Selwyn M Vickers

Publications of Selwyn M Vickers

• Delivery of interferon alpha using a novel Cox2-controlled adenovirus for pancreatic cancer therapy.

  Authors: Leonard Armstrong, Julia Davydova, Eric Brown, Joohee Han, Masato Yamamoto, Selwyn M Vickers

  Surgery. 04/2012;

  BACKGROUND: Combination therapy with interferon alpha (IFN) is correlated with improved survival in patients with pancreatic ductal adenocarcinoma (PDAc) but frequently presents side effects. WeBACKGROUND: Combination therapy with interferon alpha (IFN) is correlated with improved survival in patients with pancreatic ductal adenocarcinoma (PDAc) but frequently presents side effects. We designed a novel targeted adenovirus with replication restricted to cyclooxygenase 2 (Cox2)-overexpressing PDAcs and hypothesize that the locally delivered therapeutic gene IFN can augment oncolytic effects while minimizing systemic toxicity. METHODS: IFN-expressing vectors were tested in vitro with the use of 4 PDAc cell lines with cytocidal effect measured by crystal violet and colorimetrically and IFN production assayed by ELISA. Cox2 promoter activity was checked by a luciferase reporter assay. In vivo, subcutaneous tumor xenografts with 2 PDAc cell lines in nude mice were treated with a single intratumoral viral dose. RESULTS: All PDAc cell lines were Cox2-positive. Oncolysis from the novel Cox2-controlled virus was comparable or superior to Adwt, the wild-type virus without safety features. The absence of cytocidal effect in Cox2-negative cells with the novel virus indicated cancer specificity. In vivo, stronger tumor suppression from the novel virus was seen when compared with nonreplicating IFN-expressing vectors. CONCLUSION: We demonstrated the potent therapeutic effects of a novel tumor-specific conditionally replicative IFN-expressing adenovirus. With potential to locally deliver IFN and avoid systemic toxicity, this strategy may therefore expand the application of this robust and promising therapy.

• What happens to racial and ethnic minorities after cancer surgery at american college of surgeons national surgical quality improvement program hospitals?

  Authors: Helen M Parsons, Elizabeth B Habermann, Steven C Stain, Selwyn M Vickers, Waddah B Al-Refaie

  Journal of the American College of Surgeons. 02/2012; 214(4):539-47.

  Inadequate access has contributed to widespread racial disparities in cancer care in the United States. However, the outcomes for racial minorities at quality-seeking hospitals, such as thoseInadequate access has contributed to widespread racial disparities in cancer care in the United States. However, the outcomes for racial minorities at quality-seeking hospitals, such as those participating in the American College of Surgeons National Surgical Quality Improvement Program (ACS NSQIP), remain unknown. We hypothesized that operative outcomes for racial and ethnic minority patients after cancer surgery at ACS NSQIP hospitals are comparable with those for white patients. Using the 2005-2008 ACS NSQIP data, we identified 38,926 patients who underwent thoracic, abdominal, or pelvic cancer surgery. We used multivariate logistic regression to examine the association between race and ethnicity and short-term (30-day) operative outcomes after cancer surgery. Sensitivity analyses were performed to ensure the relationship remained consistent after stratification by procedure. Nonwhite patients constituted 16.9% of patients treated for cancer surgery in ACS NSQIP hospitals. Although nonwhite patients were more likely to have higher levels of comorbidities and undergo more complex resections (p < 0.05 for all), multivariate analyses demonstrated that these patients were as likely as white patients to have adverse short-term operative outcomes develop after cancer surgery. These results persisted after stratification by extent of surgical procedure. However, black, Hispanic, and American-Indian/Alaskan-Native patients were more likely to experience prolonged length of stay (odds ratio for black vs white patients = 1.33; p < 0.001). Racial and ethnic minority patients who undergo their cancer surgery at ACS NSQIP hospitals have short-term operative outcomes similar to white patients, but they remain hospitalized longer. These findings suggest that access to quality-driven hospitals might ameliorate racial disparities in cancer care and outcomes. Future policies should focus on expanding access to quality-driven surgical facilities as a step toward timely and optimal cancer care.

• Who receives their complex cancer surgery at low-volume hospitals?

  Authors: Waddah B Al-Refaie, Binyam Muluneh, Wei Zhong, Helen M Parsons, Todd M Tuttle, Selwyn M Vickers, Elizabeth B Habermann

  Journal of the American College of Surgeons. 11/2011; 214(1):81-7.

