Search

Few biologic markers have been studied as prognostic factors in recurrent rectal carcinoma patients. We sought to determine the influence of clinical, pathologic, and biologic (p53, bcl-2, and ki-67) variables on survival after curative resection of locally recurrent rectal cancer. Retrospective review of patients with locally recurrent rectal cancer who received surgery with curative intent. From 1988 to 1998, 134 patients with locally recurrent rectal cancer underwent operative exploration. Curative resection was performed in 85 patients. Median follow-up was 43 (range, 1.3–149) months. On multivariate analysis, negative predictors of overall survival included an elevated carcinoembryonic antigen level (P = 0.02; hazard ratio 2.41; 95 percent confidence interval, 1.19–4.89) and an R1 resection margin (P = 0.01; hazard ratio, 2.81; 95 percent confidence interval, 1.27–6.21). In 26 patients for whom biologic variables were available, p53, bcl-2, and ki-67 did not significantly impact disease-specific survival or overall survival. Five-year disease-specific survival, overall survival, and pelvic control rates were 46, 36, and 51 percent respectively. Of the 50 patients who relapsed, time to second local recurrence was longer than time to development of metastasis (median, 16.5 vs. 9 months). Median survival for patients with metastatic recurrence was 26.l vs. 41.5 months for those with a subsequent local recurrence alone. Approximately two-thirds of patients with locally recurrent rectal cancer can be resected for cure. Preoperative carcinoembryonic antigen and an R0 resection margin were the only significant predictors of overall survival. p53, bcl-2, and ki-67 did not impact survival outcomes.

Background Patients undergoing central neck surgery are at risk for hypoparathyroidism. We hypothesized that gamma probe identification of sestamibi-labeled parathyroid glands might help maximize parathyroid preservation. Methods Records of 351 patients who underwent central neck surgery were reviewed. A subgroup of patients underwent sestamibi injection followed by gamma probe-directed parathyroid gland identification. Results Operation was performed for malignancy in 73% of patients and represented a reoperation in 34%. Persistent hypoparathyroidism was more common in patients who underwent reoperation versus a primary operation (6.8% versus 1.7%; P = 0.02). Thirteen patients underwent gamma probe-directed identification of sestamibi-labeled parathyroid glands; in 6 of these patients, sestamibi-labeled parathyroid glands were salvaged from the resected specimens and autografted. None of these 13 patients developed persistent hypoparathyroidism. Conclusions Patients undergoing reoperative central neck surgery are at increased risk for postoperative hypoparathyroidism. Gamma probe-directed salvage of sestamibi-labeled parathyroid glands may help maximize parathyroid preservation, especially in complex or reoperative central neck surgery.

Pheochromocytoma is a rare tumor, but it represents a potentially curable form of hypertension. In patients with inherited pheochromocytoma, benign and bilateral tumors are more common. The diagnosis of pheochromocytoma rests in biochemical confirmation of catecholamine excess. Plasma-free metanephrine levels are arguably the most sensitive and specific test for the biochemical diagnosis of pheochromocytoma in high-risk patient populations. A timed 24-hour urine collection for total catecholamines and metabolic products (eg, vanillylmandelic acid and metanephrines) is the favored confirmatory test. Localization is most commonly accomplished with high-resolution computed tomography imaging, but magnetic resonance imaging can also be used. If both of these imaging modalities are nonlocalizing or equivocal, then radiolabeled meta-iodobenzylguanidine or somatostatin can be used to identify an adrenal or extra-adrenal tumor (paraganglioma). These imaging modalities can be used in the evaluation of patients with suspected or confirmed recurrent or metastatic disease. Systemic therapies for the treatment of patients with recurrent or metastatic disease have been disappointing. Radiation therapy is best applied for palliative relief of pain associated with bony metastases. In the absence of radiographic evidence for local tumor invasion, laparoscopic resection of small-to medium-sized (< 6 cm) pheochromocytomas is indicated. Abundant evidence indicates that this approach is safe and well tolerated and results in more rapid recovery and less long-term wound morbidity compared to open anterior or posterior adrenalectomy. Open anterior adrenalectomy is appropriate for patients with large or recurrent tumors, suspected or documented locoregional invasion, or for those patients in whom a laparoscopic approach is technically contraindicated. For selected patients with pheochromocytoma in the von Hipple-Lindau syndrome or multiple endocrine neoplasia type 2 setting in which the cumulative incidence of clinical bilateral tumors is high, a corticalsparing approach may minimize the risk of Addisonian complications.

The diagnosis of pancreatic cancer continues to produce fear in both patients and practitioners in large part owing to the likely incurability in all for whom the diagnosis is made. It is this reality that continually motivates the surgical and medical oncologists who endeavor to treat these patients. Currently, the cure rate for pancreatic cancer has improved only minimally, and the overall survival of patients remains dismal, with fewer than 5% of patients alive at 5 years and 92% of these patients dead at 2 years. This current treatment status has stimulated numerous studies endeavoring to understand the diverse mechanisms of cell growth in this tumor. Intensive investigative efforts have produced the understanding of new tumor suppressor genes such as DPC4 and an increasing understanding of tyrosine kinase receptors and signal transduction and their regulation of programmed cell death (apoptosis). Detection of these numerous genetic defects may give new insights and understanding of the highly chemo- and radioresistant nature of pancreatic cancer. These same findings also provide the basis for the development of new potential therapies for pancreatic cancer through gene therapy. This paper reviews the significant molecular biologic findings and their influence on the development of gene therapy strategies in the treatment of pancreatic adenocarcinoma.

