Using machine learning to construct nomograms for patients with metastatic colon cancer.

AIM: Patients with synchronous colon cancer metastases have highly variable overall survival (OS), making accurate predictive models challenging to build. We aim to use machine learning to more accurately predict OS in these patients and to present this predictive model in the form of nomograms for patients and clinicians. METHODS: Using the National Cancer Database (2010-2014), we identified right colon (RC) and left colon (LC) cancer patients with synchronous metastases. Each primary site was split into training and testing datasets. Nomograms predicting 3- year OS were created for each site using Cox proportional hazard regression with lasso regression. Each model was evaluated by both calibration (comparison of predicted vs observed OS) and validation (degree of concordance as measured by the c-index) methodologies. RESULTS: A total of 11 018 RC and 8346 LC patients were used to construct and validate the nomograms. After stratifying each model into five risk groups, the predicted OS was within the 95% CI of the observed OS in four out of five risk groups for both the RC and LC models. Externally validated c-indexes at 3 years for the RC and LC models were 0.794 and 0.761, respectively. CONCLUSIONS: Utilization of machine learning can result in more accurate predictive models for patients with metastatic colon cancer. Nomograms built from these models can assist clinicians and patients in the shared decision-making process of their cancer care.

Surgical management of disappearing colorectal liver metastases.

BACKGROUND: Owing to expanded surgical indications for colorectal liver metastasis (CRLM) and improved systemic therapy, hepatic surgeons are increasingly faced with the problem of disappearing (no longer visible on imaging) liver metastasis (DLM). METHODS: A review of relevant studies was performed. Studies that reported on DLM associated with preoperative chemotherapy for CRLM were identified, and data were synthesized and tabulated. The PubMed database was searched for relevant articles published between January 2000 and December 2012. RESULTS: A complete response on imaging does not necessarily equate with a complete clinical or pathological response. Rather, residual macroscopic disease is found in about 25-45 per cent of patients at the time of operation. Even among patients with a complete pathological response, long-term remission occurs in only 20-50 per cent of those treated with systemic therapy. A durable response of DLM is more common following the use of hepatic artery infusion therapy. CONCLUSION: Liver resection should include all original sites of disease if possible.

Inhibition of established pancreatic cancers following specific active immunotherapy with interleukin-2 gene-transduced tumor cells.

Pancreatic cancer has a poor prognosis even when complete resection can be accomplished. Recent studies have demonstrated that the immune system is capable of mounting effective tumor-specific immune responses even against "nonimmunogenic" tumors. The studies reported herein were conducted to determine if induction of tumor-specific immune responses of inhibiting in vivo pancreatic tumor growth could be achieved through active immunization with pancreatic tumor cells genetically engineered to secrete interleukin-2 (IL-2). A relevant poorly immunogenic subcutaneous model of murine ductal pancreatic cancer was first developed using an implantable tumor cell line Panc02 in C57BL/6 mice. Panc02 cells were then genetically engineered to secrete human IL-2 (Panc02/IL2). The ability of irradiated Panc02/IL2 cells to stimulate an immune response capable of rejecting a subsequent tumor challenge was first demonstrated. Ninety percent of animals vaccinated with irradiated parental Panc02 and subsequently challenged with parental Panc02 cells developed tumors by 48 days (mean tumor volume of 234 mm3) compared to only 40% (P < .05, chi square) of animals vaccinated with irradiated Panc02/IL2 and challenged with parental Panc02 (14 mm3, P < .004, tau test). The therapeutic benefit of active immunization in tumor-bearing animals was then examined. Mice with 3-day-old established subcutaneous tumors were administered a series of 4 weekly vaccinations with irradiated Panc02 or Panc02/IL2 cells. A significant reduction in tumor growth was present in those animals vaccinated with Panc02/IL2 (P < .005, tau test) versus Panc02 or saline. Animals whose established tumors regressed following vaccinations with IL-2-secreting Panc02 cells were found to have long-lasting immunity as demonstrated by rejection of a tumor challenge presented over 140 days following inoculation of the primary tumor. We conclude that an immune response capable of inhibiting established pancreatic tumors can be generated by vaccination with IL-2-secreting tumor cells. Furthermore, long-term immunological memory was established in mice that rejected the original established tumor. These studies provide preclinical evidence to support the use of cytokine gene-transduced tumor cell vaccinations in patients with pancreatic cancer.

