Jesus M. Matos

Acinar cell carcinoma of the pancreas in the united states: Prognostic factors and comparison to ductal adenocarcinoma

IntroductionPancreatic acinar cell carcinoma (ACC) is a rare tumor with poorly defined prognosis.ObjectiveOur objective was to compare a large population of patients with ACC to pancreatic ductal cell adenocarcinoma (DCC) in order to determine distinguishing characteristics and to assess survival.MethodsPatients were identified from the National Cancer Database. Regression methods were used to identify differences between ACC and DCC and to identify predictors of survival for resected ACC. Eight hundred sixty-five patients with ACC were identified.ResultsMedian tumor size was 6.9 cm (vs. 4.6 cm DCC); 32.1% had nodal metastases (vs. 48.0% DCC); and 47% had high-grade tumors (vs. 37.3% DCC). Resection margins were R0 77.3%, R1 13.7%, and R2 9.0%. Patients with ACC were more likely to be male, white, and have larger tumor size, no nodal involvement, or pancreatic tail tumors. Stage-specific 5-year survival was significantly better for resected ACC vs. DCC Stage I: 52.4% vs. 28.4%, II: 40.2% vs. 9.8%, III: 22.8% vs. 6.8%, and IV: 17.2% vs. 2.8%. On multivariable analysis, age < 65, well-differentiated tumors, and negative resection margins were independent prognostic factors for ACC.DiscussionACC carries a better prognosis than DCC. Aggressive surgical resection with negative margins is associated with long-term survival in these more favorable pancreatic cancers.

Pancreatic surgery: Evolution at a high-volume center

BACKGROUND Advances in imaging, minimally invasive techniques, and regionalization have changed pancreatic surgery. Therefore, the aims of this report are to determine whether the pancreatic operations or the spectrum of disease have evolved at a high-volume center. METHODS From 1996 through 2009, 2,004 pancreatic operations were performed at Indiana University Hospital. The operations, pathology, and outcomes for 1996-2003 were compared with 2004-2009. RESULTS In 2004-2009, more operations/year were performed (215 vs 89; P < .01) and patients were older (58.8 years vs 55.8 years; P < .01). In recent years, more pancreatoduodenectomies (55.0% vs 50.4%) and fewer pancreatojejunostomies (6.2% vs 12.6%) and Beger/Frey procedures (2.6% vs 4.8%) were performed (P < .05). In 2004-2009, pylorus preservation (81.1% vs 64.4%), laparoscopic distal pancreatectomy (33.9% vs 0%), and splenic preservation (25.3% vs 2.2%) were carried out more frequently (P < .001). Pathology review revealed more tumors (68.8% vs 60.4%) and less pancreatitis (29.2% vs 34.4%; P < .01). Thirty-day mortality improved from 2.5% to 1.8%. CONCLUSION At a high-volume pancreatic surgery center, the number and age of the patients, the percentage of pancreatic resections, preservation of the pylorus and spleen as well as laparoscopic procedures, and the percentage of patients with tumors all have increased, whereas the outcomes continued to improve.

A Pilot Study of Proteomic Profiles of Human Hepatocellular Carcinoma in the United States

