Jordan M Winter

Thomas Jefferson University, Philadelphia, Pennsylvania, United States

Are you Jordan M Winter?

Claim your profile

Publications (68)261.03 Total impact

  • [Show abstract] [Hide abstract]
    ABSTRACT: While many patients experience prolonged survival after pancreatic resection for benign or malignant disease, the long-term risk of pancreatogenic diabetes mellitus (DM) remains poorly characterized.
    Journal of gastrointestinal surgery : official journal of the Society for Surgery of the Alimentary Tract. 10/2014;
  • [Show abstract] [Hide abstract]
    ABSTRACT: This study was designed to determine whether the volume and type of fluid administered for pancreaticoduodenectomy impacts postoperative outcomes.
    Annals of surgery. 09/2014; 260(3):445-55.
  • [Show abstract] [Hide abstract]
    ABSTRACT: Effective treatment of pancreatic pathology relies on both preoperative and intraoperative decision making. Traditionally, the use of preoperative imaging and endoscopic modalities, in combination with intraoperative findings and pathologic evaluation, has guided the surgeons to perform the correct operative procedure. We hypothesize that the intraoperative use of pancreatoscopy (fiberoptic endoscopy of the pancreatic duct) is a valuable adjunct in selected cases to facilitate the performance of the appropriate definitive surgical treatment. We queried our IRB-approved, prospectively maintained the pancreatic surgery database identifying the uses of intraoperative pancreatoscopy in all pancreatic resections at our institution from 2005-2012. Operative notes, pathology reports, and perioperative outcomes were evaluated. During the study period, 1,016 pancreatic resections were performed at our institution. Twenty-three cases during this period included the use of intraoperative pancreatoscopy. Eighteen (78 %) of these operations were performed for presumed main duct intraductal papillary mucinous neoplasm. In five cases (22 %), the surgical resection was extended secondary to the intraoperative pancreatoscopy findings. Appropriate surgical treatment of the pancreatic lesions can be challenging in the face of preoperative imaging limitations. The selective use of intraoperative fiberoptic endoscopy to evaluate the pancreatic duct appears to help to enable the surgeon to better perform the appropriate resection and optimal treatment.
    Journal of Gastrointestinal Surgery 03/2014; · 2.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Deoxycytidine kinase (dCK) and human antigen R (HuR) have been associated with response to gemcitabine in small studies. The present study investigates the prognostic and predictive value of dCK and HuR expression levels for sensitivity to gemcitabine and 5-fluorouracil (5-FU) in a large phase III adjuvant trial with chemoradiation backbone in pancreatic ductal adenocarcinoma (PDA). The dCK and HuR expression levels were determined by immunohistochemistry on a tissue microarray of 165 resected PDAs from the Radiation Therapy Oncology Group (RTOG) 9704 trial. Association with overall survival (OS) and disease-free survival (DFS) status were analyzed using the log-rank test and the Cox proportional hazards model. Experiments with cultured PDA cells were performed to explore mechanisms linking dCK and HuR expression to drug sensitivity. dCK expression levels were associated with improved OS for all patients analyzed from RTOG 9704 (HR: 0.66, 95% CI [0.47-0.93], P = 0.015). In a subset analysis based on treatment arm, the effect was restricted to patients receiving 5-FU (HR: 0.53, 95% CI [0.33-0.85], P = 0.0078). Studies in cultured cells confirmed that dCK expression rendered cells more sensitive to 5-FU. HuR cytoplasmic expression was neither prognostic nor predictive of treatment response. Previous studies along with drug sensitivity and biochemical studies demonstrate that radiation interferes with HuR's regulatory effects on dCK, and could account for the negative findings herein based on the clinical study design (i.e., inclusion of radiation). Finally, we demonstrate that 5-FU can increase HuR function by enhancing HuR translocation from the nucleus to the cytoplasm, similar to the effect of gemcitabine in PDA cells. For the first time, in the pre-treatment tumor samples, dCK and HuR cytoplasmic expression were strongly correlated (chi-square P = 0.015). This dual-institutional follow up study, in a multi-institutional PDA randomized clinical trial, observed that dCK expression levels were prognostic and had predictive value for sensitivity to 5-FU.
