Charles A. Staley

Left-sided pancreatectomy: a multicenter comparison of laparoscopic and open approaches.

Objectives:To compare perioperative outcomes of laparoscopic left-sided pancreatectomy (LLP) with traditional open left-sided pancreatectomy (OLP) in a multicenter experience. Summary and Background Data:LLP is being performed more commonly with limited data comparing results with outcomes from OLP. Methods:Data from 8 centers were combined for all cases performed between 2002–2006. OLP and LLP cohorts were matched by age, American Society of Anesthesiologists, resected pancreas length, tumor size, and diagnosis. Multivariate analysis was performed using binary logistic regression. Results:Six hundred sixty-seven LPs were performed, with 159 (24%) attempted laparoscopically. Indications were solid lesion in 307 (46%), cystic in 295 (44%), and pancreatitis in 65 (10%) cases. Positive margins occurred in 51 (8%) cases, 335 (50%) had complications, and significant leaks occurred in 108 (16%). Conversion to OLP occurred in 20 (13%) of the LLPs. In the matched comparison, 200 OLPs were compared with 142 LLPs. There were no differences in positive margin rates (8% vs. 7%, P = 0.8), operative times (216 vs. 230 minutes, P = 0.3), or leak rates (18% vs. 11%, P = 0.1). LLP patients had lower average blood loss (357 vs. 588 mL, P < 0.01), fewer complications (40% vs. 57%, P < 0.01), and shorter hospital stays (5.9 vs. 9.0 days, P < 0.01). By MVA, LLP was an independent factor for shorter hospital stay (P < 0.01, odds ratio 0.33, 95% confidence interval 0.19–0.56). Conclusions:In selected patients, LLP is associated with less morbidity and shorter LOS than OLP. Pancreatic fistula rates are similar for OLP and LLP. LLP is appropriate for selected patients with left-sided pancreatic pathology.

A Multicenter Analysis of Distal Pancreatectomy for Adenocarcinoma: Is Laparoscopic Resection Appropriate?

BACKGROUND As compared with open distal pancreatectomy (ODP), laparoscopic distal pancreatectomy (LDP) affords improved perioperative outcomes. The role of LDP for patients with pancreatic ductal adenocarcinoma (PDAC) is not defined. STUDY DESIGN Records from patients undergoing distal pancreatectomy (DP) for PDAC from 2000 to 2008 from 9 academic medical centers were reviewed. Short-term (node harvest and margin status) and long-term (survival) cancer outcomes were assessed. A 3:1 matched analysis was performed for ODP and LDP cases using age, American Society of Anesthesiologists (ASA) class, and tumor size. RESULTS There were 212 patients who underwent DP for PDAC; 23 (11%) of these were approached laparoscopically. For all 212 patients, 56 (26%) had positive margins. The mean number of nodes (+/- SD) examined was 12.6 +/-8.4 and 114 patients (54%) had at least 1 positive node. Median overall survival was 16 months. In the matched analysis there were no significant differences in positive margin rates, number of nodes examined, number of patients with at least 1 positive node, or overall survival. Logistic regression for all 212 patients demonstrated that advanced age, larger tumors, positive margins, and node positive disease were independently associated with worse survival; however, method of resection (ODP vs. LDP) was not. Hospital stay was 2 days shorter in the matched comparison, which approached significance (LDP, 7.4 days vs. ODP, 9.4 days, p = 0.06). CONCLUSIONS LDP provides similar short- and long-term oncologic outcomes as compared with OD, with potentially shorter hospital stay. These results suggest that LDP is an acceptable approach for resection of PDAC of the left pancreas in selected patients.

Down-regulation of Vascular Endothelial Growth Factor in a Human Colon Carcinoma Cell Line Transfected with an Antisense Expression Vector Specific for c-src

Vascular endothelial growth factor (VEGF) is implicated in the angiogenesis of human colon cancer. Recent evidence suggests that factors that regulate VEGF expression may partially depend on c-src-mediated signal transduction pathways. The tyrosine kinase activity of Src is activated in most colon tumors and cell lines. We established stable subclones of the human colon adenocarcinoma cell line HT29 in which Src expression and activity are decreased specifically as a result of a transfected antisense expression vector. This study determined whether VEGF expression is decreased in these cell lines and whether the smaller size and reduced growth rate of antisense vector-transfected cell lines in vivo might result, in part, from reduced vascularization of tumors. Northern blot analysis of these cell lines revealed that VEGF mRNA expression was decreased in proportion to the decrease in Src kinase activity. Under hypoxic conditions, cells with decreased Src activity had a <2-fold increase in VEGF expression, whereas parental cells had a >50-fold increase. VEGF protein in the supernatants of cells was also reduced in antisense transfectants compared with that from parental cells. In nude mice, subcutaneous tumors from antisense transfectants showed a significant reduction in vascularity. These results suggest that Src activity regulates the expression of VEGF in colon tumor cells.

The Amount of Metastatic Melanoma in a Sentinel Lymph Node: Does It Have Prognostic Significance?