  Previous literature has consistently shown worse operative outcomes at low-volume hospitals (LVH) after complex cancer surgery. Whether patient-related factors impact this association remainsPrevious literature has consistently shown worse operative outcomes at low-volume hospitals (LVH) after complex cancer surgery. Whether patient-related factors impact this association remains unknown. We hypothesize that patient-related factors contribute to receipt of complex cancer surgery at LVH. Using the 2003-2008 National Inpatient Sample, we identified 59,841 patients who underwent cancer operations for lung, esophagus, and pancreas tumors. Logistic regression models were used to examine the impact of sociodemographic factors on receipt of complex cancer surgery at LVH. Overall, 38.4% received their cancer surgery at LVH. A higher proportion of esophagectomies were performed at LVH (70.3%), followed by pancreatectomy (38.2%) and lung resection (33.8%). Patients who were non-white, with non-private insurance, and had more comorbidities were all more likely to receive their cancer surgery at LVH (for all, p < 0.05). Multivariate analyses continued to demonstrate that non-white race, insurance status, increased comorbidities, region, and nonelective admission predicted receipt of cancer surgery at LVH across all 3 procedures. In this large national study, non-white race and increased comorbidities contributed to receipt of cancer surgery at LVH. Patient selection and access to high-volume hospitals are likely reasons worthy of additional investigation. This study provides additional insight into the volume-outcomes relationship. Given the demonstrated outcomes disparity between high-volume hospitals and LVH, future policy and research should encourage mechanisms for referral of patients with cancer to high-volume hospitals for their surgical care.

• Cancer trials versus the real world in the United States.

  Authors: Waddah B Al-Refaie, Selwyn M Vickers, Wei Zhong, Helen Parsons, David Rothenberger, Elizabeth B Habermann

  Annals of surgery. 09/2011; 254(3):438-42; discussion 442-3.

  Federal policies have been implemented to mitigate underenrollment in cancer trials in the United States. We sought to identify patterns and predictors of enrollment patterns to cancer trials in aFederal policies have been implemented to mitigate underenrollment in cancer trials in the United States. We sought to identify patterns and predictors of enrollment patterns to cancer trials in a contemporary era using a real world setting. The 2001-2008 California Cancer Registry was used to determine patterns and predictors of enrollment in clinical trials for stage 0 to IV solid organ malignant tumors. Multivariate techniques were used to identify predictors of enrollment in cancer protocols, controlling for covariates. Less than a percent (0.64%) of patients enrolled in clinical trials (1566 of 244,528). Black patients were less likely than whites to enroll in trials (0.48% vs 0.67%, P < 0.05). On multivariate analysis, older persons (>65 years), early stage cancer, and those with lung or gastrointestinal cancers were less likely to be enrolled in cancer trials. Results were consistent when evaluated among only nonbreast cancer protocols. Though approaching significance, black, underinsured, and uninsured patients showed trends toward underenrollment. In addition to profoundly low overall cancer trial accrual, vast underrepresentation by age, cancer stage, and site continue to exist. The generalizability of these trials to a real world perspective remains an open question. Physicians, payers, the National Cancer Institute, and other stakeholders need to develop broader cancer trials to benefit the millions of patients with cancer in the United States.

• Enhanced recovery programs: major benefits demonstrated again.

  Authors: Mary Kwaan, Selwyn M Vickers

  Archives of surgery (Chicago, Ill. : 1960). 05/2011; 146(5):577-8.

• Serum biomarker panels for the detection of pancreatic cancer.

  Authors: Randall E Brand, Brian M Nolen, Herbert J Zeh, Peter J Allen, Mohamad A Eloubeidi, Michael Goldberg, Eric Elton, Juan P Arnoletti, John D Christein, Selwyn M Vickers, Christopher J Langmead, Douglas P Landsittel, David C Whitcomb, William E Grizzle, Anna E Lokshin

  Clinical cancer research : an official journal of the American Association for Cancer Research. 02/2011; 17(4):805-16.

