different between NAMPT+ vs. NAMPT- PDAs, patients with NAMPT- tumors tended to have a longer median OS (26.0 vs. 20.4 months, P = 0.34).ConclusionNAMPT expression was detected in 64% of stage I/II PDAs and up to 72% in non-obese non-diabetic patients. Frequency of NAMPT expression correlated with pathological stage, consistent with published literature regarding its role in cancer progression. While RFS and OS were not statistically significantly different, patients with NAMPT+ PDAs tended to have a shorter survival. Thus, NAMPT inhibition may prove beneficial in clinical trials.

Sarcopenia is the subclinical loss of skeletal muscle and strength and has been extensively studied in both the cancer and surgical literature. Specifically, sarcopenia has gained significant recognition as an important prognostic factor for both complications and survival in cancer patients. Herein, we review the current literature to date highlighting the specific impact of sarcopenia in patients undergoing oncologic procedures.

Pancreatic resection is the standard treatment option for patients with stage I/II pancreatic ductal adenocarcinoma (PDA), yet many studies demonstrate low rates of resection. The objective of this study was to evaluate whether increasing resection rates would result in an increase in average survival in patients with stage I/II PDA.SEER (Surveillance, Epidemiology, and End Results) data were analyzed for patients with stage I/II pancreatic head cancers treated from 2004 to 2009. Pancreatectomy rates were examined within Health Service Areas (HSAs) across 18 SEER regions. An instrumental variable analysis was performed, using HSA rates as an instrument, to determine the impact of increasing resection rates on survival.Pancreatectomy was performed in 4322 of 8323 patients evaluated with stage I/II PDA (overall resection rate = 51.9%). The resection rate across HSAs ranged from an average of 38.6% (lowest quintile) to 67.3% (highest quintile). Median survival was improved in HSAs with higher resection rates. Instrumental variable analysis revealed that, for patients whose treatment choices were influenced by rates of resection in their geographic region, pancreatectomy was associated with a statistically significant increase in overall survival.When controlling for confounders using instrumental variable analysis, pancreatectomy is associated with a statistically significant increase in survival for patients with resectable PDA. On the basis of these results, if resection rates were to increase in select patients, then average survival would also be expected to increase. It is important that this information be provided to physicians and patients so that they can properly weigh the risks and advantages of pancreatectomy as treatment of PDA.

Background and Objectives Sarcopenia, which is subclinical loss of skeletal muscle mass, is commonly observed in patients with malignancy. The objective of this study is to determine the correlation between sarcopenia and operative complications following pancreatectomy for cancer.

Minimally invasive surgery (MIS) has transformed operative practices by offering patients procedures with reduced hospital stay and recovery compared to that of open operations. In spite of the advantages of a MIS approach, the application to pancreatectomy has only recently emerged. This review aims to analyze and discuss available comparative studies as they relate to resection techniques for treatment of malignant disease. A PubMed search was used to obtain original studies and meta-analyses relating to MIS pancreatectomy from 2008 to 2013. Several studies were identified that reported on the application of MIS specifically to the treatment of cancer, many of which were retrospective, single-institution studies. Notwithstanding an inherent selection bias, several studies suggest that MIS can provide equivalent R0 resection rates, number of lymph nodes harvested, and survival to that of open resection. Furthermore, parameters such as blood loss and length of stay are significantly reduced in patients treated with MIS. The current literature supports the conclusion that MIS is safe and effective as a treatment for cancer in well-selected patients in the hands of experienced surgeons. However, the published studies to date are observational in nature and therefore higher quality studies will be needed to support the application and generalizability of MIS in the treatment of pancreatic malignancies.

Background Regional lymph node status has long been used as a dichotomous predictor of clinical outcomes in cancer patients. More recently, interest has turned to the prognostic utility of lymph node ratio (LNR), quantified as the proportion of positive nodes examined. However, statistical tools for the joint modeling of LNR and its effect on cancer survival are lacking. Methods Data were obtained from the NCI SEER cancer registry on 6400 patients diagnosed with pancreatic ductal adenocarcinoma from 2004 to 2010 and who underwent radical oncologic resection. A novel Bayesian statistical approach was developed and applied to model simultaneously patients' true, but unobservable, LNR statuses and overall survival. New web development tools were then employed to create an interactive web application for individualized patient prediction. Results Histologic grade and T and M stages were important predictors of LNR status. Significant predictors of survival included age, gender, marital status, grade, histology, T and M stages, tumor size, and radiation therapy. LNR was found to have a highly significant, non-linear effect on survival. Furthermore, predictive performance of the survival model compared favorably to those from studies with more homogeneous patients and individualized predictors. Conclusions We provide a new approach and tool set for the prediction of LNR and survival that are generally applicable to a host of cancer types, including breast, colon, melanoma, and stomach. Our methods are illustrated with the development of a validated model and web applications for the prediction of survival in a large set of pancreatic cancer patients.

