Prevention of hepatic tumor metastases in rats with herpes viral vaccines and gamma-interferon.

Previous studies showed that gammaIFN decreases metastatic hepatic tumor growth by stimulating Kupffer cells (KC). The present studies examine whether lymphocyte stimulation via cells engineered to secrete GM-CSF or IL-2 decreases hepatic tumor growth, and whether stimulation of both macrophages and lymphocytes is more effective than either individually. Rats were immunized with irradiated hepatoma cells transduced by herpes viral amplicon vectors containing the genes for GM-CSF, IL-2 or LacZ. On day 18, half of each group was treated with 5 x 10(4) U gammaIFN, or saline intraperitoneally for 3 d. On day 21, all rats received 5 x 10(5) hepatoma cells intrasplenically. On day 41, rats were killed and tumor nodules were counted. Separate rats underwent splenocyte and KC harvest for assessment of lymphocyte- and macrophage-mediated tumor cell kill in vitro. GM-CSF or IL-2 vaccines or gammaIFN decreased tumor nodules significantly (GM-CSF 13+/-4, IL-2 14+/-6 vs. control 75+/-24, P < 0.001). Combination therapy was more effective, and completely eliminated tumor in 4 of 12 IFN-GM-CSF and 8 of 11 IFN-IL-2 animals. Additional rats underwent partial hepatectomy, an immunosuppressive procedure known to accelerate the growth of hepatic tumor, following tumor challenge. Therapy was equally effective in this immunosuppressive setting. Vaccination is associated with enhancement of splenocyte-mediated tumoricidal activity, whereas the effect of gammaIFN is mediated by KC. GM-CSF and IL-2 vaccine therapy and pretreatment with gammaIFN represent effective strategies in reducing hepatic tumor. Combination therapy targets both lymphocytes and macrophages, and is more effective in reducing tumor than either therapy alone.

Pretreatment with IFN-gamma decreases infectious complications after partial hepatectomy in the rat.

Infectious postoperative complications occur commonly after hepatectomy and may lead to a long hospital stay or death. The potential beneficial effects of interferon-gamma (IFN-gamma) in this setting were evaluated in a model of hepatectomy and sepsis in rodents. Incidence of bacterial translocation was measured in animals on days 1, 2, and 5 after partial hepatectomy. Macrophage function was quantified by in vitro tumoricidal activity and superoxide anion (O2-) production. Survival after partial hepatectomy and cecal ligation and puncture (CLP) was recorded. After partial hepatectomy, bacterial translocation was decreased on days 1 and 2 in animals pretreated with IFN-gamma (p < 0.05). Macrophages from animals treated with IFN-gamma had higher in vitro tumoricidal activity and production of O2- (p < 0.05). Hepatectomized animals pretreated with IFN-gamma had an increased survival after CLP (p < 0.05). IFN-gamma may be useful in decreasing the incidence of infectious complications after partial hepatectomy.

Efficient cotransduction of tumors by multiple herpes simplex vectors: implications for tumor vaccine production.

Many gene therapy strategies would be enhanced by efficient transfer of multiple genes into the same cell. Herpes simplex viral amplicon (HSV) vectors are good vehicles for gene transfer because they accommodate large pieces of foreign DNA and transfer genes rapidly and efficiently. The current studies examine whether efficient cotransduction of tumor cells can be accomplished using multiple HSV vectors in a manner useful for clinical gene therapy. Interleukin-12 (IL-12) exists as a heterodimer, with components (m35 and m40) coded for by genes on two separate chromosomes. We constructed HSV vectors carrying either IL12m35 (HSVm35) or IL12m40 (HSVm40) or both genes (HSVm75) separated by an internal ribosome entry site to assess whether gene transfer using a single HSV vector constructed to carry multiple genes has any advantage over gene transfer using multiple vectors that are each carrying single genes. Because IL-12 and IL-2 have been found to have synergistic antitumoral activity, we further analyzed the biologic activity of tumor cells cotransduced by separate HSV vectors carrying genes coding for these two cytokines. The results demonstrate that multiple genes can be inserted into the same cell efficiently using multiple HSV vectors, and that these vectors allow rapid production of tumor vaccines expressing multiple cytokine genes. Thus, gene transfer using HSV may not be limited by the size of the DNA that each vector can accommodate. Immunizations with tumors cotransduced with HSVm35 and HSVm40 were equally effective in eliciting a cytolytic T-lymphocyte response and in protecting against tumor growth in vivo as immunization with tumors treated with HSVm75. Immunization with tumors cotransduced with HSVm75 and HSVil2 was superior to immunization with tumors transduced with either alone. The combination of IL-2- and IL-12-secreting tumor cells may be used as an effective immunization strategy against solid tumors.