Intraoperative parathyroid hormone monitoring during parathyroidectomy for secondary hyperparathyroidism.

BACKGROUND: The surgical management of secondary hyperparathyroidism by experienced surgeons is associated with excellent results. The presence of supernumerary glands and inadequate initial parathyroidectomy can lead to reoperations for recurrence. Intraoperative parathyroid hormone monitoring (qPTH), which has been described during parathyroidectomy for primary hyperparathyroidism, may be helpful in preventing or predicting the need for reoperation. This report describes the use of qPTH assays during parathyroidectomy in patients with secondary hyperparathyroidism. METHODS: Intraoperative parathyroid hormone (PTH) levels were determined in 13 patients with secondary hyperparathyroidism undergoing total parathyroidectomy with autotransplantation (n = 3) or subtotal parathyroidectomy (n = 10). Levels were determined using a modified immunochemiluminometric assay (qPTH). RESULTS: The average PTH levels before and after parathyroidectomy were 1599 pg/ml (620 to 2486 pg/ml) and 230.3 pg/ml (129 to 345 pg/ml), respectively. All patients had significant decreases in PTH levels after parathyroidectomy (mean, 84.6%). Symptoms were improved in all patients after operation. PTH levels at early follow-up were consistently below intraoperative levels. CONCLUSIONS: Intraoperative PTH monitoring reproducibly demonstrates the clinically relevant decrease in PTH levels after parathyroidectomy for secondary hyperparathyroidism similar to those previously documented in patients with primary hyperparathyroidism. Long-term follow-up and increasing numbers of patients are crucial in defining the role of qPTH monitoring during parathyroidectomy for secondary hyperparathyroidism.

Local ampullary resection with careful intraoperative frozen section evaluation for presumed benign ampullary neoplasms.

BACKGROUND: Frozen section evaluation has been reported to be inaccurate in detecting foci of adenocarcinoma within adenomas of the ampulla of Vater, leading many authors to advocate pancreaticoduodenectomy as the method of treatment for these neoplasms. The authors hypothesized that (1) ampullary resection is less morbid than pancreaticoduodenectomy, and (2) frozen section evaluation following ampullary resection is accurate and allows for a selective application of pancreaticoduodenectomy to those with carcinoma or benign lesions too large to be locally resected. METHODS: A retrospective review of a single-surgeon experience was conducted. Thirty-eight patients who underwent ampullary resection and pancreaticoduodenectomy (39 procedures) for benign and malignant ampullary neoplasms were identified. Our technique of step-frozen section analysis is described. RESULTS: Twenty-one ampullary resections were performed for preoperative diagnoses of benign (16) and malignant (5) ampullary neoplasms. Frozen section evaluation accurately predicted the final histology in all patients undergoing ampullary resection. Ampullary resection (vs pancreaticoduodenectomy) was associated with a statistically lower operative time (169 minutes vs 268 minutes), estimated blood loss (192 mL vs 727 mL), mean length of stay (10 days vs 25 days), and overall morbidity (29% vs 78%). CONCLUSIONS: Frozen section evaluation of ampullary neoplasms is accurate. Because ampullary resection is less morbid than pancreaticoduodenectomy and frozen section evaluation is accurate, ampullary resection with frozen section evaluation is our current approach to the treatment of small benign ampullary neoplasms.

Active immunotherapy of pancreatic cancer with tumor cells genetically engineered to secrete multiple cytokines.