Positive peritoneal cytology (Cyt+) is an important staging tool for patients with locally advanced gastric cancer. The objective of this review is to evaluate the current literature regarding cytology evaluation in patients with gastric cancer and to provide recommendations on the inclusion of this powerful prognosticator in patients with this disease. A literature search was performed for recent and pertinent studies evaluating peritoneal cytology in patients with gastric adenocarcinoma. Peritoneal cytology as the only evidence for M1 disease is present in up to 10% of patients with locally advanced gastric cancer; survival in the setting of Cyt+ is dismal when gastrectomy is the first line of therapy. Improved survival is associated with response to chemotherapy indicated by conversion to negative cytology, good performance status, and antral tumors. Highly select patients with Cyt+ treated with gastrectomy show improved survival in only some of the available studies. There are high quality studies that support the routine practice of peritoneal cytology evaluation in patients with locally advanced gastric cancer. The role of gastrectomy remains unclear in patients with Cyt+ and clinical trials are needed to define the best treatment option for this select group of patients.

Background Unresectable tumors of the pancreatic head are encountered in up to 20% of patients taken for resection. The objective of this study was to evaluate the complications and outcome associated with palliative surgical procedures to help guide management decisions in these patients. Methods Patients with pancreatic head adenocarcinoma taken to the operating room with curative intent who did not undergo pancreatectomy were evaluated. Results From 1997 to 2013, 50 patients were explored and found be unresectable due to M1 disease (n = 27, 54.0%) or vascular invasion (n = 23, 46.0%). Among unresectable patients, 34 (68.0%) had a palliative procedure performed including double bypass (n = 13), biliary bypass (n = 7), gastrojejunostomy (n = 5), or cholecystectomy (n = 9). Complications occurred in 22 patients (44.0%), and patients who had a palliative operation had a longer hospital stay and more major complications. Overall survival was reduced in patients treated with a palliative operation. Conclusions Despite advancements in endoscopic palliation, operative bypasses are still commonplace in patients with unresectable pancreatic head cancer. In this study, patients treated with operative procedures had a high rate of complications without a notable improvement in outcome. These findings highlight the importance of identifying unresectable disease prior to surgery and support a selective approach to palliative operations. J. Surg. Oncol 2014; 109:697–701. © 2014 Wiley Periodicals, Inc.

To construct a postoperative nomogram to estimate the risk of local recurrence for patients with desmoid tumors.The standard management of desmoid tumors is resection, but many recur locally. Other options include observation or novel chemotherapeutics, but little guidance exists on selecting treatment.Patients undergoing resection during 1982-2011 for primary or locally recurrent desmoids were identified from a single-institution prospective database. Cox regression analysis was used to assess risk factors and to create a recurrence nomogram, which was validated using an international, multi-institutional data set.Desmoids were treated surgically in 495 patients (median follow-up of 60 months). Of 439 patients undergoing complete gross resection, 100 (23%) had recurrence. Five-year local recurrence-free survival was 69%. Eight patients died of disease, all after R2 resection. Adjuvant radiation was not associated with improved local recurrence-free survival. In multivariate analysis, factors associated with recurrence were extremity location, young age, and large tumor size, but not margin. Abdominal wall tumors had the best outcome (5-year local recurrence-free survival rate of 91%). Age, site, and size were used to construct a nomogram with concordance index of 0.703 in internal validation and 0.659 in external validation. Integration of additional variables (R1 margin, sex, depth, and primary vs recurrent presentation) did not importantly improve concordance (internal concordance index of 0.707).A postoperative nomogram including only size, site, and age predicts local recurrence and can aid in counseling patients. Systemic therapies may be appropriate for young patients with large, extremity desmoids, but surgery alone is curative for most abdominal wall lesions.