Regional muramyl tripeptide phosphatidylethanolamine administration enhances hepatic immune function and tumor surveillance.

BACKGROUND: Immune status of the liver may affect growth of liver metastases. We analyzed the ability of muramyl tripeptide phosphatidylethanolamine (MTP-PE), an immunomodulatory bacterial cell wall analog, to stimulate Kupffer cells (KCs) and protect against tumor growth, with or without an immunosuppressive partial hepatectomy (PH). Impact of MTP-PE's route of administration on KC function was assessed. METHODS: Buffalo rats (n = 7 to 12/group) were treated with saline, 40 microg MTP-PE intraportally (portal) or intravenously (IV) and challenged with 5 x 10(5) hepatoma cells, and tumors counted on day 21. To assess MTP-PE's impact on KC stimulation in animals undergoing PH, a known stimulant of tumor cell growth, groups were treated with saline or MTP-PE and challenged with tumor and underwent 30% PH. KCs were harvested and analyzed for superoxide production. Statistical analysis was performed with Mann-Whitney U test or chi-square test. RESULTS: MTP-PE-treated animals had fewer tumor nodules than control animals (19 vs 184, P <.005). MTP-PE-portal animals had fewer nodules than MTP-PE-IV (2 vs 36, P <.05). MTP-PE treatment before PH resulted in fewer tumor nodules compared with control animals (192 vs 276, P <. 05). MTP-PE administration increased macrophage superoxide production (20.6 +/- 2 vs 11.9 +/- 1.1 nmol/10(6) cells, P <.005). CONCLUSIONS: MTP-PE improved KC function and decreased growth of microscopic tumor cells. MTP-PE's effects persist after an immunosuppressive hepatectomy. Portal administration was the most effective. MTP-PE administration may be useful as a neoadjuvant therapy for patients undergoing resection of liver malignancies.

Partial hepatectomy accelerates local tumor growth: potential roles of local cytokine activation.

BACKGROUND: Surgical excision of liver tumors represents the only curative treatment for primary and metastatic liver malignancies. It has been suspected that hepatectomy may stimulate growth of microscopic tumors. To determine whether local or systemic factors after hepatectomy are responsible for enhancement of tumor growth, the effects of hepatectomy on the experimental growth of liver or pulmonary tumors were examined. METHODS: One hour after injection of 10(6) Morris hepatoma cells into either the portal or femoral vein, which produces isolated liver and lung tumors, respectively, animals were randomized to undergo 0%, 30%, or 70% partial hepatectomy (PH). RESULTS: Animals that underwent portal injection of tumor had significantly increased liver tumor burden after PH (sham, 25 +/- 7 vs PH, 94 +/- 17; p < 0.01), whereas animals that underwent femoral injection had no change in lung tumor burden after PH. PH was associated with significantly increased levels of transforming growth factor-alpha, transforming growth factor-beta, and basic fibroblast growth factor in the liver but not in the lung. CONCLUSIONS: Changes in liver cytokine-growth factor activation may contribute to enhanced tumor growth in the liver after hepatectomy.

Results of total pancreatectomy for adenocarcinoma of the pancreas.