BACKGROUND: Vaccination of tumor-bearing animals with tumor cells genetically engineered to secrete cytokines including interleukin-2 (IL-2) and interferon-gamma (IFN-gamma) has been shown to induce effective tumor-specific immune responses capable of inhibiting local and metastatic disease. Previous unsuccessful attempts to enhance this immune response by means of the secretion of multiple cytokines possessing different immunologic mechanisms of action may have been due to the inherent inefficiency of the gene transfer systems used. We postulated that tumor cells genetically engineered by means of a novel gene transfer method resulting in high level secretion of both cytokines would be more effective than tumor cells secreting a single cytokine in inhibiting the growth of existing tumors. METHODS: Nonimmunogenic, murine pancreatic cancer cells (Panc02) were engineered to secrete IL-2, IFN-gamma, IL-2 and IFN-gamma, or neomycin phosphotransferase. Mice were inoculated with 5 x 10(5) parental Panc02 tumor cells subcutaneously. Beginning 3 days later, animals then received a series of four weekly vaccinations with irradiated Panc02/Neo, Panc02/IL2, Panc02/IFN, or Panc02/IL-2/IFN. RESULTS: Treatment with Panc02/Neo, Panc02/IL-2, or Panc02/IFN resulted in 0%, 40%, and 30% tumor-free survival, respectively. In contrast, 80% of animals vaccinated with Panc02/IL2/IFN were free of tumor at 100 days. All animals free of disease were resistant to subsequent tumor challenges. CONCLUSIONS: These data show that vaccination with tumor cells that secrete high levels of multiple cytokines was more effective in treating established pancreatic tumors and represents an improvement over existing single cytokine strategies.

Directed enzyme pro-drug gene therapy for pancreatic cancer in vivo.

BACKGROUND: Directed enzyme pro-drug therapy incorporates the delivery of a gene to a cancer cell that will be specifically expressed and will confer sensitivity to a therapeutic agent. Tumor-specific gene expression can be achieved by coupling the promoter for the carcinoembryonic antigen (CEA) to a gene such as herpes simplex virus thymidine kinase (HSV-tk), which phosphorylates ganciclovir to a potent DNA synthesis inhibitor. METHODS: Retroviral vectors were constructed to contain the CEA promoter coupled to HSV-tk (LN-CEA-TK) and were used to transduce the CEA-expressing pancreatic carcinoma cell line BXPC3. Recombinant pancreatic carcinoma cell lines expressing HSV-tk (BXPC3CEA-TK) were then tested for sensitivity to the toxic effects on ganciclovir after engraftment into severe combined immunodeficient mice. Tumors were generated by subcutaneous inoculation of 20 x 10(6) tumor cells consisting of BXPC3 and/or BXPC3CEA-TK cells in ratios of 100:0, 90:10, 50:50, 10:90, and 0:100. After 3 days mice received daily ganciclovir (0.1 mg/kg) or phosphate-buffered saline solution by intraperitoneal injection and were monitored for tumor growth. RESULTS: All severe combined immunodeficient mice inoculated with BXPC3 or BXPC3CEA-TK cells in any proportion developed large pancreatic tumors. As expected, a significant reduction in tumor size was seen in the BXPC3CEA-TK engrafted mice receiving ganciclovir compared with mice receiving phosphate-buffered saline solution or mice engrafted with only BXPC3. In addition, all animals with any fraction of cells expressing HSV-tk exhibited a significant reduction in tumor growth, including animals with only 10% of cells expressing HSV-tk. CONCLUSIONS: These results suggest the potential utility of directed enzyme pro-drug therapy in patients with CEA-expressing pancreatic carcinoma.

Staging of pancreatic cancer before and after neoadjuvant chemoradiation.