Background and Objectives Positive peritoneal cytology equates M1 disease in patients with gastric cancer. Diagnostic peritoneal lavage (DPL) is a proven test to detect occult visceral injury in trauma patients. The objective of this study is to determine whether DPL can be used to assess peritoneal cytology in patients with gastric cancer. Methods Patients with gastric adenocarcinoma were prospectively enrolled to undergo DPL prior to diagnostic laparoscopy (DL). Saline was instilled through a percutaneous catheter and fluid was collected for cytology (DPL-cyt). Washings obtained during DL were used as controls (DL-cyt). Results DPL was successful in 22/27 patients (81.5%). Among the 22 successful DPLs, 12 had positive cytology (54.5%). Positive DPL-cyt specimens matched DL-cyt specimens in 12/12 cases (specificity = 100%). One of 10 cases with negative DPL-cyt was positive on the final DL-cyt (sensitivity = 92%). There were six patients with negative DPL-cyt who had visible M1 disease diagnosed with DL (DPL evaluation of M1 disease, sensitivity 54.5%, specificity = 100%). Conclusions DPL is a safe method of detecting positive cytology in patients with gastric cancer, however gross M1 disease may be missed without visual inspection. The specific role of DPL in the staging workup of patients with gastric cancer remains to be determined. J. Surg. Oncol. 2013;107:794–798. © 2013 Wiley Periodicals, Inc.

Objective Extent of distal resection margins in rectal cancer surgery remains controversial. We set out to determine the long-term oncologic impact of resection margins in patients with locally advanced rectal cancer using a comprehensive pathologic whole-mount section analysis. Background It has been demonstrated that there is minimal disease beyond the gross tumor margin after neoadjuvant combined modality therapy (CMT) for rectal cancer. Although this suggests that close resection margins may be used for sphincter preservation, the long-term oncologic impact of this approach is unclear. Methods We prospectively enrolled 103 patients with locally advanced rectal cancer after neoadjuvant CMT. Whole-mount pathologic analysis was performed, and clinicopathologic variables were correlated with disease-specific survival (DSS). Result : Sphincter preservation was achieved in 80% of patients, and the median distal margin was 2 cm (0.1 to 10 cm). There were 22 patients (21%) with distal margins 1 cm or less and no patient had a positive distal margin. Median radial margin was 1 cm and 4 patients (4%) had a margin of 1 mm or less. Viable distal intramural tumor spread was found in 3 patients (2.7%) and in all cases was limited to 1 cm or less from the gross tumor edge. At a median follow-up of 68 months, 5-year DSS was 86% and 1 patient experienced a local recurrence. Factors predictive of worse DSS included advanced tumor (T) and nodal (N) stage, tumor progression on neoadjuvant CMT, lack of a complete pathologic response, tumor location of 5 cm or less from the anal verge, and neurovascular invasion. The extent of the distal and radial margins of resection was not associated with DSS. Conclusions These results suggest that carefully selected patients with locally advanced rectal cancers who undergo neoadjuvant CMT can achieve excellent local control and DSS with a sphincter-sparing rectal resection and a margin distal clearance of 1 cm.

Despite significant improvements in operative mortality, morbidity remains a significant problem following pancreatectomy. Management of postpancreatectomy complications, namely pancreatic fistula, begins with a clear understanding of how these events are defined. There are now several unifying definitions for complications following pancreatectomy which have led to improved reporting of operative outcomes across institutions. Several randomized controlled trials have been performed in recent years that may lead to continued improvement in operative outcomes.

Recent population-based studies have demonstrated significant differences in outcome between patients with pancreatic and ileal neuroendocrine tumors. The objective of this study was to examine the clinicopathologic differences between ileal and pancreatic neuroendocrine tumors following resection. A retrospective chart review was performed and data on clinicopathologic variables, biochemical markers, and follow-up of patients with resected ileal (INETs) and pancreatic (PNETs) neuroendocrine tumors were collected. The t test or analysis of variance (ANOVA) was used to compare means. Survival analysis was performed using the Kaplan–Meier method. Between 1998 and 2010, 122 patients with PNETs and INETs were explored (70 PNETs and 52 INETs). Several variables were found to be significantly different between patients in both groups. INETs were more often associated with flushing (44 vs. 14%; P