    Cancer biology & therapy 03/2014; 15(6). · 3.29 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: HuR (ELAV1), an RNA-binding protein abundant in cancer cells, primarily resides in the nucleus, but under specific stress (e.g., gemcitabine), HuR translocates to the cytoplasm in which it tightly modulates the expression of mRNA survival cargo. Here, we demonstrate for the first time that stressing pancreatic ductal adenocarcinoma (PDA) cells by treatment with DNA-damaging anticancer agents (mitomycin C, oxaliplatin, cisplatin, carboplatin, and a PARP inhibitor) results in HuR's translocation from the nucleus to the cytoplasm. Importantly, silencing HuR in PDA cells sensitized the cells to these agents, whereas overexpressing HuR caused resistance. HuR's role in the efficacy of DNA-damaging agents in PDA cells was, in part, attributed to the acute upregulation of WEE1 by HuR. WEE1, a mitotic inhibitor kinase, regulates the DNA damage repair pathway, and therapeutic inhibition of WEE1 in combination with chemotherapy is currently in early phase trials for the treatment of cancer. We validate WEE1 as a HuR target in vitro and in vivo by demonstrating (i) direct binding of HuR to WEE1's mRNA (a discrete 56-bp region residing in the 3' untranslated region) and (ii) HuR siRNA silencing and overexpression directly affects the protein levels of WEE1, especially after DNA damage. HuR's positive regulation of WEE1 increases γ-H2AX levels, induces Cdk1 phosphorylation, and promotes cell-cycle arrest at the G2-M transition. We describe a novel mechanism that PDA cells use to protect against DNA damage in which HuR posttranscriptionally regulates the expression and downstream function of WEE1 upon exposure to DNA-damaging agents. Cancer Res; 74(4); 1128-40. ©2014 AACR.
    Cancer Research 02/2014; 74(4):1128-40. · 9.28 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: With the increased use of cross-sectional radiologic imaging in recent years, cystic lesions of the pancreas are being diagnosed with greater frequency. While pseuodocysts have historically accounted for the majority of benign pancreatic cysts, there are a number of rare, benign cystic lesions of the pancreas that can mimic neoplastic cysts. The objective of this study was to review a single institution's experience with these benign cystic lesions of the pancreas. We conducted a retrospective analysis of all patients who underwent surgical resection for pancreatic disease from 2005 to 2012 at our institution. Out of a total of 947 pancreatic resections, we identified those cases performed for cystic disease, and focused upon the clinicopathologic data of patients with non-neoplastic pancreatic cysts. Of the 947 pancreatic resections, 256 (27 %) were performed for cystic disease. Sixteen cases (6.3 %) out of the total of 256 pancreatic operations performed for cystic disease were found to have non-neoplastic cystic lesions of the pancreas. Preoperative imaging revealed primary lesions in all patients, eight of which were found incidentally. Of these lesions, 14 were suspected preoperatively to be mucinous neoplasms and two to harbor pancreatic adenocarcinoma. However, postoperative pathology revealed eight patients with ductal retention cysts, three squamoid cysts, one mucinous non-neoplastic cyst, one congenital ciliated foregut cyst, one lymphoepithelial cyst, and two endometrial cysts. Two patients had complications postoperatively, one pancreatic fistula and one SMV thrombosis. Both complications resolved with conservative management. Non-neoplastic epithelial pancreatic cysts are rare, benign lesions. In our institutional experience, these lesions are often indistinguishable from cystic neoplasms of the pancreas preoperatively. As such, many of these lesions are resected unknowingly. It is important for the clinician to be well informed of the nature of these lesions, in the hopes to avoid unnecessary resection whenever possible.