Neoadjuvant chemoradiation therapy is used at many institutions for treatment of localized adenocarcinoma of the pancreas. Accurate staging before neoadjuvant therapy identifies patients with distant metastatic disease, and restaging after neoadjuvant therapy selects patients for laparotomy and attempted resection. The aims of this study were to (1) determine the utility of staging laparoscopy in candidates for neoadjuvant therapy and (2) evaluate the accuracy of restaging CT following chemoradiation. Staging laparoscopy was performed in 98 patients with radiographically potentially resectable (no evidence of arterial abutment or venous occlusion) or locally advanced (arterial abutment or venous occlusion) adenocarcinoma of the pancreas. Unsuspected distant metastasis was identified in 8 (18%) of 45 patients with potentially resectable tumors and 13 (24%) of 55 patients with locally advanced tumors by CT. Neoadjuvant chemoradiation therapy and restaging CT were completed in a total of 103 patients. Thirty-three patients with potentially resectable tumors by restaging CT underwent surgical exploration and resections were performed in 27 (82%). Eleven (22%) of 49 patients with locally advanced tumors by restaging CT were resected, with negative margins in 55%; the tumors in these 11 patients had been considered locally advanced because of arterial involvement on restaging CT. Staging laparoscopy is useful for the exclusion of patients with unsuspected metastatic disease from aggressive neoadjuvant chemoradiation protocols. Following neoadjuvant chemoradiation, restaging CT guides the selection of patients for laparotomy but may overestimate unresectability to a greater extent than does prechemoradiation CT.

Gene therapy and pancreatic cancer.

In the short time since the inception of gene therapy, significant advances have been realized. Although this progress has not realized definitive breakthroughs in the treatment of solid organ tumors, including pancreatic cancer, the hope is that advances will come with improved gene delivery systems and alternative approaches. The authors review the history of gene therapy, the current treatment strategies and delivery systems, the preclinical studies on its application to pancreatic cancer, and provide an up-to-date list of federally approved gene therapy cancer trials.

Transcriptional targeting for cancer gene therapy.

Novel treatment strategies incorporating gene transfer technology represent a new frontier in the treatment of cancer made possible through recent developments in molecular biology. Targeting of gene therapy strategies that rely on in situ gene modifications can theoretically occur at the gene entry or gene expression level. Regulation of gene transcription is made possible through the incorporation of cell-specific promoter and enhancer sequences within the transgene construct. This article provides a brief review of transcriptional processes and a description of the most widely studied cell-specific regulatory elements.

Use of bioluminescence imaging to detect enhanced hepatic and systemic tumor growth following partial hepatectomy in mice.

BACKGROUND: The impact of partial hepatectomy on intra-hepatic and distant tumor growth is a matter of controversy. Utilizing a highly sensitive tumor imaging strategy, we sought to demonstrate whether this growth-acceleration occurs, and to develop an animal model with which to investigate potential therapeutic strategies. METHODS: Mice bearing constitutively-active luciferase-expressing tumor cells were subjected to either 70% partial hepatectomy (PH; n=10) or a sham operation (n=11). Mice were sacrificed 14 days later and remnant livers (or anatomic equivalents in the control group) and lungs harvested for bioluminescence detection. RESULTS: Remnant liver weights were significantly increased in PH compared to equivalent lobes in sham-operated animals (t-test; p=0.005). Tumor burden as measured by bioluminescence was significantly higher in both liver and lung specimens in the PH group (Wilcoxon's Rank Sum test; p=0.01 and 0.004, respectively). CONCLUSIONS: Following PH, enhanced metastatic growth was depicted regionally and systemically with bioluminescence imaging providing an objective measure of tumor burden. This preclinical model can help to identify adjuvant therapies that can influence both tumor growth and liver regeneration.

Gastrointestinal stromal tumors and leiomyosarcoma of the abdomen and retroperitoneum: a clinical comparison.

INTRODUCTION: The present study was undertaken to define the clinical differences between leiomyosarcomas (LMS) occurring within the abdomen and retroperitoneum and gastrointestinal stromal tumors (GIST). METHODS: It was a retrospective, single-institution review of patients treated for intra-abdominal and retroperitoneal GIST and LMS from July 1, 1982 through August 1, 1999. RESULTS: A total of 561 patients, 239 with GIST and 322 with LMS, were identified. Patients with GIST were older, with a median age of 58 years versus 54 years in the LMS group (P < .01). The majority of patients with GIST were male (58%), whereas 68% of LMS patients (excluding gender-specific sites) were female (P < .01). The 5-year disease-specific survival for GIST and LMS were 28% and 29%, respectively. The presentation status and ability to achieve a complete surgical resection were the main independent predictors of outcome for both GIST and LMS. Local and distant recurrence was common in both. The pattern of distant recurrence differed: 50% of all first-site GIST recurrences involved the liver, whereas 30% of all LMS first-site recurrences involved the lungs. CONCLUSIONS: Although the two patient populations appear to be distinct, their clinical courses are similar. The pattern of distant spread follows the known patterns of hematogenous dissemination. Complete surgical resection is the cornerstone of treatment for primary GIST and LMS and in selected patients with local and distant recurrence.