Positive peritoneal cytology is a predictor of poor survival in patients with gastric cancer. Our aim is to more clearly define the natural history of this cohort.Review of a prospectively maintained gastric cancer database of patients who had diagnostic laparoscopy with peritoneal washings. Clinicopathologic and treatment-related variables were obtained. Univariate and multivariate analyses were performed for factors associated with disease-specific survival (DSS).From January 1993 to April 2009, a total of 1241 patients with gastric cancer underwent laparoscopy with peritoneal washings; 291 (23%) had positive cytology. There were 198 patients (68%) who had visible metastases discovered at laparoscopy (M1), and 93 patients (32%) were without gross evidence of advanced disease (M1 Cyt+). The median DSS for the entire cohort was 1 year; for M1, DSS was 0.8 years, and for M1 Cyt+, DSS was 1.3 years. At baseline, independent predictors of worse DSS were poor performance status, M1 disease, and diffuse tumors. Among the subset of patients with M1 Cyt + disease, performance status was the strongest independent predictor of DSS. A total of 48 of the 291 Cyt + patients had repeat staging laparoscopy after chemotherapy. Compared with patients who had persistently positive cytology (n = 21), those who converted to negative cytology (n = 27) had a significant improvement in DSS (2.5 years vs. 1.4 years, P = 0.0003).Patients with positive cytology as the only evidence of advanced disease exhibit a poor outcome; however, clearing of Cyt + disease by chemotherapy is associated with a statistically significant improvement in DSS. The role for gastrectomy in patients with positive peritoneal cytology remains uncertain.

Hepatic artery embolization (HAE) is used commonly to treat liver tumors or hemorrhage. Infectious complications are rare but carry high rates of morbidity and mortality. Identification of clinical factors associated with postembolization abscess may improve management and outcome.Clinical and pathologic variables of patients treated with HAE were collected and analyzed to determine the etiology, incidence, and outcome of pyogenic hepatic abscess.From January 1998 to January 2010, 971 patients underwent 2,045 HAE procedures. Fourteen patients developed a pyogenic hepatic abscess after embolization, for an overall rate of 1.4%. Thirty-four patients (4%) had a history of bilioenteric anastomosis (BEA) and 21 patients (2%) lacked a competent sphincter of Oddi because of the presence of a biliary stent (n = 19) or a previous sphincterotomy (n = 2). Eleven of the 34 patients with a BEA (33%) and two of 21 patients with an incompetent sphincter (10%) developed abscesses, in contrast to only one abscess (0.05%) among the 916 patients with apparently normal sphincters (0.1%; odds ratio, 437.6; 95% CI, 54.2-3,533; P.0001). Gram-negative and Gram-positive aerobes were the most common bacteria isolated after drainage. Percutaneous drainage was the initial management strategy in all patients; two patients (14%) required subsequent surgical drainage and hepatectomy, and three (21%) died.Pyogenic hepatic abscess is rare after HAE. A history of BEA or an incompetent sphincter of Oddi caused by a biliary stent or previous sphincterotomy substantially increases the likelihood of this highly morbid and potentially fatal complication.

Background The objective of this study was to examine the current treatment for liver abscess and to assess the factors associated with failure of percutaneous drainage. Study Design Records of 58 patients with pyogenic hepatic abscess, from 1998 to 2009, were examined. Clinicopathologic variables were analyzed as predictors of failure of percutaneous drainage using multivariable logistic regression. The results of surgical intervention after failure of percutaneous treatment were also examined. Results Fifty-one patients (88%) had a history of malignancy including pancreas (36%), cholangiocarcinoma (17%), colon (12%), and gallbladder (10%). Recent hepatic artery embolization or radiofrequency ablation preceded development of abscess in 13 patients (22%). Fifteen patients (26%) had evidence of biliary tract communication, and 14 of 15 (93%) of these patients had concomitant biliary tract obstruction. Percutaneous drainage was successful in 38 patients (66%) with a median drain dwell time of 26 days (range 3 to 319 days). Five patients (9%) required operative intervention and 2 of these patients (3% overall) died postoperatively from septic complications. Fifteen patients (26%) died with percutaneous drains in place; 9 (60%) of these patients died of cancer progression without evidence of sepsis. Independent predictors of failure of percutaneous drainage included abscesses containing yeast (p = 0.003) and communication of the abscess cavity with the biliary tree (p = 0.02). Conclusions Pyogenic hepatic abscess was treated successfully in the majority of patients with advanced malignancy, although mortality remained high. The presence of yeast and communication with an untreated obstructed biliary tree were associated with failure of percutaneous drainage. The need for surgical salvage was associated with a high mortality.