  Serum-biomarker based screening for pancreatic cancer could greatly improve survival in appropriately targeted high-risk populations. Eighty-three circulating proteins were analyzed in sera ofSerum-biomarker based screening for pancreatic cancer could greatly improve survival in appropriately targeted high-risk populations. Eighty-three circulating proteins were analyzed in sera of patients diagnosed with pancreatic ductal adenocarcinoma (PDAC, n = 333), benign pancreatic conditions (n = 144), and healthy control individuals (n = 227). Samples from each group were split randomly into training and blinded validation sets prior to analysis. A Metropolis algorithm with Monte Carlo simulation (MMC) was used to identify discriminatory biomarker panels in the training set. Identified panels were evaluated in the validation set and in patients diagnosed with colon (n = 33), lung (n = 62), and breast (n = 108) cancers. Several robust profiles of protein alterations were present in sera of PDAC patients compared to the Healthy and Benign groups. In the training set (n = 160 PDAC, 74 Benign, 107 Healthy), the panel of CA 19-9, ICAM-1, and OPG discriminated PDAC patients from Healthy controls with a sensitivity/specificity (SN/SP) of 88/90%, while the panel of CA 19-9, CEA, and TIMP-1 discriminated PDAC patients from Benign subjects with an SN/SP of 76/90%. In an independent validation set (n = 173 PDAC, 70 Benign, 120 Healthy), the panel of CA 19-9, ICAM-1 and OPG demonstrated an SN/SP of 78/94% while the panel of CA19-9, CEA, and TIMP-1 demonstrated an SN/SP of 71/89%. The CA19-9, ICAM-1, OPG panel is selective for PDAC and does not recognize breast (SP = 100%), lung (SP = 97%), or colon (SP = 97%) cancer. The PDAC-specific biomarker panels identified in this investigation warrant additional clinical validation to determine their role in screening targeted high-risk populations.

• Prosurvival role of heat shock factor 1 in the pathogenesis of pancreatobiliary tumors.

  Authors: Vikas Dudeja, Rohit K Chugh, Veena Sangwan, Steven J Skube, Nameeta R Mujumdar, Mara B Antonoff, Rajinder K Dawra, Selwyn M Vickers, Ashok K Saluja

  American journal of physiology. Gastrointestinal and liver physiology. 02/2011; 300(6):G948-55.

  Several mechanisms have evolved to ensure the survival of cells under adverse conditions. The heat shock response is one such evolutionarily conserved survival mechanism. Heat shock factor-1 (HSF1)Several mechanisms have evolved to ensure the survival of cells under adverse conditions. The heat shock response is one such evolutionarily conserved survival mechanism. Heat shock factor-1 (HSF1) is a transcriptional regulator of the heat shock response. By the very nature of its prosurvival function, HSF1 may contribute to the pathogenesis of cancer. The current study investigates the role of HSF1 in the pathogenesis of pancreatobiliary tumors. HSF1 was downregulated in pancreatic cancer (MIA PaCa-2 and S2-013) and cholangiocarcinoma (KMBC and KMCH) cell lines by HSF1-specific small interfering RNA (siRNA). Nonsilencing siRNA was used as control. The effect of HSF1 downregulation on viability and apoptosis parameters, i.e., annexin V, terminal deoxynucleotidyl transferase dUTP-mediated nick end labeling (TUNEL), and caspase-3, was measured. To evaluate the cancer-specific effects of HSF1, the effect of HSF1 downregulation on normal human pancreatic ductal cells was also evaluated. HSF1 is abundantly expressed in human pancreatobiliary cancer cell lines, as well as in pancreatic cancer tissue, as demonstrated by Western blot and immunohistochemistry, respectively. Inhibition of HSF1 expression by the HSF1 siRNA sequences leads to time-dependent death in pancreatic and cholangiocarcinoma cell lines. Downregulation of HSF1 expression induces annexin V and TUNEL positivity and caspase-3 activation, suggesting activation of a caspase-dependent apoptotic pathway. Although caspase-3 inhibition protects against cell death induced by HSF1 expression, it does not completely prevent it, suggesting a role for caspase-independent cell death. HSF1 plays a prosurvival role in the pathogenesis of pancreatobiliary tumors. Modulation of HSF1 activity could therefore emerge as a novel therapeutic strategy for cancer treatment.

• Guideline recommended gastric cancer care in the elderly: insights into the applicability of cancer trials to real world.

  Authors: Vikas Dudeja, Elizabeth B Habermann, Wei Zhong, Todd M Tuttle, Selwyn M Vickers, Eric H Jensen, Waddah B Al-Refaie

  Annals of surgical oncology. 01/2011; 18(1):26-33.