Human hepatocellular carcinoma (HCC) is one of the commonest causes of mortality among solid organ malignancies. The incidence of HCC in the United States is rising. Few proteomic biomarker studies have been done in U.S. populations. Tumor and nonmalignant tissue from three American patients with hepatitis and non-hepatitis-associated HCC were analyzed to find common differences in protein expression. Proteins were separated by 2D electrophoresis (isoelectric focusing followed by 10% SDS-PAGE). Gels were fixed and then stained with Coomassie brilliant blue. Digitization and processing were performed using the PDQuest software. The Students t-test was used to detect quantitative protein changes between tumor and nonmalignant liver consistent in all sample pairs with a cutoff made at P < 0.01. This yielded a total of 20 spots with significant (>2 fold) abundance changes. Matrix-assisted laser desorption ionization mass spectrometry analysis was performed using Waters Micomass M@LDI SYSTEM. The proteins were then identified using manual ProFound. Among the 20 spots, 10 showed overexpression and 10 showed underexpression in tumor. Overexpressed proteins included beta-5-tubulin, beta-actin, vimentin, hypermethylated in cancer 2 protein, heat-shock 70-kDa protein 9B, serum albumin, 39S ribosomal protein L45, butyrophilin, autoimmune regulator, and transcription factor ETV7. Underexpressed proteins included BiP protein, superoxide dismutase, peroxiredoxin 2, inoraganic pyrophosphatase, keratin 8, carbonic anhydrase 1, repulsive guidance molecule, catalase, C-1-tetrahydrofolate synthase, and hemoglobin alpha-2. Of particular interest, the protein autoimmune regulator was expressed 14-fold higher in tumor tissue, suggesting it may have a role in HCC. Validation and further investigation of these protein changes may lead to the discovery of new molecular targets for therapy, biomarkers for early detection, and new endpoints for therapeutic efficacy and toxicity.

A Pilot Study of Perillyl Alcohol in Pancreatic Cancer

BACKGROUND Chemotherapy has been largely unsuccessful in pancreatic cancer. Measurement of cell-specific biological endpoints may clarify the evaluation of a newer generation of compounds. Perillyl alcohol has shown chemotherapeutic activity in preclinical systems through enhancing apoptosis. AIMS To pilot a new trial template for testing novel agents in pancreatic cancer and to assess the biological activity of perillyl alcohol in patients with resectable pancreatic cancer. METHODS Apoptosis was quantified with ApopTag in situ, Bak staining, and light microscopy. Tumor size, serum CA 19-9 level, and survival were also measured. RESULTS Eight patients enrolled. Toxicity was mild and perillyl alcohol was generally well tolerated. Tumor size and CA 19-9 level were unchanged with perillyl alcohol treatment. Survival time was longer in patients who received full perillyl alcohol treatment (288 +/- 32 days) compared to those who did not (204 +/- 96 days), but this result did not achieve statistical significance (P = 0.2). There was a trend toward greater apoptosis in patients receiving perillyl alcohol compared to fresh operative controls; there was also a suggestion of greater apoptosis in tumor compared to normal pancreatic tissue in the same patient. CONCLUSIONS Incorporation of cell-specific biological endpoints is challenging but feasible and should be used in clinical studies of pancreatic cancer treatment. Our pilot study suggests that perillyl alcohol may indeed have effects on biological endpoints. This study will serve as a useful template for examining cell-specific biological endpoints in the testing of future agents that are thought to induce apoptosis in pancreatic cancer.

Ethanol-TGFα-MEK Signaling Promotes Growth of Human Hepatocellular Carcinoma

BACKGROUND Chronic ethanol intake is a significant risk factor for the development of cirrhosis and hepatocellular carcinoma (HCC). The effects of ethanol on extracellular signal-regulated kinase (ERK) activation, transforming growth factor alpha (TGF-alpha), and HCC growth were examined in this study. METHODS HepG2, SKHep, Hep3B human HCC cells, or normal human hepatocytes were treated with ethanol (0-100 mM), exogenous TGF-alpha, TGF-alpha neutralization antibody or the MEK inhibitor U0126. TGF-alpha levels were quantified by ELISA. Growth was determined by trypan blue-excluded cell counts. Cell cycle phase distribution was determined by flow cytometry. Protein expression was determined by Western blot. RESULTS Ethanol treatment (10-40 mM) increased ERK activation in HepG2 and SKHep HCC cells but not in Hep3B or human hepatocyte cells. Growth increased in HepG2 (174 +/- 29%, P < 0.05) and SKHep (149 +/- 12%, P < 0.05) cells in response to ethanol treatment. Correspondingly, ethanol increased S phase distribution in these cells. U0126 suppressed ethanol-induced growth increases. Ethanol treatment for 24 h also raised TGF-alpha levels in HepG2 cells (118%-198%) and SKHep cells (112%-177%). Exogenous administration of recombinant TGF-alpha mimicked the ethanol-induced growth in HepG2 and SKHep cells; TGF-alpha neutralization antibody effectively abrogated this effect. The TGF-a neutralization antibody also prevented ERK activation by ethanol in HepG2 cells. CONCLUSIONS These data demonstrate that clinically relevant doses of ethanol stimulate ERK-dependent proliferation of HCC cells. Ethanol up-regulates TGF-alpha levels in HCC cells and enhances growth through cell cycles changes, which appear to be mediated through TGF-alpha-MEK-ERK signaling. Ethanol-MEK signaling in normal hepatocytes is absent, suggesting that ethanol promotion of HCC growth may in part depend upon the acquisition of cancer-specific signaling by hepatocytes.

