William E. Fisher

A Randomized Prospective Multicenter Trial of Pancreaticoduodenectomy With and Without Routine Intraperitoneal Drainage

Objective:To test by randomized prospective multicenter trial the hypothesis that pancreaticoduodenectomy (PD) without the use of intraperitoneal drainage does not increase the frequency or severity of complications. Background:Some surgeons have abandoned the use of drains placed during pancreas resection. Methods:We randomized 137 patients to PD with (n = 68, drain group) and without (n = 69, no-drain group) the use of intraperitoneal drainage and compared the safety of this approach and spectrum of complications between the 2 groups. Results:There were no differences between drain and no-drain cohorts in demographics, comorbidities, pathology, pancreatic duct size, pancreas texture, baseline quality of life, or operative technique. PD without intraperitoneal drainage was associated with an increase in the number of complications per patient [1 (0-2) vs 2 (1-4), P = 0.029]; an increase in the number of patients who had at least 1 ≥grade 2 complication [35 (52%) vs 47 (68%), P = 0.047]; and a higher average complication severity [2 (0-2) vs 2 (1-3), P = 0.027]. PD without intraperitoneal drainage was associated with a higher incidence of gastroparesis, intra-abdominal fluid collection, intra-abdominal abscess (10% vs 25%, P = 0.027), severe (≥grade 2) diarrhea, need for a postoperative percutaneous drain, and a prolonged length of stay. The Data Safety Monitoring Board stopped the study early because of an increase in mortality from 3% to 12% in the patients undergoing PD without intraperitoneal drainage. Conclusions:This study provides level 1 data, suggesting that elimination of intraperitoneal drainage in all cases of PD increases the frequency and severity of complications.

Aberrant expression of zinc transporter ZIP4 (SLC39A4) significantly contributes to human pancreatic cancer pathogenesis and progression

Zinc is an essential trace element and catalytic/structural component used by many metalloenzymes and transcription factors. Recent studies indicate a possible correlation of zinc levels with the cancer risk; however, the exact role of zinc and zinc transporters in cancer progression is unknown. We have observed that a zinc transporter, ZIP4 (SLC39A4), was substantially overexpressed in 16 of 17 (94%) clinical pancreatic adenocarcinoma specimens compared with the surrounding normal tissues, and ZIP4 mRNA expression was significantly higher in human pancreatic cancer cells than human pancreatic ductal epithelium (HPDE) cells. This indicates that aberrant ZIP4 up-regulation may contribute to the pancreatic cancer pathogenesis and progression. We studied the effects of ZIP4 overexpression in pancreatic cancer cell proliferation in vitro and pancreatic cancer progression in vivo. We found that forced expression of ZIP4 increased intracellular zinc levels, increased cell proliferation by 2-fold in vitro, and significantly increased tumor volume by 13-fold in the nude mice model with s.c. xenograft compared with the control cells. In the orthotopic nude mice model, overexpression of ZIP4 not only increased the primary tumor weight (7.2-fold), it also increased the peritoneal dissemination and ascites incidence. Moreover, increased cell proliferation and higher zinc content were also observed in the tumor tissues that overexpressed ZIP4. These data reveal an important outcome of aberrant ZIP4 expression in contributing to pancreatic cancer pathogenesis and progression. It may suggest a therapeutic strategy whereby ZIP4 is targeted to control pancreatic cancer growth.

Mesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer

Given the high fatality rate of pancreatic cancer, an effective treatment for this devastating disease is urgently needed. We have shown that mesothelin expression was higher in human pancreatic cancer cells than in human pancreatic duct epithelial cells, and mesothelin mRNA was substantially overexpressed in 18 of 21 (86%) clinical pancreatic adenocarcinoma specimens when compared with the surrounding normal tissues. However, the biological functions of mesothelin in tumor progression are not clearly understood. Here we studied the effects of mesothelin overexpression in pancreatic cancer cell proliferation and migration in vitro and pancreatic cancer progression in vivo. We found that forced expression of mesothelin significantly increased tumor cell proliferation and migration by 90% and 300%, respectively, and increased tumor volume by 4-fold in the nude mice xenograft model when compared with the vector control cell line. Silencing of mesothelin inhibited cell proliferation and migration in pancreatic cancer cells and ablated tumor progression in vivo. Vaccination with chimeric virus-like particles that contain human mesothelin substantially inhibited tumor progression in C57BL/6J mice. The increases in mesothelin-specific antibodies and CTL activity and the decrease in regulatory T cells correlated with reduced tumor progression and prolonged survival. This study revealed novel functions of mesothelin and suggested a new therapeutic vaccine strategy whereby mesothelin is targeted to control pancreatic cancer progression. [Mol Cancer Ther 2008;7(2):286–96]

Current Progress in Suicide Gene Therapy for Cancer

Standard chemotherapeutic agents and ionizing radiation destroy dividing cells. Because tumor cells divide more rapidly than normal cells, there is a therapeutic index in which damage to the cancer cells is maximized while keeping the toxicity to the normal host cells acceptable. Suicide gene therapy strives to deliver genes to the cancer cells, which convert nontoxic prodrugs into active chemotherapeutic agents. With this strategy, the systemically administered prodrug is converted to the active chemotherapeutic agent only in cancer cells, thereby allowing a maximal therapeutic effect while limiting systemic toxicity. A literature search was conducted using the MEDLINE database from 1990 to 2001 to identify articles related to suicide gene therapy for cancer. A number of suicide gene systems have been identified, including the herpes simplex virus thymidine kinase gene, the cytosine deaminase gene, the varicella-zoster virus thymidine kinase gene, the nitroreductase gene, the Escherichia coli gpt gene, and the E. coli Deo gene. Various vectors, including liposomes, retroviruses, and adenoviruses, have been used to transfer these suicide genes to tumor cells. These strategies have been effective in cell culture experiments, laboratory animals, and some early clinical trials. Advances in tissue- and cell-specific delivery of suicide genes using specific promoters will improve the clinical utility of suicide gene therapy.

Pancreatic resection without routine intraperitoneal drainage

BACKGROUND Most surgeons routinely place intraperitoneal drains at the time of pancreatic resection but this practice has recently been challenged. OBJECTIVE Evaluate the outcome when pancreatic resection is performed without operatively placed intraperitoneal drains. METHODS In all, 226 consecutive patients underwent pancreatic resection. In 179 patients drains were routinely placed at the time of surgery and in 47 no drains were placed. Outcomes for these two cohorts were recorded in a prospective database and compared using the χ(2) - /Fishers exact test for categorical variables, and Wilcoxons test for continuous variables. RESULTS Demographic, surgical and pathological details were similar between the two cohorts. Elimination of routine intraperitoneal drainage did not increase the frequency or severity of serious complications. However, when all grades of complications were considered, the number of patients that experienced any complication (65% vs. 47%, P= 0.020) and the median complication severity grade (1 vs. 0, P= 0.027) were increased in the group that had drains placed at the time of surgery. Eliminating intra-operative drains was associated with decreased delayed gastric emptying (24% vs. 9%, P= 0.020) and a trend towards decreased wound infection (12% vs. 2%, P= 0.054). The readmission rate (9% vs. 17% P= 0.007) and number of patients requiring post-operative percutaneous drains (2% vs. 11%, P= 0.001) was higher in patients who did not have operatively placed drains but there was no difference in the re-operation rate (4% vs. 0%, P= 0.210). CONCLUSION Abandoning the practice of routine intraperitoneal drainage after pancreatic resection may not increase the incidence or severity of severe post-operative complications.

