Steven A. Curley

Increase in activity and level of pp60c-src in progressive stages of human colorectal cancer.

Activation of the tyrosine kinase of the c-src gene product, pp60c-src, has been shown to occur in nearly every primary colorectal carcinoma, and is found as early as in polyps of high malignant potential. However, no studies have addressed potential pp60c-src changes which occur during progression. To examine this question, we have studied kinase activity and protein levels in 7 colonic polyps, 19 primary lesions, and 19 liver metastases relative to normal colonic mucosa. Significant increases in tyrosine kinase activity were seen as early as in colonic polyps of high malignant potential. Further increases were observed in activity and level in primary tumors. However, the greatest increases in activity and protein levels were observed in liver metastases. Additionally, six metastatic lesions were obtained in which synchronous primary tumor was resected. In each of these liver metastases, pp60c-src activity and level were significantly increased relative to the corresponding primary tumor, as well as to normal colonic mucosa. Our results demonstrate that progression of colon primary tumors to liver metastases correlates with increased pp60c-src kinase activity and protein level.

Nanoconjugation modulates the trafficking and mechanism of antibody induced receptor endocytosis

Treatment with monoclonal antibody (mAbs) is a viable therapeutic option in cancer. Recently, these mAbs such as cetuximab, herceptin, etc., have been used as targeting agents to selectively deliver chemotherapeutics to cancerous cells. However, mechanisms of nanoparticles-mAbs interactions with the target cells and its effect on intracellular trafficking and mechanism are currently unknown. In this paper, we demonstrate that the distinct patterning and dynamics of anti-EGFR (epidermal growth factor receptor) antibody cetuximab (C225)- induced EGFR internalization in pancreatic cancer cells with variable receptor expression is altered upon nanoconjugation. Nanoconjugation uniformly enhanced C225-induced EGFR endocytosis in PANC-1, AsPC-1, and MiaPaca-2 cells, influenced its compartmentalization and regulated the involvement of dynamin-2 in the endocytic processes. Receptor endocytosis and its intracellular trafficking were monitored by confocal microscopy and transmission electron microscopy. The role of dynamin-2 in EGFR endocytosis was determined after overexpressing either wild-type dynamin-2 or mutant dynamin-2 in pancreatic cancer cells followed by tracking the receptor-antibody complex internalization by confocal microscopy. Significantly, these findings demonstrate that the nanoconjugation cannot be construed as an innocuous reaction involved in attaching the targeting agent to the nanoparticle, instead it may distinctly alter the cellular processes at the molecular level, at least antibody induced receptor endocytosis. This information is critical for successful design of a nanoparticle-based targeted drug delivery system for future clinical translation.

Overexpression of focal adhesion kinase (p125FAK) in human colorectal carcinoma liver metastases: Independence from c-src or c-yes activation

AbstractBackground: p125FAK, pp60c-src, and pp62c-yes are protein tyrosine kinases that function in signaling pathways regulating cell adhesion, migration, and growth. The expression and tyrosine kinase activities of pp60c-src and pp62c-yes, and the expression of p125FAK are increased in colorectal tumor metastases relative to normal mucosa. This study investigates whether differences in the activation of pp60c-src and pp62c-yes in colorectal liver metastases correlated with differences in p125FAK expression and whether prognostic significance could be demonstrated from the extent of expression of p125FAK in metastases. Methods: Activities of pp60c-src and pp62c-yes were measured in the immune complex kinase assay. Relative levels of p125FAK, pp60c-src, and pp62c-yes were determined by immunoblotting. Results: p125FAK was overexpressed in 29 of 30 colorectal cancer liver metastases (range of two- to 195-fold increase compared with normal mucosa). The degree of overexpression of p125FAK was not a significant prognostic factor in survival. A differential activation of pp60c-src and pp62c-yes in colorectal carcinoma liver metastases was observed. However, overexpression of p125FAK was observed in metastases with either pp60c-src or pp62c-yes activated in colorectal carcinoma liver metastases. Conclusions: p125FAK overexpression appears to be a marker present in colorectal cancer cells with a metastatic phenotype. Furthermore, p125FAK overexpression is independent of pp60c-src or pp62c-yes activation in human colorectal carcinoma liver metastases.

Liver-Directed Surgery for Metastatic Squamous Cell Carcinoma to the Liver: Results of a Multi-Center Analysis

BackgroundThe role of hepatic resection for metastatic squamous cell carcinoma (SCC) remains unknown. The current study evaluates the role of hepatic resection in patients with metastatic SCC to the liver.MethodsBetween 1988 and 2006, 52 patients underwent hepatic resection of metastatic SCC at eight major cancer centers. Clinicopathologic factors were analyzed with regard to disease-free survival (DFS) and overall survival (OS).ResultsPrimary SCC site was anal (n = 27), head/neck (n = 12), lung (n = 4), esophagus (n = 2), and other (n = 7). Treatment of primary SCC was chemotherapy ± radiotherapy alone (n = 29), chemotherapy ± radiotherapy + surgery (n = 15), or surgery alone (n = 8). Forty-seven patients underwent resection alone, 2 resection + radiofrequency ablation (RFA), and 3 RFA only. At last follow-up, 33 (63.5%) patients had recurred. The median time to recurrence was 9.8 months, and 5-year DFS was 18.6%. Factors associated with reduced DFS were liver tumor size > 5 cm (hazard ratio (HR) = 2.02) and positive surgical margin (HR = 2.33). The overall median survival after hepatic resection was 22.3 months and 5-year actuarial OS was 20.5%. Risk factors associated with worse overall survival included synchronous disease (HR = 4.09), hepatic metastasis > 5 cm (HR = 1.71) and positive surgical resection margin (HR = 1.83).ConclusionsThe majority of patients will recur following hepatic resection of SCC. Long-term survival, however, can be achieved following surgical resection of SCC liver metastasis, especially in patients who present with limited metachronous disease amenable to margin negative resection.