Treatment of gastric cancer has evolved with the advent of randomized trials demonstrating chemotherapeutic agents with efficacy in advanced disease. Level I evidence supports delivering chemotherapy in the neoadjuvant setting; the data shows improvement in progression-free and overall survival. A clinical response to therapy is associated with improved R0 resection rates, pathologic response, and outcome in patients with locally advanced disease. Early assessment of metabolic response to therapy can potentially be utilized to tailor treatment.

Preoperative biliary drainage (PBD) prior to pancreaticoduodenectomy (PD) continues to be routine in many centers despite retrospective and randomized data showing that PBD increases perioperative infectious complications.Review of a prospectively maintained database identified 340 consecutive patients with pancreatic adenocarcinoma who underwent PD between 2000 and 2005. From this cohort, 94 PBD and 94 nonstented (no-PBD) patients were matched for age, gender, preoperative albumin, and bilirubin levels (PBD group: prestent bilirubin; no-PBD group: preoperative bilirubin).The majority of PBD patients (89%) underwent internal endoscopic biliary drainage. Stent-related complications occurred in 46 patients (23%) and resulted in a significant delay in time to resection. In the matched-pair comparison, there was more operative blood loss in PBD patients, but similar operative times, transfusions, and hospital stay. Bile cultures were positive in 82% of PBD patients versus 7% no PBD. There was a statistically significant increase in infectious complications including wound infections and intra-abdominal abscess in PBD patients, but equal incidence of anastomotic leak.In this case-matched control study, PBD was associated with a stent-related complication rate of 23% and resulted in a twofold increase in postpancreatectomy infectious complications. The routine use of PBD remains unjustified.

Objective To present the case of a man with a rightsided adrenocortical carcinoma that invaded the inferior vena cava and was managed by radical resection and vein patch repair. Methods We report the clinical, laboratory, imaging, and operative findings, and we highlight the pertinent features of this case. The literature is reviewed for the management of adrenocortical carcinoma in conjunction with inferior vena cava invasion. Results In a 34-year-old man with new-onset abdominal pain, abdominal imaging disclosed a large right adrenal mass with invasion into the inferior vena cava. Laboratory values revealed that the adrenal mass was likely nonfunctional. At surgical intervention with use of cardiopulmonary bypass, the mass was removed en bloc with the adrenal gland, right kidney, and the wall of the inferior vena cava, and the inferior vena cava was reconstructed with bovine pericardium. Conclusion Despite direct invasion or extension of tumor thrombus into the inferior vena cava (or both), complete (R0) resection can be obtained. Thus, this scenario should not preclude attempted curative resection in patients with adrenal cancer. (Endocr Pract. 2008;14: 721-725)

Injury prevention strategies for child bicyclists have focused on helmet use to prevent head trauma. Handlebars are another source of injury. A retrospective review from 2005 identified 385 admissions to a Level 1 pediatric trauma center of which 23 (5.9%) were pedal cyclists. Four cases (

Umbilical anomalies are a rare presentation in the pediatric patient. The differential diagnosis includes anomalies resulting from urachal and vitelline duct derivatives such as urachal sinus, urachal cyst, urachal diverticulum, patent urachus, herniated Meckel's diverticulum, umbilico-enteric fistula, or umbilical polyp. In this article, a case presentation of an umbilical anomaly along with the differential diagnosis and management options are discussed. Based upon this review of the literature, the authors propose a management algorithm for treating children with umbilical anomalies.

Viral oncolytic therapy has been pursued with renewed interest as the molecular basis of carcinogenesis and viral replication has been elucidated. Genetically engineered, attenuated viruses have been rationally constructed to achieve a therapeutic index in tumor cells compared with surrounding normal tissue. Many of these attenuated mutant viruses have entered clinical trials. Here we review the preclinical literature demonstrating the interaction of oncolytic viruses with ionizing radiation and provides a basis for future clinical trials.

Chemo-inducible cancer gene therapy is a potential new treatment for solid tumors that may in part enhance the anti-tumor effects of chemotherapy while minimizing toxicity. This approach combines viral vectors expressing cytotoxic transgenes that can be transcriptionally activated by DNA-damaging agents. The development of chemo-inducible gene therapy has numerous implications for the treatment of both localized and metastatic disease in patients with solid tumors.