Early recurrence after lymphatic mapping and sentinel node biopsy in patients with primary extremity melanoma: a comparison with elective lymph node dissection.

INTRODUCTION: Although sentinel node biopsy with completion lymphadenectomy in node-positive patients (SLND) has been widely adopted in the management of patients with early stage melanoma, reports detailing the outcome of patients after SLND are limited. To address this issue, we analyzed our experience with SLND and provided a comparison to patients treated with elective lymph node dissection (ELND). METHODS: All patients who underwent SLND (1991-1998) and ELND (1974-1994) were identified from single institution melanoma databases. RESULTS: A total of 152 and 329 patients with early-stage melanoma of the extremity underwent SLND and ELND, respectively. Nodal metastases were present in 44 of 329 ELND patients (13%) and in 31 of 152 SLND patients (20%). Early relapse-free and disease-specific survivals were similar for the entire population, although in patients at higher risk for recurrence (age >50 years, thickness >3.0 mm), there was an increased rate of relapse in the SLND group (P = .04). Among all sites of early recurrences, locoregional sites were more common in patients undergoing SLND (72%) compared with ELND (39%, P < .01). SLN-negative patients with nodal recurrence had evidence of metastases on retrospective enhanced pathologic analysis in four of seven cases. CONCLUSIONS: Although overall relapse-free and disease-specific survivals are similar, there is a higher rate of relapse in a subset of SLND node-negative patients who are at high risk for nodal metastases. ELND and SLNB should not be thought of as equivalent approaches until studies with longer follow-up are available.

Sentinel lymph node biopsy in the management of patients with primary cutaneous melanoma: review of a large single-institutional experience with an emphasis on recurrence.

OBJECTIVE: To analyze the authors' experience with sentinel lymph node biopsy (SLNB) and the subsequent incidence and pattern of recurrence in patients with positive and negative nodes. SUMMARY BACKGROUND DATA: Lymphatic mapping with SLNB has become widely accepted in the management of patients with melanoma who are at risk for occult regional lymph node metastases. Because this procedure is relatively new, the pattern of recurrence after SLNB is not yet clear. METHODS: All patients with primary cutaneous melanoma who underwent SLNB from 1991 through 1998 were identified from a prospective single-institution melanoma database. RESULTS: Three hundred fifty-seven consecutive patients with localized primary cutaneous melanoma who underwent SLNB were identified. The sentinel node was identified in 332 patients (93%) and was positive in 56 (17%). Fourteen percent of patients had developed a recurrence at a median follow-up of 24 months. The median time to recurrence was 13 months. The 3-year relapse-free survival rates for patients with positive and negative nodes were 56% and 75%, respectively. SLN status was the most important predictor of disease recurrence. The site of first recurrence in patients with negative and positive nodes was more commonly locoregional than distant. Reexamination of the SLN in 11 patients with negative nodes with initial nodal and in-transit recurrence showed evidence of metastases in 7 (64%). CONCLUSIONS: Patients with positive sentinel nodes have a significantly increased risk for recurrence. The early pattern of first recurrence for patients with negative and positive results is characterized by a preponderance of locoregional sites, similar to that reported in previous series of elective lymph node dissection. These data underscore the need for careful pathologic analysis of the SLN as well as a careful, directed locoregional physical examination in the follow-up of these patients.

Generation of tumor-specific T lymphocytes for the treatment of posttransplant lymphoma.