IL-6 stimulates Th2 type cytokine secretion and upregulates VEGF and NRP-1 expression in pancreatic cancer cells

BACKGROUND. Although upregulation of interleukin-6 (IL-6) is associated with many solid tumors, its role in pancreatic cancer has not been well elucidated. In this study, we examined the expression of IL-6 in pancreatic cancer cells, and determined the effect of exogenous IL-6 on cytokine secretion, gene expression, and signaling in human pancreatic cancer cells. METHODS. The mRNA levels of IL-6, VEGF165, neuropilin-1 (NRP-1), and neuropilin-2 (NRP-2) were determined by real-time RT PCR. Phosphorylation of ERK2 in pancreatic cancer cells was determined by using Bio-Plex phosphoprotein assay. The expression of IL-6 and other cytokines in human pancreatic cancer cell lines was determined with Bio-Plex cytokine assay. RESULTS. Pancreatic cancer cell lines expressed higher levels of IL-6 than normal human pancreatic ductal epithelium (HPDE) cells. Exogenous IL-6 increased the secretion of multiple Th2 type of cytokines in Panc-1, MIA PaCa-2, and BxPC-3 cells. IL-6 also upregulated the expression of VEGF165, and NRP-1, and both IL-6 and VEGF165 were inducible by hypoxia. In addition, IL-6 activated ERK2 signaling pathways in pancreatic cancer cells. CONCLUSIONS. IL-6 may be involved in promoting human pancreatic cancer development by furnishing Th2 type of cytokine environment and upregulating cell proliferation and angiogenesis related genes. Targeting IL-6 might be an effective treatment for pancreatic cancer.

Value of Pancreatic Resection for Cancer Metastatic to the Pancreas

BACKGROUND Cancer metastatic to the pancreas from other primary sites is uncommon, and it has been treated with an aggressive surgical approach in fit patients when the primary tumor is controlled and the pancreas is the only site of metastatic disease. The value of pancreatic resection in this setting is unclear. The purpose of this study was to review cases of cancer metastatic to the pancreas. METHODS We reviewed our experience with cancer metastatic to the pancreas and the literature regarding resection of pancreatic metastases. Patient and tumor characteristics were summarized using descriptive statistics. RESULTS A total of 220 patients with pancreatic metastasis were analyzed. Three patients were selected from our own experience, and 217 were selected from a literature review. In the 127 patients whose symptoms were recorded at the time of presentation, the most common presenting symptoms were jaundice (n=32, 25.2%) and abdominal pain (n=25, 19.7%). In the 189 patients for whom the location of the metastasis in the pancreas was revealed, the most common location was the head of the pancreas (n=79, 41.8%). The primary tumor site was most commonly kidney (n=155, 70.5%). Surgical resection was attempted in 177 of 220 patients; 135 patients suffering from renal cell carcinoma (RCC) metastasis also underwent pancreatic resection. In the latter group, a median survival of 70 mo was seen, as well as 78% and 65% 2- and 5 y survival rates, respectively. CONCLUSION Survival after resection of RCC with isolated metastasis to the pancreas is favorable. However, a more detailed analysis considering outcomes without surgery for each primary tumor site is needed before the value of this aggressive surgical approach can be completely assessed in the general occurrence of pancreatic metastasis.

Laparoscopic colon resection early in the learning curve: what is the appropriate setting?

Introduction:Laparoscopic colon resection (LCR) is a safe and effective treatment of benign and malignant colonic lesions. There is little question that a steep learning curve exists for surgeons to become skilled and proficient at LCR. Because of this steep learning curve, debate exists regarding the appropriate hospital setting for LCR. We hypothesize that outcomes of LCR performed early in the learning curve at a regional medical center (New Hanover Regional Medical Center; NHRMC) and a university medical center (Baylor College of Medicine; BCM) would not be significantly different. Methods:The first 50 consecutive LCRs performed at each institution between August 2001 and December 2003 were reviewed. Age, mean body mass index (BMI), gender, history of previous abdominal surgery (PAS), operative approach [laparoscopic (LAP) versus hand/laparoscopic assisted (HAL)], conversions (Conv), operative time (OR time), pathology (benign vs. malignant), lymph nodes (LN) harvested in malignant cases, length of stay (LOS), morbidity and mortality were obtained. Continuous data were expressed as mean ± SD. Data were analyzed by χ2, Fisher exact test, or t test. Results:NHRMC patients were on average older females with a higher incidence of PAS. A LAP approach was more frequently performed at BCM (86%), whereas HAL was used more frequently at NHRMC (24%). Conversions to open were similar at both institutions (12%). Benign disease accounted for the majority of operations at both institutions. In cases of malignancy, more LN were harvested at BCM. OR time and LOS were shorter at NHRMC. Complication rates were similar between institutions. There were no anastomotic leaks or deaths. Conclusions:LCR can be performed safely and with acceptable outcomes early in the learning curve at regional medical centers and university medical centers. Outcomes depend more on surgeons possessing advanced laparoscopic skills and adhering to accepted oncologic surgical principles in cases of malignancy, than on the size or location of the healthcare institution.