  Given the underrepresentation of older persons in cancer trials, the association between increasing age and receipt of recommended gastric cancer care in the United States was examined. Using theGiven the underrepresentation of older persons in cancer trials, the association between increasing age and receipt of recommended gastric cancer care in the United States was examined. Using the 1998-2006 SEER database, 8637 Medicare-eligible patients, aged ≥ 65 years who underwent gastrectomy for nonmetastatic gastric adenocarcinoma were identified. Multivariate analyses was used to assess the effect of increasing age on receipt of recommended gastric cancer care (adequate lymph node evaluation [≥ 15 lymph nodes] and adjuvant radiation therapy for AJCC Ib-IVM0) and cancer-specific mortality controlling for covariates. While 61% of gastric cancer operations were performed in patients ≥ 65 years, less than 30% received adequate lymphadenectomy or adjuvant radiation therapy. Older patients were less likely to receive adequate nodal evaluation and adjuvant radiotherapy (P < 0.0001). These findings persisted on multivariate analyses. Older age was also associated with worse cancer-specific mortality. Because an age-tumor location interaction for cancer mortality (P = 0.047) was observed, stratified analyses were performed which showed that the adverse effect of older age on cancer-specific mortality was augmented in proximal gastric cancers. This population-based study showed significant age-based variations in gastric cancer care. These results should encourage assessment of generalizability of gastric cancer trials to this expanding population of elderly in the era of comparative effectiveness research.

• The maximally invasive hepatobiliary surgeon: A dying breed?: Comment on "Laparoscopic vs open hepatectomy for benign and malignant tumors".

  Authors: Eric H Jensen, Selwyn M Vickers

  Archives of surgery (Chicago, Ill. : 1960). 11/2010; 145(11):1118.

• Triptolide and TRAIL combination enhances apoptosis in cholangiocarcinoma.

  Authors: Kimberly A Clawson, Daniel Borja-Cacho, Mara B Antonoff, Ashok K Saluja, Selwyn M Vickers

  The Journal of surgical research. 10/2010; 163(2):244-9.

  Cholangiocarcinoma originates from bile duct epithelial cells in the intrahepatic and extrahepatic biliary system. We recently observed that triptolide (a diterpenoid triepoxide) is effective inCholangiocarcinoma originates from bile duct epithelial cells in the intrahepatic and extrahepatic biliary system. We recently observed that triptolide (a diterpenoid triepoxide) is effective in inducing apoptosis in pancreatic tumors. Death receptors 4 and 5 are overexpressed in several cancer types, and their activation by tumor-necrosis factor-related apoptosis-inducing ligand (TRAIL) induces cell death. The principal objective of this study was to determine the effects of combination therapy with TRAIL and triptolide in cholangiocarcinoma. Two cholangiocarcinoma cell lines were incubated with various doses of triptolide and TRAIL, alone and in combination; cell viability was assessed at 24 and 48 h. Annexin-V staining and caspase-3 activity were measured after 24 h of triptolide, TRAIL or combination treatment. Western blots assessed protein levels of poly(ADP-ribose) polymerase (PARP) and X-linked inhibitor of apoptosis (XIAP). Combination treatment using TRAIL and triptolide decreased cell viability in all cell lines at 48 h, with greater cell killing than that which was observed with either drug alone. This decrease in viability was associated with increases in annexin-V staining and caspase-3 activity. Western blot analysis demonstrated increases in PARP cleavage and decreases in XIAP expression that were dose-dependent. TRAIL and triptolide in combination decreased cell viability and enhanced apoptosis. Furthermore, Western blot analysis suggests that triptolide sensitizes cells to TRAIL-induced apoptotic cell death by inhibiting expression of XIAP, a protein known to inhibit apoptosis. Our results demonstrate that combination of TRAIL and triptolide enhance apoptosis in cholangiocarcinoma cell lines.

• Role of Hsp-70 in triptolide-mediated cell death of neuroblastoma.

  Authors: Mara B Antonoff, Rohit Chugh, Steven J Skube, Vikas Dudeja, Daniel Borja-Cacho, Kimberly A Clawson, Selwyn M Vickers, Ashok K Saluja

  The Journal of surgical research. 09/2010; 163(1):72-8.