BACKGROUND: The incidence of lymphoproliferative disease, including B-cell lymphomas (BCL) in patients who have undergone heart or combined heart-lung transplants, has been reported to be as high as 15%. The majority of these tumors contain Epstein-Barr virus (EBV) DNA and regress when immunosuppressive agents are discontinued. This tumor regression is thought to be secondary to cytotoxic T lymphocytes (CTL) reactive to EBV-infected cells whose function is impaired in patients receiving immunosuppressive agents. We hypothesize that EBV-CTL expanded in the absence of these agents may demonstrate an antitumor effect against an EBV-expressing human BCL in vitro and in vivo. METHODS AND RESULTS: An EBV-expressing BCL from a heart transplant recipient was isolated and expanded in culture. EBV-CTL were generated by stimulation of peripheral blood leukocytes with irradiated autologous tumor cells in low-dose interleukin-2. Autologous BCL, HLA-mismatched BCL, lymphokine-activated killer target cell line (Daudi), and the natural killer target cell line (K562) were used in a standard 4-hour cytotoxicity assay using 51CrO4 after 7, 14, and 28 days of stimulation. There was significant percent specific lysis of autologous BCL targets (78%) at an effector-to-target ratio as low as 20:1 as compared with control cells. EBV-CTL were then adoptively transferred into SCID mice (provided by Duke University Vivarium) that had been engrafted with autologous BCL 7 days before. There was a significant survival advantage to those mice engrafted with EBV-CTL as compared with control cells. CONCLUSIONS: The results indicate that ex vivo expansion of EBV-CTL in the absence of immunosuppressive agents results in a population that has significant antitumor activity. This strategy may be useful in the generation of EBV-CTL that might be effective antitumor agents in transplant recipients with EBV-associated lymphomas.

Preoperative radiation and chemotherapy in the treatment of adenocarcinoma of the rectum.

OBJECTIVE: In this study, the impact of preoperative chemotherapy and radiation on the histopathology of a subgroup of patients with rectal adenocarcinoma was examined. As well, survival, disease-free survival and pelvic recurrence rates were examined, and compared with a concurrent control group. SUMMARY BACKGROUND DATA: The optimal treatment of large rectal carcinomas remains controversial; current therapy usually involves abdominoperineal resection plus postoperative chemoradiation; the combination can be associated with significant postoperative morbidity. In spite of these measures, local recurrences and distant metastases continue as serious problems. METHODS: Fluorouracil, cisplatin, and 4500 cGy were administered preoperatively over a 5-week period, before definitive surgical resection in 43 patients. In this group of patients, all 43 had biopsy-proven lesions > 3 cm (median diameter), involving the entire rectal wall (as determined by sigmoidoscopy and computed tomography scan), with no evidence of extrapelvic disease. The patients ranged from 31 to 81 years of age (median 61 years), with a male:female ratio of 3:1. A concurrent control group consisting of 56 patients (median: 62 years, male:female ration of 3:2) with T2 and T3 lesions was used to compare survival, disease-free survival, and pelvic recurrence rates. RESULTS: The preoperative chemoradiation therapy was well tolerated, with no major complications. All patients underwent repeat sigmoidoscopy before surgery; none of the lesions progressed while patients underwent therapy, and 22 (51%) were determined to have complete clinical response. At the time of resection, 21 patients (49%) had gross disease, 9 (22%) patients had only residual microscopic disease, and 11 (27%) had sterile specimens. Of the 30 patients with evidence of residual disease, 4 had positive lymph nodes. In follow-up, 39 of the 43 remain alive (median follow-up = 25 months), and only 1 of the 11 patients with complete histologic response developed recurrent disease. Six of the 32 patients with residual disease (2 with positive nodes) have developed metastatic disease in follow-up (median time to diagnosis 10 months, range 3-15 months). Three of these patients with metastases have died (median survival after diagnosis of metastases = 36 months). Local recurrence was seen in only 2 of 43 patients (< 5%). Cox-Mantel analysis of Kaplan-Meier distributions demonstrated increased survival (p = 0.017), increased disease-free survival (p = 0.046), and decreased pelvic recurrence (p = 0.031) for protocol versus control patients. CONCLUSIONS: This therapeutic regimen has provided enhanced local control and decreased metastases. Furthermore, the marked degree of tumor downstaging, as seen by a 27% incidence of sterile pathologic specimens and a low rate of positive lymph nodes in this group with initially advanced lesions, strongly suggest that less radical surgery and sphincter preservation may be used with increasing frequency.