    Journal of Gastrointestinal Surgery 01/2014; · 2.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Understanding the factors contributing to improved postoperative patient outcomes remains paramount. For complex abdominal operations such as pancreaticoduodenectomy (PD), the influence of provider and hospital volume on surgical outcomes has been described. The impact of resident experience is less well understood. We reviewed perioperative outcomes after PD at a single high-volume center between 2006 and 2012. Resident participation and outcomes were collected in a prospectively maintained database. Resident experience was defined as postgraduate year (PGY) and number of PDs performed. Forty-three residents and four attending surgeons completed 686 PDs. The overall complication rate was 44 %; PD-specific complications (defined as pancreatic fistula, delayed gastric emptying, intraabdominal abscess, wound infection, and bile leak) occurred in 28 % of patients. The overall complication rates were similar when comparing PGY 4 to PGY 5 residents (55.3 vs. 43.0 %; p > 0.05). On univariate analysis, there was a difference in PD-specific complications seen between a PGY 4 as compared to a PGY 5 resident (44 vs. 27 %, respectively; p = 0.016). However, this was not statistically significant when adjusted for attending surgeon. Logistic regression demonstrated that as residents perform more cases, PD-specific complications decrease (OR = 0.97; p < 0.01). For a resident's first PD case, the predicted probability of a PD-specific complication is 27 %; this rate decreases to 19 % by resident case number 15. Complex cases, such as PD, provide unparalleled learning opportunities and remain an important component of surgical training. We highlight the impact of resident involvement in complex abdominal operations, demonstrating for the first time that as residents build experience with PD, patient outcomes improve. This is consistent with volume-outcome relationships for attending physicians and high-volume hospitals. Maximizing resident repetitive exposure to complex procedures benefits both the patient and the trainee.
    Journal of Gastrointestinal Surgery 11/2013; · 2.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Antiplatelet therapy with aspirin is prevalent among patients presenting for operative treatment of pancreatic disorders. Operative practice has called for the cessation of aspirin 7-10 days before elective procedures because of the perceived increased risk of procedure-related bleeding. Our practice at Thomas Jefferson University has been to continue aspirin therapy throughout the perioperative period in patients undergoing elective pancreatic surgery. Records for patients undergoing pancreatoduodenectomy, distal pancreatectomy, or total pancreatectomy between October 2005 and February 2012 were queried for perioperative aspirin use in this institutional research board-approved retrospective study. Statistical analyses were performed with Stata software. During the study period, 1,017 patients underwent pancreatic resection, of whom 289 patients (28.4%) were maintained on aspirin through the morning of the operation. Patients in the aspirin group were older than those not taking aspirin (median 69 years vs 62 years, P < .0001). The estimated intraoperative blood loss was similar between the two groups, aspirin versus no aspirin (median 400 mL vs 400 mL, P = .661), as was the rate of blood transfusion anytime during the index admission (29% vs 26%, P = 0.37) and the postoperative duration of hospital stay (median 7 days vs 6 days, P = .103). The aspirin group had a slightly increased rate of cardiovascular complications (10.1% vs 7.0%, P = .107), likely reflecting their increased cardiovascular comorbidities that led to their physicians recommending aspirin therapy. Rates of pancreatic fistula (15.1% vs 13.5%, P = .490) and hospital readmissions were similar (16.9% vs 14.9%, P = .451). This is the first study to report that aspirin therapy is not associated with increased rates of perioperative bleeding, transfusion requirement, or major procedure related complications after elective pancreatic surgery. These data suggest that continuation of aspirin is safe and that the continuation of aspirin should be considered acceptable and preferable, particularly in patients with perceived substantial medical need for treatment with antiplatelet therapy.