HYPOTHESIS: Total pancreatectomy for infiltrating ductal adenocarcinoma is not superior to pancreaticoduodenectomy or distal pancreatectomy. DESIGN: A retrospective analysis of a prospective database of patients. SETTING: Memorial Sloan-Kettering Cancer Center, New York, NY. PATIENTS: All patients (n = 488) undergoing pancreatic resection. MAIN OUTCOME MEASURES: Duration of operation, estimated blood loss, complications, length of stay, number of positive lymph nodes, presence of a positive margin, and survival times were analyzed. RESULTS: Thirty-five patients were identified who underwent total pancreatectomy, 28 of whom had adenocarcinoma. Median length of stay was 32 days; 19 (54%) developed postoperative complications, of which 63% were infectious. Thirty-day mortality was 3% (1 patient). Median survival was 9.3 months (range, 0.6-172 months). There was no significant difference between patients with and without adenocarcinoma in terms of duration of operation, estimated blood loss, complications, length of stay, or number of readmissions. In patients with adenocarcinoma, margin or nodal status were not significant survival variables. Patients undergoing total pancreatectomy for adenocarcinoma had a significantly worse overall survival than those undergoing total pancreatectomy for other reasons (P<.001), or compared with a contemporaneous cohort with adenocarcinoma undergoing pancreaticoduodenectomy (n = 409) and distal pancreatectomy (n = 51) (7.9 vs 17.2 months; P<.002). CONCLUSIONS: Total pancreatectomy can be performed safely with low mortality; survival is predicted by the underlying pathologic findings: patients undergoing total pancreatectomy for adenocarcinoma have a uniformly poor outcome. Those undergoing total pancreatectomy for benign disease or nonadenocarcinoma variants can have long-term survival. In patients who require total pancreatectomy for ductal adenocarcinoma, the survival is so poor as to bring into question the value of the operation.

Soft tissue tumors of the abdominal wall: analysis of disease patterns and treatment.

HYPOTHESIS: Abdominal wall tumors, though clinically similar, have varying degrees of biological behavior. DESIGN: Retrospective review of prospective databases. SETTING: Memorial Sloan-Kettering Cancer Center. PATIENTS: Eighty-five patients with abdominal wall soft tissue tumors. MAIN OUTCOME MEASURES: Primary endpoints included time to first local recurrence, distant metastases, and disease-related mortality. Survival analysis was performed by Kaplan-Meier method, and comparisons were made by log-rank analysis. RESULTS: Thirty-nine desmoids, 32 soft tissue sarcomas (STS), and 14 dermatofibrosarcoma protuberans (DFSP) underwent surgery directed at achieving margin-negative resection. Unlike DFSP, most STS (77%) and desmoids(87%) were deep lesions requiring full-thickness abdominal wall resection and mesh reconstruction. Median follow-up time was 53 months, 101 months, and 31 months, with 5-year local recurrence-free survival rates of 97%, 100%, and 75%, for desmoids, DFSP, and STS, respectively. Desmoid tumors resected with positive microscopic margins had higher local failure rates (68% [positive margin] vs 100% [negative margin] 5-yr local recurrence-free survival, P<.05). For STS, high grade, deep location, and size at or above 5 cm were adverse prognostic factors for disease-specific and distant recurrence-free survival (P<.05); patients experiencing local recurrence was associated with decreased 5-year relapse-free survival rates (87% [primary] vs 50% [local recurrence], P<.05). Characteristically, no DFSP or desmoid developed distant metastases. Soft tissue sarcomas had significantly lower relapse-free survival rates than DFSP or desmoids (P<.05). CONCLUSION: Abdominal wall tumors demonstrate a broad spectrum of biological behavior. Desmoids and DFSP are a local problem. High grade, size at or above 5 cm, and deep location predict distant failure and tumor-related mortality for patients with STS. Complete surgical resection is the recommended treatment approach to achieve local control. Stratification by prognostic factors will facilitate selection of patients with STS for adjuvant systemic therapies.

Interferon gamma protects against hepatic tumor growth in rats by increasing Kupffer cell tumoricidal activity.

An increasing number of hepatic resections are being performed as potentially curative surgery for malignant liver neoplasms. Hepatectomy and subsequent liver regeneration produce a local environment that enhances growth of microscopic residual tumor. To determine if pretreatment with murine interferon gamma (IFN-gamma) can protect against such enhanced tumor growth, Buffalo rats were randomized to receive a 3-day treatment of IFN-gamma (50,000 U/qD intraperitoneally) or saline. Groups then underwent intrasplenic injection of 10(6) Morris hepatoma cells, followed 1 hour later by sham (control) or partial hepatectomy (PH) of 70%. PH significantly enhanced tumor growth within the liver (control, 8 +/- 3 nodules per liver; PH, 73 +/- 12 nodules per liver; P < .001). This enhancement was attenuated by prior administration of IFN-gamma IFN-gamma/PH, 16 +/- 3; P < .001 vs. PH). Growth factor release and liver regeneration were not affected significantly by pretreatment with IFN-gamma. The effect of IFN-gamma on tumor growth is associated with a significant enhancement of Kupffer cell (KC)-mediated tumoricidal activity (percentage of specific lysis, 55 +/- 10% control, 78 +/- 11% IFN-gamma, P < .01) but not lymphocyte-mediated tumoricidal activity. Because microscopic residual disease may be present after hepatectomies for cancer, IFN-gamma may be useful agent in retarding growth of residual tumors.