  Our recent work demonstrated that treatment of neuroblastoma with triptolide causes apoptotic cell death in vitro and decreases tumor size in vivo. Triptolide therapy has been associated with reducedOur recent work demonstrated that treatment of neuroblastoma with triptolide causes apoptotic cell death in vitro and decreases tumor size in vivo. Triptolide therapy has been associated with reduced expression of Hsp-70, suggesting a mechanism of cell killing involving Hsp-70 inhibition. The principal objective of this study was to investigate the role of Hsp-70 in triptolide-mediated cell death in neuroblastoma. Neuroblastoma cells were transfected with Hsp-70-specific siRNA. Viability, caspase activity, and phosphatidylserine externalization were subsequently measured. An orthotopic, syngeneic murine tumor model was developed, and randomized mice received daily injections of triptolide or vehicle. At 21 d, mice were sacrificed. Immunohistochemisty was used to characterize Hsp-70 levels in residual tumors, and terminal deoxynucleotidyl transferase dUTP nick end labeling (TUNEL) was performed to identify cells undergoing apoptosis. Targeted silencing of Hsp-70 with siRNA significantly decreased cellular viability, augmented caspase-3 activity, and resulted in increased annexin-V staining. These effects parallel those findings obtained following treatment with triptolide. Residual tumors from triptolide-treated mice showed minimal staining with Hsp-70 immunohistochemistry, while control tumors stained prominently. Tumors from treated mice demonstrated marked staining with the TUNEL assay, while control tumors showed no evidence of apoptosis. Use of siRNA to suppress Hsp-70 expression in neuroblastoma resulted in apoptotic cell death, similar to the effects of triptolide. Residual tumors from triptolide-treated mice expressed decreased levels of Hsp-70 and demonstrated significant apoptosis. These findings support the hypothesis that Hsp-70 inhibition plays a significant role in triptolide-mediated neuroblastoma cell death.

• Triptolide induces cell death in pancreatic cancer cells by apoptotic and autophagic pathways.

  Authors: Nameeta Mujumdar, Tiffany N Mackenzie, Vikas Dudeja, Rohit Chugh, Mara B Antonoff, Daniel Borja-Cacho, Veena Sangwan, Rajinder Dawra, Selwyn M Vickers, Ashok K Saluja

  Gastroenterology. 04/2010; 139(2):598-608.

  Pancreatic adenocarcinoma, among the most lethal human malignancies, is resistant to current chemotherapies. We previously showed that triptolide inhibits the growth of pancreatic cancer cells inPancreatic adenocarcinoma, among the most lethal human malignancies, is resistant to current chemotherapies. We previously showed that triptolide inhibits the growth of pancreatic cancer cells in vitro and prevents tumor growth in vivo. This study investigates the mechanism by which triptolide kills pancreatic cancer cells. Cells were treated with triptolide and viability and caspase-3 activity were measured using colorimetric assays. Annexin V, propidium iodide, and acridine orange staining were measured by flow cytometry. Immunofluorescence was used to monitor the localization of cytochrome c and Light Chain 3 (LC3) proteins. Caspase-3, Atg5, and Beclin1 levels were down-regulated by exposing cells to their respective short interfering RNA. We show that triptolide induces apoptosis in MiaPaCa-2, Capan-1, and BxPC-3 cells and induces autophagy in S2-013, S2-VP10, and Hs766T cells. Triptolide-induced autophagy has a pro-death effect, requires autophagy-specific genes, atg5 or beclin1, and is associated with the inactivation of the Protein kinase B (Akt)/mammalian target of Rapamycin/p70S6K pathway and the up-regulation of the Extracellular Signal-Related Kinase (ERK)1/2 pathway. Inhibition of autophagy in S2-013 and S2-VP10 cells results in cell death via the apoptotic pathway whereas inhibition of both autophagy and apoptosis rescues cell death. This study shows that triptolide kills pancreatic cancer cells by 2 different pathways. It induces caspase-dependent apoptotic death in MiaPaCa-2, Capan-1, and BxPC-3, and induces caspase-independent autophagic death in metastatic cell lines S2-013, S2-VP10, and Hs766T, thereby making it an attractive chemotherapeutic agent against a broad spectrum of pancreatic cancers.

• Resectability of pancreatic adenocarcinoma in patients with locally advanced disease downstaged by preoperative therapy: a challenge for MDCT.

  Authors: Desiree E Morgan, Clinton N Waggoner, Cheri L Canon, Mark E Lockhart, Naomi S Fineberg, James A Posey, Selwyn M Vickers

  AJR. American journal of roentgenology. 03/2010; 194(3):615-22.