    Surgery 07/2013; · 3.37 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Distal pancreatectomy and splenectomy (DPS) is the procedure of choice for the surgical treatment of pancreatic exocrine cancer localized to the body and tail of the pancreas. Splenic vein thrombosis (SVT) can occur in patients with malignant pancreatic exocrine tumors secondary to direct tumor invasion or compression of the splenic vein by mass effect. This study examines the effect of preoperative SVT on postoperative outcomes. In this retrospective cohort study, we queried our pancreatic surgery database to identify patients who underwent DPS from October 2005 to June 2011. These cases were evaluated for evidence of preoperative SVT on clinical records and cross-sectional imaging (CT, MRI, endoscopic US). Outcomes for patients with and without SVT were compared. From an overall cohort of 285 consecutive patients who underwent DPS during the study period, data were evaluated for 70 subjects who underwent surgery for pancreatic exocrine cancer (27 with SVT, 43 without SVT). The preoperative demographics and co-morbidities were similar between the groups, except the average age was higher for those without SVT (p < 0.05). The median estimated blood loss was significantly higher in the SVT group (675 versus 250 ml, p = <0.001). While the overall morbidity rates were similar between the two groups (48 % SVT versus 56 % no SVT, p = NS), the group with SVT had a significantly higher rate of pancreas-specific complications, including pancreatic fistula (33 versus 7 %, p < 0.01) and delayed gastric emptying (15 versus 0 %, p < 0.02). Hospital readmission rates were similar between the groups (30 versus 28 %, p = NS). Patients without SVT had a trend toward longer median survival (40 versus 20.8 months), although the difference was not statistically significant (p = 0.1). DPS for pancreatic ductal adenocarcinoma can be performed safely in patients with SVT, but with higher intraoperative blood loss, increased pancreas-specific complications, and a trend towards lower long-term survival rates. This paper was presented as a poster at the 53rd annual meeting of the Society for Surgery of the Alimentary Tract and at the 46th annual meeting of the Pancreas Club, San Diego, CA, May 2012.
    Journal of Gastrointestinal Surgery 06/2013; · 2.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Cancer cell metabolism differs from normal cells, yet the regulatory mechanisms responsible for these differences are incompletely understood, particularly in response to acute changes in the tumor microenvironment. HuR, an RNA-binding protein, acts under acute stress to regulate core signaling pathways in cancer through post-transcriptional regulation of mRNA targets. We demonstrate that HuR regulates the metabolic phenotype in pancreatic cancer cells and is critical for survival under acute glucose deprivation. Using three pancreatic cancer cell line models, HuR-proficient cells demonstrated superior survival under glucose deprivation when compared with isogenic cells with siRNA-silencing of HuR expression (HuR-deficient cells). We found that HuR-proficient cells utilized less glucose, but produced greater lactate, as compared with HuR-deficient cells. Acute glucose deprivation was found to act as a potent stimulus for HuR translocation from the nucleus to the cytoplasm, where HuR stabilizes its mRNA targets. We performed a gene expression array on ribonucleoprotein-immunoprecipitated mRNAs bound to HuR and identified 11 novel HuR target transcripts that encode enzymes central to glucose metabolism. Three (GPI, PRPS2 and IDH1) were selected for validation studies, and confirmed as bona fide HuR targets. These findings establish HuR as a critical regulator of pancreatic cancer cell metabolism and survival under acute glucose deprivation. Further explorations into HuR's role in cancer cell metabolism should uncover novel therapeutic targets that are critical for cancer cell survival in a metabolically compromised tumor microenvironment.
    RNA biology 06/2013; 10(8). · 5.56 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic ductal adenocarcinoma (PDA) is the fourth leading cause of cancer-related death in the United States with a 95% five-year mortality rate. For over a decade, gemcitabine (GEM) has been the established first-line treatment for this disease despite suboptimal response rates. The development of PARP inhibitors that target the DNA damage repair mechanism in PDA cells has generated encouraging pre-clinical results. Ubiquitin-specific peptidase 11 (USP11), an enzyme that interacts with BRCA2, was recently discovered to play a key role in DNA double-strand break repair and may be a novel therapeutic target. Using a systematic high-throughput approach, we biochemically screened 2000 FDA approved and pharmacologically active compounds for inhibition of USP11 enzymatic activity. We identified six active small molecules that inhibit USP11 enzymatic activity. An in vitro drug sensitivity assay demonstrated that one of these USP11 inhibitors, mitoxantrone, affected PDA cell survival with an IC50 of less than 10 nM. Across six different PDA cell lines, two with defects in the Fanconi Anemia/BRCA2 pathway (Hs766T and Capan-1), mitoxantrone is 40 to 20,000-fold more potent than GEM, with increased endogenous USP11 mRNA levels associated with increased sensitivity to mitoxantrone. USP11 silencing in PDA cells also enhanced sensitivity to GEM. These findings establish a model for rapid discovery of FDA approved compounds by complementing in vitro biochemical experiments with cell culture studies. Further, they provide a strong rationale to study mitoxantrone in pre-clinical and early-phase clinical settings for the treatment of PDA.