Background Preoperative combined-modality therapy (CMT) is considered the treatment approach of choice for rectal cancer. To examine the effect of CMT on distal intramural spread (DIS), we determined the extent of DIS in rectal cancer specimens after CMT. Methods Specimens from 20 patients after preoperative CMT and total mesorectal excision for rectal cancer were analyzed for extent of DIS. Specimens were washed, fixed in formalin, and sectioned in 5-mm cuts from the distal border of the residual tumor to the distal resection margin. Results Eleven patients (55%) had DIS. Two patients had a complete pathologic response (10%). The mean extent of DIS was 0.50 cm (standard deviation, 0.64 cm; range, 0.0 to 2.5 cm). Only 1 patient in the study had DIS beyond 1 cm from the residual tumor. Six of the patients have died at a median of 30.4 months after operation (range, 19.0 to 51.1 months). No correlation was found between the extent of residual DIS and survival. Conclusions Our study shows that the vast majority of patients with rectal cancer after neoadjuvant CMT have no tumor cells beyond 1 cm from the residual tumor. Our data suggest that a 2-cm margin of resection when feasible from the macroscopic tumor margin after neoadjuvant CMT is adequate.

Splenectomy is a commonly performed operation; however, data from large series regarding operative outcomes to help guide decision making and informed consent are lacking.To evaluate clinical and pathologic variables associated with morbidity and mortality following elective splenectomy for benign and malignant hematologic conditions in the United States.A review of the American College of Surgeons National Surgical Quality Improvement Program data for elective splenectomy between January 1, 2005, and December 31, 2011, was performed, and 1715 eligible individuals were identified.Elective splenectomy for hematologic conditions.Complications and operative mortality were evaluated for the entire cohort and compared between patients with benign vs malignant diseases. Multivariable logistic regression was used to evaluate factors predictive of operative complications and death.Splenectomy was performed in 1344 patients (78.4%) for benign disease and in 371 patients (21.6%) for malignant disease. Two hundred ninety-one patients (17.0%) had a complication, and operative mortality occurred in 27 patients (mortality rate, 1.6%). Patients treated for malignant disease had a higher rate of overall complications (27.2%) compared with patients treated for benign disease (14.1%) (P .001). Several variables were independent predictors of complications, including malignant disease (vs benign) (Odds Ratio [OR], 1.86; 95% CI, 1.23-2.80; P = .003), independent performance status (vs dependent) (OR, 0.33; 95% CI, 0.07-1.52; P = .02), and increasing albumin level (OR, 0.75; 95% CI, 0.66-0.86; P .001). Increasing age (OR, 1.03; 95% CI, 1.00-1.06; P = .05) was an independent predictor of mortality while increasing albumin level (OR, 0.63; 95% CI, 0.46-0.86; P = .003) predicted lower risk of operative death. From these data, a patient older than 60 years with a low preoperative albumin level has a predicted probability for operative death as high as 10.0%.Preoperative performance and nutritional status are significant risk factors for complications and mortality following elective splenectomy. Although operative mortality continues to decrease over time, specific preoperative variables may help with patient selection before elective splenectomy for certain patients.

Purpose: Pancreatic ductal adenocarcinoma (PDA) cells are known to produce excessive amounts of reactive oxygen species (ROS), particularly superoxide, which may contribute to the aggressive and refractory nature of this disease. Extracellular superoxide dismutase (EcSOD) is an antioxidant enzyme that catalyzes the dismutation of superoxide in the extracellular environment. This study tests the hypothesis that EcSOD modulates PDA growth and invasion by modifying the redox balance in PDA. Experimental Design: We evaluated the prognostic significance of EcSOD in a human tissue microarray (TMA) of patients with PDA. EcSOD overexpression was performed in PDA cell lines and animal models of disease. The impact of EcSOD on PDA cell lines was evaluated with Matrigel invasion in combination with a superoxide-specific SOD mimic and a nitric oxide synthase (NOS) inhibitor to determine the mechanism of action of EcSOD in PDA. Results: Loss of EcSOD expression is a common event in PDA, which correlated with worse disease biology. Overexpression of EcSOD in PDA cell lines resulted in decreased invasiveness that appeared to be related to reactions of superoxide with nitric oxide. Pancreatic cancer xenografts overexpressing EcSOD also demonstrated slower growth and peritoneal metastasis. Overexpression of EcSOD or treatment with a superoxide-specific SOD mimic caused significant decreases in PDA cell invasive capacity. Conclusions: These results support the hypothesis that loss of EcSOD leads to increased reactions of superoxide with nitric oxide, which contributes to the invasive phenotype. These results allow for the speculation that superoxide dismutase mimetics might inhibit PDA progression in human clinical disease. Clin Cancer Res; 21(7); 1741–51. ©2015 AACR.