Evidence for nonoperative management of acute limb ischemia in infants

Acute limb ischemia (ALI) in infants is a catastrophic event. We performed a query of our database to determine those with ALI. Twelve patients were identified. The most frequent presentation was cyanotic limbs. Eleven patients were treated nonoperatively with anticoagulation. One patient was treated surgically with Fogarty balloon thrombectomy. There were three deaths all due to associated comorbidities. All had viable limbs on follow-up examination. There were three complications in the patients managed conservatively. Our recommendation for infants presenting with ALI is conservative observation with anticoagulation and intervention only for cases with tissue loss.

Targeted nuclear factor-kappaB suppression enhances gemcitabine response in human pancreatic tumor cell line murine xenografts.

BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is an almost uniformly fatal malignancy characterized by resistance to chemotherapy. Currently, gemcitabine is the agent used most commonly but demonstrates only a partial response. The transcription factor nuclear factor-kappaB (NF-κB), known to be involved in the inflammatory response, is constitutively activated in PDAC and further activated by gemcitabine. Our aim was to examine the effects of targeted NF-κB suppression on gemcitabine resistance using an in vivo tumor growth model. METHODS To suppress the NF-κB pathway, the mutant IκBα super-repressor protein was stably expressed in PaCa-2 human PDAC cells. Athymic mice were injected subcutaneously with IκBα-super-repressor (SR) or vector-expressing PaCa-2 cells and randomized to receive phosphate-buffered saline (PBS) or 100 mg/kg gemcitabine(gem) for 4 weeks. RESULTS The mean increase in tumor volume was 47 mm(3) (89%) and 196 mm(3) (326%) in gem/SR and gem/vector groups, respectively (P = .03). The PBS-treated groups demonstrated greater tumor growth, ∼340 mm(3) (850%) increase, in both PBS/vector and PBS/SR groups. Intratumoral NF-κB activity was decreased in gem/SR compared with the gem/vector group (P = .04). Decreased Ki-67 positivity was noted in gem/SR (49%) versus gem/vector tumors (73%) (P = .04), with no difference in apoptosis (apoptag, P = .3) or angiogenesis (CD31+, P = .9). CONCLUSION Stable IκBα-SR expression in vivo potentiated the antitumor effects of gemcitabine, resulting in decreased tumor growth in association with decreased cell proliferation. Molecular suppression of the NF-κB pathway decreases successfully gemcitabine resistance in a relatively chemoresistant PDAC line. Thus, NF-κB-targeted agents may complement gemcitabine-based therapies and decrease chemoresistance in patients with PDAC.

T1739 Pancreatic Acinar Cell Carcinoma: A Multi-Institutional Study

Introduction The presentation and outcome of patients with acinar cell carcinoma (ACC) of the pancreas compared to the more common ductal cell adenocarcinoma (DCA) may be distinct. This study combines the experience with ACC from multiple academic institutions to better understand its natural history and outcomes.