    Molecular Cancer Research 05/2013; · 4.35 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: INTRODUCTION: Acinar cell cystadenoma (ACC) of the pancreas was first described as a distinct pancreatic cystic neoplasm in 2002. METHODS: We have encountered three cases of ACC at our institution in addition to the 15 cases reported to date in the world literature. The gender distribution in the total cohort of patients with ACC slightly favored females (61 % female), and the median age was 49.5 years. RESULTS: Almost half (53 %) of the cases were identified incidentally, while the remainder presented with abdominal pain. The median tumor diameter was 5 cm in size, and no patients have had documented disease recurrence or progression, even in the setting of an incomplete resection. CONCLUSION: These findings suggest a relatively indolent biology, and that complete resections are curative. As we will show, surgical resection is warranted to treat symptoms and prevent local extension or malignant transformation.
    Journal of Gastrointestinal Surgery 04/2013; · 2.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: The aim of this study was to examine whether midline, paramedian, or transverse incisions offer potential advantages for abdominal surgery. DATA SOURCES: We searched MEDLINE, Embase, Web of Science, and The Cochrane Central Register of Controlled Trials from 1966 to 2009 for randomized controlled trials comparing incision choice. METHODS: We systematically assessed trials for eligibility and validity and extracted data in duplicate. We pooled data using a random-effects model. RESULTS: Twenty-four studies were included. Transverse incisions required less narcotics than midline incisions (weighted mean difference = 23.4 mg morphine; 95% confidence interval [CI], 6.9 to 39.9) and resulted in a smaller change in the forced expiratory volume in 1 second on postoperative day 1 (weighted mean difference = -6.94%; 95% CI, -10.74 to -3.13). Midline incisions resulted in higher hernia rates compared with both transverse incisions (relative risk = 1.77; 95% CI, 1.09 to 2.87) and paramedian incisions (relative risk = 3.41; 95% CI, 1.02 to 11.45). CONCLUSIONS: Both transverse and paramedian incisions are associated with a lower hernia rate than midline incisions and should be considered when exposure is equivalent.
    American journal of surgery 04/2013; · 2.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: High-resolution, multiphase, computed tomography (CT) is a standard preoperative test prior to pancreatectomy, yet the clinical significance of routinely reported findings remains unknown. METHODS: We identified patients who underwent a pancreaticoduodenectomy for a periampullary adenocarcinoma (PA) over the previous 5 years and had a pancreas protocol CT at our institution. Clinicopathologic implications of reported CT findings were evaluated. RESULTS: There were 155 pancreatic ductal adenocarcinomas (PDA) and 47 non-pancreatic PAs. No mass was visualized on CT in 6 % of PDAs and 23 % of non-pancreatic PA. A size discrepancy of ≥1 cm between radiographic and pathologic tumor diameters was observed in 40 % of PAs, with CT underestimating the size in most instances (75 %). Radiographically enlarged lymph nodes were not associated with true lymph node metastases in PDAs (70 % lymph node positive cases were enlarged on CT vs 74 % lymph node negative, p = 0.5), but were associated with a preoperatively placed biliary endoprosthesis (63 % with endoprosthesis were enlarged vs 37 % no endoprosthesis, p = 0.013). Major visceral vessel involvement on CT was not associated with a vascular resection (3 % with CT vessel involvement vs 2 % without, p = 0.8) or a positive uncinate resection margin (24 vs 20 %, respectively, p = 0.6). DISCUSSION: While dedicated pancreas protocol CT provides unprecedented detail, the test may lead to overinterpretation of the extent of disease in some instances. A radiographic suggestion of enlarged lymph nodes and vascular involvement does not necessarily preclude exploration with curative intent. CTs with local disease should be reported in an objective template and carefully reviewed by a multidisciplinary group of surgeons, radiologists, and oncologists to avoid missing an opportunity for neoadjuvant therapy or cure by resection.