The toxicity of pharmacologic ascorbate is mediated by the generation of H2O2 via the oxidation of ascorbate. Because pancreatic cancer cells are sensitive to H2O2 generated by ascorbate, they would also be expected to become sensitized to agents that increase oxidative damage such as ionizing radiation. The current study demonstrates that pharmacologic ascorbate enhances the cytotoxic effects of ionizing radiation as seen by decreased cell viability and clonogenic survival in all pancreatic cancer cell lines examined, but not in nontumorigenic pancreatic ductal epithelial cells. Ascorbate radiosensitization was associated with an increase in oxidative stress–induced DNA damage, which was reversed by catalase. In mice with established heterotopic and orthotopic pancreatic tumor xenografts, pharmacologic ascorbate combined with ionizing radiation decreased tumor growth and increased survival, without damaging the gastrointestinal tract or increasing systemic changes in parameters indicative of oxidative stress. Our results demonstrate the potential clinical utility of pharmacologic ascorbate as a radiosensitizer in the treatment of pancreatic cancer. Cancer Res; 75(16); 3314–26. ©2015 AACR.

We examined the impact of neuropsychological (NP) impairment on activities of daily living (ADLs) and quality of life in human immunodeficiency virus type-1 (HIV-1)-infected persons of low socioeconomic status (SES). Thirty-nine patients were stratified into one of three groups: cognitively normal (n = 13), mild cognitive impairment (n = 15), and moderate/severe impairment (n = 11). Quality of life was assessed with the Sickness Impact Profile and ADLs were evaluated via structured interview performed in the patient's residence. While there were no significant differences across groups on disease stage, drug use, depression, or estimated premorbid IQ, cognitively impaired patients were more likely to be unemployed and fail social planning and medication management tasks. Our study confirms a previously reported association between NP impairment and unemployment among HIV-1-infected patients. The data also extend this relationship to a low-SES sample with a high base rate of unemployment, and to instrumental activities of daily living other than work.

Minimally invasive approaches to distal (left) pancreatectomy have been shown to produce equivalent short-term and long-term outcomes for the treatment of benign and malignant pancreatic diseases, including equivalent or better operative outcomes such as reduced blood loss, decreased pain medication requirements, and shorter hospital stay in retrospective studies from expert surgeons in high-volume centers [1–4]. Oncologically, lymph node retrieval, histologically negative margins, and recurrence have also been shown to be equivalent to open procedures in well-selected patients [3].

The effect of inflammatory bowel disease (IBD) on outcome in patients with colorectal cancer (CRC) remains unclear. Our objective is to evaluate oncologic outcomes of patients with IBD-associated CRC.We retrospectively reviewed a prospectively maintained database to identify patients with IBD-associated CRC. Clinicopathologic variables and overall survival were compared to patients with sporadic CRC using a 2:1 matched-controlled analysis.Fifty-five patients with IBD and CRC were identified. On univariate analysis, CRC patients with IBD had a significantly shorter median overall survival (68.2 months vs. 204.3 months, P = 0.01) compared to patients with sporadic CRC. On multivariate analysis, after adjusting for N and M stage, IBD was associated with an increased risk of death compared to sporadic CRC (HR = 2.011, 95% CI 1.24-3.23, P = 0.004). Stage 3 CRC patients with IBD in particular showed significantly decreased survival (23.0 vs. 133.9 months, P = 0.008).In this study, patients with node-positive IBD-associated CRC had a significant increased risk of death and a shorter overall survival than those with sporadic disease and may require tailored adjuvant therapy and surveillance protocols. Continued investigation to elucidate the mechanisms that contribute to these observations is justified.

Specific data are needed regarding the impact of transfusion on operative complications in pancreatectomy. The objectives of this study were to determine risk factors for transfusion and to evaluate the potential association between transfusion and operative complications in elective pancreatectomy procedures.We reviewed our institution's pancreatectomy and ACS-NSQIP databases. Multivariate analysis was used to determine clinicopathologic risk factors predictive of transfusion, and then a transfusion propensity score was developed to evaluate the impact of transfusion on post-pancreatectomy complications.Of the 173 patients who were treated from September 2007 to September 2011, 78 patients (45 %) were transfused ≥ 1 unit of blood (median, 3.0 units; range, 1-55). Risk factors for transfusion included increasing Body Mass Index (BMI), smoking, increasing mortality risk score, preoperative anemia, intraoperative blood loss, and benign pathology. After controlling for these risk factors using a transfusion propensity score, transfusion was an independent predictor of increased complications, infectious complications, and hospital costs.Multiple factors are predictive of transfusion in pancreatectomy, including increasing BMI and smoking. When controlling for transfusion propensity based on these risk factors, RBC transfusion is associated with worse operative outcomes including infectious complications. Development of protocols and strategies to minimize unnecessary transfusion in pancreatectomy are justified.

