Oxaliplatin but not irinotecan impairs posthepatectomy liver regeneration in a murine model.

Introduction. We examined the murine hepatectomy model of liver regeneration (LR) in the setting of neoadjuvant chemotherapy. Methods. C57BL/6 mice were randomized to receive neoadjuvant intraperitoneal (IP) injections of a control, oxaliplatin (15 mg/kg), or irinotecan (100 mg/Kg or 250 mg/Kg) solution. Hepatectomy (70%) was performed 14 days after the final IP treatment. Animals were sacrificed at postoperative day (D) 0, 1, 2, 3, and 7. Liver remnants and serum were collected for analysis. T-tests for independent samples were used for statistical comparisons. Results. For oxaliplatin, percent LR did not differ at D1 or D2 but was significantly less at D3 (89.0% versus 70.0%, P = 0.048) with no difference on D7 (P = 0.21). Irinotecan-treated mice at both dose levels (100 mg/Kg and 250 mg/Kg) showed no significant differences in LR. BrdU incorporation was significantly decreased in oxaliplatin-treated animals (D1,2,3). Conclusions. Neoadjuvant oxaliplatin but not irinotecan impairs early LR in a posthepatectomy murine model which correlates with decreased DNA synthesis.

Analysis of factors influencing outcome in patients with in-transit malignant melanoma undergoing isolated limb perfusion using modern treatment parameters.

PURPOSE In-transit disease afflicts approximately 10% of patients with extremity melanoma; no single treatment approach has been uniformly accepted as the most effective. We report long-term outcomes in patients with in-transit extremity melanoma who underwent isolated limb perfusion (ILP) in an era of increasingly accurate staging, uniform operative and treatment conditions, and regular long-term follow-up. PATIENTS AND METHODS Between May 1992 and February 2005, 91 patients (median age, 57 years; 50 women, 41 men) underwent a 90-minute hyperthermic ILP (melphalan, 10 to 13 mg/L limb volume, tumor necrosis factor [TNF; n = 44], or interferon [n = 38]) using uniform operative technique and intraoperative leak monitoring. Patients were prospectively followed for response, in-field progression-free survival (PFS), and overall survival (OS). Parameters associated with in-field PFS and OS were analyzed by standard statistical methods. Results There was one operative death (1.1%). There were 62 complete responses (69%) and 23 partial responses (26%) in 90 assessable patients. At a median potential follow-up of 11 years, median in-field PFS was 12.4 months and median OS was 47.4 months; 5 and 10-year actuarial OS probabilities were 43% and 34%, respectively. Female sex and low tumor burden (< or = 20 lesions) were associated with prolonged in-field PFS (male:female hazard ratio [HR], 2.07; 95% CI, 1.27 to 3.38; 21+ v < or = 20 tumors HR, 2.29; 95% CI, 1.21 to 4.34; P < .011 for both). Female sex was associated with improved OS (P = .027; male:female HR, 1.82; 95% CI, 1.07 to 3.09). CONCLUSION In appropriately selected patients, ILP has clinical benefit. The use of TNF was not associated with improved in-field PFS, while female sex was associated with better survival.

Totally laparoscopic gastric resection with extended lymphadenectomy for gastric adenocarcinoma.

BACKGROUND: Laparoscopic gastric resection with extended lymphadenectomy is being evaluated in North America for the surgical treatment of gastric cancer. The aim of this study is to compare short-term postoperative and oncologic outcomes of laparoscopic and open resection for gastric cancer at a single cancer center. METHODS: The study population consisted of patients with gastric adenocarcinoma who underwent a completely abdominal intervention with curative intent. Laparoscopic and open gastric resections were compared. A totally laparoscopic technique was employed with a robotic extended lymphadenectomy in a subset of patients. RESULTS: A total of 78 consecutive patients were evaluated, including 30 laparoscopic and 48 open procedures. An extended lymphadenectomy was performed in 58 patients and was executed robotically in 16 of these. There was no difference in the mean number of lymph nodes retrieved by laparoscopic or open approach (24 +/- 8 vs. 26 +/- 15, P = .66). Laparoscopic procedures were associated with decreased blood loss (200 vs. 383 mL, P = .0009) and length of stay (7 vs. 10 days, P = .0009), but increased operative time (399 vs. 298 minutes, P < .0001). CONCLUSION: Completely laparoscopic gastric resection yields similar lymph node numbers compared with open surgery for gastric cancer. It was found to be advantageous in terms of operative blood loss and length of stay. Minimally invasive techniques represent an oncologically adequate alternative for the surgical treatment of gastric adenocarcinoma.

Treatment response to transcatheter arterial embolization and chemoembolization in primary and metastatic tumors of the liver.

INTRODUCTION: Transcatheter arterial embolization (TAE) and chemoembolization (TACE) are increasingly used to treat unresectable primary and metastatic liver tumors. The purpose of this study was to determine the objective response to TAE and TACE in unresectable hepatic malignancies and to identify clinicopathologic predictors of response. MATERIALS AND METHODS: Seventy-nine consecutive patients who underwent 119 TAE/TACE procedures between 1998 and 2006 were reviewed. The change in maximal diameter of 121 evaluable lesions in 56 patients was calculated from pre and post-procedure imaging. Response rates were determined using Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. The Kaplan-Meier method was used to compare survival in responders vs. non-responders and in primary vs. metastatic histologies. RESULTS: TAE and TACE resulted in a mean decrease in lesion size of 10.3%+/-1.9% (p<0.001). TACE (vs. TAE) and carcinoid tumors were associated with a greater response (p<0.05). Lesion response was not predicted by pre-treatment size, vascularity, or histology. The RECIST partial response (PR) rate was 12.3% and all partial responders were in the TACE group. Neuroendocrine tumors, and specifically carcinoid lesions, had a significantly greater PR rate (p<0.05). Overall survival, however, was not associated with histology or radiologic response. DISCUSSION: TAE and TACE produce a significant objective treatment response by RECIST criteria. Response is greatest in neuroendocrine tumors and is independent of vascularity and lesion size. TACE appears to be superior to TAE. Although an association of response with improved survival was not demonstrated, large cohort studies are necessary to further define this relationship.