Pegylated arginine deiminase lowers hepatitis C viral titers and inhibits nitric oxide synthesis

Background:  The arginine‐degrading enzyme, arginine deiminase conjugated to polyethylene glycol (ADI‐SS PEG 20 000 mw), reduces extracellular arginine, has minimal toxicity, decreases tumor burden and improves liver function in patients with chronic hepatitis C virus infection (HCV) and inoperable hepatocellular carcinoma (HCC). Reduced extracellular arginine inhibits viral replication through unknown mechanisms. It is hypothesized that ADI‐SS PEG 20 000 mw reduces HCV viral titers through nitric oxide (NO)‐dependent effects.

Alternative Treatment Approaches to Early Stage or Unresectable Hepatocellular Carcinoma Confined to the Liver

As noted in Chapter 2, most patients diagnosed with hepatocellular cancer (HCC) are not candidates for resection. In some patients unresectability is based on the presence of extrahepatic metastasis at the time of diagnosis. Many more patients with HCC confined to the liver are not candidates for resection because of large tumor size, multicentricity, adjacency or direct invasion to major blood vessels, or concomitant cirrhosis with inadequate functional hepatic reserve.

Training for careers in academic surgical oncology: The future is bright

Heslin and colleagues have examined the academic status, clinical activities, and practice patterns of surgeons who graduated from the Memorial Sloan-Kettering Cancer Center Surgical Oncology Fellowship between 1983 and 1996. The purpose of this analysis, presented in this issue of Annals of Surgical Oncology, was to test the hypothesis that surgical oncology fellowships are a viable pathway to academic surgical careers. Grist for the analytic mill was derived from a questionnaire sent to all fellowship graduates from the years listed above. A response rate of 99% was obtained, indicating the interest of nearly all of the former fellows to “stand up and be counted.” Evidence of success in training academic surgeons can be derived from a careful read of the data. While most former fellows are working 70–75 hours a week, their overall mean job satisfaction was 4.2 on a scale of 1–5, with a median value of 5.0. Seventy-one percent are still employed in their first job, and 72% were still in academic positions 8 years after finishing their fellowship. Moreover, 27% are now associate professors, which suggests that a definable academic career trajectory is being pursued. The data from the Memorial Sloan-Kettering Cancer Center remarkably parallels the experience at the University of Texas MD Anderson Cancer Center, where 79 fellows have graduated from the Surgical Oncology Fellowship from 1986 through 1999. Of these 79 fellows, 63 (80%) are in geographic full-time academic surgical positions. Thirteen (16%) of 79 fellows switched positions at least once, with only 5 (38%) of these 13 moving from academic to private practice opportunities. Moreover, 28 (44%) of the 63 former Anderson fellows in academic positions have received or are currently funded by peer reviewed extramural mechanisms such as grants from the NIH, the American Cancer Society, or other professional organizations. Why do young surgeons aspire to fellowship positions? There seem to be both positive and negative motivators. Among the positive factors is a desire to increase knowledge and clinical management skills for certain specific diseases. Another consideration may be to focus academic pursuits and gain the clinical and research skills needed to succeed in the academic arena. On the negative side, Heslin et al. suggest that during the standard 5 years of general residency training, applicants realize that it is difficult to develop a focused clinical and academic identification with one or two malignant diseases. We suggest that there are additional positive drives for fellowship training that are now emerging. Preeminent among these goals is the desire to learn contemporary multimodality oncology care. This intent is fueled by the realization that as we enter the next millenium, solid tumor care is unequivocally multimodality. Increasingly, those in academic surgical oncology will find that they are under pressure (much of it self-imposed) to define themselves as oncologists who use surgery as their therapeutic modality rather than as surgeons who happen to operate on cancer patients. Surgical oncologists must understand all aspects of multimodality cancer management to maintain a leadership role in patient care and treatment planning. The second major goal of surgical oncology fellowship training must be to acquire familiarity with molecular medicine if one is interested in being a part of the “cutting edge” in the next generation of academic surgical oncologists. Knowledge about how genes regulate (or dysregulate) cognate protein production is necessary to understand molecular diagnostics as well as gene-based therapies that will become an integral part of the cancer Received June 10, 1999; accepted June 11, 1999. From the Department of Surgical Oncology, University of Texas, MD Anderson Cancer Center, Houston, Texas. Address correspondence to: Raphael E. Pollock, MD, PhD, Department of Surgical Oncology, Box 106, MD Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030; Fax: 713-792-4689; E-mail: rpollock@notes.mdacc.tmc.edu Annals of Surgical Oncology, 6(6):517–518 Published by Lippincott Williams & Wilkins

Radiofrequency Ablation of Carcinoid and Sarcoma Liver Metastases

Hepatic metastases from soft tissue sarcomas are rare and usually are associated with advanced and disseminated disease with a poor overall prognosis. Although complete hepatic resection may provide an increase in survival, most patients are unresectable. Given the lack of effective systemic therapy, RFA may have a role in the treatment of sarcoma metastases. Although experience is limited, RFA does appear to be well tolerated and initially effective. Local recurrence remains a problem, although the ability to repeat the ablative procedure is a distinct advantage. The use of RFA with hepatic resection and or systemic therapy remains to be evaluated but may potentially increase palliation and even long-term survival in these patients.