  The purpose of this study was to determine whether preoperative neoadjuvant therapy in patients with locally advanced pancreatic cancer affects the ability of multiphasic MDCT to predict successfulThe purpose of this study was to determine whether preoperative neoadjuvant therapy in patients with locally advanced pancreatic cancer affects the ability of multiphasic MDCT to predict successful surgical resection. From 2000 to 2006, there were 12 patients with prior neoadjuvant therapy successfully downstaged by CT and 31 age-matched pancreatic cancer patients without preoperative therapy who underwent pancreatic MDCT followed by attempted pancreaticoduodenectomy. Three readers blinded to surgical findings independently analyzed immediate preoperative MDCT scans of 43 patients comprising the retrospective data set in random order for vascular involvement (degree of contact and narrowing) and distant metastases. Individual reader sensitivity and specificity for resectability prediction were compared for study and control groups using the Fisher's exact test. Interobserver agreement was assessed using the kappa statistic. Seven (58%) of 12 neoadjuvant-treated adenocarcinomas and 10 (32%) of 31 control pancreatic carcinomas were resectable (p > 0.05). For resectable disease, sensitivities were 86%, 71%, and 14% for the neoadjuvant group and 90%, 90%, and 60% for the control group (p > 0.05). Specificities were 80%, 100%, and 100% for the neoadjuvant group and 57%, 43%, and 76% for the control group (reader 2 specificity difference, p = 0.04). The multi rater kappa value of resectability prediction for neoadjuvant patients was 0.28, and that for control subjects was 0.63 (p < 0.001). In the neoadjuvant group, the majority of individual reader errors were false-negative resectability interpretations resulting from overestimation of vascular involvement. Consideration of degrees of venous abutment did not improve estimation of resectability in patients with neoadjuvant therapy. Sensitivity for prediction of resectability tends to be lower for patients with locally advanced pancreatic cancer that has been downstaged by neoadjuvant therapy, but this trend is not statistically significant. Interobserver variability for determination of resectability is statistically higher than for controls who did not receive preoperative therapy.

• Extremity soft tissue sarcoma care in the elderly: insights into the generalizability of NCI Cancer Trials.

  Authors: Waddah B Al-Refaie, Elizabeth B Habermann, Vikas Dudeja, Selwyn M Vickers, Todd M Tuttle, Eric H Jensen, Beth A Virnig

  Annals of surgical oncology. 03/2010; 17(7):1732-8.

  The projected increase in older persons in the United States, their underrepresentation in clinical trials, and the rarity of extremity soft tissue sarcomas (ESTS) limit our understanding of ESTSThe projected increase in older persons in the United States, their underrepresentation in clinical trials, and the rarity of extremity soft tissue sarcomas (ESTS) limit our understanding of ESTS care in the elderly. We explored the extent of older age (> or =65 years) on patterns of ESTS care in NCI-sponsored population-based dataset. Using the 1991-2006 Surveillance Epidemiology and End Results registries, we identified 2586 Medicare aged persons > or =65 years with ESTS. We compared demographics, tumors, and treatments by age category. Multivariable analyses were used to examine the effect of older age on ESTS care and survival, adjusting for covariates. More than 30% of adult ESTS were diagnosed in patients older than 65 years. A significant trend was observed between increasing age and decreased use of sarcoma-directed surgery and delivery of radiotherapy after limb-sparing surgery for high-grade or T2 tumors. Limb amputation rates did not vary by age. However, both African-American (odds ratio [OR] 1.85, 95% confidence interval [95% CI] 1.05-3.27, P = .0341) and Hispanic races (OR 2.17, 95% CI 1.27-3.70, P = .0044) predicted higher rates of limb amputation than whites. Although our multivariable analyses showed that decreased use of sarcoma-directed surgery was only limited to age 85 + years, it also showed that older age predicted poorer cancer-specific mortality following sarcoma-directed surgery (P < .0001). In this US population-based study, the decreased use of sarcoma-directed surgery in the elderly was only limited to those older than 85 years. The association between older age and increased cancer-related mortality deserves future investigation to carefully examine potential effects of undertreatment.

• A new drug delivery method of bispecific ligand-directed toxins, which reduces toxicity and promotes efficacy in a model of orthotopic pancreatic cancer.

  Authors: Seunguk Oh, Brad J Stish, Selwyn M Vickers, Donald J Buchsbaum, Ashok K Saluja, Daniel A Vallera

  Pancreas. 02/2010; 39(6):913-22.

