Colin M. Parsons

Pancreatic cancer cell lines deficient in argininosuccinate synthetase are sensitive to arginine deprivation by arginine deiminase

Eukaryotic cells can synthesize the non‐essential amino acid arginine from aspartate and citrulline using the enzyme argininosuccinate synthetase (ASS). It has been observed that ASS is underexpressed in various types of cancers ASS, for which arginine become auxotrophic. Arginine deiminase (ADI) is a prokaryotic enzyme that metabolizes arginine to citrulline and has been found to inhibit melanoma and hepatoma cancer cells deficient of ASS. We tested the hypothesis that pancreatic cancers have low ASS expression and therefore arginine deprivation by ADI will inhibit cell growth. ASS expression was examined in 47 malignant and 20 non‐neoplastic pancreatic tissues as well as a panel of human pancreatic cancer cell lines. Arginine deprivation was achieved by treatment with a recombinant form of ADI formulated with polyethylene glycol (PEG‐ADI). Effects on caspase activation, cell growth and cell death were examined. Furthermore, the effect of PEG‐ADI on the in vivo growth of pancreatic xenografts was examined. Eighty‐seven percent of the tumors lacked ASS expression; 5 of 7 cell lines similarly lacked ASS expression. PEG‐ADI specifically inhibited growth of those cell lines lacking ASS. PEG‐ADI treatment induced caspase activation and induction of apoptosis. PEG‐ADI was well tolerated in mice despite complete elimination of plasma arginine; tumor growth was inhibited by ∼50%. Reduced expression of ASS occurs in pancreatic cancer and predicts sensitivity to arginine deprivation achieved by PEG‐ADI treatment. Therefore, these findings suggest that arginine deprivation by ADI could provide a beneficial strategy for the treatment of pancreatic cancer, a malignancy in which new therapy is desperately needed.

Preoperative evaluation of pancreatic adenocarcinoma

The preoperative evaluation of resectability for pancreatic cancer fails to identify up to 25% of patients who are unfortunately found to be unresectable at surgical exploration. Inoperative findings in this circumstance is usually due to either small volume metastatic disease or regional tumor invasion. While advances in computed tomography (CT) technology has increased accuracy of local tumor extent, occult metastatic disease remains a common problem. Although 2-[(18)F]fluoro-2-deoxy-D-glucose positron emission tomography (FDG-PET) has been demonstrated to be useful in the staging of many malignancies (e.g. esophageal cancer, recurrent colorectal cancer, lung cancer), it has not been found to significantly increase the accuracy of determining resectability preoperatively in pancreatic cancer, especially with regard to detection of small volume metastatic disease. There are a variety of pancreatic cancer-specific antigens which are being developed as a method for targeted molecular imaging; we provide preliminary data targeting the integrin alpha(v)beta(6) to demonstrate the potential feasibility of this approach. Further developments may allow the accurate determination of patients with resectable pancreatic cancer, and more importantly, those with unresectable disease that may forego unnecessary surgery, the associated morbidity, and the subsequent delay of appropriate therapy.

The role of radical amputations for extremity tumors: a single institution experience and review of the literature.

Major amputations are indicated for advanced tumors when limb‐preservation techniques have been exhausted. Radical surgery can result in significant palliation and possible cure.

Surgical Management of Neurofibromatosis

Neurofibromatoses are a complex set of genetic diseases with a wide spectrum of clinical manifestations. Life-threatening complications may develop as the result of tumor progression. Surgical intervention is the only effective means of treatment for progressive pain, disfigurement, functional compromise, and malignancy. In the future, molecular advances should allow for the development of targeted therapies to treat patients who have neurofibromatosis in addition to those who have sporadic tumors. Tumor profiling should allow us to guide therapies and predict responses.