Interleukin-8 increases vascular endothelial growth factor and neuropilin expression and stimulates ERK activation in human pancreatic cancer

Interleukin‐8 (IL‐8) is associated with tumorigenesis by promoting angiogenesis and metastasis. Although up‐regulation of IL‐8 is indicated in many cancers, its function in pancreatic cancer has not been well characterized. In this study we examined the expression of IL‐8 on pancreatic cancer cells and clinical tissue specimens, and investigated the effect of exogenous IL‐8 on gene expression, and signaling in human pancreatic cancer cells. We found that pancreatic cancer cells expressed higher amount of IL‐8 mRNA than normal human pancreatic ductal epithelium cells. IL‐8 mRNA was also substantially overexpressed in 11 of 14 (79%) clinical pancreatic‐adenocarcinoma samples compared with that in their surrounding normal tissues. Exogenous IL‐8 up‐regulated the expression of vascular endothelial growth factor165, and neuropilin (NRP)‐2 in BxPC‐3 cells, one of human pancreatic cancer cell lines. IL‐8 expression was inducible by hypoxia mimicking reagent cobalt chloride. In addition, IL‐8 activated extracellular signal‐regulated kinase (ERK)1/2 signaling pathway in BxPC‐3 cells. Our studies suggest that IL‐8 might be a malignant factor in human pancreatic cancer by induction of vascular endothelial growth factor and NRP‐2 expression and ERK activation. Targeting IL‐8 along with other antiangiogenesis therapy could be an effective treatment for this malignancy. (Cancer Sci 2008, 99: 733–737)

Hoosier Oncology Group Randomized Phase II Study of Docetaxel, Vinorelbine, and Estramustine in Combination in Hormone-Refractory Prostate Cancer with Pharmacogenetic Survival Analysis

Purpose: To determine the safety and efficacy of two docetaxel doublets in hormone-refractory prostate cancer (HRPC) patients and to examine the prognostic role of polymorphisms in host genes important to docetaxel metabolism and transport. Experimental Design: Sixty-four chemotherapy-naive patients with HRPC were randomized to docetaxel and vinorelbine (D, 20 mg/m2 i.v. days 1 and 8; V, 25 mg/m2 i.v. days 1 and 8) or docetaxel and estramustine phosphate (D, 60-70 mg/m2 i.v. day 1; E, 280 mg oral thrice daily days 1-5) administered q21d. Primary end point was clinically significant toxicity. A pharmacogenetic analysis of host genes was done in patients who received at least one cycle of docetaxel therapy. Results: Grade 3/4 toxicity occurred in 15.6% of DV patients and in 28.6% DE patients. Neither arm exceeded the threshold of clinically significant toxicity. In the DV arm, objective response rate was 33%, prostate-specific antigen response rate was 20%, and median survival was 16.2 months. In the DE arm, objective response rate was 67%, prostate-specific antigen response rate was 43%, and median survival was 19.7 months. Pharmacogenetic analyses showed a significant association between survival beyond 15 months and the ABCG2 421 C>A (Q141K) polymorphism compared with the wild-type (C/C) genotype (66% versus 27%; P = 0.05). Conclusions: DV and DE doublets are active with a tolerable toxicity profile in patients with HRPC; however, efficacy does not seem superior to standard single-agent docetaxel. The ABCG2 421 C>A (Q141K) polymorphism may be an important predictor of response and survival in HRPC patients treated with docetaxel-based chemotherapy.