Background: The amount of metastatic disease in the sentinel lymph node (SLN) is examined as a prognostic factor in malignant melanoma.Methods: SLN mapping was performed on 592 patients with stage I and II malignant melanoma from March 1, 1994, through December 31, 1999. One hundred four patients were found to have 134 sentinel SLNs containing metastatic melanoma. The slides were reviewed, and the size of the metastatic melanoma in each SLN was measured. The size of the metastatic deposit was defined as macrometastasis (>2 mm), micrometastasis (≤2 mm), a cluster of cells (10–30 grouped cells) in the subcapsular space or interfollicular zone, or isolated melanoma cells (1 to ≥20 individual cells) in subcapsular sinuses.Results: The number of metastases in each SLN was isolated melanoma cells, n = 5 (3.7%); cluster of cells, n = 35 (26.1%); ≤2 mm, n = 45 (33.6%); and >2 mm, n = 49 (36.7%). Seventy-nine patients (76%) had a single positive SLN. The size of the largest nodal metastasis was used to stratify patients with multiple positive SLNs. The overall 3-year survival for patients with SLN micrometastases was 90%, versus 58% for patients with SLN macrometastases (P = .004).Conclusions: The amount of metastatic melanoma in an SLN is an independent predictor of survival. Patients with SLN metastatic deposits >2 mm in diameter have significantly decreased survival.

Comparison of yttrium-90 radioembolization and transcatheter arterial chemoembolization for the treatment of unresectable hepatocellular carcinoma.

PURPOSE To compare the effectiveness and toxicity of transcatheter arterial chemoembolization (chemoembolization) and yttrium-90-labeled microspheres (radioembolization) in patients with unresectable hepatocellular carcinoma (HCC). MATERIALS AND METHODS Outcomes from patients who underwent radioembolization or chemoembolization as the only treatment for unresectable HCC from 1996 to 2006 were compared. Response was assessed with Response Evaluation Criteria in Solid Tumors, survival was assessed with the Kaplan-Meier method, and toxicity was graded with National Cancer Institute criteria. Multivariate analysis for factors affecting survival was performed. RESULTS Seventy-one patients were treated with either chemoembolization (n = 44, 62%) or radioembolization (n = 27, 38%). Treatment groups were similar in age, sex, Child class, Model for End-Stage Liver Disease score, tumor size, and vascular invasion. Progressive disease at 3 months was observed in 16 (36%) of the 44 patients treated with chemoembolization and nine (33%) of the 27 patients treated with radioembolization (P = not statistically significant). The median overall survival was similar for both groups (6 months with chemoembolization vs 6 months with radioembolization, P= .7). Grade 3 or higher toxicity was observed in 24 of the 71 patients (34%). Tumor multifocality, vascular invasion, and hepatitis C seropositivity were independently associated with worse survival, whereas method of treatment was not. CONCLUSIONS In this single-center study, preliminary evidence suggests that chemoembolization and radioembolization provided similar effectiveness and toxicity in patients with unresectable HCC.

Theranostic Nanoparticles with Controlled Release of Gemcitabine for Targeted Therapy and MRI of Pancreatic Cancer

The tumor stroma in human cancers significantly limits the delivery of therapeutic agents into cancer cells. To develop an effective therapeutic approach overcoming the physical barrier of the stroma, we engineered urokinase plasminogen activator receptor (uPAR)-targeted magnetic iron oxide nanoparticles (IONPs) carrying chemotherapy drug gemcitabine (Gem) for targeted delivery into uPAR-expressing tumor and stromal cells. The uPAR-targeted nanoparticle construct, ATF-IONP-Gem, was prepared by conjugating IONPs with the amino-terminal fragment (ATF) peptide of the receptor-binding domain of uPA, a natural ligand of uPAR, and Gem via a lysosomally cleavable tetrapeptide linker. These theranostic nanoparticles enable intracellular release of Gem following receptor-mediated endocytosis of ATF-IONP-Gem into tumor cells and also provide contrast enhancement in magnetic resonance imaging (MRI) of tumors. Our results demonstrated the pH- and lysosomal enzyme-dependent release of gemcitabine, preventing the drug from enzymatic degradation. Systemic administrations of ATF-IONP-Gem significantly inhibited the growth of orthotopic human pancreatic cancer xenografts in nude mice. With MRI contrast enhancement by IONPs, we detected the presence of IONPs in the residual tumors following the treatment, suggesting the possibility of monitoring drug delivery and assessing drug-resistant tumors by MRI. The theranostic ATF-IONP-Gem nanoparticle has great potential for the development of targeted therapeutic and imaging approaches that are capable of overcoming the tumor stromal barrier, thus enhancing the therapeutic effect of nanoparticle drugs on pancreatic cancers.

Comparison of conventional transarterial chemoembolization (TACE) and chemoembolization with doxorubicin drug eluting beads (DEB) for unresectable hepatocelluar carcinoma (HCC)

Chemoembolization with doxorubicin drug eluting beads (DEB) is a novel locoregional treatment modality for unresectable hepatocellular carcinoma (HCC). Initial animal studies and clinical trials suggest that treatment with DEB may provide safer and more effective short‐term outcomes than conventional chemoembolization. Current study explores long‐term survival benefits.