The search for level I evidence in solid-tumor oncology.

BACKGROUND: We have developed a method to identify, filter, review, and distribute the published level I evidence for solid tumor oncology. METHODS: A standardized MEDLINE search identified prospective randomized controlled trials (PRCTs) in solid tumor oncology. Only PRCTs with therapeutic end points were included. All references were reviewed by a surgical oncology fellow in consultation with experts in the field. The full citations were imported into a comprehensive database. Data on statistical methods according to the Consolidated Standard of Reporting Trials statement were tabulated along with reviewer's comments. A designation of Ia was given to articles that were well designed and significant contributions to their field. The database powers a dynamic, easily searchable Web site on our intranet and is available in personal digital assistant (PDA) format. RESULTS: By using standard search criteria, only .03% of the 11 million articles listed in MEDLINE are PRCTs concerning therapy for solid organ malignancies. Approximately 14% of reviewed articles were given a designation of Ia. Having comprehensive data readily available with intranet access or PDAs during conferences enhances their educational value and specificity. CONCLUSIONS: We have developed an exciting tool that uses a highly trained filter to screen and record the medical data available to the clinician. This information has been made available and portable by using the Internet and PDAs.

Factors influencing hepatocyte trafficking during allogeneic hepatocyte transplantation: improved liver sequestration with isolated perfusion.

Transplantation of normal or ex vivo modified hepatocytes holds promise in therapy of a variety of diseases. In order to investigate hepatocyte trafficking, and specifically to determine whether the route, method of delivery, or other host factors may affect hepatocyte sequestration in the liver, 51chromium- and 111indium-labeled hepatocytes were transplanted into allogeneic hosts. Systemic injection of hepatocytes into the femoral vein resulted in sequestration mainly in the lungs (30 +/- 4%) whereas sequestration in the liver amounted to only 5 +/- 1%. Portal injection resulted in a dramatic increase in the liver sequestration (52 +/- 4%) and a reduction in the lung (2 +/- 1%, P < 0.05 vs systemic injection). Nevertheless, nearly half of portally injected hepatocytes came to rest in other organ sites. Partial hepatectomy prior to transplantation did not change the total hepatocyte sequestration in the liver or the organ specific activity. A remote site of inflammation, in the form of a turpentine abscess, also did not alter the pattern of hepatocyte trafficking. Isolated perfusion of the liver with labeled hepatocyte, however, significantly increased the sequestration of hepatocytes at this organ (control, 52 +/- 4%; isolated perfusion, 71 +/- 9%; P < 0.05). In the delivery of potentially toxic gene products for therapy, isolated perfusion of the target organ appears to provide the greatest likelihood of restricting expression of potentially toxic gene products to the target organ.

Dermatofibrosarcoma protuberans of the head and neck.

BACKGROUND: Dermatofibrosarcoma protuberans (DFSP) of the head and neck is a rare, locally infiltrative, low-grade sarcoma. This study defines the clinical behavior of DFSP, evaluates the role of frozen section analysis, and identifies factors that predict local control. METHODS: Hospital records and pathological slides were reviewed for 33 patients with pathologically confirmed head and neck DFSP treated at Memorial Sloan-Kettering Cancer Center between 1964 and 1999. Factors were analyzed by using Fisher's exact or chi2 tests. RESULTS: For 21 primary and 12 recurrent patients, median age and tumor size at presentation was 39 years and 2.0 cm, respectively. Thirty-two (97%) patients were alive at a median follow-up of 82 months. Three patients recurred locally, all with smaller than 2-cm resection margins. Deep tumors were more likely to have a margin-positive resection than superficial lesions (P = .03). Gross margin 2 cm or more was a significant predictor of a negative histological margin (P<.001). There was a trend toward improved recurrence-free survival for tumors treated with wide (> or =2 cm) margin resection (P = .059). Accuracy, sensitivity, specificity, and false negative rates of frozen section were 80%, 43%, 100%, and 57%, respectively. CONCLUSIONS: Wide margin resection of head and neck DFSP predicts negative histological margins and impacts favorably on local recurrence-free survival. Frozen section analysis does not assess resection margins accurately.