    Journal of Gastrointestinal Surgery 04/2013; · 2.36 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: OBJECTIVE:: To determine whether SMAD4 expression is associated with recurrence pattern after resection for pancreatic ductal adenocarcinoma (PDA). BACKGROUND:: SMAD4 expression status has been reported to be associated with patterns of failure in PDA, but studies have not examined recurrence patterns after resection. METHODS:: A tissue microarray was constructed including 127 patients with resected PDA and either short-term (<12 months) or long-term (>30 months) survival. SMAD4 expression was evaluated by immunohistochemistry and categorized as present or lost in tumor cells. Conventional pathologic features (lymph node metastases, positive resection margin, poor grade, and tumor size) were recorded, and disease-specific outcomes (eg, recurrence pattern and early cancer-specific mortality) were determined. RESULTS:: Loss of SMAD4 expression in pancreatic adenocarcinoma was identified in 40 of 127 patients (32%). SMAD4 loss occurred in 27% of patients who experienced isolated local recurrence, 33% of patients with a distant recurrence, 33% of patients who experienced local and distant site recurrences, and 25% of patients who were without evidence of recurrence (Fisher exact, P = 0.9). In a multivariate analysis, the presence of regional lymph node metastases was the only factor associated with the development of distant metastases (odds ratio = 4.7, P = 0.02). SMAD4 was neither associated with recurrence pattern (odds ratio = 0.9, P = 0.9) nor associated with early death (odds ratio = 0.5, P = 0.15). CONCLUSIONS:: Primary tumor SMAD4 expression status was not a predictor of recurrence pattern in a large cohort of patients with resected PDA.
    Annals of surgery 01/2013; · 7.90 Impact Factor
  • Source
  • [Show abstract] [Hide abstract]
    ABSTRACT: BACKGROUND: The overall complication rate after pancreaticoduodenectomy (PD) approaches 50 %, with anastomotic failure being the most frequent cause of serious postoperative morbidity. Hepaticojejunostomy leaks (also called bile leaks) are the second most common type of leak, behind pancreaticojejunostomy leaks, yet have been the focus of only a single study as reported by Suzuki et al. (Hepatogastroenterology 50:254-257, 12). METHODS: We reviewed the recent experience with bile leaks at a single, high-volume pancreatic surgery center over a six-year time period. RESULTS: Bile leaks were identified in 16 out of 715 patients (2.2 %). Low preoperative albumin was associated with an increased risk. Bile leaks typically manifested within the first week after surgery as bilious drainage in a surgically placed drain. Associated warning signs included fever and leukocytosis. Patients with a bile leak frequently developed other complications, including a pancreatic fistula, wound infection, delayed gastric emptying, and sepsis. The impact on perioperative outcomes was comparable to patients with a pancreatic leak. A grading system is proposed based on the International Study Group on Pancreatic Fistula model. Grade A bile leaks were classified as those managed with prolonged drainage by operatively placed drains, grade B bile leaks with percutaneous abdominal drainage, and grade C bile leaks with insertion of a percutaneous transhepatic biliary drainage. CONCLUSIONS: Hepaticojejunostomy leaks are rare after PD. The complication severity ranges from trivial to life threatening and is comparable overall to pancreaticojejunostomy leaks. Surgical intervention is rarely, if ever, required. With prompt and aggressive management, a full recovery can be expected.
    Journal of Gastrointestinal Surgery 01/2013; · 2.36 Impact Factor
  • Zhi Ven Fong, Jordan M Winter
    [Show abstract] [Hide abstract]
    ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer-related death in the United States. There has been minimal progress with regard to cancer-specific outcomes in recent decades. Although effective therapies will undoubtedly change the natural history of the disease, effective biomarkers are a promising tool that will likely have a positive impact and will undoubtedly have an important role in the management of patients with pancreatic ductal adenocarcinoma (PDA) in the future. At present, serum CA-19-9 (carbohydrate antigen 19-9) is the only Food and Drug Administration-approved biomarker for PDA, and it has utility as a prognostic marker and as a marker of disease recurrence. There has been a recent explosion in the pancreatic cancer biomarker field with more than 2000 biomarker studies implicating thousands of informative genes as candidate biomarkers. In this review, we summarize the literature on CA-19-9 in PDA and highlight the most promising investigational biomarkers. Distinctions are made between diagnostic biomarkers (detection of disease), prognostic biomarkers (provide information on prognosis and recurrence pattern), and predictive biomarkers (predict treatment response).