Extracellular superoxide dismutase (SOD3) is a secreted enzyme that regulates levels of extracellular superoxide and protects the extracellular matrix from degradation by reactive species. The SOD3 protein contains a heparin-binding domain and resides in a microenvironment rich in other heparin-bound growth factors, raising the possibility that SOD3 may have some biological role independent of its catalytic activity. To begin to address this, we designed and created enzymatically inactive mutant constructs targeting either the copper coordinating (i.e. H96 and H98) or superoxide channeling (i.e. N180 and R186) amino acid residues of SOD3. All constructs expressed equal quantities of immature intracellular SOD proteins, but only the N180A, R186A, and combination N180A/R186A mutants produced fully processed and secreted extracellular protein. Furthermore, while SOD activity was significantly inhibited in the single N180A and R186A mutants, the activity was completely abrogated in the N180A/R186A double mutant. Overall, the use of this novel tool may have broad reaching impacts into various fields of biology and medicine, and will aid in the delineation of cellular processes that are regulated by solely the SOD3 protein, its reactive oxygen species substrates and products, or the combination of both.

resolution characterization of chromosomal abnormalities down to the kilobase level, whereas previous studies on desmoid tumors have largely employed techniques suited for the detection of megabase or larger chromosomal alterations [14]. In conjunction with SNP-A, the authors performed traditional DNA sequencing on a number of genes known to be mutated in desmoid tumors, including β-catenin (CTNNB1) and APC. Using these combined methodologies, the authors validated existing data on the presence of mutations in CTNNB1, and losses in chromosome 8q, which contains the APC locus. In addition, they detected numerous other small deletions and insertions that have previously not been reported in desmoid tumors. The most significant of these novel lesions was a heterozygous, somatic deletion affecting a small region of chromosome 8p23, which was observed in 44% of the tumors tested. This deletion falls within the CUB and Sushi multiple domains1 (CSMD1) gene, a putative tumor suppressor that is also mutated or deleted in tumors of the head and neck, colon, breast, and prostate [15, 16]. Furthermore, the authors noted a correlation between CSMD1 deletion and relapse, as 3 of the 9 patients with disease recurrence at the time of publication had exhibited a CSMD1 deletion. The small sample size and short follow-up time limit the authors’ ability to make firm conclusions regarding the prognostic significance of these otherwise exceptional and novel data. The management of desmoid tumors remains a challenge to the patient and the clinician. However, studies such as this by Erben and colleagues add to the arsenal of data that will eventually lead to novel therapies for this disease. As for all patients presenting with complex malignancies such as desmoid tumors, continued efforts for tissue collection and multi-institution and protocol-based regimens are justified.

Positive peritoneal cytology equates M1 disease in patients with gastric cancer. Diagnostic peritoneal lavage (DPL) is a proven test to detect occult visceral injury in trauma patients. The objective of this study is to determine whether DPL can be used to assess peritoneal cytology in patients with gastric cancer.Patients with gastric adenocarcinoma were prospectively enrolled to undergo DPL prior to diagnostic laparoscopy (DL). Saline was instilled through a percutaneous catheter and fluid was collected for cytology (DPL-cyt). Washings obtained during DL were used as controls (DL-cyt).DPL was successful in 22/27 patients (81.5%). Among the 22 successful DPLs, 12 had positive cytology (54.5%). Positive DPL-cyt specimens matched DL-cyt specimens in 12/12 cases (specificity = 100%). One of 10 cases with negative DPL-cyt was positive on the final DL-cyt (sensitivity = 92%). There were six patients with negative DPL-cyt who had visible M1 disease diagnosed with DL (DPL evaluation of M1 disease, sensitivity 54.5%, specificity = 100%).DPL is a safe method of detecting positive cytology in patients with gastric cancer, however gross M1 disease may be missed without visual inspection. The specific role of DPL in the staging workup of patients with gastric cancer remains to be determined.