  Biologicals targeting epidermal growth factor (EGF) and interleukin 13 receptors not only react with overexpressed markers on cancer cells but also react with receptors on normal cells. Because weBiologicals targeting epidermal growth factor (EGF) and interleukin 13 receptors not only react with overexpressed markers on cancer cells but also react with receptors on normal cells. Because we developed novel bispecific ligand-directed toxins synthesized by cloning EGF and interleukin 13 on the same molecule with toxin, our objective was to determine whether we could block normal receptors while still targeting receptors overexpressed on cancer cells, thereby decreasing toxicity while maintaining efficacy. A method, toxicity blocking (ToxBloc), was developed in which a bolus intraperitoneal dose of recombinant EGF13 (without toxin) was given to mice approximately 15 to 20 minutes before DTEGF13. Experiments were then performed to determine whether the maximal tolerated dose (MTD) was reduced and whether we were still able to eliminate progression of aggressive human, metastatic, pancreatic cancer induced by orthotopic injection (OT) in nude mice. ToxBloc permitted us to safely exceed the DTEGF13 maximal tolerated dose by 15-fold. This approach permitted repetitive high dosing with the bispecific ligand-directed toxin resulting in tumor regression (P < 0.01). Tumor effects were documented using a tumor imaging model in which OT tumor growth was monitored noninvasively in real time. ToxBloc was selective because other bispecific peptides did not block. ToxBloc represents a new method of drug delivery and a potential solution to the problem of toxicity.

• Laparoscopic distal pancreatectomy.

  Authors: Daniel Borja-Cacho, Waddah B Al-Refaie, Selwyn M Vickers, Todd M Tuttle, Eric H Jensen

  Journal of the American College of Surgeons. 12/2009; 209(6):758-65; quiz 800.

• TRAIL and Triptolide: An Effective Combination that Induces Apoptosis in Pancreatic Cancer Cells.

  Authors: Daniel Borja-Cacho, Yumi Yokoyama, Rohit K Chugh, Nameeta R Mujumdar, Vikas Dudeja, Kimberly A Clawson, Rajinder K Dawra, Ashok K Saluja, Selwyn M Vickers

  Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 12/2009;

  INTRODUCTION: An emerging therapy in oncology is the induction of apoptotic cell death through anti-death receptor therapy. However, pancreatic cancer is resistant to apoptosis including anti-deathINTRODUCTION: An emerging therapy in oncology is the induction of apoptotic cell death through anti-death receptor therapy. However, pancreatic cancer is resistant to apoptosis including anti-death receptor therapy. We have previously described how triptolide decreases resistance to apoptosis in pancreatic cancer cells in vitro and in vivo. We hypothesized that triptolide decreases tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) resistance in pancreatic cancer cells. The aim of this study was to evaluate the effects that combined therapy with TRAIL and triptolide have on different parameters of apoptosis. METHODS: Four different pancreatic cancer cell lines were exposed to triptolide, TRAIL, or a combination of both drugs. We assessed the effects that combined therapy with TRAIL and triptolide has on cell viability, apoptosis, caspase-3 and caspase-9 activities, and poly(ADP)-ribose polymerase cleavage. RESULTS: Pancreatic cancer cells were resistant to TRAIL therapy; however, combined therapy with triptolide and TRAIL significantly decreased the cell viability in all the cell lines and increased apoptotic cell death as a result of caspase-3 and caspase-9 activation. CONCLUSIONS: Pancreatic cancer is highly resistant to anti-death receptor therapy, but combined therapy with TRAIL and triptolide is an effective therapy that induces apoptotic cell death in pancreatic cancer cells.

• Variations in gastric cancer care: a trend beyond racial disparities.

  Authors: Waddah B Al-Refaie, Greer Gay, Beth A Virnig, Jennifer F Tseng, Andrew Stewart, Selwyn M Vickers, Todd M Tuttle, Barry W Feig

  Cancer. 11/2009;

  BACKGROUND:: Race is associated with patterns of presentation and survival outcomes of gastric cancer in the United States. However, the impact of race on the receipt of guideline-recommended care isBACKGROUND:: Race is associated with patterns of presentation and survival outcomes of gastric cancer in the United States. However, the impact of race on the receipt of guideline-recommended care is not well characterized. By using current recommendations, the authors examined the association between race and guideline-recommended treatments and identified factors that are predictive of variations in gastric cancer care. METHODS:: By using the National Cancer Database for 1998 through 2005, 106,002 patients with gastric adenocarcinoma were identified. Multivariate analysis techniques were used to examine the association between race, the receipt of guideline-recommended care, and survival after adjusting for covariates. RESULTS:: Although African-American and Hispanic patients were more likely to undergo adequate lymphadenectomy (>/=15 lymph nodes) and to receive care at comprehensive cancer centers and high-volume facilities (for all, P </= .001), they were less likely to receive adjuvant multimodality therapy for American Joint Committee on Cancer stage IB through IV, lymph node-negative (M0) disease. Up to 60% of all patients who underwent gastrectomy failed to receive adequate lymphadenectomy and adjuvant multimodality therapy. The delivery of multimodality therapy varied significantly by stage and lymph node evaluation (P </= .001). These findings persisted on our multivariate analyses, indicating that African-American and Hispanic patients received adequate lymph node evaluation (P </= .001), whereas they were associated with receiving no adjuvant multimodality therapy (P </= .025). CONCLUSIONS:: There were significant variations in treatment for gastric cancer among ethnic groups in the United States. It was noteworthy that, although nonwhite race was associated with improved surgical care, gastric cancer care remained suboptimal overall. Cancer programs need to identify procedures to maximize the delivery of adequate gastric cancer care to all patients. Cancer 2010. (c) 2009 American Cancer Society.