    The Cancer Journal 11/2012; 18(6):530-8. · 3.66 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Apoptosis is one of the core signaling pathways disrupted in pancreatic ductal adenocarcinoma (PDA). Death receptor 5 (DR5) is a member of the tumor necrosis factor (TNF)-receptor superfamily that is expressed in cancer cells. Binding of TNF-related apoptosis-inducing ligand (TRAIL) to DR5 is a potent trigger of the extrinsic apoptotic pathway, and numerous clinical trials are based on DR5-targeted therapies for cancer, including PDA. Human antigen R (HuR), an RNA-binding protein, regulates a select number of transcripts under stress conditions. Here we report that HuR translocates from the nucleus to the cytoplasm of PDA cells upon treatment with a DR5 agonist. High doses of DR5 agonist induce cleavage of both HuR and caspase 8. HuR binds to DR5 mRNA at the 5'-untranslated region (UTR) in PDA cells in response to different cancer-associated stressors and subsequently represses DR5 protein expression; silencing HuR augments DR5 protein production by enabling its translation and thus enhances apoptosis. In PDA specimens (n = 53), negative HuR cytoplasmic expression correlated with elevated DR5 expression (odds ratio 16.1, p < 0.0001). Together, these data demonstrate a feedback mechanism elicited by HuR-mediated repression of the key apoptotic membrane protein DR5.
    Cancer biology & therapy 08/2012; 13(10):946-55. · 3.29 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Whether liver resection or liver transplantation is optimal therapy for patients with hepatocellular carcinoma (HCC) remains undefined. A meta-analysis was conducted to answer this question. This study performed a systematic review of the published literature between January 2000 and April 2012. Nine retrospective studies, totaling 2,279 patients (989 resected and 1,290 transplanted), met the selection criteria. Older patients with larger tumors and less severe cirrhosis were identified in the resection group. At 1 year, resection demonstrated significantly higher overall [odds ratio (OR) = 1.54; 95 % confidence interval (CI), 1.19-1.98; p = 0.001], but equivalent disease-free survival (OR = 0.93; 95 % CI, 0.53-1.63; p = 0.80). At 5 years, there was no difference in overall survival (OR = 0.86; 95 % CI, 0.61-1.21; p = 0.38), but a higher disease-free survival in transplanted patients was observed (OR = 0.39; 95 % CI, 0.24-0.63; p < 0.001). When limiting our analysis to studies conducted in an intent-to-treat fashion, there was no difference in 5 year overall survival (OR = 1.18; 95 % CI, 0.92-1.51; p = 0.19), but a significantly higher disease-free survival (OR = 0.76; 95 % CI, 0.57-1.00; p = 0.05) in transplanted patients. At 10 years, transplantation had higher overall and disease-free survival rates. Liver transplantation in patients with HCC results in increased late disease-free and overall survival when compared with liver resection. Nonetheless, the benefit of liver transplantation is offset by higher short-term mortality, donor organ availability, and long transplant wait times associated with more patient deaths. Understanding these differences in survival is helpful in guiding treatment. However, a properly controlled prospective trial is needed to define how best to treat HCC patients who are candidates for either therapy.
    Journal of Gastrointestinal Surgery 07/2012; 16(10):1897-909. · 2.36 Impact Factor

Publication Stats

2k Citations
261.03 Total Impact Points

Institutions

  • 2009–2014
    • Thomas Jefferson University
      • • Department of Surgery
      • • Center for Pancreatic, Biliary And Related Cancer
      Philadelphia, Pennsylvania, United States
  • 2013
    • Massachusetts General Hospital
      • Department of Surgery
      Boston, MA, United States
  • 2011–2013
    • Memorial Sloan-Kettering Cancer Center
      • Department of Surgery
      New York City, New York, United States
  • 2005–2012
    • Johns Hopkins University
      • Department of Radiation Oncology and Molecular Radiation Sciences
      Baltimore, MD, United States
  • 2006–2011
    • Johns Hopkins Medicine
      • • Department of Surgery
      • • Department of Radiation Oncology and Molecular Radiation Sciences
      Baltimore, MD, United States
    • University of Maryland, Baltimore
      • Department of Surgery
      Baltimore, Maryland, United States