The anatomic location of pancreatic cancer is a prognostic factor for survival.

BACKGROUND: Pancreatic cancers of the body and tail (BT) appear to have poorer survival compared with head (HD) lesions. We hypothesized that potential disparities in outcome may be related to tumor location. Our objective was to examine the relationship between tumor location and survival. METHODS: The Surveillance, Epidemiology, and End Results registry identified 33,752 patients with pancreatic adenocarcinoma and 6443 patients who underwent cancer-directed surgery between 1988 and 2004. Differences in survival and relationships between tumor location and clinical factors were assessed. Multivariate analysis was performed to determine the prognostic significance of tumor location. RESULTS: Median survival for the entire cohort was five months and was significantly lower for BT compared to HD lesions (four vs. six months, p<0.001). Distant metastases (67% vs. 36%, p<0.001) were greater and cancer-directed surgery (16% vs. 30%, p<0.001) was lower for BT tumors. Of 6443 resected patients, HD patients (n=5118) were younger, had a greater number of harvested lymph nodes, were more likely to be lymph node-positive, and had a higher proportion of T3/T4 lesions. Significant univariate predictors of survival included age, T-stage, number of positive and harvested lymph nodes. On multivariate analysis, BT location was a significant prognostic factor for decreased survival (OR 1.11, 95% CI 1.00-1.23, p=0.05). DISCUSSION: Pancreatic BT cancers have a lower rate of resectability and poorer overall survival compared to HD lesions. Prospective large-cohort studies may definitively prove that tumor location is a prognostic factor for survival in patients with pancreatic cancer.

Metastatic gastrointestinal stromal tumors in the era of imatinib: improved survival and elimination of socioeconomic survival disparities.

BACKGROUND: Imatinib was approved in 2002 for unresectable and metastatic gastrointestinal stromal tumors. Our objective was to determine if the introduction of imatinib coincided with improved survival from metastatic gastrointestinal stromal tumor in the U.S. population and in specific socioeconomic groups. METHODS: Query of the Surveillance, Epidemiology, and End Results registry identified 552 patients with metastatic gastrointestinal stromal tumor between 1995 and 2004. Year of diagnosis was categorized into two periods, 1995 to 2000 and 2001 to 2004, to account for the effect of imatinib. Kaplan-Meier and multivariate Cox regression analyses were used to examine differences in survival between periods and among socioeconomic groups. RESULTS: Median survival increased from 12 to 33 months from 1995 to 2000 to 2001 to 2004 (P < 0.001); survival at 47 months increased from 21% to 41%, respectively (P < 0.001). Median survival times for White, Black, Hispanic, and Asian or Pacific Islander, and for low-, middle-, and high-income groups increased significantly in the era of imatinib (all P < 0.05). On multivariate analysis, Black race [hazard ratio, 1.96; 95% confidence interval (95% CI), 1.15-3.32; P = 0.013], Hispanic race (hazard ratio, 2.11; 95% CI, 1.14-3.88; P = 0.017), and low income (hazard ratio, 1.81; 95% CI, 1.13-2.89; P = 0.014) were associated with the poorest survival during the 1995 to 2000 period. During 2001 to 2004, these disparities in survival were no longer statistically apparent. CONCLUSIONS: Survival from metastatic gastrointestinal stromal tumor has improved significantly in the era of imatinib. This improvement has been uniform across all socioeconomic groups, with concomitant elimination of socioeconomic survival disparities potentially due to an assistance program intended to provide universal access to imatinib therapy.

Direct evidence for rapid and selective induction of tumor neovascular permeability by tumor necrosis factor and a novel derivative, colloidal gold bound tumor necrosis factor.

Tumor necrosis factor (TNF) causes regression of advanced cancers when used in isolation perfusion with melphalan; evidence suggests these effects are mediated via selective yet uncharacterized actions on tumor neovasculature. A novel derivative, colloidal gold bound TNF (cAu-TNF) has been shown to have similar antitumor effects as native TNF with less systemic toxicity in mice. These studies were done to determine their effects on tumor neovasculature, using in vivo video microscopy. Female C57BL/6 mice bearing 20 mm(2) MC38 or LLC tumors that are TNF sensitive and resistant tumors, respectively, had dorsal skinfold chambers implanted. The rate of interstitial accumulation of Texas red fluorescently labeled albumin in tumor and normal vasculature was measured after intravenous TNF, cAu-TNF or PBS. Changes in interstitial fluorescent intensity over time were quantified as a reflection of alterations in vascular permeability. MC38 bearing mice treated with TNF or cAu-TNF demonstrated a rapid, selective and significant increase in tracer accumulation in areas of neovasculature compared to those of normal vasculature. Experiments in LLC tumor bearing mice showed similar results. Monoclonal antibody against tissue factor partially abrogated the effects of TNF on MC38 neovasculature. These data provide direct evidence that TNF and cAu-TNF selectively and rapidly alter permeability in tumor neovasculature; a phenomenon that may be exploited to enhance selective delivery of chemotherapeutics to tumor.