Active immunization with tumor cells transduced by a novel AAV plasmid-based gene delivery system.

Ex vivo genetically engineered cytokine-secreting tumor cell vaccines have been shown to prevent metastatic disease in animal models of lung and breast cancer. Because of the inefficiency of existing modes of gene delivery in transducing primary human tumor cells, it has been difficult to clinically apply this strategy. In this study, liposome-mediated delivery of an adeno-associated virus (AAV)-based plasmid containing the sequence for murine gamma-interferon (gamma-IFN) (pMP6A-mIFN-gamma) was used to generate cytokine-secreting murine tumor cell vaccines. High levels of gamma-IFN and elevated class I major histocompatibility complex expression after transfer of pMP6A-mIFN-gamma into the murine lung cancer cell line, D122, was demonstrated. The efficiency of gene transfer was determined by two different methods and was estimated to be 10-15%. Irradiated gamma-IFN D122 cells generated by this novel gene delivery system (D122/pMP6A-mIFN-gamma) and also by standard retroviral methods (DIF2) were administered as weekly vaccinations by intraperitoneal injection to animals bearing 7-day-old intrafootpad D122 tumors. Hindlimb amputation was performed when footpad diameters reached 7 mm, and lungs were harvested 28 days later. Animals vaccinated with gamma-IFN-secreting D122 cells produced by AAV-based plasmids delivery demonstrated a significant delay in footpad tumor growth when compared with controls and DIF2 cells. Fifty-seven percent of animals vaccinated with D122/pMP6A-mIFN-gamma were free of pulmonary metastases 28 days after amputation, significantly improved from the 0, 7, and 15% observed in animals vaccinated with irradiated parental D122 cells, irradiated D122 cells lipofected with an empty-cassette vector (pMP6A), or DIF2 cells, respectively. These results and the ability to transfer genes with this delivery system to a broad range of tumor types support its use in the generation of cytokine-secreting tumor cell vaccinations for use in clinical trials.

Neoadjuvant chemoradiation for localized adenocarcinoma of the pancreas.

BACKGROUND: The use of neoadjuvant (preoperative) chemoradiotherapy (CRT) for pancreatic cancer has been advocated for its potential ability to optimize patient selection for surgical resection and to downstage locally advanced tumors. This article reports our experience with neoadjuvant CRT for localized pancreatic cancer. METHODS: Since 1995, 111 patients with radiographically localized, pathologically confirmed pancreatic adenocarcinoma have received neoadjuvant external beam radiation therapy (EBRT; median, 4500 cGy) with 5-flourouracil-based chemotherapy. Tumors were defined as potentially resectable (PR, n = 53) in the absence of arterial involvement and venous occlusion and locally advanced (LA, n = 58) with arterial involvement or venous occlusion by CT. RESULTS: Five patients (4.5%) were not restaged due to death (n = 3) or intolerance of therapy (n = 2). Twenty-one patients (19%) manifested distant metastatic disease on restaging CT. Twenty-eight patients with initially PR tumors (53%) and 11 patients with initially LA tumors (19%) were resected after CRT. Histologic examination revealed significant fibrosis in all resected specimens and two complete responses. Surgical margins were negative in 72%, and lymph nodes were negative in 70% of resected patients. Median survival in resected patients has not been reached at a median follow-up of 16 months. CONCLUSIONS: Neoadjuvant CRT provided an opportunity for patients with occult metastatic disease to avoid the morbidity of resection and resulted in tumor downstaging in a minority of patients with LA tumors. Survival after neoadjuvant CRT and resection appears to be at least comparable to survival after resection and adjuvant (postoperative) CRT.