Arterial and venous resection for pancreatic adenocarcinoma: operative and long-term outcomes.

HYPOTHESIS Aggressive preoperative and intraoperative management may improve the resectability rates and outcomes for locally advanced pancreatic adenocarcinoma with venous involvement. The efficacy and use of venous resection and especially arterial resection in the management of pancreatic adenocarcinoma remain controversial. DESIGN Retrospective review of patients entered into prospective databases. SETTING Two tertiary referral centers. PATIENTS AND METHODS A retrospective review of 2 prospective databases of 593 consecutive pancreatic resections for pancreatic adenocarcinoma from January 1, 1999, through May 1, 2007. RESULTS Of the 593 patients, 36 (6.1%) underwent vascular resection at the time of pancreatectomy. Thirty-one of the 36 (88%) underwent venous resection alone; 3 (8%), combined arterial and venous resection; and 2 (6%), arterial resection (superior mesenteric artery resection) alone. Patients included 18 men and 18 women, with a median age of 62 (range, 42-82) years. The 90-day perioperative mortality and morbidity rates were 0% and 35%, respectively, compared with 2% and 39%, respectively, for the group undergoing nonvascular pancreatic resection (P = .34). Median survival was 18 (range, 8-42) months in the vascular resection group compared with 19 months in the nonvascular resection group. Multivariate analysis demonstrated node-positive disease, tumor location (other than head), and no adjuvant therapy as adverse prognostic variables. CONCLUSIONS In this combined experience, en bloc vascular resection consisting of venous resection alone, arterial resection alone, or combined vascular resection at the time of pancreatectomy for adenocarcinoma did not adversely affect postoperative mortality, morbidity, or overall survival. The need for vascular resection should not be a contraindication to surgical resection in the selected patient.

Local Recurrence After Skin-Sparing Mastectomy: Tumor Biology or Surgical Conservatism?

Background:Long-term follow-up of the use of skin-sparing mastectomy (SSM) in the treatment of breast cancer is presented to determine the impact of local recurrence (LR) on survival.Methods:A total of 539 patients were treated for 565 cases of breast cancer by SSM and immediate breast reconstruction from January 1, 1989 to December 31, 1998. The American Joint Committee on Cancer pathological staging was stage 0 175 (31%), stage I 135 (23.9%), stage II 173 (30.6%), stage III 54 (9.6%), stage IV 8 (1.4%), and recurrent 20 (3.5%). The mean follow-up was 65.4 months (range, 23.7–86.3 months). Five patients were lost to follow-up.Results:Thirty-one patients developed a LR during the follow-up including five who received adjuvant radiation. The distribution of LR stratified by cancer stage was stage 0 1, stage I 5, stage II 17, stage III 6, and recurrent 2. The overall LR was 5.5%. Twenty-four patients (77.4%) developed a systemic relapse and 7 (22.6%) patients remained free of recurrent disease at a mean follow-up of 78.1 months. The cancer stage of those remaining disease free was stage 0 1 (100%), stage I 4 (80%), and stage II 2 (11.8%).Conclusions:LR of breast cancer after SSM is not always associated with systemic relapse.

Molecular Imaging of Pancreatic Cancer in an Animal Model Using Targeted Multifunctional Nanoparticles

BACKGROUND & AIMS Identification of a ligand/receptor system that enables functionalized nanoparticles to efficiently target pancreatic cancer holds great promise for the development of novel approaches for the detection and treatment of pancreatic cancer. Urokinase plasminogen activator receptor (uPAR), a cellular receptor that is highly expressed in pancreatic cancer and tumor stromal cells, is an excellent surface molecule for receptor-targeted imaging of pancreatic cancer using multifunctional nanoparticles. METHODS The uPAR-targeted dual-modality molecular imaging nanoparticle probe is designed and prepared by conjugating a near-infrared dye-labeled amino-terminal fragment of the receptor binding domain of urokinase plasminogen activator to the surface of functionalized magnetic iron oxide nanoparticles. RESULTS We have shown that the systemic delivery of uPAR-targeted nanoparticles leads to their selective accumulation within tumors of orthotopically xenografted human pancreatic cancer in nude mice. The uPAR-targeted nanoparticle probe binds to and is subsequently internalized by uPAR-expressing tumor cells and tumor-associated stromal cells, which facilitates the intratumoral distribution of the nanoparticles and increases the amount and retention of the nanoparticles in a tumor mass. Imaging properties of the nanoparticles enable in vivo optical and magnetic resonance imaging of uPAR-elevated pancreatic cancer lesions. CONCLUSIONS Targeting uPAR using biodegradable multifunctional nanoparticles allows for the selective delivery of the nanoparticles into primary and metastatic pancreatic cancer lesions. This novel receptor-targeted nanoparticle is a potential molecular imaging agent for the detection of pancreatic cancer.