• Anti-ERBB2 sh-RNA suppress both cell growth and tumor growth in ERBB2-overexpressing upper gastrointestinal adenocarcinomas.

  Authors: Amanda K Arrington, Julia Davydova, Selwyn M Vickers, Masato Yamamoto

  Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 10/2009; 13(10):1754-61.

  INTRODUCTION: ERBB2 is overexpressed in 15-25% of upper gastrointestinal adenocarcinomas. We use a stable lentiviral shRNA model to demonstrate that ERBB2 suppression in upper gastrointestinalINTRODUCTION: ERBB2 is overexpressed in 15-25% of upper gastrointestinal adenocarcinomas. We use a stable lentiviral shRNA model to demonstrate that ERBB2 suppression in upper gastrointestinal adenocarcinomas with documented ERBB2 amplification effectively decreases ERBB2 protein levels and decreases cell viability. Further, we evaluate tumor growth of cells treated with the ERBB2 shRNA. METHODS: Three upper gastrointestinal adenocarcinoma cells lines with varying ERBB2 levels were treated with one of three separate lentiviral green fluorescent protein (GFP)-labeled ERBB2 shRNA vectors or a nonsilencing control shRNA vector for 6 h. Protein levels on day 6 and cell viability was evaluated on days 3-10. A xenograft in vivo experiment was performed using OE19 cells pretransduced with ERBB2 shRNA to evaluate tumor growth. RESULTS: ERBB2 protein levels decreased by 80%. ERBB2 knockdown significantly decreased cell viability in cell lines with high ERBB2 levels. In vivo tumor growth was suppressed in ERBB2-shRNA-treated groups. CONCLUSION: ERBB2 suppression based on a stable lentiviral shRNA transfection system effectively decreases cell viability in cell lines with amplification of ERBB2 as compared to cell lines without overexpression. ERBB2 knockdown significantly decreases tumor growth in vivo. ERBB2-directed therapy may be of benefit in the subset of patients with gastrointestinal adenocarcinomas exhibiting overamplification of ERBB2.

• In vivo bioimaging tracks conditionally replicative adenoviral replication and provides an early indication of viral antitumor efficacy.

  Authors: Julia Davydova, Tatyana Gavrikova, Eric J Brown, Xianghua Luo, David T Curiel, Selwyn M Vickers, Masato Yamamoto

  Cancer science. 10/2009;

  In vivo monitoring of conditionally replicative adenovirus (CRAd) replication and assessing its correlation to CRAd biological effects are necessary for the clinical development of gene therapy.In vivo monitoring of conditionally replicative adenovirus (CRAd) replication and assessing its correlation to CRAd biological effects are necessary for the clinical development of gene therapy. Noninvasive bioimaging is one current approach which can monitor in vivo CRAd replication and functional effect. Here we describe a novel cyclooxygenase-2 (Cox2) promoter-controlled CRAd that was modified to contain firefly luciferase in its E3 region; this modification permitted serial bioluminescence imaging of viral replication in vitro and in vivo. In vitro luciferase expression correlated with viral replication and cytolytic effect. In vivo bioluminescence imaging showed dynamic representation of the viral replication level in athymic nude mice bearing subcutaneous tumor xenografts. Importantly, in vivo luciferase bioluminescence measured 6 days after viral administration significantly correlated with CRAd antitumor effect at day 36. Thus, our system could detect viral replication and predict in vivo therapeutic outcome based on early imaging. Further development of this approach may improve patient safety, enhance clinical trial conduct, and provide mechanistic insight into CRAd function in vivo. (Cancer Sci 2009; 00: 000-000).