Radiosensitization of human gastrointestinal tumors by 5-fluorouracil (5-FU) has been studied in vitro and clinically in human cancer therapy trials. The bacterial enzyme cytosine deaminase (CD) converts the nontoxic prodrug 5-fluorocytosine (5-FC) into 5-FU. Human colon cancer cells stably expressing CD have been shown by other investigators to be sensitized to radiation following treatment with 5-FC. We previously used an adenoviral vector under control of the cytomegalovirus promoter (AdCMVCD) encoding the CD gene in combination with 5-FC and a single fraction of radiation exposure to enhance cytotoxicity to human cholangiocarcinoma cells in vitro and in vivo. The purpose of this study was to determine whether AdCMVCD infection and 5-FC with multiple fraction low-dose radiotherapy results in enhanced cytotoxicity. In the present study, we utilized AdCMVCD and 5-FC with single fraction radiotherapy to demonstrate enhanced cytotoxicity to WiDr human colon carcinoma cells in vitro. Additionally, we tested this gene therapy/prodrug treatment strategy employing a fractionated radiation dosing schema in animal models of WiDr colon carcinoma and SK-ChA-1 cholangiocarcinoma. A prolonged WiDr tumor regrowth delay was obtained with AdCMVCD infection in combination with systemic delivery of 5-FC and fractionated external beam radiation therapy compared with control animals treated without radiation, without 5-FC, or without AdCMVCD. The results of treatment with AdCMVCD + 5-FC + radiation therapy to cholangiocarcinoma xenografts were equivalent to those obtained with systemic 5-FU administration + radiation. Thus, the use of AdCMVCD can be effectively combined with clinically relevant 5-FC and radiation administration schemes to achieve enhanced tumor cell killing and increased control of established tumors of human gastrointestinal malignancies.

Radioimmunotherapy is limited by a variety of factors, including poor tumor penetration of monoclonal antibodies and low levels of intratumoral antigen expression. To address these limitations, a gene therapy strategy was devised to genetically induce tumor cells to express enhanced levels of membrane receptors with high affinity for a radiolabeled peptide. We designated this approach as genetic radioisotope targeting strategy. To this end, an adenoviral vector (AdCMVGRPr) encoding the murine gastrin-releasing peptide receptor (GRPr) was used to achieve a high level of binding of radiolabeled bombesin (BBN). To achieve genetic induction of membrane GRPr specifically to tumor cells, we constructed two adenoviral vectors encoding the GRPr gene under the control of the tumor-specific regulatory elements, DF3 (AdDF3GRPr) or erbB-2 (AderbGRPr). We investigated the binding of [125I]BBN to the GRPr following infection with AdDF3GRPr and AderbGRPr in a panel of human breast, pancreatic, and cholangiocarcinoma tumor cell lines. [125I]BBN binding and GRPr expression increased with increasing multiplicities of infection of AdCMVGRPr in all of the cell lines tested. Breast cancer cell lines expressing erbB-2 showed significant GRPr expression using AderbGRPr. A similar result was observed in breast and cholangiocarcinoma cells infected with AdDF3GRPr expressing MUC1 as detected by immunohistochemistry but was not seen in the pancreatic cell lines tested. Thus, adenoviral vectors with tissue-specific promoter elements can be used to achieve a selective expression of membrane receptors that can be targeted with a radiolabeled peptide. The use of such a transcriptional targeting approach may restrict gene expression to tumors and limit the radiation dose deposited in normal tissues in vivo.

Cholangiocarcinoma is a malignancy that is resistant to current therapy. We applied the toxin gene therapy strategy of cytosine deaminase conversion of the nontoxic producing 5-fluorocytosine to 5-fluorouracil combined with radiotherapy to cholangiocarcinoma. The transduction efficiency of SK-ChA-1 cholangiocarcinoma cells was determined by fluorescence-activated cell-sorting analysis following infection with recombinant adenovirus AdCMVLacZ, which encodes thc gene for Beta-galactosidase. To evaluate cytosine deaminase-mediated conversion of 5-fluorocytosine to 5-fluorouracil and subsequent cytotoxicity, SK-ChA-1 cells were infected with the recombinant adenovirus AdCMVCD, which encodes cytosine deaminase, and exposed to 5-fluorocytosine for 6 to 8 days. Additive cytotoxicity of radiation therapy was evaluated by cobalt-60 exposure following AdCMVCD infection and 5-fluorocytosine treatment. SK-ChA-1 cells were transduced (98.4%) by AdCMVLacZ at 100 plaque-forming units per cell. Following infection with AdCMVCD and exposure to 5 to 100 microgram/ml of 5-fluorocytosine, 20% to 64% of SK-ChA-1 cells were killed. A combination of radiation and cytosine deaminase/5-fluorocytosine therapy resulted in enhanced cell killing (83.5% to 91.5%). Cholangiocarcinoma cells were transduced by recombinant adenoviral vectors and were killed by cytosine deaminase-mediated production of 5-fluorouracil. Enhanced cytotoxicity was seen with the addition of external beam radiation. These results provide a foundation for multimodality therapy for human cholangiocarcinoma that combines gene therapy technology with radiation therapy.